Modern Surgical Care: Physiologic Foundations and Clinical Applications (Two-Volume Set)

MODERN SURGICAL CARE Third Edition Volume 1

Associate Editors

Barbara L. Bass, M.D. Professor of Surgery Department of Surgery Weill Medical College of Cornell University New York, New York, USA Carolyn and John F. Bookout Chair Department of Surgery The Methodist Hospital Houston, Texas, USA

Peter J. Fabri, M.D. Professor of Surgery Associate Dean for Graduate Medical Education University of South Florida College of Medicine Tampa, Florida, USA

Carl E. Haisch, M.D. Professor of Surgery Department of Surgery East Carolina University Brody School of Medicine Director of Surgical Immunology and Transplantation Attending Surgeon Pitt County Memorial Hospital Greenville, North Carolina, USA

David W. Mercer, M.D. Professor and Vice Chairman of Surgery Department of Surgery The University of Texas Health Science Center–Houston Chief of Surgery Lyndon Baines Johnson General Hospital Houston, Texas, USA

Ronald C. Merrell, M.D. Professor of Surgery Department of Surgery Virginia Commonwealth University School of Medicine and Medical Center Richmond, Virginia, USA

Stuart I. Myers, M.D. Professor of Surgery Division of Vascular Surgery Department of Surgery Virginia Commonwealth University School of Medicine and Medical Center Attending Surgeon Hunter Holmes McGuire Veterans Affairs Medical Center Richmond, Virginia, USA

MODERN SURGICAL CARE Physiologic Foundations and Clinical Applications

Third Edition Volume 1

editor-in-chief

Thomas A. Miller, M.D. Ammons Professor of Surgery Division of General Surgery Department of Surgery Virginia Commonwealth University School of Medicine and Medical Center Chief of Surgery Hunter Holmes McGuire Veterans Affairs Medical Center Richmond, Virginia, USA

Informa Healthcare USA, Inc. 270 Madison Avenue New York, NY 10016 © 2006 by Informa Healthcare USA, Inc. Informa Healthcare is an Informa business No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-10: 0-8247-2869-6 (Hardcover) International Standard Book Number-13: 978-0-8247-2869-4 (Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Visit the Informa Web site at www.informa.com and the Informa Healthcare Web site at www.informahealthcare.com

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Dedication

DEDICATION

To all trainees in surgery, medical students rotating on surgical services, and surgeons in practice who recognize the importance of understanding the physiologic underpinnings of treating surgical disease in order to ensure optimal patient care.

Preface

not involved in the previous editions. These associate editors include Drs. Barbara Bass, Jeff Fabri, Carl Haisch, Dave Mercer, Ron Merrell, and Stuart Myers. To each of them, I offer my utmost thanks and gratitude. As reflected in the previous editions, the needs of the general surgeon continue to be emphasized in the present edition. Further, the goal of this third edition remains the same, namely to approach surgical disease as a derangement in normal physiology, which needs to be corrected to as near normal as possible to effectively manage and treat the underlying disorder. This book is divided into nine parts, with the first part devoted to information pertinent to the body as a whole, and the eight remaining sections focused on specific organ systems or themes. Diseases affecting the reproductive organs, disorders of the head and neck (other than the thyroid and parathyroid glands), and disorders of the musculoskeletal system are not specifically dealt with because the current practice of surgery only rarely involves these disciplines. Finally, this book is not meant to replace standard textbooks of surgery and, accordingly, is not a comprehensive discussion of all surgical diseases. For less common types of surgical problems or those not regularly encountered in the practice of general surgery, such books should be consulted. I would personally like to offer my sincere appreciation to the folks at Informa Healthcare who have worked with us during the production of the book. I have found everyone with whom I have collaborated to be extremely professional, cordial, and helpful in making sure that this third edition meets the goals that we have set. I would especially like to recognize two people with whom I have had a very close working relationship. The first is Joe Stubenrauch who has been the project editor. He has more than met my expectations and has demonstrated unusual adaptability when I thought something should be done for which initially he and I had differing viewpoints. The second individual is Joanne Jay who was responsible for the final editing of each chapter and preparing the galley proofs. Her attention to detail has been exemplary. I have been very pleased with the outstanding quality of her editorial review. To both of these individuals I say ‘‘Thank you!’’ They made the process of finalizing this book most pleasurable.

When the first edition of this book was published in 1988 under the title Physiologic Basis of Modern Surgical Care, its goal was to bridge the gap that commonly exists between basic science information regarding human disease and the ability to apply this knowledge to everyday clinical care. In teaching medical students rotating on surgery, as well as residents embarking on surgical careers, many of my colleagues and I, serving on medical school faculties across the country, were all too acutely aware that management of surgical disorders by these trainees was frequently based on memorized schemes or protocols rather than a thorough understanding of the pathophysiology underlying a particular disease. To address this issue, we published the initial edition with the intent to approach surgical disease as a derangement in normal physiology and that the best way to diagnose and treat it was to understand thoroughly this deviation from normal. We were very gratified with the acceptance of the book by the surgical community and its adoption by many program directors as essential reading to prepare residents for various examinations, such as the annual in-service training examination in surgery and the board certification examination following completion of surgical training. We also received many positive comments from established surgeons regarding its usefulness in preparing for recertification exams. Because of the wide acceptance of the first edition as an important vehicle to train house officers in the physiologic underpinnings of surgical disease, a second edition was published in 1998 under the title Modern Surgical Care: Physiologic Foundations and Clinical Applications. The title change was made to more adequately reflect the linkage between physiology and clinical care. We have been especially pleased with the continuing acceptance of the second edition as an important educational tool and were extremely grateful when Informa Healthcare (formerly Marcel Dekker, Inc.) asked us to produce a third edition. In addition to being thoroughly updated, the third edition reflects the capable assistance and counsel of a group of associate editors who have contributed greatly in streamlining chapters, minimizing repetitive material, adding new chapters to include cutting-edge material, and selecting a more diverse and mainstream authorship who are the current leaders in their fields. Their recommendations were responsible for the inclusion of 91 new authors

Thomas A. Miller, M.D.

v

Contents

6. Surgical Infection: Principles of Management and Antibiotic Usage / 127

Preface / v Contributors / xiii

Christina Paylan and Rodney Durham Introduction / 127 Pathophysiology of Surgical Infections / 127 Systemic Inflammatory Response / 128 Overall Approach to Sepsis / 129 Definitions of Surgical Infections / 130 Evaluation of Suspected Infection in the Surgical Patient / 131 Role of the Laboratory in Infection Diagnosis / 131 Types of Postoperative Infections / 133 Pathogens Responsible for Surgical Infection / 140 Antibiotics in the Management of Infection / 141 Clinical Use of Antibiotics / 148 Summary / 153 References / 153

VOLUME 1 PART ONE: GENERAL CONSIDERATIONS IN THE MANAGEMENT OF SURGICAL PATIENTS

1. Metabolic Response to Starvation, Stress, and Sepsis / 1 Joseph F. Amaral, Michael D. Caldwell, and Thomas A. Miller Introduction / 1 Body Composition / 1 Normal Metabolism: Intermediary Metabolism and Substrate Interactions / 8 Neuroendocrine Regulatory Mechanisms / 15 Metabolic Response in Starvation, Injury, and Sepsis / 21 Cytokines / 26 Summary / 28 References / 28

7. Hemostasis and Thrombosis in the Surgical Patient / 157 Stuart I. Myers, Mark R. Jackson, Michael Sobel, and G. Patrick Clagett Introduction / 157 Mechanisms of Hemostasis / 157 Regulation of Hemostasis / 159 Inherited Disorders of Coagulation / 161 Inherited Qualitative Platelet Disorders / 163 Acquired Disorders of Hemostasis / 164 Acquired Disorders of Platelet Function / 164 Bleeding in the Surgical Patient / 165 Congenital Disorders of Hypercoagulability / 167 Acquired Hypercoagulable Disorders / 168 Antithrombotic Therapy / 170 Therapeutic Agents / 171 Summary / 174 References / 174

2. Pathophysiology of Fluid and Electrolyte Disorders / 33 Peter J. Fabri and Mark Bloomston Introduction / 33 Maintenance of the Internal Milieu / 33 Homeostatic Control Mechanisms / 35 Pathophysiology and Treatment of Specific Electrolyte and Acid/Base Abnormalities / 38 Principles of Fluid Therapy / 45 Summary / 46 References / 46

3. Surgical Nutrition / 49 Rosemary A. Kozar, Margaret M. McQuiggan, and Frederick A. Moore Introduction / 49 Metabolic Response to Stress vs. Starvation / 49 Rationale for Nutritional Support / 50 Initiation of Nutritional Support / 50 Enteral Nutrition / 53 Total Parenteral Nutrition / 56 Disease-Specific Nutrition / 60 Summary / 61 References / 61

8. Pathophysiology of Shock / 181 Ajai K. Malhotra Introduction / 181 Definition of Shock / 181 Cardiovascular Physiology and Types of Shock / 182 Pathophysiologic Response to Shock / 184 Management Considerations / 190 The Future / 193 Summary / 193 References / 194

4. The Immune System and the Immunocompromised Patient / 65 Kathryn M. Verbanac, Lorita Rebellato, and Carl E. Haisch Introduction / 65 An Overview of the Immune System / 65 The Immunocompromised Surgical Patient / 76 Summary / 86 References / 87

9. Neoplastic Disease: Pathophysiology and Rationale for Treatment / 197 Gregory Kennedy and John E. Niederhuber Introduction / 197 Basic Concepts of Cancer Biology / 197 Biologic Rationale for Therapy / 202 Summary / 208 References / 208

5. Physiologic Basis of Transplantation / 91 Yuan Zhai and Rafik M. Ghobrial Introduction / 91 Allograft Rejection / 91 Immunosuppressive Therapy / 112 Clinical Transplant Outcomes / 120 Summary / 124 References / 124

10. The Physiology of Anesthesia and Pain / 213 Charles Williams and Denise Lester Introduction / 213 The Physiology of Anesthesia / 213 Preoperative Decisions / 213

vii

viii

Contents Regional Anesthesia / 214 General Anesthesia / 215 Conscious Sedation / 217 Anesthetic Implications of Selected Disease States / 217 Anesthesia Emergencies / 218 The Physiology of Pain and Analgesia / 219 The Physiology of Nociception / 219 Pain Measurement / 221 The Management of Acute Postoperative Pain / 221 Summary / 224 References / 224

15. Gastric Physiology and Acid-Peptic Disorders / 333 Kenneth S. Helmer and David W. Mercer Introduction / 333 Normal Physiology / 333 Gastric Physiology / 338 Abnormal Physiology / 346 Summary / 362 References / 362

& Small and Large Intestine

16. Physiology of Digestion and Absorption / 369 11. Sepsis and the Syndrome of Multiple Organ Failure / 227 Lena M. Napolitano Introduction / 227 Sepsis: Definitions / 227 Incidence and Outcomes of Sepsis / 229 Pathophysiology of Sepsis / 230 Genetic Variability in Sepsis / 232 Treatment Strategies in Sepsis / 234 Multiple Organ Dysfunction and Failure: Definitions / 244 Incidence and Outcome of MODS / 244 Pathophysiology of MODS / 246 Potential Treatment Strategies for Reduction of MODS / 246 Summary / 247 References / 248

12. Application of Cellular and Molecular Biology in Modern Surgical Practice / 253 Huiping Zhou and Jian-Ying Wang Introduction / 253 Basic Genetic Mechanisms / 253 Cellular and Molecular Biological Technology: From Recombinant DNA to Transgenic Animals / 259 The Molecular Organization of the Cells / 263 Novel Treatment Strategies in Modern Surgical Care / 267 Summary / 269 References / 269

13. Physiologic Principles in Preparing Patients for Surgery / 271 Henry J. Schiller, Kara C. Kort, and Lelan F. Sillin Introduction / 271 General Aspects of Preoperative Preparation / 271 Specific Aspects of Preoperative Preparation / 273 Risks of Hematologic Disease / 286 Prophylaxis Against Thromboembolism / 289 HIV Infection and AIDS / 289 Summary / 290 References / 290

Bobby S. Glickman and Jon S. Thompson Introduction / 369 Fluid and Electrolyte Secretion and Absorption / 369 Overview of Digestion / 371 Protein Absorption / 372 Carbohydrate Absorption / 374 Fat Absorption / 376 Vitamins and Minerals / 377 Regulation / 378 Diarrhea and Malabsorption / 378 Summary / 379 References / 379

17. Circulation and Vascular Disorders of the Splanchnic Vascular Bed / 381 Stuart I. Myers and Patricia A. Lowry Introduction / 381 Normal Anatomy and Collateral Circulation / 381 Physiology of Intestinal Circulation / 384 Reperfusion Injury of the Intestine / 386 Clinical Evaluation of Intestinal Blood Flow / 392 Radiologic Evaluation of Patients with Acute Mesenteric Ischemia / 393 Intraoperative Assessment of Intestinal Viability / 396 Diseases That Affect the Visceral Vessels / 397 Miscellaneous Diseases That Affect the Viscera / 403 Summary / 406 References / 408

18. Inflammatory Disorders of the Small Bowel and Colon / 415 Douglas J. Turner and Barbara L. Bass Introduction / 415 Inflammatory Bowel Disease / 415 Appendicitis / 419 Meckel’s Diverticulum / 421 Jejunoileal Diverticuli / 421 Colonic Diverticular Disease / 422 Clostridium difficile Colitis / 423 Radiation Enteritis / 423 Summary / 424 References / 424

PART TWO: THE ALIMENTARY TRACT & Liver, Biliary Tract, Pancreas, and Spleen & Esophagus and Stomach

14. Physiologic Dysfunction of the Esophagus / 295 Nahid Hamoui and Peter F. Crookes Introduction / 295 Anatomy and Physiology / 295 Symptoms of Esophageal Disease / 296 Physical Examination / 297 Investigations / 297 Esophageal Diseases / 304 Esophageal Motor Disorders / 316 Esophageal Emergencies / 321 Esophageal Tumors / 323 Summary / 328 References / 328

19. Hepatic Physiology / 427 Jose M. Prince and Timothy R. Billiar Introduction / 427 Embryology / 427 Histology / 428 Anatomy / 429 Hepatic Functions / 431 Metabolic Homeostasis / 432 Pathophysiology / 435 Diagnostic Testing / 436 Regeneration / 438 Future / 438 Summary / 438 References / 439

Contents

20. Portal Hypertension / 443 Alexander S. Rosemurgy and Emmanuel E. Zervos Introduction / 443 Anatomy / 443 Variceal Hemorrhage / 443 Summary / 452 References / 452

21. Calculous Disease of the Gallbladder and Common Bile Duct / 455 Lillian S. Kao and Terrence H. Liu Introduction / 455 Epidemiology / 455 Bile Physiology / 455 Pathogenesis of Gallstones / 459 Clinical Manifestations of Gallstone Disease / 461 Treatment / 463 Summary / 465 References / 465

22. Normal Exocrine Function and Inflammatory Diseases of the Pancreas / 469 David J. Bentrem and Raymond J. Joehl Introduction / 469 Embryology / 469 Gross Anatomy / 469 Acinus / 470 Pancreatic Exocrine Function / 470 Control of Pancreatic Secretion / 471 Acute Pancreatitis / 471 Treatments / 475 Summary / 479 References / 479

23. The Jaundiced Patient / 483 Attila Nakeeb and Henry A. Pitt Introduction / 483 Bilirubin Metabolism / 483 Classification of Jaundice / 483 Pathophysiology of Jaundice / 484 Diagnostic Approach / 487 Patient Management / 492 Benign Disease / 495 Malignant Disease / 497 Summary / 499 References / 499

24. The Spleen / 503 Haytham M. A. Kaafarani and Kamal M. F. Itani Introduction / 503 Gross Anatomy / 503 Embryology / 503 Histology / 504 Physiology and Function of the Spleen / 505 Hematologic Disorders and Splenectomy / 507 Malignancies and Splenectomy / 511 Miscellaneous Conditions / 513 Splenic Trauma / 515 Splenectomy / 520 References / 522

26. The Anatomy, Physiology, and Differential Diagnosis of Acute Abdominal Pain / 539 Kathryn A. Richardson, Ryan M. Wolfort, and Richard H. Turnage Introduction / 539 Types of Abdominal Pain / 539 Anatomy and Physiology of Abdominal Pain / 539 Pathophysiologic Stimuli for Somatic and Visceral Nociceptors / 541 Evaluation of Patients with Acute Abdominal Pain / 541 Prototypical Examples of Acute Abdominal Pain / 547 Abdominal Pain in Special Patient Groups / 550 Summary / 553 References / 553

27. Neoplastic Disorders of the Gastrointestinal Tract / 555 Carlos A. Murillo, Kenneth J. Woodside, Lindsey N. Jackson, and B. Mark Evers Introduction / 555 Cellular and Molecular Biology of GI Cancers / 555 Neoplastic Diseases of the Stomach, Small Bowel, and Colorectum / 562 Summary / 579 References / 580

28. Mechanical Disorders of the Stomach, Duodenum, and Intestine / 587 Sean P. Harbison and Daniel T. Dempsey Introduction / 587 Mechanical Disorders of the Stomach and Duodenum / 587 Mechanical Disorders of the Small Bowel / 590 Mechanical Disorders of the Colon / 595 Summary / 597 References / 597

29. Physiologic Derangements of the Anorectum and the Defecatory Pelvic Floor / 599 Janette Gaw and Walter E. Longo Introduction / 599 Anorectal Anatomy / 599 Normal Physiology of the Anus and Rectum / 603 Colonic Function and Anorectal Physiology Testing / 604 Disordered Anorectal Physiology / 605 Neoplasms of the Anal Canal and Anal Margin / 611 Summary / 613 References / 613

30. Derangements in Gastrointestinal Function Secondary to Previous Surgery / 617 Jeannie F. Savas, Thomas A. Miller, and David W. Mercer Introduction / 617 Gastric Dysfunction / 617 Intestinal Dysfunction / 625 Summary / 628 References / 629 Index / I-1

VOLUME 2 PART THREE: THE CARDIOTHORACIC SYSTEM

& Other Conditions

& Lung

25. Gastrointestinal Hemorrhage / 527

31. Pathobiology of Surgically Relevant Pulmonary Disease / 631

Kevin Bruen and Leigh Neumayer Introduction / 527 Initial Evaluation and Management / 527 Upper Intestinal Bleeding / 528 Lower Intestinal Bleeding / 532 Occult Bleeding / 535 Summary / 536 References / 536

ix

Daniel G. Tang, Jonathan Kiev, and Neri M. Cohen Introduction / 631 Anatomy and Physiology / 631 Perioperative Pulmonary Assessment / 636 Common Pulmonary Disorders / 637 Neoplastic Conditions / 643 Lung Transplantation / 645

x

Contents Summary / 646 References / 647

& Heart

32. Normal Cardiac Function / 649 Andrew C. Fiore and Andrew S. Wechsler Introduction / 649 Molecular Mechanisms in Contraction and Relaxation / 649 Mechanics of Isolated Muscle / 651 Function of the Intact Heart / 653 Heart Failure / 660 Summary / 661 References / 661

33. Heart Failure and Resuscitation / 663 Heinrich Taegtmeyer Introduction / 663 Heart Failure / 663 Resuscitation / 671 Summary / 673 References / 674

34. Mechanical Support for the Failing Heart: Current Physiologic Concepts of Management / 677 Sina L. Moainie and Bartley P. Griffith Introduction / 677 Cardiac Support in End-Stage Heart Failure / 677 Summary / 683 References / 683

35. Congenital Heart Lesions / 685 Ralph S. Mosca and Edward L. Bove Introduction / 685 Adjustments in the Circulation After Birth / 685 Congestive Heart Failure / 685 Obstructive Lesions / 686 Left-to-Right Shunts / 689 Right-to-Left Shunts / 691 Inadequate Mixing / 693 Hypoplastic Left Heart Syndrome / 695 Summary / 695 References / 696 Further Reading / 697

38. Urinary Tract Obstruction / 767 J. Robert Ramey and Deborah T. Glassman Introduction / 767 The Upper Urinary Tract / 767 The Lower Urinary Tract / 770 Summary / 772 References / 772

39. Neurogenic Lower Urinary Tract Dysfunction / 775 Hari Siva Gurunadha Rao Tunuguntla and Unyime O. Nseyo Introduction / 775 Anatomy and Physiology of Continence and Micturition / 775 Pathophysiology of LUT Dysfunction / 780 Definition of Common Terms in Neurogenic Voiding Dysfunction / 781 Specific Neurologic Lesions / 781 Classification of NLUTD / 783 Diagnosis of NLUTD / 783 Management of NLUTD / 787 Device Therapy / 791 Urinary Diversion / 792 Quality of Life / 792 Follow-Up / 792 Summary / 793 References / 793

PART FIVE: THE CENTRAL AND PERIPHERAL NERVOUS SYSTEMS

40. Pathophysiology and Management of Head Injury / 795 Egon M. R. Doppenberg, M. Ross Bullock, and William C. Broaddus Introduction / 795 Pathophysiology / 795 General Considerations in the Care of the Head-Injured Patient / 798 Specific Management of the Head-Injured Patient / 799 Monitoring the Injured Brain / 802 Summary / 802 References / 802

41. Spinal Cord Injury / 805 36. Acquired Cardiac Disorders / 699 Dipin Gupta, Andrew C. Fiore, and Glenn J. R. Whitman Introduction / 699 Ischemic Heart Disease / 699 Valvular Heart Disease / 709 Heart Failure / 715 Cardiac Dysrhythmias / 716 Pericardial Disease / 719 Cardiac Tumors / 721 Summary / 721 References / 722

Kangmin Lee and R. Scott Graham Introduction / 805 Epidemiology / 805 Pathophysiology / 805 Evaluation / 807 Classic Injury Patterns / 807 Imaging / 812 Management of Acute SCI / 812 Rehabilitation / 814 Advanced Therapies / 814 Restoration of Function / 814 Summary / 814 References / 814

PART FOUR: THE URINARY SYSTEM

37. Urine Formation: From Normal Physiology to Florid Kidney Failure / 725 Akinsan Dosekun, John R. Foringer, and Bruce C. Kone Introduction / 725 Overview of Renal Physiology / 725 Acute Kidney Failure / 735 Chronic Kidney Disease / 740 Renal Transplantation / 755 Summary and Conclusions / 761 References / 761

42. Injuries to Peripheral Nerves / 817 Irvine G. McQuarrie, Thomas C. Chelimsky, and Karen Bitzer Introduction / 817 Anatomy and Physiology / 817 Pathology / 820 Assessment of the Deficit / 821 Treatment Approach / 824 Rehabilitation After Neurorrhaphy / 826 Summary / 828 References / 828

Contents

PART SIX: THE PERIPHERAL VASCULAR SYSTEM

PART SEVEN: THE ENDOCRINE SYSTEM

43. Physiology of Arterial, Venous, and Lymphatic Flow / 831

49. Calcium and Phosphorus Metabolism and the Parathyroid Gland / 927

Dennis F. Bandyk and Paul A. Armstrong Introduction / 831 Peripheral Arterial System / 831 The Venous System / 841 Lymphatic System / 846 Summary / 847 References / 848 Further Readings / 848

44. Aorta and Arterial Disease of the Lower Extremity / 849 Christopher K. Zarins and Sheila M. Coogan Introduction / 849 Atherosclerosis / 849 Pathophysiologic Processes Affecting the Aorta and Lower Extremity Arteries / 851 Arterial Occlusive Disease of the Aorta and Peripheral Arteries / 852 Evaluation of Peripheral Vascular Occlusive Disease / 854 Treatment of Peripheral Vascular Occlusive Disease / 856 Aneurysmal Disease of the Aorta / 862 Peripheral Artery Aneurysms / 865 Complications of Vascular Procedures / 865 Summary / 866 References / 866

45. Cerebrovascular Disease and Upper-Extremity Vascular Disease / 869 Bruce L. Gewertz and James E. McKinsey Introduction / 869 Cerebral Blood Flow / 869 Clinical Presentation of Cerebrovascular Disease / 871 Types of Cerebrovascular Disease / 872 Upper-Extremity Vascular Disease / 876 Summary / 880 References / 880

46. Venous and Lymphatic Abnormalities of the Limbs / 883 Jose R. Parra and Julie A. Freischlag Introduction / 883 Anatomy / 883 Venous Physiology / 884 Venous Disorders of the Lower Extremity / 884 Venous Disorders of the Upper Extremity / 891 Lymphedema / 892 Summary / 894 References / 894

47. Diseases of the Thoracic Aorta / 897 Michael P. Macris and O. Howard Frazier Introduction / 897 Intrinsic Thoracic Aortic Disease / 897 Traumatic Pseudoaneurysms / 902 Summary / 903 References / 904

48. Secondary Hypertension: Pathophysiology and Operative Treatment / 907 James C. Stanley and Gerard M. Doherty Introduction / 907 Adrenal Disease and Hypertension / 907 Renal Artery Occlusive Disease and Hypertension / 912 Summary / 922 References / 922

Fiemu E. Nwariaku Introduction / 927 Calcium Homeostasis / 927 Hormonal Regulation of Extracellular Calcium Concentration / 928 Disorders of Calcium Metabolism / 931 Phosphate Metabolism / 937 The Parathyroid Glands / 938 Multiple Endocrine Neoplasia Syndromes / 944 Summary / 945 References / 945

50. Pituitary Dysfunction / 947 Henry Ty and Kathryn Holloway Introduction / 947 Anatomy of the Pituitary Gland / 947 Physiology of the Pituitary Gland / 948 Hormones of the Adenohypophysis / 948 Hormones of the Neurohypophysis / 950 Regulation of Hormone Secretion / 950 Hypopituitarism / 952 Sellar and Parasellar Lesions / 954 Syndrome of Inappropriate Secretion of ADH / 960 Summary / 961 References / 961

51. Adrenal Glands / 965 Maria A. Kouvaraki, Douglas B. Evans, Ana O. Hoff, and Jeffrey E. Lee Introduction / 965 Embryology, Anatomy, and Histology / 965 Physiology / 966 Neoplasms of the Adrenal Gland / 968 Controversies in the Surgical Management of Adrenal Disease / 982 Adrenal Insufficiency / 983 References / 984

52. The Thyroid Gland / 989 Ronald C. Merrell and Lucian Panait Introduction / 989 Thyroid Anatomy / 989 Physiology / 990 Assessment of Patients with Thyroid Disease / 993 Sick Euthyroid Syndrome / 994 Hyperthyroidism (Thyrotoxicosis) / 995 Hypothyroidism / 997 Thyroiditis / 997 Thyroid Nodule / 998 Thyroid Cancer / 999 Summary / 1003 References / 1003

53. Endocrine Pancreas / 1005 Ronald C. Merrell, Giacomo P. Basadonna, and Cristiana Rastellini Introduction / 1005 Anatomy and Embryology of the Islets / 1005 Physiology of the Islets / 1007 Islets in Health and Disease / 1010 Endocrine Tumors of the Pancreas / 1016 Summary / 1020 References / 1021

xi

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Contents

54. Multiple Endocrine Neoplasia: Types 1 and 2 / 1025 Frank J. Quayle and Jeffrey F. Moley Introduction / 1025 Multiple Endocrine Neoplasia Type 1 / 1025 Multiple Endocrine Neoplasia Type 2 / 1028 Summary / 1032 References / 1032

Metabolic Alterations / 1091 Organ System Alterations / 1093 Resistance to Infection / 1095 Pulmonary Consequences of Thermal Injury / 1096 Physiologic Considerations in Managing the Burn Patient / 1097 Summary / 1101 References / 1102

PART EIGHT: THE INTEGUMENT AND BODY WALL

55. The Biology of Wound Healing / 1035 Dorne R. Yager and Ashley E. Ducale Introduction / 1035 Phases of Healing / 1035 Other Aspects of Repair / 1038 Wound-Healing Pathologies / 1038 Wound Management / 1040 Summary / 1044 References / 1044

56. Breast: Physiologic Considerations in Normal, Benign, and Neoplastic States / 1047 Rakhshanda Layeeque and V. Suzanne Klimberg Introduction / 1047 Physiology of Development / 1047 Pregnancy / 1050 Physiology of Lactation / 1051 Lactogenesis / 1052 Breast-Feeding / 1053 Physiology of Involution / 1053 Clinical Approach to Breast Pathology / 1054 Work-Up of Common Clinical Symptoms / 1055 Treatment of Benign Breast Pathology / 1057 Treatment of Malignant Breast Pathology / 1058 Summary / 1062 References / 1062

57. Hernias of the Abdominal Wall and Its Contents / 1067 Philip E. Donahue Introduction / 1067 Concepts and Definitions / 1067 Pathophysiology of Hernia Development / 1068 Types of Abdominal Wall Hernias / 1070 Summary / 1082 References / 1083

58. Pathophysiology of Thermal Injury / 1085 Ronald M. Barton, Evan R. Kokoska, David J. Wainwright, and Donald H. Parks Introduction / 1085 The Burn Wound / 1085

PART NINE: SPECIAL PHYSIOLOGIC CONSIDERATIONS

59. Physiologic Problems in the Pediatric Surgical Patient / 1107 Daniel J. Ostlie, Shawn D. St. Peter, Sheilendra S. Mehta, and George K. Gittes Introduction / 1107 Physiologic Considerations / 1107 Glucose, Fluid, and Electrolyte Management / 1107 Thermoregulation / 1109 Pulmonary and Cardiac Transitional Physiology / 1109 Nutritional Support / 1110 Specific Pediatric Surgical Conditions / 1111 Summary / 1123 References / 1124

60. Physiologic Considerations in the Elderly Surgical Patient / 1129 Ronnie Ann Rosenthal and Melissa F. Perkal Introduction / 1129 Physiology and Pathology of Aging / 1129 Preoperative Evaluation, Risk Assessment, and Outcome / 1141 Summary / 1144 References / 1145

61. Surgery for Morbid Obesity / 1149 Eric J. DeMaria, Ramzi Alami, and Robert E. Brolin Introduction / 1149 Etiology and Pathophysiology / 1149 Risks and Complications of Severe Obesity / 1150 Treatment of Severe Obesity / 1151 Patient Management / 1156 Results of Surgical Treatment / 1158 Summary / 1161 References / 1161 Index / I-1

Contributors

of Bariatric Surgery, University Medical Center at Princeton, Princeton, New Jersey, U.S.A.

Ramzi Alami, MD Fellow in Advanced Laparoscopic Surgery, Department of Surgery, Stanford University Medical Center, Palo Alto, California, U.S.A.

Kevin Bruen, MD Resident in Surgery, Department of Surgery, University of Utah School of Medicine, Salt Lake City, Utah, U.S.A.

Joseph F. Amaral, MD President and CEO, Rhode Island Hospital, Professor of Surgery, Brown University Medical School, Providence, Rhode Island, U.S.A.

M. Ross Bullock, MD, PhD Reynolds Professor, Department of Neurosurgery, Virginia Commonwealth University Health System, Richmond, Virginia, U.S.A.

Paul A. Armstrong, DO Clinical Assistant Professor of Surgery, Department of Surgery, University of South Florida College of Medicine, Tampa, Florida, U.S.A.

Michael D. Caldwell, MD, PhD Director of Marshfield Medical Research and Education Foundation, Director of the Wound Healing Clinic, Marshfield, Wisconsin, U.S.A.

Dennis F. Bandyk, MD Professor of Surgery, Director, Division of Vascular Surgery, University of South Florida College of Medicine, Tampa, Florida, U.S.A.

Thomas C. Chelimsky, MD Associate Professor of Neurology, Department of Neurology, Case Western Reserve University School of Medicine, Cleveland, Ohio, U.S.A.

Ronald M. Barton, MD Associate Professor of Surgery Emeritus, Director of the Burn Center Emeritus, Division of Plastic Surgery, Department of Surgery, Virginia Commonwealth University School of Medicine and Medical Center, Richmond, Virginia, U.S.A.

G. Patrick Clagett, MD Professor and Chairman, Division of Vascular and Endovascular Surgery, Department of Surgery; Ian and Bob Pickens Distinguished Professorship in Medical Science; Director, Center for Vascular Disease, University of Texas Southwestern Medical Center, Dallas, Texas, U.S.A.

Giacomo P. Basadonna, MD Professor of Surgery, Department of Surgery, University of Massachusetts Medical School, Worcester, Massachusetts, U.S.A.

Neri M. Cohen, MD, PhD Chief, Division of Thoracic Surgery, Greater Baltimore Medical Center Health Care, Baltimore, Maryland, U.S.A.

Barbara L. Bass, MD Professor of Surgery, Department of Surgery, Weill Medical College of Cornell University, New York, New York; Carolyn and John F. Bookout Chair, Department of Surgery, The Methodist Hospital, Houston, Texas, U.S.A.

Sheila M. Coogan, MD Assistant Professor of Surgery, Vascular Surgery Service, Palo Alto Veterans Affairs Hospital, Stanford University School of Medicine, Palo Alto, California, U.S.A.

David J. Bentrem, MD Assistant Professor of Surgery, Department of Surgery, Surgical Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, U.S.A.

Peter F. Crookes, MD Associate Professor of Surgery, Director of Bariatric Surgery Program, Department of Surgery, University of Southern California Keck School of Medicine, Los Angeles, California, U.S.A.

Timothy R. Billiar, MD The George Vance Foster Professor and Chair, Department of Surgery, Presbyterian University Hospital, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, U.S.A.

Eric J. DeMaria, MD Professor and Chief, Endoscopy and Bariatric Surgery, Vice Chair, Network General Surgery, Chief, Duke General Surgery at Durham Regional Hospital, Duke University Medical Center, Durham, North Carolina, U.S.A.

Karen Bitzer, OTR/L, CHT Musculoskeletal Division Coordinator, Department of Rehabilitation Services, University Hospitals of Cleveland, Cleveland, Ohio, U.S.A. Mark Bloomston, MD Fellow in Surgical Oncology, Ohio State University Medical Center, Columbus, Ohio, U.S.A.

Daniel T. Dempsey, MD Professor and Chairman, Department of Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania, U.S.A.

Edward L. Bove, MD Helen and Marvin Kirsh Professor of Surgery, Professor and Section Head, Cardiac Surgery, Director, Pediatric Cardiac Surgery, University of Michigan, C. S. Mott Children’s Hospital, Ann Arbor, Michigan, U.S.A.

Gerard M. Doherty, MD Norman W. Thompson Professor of Surgery, Head, Section of General Surgery; Chief, Division of Endocrine Surgery, University of Michigan, Ann Arbor, Michigan, U.S.A.

William C. Broaddus, MD, PhD Hord Professor, Department of Neurosurgery, Virginia Commonwealth University Health System; Chief of Neurosurgery, Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, Virginia, U.S.A.

Philip E. Donahue, MD Professor of Surgery, Department of Surgery, University of Illinois Medical Center at Chicago; Chairman, Division of General Surgery, John H. Stroger, Jr. Hospital of Cook County, Chicago, Illinois, U.S.A.

Robert E. Brolin, MD Adjunct Professor of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, Director

Egon M. R. Doppenberg, MD Former Chief Resident, Department of Neurosurgery, Virginia Commonwealth University

xiii

xiv

Contributors

Health System, Richmond, Virginia; presently in neurosurgery private practice in Chicago, Illinois, U.S.A. Akinsan Dosekun, MD Associate Professor of Internal Medicine, Department of Internal Medicine, The University of Texas Medical School at Houston, Houston, Texas, U.S.A. Ashley E. Ducale, MPT, PhD Post-Doctoral Fellow, Department of Surgery, Wound Healing Laboratory, Virginia Commonwealth University School of Medicine, Richmond, Virginia, U.S.A. Rodney Durham, MD Professor of Surgery, Department of Surgery, Division of Trauma and Critical Care, University of South Florida College of Medicine, Tampa General Hospital, Tampa, Florida, U.S.A. Douglas B. Evans, MD Professor of Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, U.S.A. B. Mark Evers, MD Professor and Robertson-Poth Distinguished Chair in General Surgery, Department of Surgery, The University of Texas Medical Branch, Galveston, Texas, U.S.A. Peter J. Fabri, MD Professor of Surgery, Associate Dean for Graduate Medical Education, University of South Florida College of Medicine, Tampa, Florida, U.S.A. Andrew C. Fiore, MD Professor of Surgery, Division of Cardiothoracic Surgery, Department of Surgery, St. Louis University School of Medicine; Chief of Cardiothoracic Surgery, Cardinal Glennon Children’s Hospital, St. Louis, Missouri, U.S.A. John R. Foringer, MD Assistant Professor of Internal Medicine, Department of Internal Medicine, The University of Texas Medical School at Houston, Houston, Texas, U.S.A. O. Howard Frazier, MD Professor of Surgery, University of Texas Health Science Center at Houston; Professor of Surgery, Baylor College of Medicine; Chief of Cardiopulmonary Transplantation; Director of Cardiovascular Surgery Research, Texas Heart Institute, Houston, Texas, U.S.A. Julie A. Freischlag, MD William Stewart Halstead Professor of Surgery, Chair, Department of Surgery; Surgeon-in-Chief, Johns Hopkins Medical Center, Baltimore, Maryland, U.S.A.

Deborah T. Glassman, MD Clinical Assistant Professor, Department of Urology, Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A. Bobby S. Glickman, MD Instructor of Surgery, Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska, U.S.A. R. Scott Graham, MD Associate Professor of Neurosurgery, Department of Neurosurgery, Virginia Commonwealth University School of Medicine and Medical Center, Richmond, Virginia, U.S.A. Bartley P. Griffith, MD Professor of Surgery, Chief, Division of Cardiac Surgery, Director, Heart and Lung Transplantation, Maryland Heart Center, University of Maryland Medical Center, Baltimore, Maryland, U.S.A. Dipin Gupta, MD Fellow, Cardiovascular Surgery, New York University School of Medicine, New York, New York, U.S.A. Carl E. Haisch, MD Professor of Surgery, Department of Surgery, East Carolina University Brody School of Medicine, Director of Surgical Immunology and Transplantation; Attending Surgeon, Pitt County Memorial Hospital, Greenville, North Carolina, U.S.A. Nahid Hamoui, MD Assistant Professor of Surgery, Department of Surgery, University of Southern California Keck School of Medicine, Los Angeles, California, U.S.A. Sean P. Harbison, MD Associate Professor of Surgery, Department of Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania, U.S.A. Kenneth S. Helmer, MD Assistant Professor of Surgery, Department of Surgery, University of Texas Medical School at Houston, Houston, Texas, U.S.A. Ana O. Hoff, MD Assistant Professor of Endocrinology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, U.S.A. Kathryn Holloway, MD Professor of Neurosurgery, Department of Neurosurgery, Virginia Commonwealth University Health System; Neurosurgical Director of the Southeast Parkinson’s Disease Research, Education and Clinical Care Center of Excellence (PADRECC) at Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, Virginia, U.S.A.

Janette Gaw, MD Former Chief Resident, Department of Surgery, Yale University School of Medicine, New Haven, Connecticut; presently in colorectal surgery private practice, Fort Myers, Florida, U.S.A.

Kamal M. F. Itani, MD Professor of Surgery, Boston University Medical Center, Chief of Surgery, VA Boston Health Care System, Boston, Massachusetts, U.S.A.

Bruce L. Gewertz, MD Dallas B. Phemister Professor and Chair, Department of Surgery, The University of Chicago, Chicago, Illinois, U.S.A.

Lindsey N. Jackson, MD Resident in General Surgery, Department of Surgery, The University of Texas Medical Branch, Galveston, Texas, U.S.A.

Rafik M. Ghobrial, MD, PhD Professor of Surgery, Director, Liver, Pancreas and Small Bowel Transplantation, The DumontUCLA Transplant Center, David Geffen School of Medicine of the University of California at Los Angeles, Los Angeles, California, U.S.A.

Mark R. Jackson, MD Former Associate Professor of Surgery, Division of Vascular Surgery, University of Texas Southwestern Medical School, Dallas, Texas; presently in vascular surgery private practice, St. Francis Hospital, Greenville, South Carolina, U.S.A.

George K. Gittes, MD Surgeon-in-Chief, Children’s Hospital of Pittsburgh, Professor of Surgery, Division Chief, Pediatric Surgery, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, U.S.A.

Raymond J. Joehl, MD Professor of Surgery, Program Director General Surgery Residency, Department of Surgery, Loyola University Medical Center, Maywood; Chief, Surgical Service and Manager, Surgery Service Line, The Charles B. Puestow Surgical Service, Edward Hines, Jr VA Hospital, Hines, Illinois, U.S.A.

Contributors

xv

Haytham M. A. Kaafarani, MD Resident in Surgery, Department of Surgery, University of South Florida Medical School, Tampa, Florida, U.S.A.

Walter E. Longo, MD Professor and Vice Chairman, Chief, Division of General Surgery, Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, U.S.A.

Lillian S. Kao, MD Assistant Professor of Surgery, Department of Surgery, University of Texas Medical School at Houston, Houston, Texas, U.S.A.

Patricia A. Lowry, MD Associate Professor of Radiology, Department of Radiology, Virginia Commonwealth University School of Medicine and Medical Center, Richmond, Virginia, U.S.A.

Gregory Kennedy, MD Chief Resident in Surgery, Department of Surgery, University of Wisconsin Medical School, Madison, Wisconsin, U.S.A.

Michael P. Macris, MD Medical Director, Cardiovascular Surgery, Memorial Hermann Northwest Hospital, Houston, Texas, U.S.A.

Jonathan Kiev, MD Assistant Professor of Surgery, Division of Cardiothoracic Surgery, Department of Surgery, Virginia Commonwealth University School of Medicine and Medical Center, Richmond, Virginia, U.S.A. V. Suzanne Klimberg, MD Professor of Surgery, Department of Surgery, Director, Breast Surgical Oncology, University of Arkansas for Medical Services and the Arkansas Cancer Research Center, Little Rock, Arkansas, U.S.A. Evan R. Kokoska, MD Assistant Professor of Surgery, Department of Surgery–Pediatric Surgery Service, University of Arkansas for Medical Sciences, Little Rock, Arkansas, U.S.A. Bruce C. Kone, MD The James T. and Nancy B. Willerson Chair, Chairman, Department of Medicine, Professor of Internal Medicine and of Integrative Biology and Pharmacology, The University of Texas Medical School at Houston, Houston, Texas, U.S.A. Kara C. Kort, MD Assistant Professor of Surgery, Department of Surgery, State University of New York–Upstate Medical University, Syracuse, New York, U.S.A. Maria A. Kouvaraki, MD, PhD Fellow in Endocrine Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, U.S.A. Rosemary A. Kozar, MD, PhD Associate Professor of Surgery, Department of Surgery, University of Texas Medical School at Houston, Houston, Texas, U.S.A. Rakhshanda Layeeque, MD Assistant Professor of Surgery, Department of Surgery, Surgical Oncology Section, University of Massachusetts Memorial Medical Center, Worcester, Massachusetts, U.S.A. Jeffrey E. Lee, MD Professor of Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, U.S.A. Kangmin Lee Resident in Neurosurgery, Department of Neurosurgery, Virginia Commonwealth University Health System, Richmond, Virginia, U.S.A.

Ajai K. Malhotra, MD Assistant Professor of Surgery, Division of Trauma and Critical Care, Department of Surgery, Virginia Commonwealth University School of Medicine and Medical Center, Richmond, Virginia, U.S.A. James F. McKinsey, MD Associate Professor of Clinical Surgery and Site Chief of Vascular Surgery, Columbia University of New York Presbyterian Hospital System, New York, New York, U.S.A. Irvine G. McQuarrie, MD, PhD Associate Professor of Neurosurgery and Neuroscience, Department of Surgery, School of Medicine, Case Western Reserve University; Cleveland VA Medical Center, Cleveland, Ohio, U.S.A. Margaret M. McQuiggan MS, RD, CNSD Clinical Instructor, Department of Surgery, University of Texas Medical School at Houston, Houston, Texas, U.S.A. Sheilendra S. Mehta Former Research Fellow in Pediatric Surgery, Division of Pediatric Surgery, Children’s Mercy Hospital, Department of Surgery, University of Missouri School of Medicine at Kansas City, Kansas City, Missouri, U.S.A. David W. Mercer, MD Professor of Surgery and Vice Chairman, Department of Surgery, The University of Texas Health Science Center–Houston; Chief of Surgery, Lyndon Baines Johnson General Hospital, Houston, Texas, U.S.A. Ronald C. Merrell, MD Professor of Surgery, Department of Surgery, Virginia Commonwealth University School of Medicine and Medical Center, Richmond, Virginia, U.S.A. Thomas A. Miller, MD Ammons Professor of Surgery, Division of General Surgery, Department of Surgery, Virginia Commonwealth University School of Medicine and Medical Center; Chief of Surgery, Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, Virginia, U.S.A. Sina L. Moainie, MD Resident in Cardiothoracic Surgery, Maryland Heart Center, University of Maryland Medical Center, Baltimore, Maryland, U.S.A. Jeffrey F. Moley, MD Professor of Surgery and Chief, Endocrine and Oncologic Surgery, Washington University School of Medicine; Associate Director, Alvin J. Siteman Cancer Center; Attending Surgeon, Barnes-Jewish Hospital, St. Louis, Missouri, U.S.A.

Denise Lester, MD Assistant Professor, Department of Anesthesiology, Virginia Commonwealth University School of Medicine and Medical Center; Director, Chronic Pain Clinic, Anesthesiology Service, McGuire Veterans Affairs Medical Center, Richmond, Virginia, U.S.A.

Frederick A. Moore, MD Professor of Surgery and Vice Chairman, Department of Surgery, Medical Director, Trauma Services, University of Texas Medical School at Houston, Houston, Texas, U.S.A.

Terrence H. Liu, MD Associate Clinical Professor of Surgery, Residency Program Director, UCSF–East Bay Surgery Program, University of California San Francisco School of Medicine, East Bay Campus, Oakland, California, U.S.A.

Ralph S. Mosca, MD Associate Professor of Surgery, Columbia University College of Physicians and Surgeons; Associate Attending Surgeon, New York Presbyterian Hospital/Columbia University Medical Center, New York, New York, U.S.A.

xvi

Contributors

Carlos A. Murillo, MD Resident Instructor, Department of Surgery, Texas Tech University Health Sciences Center, El Paso School of Medicine, El Paso, Texas, U.S.A.

Jose M. Prince, MD Surgical Resident, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, U.S.A.

Stuart I. Myers, MD Professor of Surgery, Division of Vascular Surgery, Department of Surgery, Virginia Commonwealth University School of Medicine and Medical Center; Attending Surgeon, Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, Virginia, U.S.A.

Frank J. Quayle, MD Resident in Surgery, Department of Surgery, Division of General Surgery, Washington University School of Medicine, St. Louis, Missouri, U.S.A.

Attila Nakeeb, MD Associate Professor of Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, U.S.A. Lena M. Napolitano, MD Professor of Surgery, Director, Surgical Critical Care; Associate Chair, Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, U.S.A. Leigh Neumayer, MD Professor of Surgery, Program Director, Utah Building Interdisciplinary Research Careers in Women’s Health, University of Utah Medical Center, Salt Lake City, Utah, U.S.A. John E. Niederhuber, MD Acting Director, National Cancer Institute, Bethesda, Maryland; Former Director, University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin, U.S.A. Unyime O. Nseyo, MD Adjunct Professor, Department of Urology, University of Florida School of Medicine; Chief, Urology Section, Malcom Randall VA Medical Center, Gainesville, Florida, U.S.A. Fiemu E. Nwariaku, MD Associate Professor and Vice Chairman, Division of Gastrointestinal and Endocrine Surgery, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, U.S.A. Daniel J. Ostlie, MD Associate Professor of Surgery, Division of Pediatric Surgery, Children’s Mercy Hospital, Department of Surgery, University of Missouri School of Medicine at Kansas City, Kansas City, Missouri, U.S.A. Lucian Panait, MD Former Postdoctoral Research Fellow, Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, Virginia, U.S.A. Donald H. Parks, MD Professor and Chief, Division of Plastic and Reconstructive Surgery, Department of Surgery, University of Texas Medical School at Houston, Houston, Texas, U.S.A. Jose R. Parra, MD Former Assistant Professor of Surgery, Division of Vascular Surgery, Department of Surgery, Johns Hopkins Medical Center, Baltimore, Maryland, U.S.A.

J. Robert Ramey, MD Chief Resident in Urology, Department of Urology, Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A. Cristiana Rastellini, MD Associate Professor, Department of Surgery, University of Massachusetts Medical School, Worcester, Massachusetts, U.S.A. Lorita Rebellato, PhD Associate Professor of Pathology, Department of Pathology, East Carolina University Brody School of Medicine, Greenville, North Carolina, U.S.A. Kathryn A. Richardson, MD Assistant Professor, Department of Surgery, Louisiana State University Health Sciences Center, Shreveport, Louisiana, U.S.A. Alexander S. Rosemurgy, MD Professor of Surgery and Medicine, Director, Division of General Surgery, Surgical Director, Tampa General Hospital Digestive Disorders Center, University of South Florida College of Medicine, Tampa, Florida, U.S.A. Ronnie Ann Rosenthal, MS, MD Associate Professor of Surgery, Yale University School of Medicine, New Haven; Chief, Surgical Service, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, U.S.A. Shawn D. St. Peter, MD Assistant Professor of Surgery, Division of Pediatric Surgery, Children’s Mercy Hospital, Department of Surgery, University of Missouri School of Medicine at Kansas City, Kansas City, Missouri, U.S.A. Jeannie F. Savas, MD Associate Professor of Surgery, Division of General Surgery, Department of Surgery, Virginia Commonwealth University School of Medicine and Medical Center; Attending Surgeon, Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, Virginia, U.S.A. Henry J. Schiller, MD Associate Professor of Surgery, Department of Surgery, Mayo Clinic School of Medicine, Rochester, Minnesota, U.S.A. Lelan F. Sillin, MD, MS(Ed) Professor of Surgery, Vice Chair for Educational Affairs, Department of Surgery, University of Rochester Medical Center, Rochester, New York, U.S.A.

Christina Paylan, MD Former Fellow in Trauma and Critical Care, Department of Surgery, University of South Florida College of Medicine, Tampa General Hospital, Regional Trauma Center, Tampa, Florida, U.S.A; presently in plastic surgery private practice, Tampa, Florida, U.S.A.

Michael Sobel, MD Professor and Vice Chairman, Department of Surgery, University of Washington; Professor and Chief, Puget Sound Veterans Affairs Health Care System, Seattle, Washington, U.S.A.

Melissa F. Perkal, MD Assistant Professor of Surgery, Director, Veterans Affairs Hospital Surgical Intensive Care Unit, Director, Surgical Preceptor Program, Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, U.S.A.

James C. Stanley, MD Handleman Professor of Surgery, Section of Vascular Surgery, Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan, U.S.A.

Henry A. Pitt, MD Professor and Vice Chairman, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, U.S.A.

Heinrich Taegtmeyer, MD, DPhil Professor of Medicine, Division of Cardiology, Department of Internal Medicine, University of Texas Medical School at Houston, Houston, Texas, U.S.A.

Contributors

xvii

Daniel G. Tang, MD Chief Resident in General Surgery, Department of Surgery, Virginia Commonwealth University School of Medicine and Medical Center, Richmond, Virginia, U.S.A.

Glenn J. R. Whitman, MD Professor of Surgery, Division of Cardiothoracic Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania, U.S.A.

Jon S. Thompson, MD Professor and Vice Chairman, Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska, U.S.A.

Charles Williams, MD Associate Professor, Vice Chair for Veterans Affairs, Department of Anesthesiology, Virginia Commonwealth University School of Medicine and Medical Center; Chief, Anesthesiology Service, Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, Virginia, U.S.A.

Hari Siva Gurunadha Rao Tunuguntla, MD, MBBS, MS (Surgery), MCh Resident, Department of Urology, University of Miami, Miller School of Medicine, Miami, Florida, U.S.A. Richard H. Turnage, MD Professor of Surgery and Chairman, Department of Surgery, Louisiana State University Health Sciences Center, Shreveport, Louisiana, U.S.A. Douglas J. Turner, MD Assistant Professor of Surgery, Division of General Surgery, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, U.S.A. Henry Ty, MD Former Chief Resident in Neurosurgery, Department of Neurosurgery, Virginia Commonwealth University Health System, Richmond, Virginia; presently in neurosurgery private practice, North Andover, Massachusetts, U.S.A.

Ryan M. Wolfort, MD Resident in Surgery, Department of Surgery, Louisiana State University Health Sciences Center, Shreveport, Louisiana, U.S.A. Kenneth J. Woodside, MD Chief Resident in General Surgery, Department of Surgery, The University of Texas Medical Branch, Galveston, Texas, U.S.A. Dorne R. Yager, PhD Associate Professor of Surgery, Physiology and Biochemistry, Director, Wound Healing Laboratory, Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, Virginia, U.S.A.

Kathryn M. Verbanac, PhD Professor of Surgery, Division of Transplantation, Department of Surgery, East Carolina University Brody School of Medicine, Greenville, North Carolina, U.S.A.

Christopher K. Zarins, MD Chidester Professor of Surgery, Chief, Division of Vascular Surgery, Stanford University Medical Center, Palo Alto, California, U.S.A.

David J. Wainwright, MD Associate Professor of Surgery, Division of Plastic and Reconstructive Surgery; Department of Surgery, University of Texas Medical School at Houston, Houston, Texas, U.S.A.

Emmanuel E. Zervos, MD Assistant Professor of Surgery, Department of Surgery, Surgical Oncology, University of South Florida College of Medicine, Tampa General Hospital, Tampa, Florida, U.S.A.

Jian-Ying Wang, MD, PhD Professor of Surgery and Pathology, Associate Chair for Basic Research, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, U.S.A. Andrew S. Wechsler, MD Stanley K. Brockman Professor and Chairman, Department of Cardiovascular Medicine and Surgery, Drexel University College of Medicine, Philadelphia, Pennsylvania, U.S.A.

Yuan Zhai, MD Assistant Professor of Surgery, Department of Surgery, Section of Liver and Pancreas Transplantation, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California, U.S.A. Huiping Zhou, PhD Assistant Professor, Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, U.S.A.

PART ONE: General Considerations in the Management of Surgical Patients

1 Metabolic Response to Starvation, Stress, and Sepsis Joseph F. Amaral, Michael D. Caldwell, and Thomas A. Miller

for the relatively high boiling point of water, its relatively high freezing point, and its high specific heat (the energy required to raise the temperature of 1 g of a substance by 1
C). This latter property allows water to exert a major role in temperature regulation, because a large amount of heat is lost as water evaporates (perspiration) and a large amount of heat is required to raise the temperature of water. The extensive hydrogen bonding of water also makes it important in establishing the tertiary structure of proteins and other molecules. Total body water (TBW) is divisible into two components: intracellular water (ICW) and extracellular water (ECW). These two components are separated by cell membranes. Measurement of body fluid compartments uses dilution techniques, based on the concept that a substance that distributes itself equally and exclusively throughout a given compartment (e.g., TBW) can be used to determine the volume of that compartment. This procedure is done by injecting a known amount of the substance and measuring its concentration at steady state, as well as measuring the amount excreted during the period of time required to reach steady state. Thus:

INTRODUCTION The metabolic response to stress, starvation, and sepsis should be viewed as a complex series of neuroendocrine reflexes resulting in an integrated attempt by the organism to mobilize energy substrates, to preserve oxygen and substrate delivery, and to maintain essential body functions (1). These alterations involve changes in the distribution and use of water, proteins, fats, and carbohydrates. As such, an understanding of normal body composition is essential to make discussion of the metabolic response meaningful.

BODY COMPOSITION Body composition has been defined by Moore (2) as ‘‘the study of the total mass and volume of body components in relation to body size, body configuration, age, sex, disease, and concentration changes.’’ It can be considered from several aspects, including tissue anatomy, chemical composition, and metabolic structure (Fig. 1), with the latter two being the most important with regard to energy stores and ‘‘intermediary metabolism.’’

Chemical Composition

Volume ¼

All living organisms may be considered as complex and organized arrangements of fats, proteins, carbohydrates, minerals, and electrolytes in an aqueous environment. Although the percentage of each of these chemical groups varies among and within species, by far the largest component of all living organisms is water.

Amount injected  Amount excreted Steady state concentration

Because the amount lost is usually negligible, the convention is to use: Volume ¼

Amount injected Steady state concentration

Water Water is an important substance involved in virtually all physiologic processes. Its physiochemical properties result largely from its electron structure. The hydrogen ions have a slightly positive charge, whereas the oxygen molecule, with its lone pair of electrons, has a negative charge. This difference allows extensive hydrogen bonding and a relatively high dipole moment (5) that causes the water molecules to orient themselves in an external electric field in such a way that they act as an electric buffer. When ionic substances are placed in water, a hydrational shell forms around the individual ions, reducing their electrochemical attraction and thus forming a solution (5). Water thus keeps electrolytes and other polar molecules in solution and allows them independent motion, which is critical to nutrient transport. The extensive hydrogen-bonding capacity of water molecules causes them to orient themselves in a highly organized structure similar to ice. This structure accounts

Numerous substances are available that allow measurement of various fluid compartments (Fig. 2). Generally, the TBW is the most accurately measured compartment. The TBW varies with age, sex, body build, physical activity, disease, and state of hydration. The TBW can be measured accurately using deuterium oxide or tritiated water. For a healthy man, TBW constitutes approximately 60% of total body weight, and for a healthy woman, it constitutes approximately 50% (Table 1). The differences in the proportion of TBW reflect the quantity of skeletal muscle and adipose tissue present in the two sexes. Adipose tissue contains little ICW, whereas skeletal muscle has one of the largest water contents of all tissues (Table 2). Women, with their larger adipose tissue stores and smaller skeletal muscle mass, have less TBW than men. Similarly, the TBW of young, lean athletes is greater than that of elderly, obese nonathletes. The TBW as a percentage of body weight decreases steadily with age (Table 1). Newborns have the highest

1

2

Part One: General Considerations

Table 1 Distribution of Total Body Water in Infants, Children, and Adults 100

CHO Mineral

Other

Other nitrogen

Protein

Vital organs

Fat

Blood Nerve

Hydrogen Carbon

Fat

Skin Adipose

% 50

Extracellular water

Extracellular mass

Intracellular water

Body cell mass

Oxygen

Bone

Muscle

0 TISSUE

CHEMICAL

METABOLIC MOLECULAR

Figure 1 Body composition in adult man. Source: From Refs. 3, 4.

percentage, with 75% to 80% of body weight representing water. This percentage decreases during the first few months after birth to approximately 65% of the body weight, where it remains for the remainder of infancy and childhood. This reduction in TBW is primarily the result of reduction in ECW (Fig. 3). Until the age of 12, no difference in TBW is noted between boys and girls. With advancing age, TBW as a percentage of body weight decreases to a low of 52% and 47% in males and females, respectively (2). This results primarily from a decrease in

ECF

ICF

PlasRBC ma ISF

RBC Plasma

Cr54

T1824

131

I ECF

Inulin Sucrose

Mannitol S2O3

TBW (%) Age

Men

Women

0–1 day 1–10 days 1–3 mo 3–6 mo 6–12 mo 1–2 yr 2–3 yr 3–5 yr 5–10 yr 10–16 yr 17–39 yr 40–59 yr 60 þ yr

79 74 72.3 70.1 60.4 58.7 63.5 62.2 61.5 58.9 60.6 54.7 51.5

79 74 72.3 70.1 60.4 58.7 63.5 62.2 61.5 57.3 50.2 46.7 45.5

Abbreviation: TBW, total body water. Source: Adapted from Ref. 7.

ICW, because ECW remains unchanged (5). The size of the ECW space depends on the method used for determining it. Large molecules such as insulin, mannitol, or sucrose appear to underestimate the ECW compartment because of the slower diffusion of these larger molecules into noncellular spaces (5). An ECW space of 15% to 16% of body weight is usually reported with these methods (5). Assessment of the ECW with small molecules such as 35SO4,82Br, and 24Na appears to overestimate the ECW space because of the ability of these small ions to diffuse into cells. An ECW space of 21% to 27% of body weight is usually reported when these methods are used (5). In general, it is estimated that the ECW occupies 20% of the body weight (and therefore 30–40% of TBW). It is divided into plasma (5% of body weight) and interstitial fluid (15% of body weight). The interstitial fluid occupies a rapidly equilibrating functional space between cells and a slowly equilibrating (or nonequilibrating) space composed of epithelial cell secretions, connective tissue, joint space, and cerebrospinal fluids, the so-called transcellular space (9). The functional interstitial fluid accounts for 90%, and the transcellular space accounts for 10% of the total interstitial fluid. The transcellular space should not be equated with the ‘‘third space.’’ The transcellular fluids are a normal component of the ECW and do not affect the functional volume of the extracellular space. The third space results

SO4 Br

Table 2 Distribution of Water in the Various Tissues of a 70 kg Man

Cl Na SCN D 2O

TBW

THO Antipyrine

RBC Plas- ISF ma ECF

Conn. tissue ICF

Figure 2 Substances used to measure the body fluid compartments. Abbreviations: ECF, extracellular fluid; ICF, intracellular fluid; ISF, interstitial fluid; RBC, red blood cell; TBW, total body water; THO, titrated water. Source: From Ref. 6.

Tissue Skin Muscle Skeleton Brain Liver Heart Lungs Kidneys Spleen Blood Intestine Adipose tissue Source: From Ref. 8.

Water (%)

Body weight (%)

Liters of water per 70 kg

72 75.6 22 74.8 68.3 79.2 79 82.7 75.8 83 74.5 10

18 41.7 15.9 2 2.3 0.5 0.7 0.4 0.2 8 1.8 10

9.07 22.1 2.45 1.05 1.03 0.28 0.39 0.25 0.1 4.65 0.94 0.7

Chapter 1: Metabolic Response to Starvation, Stress, and Sepsis

3

Table 3 Electrolyte Composition of the Body Fluid Compartments Serum Serum water (mEq/L) (mEq/L)

100 90

Electrolytes

BODY WEIGHT (%)

80

Total body water (TBW)

70 60

Intracelluar fluid (ICF)

50 40

Extracellular fluid (ECF)

30 20

+

+

+

10 2 4 6 8 Birth 6 12 3yr 6yr 9yr 12yr 15yr Adult mo mo AGE

Figure 3 Distribution of body fluids in children as a function of age and sex. Source: From Ref. 6 and courtesy of Pediatrics 1961; 28:169.

Interstitial fluid (mEq/L)

Intracellular fluid (muscle) (mEq/kg of H2O)

Cations Sodium (Naþ) Potassium (Kþ) Calcium (Ca2þ) Magnesium (Mg2þ)

142 4 5 2

152.7 4.3 5.4 2.2

145 4


10 156 3.3 26

Total cations

153

165

149

195

102 26

109.7 28

114 31


2
8

2

2.2

95

1 6 16

1.1 6.5 17.2

20

Anions Chloride (Cl) Bicarbonate (HCO2 3 ) Phosphate (HPO2 4 ) Sulfate (SO2 4 ) Organic acids Protein Total anions

153

165

55 145

180þ

Source: Adapted from Ref. 7.

from abnormalities in the permeability of cells, such as the abnormalities seen after ischemia and those seen with inflammation that increases the size of the extracellular space but not, a priori, the volume of the ECW. Third-space size is proportional to the severity of the injury. Because fluid and electrolytes in the third space are derived from functional extracellular fluid, the increase in size of the space reduces the functional extracellular volume. Direct measurement of the ICW compartment is extremely difficult, because substances that equilibrate only in the intracellular space have not been defined. Consequently, the ICW space is estimated as the difference between TBW and ECW. The ICW space varies from individual to individual. In healthy normal adults, it constitutes approximately 30% to 40% of body weight (55% of TBW). Because fat has little ICW and skeletal muscle has the highest percentage of ICW, athletic muscular individuals have a higher proportion of ICW; but women, the obese, and the elderly have a smaller muscle mass and therefore have a smaller percentage of their body weight as ICW. The electrolyte composition of the various fluid compartments is noted in Table 3. The major cations are sodium and potassium, and the major anions are chloride and bicarbonate. The absolute amount of a particular ion can only be measured by cadaveric analyses, but the total exchangeable amount of an ion can be estimated by dilution with a labeled

form of the compound. Total exchangeable sodium is not equivalent to total body sodium. A large amount, approximately 1000 mEq, is present in a nonexchangeable form in bone (10). The total exchangeable potassium is more closely equivalent to the total body potassium (TBK) (less than 0.5% is nonexchangeable) (10). Sodium is the major extracellular cation, and potassium is the major intracellular cation (Table 4). The ECW space is approximated by the total body sodium, the ICW space by the TBK, and the TBW by the sum of total body sodium and TBK. Moore (10) has used this relationship to estimate TBW from total exchangeable sodium (Nae) and potassium (Ke) using the following formula: TBM ¼

ðNae þ Ke Þ þ 70
ð2LÞ 163

The differing ionic compositions of the various fluid compartments are the result of variations in the permeabilities and active transport mechanisms present great diversity among the transcellular fluids in this regard (Table 5).

Fat (Lipids) Until the 1950s, lipids, the second largest chemical constituent of the body, were considered to be relatively inert

Table 4 Total and Exchangeable Amounts of Electrolytes in Fluid Compartments of Adult Man Sodium

Potassium

Compartment Total extracellular Total intracellular Total body Total exchangeable Total body intracellular concentration (milliequivalent per liter intracellular water) a

Magnesium

Chloride

Bicarbonate

27.8 5.2 33 33 14.4

6.8 5.9 12.7 12.7 16.4

(mEq/kg of body weight) 52.8 5.2 58 41 14.4

2.5 51.3 53.8 52.8 14.3

21.8 8.2 30 3.4, 4.9, 10a 22.8

Equilibrated for 24, 48, and 89 hours, respectively. Total exchangeable magnesium is a function of time of equilibration. Source: From Ref. 11.

4

Part One: General Considerations

Table 5 Mean Electrolyte Composition of Transcellular Fluids Fluid Saliva Gastric juice Bile Pancreatic juice Ileal fluid Cecal fluid Cerebrospinal fluid Sweat

Na (mEq/L)

K (mEq/L)

Cl (mEq/L)

HCO3 (mEq/L)

Hþ (mEq/L)

33 60 149 141

20 10 5 5

34 130 101 77

0 0 45 92

– 90 – –

129 80 141

11 21 3

116 48 127

29 22 23

– – –

45

5

58

0

–

Source: Adapted from Ref. 12.

substances that served as a source of protection and insulation. They now are recognized as essential components of energy metabolism (providing 9.3 kcal/g), hormonal synthesis (steroids), hormonal regulation and action (prostaglandins), and neural transmission (sphingomyelins). In addition, they are required for general cellular integrity and stability (cell membrane phospholipids and cholesterol). Many of the functions of lipids require fatty acids that cannot be synthesized by human beings. The three major essential fatty acids are arachidonic acid, linoleic acid, and linolenic acid. Total body fat (TBF) varies inversely with TBW in normal individuals. During the first four months of life, there is a decrease in the percentage of TBF, expressed as percent of total body weight (Table 6). After puberty, the TBF content increases, with the increase being greater in girls than in boys. In healthy men, TBF accounts for approximately 25% of body weight, and in healthy women, fat accounts for approximately 35% of body weight. With age, there is an increase in the percentage of body weight occupied by fat. However, it is of note that body weight often remains unchanged with age. Because total body weight equals body fat plus fat-free tissues, a decrease in fat-free tissue is thought to occur with aging (14). The percentage of body weight occupied by fat is also inversely related to the level of physical activity. Muscular athletic individuals have a greater muscle mass and smaller percentage of body fat than sedentary individuals of similar body weight (15). However, these changes are somewhat adaptive. For example, a long-distance swimmer benefits from the buoyancy and insulation provided by fat and often has a greater amount of fat than a long-distance runner of equivalent body build (15). This presumably results from a difference in caloric intake between these two groups. Approximately 50% of the fat in human beings is located in the subcutaneous tissue, but the distribution of the subcutaneous tissue varies with age, sex, and physical activity (14). Children have a large amount of subcutaneous

Table 6 Body Composition of Infants and Children as Function of Age

Age (mo) Birth 4 12 24 36

Whole body (g/100 g)

Body weight (kg)

Water

Protein

Lipid

Other

3.5 7 10.5 13 15

75.1 60.2 59 61 62

11.4 11.4 14.6 15.7 16.4

11 26.3 23.9 20.6 18.3

2.5 2.1 2.5 2.7 3.3

Source: From Ref. 13.

tissue over their triceps, but only a small amount of subcutaneous tissue in their abdominal walls. The distribution is reversed in adults. Changes in the body fat distribution occurring as a result of weight gain are not equally distributed (14). For this reason, serial measurement of an isolated anthropometric index may not adequately reflect body composition changes in malnourished individuals who are being repleted. However, changes in the body fat distribution occurring as a result of weight loss are equally distributed. A 10% loss in triceps skinfold is accompanied by a concomitant 10% loss in the size of the subcutaneous tissues of other areas such as the hips, abdomen, thighs, and breasts (14). TBF is defined as the difference between total body weight and fat-free mass (see the equation given below). Fat contains very little water and virtually no potassium. On the other hand, the total water content of fat-free tissue averages 73.2% of TBW (16), and the potassium content of fat-free tissues averages 68.1 mEq/kg (14). Consequently, fatfree tissue may be approximated from either TBW or total exchangeable potassium (Ke), and the TBF is estimated by inference. Equations for these calculations are: For TBW: TBF ¼ BWt  ðTBW=0:732Þ

and

%TBF ¼ 1  ð%TBW=0:732Þ For Ke : TBF ¼ BWt  ðKe Þ=68:1 and %TBF ¼ ½BWt  ðKe =68:1Þ=BWT where BWt is body weight. It should be noted that these methods assume that the hydration and potassium content of that portion of the body that is fat free is constant. However, these assumptions are not always valid because the hydration of the fat-free tissue can vary considerably (e.g., greatest in edematous states and least in dehydrated states). A third method used in calculating TBF involves the measurement of the specific gravity of the individual by underwater weighing procedure (14,15,17,18). This method is based on the findings that normal human fat has a density of 0.9 g/mL and nonfat tissue has an average density of 1.1 g/mL at 37
C. At 37
C, the density of an average reference male containing 15.3% body fat is 1.064 g/mL (19). With the use of these values, the percentage fat in an individual can be determined by measuring the density (D) in water as indicated by the equation: %Fat ¼ ½ð4:570=DÞ  4:142  100 Although the density of human fat changes only with temperature, the density of fat-free tissue changes with age, degree of obesity, and degree of hydration (14). When estimates of TBF made by densitometric methods are compared to calculations of TBF made from TBW, the densitometric methods give a higher estimate of TBF (15,17). Densitometric methods give a lower estimate of TBF when compared to calculations of TBF made from total exchangeable potassium (17,20). A fourth method used to calculate TBF involves the measurement of the uptake of an inert, highly fat-soluble gas such as cyclopropane or krypton (21). The assumption made in this technique is that the gas will only go into fat cells. Thus it should yield a more accurate measurement of TBF than the other methods noted. When compared to measurements made by TBW determination, similar results

5

Chapter 1: Metabolic Response to Starvation, Stress, and Sepsis

protein turnover per kilogram of body weight are the result of a decrease in skeletal muscle mass. TBP may be estimated by one of two methods: (i) measurement of total exchangeable potassium or (ii) measurement of total body nitrogen (TBN) by neutron activation. TBN is linearly related to total exchangeable potassium in both normal and decreased conditions (26,27). The average exchangeable potassium to nitrogen ratio in tissue is 3 mEq/g nitrogen (10). Thus:

are obtained (22). When compared to total exchangeable potassium measurements or densitometric measurements, lower values are obtained (23). However, no data are available comparing the inert gas method with cadaver analyses.

Proteins Proteins are chains of amino acids. Proteins and amino acids form essential components of all living cells and are involved in virtually all body functions. These molecules serve as enzymes, hormones, neurotransmitters, immunoglobulins, and transport molecules. They are also essential components of all cell membranes and various cellular components, including receptors, transport systems, and contractile elements. As such, they are necessary for the metabolism, growth, regulation, replication, protection, repair, communication, and motion of individual cells and the coordinated function of the entire organism. Consequently, it is somewhat remarkable that total body proteins (TBPs) account for only 15% of the body weight in a healthy man and that over 80% of the TBP is present in skeletal muscle and connective tissue. Unlike fat, there are no storage depots for protein. All the body’s protein is functional. As a result of its numerous and varied functions, protein, unlike fat, undergoes considerable daily turnover. Approximately 2.5% of the TBP (250 g in a 70 kg man) is broken down and resynthesized each day (23). More than half this turnover is accounted for by daily secretory processes, white cell turnover, hemoglobin turnover, muscle-protein turnover, and plasma protein turnover. The total turnover rate of body protein diminishes progressively with age (24). The protein synthesis rate per kilogram of body weight decreases from 25 g/kg/day in the neonate to 7 g in a one-year-old infant. In the average man and woman, protein synthesis is 3.2 and 2.6 g/kg of body weight per day, respectively; in an elderly man and woman, it is 2.6 and 1.9 g, respectively. The synthesis rate of transport protein, such as albumin, remains unchanged with increasing age, but the breakdown rate (and presumably synthesis rate) of skeletal muscle decreases (Table 7). If the total turnover rate of protein is expressed per lean body mass rather than body weight, an increase in turnover is noted with aging. Because the lean body mass decreases with aging as a result of a reduction in skeletal muscle mass and the synthesis rate of albumin is unchanged, it is apparent that the changes in

TBN ¼ Ke =3 where Ke equals exchangeable potassium. TBP is directly proportional to TBN by a factor of approximately 6.25. Thus: TBP ¼ ð6:25ÞðTBNÞ ¼ ð6:25ÞðKe =3Þ ¼ 2:08 Ke TBN can also be measured using neutron activation analysis (26,28). When tissues are irradiated with neutrons from either a cyclotron or a plutonium source, gamma rays specific for a substance capturing the neutron are emitted. For nitrogen, gamma rays of 10.83 meV are emitted. Consequently, measurement of the gamma rays produced after neutron activation allows determination of TBN. In general, the results obtained with either method correlate well with each other.

Carbohydrates Carbohydrates serve as the energy source of the body when energy is rapidly required, providing approximately 4 kcal/g. They also play important roles in cell membrane function and stability (glycoproteins and glycolipids), in hormone function (glycoproteins), and as precursors of lipid and nonessential amino acid synthesis. In addition, the brain, RBCs, WBCs, and wounds are to a large extent glucose-dependent tissues. Of the three major sugars found in the human body (glucose, fructose, and galactose), glucose is the primary carbohydrate. In addition to ingested carbohydrates, glucose is readily available from pyruvate and lactate, gluconeogenic amino acids (alanine and glutamine), the glycerol moiety of lipids, and its storage form, glycogen. Most of the body’s glycogen is stored in the liver, skeletal muscle, and cardiac muscle. Muscle glycogen is used primarily by the muscle itself, because muscle lacks

Table 7 Comparison of Whole Body Protein Breakdown with Estimates of Muscle-Protein Breakdown and Albumin Synthesis in Young and Old Adult Human Beings Whole body protein breakdowna (g/day) Group Males Young Old Females Young Old a

Muscle-protein breakdownb (g/day)

Mean age (yr)

Per kg body weight

Per kg BCM

Per g creatinine

Per kg body weight

Per kg BCM

Per g creatinine

Per kg body weight

Per kg BCM

Per g creatinine

22 70

2.94 2.64

6.7 7.5

115 163

0.76 0.53

1.74 1.50

30 32

0.19 0.15

0.39 0.40

7 8.4

20 76

2.35 1.94

6.1 6.6

103 166

0.64 0.31

1.69 1.05

28 26

– –

– –

Measured by administration of 15N-glycine. Measured as 3-methylhistidine output in urine and computed as muscle protein. c Measured by administration of 15N-glycine. Abbreviation: BCM, body cell mass. Source: From Ref. 25. b

Albumin synthesisc (g/day)

– –

6

Part One: General Considerations

glucose-6-phosphatase. In contrast, hepatic glycogen is primarily used in providing glucose to glucose-dependent tissues. Because only a little glycogen is stored in the liver, the hepatic stores of glycogen are rapidly depleted by an overnight fast. Cahill (29) has estimated the total hepatic glycogen content of a 70 kg man to be 75 g, and the total muscle glycogen content to be 105 g. The total carbohydrate content of the body is approximately 300 g (30). Except by cadaver analysis, no method is available to measure total body carbohydrate. However, it is of note that the daily intake of carbohydrate approximates the total body stores.

Lean Body Mass and Body Cell Mass Based on densitometric measurements, Behnke (17) and Behnke and Wilmore (15) proposed the division of total body weight into fat and lean body mass. The lean body mass was defined as that portion of the body mass with the least amount of essential body fat compatible with health. The essential body fat was thought to represent 2% to 10% of the total body weight. However, because the essential body fat cannot be differentiated from the nonessential body fat, most investigators have redefined lean body mass as the portion of body mass devoid of all fat, the so-called fat-free body (14). Although ‘‘fat-free body’’ and ‘‘lean body mass’’ are often used interchangeably, there is a small (2–10%) difference between them (Table 8). This chapter subsequently refers only to the fat-free body, but it should be kept in mind that the same statements are generally true for lean body mass. Because the total body weight is equal to TBF plus the fat-free body, the size of the fat-free body can be determined by the same methods used to determine the size of the TBF.

The fat-free body is divisible into the extracellular mass, composed primarily of water, and the body cell mass (BCM), composed of all the metabolically active cells in the body (2,10). The cells in the BCM are actively involved in energy exchange, protein synthesis, enzyme replication, and morphogenesis (2). Therefore the BCM is composed of the skeletal muscle mass (60%), visceral cell mass (20%), and the peripheral cell mass (20%) (Table 8) (10). The peripheral cell mass includes blood cells and connective tissue cells. Although the BCM cannot be measured directly, it can be calculated from the exchangeable potassium, the exchangeable sodium, the TBN, or the ICW. Because more than 98% of the TBK is intracellular, a linear relationship exists between BCM, TBK, total exchangeable potassium, and ICW. Histochemical analysis has demonstrated that approximately one-fourth of the wet weight of cells is protein (31). Consequently: BCM ¼ ðTBKÞð4Þ ¼ ð2:08 Ke Þð4Þ ¼ 8:33 Ke BCM ¼ ðTBNÞð6:25Þð4Þ ¼ 25ðTBNÞ Because the average cell has 150 mEq of intracellular potassium per liter (10) and because each cell is composed of 25.8% solids (74.2% water) (31), BCM is also equivalent to: Ke ð1000=0:732Þ=150 ¼ ðKe Þð9:10Þ or ICW=0:742 Each of these methods yields a different value for the BCM of a given individual. This is most obvious when

Table 8 Comparison of Body Cell Mass, Lean Body Mass, and Fat-Free Body BCM Anatomy

All body cells Protoplasm Nucleus Membrane [ICK]av ¼ 150 mEq/LICW

LBM

g

g

Function

Composition

Cellular metabolism Respiration Oxidation Synthesis Cretion Mitosis [Ke  ECK]  f ¼ BCM f ¼ 7.510 or Ke  8.33 ¼ BCM 70 kg man 3200  8.33 ¼ 26.6 kg Calories 2.73.6 kcal/hr/kgBCM

FFB

All body cellsg BCM Plus: Plasma ECF ECF TCF Tendon ECT Fascia Collagen Elastin ECS Dermis Skeleton ‘‘2% ¼ 10% essential lipid’’: Fat Cellular metabolism Support Transport Circulation Protection Integument Density ¼ 1100 % LBM ¼ 100  495/d  450 70 kg man Approximately 50 kg Calories 110 kcal/hr/kgLBM

Same as LBM but no lipid at all

g

Same as LBM

FFB ¼ TBW/f f ¼ 0.695  0.735 70 kg man 36.4/0.732 ¼ 49.7 Calories (same as LBM)

Abbreviations: BCM, body cell mass; ECF, extracellular fluid; ECK, extracellular potassium; ECS, extracellular supporting structure; ECT, total extracellular space; f, coefficient; FFB, fat-free body; ICK, intracellular potassium; ICW, intracellular water; Ke, exchangeable potassium; LBM, lean body mass; TBW, total body water; TCF, total cellular fluid. Source: From Ref. 10.

Chapter 1: Metabolic Response to Starvation, Stress, and Sepsis

2400

× 2100

×

1500 1200

×

900

× ×

× ×× × ××

= Healthy young males = Healthy young females = Healthy elderly males × = Surgical patients

× ×

600 300

TME = –8.99 = 10–5Ke + 250

Nae þ Ke =TBW ¼ R where R is constant. Total exchangeable sodium and TBW can be easily measured by isotope dilution with deuterium oxide or tritiated water and 22Na. The constant, R, can be approximated by measurement of the sodium, potassium, and water of whole blood. Thus:

× ×× × ×

1800 IRME (cal/day)

the two methods presented for total exchangeable potassium are used. However, any of these methods provide accurate estimates of sequential changes in an individual or differences among populations, if the same method is used throughout the study. Measurements of total exchangeable potassium by whole body 40K counting or of TBN by neutron activation are difficult to perform and require equipment that is expensive and not readily available. To avoid these practical problems, Shizgal et al. (32) developed a method to estimate total exchangeable potassium from isotope dilution measurements of TBW and total exchangeable sodium. As noted previously, TBW is approximately equal to the sum of the total exchangeable sodium and potassium. Thus:

7

400 800 1200 1600 2000 2400 2800 3200 3600 4000 4400 4800 Ke (mEq)

Figure 4 Relationship of total body energy expenditure to the total Ke. Abbreviations: Ke, exchangeable potassium; IRME/TME, total metabolized energy. Source: From Ref. 34.

Ke ¼ ½ðRÞðTBWÞ  Nae and BCM ¼ 8:33 Ke or 9:10 Ke As might be expected, BCM increases with age until the middle years of life. With advancing age, the percentage of body weight composed of the BCM decreases as a result of a decrease in skeletal muscle mass. In addition, men generally have a greater percentage of body weight composed of BCM than women; athletic individuals have a greater percentage of body weight composed of BCM than sedentary individuals; and lean individuals have a greater percentage of body weight composed of BCM than obese individuals. Thus the BCM varies from 20% of body weight in morbidly obese individuals to 54% in lean athletic men (33). A direct correlation exists between total energy expenditure and BCM, whereas other measurements of body composition such as total body mass and fat-free body demonstrate a variable or poor correlation (34). Kinney et al. (34) have demonstrated an oxygen consumption of 8 to 10 mL oxygen per kilogram BCM and an energy expenditure of 2.7 to 3.6 kcal/kg/hr: As noted in Figure 4, total exchangeable potassium (and therefore BCM) is linearly related to the total metabolic energy expenditure in healthy adults and surgical patients until 1800 cal/day are expended. However, when measurements of total metabolic energy expenditure greater than this are included, the relationship is parabolic. This relationship is believed to reflect the lower resting metabolic rate of skeletal muscles per milliequivalent intracellular potassium when compared to visceral tissues. Skeletal muscle, which provides approximately 50% of the TBK, accounts for only 15% of the body’s resting energy expenditure. On the other hand, visceral tissues, such as brain, heart, and kidneys, which provide only 10% of the TBK, account for 70% of the body’s resting energy expenditure (35). Consequently, individuals with a small BCM have less skeletal muscle mass and a good correlation of total exchangeable potassium with total metabolic energy expenditure. In contrast, individuals with a large BCM have a smaller increase in total metabolic

energy expenditure when compared to total exchangeable potassium because skeletal muscle at rest contributes significantly to total exchangeable potassium but not to total metabolic energy expenditure.

Changes in Body Composition with Stress, Sepsis, and Starvation The body composition of a human being at any given moment is influenced significantly by the individual’s age, sex, physical activity, and previous nutritional status, as well as by concurrent infections, injuries, and disease processes. Changes produced by age, sex, and physical activity have been discussed at length. Tables 9 and 10 and Box 1 provide a summary of the formulas derived from multiple body composition studies of normal individuals (2,10). These formulas can be applied to any healthy adult under normal circumstances to estimate the components of body composition. Ultimately, body composition is the net result of the total chemical constituents taken in minus the total chemical constituents used and excreted. Because carbohydrates and lipids primarily serve as a source of calories, this relationship can be estimated by: DBC ¼ ½ðCin þ Nin þ WSin Þ  ½ðCout þ Nout þ WSout Þ where D is change, BC is body composition, C is calories, N is nitrogen, W is water, and S is solutes (electrolytes and Table 9 Estimation of Total Body Water by Age, Sex, and Body Weight Sex

Age (yr)

TBW (L)

95% conf. limits (%)

Males

16–30 31–60 61–90 16–30 31–90

0.4 (BWt) þ 13 0.4 (BWt) þ 11 0.34 (BWt) þ 12 0.31 (BWt) þ 11.6 0.33 (BWt) þ 8.84

16 17 16 13 21

Females

Abbreviations: TBW, total body water; BWt, body weight. Source: From Ref. 10.

8

Part One: General Considerations

Table 10 Estimation of Total Exchangeable Potassium by Age, Sex, and Body Weight Sex

Age (yr)

Exchangeable potassium (mEq)

Males

16–30 31–60 61–90 16–30 31–90 61–90

38 (BWt) þ 735 26 (BWt) þ 1383 27 (BWt) þ 723 18 (BWt) þ 1250 17 (BWt) þ 1176 18 (BWt) þ 757

23 20 16 20 23 29

20–60 61–84

97.4 (TBW)  409 2 þ 77 (TBW)

10 17

Females

By TBW Males and Females

Injury and infection

Normal

95% conf. limits (%)

+110 +100 +90 +80

Abbreviations: BWt, body weight; TBW, total body water. Source: From Ref. 10.

minerals). Under normal steady-state conditions, the quantities of these components taken in equal the quantities used or lost, and there is no net change in body composition (BC ¼ 0). If the quantity of a component taken in is greater than the quantity used, this component either is stored (BC > 0), thus changing body composition, or is lost (BC < 0). For example, if caloric intake is greater than caloric loss or expenditure, energy is stored in the body in the form of lipids and carbohydrates. If water intake is greater than output, water is retained (e.g., edema). Fortunately, regulatory mechanisms exist that protect against an increase in body water (Chapter 2) and other nutrients. Consequently, for a net increase to be seen in TBW, there must be a neuroendocrine alteration present as well. Such is the case after trauma and surgery when elevated secretion rates of aldosterone and vasopressin promote the retention of salt and water. On the other hand, excess nitrogen intake is not stored, and, as already noted, maximum rates of protein synthesis exist in each individual. When the intake of nitrogen exceeds the need, the excess nitrogen is converted into urea and is excreted. There are five basic situations in which intake does not equal output—dehydration and the four catabolic stresses defined by Moore (2) as fasting, starvation, injury, and febrile illness. In dehydration, the loss of water exceeds the intake resulting in a reduction in TBW that is distributed throughout the ICW and ECW. In fasting and in starvation (prolonged fasting), caloric and nitrogen expenditures are the same or less than those of a normal individual, but the

Box 1 Estimation of Body Composition by Sex and Body Weight TBW ¼ 0.7945 (BWt)  0.0024 (BWt)2  0.0015 (age) (BWt) (males) TBW ¼ 0.6981 (BWt)  0.0026 (BWt)2  0.0012 (age) (BWt) (females) ICW ¼ 0.623 (TBW)  0.0016 (age) (TBW) (males) ICW ¼ 0.553 (TBW)  0.0007 (age) (TBW) (females) Fat ¼ BWt  TBW/0.732 ECW ¼ TBW  ICW Ke ¼ 150 (ICW) þ 4 (ECW) Nae ¼ 163.2 (TBW)  Ke  69 Abbreviations: BWt, body weight; ECW, extracellular water; ICW, intracellular water; Ke, exchangeable potassium; Nae, exchangeable sodium; TBW, total body water. Source: From Ref. 2.

+70 +60

Third degree burns >20% BSA

+50 +40 +30 +20 Basal

Resting 10%

+10 Normal _10 _20 _30

Severe infection

Multiple fractures Postoperative Partial starvation

_40

Figure 5 Resting energy expenditure during injury and starvation in man. Abbreviation: BSA, body surface area. Source: From Ref. 36.

intake of these substrates is markedly reduced or absent. As a result there is a loss of total body lipids, carbohydrates, and nitrogen. In patients with injury or febrile illness, caloric and nitrogen expenditures are greater than those of the normal individual. The increase in energy expenditure produced by an injury or infection is in proportion to the severity of the insult. Burns are the most severe injury, and generalized sepsis is the most severe febrile illness (Fig. 5). A healthy adult undergoing an elective operation increases the resting energy expenditure by approximately 10%, but the same individual with a severe burn increases the resting energy expenditure by 40% to 120%, depending on the size and the degree of the burn injury (37). A minor febrile illness or a minor febrile complication after an elective operation increases the resting energy expenditure by 13% for each degree Celsius of temperature elevation (38), but generalized sepsis increases the resting energy expenditure by 15% to 50% (37). The changes in body composition resulting from an increase in caloric and nitrogen expenditure during injury and febrile illness are frequently compounded by reductions in intake as a result of anorexia and ileus. However, if the increased measurements are adequately met by exogenous substrate sources (enteral or parenteral), little change in the body composition occurs (10,28,39,40).

NORMAL METABOLISM: INTERMEDIARY METABOLISM AND SUBSTRATE INTERACTIONS Body composition remains in a steady state when four essential conditions are met: (i) energy is supplied in sufficient quantities to meet the metabolic demands of all the body’s tissues, (ii) carbohydrates are supplied in sufficient quantities to meet the requirements of glucosedependent tissues, such as those of the brain, RBCs, and WBCs, (iii) nitrogen is supplied in sufficient quantities to meet the obligatory synthesis of protein, and (iv) water

Chapter 1: Metabolic Response to Starvation, Stress, and Sepsis

and solutes (electrolytes and minerals) are supplied in sufficient quantities to replace daily obligatory losses (water and electrolyte metabolism). In addition, these conditions must be met in the face of varying dietary intakes and varying daily energy requirements. This achievement is possible as a result of numerous substrate-to-substrate interactions (e.g., conversion of protein to carbohydrates) and the neuroendocrine regulation of intermediary metabolism.

Energy Metabolism All metabolic processes in cells either produce energy (exergonic reactions) or use energy (endergonic reactions). The energy required for the operation of all biologic processes in mammalian cells is derived from the inherent energy present in the structure of organic molecules (41). The chemical energy produced by the processing of these organic molecules is transferred to the phosphate bonds of purine nucleotides and other molecules with phosphate bonds such as phosphagens. As noted in Table 11, the hydrolysis of the phosphate bonds of adenosine triphosphate (ATP) or its precursors releases a considerable amount of energy that can be used to drive other biologic processes. The formation of these compounds with high-energy phosphate (HEP) group transfer potential is usually a result of the transfer of reducing equivalents from the substrate by reduction of nicotinamide adenine dinucleotide (oxidized form) (NADþ), flavoproteins, and other coenzymes followed by coupled oxidative phosphorylation of adenosine diphosphate (ADP) in the mitochondria (42). Although ATP serves as a carrier of chemical energy in all living cells, it is not a reservoir of energy (41). The intracellular concentrations of ATP are small, highly regulated, and rapidly depleted. Reservoirs of energy (phosphagens), such as phosphocreatine, do exist in some cells (41). These reservoirs accept HEP bonds when the intracellular concentration of ATP is high and transfer a phosphate group to ADP nucleotides when the availability of ATP is low (41). The intracellular concentrations of adenine nucleotides also provide the cell with a sensitive control mechanism for regulating energy-producing and energy-using processes in cells. Atkinson (43) has introduced the concept of energy charge to explain this regulatory mechanism. Adenylate energy charge (EC) represents the balance between energyusing processes and energy-producing processes. It is defined by the equation: EC ¼ ðATP þ 0:5ADPÞ=ðATP þ ADP þ AMPÞ A normal energy charge signals that energy-producing processes and energy-using processes are in balance. If the 0

Table 11 Energy Released (Go ) During Hydrolysis of High-Energy Phosphate Compounds 0

Reaction

Go (J/mol)

ATP þ H2O ! ADP þ Pi ADP þ H2O ! AMP þ Pi ATP þ H2O ! AMP þ PPi PPi þ H2O ! 2Pi AMP þ H2O ! A þ Pi

36,800 36,000 40,600 31,800 12,600

Abbreviations: A, adenine; ADP, adenosine diphosphate; AMP, adenosine monophosphate; ATP, adenosine triphosphate; Pi, inorganic phosphate; PPi, inorganic pyrophosphate. Source: From Ref. 41.

9

energy charge is increased, energy-producing processes are exceeding energy-using processes, and a resultant reduction of energy-producing processes occurs. If the energy charge is decreased, energy-using processes are exceeding energyproducing processes, resulting in a decrease in energy-using processes that may jeopardize cell survival. The major energy-producing processes include the catabolism of carbohydrates, proteins, and lipids. Each of these substrate groups can provide part of the energy present in their structure through cytoplasmic catabolic reactions (e.g., glycolysis). The remainder of the available energy present in these substrates is released during oxidation of the remaining carbon fragments in the intramitochondrial tricarboxylic acid (TCA) cycle. The final common pathway into the TCA cycle for carbohydrates, proteins, and lipids is through the formation of acetyl coenzyme A(CoA) (Figs.6–8). Foreachmolecule ofacetylCoA completely oxidized in the TCA cycle, two molecules of carbon dioxide, three molecules of nicotinamide adenine dinucleotide (reduced form) (NADH), one molecule of flavin adenine dinucleotide (FADH), and one molecule of guanosine triphosphate (GTP) are produced. In total, 12 HEPs are formed primarily by way of transfer of the reducing equivalents from NADH and FADH to oxygen in the electron transport system with the subsequent phosphorylation of ADP linked to this oxidative process (oxidative phosphorylation). Unlike carbohydrates and lipids, amino acids may directly enter the TCA cycle at one of the intermediate reactions (Fig. 6).

Carbohydrate Metabolism In the cytoplasm of all cells, one molecule of glucose is catabolized to pyruvate through the Embden–Meyerhof pathway to yield two molecules of pyruvate, two molecules of ATP, and one molecule of NADH (Fig. 7). The completion of glycolysis (i.e., glucose to lactate) uses one molecule of NADH in the conversion of pyruvate to lactate. Conversely, the conversion of pyruvate to acetyl-CoA produces one molecule of NADH. Because the oxidation of acetyl-CoA in the TCA cycle produces 15 HEPs, the complete oxidation of one molecule of glucose to carbon dioxide and water produces 26 HEPs [(2  12) þ 2] and four molecules of NADH. The latter molecules produce 12 HEPs (three HEPs per molecule of NADH) through coupled oxidative phosphorylation. Consequently, the total energy produced in the complete oxidation of one molecule of glucose to carbon dioxide and water is equivalent to 38 HEPs. This result is in contrast to glycolysis where only two HEPs are produced in the conversion of glucose to lactate. As noted in Fig. 7, there are two nonreversible reactions in glycolysis: (i) the conversion of glucose to glucose 6-phosphate, catalyzed by hexokinase, and (ii) the conversion of phosphoenolpyruvate to pyruvate, catalyzed by pyruvate kinase. These reactions are irreversible because they lose a considerable amount of energy as heat. It is the presence of these two nonreversible reactions that drives glucose to pyruvate. In addition, phosphofructokinase (PFK) and pyruvate kinase act as the major regulators of glycolysis (45). Once the catabolism of glucose has begun, it rapidly proceeds to pyruvate. Under aerobic conditions, most tissues oxidatively decarboxylate pyruvate to acetyl-CoA and then oxidize the acetyl-CoA in the TCA cycle. Under an anaerobic condition, pyruvate cannot be decarboxylated, and it is converted instead to lactate. As a result, elevated tissue and plasma concentrations of lactate (and pyruvate) are characteristic of ischemia and anoxia. Some tissues with a paucity of mitochondria, such as erythrocytes and leukocytes, are capable of glycolysis only. These cells lack

10

Part One: General Considerations

Protein Glycogen

Proteolysis

Glucose Lactate

Glycolysis Pyruvate

Beta-oxidation

Fatty acyl-CoA

Phenylalanine Tyrosine Leucine Lysine Tryptophan

Cystine Glycine Alanine Serine Threonine

Fatty acid

Acetoacetyl-CoA

Acetyl-CoA

Cholesterol Oxaloacetate Malate Fumarate Succinate

Citrate

TCA cycle (15 ATP/TURN)

Ketone bodies

Isocitrate Alpha-ketoglutarate

Succinyl-CoA Glutamate

Phenylalanine Tyrosine

Isoleucine Methionine Valine

Aspartate Asparagine

the ability to oxidize pyruvate and acetyl-CoA even under aerobic conditions. Therefore they derive all their energy from conversion of glucose to pyruvate and lactate. Carbohydrates other than glucose can also be metabolized through glycolysis. For example, fructose, galactose, mannose, and triose sugars can enter glycolysis after modification by endergonic reactions. Similarly, pentose sugars may also enter the glycolytic pathway. As noted earlier, the total carbohydrate stores of the human body are limited and are rapidly depleted (31). In addition, RBCs, WBCs, and the brain are glucose-dependent tissues that are unable to use nonglucose energy substrates. Thus glucose must be made continuously available. The synthesis of glucose through a process called gluconeogenesis can proceed from lactate, pyruvate, and amino acids. Gluconeogenesis is not simply the reversal of glycolysis, because the unidirectional reactions make glycolysis irreversible. However, gluconeogenic tissues, such as the liver and the kidney, contain four enzymes that essentially allow glycolysis to proceed in reverse fashion from pyruvate (and lactate) to glucose (Fig. 8). The first of these enzymes, pyruvate carboxylase, in the presence of ATP, carbon dioxide, and biotin, converts pyruvate to oxaloacetate in the mitochondria. [Although it does not act as a cofactor, acetyl-CoA must be present in excess for this reaction to proceed (46).] Oxaloacetate is then converted to phosphoenolpyruvate by the cytoplasmic enzyme phosphoenolpyruvate carboxylase and GTP. Because the oxaloacetate is found in the mitochondria and phosphoenolpyruvate carboxylase in the cytoplasm, oxaloacetate must cross the mitochondrial membranes into the cytoplasm. However, because the mitochondrial membranes are relatively impermeable to oxaloacetate, it is thought that oxaloacetate leaves the mitochondria as either malate or aspartate, which

Arginine Histidine Glutamine Proline

Figure 6 Pathways for production and use of acetyl-CoA. Abbreviations: TCA, tricarboxylic acid; CoA, coenzyme A. Source: From Ref. 44.

can be transported through the mitochondrial membranes and then reconverted to oxaloacetate in the cytoplasm (47). Once phosphoenolpyruvate is formed, glycolysis can easily proceed in reverse fashion to fructose-1,6-biphosphatase. The enzyme fructose-1,6-bisphosphatase is required to form fructose 6-phosphate. This enzyme is present in the liver and kidney and to a lesser extent in skeletal muscle. However, it is not present in adipose tissue, smooth muscle, or cardiac muscle (48). Fructose 6-phosphate can then proceed to glucose 6-phosphate by the reversible glycolytic reaction catalyzed by glucose phosphate isomerase, but the conversion of glucose 6-phosphate to glucose requires the last of the gluconeogenic enzymes, glucose 6-phosphatase. This enzyme is present in the liver and kidney but not in skeletal, smooth, or cardiac muscle. Any glucose 6-phosphate that might be formed in skeletal muscle must be converted to glycogen, be used in glycolysis, or be used in the hexose monophosphate shunt, because skeletal muscle cannot release free glucose as a result of the absence of glucose 6-phosphatase. The glucose 6-phosphate formed in the liver and kidney can be converted to glucose and released into the circulation. Because there is a constant production of lactate and pyruvate in aerobic glycolytic tissues, in all tissues during anaerobic conditions, and from the reticuloendothelial system during sepsis and locally inflamed tissues, a constant source of lactate and pyruvate is available to gluconeogenic tissues such as the liver and kidney. In the liver and kidney, these substrates can be converted back to glucose and released into the circulation. The newly formed glucose is then available to glucose-dependent tissues for reconversion to lactate in the so-called Cori cycle (Fig. 9). However, it should be noted that this reconversion does not result in a net increase in glucose carbon, because lactate is itself derived from glucose (49).

Chapter 1:

Metabolic Response to Starvation, Stress, and Sepsis

Glycogen

11

Pyruvate + CO2 ATP Pyruvate carboxylase ADP

Glucose 1-phosphate

Oxaloacetate

ATP ADP

GTP Glucose

Glucose 6-phosphate Hexokinase

Phosphoenolpyruvate carboxylase

GDP

Glucose phosphate isomerase

Phosphoenolpyruvate

Fructose 6-phosphate ATP Phosphofructokinase

ADP

Fructose 1,6-diphosphate

Glyceraldehyde 3-phosphate NAD

Pi

NADH

Triose phosphate isomerase Dihydroxyacetone phosphate

Phosphoglycerate kinase Phosphoglyceromutase Enolase

ADP

Lactate dehydrogenase

Phosphoenolpyruvate ATP Pyruvate kinase ADP

Lactate

H 2O Pi Fructose 1,6-bisphosphate

Glyceraldehyde phosphate dehydrogenase

3 phospho-glycerol phosphate ATP

Triose phosphate

Fructose-bisphosphatase Fructose 6-phosphate H2O Pi Glucose 6-phosphatate Glucose 6-phosphatase

Pyruvate NAD Pyruvate dehydrogenase

NADH NAD NADH

Glucose

TCA cycle CO2

Figure 7 Catabolism of glucose and major carbohydrate precursors. Abbreviations: ADP, adenosine diphosphate; ATP, adenosine triphosphate; NAD, nicotinamide adenine dinucleotide; NADH, reduced form of NAD; Pi, inorganic phosphate; TCA, tricarboxylic acid. Source: From Ref. 44.

Protein and Amino Acid Metabolism Energy and glucose can also be derived from the metabolism of amino acids. Although the partial catabolism and transformation of all a-amino acids to their a-keto acid derivatives can occur in most tissues, the complete oxidation of a-amino acids to urea and carbon dioxide occurs primarily in the liver and secondarily in the kidney (50). In general, the catabolism of all amino acids (except lysine) involves the removal of the a-amino acid group from the carbon skeleton to form ammonia and an a-keto acid. This is followed by the conversion of ammonia to urea and by the conversion of the a-keto acids to TCA-cycle intermediates or precursors (51,52). Removal of the a-amino group can occur by one of three processes: (i) transamination, (ii) oxidative deamination, and (iii) nonoxidative deamination (47,48). The most common mechanism is transamination. Transaminases (aminotransferases) interconvert a pair of amino acids and a pair of a-keto acids (Fig. 10). This process requires the presence of pyridoxal phosphate (vitamin B6) for the transfer of the amino group. These reactions are freely reversible and function both in synthesis and in catabolism. At least 12 of the amino acids undergo transaminations, including the branched-chain amino acids, valine, leucine, and

Figure 8 Gluconeogenic pathway in the liver and the kidney. Source: From Ref. 44.

isoleucine. The most notable transaminases are glutamineoxaloacetic transaminase (or aspartate transaminase) and glutamic-pyruvic transaminase (or alanine transaminase). Through the collective action of all the transaminases, the a-amino groups are usually collected in the form of glutamate or alanine. Because a-ketoglutarate can accept the a-amino group of all the amino acids that are transaminated, including alanine, it serves as the final common amino group acceptor to form glutamate. Mallette et al. (53) have proposed and Felig (54) has expanded the concept of an alanine–glucose cycle similar to the Cori cycle (Fig. 9). In peripheral tissues, amino acids are transaminated with pyruvate to form alanine and an a-keto acid. The alanine is then transported to the liver, where it is transaminated with a-ketoglutarate to form pyruvate and glutamate. The pyruvate can then be converted back to glucose and released into the circulation, where it may be taken up by peripheral tissues and converted to pyruvate and lactate. The oxidative deamination of glutamate by glutamate dehydrogenase is an important mechanism in the liver for the removal of the amino group (Fig. 10). Because a-ketoglutarate is the common acceptor for all transaminases, substantial amounts of glutamate are formed. Consequently, the oxidative deamination of glutamine allows for the regeneration of a-ketoglutarate and the removal of free ammonia. Oxidative deamination of other amino acids is also possible through the action of a-amino

12

Part One: General Considerations

Figure 9 Glucose–lactate (Cori) cycle and glucose–alanine cycle. Source: From Ref. 1.

acid oxidases that are present in the liver and kidney. However, with the exception of glutamate dehydrogenase, these enzymes do not appear to exert a major physiologic role in humans (50,52). Three amino acids, serine, threonine, and histidine, are primarily deaminated nonoxidatively (Fig. 10) (47). The former two amino acids undergo nonoxidative deamination by dehydration, whereas histidine undergoes direct deamination. The non–a-amino groups of glutamine and asparagine are removed by hydrolytic deamination (47). Free ammonia, even in small concentrations, is poorly tolerated by cells. Four mechanisms exist to handle the free

OXIDATIVE DEAMINATION Alpha-amino acid

Amino acid oxidase [Alpha-imino acid]

Flavin Flavin

H2O

H2

Alpha-Keto acid

ammonia produced by oxidative or nonoxidative deamination, thereby keeping the intracellular (and extracellular) concentration of this substance low. Free ammonia can be added to glutamate by glutamine synthetase to form glutamine. This is the primary mechanism for the elimination of ammonia in brain cells and muscle cells. The free ammonia may also be added to a-ketoglutarate, forming glutamate in the freely reversible reaction catalyzed by glutamate dehydrogenase. The resulting glutamate may be used as an amino acid in protein, as a precursor in arginine and citrulline syntheses, or as an a-amino group donor in transaminase reactions. A third mechanism for ammonia elimination is through its excretion by the kidney. Two-thirds of the ammonia excreted by the kidney is derived from the amide nitrogen of glutamine from renal arterial blood and one-third from the a-amino nitrogen of renal arterial amino acids (55). Although these three mechanisms remove a substantial amount of the ammonia formed, most of it is cleared by the liver, after which it enters into the urea cycle (Krebs– Henseleit cycle) (50). As noted in Figure 11, the urea cycle essentially involves the cleavage of a molecule of urea from arginine. The ammonia is first combined with carbon dioxide in the presence of ATP to form carbamylphosphate. Carbamylphosphate then condenses with ornithine to form citrulline, which, through a series of reactions, forms arginine. The arginine is then cleaved into urea and ornithine, thereby reestablishing the cycle. The net energy cost of this cycle is four HEPs, derived from three molecules of ATP. Atkinson and Bourke (56) have suggested an important role for ureagenesis in the maintenance of pH homeostasis. Because the oxidation of amino acids yields both bicarbonate and ammonium ions, the urea cycle promotes the neutralization of the bicarbonate ion by the proton of the ammonium ion during the formation of carbonyl phosphate. The remaining carbon skeletons of amino acid deamination or transamination are converted either to intermediates of the TCA cycle or to precursors of acetyl-CoA, such as pyruvate and acetoacetate. Consequently, all the carbon skeletons of amino acids can be oxidized in the TCA cycle to carbon dioxide and water. The carbon skeletons of all the amino acids may also be converted to glucose or fat. As such, they may be classified as glucogenic, ketogenic, or glucogenic and ketogenic (Table 12). Seven (alanine, serine, glycine, cysteine, cystine, proline, and hydroxyproline) of the 22 most common amino

NH3

NONOXIDATIVE DEAMINATION BY DEHYDRATION H2 O Amino acid oxidase Serine [Intermediates] Pyruvate H 2O

NH3

Pi Citrulline

2 ADP+Pi

DIRECT NONOXIDATIVE DEAMINATION Histidase Serine

CO2+NH4 ATP

[Histidine-enzyme]

Pyruvate

Aspartate ATP

Carbamyl phosphate

AMP+PPi Ornithine

UREA CYCLE

Argininosuccinate

NH3 HYDROLYTIC DEAMINATION OF NONALPHA AMINO GROUP Arginine

Asparaginase Asparagine

Aspartate

Urea

Fumarate

H2O NH 3

Figure 10 Mechanisms for removal of the amino group. Source: From Ref. 44.

Figure 11 Urea cycle. Abbreviations: ADP, adenosine diphosphate; AMP, adenosine monophosphate; ATP, adenosine triphosphate; PPi, inorganic pyrophosphate. Source: From Ref. 44.

Chapter 1:

Table 12 Pathways for the Use of Amino Acid Carbon Fragments Gluconeogenesis Alanine Arginine Aspartic acid Asparagine Cystine Glutamic acid Glycine Histidine Hydroxyproline Methionine Proline Serine Threonine Valine

Ketogenesis Leucine

Gluconeogenesis and ketogenesis Isoleucine Lysine Phenylalanine Tyrosine Tryptophan

acids in proteins are converted to pyruvate. Depending on the redox state of the cell, the pyruvate can either be used for gluconeogenesis or converted to acetyl-CoA. Five amino acid carbon skeletons (phenylalanine, tyrosine, tryptophan, leucine, and lysine) form acetoacetate that may be converted to acetyl-CoA and either oxidized in the TCA cycle or used in fatty acid–synthesis. In addition, in the process of producing acetoacetate, phenylalanine and tyrosine are also cleaved to fumarate, and tryptophan is cleaved to alanine. Thus, phenylalanine, tyrosine and tryptophan may be used both in glucogenesis and in ketogenesis. Lysine may also be used both in glucogenesis and ketogenesis, but its precursor for gluconeogenesis is not known. In contrast, leucine forms one molecule of acetyl-CoA and one molecule of acetoacetate. Because neither acetyl-CoA nor acetoacetate can be converted to pyruvate, the carbon skeleton of leucine can only be used for ketogenesis or oxidation.

Metabolic Response to Starvation, Stress, and Sepsis

13

It should be apparent that any compound that enters the TCA cycle as acetyl-CoA cannot be used as a precursor of glucose. This relates to the fact that by the time it reaches malate, the acetyl-CoA that entered the TCA cycle has been completely oxidized. However, the carbon skeletons of amino acids that are TCA-cycle intermediates can be used for gluconeogenesis. In addition to phenylalanine and tyrosine, which enter the TCA cycle as fumarate, three amino acids enter as succinyl-CoA (isoleucine, methionine, and valine), and two other amino acids enter as oxaloacetate (aspartate and asparagine) and give amino acids that enter as a-ketoglutarate (glutamate, glutamine, proline, histidine, and arginine) (Fig. 12). Consequently, all these amino acids may be used either in gluconeogenesis or in oxidation. Quantitatively, in the isolated perfused liver, only alanine, serine, threonine, and glycine are used in significant amounts for gluconeogenesis (57). As noted previously, excess nitrogen cannot be stored. When the protein intake is excessive, the amino acids resulting from proteolysis are catabolized to nitrogen and a carbon skeleton. The nitrogen is converted to urea, and the carbon skeleton is converted to glucose, lipid, or carbon dioxide, depending on the needs of the cell and the redox state present. Similarly, when glucose is needed but unavailable, excess ingested proteins or existing body proteins are degraded. Although it may be imperceptible, the use of existing body protein for energy or gluconeogenesis always results in the loss of some cellular function.

Lipid Metabolism The final and greatest source of energy in the body is lipid. Stored in adipose tissues as triglycerides, lipids can be released on demand and transported to most tissues for use as an energy source. Tissues capable of using lipids include the liver, kidney, heart, and skeletal muscle; such use,

Figure 12 Pathways through which the carbon skeletons of a-amino acids enter the tricarboxylic acid cycle.

14

Part One: General Considerations

however, must occur under aerobic conditions. Non–lipidusing tissues include erythrocytes, leukocytes, and nerve cells. Triglycerides are composed of three fatty acid–chains linked together by a glycerol molecule. During lipolysis, the fatty acids are sequentially cleaved off the glycerol moiety by lipases. The remaining glycerol moiety can then be used for glucose synthesis or converted to pyruvate (Fig. 7). In contrast, fatty acids themselves cannot be used as substrate for gluconeogenesis, because they are ultimately broken down to acetyl-CoA. The catabolism of fatty acids can be divided into two stages. These stages include b-oxidation in the outer mitochondrial membrane to produce molecules of acetyl-CoA, and the processing of acetyl-CoA in the mitochondria to produce carbon dioxide and energy or ketone bodies (Fig. 13) (58,59). Only the first step in fatty acid–catabolism requires energy. In this step, the enzyme thiokinase adds CoA to a fatty acid, producing a fatty acetyl-CoA (Fig. 13). After a sequence of reactions, the final two carbons on the fatty acetyl-CoA are cleaved, resulting in the production of one molecule of acetyl-CoA and a new fatty acetyl-CoA that is two carbon atoms shorter than the parent fatty acetyl-CoA. This process of b-oxidation yields five HEPs per acetyl-CoA formed and, with even-numbered fatty acid chains, continues until the entire fatty acid has been cleaved to acetyl-CoA. In the case of odd-numbered fatty acid chains, b-oxidation continues until a three-carbon fatty acetyl-CoA (propionyl-CoA) remains. The latter substance may then be converted to succinyl-CoA and enter the TCA cycle. The acetyl-CoA that results from the oxidation of fatty acids can be used in one of the three available pathways (Fig. 13) (58,60). The first involves the intramitochondrial oxidation of acetyl-CoA through the TCA cycle to two molecules of carbon dioxide and 12 HEPs. Thus the total

oxidation of a 20-carbon fatty acid, for example, yields: 169 HEPs ¼ ½ð10  5Þ þ ð10  12Þ  1 The second pathway involves the ketogenic pathway in the liver (Fig. 14). Through the action of the enzyme thiolase, two molecules of acetyl-CoA combine to form acetoacetyl-CoA in a freely reversible reaction. AcetoacetylCoA can then be converted to 3-hydroxy-3-methylglutaryl CoA, the precursor in cholesterol synthesis and ketone body formation. The three ketone bodies, acetoacetate, b-hydroxybutyrate, and acetone, are normally produced and released by the liver. Under conditions in which there is an abundance of hepatic glycogen, b-hydroxybutyrate predominates; under conditions in which the liver glycogen is low, acetoacetate predominates. The ketone bodies that are released by the liver can then be used by a variety of peripheral tissues, such as cardiac and skeletal muscle, as a source of energy by conversion back to acetyl-CoA. The final pathway for use of acetyl-CoA is in the synthesis of fatty acids and triglycerides (Fig. 13). This pathway is stimulated by neuroendocrine mechanisms and low cytoplasmic concentrations of fatty acids. Lipogenesis is a cytoplasmic process that requires malonyl-CoA. MalonylCoA is formed from acetyl-CoA by acetyl-CoA carboxylase. When fatty acid–levels are low, the rate-limiting enzyme in malonyl-CoA formation, acetyl-CoA carboxylase, is stimulated, leading to increased intracellular concentrations of malonyl-CoA (61). In turn, the elevated concentration of malonyl-CoA inhibits carnitine acetyl transferase, the enzyme necessary for transport of acetyl-CoA into the mitochondria (62), resulting in an increased concentration of cytoplasmic acetyl-CoA that can then be used for malonyl-CoA synthesis and ultimately for the synthesis of triglycerides and other lipids. In contrast, when the intracellular concentrations of

Figure 13 Metabolic pathways of fatty acid metabolism in the liver. Abbreviations: GAA, gossypol acetic acid; TCA, tricarboxylic acid. Source: From Ref. 1.

Chapter 1:

Acetyl-CoA Thiolase CoA

SH

Acetoacetyl-CoA H 2O HMG-CoA synthetase

Acetyl-CoA CoA

SH

3-Hydroxy-3-methylglutaryl CoA Acetyl CO2 CoA Acetone

HMG-CoA lyase

Acetoacetate

Beta-hydroxybutyrate dehydrogenase

Steroids

Cholesterol NADH NAD+

Beta-hydroxybutyrate

Bile salts

Cholesterol esters

Figure 14 Ketogenic pathway and cholesterol pathway in the liver. Abbreviations: CoA, coenzyme A; HMG, 3-hydroxy-3-methylglutaryl; NADH, reduced nicotinamide adenine dinucleotide. Source: From Ref. 44.

fatty acids are elevated, the rate-limiting enzyme in malonylCoA synthesis (acetyl-CoA carboxylase) is inhibited. Malonyl-CoA concentrations decrease, thereby stimulating carnitine acetyl transferase and increasing the transport of acetyl-CoA into the mitochondria for oxidation and ketogenesis (62). The inhibition of acetyl-CoA carboxylase also results in the accumulation of cytoplasmic citrate that in turn inhibits glycolysis through inhibition of PFK, the so-called Randle effect (45).

NEUROENDOCRINE REGULATORY MECHANISMS Stimuli and Mechanism of Action of the Neuroendocrine System The pathways of intermediary metabolism and substrateto-substrate interactions noted previously are under the local control of substrate availability, cellular redox potential, and cellular energy availability. The integration of this control is governed by the neuroendocrine system. This system may be thought of as a reflex physiologic network in which alterations in homeostasis are perceived by specialized receptors that are located both peripherally and centrally. The receptors

Metabolic Response to Starvation, Stress, and Sepsis

15

transmit their information to the central nervous system (CNS), where the afferent signals are processed and modulated, resulting in release or inhibition of numerous neuroendocrine effectors that produce physiologic changes aimed at correcting the alterations in homeostasis. In the absence of significant injury, sepsis, or starvation, alterations in homeostasis are small, and the responses of the neuroendocrine system to stimuli are directed at fine tuning and integrating the functioning of the organism. In the presence of significant injury, sepsis, or starvation, the stimuli are multiple and intensified, and the reflexes are directed at an integrated attempt by the organism to preserve oxygen delivery, mobilize energy substrates, and minimize pain (Fig. 15) (1). The major stimuli affecting neuroendocrine reflexes include (i) changes in the circulating body fluids; (ii) changes in the oxygen, hydrogen ion, and carbon dioxide concentrations in tissues and blood; (iii) changes in ambient and core temperature; (iv) changes in substrate availability; (v) emotional arousal; (vi) pain; and (vii) infection. Critical to the initiation of the neuroendocrine response is the perception of the stimulus. Paraplegics do not respond to stimuli below the level of cord transection. This lack of response is thought to be the result of the absence of afferent impulses reaching the brain (63). However, conscious perception of the stimulus is not required. An individual responds to a stimulus in the presence of anesthesia, but the response may not be the same as that in the absence of anesthesia. Changes in the circulating body fluids may result from the direct loss of blood (as in hemorrhage), from the loss of plasma volume (as in third-space losses and dehydration), or from the inability of the body fluids to circulate (as in cardiac failure or pulmonary embolism). The changes in circulating body fluids are sensed by high-pressure baroreceptors in the carotid arteries and aorta and by low-pressure stretch receptors in the right atrium. Under normal conditions, the afferent signals from these receptors exert a tonic inhibition of the release of many hormones and of the activities of the CNS and autonomic nervous system (64). When baroreceptor or stretch-receptor activities decrease (e.g., a decrease in blood pressure or blood volume), the tonic inhibition is released, resulting in the increased secretion of adrenocorticotropic hormone (ACTH), vasopressin, b-endorphin, and growth hormone through central pathways and resulting in the increased secretion of epinephrine, norepinephrine, renin, and glucagon through peripheral

Infection Pain

+

Hemorrhage plus ECF loss

Peripheral nerves

Baroreceptors + +

Hypoxemia

+

Fear and anxiety + + + Central _ nervous system +

+ Endocrine glands + + Sympathetic nervous system

Chemoreceptors – + Cardiac stimulation Vascular resistance Fluid shifts + Respiratory stimulation

Figure 15 Overview of the neuroendocrine reflexes induced by shock and trauma. Abbreviation: ECF, extracellular fluid. Source: From Ref. 1.

16

Part One: General Considerations

autonomic neural pathways. These responses bring about further neuroendocrine changes such as the inhibition of insulin secretion by epinephrine (65) and the stimulation of aldosterone secretion by renin and ACTH (66). Changes in blood concentrations of oxygen, hydrogen ion, and carbon dioxide initiate neuroendocrine responses through the activation of peripheral chemoreceptors. The chemoreceptors, which are located in the aortic and carotid bodies, have an extremely high–blood flow rate (67). Under normal conditions, these receptors are not activated. However, changes primarily in oxygen and secondarily in carbon dioxide and in hydrogen ions are sensed by these receptors, which result in the activation of neuroendocrine pathways. Because of the high blood flow through the chemoreceptors, the partial pressure of oxygen (PO2) of arterial blood, chemoreceptor tissue, and venous blood is nearly the same. However, a drop in blood flow increases the oxygen extraction by the chemoreceptor tissue, decreases the venous PO2, and through an unknown mechanism, activates the chemoreceptor (67). Consequently, a decrease in circulating volume or pressure not only inhibits baroreceptors and stretch receptors, but also activates chemoreceptors. Pain and emotion also activate the neuroendocrine system. The former acts through the projections of peripheral nociceptive receptors to the CNS, and the latter acts through projections from the limbic areas of the brain to the hypothalamus and lower brain stem nuclei (68). Through these pathways, pain and emotional arousal bring about increased hypothalamic, autonomic, adrenomedullary, and adrenocortical activities, the so-called fight- or-flight reaction of Cannon (69). Abnormalities in core and ambient temperatures, as well as infection, also stimulate neuroendocrine reflexes. Changes in the core temperature of the body are sensed in the preoptic area of the hypothalamus. These changes may result from alterations in ambient temperature, a loss of the normal insulating barrier of the skin (e.g., burns), or a reduction in hepatic thermogenesis produced by inadequate blood flow or substrate supply or in response to inadequate peripheral vasoconstriction or vasodilation. Infection may also decrease the core temperature through the action of endotoxin. Infection may further stimulate neuroendocrine reflexes through a direct action of endotoxin on the hypothalamus (70) or through secondary changes in blood volume, oxygen concentration, substrate concentrations, and pain. The primary substrate alterations that activate the neuroendocrine system are those induced by changes in the plasma glucose concentration. Plasma glucose alterations are sensed by receptors in the hypothalamus and the pancreas. A decrease in plasma glucose concentration stimulates the release of catecholamines, cortisol, growth hormone, and vasopressin through central mechanisms and stimulates the release of glucagon both by central pathways (autonomic nervous system) and peripheral pathways (direct pancreatic activation) (71). In addition, the secretion of insulin is inhibited through central pathways (autonomic nervous system) and directly by the pancreas itself (65). All these stimuli are commonly produced by injury, sepsis, and starvation. Furthermore, these stimuli rarely occur singly. Generally, the individual perceives multiple stimuli that occur both simultaneously and sequentially. Thus the neuroendocrine response is the summation of all the stimuli the individual perceives and processes. According to classic endocrine feedback mechanisms, the

elevation of serum cortisol resulting from one set of stimuli would be expected to inhibit the release of ACTH by a new set of stimuli. Following most injuries, this is not true. The secretion of ACTH is unchanged or increased (potentiated), and the secretion of cortisol may also increase. The mechanism of action of this physiologic facilitation is incompletely understood, but it appears to take 60 to 90 minutes to be of sufficient magnitude to offset the inhibition, and lasts for at least 24 hours (72). Physiologic facilitation and potentiation have been demonstrated with sequential hemorrhages (73) and repeated operations (74), in response to hypoxia and surgery (75), with pain and hemorrhage (20), and with elevated core temperature and hemorrhage (76). Consequently, the response to an injury or an alteration in homeostasis may be modified by previous stimuli, and the response to a second set of stimuli may be different if they had occurred first. The efferent limb of the neuroendocrine system arises from two primary areas, the hypothalamic–pituitary axis and the autonomic regions of the brain stem. The output from the former region involves the release of numerous pituitary hormones, and the output from the latter region involves changes in the neural activities of the sympathetic and parasympathetic nervous systems. Both sets of output either may cause direct changes in physiologic functions or may stimulate or inhibit the secretion of peripheral endocrine organs. The hormones secreted by endocrine organs and the autacoids produced by tissues fall into one of five chemical classes. These include the fatty acid–derivatives of cholesterol (cortisol and aldosterone) or arachidonic acid (prostaglandins), proteins (insulin and glucagon), glycoproteins [thyroid-stimulating hormone (TSH) and corticotropin], small polypeptides (vasopressin and enkephalin), and the amines (catecholamines and serotonin). All these agents act on cellular receptors that are either on the surface of cell membranes or in the cytoplasm of the cell. These cellular receptors are neither fixed nor unchangeable. Instead, they are in a dynamic state in which the number of receptors on cells can be increased (up regulation) or decreased (down regulation) according to need. Furthermore, the affinity of these receptors for their specific hormone can also be changed (77). Steroid hormones (and possibly thyroxine), which are freely permeable to cell membranes, bind to cytosolic receptors in target cells (78,79). The hormone–receptor complex migrates to the cell nuclei, where it interacts with DNA to modulate the transcription of messenger RNA and ultimately the synthesis of enzymatic, structural, and regulatory proteins (Fig. 16A) (78). This may, in part, explain the one- to two-hour delay in the action of steroid hormones. In contrast, the action of most peptide and amine hormones, which generally bind to cell surface receptors, is faster and of shorter duration. In general, these hormones act either through alterations in the intracellular concentrations of cyclic adenosine monophosphate (cAMP) or calcium, the so-called second messengers (81,82), or through other intermediates (growth hormone through somatomedins). The second messenger system of hormonal action operates primarily through the activation and inactivation of regulatory proteins and enzymes rather than through the synthesis of new proteins. This difference explains the faster onset of action and shorter duration of effect of hormones that operate through this system in contrast to those of steroid and other lipid-soluble hormones. The adrenergic receptor system may be considered the prototype for examining the mechanisms of second

Chapter 1:

Metabolic Response to Starvation, Stress, and Sepsis

17

Figure 16 (A) Proposed mechanism of action of steroid hormones. (B) Proposed mechanism of action of peptide hormones through the second messenger system. Abbreviations: ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; m, molecular; MW, molecular weight. Source: From Refs. 1, 80.

messengers, because all the second messenger pathways known are represented in the four adrenergic receptors (a1, a2, b1, and b2) (Fig. 16B). b1- and b2-receptors (differentiated on the basis of radioligand-binding affinity) both function through the activation of membrane-bound adenylate cyclase, which in turn leads to the production of cAMP (81). The increased intracellular concentration of cAMP activates an inactive protein kinase by attaching to a binding protein on the protein kinase molecule. The attachment of cAMP to the regulatory subunit protein results in the release of an active protein kinase that in turn phosphorylates an inactive phosphorylase kinase to an active form. The active phosphorylase kinase then phosphorylates dephosphoregulatory enzymes, possibly resulting in the activation of the regulatory enzyme (e.g., glycogen phosphorylase) or in its inactivation (e.g., glycogen synthetase) (Fig. 17) (83). In addition, active protein kinase may directly act on dephosphoregulatory enzymes without the activation of phosphorylase kinase. In contrast, a2-receptor activation inhibits membrane-bound adenylate cyclase, thereby decreasing the concentration of cAMP and active protein kinase. Activation of a1-adrenergic receptors results in an increase in phosphatidylinositol turnover that then mediates an increase in intracellular

calcium from intracellular and extracellular sources (81,84). The increase in intracellular calcium activates a calciumbinding protein kinase or phosphorylase kinase (Fig. 16B). The actions of intracellular cAMP and calcium in the coupling of receptor activation with hormonal action (stimulus–response coupling) are not independent. Instead, there is a duality to this system in which the actions of calcium and cAMP are highly interrelated, termed synarchic control by Rasmusen (81). As noted in Fig. 18 and Box 2, there are five basic patterns to the synarchic control of hormone-response coupling through cAMP and calcium. In co-ordinate control, a hormone activates both a calciumactivating receptor and a cAMP-activating receptor, either one of which may produce the response alone. In hierarchal control, separate stimuli activate independently the calcium and cAMP pathways that are both necessary for a given response. In sequential control, the activation of one of the two lines of the system leads to the activation of the other limb. Although the first limb can produce the response, activation of the second limb augments the response. In redundant control, two separate stimuli independently activate the two different limbs of the messenger system, either one of which can produce the response. Finally, in

18

Part One: General Considerations

Box 2 Calcium–Cyclic AMP Interactions in Stimulus-Response Coupling

Figure 17 Activation of protein kinase leading to enzymatic or physiologic response. Activation of the dephosphoenzyme by phosphorylation may be brought about either directly by the active protein kinase or indirectly through the activation of a phosphorylase kinase by the active protein kinase. Abbreviations: ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate. Source: From Ref. 80.

antagonist control, one stimulus activates one limb of the messenger system that leads to the response, and a second stimulus activates the second limb, which inhibits the ability of the first limb to produce the response. Although each of these control mechanisms can occasionally be found in cells in pure form, most of the presently known hormone– response coupling mechanisms involve mixed patterns (81).

1. Effects of calcium on cAMP messenger systems a. Stimulates cAMP production—brain, adrenal cortex, pancreatic islets, adrenal medulla, slime mold b. Stimulates cAMP hydrolysis—brain, heart, liver, kidney, fly salivary gland, many other tissues c. Activates phosphoprotein product of cAMP-dependent protein kinase, glycogenolysis in many tissues 2. Effects of cAMP on calcium messenger system a. Increases calcium entry across plasma membrane—heart, synapse b. Increases calcium release from mitochondria—kidney, liver, fly salivary gland, others c. Increases calcium uptake by microsomes—heart, uterus, liver, smooth muscles d. Increases calcium efflux across plasma membrane—smooth muscle, heart e. Decreases sensitivity of response elements to calcium—smooth muscle, heart f. Increases sensitivity of response element to calcium—phosphorylase beta kinase, liver, muscle 3. Interrelated activities a. cAMP-dependent and calcium-dependent protein kinases act upon same protein substrate—liver, brain, adrenal cortex b. Regulate sequential steps in metabolic or transport process—secretion in fly salivary gland, glycogenolysis Abbreviation: cAMP, cyclic adenosine monophosphate. Source: From Ref. 81.

Hormonal Regulation of Metabolism The neuroendocrine system is able to regulate metabolic reactions through three basic processes. First, it may increase substrate availability so that by simple stoichiometry (mass action), reactions proceed in a desired direction. This process can be brought about either by an increase in the plasma

COORDINATE CONTROL ++

R1

Ca

R2

cAMP

Response

H

HIERARCHICAL CONTROL H1

R1

++

Ca

+

Response

SEQUENTIAL CONTROL H

R

Ca

H2

R2

++

Response

+

cAMP

cAMP H

cAMP

R +

Ca

REDUNDANT CONTROL H1

R1

++

Ca

Response

++

ANTAGONISTIC CONTROL ++

H1

R1

Ca

H2

R2

cAMP

–

Response

Response H2

R2

cAMP

Figure 18 Patterns of synarchic regulation by calcium and cyclic adenosine monophosphate. Source: From Ref. 81.

concentration of a substrate or by alterations in blood flow and its distribution. Second, the neuroendocrine effectors can alter the membrane transport properties of cells for a given substrate so that more or less of the substrate enters or leaves the cell. Third, the neuroendocrine effectors can alter the activity or synthesis of key regulatory enzymes that are necessary for reactions to proceed. Most hormones operate through more than one of these processes. For example, insulin stimulates both glycogen synthetase and the transport of glucose into cells. In this manner, insulin not only activates the enzymatic mechanisms necessary for glycogenesis, but also increases the availability of the necessary substrates. It would be futile for a hormone to stimulate opposing processes in a given cell. If a hormone stimulated both glycogenesis and glycogenolysis, there would be no net effect. As a result, most hormones not only activate the enzymes necessary for one metabolic pathway, they also inhibit the enzymes necessary for the opposing process. Thus epinephrine, through an a-mechanism, activates glycogen phosphorylase and inactivates glycogen synthetase, whereas insulin inactivates glycogen phosphorylase and activates glycogen synthetase. The coordinated control of metabolism also requires that a hormone not have opposing actions in different tissues. Thus by increasing amino acid uptake in skeletal muscle and decreasing amino acid degradation in the liver, insulin promotes the availability of an abundant substrate supply for the enzymes of protein synthesis it activates. Cortisol produces an inhibition of amino acid uptake in skeletal muscle, increases amino acid uptake by the liver, and stimulates hepatic gluconeogenic enzymes. These processes ensure that an abundant supply of amino acids is available to the liver for cortisol-stimulated gluconeogenesis.

Chapter 1:

The primary hormones involved in the regulation of metabolism include insulin, cortisol, epinephrine, glucagon, growth hormone, vasopressin, and somatostatin. Insulin is the primary anabolic hormone promoting the synthesis of glycogen, proteins, and lipids. Cortisol, epinephrine, glucagon, and vasopressin are the primary catabolic hormones promoting the breakdown of glycogen, proteins, and lipids and the synthesis of glucose from gluconeogenic amino acids, lactate, and pyruvate. In contrast, the actions of growth hormone initially are anabolic, but its late effects are primarily catabolic.

Insulin, Glucagon, and Somatostatin Insulin, composed of two polypeptide chains, one containing 21 amino acids and the other 30 amino acids, and glucagon, a 29–amino acid polypeptide, are produced and secreted by the pancreatic B cells (beta islets of Langerhans) and A cells (alpha islets of Langerhans), respectively. The secretion of both of these hormones is under the control of at least three mechanisms: (i) circulating substrates (glucose, amino acids, and free fatty acids); (ii) the autonomic nervous system; and (iii) other circulating hormones. Under normal physiologic conditions, glucose is the most important regulator of insulin and glucagon secretion. When the plasma concentration of glucose increases, the secretion of insulin increases, and the secretion of glucagon decreases. When the plasma concentration ofglucosedecreases, the secretion of insulin decreases, and the secretion of glucagon increases. These changes are probably the result of a direct action of glucose on pancreatic islet cells and not a result of neuroendocrine modulation of the pancreas by other neuroendocrine effectors (85). The direct action of glucose on islet cell function may be mediated either through a glucoreceptor on the surface of the islet cell or through the intracellular metabolism of glucose in the islet cells (86). Elevations in the plasma concentration of amino acids stimulate the release of both insulin and glucagon. Most, if not all, of the amino acids increase insulin secretion, but the potency of amino acids in stimulating glucagon secretion is variable (87). In general, more gluconeogenic amino acids appear to stimulate glucagon secretion (87). High concentrations of fatty acids stimulate the secretion of insulin and inhibit the secretion of glucagon. Conversely, low concentrations of free fatty acids inhibit the secretion of insulin and stimulate the secretion of glucagon. The potency of fatty acids in regulating insulin and glucagon secretion is substantially less than that of glucose (87). The stimulation of insulin secretion and the inhibition of glucagon secretion after the administration of an oral glucose load are greater than that following the intravenous administration of glucose (88). Similarly, the stimulation of both insulin and glucagon secretion is greater after an oral protein or amino acid load than it is after the intravenous administration of amino acids and protein (89). This effect is thought to be the result of the higher concentrations of substrate in the pancreas, the potentiation by gastrointestinal hormones of the substrate effect on the pancreas, and the effect of neural input to the pancreas that has been stimulated by eating (87). The gastrointestinal hormones, cholecystokinin, gastrin, vasoactive intestinal peptide, substance P, neurotensin, and gastric inhibitory peptide (GIP), increase the secretion of both insulin and glucagon in pharmacologic concentrations (87,90). Although gastrin does appear to potentiate the release of glucagon and insulin induced by amino acids and GIP in physiologic concentrations and

Metabolic Response to Starvation, Stress, and Sepsis

19

appears to augment the release of insulin by glucose (87), and the physiologic role of gastrointestinal hormones is not certain. The pancreatic A cells and B cells both have a- and b-adrenergic receptors that alter the secretion of insulin and glucagon. a-Adrenergic stimulation of the pancreas inhibits the secretion of both insulin and glucagon, whereas b-adrenergic stimulation of the pancreas stimulates the secretion of both insulin and glucagon (91,92). However, the a- and b-adrenergic receptor density of A cells and B cells is not the same. The b-adrenergic receptor density of A cells is greater than that of B cells (92). As a result, increased sympathetic stimulation of the pancreas or increased circulating concentrations of epinephrine or norepinephrine increase the secretion of glucagon but decrease the secretion of insulin (91,92). In contrast, isoproterenol infusion increases the secretion of both insulin and glucagon (92). In addition to sympathetic stimulation, the parasympathetic limb of the autonomic nervous system alters pancreatic hormone secretion. Both acetylcholine infusion and direct parasympathetic stimulation of the pancreas increase the secretion of both insulin and glucagon (87). In addition to the gastrointestinal hormones and the autonomic nervous system, other hormones alter the secretion of insulin and glucagon. b-Endorphin appears to directly increase the secretion of insulin and glucagon (93), insulin inhibits the release of insulin and stimulates the release of glucagon (87), and glucagon inhibits the release of glucagon and stimulates the release of insulin (87,94). Insulin and glucagon appear to exert their action both directly on islet cells and by the alterations they produce in circulating substrates (87). Cortisol stimulates the release of insulin and glucagon, but it appears to have no direct activity on the secretory ability of A cells and B cells. Instead, cortisol is believed to increase glucagon secretion through an increase in plasma amino acids and to increase insulin secretion by an increase in plasma glucose. In this regard, both cortisol and epinephrine are able to inhibit the peripheral actions of insulin, and both are thought to exert a major role in insulin resistance (95,96). Somatostatin, a tetradecapeptide, is a potent inhibitor of both insulin and glucagon secretion (90,97). In addition to its location in pancreatic D cells, somatostatin is found in the hypothalamus, limbic system, brain stem, spinal cord, other neural tissue, salivary glands, parafollicular thyroid cells, kidneys, and gastrointestinal tissue (90). Although somatostatin was originally named for its ability to inhibit growth hormone secretion, somatostatin is now recognized to inhibit the secretion of TSH, renin, calcitonin, gastrin, secretin, cholecystokinin, insulin, and glucagon (90). In addition, somatostatinergic nerve fibers are involved in the projection of impulses from peripheral sensory organs to the neuroaxis (90). The role somatostatin exerts in the physiologic regulation of insulin and glucagon secretion is not known precisely. The A, B, and D cells have somatostatin receptors that, when activated, inhibit the secretion of glucagon, insulin, and somatostatin, respectively. Although the mechanism of action of somatostatin is thought to be mediated primarily by the local diffusion of somatostatin from D cells to A cells and B cells (90,97), current evidence suggests that somatostatin reaching the pancreas through the blood stream may be more important (98). The effects of somatostatin on A cells are transient, but the effects on B cells are persistent (97). This persistence may account for the relative hyperglycemia that occurs in patients with somatostatinomas or after the longterm administration of somatostatin (97).

20

Part One: General Considerations

The physiologic actions of glucagon occur primarily in the liver and are mediated through an increase in intracellular cAMP. The activation of glycogen phosphorylase and the inhibition of glycogen synthetase by glucagon promote the breakdown of glycogen to glucose (glycogenolysis) (45). In addition, glucagon stimulates gluconeogenesis through the stimulation of phosphoenolpyruvate carboxykinase, amino acid transport, and amino acid transamination (45,99). The net result is an increase in hepatic production and release of glucose that under basal conditions accounts for 75% of the glucose produced by the liver (100). Glucagon also exerts an important influence over hepatic lipid metabolism. In addition to stimulating lipolysis in adipose tissue and the liver, glucagon inhibits acetyl-CoA carboxylase, the enzyme that converts acetyl-CoA to malonyl-CoA (87). In turn, the reduction in malonyl-CoA produces inhibition of triglyceride synthesis and activation of carnitine acyl transferase. The latter increases fatty acid transfer to the mitochondria and therefore increases the oxidation of acetyl-CoA and ketogenesis (58,87). Peripheral actions of glucagon include the stimulation of lipolysis in adipose tissue, of glycogenolysis in skeletal muscle, and of myocardial contractility (101–103). However, these actions do not appear to be of physiologic significance in human beings (101–103). As a result of glucagon’s ability to increase hepatic glucose production, mobilize fat, and increase ketogenesis, glucagon is important in normal metabolism and more so in the metabolism of altered states. However, the effects of glucagon are evanescent (104). After 30 to 60 minutes, the activity assigned to glucagon decreases even if plasma glucagon concentrations remain elevated. Therefore it appears that an increase in glucagon concentration rather than the absolute amount of glucagon present is a key determinant of glucagon activity (104). This effect also appears to be true of other cAMP-mediated hormones (the burst effect). The physiologic activity of insulin is primarily in the liver, skeletal muscle, and adipose tissue, but insulin does affect many other peripheral tissues. Notable exceptions include erythrocytes and wounded tissue. Insulin promotes the entry of glucose into cells by stimulating the membrane transport of glucose. The increased intracellular concentrations of glucose are used in glycogen synthesis (stimulation of glycogen synthetase and inhibition of glycogen phosphorylase) and in glycolysis (stimulation of glucokinase, PFK, and pyruvate kinase) to produce energy (45). In addition, insulin inhibits gluconeogenesis through the inhibition of phosphoenolpyruvate carboxylase and the stimulation of PFK and pyruvate kinase (45). Insulin also increases the membrane transport of amino acids into the liver and peripheral tissues. The increased intracellular concentrations of amino acids are used in protein synthesis (stimulation of protein synthesis and inhibition of proteolysis). By inhibiting gluconeogenesis and amino acid oxidation, insulin further directs the intracellular amino acids to protein synthesis (99). In adipose tissue, insulin stimulates lipogenesis and inhibits lipolysis, as it does in the liver. By stimulating lipoprotein lipase, insulin also makes triglycerides more available for uptake from the plasma by adipose tissue. Glycerol synthesis and the action of the pentose-phosphate shunt also are increased by insulin in adipose tissue and the liver. Thus insulin is the primary anabolic hormone promoting the storage of lipid, glucose, and protein.

Although insulin and glucagon oppose each other in the metabolic processes each stimulates, a bihormonal response is necessary for maintenance of glucose homeostasis after a protein meal (90). If insulin were secreted alone in response to a protein meal, the increase in protein synthesis and decrease in hepatic glucose production would result in hypoglycemia. Conversely, if glucagon were secreted alone, the decrease in protein synthesis and the increase in hepatic gluconeogenesis would result in hyperglycemia. However, when a rise in glucagon is accompanied by an increase in insulin, hepatic glucose production remains unchanged and euglycemia is maintained. In this regard, Unger (105) has proposed the insulin/glucagon (I/G) ratio as a quantitative measure of hepatic glucose balance. When the I/G ratio is greater than 5, anabolism and protein synthesis are favored. When the I/G ratio is less than 3, glycogenolysis, gluconeogenesis, and lipolysis are favored. However, the validity of this relationship has been questioned (86).

ACTH, Cortisol, and Epinephrine The primary hormones released in response to any physiologic or psychologic stress are the glucocorticoids and catecholamines. These hormones are in large part responsible for the ‘‘fight-or-flight reaction.’’ The release of cortisol is under the control of ACTH, a 39–amino acid polypeptide released from the chromophobe cells in the anterior pituitary gland. In turn, the release of ACTH is itself under the inhibitory influence of cortisol and the stimulatory influence of corticotropin-releasing factor (CRF) produced by the hypothalamus. The release of CRF (and ACTH–cortisol) is stimulated by all the stimuli noted previously and is potentiated by vasopressin, oxytocin, and angiotensin II (106,107). ACTH acts directly on cells of the adrenal zona fasciculata, stimulating the production and release of cortisol through a cAMPmediated conversion of cholesterol to pregnenolone (108). The catecholamines (epinephrine, norepinephrine, and dopamine) are the prototypical neuroendocrine effectors that act as neurotransmitters and hormones (109). Epinephrine, produced almost exclusively by the adrenal medulla, functions primarily as a hormone, whereas norepinephrine and dopamine function primarily as neurotransmitters (109). Although the adrenal medulla may be viewed as a collection of postganglionic sympathetic neurons without axons that release their neurotransmitters into the general circulation, the activation of the sympathetic nervous system does not occur in an all-or-none fashion, and it is not synonymous with adrenomedullary secretion (110). Similarly, adrenomedullary stimulation is not synonymous with the complete activation of the sympathetic nervous system. Numerous stimuli have been identified that lead to increased secretion of catecholamines from the adrenal medulla (e.g., hypotension, hypoxia, hypoglycemia, pain, and fear), but the exact mechanisms involved in adrenomedullary control remain poorly understood (110). Both cortisol and epinephrine function as ‘‘counterregulatory’’ hormones, mediating catabolic processes throughout the body. In the liver, cortisol inhibits several key glycolytic enzymes (glucokinase, PFK, and pyruvate kinase), the pentose-phosphate shunt, and the actions of insulin (45,108). In addition, cortisol stimulates the hepatic uptake of amino acids, transaminases, and several gluconeogenic enzymes (pyruvate carboxylase, phosphoenolpyruvate carboxykinase, and glucose 6-phosphatase), as well as potentiating the actions of glucagon and epinephrine (45,95,111). As a result, the production of glucose, lactate, and pyruvate by the liver is increased.

Chapter 1:

The metabolic effects of epinephrine are similar to those of glucagon but are more widespread, affecting peripheral tissues and the liver. In the liver, epinephrine stimulates glycogenolysis (a1-mediated stimulation of glycogen phosphorylase and inhibition of glycogen synthetase) (81), lipolysis (b1-mediated activation of triacylglycerol lipase) (112), ketogenesis (b1-mediated inhibition of acetylCoA carboxylase leading to decreased malonyl-CoA and increased carnitine acyl transferase) (68), and gluconeogenesis (b1-mediated inhibition of PFK and hexokinase by the products of glycolysis and glycogenolysis) (113). Thus epinephrine serves to increase hepatic glucose production and lipid breakdown. Although both glucagon and epinephrine increase glucose production by the liver, glucose use by peripheral tissues is not the same in the presence of epinephrine as it is in the presence of glucagon (99). Glucagon promotes the use of glucose by peripheral tissues through the stimulation of insulin secretion. In contract, epinephrine inhibits both the release and the action of insulin, thereby decreasing glucose use in insulin-dependent peripheral tissues. However, epinephrine serves to increase glucose availability to insulin-insensitive tissues such as the brain, whereas glucagon does not shunt glucose to insulininsensitive tissues (99). In adipose tissue, epinephrine increases lipolysis (b-mediated activation of triacylglycerol lipase). In peripheral tissues, epinephrine stimulates glycogenolysis (a1) and inhibits stimulated glucose uptake through a b2- and a1-mechanism (114,115). As a result of increased substrate availability, glycolysis is increased in skeletal muscle, and large amounts of lactate are produced and released into the circulation. The lactate can then be taken up by the liver for subsequent gluconeogenesis (Cori cycle). Therefore during stressful conditions, epinephrine and cortisol both promote a rise in blood glucose and make glucose more available to glucose-dependent tissues. Both of these hormones also promote the breakdown of lipid and thereby its use as a source of fuel. Whereas the actions of epinephrine are direct, many of the actions of cortisol occur as a result of the potentiation or inhibition of other hormones, the so-called permissive action of cortisol.

Growth Hormone and Vasopressin Growth hormone is a 191–amino acid polypeptide that is released from acidophilic cells in the anterior pituitary gland. Its secretion is under the control of a releasing factor (growth hormone–releasing factor) and by an inhibiting factor (somatostatin) (116). Elevation of blood glucose or free fatty acids stimulates the release of growth hormone (116). In addition, the release of growth hormone is stimulated by vasopressin, ACTH, a-melanocyte–stimulating hormone, and estrogen; release of growth hormone is inhibited by cortisol, thyroxine, and growth hormone itself. In addition to its ability to promote protein synthesis and RNA synthesis and to increase linear growth, growth hormone exhibits an important role in the regulation of metabolic processes. Its effects are biphasic, composed of early effects of three to four hours duration and late effects of longer duration (116). In muscle and liver, growth hormone increases amino acid uptake and protein synthesis (117). In addition, growth hormone stimulates glucose uptake in skeletal muscle and antagonizes the lipolytic effects of catecholamines in adipose tissue while increasing protein synthesis (117). Therefore the early effects of growth

Metabolic Response to Starvation, Stress, and Sepsis

21

hormone are similar to insulin. In fact, growth hormone directly stimulates the secretion of insulin by pancreatic B cells during its early phase (66). The late effects of growth hormone include an increased mobilization of fatty acids and ketone bodies by adipose tissue as a result of increased lipolysis. This action of growth hormone occurs only in the presence of cortisol (118). In addition, growth hormone inhibits insulin-stimulated glucose uptake and use, thereby producing a profound stimulation of insulin release by hyperglycemia (66). Arginine vasopressin (antidiuretic hormone) is a nonapeptide that is released by the posterior pituitary gland. Although released primarily in response to an increase in plasma osmolality and to a reduction in effective circulating volume (98,119), vasopressin release is also stimulated by hypoglycemia through nonosmotic pathways (120). Vasopressin is a powerful stimulator of hepatic glycogenolysis (a-receptor) and also stimulates hepatic gluconeogenesis (121,122). As such, it may exert an important role in elevating the blood glucose after injury and during hypoglycemia.

METABOLIC RESPONSE IN STARVATION, INJURY, AND SEPSIS Fasting and Starvation In the absence of food, fasting humans must supply the energy required for daily activities, glucose for glucosedependent tissue, essential amino acids (Table 12), and essential fatty acids from existing body stores. Cahill (29) has estimated that the average resting 70 kg man using 1800 kcal of energy per day requires 180 g of glucose daily—for the metabolism of nervous tissue (144 g) and for other glycolytic tissue (RBCs, WBCs, and the renal medulla) (36 g) (Fig. 19). Because the available glycogen in the liver is only 75 g (Table 13), this amount will not suffice for either the energy requirements or the glucose needs of a fasting man. Although an additional 150 g of glucose is in skeletal muscle as glycogen, as noted previously, it cannot be released from skeletal muscle as free glucose as a result of the absence of glucose 6-phosphatase. Thus, it is apparent that the energy requirements and glucose requirements of fasting human beings must be supplied from noncarbohydrate sources and by gluconeogenesis. The daily energy requirements can be met by the mobilization of approximately 160 g of triglycerides from adipose tissue in the form of free fatty acids (19). The free fatty acids, as well as ketone bodies produced by the liver, are used throughout the body by nonglycolytic tissues such as the heart, kidney, muscle, and liver. In the liver, energy derived from b-oxidation of fat and from oxidation of acetyl-CoA is used to drive the necessary gluconeogenic processes. Gluconeogenic substrates are available from three sources (Table 14). First, the lipolysis of 160 g of triglycerides releases 16 g of glycerol that can be converted by the liver to glucose. Second, some glucose-dependent tissues (i.e., RBCs and WBCs) convert glucose to lactate and pyruvate that may then be reused in the liver by the Cori cycle to produce new glucose. In addition to the 36 g of lactate and pyruvate produced in this manner, skeletal muscle can also release lactate and pyruvate by the breakdown of glycogen and glucose. Third, approximately 75 g of skeletal muscle protein is degraded daily during starvation, and the resulting amino acids are used in the liver for gluconeogenesis. Consequently, the energy required during brief fasting is derived primarily from adipose tissue. In contrast, the

22

Part One: General Considerations

FASTING MAN (24 hours, basal: –1800 calories) FUEL CONSUMPTION

ORIGIN OF FUEL

Nerve Muscle protein 75 g

Amino acids Glycerol 16 g

Adipose tissue Triglyceride 160 g

40 g Fatty acid 160 g

144 g Glucose 180 g 36 g 36 g

Liver Glycogen Gluconeo genesis O2 H2O _P

Ketone 60 g

(Fatty acid) 120 g

glucose required is supplied from lactate, pyruvate, glycogen, and amino acids. During the first two to four days of fasting, there is a rapid increase in the urinary nitrogen excretion from 5 to 7 g/day to approximately 8 to 11 g/day (123). This increase is associated with the previously noted breakdown of 50 to 75 g of protein per day. The rapid proteolysis of skeletal muscle protein does not continue during more prolonged fasting. During the next 20 to 40 days of fasting, the urinary nitrogen excretion begins gradually to decline and eventually reaches its nadir of 2 to 4 g of nitrogen per day (123). This decline is the result of ketoadaptation to starvation. In this process, the brain, which does not normally use ketone bodies for fuel, adapts its metabolism and transport systems to use ketone bodies (124). This adaptation results in a significant reduction in the amount of glucose needed by this glucose-dependent tissue and consequently in the amount of amino acid substrate necessary for gluconeogenesis (Fig. 20). Protein conservation follows with only 20 to 30 g of protein catabolized per day (29). The molecular mechanisms responsible for these adaptive responses are incompletely understood. With respect to skeletal muscle proteolysis, an ATP-ubiquitin-proteasome pathway seems to be involved (125,126). Early in the starvation process, this pathway is activated so that muscle-protein degradation occurs during fasting. As the starvation is prolonged, down-regulation of this process occurs so as to conserve muscle protein stores. Concurrent with these adaptations to starvation is a reduction in the resting energy expenditure by as much as 31% (120). In part, the reduction in resting energy expenditure is the result of a reduction in BCM produced by the breakdown of muscle and other proteins. However, the reduction in body size is less than the reduction in resting energy expenditure (120,127). Other factors that may contribute to the reduction in resting energy expenditure include a reduction in voluntary work, a decrease in body temperature, a decrease in cardiac work, a decrease in sympathetic nervous system activity, and a decrease in muscle activity. The changes in metabolism accompanying fasting and starvation are primarily regulated by decreased concentrations of insulin and increased concentrations of glucagon in response to decreasing glucose concentrations (29,58,123). The decreased insulin concentrations promote an increase in lipolysis in adipose tissue and a decrease in glucose uptake

_P

CO2 + H2O

RBC, WBC, etc. _P Lactate and pyruvate O2 Heart, kidney, muscle, etc.

~P

CO2 + H2O

Figure 19 Flow diagram of fuel metabolism in normal fasted man. Abbreviations: RBC, red blood cell; WBC, white blood cell. Source: From Ref. 29.

in insulin-dependent tissues. The increased concentrations of glucagon promote hepatic gluconeogenesis. These changes (including the decreased secretion of insulin and increased secretion of glucagon) may be further augmented by slight increases in the concentrations of epinephrine, ACTH, cortisol, and growth hormone (103,128). However, an actual increase in these hormones is not necessary, because basal concentrations of the counter-regulatory hormones are unopposed by the reduced secretion of insulin that is stimulated by hypoglycemia. Thus through four major adaptive mechanisms, a reduction in resting energy expenditure, the use of protein for gluconeogenesis, the use of fat for energy, and ketoadaptation of the brain, a human is able to survive for prolonged periods of time without food. As a result of the decreased excretion of urea and nitrogen during prolonged starvation, water intake is also reduced. However, it is apparent that this condition cannot be maintained indefinitely. In the average 70 kg man, there are approximately 170,000 calories and 6000 g of protein (Table 13). If it could all be used, starvation for up to 100 days would be tolerated. However, this is not possible because of the loss of essential body functions as body protein is consumed and not replenished. In fact, acute weight losses of 30% to 40% of body weight are usually fatal and associated with a rapid increase in urinary nitrogen excretion and a rapid decline in plasma glucose (123,129,130).

Table 13 Fuel Composition of Normal Humans Fuel Tissues Fat (adipose triglyceride) Protein (mainly muscle) Glycogen (muscle) Glycogen (liver) Total Circulating fuels Glucose (extracellular fluid) Free fatty acids (plasma) Triglycerides (plasma) Total Source: From Ref. 29.

Weight (kg)

Calories

15 6 0.15 0.075

141,000 24,000 600 300 165,900

0.02 0.0003 0.003

80 3 30 113

Chapter 1:

Metabolic Response to Starvation, Stress, and Sepsis

23

Table 14 Amount of Glucose Produced from Lactate, Glycerol, and Amino Acids During Starvation Grams of glucose produced per day Glucose precursor Glycerola Lactate þ pyruvateb Amino acidsc Total glucose produced from above precursors by liver and kidney cortexd Maximum glucose available for oxidation by the brain (i.e., glycerol and amino acid as precursors)e Fuel requirement of brain (glucose equivalents)f Suggested alternative fuel to glucose for braing

3 or 4 days of starvation

Several weeks of starvation

19 39 41 99

19 39 16 74

60

35

120 Ketone bodies

120 Ketone bodies

a

Amount of glucose produced from glycerol is estimated from the amount of triglyceride hydrolyzed per day. In starvation, 190 g of triglyceride is required to satisfy the caloric needs of the subject. Because glycerol represents 10% of triglyceride, it can provide 19 g of glucose per day. This amount is confirmed by measurement of glycerol uptake by liver and kidney using catheterization techniques. b Amount calculated from glucose 1-C turnover studies in man that gives values between 27 and 58 g/day, and this is not affected by the dietary state. Also, the measurement of lactate and pyruvate uptake by the liver and kidney in man by catheterization techniques estimates glucose formation as 39 g/day. c Amount calculated from nitrogen excreted in urine (100 g protein produces 57 g glucose; 1 g nitrogen is equivalent to 6–25 g protein). In early stages of starvation approximately 12 g nitrogen is excreted per day, but this is decreased in prolonged starvation to 4 to 7 g/day. Catheterization studies in subjects undergoing prolonged starvation indicate an uptake of amino acids by liver and kidney that could theoretically produce 26 g glucose per day. d In prolonged starvation, the hepatic–renal glucose production as measured by catheterization techniques provides an estimate of 86 g glucose per day, which is in good agreement with the 74 g obtained in this calculation. e Catheterization techniques have been used to measure the arterio–venous (A–V) differences across the brain. In prolonged starvation, glucose oxidation by the brain (excluding glucose converted to lactate, which is converted back to glucose in the liver and kidney) is estimated as 24 g/day. f Oxygen uptake or total fuel use is measured by catheterization techniques. g The rate of ketone body uptake by the brain has been estimated from A–V differences using catheterization techniques. These studies strongly suggest that ketone bodies are the alternative fuel to glucose during starvation. Source: From Ref. 45.

Injury and Sepsis Cuthbertson (131,132), in his classic studies of the metabolic response to long-bone fractures, defined two phases of the metabolic response to injury—an ebb or shock phase and a flow phase. Moore (133) subsequently divided the flow phase into catabolic and anabolic stages. The ebb phase, constituting the first several hours after injury, is characterized by hyperglycemia and the restoration of circulatory

volume and tissue perfusion. Once perfusion is restored, the flow phase begins. It is characterized by generalized catabolism, negative nitrogen balance, hyperglycemia, and heat production. The flow phase is the best-studied phase and may last from days to weeks, depending on the severity of the injury, the previous health of the individual, and medical intervention. Finally, once volume deficits have been corrected, pain has been eliminated, wounds have been

FASTING MAN, ADAPTED (5_6 weeks) (24 hours, basal: – 1500 calories) FUEL CONSUMPTION

ORIGIN OF FUEL

O2

47g

Muscle Protein 20 g

Glycerol 15 g Adipose tissue Triglyceride 150 g

O2 30 g

Fatty acid 150 g

H 2O –P

–P CO2 + H2O

44 g

Liver, kidney Glycogen Gluconeogenesis

Amino acids

Nerve

Glucose 80 g 50 g

Ketone 57g

(Fatty acid) 112 g

36 g

RBC, WBC, etc. –P 14 g

Lactate and pyruvate O2 Heart, kindly muscle, etc.

Urine 10 g ketone = ~100 mEq

–P CO2 + H2O

Figure 20 Flow diagram of fuel metabolism in starved man after adaptation. Source: From Ref. 29.

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Part One: General Considerations

closed, infection has been controlled, and complete oxygenation has been restored, the anabolic phase begins (1). This phase can be divided into a slow but progressive reaccumulation of protein, followed by the reaccumulation of body fat. Because protein synthesis cannot exceed 3 to 5 g of nitrogen per day, the protein repletion phase may be considerably longer than the catabolic phase in which protein is broken down. The posttraumatic state is characterized by starvation, immobilization, and repair. Although starvation and immobilization are both associated with decreased energy requirements, reparative processes increase energy needs. As a result, the overall energy requirements of traumatized and septic individuals are increased. The increase in energy need varies directly with the severity of injury and the complications that develop. In this regard, the most severe injury is the burn, and the most severe complication is sepsis (Fig. 5). Despite the use of protein and carbohydrate for calories, most of the energy used after trauma and after sepsis is derived from fat. This use is reflected in the low respiratory quotients noted after injury and sepsis. For example, Wilmore et al. (134) found respiratory quotients of 0.70 to 0.76 after severe burns. In addition, septic injury appears to have a greater lipid dependence for energy than nonseptic injury (100,135). Increased lipolysis is seen in both the ebb phase and the flow phase of the metabolic response to injury. During the ebb phase, elevated concentrations of cortisol, catecholamines, glucagon, growth hormone, ACTH, increased sympathetic nervous system activity, and depressed concentrations of insulin favor lipolysis. The presence of cortisol appears to be necessary for the remainder of the hormonal agents to be effective (136,137). Elevated concentrations of glycerol and free fatty acids during the ebb phase are well documented (138–140). However, Kovach et al. (141) have noted that elevation of plasma free–fatty acids may not occur after severe hemorrhage as a result of intense vasoconstriction in adipose tissue, producing minimum blood flow. During the flow phase, net lipolysis persists despite an increase in the concentration of insulin. Increased free fatty acids have been documented after trauma, burns, and sepsis (100,133,142–146). The fatty acids are used throughout the body for energy. In both the ebb and flow phases, the high concentration of intracellular fatty acids and the elevated concentration of glucagon inhibit acetyl-CoA carboxylase, thereby decreasing malonyl-CoA concentrations and fatty acid synthesis. In hepatocytes, the decreased concentration of malonyl-CoA also stimulates carnitine acyl transferase, thereby increasing the transport of acetyl-CoA into the mitochondria for oxidation and ketogenesis. However, the activity of ketogenesis after shock, injury, and sepsis is variable and correlates with the severity of injury (144–146). After major injury and sepsis, ketogenesis is low or absent, whereas after minor injury and sepsis, it is increased but to a lesser extent than is seen during nonstressed starvation (142,147). During starvation, the inhibition of acetyl-CoA carboxylase also results in the accumulation of cytoplasmic citrate that in turn inhibits glycolysis through PFK inhibition (Randle effect) (45). However, after shock and major injury, citrate does not accumulate (148,149). This lack of accumulation may play a role in the persistence of glycolysis after injury. Unlike fasting and starvation, hyperglycemia is a hallmark of the response to injury, sepsis, and stress. An increase in blood glucose occurs during both the ebb and

flow phases and is proportional to the severity of the injury (150,151). There is also an increased concentration of lactate, pyruvate, organic phosphates, total amino acids, glycerol, and free fatty acids. Changes in lactate, pyruvate, and alanine have also been found to correlate with the severity of injury (144). The rise in the concentrations of glucose and other solutes contributes to an elevated plasma osmolality after hemorrhage and injury that is thought to be critical in the complete restitution of blood volume and plasma proteins (119,152–155). The hyperosmolality appears to augment the transcapillary refill phase and the plasma protein– restoration phase of blood volume–restitution by mediating the movement of water from cells to the interstitium and ultimately to the plasma (153–155). The metabolic changes in carbohydrate metabolism arise primarily as the result of the actions and interactions of catecholamines, cortisol, glycogen, insulin, growth hormone, and somatostatin (65,95,96,150,156,157). It is apparent that the elevated blood glucose concentration results from increased hepatic production and from impaired peripheral uptake that are under endocrine control. Both the ebb and the flow phases are associated with hyperglycemia, increased gluconeogenesis, and hepatic and peripheral insulin resistance. However, the mechanisms involved in these carbohydrate ‘‘abnormalities’’ are different. During the ebb phase, plasma insulin is clearly depressed in relationship to the degree of hyperglycemia (111,150,158,159). This results from decreased B-cell sensitivity to glucose that is secondary to catecholamines, somatostatin, reduced pancreatic blood flow, and the increased activity of the sympathetic nervous system (92,115,139,160,162). However, during the flow phase, B-cell sensitivity returns to normal, and insulin concentrations rise to more appropriate values. Nevertheless, hyperglycemia persists (111,163). In both the ebb and the flow phases, there is a delayed rate of assimilation of a glucose load, glucosuria, and a resistance to exogenously administered insulin (156,160,164). Despite this ‘‘diabetes of injury,’’ glucose uptake and use by peripheral tissues in both the ebb and the flow phases have been demonstrated consistently to be greater than that under normal circumstances (111,165–169). The resistance to insulin is manifested in a decreased glucose clearance. Consequently, the high plasma glucose concentration and the attendant increase in plasma–tissue glucose concentration gradient appear to overcome the resistance of peripheral tissues to glucose entry. The insulin resistance that develops appears to result from the action of catecholamines, cortisol, and other factors (65,95,96,115,157). Hepatic carbohydrate metabolism is also affected by insulin resistance. During the ebb phase, elevated concentration of catecholamines, cortisol, and glucagon and a decreased concentration of insulin result in rapid glycogenolysis and an outpouring of glucose from the liver. In addition, these hormonal alterations stimulate gluconeogenesis from alanine, lactate, and pyruvate. Growth hormone also is involved in these processes by inhibiting glucose uptake through inhibition of glucokinase. During the flow phase, gluconeogenesis persists despite nearnormal concentrations of insulin. This persistence appears to result from insulin resistance and produces a continued flow of glucose from the liver. Therefore the hyperglycemia that occurs after injury results from a combination of increased glucose production and glucose release and from a peripheral resistance to the entrance of glucose. After injury and during sepsis, glucose must be provided not only to RBCs, WBCs, renal medulla, and

Chapter 1:

neural tissues, but also to wounded tissue (162,170,171). Glucose uptake in wounded tissue is increased by up to 100%. Wounds demonstrate a lack of insulin sensitivity and do not increase their glucose uptake or glycogenesis in response to insulin (60,172,173). The accelerated glucose uptake in wounded tissue and possibly in septic tissue appears to correlate with the degree of inflammatory cellular infiltrate (171). In addition, it has been demonstrated that the accelerated glycolysis of wounded tissue may be aerobic and not anaerobic, as thought previously (170). The aerobic glycolysis proceeds to lactate in the presence of adequate oxygen. Thus oxygen consumption and carbon dioxide production are normal, but lactate production is accelerated. Increased lactate production may be related to an inability of the NADH shuttle to transfer reducing equivalents from the cytoplasm to the mitochondrion (85,174). Metabolic derangements suggestive of aerobic glycolysis have also been seen in septic tissue (175). In this regard, it is of note that aerobic glycolysis is characteristic of the cellular infiltrate (176). As one might expect, negative nitrogen balance and net proteolysis are characteristic of the posttraumatic and the septic states (177,178). However, only 20% of the protein broken down is used for calories (71). The remainder is used in gluconeogenesis. As noted previously, the production of lactate in the presence of oxygen primarily results from the actions of cortisol, glucagon, catecholamines, and the decreased effectiveness of insulin. The rise in urinary nitrogen is associated with an increased excretion of urea, sulfur, phosphorus, potassium, magnesium, and creatinine, suggesting the breakdown of intracellular material (131,179). Isotope dilution studies suggest that this loss of protein results from the loss of cell mass rather than cell number (131). The nitrogen-to-sulfur and nitrogen-to-potassium ratios suggest that this loss occurs mainly from muscle (131). The marked increase in the urinary excretion of 3-methylhistidine during trauma, sepsis, and burns also suggests the importance of skeletal muscle in response (180,181). Analysis of the protein content and the incorporation of radiolabeled amino acids in visceral tissues and skeletal muscle confirm that it is skeletal muscle that is depleted and the visceral tissue (liver and kidney) is spared (182). This is the opposite of nonstress starvation in which visceral protein is used before muscle protein and has been termed visceral translocation of protein (37,182). In fact, one of the molecular tragedies associated with trauma, burns, and especially sepsis is that the proteolytic suppression accompanying prolonged starvation is not observed. Consequently, continued breakdown of protein results. The alterations in plasma amino acids are not well defined during the ebb and flow phases. During the ebb phase, little change in total amino acid concentrations were noted by Elwyn et al. (183) until the late phases of shock. In addition, it appears that these changes result primarily from a decreased hepatic uptake (183) and not an increased peripheral release as was thought previously (184). During the flow phase, alterations in plasma amino acids appear to be related to the severity of injury and the specific type of injury (121,185–187). Alanine, the major gluconeogenic amino acid, appears to be released from peripheral tissues and taken up by the liver for gluconeogenesis. Early in the flow phase, the concentration of alanine in plasma is increased; but as the injury persists, serum alanine decreases, presumably as a result of its lack of availability in peripheral tissues and its continued hepatic uptake.

Metabolic Response to Starvation, Stress, and Sepsis

25

Branched-chain amino acids and aspartate and asparagine are transaminated in peripheral tissues, and their remaining carbon fragments are used in the TCA cycle. Nonetheless, muscle concentrations of amino acids generally reveal normal or elevated concentrations of all amino acids except alanine, glutamine, and arginine (188). The net catabolism of protein can result from increased catabolism, decreased synthesis, or a combination of the two. Available data on TBP turnover suggest that after injury the net changes in catabolism and synthesis depend on the severity of the injury (189). Elective operations and minor injury appear to result in a decreased rate of synthesis with a normal rate of protein catabolism (118,140). Severe trauma, burns, and sepsis appear to be associated with increases in both synthesis and catabolism but with a greater increase in the latter, resulting in net catabolism (122,189–191). In this regard, it is important to note that the accelerated proteolysis and a high rate of gluconeogenesis persist after injury and during sepsis (185,192). This persistence appears to result from an inhibition of ketoadaptation after injury and sepsis. Unlike starvation, ketogenesis is not prominent, and it does not fuel the brain in significant amounts. Therefore a high requirement for glucose and therefore gluconeogenesis persist. The mechanism for this inhibition of ketoadaptation is not understood presently. Clowes et al. (193) have presented evidence suggesting the involvement of a circulating peptide containing 33 amino acids in this response. In addition, Baracos et al. (194) have proposed that interleukin-1 (IL-1) (a human leukocyte pyrogen) may be responsible for the accelerated proteolysis that accompanies fever and sepsis (see section on ‘‘Cytokines’’). As noted previously, activation of an ubiquitin-proteasome pathway appears to be involved in skeletal muscle degradation during starvation (125,126). In septic states, rates of ubiquitination of muscle proteins are profoundly increased (125,195,196). Further, inhibition of this process significantly reduces proteolysis in septic conditions (197). The net catabolism of protein that occurs after any injury is dependent on the prior nutritional status and intake, sex and age of the individual, and the severity of the injury. Young healthy males lose more protein in response to an injury than do women or the elderly (40). In addition, the urinary excretion of nitrogen is less after a second operation if it closely follows the first (145,178). This decline is presumably the result of a reduction in available protein stores. Finally, negative nitrogen balance can be reduced or virtually eliminated by high caloric and nitrogen supplementation (34,156,191,198,199). Together, these facts suggest that the loss of protein that occurs after injury is not entirely obligatory to the injury, but is also a manifestation of acute starvation (146).

Local Wound Metabolism Injury is associated with a negative bodily balance of many substrates (200–203). Despite injury-induced abnormalities in cofactors and substrates known to be important in wound healing, most wounds heal after injury (203–205). The ability of the wound to heal in the face of varying hormone and substrate supply suggests that the wound has a biologic priority over the host. This concept of biologic priority of healing wounds was described by Moore and Brennan (206), who stated that 75% of wounds or surgical incisions healed to the point of tensile integrity during a period of negative energy and nitrogen balance. The other 25% healed in patients who returned to eating so rapidly that the

26

Part One: General Considerations

period of negative balance was of minimal duration (206). It is therefore evident that during a period of postinjury hormonal alterations and general catabolism, the wound has a favored status. This concept suggests that the metabolic and functional determinants of normal wound repair are inherent within the local wound environment. This further suggests that the local wound environment is differently sensitive to substrate and hormonal alterations than are other organ systems.

Cellular Infiltrate as a Determinant of Biologic Priority Following injury, there is a local ordered infiltration of inflammatory cells and a characteristic pattern of cellular predominance within the wound over time. This ordered sequence of cellular predominance leads to characteristic alterations in extracellular substrate concentrations, temporal effects of wound fluid on wound cell function, an altered sequence of expression for peptide growth factors, and degradation of classical peptide hormones. It appears that the metabolism of the wound is determined by the cellular infiltrate and is independent of systemic hormonal and substrate alterations. This is supported by the following findings: 1. 2.

3. 4. 5.

6. 7. 8. 9. 10. 11. 12. 13.

A direct relationship exists between DNA content of wounded tissue and the cellular infiltrate (207). Wounded tissue metabolizes glucose rapidly through aerobic glycolysis. This unusual form of glycolysis is characteristic of the leukocytes that comprise the cellular infiltrate (170). A time course for glucose uptake and lactate production by wounded tissue appears to correlate with the development of the cellular infiltrate (207). Autoradiographic studies using [3H]-2-deoxyglucose reveal that the majority of the glucose uptake in wounded tissue occurs in the cellular infiltrate (208). Both wounded tissue and macrophages increase their glucose uptake in response to increasing glucose concentrations in the environment, and this glucose clearance is concentration independent. Thus the lack of saturation of glucose uptake of wounded tissue appears to be determined by the macrophages in the cellular infiltrate (209). A high PFK activity of wounded tissue can be explained by the PFK activity of the cellular infiltrate as measured by 5-[3H]-glucose (208). Macrophage glucose uptake and lactate production are independent of local epinephrine concentrations (208). Macrophages have a stimulatory effect on the HEP content of resident host tissue (210). A decreased HEP content of wounded tissue appears to be secondary to the dilutional effect of the cellular infiltrate (211). The presence of macrophages seems to explain the pattern of purine release from wounded muscle (212). Glutamine utilization by the cellular infiltrate appears to explain the decrease in glutamine content of wounded tissue (213). In the isolated perfused system, hormone and substrate profiles similar to those found following injury do not affect wound metabolism. A prior adrenalectomy does not affect wound metabolism despite substantial effects on noninjured tissue.

In addition, other investigators have shown a lack of effect of exogenous insulin on local wound metabolism in an incubated system (171). Thus there are substantial data to support the position of the wound as independent of circulating hormone and substrate concentrations. Yet it is known that several of the more common clinical examples of impaired wound healing involve systemic hormonal and substrate changes. Specifically, diabetes mellitus (214– 217), steroid therapy (218–220), amino acid deprivation (221,222), and hypophysectomy (223) have been shown to impair wound healing. In summary, generalized catabolism, hyperglycemia, persistent gluconeogenesis, protein wasting, negative nitrogen balance, heat production, and loss of the body mass that parallel the severity of the injury are characteristic after trauma and during sepsis. Most of the energy necessary for biologic processes to proceed is derived from fat. The net catabolism of 300 to 500 g of lean body mass per day is apparently required as a source of amino acids for gluconeogenesis. The persistence of the injury, particularly sepsis, through unknown mechanisms produces inhibition of the usual adaptive mechanisms that occur in starvation, resulting in the persistence of a highly catabolic state. This state in turn leads to protein wasting and malnutrition and ultimately in multiple organ failure (224) and death if the stimuli are not eliminated. (For further information on wound healing, the reader is referred to the chapter 55).

CYTOKINES In addition to the important role that neurohumeral mediators have been shown to play in the metabolic response to stress and injury, emerging evidence is also defining a role for cytokines (225,226). Often these two systems appear to work in tandem to carry out a particular response. Because cytokines are primarily proinflammatory agents, the magnitude of their involvement is related to the severity of the underlying stress or injury. For example, in an elective surgical procedure, the wound is the primary locus of the inflammatory response. Thus, cytokines involved in this response are targeted toward healing this wound; accordingly, their access to the systemic circulation is minimal and the resultant systemic response is modest or nonexistent. In a more traumatic situation in which massive tissue destruction has occurred (e.g., motor vehicle accident and blast injury), the local production of cytokines may be profound with an equally excessive egress of these substances into the systemic circulation. In this situation, the systemic response may result in hemodynamic instability and even distant organ failure. Cytokines comprise a family of small proteins or glycoproteins that alter the function of a target cell through an autocrine or paracrine process; rarely this targeting may be accomplished in an endocrine fashion. Many different cells may secrete cytokines but those commonly involved include lymphocytes, macrophages, Kupffer cells of the liver, and various components of the intestinal epithelium. The biologic response induced by cytokines is considerably diverse and will depend upon the particular cytokine secreted and the target cell affected. Since first being discovered in the 1970s, dozens of cytokines have been identified, and it is likely that many more will become recognized in the years to come. Accordingly, a comprehensive review of cytokines and their physiology is beyond the scope of this chapter [the reader is referred to several excellent references for this information

Chapter 1:

(225–228)]. This discussion will focus on those cytokines that have been shown to influence the metabolic response to stress. These include interleukin 1 (IL-1), interleukin 6 (IL-6), tumor necrosis factor [(TNF)/cachectin], and interferon-gamma. Cytokines are commonly categorized as being proinflammatory, anti-inflammatory, or both. This is based on their ability to invoke local or systemic inflammation and alter the immune response. The four cytokines involved in the metabolic response to stress are primarily proinflammatory, with the exception of IL-6, which possesses both proinflammatory and anti-inflammatory characteristics. Their effects on the immune response will not be discussed in this context, because this function is extensively covered in the chapter on immunity and the immunocompromised patient (Chapter 4). As mentioned above, cytokines can elicit both local and systemic effects. Because they are produced at the site of injury, their major action will be targeted to that site if the wound is uncomplicated. Thus, in situations such as setting a simple fracture, repairing an inguinal hernia, or removing a diseased gallbladder (particularly if done laparoscopically), a systemic response is highly unlikely. Rather, locally released cytokines will be confined to the site of injury to both induce and modulate the healing process. Important healing factors such as enhancement of blood flow through vasodilation, recruitment of neutrophils, monocytes, and other blood elements to the wound site to prevent or contain infection, maintenance of hemostasis through alterations in coagulation, and induction of angiogenesis and cell proliferation to issue adequate healing may all be cytokine mediated (226). TNF, for example, has been shown to induce microvascular angiogenesis, bone remodeling, and fibroblast proliferation (226). IL-1 induces procoagulant activity, collagenase activity, and collagen synthesis. Further, it has been shown to stimulate osteoclastic activity, which may be important in bone remodeling during injury (226). In situations where the injury is more severe, and particularly if extensive devitalization is present, excessive production of cytokines at the wound site results in their entrance into the systemic circulation that can often be measured. When this situation occurs, a variety of metabolic aberrations have been shown to occur. Release of IL-6 into the circulation appears to play a prominent role in many of these metabolic effects. Paramount among them is its induction of the acute phase response (229). This response is characterized by the reprioritization of hepatic synthesis and release of certain proteins into the blood during inflammation and sepsis and following severe injury (230). Thus, albumin and transferrin, which are normally important proteins synthesized by the liver, are reduced in favor of a number of acute phase proteins whose plasma concentrations increase substantially (sometimes as much as 10–1000-fold) (231). Examples of such proteins include C-reactive protein, a2 macroglobulin, a1 acid glycoprotein, amyloid, and fibrinogen. The physiologic role of many acute phase proteins is unknown, while emerging evidence has shown that others act as opsonins, influence coagulation mechanisms, and contain generalized tissue destruction. Acute phase proteins that possess antiprotease activity can significantly reduce tissue destruction from dead or dying cells. Similarly, fibrinogen can elicit thrombus formation to prevent bleeding in wounded tissue. It would appear, therefore, that an important role for the acute phase response is to set into motion a variety of survival mechanisms to contain the injury and/or associated infection and restore homeostasis (232).

Metabolic Response to Starvation, Stress, and Sepsis

27

Other cytokines that also have been shown to induce the acute phase response in the liver include TNF and IL-1 (226,233,234). Their role appears to be less important, and certainly less sustained, than that of IL-6. An explanation for this is the different half-lives of these cytokines. The half-life of TNF is 20 minutes or less whereas that of IL-1 is approximately six minutes (225). In contrast, IL-6 levels in the circulation are detectable within an hour after injury, reach peak levels within four to six hours, and can be sustained for a week or more (225). It may be that these three cytokines interact to initially induce the acute phase response and that IL-6 keeps it sustained. Because glucocorticoids also regulate hepatocyte biosynthetic activity, it has been proposed that such substances may be important cofactors to IL-6 and other cytokines in inducing and modulating the acute phase response (232). In support of this hypothesis is the finding that IL-6, TNF, and IL-1 stimulate the hypothalamic–pituitary–adrenal axis to secrete ACTH and glucocorticoids (235). Thus, there is likely to be a feedback mechanism involving glucocorticoids and cytokines (236,237). It is well known that injury and inflammation induce a metabolic response in skeletal muscle that results in net catabolism. Thus, amino acids released from skeletal muscle catabolism are preferentially taken up by the liver for gluconeogenesis and protein synthesis (especially acute phase proteins), as needed. Although the preponderance of evidence suggests that glucocorticoids are the major mediator of muscle proteolysis, various cytokines may also be involved (232). In differing models of sepsis, IL-1, TNF, and IL-6 have all been shown to stimulate muscle-protein breakdown (238–240). It would appear, therefore, that regulation of muscle-protein degradation following stress or injury is a multifaceted response. Conceivably, glucocorticoids may orchestrate the primary role, but cytokines may modulate this response in specific settings (232,241). During massive tissue destruction or endotoxemia, for example, cytokines may play a key role, whereas in other conditions such as starvation or differing forms of stress, glucocorticoids play the central role. An interesting effect of cytokines on protein catabolism is that induced by TNF. Chronic excessive production of this cytokine can lead to a state of profound cachexia (hence, its other name, cachectin). Administration of TNF to rodents induces nitrogen loss, decreased food intake, depletion of body lipid stores, and excessive weight loss (242–244). In a mouse model, tumors secreting TNF can cause profound weight loss and cachexia (245). IL-1 has also been shown to induce cachexia (242). Whether TNF or IL-1 are responsible, either alone or in combination, for the cachectic state observed in many cancer patients remains to be elucidated. TNF is also thought to be the primary mediator of many of the systemic manifestations of endotoxemia. In various animal models, administration of this cytokine in high doses can induce fever, tachypnea, tachycardia, hypotension, and death, not dissimilar to that observed in patients in septic shock (226). Pathologic findings are also characteristic of those reported in human septic shock, including pulmonary congestion, intestinal infarction, and adrenal necrosis (246). Other effects of cytokines include reductions in iron and zinc levels, which are commonly observed in septic patients. Both TNF and IL-1 have been shown to elicit these effects, which may actually confer a survival benefit by inhibiting the growth of various microorganisms and limiting the production of oxygen radical formation, both of which

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Part One: General Considerations

depend on trace metals (226). Finally, interferon-gamma can upregulate the number of TNF receptors on various cells, particularly monocytes. Although this interferon is primarily an immune modulator with antiviral activity, its TNF-related action may enhance cytotoxicity of devitalized tissue and thereby aid in the hearing of wounded tissue (226). It seems clear that cytokines play a major role in the metabolic response to injury and stress that is just now being unraveled. As our knowledge of this role is clarified, modulation of these substances and their physiologic and pathophysiologic mechanisms should prove beneficial in altering responses that are detrimental to recovery and survival.

SUMMARY Starvation, stress from injury or surgical procedures, and sepsis induce a series of metabolic changes that are regulated by neuroendocrine reflexes and cytokines and result in mobilization of substrates from endogenous tissue stores. These metabolic changes ensure that energy is available for vital functions, oxygen delivery is maintained, and reparative processes take place. An understanding of these complex metabolic interactions depends on an appreciation of normal homeostasis and the distribution of body water, proteins, fat, and carbohydrates. The role of each component of body tissue is important in periods of starvation, stress, and sepsis, especially when the ability to replenish endogenous food stores is impaired as a result of either the inability to consume adequate nutrients or the excessive consumption of tissue stores. The mechanisms described in this chapter illustrate the complexity of the metabolic response to stress, the interrelationships between the neuroendocrine responses, cytokine release and substrate mobilization and use, and the importance of adequate energy and tissue stores for survival and repair of the organisms under conditions of nutrient deprivation.

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178. Siegel JH, et al. Physiological and metabolic correlations in human sepsis. Surgery 1979; 86:163. 179. Frawley JP, Artz CP, Howard JM. Muscle metabolism and catabolism in combat casualties. Arch Surg 1955; 71:612. 180. Bilmazer C, et al. Quantitative contribution by skeletal muscle to elevated rates of whole-body protein breakdown in burned children as measured by 3-MEH output. Metabolism 1978; 27:671. 181. Williamson OH, et al. Muscle-protein catabolism after injury in man, as measured by urinary excretion of 3-methyl histidine. Clin Sci Mol Med 1977; 52:527. 182. Ryan NT. Metabolic adaptations for energy production during trauma and sepsis. Surg Clin North Am 1976; S6:1073. 183. Elwyn DH, et al. Interorgan transport of amino acids in hemorrhagic shock. Am J Physiol 1976; 231:377. 184. Engel FL. The significance of the metabolic changes during shock. Ann NY Acad Sci 1956; 55:383. 185. Clowes GHA, Randall H, Cha C. Amino acid and energy metabolism in septic and traumatized patients. JPEN 1980; 4:195. 186. Dale G, et al. The effect of surgical operation on venous plasma free amino acids. Surgery 1977; 81:295. 187. Woolfe LI, Groves AC, Moore JP. Arterial plasma amino acids in patients with serious postoperative infections and in patients with major fractures. Surgery 1976; 79:283. 188. Askanazi J, et al. Muscle and plasma ammo acids following injury. Ann Surg 1980; 192:78. 189. Birkhain RH, et al. Effects of major skeletal trauma on whole body protein turnover in man measured by L-[l,14C]-leucine. Surgery 1980; 88:294. 190. Long CL, et al. Muscle protein catabolism in the septic patient as measured by 3-methyl histidine excretion. Am J Clin Nutr 1977; 30:1349. 191. Stein TP, et al. Changes in protein synthesis after trauma: importance of nutrition. Am J Physiol 1977; 233:E348. 192. O’Donnell TF, et al. Proteolysis associated with a deficit of peripheral energy fuel substrates in septic man. Surgery 1976; 80:192. 193. Clowes GHA, et al. Muscle proteolysis induced by a circulating peptide in patients with sepsis or trauma. N Engl J Med 1983; 308:545. 194. Baracos V, et al. Stimulation of muscle protein degradation and prostaglandin E2 release by leukocyte pyrogen (interleukin-1). N Engl J Med 1983; 308:553. 195. Tiao G, Fagan J, Roegner V, et al. Energy-ubiquitin-dependent muscle proteolysis during sepsis in rats is regulated by glucocorticoids. J Clin Invest 1996; 97:339. 196. Hobler SC, Williams AB, Fischer D, et al. Activity and expression of the 20S proteasome are increased in skeletal muscle during sepsis. Am J Physiol 1999; 277:R434. 197. Tawa NE Jr, Odessey R, Goldberg AL. Inhibitors of the proteasome reduce the accelerated proteolysis in atrophying not skeletal muscles. J Clin Invest 1997; 100:197. 198. Schrier RW, Berl WT, Anderson RJ. Osmotic and nonosmotic control of vasopressin release. Am J Physiol 1979; 236:F321. 199. Stephens RV, Randall HT. Use of a concentrated, balanced, liquid elemental diet for nutritional management of catabolic states. Ann Surg 1969; 170:642. 200. Levenson SM, Green RW, Taylor FH. Ascorbic acid, riboflavin, thiamine and nicotinic acid in relation to severe injury, hemorrhage and infection in the human. Ann Surg 1946; 124:840. 201. Lund CC, Levenson SM, Green RW. Ascorbic acid, thiamine, riboflavin and nicotinic acid in relation to acute burns in man. Arch Surg 1947; 55:557. 202. Cuthbertson DP. Interrelationships of metabolic changes consequent to injury. Br Med Bull 1954; 10:33–37. 203. Moore FD. Metabolic Care of the Surgical Patient. Philadelphia: WB Saunders, 1959. 204. Hunt TK, Van Winkle W. In: Hunt TK, Dunphy JE, eds. Fundamentals of Wound Management. New York: AppletonCentury-Crofts, 1979:2. 205. Levenson SM, Seifter E, Van Winkle W. In: Hunt TK, Dunphy JE, eds. Fundamentals of Wound Management. New York: Appleton-Century-Crofts, 1979:286.

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206. Moore FD, Brennan ME. Manual of Surgical Nutrition, by the Committee on Pre- and Post-operative Care of the American College of Surgeons. Philadelphia: WB Saunders, 1975:169. 207. Daly JM, et al. Does wounded tissue regulate hepatic glucose production. Surg Forum 1987; 38:23. 208. Forster J, et al. Glucose uptake and flux through phosphofructokinase in wounded rat skeletal muscle. Am J Physiol (Endocrinol Metab 19) 1989; 256:E788. 209. Caldwell MD. Carbohydrate and energy metabolism in healing wounds. In: Barbul A, et al., eds. Growth Factors and Other Aspects of Wound Healing: Biological and Clinical Implications. New York: Alan R Liss, 1988:183. 210. Morris A, et al. A macrophage-mediated factor that increases the high energy phosphate content of skeletal muscle. J Surg Res 1985; 38:373. 211. Morris A, et al. Macrophage interaction with skeletal muscle: potential role of macrophages in determining the energy state of healing wounds. J Trauma 1985; 25(8):751. 212. Morris AS, et al. The role of purine metabolism in the macrophage mediated increase in high energy phosphates in skeletal muscle. J Surg Res 1986; 41:339. 213. Caldwell MD. Local glutamine metabolism in wounds and inflammation. Metabolism 1989; 38(suppl 1):34. 214. Goodson WH, Hunt TK. Studies of wound healing in experimental diabetes mellitus. J Surg Res 1977; 22:221. 215. Spanheimer RG, Umpierrez GE, Stumpf V. Decreased collagen production in diabetic rats. Diabetes 1988; 37:371. 216. Yue EK, et al. Effects of experimental diabetes, uremia, and malnutrition on wound healing. Diabetes 1987; 36:295. 217. Rosenberg CS. Wound healing in the patient with diabetes mellitus. Nurs Clin North Am 1990; 25:247. 218. Ehrlich HP, Hunt TK. Effects of cortisone and vitamin A on wound healing. Ann Surg 1968; 167:324. 219. Hunt TK, et al. Effects of vitamin A on reversing the inhibitory effect of cortisone on healing of open wounds in animal and man. Ann Surg 1969; 170:633. 220. Salmela K, et al. The effect of local methylprednisolone on granulation tissue formation. Acta Chir Scand 1980; 146:541. 221. Seifter E, et al. Arginine: an essential amino acid for injured rats. Surgery 1978; 84:224. 222. Barbul A. Arginine: biochemistry, physiology and therapeutic implications. J Parenter Enter Nutr 1986; 10:227. 223. Skottner A, et al. Anabolic and tissue repair functions of recombinant insulin-like growth factor l. Acta Paediatr Scand (Suppl) 1990; 367:63. 224. Hassett J, Border JR. The metabolic response to trauma and sepsis. World J Surg 1983; 7:125. 225. Lin E, Lowry SF, Calvano SE. Mediators of inflammation and injury. In: Norton JA, Bollinger RR, Chang AE, et al., eds. Surgery: Scientific Basis and Evidence-Based Practice. New York: Springer-Verlag, 2001:69–94. 226. Fong Y, Lowry SF. Cytokines and the cellular response to injury and infection. In: Wilmore DW, et al., eds. ACS Surgery: Principles and Practice. New York: Wed MD, 2002:1603–1622. 227. Fink MP. The role of cytokines as mediators of the inflammatory response. In: Townsend CM Jr, ed. Sabiston Textbook, of Surgery. Philadelphia: Elsevier Saunders, 2004:45–66.

228. Bessey PQ. Metabolic response to critical illness. In: Wilmore DW, et al., eds. ACS Surgery: Principles and Practice. New York: Wed MD, 2002:1495–1520. 229. Heinrich PC, Castell JV, Andus T. Interleukin-6 and the acute phase response. Biochem J 1990; 265:621. 230. Koj A. Definition and classification of acute phase proteins. In: Gordon AH, Koj A, eds. The Acute Phase Response to Injury and Infection. New York: Elsevier, 1985:139–147. 231. Kushner I. The acute phase response: an overview. Methods Enzymol 1988; 163:373. 232. Hasselgren PO. Protein metabolism in surgery. In: Norton JA, Bollinger PR, Chang AE, et al., eds. Surgery: Scientific Basis and Evidence-Based Practice. New York: Springer-Verlag, 2001:105–121. 233. Enayati P, Brennan MF, Fong Y. Systemic and liver cytokine activation. Arch Surg 1994; 124:1159. 234. Lin E, Calvano SE, Lowry SF. Cytokine response in abdominal surgery. In: Schein M, Wise L, eds. Cytokines and the Abdominal Surgeon. Austin: Landes, 1998:17–34. 235. Del Rey A, Besedovsky HO. Metabolic and neuroendocrine effects of pro-inflammatory cytokines. Eur J Clin Invest 1992; 22:10. 236. Besedovsky H, Del Rey A, Sorkin E, et al. Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science 1986; 233:652. 237. Hocke GM, Barry D, Fey GH. Synergistic action of interleukin6 and glucocorticoids is mediated by the interleukin-6 response element of the A2-macroglobulin gene. Mol Cell Biol 1992; 12:2282. 238. Zamir O, Hasselgren PO, Higashiguchi T, et al. Tumor necrosis factor (TNF) and interleukin-l (IL-1) induce muscle proteolysis through different mechanisms. Mediat Inflamm 1992; 1:247. 239. Zamir O, Hasselgren PO, Kunkel S, et al. Evidence that tumor necrosis factor participates in the regulation of muscle proteolysis during sepsis. Arch Surg 1992; 127:170. 240. Goodman MN. Interleukin-6 includes skeletal muscle protein breakdown in rats. Proc Soc Exp Biol Med 1994; 205:182. 241. Mealy K, van-Lanschot JJ, Robinson BG, et al. Are the catabolic effects of tumor necrosis factor mediated by glucocorticoids? Arch Surg 1990; 125:42. 242. Fong YM, Moldawer LL, Marano MA, et al. Cachectin/TNF or IL-1 alpha induces cachexia with redistribution of body proteins. Am J Physiol 1989; 256:R659. 243. Tracey KJ, Wei H, Manogue KR, et al. Cachectin/tumor necrosis factor induces cachexia, anemia, and inflammation. J Exp Med 1988; 167:1211. 244. Moldawer LL, Anderson C, Gelin J, et al. Regulation of food intake and hepatic protein synthesis by recombinant-derived cytokines. Am J Physiol 1988; 254:G450. 245. Oliff A, Defeo-Jones D, Boyer M, et al. Tumors secreting human TNF/cachectin induce cachexia in mice. Cell 1987; 50:555. 246. Tracy KJ, Beutler B, Lowry SF, et al. Shock and tissue injury induced by recombinant human cachectin. Science 1986; 234:470.

2 Pathophysiology of Fluid and Electrolyte Disorders Peter J. Fabri and Mark Bloomston

controlled by active systems that are under homeostatic (nervous or hormonal) control. Thus the composition of this open, extracellular system can be maintained within relatively tight limits (1). Nonstandard entrance routes, such as the administration of fluids intravenously, bypass the normal entry control mechanisms and directly add water and solute to the extracellular space. In this circumstance, the intrinsic ability of the excretory systems to maintain osmotic and ionic stability becomes the limiting factor in maintaining ionic stability and composition of the extracellular space. Failure of these excretory control mechanisms, by inability to either conserve or increase loss, threatens the chemical stability of the extracellular fluids. The intracellular space, on the other hand, is a closed space and is represented by the numerous cells floating within the extracellular water in Figure 1. The only route of entrance and exit is across the semipermeable cellular membrane and its contained enzyme systems. Therefore, extracellular space can be thought of as a conduit and buffer zone to the intracellular space. Only by transfer from or to the extracellular water can intracellular composition be changed. This complex system, richly furnished with active transport mechanisms and buffer zones, rigidly protects the stability of the body fluids and maintains constancy of

INTRODUCTION The human body can be likened to a sac of electrolyte-rich fluids in which is suspended or dissolved a complex network of solids known collectively as ‘‘organs.’’ The common medium of these fluids is water; the electrolytes are a mixture of primarily monovalent and divalent ions. The total volume of water, known as total body water, accounts for approximately 60% of total body mass. Substances are continually added to and excreted from this aqueous environment, and only through a system of homeostatic, protective mechanisms is the composition and distribution of this fluid-based system maintained. Disease, pharmaceuticals, and medical interventions all have the potential to disrupt the balance of this fluid medium and result in clinically evident fluid and electrolyte disturbances. To achieve the desired goal of preventing or treating such disturbances, the nature, composition, and interrelationships of these fluids and the homeostatic mechanisms that maintain them must be clearly understood.

MAINTENANCE OF THE INTERNAL MILIEU Total Body Water Water is the universal solvent of the human body. The total volume of this substance is subdivided into discrete parts known as intracellular, extracellular, and transcellular water (Fig. 1). These parts are separated by semipermeable membranes equipped with energy-consuming, work-producing pumps that are usually based on an adenosine triphosphatase (ATP-ase) enzyme system. These pumps are able to maintain electrochemical and concentration gradients across membranes, which result in a marked difference in composition between the intracellular and extracellular spaces. Water, on the other hand, passively follows the laws of osmotic and ionic equilibrium. It traverses these membranes freely to maintain an equal number of solute molecules (osmolality) and ionic particles (tonicity) per unit volume on each side of such semipermeable membranes. This difference between the control of solutes/ions and that of water results in marked differences in volume and electrolyte composition of the two spaces. The normal balance can be disturbed by changing the number of solute molecules on either side of the membrane (e.g., hypoalbuminemia and hyperglycemia) or by disrupting its enzyme-based pumps (e.g., shock and digitalis). The extracellular space can be considered an open system in that the alimentary tract serves as a mode of entrance and exit of water and solute, as shown in Figure 1. Similarly, the lungs, kidneys, and skin also serve as excretory conduits. Entrance and excretion of water and solute are

Figure 1 Conceptualized model of the human body. Note that everything enters into, is excreted from, and is sampled in extracellular water.

33

34

Part One: General Considerations

Table 1 Normal Distribution of Body Water as Percent of Body Weight

Total body water Extracellular water Intracellular water a

a

Men (%)

Women (%)

60 15 45

55 15 40

Values are less than equivalent for men because women have a relatively greater amount of adipose tissue.

the internal milieu. Although not depicted accurately in our model, two-thirds of total body water is intracellular and one-third is extracellular. This translates to about 40% and 20% of total body weight for the intracellular and extracellular compartments, respectively (Table 1).

Extracellular Water The extracellular space is composed of the intravascular space (blood cells plus plasma) (comprising about 8% of total body weight) and the extravascular space (interstitial fluid and lymph). Cerebrospinal fluid is a specialized subspace of extracellular fluid. The vascular and extravascular spaces are in relative continuity, separated only by the rather permeable basement membranes of the blood vessel walls. When these vessels are intact, the formed cellular elements of the blood remain contained in the intravascular space, whereas the aqueous, noncellular plasma undergoes continuous ‘‘filtration’’ through the relatively leaky vessel walls into the extravascular space. The extravascular space, however, is continuously ‘‘drained’’ by a system of lymphatic channels that return protein-rich extracellular fluid to the vascular space through the lymphatic ducts. This continuous-cycle system results in moment-to-moment renewing of the interstitial, pericellular space, bringing fresh nutrients from and carrying waste products to the vascular space, which is in direct continuity with normal routes of intake and excretion. The volume of intravascular fluid (blood) is determined by the oncotic effect of blood cells and large molecules such as albumin, as well as the rate of return of lymph. The volume of the extravascular fluid space depends on the balance between ‘‘filtration’’ of plasma and ‘‘drainage’’ of lymph. Plasma is continuously filtered across the vascular pores, particularly at the capillary level. The rate of filtration is governed by Starling’s law, which takes into account net hydrostatic pressure, net oncotic pressure, and pore size (reflectance and permeability). Fluid shifts across the vascular membrane are controlled by the summed effect of hydrostatic and oncotic pressures. Hydrostatic pressure exists in both the vessel (mean capillary pressure) and the tissue (mean tissue pressure). The difference results in a vector force that typically acts to drive fluid into the extravascular space. Simultaneously, this vector is offset by an oncotic pressure vector, which is the net difference between plasma oncotic pressure and tissue oncotic pressure adjusted for a permeability factor (reflectance) that varies as the ‘‘size’’ of the pores changes. Ordinarily, these vectors, on the average, tend to cancel, and there is only a small flux of fluid across the membrane. However, alteration in any of the main forces can lead to marked derangement in fluid distribution and the development of increased interstitial fluid, a condition recognized as clinical edema. The balanced forces in Starling’s equation result in the passage of fluid across the vascular membrane into the interstitial (extravascular) space. Not addressed in Starling’s equation is the ‘‘drainage’’ effect of the lymphatic system that tends to remove filtered plasma

from the interstitium. Obstruction of lymphatics by conditions such as tumor and infection can further impair fluid clearance and result in localized edema or lymphedema.

Osmolality and Tonicity The composition of extracellular water is reflected by the concentration of solutes. Ordinarily, extracellular composition is maintained within narrow limits by accurate renal control mechanisms [e.g., antidiuretic hormone (ADH) and aldosterone]. These control mechanisms, however, tend to respond to the concentration of a given substance rather than to the total amount of all substances. Concentration represents the combined effect of the amount of a given substance (numerator) dissolved in a given amount of water (denominator). Thus abnormalities in concentration may represent changes in the amount of solute, amount of water, or both. The concentration of total solute is most easily measured by plasma osmolality (mOsm/kg). This value indicates the ratio of solute to water in the plasma and in the extravascular space. Because extracellular water is in equilibrium with intracellular water, shifts of membrane permeable water result in maintenance of osmotic equality throughout total body water. In other words, accumulation of intracellular solute is compensated by a shift in water from the extracellular space to the intracellular space until osmolality is equal and vice versa. The concentration of total ions, indicating ionic strength, is approximated by assessing the concentration of the principal extracellular cation, sodium. Changes in sodium concentration represent changes in tonicity, a term related to but not synonymous with osmolality. Typically, tonicity and osmolality change together, and hyperosmolality usually includes hypertonicity (2). However, any substance that has a low molecular weight and a sizable concentration will contribute to serum osmolality. Thus conditions such as hyperglycemia, azotemia, hyperlactatemia, and accumulation of ethanol, which add solute but not ions, will raise osmolality without a change in tonicity. The contributing factors to osmolality can be understood more clearly by determining the osmolal gradient. This represents the difference between calculated (Osm[c]) and measured (Osm[m]) osmolality. Calculated osmolality is estimated by the formula Osm½c
¼ 1:86½Na
þ Glu=18 þ BUN=2:8 where Na is serum sodium concentration in mequiv/L, Glu is serum glucose in mg/100 mL, and BUN is blood urea nitrogen in mg/100 mL. [1.86 is twice the osmotic activity coefficient of a monovalent ion; 18 is the molecular weight of glucose divided by 10 (a correction factor to convert mg/dL to mg/L); and 2.8 is the molecular weight of urea nitrogen divided again by the correction factor 10.] Ordinarily the osmolal gradient is less than 10 mOsm/kg where Osmolal gradient ¼ Osm½m
 Osm½c
A gradient greater than 10 mOsm/kg represents the accumulation of some unmeasured, osmotically active (low molecular weight) substance such as lactate, ethanol, or mannitol. A common error in clinical practice is to assume that a change in measured osmolality represents an increase or decrease in water. As might be anticipated, osmolality is a concentration term and therefore can be disrupted by a change in amount of solute (e.g., azotemia) or amount of water (e.g., dehydration) or both (e.g., hyperosmolar coma).

Chapter 2:

Table 2 Electrolyte Composition

Total body content (mequiv/kg) Exchangeable content (mequiv/kg) Intracellular concentration (mequiv/L) Plasma water concentration (mequiv/L) Serum concentration (mequiv/L)

Na

K

Cl

Ca

Mg

67

58

42

940

32

41

44

30

–

–

10

160

3

2

26

152

5

110

5

3

142

5

103

5

–

Because measured osmolality equals the ratio of solute molecules to water: Osm ¼ solute=water By rearrangement, the amount of solute determines the osmolality multiplied by total body water (which can be estimated as 60% of total body weight), as shown by the formula: Solute ¼ Osm  0:6  wt Estimation of this variable allows assessment of changes in total body solute, and, by comparison, permits an appraisal of relative changes in body water versus body solute.

Electrolyte Composition As previously indicated, intracellular and extracellular fluids vary in concentration of electrolytes. The total body content of each electrolyte (3) has been estimated by direct assay (4) and by radionuclide exchange (exchangeable ion) (5–7). The distribution of these electrolytes is unequal and results in marked concentration differences throughout the body (Table 2). Most of the difference between total body content (gravimetric) and exchangeable content is accounted for as substance in bone. As a glance at Table 2 will confirm, and contrary to the impression gained from evaluating serum electrolytes, the content of total exchangeable sodium (Na) is roughly equal to the content of total exchangeable potassium (K). The sum of these ions (exchangeable Na þ K) validly estimates total body cations that are roughly equally divided between intracellular and extracellular water. Accordingly, the serum sodium concentration (or conversely the intracellular potassium concentration) represents the ratio of total body cations to total body water, as shown below: Na ðserumÞ ¼ ðNa þ KÞ=ð0:6  wtÞ By a process analogous to osmolality, cross-multiplying serum sodium concentration by an estimate of total body water yields total body exchangeable cations. An estimate, therefore, of total body water, total body solute, and total body cations allows a more detailed serial assessment of fluid and electrolyte balance for patients in whom derangements are suspected.

HOMEOSTATIC CONTROL MECHANISMS General Concepts The kidney is the cornerstone of the homeostatic mechanisms controlling fluid and electrolyte balance. Although it is true that fluid losses from the skin, lungs, and gastrointestinal (GI) tract may be impressive, the kidney is the

Pathophysiology of Fluid and Electrolyte Disorders

35

only part of the system that is able to ‘‘control’’ its output. Accepting that fact, it is helpful to think of renal homeostasis as ‘‘throwing the baby out with the bath water, and catching the baby before it goes down the drain.’’ In other words, glomerular filtration, the frontline initiator of renal excretion, is relatively nonspecific. It only limits excretion of substances that are associated with large proteins and therefore too big to pass through the renal vascular pores. Glomerular filtrate, therefore, is an ultrafiltrate of plasma. This ultrafiltrate passes through the proximal tubule where approximately 95% of most solutes and water are reabsorbed. In effect, control of excretion to this point is really a question of ‘‘what isn’t reabsorbed.’’ Final modification of urinary composition takes place in the distal tubule and collecting duct, where sodium is, in a matter of speaking, ‘‘exchanged’’ for hydrogen or potassium and the remaining water is either reabsorbed or not (8–11).

Sodium and Water Homeostasis Intracellular water is in equilibrium with extracellular water through osmotic and ionic neutrality. A small gradient is accounted for by anion proteins, which results in a concentration inequality referred to as the Gibbs–Donnan distribution. Extracellular water is controlled largely by plasma volume and serum sodium concentration. Sodium and water conservation must be considered together because their control mechanisms are inseparable. Water deficits or excesses are compensated by changes in ADH release from the pituitary, and its effects within the renal collecting duct (12–14). Changes in sodium composition are accompanied by both ADH and mineralocorticoid responses. A decrease in plasma volume stimulates baroreceptors located in sites such as the right atrium and carotid body, as well as in the juxtaglomerular apparatus and macula densa of the kidney (15). The baroreceptor response results in an increase in ADH release from the posterior pituitary and causes decreased loss of solute-free water in the collecting duct of the kidney. Conversely, as the serum sodium concentration falls, ADH release will be inhibited, and further water conservation will be blunted. The simultaneous effects of decreased glomerular filtration leading to decreased sodium delivery to the juxtaglomerular apparatus results in renin release, which subsequently causes cleavage of angiotensinogen into the decapeptide angiotensin I. This latter substance is converted in the lung to the octapeptide angiotensin II by the angiotensin-converting enzyme (ACE). Angiotensin II is a very potent vasoconstrictor that also directly stimulates aldosterone release from the zona glomerulosa of the adrenal cortex. The resultant increase in circulating aldosterone increases sodium reabsorption in the distal tubule of the kidney, in exchange for potassium and/or hydrogen ions. As serum sodium concentration changes, release of ADH from the posterior pituitary is altered by osmoreceptors in the hypothalamus. Very small changes (e.g., 2 mOsm) can predictably result in a measurable change in plasma ADH levels. Corresponding changes in thirst perception and in the permeability of the collecting duct of the kidney to water also occur. In the case of hypernatremia, thirst increases, and maximum retention of solute-free water occurs in the kidney. This can be corroborated by a high measured urine osmolality (usually >500 mOsm). During hyponatremia, ADH release is inhibited, the stimulus for water conservation in the collecting duct ceases, and solute-free water (‘‘free water’’) is excreted, resulting in hypotonic (< 280 mOsm/kg) urine and a return of serum sodium to normal. In addition, the zona glomerulosa

36

Part One: General Considerations

of the adrenal appears to be sensitive to changes in serum sodium concentration, resulting in feedback control of aldosterone release.

Potassium Homeostasis Control of serum potassium levels is quite unlike that of sodium. Sodium is controlled at both the intake and excretion level, whereas potassium intake is unregulated. Potassium, then, is controlled entirely by excretion. Potassium is primarily an intracellular ion, with a concentration many fold greater than plasma. Yet, the extracellular concentration is extremely important in maintaining electrochemical gradients across cell membranes that facilitate depolarization of electrically active cells such as cardiac muscle and specialized conduction cells. Therefore control of extracellular potassium is vitally important. Typically, mammalian diets contain very large amounts of potassium, such that conservation of potassium is not usually a problem unless losses are excessive (diuresis and diarrhea) or renal mechanisms are abnormal (hyperaldosteronism). Potassium conservation and excretion tends to be a direct contrast to sodium conservation. Excess potassium, for example, stimulates the release of aldosterone from the adrenal, whereas too little sodium would result in the same response (16,17). While the majority of potassium reabsorption (like sodium) occurs in the proximal tubule, it is excreted in the distal tubule in response to the aldosterone stimulus. Sodium can be reabsorbed almost entirely within the nephron, whereas potassium conservation is less complete until profound body deficits occur. Distal tubular flow rate is also a major factor in potassium homeostasis. As flow rates increase, potassium excretion becomes inappropriately high. Although total body potassium distribution is greatly affected by renal mechanisms, it is also subject to exchange mechanisms at the cell surface of all cells such that, as sodium (or hydrogen) is transported out, potassium reenters the intracellular fluid (probably insulindependent). Likewise, in severe acidosis or alkalosis, plasma potassium levels may change as a result of the fluxes of potassium that are consequent to the hydrogen ion shifts.

Calcium Homeostasis The majority of calcium in the human body is complexed within the rigid crystal lattice of bone. This phase of calcium hydroxyapatite and phosphate is in equilibrium with three other forms of calcium: protein-bound, ionic complex, and ionic. Only the latter, ionic calcium, is physiologically active. In normal physiology, this very small amount of calcium is responsible for a large number of functions, including extracellular, transcellular, and intracellular communication; coordination of protein structure, including clotting factors; electrical triggering of active cells, such as myocytes; second messenger function together with calmodulin; activation of enzymes; and many others. Because of the many life-critical functions of calcium, its concentration is very tightly controlled and the cell is capable of functioning normally in an environment with little calcium intake. Consequently, normal homeostatic mechanisms do an admirable job at maintaining calcium-dependent physiologic processes in a wide variety of situations. Said another way, clinical abnormalities of calcium metabolism are very rare except in specific circumstances. Normal laboratory measurement of calcium assays all three components of nonbone calcium, yet only the ionized fraction is active. Numerous nomograms and algorithms have attempted to allow the physiologic fraction to be estimated based on serum protein concentrations, but

recent studies suggest that such estimates have little clinical utility and that ionized calcium must be measured to identify clinical hyper- or hypocalcemia. Calcium in the serum is regulated by the interplay of two hormones, parathyroid hormone (parathormone, PTH) and 1,25 dihydroxyvitamin D3. Calcitonin, which is important in other animal species, has not been identified as being of importance in calcium homeostasis in humans. PTH is produced as a very large macropeptide, undergoes posttranslational cleavage to the smaller 84–amino acid peptide, and is released by the parathyroid glands. The parathyroid glands, in turn, have calcium receptors (CaR), which recognize the level of ionized calcium in the extracellular fluid within the parathyroids. Even a small decrease in ionized calcium produces an immediate increase in PTH release and, if of long duration, hyperplasia of the parathyroids themselves. Similarly, a small increase in ambient calcium turns off PTH release and, if of long duration, regression of the parathyroids. This increase in PTH increases the mobilization of calcium from bone, increases the resorption of calcium in the renal tubule, and enhances excretion of phosphate in the renal tubule. Additionally, prolonged increase in PTH elevation induces an increase in hydroxylation of vitamin D in the kidney. 1,25 dihydroxyvitamin D3 increases the absorption of both calcium and phosphate from the intestine. A second hormone, parathyroid hormone–related peptide, homologous with PTH, is often produced in tumors, particularly squamous cell neoplasms, and leads to tumoral hypercalcemia. This must be distinguished from an alternative form of malignancy-related hypercalcemia seen in advanced disease where the tumor is actively invading the bone, leading to osteoclast and osteoblast mobilization and subsequent hypercalcemia. Hypercalcemia can also be produced by diseases that cause an increase in active vitamin D, such as lymphoma, granulomatous diseases including sarcoidosis, and excessive intake of vitamin D in the diet or supplements. When a patient is identified with hypercalcemia, the urgency of correction must be established. Mild hypercalcemia or intermittent hypercalcemia rarely produces physiologically important abnormalities or even symptoms and therefore does not require management. Calcium levels above 12 mg/dL have traditionally been considered urgent, requiring aggressive treatment, and above 14 mg/dL, as a medical emergency (hypercalcemic crisis). Saline diuresis and inhibition of bone resorption with biphosphonates or calcitonin is the mainstay of treatment. Hypercalcemia, if persistent, produces a physiologic equivalent of nephrogenic diabetes insipidus, resulting in volume loss and hypernatremia, with the symptoms of polydypsia and polyuria. Treatment with fluids alone will correct the electrolyte abnormalities but will not correct the underlying cause of the hypercalcemia (18). Hypocalcemia is often seen in critically ill individuals and in individuals who have hypoalbuminemia. Because serum calcium levels are often measured in the basic metabolic panel used in hospitalized patients, the treatment of hypocalcemia as an electrolyte problem is often considered. Current evidence suggests that the hypocalcemia seen in hospitalized patients (except hypoparathyroidism following thyroid or parathyroid surgery) is almost never of clinical significance and does not require treatment. Furthermore, evidence is accumulating that PTH release and responsiveness of the CaR are altered as part of the acute injury response, suggesting that hypocalcemia is actually a programmed component of acute injury (19).

Chapter 2:

In the final analysis, ionized calcium is very tightly controlled and is not often a fluid and electrolyte issue. Treatment of asymptomatic hypocalcemia does not appear to be needed and may even be detrimental. Although the discovery of hypercalcemia clearly requires the establishment of a diagnosis, mild hypercalcemia also does not usually require treatment as a fluid and electrolyte issue unless the calcium level is greater than 12 mg/dL.

Acid/Base Conservation With the exception of several specialized body fluids, the pH of body water is very closely guarded in a narrow range. Normal plasma pH (7.4 0.05) generally is representative of the pH of total body water, although the pH of fluids such as cerebrospinal fluid and intracellular fluid may transiently diverge from that of plasma because of differing controlling factors and influences. For practical purposes, however, the pH of all compartments of body water can be assumed to be equal. To appreciate the intricacies of acid/base balance, a solid understanding of the basic chemical concepts of acids, bases, and dissociation is essential. Acids are substances that have the capability of donating protons (hydrogen ions and hydronium ions). Bases, conversely, are substances that have the ability to accept protons during chemical reactions. Both acids and bases are ionic compounds that, when dissolved in water, have the ability to dissociate into cationic and anionic species. For most organic acids and bases in the body, dissociation is only partial, and the ratio of dissociated to nondissociated forms is determined by the dissociation constant. Acids, when dissociated, contribute hydrogen ions (Hþ) and a corresponding anion (An) to the total ionic composition of the solution. Bases typically contribute a cation and a hydroxyl (OH) ion. A typical acid (or base) dissociation can be described by the chemical reaction: HAn ¼ Hþ þ An: The dissociation constant is determined by the ratio of products to reactants; therefore: K ¼ ½Hþ
½An
=½HAn
; where the brackets represent concentration in solution. Taking the logarithm of both sides of this equation results in a useful and familiar form of the dissociation equation: logK ¼ log Hþ þ logð½An
=HAn
Þ pK ¼ pH  logð½An
=½HAn
Þ pH ¼ pK þ logð½An
=½HAn
Þ: The dissociation constant (and consequently the pK) takes into account the simultaneous equilibrium of water. In the human, many acid/base pairs (buffer pairs) exist in simultaneous equilibrium. This means that the ambient pH of the body determines the ratio of anion to dissociated acid for a number of acids present in the body. Although substances such as phosphoric acid, proteins, and amino acids are all present in abundance and could be used as estimates of acid/base status, the carbonic acid/bicarbonate buffer system is most commonly used for this purpose. Bicarbonate is not the major buffer in the human body (pKa ¼ 6.1). In fact, hemoglobin and proteins make up the bulk of the buffering capacity (maintenance

Pathophysiology of Fluid and Electrolyte Disorders

37

of pH within narrow limits). The reason for measuring the bicarbonate/carbonic acid component of the buffer system is clear. Again, the organic acids and bases in extracellular water are in equilibrium with each other, so any pair could be used to evaluate acid/base status. The major homeostatic mechanisms of acid/base control are pulmonary (the excretion of carbon dioxide) and renal (the conservation of bicarbonate and excretion of hydrogen ions). Consequently, this buffer pair reflects the efficacy of the homeostatic mechanisms that are operative in compensating for changes in the gain or loss of acid or base. In addition, bicarbonate and carbon dioxide (pCO2) are easily measured in plasma. The general dissociation equation, when applied to the bicarbonate/carbonic acid buffer system, is known as the Henderson–Hasselbach equation: pH ¼ 6:1 þ logð½HCO 3
=½H2 CO3
Þ; where [HCO 3 ] is the concentration of bicarbonate and [H2CO3] is the concentration of carbonic acid. Because the concentration of carbonic acid is determined by the partial pressure of carbon dioxide, and the solubility of carbon dioxide in water is 0.03 pH ¼ 6:1 þ logð½HCO 3
=0:03 pCO2 Þ and ½Hþ
¼ 24ðpCO2 =½HCO 3
Þ: Current technology allows the direct measurement of pH and pCO2 in arterial (or venous) blood, enabling the estimation of bicarbonate concentration by the above equation. Alternatively, measurement of bicarbonate concentration and pH would enable calculation of pCO2. In normal circumstances, the ratio of [HCO 3]/0.03 pCO2 is 20/L. Other electrolytes enter the body pool only by ingestion (or injection), but acids (and bases) are rarely present in the diet. Acid is a product of metabolism of other substances and is added to total body water as a function of the rate of metabolism and the fractional use of acidproducing metabolites (Table 3). In general, net acid production is approximately 1 mequiv/kg/day (2 to 3 mequiv/kg/day in infants) and is primarily caused by the production of sulfuric acid from metabolism of thiols; phosphoric acid from metabolism of organic phosphates; and other organic acids from the metabolism of proteins, carbohydrates, and fats. Any addition of base (e.g., antacids) or compounds that generate base (e.g., citrate and lactate) will tend to offset the daily endogenous acid load. Table 3 Physiologic Factors Affecting Plasma Acidity Through plasma bicarbonate changes Rate of hydrogen ion input Rate of hydrogen ion or bicarbonate loss (gastrointestinal) Availability of buffers Bicarbonate space of distribution Rate of net renal acid excretion

Through plasma pCO2 Rate of carbon dioxide production Rate of alveolar ventilation

38

Part One: General Considerations

To maintain acid/base equilibrium, the body must excrete a quantity of acid equal to endogenous production (plus any exogenous acid and minus any exogenous base). This is accomplished primarily by renal excretion of fixed acid in the form of phosphates and ammonia. Ammonia is actively produced by metabolism of glutamine in the kidney and subsequently excreted into the renal tubular lumen. Simultaneously, monohydrogen phosphate is filtered at the glomerulus. Hydrogen ions, filtered or secreted, are trapped by the buffering capability of these two proton acceptors and excreted. In addition, through a carbonic anhydrase– dependent system, the tubular epithelial cell is capable of generating a hydrogen ion and a bicarbonate ion from carbonic acid (dissolved carbon dioxide) and reabsorbing the bicarbonate while the hydrogen ion is excreted. This regenerates the bicarbonate pool and facilitates acid/base stability. If the bicarbonate pool becomes excessive, renal excretion of bicarbonate is increased by a complex mechanism dependent on the decreased hydrogen ion in the tubular fluid. In effect, therefore, the kidney is able to directly influence acid excretion by three mechanisms: excretion of phosphate (affected by glomerular filtration and parathyroid hormone), synthesis of ammonia, and control of the directional flow of bicarbonate. The last of the three mechanisms just enumerated requires further comment. Because of the ready availability of carbon dioxide and water (and consequently carbonic acid), the kidney, through carbonic anhydrase, can control the abundance of hydrogen ions and bicarbonate. By directing the excretion of hydrogen ions into the tubular lumen and the return of bicarbonate to plasma, the kidney has a great capacity to excrete acid and control base levels. Only when the renal mechanisms responsible for reabsorption of base or excretion of acid are compromised does the renal contribution to acid/base balance become limited. In normal circumstances, the rate at which the kidney returns bicarbonate to the body is equivalent to the rate of sodium/hydrogen exchange in the distal tubule. Although the proximal tubule is quantitatively the most important site of bicarbonate reabsorption in the kidney, with a small contribution from the loop of Henle, the distal segment is capable of ‘‘fine-tuning’’ the acid/base excretory balance.

Acute Injury Response Since the discovery of interleukin-1 in 1981, we have continued to learn about the system of cytokines and chemokines, which mediates what is often called the ‘‘acute injury response.’’ Current evidence suggests that the macrophage reacting to surface receptor signals from infectious agents, allergens, trauma, chemokines, and other agonists initiates a vigorous biochemical response leading to a cascade of interrelated events that alter metabolism, body temperature, cellular response, hepatic protein synthesis, and renal handling of fluid and electrolytes (20). More recent evidence suggests that many, if not all, of the observations usually referred to as ‘‘sepsis’’ can actually be explained by the human response to activation of a cell receptor (toll-like receptor). This would imply that what historically has been considered to be an effect of gram-negative endotoxin may actually be the host response to the presence of chemical substances (lipopolysaccharide from the cell wall) rather than a toxic effect of the substances themselves. The impact on fluid and electrolyte balance appears to be primarily mediated by a ‘‘nonphysiologic’’ release of ADH and mineralocorticoids. This increase in the substances that control the reabsorption of salt and water in the distal portion of

the nephron results in decreased renal excretion (often manifested as oliguria) in an attempt to protect the volume and composition of extracellular water. The recognition of the importance and ubiquity of this acute injury response may result in a change in our methods of intravenous fluid therapy as we more fully understand the significance of this hormonal response to injury.

Effect of Medications It is beyond the scope of this chapter to address specific effects of drugs used in clinical practice. It is nevertheless important to recognize that commonly used pharmaceutical agents can produce significant fluid and electrolyte abnormalities. One hundred fifty-two separate drugs are identified as having hyponatremia as a major side effect. These are broadly categorized as agents that cause loss of sodium in the kidney (e.g., diuretics) or that enhance the retention of water in the renal collecting duct [e.g., syndrome of inappropriate antidiuretic hormone (SIADH)]. Hypokalemia is also commonly produced by drugs. Loop-active diuretics, amphotericin B, and drugs producing metabolic alkalosis are commonly responsible. It is prudent to consider the possibility of an adverse drug effect early in the course of evaluating new onset fluid and electrolyte abnormalities (21–24).

PATHOPHYSIOLOGY AND TREATMENT OF SPECIFIC ELECTROLYTE AND ACID/BASE ABNORMALITIES To understand abnormalities of electrolyte homeostasis, some attention must be given to normal daily requirements (Table 4) (25). Although it is true that a state of electrolyte balance requires that intake be equal to losses (and losses can be minimized), realistically there will be daily excretion of electrolytes of a fairly predictable magnitude, allowing a range of estimated daily needs. Under normal conditions, water losses occur primarily through urinary excretion, evaporation from the skin, and water losses through the lungs. The latter two sources are referred to as insensible losses because they are not visible or readily measurable and amount to 500 to 800 mL [300 mL/m2 body surface area (BSA)] of water daily, with almost negligible amounts of sodium and chloride. Urine is the major sensible loss (one that is visible and measurable) and averages between 1200 and 1500 mL of water daily, with 10 to 30 mequiv of sodium and 20 to 60 mequiv of potassium. Another sensible loss is water loss through the feces, which is usually quite minimal. Losses greater than those routinely encountered (e.g., diarrhea) will result in corresponding increases in requirements; increases in normal excretion rates (e.g., renal failure) will necessitate a reduction in intake.

Abnormalities of Water Balance Disturbances in the amount and distribution of total body water are common in clinical practice. Because water Table 4 Adult Daily Requirements Normal Water (total) Water (insensible) Sodium Potassium Chloride Calcium Magnesium Source: From Ref. 25.

2

1500 mL/m 500 mL/m2 0.7–3.6 mequiv/kg 0.7–2.1 mequiv/kg 0.7–3.6 mequiv/kg 0.4–1.1 mequiv/kg 0.3–0.7 mequiv/kg

Minimal 870 mL/m2 – 0.3 mequiv/kg 0.3–0.5 mequiv/kg 0.3 mequiv/kg 0.2 mequiv/kg 0.2–0.4 mequiv/kg

Chapter 2:

distributes throughout the body, restricted in its movement only by osmotic and ionic barriers, abnormalities in amount, with maintenance of normal electrolyte concentrations (i.e., isotonic), are frequent. An isotonic increase in total body water results in edema, whereas an isotonic decrease produces clinical dehydration. Because electrolyte conservatory mechanisms are extremely efficient, deviation from isotonicity is uncommon except at the extremes of age, when compensatory mechanisms are less adequate or access to water or salt is restricted. In infants and the elderly, therefore, hypertonic (sodium > 145 mequiv/L) and hypotonic (sodium < 135 mequiv/L) abnormalities are more common and require that attention be given to the volume as well as the concentration problems. It is important to realize that isotonic abnormalities in total body water are more prevalent than other fluid derangements in adults, only because compensatory mechanisms maintain the concentration of important solutes. In circumstances where a coexistent problem compromises these compensatory mechanisms (e.g., renal disease, inappropriate ADH secretion, diuretic use, and adrenal insufficiency), a superimposed fluid loss or gain may very well not be isotonic. Dehydration is an absolute decrease in total body water and usually represents a balanced loss between intracellular and extracellular volume. Dehydration can be assessed on clinical grounds alone, and in fact, there is no readily available ‘‘test’’ that identifies dehydration unless there is a coexistent abnormality of concentration. Blood urea nitrogen and consequently osmolality are frequently elevated, however, and may be supportive of the diagnosis when the creatinine concentration is normal and the blood urea nitrogen/creatinine ratio is greater than 20. Up to a 5% decrease in total body water can escape clinical detection, without appropriate suspicion by history. Thirst is usually present, however, and is an accurate sign of water deficit. Losses greater than 5% usually lead to conditions such as sunken eyes, loss of skin turgor with tenting of presternal skin, and dry mucous membranes. Greater than 10% dehydration will commonly demonstrate hemodynamic changes with tachycardia and postural hypotension. Treatment of dehydration requires an understanding of the composition of the fluid deficits. Isotonic dehydration reflects a loss of all fluid compartments (and their contained electrolytes) and is corrected by intravenously infusing a balanced salt solution such as Ringer’s lactate (Table 5). Concomitant abnormalities in concentration or tonicity are best assessed by the serum sodium concentration; such electrolyte abnormalities should be treated simultaneously with management of the volume deficit. For example, in hypernatremic dehydration (Table 5), water alone as 5% dextrose in water is used for replacement of the water deficit and a balanced salt solution, for volume restoration. The appropriate intravenous fluid should be administered to correct one-half of the estimated abnormality over 24 hours. This

39

Pathophysiology of Fluid and Electrolyte Disorders

approach is used because most deficits develop over a period of days or weeks and the patient has usually adjusted to them. Rapid replacement of losses may actually impose a greater risk than the deficit itself. Edema can be related to an underlying disease (cardiac, renal, or hepatic) or, as is common in modern practice, to abundant or excessive intravenous fluid administration. Excesses in extracellular fluid typically are susceptible to gravity and hence are most pronounced in dependent areas. Conditions such as pretibial and ankle edema are common in the upright patient. Presacral edema or pitting of the skin overlying the iliac crest is more likely in the recumbent patient. Water intoxication represents a specific abnormality of water balance. Ordinarily, large amounts of ingested or administered water can be excreted quantitatively, without a resultant volume excess or ionic dilution. Very marked amounts, however, particularly in a setting of compromised homeostatic mechanisms, can result in edema, hyponatremia, and dilution of other electrolytes as well (for a further discussion, refer to section on hyponatremia). Treatment of fluid excess requires an understanding of the cause and an assessment of the integrity of homeostatic mechanisms, particularly renal, hepatic, and central nervous system (CNS) function. In the setting of normal compensation, simple fluid restriction or decreased administration is likely to be effective. When simultaneous abnormalities in renal, hepatic, adrenal, or cardiac physiology exist, careful attention to intake and output (an ‘‘accountant’’ approach) is indicated. Only by specific accounting of all volumes, concentrations, and amounts can aggravation or creation of abnormalities be prevented.

Abnormalities of Sodium Because sodium is the major cation within extracellular water and is regularly analyzed in the laboratory, it is surprising that abnormalities in sodium concentration are not discovered more frequently. Although hypernatremia and hyponatremia are seen, they are rigorously prevented by compensatory mechanisms within the kidney. In fact, very small changes in sodium concentration (and subsequently osmolality) result in a measurable change in ADH release in the same direction. When renal concentrating mechanisms are defective (2) (e.g., wash out of renal medullary concentration gradient as with diuretics, partial tubular dysfunction from incipient or resolving acute tubular necrosis, or massive sodium loss in interstitial nephritis), abnormalities in serum sodium are more common.

Hyponatremia Virtually all acute, stressful situations (e.g., infection, anesthesia, and surgery) are accompanied by release of ADH and conservation of free water (26,27). This homeostatic mechanism is very effective in preserving extracellular volume, when combined with sodium conservation, which

Table 5 Composition of Common Solutions Used for Intravenous Therapy Solutions 5% Dextrose and water 0.9% Sodium chloride (normal saline) 0.45% Sodium chloride (half-normal saline) 3% Sodium chloride (hypertonic saline) Lactated Ringer’s solution

Glucose (g/L)

Na (mequiv/L)

Cl (mequiv/L)

HCO3 (mequiv/L)

K (mequiv/L)

Ca (mequiv/L)

50 – – – –

– 154 77 513 130

– 154 77 513 109

– – – – 28a

– – – – 4

– – – – 2.7

Exists in solution as lactate and is ultimately metabolized to bicarbonate (HCO3).

a

40

Part One: General Considerations

depends on a decrease in perfusion pressure or delivered sodium at the juxtaglomerular apparatus (28,29). Consequently, hyponatremia in adult patients at the time of admission for elective surgery is distinctly uncommon. However, once a patient has received intravenous administration of hypotonic fluids (e.g., 0.45% saline), the inability to excrete the ‘‘free’’ water due to an obligatory ADH release will frequently result in a dilutional decrease in serum sodium to some degree. When hyponatremia is present, spurious causes must be excluded. This is accomplished most simply by evaluating the serum osmolality. Because osmolality measures the amount of solute per ‘‘mass’’ of water instead of volume, it is independent of the amount of water in a volume of serum. Normally, serum is 94% water. Increases in protein or lipid concentrations can, however, alter the amount of water and lead to an analytic error in sodium determination. Osmolality is not affected so. Consequently, hyponatremia in the setting of normal osmolality would raise the suspicion of paraproteinemia (e.g., multiple myeloma and macroglobulinemia) or hyperlipidemia. Alternatively, an increase in an extracellular solute such as glucose (or mannitol) causes a shift in water from the intracellular to extracellular space, to conserve osmotic equality. This results in a subsequent ‘‘dilution’’ of extracellular sodium, but a maintained osmolality because of the presence of another osmotically active substance, glucose. Identification of hyperglycemia in the setting of normal osmolality will explain a fall in sodium levels of approximately 1.6 mequiv/L for each 100 mg/100 mL rise in blood sugar above normal. When true hyponatremia does occur (low sodium plus low osmolality), evaluating how the kidney is behaving allows a rational interpretation of the probable pathophysiology. A careful assessment of overall fluid and electrolyte status (weight change, input and output summaries, presence or absence of edema, etc.) is essential (30). Characterizing the patient as ahead or behind in volume by clinical assessment allows appropriate interpretation of the renal response, which is best ascertained by measuring the urinary osmolality and sodium concentration. During active sodium conservation, urinary sodium is typically low (< 5 mequiv/L). This indicates either that there is a true deficit in sodium or that the kidney ‘‘thinks’’ there is one. The latter occurs when circulating substances (e.g., aldosterone) are inappropriately present in edematous states such as cirrhosis and chronic congestive heart failure (28,31). In each of these settings, however, the patient is edematous and probably has ascites. In the absence of either of these findings, true sodium depletion is probably present. Sodium administration should be guided by an estimate of the deficit, which must be considered independently of (added to) volume deficits that are isotonic (Na ¼ 140 mequiv/L). The sodium deficit approximates 0.6 mequiv/kg per milliequivalent fall in serum sodium. Unless neurologic symptoms are present, which would mandate urgent treatment, the sodium replacement should take 24 to 48 hours. After one-half of the deficit has been replaced, serum electrolyte levels should be rechecked. When urinary sodium is increased (>20 mequiv/L), simple sodium depletion can be excluded. Sodium conservation either will not or cannot take place. This occurs in the setting of abnormal ADH release, adrenal insufficiency, severe hyperthyroidism, recent use of diuretics, or intrinsic renal tubular dysfunction as in renal failure or interstitial nephritis. This can be clarified by measuring urinary osmolality.

Because the normal response to hyponatremia and hypo-osmolality is excretion of solute-free water (or dilute urine), the finding of a urine osmolality above that of serum, plus hyponatremia, indicates an abnormal ADH response (27,32). This implies a continued release of ADH in spite of a hypo-osmolar state. If this is present at the time of admission or in the absence of intravenous fluids, it implies a CNS abnormality (e.g., head trauma and intracranial tumor) or an ectopic site of production (e.g., bronchogenic carcinoma). In the patient receiving hypotonic fluids, this finding more commonly reflects the release of ADH associated with a central ‘‘acute phase response’’ or ‘‘systemic inflammatory response’’ to stress or illness. In either event, fluid balance will be ‘‘ahead’’ as is the total amount of sodium in the body. The hyponatremia means that water is ‘‘more ahead’’ than sodium. This paradoxic increased total sodium in the face of decreased serum sodium concentration results in a high urinary sodium excretion (>20 mequiv/L) and a high salt excretion fraction (>5%) (33). The finding of isosthenuria (urine osmolality equals serum osmolality) implies intrinsic renal dysfunction or pharmacologic dysfunction from diuretics. The finding of low urine osmolality and high urine sodium, however, suggests that ADH release is appropriately terminated, but that sodium is not being conserved. This situation is seen in mineralocorticoid insufficiency. Laboratory evaluation of the renal response to hyponatremia can be enlightening but does not replace clinical assessment. Because hyponatremia means either a decrease in sodium or an increase in water, appropriate interpretation of readily available data should allow discrimination. A decrease in sodium requires the presence of a route of loss and usually is associated with weight loss. Alternatively, an increase in water should be manifested by a gain in weight and excess fluid intake over output. In the patient who is not receiving intravenous fluids, a serum sodium below 135 mequiv/L constitutes hyponatremia and deserves investigation. In the patient who is receiving hypotonic fluids, however, mild hyponatremia is common enough to be expected. Although it is not normal, mild hyponatremia down to 130 mequiv/L can probably be ignored. A sodium level of 125 to 130 mequiv/L justifies vigorous diagnostic efforts to identify the cause. A serum sodium level of 120 to 125 mequiv/L necessitates vigorous institution of appropriate therapy. A sodium level of less than 120 mequiv/L is a medical emergency and frequently requires careful administration of hypertonic saline for correction. It is not the low sodium per se that is detrimental, but rather the increase in the intracellular fluid compartment, which accompanies this circumstance. This intracellular volume increase is especially detrimental to brain cells because the brain is contained within a fixed space with little or no room for expansion. When brain cells swell, an increase in intracranial pressure ultimately develops and presents clinically as a variety of manifestations, including apathy, confusion, weakness, nausea, and occasionally vomiting. If this water intoxication is not corrected, it will ultimately lead to convulsions, stupor, and possibly even death. When hyponatremia occurs in the setting of brain injury or intracranial surgery (particularly for cerebral aneurysms), the term ‘‘cerebral salt wasting’’ is often applied (34). The hypothesis is that humoral substances are released from the injured brain, either directly or as a result of the injury, which leads to an excessive loss of sodium in the kidney (35). More recent studies question whether this is actually a specific syndrome, or whether it is a manifestation

Chapter 2:

of increased ADH release in patients who have received very large amounts of isotonic crystalloid solutions. Although it is not clear which explanation is correct, it is certainly true that hyponatremia occurs in neurosurgical patients and that this hyponatremia may be multifactorial. Central to appropriate treatment is the assessment of actual fluid status (hypervolemia vs. hypovolemia) and a decision whether to administer fluids containing a high concentration of sodium or to restrict the amount of water being administered. In the absence of objective evidence of a sodium deficiency, it may be more appropriate to restrict water intake, as in the syndrome of increased ADH release, seen both in SIADH and in the acutely injured patient.

Pathophysiology of Fluid and Electrolyte Disorders

41

the very narrow range of normal potassium concentration in plasma and the relatively massive adjacent intracellular pool (5) (with exchange influenced by variables such as pH and drugs) make control of serum potassium both important and tenuous. This importance is underscored by the critical nature of severe potassium abnormalities on the cardiac, neural, and muscular systems and evidenced by the diligent monitoring of potassium concentrations, which occurs in operating suites and intensive care units. An understanding of the common circumstances leading to potassium abnormalities will facilitate maintenance of normal homeostasis and simplify treatment of abnormalities (16).

Hyperkalemia Hypernatremia The body rigorously defends itself against hyperosmolality. Even a small rise results in increased ADH release and subsequent free-water retention by the kidney, unless, of course, ADH release cannot occur (e.g., diabetes insipidus), ADH is ineffective (e.g., nephrogenic diabetes insipidus), or the patient is denied access to water (e.g., infants, geriatric patients, and unconscious or restrained patients). A simple review of the clinical situation will often identify the cause. Because hypernatremia implies either an increase in sodium or a decrease in water, both must be considered. An increase in sodium can result from aggressive administration of normal saline or sodium bicarbonate. A decrease in water can occur by renal or extrarenal mechanisms. Nonrenal causes should be clinically apparent and include such symptoms as diarrhea and excessive sweating. In addition to the forms of diabetes insipidus (pituitary dysfunction or nephrogenic), renal sources must include osmotic diuresis with obligatory ‘‘free-water’’ loss. In all cases, treatment is simple. Administration of hypotonic solutions will restore sodium concentration, and, when sodium excess is a component, judicious diuretic use will hasten sodium excretion. Care in treating hypernatremia must be exercised, however, because a rapid change in sodium concentration is of greater clinical importance than the actual sodium concentration (36). Too rapid a correction of sodium abnormalities can result in dramatic CNS effects, including seizures secondary to rapid changes in intracellular volume. Accordingly, treatment should be planned to correct one-half of the estimated deficit over 24 hours. In the case of hypernatremia, this usually translates into the administration of 2 mL of free water/kg over 24 hr for each milliequivalent of planned decrease in serum sodium concentration. In the patient with head injury or recent neurosurgical intervention with accompanying diabetes insipidus, unless actual hypophysectomy has been performed, early administration of vasopressin should be avoided. Careful replacement of losses will maintain fluid and electrolyte balance until the usually transient abnormality resolves. Accordingly, hypernatremia should be avoidable. If permanent diabetes insipidus is anticipated, however, administration of vasopressin or its synthetic analog, desmopressin acetate (DDAVP), should be instituted. Serious complications of diabetes insipidus (or inappropriate ADH secretion) are not a function of difficulty in treatment, but rather failure of recognition. Anticipation of such problems will greatly simplify their subsequent management.

Abnormalities of Potassium Because mammals usually ingest large amounts of potassium, it is not surprising that most abnormalities in potassium balance are the result not of intake, but of excretion. Further,

Because the kidney is the major site of potassium excretion, compromised renal function is almost always a factor contributing to hyperkalemia (9,11,13). Although increased potassium levels can occur from either excess intake or decreased excretion, the former is quite rare, is usually iatrogenic, and occurs in the setting of administering very large intravenous doses of potassium (or potassium-containing drugs such as penicillin) or giving potassium to a patient receiving a drug that inhibits potassium excretion (e.g., spironolactone, triamterene, and ACE inhibitors). Abnormalities of excretion are common and can be caused by intrinsic abnormalities of renal function (acute oliguric renal failure), disturbances in hormonal control of potassium exchange (hypoaldosteronism, adrenal insufficiency, etc.), or alterations in the potassium exchange mechanism per se (drugs, acidosis, etc.). Occasionally serum potassium is factitiously elevated (compared to plasma potassium) because of in vitro Kþ release from platelets during phlebotomy, in the setting of thrombocytosis (37). Hyperkalemia produces predictable clinical consequences that affect neuromuscular function (weakness, irritability, etc.) and cardiac conduction (peaking of T waves, prolongation of PR and QT intervals, widening of QRS complexes, and eventual heart block). Monitoring of the electrocardiogram provides a simple, noninvasive method of assessing change in the hyperkalemic or potentially hyperkalemic patient. Predictable changes, beginning with T-wave peaking, are the harbingers of subsequent complications, which are evidenced by alterations in the shape and duration of the major electrocardiogram complexes. Because hyperkalemia poses a life-threatening problem, urgent and definitive correction is imperative (17). A transient decrease in serum potassium can be accomplished by translocating extracellular potassium back into cells with glucose and insulin, and the membrane effects of hyperkalemia can be offset by the administration of calcium. In the rare patient with reasonable renal function and the need for a rapid decrease in serum potassium, a potassium diuresis can be induced by the use of loop-active diuretics. More commonly, potassium is removed from the body by the use of potassium-exchanging resins [sodium polystyrene sulfonate (Kayexalate)] that can be given by mouth or rectum and will predictably lower serum potassium. This is accomplished, however, through exchange with sodium and may alter fluid and sodium balance. Institution of peritoneal or hemodialysis is clearly the most effective, long-term approach to potassium control in the patient with renal compromise. It is important to remember, however, that continued administration of hypertonic glucose, as in parenteral nutrition, will result in a predictable and sustained fall in serum potassium because the egress of potassium associated with catabolism is prevented.

42

Part One: General Considerations

Hypokalemia Hypokalemia is a common electrolyte abnormality in both hospitalized and ambulatory patients (16,38). Although it may be precipitated by an underlying disease (mineralocorticoid excess as in Cushing’s syndrome, potassium loss from a colonic villous adenoma, potassium wasting in renal disease, etc.) or by decreased potassium intake (low-potassium diet), most hypokalemia is iatrogenic in that it is induced pharmacologically by agents having potassium wasting as a side effect (36,39,40). Most notable are the diuretic agents currently used in the management of hypertension and fluid overload. The loop-active agents in particular are associated with a substantial potassium loss in the urine. Other classes of drugs, however, can also induce hypokalemia (21,41). The recent increased use of amphotericin B in the treatment of immune-compromised patients has uncovered a profound and difficult-to-manage hypokalemia (42). Use of newer synthetic penicillins in ultrahigh concentration is also associated with increased renal potassium loss and subsequent hypokalemia. Hypokalemia may manifest itself in various ways (e.g., muscle weakness and paralysis). More frequently, however, hypokalemia produces myocardial irritability and subsequent arrhythmias such as frequent premature contractions, sustained tachycardias, and potentiation of digitalis toxicity. Although these complications are more feared than common, they are serious complications and justify both respect and careful monitoring. Treatment is simple. Administration of potassium as the chloride salt will correct the usual associated chloride-dependent alkalosis, decrease renal potassium loss, and correct the hypokalemia. Beware, however, because the degree of hypokalemia is very poorly correlated to the magnitude of potassium deficit. Therefore, strict guidelines for replacement are dangerous. Because the hazards of hypokalemia appear to be virtually eliminated by institution of treatment rather than total correction, the identification of the abnormality and institution of treatment are more important than the rapidity of treatment. Frequently, discontinuation of the offending drug or control of the underlying disease will be necessary for long-term potassium control.

Abnormalities of Chloride Because chloride is the most abundant anion in plasma and extracellular water, it is not surprising that its range of variation is large and its mechanism of variation somewhat passive. The high concentration of chloride in gastric juice accounts for the hypochloremia that accompanies the metabolic alkalosis of conditions such as gastric outlet obstruction, repetitive vomiting, and pyloric stenosis. Chloride is absorbed in large quantities from the gut, and its level is controlled by urinary excretion. Most reabsorption of chloride occurs in the proximal tubule of the kidney, in association with sodium reabsorption. A considerable component is also actively reabsorbed in Henle’s limb (43). Alterations in proximal tubule absorption (osmotic diuretics) or Henle’s limb (loop-active diuretics) can lead to hypochloremia and metabolic alkalosis. In addition, in the presence of ‘‘hormone-dependent’’ (e.g., aldosterone) alkalosis, the fraction of chloride that is reabsorbed is decreased. This interaction of chloride and bicarbonate is important in the evaluation of the patient with metabolic alkalosis. Chloride is present in abundance in GI secretions. Substantial chloride loss can result from GI fluid losses from the upper tract (e.g., gastric outlet obstruction) or lower tract

(e.g., diarrhea). Assessment of the chloride deficit provides complementary information in the evaluation of volume depletion, secondary to GI losses.

Abnormalities of Calcium The most important factor in assessing calcium as an electrolyte is that clinically important abnormalities are very, very rare and easily categorized into hypocalcemia caused by hypoparathyroidism and hypercalcemia caused by hyperparathyroidism, tumors, systemic diseases, and medications. Hypocalcemia is rarely of clinical importance, except following parathyroid and thyroid surgery, and therefore infrequently requires treatment. Hypercalcemia, when the serum calcium is greater than 12, can be treated with aggressive saline administration, loop-active diuretics to minimize the fluid overload, and biphosphonates to reduce resorption of calcium from bone. Identification of the specific cause of the hypercalcemia (by measurement of ionized calcium, PTH, parathyroid hormone related peptide (PHRP), and 1,25-dihydroxyvitamin D3) is necessary to effect long-term control of the calcium level (18).

Isolated Acid/Base Abnormalities The availability of routine measurement of ‘‘arterial blood gases’’ has resulted in a much clearer understanding of the nature and treatment of acid/base disturbances in clinical practice. On the basis of the normal physiologic determinants previously described and the pathophysiologic mechanisms that will be enumerated, acid/base disturbances can be classified into acidosis or alkalosis. Both of the categories can be further subdivided into metabolic and respiratory, as well as combined metabolic/respiratory. Tables, nomograms, and algorithms have been developed for the assessment of the excess or deficit of acid (or base) to assist the clinician in management. Unfortunately, all of these aids are of only limited practical value because of the concurrent and efficient efforts of the compensatory mechanisms of the body to correct the acid/base disturbance. In other words, the onset of a disturbance in pH (by change in either HCO3 or pCO2) results in very rapid initiation of respiratory and/or metabolic compensatory mechanisms to partially correct the pH. It is essential in planning the treatment of acid/base disturbances to keep this compensation in mind, lest overaggressive management result in new, iatrogenic acid/base disturbances in the opposite direction.

Acidosis As described previously, acidosis can occur by the absolute gain in acid or loss of base from the body. Because the buffering system of the body is ‘‘open’’ in the sense that the CO2/HCO 3 system uses both respiratory and renal control systems, all but the most acute form of acidosis will be combined with compensatory adjustments. Consequently, all respiratory disturbances will have a metabolic compensatory component, and metabolic imbalances will stimulate respiratory compensation. Frequently, the pH is remarkably well corrected, and only a careful review of the historical facts associated with the illness will allow a clear analysis of the inciting cause. Occasionally, the cause is so elusive that only by disturbing the system with exogenous alkali and observing the respiratory response (or lack thereof) will the primary problem become apparent.

Respiratory Acidosis Pure respiratory acidosis is the simplest of the acid/base disturbances conceptually, because it results from a decrease

Chapter 2:

in effective alveolar ventilation (relative to carbon dioxide production). Normal carbon dioxide production from metabolic processes is approximately 450 L/day (20,000 mmol). Whenever carbon dioxide elimination lags behind production, respiratory acidosis ensues. The consequent laboratory abnormalities include a decrease in pH and an increase in pCO2. It is important to consider the pH first, because compensatory hypercapnea (increase in serum pCO2) in the setting of profound metabolic alkalosis is not uncommon, particularly in patients receiving mechanical ventilation by an intermittent (synchronized intermittent mandatory ventilation, pressure support ventilation, etc.) modality. Once respiratory acidosis is identified, a differential consideration of causes must include central respiratory depression (e.g., narcotics and intrinsic CNS disease), mechanical causes of decreased ventilation and/or increased dead space (e.g., tension pneumothorax, hemothorax, and massive pleural effusions), or pathophysiologic causes of increased carbon dioxide production. The common causes of acute or chronic respiratory acidosis are summarized as follows: & & & & & &

Airway obstruction Respiratory center depression Neuromuscular defects Restrictive lung diseases Smoke inhalation Inadequate mechanical ventilation

Appropriate treatment logically follows identification of the underlying mechanism and may include ventilatory assistance to enhance alveolar ventilation to eliminate the retained carbon dioxide and thereby correct the acidic pH. Occasionally, respiratory acidosis is produced by an increase in carbon dioxide production, because of either marked increase in oxygen consumption (active rewarming after heart surgery) or alteration in the respiratory quotient (excessive administration of carbohydrate-based parenteral nutrition). Because the pCO2 is proportional to the ratio of carbon dioxide production and minute alveolar ventilation, pCO2 ¼ kðV CO2 Þ=ðV AlvÞ; recognition of a high pCO2 and a high minute ventilation should assist in identifying patients with excessive carbon dioxide production.

Metabolic Acidosis In marked contradistinction to respiratory acidosis, metabolic acidosis can result from a variety of causes that include the gain of metabolic acids above excretion rates or the loss of bicarbonate greater than its rate of regeneration (44–47). Again, clinical evaluation and elucidation of the underlying mechanism greatly simplifies the task of evaluating the data. Also, it is important to avoid jumping to a conclusion of acidosis on the basis of only a decrease in the bicarbonate concentration of the serum, because this finding may also represent a normal metabolic compensation for a respiratory alkalosis. As is true with all biologic systems, electrical neutrality is maintained in all fluid compartments throughout the body by balancing the total number of cations with the total number of anions. In the extracellular compartment under normal conditions, the concentration of the cation sodium roughly equals the sum of the concentrations of the anions, chloride and bicarbonate, except for a small anion gap of

Pathophysiology of Fluid and Electrolyte Disorders

43

12 2 mequiv/L. An increase in this gap can give an important clue concerning the cause of acidosis. Thus it is helpful to subdivide metabolic acidosis into those categories that manifest an increase in unmeasured anions (increased anion gap) and those that do not and subsequently have a normal anion gap (nonanionic gap). As a generality, metabolic acidosis associated with the accumulation of organic acid will have an associated increased anion gap, whereas that caused by a loss of bicarbonate will have a normal or decreased anion gap. The distinction is important. Although both causes may require replacement of bicarbonate to correct the acidosis, the former group will require correction of an associated metabolic abnormality, and the latter will require attention to the site of bicarbonate loss (e.g., fistula).

Increased Gap Acidosis Any metabolic acidosis that is caused by the accumulation of organic acid (which is not measured by routine electrolyte analysis) will have a calculated anion gap that is greater than normal (uremia, diabetic ketoacidosis, lactic acidosis, and drug ingestion/poisoning). In some circumstances, e.g., diabetic ketoacidosis, combined mechanisms are operative, and the component caused by ketoacids is proportional to the anion gap. The presence of an acidosis with an anion gap greater than 14 mequiv/L implies either ingestion of an organic substance or an endogenous metabolic abnormality. Of the four commonly ingested ‘‘toxins’’ (methanol, ethylene glycol, ethanol, and isopropanol) only methanol (formic acid) and ethylene glycol (oxalic acid) produce a metabolic acidosis. Ethylene glycol also produces oxaluria, whereas methanol ingestion usually produces rapid retinal blindness. Acetylsalicylic acid (aspirin) and paraldehyde can also produce metabolic acidosis if ingested in large amounts, although paraldehyde is no longer available in the United States. Endogenous production of organic acid in excess of excretory capacity is seen in uremia, diabetic ketoacidosis, and lactic acidosis. Each is usually identifiable by the company it keeps: acidosis caused by renal failure is associated with the clinical and metabolic abnormalities of uremia; diabetic ketoacidosis is usually seen in known diabetics and is associated with hyperglycemia, dehydration, and ketosis in urine and serum (48); lactic acidosis can be caused by a variety of clinical states, but usually represents some form of hypoperfusion, such as sepsis or trauma (49). Lactic acidosis is associated with an increase in lactate in the blood (>4 mequiv/L) and an altered ratio of lactate to pyruvate (>30:1) and other oxidation–reduction pairs [e.g., acetoacetate/ betahydroxybutyrate and reduced nicotinamide adenine dinucleotide (NAD)/oxidized nicotinamide adenine dinucleotide (NADH)]. The actual cause of the increased lactic acid concentration is impairment of electron-to-oxygen transfer and subsequent accumulation of NADH, which shifts the equilibrium of pyruvate and lactate in the direction of lactate. Lactate serves as a reservoir or ‘‘cul de sac’’ during periods of deficient electron-to-oxygen transfer. Restoration of NADþ levels results in a prompt conversion of lactate back to pyruvate. It is often erroneously assumed that lactic acid is part of the pathophysiology of ‘‘lactic acidosis,’’ whereas it is actually only a secondary biochemical consequence of the underlying oxidation–reduction disorder. It is a quantitatively useful test to confirm the diagnosis and estimate the magnitude, however. Because it is often included in the battery of tests known as ‘‘blood gases,’’ it is important to confirm that a metabolic acidosis with an increased anion gap is

44

Part One: General Considerations

present before suggesting a diagnosis of lactic acidosis, because lactate levels may be elevated in the absence of lactic acidosis. When lactic acidosis is present, attention needs to be paid to the underlying cause of the inadequate delivery of oxygen to tissues. It is also important to recognize that lactic acid may also be a component of the metabolic acidosis caused by diabetic ketoacidosis, methanol poisoning, and salicylate intoxication. Treatment of all forms of anion gap acidosis is both supportive (restore circulation, correct acidosis with bicarbonate, etc.) and specific (correct underlying abnormality). Bicarbonate should be given in adequate quantities to keep the pH above 7.2 and/or the bicarbonate level above 15 mequiv/L. Situations with ongoing tissue hypoxia may require substantial replacement, whereas transient problems such as postictal lactic acidosis usually correct themselves spontaneously. When bicarbonate is required, the bicarbonate deficit can be determined by a variety of formulas. An easy-toremember fact is that the bicarbonate space (apparent volume of distribution of the effective buffering system) corresponds roughly to one-half of total body water (approximately 30% of total body weight in kilograms). Thus:  HCO 3 deficit ¼ 0:3  wt  ð24  HCO3 Þ:

Usually one-half of the calculated deficit is replaced to avoid overcorrection, following which blood gases are repeated before infusing additional bicarbonate. In patients with compromised renal function and metabolic acidosis, it is important to remember that disorders associated with levels of potassium, magnesium, and phosphate are commonly found and should be sought. In lactic acidosis produced by hypovolemic shock, the treatment should focus on restoring circulation and perfusion, rather than on correcting the acidosis itself.

in conditions such as sepsis and hypovolemia) can be estimated by the following formula: pCO2 ¼ 1:5ðHCO 3 Þ þ D; where HCO3 is mequiv of HCO 3 and D is 8 2 mequiv/L. Recognition of this compensatory phenomenon will assist in preventing iatrogenic metabolic alkalosis from overtreatment with bicarbonate. It is also helpful to test whether the change in pCO2 is of an appropriate amount, because each increase or decrease of pCO2 of 10 torr should result in a change in pH in the opposite direction of 0.08.

Alkalosis As is the case with acidosis, alkalosis may be either respiratory or metabolic in origin. In contradistinction to acidosis, it is the metabolic component that is rather simple to define and correct, whereas respiratory alkalosis may have a myriad of causes.

Respiratory Alkalosis Respiratory alkalosis is probably the most common acid/ base disturbance in clinical medicine and can be induced by a multitude of underlying conditions. The pathophysiologic mechanism is excess alveolar ventilation above the requirements of carbon dioxide production. This abnormality typically represents some form of CNS overstimulation but may include as causes the factors summarized below: & & & & & &

Nonanion Gap Acidosis (Hyperchloremic) Causes of metabolic acidosis with a normal anion gap include bicarbonate loss, inability to excrete hydrogen ion, or administration of exogenous HCl or NH4Cl. Most commonly, there is either a recognized source of bicarbonate loss or an abnormality in the kidney (or adrenal). Recognized bicarbonate loss is usually from the GI tract distal to the pylorus and may include duodenal fistula, biliary drainage, pancreatic fistula, small intestinal fistula, ureterosigmoidostomy, and diarrhea. Intrinsic renal losses of bicarbonate include interstitial nephritis, renal tubular acidosis, adrenal insufficiency, hypoaldosteronism, and acetazolamide administration (50). Treatment of nonanion gap acidosis requires correction of the existing acidosis plus routine administration of a bicarbonate source on a regular basis. The dosage of bicarbonate required will depend on the underlying disease, its magnitude, and the need for dialysis. Guidelines for acute correction are the same as for anion gap acidosis: calculate the bicarbonate deficit (base deficit), estimate the bicarbonate space, and administer only as much as should correct one-half of the predicted deficit over a period of 24 hours. As indicated previously, compensation for metabolic acidosis is usual and is manifested as hyperpnea, tachypnea, nasal flaring, or even Kussmaul’s respiration. The degree of compensatory hyperventilation in a stable, chronic metabolic acidosis (as opposed to the acute changes seen

& & & &

Anxiety Fever Salicylate intoxication CNS disorders Intrathoracic processes Hypoxemia Hepatic insufficiency Gram-negative septicemia Pregnancy Mechanical hyperventilation

Treatment of respiratory alkalosis must be directed at correcting the underlying cause (e.g., correct fever with antipyretics). In patients requiring assisted ventilation, use of intermittent or partial ventilation systems will tend to minimize the overventilation that is often seen with controlled or assist/controlled ventilation. Other attempts at increasing pCO2, such as inspired carbon dioxide, rebreathing devices, and added mechanical dead space, are relatively ineffective.

Metabolic Alkalosis The fundamental abnormality in pure metabolic alkalosis is an absolute or relative excess of base (primarily bicarbonate) in extracellular fluid (44,51,52). This excess tends to be offset by a compensatory decrease in minute alveolar ventilation with subsequent hypercarbia. The mechanisms underlying metabolic alkalosis include the loss of hydrogen ion (with chloride), gain of exogenous base, or extracellular fluid–volume contraction. Identification of the latter two mechanisms should be straightforward by clinical evaluation, although gain of exogenous base may be masked as in blood or fresh frozen plasma transfusions (citrate is converted to bicarbonate) or excessive infusion of lactated Ringer’s solution.

Chapter 2:

The most common, clinically important forms of metabolic alkalosis are a result of loss of hydrogen ion and chloride from the stomach or hydrogen ion alone from the kidney. These two varieties can be separated by attention to the amount of chloride measured in the urine. Low urinary chloride ( 31 were found to have an eightfold higher rate of mortality following blunt trauma, frequently due to pulmonary complications (22). While controversial, hypocaloric feeding in the obese patient has also been suggested to lessen infectious complications secondary to hyperglycemia. Comparable nitrogen balance is achieved in this patient population when hypocaloric feeds are administered (23). Monitoring for clinical evidence of overfeeding (hypercapnea, hyperglycemia, insulin resistance, hypertriglyceridemia, diarrhea, and distention) is used to refine predictions. Obesity is defined as a BMI  30 (Table 3). Energy needs should be based on adjusted body weight (ABW) when actual body weight exceeds 120% of the ideal body weight (IBW) and is calculated as: ABW ¼ 0:25 ðactual body weight  IBWÞ þ IBW: The ABW takes into account the increased lean body mass seen in obese patients and should be used in the Harris–Benedict equation or in caloric predictions (kcal/kg) of energy needs. Obese patients experience a similar metabolic response to critical illness but tend to be more resistant to insulin. Obese patients should be started on nutritional support as early as their nonobese counterparts. Hypocaloric feeding provides the obese individual with high protein (1.5–1.75 g/kg ABW) but low total calories (20–25 kcal/kg ABW).

Nutrition After Bariatric Surgery Nutritional treatment for uncomplicated bariatric procedures is somewhat standardized across the country, although little evidence-based research has been performed in this patient population. Immediately after surgery, most programs begin clear liquids for several days, which are consumed in 30 cc/hr increments. This is followed by a progressive diet (advanced every two weeks) of full liquids, then pureed, soft foods, and finally a regular diet as tolerated. Maintenance goals are set at 1000 to 1200 kcal daily. Protein goals are typically 60 to 80 g protein/day, which may deliver as little as 0.48 g protein/kg ABW, which is less than the recommended daily intake of 0.8 g/kg body weight of protein. Liquid multivitamins with mineral supplements, iron, vitamin C, vitamin B12, and calcium may also be added. The amount of nutritional follow-up and level of expertise varies greatly between programs. For the majority of patients, a standard bariatric diet can be followed. However, patients who develop postoperative complications necessitating admission to the ICU will generally require an alternative feeding regimen. If the complication is intra-abdominal, particularly if secondary to an anastomotic leak, nutrition will usually be provided by the parenteral route, as enteral access (to the small bowel) will generally require operative placement. An initial goal of adjusted weight at 10 to 20 kcal/kg and protein at 1.5 g/kg can be instituted, depending on the degree of insulin resistance. Indirect calorimetry is helpful and, if performed, feeds should be instituted at 60% to 75% REE. A UUN can then be used as a guide to achieve positive nitrogen balance. Type 2 diabetes is a

Chapter 3: Surgical Nutrition

frequent comorbidity and strict glycemic control (glucose < 110 mg/dL) should be employed in all patients. Intravenous lipids are not provided in the first one to two weeks, and then provided sparingly to prevent essential fatty acid deficiency. Enteral support typically requires a specialized combination of a high-protein polymeric formula with the addition of a protein modular product. A liquid multivitamin and mineral supplement may also be added. Bariatric patients who experience delayed complications or significant remote illnesses can pose a challenge. Many of these patients have been on the bariatric diet for a prolonged period of time and may have some degree of protein malnutrition from a low-calorie, low-protein diet. Due to malabsorption, micronutrient deficits may be present and the refeeding syndrome is likely to occur. Organ function may also be compromised through body cell mass depletion, and immunocompetence decreased via protein malnutrition. Kilocalorie and protein requirements can be extraordinary, especially with large wounds such as necrotizing fasciitis or decubiti. However, the approach is similar to that taken with early postoperative complications. Indirect calorimetry, 24-hour UUN, and sequential monitoring of C-reactive protein and prealbumin should be employed. If renal failure occurs, continuous dialysis is typically employed to facilitate adequate feeding. Depending on the length of time since the original surgery and the adequacy of postoperative nutritional follow-up, the patient may exhibit varying degrees of protein, iron, zinc, calcium, folate, and B12 deficiency.

ENTERAL NUTRITION Benefits of Enteral Nutrition Three prospective randomized controlled trials (PRCTs) performed in the 1980s had significant impact on clinical practice in surgical, and particularly trauma ICUs (4–6). These single-institution trials all randomized trauma patients to early enteral nutrition or TPN and all demonstrated that patients receiving early enteral nutrition had significantly fewer infectious complications. A meta-analysis that

53

combined data from eight PRCT (six published, two not published) was then conducted to assess the nutritional equivalence of enteral nutriton compared to TPN in highrisk trauma and/or postoperative patients (24). Similar to the single-institution trials, fewer infectious complications developed in patients receiving enteral nutrition. Even when patients with catheter-related sepsis were removed from the analysis, a significant difference in infections between groups remained. Taken together, these trials provide convincing evidence that enteral nutrition is preferred to TPN in patients sustaining major torso trauma. A recent meta-analysis evaluating the effect of early versus delayed enteral nutrition in acutely ill (medical and surgical) patients also confirmed a decrease in infectious complications in patients receiving early enteral nutrition (25).

Role of Immune-Enhancing Agents in Surgical Patients Recent basic and clinical research suggests that the beneficial effects of enteral nutrition can be amplified by supplementing specific nutrients that exert pharmacologic immune-enhancing effects beyond the prevention of acute protein malnutrition. There are at least 18 PRCT (Table 6) and three meta-analyses (24,26,27) where an immuneenhancing enteral diet is compared with a standard enteral diet or no diet, and where the patient outcome was a predetermined end point. Of the 18 PRCTs, 11 trials demonstrated improved outcome, four trials were highly suggestive of improved outcome, and three trials did not demonstrate any clinical outcome advantage. The majority of trials are in trauma and cancer patients, though a few trials include mixed ICU and septic ICU patients. The proposed immune-enhancing agents include glutamine, arginine, omega-3 polyunsaturated fatty acids (PUFA), and nucleotides, though the individual contributions of each have not been well investigated. Glutamine is actively absorbed across the intestinal epithelium and then metabolized in the small bowel to ammonia, citrulline, alanine, and proline, and serves as an energy source for the

Table 6 Patient Outcome in Prospective Randomized Controlled Trials Comparing IEDs vs. Standard Enteral Diets Author

Year, Journal

Patient type (Number)

Gottschlich Daly Brown Moore

1990, 1992, 1994, 1994,

JPEN Surgery Pharmacotherapy J Trauma

Burns (50) Cancer (77) Trauma (37) Trauma (98)

Bower Daly Kudsk Senkel Mendez Saffle Heslina Braga Atkinson Weimann Senkel Braga Snyderman Galban

1995, 1995, 1996, 1997, 1997, 1997, 1997, 1998, 1998, 1998, 1999, 1999, 1999, 2000,

Crit Care Med Ann Surg Ann Surg Crit Care Med J Trauma J Trauma Ann Surg Crit Care Med Crit Care Med Nutrition Arch Surg Arch Surg Laryngoscope JPEN

Mixed ICU (296) Cancer (60) Trauma (35) Cancer (154) Trauma (43) Burns (50) Cancer (154) Cancer (154) Mixed ICU (369) Trauma (32) Cancer (154) Cancer (206) Cancer (129) Septic ICU (181)

a

Results with IED (decrease in) Wound infection, LOS Wound complication, infections Infections Intra-abdominal infection, multiple organ failure Infections, LOS Wound complications, infections, LOS Antibiotics, infection, LOS Late infections * ARDS

Infections, LOS Ventilator days, LOS SIRS, multiple organ failure Late infections Infections Infections Late infections

Improved outcome Yes Yes Yes Yes ? Yes Yes Yes Yes No No No Yes ? Yes ? Yes Yes Yes Yes Yes

Compared IED to no diet. Abbreviations: ARDS, adult respiratory distress syndrome; ICU, intensive care unit; IED, immune-enhancing diet; SIRS, systemic inflammatory response syndrome; LOS, length of stay.

54

Part One: General Considerations

enterocyte. Glutamine is therefore acknowledged to be the preferred fuel of the enterocyte, and stimulates lymphocyte and monocyte function. The demand for glutamine is increased during stressed states and supplementation at pharmacologic doses may be required. It also promotes protein synthesis, is a precursor for nucleotides as well as glutathione, and is thought to play a role in maintaining gut integrity. In a recent meta-analysis, glutamine (parenteral and enteral) administered to critically ill and surgical patients resulted in a lower mortality, less infectious complications, and shorter hospital stays (28). High-dose and parenteral glutamine had the greatest effect, though the study was not designed to examine these parameters. Additionally, a mixed patient population was included with limited (randomized) studies and clinical end points. A randomized trial of glutamine-enriched enteral nutrition in severely injured patients demonstrated a decrease in pneumonia, sepsis, and bacteremia (29). Arginine is a semiessential amino acid that is important for T-cell function and wound healing. Endogenous production is insufficient during periods of metabolic stress (such as illness) and exogenous supplementation is required for maximal function of the immune system. It is also a powerful secretagogue, increasing the production of growth hormone, prolactin, somatostatin, insulin, and glucagon. Additionally, arginine is the chief precursor of nitric oxide and has been shown to increase protein synthesis and improve wound healing (30). It is the association with nitric oxide production that has led to speculation that arginine may enhance the systemic inflammatory response and, therefore, be potentially harmful, particularly in septic patients (31). Sepsis increases levels of inducible nitric oxide synthetase (iNOS). Arginine is a substrate for iNOS, and in its presence arginine combines with molecular oxygen to produce citrulline and nitric oxide. The resulting nitric oxide could have numerous adverse effects in sepsis, including vasodilation, cardiac dysfunction, and direct cytotoxic injury by generating potent reactive oxygen species. Increased mortality has been demonstrated in some critically ill septic patients when receiving an immune-enhancing diet, and arginine has been implicated as the causative agent (32,33). Although traditional enteral products contain a high proportion of omega-6 PUFA, diets with a low omega-6 PUFA and high omega-3 PUFA content more favorably alter the fatty acid composition of membrane phospholipids toward reduced inflammation (34). Finally, nucleotides (purines and pyrimidines) are needed for DNA as well as RNA synthesis and may be necessary in stressed states to maintain rapid cell proliferation and responsiveness (35). In the setting of increased demand, most tissues can increase intracellular de novo synthesis of nucleotides. Lymphocytes, macrophages, and enterocytes, however, rely on increased salvage from the extracellular pool, which may be depleted during stress.

Contraindications to enteral nutrition can be divided into absolute and relative. Absolute contraindications would include functional complications such as bowel obstruction, peritonitis, progressive ileus, massive gastrointestinal hemorrhage, and gastrointestinal ischemia associated with shock and vasopressors. Relative contraindications include proven intolerance to enteral nutrition and intolerance associated with short-gut syndrome, high-output fistula, pancreatitis, and inflammatory bowel disease. A recent bowel anastomosis is not a contraindication. Laboratory data in fact suggests that healing may be hastened by early feeding (36).

Gastric Feeding Controversy exists as to the optimal site for delivery of enteral nutrients. Although there is a trend toward decreased ventilator-associated pneumonias with jejunal feeding, no significant differences have been demonstrated between postpyloric and gastric feeding (37–40). None of these studies, however, have been appropriately powered to demonstrate statistical significance. Additionally, a greater percentage of caloric goals are reached (37,41) and gastrointestinal complications are less frequent with postpyloric feeding. The stomach, but not the small bowel, commonly exhibits an ileus after surgery, major trauma, or other critical illnesses. Ritz et al. demonstrated that up to 45% of ventilated patients had delayed gastric emptying, impeding adequate delivery of gastric feeds (42). Several studies have shown that this can be modulated by the use of prokinetic agents (43,44). Erythromycin has a direct effect on the motilin receptors of the stomach and has been shown to improve the effectiveness of gastric feedings. Gastric feeding is appropriate for some surgical patients, particularly those farther out from their initial injury or insult. Prior to starting gastric feeds, however, patients should be screened for risk of aspiration (Table 7) (45). Aspiration is the second most common cause of nosocomial infection in hospitalized patients (46). The presence of an inflated endotracheal cuff does not preclude aspiration in intubated patients, as there is as high as a 50% to 75% incidence of aspiration in patients with endotracheal tubes and/or tracheostomies (47,48). Altered mental status, whether from dementia, sedation, or a closed head injury poses a risk as do neuromuscular disorders and stroke. Recent major abdominal surgery and the need for prolonged supine position can also increase the risk of aspiration. Persistently high gastric residual volumes have also been sited as a risk factor. What constitutes a high volume, however, has not been well defined. Approximately 1.5 L of saliva and 3 L of gastric secretions are produced daily and the stomach empties about a third to one-half of its contents hourly (49). Therefore, residual volumes approaching 500 cc/4 hr should be safe. To minimize the risk of aspiration, the head of the bed should remain elevated, oral care should be diligent,

Indications and Contraindications for Enteral Nutrition

Table 7 Factors Posing a Major Risk of Aspiration

Hospitalized patients who cannot adequately meet their nutritional goals by oral intake alone for a period of seven days should be considered for enteral supplementation. Additionally, early enteral nutrition should be considered for all acutely ill patients, such as patients with major torso trauma, chronically malnourished patients, and patients with limited physiologic reserve.

Endotracheal intubation Decreased level of consciousness Neuromuscular disorders or anatomical abnormalities of the upper gastrointestinal tract Recent stroke Recent major abdominal surgery Persistently high gastric residual volumes

Chapter 3: Surgical Nutrition

55

tolerance should be regularly assessed, narcotics minimized, electrolyte abnormalities corrected, and glucose control optimized. Numerous strategies have been employed to identify occurrences of aspiration. Use of food, drug, and cosmetic (FD&C) blue No. 1 and methylene blue as means of visual detection for aspiration has been associated with clinically significant toxicity and this practice is discouraged (50). Furthermore, the presence of glucose in the tracheal aspirate has been found to be neither a reliable nor specific indicator of enteral feeding aspiration.

more partially digested macronutrients or combinations of nutrients and can be absorbed in patients with compromised gastrointestinal tracts), and modular formulas (which are composed of individual nutrients or combinations of nutrients, but are nutritionally incomplete and intended for use as supplements or in combination with other products). Unfortunately, with the exception of the immune-enhancing formulas, very little comparative data exists to guide clinicians in selecting the most appropriate formula. A recommended formula selection is reviewed in Table 9.

Obtaining Enteral Access

Administration of Feeds

Access can be divided into gastric (and duodenal) and jejunal with push, endoscopic, radiologic, and surgical options available (Table 8). For patients to be fed through an intragastric approach, a soft, nonsump nasogastric tube can be placed. For patients known to require long-term feeding access, a percutaneous endoscopic gastrostomy (PEG) can be obtained. For those patients identified as candidates for jejunal feeds, access can be obtained at the time of initial laparotomy, or at subsequent laparotomy if damage control is initially performed. The needle catheter jejunostomy (NCJ) is the preferred method of access and a commercially available kit containing a silastic 7 French catheter is available. Patients not undergoing laparotomy could have a ‘‘push’’ nasojejunal tube (Corpak Medsystems, Wheeling, Illinois) placed. If this is unsuccessful, an endoscopically placed nasojejunal tube can be placed through the biopsy channel of a flexible endoscope that has been advanced into the duodenum (51). Nasojejunal feeding may be done indefinitely, but if the need for long-term access becomes apparent, a PEG with a jejunal extension limb (PEG-J) can be placed.

Once enteral access has been obtained, feeds are begun at 15 cc/hr of full-strength formula and advanced by 15 cc/hr every 12 hours to a set goal of 60 cc/hr. To assure tolerance, this rate is maintained for 24 hours and then advanced by 15 cc/hr every 12 hours to a patient-specific targeted goal.

Formula Selection Many of the early clinical trials were performed using elemental formulas that were low in fat and surmised to be better tolerated. However, more recent studies suggest other formulas to be equally well tolerated. The numerous available formulas may be categorized into polymeric formulas (which contain nutrients in high-molecular-weight form, moderate fat loads, and require normal digestive and absorptive ability), predigested formulas (which contain one or

Complications of Enteral Nutrition Overview of Complications Technical complications that can be associated with the administration of enteral nutrition include aspiration, bowel perforation, clogged tubes, and tube malposition/dislodgement. Tube clogging can be prevented by routine saline irrigation of the tube and by administering only liquid medications through smaller bore tubes such as NCJs. Functional complications are the gastrointestinal manifestations frequently associated with intolerance and include emesis, nausea/ vomiting, cramping pain or distention, and diarrhea.

NCJ-Related Complications NCJs, although an ‘‘invasive’’ technique, are a safe and effective means to deliver jejunal feeds. Myers et al. reported only a 1% incidence of major complications and a 1.7% incidence of minor complications in a large study examining the safety of NCJs in patients undergoing major elective and emergency abdominal operations (52). The jejunostomyrelated complication rate in trauma patients has been reported to be slightly higher, with a major complications rate of 4% (53). However, the majority of these complications (10%) occurred in patients with a standard, open

Table 9 Formula Selection for Delivery of Enteral Nutrition Table 8 Options for Enteral Access Gastric tubes Manual Endoscopic Radiographic Surgical Jejunal tubes Manual Endoscopic

Radiographic

Nasogastric/nasoduodenal PEG Endoscopically placed nasoenteric (nasoduodenal tube) Fluoroscopy-guided nasoenteric tube PRG Open: Stamm, Witzel, or Janeway gastrostomy Laparoscopic gastrostomy ‘‘Push’’ nasojejunal tube PEJ PEG/JET Endoscopically placed nasojejunal tube PRG/PRJ PRG/JET

Abbreviations: JET, jejunal extension tube; PEG, percutaneous endoscopic gastrostomy; PRG, percutaneous radiographic gastrostomy; PEJ, percutaneous endoscopic jejunostomy; PRG/PRJ, percutaneous radiographic gastrostomy/jejunostomy.

Immune-enhancing diet Patients who have sustained major torso trauma, undergone major upper gastrointestinal surgery, or have limited physiologic reserve and who are at known risk for septic complications and multiple organ failure Polymeric high-protein formula Patients who do not meet the criteria for an immune-enhancing diet, have normal gut function, and are believed to have increased nitrogen requirements due to major injury, illness, or surgery. A modular protein component may be used in addition to the polymeric high-protein formula for use in the morbidly obese patient or in any patient that requires protein supplementation Elemental formula Patients who are intolerant to a polymeric formula or are acutely ill and who have not received enteral feeds for prolonged period of time Renal failure formula A concentrated, reduced electrolyte formulation is selected for use only in patients requiring intermittent hemodialysis. Often a modular protein component is used in addition to the commercially available renal formula to meet the increased nitrogen demands of the critically ill patient

56

Part One: General Considerations

jejunostomy (typically a 14 French catheter), rather than with a NCJ (5–7 French, 2% incidence of complications). Major complications reported included volvuli with infarction, small bowel perforation, intraperitoneal leaks, and nonocclusive small bowel necrosis.

Nonocclusive Bowel Necrosis A rare but devastating complication of bowel necrosis has been associated with the administration of enteral feeds. The clinical presentation is similar to that of neonatal necrotizing enterocolitis, though the consistent association with enteral nutrition suggests that the inappropriate administration of nutrients into a dysfunctional gut plays a pathogenic role. The incidence is less than 1%, but the mortality frequently exceeds 50% (54,55). Most cases of nonocclusive bowel necrosis occur in a delayed fashion in critically ill patients with a complicated course (pneumonia, sepsis, renal failure, etc.) that requires progressively higher acuity care. Gastrointestinal signs and symptoms tend to occur late and, as a result, clinical monitoring fails to detect this entity early in its course. Computed tomography scan may reveal pneumatosis intestinalis or thickened bowel. Although most cases will require exploratory laparotomy, less advanced presentations may be managed with cessation of feeds, broadspectrum antibiotics, and aggressive fluid resuscitation.

Enteral Nutrition Protocol Rationale for an Enteral Nutrition Protocol An enteral feeding protocol can assist in providing a systematic, evidence-based approach to enteral nutrition and in minimizing complications. Assessing tolerance parameters are an important part of any enteral protocol. Frequently identified indicators of intolerance are vomiting, abdominal distention or cramping/tenderness, diarrhea, and high nasogastric tube output (56). Symptoms can be graded as mild, moderate, or severe. Mild symptoms of intolerance, such as mild abdominal distention or diarrhea, can just be monitored by repeat physical examinations with no change in the current rate of feeding. Moderate symptoms are managed based on the particular symptom. For distention, enteral feeds should be stopped and the patient assessed for evidence of a mechanical obstruction. If distention remains moderate, an elemental formula should be considered. Moderate diarrhea can be managed by maintaining but not increasing the current feeding rate and repeat examinations. Finally, for severe distention, enteral feeds should be stopped, intravenous hydration begun, and the possibility of nonocclusive bowel necrosis should be considered. For severe diarrhea, tube feeds can be reduced and the patient should be evaluated for possible Clostridium difficile infection. Vomiting is managed by ensuring adequate gastric decompression and either stopping gastric feeds or decreasing the tube feed infusion rate by half for jejunal feeds. Additionally, high nasogastric output in patients fed into the small bowel can be managed by verifying postpyloric placement of the feeding tube and checking the nasogastric aspirate for glucose. Any amount of glucose is considered abnormal and enteral feeds should be withheld. In general, enteral feeds should be discontinued if vasopressors are instituted.

Results of an Enteral Nutrition Protocol The incidence of enteral tolerance while using a protocol was analyzed in a prospective multi-institutional study

(57). Early tolerance (during advancement of enteral feeds to a goal of 60 cc/hr) was good in 84% (41/49) of patients and moderate in 16% (8/49). No patients experienced poor tolerance or complete intolerance. Late tolerance (after standard goal rate was met) was good in 80% (39/49), moderate in 16% (8/49), and poor in 4% (2/49) of patients. The site of feeding (gastric vs. jejunal) was not dictated by the protocol. Moderate intolerance was primarily due to high gastric output in patients fed via the stomach. All patients were successfully maintained on early enteral nutrition using this standardized protocol.

Specialized Enteral Diets Formulas with reduced carbohydrate and increased fat loads are available for use in patients with diabetes to potentially improve glycemic control. These products have not, however, undergone PRCT to demonstrate superior outcome in ICU patients. The use of standard high-protein formulas in an isocaloric or hypocaloric load, combined with aggressive insulin therapy, may be the most effective treatment for insulin resistance in the stressed, diabetic patient as opposed to carbohydrate restriction. Additionally, gastric feedings in the diabetic patient with gastroparesis may be associated with delayed gastric emptying and increased risk of aspiration, especially when high in fat content. There is one PRCT that demonstrated superior outcome, as demonstrated by reduced days on the ventilator, reduced ICU length of stay, and decreased incidence of organ failure in patients with adult respiratory distress syndrome (ARDS) when provided a high omega-3 fatty acid enteral product versus a high omega-6 ‘‘pulmonary’’ formula (58). However, the control diet was not the standard of care and may worsen ARDS. High omega-6 fatty acids increase inflammation and production of lipid mediators, which can worsen V/Q mismatch and thus worsen oxygenation in these patients. Although an enteral diet high in omega-3 fatty acids may be beneficial in early ARDS (59), prior to recommending such a diet, additional studies need to be performed.

TOTAL PARENTERAL NUTRITION Indications for TPN Whenever possible, the gastrointestinal track should be utilized for nutritional support. Table 10 reviews the basic indications for the administration of TPN. In general, TPN should not be started for at least seven days postoperatively if the patient is well nourished at baseline. Critically ill patients should be started on TPN if they are unable to achieve adequate caloric intake by postoperative day 6. Unlike with enteral feeding, there is no benefit to early TPN. Patients with persistent ileus, bowel obstruction, short gut, high-output fistulas, and malabsorption, may all benefit from TPN. Additionally, patients unable to tolerate enteral Table 10 Indications for TPN Persistent or progressive ileus Bowel obstruction Massive bowel resection refractory to enteral diet High-output fistula refractory to elemental diet Malabsorption High risk for nonocclusive bowel necrosis if fed enterally (shock resuscitation, a-agonists, persistent severe distention, or cramping) Documented intolerance to enteral nutrition Abbreviation: TPN, total parenteral nutrition.

Chapter 3: Surgical Nutrition

nutrition or who are at high risk for nonocclusive bowel necrosis (hypoperfusion or high vasopressor requirements) may benefit from TPN.

Preoperative and Perioperative TPN It is well documented that malnourished patients are at an increased risk for septic complications, problems with wound healing, longer hospital stays, and increased mortality (60). The unproved contention is that preoperative TPN can improve nutritional status and thereby reduce postoperative morbidity and mortality. However, studies evaluating preoperative TPN and outcome are variable. Results of randomized trials and a meta-analysis suggest that preoperative TPN for 7 to 10 days in severely malnourished patients may be beneficial in reducing the rates of infectious complications (61–65). For the mild to moderately malnourished patients, however, the risks of preoperative TPN (increase in septic morbidity) appear to outweigh the potential benefits. One of the confounding variables in preoperative TPN trials is that many of the patients were undergoing resection of a gastrointestinal cancer. Cancer patients in general, and particularly those with gastrointestinal malignancies, have cancer-associated weight loss, which can be very difficult to reverse. Prospective randomized trials of patients undergoing gastrointestinal surgery also failed to demonstrate any benefit, with the TPN group experiencing higher complication rates. Thus, routine postoperative TPN is not indicated and should be reserved for patients who cannot resume a diet by postoperative day 6 (66).

Initiation of TPN Components of TPN Components of TPN include (i) dextrose, (ii) fatty acids, (iii) amino acids, (iv) electrolytes, (v) vitamins, (vi) trace minerals, and (vii) fluids. Protein is provided based on grams per kilogram body weight, lipid is provided to deliver approximately 10% of total kilocalories needed, and dextrose provides the balance of kilocalories. Dextrose monohydrate (caloric density 3.4 kcal/g) is the carbohydrate. Fat emulsions (caloric density 2.0 kcal/cc of 20%) made from either soybean oil or a mixture of soybean oil and safflower oil provide fat calories and are the source of essential fatty acids (linoleic, linolenic, and arachidonic acids). Protein (caloric density 4 kcal/g) is provided as crystalline amino acids. Standard amino acid solutions contain a balance of essential and nonessential amino acids. The electrolyte cations, which include sodium, potassium, magnesium, phosphorus, and calcium, are admixed into the TPN solution using one of several anions. Acid–base status may be affected by the amount of chloride or acetate used in providing sodium and potassium. The concentrations of calcium and phosphorus are limited to avoid precipitation of a calcium phosphate salt. Multivitamin products that meet American Medical Association recommendations contain vitamins A, C, D, and E and the B vitamins, including folate, but not vitamin K, which must be added separately. A multi–trace mineral product is added to provide copper, chromium, manganese, zinc, and selenium. Symptoms of trace mineral deficiencies are reviewed in Table 11. TPN solutions are hyperosmolar and must be delivered through a large-lumen vein. When central access is unavailable or undesirable, peripheral parenteral nutrition (PPN) with a dilute solution (less than 800 mOsm/L) may be delivered through a peripheral vein for 7 to 10 days. Infusion sites must be rotated often to

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Table 11 Trace Element Deficiencies Trace element Iron Zinc Copper Chromium Selenium Manganese Molybdenum

Symptom of deficiency Anemia Maculopapular rash, poor wound healing, cutaneous anergy, alopecia Anemia unresponsive to iron, pancytopenia Sudden glucose intolerance during TPN Proximal neuromuscular weakness and cardiac failure Weight loss, altered hair pigmentation, nausea Nausea/vomiting, tachycardia, central nervous system disturbances

Abbreviation: TPN, total parenteral nutrition.

reduce the incidence of thrombophlebitis. This therapy is best reserved for younger patients with easy peripheral access. PPN is seldom utilized. The combination of amino acids, dextrose, and lipids is referred to as total nutrient admixture (TNA) or a 3-in-1 solution. Typically an 8.5% or 10% amino acid solution is employed, although a 15% solution is available for patients requiring fluid restriction, such as those with congestive heart failure, renal failure, or hepatic failure. Dextrose 50% is the usual carbohydrate solution, although 70% solution may be used to restrict volume. Lipids are available in 10%, 20%, and 30% and are needed to prevent essential fatty acid deficiency. Ten percent of total kilocalories will accomplish this goal. Additional lipids can be given to provide an alternative calorie source in patients intolerant of high glucose loads. If lipids are administered separately, they must be infused for no greater than over 12 hours to prevent bacterial growth. Lipids are stable in TNA for 24 hours because the osmolarity and pH are less favorable to bacterial growth. The following is an example of TPN in an 80 kg male patient with significant injuries requiring 2400 kcal (30 kcal/kg) and 140 g protein (1.75 g/kg). A typical institutional TPN form is shown in Table 12.

Calculations (see Table 13): 1. 2.

Establish the kilocalories and protein desired: 2400 kcal, 140 g protein. Select the appropriate amino acid formula and quantity: using 10% amino acids 10 gm=100 mL
140 gm ¼ 1400 mL

3.

Calculate 10% of kcal as lipid emulsion: using 20% lipids 10%
2400 ¼ 240 kcal 240 kcal
1 mL=2 kcal ¼ 120 mL

4.

Add the kcal from amino acids and fat and subtract from goal: acids ¼ 140 g protein
4 cal=g ¼ 560 kcal kcal from fat ¼ 240 kcal goal kcal  ðamino acid þ fatÞ kcal ¼ 2400  ð800 þ 240Þ ¼ 1600 kcal

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Part One: General Considerations

Table 12 Example of a Standard TPN Order Sheet

This is the amount of dextrose kcal needed. To determine the volume, 1600 kcal=3:4 kcal=g glucose ¼ 470 g glucose 470 g glucose=50 g=100 mL ¼ 940 mL The patient’s electrolyte profile is reviewed. If it is relatively normal, infusion is started with standard electrolyte requirements.

Complications Complications of TPN can be divided into technical, infectious, and metabolic. Administration of TPN requires central venous access due to its hypertonicity. Administration

through a large, central vein allows rapid dilution and therefore prevention of venous sclerosis and thrombophlebitis, which will occur with peripheral venous administration. The insertion of a central venous line, however, is not without risk. More than 15% of patients receiving central lines have some type of complication (67). Technical complications range from injury to major veins, arteries, or nerves, and violation of the pleural space. Complications can be minimized by strict observation of well-established guidelines for insertion, including adequate supervision. If a major artery is punctured, the needle should be withdrawn and pressure applied. If the vessel has been cannulated and it is unclear into which vessel (artery or vein) the catheter has been inserted, the catheter should be transduced. A venous tracing should be seen and the measured pressure should be approximately 4 to 10 mmHg.

Chapter 3: Surgical Nutrition

Table 13 Sample TPN Order Nonstandard TPN solution Base solution Standard amino acid (10 g/100 mL) Dextrose 50% (50 g/100 mL:3.4 kcal/g) Volume of base solution to be delivered in 24 hr Electrolytes Sodium chloride Sodium phosphate Potassium acetate Calcium gluconate Magnesium sulfate Multivitamins Trace elements Fat emulsion 20% (1 kcal/mL) Infusion rate

1400 mL 940 mL 2300 mL

35 mEq/L 8.3 mEq/L 35 mEq/L 4.16 mEq/L 3.3 mEq/L 10 mL 1 mL 120 mL 101 mL/hr

Abbreviation: TPN, total parenteral nutrition.

The pathogenesis of infectious complications most commonly stems from colonization of the skin and catheter hub. Short-term, noncuffed catheters (such as single- or triple-lumen catheters) become colonized from skin flora that migrate from the insertion site along the external surface of the catheter to the catheter tip and lead to catheterrelated bloodstream infections. Long-term catheters such as cuffed, tunneled, silicone catheters (Hickmans or Broviacs) or implanted catheters (ports) become colonized as bacteria migrate through the lumen of the hub, which becomes contaminated by skin flora. Other less frequent sources of contamination include infusion of contaminated solutions or hematogenous seeding from a distal site of infection. Preventative measures can be broken down into three categories: (i) catheter insertion, (ii) catheter care, and (iii) catheter removal. Important components of catheter insertion include skin preparation (chlorhexidine is more efficacious than alcohol or povidone iodine) and the use of

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maximal sterile barriers (68). Although it is commonly believed that multiple-lumen catheters have a higher rate of catheter-related sepsis compared to single-lumen catheters, randomized studies have not confirmed this practice (69). Recent randomized trials indicate that catheter-related sepsis can be reduced by the use of antibiotic- or antisepticbonded catheters (70). However, these catheters are considerably more expensive, can be associated with anaphylaxis, and have the potential to cause resistant organisms. Therefore, they should be used in select patients whose catheters are going to be in place for extended periods of time. With regard to catheter care, dressings may be either a transparent, semipermeable, polyurethane dressing or gauze. Insertion site antibiotic or antiseptic ointments are not recommended because of the potential to promote antibiotic resistance and fungal colonization. A meta-analysis of 12 randomized trials of catheter replacement did not support scheduled exchange of catheters over a guide wire or scheduled, routine replacement at a new site (71). Metabolic complications can include hyper- or hypoglycemia, electrolyte abnormalities, acid/base abnormalities, liver function abnormalities, and trace mineral deficiencies (Table 14) (72). Critical illness is accompanied by increased plasma counter-regulatory hormone levels, which have multiple effects on glucose homeostasis. The end result is hyperglycemia with resistance to insulin. Other factors that contribute include obesity, inflammatory cytokines associated with the SIRS (such as TNFa, IL-1, IL-2, and IL-6), advanced age, exogenous steroid or catecholamines, increased free fatty acids, and nutritional support (parenteral route greater than enteral route). The resulting hyperglycemia can adversely affect outcome through several mechanisms, including glycosuria with inappropriate diuresis, increase risk of infection by impairing neutrophil and immunoglobulin function, and exacerbation of cerebral edema. Van Den Berghe et al. (73) have recently demonstrated in a prospective randomized fashion a reduction of mortality in critically ill surgical patients, from 8% to 4.6%,

Table 14 Metabolic Complications Associated with TPN Abnormality Electrolyte Hyperkalemia Hypokalemia Hyperphosphatemia Hypophosphatemia Hypercalcemia Hypocalcemia Hypermagnesemia Hypomagnesemia Glucose Hyperglycemia Hypoglycemia Amino acids Hypercholeremia Metabolic acidosis Fatty acid deficiency Bleeding Abnormal liver functions

Etiology

Correction # " # " # "

Renal insufficiency/failure Inadequate intake, diuresis, diarrhea, refeeding Renal insufficiency/failure Inadequate administration, refeeding Excessive administration Inadequate administration, hypoalbuminemia, refeeding, rapid phosphorus repletion Excessive administration, renal failure Inadequate intake, diuresis, refeeding

# Administration " Administration

Excessive administration, sepsis, inadequate secretion of insulin Abrupt cessation of TPN, liver dysfunction

Strict glucose control with exogenous insulin, consider reducing glucose calories Taper TPN rate, administer 5% or 10% dextrose

Excessive chloride administration Excessive chloride administration Sepsis, inadequate perfusion, renal failure Inadequate administration Vitamin K deficiency Excessive fat or glucose administration, amino acid imbalance

# Administration Administer acetate Reassess patient " Administration " Administration Reassess patient

Abbreviation: TPN, total parenteral nutrition.

Administration Administration Administration Administration Administration Administration

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Part One: General Considerations

when glucose levels were strictly controlled between 80 and 110 mg/dL versus conventional therapy (120–180 mg/dL). In a follow-up analysis, the same investigators demonstrated that the reduction in critical illness polyneuropathy, bacteremia, inflammation, and mortality was related to the lowering of blood glucose levels and not the amount of infused insulin per se (74). These data strongly support the maintenance of normoglycemia. The refeeding syndrome is a dramatic example of a metabolic complication that can be associated with TPN administration. It occurs with rapid and excessive feeding of patients with severe malnutrition due to conditions such as starvation, alcoholism, delayed nutritional support, anorexia nervosa, hyperemesis gravidarum, and massive weight loss after bariatric surgery (75). As a result of ion fluxes into the cell with refeeding, serum phosphate, magnesium, potassium, and calcium levels can drop rapidly. In the case of blunted basal insulin secretion, severe hyperglycemia may arise. Symptoms include cardiac arrhythmias, confusion, respiratory failure, and even death. This can be prevented by initiating TPN at a rate lower than the required goal, primarily by reducing dextrose calories. Exogenous insulin is frequently required.

patients have poor response to chemotherapy, radiation, and surgery as well as increased morbidity and mortality. When feasible, use of the gastrointestinal tract is the preferable mode of feeding. Immune-enhanced enteral diets in patients with gastrointestinal cancers have been shown to decrease postoperative infections (78,79). A recent metaanalysis that carried out a separate analysis of patients with gastrointestinal cancer, similarly demonstrated a reduction in major infectious complications but not death in the postoperative period (26). Traditionally, concern exists that perioperative TPN may promote tumor growth, i.e., feed the tumor not the patient. However, many studies supporting this theory were performed in animals whose life span is much shorter than humans (80). Thus, a 10-day course of TPN would represent a far greater segment of an animal’s life. Furthermore, the tumor size in these studies was large, representing up to 30% to 40% of the animal’s body weight. Nonetheless, the use of TPN in this patient population offers little benefit and may increase infection rates (81). Severely malnourished patients receiving a bone marrow transplant may be one subset of patients who can benefit from perioperative TPN.

Monitoring TPN

Short Gut

This is done to (i) determine the efficacy of the TPN therapy; (ii) determine changes in metabolic status (stress level); and (iii) detect complications associated with TPN. Measurements of efficacy in the acute-care setting include weight, constitutive protein status (e.g., albumin, transferrin, and prealbumin), nitrogen balance, and wound healing. Metabolic status should be viewed first from the clinical perspective. The presence of SIRS, infection, or high ventilation requirements all indicate a high metabolic rate. Metabolic status can be further assessed by laboratory variables that evaluate substrate tolerance (e.g., blood glucose and serum triglyceride concentrations) as well as protein catabolic rate (24-hour UUN).

Specialized Amino Acid TPN Solutions These formulas are designed to meet organ-failure specific requirements and include high-branched-chain, hepatic failure (low aromatic amino acid), and renal failure (high essential amino acids) formulations. The use of these specialty formulas remains controversial because of the expense and lack of outcome data. Studies comparing high-branchedchain amino acid solutions with standard formulas in stressed patients have shown improvements in nitrogen retention, constitutive protein levels, and immune function, but have failed to demonstrate reduced morbidity or mortality (76). One recent trial in Europe was able to demonstrate a reduced mortality in septic patients receiving a high-branched-chain formula (77). The use of hepatic and renal formulas has also not shown any proven benefit.

DISEASE-SPECIFIC NUTRITION Nutrition and Cancer Many forms of cancer are associated with weight loss and wasting or cachexia. Intake can be impaired due to the disease process, physical anomalies related to surgery or to the cancer itself, side effects of therapy, and psychosocial factors. Utilization of nutrients may be altered by malabsorption, cytokine activity, or the preponderance of inefficient cycles for energy metabolism. Malnourished cancer

Mesenteric infarction, Crohn’s disease, radiation enteritis, tumors, and trauma are the leading causes of short gut in adults (82). Factors that influence the management of short bowel syndrome include (i) the extent of resection; (ii) the site of resection; (iii) the presence or absence of the ileocecal valve; (iv) the residual function of the remaining small bowel; (v) the adaptive capacity of the intestinal remnant; (vi) the primary disease that precipitated the bowel loss; and (vii) the amount and the activity of the residual disease in the remnant (83). The average adult has 25 cm duodenum, 240 cm jejunum, and 360 cm ileum (84). In adults, the minimal length of small intestine (distal to the Ligament of Treitz) required for adequate digestive function is approximately 75 cm, although there are interindividual differences (85). For lesser amounts, patients will require long-term TPN. Additionally, patients requiring TPN three months after surgical resection can be considered as having short gut regardless of the extent of resection. The small bowel is the site of absorption for a variety of nutrients and electrolytes. Duodenectomy results in malabsorption of calcium, folate, and iron. Although the proximal jejunum is the usual site for protein, carbohydrate, and fat absorption, jejunectomy usually results in no major change in macronutrient and electrolyte absorption because the ileum can take over this role (86). Because the jejunum is the site of hormones that inhibit gastric secretion such as gastric inhibitory peptide and vasoactive intestinal polypeptide, gastric hypersecretion begins within 24 hours after jejunal resection. This produces a high sodium load in the stomach and reduces pH downstream, thus inactivating digestive enzymes and increasing diarrhea. The ileum plays an important role in slowing intestinal transit and concentrating luminal contents. Both vitamin B12 and bile salts are normally absorbed from the ileum. Following resection, the liver increases production of bile salts to compensate for the loss of absorption. However, this production can never be fully compensated for and bile salt depletion occurs, leading to steatorrhea and cholelithiasis. Cholestyramine is sometimes employed to treat the ensuing diarrhea and cholecystectomy is commonly required within two years after

Chapter 3: Surgical Nutrition

bowel resection. Steatorrhea promotes calcium binding to fatty acids rather than oxalate and allows more oxalate to be absorbed, leading to oxalate stones. Three stages of intestinal adaptation after resection have been identified (84): Stage I is characterized by fluid and electrolyte loss and lasts for approximately two weeks. It is treated with electrolyte replacement, an H2 blocker (to minimize hypersecretion), and parenteral nutrition. Hypersecretion of gastrin may result in peptic ulcer disease, gastroesophageal reflux disease, and proximal small bowel inflammation, so that H2 antagonists are a mainstay of therapy after intestinal resection. Stage II is a period of adaptation where oral intake begins and lasts from a few months up to one year. Feedings are advanced as stool and/or ostomy output becomes manageable. Stage III is maximal adaptation where normal home life may resume, although some patients may still require TPN. The residual small bowel as well as the colon undergo dilatation, lengthening, and mucosal proliferation along the course of adaptation. Experiments in rats have demonstrated superior adaptation in animals fed TPN and complex enteral diets as opposed to elemental diets (87). Aggressive use of enteral nutrition is thought to maximize gut adaptation (88). Although somatostatin may slow intestinal transit and reduce fluid and electrolyte loss acutely, it may also decrease enteroglucagon release, which exerts beneficial effects in bowel adaptation after resection. Octreotide is a synthetic analog of somatostatin with a longer half-life (three hours vs. three minutes). Octreotide reduces splanchnic blood flow and inhibits gastric, pancreatic, and small bowel secretions. These mechanisms may limit intestinal adaptation after bowel resection and reduce dietary fat digestion. Bowel output is reduced due to decreased secretions rather than improved absorption. Octreotide is generally recommended for use in patients with severe diarrhea/ostomy output (greater than 4 L daily) that is intractable to antidiarrheal agents. The use of antimotility agents may prove helpful in this circumstance. Although glutamine has been recommended, its role in morphological adaptation after bowel resection remains to be elucidated. Administering probiotics, the addition of live bacteria to the gastrointestinal tract, may also be beneficial in short gut. Healthy bacteria may be altered due to antibiotics, antimotility agents, H2 blockers, proton-pump inhibitors, and narcotics. Growth of healthy flora decreases growth of enteropathogens that may adhere to the mucosa and initiate inflammatory or immune sequelae (89). Structured programs have emerged that are geared toward decreasing TPN dependence after intestinal resection (90). Therapy consists of TPN (when necessary), peptide-based enteral nutrition, a low-fat, low-oxalate, high-protein, high–dietary fiber oral diet, and enteral glutamine in dipeptide form. Recombinant human growth hormone is provided for a specified period. Long-term follow-up of patients after intestinal resection should consist of monitoring sodium, potassium, chloride, zinc, copper, magnesium, iron, B12, folic acid, and fat-soluble vitamins. Zinc losses in diarrhea are substantial and may require supplementation above the quantity provided by intravenous multi–trace element products. Intramuscular vitamin B12 should be given if more than 60 cm of terminal ileum is resected. Chronic complications of short bowel syndrome include liver failure, gallstones, nutrient deficiencies, osteopenia, catheter-related sepsis, and small bowel bacterial overgrowth. Surgical approaches to increase functional bowel, including transplantation, remain an option.

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Enterocutaneous Fistula Abdominal operations account for over 80% of enterocutaneous fistulae. The remainder are due to Crohn’s, cancer, radiation, and infection. The nutritional management depends on the location of the fistula, the health of the bowel distal to the fistula, and the amount of fistula output. The advent of TPN in the 1960s greatly reduced mortality from fistulae. Spontaneous closure depends on location, comorbid factors, and nutritional state. Ninety percent of fistulae that are likely to close spontaneously will do so in the first 30 days (91). If fistulae are in the proximal bowel, full enteral feeds may be delivered distally.

Pancreatitis Acute pancreatitis induces severe hypercatabolism and without exogenous nutritional support, acute protein malnutrition can quickly occur. Due to concerns that enteral feeding would stimulate further secretion of pancreatic enzymes and worsen autolysis, TPN has been the mainstay of nutritional therapy. However, recent studies have indicated that enteral feeding into the jejunum in patients with acute pancreatitis is both safe and effective. Initial trials of enteral support recommended low-fat, elemental formulas (92–95), again due to concerns over pancreatic stimulation. However, Duerksen et al. demonstrated that, in patients who underwent partial pancreatectomy with exteriorization of pancreatic stents, there was no statistically significant difference in pancreatic secretion between polymeric and elemental formulas (96). When compared with TPN, enteral nutrition is associated with an attenuation of the acute-phase response (97), reduced septic complications (94), and markedly decreased cost.

SUMMARY Protein-calorie malnutrition has become increasingly recognized in hospitalized patients and has been shown to be present in as many as 50% of patients requiring surgical procedures. Understanding the metabolic response to starvation and surgical stress, and how a suboptimal nutritional environment can adversely affect this response is mandatory if postoperative morbidity and mortality are to be lessened. Fortunately, the last several decades have unraveled an enormous amount of new knowledge regarding the role that malnutrition plays in altering fundamental metabolic pathways that are essential to good patient care. Further, the ability to provide nutritional support by way of enteral or parenteral routes has enabled the provision of optimal nutritional therapy in even the patient with profound malnutrition requiring surgical intervention. Such advances have greatly minimized the attendant negative effects that suboptimal nutrition would otherwise have on patient outcome and survival following operation.

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27. Beale RJ, Bryg DJ, Bihari DJ. Immunonutrition in the critically ill: a systematic review of clinical outcome. Crit Care Med 1999; 27:2799. 28. Novak F, Heyland DK, Avenell A, Drover JW, Su X. Glutamine supplementation in serious illness: a systematic review of the evidence. Crit Care Med 2002; 30:2002–2029. 29. Houdijk APJ, Rijnsburger ER, Jansen J, et al. Randomized trial of glutamine-enriched enteral nutrition on infectious morbidity in patients with multiple trauma. Lancet 1998; 352: 772–776. 30. Barbul A, Lazarou SA, Efron DT. Arginine enhances wound healing and lymphocyte immune responses in humans. Surgery 1990; 108:331–336. 31. Suchner U, Heyland DK, Peter K. Immune-modulatory actions of arginine in the critically ill. Br J Nutr 2002; 87(suppl 1):S121. 32. Bower RH, Cerra FB, Bershadsky B, et al. Early administration of a formula (Impact) supplemented with arginine, nucleotides, and fish oil in intensive care patients: results of a mulitcenter, prospective, randomized, clinical trial. Crit Care Med 2001; 23:436–449. 33. Bruzzone R, Radrizzani D. Early enteral immunonutrition in patients with severe sepsis. Results of an interim analysis of a randomized multicenter clinical trial. Intensive Care Med 2003; 29:834–840. 34. Alexander JW, Saito H, Ogle CK, Trocki O. The importance of lipid type in the diet after burn injury. Ann Surg 1986; 204:1–8. 35. Van Buren CT, Kulkarni A, Fanslow WC, Rudoph FB. Dietary nucleotides, a requirement for helper/inducer T lymphocytes. Transplantation 1985; 40:694–697. 36. Khalili TM, Navarro A, Middleton Y, Margulies DR. Early postoperative enteral feeding increases anastomotic strength in a peritonitis model. Am J Surg 2001; 182:621–624. 37. Montecalvo MA, Steger KA, Farber HW, et al. Nutritional outcome and pneumonia in critical care patients randomized to gastric versus jejunal tube feedings. The Critical Care Research Team. Crit Care Med 1992; 20:1377–1387. 38. Montejo JC, Grau T, Acosta J, et al. Nutritional and Metabolic working group of the Spanish Society of Intensive Care Medicine and Coronary Units. Multicenter, prospective, randomized, single-blind study comparing the efficacy and gastrointestinal complications of early jejunal feeding with early gastric feeding in critically ill patients. Crit Care Med 2002; 30(4):796–800. 39. Kearns PJ, Chin D, Mueller L, Wallace K, Jensen WA, Kirsch CM. The incidence of ventilator-associated pneumonia and success in nutrient delivery with gastric versus small intestinal feeding: a randomized clinical trial. Crit Care Med 2000; 28(6):1742–1746. 40. Kortbeek JB, Haigh PI, Doig C. Duodenal versus gastric feeding in ventilated blunt trauma patients: a randomized controlled trial. J Trauma 1999; 46(6):992–996; discussion 996–998. 41. McClave SA, Sexton LK, Spain DA, et al. Enteral tube feeding in the intensive care unit: factors impeding adequate delivery. Crit Care Med 1999; 27(7):1252–1256. 42. Ritz MA, Fraser R, Edwards N, et al. Delayed gastric emptying in ventilated critically ill patients: measurement by 13 C-octanoic acid breath test. Crit Care Med 2001; 9(9):1744–1749. 43. Chapman MJ, Fraser RJ, Kluger MT, Buist MD, De Nichilo DJ. Erythromycin improves gastric emptying in critically ill patients intolerant of nasogastric feeding. Crit Care Med 2000; 28(7):2334–2337. 44. Boivin MA, Levy H. Gastric feeding with erythromycin is equivalent to transpyloric feeding in the critically ill. Crit Care Med 2001; 29(10):1916–1919. 45. McClave SA, DeMeo MT, DeLegge MH, et al. North American Summit on Aspiration in the Critically Ill Patient: consensus statement. J Parenter Enteral Nutr 2002; 26(suppl 6):S80–S85. 46. DeLegge MH. Aspiration pneumonia: incidence, mortality, and at-risk populations. J Parenter Enteral Nutr 2002; 26(suppl 6): S19–S24; discussion S24–S25.

Chapter 3: Surgical Nutrition 47. Elpern EH. Pulmonary aspiration in hospitalized adults. Nutr Clin Pract 1997; 12(1):5–13. 48. Seegobin RD, van Hasselt GL. Aspiration beyond endotracheal cuffs. Can Anaesth Soc J 1986; 33(3 Pt 1):273–279. 49. Lin HC, Van Citters GW. Stopping enteral feeding for arbitrary gastric residual volume may not be physiologically sound: results of a computer simulation model. J Parenter Enteral Nutr 1997; 21(5):286–289. 50. Maloney JP, Ryan TA. Detection of aspiration in enterally fed patients: a requirement for bedside monitors of aspiration. J Parenter Enteral Nutr 2002; 26(suppl 6):S34–S42. 51. Reed RL, Eachempati SR, Russell MK, Fahky C. Endoscopic placement of jejunal feeding catheters in critically ill patients by a ‘‘push’’ technique. J Trauma 1998; 45:388–393. 52. Myers JG, Page CP, Stewart RM, Schwesinger WH, Sirinek KR, Aust JB. Complications of needle catheter jejunostomy in 2002 consecutive applications. Am J Surg 1995; 170:547–551. 53. Holmes JH, Brundage SI, Hall RA, Yuen P, Maier RV, Jurkovich GJ. Complications of surgical jejunostomy in trauma patients. J Trauma 1999; 47:1009–1012. 54. Munshi I, Steingrub JS, Wolpert L. Small bowel necrosis associated with early post operative tube feeding in a trauma patient. J Trauma 2000; 49(1):163–165. 55. Marvin RG, McKinley BA, McQuiggan M, Cocanour CS, Moore FA. Nonocclusive bowel necrosis occurring in critically ill trauma patients receiving enteral nutrition manifests no reliable signs for early detection. Am J Surg 2000; 179:7–12. 56. McQuiggan MM, Marvin RG, McKinley BA, Moore FA. Enteral feeding following major torso trauma: from theory to practice. New Horizons 1999; 7:131–140. 57. Kozar RA, McQuiggan MM, Moore EE, Kudsk KA, Jurkovich GJ, Moore FA. Postinjury enteral tolerance is reliably achieved by a standardized protocol. J Surg Res 2002; 104:70–75. 58. Gadek JE, DeMichele SJ, Karlstad MD, et al. Effect of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in patients with acute respiratory distress syndrome. Crit Care Med 1999; 27(8):1409–1420. 59. American Society of Parenteral and Enteral Nutrition: Guidelines for the use of parenteral and enteral nutrition in adult and pediatric patients. J Parenter Enteral Nutr 2002; 17(suppl): 61SA–65SA. 60. Kudsk KA, Tolley EA, DeWitt RC, et al. Preoperative albumin and surgical site identify surgical risk for major postoperative complications. J Parenter Enteral Nutr 2003; 27:1–9. 61. Souba WW. Drug therapy: nutritional support. N Engl J Med 1997; 336:41–48. 62. Muller JM, Brenner U, Dienst C, Pichlmaier H. Preoperative parenteral feeding in patients with gastrointestinal cancer. Lancet 1982; 1:68–71. 63. The Veterans Affairs Total Parenteral Nutrition Cooperative Study Group. Perioperative total parenteral nutrition in surgical patients. N Engl J Med 1991; 325:525–532. 64. Bellantone R, Doglietto GB, Bossola M, et al. Preoperative parenteral nutrition in the high risk surgical patient. J Parenter Enteral Nutr 1988; 12:195–197. 65. Detsky AS, Baker JP, O’Rourke K, Goel V. Perioperative parenteral nutrition: a meta-analysis. Ann Intern Med 1987; 107: 195–203. 66. Sandstrom R, Drott C, Hyltander A, et al. The effect of postoperative intravenous feeding (TPN) on outcome following major surgery evaluated in a randomized study. Ann Surg 1993; 217:185–195. 67. McGee DC, Gould MK. Preventing complications of central venous catheterization. N Engl J Med 2003; 348:1123– 1233. 68. O’Grady NP, Alexander M, Pellinger EP, et al. Guidelines for the prevention of intravascular catheter-related infections. Clin Infect Dis 2002; 35:1281–1307. 69. Ma TY, Yoshinaka R, Banaag A, Jphnson B, Davis S, Berman SM. Total parenteral nutrition via multilumen catheters does not increase the risk of catheter-related sepsis: a randomized, prospective study. Clin Infect Dis 1998; 27:500–503.

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70. Raad I, Darouiche R, Dupuis J, et al. Central venous catheters coated with minocycline and rifampin for the prevention of catheter-related colonization and bloodstream infections: a randomized trial. Ann Intern Med 1997; 127:257–266. 71. Cook D, Randolph A, Kernerman P, et al. Central venous catheter replacement strategies: a systematic review of the literature. Crit Care Med 1997; 25:1417–1424. 72. Rombeau JL, Rolandelli RH, Wilmore DW, Daly JM. Nutritional support. In: Wilmore DW, Cheung LY, Harken AH, Holcroft JW, Meakins JL, eds. Care of the Surgical Patient. New York: Scientific American Surgery, 2001:15. 73. Van der Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001; 345: 1359–1367. 74. Van den Berghe G, Wouters PJ, Boullion R, et al. Outcome benefit of intensive insulin therapy in the critically ill: insulin dose versus glycemic control. Crit Care Med 2003; 31:359–366. 75. Crook MA, Hally V, Panteli JV. The importance of the refeeding syndrome. Nutrition 2001; 17:632–637. 76. Cerran FB, Mazuski JE, Chute E, et al. Branched chain metabolic support. A prospective, randomized, double-blind trial in surgical stress. Ann Surg 1984; 199:286–291. 77. Garcia-de-Lorenzio A, Ortiz-Leyba C, Planas M, et al. Parenteral administration of different amounts of branch-chain amino acids in septic patients: clinical and metabolic support. Crit Care Med 1997; 25:418–429. 78. Daly JM, Weintraub FN, Shou J, Rosato EF, Luci M. Enteral therapy in upper gastrointestinal cancer patients. Ann Surg 1995; 221:337–338. 79. Gianotti L, Braga M, Vignali A, et al. Effect of route of delivery and formulation of postoperative nutrition support in patients undergoing major operations for malignant neoplasms. Arch Surg 1997; 132:1222–1229. 80. Copeland EM. Historical perspective on nutritional support of cancer patients. CA Cancer J Clin 1998; 48:67–68. 81. Rivadeneira DE, Evoy D, Fahey TJ, Lieberman MD, Daly JM. Nutritional support of the cancer patient. CA Cancer J Clin 1998; 48:69–80. 82. Rombeau JL, Rolandelli RH. Enteral and parenteral nutrition in patients with enteric fistulas and short bowel syndrome. Surg Clin N Am 1987; 67:551–571. 83. Dudrick SJ, Latifi R, Fosnocht DE. Management of the short bowel syndrome. Surg Clin N Am 1997; 71(3):625–643. 84. Shanbhogue LKR, Molenar JC. Short bowel syndrome: metabolic and surgical management. Br J Surg 1994; 81:486–499. 85. Li JS. Short bowel syndrome. In: Shao JZ, Gu JF, Zhang SY, eds. Enteral Nutrition. Bejing: Military Medical Science Press, 1999:205–206. 86. Allard JP, Jeejeebhoy KN. Nutritional support and therapy in the short bowel syndrome. Gastroenterol Clin N Am 1989; 589–601. 87. Al-Jurf AS, Younasazi MK, Chapman-Furr F. Effect of nutritional method on adaptation of the intestinal remnant after massive small bowel resection. J Pediatr Gastroenterol Nutr 1985; 4:245–252. 88. Vanderhoof JA, Langnas AN. Short-bowel syndrome in children and adults. Gastroenterology 1997; 113:1767–1778. 89. Vanderhoof JA, Young RJ. The role of probiotics in the treatment of intestinal infections and inflammation. Curr Opin Gastroenterol 2001; 17:58–62. 90. Byrne TA, Persinger RL, Young LS, Ziegler TR, Wilmore DW. A new treatment for patients with short bowel syndrome. Ann Surg 1995; 222:243–255. 91. Pipkin WL, Gadacz TR. Nutritional considerations for dealing with intestinal diseases in the ICU. In: Shikora SA, Martindale RG, Schwaitzberg SD, eds. Nutritional Considerations in the ICU. Iowa: Kendall Hunt Publishing, 2002:279–285. 92. Olah A, Pardavi G, Belagyi T, Nagy A, Issekutz A, Mohamed GE. Early nasojejunal feeding in acute pancreatitis is associated with a lower complication rate. Nutrition 2002; 18:259–262. 93. Abu-Assi S, Craid K, O’Keefe SJ. Hypocaloric jejunal feeding is better than TPN in acute pancreatitis: results of a

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randomized comparative study. Am J Gastroenterol 2002; 97: 2255–2262. 94. Kalfarentzos F, Kehagias J, Mead N, Kokkinis K, Gogos CA. Enteral nutrition is superior to parenteral nutrition in severe acute pancreatitis: results of a randomized prospective trial. Br J Surg 1997; 84:1665–1669. 95. Braunschweig CL, Levy P, Sheean PM, Wang X. Enteral compared with parenteral nutrition: a meta-analysis. Am J Clin Nutr 2001; 74:534–542.

96. Duerksen DR, Bector S, Parry D, Yaffe C, Vajcner A, Lipschitz J. A comparison of the effect of elemental and immune-enhancing polymeric jejunal feeding on exocrine pancreatic function. J Parenter Enteral Nutr 2002; 26(3): 205–208. 97. Windsor AC, Kanwar S, Li AG, et al. Compared with parenteral nutrition, enteral feeding attenuates the acute phase response and improves disease severity in acute pancreatitis. Gut 1998; 42:431–435.

4 The Immune System and the Immunocompromised Patient Kathryn M. Verbanac, Lorita Rebellato, and Carl E. Haisch

International Workshops on Leukocyte Differentiation Antigens (6). Because the expression of cell surface antigens will vary qualitatively and quantitatively with both the maturation stage and activation state of the cell, monoclonal antibodies are also valuable for monitoring the phenotype of a specific leukocyte subpopulation (Table 1). Many of the cell surface antigens serve as specific receptors for ligands, thus ligand binding and receptor engagement have important immunological consequences. These ligands include immunoglobulins (Igs), complement, cytokines, viruses, and bacterial products.

INTRODUCTION The immune system functions to protect the body’s internal environment from a variety of potential insults such as foreign proteins, potentially adverse cells, microorganisms, and other noxious substances. Since immune competence plays such an important role in the insurance of good health and the response of a patient to surgical intervention, alterations in the immune system can greatly affect the outcome of an operation both in terms of morbidity and mortality. Immune competence reflects the highly integrated, carefully orchestrated homeostatic interplay of a number of physiologic processes whose primary function is to discriminate between substances that are part of the body’s own makeup (‘‘self’’) and those that are foreign to it (‘‘noself’’). The purpose of this chapter is to review the components of this immune system, how they interrelate, how this recognition of self and nonself occurs, and the impact that alterations in these processes can have on the surgical patient.

B-Lymphocytes A schematic diagram of an Ig is presented in Figure 2. The development of the B-lymphocyte occurs predominantly in the bone marrow of mammals and is centered around the expression of membrane-bound Ig. Because the antigenbinding variable region of the membrane Ig is extracellular, it readily binds to soluble antigen. The expression of surface Ig will imbue the B-lymphocyte with both antigen specificity and memory. After antigen binding, signal transduction is mediated by another component of the B-cell receptor, a disulfide-bonded heterodimer that is noncovalently complexed with surface Ig and is designated as Ig-a/Ig-b or CD79a/CD79b (7). The DNA encoding antibody heavy chains, k light chains, and l light chains are located on different chromosomes. Within each chromosome, Ig sequences are present in germ line DNA as multigene families that contain numerous gene segments (Fig. 3). In progenitor and precursor B-cells, the variable region–D region–joining region (V-D-J) gene segments that comprise the variable region of the heavy chain undergo random gene rearrangement to form a functional Ig heavy chain (8). This is followed by light chain gene rearrangements that result in the expression of membrane-bound IgM. These rearrangements are regulated so that only one of the allelic forms of the Ig is expressed, that is, DNA from only one of the parental chromosomes is rearranged. This is referred to as allelic exclusion and insures that Ig with a single antigenic specificity is expressed by a given B-cell. B-cells at this developmental stage are released from the bone marrow into the blood. Most B-cells encounter antigen in regional lymph nodes or in the spleen, where they undergo antigen-dependent stages of differentiation. In the absence of antigen activation, peripheral B-cells will die within several days. If the membrane-bound antibody present on the surface of the B-cell encounters specific antigen, these cells undergo class switching by additional gene rearrangements of the constant region of the heavy chain and by changes in RNA processing. These classswitching events lead to different clones of B-cells that

AN OVERVIEW OF THE IMMUNE SYSTEM In this section, we introduce the cellular components of the immune system, describe the initiation and effector stages of the humoral and cellular immune response, and discuss clinical assessment of immune function. This is to serve as a general introduction and review and to provide a basis for the clinical considerations that follow. There are several excellent textbooks on immunology, which should be referred to for a more comprehensive description of the immune system (1–5). In addition, we have cited key articles within each section that provide current reviews and references of the primary literature.

Cellular Components Leukocytes, the white blood cells that participate in the immune response, are derived from a common pluripotent stem cell in the bone marrow (Fig. 1). The mature cellular components of the immune system are distinguished on the basis of function and phenotype. Lymphocytes are distinguished from the other cells of the immune system because only lymphocytes exhibit diversity, specificity, memory, and self-/non–self-recognition. The cellular phenotype is principally defined by cell surface markers, the majority of which are designated cluster of differentiation (CD) antigens and are identified by monoclonal antibodies. Monoclonal antibodies serve as important immunological reagents for both the identification and quantitation of leukocyte and lymphocyte subpopulations that express these markers. There are currently 247 CD antigens that have been designated by the 65

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Part One: General Considerations

Pluripotent Stem Cell

Myeloid Progenitor

Lymphoid Progenitor THYMUS

B Lymphocyte

Erythroid Megakaryocyte Basophil Precursor Precursor

T Lymphocyte

Platelets

Basophils

Lymphoid/ Plasmacytoid Dendritic Cell DC2

Granulocyte-Monocyte Precursor

Eosinophil Precursor

Neutrophils

Erythrocytes

Natural Killer Cell

Monocytes

Eosinophils Macrophage

express different isotypes or classes of antibody with the same antigenic specificity. Different antibody isotypes have different effector functions, thus the range and type of immune response is broadened (Table 2). At this stage, some B-cells will clonally expand and differentiate into plasma cells that secrete various isotypes. Other B-cells will differentiate into memory B-cells that have a longer life span and express membrane-bound Ig of different isotypes. Memory B-cells are able to undergo somatic mutation to generate higher affinity antibodies, that is, antibodies with a greater binding strength or association constant, but of the same specificity. This process is termed affinity maturation. All of these mechanisms contribute to the generation of a high degree of antibody diversity; it is estimated that humans can produce antibodies that have 108 to 1011 different specificities.

T-Lymphocytes T-lymphocytes are termed ‘‘thymus dependent’’ because the lymphoid stem cell migrates from the bone marrow

Myeloid Dendritic Cell DC1

Figure 1 Maturation of blood cells from the pluripotent stem cell in bone marrow.

to the thymus, where it differentiates and matures during normal fetal development. It is in the thymus that T-cell receptor (TCR) rearrangement occurs to generate the diverse repertoire of antigen specificities exhibited by T-cell clones in the periphery. During thymic education, negative and positive selection processes result in the death of most high-affinity self-reactive T-cells (9). A large number of major histocompatibility complex (MHC)restricted T-lymphocyte clones survive that are tolerant to self-antigens and bear different antigen receptors, thus enabling adaptive immune responses to a large variety of pathogens. The TCR is the antigen-binding receptor on the surface of T-cells. It is expressed either as an a/b or a g/d heterodimer and is associated on the membrane with the multiple components of CD3 (Fig. 4). The invariant CD3 components (g, d, e, and z) are critical for the signal transduction events that occur after antigen binding (10). Interaction between an appropriate TCR and a peptide–MHC complex on antigen-presenting cells (APCs) or target cells induces

Table 1 Characteristic Leukocyte Cell Surface Markersa B-cell T-cell Th T cytotoxic NK cell Monocyte/macrophage Granulocytes a

CD19, CD20, CD21, CD22, slg, CD45RB, CD40, CD80/CD86 (B7-1/B7-2) CD2, CD3, CD5, TCR, CD28 CD4 CD8 CD2, CD16 (FcgRIII), CD56, CD11b (iC3bR), CD11c CD11b, CD11c, CD14, CD16, CD32 (FcgRII), CD64 (FcgRI), CD91 CD10 (CALLA), CD11b, CD11c, CD14, CD15 (Lewisx), CD16, CD32

This list is not comprehensive. The cell surface antigens unique to the cell type are in italics. The combination of coexpressed antigens is often most characteristic of a cell type. Abbreviations: CD, cluster of differentiation; Th, T helper; TCR, T-cell receptor.

Chapter 4: The Immune System and the Immunocompromised Patient

Figure 2 Schematic diagram of an immunoglobulin molecule. Each heavy (H) and light (L) chain contains an amino-terminal variable (V) region that is unique to each B-cell clone and which together form the antigen-binding site. The constant (C) domains exhibit limited variation and define the immunoglobulin isotype and effector functions. Intrachain and interchain disulfide bonds play a major role in the folding of the protein domains and in the formation of the polypeptide chain tetramer. The g, d, and a heavy chains contain a hinge region and the m and E heavy chains contain a fourth central CH domain.

the redistribution and/or catalytic activation of intracellular protein tyrosine kinases. These kinases then phosphorylate immunoreceptor tyrosine-based activation motifs (ITAM) within the cytoplasmic domains of the invariant chains of the CD3 subunits. This initial phosphorylation is followed

67

by a cascade of diverse intracellular signals, whose key outcome is to affect the expression of cytokine genes. Although the TCR is the unique distinguishing marker for the T-cells today, T-cells were historically distinguished from B-cells on the basis of the so-called E rosette receptor, now designated CD2. T-cells have been subdivided into two subtypes: those with helper function (primarily CD4þ) and those with cytotoxic function (primarily CD8þ). In the thymus, CD4
CD8
bone marrow progenitors go through sequential developmental changes before the so-called single positive T-cells, expressing either CD4 or CD8, and the abTCR are produced. Although these latter cells comprise the vast majority of peripheral T-cells, it has recently been discovered that a small number of T-cells expressing the gdTCR are present in adult epithelial tissues and they can also be found in lymphoid organs. The majority of the abTCRþ T-cells in the periphery are naive or precursor T-cells that have not yet encountered antigen and are in the G0 stage of the cell cycle. Once antigen activated (as discussed below), these cells become effectors that perform helper, cytotoxic, or delayed-type hypersensitivity (DTH) functions. Memory T-cells are also generated during a primary response to antigen and recirculate in the blood and lymph as extremely long-lived resting cells with less stringent requirements for activation. Antigen-stimulated T helper (Th) cells have been classified into Th1 and Th2 cells on the basis of the distinct cytokines they secrete and on the functional effects of these cytokines. Originally discovered in mice, Th1 and Th2 patterns of cytokine exist in humans as well, but the cytokine patterns are less exclusive. In humans, interferon (IFN)-g is most consistently expressed by Th1 cells, and interleukin (IL)-4, IL-5, and IL-9 are most consistently produced by Th2 cells. IL-2 and tumor necrosis factor (TNF)-b (predominantly Th1 cytokines) and IL-6, IL-10, and IL-13 (predominantly Th2

Germ-line H-chain DNA (Chromosome 14) L VH1−L VH100

DH1−DH30 JH1−JH6

Cµ1 Cµ2

Cµ3

Cµ4

Cδ−Cγ−Cε−Cα

5'

3'

L Vκ1−L Vκ100 Germ-line κ-chain DNA (Chromosome 2)

Jκ1−Jκ100 Cκ

5'

3'

Germ-line λ-chain DNA (Chromosome 22) L Vλ1−L Vλ100

Jλ1 Cλ1

Jλ2 Cλ2 Jλ3 Cλ3 Jλ4 Cλ4 Jλ5 Cλ5 Jλ6 Cλ6

5'

3'

GENE REARRANGEMENT - DJ Joining, VDJ Joining, VJ Joining GENE TRANSCRIPTION - Polyadenylation and Splicing RNA TRANSLATION

Nascent Polypeptides VDJ Cµ1 Cµ2 Cµ3 Cµ4

VJ Cκ +

VHCµ

= VκCκ

Membrane lgM

Figure 3 Immunoglobulin gene rearrangement for surface IgM expression in B-cells. Abbreviation: IgM, immunoglobulin M.

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Part One: General Considerations

Table 2 Properties and Biological Activitiesa of Serum Igs Property/activity c

Molecular weight (kDa) Heavy-chain component Normal serum level (mg/mL) In vivo serum half-life (days) Activates classical complement pathway Crosses placenta Present on membranes of mature B-cells Binds to phagocyte Fc receptors Mucosal transport Induces mast-cell degranulation

IgG1

IgG2

IgG3

IgG4

IgA1

IgA2

IgMb

IgE

IgD

150 1 9 23 þ

150 2 3 23 þ/


150 3 1 8 þþ

150 4 0.5 23 –

150–600 1 3 6 –

150–600 2 0.5 6 –

900 m 1.5 5 þþþ

190 E 0.0003 2.5 –

150 d 0.03 3 –

þ –

þ/
–

þ –

þ –

– –

– –

– þ

– –

– þ

þþ

þ/


þþ

þ

–

–

?

–

–

– –

– –

– –

– –

þþ –

þþ –

þ –

– þ

– –

a

Activity levels indicated as follows þþ, high; þ, moderate; þ/
, minimal; ?, questionable; and
, none. þ IgM is the first isotype produced by the neonate and during a primary immune response. c þ IgG, IgE, and IgD always exist as monomers; IgA can exist as a monomer, dimer, trimer, or tetramer. Membrane-bound IgM is a monomer, but secreted IgM in serum is a pentamer. Abbreviation: Ig, Immunoglobulins. Source: From Ref. 5. b

cytokines) tend to segregate less clearly among human subsets than in the mouse. Cytokines produced by APCs are the dominant factors guiding the development of Th1 and Th2 cells. Furthermore, specific transcription factors are required to be activated for each pathway: T-bet and signal transducer and activator of transcription (STAT)-4 for Th1 cells and GATA-3 and STAT-6 for Th2 cells (11,12). Reciprocal regulation occurs between the Th1 and Th2 subsets, mediated by Th cytokine effects on differentiation and on effector functions.

Figure 4 Schematic diagram of the TCR-CD3 complex. The polypeptide chains of CD3 noncovalently associate with the TCR a/b chains and with each other as heterodimers as well as ZZ homodimers. The solid rectangle represents an ITAM. Abbreviations: TCR, T-cell receptor; ITAM, immunoreceptors tyrosme-based activation motifs.

Antigens derived from pathogens stimulate the clonal proliferation of T-lymphocyte precursors that carry receptors specific for that antigen. Thus, in response to different pathogen-derived antigens, CD4 T-cells become either Th1 or Th2 cells. Th1 cells produce the cytokine IFN-g and are effective against intracellular bacteria, viruses, and protozoa, whereas Th2 cells produce IL-4, IL-5, and IL-13 and eliminate extracellular parasites. Like Th1 cells, CD8 T-cells are activated in response to intracellular pathogens and share some of the same effector mechanisms, particularly production of IFN-g. Upon antigenic stimulation, Th1 cells secrete IL-2, IFN-g, and TNF-b, which serve to channel the immune system toward cell-mediated immunity (CMI), including macrophage activation and DTH responses. Th1 cells are thus effective in the defense against intracellular pathogens (e.g., Leishmania) and are thought to be involved in the pathogenesis of acute allograft rejection, organ-specific autoimmune disorders, contact dermatitis, and certain chronic inflammatory diseases. In contrast, Th2 cells secrete IL-4, IL-5, IL-6, and IL-10, induce humoral and allergic responses, and are most effective against extracellular microorganisms and soluble toxins. Studies of Th2 cells have concentrated on IgE responses to helminth antigens and allergens. Th2 cytokines generally exert anti-inflammatory, immunosuppressive effects, and Th2 responses have been associated with transplantation tolerance, the immunopathology of chronic graft-versus-host disease, and systemic autoimmune disease. It is clear that reciprocal regulation occurs between the Th1 and Th2 subsets, mediated by specific cytokine effects on differentiation and on effector functions. Over the past five years, a great deal of interest has focused on regulatory T-cells (Treg) that appear to control the development of autoimmune disease and transplant rejection, and that might also play a critical role in controlling the expression of asthma and allergy. The term ‘‘regulatory T-cell’’ refers to cells that actively control or suppress the function of other cells, generally in an inhibitory fashion. CD4þCD25þ Treg cells have emerged as a unique population of suppressor T-cells that maintain peripheral immune

Chapter 4: The Immune System and the Immunocompromised Patient

tolerance (12,13). Transforming growth factor (TGF)-b has been implicated in the conversion of na€
ve CD4þCD25
T-cells into CD4þCD25þ anergic/suppressor T-cells (14). The Treg subset has been isolated in humans, but it is still unclear if these regulatory cells can be used to inhibit ongoing T-cell responses in vivo or to reverse established pathology. There have not been similar functional divisions of CD8þ T-cell subpopulations. Although CD8 originally characterized suppressor and cytotoxic cells, a definitive CD8 suppressor cell has been elusive and has not been isolated or cloned. Therefore, most contemporary immunologists view the suppressor cell as a functional designation rather than the definition of a separate subpopulation. The classical CD8þ T-lymphocyte is the cytotoxic T-lymphocyte (CTL). CTL are MHC class I–restricted cells, which recognize and eliminate ‘‘altered self’’ target cells. Target cells include virally infected cells, malignant cells, and allogeneic cells. The primary mechanism of CTL-mediated killing, at least in vitro, involves granule exocytosis and release of a poreforming protein (perforin) and a battery of serine proteases (granzymes) that rapidly induce target cell lysis (15). CTL can also use the Fas (CD95) pathway to induce apoptosis, or programmed cell death, of target cells (16).

NK Cells Although their developmental pathway is not fully understood, natural killer (NK) cells, like T- and B-lymphocytes, arise from CD34þ lymphoid stem cells in the bone marrow. NK cells make up 5% to 10% of human peripheral blood mononuclear cells (PBMC). NK cells are termed null cells, because they do not express the distinct cell membrane markers that would characterize them as T- or B-cells, including the T-cell and B-cell antigen-binding receptors. NK cells and T-cells are both CD2þ and are thought to share a common thymic developmental precursor. Unlike CTL, NK cells typically express the phenotype CD16 and CD56 and do not typically express CD3 or CD8. Distinct subpopulations of NK cells with atypical phenotypes have been observed at very low levels in normal individuals, and at significant levels in recovering bone marrow–transplant recipients. NK cells were originally referred to as large granular lymphocytes, and discovered on the basis of their tumoricidal activity. The granules contain cytotoxic agents, including perforin and granzymes. The adjective ‘‘natural’’ refers to the important fact that NK cell–effector activity does not require antigen activation or sensitization and thus provides ‘‘natural immunity’’ or ‘‘innate’’ antiviral and antitumor protection. This immunity is critical in the early days of exposure, before CTL precursor cells can become activated and proliferate and differentiate into mature CTLs. Unlike CTLs, most NK cells do not express antigen receptors, hence they do not exhibit immunological specificity or memory. NK cells uniquely express inhibitory NK-cell receptors (NKR) that recognize polymorphic epitopes common to groups of human leukocyte antigen (HLA) alleles and transduce inhibitory signals, which suppress the NK-mediated cytolysis (17). NK cells thus recognize ‘‘absence of self,’’ and healthy cells avoid being killed via their expression of self-HLA. If HLA class I expression is downregulated by a viral infection or tumor transformation, no inhibitory signal is generated and the NK cells release their lytic mediators to kill these abnormal cells. In addition to inhibitory NKR, NK cells may also express activating NKR that are specific to MHC class I–related molecules expressed during infection, tumor transformation, or stress. The ligation of activating

69

NKR will further enhance the NK-cell lytic activity. Each NK cell of an individual can express a unique receptor repertoire, with a spectrum of different numbers (1–19) and combinations (inhibitory and activating types) of killer immunoglobulin-like receptors (KIR) and NKG2 receptors with multiple class I specificities. NK cells also identify target cells and mediate antibody-dependent cell-mediated cytotoxicity (ADCC), which is described in detail later in this chapter. In short, NK cells express CD16 (the Fc gamma receptor IIIA) and can thus bind IgG that is bound to target cell membranes. CD16 engagement activates the NK cell, inducing the lytic mechanism and cytokine production. NK cells appear to kill target tumor cells and virally infected cells by mechanisms similar to those described for CTL, namely the release of lytic granules. NK cells have also been recently shown to induce apoptosis via direct target cell killing or in ADCC. These two mechanisms are probably not mutually exclusive and some studies suggest that perforin and granzymes may synergistically trigger apoptosis.

Monocytes/Macrophages The remaining cellular components to be described also develop from the pluripotent hematopoietic stem cell in the bone marrow, but from the myeloid lineage, rather than the lymphoid lineage. These cells differ from lymphocytes in several significant properties; they lack antigen specificity and they lack memory. The monocyte is a phagocytic mononuclear myeloid cell that circulates briefly before migrating into tissue where it differentiates into a macrophage. The macrophage can take up permanent residence in particular tissues or remain motile. The primary function of the monocyte/macrophage is to phagocytose and eliminate antigen (18). Their digestive granules contain lytic enzymes, reactive oxygen and nitrogen intermediates, and TNF. Macrophages can ingest and digest whole microorganisms as well as injured and dead cells, cellular debris, and activated clotting factors. The macrophage also digests internalized proteins and presents peptides in association with MHC class II on its surface. It plays a critical role in Th cell activation, both as an APC and as a source of IL-1. The Th cell, in turn, promotes macrophage activation by secretion of IFN-g. Activated macrophages have increased phagocytic and microbicidal activity and secrete many factors that promote the inflammatory response. Finally, monocytes and macrophages express all three forms of the FcgR (CD16, CD32, and CD64), and thus can participate in ADCC, which is discussed later.

Dendritic Cells The dendritic cell (DC) has achieved recent prominence as the most highly specialized APC due to its superior ability to activate na€
ve T-cells to initiate immune responses (19). DCs appear to originate from bone marrow precursors of two different hematopoietic lineages. CD11cþ Type 1 DC (DC1) is myeloid derived, either directly from myeloid progenitors or from monocytes (20). CD11c Type 2 DC (DC2) appear to be lymphoid derived, and DC2 CD4þ precursors have been referred to as plasmacytoid T-cells, plasmacytoid monocytes, type 1 IFN-producing cells, and plasmacytoid DC (21). Although DC1 and DC2 were initially thought to secrete cytokines to induce respective Th1 and Th2 responses, it now appears that this functional correlation is not rigid. DCs are located throughout the body in different maturation states and they mature into potent APCs during

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Part One: General Considerations

conditions of infection or inflammation. DCs are characterized by branch-like membrane projections, motility in response to chemokine gradients, and surface expression of MHC class I and II and of the costimulatory molecules CD40, CD80, and CD86. These properties are responsible for their superior ability to capture and present antigen, to travel from the sites of infection to lymphoid organs where they activate na€
ve T–cells, and initiate immune responses.

Granulocytes Granulocyte is a general term for a motile cell that contains cytoplasmic granules. These cells are categorized into basophils, eosinophils, and neutrophils on the basis of cell morphology and cytoplasmic staining properties. Granulocytes characteristically play a major role in the inflammatory response, which can be beneficial in host defenses and detrimental in inflammatory diseases. Neutrophils are also referred to as polymorphonuclear leukocytes (PMNs), and constitute 50% to 70% of the circulating white blood cells in humans. Neutrophils are active phagocytic scavengers of the immune system and are usually the first cells to arrive at an inflammatory site. Their granules contain lytic enzymes, bactericidal defensin peptides, and reactive oxygen and nitrogen intermediates; however, unlike macrophages, they do not contain TNF. The neutrophil is a critical effector cell in humoral and innate immunity and plays a key role in bacterial killing (22). Eosinophils are also phagocytic and function primarily against parasites via ADCC. They are the principal effector cell for the pathogenesis of allergic inflammation, caused by granular proteins that include eosinophil cationic protein, major basic protein, and eosinophil protein X (23). The nonphagocytic basophils play a major role in allergic responses when they release their granules of pharmacologic agents, including histamine.

The Innate Immune Response The innate immune response refers to the rapid response to microbial infection that relies on preexisting mechanisms (24). The innate immune system includes epithelial barriers, phagocytic cells, NK cells, the complement system, and cytokines. The innate immune response lacks both specificity and memory and is activated by a large variety of conserved molecular structures that are unique to microorganisms. These are primarily microbial metabolites that are referred to as pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS), peptidoglycan, b-glucans and mannans, and double-stranded RNA. Families of Toll-like receptors (TLRs) on macrophages and DCs that recognize distinct PAMPs are now known to be the primary sensors of microbial infection. In addition to contributing to the signal transduction induced by many PAMPs, TLRs may also contribute to endogenous damage signals at inflammatory sites (25).

The Acquired Immune Response The interaction of a Th cell with an APC is the central event that initiates virtually all acquired immune responses, for generation of both CMI and antibody-mediated immunity (humoral). The T-cell and APC interact primarily in the secondary lymphoid organs—the lymph nodes and the spleen. Antigen can be transported to these organs as soluble antigen, as antigen-antibody complexes, or via mobile APC (including certain DCs and macrophages). After recognition of a peptide–MHC class II complex on an APC, Th cells are

activated and proliferate extensively. The Th cell progeny secrete cytokine ‘‘help’’ and play a central role in the activation of B-cells, T cytotoxic cells, and macrophages.

T-Cell–APC Interactions This association is based upon specific antigen recognition and is mediated by the requisite binding of two cell surface molecules, the TCR of the Th cell with the MHC–peptide complex of the APC. MHC molecules (termed ‘‘HLA’’ in humans) are cell surface molecules encoded by the MHC gene complex, which control the ability of an animal to respond immunologically to a given antigen. The multiple alleles (estimated at greater than 300) within a given HLA locus encode highly polymorphic gene products that vary in their individual ability to bind a specific peptide. The inherited HLA polymorphisms provide a large repertoire of specificities for antigen-derived peptides and thus provide the host with the ability to respond immunologically to a large range of different antigens. T-cells can also recognize microbial lipid and glycolipid antigens presented by CD1 proteins. CD1 belongs to MHC class I molecules that map outside of the MHC, have limited tissue distribution, and include H2M3 and MICA as members. CD1 proteins (CD1a, -b, and -c) can present foreign microbial lipid antigens, including several mycobacterial antigens. CD1d-restricted natural killer T-cells (NKT) play a role in immunity to bacteria, parasites, yeasts, and viruses (26). In particular, CD1d-restricted NKT-cells can activate innate and adaptive immune responses and appear to modulate immunity to infectious agents (27). Although difficult to characterize in humans, NKT-cells express a/b TCR and NKR1.1, a C-type lectin receptor. Many cell types can present antigen to T-cells, that is, they can degrade and present antigen-derived peptides via their MHC class I and class II molecules. The so-called ‘‘professional antigen presenting cells (APC)’’ are those cells that constitutively express MHC class II antigens, and, in humans, include DCs, macrophages, B-cells, and vascular endothelial cells. These cell types can vary in the effectiveness with which they present antigen and stimulate an immune response in vitro. The DC appears to be one of the most potent APC in vitro, expressing high levels of MHC class II and possessing long dendrite-like membrane processes that provide a large surface area for cell–cell interactions. The concentration of antigen, as well as other variables, may determine which cell type is the operative APC in vivo. Because a B-cell recognizes an antigen specifically via its surface Ig, it can present antigen effectively even at very low antigen concentrations. After intracellular degradation of foreign proteins, the MHC class I and class II molecules of the APC bind certain processed peptides within a groove formed by the polymorphic residues of the MHC. The TCR thus recognizes the specific amino acid sequence of a peptide (processed antigen) in association with self-MHC. This interaction is termed self-MHC restriction or associative recognition. APC generally ‘‘present’’ processed foreign antigen that are in association with MHC class II to CD4 T-cells and in association with MHC class I to CD8 T-cells (Fig. 5). CD4 and CD8 specifically recognize residues within the monomorphic conserved domains of MHC class II and class I antigens, respectively; thus CD4 and CD8 cells are termed MHC class II– and MHC class I–restricted, respectively. There are additional accessory cell surface proteins that play important roles in the T-cell–APC interaction. Some act as adhesion molecules to stabilize or increase the strength of T-cell–APC interactions and redistribute within the membrane to contribute to the formation of the immunological synapse

Chapter 4: The Immune System and the Immunocompromised Patient

Figure 5 Antigen presentation and recognition.

between the two cell types. Examples of such T-cell–APC ligand pairs include CD2–leukocyte function antigen (LFA)-3; LFA-1– ICAM-1 or ICAM-2; CD4–MHC class II; and CD8– MHC class I. Some ligand pair interactions provide signals to enhance T-cell activation—many ligands have cytoplasmic domains possessing enzymatic activity, usually kinase activity (phosphorylating enzymes). Such ligands are often called signal transducers because they send a signal from outside the cell to the inside. CD4 and CD8 molecules are associated with intracellular T-cell protein tyrosine kinases that appear to be activated by binding to the monomorphic domains of MHC molecules. There is compelling evidence that certain ligand pair interactions provide critical ‘‘second signals’’ required for T-cell activation after the antigenic ‘‘signal 1’’ is delivered via TCR ligation to the MHC peptide. In addition to the TCR, T-cells have multiple so-called ‘‘coreceptors’’ with both shared and unique properties that regulate the T-cell response. The most significant activating ligand pairs that have been identified on T-cells and APC, respectively, are CD40L–CD40 and CD28–CD80 (28,29). In the current working model of Th cell activation (Fig. 6), CD40L expression is upregulated by T-cells that have received signal 1 (ligation

Figure 6 T-cell activation.

71

of the TCR with MHC antigen). CD40L can then engage CD40, its cognate ligand on the APC, which in turn triggers the APC to upregulate the expression of CD80 and CD86 (originally named B7.1 and B7.2). CD80 binding to CD28, which is constitutively expressed on T-cells, results in full T-cell activation. Inducible costimulatory molecule is a coreceptor that is induced in na€
ve and memory T-cells, binds to B7H on APC, and apparently provides signals that can substitute for CD28. Finally, CTL antigen-4 is a T-cell coreceptor that is homologous to CD28, and is a negative regulator of T-cell responses by inhibiting proliferation. It is important to note that APC activation is usually a corollary to these interactions and is also dependent on CD40–CD40L engagement. Activated B-cells, macrophages, and DCs are key players in the effector phase of an immune response. Soluble cytokines are also involved in mediating this ‘‘cross-talk,’’ and include T-cell–derived IL-4 as well as IL-1, IL-6, and IL12, which are secreted by specific APC cell types. Once the Th cell is activated by productive engagement of the appropriate receptor ligand pairs, and after receipt of the appropriate signals, it produces IL-2 ‘‘help,’’ which functions in an autocrine manner to induce proliferation and clonal expansion. These Th progeny can now produce cytokines that ‘‘help’’ B-cells, macrophages, and CTLs differentiate and perform their full effector functions. The central role of the Th cell in the effector mechanisms of the immune response is presented in Figure 7.

The Humoral Immune Response It is clear that B-cells, T–cells, and APC are required for the generation of most humoral immune responses. As described above, the B-cell antigen receptor is a multicomponent receptor consisting of surface Ig noncovalently associated with two other distinct transmembrane proteins. The surface antibody mediates the internalization of specific antigen via receptor-mediated endocytosis. In the B-cell endosome, newly synthesized MHC class II antigens encounter peptides derived from antigen proteolysis and present certain peptides on the surface of the B-cell. These ‘‘antigen primed’’ B-cells act as APC to interact with activated Th cells (which are antigen specific on the basis of their TCR) and form specific B–Th cell conjugates. Antigen-specific conjugate formation appears to actually cause redistribution of the TCR, LFA-1, and CD4 molecules within the T-cell at the interface of the cell-to-cell contact. Conjugate formation induces T-cell expression of CD40L, which then engages CD40 on the B-cell surface, as described above. The B-cell receptor itself is associated with cytoplasmic src-family tyrosine protein kinases that are activated upon antigen binding and initiate an intracellular signaling cascade that leads to many cellular responses, including cytokine production. B-cell activation ensues, triggered by a combination of membrane events and cytokine signaling. The Th cytokines IL-1 and IL-4 play predominant roles as the costimulatory signals in B-cell activation. The activated B-cell is driven into the S (or DNA synthesis) phase of the cell cycle by IL-2, IL-4, and IL-5. As discussed earlier, IgM is the first isotype expressed by plasma cells during a primary immune response. Numerous Th1 and/ or Th2 cytokines (including IL-2, IL-4, IL-5, IFN-g, and TGF-b) induce differentiation into plasma cells, producing different Ig isotypes. The changes in the activation and maturation stage of the cells are caused as well as marked by changes in gene expression.

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Part One: General Considerations

APC

T helper cell

IL-2, IL-4, IL-5, IL-6 IL-2

TDTH

Activated macrophage

IL-2

+

+

CD8 TC

CD4 TC

B cell

IFN-γ TNF-β

Cytotoxicity MHC expression

CD8+ CTL

Lytic enzymes Class I MHC alloantigen

Membrane damage Class II MHC alloantigen

CD4+ CTL

NK cell or macrophage C

Lysis

Target tissue

It must be noted that ‘‘T-independent’’ antigens exist that can directly stimulate B-cells and elicit antibody responses without the assistance of Th cells (30). This type of antigen, usually carbohydrate in nature and comprised of repeating epitopes, is best exemplified by bacterial polysaccharides. Complement-Mediated Cytolysis It is the major effector of the humoral immune response. Complement refers to a group of at least 20 distinct serum proteins that participate in a highly regulated enzymatic cascade (31,32). There are two pathways of complement activation, the classical and the alternative pathways. Both pathways generate a membrane attack complex that forms pores in cell membranes and causes cell lysis. A conformational change occurs when an antibody binds to its antigen on a cell surface, such that a binding site on the Fc portion of the molecule is exposed. Binding of the C1 component of the complement system to the Fc sites exposed on two adjacent antibody molecules activates the classical pathway. In humans, IgM and certain subclasses of IgG (IgG-1, -2, and -3) are capable of ‘‘fixing’’ complement in this manner. The alternative pathway is usually initiated by bacteria, yeast, and certain viruses in an antibody-independent fashion. Complement reaction products cause vasodilation and chemotaxis to promote a localized inflammatory response and also act as opsonins to promote phagocytosis of antigen. Anaphylaxis It is an immediate hypersensitivity reaction that is triggered by IgE-mediated mast cell or basophil degranulation and

ADCC

Fc receptor

Figure 7 Schematic of the central role of the Th cell in the effector mechanisms of the immune response. Abbreviations: C, complement; ADCC, antibody-dependent cell-mediated cytotoxicity; Th cell, T helper cell. Source: From Ref. 5.

is initiated within 2 to 30 minutes of antigen exposure. Anaphylaxis can be localized to a specific target tissue or can occur throughout the organism, inducing systemic effects that can be fatal. Upon primary exposure to parasitic antigens or allergens, B-cells are activated to become IgEsecreting plasma cells. IgE binds to the cell surface of mast cells and basophils via the high-affinity FceRI, thus increasing the half-life of IgE from days to weeks. Mast cells are bone marrow–derived cells that differentiate in connective tissues where they reside. Upon secondary exposure to antigen, the IgE on these sensitized cells is cross-linked, which triggers degranulation and the release of pharmacologically active mediators. These mediators include histamine and serotonin, which cause increased vascular permeability and smooth muscle contraction, as well as granulocyte chemotactic factors and proteases that mediate tissue destruction. Additional secondary mediators such as leukotrienes are generated by the breakdown of the mast cell membrane phospholipids after degranulation. Eosinophils are also attracted to the site and can bind directly to antibody-coated antigen. They in turn are activated, degranulate, and release inflammatory mediators. Opsonization It refers to the deposition of molecules on an antigen (including a microorganism) that promotes contact with an appropriate phagocytic cell. Such molecules, or opsonins, are usually antibodies or components of complement. Because macrophages and granulocytes express receptors for both antibody and complement on their cell surfaces, opsonization increases antigen binding by these phagocytes.

Chapter 4: The Immune System and the Immunocompromised Patient

Opsonins thus serve as a bridge between antigens and effector cells. The enhanced antigen binding results in a significant increase in the rate of phagocytosis.

Antibody-Dependent Cell-Mediated Cytotoxicity Antibodies can also affect cell-mediated responses to foreign cells in a complement-independent process termed ADCC (22). In this scenario, antibody serves as a bridge connecting a foreign target cell to an immune effector cell, and thus provides antigen specificity to a nonspecific cytotoxic cell. NK cells, neutrophils, macrophages, and eosinophils express Fc receptors on their cell surfaces. These receptors can thus recognize the carboxy terminal region of an Ig molecule that is bound to foreign cells via its amino-terminal antigen-binding hypervariable domains. This binding stimulates the cytotoxic cell to increase the lytic components in their cytoplasmic granules (including enzymes, TNF, and perforin) and then to release the granule contents, culminating in destruction of the target cell.

CTL-Mediated Cytotoxicity The CTL-mediated immune response is initiated by the activation and differentiation of precursor CTL (CTLp) into functional effectors. The interaction of the TCR of a resting CTLp with the MHC class I–peptide complex of its target cell induces the expression of T-cell IL-2 receptors. As described earlier, IL-2 ‘‘help’’ is produced as a result of a similar interaction between CD4þTh and MHC class IIþ APC. This IL-2 provides the principal ‘‘second signal’’ required by CTLp for activation, triggering its clonal proliferation and differentiation into a mature CTL effector. As discussed above, other ligand interactions also appear to supply strong costimulatory signals. The B7/CD28 interaction has been reported to induce CTLp to express IL-2 by themselves, bypassing the requirement for Th cells. The CTL progeny, mature effectors, are now able to form conjugates with target cells that bear the appropriate MHC class I–peptide complexes. Exocytosis of cytoplasmic granules at the interface of cell–cell contact releases lytic molecules that damage the membrane of the target cell and cause death, as described above. Secondary to antigen recognition, the LFA-1/ICAM interaction between the T-cell and target cell appears to be critical for both conjugate formation and subsequent dissociation of the CTL from the target cell.

DTH Reactions DTH responses refer to an increased reactivity to a specific antigen, which is T-cell–mediated. The increased reactivity is a function of previous antigen sensitization (via APC–T-cell interactions described above) that has induced T-cells to proliferate and differentiate into a subset of T-cells (usually CD4þ Th1), designated TDTH cells. Following the second exposure to an antigen, TDTH cells secrete a myriad of cytokines, which induce a localized inflammatory reaction (DTH). Macrophages are attracted by these cytokines and activated. The DTH response usually peaks 48 to 72 hours after secondary contact. This response is important and generally very effective in the defense against intracellular pathogens and contact antigens.

Mediators of Immune Function As previously discussed, cytokines play a major role in immune function and regulation (33). Cytokines are regulatory proteins that have pleiotropic effects on cells that participate

73

in host defense and repair processes via control of cell differentiation, activation, and proliferation. Originally termed ‘‘lymphokines,’’ the cytokine terminology evolved to indicate that these factors can be non–lymphocyte derived and can also have nonlymphoid targets. The current ‘‘interleukin’’ terminology was born at the 1978 Second International Lymphocyte Workshop, and incorporates the concept of bidirectional, intercellular signaling between somatic, myeloid, and lymphoid cells. At this writing, IL-30, a member of the IL-2 subfamily, is the most recent cytokine named by the IUIS/WHO Standing Committee on Interleukin Designation (34). Cytokines typically are very potent—they act at picogram-nanogram levels and exert paracrine and autocrine effects. The expression of cytokines is inducible, triggered by diverse stimuli from diverse cellular sources. Cytokines operate in a network that can be overlapping, redundant, synergistic, additive, and/or antagonistic. Cytokines are grouped into families based on structural homologies and are also classified by function (see Table 3 for representative examples). Finally, they act by binding to high-affinity receptors that are transmembrane proteins, many possessing kinase activity or enzymatic activities, which activate the kinases that effect signal transduction. Further comprehensive descriptions of the cytokines are beyond the scope of this chapter and can be found elsewhere (35,36).

Clinical Assessment of Immune Function Clinical assessment of human immune function can help define defects in local and systemic defense mechanisms. This is true for both patients with primary hereditary immunodeficiencies and for those with acquired immunodeficiencies. Although some of the tests described below are not routinely conducted clinically, they are available at most tertiary care centers and can be valuable for the identification of the immunocompromised patient at increased risk for local and systemic infections. A summary of laboratory tests used to detect immunodeficiencies is found in Figure 8. An obvious key to the successful treatment of infection in the immunocompromised host is early diagnosis of infection. Discussion of these detection techniques is beyond the scope of this review; however, it should be noted that advances in molecular biology have brought innovations to these analyses. Molecular techniques include the use of chemiluminescent-labeled DNA probes that hybridize to DNA of specific bacteria and viruses as well as virus- and bacteria-specific DNA primers that have been developed for DNA amplification in the polymerase chain reaction. In this section, we will briefly discuss some of the clinical predictors and laboratory tests that are available.

Leukocyte Enumeration and Subsets Quantitative determinations of circulating leukocytes are routinely determined by critical blood count (CBC), including platelet size and number and differential analysis (Table 4). This test will detect gross changes in cells that might occur in conditions such as leukemia or in certain immunodeficiency diseases. CBC is the first step to evaluating all suspected immune defects and the absolute counts must be compared to age-appropriate normative values. Small-sized platelets are a characteristic finding in Wiskott– Aldrich syndrome. The absolute neutrophil count is very important in cancer patients; less than 1000 cells/mL strongly correlates with an increased incidence of sepsis and less than

74

Part One: General Considerations

Table 3 Cytokine Classification by General Function Hematopoietic B-cell Growth T-Cell Growth Antiviral Inflammatory Chemotactic Antimitotic Immunosuppressive

IL-3, IL-11, IL-17, colony-stimulating factors, stem cell factor, erythropoeitin IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IL-14, IL-15, IL-21, TGF-b IL-2, IL-4, IL-7, IL-9, IL-12, IL-15, IL-16, IL-18, IL-21, IL-23, IL-27 Interferon family (a/b/c/x, s), IL-28, IL-29 TNF family (TNFa/b, Lymphotoxin), IL-1 family (IL-1a/b, IL-1RA), MIF, IL-6, IL-8, IL-17 IL-8, MCP-1-MCP-5, MIP-1, MGSA/GRO, RANTES, IL-16 TNF family IL-4, IL-10, IL-13, TGF-b

Abbreviations: IL, interleukin; TGF, transforming growth factor; TNF, tumor necrosis factor; IL-1 RA, IL-1 receptor antagonist; MCP, macrophage chemotactic protein; MIF, migration inhibitory factor; MGSA, melanocyte growth stimulatory activity; GRO, growth-related oncogenes.

500 cells/mL, if not corrected, is associated with an increased incidence of death. The CBC may be normal, however, in the most common immune deficiency, asymptomatic selective IgA (SIGA) deficiency. If lymphopenia is observed, screening for T- and B-cell disorders should be initiated. Enumeration of lymphocyte subsets can be performed by flow cytometric analysis, and characteristic markers have been described in the previous sections. Flow cytometry has become an important part of the workup of patients suspected of having primary immunodeficiency diseases (38). For example, there is a marked reduction of both T- and B-cell counts in severe combined immunodeficiency disease (SCID). Although lymphocytes comprise about 25% of the mononuclear cells in the human circulation, the blood actually contains a small proportion (about 2%) of the body’s total T- and B-lymphocyte pool (39). Lymphocyte trafficking is regulated largely by differential expression of adhesion molecules and chemokine receptors on T-cells (40). The

majority of the lymphocytes are concentrated in the lymph nodes and the spleen, however, it is estimated that about 500  109 lymphocytes travel through the blood compartment each day. The CD4:CD8 ratio in peripheral blood cells is approximately 2:1 in healthy individuals, and deviations from this ratio can be prognostic indicators of immune dysfunction, especially of immunodeficiency and autoimmune diseases. This ratio is monitored closely clinically in conditions such as AIDS. However, the blood does not always mirror lymphocyte alterations in other tissues, and inferences about pathological changes in other organs must be made judiciously. As a further caution, CD4 and CD8 are not absolute indicators of cell function. Bone marrow and lymph nodes may also be examined in addition to blood, to determine if the immune cell distributions are normal. Flow cytometry can also analyze cell surface antigens that are unique to cells at different stages of differentiation,

Figure 8 A diagnostic testing algorithm for primary immunodeficiency diseases. Source: From Ref. 37.

Chapter 4: The Immune System and the Immunocompromised Patient

Table 4 Normal Adult Circulating White Blood Cell Populations Cell type White blood cells Lymphocytes T-cells B-cells NK cells Monocytes Granulocytes Neutrophils Eosinophils Basophils

Absolute counta 4.5–11.0 1–4.8

0–0.8 1.8–8.4 1.8–7.7 0–0.5 0–0.2

Percentage 25–30% of white blood cells ~70% of lymphocytes 15–25% of lymphocytes 5–15% of lymphocytes

50–70% of white blood cells

(103 cells mm
3) Abbreviation: NK, natural killer. a

as described earlier for surface Ig isotypes in B-cell development. Flow cytometry has basically replaced previous tests such as E-rosette formation for T-cell detection and fluorescent microscopy detection of surface Igs for B-cells. Flow cytometry can be used to enumerate a specific cell type, evaluate function, or detect a specific gene product. Most major immunodeficiency diseases can be diagnosed by flow cytometry, with the exception of Che´diak–Higashi syndrome, ataxia telangiectasia, and complement deficiencies (38). The enzyme-linked immunospot (ELISPOT) was developed to detect and quantitate plasma (antibody-secreting) cells and provided a rapid and versatile alternative to conventional plaque-forming assays. The ELISPOT is very sensitive and detects the high concentration of antibody that surrounds each plasma cell. The ELISPOT has more recently been used to enumerate antigen-specific T-cells via detection of cell-associated cytokine production in patients with viral infections, cancer patients, and transplant recipients. Peripheral blood cells can be measured directly or after ex vivo stimulation with antigen. The frequency of antigen-specific CTL, Th cells, and their precursors can be measured in peripheral blood by in vitro limiting dilution analysis (LDA) of PBMC. LDA is not routinely available in clinical laboratories. Although LDA is a standard immunological method in many research laboratories, it is cumbersome, labor intensive, and operator dependent.

Serum Components Serum Ig levels can be determined electrophoretically and by enzyme-linked immunoabsorbent assay (ELISA). In humoral immunodeficiency diseases, serum Igs may be totally absent, as occurs in X-linked agammaglobulinemia, or decreased, as occurs in common variable hypergammaglobulinema. There may also be selective increases or decreases in certain classes of Igs in the immunocompromised patient. Complement components can also be accurately measured in serum (41), most typically by the CH50 test, which simply measures the amount of serum required to lyse 50% of antibody-coated sheep red cells. If abnormal, this test is followed by analysis of individual complement components, usually C3 and C4. Although not commonly occurring in the homozygous state in humans, genetic deficiencies have been identified in each of the complement components and are associated with increased susceptibility to bacterial infections and/or immune complex diseases, including systemic lupus erythematosus and glomerulonephritis (31). Interestingly, an inherited deficiency in C1 inhibitor, a complement regula-

75

tory protein, occurs more frequently and results in hereditary angioedema. The functional activity of lymphoid cells can be evaluated on the basis of the cytokines they secrete. As described above, the different populations and subpopulations of leukocytes secrete distinct cytokines and all of the major human cytokines can be measured by ELISA or bioassay and more recently by flow cytometry. However, accurate methods are still lacking for the standard quantitation of many immune mediators in biological fluids and cells (42). For many cytokines, serum levels have not proven to be consistent indicators of immune status. This is partly due to their short half-lives and the fact that many cytokines are associated with protein carriers in the serum or are predominantly present in latent, inactive forms. In addition, cytokines typically act locally in an autocrine or paracrine manner and are not usually systemic effectors. Cytokine production is thus often measured after the isolation of leukocytes from an individual and subsequent in vitro culture with antigen. In bacterial septic shock, high levels of both pro- and anti-inflammatory cytokines are detectable within the bloodstream (43). In this condition, bacterial cell wall endotoxins stimulate macrophages to overproduce IL-1 and TNF-a, and high blood levels of these cytokines have been associated with poor survival. These and other proinflammatory cytokines mediate drastic systemic effects that can be fatal, including a drop in blood pressure, fever, diarrhea, and extensive blood clotting. However, therapies targeting these cytokines have been clinically ineffective (44). Although not routinely analyzed clinically, other regulatory molecules circulate in the serum in soluble form and may modulate the immune response. Many of these are cell surface antigens that can be synthesized in a soluble form by alternative mRNA splicing or can be ‘‘shed’’ or generated via proteolytic cleavage from the cell surface. Soluble forms of certain antigens are frequently produced by activated cells, thus elevations may indicate an ongoing immune response. For example, many cytokine receptors exist as secreted/soluble proteins (45) and are involved in the endogenous regulation of cytokine activity. Certain soluble cytokine receptors appear to serve as markers of immune suppression (IL-2R) and sepsis (TNFR). There is substantial interest in the potential application of soluble cytokine receptors in biological therapy (46). Serum components can also be assayed indirectly by measuring their mRNA levels. Quantitative molecular methods are being implemented, such as real time reverse transcriptase–polymerase chain reaction, and offer the advantages of speed and specificity.

Leukocyte Function Analyses can also be conducted to determine if the leukocytes that are present in a patient exhibit normal functional activities. PBMC are generally isolated by density gradient centrifugation on Ficoll-Hypaque, prior to analysis in one of the following tests. Mitogenic Proliferation Mitogens are substances that induce DNA synthesis and cell division. Mitogens are often termed polyclonal activators, because they activate cells without regard to their clonal antigenic specificities. Many mitogens are plant proteins termed ‘‘lectins,’’ which have affinities for specific carbohydrate moieties on cell surface glycoproteins and glycolipids. Some

76

Part One: General Considerations

mitogens are T-cell specific [such as concanavalin A (ConA) and phytohemagglutinin (PHA)], some are B-cell specific (such as the LPS of gram-negative bacteria), and some mitogens activate both T- and B-cells (such as pokeweed mitogen). Proliferation is generally measured in the laboratory by incorporation of 3H-thymidine into DNA. Finally, many superantigens are potent activators of T-cells (e.g., staphylococcal enterotoxin A) and B-cells (e.g., staphylococcal protein A). Mixed Lymphocyte Reaction The mixed lymphocyte reaction (MLR) is an assay in which lymphocytes from different individuals are cultured together, and proliferate in response to allogeneic antigens. In the typical one-way MLR, cells from the individual to be tested (the responder cells) are mixed with different allogeneic stimulator cells that have been irradiated to prevent proliferation. This assay can also be used to test the ability of the stimulator lymphocytes (the APC) to present antigen. The amount of 3H-thymidine incorporated into DNA is determined after four days of culture and is proportional to the proliferative response. The MLR primarily measures the proliferation of Th cells and thus is a strong indicator of differences in the MHC class II antigens of responder and stimulator cells. However, MHC class I antigens as well as minor transplantation antigens have also been reported to contribute to this response. Nowadays, this assay is no longer used to measure compatibility at the MHC class II region. Molecular methods using polymerase chain reaction–based methods are being used to determine MHC alleles. Cell-Mediated Lympholysis It is an analogous assay to the MLR, but analyzes the activity of CD8þ CTL instead of CD4þ Th cells. This assay can evaluate in vivo–generated CTL (isolated from the circulation) or CTL that are induced in vitro by MLR. In either case, effector function is measured by the ability of these cells to lyse target cells. Target cells are generally allogeneic or virally infected syngeneic cells. Target cells are genetically identical to the cells injected or transplanted in vivo or identical to the stimulator cells for in vitro MLR-induced cell-mediated lympholysis (CML) assays. Target cells are prelabeled intracellularly with 51chromium or a dye that, upon lysis, is released from the cell into solution at a level proportional to the level of cell-mediated cytotoxicity. When conducted as an MLR-induced CML, this assay can also be used to evaluate the functional ability of Th cells to induce CTL effectors.

In Vivo Tests DTH is the most common in vivo assay of cell-mediated immune status in humans. The presence of a DTH reaction can be measured in vivo by injecting the antigen intradermally. A characteristic skin lesion caused by erythema at the injection site indicates a positive reaction and is evident 48 to 72 hours after antigen application. DTH can be used to assess cellular immune function by evaluating the response of an individual to recall antigens—antigens to which the patient presumably had been previously exposed. The CMI multitest includes eight recall antigens. Dinitrochlorobenzene (DNCB) has also been used as an antigen to test for cellular immune function, and patient response to de novo antigen challenge is measured two weeks after the initial DNCB skin contact. DTH has been used in a variety of clinical settings, including patients in intensive care units, surgical populations,

and transplant and HIV patients. This assay has been used to predict prognosis, overall survival, and response to therapies. The prototype of this test in humans is the administration of the purified protein derivative (PPD) extracted from the cell wall of Mycobacterium tuberculosis; however, other test antigens from the organisms causing histoplasmosis, candidiasis, and nocardiosis are also used. This test is usually given to determine if an individual has been previously exposed to the bacteria (either through infection or prior immunization). A more sensitive ELISPOT has been developed to detect T-cells specific for M. tuberculosis using antigens that are absent from Mycobacterium vaccines and most environmental mycobacteria (47). The status of humoral immune function can be tested in vivo by testing antibody titers to recall antigens such as diptheria and tetanus toxins. If titers are low, antibody responses to these antigens can also be tested two weeks after antigen boost or after active vaccination. Pneumococcal vaccine has been used in this manner to test human antibody responses to carbohydrate antigens. B-cell function can also be tested by analyzing serum for appropriate isohemagglutinin titers (antibodies against the A or B blood group antigens). In addition, if the patient has experienced a documented infection, the current antibody titer against the specific organism can be informative. Finally, the function of circulating neutrophils and monocytes can be evaluated by the nitroblue tetrazolium (NBT) test. NBT is reduced during the normal respiratory oxidative burst and can provide both qualitative and quantitative data on freshly isolated cells.

THE IMMUNOCOMPROMISED SURGICAL PATIENT Immunodeficiency Clinical States Primary Immunodeficiency There are more than 95 primary immunodeficiency diseases (Table 5). Some are manifest from birth while others are not identified until much later in life. The World Health Organization has categorized primary immunodeficiencies into five basic groups: (i) combined deficiencies, (ii) predominantly antibody deficiencies, (iii) cellular deficiencies, (iv) complement deficiencies, and (v) defects of phagocytic function (49). The major complication of primary immunodeficiencies is an increased susceptibility to viral or bacterial infection, although there are increases in certain types of cancer. Patients with severe T- or B-cell immune defects have an increased incidence of cancer and autoimmune diseases. The type of immunodeficiency can determine the type of cancer that develops. In those patients with combined immunodeficiencies, non-Hodgkin’s lymphomas represent the major type of tumor reported. This was the case even though almost half of the patients had received some therapy aimed at immunoreconstitution (50). In patients with SCID, the major cause of death is infection. Those patients with primary antibody deficiencies have an increased propensity to recurrent and chronic pyogenic infections, usually involving the respiratory tract. The usual tumor is a lymphoma, with gastrointestinal carcinomas following. Compared to other immunodeficiency states, central nervous system lymphomas are less common. The incidence of gastric carcinoma may be related to the gastric atrophy, achlorhydria, and decreased acid secretions. Many of these patients have low IgA levels and may be at increased risk of Helicobacter or related infections (51).

Chapter 4: The Immune System and the Immunocompromised Patient

77

Table 5 Examples of Primary Immunodeficiency Diseases Designation

Gene

Description/pathogenesis

Antibody deficiencies XLA

BTK

Mutations in the gene encoding BTK, a regulator of B-cell development; absence of mature circulating B-cells and undetectable or substantially low serum Ig levels lead to recurrent bacterial infections during the first year of life. Absent or marked reduction of serum IgA; majority of patients are asymptomatic; others have recurring respiratory infections, chronic diarrhea, allergies, or autoimmune disease. Defect in the AICDA required for Ig isotope switching and somatic hypermutation in Bcells; low IgG and IgA, normal or increased IgM. Low IgG, IgA; normal or increased IgM; bacterial and opportunistic infections.

IgA deficiency

Hyper-IgM syndrome type 2 (AID deficiency) Hyper-IgM syndrome type 3

IGAD1

AID (AICDA) CD40

Combined B- and T-cell deficiencies X-linked SCID

IL2RG

Jak3 deficiency

JAK3

RAG1 deficiency RAG2 deficiency ADA deficiency

RAG1 RAG2 ADA

X-linked hyper-IgM syndrome

CD40L

WAS

WASP

Ataxia-telangiectasia X-linked lymphoproliferative syndrome

ATM SH2D1A (SAP)

Phagocytic defects LAD1

ITGB2

LAD2

FUCT1

Most common form of SCID; caused by a mutation in the IL-2 receptor gene on the X chromosome needed for the normal growth and function of T-cells and B-cells; lymphopenia occurs primarily from the absence or near absence of T-cells and natural killer cells; B-cells are immature and defective. Mutation in the gene that encodes JAK3 needed for differentiation of hematopoietic cells; lymphopenia occurs primarily from the absence or near absence of T-cells and natural killer cells; B-cells are present but defective. Mutations in RAG1 lead absence of mature B- and T-cells. Mutations in RAG2 lead absence of mature B- and T-cells. Mutation in a gene encoding the enzyme ADA; lymphopenia occurs from the death of B-cells because of accumulation of toxic metabolite and functional antibodies are decreased or absent. Mutations in the CD40 ligand gene lead to impairment of T-cell/B-cell interaction, lack of Ig isotope switching; recurrent and opportunistic infections. Defect in cytoskeletal WASP, affecting platelets and T-cells, leads to thrombocytopenia, small defective platelets, eczema, lymphomas, autoimmune disease, and infections. Progressive multisystem disorder characterized by neurologic impairment with ataxia, telangiectasia of the conjunctiva and skin, malignancy, and radiation sensitivity. Uncontrolled lymphoproliferation induced by severe EBV infections, B-cell lymphoma.

Disorder of neutrophil adhesion caused by lack of CD18 characterized by recurrent or progressive necrotic soft-tissue infection, periodontitis, poor wound healing, leukocytosis, and delayed umbilical cord detachment. Defect in GDP fucose transporter 1; associated with mental retardation, soft-tissue infection, and delayed healing.

Complement deficiencies Deficiency of individual complement CIQA, C1QB, C1QG, Absence of complement components; results in increased infections and lupus-like components C1q, C1r, C1s, C2, C3, C4, C5, C1R, C15, C2, C3, diseases; C1, C2, C3, and C4 associated with autoimmunity and pyogenic C6, C7, C8, C9 C4A, C4B, C5, C6, C7, infections. C8A, C8B, C8G, C9 Factor B, Factor H1 BF, HF1 C5–C9 and properdin deficiencies associated with neisserial infections. Abbreviations: Ig, immunoglobulin; SCID, severe combined immunodeficiency disease; WAS, Wiskott–Aldrich syndrome; BTK, Bruton’s tyrosine kinase; AICDA, activation-induced cytidine deaminase; XLA, X-linked agammaglobulinemia; JAK3, Janus-associated kinase 3; RAG, recombinase activity gene; ADA, adenosine deaminae; WASP, WAS protein; EBV, Epstein–Barr virus; GDP, guanosine diphosphate. Source: From Ref. 48.

Those patients with well-characterized immunodeficiencies such as Wiskott–Aldrich syndrome also have an increased risk of developing malignant tumors. This risk is almost 100% by the age of 30 in patients with Wiskott–Aldrich syndrome, with the most common site of involvement being the brain (52). Respiratory infections are common in ataxia telangiectasia. Non-Hodgkin’s lymphomas account for almost half of the malignancies in this group of patients, however, almost a quarter of the patients develop leukemia. Bone marrow transplantation has been used successfully in the treatment of patients with immunodeficiencies. Gene therapy has also been used but with limited success. The patients who have a primary immunodeficiency and those who develop a secondary immunodeficiency develop a high proportion of lymphoproliferative disorders.

The incidence of cancer in patients with primary immunodeficiencies is approximately 1% to 4% (47). It must be remembered that this apparently low figure is for all patients with immunodeficiencies and that there are specific immunodeficiencies that have a very high incidence of cancer. This incidence is comparable to the incidence of cancer in organ transplant patients, which is approximately 1% to 5% (53). In cardiac transplant patients, the risk of posttransplant B-cell lymphoproliferative disease is 5% to 6% of patients. This is believed to be due to the very high immunosuppressive drug doses that cardiac recipients receive (54). The increased use of powerful immunosuppressants as induction agents for many solid organ transplants has increased the incidence of post-transplant lymphoproliferative disease. This has been shown to be associated with the

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Part One: General Considerations

use of OKT3 or antithymocyte globulin, but not with antiCD25 antibody (55). Together, these data would lead to the conclusion that there may be a common mechanism to explain the incidence of cancer in patients who have been immunosuppressed to maintain an organ transplant and in patients suffering from primary immunodeficiencies.

Transplant Recipients as Secondary Immunodeficiency Patients Transplant recipients can be viewed as secondary immunodeficiency patients due to the chronic use of immunosuppressive agents (Table 6). The interval between transplantation and the onset of a cancer after transplant (approximately 32 months) is much shorter than that in the general population that has been exposed to a carcinogen (5–20 years) (56). The time of appearance of the cancer after transplant is dependent on the type of cancer that occurs. Kaposi’s sarcoma appears an average of 21 months after transplant compared with anogenital carcinomas, which occur an average of 115 months after transplant. The incidence of most common cancers such as lung, breast, prostate, colon, and invasive uterine cancer observed in the general population is not changed in transplant recipients. However, squamous cell carcinomas of the skin are markedly increased. A variety of tumors in the transplant recipients compared to the general population are as follows: lymphomas, 23% versus 5%; lip cancers, 7% versus 0.3%; Kaposi’s sarcoma, 6% versus minimal; carcinoma of the kidney, 5% versus 2%; and sarcomas, 1.7% versus 0.5%, respectively (57). A population-based study from Sweden shows the same patterns: an excess of nonmelanomatous skin cancers with a standardized incidence ratio (SIR) of 56, lip cancer (SIR 53), and non-Hodgkin’s lymphoma (SIR 6). There was also a 10-fold increased incidence of anal cancer and a 20-fold increase in vulvar and vaginal cancer compared to the general population. Those patients with a nonrenal transplant had a higher risk of cancer compared to those with a renal transplant (58). Thus in certain tumors the incidence is markedly different from the general population. Viral infections have been postulated to play a role in the etiology of cancer development in these immuno-incompetent patients. Epstein–Barr virus (EBV) has been associated with Burkitt’s lymphoma and Hodgkin’s disease in the general population. Approximately 30% to 60% of patients with primary disorders are EBV positive. The postulated mechanism is that the virus infects B-cells and stimulates a polyclonal B-cell proliferation (59). B-cell proliferation is abated in normal patients by cytotoxic T-lymphocytes, but in immunocompromised individuals the proliferation continues

unchecked. This proliferation of multiple B-cells is occasionally interrupted by an unknown event, which results in the emergence of a monoclonal tumor, thus explaining the incidence of EBV-DNA–specific sequences in tumor specimens of patients who have received a transplant, who are congenitally immunodeficient, or who have AIDS (60,61). The reasons why patients with primary immunodeficiency or transplants develop disturbances in immunity that result in cancer are not clear. There are several theories that are open to discussion. The first theory is that the patients have a defective surveillance system. If this were the case, then one would expect a higher percentage of cancers of all types and not an increase in certain cancers that have been described. Indeed in those patients who develop a non-Hodgkin’s lymphoma or a Kaposi’s sarcoma, when immunosuppression is withdrawn, the patients will frequently have a regression of their tumor. Thus the innate immune response can be effective. Another popular theory is that patients have chronic antigenic stimulation. Animal models have shown that continuous stimulation with a foreign antigen can give a high yield of lymphomas (57). AIDS patients have chronic infections, which could result in continued immunologic stimulation. Transplant patients have a chronic source of antigenic stimulation from the transplant, which could thereby result in the development of lymphomas. Transplant patients may also develop cancer because of the carcinogenic effects of the immunosuppressive agents. Azathioprine, cyclophosphamide, and cyclosporin may directly damage DNA and cause malignant changes (57). However, most animal models require these drugs in combination with another chemical or physical agent to develop cancer. There is also an established increased incidence of skin cancer in patients who reside in climates with sun exposure, such as the Southwestern United States or Australia. The most fascinating question regarding cancer development in immunocompromised patients is why such a small percentage of these patients develop cancer. There may be a genetic predisposition in a small number of patients for an increased susceptibility to viral infections or malignancies. There are several studies that link HLA types to susceptibility or resistance to Kaposi’s sarcoma.

Malnutrition General Malnutrition is an important problem in surgical patients. In fact it is the most common cause of acquired immunodeficiency in the world. Surgical patients who present with cancer, fistulas, burns, and trauma are predisposed to the

Table 6 Effects of Major Immunosuppressive Agents

Myelosuppression Cell specificity Delayed wound healing Impaired microbial defense Organotoxicity Tumorigenesis Diabetogenicity Therapeutic monitoring possible a

Calcineurin inhibitors

Sirolimus (Rapamycin)

Mycophenolate mofetil

–  – þ   þa Yes

þ  þ þ –  – Yes

  þ þ – – – Yes

Significant for Tacrolimus (FK506), not cyclosporin. Abbreviations:
, No effect; þ, small, variable effect; , significant effect.

Corticosteroids

Anti-CD3 monoclonal antibody

Anti-CD25 monoclonal antibody

Polyclonal antilymphocyte antibody

– –   – – þ No

–  – þ –  – No

–  – – – – – No

þ  –  – – – No

Chapter 4: The Immune System and the Immunocompromised Patient

development of sepsis and infection. The relationship between host nutrition and wound healing has been recently reviewed (62). A consistent finding in malnutrition is the lack of maturation of T-lymphocytes in the thymic environment. This is caused by decreased amounts of thymic hormones and a defect in the thymic epithelium, and results in the release of immature cells to the periphery (63). The decrease in mature T-lymphocytes is manifested by in vivo abnormalities such as lack of impaired DTH responses. In vitro, this is detected as a decrease in mitogen and antigen lymphocyte proliferative responses to mitogens and antigens (64). Malnourished patients exhibit many abnormal T-cell responses that lead to additional host abnormalities in those processes that are dependent on the T-cell response. These include macrophage activation, T-cell–dependent antibody production, and T-cell–mediated cytotoxic responses to viruses. The patient who is malnourished as well as vitamin A deficient has depressed CMI. These individuals also exhibit decreases in antibody response, and there can be defects in B-cell clonal expansion. One can show that Ig levels are normal or even high in these malnourished patients (65). Even with the above changes, the use of live vaccines in malnourished children is generally safe. The complement cascade is very important in the defense against infection. Malnutrition results in decreased serum levels of most complement components, particularly C3. In addition, the normal increase in complement levels seen in stress situations is blunted. In malnourished children, complement activation by both pathways appears to be intact but diminished (particularly the alternative pathway). This may be a major predisposing factor to the increased susceptibility of malnourished patients to gramnegative sepsis (66). Clinically malnourished patients tend to fare poorly and are found to have prolonged infections or infections of greater severity than patients with normal nutritional levels. Malnutrition and infection can become part of a vicious cycle, with infection causing increased malnutrition, which in turn causes prolonged or exacerbated infection. Malnutrition is a major predisposing factor for complications in postoperative patients. It is associated with decreased wound healing, an increased complication rate, and an increased death rate (67). The route of nutritional support has also been determined to be of importance in the posttraumatic care of patients. Moore et al., have shown that among patients with abdominal trauma, those who received early enteral feedings had significantly fewer intra-abdominal abscesses and lower rates of pneumonia, compared to patients who received delayed total parenteral nutrition (TPN) (68). These findings were confirmed by Kudsk et al., who found a decreased incidence of intra-abdominal abscesses, pneumonia, and number of infections in patients who received enteral feeding (69). Interestingly, these findings are opposite to those found by authors who reviewed enteral and parenteral nutrition in patients with severe head injuries, who show that parenteral feedings were more favorable (70). Thus one must evaluate a patient carefully and make sure that there are no contraindications for a particular form of nutrition. A recent review of data published in 2001 and 2002 confirmed the benefits of preoperative administration of immunonutrition in surgical patients (71). Decreased infectious complications were observed in critically ill patients receiving immune-enhancing diets. However, postoperative

79

administration offered no advantages to surgical, critically injured, or critically ill patients in this data review.

Nutritional Supplements The number of nutritional supplements that have been identified in nutritional support has continued to increase. There are some agents that have been shown to have clinical utility and others that are still experimental. These agents include vitamins, prostaglandins, lipids, and amino acids. Vitamins that have been studied include A, D, E, and K. Vitamin A deficiency has been shown to have a markedly favorable influence on the survival of children who have measles and in patients with bacterial, protozoal, and viral infections. Vitamin A levels are markedly decreased in postoperative patients or in those who have suffered a major burn. In these groups of patients, vitamin A supplementation is crucial and can reverse the postinjury immunosuppression (72). Other fat-soluble vitamins such as D, E, and K are important in immune function. Vitamin E has a major influence on immune function and its deficiency results in a decrease in T-cell–mediated antibody response. Fatty acids also have an influence on immune function. Linoleic acid can prolong graft survival in mice, whereas a deficiency in the same fatty acid decreases allograft survival in the same model. These results indicate the importance of linoleic acid in immunomodulation (73). Diets high in soybean, corn, sunflower, and safflower oil suppress the response of splenocytes and T-cells to mitogens, in mice and guinea pigs. These same sources of fatty acids also result in decreased immune competence. Large amounts of prostaglandin E2 (PGE2) are produced by suppressor cells in chronic inflammatory conditions such as multiple sclerosis, rheumatoid arthritis, and infections (74). PGE2 is produced by monocytes and macrophages and can modulate the responses of immune cells. The importance of PGE2 has been studied in patients with chronic infections, who have abnormally high circulating levels of PGE2. Postoperative patients who experience a suppressed immune function have a marked increase in PGE2 synthesis (75). Tumor cells can also stimulate large amounts of PGE2 to be released by macrophages. These macrophages seem to produce PGE2 in an uncontrolled fashion and are not subject to the normal feedback mechanism. PGE2 can suppress NK cells, T-cell proliferation, and cytotoxic T-cells and cause an overall decrease in immune surveillance, and may be one mechanism by which tumor cells escape normal immune surveillance (76). Patients with Hodgkin’s disease produce four times the normal amount of PGE2. This suppresses the immune response by inhibiting the production of lymphokines necessary for lymphocyte function. Prostaglandin synthetase inhibitors have been shown in some models to improve immune function and inhibit tumor growth. An amino acid that has been shown to be of major importance in stress situations is arginine. L-Arginine is the substrate for the synthesis of nitric oxide as well as other biologically active molecules. It is now viewed as an essential amino acid for young mammals (including parentally fed human infants), and as a conditionally essential amino acid for adults under conditions such as trauma and burn injury (77). Arginine has also been shown to be of importance in wound healing (62). Through both nitric oxide– dependent and nitric oxide–independent effects, it has been shown to reverse endothelial dysfunction and improve many common cardiovascular disorders (78).

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Finally, arginine has documented effects on immune functions. However, both animal and human studies have shown that enteral arginine supplementation as a single variable does not show clear immunologic benefit (79). Inconsistent results to date may be due to differences in the amount and timing of arginine administration, the animal species, and model. A recent study suggests that expression of the arginine-metabolizing enzyme arginase may be essential in regulating the cellular immune response and the inflammatory process during a critical illness (80). In human studies, oral arginine significantly increases peripheral blood lymphocyte blastogenesis in response to ConA and PHA. This change begins within three days of supplementation. Supplementation has also been studied in the clinical setting of patients receiving TPN with and without arginine. Those patients who received arginine showed an increased response of both PHA and ConA stimulation at days 3 and 7 after surgery, compared to those patients who did not receive arginine (81). The same author completed a study of HIV patients with a CD4/CD8 ratio of 0.8 or less (normal ¼ 2.0). These patients were supplemented with 20 g of arginine daily for at least two weeks. There were no changes in the CD4/CD8 ratio but there was a significant increase in the mitogenic responses to ConA and PHA in the patients tested. Arginine has also been used in postoperative surgical patients and has been shown to give an increased T-cell response to ConA and PHA as well as increased Th cell numbers. There was no change in other T-cell subsets (82). As a note of caution, Sucher et al. indicate that arginine in larger amounts may increase systemic inflammation and result in poorer clinical outcomes (83). Glutamine, a nonessential amino acid that has large body stores, is depleted following major insults such as infection and injury. Supplementation with additional glutamine in adult trauma patients resulted in a decrease in soluble tumor necrosis receptors and a lower incidence of sepsis and pneumonia (84). Similar improved outcomes were shown in severely burned patients (total body surface area greater than 25%). Intravenous glutamine was given to isonitrogenous controls or treatment patients. C-reactive protein levels and the incidence of gram-negative bacteremia were significantly decreased in treated patients. Nutritional parameters such as transferrin and prealbumin were improved compared to controls at 14 days. These studies suggest the benefits of glutamine, but the mechanisms and eventual place in surgical therapy remain to be defined (85). Cerra et al. reported the use of arginine, RNA precursor purines and pyrimidines, and n-3 polyunsaturated fatty acids, a major component of the cell membrane, in a group of intensive care unit (ICU) patients (86). These three agents in combination were associated with an improvement in the in vitro responses to ConA, PHA, and tetanus antigen. This study showed that nutritional supplementation must not only supply calories but must also supply elements that are essential to the improvement of immune parameters.

Trauma, Burns, and Surgery Trauma and Surgery The importance of immune changes during trauma, burns, or surgery is becoming better understood. Much of the data that have been discovered are now being used as a basis for intervention and treatment to prevent further morbidity after the traumatic event. These immune changes may occur secondary to blood transfusions, tissue injury, or the neuroendocrine changes that have occurred (Table 7).

Even in the individual who has undergone uncomplicated surgery there are postoperative changes in the immune system, which include a depression of both T- and B-lymphocytes. There is also a decrease in the response to a number of agents that cause a blastogenic response, including PPD, Staphylococcus aureus, and Escherichia coli, pokeweed mitogen, and phytohemagglutinin. Even with uncomplicated surgery there can be major depression in these blastogenic responses. The major change occurs on day 3 and normality is restored by day 9 (88). In patients who were judged to have moderate to severe injuries, creatine phosphokinase (CPK), cortisol, and white blood cell and T- and B-cell counts were performed. There were depressions in the total number of T- and B-lymphocytes as well as in the WBC by injury day 1, which returned to normal within approximately five days. During these changes in lymphocyte levels, the serum cortisol and CPK levels also increased markedly and returned to normal within five to seven days (89). The realization that major trauma caused a change in immune status provided impetus to examine other measures of immune reactivity. Keane et al. studied 31 injured patients and their lymphocyte responsiveness for up to 20 days after injury, comparing patients who became septic with those who did not. When compared to normals, the immune responses in trauma patients were depressed for over 20 days. In addition, the immune responses studied were significantly lower in the septic compared to the nonseptic patients. Afterinjury responses to streptokinase, streptodornase, mumps antigen, ConA, and PHA were all depressed and did not return to normal levels even after 20 days. In addition, the mixed lymphocyte culture was also abnormally depressed. Those patients were severely injured as indicated by the number of units of blood required and by the number of organ systems injured. Blood transfusions may also have contributed to the observed immune depression (90). Another study reviewed cellular immune depression after multiple trauma in patients who did not become septic during their hospital course. Significant suppression of lymphocyte responses to mitogens was noted, and there was a reversal of the Th–suppressor ratio (normal 2.0:1 vs. patients 0.96:1) suppressor cell functional activity was also detected early after trauma. This suppressor cell activity decreased, but persisted in three patients who developed sepsis (one of whom died). These data indicate that lymphocyte abnormalities exist after major trauma and some of these depressions can be associated with ultimate sepsis (91). This depression in cellular immunity is also reflected in antibody production in surgical patients. Nohr et al. have shown that abnormalities of both in vivo and in vitro antibody production are decreased in all surgical patients and antibody production is most depressed in those patients who have demonstrated reduced DTH responses (92). The studies outlined above have basically examined lymphocyte function. There are also abnormalities in the PMN in these seriously injured patients. Defects in the adherence and killing ability of PMNs have been reported along with migration abnormalities (93). These latter patients showed marked depression of both serum and cell-mediated migration that was proportional to the degree of trauma suffered. The macrophage is a pivotal cell in the immune response exerting both helper and suppressive effects, and may play a major role in the immunosuppressive effects of trauma. In one study, macrophage function was measured in a group of traumatized patients with a mean injury

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Chapter 4: The Immune System and the Immunocompromised Patient

Table 7 Effect of Illness, Injury, or Treatment on Host Defense Mechanisms Condition Primary immunodeficiencies Secondary (acquired) immunodeficiencies Age Malnutrition Malignancy Burns Infection Trauma or surgery Anesthesia Blood transfusion Diabetes mellitus Renal failure Liver disease Splenectomy Radiation Protein-losing diseases Foreign bodies Drugs

Local immunity

T-cell function

B-cell function

Phagocytic function

Complement

#

#

#

#

#

NC NC NC # # # NC NC # NC NC NC # NC # NC

# # # # # # # # # # # NC ? # NC #

# " or # # # ? ? ? ? ? NC or # # # ? # NC " or #

NC # NC # # # # ? # # ? # ? NC NC #

NC # NC # ? ? ? ? ? ? ? ? ? ? ? ?

Abbreviations: NC, no change; ", increased; #, decreased; ?, unknown. Source: From Ref. 87.

severity score (ISS) of 38 (ISS of 25–40 gives approximately 50% mortality). The number of macrophages increased almost threefold from day 3 to 14 and the number of Th cells markedly decreased. During this same period, the level of PGE2 synthesis in vitro of isolated monocytes was also found to be highly elevated and, in fact, correlated with the level of injury reflected by the ISS. The level of IL-2 generated in an in vitro assay was also decreased, which would lead to decreased clonal expansion of T-cells (94). Changes in the surface expression of MHC antigens on monocytes and T-cells can be detected in postoperative patients. Because these molecules are critical for antigen presentation, their expression is central to the specific immune response that an individual can mount to a unique antigen. Wakefield et al. detected changes in MHC class II expression in a group of patients after surgery. HLA-DR expression on monocytes declined in all postoperative patients, with a more marked decline in those who developed sepsis. All postoperative patients had a marked increase in the number of T-cells that expressed HLA-DR, with a larger increase in those patients who did not develop sepsis (95). The exact mechanism of these changes is not known, but it appears that the patients who developed sepsis were unable to mount an appropriate immune response and had major defects in antigen presentation and T-cell activation. IFN-g production has been reported to be decreased after trauma, and it has been suggested that exogenous administration of IFN-g may be effective in reducing infection in trauma patients. This effect may be related to effects on HLA-DR expression (96). Polk et al. have tested the hypothesis that increased HLA class II expression may make a difference in the survival of patients after use of recombinant IFN-g. In a randomized, prospective trial, the authors were able to show that those trauma patients who received IFN-g for 10 days had an increased level of HLA-DR expression on their monocytes, compared to those patients who received placebo only. Although there was a trend for a decreased death rate among IFN-g–treated patients, the changes were not statistically significant. There were also fewer severe infections in the treatment group that required reoperation or computerized axial tomography (CAT) scan– guided drainage. The authors believed that a larger trial or a

longer treatment period would be useful to determine the utility of IFN-g in these patients (97). Other cytokines also appear to act in part by this mechanism; granulocyte-macrophage colony-stimulating factor (GM-CSF) is known to increase the HLA-DR expression of monocytes and thus their antigen presenting capacity (98). It may be possible to predict the potential for infection in patients based on postoperative levels of HLA-DR expression on monocytes or T-cells. Peripheral blood monocytes have also been examined for the expression of CD4, CD14, and CD16. Kampalath et al. have shown a pattern in trauma patients, which is similar to that of cord blood from immunologically naive newborns. Thus monocytes may be central to both antigen presentation as well as to the clearance of bacteria in the trauma patients (99). IL-4 and IL-10, two cytokines associated with the Th2 lymphocyte subset, have also been implicated in the occurrence of sepsis after surgery. These cytokines are generally considered immunosuppressive. In a posthemorrhage mouse model, splenocytes and T-cells showed increased levels of IL-10 release compared to macrophages. PGE2 was shown to stimulate the release of IL-10, suggesting that IL-10 may be the ultimate effector of posttrauma PGE2 (100). Mack et al. have used a mouse model in which the animals received a femur fracture and hemorrhage to show that the cytokine pattern in splenocytes after injury was consistent with Th2. This pattern may explain some of the changes in the cellular immune response after injury (101). IL-4 activity has been studied in a group of trauma patients with an ISS > 25. Plasma IL-4 was found to be higher in those with greater severity of injury, lower patient age (age 30 years or younger), and hypotension, when admitted to the hospital. Those patients who had high levels of IL-4 on admission had a lower incidence of nosocomial infection compared to those patients with a lower IL-4 level. However, if the IL-4 increased during the ICU stay, the patients had a greater incidence of sepsis, pneumonia, or renal dysfunction even if they had shown low IL-4 levels on admission (102). IL-6 in septic patients who died was elevated compared to nonseptic patients. Those patients who had a poor cytokine response to a septic challenge had a poor clinical outcome (103).

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In studying the interrelationship between Th1 and Th2 cells in trauma and burns, Goebel et al. studied the occurrence of IL-2 and IFN-g (Th1 cytokines) and IL-4 (Th2 cytokine). Following trauma (ISS > 25) in human subjects, the authors showed a markedly decreased level of IL-2 when compared to normal controls. However, the production of IL-4 was markedly increased. The same pattern was observed in a murine burn model. IL-12 was found to be significantly decreased in injured humans. In the concurrent murine model in the study, when IL-12 was given to the animals after cecal puncture and ligation, a significant decrease in death from sepsis resulted. This study suggests that there may be a shift away from Th1 cells toward Th2 cells, and this may result in an increased susceptibility to sepsis after trauma but replacement may improve survival (104). The cause of the shift from Th1 to Th2 cytokine pattern is still being investigated. The change may be due to increased levels of glucocorticoids and epinephrine, both of which inhibit Th1 but not Th2 cytokine production. The changes in cytokine levels in the traumatized and septic patient have yielded information that may be helpful in treating the patient. However, understanding of the recruitment of active cells to the site of injury has been shown to be an important aspect of medicine. Chemokines, a class of chemoattractant cytokines, are being studied in trauma, transplantation, atherosclerosis, and infectious disease. There are four main families of chemokines, represented as CC, CXC, C, and CX3C based on the cysteine motif at the amino terminal of the protein. These families are specific chemoattractants for different leukocyte subgroups. CC chemokines attract macrophages and lymphocytes, whereas CXC attract leukocytes. These proteins are major players in augmenting the ability of leukocytes to adhere to endothelial cells and then to move through the vessel wall into tissues. Chemokines have been identified in patients after trauma. Adams et al. found growth-related oncogenes (GRO)-alpha (a chemokine with a new designation CXCL1) in laparotomy pads of patients who had undergone a laparotomy and had damage control laparotomy performed (105). A subsequent study by the same authors showed the presence of IL-8, a proinflammatory chemokine, in the plasma of patients who had undergone exploration of the abdomen after damage-control laparotomy (106). Thus the homing of leukocyte subclasses is dependent on chemokines. Understanding of the role of these proteins in the surgical patient may allow manipulation to improve patient outcomes by increasing the number of cells at the damaged site.

Burns Those patients who have undergone a severe burn injury also have major changes in immune status. In addition to nonspecific loss of the skin barrier, they have other immune defects. The total number of lymphocytes is reduced, as in severe nonburn trauma, and there is a decrease in the number of Th cells as well as T suppressor cells. Lymphocytes from severely burned patients exhibit decreased expression of HLA-DR and IL-2 receptor, both markers of T-cell activation. Serum from burned mice has been shown to inhibit lymphocyte proliferation and surface antigen expression in vitro. This may be due to PGE2 effects. Patients who have experienced large burns exhibited a 5- to 10-fold increase in PGE2, which results in a concomitant suppression of the T-lymphocyte response. The lymphocyte response can be restored when PGE2 synthesis is blocked (107). Burn patients have a decreased level of IL-2, which may also contribute to the immunosuppression evident

in them. IL-2 plays a central role in immunoregulation— supporting lymphocyte proliferation, increasing Th cell proliferation, and causing CTL precursors to differentiate into cytotoxic T-cells (108). Surgery and other trauma can result in marked changes in the immune system. These changes are being studied and defined and various measures are being designed for intervention. It is hoped that these interventions will result in decreased morbidity and mortality.

Aging Surgery in the aged patient is fraught with many physiological concerns such as cardiac and pulmonary disease. The mortality rate increases with age after major surgery and after major trauma. In the aged patient, the natural barriers against infection are impaired. The skin becomes thinner and there is a loss of Langerhans cells. There is also a decrease in blood supply to the skin. There is loss of bacteriostatic effects of urine and decline of renal function leading to less acidification of the urine, and a propensity for urinary tract infection. The pulmonary tree is also compromised by decreased ventilation and decreased saliva. There are also immunological changes that occur with aging, which influence the susceptibility to infection in these patients. A study by Charpentier et al. found that there were no significant differences in T-cell function between young patients and those over 70 years of age, when T-cell levels, PHA stimulation, and allogeneic responses were compared. However, if low levels of mitogens were used, lower levels of stimulation were observed in the older patients (109). Age-related changes have also been detected in B-cell function. A Japanese group showed that there was a decrease in IgG antibody synthesis after administration of tetanus toxoid in aged patients (110). Most T- and B-cells decrease in numbers with age, however, the changes in NK cells are less straightforward. NK cells with high activity actually increase with age in humans, which is in contrast to NK cells with low activity, which may be a compensatory mechanism to cope with a decreased T-cell number (111). The activity of NK cells in different compartments of the body may provide insights into the reason for increased occurrence of neoplasms in elderly. NK cells isolated from murine spleen and lymph nodes exhibited markedly decreased NK activity. This is in contrast to those NK cells isolated from human peripheral blood cells that showed normal activity. Thus, in solid organs, cells that could prevent neoplasm may be lacking effective activity. Specific cytokines and lipid mediators are also decreased during aging. As mentioned above, there is an in vivo decrease of delayed hypersensitivity to common antigen skin tests. This decrease may also be due to decreased production of IL-2 by stimulated cells, and therefore a decrease in the number of Th cells and T suppressor cells. This decrease may be due to a decrease in the level of thymic hormones. During the aging process, there are markedly decreased levels of natural antibodies and a decrease in the primary immune response to an antigen. It has been postulated that the immunosuppression of old age is due to the development of a greater sensitivity to PGE2, which would cause increased activation of suppressor T-cells by PGE2. Newer evidence indicates an increase in IL-10 production, indicating a shift toward the anti-inflammatory Th2 cytokine response (112). These changes in delayed cellular immunity increase the susceptibility to all infectious agents. This can result in an increase in colonization and frank infection and increase the incidence of bacteremia, septicemia, and infections that

Chapter 4: The Immune System and the Immunocompromised Patient

are spread via the hematogenous route. Because of these changes, care must be taken to make certain the aged patient is as well physiologically as possible prior to elective surgery. Adequate nutrition is required. Underlying diseases must be controlled prior to any invasive procedures. Vaccinations also decrease morbidity and mortality in these patients.

Splenectomy and Blood Transfusion Splenectomy The incidence of overwhelming sepsis after splenectomy is increased compared to patients with an intact spleen. The important phagocytic and antibody production capabilities of the spleen are lost after splenectomy. The greatest risk for sepsis is from encapsulated organisms and appears to be the greatest within the early postsplenectomy period, however, this risk remains lifelong. In a study in adult patients who had either underlying malignancy or trauma as the reason for splenectomy, lethal sepsis occurred in 2.7% of adult patients approximately two years after splenectomy (113). The highest risk was in those patients who had an underlying malignancy. In this study, the most common organism involved was Streptococcus pneumoniae. Splenectomy is known to be associated with gram-negative rods, Neisseria menigitidis, E. coli, and H. influenza. Less common problems include babesiosis, histoplasmosis, and malaria. Splenectomy decreases a major protective mechanism in the body. Splenectomy in animals has been shown to decrease the removal of bacteria from the bloodstream. The liver can remove organisms that are well opsonized, but the spleen can remove those organisms that are not well opsonized. The spleen is a major site of antigen presentation to B-cells; splenic removal of an organism not only removes the organism but also promotes an antibody response in which the spleen plays a pivotal role. The spleen is the first site in which antibody to an organism is detected after exposure to the offending agent. Consistent with this observation, splenectomy also causes IgM antibody levels to decrease. Strategies for prophylaxis include prophylactic antibiotics or starting prescribed antibiotics at the first sign of infection. Pneumococcal vaccine is ideally given to patients after splenectomy. Those patients who have had splenectomy for malignancy show a poor antibody response to the vaccine. Those who have received it for trauma apparently have a better response, but this is less than in normal controls in terms of absolute titer, relative rise, and rate of rise. Those patients who receive meningococcal and H. influenza vaccine show similar titers to those obtained with pneumococcal vaccine. Clearly patients must be educated about the risks, have a supply of antibiotics, and be given the vaccines. Some physicians recommend repeating pneumococcal vaccination at 5- to 10-year intervals or in the face of a falling titer.

Hemorrhage and Blood Transfusion Hemorrhage itself can have an effect on the immune response. Experimentally, there are many changes that are documented in animal models. In a rat model, there is a marked decline in the mitogen-induced response of lymphocytes and a decrease in the production of IL-2. However, this response did return to normal within 48 hours after hemorrhage without resuscitation (114). The serum from these animals will also depress the mitogen response of lymphocytes from normal animals. The above results were confirmed using a mouse model. In addition, although there was no change in the

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relative numbers of T- and B-cells, there was still the depression of splenocyte mitogenic responses. An additional murine study added resuscitation after the hemorrhage and showed the same impairment in mitogen responses, which were evident up to day 10 when they returned to normal. The production of IL-2 was also depressed during this time course (115). Additional studies confirmed the finding that murine splenocyte IL-2 levels were depressed after hemorrhage, but also showed that IL-3, IL-6, and IFN-g were also depressed. The depression of IFN-g might result in the marked decline of macrophage function, depression of NK cell function, and decreased activation of cytotoxic T-cells. The lack of IL-6 production may result in the depressed humoral function because this cytokine is heavily involved in B-cell activation (116). Humoral immunity can also be shown to be depressed after hemorrhage in a murine model. The cause of nonspecific immune dysfunction after hemorrhage is unknown. There is data to indicate that this depression may be due to macrophage dysfunction. The macrophage is also key to antigen presentation in a shock state. In a murine model, Stephan et al. demonstrated that antigen presentation was markedly depressed after hemorrhage and resuscitation one hour later (117). The length of this depression is at least 120 hours, with an onset of as early as 15 minutes with a blood pressure of 35 mmHg. Thus this change in antigen presentation in a murine model can be early and prolonged even in the face of adequate resuscitation. Additional studies using Kupffer cells have shown similar findings. The cause of the changes in immune function after hemorrhage is yet to be clearly elucidated. The agent that is most widely implicated is endotoxin, believed to come from the gastrointestinal tract. The poor O2 and nutrient delivery during severe hemorrhage may also cause immune suppression. Hemorrhage is also a major stimulator of catecholamine release. Epinephrine has been shown in humans to result in altered mitogen-induced proliferation of lymphocytes and changes in the ratios of different subsets of lymphocytes. Catecholamines can also suppress phagocyte function and B-cell function. These changes may be addressed by various specific pharmacologic interventions. Hemorrhage plus injury has an additive detrimental effect on immune function. Wichmann et al. have shown in a murine model that hemorrhage caused a depression in splenic and macrophage function; however, the addition of a femur fracture caused an even deeper depression in these parameters (118). Thus trauma patients may be experiencing an immune depression secondary to the blood loss and shock as well as the injury. Blood transfusions are given with little thought to the potential immunological consequences. Blood transfusions are believed to have some deleterious effects on the immune system in those patients who have cancer. These changes have been studied in a number of types of cancers. In those patients with colorectal cancer, cancer recurrence was increased in patients who received blood. The results of this retrospective study took into account the complexity of the surgery. Foster et al. confirmed these findings showing that those patients who did not receive any blood during their hospitalization did significantly better than those who received blood transfusions (119). In evaluating those patients who underwent surgery for lung cancer, similar findings have been discovered. Hyman et al. reported that a group of patients who underwent resection for non–small cell carcinoma of the lung and

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were transfused showed a significantly worse five-year survival rate than those patients who had not been transfused (120). The same sort of association between blood transfusion and long-term survival has been identified in patients suffering from soft tissue sarcomas. Those patients who received blood transfusions had a 20% decrease in five-year survival. The three major cancer groups examined above are in contrast to breast cancer, renal cell carcinoma, and head and neck cancers. Breast cancer patients who had invasive breast cancer and had either a complete or partial mastectomy showed no effect of blood transfusion on long-term survival (121). Likewise, no effects of blood transfusion can be found in those patients with renal cell carcinoma and those with head and neck cancer in long-term survival. It is unclear why transfusion effects in cancer patients appear to be tissue specific. This immunosuppressive effect is clearly seen in those patients who have received a renal transplant. Early in the history of transplantation, blood transfusions to the recipient were largely avoided; however, in 1973, Opelz et al. reported a beneficial effect of transfusions on graft survival. The major reason for this effect was believed to be the immunosuppressive action of blood (122). This finding could not be replicated in those patients who received frozen packed red cells. Fischer et al. showed that transfusion with one to three units of blood caused suppression of cellular immunity, defined by a mixed lymphocyte response. When he compared the effects to autologous units, there was no depression in cellular immunity (123). Matsumoto et al. studied MLR in patients who had undergone donor-specific transfusions while being readied for transplant. He found both suppressor cells and antibodies, which he thought were anti-idiotypic antibodies. This latter finding was confirmed by Singal who showed that sera from transfused patients resulted in depression of MLR, while sera from nontransfused patients did not give the same depression (124,125). Animal studies suggested that prostaglandin E may be a mediator of these changes. There is no doubt that blood transfusion has a major influence on the immune system. Some of these immunosuppressive effects maybe desirable, as in the case of a transplant in which transfusion improves graft survival. Transfusion effects are also undesirable in the case of patients with certain types of cancer. The use of transfusions is always worth careful evaluation for the individual patient.

Renal Failure Infections are common in patients with renal failure and are a major cause of death in patients with end-stage renal disease. One would expect major changes in the immune system of these patients and, in fact, they show defects in specific as well as nonspecific immunity. Abnormal cellular immunity has been confirmed clinically in various ways. These patients also have a markedly decreased response to cutaneous injection of various antigens (126). Hepatitis B vaccination in chronic renal failure patients on dialysis resulted in a very low rate of seroconversion after vaccination compared to the general population (127). This was in the face of the normal levels of Ig in the dialysis patients. Lymphocyte counts have also been shown to be decreased in these patients; however, the CD4/CD8 ratios are reported to be normal (128). In vitro studies have shown that uremic patients have impaired responses to mitogens and allogeneic lymphocytes. Because these findings are marked in the presence

of uremic serum, there may be a soluble factor that causes this depression (129). Because these changes were seen in patients who are being dialyzed, the substance is not dialyzable. There were indications that the TCR/CD3 antigen complex in the uremic patient may be downregulated. This finding may be due to a combination of uremia, hyperparathyroidism, and dialysis itself (130). Other cells that are affected in uremia are B-cells and NK cells. Uremic patients show normal to supranormal levels of IgG and IgM, although the actual mechanism for this finding is not well delineated. There is recent evidence that monocytes may be defective in uremic patients (131). This defect also influences how the monocytes present antigens. Thus, the defects that are seen may be a combination of both T-cell and APC deficiencies. The disturbances outlined above undoubtedly have an influence on the decreased ability of these patients to handle both bacterial and viral infectious challenges. Vigilance for infection is necessary in these patients. This concern is heightened for the large number of dialysis patients who are diabetic. Patients who are diabetic and on dialysis appear to be at an especially high risk of developing infections.

Diabetes Mellitus Most of the deaths in these patients can be attributed to cardiovascular disease; however, infection is a major cause of morbidity in these patients. Early studies indicated that diabetics had a greater number of infections than did control subjects. For example, one early study reported a 2.4% incidence of limb infection in diabetic patients compared to 0.5% in nondiabetic subjects (132). In addition, those patients with diabetes for longer than 20 years were found to have a prevalence of bacteriuria (19% compared to controls with a prevalence of 8%) (133). Most clinicians agree that diabetics will have more severe infections and a more protracted clinical course than nondiabetics. The World Health Organization classifies diabetes as a secondary immunodeficiency disease. The ability of patients to fight infection is altered in diabetics. PMN granulocytes have several functional abnormalities, with decreased migration characteristics, especially in those patients with poorly controlled serum glucose levels (134). Phagocytosis is defective in diabetics, especially when the glucose level is elevated (135). However, following normalization of glucose levels, these abnormalities disappear. Lymphocyte subsets can be altered in diabetics. A study of type 1 diabetics reported a decrease in circulating CD4 cells, which results in a decrease of the CD4/CD8 ratio (136). This change may be due to decreased levels of insulin or decreased insulin activity. As was found with neutrophil function, normalization of insulin levels results in normal lymphocyte transformation upon stimulation, as well as normalization of lymphocyte levels (137). However, the report that approximately 50% of the diabetic patients who received hepatitis B vaccine responded poorly indicates that there may be additional immunosuppressive factors operative in these patients. Patients who have a well-controlled glucose level do not have a higher susceptibility to Staphyloccus infections. However, in older patients, the risk of bacteremia is higher. Specific infections can be more fatal in diabetics compared to normal patients, and those patients who are diabetic and develop bacteremia have a higher mortality rate than those without diabetes (138). Candida infections are more prevalent

Chapter 4: The Immune System and the Immunocompromised Patient

in diabetics compared to the normal population and are particularly more common in those patients whose glucose levels are poorly controlled. However, this was not the case with other fungal infections. The treatment of fungal and bacterial infections requires the initiation of good glucose control and appropriate antibiotic or antifungal therapy. Major factors that lead to increased infections in diabetics in addition to poor glucose control include underlying vascular disease and nerve damage. Poor blood supply results in inadequate oxygenation, which leads to anaerobic infection and also limits host-defense mechanisms. If a patient has a peripheral neuropathy, the result can be an ulcer, which can become secondarily infected. The key to prevention of infection in the diabetic includes control of hyperglycemia; if one reduces the glucose to normal levels the incidence of infections decreases. Complications that lead to increased levels of insulin must be avoided. One must also aggressively look for infection and treat those conditions that can result in the infection becoming widespread or locally uncontrollable.

Prevention and Therapy Clinical Guidelines Prevention of infection in the immunocompromised patient calls for an awareness of the possible infections these patients can develop and an approach to deal with the problem. One must also be aware that patients with certain immune defects can develop cancer. When these patients are examined, one must check for the presence of palpable lymph nodes and also carefully examine the skin to look for suspicious lesions. The risk of infection in these patients is dependent on both the immunosuppressive status of the patient and environmental factors. The amount of immunosuppression is dependent on the level of nutrition, the state of the various portions of the immune system, defects in the skin or mucus membranes, and any invasive lines or procedures that have been undertaken. The importance of environmental factors is illustrated by the realization that even a normal healthy individual can be infected if in contact with a large enough inoculum of an infectious agent. Thus a patient who is immunosuppressed can become infected on exposure to a proportionately smaller number of infectious agents, depending upon his overall immune status. In caring for these patients, one must apply the principles outlined in Table 8. Hand washing is particularly critical in these patients to prevent patient-to-patient transmission of infection. Deep lines such as subclavian and internal jugular lines, and Swan–Ganz catheters must be watched particularly carefully. In immunosuppressed patients, there will be no evidence of infection, and therefore changing the lines or making sure they are absolutely necessary is imperative. Nutritional support will bolster the immune system and prevent a catabolic state in the immunocompromised patient. One must also be certain that the integument is intact and that the skin does not become a site for entrance of bacteria. The Guidelines for Prevention of Surgical Site Infection from the Centers for Disease Control should be rigorously followed in this group of patients. Immunocompromised patients can develop infections in a number of places. These infections can include skin, respiratory, gastrointestinal or central nervous systems. Suspicious skin lesions should be biopsied, aspirated, or cultured. The neutropenic patient who develops a fever requires careful evaluation. Approximately 40% of patients who are

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neutropenic and develop a fever will have a documented infection (140). Only 20% of fevers in these patients are due to the underlying disease or to other noninfectious causes. The remaining 40% are due to possible but nonproven infections. The classical signs of infection in these patients frequently are missing. They will not exhibit fluctuance, calor, rubor, or lymphadenopathy as commonly as patients with a normal neutrophil count do. The physical examination should focus on skin, mucosa, and perianal areas. The therapy early on should include broad-spectrum antibiotics after adequate cultures have been obtained. The optimal drug choice is still debated. Antibiotics are useful in these patients but other methods of stimulating the immune response are being sought.

Biologic Response Modifiers Biologic response modifiers (BRM) are being explored in hopes of increasing the activity of specific groups of cells in the body. Commonly used biological response modifiers include cytokines, colony-stimulating factors, IFNs, and TNFs, but can include microorganisms, polysaccharides, polypeptides, thymic factors, synthetic compounds, polyribonucleotides, and vaccines. Most were named based upon a primary property, but these agents have a large amount of overlap in their individual effects and have many diverse effects. IL-1 is a product of monocytes and has a myriad of effects. These include activation of T, B, and NK cells and activation of vascular endothelium, fibroblast proliferation, and activity against human tumors. It has also been shown to prevent infection and protect against IL-2 toxicity. It has been shown to protect against bacterial infections in mice (141). IL-1 has also been used in patients with cancers and has been shown to increase the white blood cell count, increase the cellularity in bone marrow, and give rise to major hypotension after use (142). IL-2 is produced primarily by Th1 cells. Treatment of NK cells with IL-2 results in their differentiation into lymphokineactivated killer cells, which appear to home to the site of viral infection. Because of these promising results it was the first BRM used in clinical trials. The cytokine has been shown to be effective in a number of animal models, yet its use in clinical trials has been disappointing. Surprisingly, when used in AIDS patients, it was shown to decrease some immune functions such as that of NK cells. Because of its general effectiveness in increasing the activity of NK cells, it is still used in cancer patients. The precise dose and combination of additional chemotherapeutic agents are being evaluated in metastatic melanoma, acute myelogenous leukemia, and metastatic renal cell carcinoma. It is used at the maximal tolerated dose with the major side effects being cardiovascular. Colony-stimulating factors are commonly used in cancer chemotherapy. The major interest in these agents is because they can reverse the severe neutropenia after chemotherapy, which can lead to severe bacterial infections. Granulocyte colony-stimulating factor (G-CSF) is produced by a number of cells in the body including endothelial cells, fibroblasts, and macrophages. The agent has been used in cancer chemotherapy to prevent the periods of severe neutropenia and the use of broad-spectrum antibiotics (143). G-CSF has minimal toxicities, which include mild bone pain and cellulitis at the injection site. G-CSF is not useful in patients who have an established infection, but is only useful in preventing the neutropenia associated with cancer chemotherapy (144).

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Table 8 Principles of Infection Prevention in the Compromised Host Reduce acquisition of ambient organisms from hospital environment Avoid hospitalization Segregate patients with potentially communicable diseases Avoid overcrowding in wards and ICU Enforce strict hygiene, particularly hand washing, among physicians, nurses, and aides Avoid invasive procedures whenever possible Employ indwelling intravenous and urinary catheters only if absolutely necessary Change scalp vein needles, tubing, and intravenous bottles daily Use respiratory assistance devices, particularly those requiring intubation, with great care and with close monitoring to ensure that they are adequately decontaminated Reduce number of colonizing organisms Remove or reduce sites of prior infection Consider the use of isoniazid prophylaxis in patients with histories, positive skin tests, or chest X-ray findings of old tuberculosis Closely monitor serologic tests and clinical course in patients with evidence of old coccidioidomycosis or histoplasmosis who have now become immunosuppressed Bolster host defense mechanisms Successfully treat the underlying disease Prescribe adequate nutrition and exercise Improve respiratory toilet Control diabetes mellitus, congestive heart failure, or respiratory insufficiency Reduce local obstruction caused by tumor Protect the integrity of oral and anorectal mucosae When appropriate, prescribe immunotherapy with vaccines and/or immunoglobulin preparation Abbreviation: ICU, intensive care unit. Source: From Ref. 139.

GM-CSF factor has an effect on both stem cells and megakaryocytes and stimulates the production and antibacterial function of neutrophils and monocytes. Like G-CSF, it is produced by endothelial cells, fibroblasts, and T-lymphocytes. GM-CSF has been used in patients with aplastic anemia and those who have undergone bone marrow transplantation. It has also found clinical applications in patients with acute and chronic leukemia, Hodgkin’s and non-Hodgkin’s lymphomas, treatment-related cytopenias from chemotherapy in solid tumors (145,146), and AIDSrelated neutropenia (147). The functional capabilities of the induced cells are normal. The therapy results in increased numbers of leukocytes in peripheral blood. The toxicity is mild when used in small doses; however, there is marked toxicity in large doses, including fever, capillary leak syndrome, and pericarditis. Data from animal experiments and ex vivo human experiments suggested that administration of GM-CSF might provide clinical benefit in the treatment or prevention of neonatal infections. Although a significant number of clinical studies have administered GM-CSF to neonates, there is insufficient evidence of clear efficacy or benefit to support their routine use. Several recent clinical reviews agree that further adequately powered, randomized, placebo-controlled clinical trials of this promising immunotherapy are warranted (148). The IFNs were among the first BRM discovered to have clinical application. IFN-a has shown clinical use in hairy cell leukemia, condyloma acuminatum, AIDSassociated Kaposi’s sarcoma, melanoma, lymphoma, and chronic myelogenous leukemia (149–151). The side effects are primarily a flu-like syndrome including, fever, headache, nausea, vomiting, anorexia, and occasionally impaired cognitive function. In most patients, these symptoms abate and therapy is not limited. IFN-g is important in macrophage activation and in B- and T-cell responses (152,153). IFN-a has been used to treat hepatitis B. It has been shown to give a serocoversion rate of approximately 25% to 40%

(154). Hepatitis C has been especially prominent in the dialysis population and is associated with a chronic carrier state. Treatment with IFN-a for approximately six months has been shown to give a response rate of approximately 50%, but about half of those who respond will relapse (155). The response rate has been shown to increase with the addition of ribavirin to the IFN-a. The last group of BRM to be discussed is TNFs. This group of agents was discovered when it was shown that certain bacterial products could reduce the size of tumors (156). TNF-a is released by macrophages. It has many biological effects including: proliferation of T-cells and NK cells; adherence of neutrophils to endothelium; increased cytolytic activity of T- and NK cells; and stimulation of other BRM such as IL-1 and IL-6. It has been proved useful in hairy cell leukemia and in patients with Kaposi’s sarcoma (149,157). During clinical use the side effects of TNF-a are quite mild, including fever, headache, nausea, and vomiting. TNF-b carries some similarity to TNF-a and is produced by T-, B-, and NK-cells. It mediates the biological response to microbial infections. The agent has been used in an attempt to improve outcomes in infection in an animal model (158). Antibodies to TNF have been used in septic patients, however, there was no survival benefit noted in this group of patients (159). The use of these agents in the treatment of human disease is still being explored. The importance of BRM is now being realized, as is the complexity of their interactions. Much additional work will need to be completed before their potential for therapy can be realized.

SUMMARY The causes of immunosuppression in surgical patients have been outlined. These include malnutrition, trauma, blood transfusions, sepsis, diabetes mellitus, and cancer. Each of these causes can be evaluated and the individual problem

Chapter 4: The Immune System and the Immunocompromised Patient

corrected if possible. The individual patient with severe neutropenia must be evaluated very carefully and steps taken to prevent infection. The place of BRMs has been defined in neutropenia in certain disease states but additional uses still are to be defined.

ACKNOWLEDGMENTS The authors wish to thank Mrs. Valerie Brookins and Mr. Dorian Araneda for their assistance in the preparation of Figures and Tables.

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5 Physiologic Basis of Transplantation Yuan Zhai and Rafik M. Ghobrial

carry distinctive pathogen-associated molecular patterns, which are often lipid and carbohydrate moieties, constituents of microbial cell walls (2). They can be recognized by various cell–surface pattern recognition receptors, including toll-like receptors (TLRs), scavenger receptors (sialic acid), macrophage mannose receptor, b-glycan receptor, and galactose-specific lectin. Phagocytosis is one of the classical outcomes of the innate immune reaction. Recently, it has been recognized that the activation of innate immunity is in fact a prerequirement for effective adaptive immunity involving antigen-specific T- and B-cell responses. Despite its sentinel role in host immune responses, innate immunity has long been ignored in allograft rejection because of a common but misleading observation, in animal models, that allografts survive long term in T- and B-cell–deficient recipients. In fact, the first wave of graft-infiltrating lymphocytes are macrophages and neutrophils, but not T- or B-cells, in both allo- and xenograft transplantation (3). While it is true that innate immune responses alone may not be sufficient to acutely reject allografts, it was recently demonstrated that inhibition of innate responses could disrupt the development of alloantigen-specific T-cell responses and prolong allograft survival. An elegant example is the observation that the absence of local synthesis of the complement component C3 can promote major histocompatibility complex (MHC)–fully mismatched renal allograft survival in a murine model (4). On the other hand, with the effective control of acute allograft rejection by current immunosuppressive agents, innate immune responses, possibly spared from T-cell or B-cell targeted therapies, may show critical impact on chronic allograft rejection. In the solid organ transplantation setting, the surgical procedure and ischemia–reperfusion injury are two major antigen-independent stimulants that trigger innate immune responses in the early post-transplantation phase. Cell death is a key event in initiating the inflammation cascade, which is enhanced during reperfusion by reactive oxygen species, cellular adenosine triphosphate depletion, expression of death ligands [tumor necrosis factor (TNF)-a, FasL], and complement activation. Although, the molecular mechanism activating the innate immune system in transplantation has not been determined, the finding of endogenous ligand for TLR implied the potential role for this particular innate receptor system (5). TLRs were initially identified as homologues of the Drosophila Toll proteins, and developed in mammalians to a highly conserved receptor system that recognizes functionally essential molecules shared by microbial pathogens (6). TLRs are expressed on different cell types, particularly APCs, such as macrophages and dendritic cells (DCs). TLR engagement by microbial products initiates the process of DC maturation, resulting in the upregulation of surface expression of MHC and costimulatory

INTRODUCTION Successful clinical transplantation is limited not by technical pitfalls but rather by the immune process that mediates rejection of the transplanted tissue or organ (1). Thus, the physiologic basis of transplantation rests on understanding the immunologic rejection process. The goal of the transplant surgeon is to manipulate either the host (i.e., the recipient of the transplanted organ or tissue) or the allograft (i.e., the organ or tissue being transplanted from a donor, within the same species) to avert, minimize, or reduce this physiologic process. Immunologic events leading to allograft rejection can be divided into afferent, central, and efferent limbs. The afferent limb is the initiation of immune responses, which includes presentation of foreign histocompatibility antigens to T-lymphocytes by antigen-presenting cell (APC). The activation of antigen-nonspecific innate immunity is critical for this process, which by itself is also able to directly cause damage to allografts. The central limb is the activation of alloantigen-specific T- and B-lymphocytes, including their proliferation and differentiation. The efferent limb is execution of effector functions of activated lymphocytes, including both cellular and soluble cytotoxicities to destroy grafts. In the following discussion, we will use alloreactive T-cells as an example, and provide a mechanistic overview of various components of alloimmune responses and how alloimmune responses proceed.

ALLOGRAFT REJECTION Afferent Limb This section aims to delineate the molecular and cellular components of the immune system, which provide the structural basis of T-cell recognition of allogeneic antigens. As we know now, organ transplantation presents both physical and biological stresses to the host immune system. The first response to these stresses is inflammation, which is mediated by the host innate immune system and provides the initial milieu for subsequent activation of the host’s antigen-specific adaptive immune system.

Innate Immunity The innate immune system consists of both cellular and soluble components. Dendritic cells, macrophages, neutrophils, eosinophils, mast cells, natural killer (NK) cells, as well as intraepithelial lymphocytes at the mucosal surface, form the first line of cellular defence against infectious agents in mammalian tissues. Soluble components include complements, C-reactive protein, mannan-binding lectin, cytokines, and chemokines. Activation of the innate immune system is mediated by receptor–ligand interactions. Infectious agents 91

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molecules, and the production of immunostimulatory cytokines. These matured DCs are the key leading to T-cell activation and the development of adaptive immunity. Molecules generated during tissue damage and inflammation including heat shock proteins (HSPs), hyaluronan, heparin sulfate, and fibronectin have been shown to act as endogenous TLR ligands and effectively stimulate DCs via TLR system (5). Upregulation of chemokine and cytokine production as a result of intragraft DC and endothelial activation leads to the recruitment and activation of infiltrating lymphocytes, including macrophages, NK cells, and T-cells. Clearly, there are bidirectional interactions between innate and adaptive immune responses during this progressive graft rejection process: the initial innate immune activation probably starts the cellular cascade in an antigen-nonspecific fashion to trigger T-cells, whose activation then not only elicits antigen-specific adaptive immune responses, but also feeds back and amplifies the innate immune responses. Chemokines and Their Receptors As one of the major products from innate immune system activation, chemokines play critical roles in intragraft recruitment and activation of not only antigen-nonspecific leukocytes of innate immunity, but also T- and B-cells of adaptive immunity. Chemokines are a large family of low-molecular-weight (8–11 kDa), heparin-binding proteins initially recognized with chemoattractant activity for leukocytes and later with other important developmental functions, e.g., hematopoiesis and organogenesis (7). Currently, there are approximately 60 chemokines divided into four subfamilies, based on cysteine motifs near the amino-terminal end of the molecules: C, CC, CXC, and Cx3C. Functionally, however, chemokines within the same subfamily vary significantly in their biological targets and effects. Two major functional groups of chemokines involve either inflammation or homeostasis, which also differ in their expression regulation (inducible by proinflammatory or constitutive stimuli, respectively). Chemokine receptors are members of the serpentine, heterotrimeric G-protein–coupled, seven-transmembrane– spanning receptor superfamily. Eighteen chemokine receptors have been identified so far, with each binding a distinct set (more than one) of chemokines (7). The complexity and specificity of the chemokine system stem from not only the multitude of receptor–ligand pairing but also the regulated expression of ligands and receptors, which differ according to cell subsets and state of cell activation. The array of chemokine receptors displayed on a leukocyte surface regulate its homing and chemotactic potentials. Thus, each chemokine recruits only specific cell types at a particular activation or differentiation state. Table 1 lists some of the common chemokines and their receptors that have been implicated in transplant immune responses (8,9).

Alloantigen Presentation and Recognition Alloantigen-specific immune responses involve three types of lymphocytes: T-cells, B-cells, and APCs (particularly DCs). As in the innate immune response, the ‘‘adaptive immune response’’ is also mediated by receptor–ligand interactions, but in a much more complicated fashion. Multiple pairs of receptor–ligand interactions are required for effective T (or B) -cell activation. In this section, we will review the molecular structure of such receptors or ligands, including the MHC, minor histocompatibility antigens, T- or B-cell receptors, and costimulation molecules.

Table 1 Chemokine Cascades Following Organ Transplantation Chemokine cascade

Receptor

Early (3–72 hr) Gro-a/MIP-2

CXCR2

Neutrophils

IL-8 MCP-1/JE

CXCR1/2 CCR2

Neutrophils Macrophages, T

MIP-1a

CCR1/5

MIP-1b

CCR1/5

IP-10

CXCR3

Fractalkine

CX3CR1

Late (48–72þ hr) RANTES

CCR1/3/5

Target lymphocyte

Murine cardiac allograft outcome after treatment Delayed rejection (38
C or 90 beats/min Respiratory rate >20 breaths/min or PaCO2 38
C or 90 beats/min Respiratory rate >20 breaths/min or PaCO2 12,000 cells/mm3, 10% immature (band) forms Severe sepsis: Sepsis associated with organ dysfunction, hypoperfusion, or hypotension. Hypoperfusion and perfusion abnormalities may include, but are not limited to lactic acidosis, oliguria, or an acute alteration in mental status Septic shock: Sepsis with hypotension, despite adequate fluid resuscitation, along with the presence of perfusion abnormalities that may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status. Patients who are receiving inotropic or vasopressor agents may not be hypotensive at the time that perfusion abnormalities are measured Hypotension: A systolic blood pressure of 104 or 105 colony-forming units per milliliter). However, the role of quantitative culture techniques in the diagnosis of hospital-acquired pneumonia remains controversial, and the techniques for obtaining the cultures and concentration of bacteria that establish the presence of infection have not been standardized. The choice of antibiotics for the treatment of nosocomial pneumonias is based on likely pathogens and the spectrum of activity, pharmacodynamic profile, and adverse reactions associated with individual drugs (38). Likely pathogens may be deduced from the timing of the onset

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and the severity of the pneumonia, as well as from the presence of patient-associated risk factors. The choice of antibiotic is also influenced by the concentrations of the agent attainable in respiratory secretions. Quinolones attain concentrations in respiratory secretions close to those attained in serum. On the other hand, aminoglycosides penetrate respiratory secretions poorly and should not be used alone to treat gram-negative respiratory infections (39). Clinical improvement should be used as the ultimate end point of therapy. In general, clinical improvement does not occur before 48 to 72 hours after the initiation of therapy. Changes in antibiotics during this period should not be undertaken unless progressive deterioration of the patient’s clinical status is apparent. Every effort should be made to determine the reason for failure in patients who are unresponsive to therapy after this time period (40). The optimal duration of treatment for nosocomial pneumonias has not been established. For gram-negative pneumonias, which are associated with high rates of treatment failure, relapse, and death, 14 to 21 days of treatment has been recommended. Other less virulent organisms may be adequately treated with a 7- to 10-day course of antibiotics.

Urinary Tract Infections The largest percentage of infections that occur on surgery services arise in the urinary tract (approximately 13.3 cases per 1000 hospital discharges) (41). This circumstance is a simple consequence of the placement of urinary bladder catheters. Although serious infectious problems may ensue from the catheterization of the elderly male with an unrecognized prostate infection or obstruction, most urinary tract problems occur because closed urinary drainage systems eventually become colonized by enteric bacteria such as Escherichia from which the patient may become infected. No measure is particularly effective in preventing these catheter-related infections, although a number of approaches have been tried including the administration of antibiotics (both systemic and local), the use of special tubes with irrigants, and various regimens of catheter care (42). Use of prophylactic antibiotics encourages infection by resistant bacteria or the fungus Candida (especially in diabetic patients). Frequent catheter care with cleansing of the urethral meatus leads to an increased frequency of urinary tract infections so that only daily (rather than more frequent) catheter care has become standard practice. The best prevention of urinary tract infections is to avoid prolonged catheterization and to use alternatives such as intermittent catheterization or, in the case of men, condom catheters whenever possible. Regardless of the technique of drainage, patients should be kept well hydrated so that the bladder is constantly flushed, thereby decreasing the number of potentially infecting bacteria. Many physicians overreact to the presence of more than 105 organisms in the patient’s urine without first obtaining a urinalysis to prove the presence (or absence) of pyuria. Colonization without pyuria can usually be resolved without the use of antibiotics, simply by removing the patient’s catheter and maintaining adequate hydration. In the patient with significant bacteriuria and pyuria in combination and a high temperature elevation in the range of 103
to 104
F, a source of infection other than the bladder should be sought. Pyelonephritis with its attendant high frequency of bacteremia may be present under these circumstances and require aggressive antibiotic therapy; simple cystitis rarely causes high fever (43). The majority

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of catheterized patients with bacteriuria and pyuria have a low-grade fever secondary to a simple catheter-related cystitis. The principles of management in this latter circumstance include removal of the catheter, if possible, and in most instances a single dose of an antimicrobial agent that is excreted in the urine. For those patients in whom catheter placement must remain in the presence of pyuria, the use of a brief course of an antibiotic is warranted to prevent the bladder from becoming a nidus for systemic infection. This latter condition is most likely to occur if the catheter becomes obstructed. Although most postoperative urinary tract infections occur in association with indwelling urethral catheters, occasionally such infections develop in the early postoperative period secondary to urinary stasis and necessitate catheter placement as a therapeutic measure. Patients at risk for this problem include those with prostatic hypertrophy and various neuromuscular disorders such as multiple sclerosis, those who had undergone previous anorectal procedures that have resulted in ineffective postoperative voiding, and those individuals in whom a spinal anesthetic was used. Under most circumstances, a urinary catheter should be prophylactically placed in such patients before surgery to prevent these stasis problems and should be removed as soon as normal voiding can be ensured. If a catheter-associated infection develops, the principles of treatment outlined previously should be followed.

Table 4 NRC Wound Classification Criteria Classificationa

Criteria

Clean (< 2%)

Elective (not urgent or emergency), primarily closed; no acute inflammation or transection of GI oropharyngeal, genitourinary, biliary, or tracheobronchial tracts; no technique break (e.g., elective inguinal herniorrhaphy) Clean contaminated Urgent or emergency case that is otherwise ‘‘clean’’; (< 10%) elective, controlled opening of GI, oropharyngeal, biliary, or tracheobronchial tracts; minimal spillage and/or minor technique break; reoperation via ‘‘clean’’ incision within 7 days: blunt trauma, intact skin, negative exploration (e.g., vagotomy and pyloroplasty) Contaminated (20%) Acute, nonpurulent inflammation (note absence of purulence); major technique break or major spill from hollow organ; penetrating trauma 4 hr old (e.g., perforated appendicitis with abscess) a

Wound infection rate after Ref. 44. Abbreviations: NRC, National Research Council; GI, gastrointestinal. Source: From Ref. 45.

Wound and Soft Tissue Infections The development of SSI, usually in the skin and subcutaneous tissues of the operative side, is a common postoperative problem. Overall, it is estimated that 4% to 7% of surgical patients develop these infections postoperatively. These infections contribute to postoperative morbidity and increased length of stay, with attendant increased costs of medical care. The prevention of SSIs relies on correct surgical technique, modification of host risk factors, and adequate antimicrobial prophylaxis. Both local factors, such as the degree of contamination of the wound, and systemic factors, such as the overall condition of the patient, influence the rates of wound infections. Systemic factors, such as hypoxic lung disease, should not be underestimated when evaluating SSI. The degree of contamination of the surgical wound has traditionally been assessed according to the National Research Council (NRC) wound classification scheme. In this system, wounds are classified as clean, clean contaminated, contaminated, or dirty (Table 4). The NRC wound classification does not, however, take into consideration any other risk factors for wound infection (44,45). Additional risk factors for wound infection have been defined. In one prospective study involving nearly 24,000 patients, advanced age, the presence of diabetes, obesity, or malnutrition, and a perioperative hospital stay of more than two weeks were identified as risk factors (46). In other studies, malignancy, alcoholism, recent cigarette smoking, hypoxemia, remote infection, chronic inflammation, prior surgical site irradiation, recent operation, prior use of antibiotics, and recent use of corticosteroids or cytotoxic agents have also been associated with an increased risk of postoperative infection (45,47). The interaction between these and other factors and the NRC wound classification was investigated in two very large epidemiologic evaluations. One of these took place during the Study on the Efficacy of Nosocomial Infection

Control (SENIC) project (48). This analysis of nearly 60,000 patients undergoing surgical procedures identified four factors of nearly equal weight in predicting postoperative wound infection: an abdominal operation, an operation that took longer than two hours, a wound classified as either contaminated or dirty, and the presence of three or more diagnoses at the time of discharge. The surgical wound infection rates in patients ranged from 1.0% in patients with no risk factors to 27.0% in patients with four risk factors (Table 5). Even in patients with clean wounds, the postoperative wound infection rate ranged from 1.1% to 15.8% as the number of risk factors increased from zero to three (49). The second large study involved patients evaluated as part of the National Nosocomial Infection Surveillance System (NNISS), sponsored by the Centers for Disease Control and Prevention (50). In this survey of nearly 85,000 operations, three risk factors were identified: a patient having an American Society of Anesthesiologists (ASA) score of 3, 4, or 5, an operation considered contaminated or dirty-infected, and an operation that took longer than T hours, where the value of T depended on the actual operative procedure and ranged from one hour for a simple procedure such as appendectomy to four hours for complex procedures on the liver, bile ducts, or pancreas. The risk of a surgical wound infection varied from 1.5% to 13% as the number of risk factors increased from zero to three (Fig. 2). In patients with clean wounds, the infection rates varied from 1% to 5.4% as the number of risk factors increased from zero to two. The NNISS data also showed that there was an increased risk of other nosocomial infections, including pneumonias, blood stream infections, and urinary tract infections as the number of risk factors increased. Thus the inclusion of additional factors along with the NRC wound classification predicted the risk of surgical

Chapter 6:

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Surgical Infection: Principles of Management and Antibiotic Usage

Table 5 Distribution of Patients and Infections by the SENIC Risk Factors and NRC Wound Classification % Infection by NRC wound classification SENIC risk factors 0 1 2 3 4 NRC, % of all patients NRC, % of patients with infection NRC, % of group with infection

SENIC, % of patients with infection

SENIC, % of group with infection

Clean contaminated

Contaminated

Dirty

SENIC, % of all patients

1.1 3.9 8.4 15.8 N/A 55d

0.6 2.8 8.4 17.7 N/A 36

N/A 4.5 8.3 11.0 23.9 2

N/A 6.7 10.9 18.8 27.4 7

46a 32 16 5 1 100

10b 29 35 20 6 –

1c 3.6 8.9 17.2 26.7 –

39e

35

4

22

–

100

–

8.5

12.6

–

–

Clean

2.9f

3.9

4.1

Note: SENIC risk factors include abdominal operations, operations longer than two hours, three or more associated diagnoses, and dirty or contaminated wounds, as defined by NRC wound classification. Patients with contaminated or dirty wounds cannot have zero SENIC risk factors. Patterns with clean or clean-contaminated wounds cannot have four SENIC risk factors. Example statements indicating how to read this table: a Patients with zero SENIC risk factors accounted for 46% of all patients. b Patients with zero SENIC risk factors accounted for 10% of all infected patients. c The infection rate for patients with zero SENIC risk factors was 1%. d The NRC clean wounds accounted for 55% of all patients. e The NRC clean wounds accounted for 39% of all infected patients. f The infection rate for patients with NRC clean wounds was 2.9%. Abbreviations: NRC, National Research Council; SENIC, Study on the Efficacy of Nosocomial Infection Control. Source: From Ref. 49.

wound infection better than did the NRC wound classification scheme alone. Although the variables identified in these two large prospective studies were different, it is apparent that the length of the procedure and the patient’s premorbid condition, as assessed in the SENIC study by the number of discharge diagnoses and in the NNISS study by the ASA classification, have as much bearing on wound infection rates as the NRC wound classification category. Rational interventions designed to decrease the risk of surgical wound infection can be developed on the basis of this risk factor data. Currently, one of the most commonly used interventions is the use of perioperative prophylactic antibiotics. Because of the low rate of infections (approximately 1–3%) usually observed in patients classified as having clean wounds, it had been argued that prophylactic antibiotics were not needed in that group of patients.

Figure 2 SWI rates within categories of the surgical patient risk index. Abbreviations: G, Goodman–Kruskal correlation coefficient; s.e., standard error; SWI, surgical wound infection. Source: From Ref. 44.

However, both the SENIC and the NNISS studies indicate that there are patients with clean wounds who have a much higher risk of wound infection. Thus, selected patients having clean operations might warrant prophylaxis. The use of perioperative antibiotics is discussed in more detail later in this chapter. Other factors might also be subject to modification. The length of the surgical procedure was identified in both studies as a risk factor for the development of surgical wound infection. This might suggest that efforts made by the surgeon to increase the speed of the operation would result in decreased infectious complications. However, it is unclear from these studies if the length of the surgical procedure was actually a surrogate end point for surgical skill or was rather related to the difficulty of the particular procedure as determined by the complexity of the patient’s pathologic condition. Thus if the latter were true, it is unlikely that efforts designed to increase the rapidity with which an operative procedure is carried out would have a significant effect on postoperative infections. From additional studies, it does appear that the prevention of intraoperative hypothermia reduces the likelihood of surgical wound infections. In a recent prospective, randomized study, the maintenance of normothermia during elective colorectal surgery decreased the rate of wound infections threefold (51). It was speculated that hypothermia interfered with blood flow to the surgical wound by triggering vasoconstriction or, in some other way, impaired the immunologic response in those areas. Many of the risk factors related to the patient’s pathologic process and underlying physiologic reserves cannot be readily controlled. However, several factors are related directly or indirectly to nutritional status. Thus interventions designed to improve the patient’s nutritional status, particularly the use of parenteral nutrition, have been

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proposed as a means of reducing postoperative infectious morbidity. However, preoperative parenteral nutritional support has not been found to benefit the majority of patients and may even contribute to postoperative infections. In the Veterans Affairs Total Parenteral Nutrition Cooperative Study, only the patients with severe malnutrition had a slight benefit from preoperative nutritional support (52). In the remainder of the patients, who had mild-to-moderate malnutrition, preoperative therapy may actually have been detrimental. This investigation did not examine the potential role of oral or enteral nutrition preoperatively, and there is no reason to discourage adequate nutrition during the preoperative period if it does not unnecessarily delay a needed procedure. However, exhaustive efforts to improve nutritional intake, particularly using parenteral nutrition, are unlikely to be useful except in the most severely malnourished patients. One final intervention that appears useful in reducing global rates of surgical wound infections is an effective infection control program (53). This intervention has been estimated to provide reductions in wound infection rates of 20% to 38%. Effective programs should include wound surveillance, both in the inpatient and outpatient setting, to detect the presence of surgical wound infections. However, of greater importance is feedback to individual practitioners with regard to their own wound infection rates and an effective program for policy development and teaching that allows individual practitioners to adapt effective techniques in controlling wound infection rates.

Phlebitis Although phlebitis of the lower extremities may develop in any patient following surgery and result in postoperative fever, it seldom has a bacterial cause. In contrast, catheterrelated phlebitis is a true infection. Bacteremias secondary to intravascular devices occur in as many as 25,000 to 50,000 patients per year in the United States (54). An intravenous catheter breaches local skin defenses and allows several portals of entry for bacteria. The most common portal of entry is along the skin tract on the outside of the catheter. The predominant organisms that gain entry by this route are skin flora (e.g., S. aureus, but also, with increasing recognition, Staphylococcus epidermidis). Contamination of the catheter hub infusion junction has also been implicated as a cause of bacteremia in patients with central venous lines. Again, organisms of the skin flora are the most common ones. Rarely, bacteremias may occur from the infusion of contaminated solutions. These infections are most commonly due to gram-negative organisms (e.g., Pseudomonas and Enterobacteriaceae). Definitive diagnosis of a catheter-related infection can only be made if there is purulence or inflammation at the insertion site with recovery of a pathogen on culture or if blood culture results and culture results from of the catheter tip are positive for the same organism and there is no other identifiable source of bacteremia. The diagnosis is considered probable if (i) there is purulence at the insertion site but no pathogen is recovered, (ii) blood and catheter-tip culture results are positive for the same organism and a separate identifiable source of bacteremia is present, or (iii) bacteremia is present without an identifiable source and the catheter tip and insertion site were not cultured. Catheter-tip cultures are obtained when a blood stream infection is thought to be related to contamination of the catheter. Under these circumstances, the tip of the catheter is cut off with sterile scissors and placed in a sterile

container so that semiquantitative cultures can be obtained. Maki et al. (55) reported that these cultures have a 76% to 96% specificity and a positive predictive value of 16% to 31% for identifying the presence of a catheter-related infection. Prevention of infection requires careful use of sterile technique for the placement of all intravascular catheters and particularly for central venous lines. In addition, the insertion site must be dressed appropriately. A metaanalysis (56) found a significantly increased risk of catheter colonization when transparent semipermeable dressings were used compared with gauze dressings. This study also found a trend toward an increase in bacteremia with the use of transparent dressings, but this difference was not statistically significant. Frequent catheter changes (every 72–96 hours) may be necessary in patients with clinical signs of infection. This is especially true if the catheters are being frequently manipulated to administer medications or to draw blood samples. In the absence of clinical signs of infection and, particularly, if the catheter is dedicated for a single purpose (i.e., total parenteral nutrition administration), the catheters may be left in place indefinitely. Exchange over a guide wire should not be used if a device infection is suspected (57). Three therapeutic decisions involving intravenous catheters are particularly controversial. The first is bacteremia caused by S. aureus, which may be secondary to infected intravenous catheters. S. aureus is notorious for persisting within leukocytes and disseminating widely throughout the body (58). A body of data has suggested that if the focus of infection is removable (e.g., an intravenous catheter that can be removed or a furuncle that can be rapidly drained), the patient can be treated with a relatively short course of antibiotics, specifically, two weeks. Conflicting evidence reveals the occasional case of endocarditis that develops despite adherence to appropriate principles of short-course antistaphylococcal therapy (59). This has led some infectious disease experts to recommend a long (4–6 weeks) course of antibiotics, particularly if the patient is immunocompromised or if the patient has persistent staphylococcal bacteremia. A second and relatively common therapeutic dilemma is the approach to C. albicans fungemia related to an infected intravenous catheter site. Until recently, the usual approach was to remove the catheter and, because C. albicans is an avirulent pathogen, to rely on host defenses to clear the infection. With the introduction of less toxic antifungal agents, therapy is commonly administered to almost all patients with fungemia. Compelling data have documented that fluconazole can replace amphotericin B for the treatment of susceptible fungi in patients without neutropenia (60). Fluconazole should not be used to treat Candida krusei, Torulopsis glabrata, and Candida lusitaniae because of the high incidence of resistance of these organisms to triazoles. In patients with obvious host deficits (e.g., neutropenia and immunosuppressive drugs), the current recommendation is removal of the catheter followed by a short course (7–10 days) of amphotericin B. The third difficulty in the treatment of infected intravenous catheter sites arises when thrombophlebitis supervenes. If a central vein is thrombosed and infected, high-dose antimicrobial therapy often suffices. The incidence of pulmonary embolism in this setting is probably higher than previously thought, and the use of heparin may be appropriate for selected patients. When a peripheral vein is thrombosed, as evidenced by a palpable venous cord, and is believed to be a source of continuing infection, efforts

Chapter 6:

Surgical Infection: Principles of Management and Antibiotic Usage

to aspirate the vein are usually unrevealing but worth attempting. In general, treatment consists of a conventional course of antibiotics for approximately 10 days. If the patient does not exhibit a clinical response to antibiotic therapy, excision of the vein may be necessary. It should be recognized that veins that appear grossly normal at the time of surgery may in fact contain multiple microabscesses in their walls when they are examined microscopically.

Intra-Abdominal Infections Intra-abdominal infection may occur with or without contamination of the peritoneal cavity. Infections (e.g., appendicitis and simple cholecystitis) confined to a diseased organ that is resectable are usually easily cured surgically, may not require prolonged antibiotic therapy, and are not associated with diffuse peritonitis. Peritonitis is defined as inflammation of the peritoneum from any cause, with the most common cause being intra-abdominal infection secondary to bacteria or other microorganisms. Bacterial peritonitis has been classified into primary, secondary, and tertiary peritonitis. Primary peritonitis occurs because of seeding of the peritoneum with bacteria from the blood stream or the lymphatic system and occurs most commonly in cirrhotic patients with ascites. It accounts for less than 1% of peritonitis and treatment is primarily medical with antibiotic therapy (61). Tertiary peritonitis is a peritonitis-like syndrome occurring after a patient has had persistent intra-abdominal infection. Organisms causing tertiary peritonitis are generally nosocomial pathogens such as multiply resistant bacteria or fungi. Most of these patients have been on multiple antibiotics and have had numerous abdominal procedures performed. Secondary peritonitis is the most common form of peritonitis encountered by the surgeon and occurs because of a loss of integrity of the GI tract with resultant contamination of the peritoneal cavity by GI contents (62). The natural history of secondary peritonitis has been demonstrated in animal experiments. In these studies, a two-stage process was noted to occur (63,64). The first stage, lasting approximately five days, was a generalized peritonitis in which gram-negative enteric aerobes were the predominate organism. E. coli bacteremia was common, and a mortality rate of 43% occurred during this stage without treatment. The second stage occurred after five days as the peritoneal defenses attempted to wall off the infection. This resulted in multiple intra-abdominal abscesses with grossly purulent material contained within a collagen wall. The predominant organism within these abscesses was Bacteroides fragilis. Antibiotic therapy (e.g., aminoglycosides) directed toward aerobic enteric organisms decreased early mortality and the incidence of E. coli bacteremia, but did not prevent abscess formation. Conversely, treatment directed against anaerobic organisms (metronidazole and clindamycin) did not affect early mortality but prevented the formation of abscesses. Other studies have demonstrated that mortality rates are directly correlated with the E. coli inoculum size. In addition, large inoculums of bacteria within an abscess cavity inactivate antimicrobial agents at a rate proportional to bacterial density and to the individual inactivating ability. Dead bacteria and debris within the abscess cavity can bind to and inactivate antimicrobial agents. Finally inactivation of antibiotics, particularly clindamycin and aminoglycosides, occurs because of the acidic conditions within the abscess. The diagnosis of secondary peritonitis in an alert patient may be made by physical examination, which characteristically demonstrates diffuse tenderness, rebound

139

tenderness, involuntary muscle guarding, and abdominal wall rigidity. The presence of these signs of generalized peritonitis should lead to prompt operation without further diagnostic studies. However, the physical examination may be difficult to interpret in critically ill patients, patients with altered mental status, postoperative patients, and patients with intra-abdominal abscesses. In addition, elderly patients and patients who are immunosuppressed may not exhibit signs of peritonitis even in the face of generalized infection. Ancillary diagnostic tests may be necessary in these patients (65). Plain films may be of use in detecting a perforated viscus if free peritoneal air is demonstrated. In the absence of significant findings on plain films, ultrasonography has been used as the initial procedure to diagnose intra-abdominal infection in some studies. It offers the advantage of the ability to perform the test at the bedside in critically ill patients, low cost, and rapid results. However, interpretation of the scans may be limited by wounds, dressings, ostomies, obesity, and air-filled bowel loops. Ultrasound may be most useful for detecting infections originating in the liver or biliary tree. Overall sensitivity of ultrasound for the detection of intra-abdominal infection is between 75% and 82%. For the majority of patients, CT scan is the most appropriate initial study. Although CT scan is more costly than ultrasound, it has a sensitivity of 78% to 100% for the detection of intra-abdominal infection. Suspicious fluid collections identified on CT scan should be aspirated for gram’s stain and culture. When aspiration is used in conjunction with CT scans, specificity for the identification of intra-abdominal abscesses is 98%. Optimal management of intra-abdominal infection requires physiologic support of the patient, resection or repair of the source of infection, drainage of any established abscesses, and elimination of residual contamination with antimicrobial therapy (66). Patients with diffuse peritonitis exhibit marked sequestration of extracellular fluid within the inflamed peritoneal cavity, and the intestine and may require large amounts of volume resuscitation. In addition, these patients may develop multiple organ dysfunction syndrome (MODS) secondary to intra-abdominal sepsis and require support of other organ systems (i.e., mechanical ventilation and dialysis) while the primary focus of sepsis is being addressed. Operation is usually necessary to control the source of infection. When frank perforation of the GI tract is the source of infection, the operation may involve resection or repair of the intestine with or without anastomoses or exteriorization of the intestine. Established abscesses should be drained to reduce the bacterial inoculum. This may be accomplished by CT-guided percutaneous drainage or by operative drainage (67–69). A safe percutaneous drainage route that avoids puncturing solid or hollow viscera can be identified in 85% to 90% of patients. After successful drainage, there should be prompt clinical improvement within 48 to 72 hours. Failure to improve within this time frame requires a repeat CT scanning. If residual fluid cannot be evacuated with the placement of additional drains, surgical drainage should be performed. The success of percutaneous drainage of well-defined unilocular abscesses ranges from 80% to 90% and CT-guided drainage has become the procedure of choice for these abscesses (63,70). Percutaneous drainage of complex abscesses (i.e., loculated, pancreatic, interloop, or multiple, or abscesses associated with enteric fistula) has been less successful and may require surgery. Based on the experimental data just discussed, antibiotic therapy should be directed toward both aerobic and

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anaerobic enteric organisms to prevent early mortality and subsequent abscess formation. This may be accomplished with combination therapy or with broad-spectrum single-agent therapy. The requirement for treatment of enterococcus and Candida recovered from intra-abdominal infections continues to be an area of controversy. In animal studies and in past clinical experience, successful treatment of intra-abdominal infection has been accomplished with agents that have no activity against these organisms. However, both organisms are commonly found in the GI tract and have become major nosocomial pathogens over the last 15 to 20 years. Currently, recommendations are that these organisms do not require antibiotic coverage if they are a part of a polymicrobial infection. However, if these organisms are isolated in pure culture or are recovered from the blood stream or, in the case of Candida, if disseminated infection is present, treatment of these organisms should be initiated. A complete discussion of antibiotic therapy in the treatment of intra-abdominal infection is beyond the scope of this chapter but may be found in a consensus statement by the Surgical Infection Society (71).

Miscellaneous Infections Although the foregoing discussion has considered the usual causes of postoperative infection, in reality many other causes can exist. For this reason, the surgeon must always maintain an open mind and frequently reexamine the patient to look for the underlying source of infection if the patient continues to exhibit clinical signs of infection. An unexplained heart murmur may lead to a diagnosis of endocarditis on echocardiogram, whereas unusual obtundation may be secondary to undiagnosed meningitis or brain abscess. In traumatized patients with facial fractures, sinusitis may occur, particularly in patients who are nasotracheally intubated. Parotitis from an obstructed salivary gland duct may also be an incipient source of infection. Conversely, in some patients, fever may not be related to infection at all, but may be secondary to a drug reaction or may be an allergic reaction to a blood transfusion. Finally, an additional type of infectious process is the intrinsic infections of the GI tract that may occasionally occur following surgery. The most common manifestations of these infections are fever and diarrhea. However, these are nonspecific findings, and in some patients, diarrhea may be related to enteral feedings and have nothing to do with the fever. Of more concern to the surgeon is the patient who has received antibiotic therapy and then has developed diarrhea. In many instances, this diarrhea is caused by an overgrowth of C. difficile, which produces a cytotoxin (72,73). Antibiotics that are notably linked with AAC include ampicillin, cephalosporins, and clindamycin, but the syndrome may occur with the administration of almost any antibiotic. AAC may be accompanied by fever and toxicity and is frequently overlooked as the potential source of postoperative fever. Diagnosis includes an assessment of stool for the presence of C. difficile toxin. The fecal leukocyte examination results may be positive, but negative results do not exclude AAC. The diagnosis may also be made by sigmoidoscopy if the typical pseudomembranous lesions associated with this entity are seen. After diagnosis, therapy is oral vancomycin—125 mg four times daily for 10 days. Parenteral vancomycin is not recommended because the object of therapy is to obtain intraluminal levels of antibiotic, which intravenous vancomycin does not provide. An alternative therapeutic option is oral (250 mg four times

daily) or intravenous metronidazole, because both routes of administration of metronidazole are effective. Because Clostridium spores may survive a course of vancomycin or metronidazole, relapses of AAC may occur. These are treated by an additional course of the same antimicrobial agent.

PATHOGENS RESPONSIBLE FOR SURGICAL INFECTION A common approach to characterizing surgical infection is to list the microbial agents that cause such infections. Considering the phenomenal number of organisms that can infect compromised hosts, a list of ‘‘surgical microbes’’ becomes merely a weak attempt at a review of the entire field of microbiology. Equally inappropriate are lists of microbes and the preferred antimicrobial agents to treat them. Memorizing such lists is a relatively fruitless exercise because many surgical infections are polymicrobic; thus the surgeon must more realistically design an empiric therapy with a broad-spectrum agent or a combination of agents The rational approach to surgical microbiology is to learn those microbes that can singly cause important infections and that may have classic clinical presentations. Also the surgeon must learn the combinations of microbes that are frequently encountered in surgical situations so that empiric therapy can be instituted, until the results of appropriate Gram’s stains and cultures are available. Table 6 lists the most common pathogens identified by the NNISS from 1986 to 1989 (74). Among the fungi, C. albicans is the most important and is not infrequently involved in intravenous catheter-related fungemia. A recent multicenter study has documented the efficacy of fluconazole in the treatment of candidemia in non-neutropenic patients (60). In immunocompromised hosts, however, amphotericin B should be used until further data are available. Two new lipophilic preparations of amphotericin B may reduce the toxicity of this agent (75). The easiest way to control Candida infections in routine surgical practice is to prevent their occurrence by choosing the most narrow spectrum antibiotic or combination of antibiotics and using them for the briefest duration consistent with guaranteed clinical success (76). Other fungal pathogens, including Aspergillus and Mucor, are still occasionally problems for the surgeon and may cause systemic infections in debilitated patients The source of these infections (e.g., the burn wound or diabetic abscess) requires aggressive surgical excision in conjunction with high-dose (as much as 1 mg/ kg/day for the 1st week) amphotericin B if effective treatment is to be rendered (77). The role of viruses in surgical infection is poorly studied except for the blood-borne hepatitides such as hepatitis B and C and cytomegalovirus. Cytomegalovirus is a common problem in transplantation recipients. Presently, no effective therapy exists for cytomegalovirus, but new agents are being tested. HIV is an uncommon cause of postoperative infection in surgical patients; however, most surgeons will be called on to treat patients with HIV infections. Although occupational risks for the infection of health care workers is low, all surgeons should be aware of preventive strategies to limit transmission of this disease (78,79). In addition, a number of parasites that are not commonly seen, including Pneumocystis carinii and Toxoplasma gondii, are encountered routinely in AIDS patients, obliging all physicians, including surgeons, to become reacquainted with their clinical presentations.

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Table 6 Pathogen Distribution for Major Sites of Nosocomial Infection, NNISS, 1986–1989 Pathogen E. coli Enterococci P. aeruginosa S. aureus Coagulase-negative staphylococci Enterobacter sp. K. pneumoniae C. albicans P. mirabilis Streptococcal species Citrobacter sp. Candida sp. S. marcescens

Urinary tract infection 11,135 6720 5127 823 1634 2339 2664 2978 2312 207 812 853 367

(26) (16) (12) (2) (4) (6) (6) (7) (5) (0) (2) (2) (1)

a

Wound

Pneumonia

Blood stream

1951 2645 1668 3439 2472

(10) (13] (8) (17) (12)

946 342 2598 2401 293

(6) (2) (17) (16) (2)

733 1037 543 1984 3384

(6) (8) (4) (16) (27)

1529 618 481 712 539 321 81 271

(8) (3) (2) (4) (3) (2) (0) (1)

1625 1042 615 503 231 226 109 579

(11) (7) (4) (3) (1) (1) (1) (4)

610 548 617 105 465 82 330 152

(5) (4) (5) (1) (4) (1) (3) (1)

Total 14,765 10,744 9936 8647 7783 6103 4872 4691 3632 1442 1441 1373 1369

(16) (12) (11) (10) (9) (7) (5) (5) (4) (2) (2) (2) (2)

Note: A site may have up to four pathogens. a Number (%). Abbreviation: NNISS, National Nosocomial Infection Surveillance System. Source: From Ref. 74.

Knowledge of other parasitic infections may also be relevant to surgical practice. The classic example is the huge solitary liver abscess in the right lobe of the liver. In such cases, amebic disease must be suspected and confirmed by an ameba serology test. Metronidazole is the antibiotic of choice for these infections. Unless such abscesses threaten to rupture, they are usually managed with antimicrobial agents alone, and surgery or percutaneous drainage is generally not necessary (80). When hydatid disease is suspected, it should be confirmed serologically, and serious consideration should be given to treating the patient with benzimidazole compounds (mebendazole and albendazole) before surgery (81).

of a particular antibiotic. It is for these reasons that an antibiotic, although once effective therapeutically against a specific pathogen, may lose its efficacy. A discussion of the various classes of antibiotics is warranted in order to appreciate the understanding of the mechanism by which they are designed to overcome the numerous pathogens causing postoperative infectious complications.

Table 7 Mechanisms of Action Responsible for Efficacy of Antibiotics Against Different Microorganisms

ANTIBIOTICS IN THE MANAGEMENT OF INFECTION

Antibiotic

It is beyond the scope of this chapter to discuss the use of antibiotics in the treatment of infection in a comprehensive fashion. Therefore a brief discussion of the mechanisms of antibiotic action, antibiotic prophylaxis, and the therapeutic use of antibiotics is presented.

Aminoglycoside Inhibit protein synthesis by binding to 30S ribosome b-Lactams Inhibit cell wall synthesis by interleukin with the production or cross-linking of peptidoglycans Clindamycin Binds to 50S ribosome subunits and inhibits peptide bond formation Macrolides Binds to 50S ribosome subunit and inhibits protein synthesis Metronidazole Redox reaction produces toxic metabolites that damage bacterial DNA, inhibits DNA gyrase Quinolones Interfering with DNA replication and repair Rifampin Blocks RNA synthesis by inhibiting DNA-dependent RNA polymerase Sulfonamides/ Blocks folic-acid synthesis; binds to trimethoprim 30S ribosomal subunit and inhibits protein synthesis Tetracyclines Interfering with production of purine and pyrimidine, blocks dihydrofolate reductase Vancomycin Inhibits cell wall synthesis by interfering with peptidoglycan production at a different site from penicillins; also may alter membrane permeability and inhibit RNA synthesis

Mechanisms of Action Differing modes of action are responsible for the efficacy of individual antibiotics against various microorganisms (Table 7). The extent to which these antibiotic effects prevent bacterial growth often influences the efficacy of an antibiotic under a given set of clinical conditions. A bactericidal antibiotic is often preferable to a bacteriostatic antibiotic, which inhibits growth or multiplication of bacteria and allows normal host defenses to actually effect bacterial destruction. In an immunocompromised patient in whom host defenses may be severely depleted, use of a bactericidal drug is even more important. In the same way that antibiotics differ in their modes of action, microorganisms develop bacterial resistance in a variety of ways. These ways may include mutation to a resistant strain or the production of an enzyme such as penicillinase or b-lactamase that can destroy the antibiotic effects of penicillins and cephalosporins, respectively. In addition, a given pathogen may activate a latent biochemical process or acquire, by transfer, a chromosome-like factor, known as a resistance factor that may block the mode of action

Mechanism of action

Bacteriostatic/ bactericidal Bactericidal Bactericidal

Bactericidal Bacteriostatic Bactericidal

Bactericidal Bactericidal Bacteriostatic

Bacteriostatic

Bactericidal

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b-Lactam Antibiotics b-lactam antibiotics are among the most commonly prescribed drugs, grouped together because of their shared structural feature, the b-lactam ring. They include: & & & & &

Penicillins Cephalosporins Carbapenems Monobactams b-lactamase inhibitors

b-lactam antibiotics cause the inhibition of synthesis of the bacterial cell wall, leaving bacteria without a protective outer shield. Without this protective outer shelf, water from isotonic body fluids move in freely into bacteria, creating a bursting effect. Bacteria with cell wall susceptible to b-lactam antibiotics are typically known as gram-positive organisms. The mechanism of action involves prevention of the normal cross linkage of peptidoglycan, an essential structural component of bacterial cell wall, or by interference of the biosynthesis of peptidoglycans (82). b-lactam inhibition of cell wall synthesis leads to activation of the autolytic system through a twocomponent system, VncR/S, which initiates a cell death program. An understanding of the generational differences among the b-lactams remains essential for the surgeon who is often challenged with the decision to choose from a variety of antimicrobial agents, with the precaution that resistant strains may emerge. Thus, while better and stronger agents have been synthesized and are available to the surgeon today, the surgeon must still remain cognizant of treating simpler infections with the simpler, narrower spectrum antibiotics in order to combat the fight against the emergence of resistant strains. Penicillins Penicillins can be classified into three groups: & &

&

Penicillin G Antistaphylococcal penicillins (nafcillin, oxacillin, cloxacillin, and dicloxacillin) Broad spectrum penicillins

Blood spectrum penicillins are further classified into: &

& &

Second generation (ampicillin, amoxicillin, and related agents) Third generation (carbenicillin and ticarcillin) Fourth generation (mezlocillin and piperacillin)

Spectrum of Activity. Penicillin G is effective against &

& &

&

Gram-positive cocci (except penicillinase-producing staphylococci, penicillin-resistant pneumococci and enterococci, and oxacillin-resistant staphylococci) Gram-positive rods such as Listeria Gram-negative cocci such as Neisseria sp. (except penicillinase-producing Neisseria gonorrhoeae) Most anaerobes (with certain exceptions such as Bacteroides)

Antistaphylococcal penicillins inhibit penicillinaseproducing staphylococci but are inactive against oxacillinresistant staphylococci. Broad-Spectrum Penicillins. The broad-spectrum penicillins are distinguished by their-activity against gram-negative

bacilli. These agents have been stratified into the secondgeneration penicillins (ampicillin and amoxicillin), the third-generation penicillins (carbanecillin and ticarcillin), and the fourth-generation penicillins (mezlocillin and piperacillin). None of the broad-spectrum penicillins are effective against penicillinase-producing staphylococci. Second-Generation Penicillins. Ampicillin, amoxicillin, and closely related antibiotics are able to penetrate the porin channel of gram-negative bacteria but are not stable to b-lactamases. These antibiotics are active against the majority of strains of E. coli, Proteus mirabilis, Salmonella, Shigella, and H. influenzae. Whereas a large percentage of encapsulated H. influenzae type b from the blood and cerebrospinal fluid of children are b-lactamase positive (and ampicillin resistant), only 15% of the non–type b isolates from adult patients with community-acquired pneumonia are b-lactamase positive (83). Amoxicillin and ampicillin have an identical spectrum of activity, but amoxicillin is better absorbed from the intestine when administered orally and yields higher blood and urine levels. Amoxicillin is available generically and is preferable to ampicillin for oral use except in the therapy of Shigella infections sensitive to ampicillin. Third-Generation Penicillins. Carbenicillin and ticarcillin also can penetrate the porin channel of gram-negative bacteria in high doses, but they are less active than ampicillin on a weight basis. However, the carboxy group on the side chain of these antibiotics expands the spectrum of activity by rendering them more resistant to the chromosomal b-lactamases of certain organisms, such as indole-positive Proteus species, Enterobacter species, and P. aeruginosa. Third and fourth generation penicillins are most useful in infections caused by these organisms. Ticarcillin has the same spectrum of activity as carbenicillin but is two to four times more active on a weight basis against P. aeruginosa; the normal maximum parenteral dose is 18 g/day. Fourth-Generation Penicillins. Mezlocillin and piperacillin are derivatives of ampicillin. They cover much the same spectrum as carbenicillin and ticarcillin but are more active in vitro on a weight basis. In addition, they have some activity against strains of Klebsiella, although cephalosporins remain the preferred agents. They are more active than carbenicillin or ticarcillin against enterococci and B. fragilis, but other agents are preferred for the treatment of these organisms as well. Mezlocillin is comparable to ticarcillin against P. aeruginosa and somewhat more active against Enterobacteriaceae than carbenicillin or ticarcillin. Piperacillin is as active as mezlocillin against Enterobacteriaceae and more active than mezlocillin or ticarcillin against P. aeruginosa. As with ticarcillin, clinical failures have occurred when these newer penicillins are used as single agents to treat serious Pseudomonas infections. The third- and fourth-generation penicillins are generally considered together as antipseudomonal penicillins and only a single representative employed as standard therapy at a given hospital. Several factors are considered in deciding which of these agents should be chosen: &

The fourth-generation penicillins are more active in vitro on a weight basis in inhibiting bacterial growth but not in bacterial killing; for P. aeruginosa, ticarcillin is more rapidly bactericidal.

Chapter 6: &

&

Surgical Infection: Principles of Management and Antibiotic Usage

The fourth-generation penicillins have little enhanced stability to b-lactamases compared with the thirdgeneration agents. The fourth-generation penicillins, especially mezlocillin, have less effect than ticarcillin on platelet function.

Cephalosporins Cephalosporins include the closely related cephamycin compounds. The parenteral agents are commonly classified into the following categories: & & & &

First generation Second generation Third generation Fourth generation (cefepime)

Spectrum of Activity. Most of the available cephalosporins are semisynthetic derivatives of cephalosporin C, a compound with antibacterial activity produced by the fungus Cephalosporium. The closely related cephamycin compounds (derived from Streptomyces spp.) are regarded as members of the cephalosporin class. In clinical practice, these antibiotics have frequently been grouped into four ‘‘generations’’ based upon their spectrum of activity against aerobic and facultative gram-negative bacilli. First-Generation Cephalosporins. Cephalothin is the oldest of the first-generation cephalosporins and was previously used as the prototype of this group. Cephalothin is active against most gram-positive cocci (including penicillinase-producing staphylococci), but does not have clinically useful activity against enterococci, Listeria, oxacillin-resistant staphylococci, or penicillin-resistant pneumococci. Cephalothin is active against most strains of E. coli, P. mirabilis, and K. pneumoniae, but has little activity against indole-positive Proteus, Enterobacter, Serratia, and the nonenteric gram-negative bacilli such as Acinetobacter and P. aeruginosa. Gram-negative cocci (such as the gonococcus and meningococcus) and H. influenzae are generally resistant. Cephalothin is active against most of the common anaerobic pathogens, with certain exceptions such as Bacteroides species, particularly B. fragilis. Second-Generation Cephalosporins. The second-generation cephalosporins are somewhat less active against grampositive cocci than the first-generation agents, but are more active against certain gram-negative bacilli. This generation of compounds can be divided into two subgroups, one with activity against H. influenzae and the other, the cephamycins, with activity against Bacteroides. Cephamycin Subgroup (Active Against Bacteroides). The cephamycin subgroup of the second-generation cephalosporins includes cefoxitin and cefotetan. This subgroup is active against most strains of E. coli, P. mirabilis, and Klebsiella, like the first generation cephalosporins. Unlike the first-generation cephalosporins, the cephamycins are active against many strains of Bacteroides. The combination of activity against common aerobic and facultative gram-negative bacilli plus Bacteroides has led to the use of the cephamycins in the prophylaxis and therapy of infections in the abdominal and pelvic cavities (where these organisms predominate). The cephamycins have no clear advantages over the first-generation cephalosporins for infections outside of the abdominal and pelvic areas.

143

Cefotetan has a substantially longer serum half-life than cefoxitin, allowing for less frequent dosing for therapy and single-dose prophylaxis. Cefotetan is more active than cefoxitin against aerobic and facultative gram-negative bacilli although not comparable to third-generation cephalosporins, but less active against Bacteroides. Third-Generation Cephalosporins. The third-generation cephalosporin class is marked by stability to the common blactamases of gram-negative bacilli, and these compounds are highly active against Enterobacteriaceae (E. coli, P. mirabilis, indole-positive Proteus, Klebsiella, Enterobacter, Serratia, and Citrobacter), Neisseria, and H. influenzae. Mutants of Enterobacter, indole-positive Proteus, Serratia, and Citrobacter, with stable derepression of the chromosomal b-lactamase, however, are resistant to these antibiotics. The third-generation cephalosporins are less active against gram-positive organisms than the first-generation cephalosporins and are inactive against enterococci, Listeria, oxacillin-resistant staphylococci, and Acinetobacter. Cefotaxime and ceftriaxone are usually active against pneumococci with intermediate susceptibility to penicillin, but strains fully resistant to penicillin are often resistant to the third generation cephalosporins as well. In the late 1990s, for example, 25% of strains of Streptococcus pneumoniae in the United States were intermediately or fully resistant to penicillin and 14% were resistant to third generation cephalosporins (84,85). Fourth-Generation Cephalosporins. Cefepime is a member of a new class of cephalosporins. It has a positively charged quaternary ammonium attached to the dihydrothiazone ring, which results in better penetration through the outer membrane of gram-negative bacteria and a lower affinity than the third-generation cephalosporins for certain chromosomal b-lactamases of gram-negative bacilli. Cefepime has similar activity to cefotaxime and ceftriaxone against pneumococci (including penicillin-intermediate strains) and oxacillin-sensitive S. aureus. Like the earlier third-generation agents, it is active against the Enterobacteriaceae, Neisseria, and H. influenzae, but has greater activity against the gram-negative enterics that have a broad-spectrum, inducible, chromosomal b-lactamase (Enterobacter, indole-positive Proteus, Citrobacter, and Serratia). The role of cefepime in therapy of infections due to stably derepressed mutants of these organisms, however, has not yet been fully defined. Cefepime is as active as ceftazidime for P. aeruginosa, and is active against some ceftazidime-resistant isolates. However, cefepime is not yet approved for the therapy of meningitis. Summary of Treatment Indications for Third- or Fourth-Generation Drugs & &

& &

&

Gram-negative meningitis caused by Enterobacteriaceae. Penicillin-resistant gonococcal infections—Ceftriaoxone is therapy of choice, which is also the recommended therapy for Lyme disease involving the CNS or joints. H. influenza that are ampicillin resistant. In renal dysfunction, later-generation cephalosporins are useful alternatives to the aminoglycosides in treating gram-negative infections, particularly, resistant to other b-lactams. Caution should be used, however, in using a latergeneration cephalosporin as a single agent for the

144

&

&

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treatment of serious infections with Enterobacter, indolepositive Proteus, Serratia, and Citrobacter, because of the possibility of resistance emerging during therapy. Ceftazidime and cefepime are effective therapies for serious infections due to P. aeruginosa, when the organism is resistant to the antipseudomonal penicillins or the patient is penicillin allergic; as with the antipseudomonal penicillins, however, ceftazidime and cefepime should generally be given in combination with an aminoglycoside for treatment of serious P. aeruginosa infection. Ceftazidime is effective therapy for meningitis caused by P. aeruginosa. Later-generation cephalosporins are not particularly useful in treating infections due to gram-positive cocci (except penicillin-resistant pneumococci) or Acinetobacter. They are not currently recommended for prophylactic use in surgery.

Carbapenems Imipenem and meropenem are carbapenems that are exceedingly resistant to cleavage by most plasmid and chromosomal b-lactamase (86). They have a very broad spectrum of activity encompassing: &

&

&

Gram-positive organisms (including Enterococcus faecalis and Listeria) Gram-negative organisms (including b-lactamase– producing H. influenzae and N. gonorrhoeae, the Enterobacteriaceae, and P. aeruginosa) Anaerobes (including B. fragilis)

Neither drug is generally active against Stenotrophomonas maltophilia (which has a carbapenem-hydrolyzing chromosomal b-lactamase) Although initial isolates of P. aeruginosa are usually susceptible to the carbapenems, resistance may emerge during therapy when these drugs are used as a single agent. Evidence suggests that carbapenems do not traverse the outer membrane of P. aeruginosa through the normal porin channel used by the other b-lactams but rather through a different channel (86). Carbapenem-resistant strains of P. aeruginosa arising on therapy generally have altered permeability to these drugs and specific changes in their outer membrane proteins; such strains are generally not crossresistant to other b-lactams nor do they produce increased or novel b-lactamase activity. Imipenem is inactivated in the proximal renal tubule by the normal human enzyme dehydropeptidase I, with resultant low urinary levels of active drug and necrosis of the proximal tubule in the rabbit model. Such cleavage of imipenem is prevented by coadministration of cilastatin, a specific inhibitor of this dehydropeptidase. Imipenem–cilastatin therapy has been associated with CNS toxicity, including change in mental state, myoclonus, and, particularly, seizures (86). These effects are especially evident in patients with underlying CNS disease or impaired renal function. Imipenem should not be used for the therapy of meningitis. The dosage of imipenem administered should be carefully titrated; patients with glomerular filtration rates of less than 5 mL/min should generally not receive imipenem unless hemodialysis is ongoing or will start within 48 hours. Meropenem is another carbapenem approved for use in the United States; its spectrum of activity is quite similar to imipenem. Meropenem is stable to human renal dehydropeptidase I, and the compound is administered without

cilastatin. Meropenem appears to have a lower risk of producing seizures than imipenem–cilastatin, and it is approved for the treatment of bacterial meningitis. Ertapenem, a new carbapenem, has recently been approved by the U.S. Food and Drug Administration (FDA). This drug has a narrower spectrum of activity than imipenem or meropenem. It is active against most Enterobacteriaceae and anaerobes but less active than the other carbapenems meant for the treatment of infection caused by P. aeruginosa, Acinetobacter, and gram-positive bacteria, particularly enterococci and penicillin-resistant pneumococci. Clinical trials of this new drug have mainly been published as abstracts thus far; its major benefit over other carbapenems is that it has a long half-life and can be administered once daily. Unlike meropenem, ertapenem is not approved for the therapy of meningitis. b-Lactamase Inhibitors Clavulanate, sulbactam, and tazobactam are b-lactamase inhibitors, which have little intrinsic antibacterial activity but inhibit the activity of a number of plasmid-mediated b-lactamases (87). They generally do not inhibit chromosomally mediated b-lactamases. Combination of these agents with ampicillin, amoxicillin, ticarcillin, or piperacillin results in antibiotics with an enhanced spectrum of activity against many, but not all, organisms containing plasmid-mediated b-lactamases. In addition, these compounds inhibit the chromosomal b-lactamase of many Bacteroides species, extending the spectrum of coverage for these organisms as well. Amoxicillin–clavulanate, Unasyn, will inhibit most strains of oxacillin-sensitive S. aureus and b-lactamase–producing H. influenzae in addition to the usual organisms inhibited by amoxicillin alone. At the high drug concentrations achieved in urine, the combination is also active against certain b-lactamase–producing Enterobacteriaceae. Unasyn is a parenteral formulation that expands the spectrum of ampicillin to include most strains of S. aureus and b-lactamase–producing H. influenzae, some Enterobacteriaceae, and anaerobes (including B. fragilis). This combination has been used for prophylaxis and therapy of intra-abdominal and pelvic infections instead of cefoxitin or cefotetan. Randomized, double-blind trials showed ampicillin–sulbactam to be equivalent to cefoxitin in the prophylaxis for abdominal surgery and in the treatment of intra-abdominal and pelvic infections. It has also been used to treat patients with diabetic foot ulcers. Ticarcillin–clavulanate (Timentin) and piperacillin– tazobactam (Zosyn) expand the spectrum of the respective penicillins to include b-lactamase–producing S. aureus, H. influenzae, N. gonorrhoeae, some Enterobacteriaceae, and anaerobes (including B. fragilis) (88). These combinations are generally not effective against ticarcillin- or piperacillinresistant strains of P. aeruginosa. In addition, piperacillin– tazobactam, dosed at 3.375 g every six hours, may not be effective for the treatment of P. aeruginosa infections. Thus, the spectrum and clinical utility of these two agents are similar to ampicillin–sulbactam. Monobactams Aztreonam is a monocyclic b-lactam antibiotic with good activity against the majority of gram-negative aerobic and facultative bacteria, including the Enterobacteriaceae and P. aeruginosa. It has virtually no activity against grampositive organisms or anaerobes: the majority of strains of Acinetobacter and S. maltophilia are resistant, and resistant strains of P. aeruginosa frequently emerge during therapy with aztreonam alone. The spectrum of activity of

Chapter 6:

Surgical Infection: Principles of Management and Antibiotic Usage

aztreonam is similar to that of the aminoglycosides. However, it is less reliable therapy than aminoglycosides for the nonenteric gram-negative bacilli such as Acinetobacter, P. aeruginosa, and S. maltophilia. Data support the absence of cross allergenicity between aztreonam and other b-lactam antibiotic (86). However, patients with ceftazidime allergy may be allergic to aztreonam. The clinical situation in which aztreonam is most useful is in place of an extended spectrum penicillin or cephalosporin, in situations when these compounds are indicated but cannot be used because of allergy. Aztreonam is the only monobactam currently marketed. The dosing of these novel b-lactams and dose modifications in patients with renal dysfunction are important considerations in prescribing these drugs. A number of these drugs have unique properties compared to other b-lactams, such as inhibition of b-lactamases or inherent resistance to cleavage by b-lactamases, which extend the spectrum of the combination agents and carbapenems. The monobactams have a narrower spectrum of activity but less cross allergenicity. These agents should not be used widely, to avoid expense and the development of drug resistance. Resistance to b-Lactam Antibiotics Mechanisms of Bacterial Resistance. Three general mechanisms of bacterial resistance to antibiotics, including the b-lactams, have been well characterized: decreased penetration to the target site, alteration of the target site, and inactivation of the antibiotic by a bacterial enzyme (86,87). Decreased Penetration to the Target Site. The outer membrane of gram-negative bacilli provides an efficient barrier to the penetration of b-lactam antibiotics to their target pencillin binding proteins (PBPs) in the bacterial plasma membrane. b-lactams usually must pass through the hydrophilic porin protein channels in the outer membrane of gram-negative bacilli to reach the periplasmic space and plasma membrane. The permeability barrier of the outer membrane is a major factor in the resistance of P. aeruginosa to many b-lactam antibiotics. Alteration of the Target Site. The target sites for the b-lactams are the PBPs in the cytoplasmic membrane. Alterations in PBPs may influence their binding affinity for b-lactam antibiotics and, therefore, the sensitivity of the altered bacterial cell to inhibition by these antibiotics. Such a mechanism is responsible for penicillin resistance in pneumococci, methicillin (oxacillin) resistance in staphylococci, and for an increasing number of bacteria with intrinsic resistance to b-lactams, such as gonococci, enterococci, and H. influenzae (86). Inactivation by a Bacterial Enzyme. Production of b-lactamase is the major mechanism of resistance to the b-lactam antibiotics in clinical isolates. Such bacterial enzymes may cleave predominantly penicillins (penicillinases), cephalosporins (cephalosporinases), or both (b-lactamases). Their production may be encoded within the bacterial chromosome (and hence be characteristic of an entire species), or the genes may be acquired on a plasmid or transposon (and hence be characteristic of an individual strain rather than the species). Bacteria may synthesize the b-lactamase constitutively (as occurring in the case of many plasmid-mediated enzymes) or synthesis may be inducible in the presence of antibiotic (as occurring in the case of many chromosomal enzymes). Inducible b-lactamases may not be reliably detected by initial susceptibility testing, particularly with the newer rapid methods.

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Chromosomal b-Lactamases. Although virtually all gramnegative bacilli possess a chromosomal b-lactamase gene, certain species produce insignificant amounts of this enzyme, and their susceptibility to b-lactams is largely determined by plasmid-mediated b-lactamases and antibiotic permeability. These include E. coli, P. mirabilis, Salmonella, Shigella, and H. influenzae. K. pneumoniae produces a chromosomal b-lactamase that is primarily a penicillinase; thus, these strains are frequently susceptible to the cephalosporins. The last group of species within the Enterobacteriaceae, including Enterobacter, indole-positive Proteus, Serratia, and Citrobacter, produce an inducible chromosomal b-lactamase that may be difficult to detect on initial susceptibility testing but that can mediate resistance to all currently available b-lactams with the exception of the carbapenems. In addition to inducible production of this chromosomal enzyme, these species may give rise to regulatory mutants that are ‘‘derepressed’’ and produce high levels of this broadspectrum chromosomal enzyme constitutively. Plasmid-Mediated b-Lactamases. The most common plasmidmediated b-lactamases of gram-negative bacteria (such as TEM-1, TEM-2, and SHV-1) mediate resistance to the penicillins and first- and second-generation cephalosporins, but not cefuroxime, cephamycins, third- and fourth-generation cephalosporins, or the novel b-lactam compounds such as the carbapenems or aztreonam. More recently, extended-spectrum plasmid-mediated b-lactamases (derived from the common TEM and SHV enzymes) have arisen, which are capable of cleaving later-generation cephalosporins and aztreonam (86). Originally described in strains of Klebsiella from Europe, these b-lactamases have now been found in a variety of gramnegative bacilli (i.e., E. coli and K. pneumoniae) in several areas of the United States, and the spread of these organisms between patients in intensive care units has been documented. It has also been documented that nursing home patients may be an important reservoir for strains of Enterobacteriaceae producing extended-spectrum plasmid-mediated b-lactamases (89). Although the strains of resistant E. coli and K. pneumoniae usually differ, most harbor a common plasmid encoding the extended-spectrum b-lactamase, suggesting intragenic and intraspecies transfer of the plasmid between strains, rather than transfer of a single strain between patients. These strains are almost always resistant to ceftazidime, gentamicin, and tobramycin, and frequently are also resistant to trimethoprim–sulfamethoxazole and ciprofloxacin. These enzymes mediate high-level resistance to the third- and fourth-generation cephalosporins and aztreonam, but not to the cephamycins (cefoxitin and cefotetan) or the carbapenems. However, use of the cephamycins against strains containing these new enzymes is limited by the development of permeability mutants in the porin protein, OmpF. The b-lactamase inhibitors, clavulanate, sulbactam, and tazobactam, have generally retained the ability to inhibit these newer plasmid-mediated b-lactamases. Another plasmid-mediated b-lactamase has been described in Klebsiella, which is homologous to the chromosomal cephalosporinase of Enterobacter cloacae (89). This plasmid-mediated b-lactamase is capable of cleaving all of the currently available b-lactams (with the exception of the carbapenems), and its activity is not inhibited by clavulanate, sulbactam, or tazobactam. This plasmidmediated b-lactamase confers a broad resistance pattern similar to stably derepressed mutants of Enterobacter.

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Part One: General Considerations

Resistance to b-lactam antibiotics occurs through one or a combination of three mechanisms: production of a b-lactamase, which inactivates the b-lactam ring, alteration of the target penicillin-binding protein of the cell surface, or interference with the antibiotic’s ability to reach the protein target. The problem with resistance to b-lactam antibiotics has been partially addressed by the introduction of a number of b-lactamase inhibitors. These inhibitors are most effective against plasmid-encoded b-lactamases. Enterobacteriaceae produce chromosomal b-lactamases that are only weakly inhibited. Currently, three b-lactamase inhibitors are commercially available: clavulanate, sulbactam, and tazobactam. Although there are some minor pharmacologic differences in these compounds, therapeutic efficacy is similar. These products are only available in fixed combinations with certain b-lactam antibiotics in which the antibacterial activity of the combination is determined by the spectrum of the antibiotic.

Aminoglycosides The aminoglycosides cause a misreading of the mRNA by irreversibly binding to the 30S subunit of bacterial ribosomes (90). This causes a subsequent interference with amino acid replication. Without amino acid replication, bacteria lose their capacity to sustain or proliferate. Nine aminoglycosides (gentamicin, tobramycin, amikacin, streptomycin, neomycin, kanamycin, paromomycin, netilmicin, and spectinomycin) are approved by the FDA for clinical use in the United States. Of these, gentamicin, tobramycin, and amikacin are the most frequently prescribed, although netilmicin possesses comparable efficacy for select indications. The most common clinical application (either alone or as part of combination therapy) of the aminoglycosides is in the treatment of serious infections caused by aerobic gramnegative bacilli (86,91). In addition, selected aminoglycosides have demonstrated clinically relevant activity against protozoa (paromomycin), N. gonorrhoeae (spectinomycin), and mycobacterial infections (amikacin). The aminoglycosides have demonstrated relative stability against resistance, and the emergence of resistance during therapy (especially when used in combination with other agents) is rare. The most frequently encountered toxicity resulting from aminoglycoside administration is nephrotoxicity. Ototoxicity can also result from aminoglycoside administration, but its prevalence and clinical detection are more problematic to determine. These side effects may be reduced by identification and avoidance in patients at risk, and by appropriate dosing and monitoring of serum drug concentration. Neurotoxicity is rarely encountered, but may be severe and life threatening. Newer strategies for dosing include consolidated administration (also known as ‘‘oncedaily’’ administration) in selected patients to take advantage of the postantibiotic effect (PAE), concentration-dependent killing, and the potential for reduced toxicity. This overview will focus on the use of gentamicin, tobramycin, amikacin, and netilmicin against aerobic gram-negative bacilli and for synergy in the treatment of aerobic gram-positive cocci. Mechanism of Action The aminoglycosides are generally considered bactericidal antibiotics. They impair bacterial protein synthesis (90). These drugs work primarily by binding to the 30S ribosomal subunit, leading to misreading of the genetic code and

inhibition of translocation (90). The initial steps required for peptide synthesis are uninterrupted, such as binding of mRNA and the association of the 50S ribosomal subunit, but elongation fails to occur due to disruption of the mechanisms for ensuring translational accuracy (86,90). The ensuing antimicrobial activity is usually bactericidal against susceptible aerobic gram-negative bacilli. Aminoglycosides initially penetrate the organism by disrupting the magnesium bridges between lipopolysaccharide moieties. They are transported across the cytoplasmic membrane in an energy-dependent manner. This step can be inhibited in vitro by divalent cations, increased osmolality, acidic pH, and an anaerobic environment. The microbiologic activity of aminoglycosides is pH dependent. As a result, the antimicrobial effect may be reduced at the low pH found in lung and bronchial secretions. As an example, the MIC of aminoglycosides was increased almost fivefold at pH < 6.5 in one in vitro study. Two important pharmacodynamic properties of aminoglycosides are the PAE and concentration-dependent killing: &

&

The PAE refers to the persistent suppression of bacterial growth that occurs after the drug has been removed in vitro or cleared by drug metabolism and elimination in vivo. Initially described for gram-negative bacilli, aminoglycosides also exhibit PAE against S. aureus but not against other gram-positive cocci. The duration of the PAE [approximately 3 hours (range 1–7.5 hours)] depends upon the method of evaluation and the organism studied. The duration of the PAE is reduced in the absence of polymorphonuclear leukocytes. Concentration-dependent killing refers to the ability of higher concentrations of aminoglycosides (relative to the organism’s MIC) to induce more rapid, and complete, killing of the pathogen. Aminoglycosides exhibit concentration-dependent microbiologic activity in both in vivo and in vitro models. Achieving optimal peak concentrations of aminoglycosides with standard dosing regimens can be difficult, because efforts must be made to avoid sustained elevated trough concentrations (which are believed to be important in avoiding nephrotoxicity). Relative to traditional dosing methods, the consolidated dosing approach is more likely to achieve optimal peak concentrations that result in concentrationdependent killing.

A synergistic effect has been demonstrated in vitro for selected organisms when aminoglycosides are used in combination with other antibiotics, most consistently with cell wall–active agents (e.g., b-lactam antibiotics). Spectrum of Activity Aminoglycosides exhibit potent in vitro activity against a wide range of aerobic gram-negative pathogens, including Enterobacteriaceae, Pseudomonas spp., and H. influenzae. However, in vitro activity against Burkholderia cepacia, S. maltophilia, and anaerobic bacteria is usually poor or absent. Aminoglycosides also demonstrate activity against gram-positive organisms such as methicillin-susceptible S. aureus. However, most authorities believe these drugs are not adequate therapy for serious infections caused by MRSA and S. pneumoniae (see ‘‘Treatment and prevention of methicillin-resistant S. aureus infection’’).

Chapter 6:

Surgical Infection: Principles of Management and Antibiotic Usage

Minor differences exist among the in vitro potencies of the various aminoglycosides. Gentamicin usually demonstrates superior in vitro activity to tobramycin against Serratia spp., whereas tobramycin is usually more potent than gentamicin against P. aeruginosa. Clinical Uses. The most frequent clinical use of aminoglycosides (most commonly in combination with other antibacterial agents) is empiric therapy of serious infections such as septicemia, respiratory tract infections, complicated urinary tract infections, intra-abdominal infections, and osteomyelitis caused by aerobic gram-negative bacilli. Once an organism has been identified and susceptibilities determined, aminoglycosides are usually discontinued in favor of less toxic antibiotics to complete a treatment course. Aminoglycosides are also employed frequently in combination (usually with a b-lactam antibiotic to which the organism is susceptible in vitro) for serious infections caused by Serratia spp., Pseudomonas spp., indole-positive Proteus, Citrobacter spp., Acinetobacter spp, and Enterobacter spp., due to the pathogen’s potential to exhibit inducible resistance to the b-lactam. For infections caused by Enterobacter spp., the addition of an aminoglycoside to a third-generation cephalosporin (most frequently associated with ceftazidime) has not been shown to decrease the development of resistance that the latter drug promotes. Combination therapy with gentamicin is frequently used for the treatment of invasive enterococcal infections not exhibiting high-level aminoglycoside resistance (such as bacteremia) and sometimes for serious staphylococcal infections. Prophylactic use of aminoglycosides (in combination with ampicillin or, in penicillin-allergic patients, vancomycin) should be restricted to procedures involving the GI or genitourinary tract. As an example, aminoglycosidecontaining combinations maybe employed for patients undergoing endoscopic retrograde cholangiopancreatography, in patients with biliary obstruction, or those at risk for the developingment of infective endocarditis. Resistance to Aminoglycosides Bacteria become resistant to aminoglycosides by a combination of three mechanisms: prevention of uptake of the antibiotic into the cell, synthesis of enzymes that modify the antibiotic, or change of the ribosomal binding sites. Unlike third-generation cephalosporins in which resistance may emerge during a two- to three-week course of therapy, resistance to aminoglycosides appears to require long periods of exposure or a large inoculum of bacteria, as is found in cystic fibrosis or burn patients.

Quinolone The fluoroquinolones have become an increasingly popular class of antibiotics in clinical use (92). Newer drugs in this class have been developed with a broader spectrum of activity including better coverage of gram-positive organisms and, in one case, even anaerobes. However, toxicities associated with some of the newer agents have limited their use. For instance, Trovafloxacin has limited availability because of risks of hepatic toxicity. Gatifloxacin and moxifloxacin are the two newer fluoroquinolones. Gemifloxacin was approved on April 4, 2003, by the U.S. FDA for the treatment of mild to moderate community-acquired pneumonia and acute exacerbation of chronic bronchitis. Fluoroquinolones are the only class of antimicrobial agents in clinical use that are direct inhibitors of bacterial

147

DNA synthesis. They are also classified as bactericidal agents. Fluoroquinolones inhibit two bacterial enzymes, DNA gyrase and topoisomerase IV, which have essential and distinct roles in DNA replication (93). The quinolones bind to the complex of each of these enzymes with DNA; the resulting complexes, including the drug, block progress of the DNA replication enzyme complex. Ultimately, this results in damage to bacterial DNA and bacterial cell death. Activity Against Conventional Bacteria The greatest activity of the fluoroquinolones is against aerobic gram-negative bacilli, particularly Enterobacteriaceae, and against Haemophilus spp. and against gram-negative cocci such as Neisseria spp. and Moraxella catarrhalis. Relative to nalidixic acid, the fluoroquinolones also have additional activity against nonenteric gram-negative bacilli such as P. aeruginosa and against staphylococci. Ciprofloxacin remains the most potent marketed fluoroquinolone against gram-negative bacteria. The effect of norfloxacin, ciprofloxacin, and ofloxacin against streptococci and many anaerobes is limited. Levofloxacin, gatifloxacin, and moxifloxacin, however, have greater potency against gram-positive cocci, and gatifloxacin and moxifloxacin also have enhanced activity against anaerobic bacteria. Activity Against Mycobacteria Some fluoroquinolones also have activity against mycobacteria. Ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, and moxifloxacin are active against Mycobacterium tuberculosis, M. fortuitum, M. kansasii, and some strains of M. chelonae, but have only fair or poor activity against M. avium complex. Activity Against Other Bacteria Other bacteria are also inhibited by quinolones in vitro. Ciprofloxacin, ofloxacin, levofloxacin, trovafloxacin, gatifloxacin, and moxifloxacin all have activity against the agents of atypical pneumonias, including Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydia pneumoniae, and against genital pathogens such as Chlamydia trachomatis, Ureaplasma urealyticum, and Mycoplasma hominis. Treponema pallidum is resistant to ofloxacin in animal models, and no other quinolone has been shown to have activity against this spirochete. Activity of Newer Quinolones The newer fluoroquinolones have retained much of the activity of ciprofloxacin and ofloxacin against enteric gram-negative bacteria. Ofloxacin is a racemic mixture of two stereoisomers, whereas levofloxacin is composed solely of the active stereoisomer. Thus, levofloxacin has the same spectrum of activity as ofloxacin but is generally twofold more potent. Activity Against Gram-Negative Organisms. Levofloxacin, gatifloxacin, and moxifloxacin generally have gram-negative coverage similar to that of ciprofloxacin, but all may be less active particularly against some strains of P. aeruginosa as well as against some strains of Providencia spp., Proteus spp., and Serratia marcescens. Activity Against Respiratory Pathogens. All of the newer quinolones, as well as ciprofloxacin and ofloxacin, are highly active against H. influenzae and M. catarrhalis. However, levofloxacin, gatifloxacin, and moxifloxacin exhibit increased potency relative to ciprofloxacin and ofloxacin against S. pneumoniae. Other respiratory pathogens, such

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Part One: General Considerations

as L. pneumophila, M. pneumoniae, and C. pneumoniae, are also highly susceptible to all four newer quinolones. Activity Against Gram-Positive Organisms. Although the newer quinolones all have increased potency relative to ciprofloxacin against other gram-positive cocci in addition to S. pneumoniae, they will have a more limited role in the treatment of staphylococcal and enterococcal infections. Among staphylococci, most methicillin-susceptible strains of S. aureus are susceptible to levofloxacin, gatifloxacin, and moxifloxacin. By contrast, many methicillin-resistant strains of S. aureus have acquired high-level resistance to ciprofloxacin, which causes substantial cross-resistance to all of the newer agents. These same patterns of differing quinolone susceptibility have been seen with methicillin-susceptible and methicillin-resistant strains of coagulase-negative staphylococci. Activity against enterococci is marginal. Activity Against Anaerobes. Of all available quinolones, only gatifloxacin and moxifloxacin have sufficient activity against anaerobic bacteria for potential clinical applicability. B. fragilis and other Bacteroides species may be susceptible, but some studies have already noted resistance in 25% to 30% of strains (86).

Vancomycin Vancomycin inhibits cell wall formation by interfering with peptidoglycan synthesis by binding to a cell surface receptor. Vancomycin may also injure protoplasts by affecting cytoplasmic permeability and by interfering with RNA synthesis. Vancomycin is frequently prescribed for patients with suspected or proven, invasive gram-positive infections. Appropriate dosing requires consideration of the site of the infection, patient weight, renal function, and the concomitant use of high-flux hemodialysis (which enhances the clearance of vancomycin from the serum). Careful attention to individualizing therapy must be exercised in selecting the appropriate dose. The potential for vancomycin-induced nephrotoxicity and ototoxicity must be considered in use of this antibiotic especially given the fact that they have been proposed to relate to serum concentrations. Other toxicities have not been associated with specified serum concentrations. Vancomycin-Related Nephrotoxicity Nephrotoxicity associated with vancomycin monotherapy is considered uncommon. Whereas studies have noted that 5% to 15% of patients treated with vancomycin alone develop an acute decline in renal function, it is difficult to isolate such morbidity to the use of vancomycin alone when other comorbidities exist, which may contribute to the cause of such decline in renal function. Relationships between serum vancomycin concentrations and nephrotoxicity have not been clearly established. Whereas the nephrotoxic potential of vancomycin monotherapy is unclear, studies have established an increased incidence and severity of renal insufficiency when vancomycin is administered concomitantly with an aminoglycoside. The incidence of acute renal failure in this setting may be as high as 20% to 30%. Vancomycin-Related Ototoxicity Vancomycin administration and subsequent ototoxicity have been the subject of various case reports. However, ototoxicity secondary to vancomycin has been poorly studied, because few clinical studies have involved serial

audiometric testing. Those that have tested hearing after vancomycin administration have shown inconsistent findings. Although risk factors for ototoxicity have been reported to include preexisting hearing problems, underlying renal dysfunction, older age, and excessive peak concentrations data to support these risk factors are lacking. Resistance to vancomycin occurs primarily because of a plasmid-mediated change in the target protein on the cell surfaced. However, because of its multiple sites of action, resistance to vancomycin has been slow to emerge (94). This has led to vancomycin being widely used in the prophylaxis and treatment of infections caused by MRSA. As a result, vancomycin use increased 20-fold at one teaching hospital in the 10-year period from 1981 to 1991 (95). With the increase in the use of vancomycin, isolated reports of vancomycin resistance in enterococci began to surface in the mid-1980s. Since this time, vancomycin-resistant enterococci (VRE) have become a major problem in the United States. Data from the Centers of Disease Control and Prevention indicate that the incidence of vancomycin resistance in nosocomial isolates of enterococci has risen from 0.5% in 1989 to 10% in 1995, with mortality rates secondary to VRE bacteremia approaching 50% (96). The emergence of VRE is just one example of the increasing emergence of antimicrobial resistance that is rapidly becoming a worldwide crisis. A consensus statement sponsored by the Centers for Disease Control and Prevention and the National Foundation for Infectious Diseases identified excessive and inappropriate prescribing of antimicrobials and the failure to use basic infection control techniques as the primary causes of this crisis. These problems must be resolved to prevent the farther spread of multidrug-resistant organisms (97).

CLINICAL USE OF ANTIBIOTICS An antibiotic may be administered prophylactically to prevent the subsequent development of an infection, empirically to treat presumed infection in a critically ill or neutropenic patient, or therapeutically to treat an infection when it has actually occurred. The following discussion outlines a rational approach to each of these types of antibiotic usage.

Prophylaxis Prophylaxis in the strictest sense refers to the administration of antibiotics prior to the occurrence of contamination. However, this term is also commonly applied to instances in which surgery is the primary treatment for a patient with presumed contamination or with a possible infection (e.g., penetrating abdominal trauma treated within 6 hours, simple acute appendicitis, or cholecystitis). Under these circumstances, antibiotic coverage is limited to 24–48 hours. This prophylactic use of antibiotics to prevent wound infections is currently the most common reason for administration of antibiotics in surgical patients. Surgical wound infections significantly prolong hospital stay, increase cost, and can result in systemic sepsis and death in some patients. Appropriate use of prophylactic antibiotics has been shown to reduce infectious morbidity and hospital costs. However, indiscriminate use of antibiotics does not further decrease the incidence of wound infections and may result in increased costs and in the emergence of resistant infections. An approach to prophylaxis is outlined in Table 8. The use of prophylactic antibiotics is recommended in

Chapter 6:

Surgical Infection: Principles of Management and Antibiotic Usage

149

Table 8 Recommendations for Prophylactic Antibiotic Agents by Site Operations Cardiac: all with sternotomy, cardiopulmonary bypass Noncardiac vascular: aortic resection and prosthetic bypass Orthopedic: insertion of prosthetic joints, open operations Neurosurgery Head and neck: operations involving the mucous membranes and deep tissue General thoracic: pulmonary and esophageal Gastroduodenal: bariatric, ulcer patients treated with H2 blockers, bleeding duodenal ulcer, genitourinary or gastric cancer Biliary: all open and laparoscopic procedures (chronically intubated biliary tract) Colorectal: operations that open the colon and/or rectum Appendectomy: simple appendicitis (antibiotics are empiric or definitive for complicated appendicitis) Cesarean section Hysterectomy Abdominal trauma

Bacteria

Intravenous administration of antimicrobial

Dosea

Staphylococcus aureus, S. epidermidis, diphtheroids, gramnegative enterics S. aureus, S. epidermidis, diphtheroids, gram-negative enterics S. aureus, S. epidermidis

Cefazolin (Vancomycin)

l–2 g (1 g slowly) preinduction, 1–2 g every 8 hr for 48 hr

Cefazolin (Vancomycin)

1 g (1 g slowly) preinduction, 2 postoperative doses

Cefazolin (Vancomycin)

1 g (1 g slowly) preinduction

S. aureus, S. epidermidis, oral aerobes and anaerobes, S. aureus, streptococci

Cefazolin

1 g (1 g slowly) preinduction, 2 g preinduction

Oral anaerobes, S. aureus, streptococci, gram-negative enterics Oropharyngeal flora and gramnegative enterics, S. aureus

Cefazolin

1–2 g preinduction

Cefazolin

1–2 g preinduction

Gram-negative enterics, S. aureus, Enterococcus fecalis, clostridia (above plus Pseudomonas species)

Cefazolin (culture-based selection)

1–2 g preinduction (preinduction dose and repeat interval based on drug kinetics)

Enteric aerobes and anaerobes

Oral neomycin or erythromycin (cefoxitin or cefotetan or cefmetazole) Cefoxitin or cefotetan or cefmetazole

Operating room day 1:1 g at 1, 2 and 11 P.M. (1 g preinduction)

Enteric aerobes and anaerobes

Enteric aerobes and anaerobes, E. fecalis, group B streptococci Enteric aerobes and anaerobes, E. fecalis, group B streptococci Enteric aerobes and anaerobes

1 g preinduction

Cefazolin

1 g after umbilical cord is clamped

Cefazolin

1 g preinduction

Cefoxin

2 g preinduction

a

Parenthetic text refers to alternate antibiotic or situation. Current data suggest repeat dosing for operations lasting longer than the serum half-life. Preinduction indicates administration of the drug in operating room before initiating anesthesia. Source: From Ref. 49.

high-risk patients or in high-risk surgical procedures. Patient-related risks include such factors as extremes of age, malnutrition, chronic illnesses [diabetes and chronic obstructive pulmonary disease (COPD)], remote infections, immunosuppression, recent operations, and prior irradiation of the surgical site. Risks have been classified by two scoring systems as previously discussed. In general, the use of the SENIC classification is preferred because it incorporates both wound and patient factors. Patients with clean wounds, as defined by the NRC wound classification, who have two or more patient-related risk factors as defined by the SENIC classification have an 8% to 15% incidence of wound infection (Tables 4 and 5) (49,98). This is similar to the incidence found with clean contaminated wounds using the NRC wound classification and qualifies these patients for the administration of prophylactic antibiotics. This approach also addresses questions that have been raised by Platt et al. (99) concerning the use of prophylactic antibiotics in clean operations. These investigators

found a trend toward a decrease in rates of infection in patients undergoing clean operations (breast and hernia) with the use of prophylactic cefonicid. However, this study has been criticized because patient-related risk factors were not evaluated, all infectious complications (wound, pneumonias, and urinary tract infection) were included in the analysis, and a higher incidence of infection was found with breast operations in this study than has been reported in other studies (100). At present, chemoprophylaxis is not recommended in clean operations unless two or more patient-related risk factors are present as defined by SENIC, or prosthetic materials such as cardiac valves, prosthetic joints, or vascular grafts are being implanted. Although the risk of infections is low in these operations, the use of prophylactic antibiotics is justified because the consequences of infection in terms of morbidity and mortality are great. In addition, although definitive evidence to support the use of chemoprophylaxis is not available, prophylaxis is commonly used in cardiac and

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Table 9 Suggested Initial Dose and Time to Redosing for Antimicrobial Drugs Commonly Utilized for Surgical Prophylaxis Renal half-life (hr) Patients with normal renal function

Patients with endstage renal disease

Recommended infusion duration

Standard dose

1.5–2

6

3–5 minc, 20–60 mind

1–2 g i.v.

Ciprofloxacin Cefazolin

3.5–5 1.2–2.5

5–9 40–70

60 min 3–5 minc, 15–60 mind

400 mg i.v. 1–2 g i.v.

Cefuroxime Cefamandole Cefoxitin Cefotetan Clindamycin

1–2 0.5–2.1 0.5–1.1 2.8–4.6 2–5.1

15–22 12.3–18e 6.5–23 13–25 3.5–5.0f

3–5 minc, 15–60 mind 3–5 minc, 15–60 mind 3–5 minc, 15–60 mind 3–5 minc, 20–60 mind 10–60 min (do not exceed 30 mg/min)

1.5 g i.v. 1 g i.v. 1–2 g i.v. 1–2 g i.v. 600–900 mg i.v.

Erythromycin base Gentamicin

0.8–3

5–6

NA

2–3

50–70

30–60 min

1 g po 19, 18, and 9 hr before surgery 1.5 mg/kg i.v.g

Antimicrobial Aztreonam

Neomycin

Metronidazole

Vancomycin

2–3 (3% absorbed under normal GI conditions) 6–14

4–6

12–24 or longer

NA

1 g po 19, 18, and 9 hr before surgery

7–21: no change

30–60 min

0.5–1 g i.v.

44.1–406.4 (CCR < 10 mL/min)

1 g over 60 min (use longer infusion time if dose > 1 g)

1 g i.v.

Weight-based dose recommendationa 2-g maximum (adults) 400 mg 20–30 mg/kg (if < 80 kg, use 1 g; if > 80 kg, use 2 g) 50 mg/kg 20–40 mg/kg 20–40 mg/kg If 10 kg, use 3–6 mg/kg 9–13 mg/kg

Recommended redosing intervalb (hr) 3–5 4–10 2–5

3–4 3–4 2–3 3–6 3–6

NA 3–6

–g 20 mg/kg

15 mg/kg initial dose (adult); 7.5 mg/kg on subsequent doses 10–15 mg/kg (adult)

NA

6–8

6–12

Note: Data are from Refs. 59, 60, 102. a Data are primarily from published pediatric recommendations. b For procedures of long duration, antimicrobials should be readministered at intervals one to two times the half-life of the drug. The intervals in the table were calculated for patients with normal renal function. c Dose injected directly into vein or via running intravenous fluids. d Intermittent intravenous infusion. e In patients with serum creatinine level of 5 to 9 mg/dL. f The half-life of clindamycin is the same or slightly increased in patients with end-stage renal disease, compared with patients with normal renal function. g If the patient’s body weight is > 30% higher than their IBW, the DW can be determined as follows: DW ¼ IBW þ [0.4  (total body weight  IBW)]. Abbreviations: CCR, creatinine clearance rate; IBW, ideal body weight; DW, dosing weight; GI, gastrointestinal.

neurosurgical procedures even when prosthetic materials are not inserted because of the morbidity of sternal or skull infections (101). The choice of a specific antibiotic agent depends on the operation to be performed, the spectrum of coverage, toxicity, and lastly cost. Commonly used drugs for prophylaxis and accompanying dosage schedules are shown in Table 9 (59,60,102). Antimicrobial prophylaxis should be directed toward common bacterial flora encountered in the course of a specific operation and most importantly toward the most common pathogens responsible for infection after a given procedure. Therapy should be tailored to flora endemic to individual hospitals, because patterns of antibiotic use may result in the emergence of resistant organisms. If MRSA or methicillin-resistant S. epidermidis is a common colonizer in a given hospital setting, methicillin would obviously be contraindicated and another prophylactic antibiotic such as vancomycin should be substituted (103–105). Prophylaxis should be limited to common pathogens, because use of antibiotics with an

unnecessarily wide spectrum also leads to the development of resistant strains of bacteria and to the occurrence of difficult-to-treat infections The least toxic antibiotic that has an appropriate spectrum of activity should be chosen. In general, in the absence of allergies, b-lactam antibiotics (particularly cephalosporins) have acceptable safety profiles. Although the use of aminoglycosides for less than 48 hours rarely results in major toxicity, the potential for both renal and ototoxicity is present, and these drugs are best reserved for therapeutic regimens. The timing and duration of antibiotic therapy are critical for successful prophylaxis. Antibiotics are most effective in preventing infection when present in adequate tissue levels at the time of bacterial contamination (106). Parenteral administration is necessary to reliably attain adequate tissue levels. Administration of the antibiotic at intervals greater than one hour prior to operation have been associated with falling antibiotic tissue levels and an increased incidence of infection (107). In most cases, antibiotics should be administered in the operating room no

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greater than 30 minutes prior to making the incision (103). This approach ensures adequate tissue levels at the time of operation. When administration prior to contamination is not possible (i.e., penetrating abdominal trauma and ruptured viscus), antibiotics should be administered as soon as possible after contamination. Adequate tissue levels should be maintained throughout the procedure. This requires frequent dosing at intervals of two times the plasma half-life for drugs that are rapidly cleared from the circulation (106). For many cephalosporins, dosing at two- to threehour intervals during a procedure may be necessary. Postoperatively, the shortest effective course of antibiotics limits costs, toxicity, and the development of resistant infections. Several studies have demonstrated the efficacy of single-dose prophylaxis in operations (GI, gynecologic, and orthopedic) lasting less than two to three hours (45,103). The need for prophylaxis longer than 24 to 48 hours is extremely rare even in cases of preexistent contamination, such as penetrating abdominal trauma or open fractures (108–110). Finally, it should be remembered that antibiotics are an adjunctive measure for decreasing the incidence of wound infection and do not replace adequate patient preparation, infection control protocols, and the use of eticulous surgical technique.

Other Methods of Prophylaxis Mechanical means to decrease the concentration of infective organisms in the wound should be used whenever possible. For example, in operations involving the large bowel, a period of mechanical cleaning through the use of cathartics and/or enemas before surgery decreases the enteric bacterial count and thereby lessens the risk of infection. In such clean contaminated cases involving the colon, oral antibiotics (neomycin and erythromycin base) administered on the day prior to operation reduce the concentration of bacteria within the colon and provide a significant reduction in the incidence of wound infection with or without the use of systemic antibiotics (111). Topical antibiotic prophylaxis has been most successfully applied to burn wound sepsis (112). The goal with such therapy is not to prevent colonization of the wound but to control bacterial proliferation. The ideal agent possesses a broad spectrum of activity against bacterial and fungal pathogens, penetrates the burn eschar, has limited systemic toxicity, is inexpensive, and is easy to apply and remove. Although none of the available agents meets all these criteria, the most commonly used agents are silver sulfadiazine, silver nitrate, and mafenide acetate.

Empiric Use Empiric antibiotic therapy differs from the therapeutic use of antibiotics in that antibiotics are administered early to treat presumptive infections. Antibiotics have been used in this fashion primarily in immunocompromised patients or in patients with presumed septic shock in an attempt to prevent death during the early phases of an infection before the infecting organism or the source of infection has been identified (38,113–116). In general, broad-spectrum therapy is used to cover the most likely pathogens. This therapy is then tailored to the specific infection, usually after 72 hours, when the culture results are available. In neutropenic patients (granulocyte counts < 500 mm3) prior to the institution of empiric therapy in the 1970s, mortality secondary to gram-negative bacteremias approached 90%. With the early use of antibiotics, mortality has decreased to about 10% currently. The classic organisms associated with

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infections in neutropenic patients have been the Enterobacteriaceae, specifically Pseudomonas, and more recently Enterobacter species. However, in the 1980s, an increasing incidence of gram-positive organisms, including S. aureus, S. epidermidis, and a-hemolytic streptococci, has been observed (115). In addition, with more prolonged hospitalization, the frequent use of immunosuppressive agents in transplantation recipients, and the frequent previous antibiotic usage, fungal infections, particularly with Candida and Aspergillus organisms, are becoming more common. In patient populations with other disease processes such as AIDS, P. carinii and M. tuberculosis are the most common pathogens. Choices for empiric antibiotic therapy fall into three basic categories: (i) the classic approach of a broad-spectrum b-lactam antibiotic in combination with an aminoglycoside, (ii) the use of two b-lactam antibiotics, and (iii) broadspectrum monotherapy with or without additional gram-positive (i.e., vancomycin) or anaerobic coverage (i.e., clindamycin or metronidazole). Data exist to support each regimen. The first regimen provides broad-spectrum coverage and rapid bactericidal activity and has the advantage of synergy between the b-lactam and the aminoglycoside, thereby limiting the emergence of resistant organisms. Under most circumstances, an antipseudomonal penicillin with an aminoglycoside has been demonstrated to be the best combination. The primary disadvantage of this regimen is the potential toxicity from the use of aminoglycosides. The combination of two b-lactam antibiotics has also been demonstrated to be effective empiric therapy. The primary disadvantage with this regimen is the selection of organisms resistant to lactams. Monotherapy with a number of different agents (extended-spectrum penicillins, third-generation cephalosporins, penicillins, or cephalosporins plus b-lactamase inhibitors, carbapenems, or quinolones) has been used with success. The most extensively studied regimens in neutropenic patients have used imipenem or ceftazidime (113). These regimens have the advantage of ease of administration, lower cost, and toxicity, but again, the occurrence of resistance is the major disadvantage. Regardless of the initial regimen, additions and modifications are frequently necessary when culture results become available. In addition, overall clinical response should be evaluated at 72 hours to determine the effectiveness of the regimen. Patients with documented infections and patients remaining neutropenic after 7 to 10 days of therapy are most likely to require changes in antibiotics (115). For the latter patients, infections with nonbacterial pathogens, particularly viruses and fungal agents, should be considered. Debate continues about the inclusion of vancomycin in the initial empiric regimen. Several randomized studies have demonstrated no survival advantage when all neutropenic patients are considered. However, vancomycin should be included initially in hospitals in which MRSA is endemic. In addition, vancomycin should be added in severely septic patients and in patients in whom MRSA is a likely pathogen (i.e., patients suspected of intravenous line sepsis). In such cases, vancomycin may be deleted after 72 hours if culture results are negative for gram-positive organisms. The optimal duration of antibiotic therapy has also been debated. For patients with negative culture results, in whom the neutropenia resolves, antibiotics may be discontinued after seven days. Antibiotics may be discontinued earlier in nonneutropenic patients with negative culture results, usually after three days. A reasonable approach in patients who remain neutropenic is to continue antibiotics for 14 days or

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for seven days after they become afebrile. About one-third of these patients become febrile again and require additional therapy. Patients with severe neutropenia (< 100 mm3) may require therapy until granulocyte counts increase above 500 mm3. In conclusion, the regimen chosen must be adapted to the individual patient and the profile of common pathogens in a given institution. Regardless of the initial regimen chosen, the clinician must recognize the need for and the indications to modify initial therapy, based on culture results and the patient’s clinical response.

Therapeutic Use A complete listing of suggested therapy for surgical infections and recommendations for antibiotic therapy of the various pathogens is beyond the scope of this chapter, but may be found in standard texts on infectious diseases. Several aspects of the basic principles governing the therapeutic use of antibiotics to treat established infections are discussed in Table 10. Essential to these principles is a knowledge of the pharmacodynamic effects of antimicrobial agents (117,118). These effects are determined by the drug interaction with the microorganism, as well as by host factors. Bactericidal antimicrobials can be classified as having concentrationdependent or concentration-independent bacterial killing. Overlap exists, with many antibiotics demonstrating both types of behavior depending on the microorganism targeted. In general, aminoglycoside antibiotics are noted for having concentration-dependent killing. Although conflicting data have been reported regarding the usefulness of serum concentrations to titrate therapy, most investigators have found a relationship between serum concentrations and the efficacy, as well as the toxicity, of aminoglycoside (119). Traditionally, for life-threatening infections, peak serum concentrations of 8 to 10 mg/dL and trough concentrations of 1 to 2 mg/dL have been used. More recently, the ratio of peak serum concentration to the MIC, defined as the lowest serum concentration that inhibits bacterial growth, has been directly related to the bacterial killing rate. This increase in bacterial killing is seen up to peak/MIC ratios of about 10

to 12. Early achievement of these therapeutic levels has been associated with improved outcome in patients with intraabdominal infections (71,117). The relationship of serum levels to toxicity is less well defined. Some investigators have reported that both nephrotoxicity and ototoxicity are associated with peak serum concentrations of gentamicin greater than 12 to 14 mg/dL and trough concentrations greater than 2 mg/dL. However, toxicity may occur with therapeutic serum concentrations, and in some patients, it may be difficult to determine if increased serum levels of aminoglycosides are the cause or the result of decreased renal function. To maintain therapeutic aminoglycoside levels, it is important to recognize that critically ill patients have marked interpatient variability in pharmacodynamics, particularly with respect to volume of distribution (Vd) and clearance of the antibiotic. The major factor associated with the increase in Vd in critically ill surgical patients is volume replacement resulting in intracellular fluid shifts. Other factors involved include fever, ascites, peritonitis, vasodilator therapy, and parenteral nutrition. In addition to having increased Vd, critically ill patients have been demonstrated to have lower elimination constants and lower total body clearance of aminoglycosides compared to noncritically ill patients. The increase in Vd and decrease in clearance of the drug result in the need to increase the dose and interval of administration of aminoglycosides in these patients, compared to that followed in conventional regimens (90,119). Chelluri and Jastremski (120,121) demonstrated that a loading dose of 3 mg/kg of tobramycin or gentamicin was necessary to achieve a peak serum concentration greater than 8 mg/dL in 11 of 14 critically ill patients. In addition, it has been recommended that the dose be increased to 7 mg/kg/day, given in divided doses (i.e., every 12 hours) or as a single daily dose. Once-daily dosing is possible in these patients because of the pharmacodynamics and because aminoglycosides exhibit a relatively long PAE (122). The PAE is manifested by the ability of some antimicrobials to suppress bacterial growth despite serum concentrations well below MIC. Several clinical trials have

Table 10 Principles of Antibiotic Therapy The organism should be sensitive to the antibiotic chosen. Obtain an appropriate culture with susceptibility testing to guide possible changes in antibiotic coverage. Recall in vitro/in vivo disparity in susceptibility of some organisms (e.g., cephalosporins are not effective in vivo against MRSA) Antibiotics should be in doses that ensure adequate peak concentrations and tissue penetration. Blood levels should exceed minimum inhibitory concentration, by 2–3 times to ensure penetration of infected tissues Host factors must be taken into consideration (preexisting diseases, allergies, age, immunosuppression, remote infections, etc.) The antibiotic must come in contact with the organism. The blood–brain, prostatic, obstructed bile, and other barriers prevent penetration of some antibiotics Frequency of administration is based on the half-life and the route of elimination of the antibiotic. Inadequate antibiotic serum concentrations at the end of a dosing interval may lead to ‘‘break-through’’ bacteremia. With developing renal or hepatic dysfunction, the dosing interval is lengthened and, as function improves, is shortened again Choose a bactericidal antibiotic when appropriate. Patients with endocarditis and osteomyelitis, and the infected, compromised host with neutropenia require bactericidal antibiotics Use synergistic therapy when appropriate, such as Pseudomonas infections (especially compromised host), serious enterococcal infection, Staphylococcus epidermidis endocarditis, or ventriculoperitoneal shunt infections deserve synergistic therapy Avoid antagonistic combinations of antibiotics. Antagonism is most likely when 2 ‘‘bacteriostatic’’ antibiotics are used together Choose the most-narrow-spectrum antibiotic. Super-infection is minimized. Often cost is less Avoid side effects when possible. Decreasing the side effects should dictate choice of antibiotic more than cost or convenience of administration. Many antibiotics may interact adversely with other drugs (e.g., metronidazole with ethanol) Control potential interfering conditions or substances. Acidic pus may render an antibiotic useless; therefore drain pus. Organisms may survive an antibiotic when a foreign body is present; therefore remove the foreign body Ensure the proper duration of therapy. For many surgical infections, continuing antibiotics 3 or 4 days past the day of afebrility suffices; however, undrained pus may require long therapy, and an unremoved foreign body (e.g., infected vascular graft) may require therapy for life. Clinical response is the most important factor in determining efficacy and duration of treatment Abbreviation: MRSA, methicillin-resistant Staphylococcus aureus.

Chapter 6:

Surgical Infection: Principles of Management and Antibiotic Usage

demonstrated efficacy with some decrease in toxicity with once-daily dosing of aminoglycosides. However, the benefits of once-daily dosing have not been conclusively demonstrated, particularly in neutropenic patients. Regardless of the dosing interval, serum concentrations should be followed to maximize efficacy. In contrast to aminoglycosides, most b-lactam antibiotics exhibit concentration-independent bacterial killing (117). For these antimicrobials, the length of time that serum levels remain above MIC, rather than peak concentrations, appears to be the primary determinant of bacterial killing. These characteristics support the use of frequent dosing intervals, with lower doses or alternatively continuous infusions of b-lactam antibiotics, to ensure that serum concentrations remain above MIC for prolonged periods of time. Although several animal and human studies have been carried out, it is difficult to demonstrate a definite benefit of continuous dosing over intermittent dosing at present. However, if continuous dosing is used, a loading dose should be given to ensure that the MIC is rapidly exceeded. As with empiric therapy, there has been a recent trend toward the use of single broad-spectrum b-lactam antibiotics as substitutes for combination therapy with aminoglycosides to treat established infections caused by aerobic, gramnegative bacilli. These organisms are usually a part of a mixed aerobic–anaerobic flora causing intra-abdominal infections. Current recommendations are that all regimens for intra-abdominal infections cover both aerobic, gramnegative organisms and anaerobic organisms. Overall, no clear benefit of combination therapy over monotherapy with broad-spectrum b-lactams has been demonstrated. However, combination therapy should be strongly considered in neutropenic patients with gram-negative bacteremia and in patients with infections secondary to bacteria that are known to develop resistance to b-lactam antibiotics (71,116,123,124). Finally, it cannot be emphasized too strongly that the use of antibiotics in most surgical infections is an adjunct to the proper management of the locus of infection. Thus abscesses must be drained, devitalized tissue must be debrided, and grossly contaminated wounds must be packed and left open to heal by secondary intention. Equally important is the maintenance of the immune system through nutritional support of the infected patient. It is not uncommon for a patient with surgical infection to be grossly malnourished with subsequent compromise of the immune system. In providing optimum care, surgical management of infection and maintenance of metabolic homeostasis are the primary components of therapy and are supported by the adjunctive use of antibiotics.

SUMMARY Despite advances in surgical management and antibiotic therapy, infection continues to be the most important cause of morbidity and mortality in postoperative surgical patients. The most common surgical infections are hospital acquired, and the responsible microorganisms are usually endogenous. If the development of such infections is to be minimized, efforts at preventing derangements in hostdefense mechanisms must be ensured, and meticulous surgical techniques must be employed. When infections do occur, rational treatment should stress the importance of accurate identification of the responsible microorganism, logical investigation of the underlying source of infection, and adherence to sound principles governing antibiotic

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prophylaxis and treatment. The application of these guidelines to the clinical management of the surgical patient should lead to substantial improvements in the outcome of surgical disorders that are complicated by infection, in terms of both a reduction in complications and an enhancement of survival.

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101. Waddell TK, Rotstein OD. Antimicrobial prophylaxis in surgery. Committee on Antimicrobial Agents, Canadian Infectious Disease Society. Can Med Assoc J 1994; 151:925. 102. Bratzler DW, Houck PM. Antimicrobial prophylaxis for surgery: an advisory statement from the National Surgical Infection Project. Infec Dis Clin Prac 2004; 72:384–385. 103. Nichols R. Surgical antibiotic prophylaxis. Med Clin North Am 1995; 79:509. 104. Paluzzi R. Antimicrobial prophylaxis of surgery. Med Clin N Am 1993; 77:427. 105. Leaper D. Prophylactic and therapeutic role of antibiotics in wound care. Am J Surg 1994; 167:15S. 106. Bergamini T, Polk HJ. Pharmacodynamics of antibiotic penetration of tissue and surgical prophylaxis. Surg Gynecol Obstet 1989; 168:283. 107. Galandiuk S. Re-emphasis of priorities in surgical antibiotic prophylaxis. Surg Gynecol Obstet 1989; 169:223. 108. Gustilo RB, Merkow RL, Templeman D. The management of open fractures. J Bone Joint Surg 1990; 72-A:299. 109. Fabian T, et al. Duration of antibiotic therapy for penetrating abdominal trauma: a prospective trial. Surgery 1992; 112:788. 110. Dellinger E. Antibiotic prophylaxis in trauma: penetrating abdominal injuries and open fractures. Rev Infect Dis 1991; 13:S847. 111. Gorbach S. Antimicrobial prophylaxis for appendectomy and colorectal surgery. Rev infect Dis 1991; 13(suppl 10):S815. 112. Pruitt B, McManus A. The changing epidemiology of infection in bun patients. World J Surg 1992; 16:57. 113. Pizzo PA. Drug therapy—Management of fever in patients with cancer and treatment-induced neutropenia. N Engl J Med 1993; 238:1323. 114. Shands JJ. Empiric antibiotic therapy of abdominal sepsis and serious perioperative infectious. Surg Clin N Am 1993; 73:291. 115. Giamarellou H. Empiric therapy for infections in the febrile, neutropenic, compromised host. Med Clin N Am 1995; 79:559. 116. Dunn DL. Gram-negative bacterial sepas and sepsis syndrome review. Surg Clin N Am 1994; 74:621. 117. DiPiro J, Edmiston C. Pharmacodynamics of antimicrobial therapy in surgery. Am J Surg 1996; 171:615. 118. Solomkin JS, Miyagawa CI. Principles of antibiotic therapy review. Surg Clin N Am 1994; 74:497. 119. Miyagawa C. Aminoglycosides in the intensive care unit: an old drug in a dynamic environment. New Horizons 1993; 2:172. 120. Chelluri L, Jastremski M. Inadequacy of standard aminoglycoside pharmacokinetics in critically ill surgical patients. Crit Care Med 1987; 15:1143. 121. Chelluri L, Warren J, Jastremski M. Pharmacokinetics of a 3 mg/kg body weight loading dose of gentamicin or tobramycin in critically ill patients. Chest 1989; 95:1295. 122. Perriols-Lisart R, Alos-Alminana M. Effectiveness and safety of once-daily aminoglycosides: a meta-analysis. Am J Health Syst Pharm 1995; 53:1141. 123. DiPiro JT, Forston N. Combination antibiotic therapy in the management of intra-abdominal infection. Am J Surg 1993; 165:82S. 124. Shands JW Jr. Empiric antibiotic therapy of abdominal sepsis and serious perioperative infections. Surg Clin N Am 1993; 73:291.

7 Hemostasis and Thrombosis in the Surgical Patient Stuart I. Myers, Mark R. Jackson, Michael Sobel, and G. Patrick Clagett

the end result of which is a hemostatic plug. The two most potent agonists for platelet aggregation are collagen and thrombin. Once platelet activation is initiated, the platelet changes shape from discoid to spherical and develops pseudopods as a result of changes in the platelet cytoskeleton (7). Thromboxane A2 is then produced through the cyclooxygenase pathway of arachidonic acid metabolism and further stimulates platelet aggregation (8). Platelets contain numerous intracellular and membrane components that contribute to their hemostatic function. Platelet activation is initiated following the binding of thrombin or other agonists to the extracellular domain of specific membrane receptors (Fig. 1) (9). As in other cells, platelet receptors for agonists and inhibitors are transmembrane proteins with cell surface and cytoplasmic components. The signal, initiated by receptor occupancy, is then transmitted by the cytoplasmic domain of the receptor through guanosine triphosphate-binding regulatory proteins (G proteins) to membrane-bound, signalgenerating enzymes such as phospholipase C (Fig. 2) (10). Activation of these enzymes induces generation of second-messenger molecules such as inositol 1,4,5triphosphate (IP3) and diacylglycerol (DAG). Inositol triphosphate induces calcium release from the platelet-dense tubular system. A rise in free calcium in the cytosol is a critically important aspect of platelet activation. DAG activates protein kinase C, which in turn promotes protein phosphorylation and causes platelet secretion and the expression of the fibrinogen receptor (GPIIb/IIIa) on the platelet surface that leads to platelet aggregation (11,12). Platelets contain two major types of secretory granules, the most predominate of which is the a-granule. Contents of the a-granule include PF4, transforming growth factor-b, platelet-derived growth factor (PDGF), coagulation factor V, and b-thromboglobulin. The dense granules contain serotonin, adenosine triphosphate, adenosine diphosphate (ADP), and calcium. Release of these biologically active substances occurs by exocytosis during platelet aggregation and results in platelet recruitment to the site of injury, vasoconstriction, and other hemostatic and vascular responses. The platelet membrane contains a number of glycoprotein receptors that bind various ligands during platelet activation, and thereby promote adhesion and aggregation. GPIb/IX functions as a receptor for von Willebrand factor (vWF) at high shear rates such as during arterial injury and allows vWF to bridge the platelet to the subendothelial matrix at the site of arterial injury (13–15). GPIIb/IIIa is the platelet membrane receptor for fibrinogen and is essential for aggregation. GPIIb/IIIa binds fibrinogen only after undergoing a conformational change mediated by the platelet cytoskeleton and actin, its major contractile protein (16,17). Deficiency of GPIIb/IIIa results in Glanzmann’s

INTRODUCTION The safe practice of surgery requires a fundamental understanding of the concepts of hemostasis. Traditionally, standard textbooks of surgery have focused on the basics of the coagulation pathways and platelet function, with an overview of inherited and acquired defects of these mechanisms. In organizing this chapter, we have sought to summarize these basic concepts and provide additional information on more recent developments that have enhanced our understanding of hemostasis in vivo. The central roles of the tissue factor pathway and thrombin in the coagulation cascade, for example, are emphasized. In addition, newer information on the hypercoagulable syndromes and their role in thrombotic disorders are also presented. Developments in molecular biology are providing unprecedented insight and fundamental understanding of the genetics of inherited bleeding and hypercoagulable disorders that have translated into improved diagnostic testing, such as with resistance to activated protein C and hyperhomocystinemia. Similarly, as the molecular mechanisms of hemostasis are increasingly understood, potent antiplatelet and antithrombotic agents are being developed and made available for clinical use. An appreciation of their therapeutic potential and challenge to surgical hemostasis requires a basic understanding of their mechanisms of action.

MECHANISMS OF HEMOSTASIS Platelets Platelets are anucleate cells produced in the bone marrow by fragmentation of megakaryocytes. The megakaryocytes are located in the subendothelial space of bone marrow vascular sinuses, where proliferation and maturation is regulated. Platelet production is stimulated by thrombopoietin, interleukin-3 (IL-3), and IL-6 (1). Factors that inhibit this process include platelet factor 4 (PF4), transforming growth factor-b, and interferon-a (2–4). Thrombopoiesis is also influenced by circulating platelet mass. The identification, purification, and cloning of thrombopoietin, or the c-Mpl ligand, followed characterization of the c-mpl gene that encodes for a cell surface receptor present on megakaryocytes and platelets (5). Thrombopoietin bound to c-mpl on megakaryocytes stimulates all stages of megakaryocyte maturation, thus leading to platelet production. Thrombopoietin bound to platelet c-mpl aids in its removal from the circulation, a possible mechanism by which platelet mass regulates the plasma concentration of thrombopoietin. Once released into the circulation, platelet hemostatic function is initiated with adhesion of the platelet to the subendothelial matrix of the injured blood vessel (6). Platelet activation is followed by platelet aggregation and secretion, 157

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Another function of the platelet is to provide a surface for activation of clotting factors. Many of the reactions in the coagulation cascade are greatly enhanced by the phospholipid surface of the platelet membrane. This enhancement of coagulation by platelets is termed ‘‘platelet coagulant activity’’ and is an important factor during thrombogenesis (20). Because platelets adhere to the site of vascular injury where bleeding occurs, this allows an increased local concentration of clotting factors. Activated factor X (factor Xa) is a pivotal enzyme in the coagulation cascade; when bound to platelet factor Va, its efficiency in thrombin generation is dramatically increased. In addition, factor Xa bound to activated platelets is protected from inactivation by the heparin/ antithrombin III (AT-III) complex.

Coagulation Cascade

Figure 1 The receptor-mediated events of platelet activation, adhesion, secretion, and aggregation. Abbreviations: R, receptor; ADP, adenosine diphosphate; 5HT, serotonin; FG, fibrinogen; vWF, von Willebrand factor; TSP, thrombospondin. Source: From Ref. 9.

thrombasthenia, an autosomal recessive bleeding disorder characterized by absence of platelet aggregation and clot retraction (18,19). Under conditions of low shear stress, such as with venous injury and thrombosis, platelet adherence to subendothelial collagen occurs through the action of receptors GPIa/IIa and GPIb.

In vivo, the primary role in the activation of the coagulation cascade involves the tissue factor/factor VIIa (TF/VIIa) complex (Fig. 3) (21–23). Tissue factor is a 45 kDa transmembrane protein present in the subendothelium and endothelial cells that have been exposed to thrombin or endotoxin. Following vascular injury, factor VII binds to tissue factor and activates small amounts of factor X, which in turn activates additional factor VII. The TF/VIIa complex then activates additional factor X, either directly or through the activation of factor IX. Under basal conditions, the TF/VIIa complex is the primary activator of factors IX and X (Fig. 3) (24,25). Sustained generation of factor Xa requires the factor IXa/factor VIIIa complex. The VIIIa-IXa-X-Ca2þ assembly is known as the Xase (‘‘tenase’’) complex that leads to the rapid conversion of factor X to Xa. Similarly, while TF/VIIa is the primary activator of factor IX, factor XIa is required for sustained generation of factor IXa. Factor XI is autoactivated as well as activated by thrombin in vivo; therefore the contact activation system, or intrinsic pathway, is not required for hemostasis in vivo. Initiation of the intrinsic pathway (termed ‘‘contact activation’’) involves a complex interaction in which factor XII undergoes a conformational change following exposure

Figure 2 Agonists of platelet activation bind to membrane receptors that activate a Gp0, which activates PLC, which in turn stimulates the phosphoinositide pathway. The second messengers, DAG and IP3, lead to exposure of the GPIIb:IIIa complex, platelet secretion, and TXA2 generation. This signal transduction system also regulates intraplatelet cAMPformation.Thrombin stimulates a Gi that inhibits adenylate cyclase and prevents cAMP formation. In contrast, PGI2 interacts with a G5 that stimulates adenylate cyclase activity in the formation of cAMP. cAMP lowers intracellular calcium levels and inhibits platelet activation. Abbreviations: Gp0, G protein; PLC, phospholipase C; DAG, diacylglycerol; IP3, inositol triphosphate; TXA2, thromboxane A2; cAMP, cyclic adenosine monophosphate; Gi, inhibitory G protein; PGI2, prostacyclin; G5, stimulatory G protein.

Chapter 7:

Figure 3 Proposed coagulation pathway under in vivo conditions. Coagulation is initiated by the TF/VII complex, which can activate factor X directly or through the activation of factor IX. Thrombin can reciprocally activate factors XI, V, and VIII. Factor Xa can promote activation of factor VII. The contact system appears to play no role in hemostasis in vivo. Abbreviations: TF/VII, tissue factor/factor VII; factor Xa, activated factor X. Source: From Ref. 15.

to nonendothelialized surfaces. The activation of factor XII occurs principally through the action of kallikrein, with highmolecular-weight kininogen acting as a necessary cofactor. This complicated surface-mediated series of reactions can lead not only to clotting but also to kinin formation, complement activation, and fibrinolysis. In fact, the higher reactions in the intrinsic coagulation cascade are probably more important in triggering inflammatory responses and other defense reactions than they are in hemostasis with. Patients with factor XII (Hageman factor) deficiency have no bleeding diathesis, and patients with factor XI deficiency generally have only mild bleeding. The tissue factor pathway is also referred to as the extrinsic pathway and is the dominant system of the coagulation cascade in vivo. Factor Xa then binds with factor Va to convert prothrombin to thrombin. Assembly of the Va-Xa-IICa2þ complex occurs on the platelet membrane where Va is located, and this thrombin-generating unit is known as the IIase (‘‘prothrombinase’’) complex. Thrombin generation results in the cleavage of prothrombin fragment F1.2, which has been used as a sensitive marker of thrombin generation and hemostatic activation (26). Thrombin then converts fibrinogen to fibrin monomers, which are subsequently cross-linked by factor XIII. The cross-linked fibrin clot is comparatively stable and more resistant to lysis because it incorporates a2-antiplasmin into the clot. The central role of thrombin in the coagulation cascade is demonstrated through its other multiple procoagulant functions, which include the activation of factors V, XI, VIII, and XIII, as well as its potent effect as an inducer of platelet aggregation (27).

REGULATION OF HEMOSTASIS Endothelium The endothelium is a dynamic organ that provides an interface between flowing blood and the vessel wall.

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The endothelium is highly heterogeneous and undergoes ‘‘transdifferentiation,’’ in which the endothelium can be influenced by local factors to acquire specialized characteristics unique to that local environment. ‘‘Thromboregulation’’ is a term that refers to three different basic processes by which cells of the vessel wall and the blood cells interact to facilitate or inhibit thrombus formation (28–31). The initial phase of thromboregulation refers to those vasoactive substances that help to prevent platelet deposition and affect the contractile state of the blood vessel. These early thromboregulators include nitric oxide (NO), eicosanoids, and the ectoADPase/CD39. NO is a potent inhibitor of platelet aggregation and is a potent vasodilator. The endothelial cell eicosanoids include prostacyclin (PGI2) and prostaglandin D2 (32,33). These fatty acid–derived hydrocarbons can inhibit platelet aggregation and cause vasodilatation of the vessel wall. Endothelial cell ectoADPase/CD39 is a membranebased protein that metabolizes ADP in the primary platelet release product, which will then prevent platelet recruitment. In addition to these three early thromboregulators, endothelial cells release endothelins, which are potent vasoconstrictors (34–44). Normal endothelium expresses thrombomodulin (TM), which serves as a binding site for thrombin to activate protein C; heparin-like molecules that can activate AT-III; and ectoadenosine diphosphatase that inhibits platelet aggregation by degrading ADP. Endothelium also produces vWF and releases it into subendothelial matrix, where it mediates platelet adhesions when endothelium is lost. The second group of thromboregulators includes those acting as ‘‘late thromboregulators.’’ These late thromboregulators act to regulate thrombin generation, neutralize thrombin, or lyse clot. These include endothelin, AT-III, tissue factor pathway inhibitor (TFPI), the TM/endothelial cell protein C receptor (EPCR/protein C system), and the fibirinolytic system. Endothelin, as mentioned above, is a potent vasoconstrictor. AT-III is a natural anticoagulant, which inhibits thrombin and factor Xa. TFPI is a protein that inhibits factor VIIa tissue factor activity. The EPCR/protein C system of the vascular wall has direct anticoagulant effects on thrombin. Endothelial cells synthesize and secrete elements of the fibrinolytic system and also regulate the formation of plasmin (45). The third subcategory of thromboregulators includes alterations due to inflammation. These changes include increases in expression of tissue factor and modulation of the TM/EPCR/protein C system. The endothelial cells also upregulate cell adhesion molecules and the selectins. These changes create an interface between the endothelium and various classes of leukocytes. Endothelial injury is accompanied by the loss of antithrombotic, protective molecules and expression of procoagulant properties, white blood cell adhesion molecules, and mitogenic activities that can engender thrombosis, smooth muscle cell migration and proliferation, and atherosclerosis. These multiple endothelial functions and their regulatory effects on platelets, coagulation proteins, and the fibrinolytic system are illustrated in Figure 4 (29–33).

Tissue Factor Pathway Inhibitor The primary regulator of the TF/VIIa complex in hemostasis is the TFPI (22,23). TFPI is present in circulating form and bound to endothelium (Fig. 4). The inhibitory process of TFPI involves two steps (23,34). First, TFPI inactivates factor Xa by forming a TFPI/Xa complex. This complex then binds the TF/ VIIa complex, forming a quaternary Xa/TFPI/VIIa/TF complex, which lacks TF/VIIa activity. Heparin causes the release of TFPI from endothelial stores bound to heparin sulfate or

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Figure 4 Vasoprotective and procoagulant properties of EC. On the left, inhibition of platelet function and coagulation by several endothelial molecules and factors and the targeted coagulation factors are shown. In addition, activation of fibrinolysis of EC tPA and its PAI-1 is depicted. TM is a surface molecule that binds thrombin, thereby activating PC to aPC, which in the presence of PS degrades factor Va and VIIIa-heparin-like molecules expressed on endothelial surface serve as a cofactor for AT-III, thereby ILa and several other activated coagulation factors shown. On the right, TF expressed on EC surface during activation serves as a cofactor factor VIIa to activate X and IX, respectively. Generated thrombin activates platelets, coagulation, and fibrinolysis. Abbreviations: EC, endothelial cells; tPA, tissue plasminogen activator; PAI-1, inhibition by plasminogen activator; PC, protein C; aPC, activated protein C; PS, protein S; ILa, inactivating thrombin; TF, tissue factor; TM, thrombomodulin; AT-III, antithrombin III. Source: From Ref. 28.

other glycosaminoglycans (46). More TFPI is available from the endothelial source than that circulating in plasma.

Activated Protein C and Protein S Endothelium possesses a thrombin receptor, TM. TM is the cellular cofactor for thrombin and is expressed on endothelial cell surfaces (47,48). TM appears to help prevent thrombosis in intact endothelium in the microcirculation (TM), binds to thrombin and thus helps localize thrombin to endothelial cell surfaces and enhances Protein C activation 1000- to 2000-fold (49–51). Protein S is the cofactor for protein C; both protein S and protein C are vitamin K–dependent proteins. Activated protein C is the major inhibitor of factors Va and VIIIa (Fig. 4) (50–52). Thrombin bound to TM cannot activate factors V, VIII, XIII, fibrinogen, or platelets. The expression of TM is downregulated by endotoxin, tumor necrosis factor, and IL-1.19. Thus thrombosis may be favored at sites of inflammation by a concurrent elevation of tissue factor and a depression in endothelial TM expression.

conversion product plasmin from the natural inhibitor a2-antiplasmin, which efficiently neutralizes plasmin in the fluid phase only. Thus the action of plasmin is localized to the site of clotting or thrombus formation, where fibrin is digested. Free plasmin is thus prevented from escaping into the general circulation. Small amounts of plasmin that leak into the circulation or are generated in flowing blood are rapidly inactivated by the action of a2-antiplasmin and other inhibitors. T-PA is inactivated by plasminogen activator inhibitor (PAI-1), a 52 kDa protein synthesized in the endothelial cell (Fig. 4). PAI-1 is the primary regulator of endogenous t-PA activity (56–59). a2-Antiplasmin is a specific inhibitor of plasminogen and is incorporated into the fibrin clot, thereby rendering it resistant to lysis by plasmin (40). Plasma levels of a2-antiplasmin are less than those of plasminogen, so that depletion of a2-antiplasmin, such as during disseminated intravascular coagulation (DIC), can result in uninhibited plasmin activity and worsening of the coagulopathy.

Nitric Oxide Antithrombin-III AT-III is a 58 kDa glycoprotein that is synthesized in the liver and is the major inhibitor of thrombin and factor Xa. AT-III also inactivates factors XIIa, XIa, and IXa. Heparin accelerates the activity of AT-III by 1000-fold (52–55). Heparin dissociates from AT-III once covalent bonds are formed between AT-III and thrombin or other factors, and is then able to activate additional AT-III. AT-III activity is also accelerated by heparin sulfate present on endothelium (Fig. 4).

Fibrinolytic System Fibrinolysis is stimulated by vascular injury and release of plasminogen activator from endothelial cells (Fig. 4). By the action of tissue-type plasminogen activator (t-PA) or urokinase, the inactive plasma precursor molecule plasminogen is converted to the proteolytic enzyme plasmin, which can digest fibrin and fibrinogen. There are two major forms of circulating plasminogen, lys-plasminogen and gluplasminogen (56–59). Lys-plasminogen selectively binds to fibrin during clotting and is more easily converted to plasmin than is glu-plasminogen. Selective incorporation of lysplasminogen into thrombus also protects the subsequent

NO is a free radical produced from the amino acid L-arginine (L-Arg) and has a half-life of three to five seconds (42–44). NO is produced by the action of NO synthase (NOS), which converts the terminal guanidine group of L-Arg to NO. Two forms of NOS have been identified, an inducible form, found primarily in macrophages, and a constitutive form, found in neuronal tissue, platelets, and vascular endothelium. In addition to its potent vasodilator function, NO interacts with platelets, inhibiting both adhesion and aggregation by increasing intracellular cyclic guanosine monophosphate. Platelets can also release NO, which acts in an autocrine fashion to prevent aggregation. In vivo, platelet deposition at the site of endothelial injury is increased by free hemoglobin, an NO inhibitor, in the cell. This augmented platelet deposition can be blocked by L-Arg, but not by aspirin (60–62).

Prostacyclin Endothelial cells synthesize prostacyclin, which inhibits platelet aggregation and causes smooth muscle relaxation and vasodilation (30,63). Released endothelial cell prostacyclin can react with the platelet surface domain of a specific

Chapter 7:

receptor, thereby initiating a signal transduction pathway that is G protein linked and of the type described for activation of phospholipase C. In this case, the signal-generating enzyme is adenylate cyclase, which catalyzes the formation of the second-messenger cyclic adenosine monophosphate (cAMP) from adenosine triphosphate, resulting in inhibition of platelet function. Continuous, basal endothelial prostacyclin production occurs in vivo, and marked increases are seen in response to increases in shear stress, local thrombin generation, and cytokines. Another product of endothelial prostaglandin metabolism includes lipoxygenase products that inhibit platelet adhesion. By reducing platelet adhesion, inhibiting platelet aggregation, and causing vasodilation, prostacyclin can lead to local increases in blood flow that help to wash away any thrombi that may be forming.

INHERITED DISORDERS OF COAGULATION Inherited disorders of hemostasis are generally characterized by a history of prior bleeding episodes, particularly hemarthrosis, which can result in significant joint damage. Surgical treatment in these individuals is best provided at a center where the expertise of a hematologist and others skilled at providing care for these patients is available. A summary of these deficiencies and their inheritance patterns and treatment are provided in Table 1.

Hemophilia A (Factor VIII Deficiency) Hemophilia A is an X-linked disorder and has an incidence of 10 to 20 cases per 100,000 live births (15, 64–66). As many as 30% of new cases are not associated with a family history, thereby suggesting that the factor VIII gene undergoes frequent mutation. Hemophilia A is suspected in any male with a history of excessive bleeding following trauma or spontaneous hemarthrosis. The severity of hemophilia A is correlated with the level of factor VIII. Patients with factor VIII levels greater than 5% have mild hemophilia and are at reduced risk for spontaneous bleeding but are at increased risk for bleeding following surgery or trauma. Patients with factor VIII levels between 1% and 4% have moderate hemophilia. Patients with factor VIII levels less than 1% have severe hemophilia and are at risk for spontaneous bleeding. Laboratory abnormalities in hemophilia A, other than reduced factor VIII levels, can include a variable prolongation of the activated partial thromboplastin time (aPTT). Analyzing the DNA from blood samples, following amplification using the polymerase chain reaction, can help perform carrier and prenatal testing and then using restriction enzymes that recognize and cleave specific DNA base sequences. The DNA is then analyzed using gel electrophoresis and compared with known patterns of abnormal DNA polymorphism. Treatment of hemophilia A depends on the severity of the disease and the indication (Table 1). For example, patients with mild hemophilia undergoing dental procedures can be effectively treated with desmopressin (DDAVP, 0.3 mg/kg intravenously), which releases stores of factor VIII and vWF and will increase factor VIII to a median level of 62%. DDAVP cannot be used in patients with severe hemophilia A, because they have no stored form of factor VIII. Patients with hemophilia A who are undergoing surgery should be treated with factor VIII concentrates (Table 2). Since 1985, all factor VIII concentrates in the United States have undergone viral inactivation using heat

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or solvent-detergent treatment, which has essentially eliminated the risk of transmitting HIV or hepatitis B and C. Commercial factor VIII concentrates are available in a range of purity and specific activity, depending on their source and methods of purification. The half-life of factor VIII is approximately 12 hours, so replacement therapy should be given at 8- to 12-hour intervals during periods of increased bleeding risk. The Food and Drug Administration (FDA) has approved recombinant factor VIII from genetically engineered mammalian cells.

Hemophilia B (Factor IX Deficiency) Hemophilia B is inherited in an X-linked fashion and has a clinical presentation similar to hemophilia A (15, 65,66). The incidence of hemophilia B is approximately 10-fold lower. As with hemophilia A, spontaneous mutations of the factor IX gene can cause the disorder without a prior family history. Hemophilia B is a heterogeneous disorder characterized by a number of point mutations and deletions of the factor IX gene on the X chromosome. The degree of severity of hemophilia B is categorized as with hemophilia A based on the factor IX levels: severe is less than 1% of normal, moderate is 1% to 5%, and mild is 6% to 60% of normal. Treatment principles for factor IX replacement are similar to those with hemophilia A (Table 1). For major surgery or active bleeding, a factor IX level of 50% to 100% should be achieved using factor IX concentrates. A level of 30% may be adequate for prophylaxis or minor bleeding. The biologic half-life of factor IX is 18 to 30 hours, so concentrates should be readministered at 12- to 24-hour intervals during periods of increased bleeding risk. Replacement therapy for factor IX and VIII can also be guided by periodic assessment of factor levels. The aPTT is inadequate for monitoring factor replacement therapy, because some factor IX products also contain activated clotting factors. The availability of high-purity virally inactivated factor IX concentrates since 1991 has essentially eliminated the risks of viral transmission and thrombogenicity (Table 3). Approximately 50% of patients exposed to factor IX concentrates before the introduction of virus attenuation procedures in 1985 are HIV positive, and virtually all are seropositive for hepatitis C.

von Willebrand Disease The functions of vWF during normal hemostasis are to promote platelet adhesion in conditions of high shear stress (such as in arterial injury) by binding of the subendothelial vWF to the platelet GPIb receptor and the promotion of platelet aggregation by binding of vWF and fibrinogen to the platelet GPIIb/IIIa receptor. vWF is synthesized in the megakaryocyte and in endothelial cells and is then stored in the Weibel–Palade bodies of the endothelial cell and the a-granules of the platelet. von Willebrand disease (vWD) results from a quantitative or qualitative deficiency of vWF and has an estimated prevalence of 0.8%, making this the most common inherited bleeding disorder (7,13,14). It is usually transmitted as an autosomal dominant trait with variable expression. However, there is considerable heterogeneity in the spectrum of this disorder, with at least 20 distinct subtypes (67–70). Clinically, vWD is characterized by easy bruisability, mucosal bleeding, and potentially heavy bleeding during surgery or from trauma. The laboratory diagnosis includes measurement of vWF activity and antigen. The bleeding time is frequently abnormal as is the aPTT (7,13,14,67–70).

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Table 1 Genetics, Epidemiology, and Therapy of Inherited Coagulation Protein Deficiencies Coagulation protein deficiency Factor I (fibrinogen) Afibrinogenemia Hypofibrinogenemia Dysfibrinogenemia

Inheritance pattern Autosomal recessive Autosomal dominant or recessive Autosomal dominant or recessive Autosomal dominant or recessive

Prevalence Rare (200 types described) Extremely rare (approximately 25 kindreds) One per million births One per 500,000 births

Factor VIII (antihemophilia factor)

X-linked recessive

One per 10,000 births

Usually autosomal dominant

One per 5000 male births Approximately one per 100 births

Factor II (prothrombin)

Hemophilia A vWF

Type III

Minimum desired level to control active bleeding or prevent surgical bleeding

Replacement sources

100 mg/dL

Cryoprecipitate/FFP

30% of normal

FFP/factor IX complex concentrates

25% of normal 25% of normal

FFP FFP/factor IX complex concentrates 80–100% of normal for life- Factor VIII concentrates; threatening bleeding, 50% desmopressin for mild to of normal for significant moderate disease bleeding, 30% of normal for minor bleeding Total or partial correction of bleeding time and raising vWF activity to 50% of normal

Desmopressin for mild to moderate vWD (except IIB) (variable responses in IIA); cryprecipitate; intermediate-purity factor concentrates containing a full complement of vWF multimers

Factor IX

Severe type III disease usually recessive X-linked recessive

One per 30,000 male births

25–50% of normal depending on extent of surgery or bleeding

Factor IX complex concentrates or factor IX (human) concentrates

Hemophilia B Christmas disease Factor X

Autosomal recessive

One per 500,000 births

10–25% of normal

Approximately 4% of Ashkenazi Jews Extremely rare

20–40% of normal

Factor XII

Autosomal dominant; severe type homozygous Autosomal recessive

FFP or factor IX complex concentrates FFP

Prekallikrein (Fletcher factor)

Autosomal recessive

Extremely rare

High-molecular-weight fibrinogen (Williams, Flaujeac, or Fitzgerald factor) Factor XIII

Autosomal recessive

Extremely rare

Autosomal recessive

One per several million births

Factor XI

One per million births

No replacement therapy required No replacement therapy required No replacement therapy required

5% of normal

FFP or cryoprecipitate

Abbreviations: vWD, von Willebrand disease; vWF, von Willebrand factor; FFP, fresh frozen plasma. Source: From Ref. 15.

There are at least three main types of vWD, each with subtypes. The types are categorized based on a quantitative or qualitative deficiency of vWF. Types I and III are due to quantitative deficiencies, and type II (and other variants) results from a qualitative deficiency in vWF. Type I is most common and is responsible for 70% to 85% of all forms of vWD. Type I vWD results from a quantitative deficiency of vWF of 50% or less of normal. In type IIB, thrombocytopenia can result from treatment with DDAVP because the release of additional abnormal vWF can cause platelet agglutination. Type III vWD is the most

severe and results from greatly reduced levels of vWF caused either by an autosomal recessive homozygous state or double heterozygote with an autosomal dominant mode of inheritance. In addition, a platelet type of vWD is caused by an abnormal platelet GPIb receptor, which has an increased affinity for normal vWF, and is associated with platelet agglutination when more vWF is administered. Patients with type I vWD generally respond well to DDAVP with adequately increased vWF levels for four to eight hours. This effect is presumably mediated through

Chapter 7:

Hemostasis and Thrombosis in the Surgical Patient

163

Table 2 Recombinant and Immunoaffinity-Purified Factor VIII Products Specific activity (U/mg) Recombinanta

Immunoaffinity purifiedb

Product name

Manufacturer

Cell of origin

Recombinate

Chinese hamster ovary

2.2–5

4000þ

Kogenate

Baxter-Hyland Genetics Institute Miles-Cutter

Method of viral inactivation

Final

Discounting albumin

Baby hamster kidney

8–30

4000–6000

Monoclate P

Armour

Pasteurized (60
C, 10 hr)

5–10

3000þ

Hemofil M

Baxter-Hyland

2–11

3000þ

Coagulation FVIII, M method

Baxter-Hylandc

Solvent detergent (TNBP/Triton X-100, 25
C, 10 hr) Solvent detergent (TNBP/Triton X-100, 25
C, 10 hr)

2–11

3000þ

a

Genetically engineered. Derived from human plasma. c Manufactured for the American Red Cross. Abbreviation: TNBP, tri-(n-butyl) phosphate. Source: From Ref. 15. b

the release of endogenous vWF from the endothelium, although the mechanism for this is not completely understood. For patients with type IIA vWD response to DDAVP is unpredictable and should be tested in advance. Use of DDAVP in type IIB and platelet type vWD is contraindicated due to resulting thrombocytopenia. For patients in whom DDAVP is not effective or contraindicated, replacement therapy using cryoprecipitate or intermediate-purity factor VIII concentrates that contain functional vWF is indicated. A retrospective review of the use of cryoprecipitate and factor VIII concentrates in vWD unresponsive to DDAVP in 21 treatment centers showed equivalent efficacy (13,14,69). Because factor VIII concentrates are virally inactivated and cryoprecipitate is not, and because there appears to be no advantage to the use of cryoprecipitate, factor VIII concentrates should be considered the treatment of choice in vWD when DDAVP cannot be used.

INHERITED QUALITATIVE PLATELET DISORDERS Glanzmann’s Thrombasthenia Glanzmann’s thrombasthenia results from a congenital absence of functional platelet GPIIb/IIIa receptor to bind fibrinogen and participate in clot retraction, which is mediated by interaction of GPIIb/IIIa with the platelet cytoskeleton (16,18,19,70,71). The genetic defects that result in Glanzmann’s thrombasthenia are remarkably heterogeneous, can result in abnormal GPIIIa or GPIIb, and are generally inherited in an autosomal recessive pattern (46). A deficiency in either glycoprotein causes a functional abnormality of GPIIb/IIIa. Clinically, the disorder is characterized by a history of excessive bleeding at an early age, easy bruisability, and menorrhagia. Hemarthroses are rare. Laboratory diagnosis is established by the absence of the GPIIb/IIIa receptor by flow cytometry or gel electrophoresis. The platelet count and morphology are normal. Platelet aggregometry reveals agglutination of Glanzmann’s

Table 3 Factor IX Products Product name Coagulation products

Complex concentrates

Activated complex concentrates

Manufacturer

Method of virus inactivation

AlphaNine

Alpha Therapeutic

AlphaNine SD

Alpha Therapeutic

Mononine Konyne 80 Proplex T Profilnine HT (wet method) Bebulin

Armour Miles-Cutter Baxter-Hyland Alpha Therapeutic

Autoplex T

Baxter-Hyland

Heated in N-heptane solution, 60
C, 20 hr TNBP and polysorbate 80, 24–30
C, > 24 hr Sodium thiocyanate, ultrafiltration Dry heat, 80
C, 72 hr Dry heat, 68
C, 144 hr Heated in N-heptane solution 60
C, 20 hr Vapor heated (10 hr, 60
C, 1190 mb pressure plus 1 hr, 80
C, 1375 mb) Dry heat, 68
C, 144 hr

FEIBA VH

Immuno-U.S.

Abbreviation: TNBP, tri-(n-butyl) phosphate. Source: From Ref. 15.

Immuno

Vapor heated (10 hr 60
C, 1190 mb plus 1 hr, 80
C, 1375 mb)

Specific activity (U/mg) 84 190 160þ 1.3 47 4.5 2

5 0.8

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platelets with ristocetin, but not with ADP, epinephrine, thrombin, or collagen. Treatment of Glanzmann’s thrombasthenia requires antifibrinolytic agents, either e-aminocaproic acid (EACA) or tranexamic acid, for epistaxis, dental surgery, or minor bleeding (19). Oral contraceptives are effective in treating menorrhagia. Platelet transfusions, preferably human leukocyte-matched, are required for surgery. Development of alloimmunization or antibodies to GPIIb/IIIa limits the usefulness of platelet transfusion; so this should be used only when serious bleeding occurs or is likely. DDAVP does not prevent bleeding with this disorder. Although Glanzmann’s thrombasthenia is a rare disorder, the understanding of its molecular basis has led to advances in antiplatelet therapy. Antibody inhibitors of the GPIIb/IIIa receptor are now used as antiplatelet agents and are discussed in a subsequent section.

Bernard–Soulier Disease (Syndrome) Bernard–Soulier disease (syndrome) results from congenital absence of platelet GPIb/IX, the receptor for vWF (72–75). This is a rare disorder, with only approximately 100 reported cases. The pattern of inheritance is usually autosomal recessive, although an autosomal dominant form has been described. These patients have a similar clinical presentation to that of Glanzmann’s thrombasthenia but have thrombocytopenia and large platelets (19). The thrombocytopenia can be as low as 20,000/mL. Because the interaction with vWF is affected, platelets do not aggregate in high shear conditions, such as with arterial injury. Platelet aggregometry reveals agglutination in the presence of ADP, collagen, and epinephrine but not to ristocetin. Aggregation response to thrombin is dose dependent. Treatment principles using oral contraceptives, antifibrinolytic agents, and platelet transfusion are as for Glanzmann’s thrombasthenia. Similarly, DDAVP is not considered effective.

ACQUIRED DISORDERS OF HEMOSTASIS Disseminated Intravascular Coagulation DIC is a hemorrhagic and thrombotic disorder that is triggered by a variety of underlying illnesses, and results in generation of tissue factor with consequent activation of coagulation. Excess thrombin generation and fibrinolysis characterize the disorder. Microvascular thrombosis occurs and can exacerbate underlying tissue and organ injury (76). In surgical patients, multiple clinical settings are associated with DIC and intraoperative coagulopathy. Severe bacterial infections with septicemia and endotoxemia, particularly from gram-negative enteric organisms, can trigger DIC. Gram-positive bacterial infections also can be etiologic. Massive tissue trauma, especially when associated with shock, can flood the circulation with thromboplastic and procoagulant substances and lead to acute consumption of hemostatic elements sufficient to incite bleeding. Localized trauma in the form of brain injury (usually severe and penetrating) and long bone fractures can trigger DIC by similar mechanisms. Malignancy can be associated with acute or chronic DIC. An association between DIC and aortic aneurysms has been well documented (77–82). In one series, 40% of patients with aortic aneurysms had elevated fibrin split products, but only 4% had significant bleeding and laboratory evidence of DIC. The clinician must be careful to look for clinical or laboratory signs of DIC prior to surgical repair to avoid excessive bleeding. The initiation of localized or generalized DIC has been thought

to be caused by activation of tissue factor pathway by the large amount of tissue factor in the atherosclerotic plaque and by loss of clotting factors into the large clot present in many aneurysms. Coagulation defects that are found prior to surgical repair of the aortic aneurysm should be corrected by appropriate replacement therapy and continuous infusion of heparin (83,84). A major transfusion reaction can cause DIC and should be suspected when sudden intraoperative bleeding occurs in the absence of a surgical source during blood transfusion. This can occur with the infusion of as little as 25 mL of mismatched blood. The clinical manifestations of shaking chills, fever, and back pain can be obscured by general anesthesia. Hypotension, diffuse bleeding, and darkening of the urine may be the only clues of intraoperative transfusion reaction. Treatment is directed at (i) stopping transfusion, (ii) restoring normal blood pressure and volume with crystalloid and appropriate pharmacologic support, (iii) attaining alkalinization with sodium bicarbonate, and (iv) administering mannitol to protect against renal tubular necrosis. Fortunately the DIC that attends a major transfusion reaction is transient and usually requires no treatment once the causative agent has been stopped. The laboratory diagnosis of DIC is demonstrated by the evidence of platelet and fibrinogen consumption as well as fibrinolysis. Fibrinogen levels can, however, be normal in up to 57% of patients with DIC (76,85). The prothrombin time (PT) and thrombin times are elevated in DIC. The aPTT is variable depending on the level of factor VIII activation. Elevated levels of fibrinopeptide A indicate conversion of fibrinogen to fibrin. Elevated prothrombin fragment F1.2 indicates thrombin generation from the action of factor Xa on prothrombin. D-Dimer is generated by the lysis of cross-linked fibrin and forms the basis of a sensitive laboratory test (86). Elevation of D-dimer is typically seen in DIC but can occur in other conditions where there is physiologic fibrinolysis. The treatment of all forms of DIC occurring intraoperatively is aimed primarily at supporting normal blood volume and pressure and expeditious removal of the stimulus for DIC. Specific therapies directed against DIC, such as heparinization, have no place in an acutely bleeding patient and are contraindicated in this setting. Heparin may be used in conditions where DIC is not associated with bleeding, such as sepsis or chronic DIC with an intact aortic aneurysm. Likewise, antifibrinolytic agents are not advised, because a degree of fibrinolysis protects against occlusive thrombosis of capillaries and prevents organ ischemia. Most authorities believe that EACA should not be used for DIC unless the patient is heparinized. In a patient with DIC undergoing operation, control of bleeding must, by necessity, be affected by infusion of fresh frozen plasma (FFP), cryoprecipitate, and platelets. The fear of ‘‘fueling the fire’’ and making the process worse has been overemphasized in the past. Component therapy can be lifesaving in this difficult clinical circumstance.

ACQUIRED DISORDERS OF PLATELET FUNCTION Of the long list of substances that have been shown to inhibit platelet function (Table 4), only aspirin has been clearly documented to increase the clinical risk of bleeding. Aspirin irreversibly inactivates cyclooxygenase, thereby preventing the production of thromboxane A2, from arachidonic acid (6–8). One 80 to 100 mg dose of aspirin can totally inhibit thromboxane production for the 10-day lifespan of the platelet (87).

Chapter 7:

Table 4 Acquired Platelet Dysfunction Associated with medication

Associated with medical conditions

Aspirin NSAIDs Cephalosporin antibiotics

Chronic renal failure Cardiopulmonary bypass Disseminated intravascular coagulation Chronic hepatic disease Multiple myeloma Collagen vascular diseases, particularly SLE Chronic myeloproliferative disorders Myelodysplastic syndromes

Penicillins Thrombolytic agents Dextran Prostacyclin (iloprost) b-Blockers Calcium channel blockers nifedipine, verapamil, diltiazem Nitroprusside Nitroglycerin Quinidine Tricyclic antidepressants or antipsychotics Antihistamines Eicosapentaenoic acid (o-3 fatty acids) Ticlopidine

Abbreviations: NSAIDs, nonsteroidal anti-inflammatory drugs; SLE, systemic lupus erythematosus. Source: From Ref. 15.

The true impact of aspirin on intraoperative bleeding is difficult to determine. Several trials have shown an increased amount of surgical bleeding in aspirin-treated patients undergoing coronary artery bypass grafting (88–90), but other studies in this clinical setting have shown no increased risk of bleeding (91,92). Results of the Physician’s Health Study on the efficacy of aspirin for primary prevention of myocardial infarction showed an increased risk of bleeding episodes compared to subjects taking placebo (27% vs. 20%) (93). The ubiquitous use of aspirin is reflected in a study that reported that approximately one half of patients undergoing unexpected surgery had taken aspirin within the previous 72 hours (94). In this study, however, there was no increased risk of bleeding or increased use of blood transfusions. However, aspirin can increase bleeding in surgical patients who have other hemostatic problems such as those induced by cardiopulmonary bypass and anticoagulant (e.g., heparin and warfarin) use, and should be used with caution in these settings. Although other nonsteroidal anti-inflammatory drugs inhibit platelet function, they do so reversibly and have not been shown to cause clinically important bleeding. The various penicillins contain a b-lactam ring and a unique side chain. Most penicillins induce an increase in bleeding time in normal volunteers (95,96). Penicillin decreases both platelet secretion and aggregation and ristocetin-induced platelet agglutination. Tests of platelet aggregation are abnormal in 50% to 75% of individuals taking carbenicillin, penicillin G, ticarcillin, ampicillin, nafcillin, and azlocillin, whereas patients taking piperacillin, azlocillin, apalclillin, or mezlocillin demonstrate abnormal aggregation from 25% to 50% of patients (96–99). Penicillins may impair the interaction of agonists (ADP and epinephrine) and vWf with their platelet membrane receptors (100). Penicillins probably inhibit platelet function by binding to one or more membrane receptors necessary for adhesion and aggregation (101). Laboratory tests of platelet function as used by the clinician are the bleeding time and platelet-aggregation

Hemostasis and Thrombosis in the Surgical Patient

165

studies. Platelet aggregometry measures the change in optical density over time in a sample of platelet-rich plasma to which an agonist of platelet aggregation has been added. The optical density decreases as the platelets in suspension cluster into aggregates. Although most acquired disorders of platelet function are associated with abnormal platelet aggregometry, the clinical usefulness of these studies is limited (70). Normal criteria are specific only for individual laboratories (102). Furthermore, abnormalities in platelet aggregometry assays have not always correlated with risk of bleeding (103). Measurement of the forearm template bleeding time is probably the most commonly used laboratory measure of platelet function. The test is performed by making a standard skin incision on the medial aspect of the forearm using a template blade, blotting the incision every 30 seconds, and measuring the time until bleeding stops. While antiplatelet agents generally prolong the bleeding time, a review of the literature shows no clear evidence that a prolonged bleeding time predicts excessive bleeding during surgery (104,105). Bleeding is a serious complication of uremia. In the predialysis era, bleeding was a cause of morbidity in approximately 50% of patients and death in approximately 30% of patients (106,107). Although 90% of patients with renal failure and gastrointestinal hemorrhage have an identifiable source of bleeding, abnormalities with platelet function contribute to the incidence and magnitude of hemorrhage (108). Defects in platelet adhesion, aggregation, and procoagulant activity have been reported in uremia. One defect proposed is that of platelet GPIb–IX complex that is necessary for binding with vWF (109–111). A second platelet defect associated with uremia is platelet activation. Uremic platelets show reduced binding to fibrinogen, aggregation, and secretion in response to agonists. Several of the biochemical abnormalities proposed include a decrease in the rise in cytoplasmic free calcium levels, reduced release of arachidonic acid from membrane phospholipids, decreased conversion of arachidonic acid to thromboxane A2, and a decrease in platelet dense granule content of ADP and serotonin as well as an increase in intracellular cAMP (112–116). Other factors that contribute to hemorrhage in uremia include thrombocytopenia, anemia, and concurrent medications such as aspirin (109,117). Platelet function abnormalities can be improved following dialysis (109,118). DDAVP has been used to correct qualitative platelet dysfunction due to uremia and other causes (109,119).

BLEEDING IN THE SURGICAL PATIENT Preoperative Assessment The most important element in the preoperative evaluation of risk of bleeding is obtaining the patient’s history and physical examination. The history should elicit whether the patient bleeds unusually in response to minor trauma or spontaneously in the absence of trauma (see accompanying box). The responses to major and minor surgery and to dental extractions are particularly helpful. A patient who has recently undergone surgery without bleeding complications has had a far better ‘‘stress test’’ of hemostasis than any laboratory can provide. The manifestations of abnormal bleeding can provide clues to the nature of the underlying hemostatic defect. Easy bruisability, ecchymoses, petechial hemorrhages, nosebleeds, and oral mucosal and gingival bleeding generally indicate thrombocytopenia or a qualitative platelet disorder, whereas joint hemorrhages, deep muscular hematomas, and retroperitoneal bleeding are

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usually signs of a coagulation defect (congenital factor deficiency or anticoagulant use) (64,65,120). These distinctions are not specific, however, and the presence of any of these abnormalities should prompt a more thorough laboratory evaluation for an underlying hemostatic deficit. The family history is relevant and a pedigree chart of a familial bleeding tendency may provide important clues. The family history is not always positive with the ‘‘inherited’’ clotting disorders. Up to 30% of new cases of hemophilia A are not associated with a positive family history and are thought to represent spontaneous mutation (64,65,120). The routine use of preoperative laboratory screening tests is unnecessary when an underlying coagulation disorder is not clinically suspected. The inability of the bleeding time to predict surgical bleeding has been described previously. Similarly, preoperative assessment of the PT and the aPTT in the absence of a clinically suspected clotting disorder has been shown not to predict surgical bleeding complications (121–123). When evaluating a patient for a major operation that has greater potential to impair clotting mechanisms, such as coronary artery bypass or major vascular reconstruction, or where the consequences of excessive bleeding, are particularly hazardous, such as with neurologic surgery or tissue flaps, it is reasonable to routinely perform basic coagulation tests such as a platelet count, PT, and partial thromboplastin time. This recommendation should not be viewed as a substitute for a proper clinical assessment (Box 1).

Intraoperative and Postoperative Bleeding The most common cause of significant intraoperative bleeding is inadequate surgical hemostasis, the so-called ‘‘silk deficiency.’’ There are no pharmacologic or blood bank substitutes for a careful dissection and attention to technical detail. Even what seems like trivial bleeding from skin edges and subcutaneous tissue can add up, and such bleeding can account for up to 100 to 200 mL of blood loss if unattended (124). Dissection using electrocautery rather than a scalpel has been shown to reduce blood loss (125,126). Intraoperative disorders of hemostasis can be acquired for a number of reasons. Coagulopathy in vascular disorders and trauma has been shown to be related more to hypotension and hypoperfusion than to dilutional factors (127). Tissue hypoxia can cause release of plasminogen activators, thereby stimulating fibrinolysis. Hypothermia may be another contributing factor, particularly in the traumatized patient. Dilutional thrombocytopenia may occur in the massively transfused patient, particularly following 20 or more units of banked or cell salvage blood (128). In a prospective, randomized clinical trial evaluating the efficacy of prophylactic transfusion of either 6 U of platelets or 2 U of FFP given after transfusion of every 12 U of blood, there was no difference in platelet counts or microvascular bleeding (18% in platelet group, 19% in FFP group) between groups, leading the authors to conclude that prophylactic platelet transfusion is unnecessary in the massively transfused patient (129). Of the six patients who developed microvascular bleeding, however, four subsequently required platelet transfusions to correct persistent thrombocytopenia and oozing. This study also illustrates that measured platelet counts are significantly higher following massive transfusion than would be predicted on the basis of dilution alone, indicating that endogenous release of platelets, presumably from the spleen, is responsible for continued release of platelets into the circulation in such patients. Because there was not a control group that did not receive prophylactic

Box 1 Suggested Questions to Determine Bleeding History

Hemostatic Response to Surgery and Trauma 1. What operations have you had, including minor ones, such as tonsillectomy, circumcision, or biopsies? Was bleeding after surgery hard to stop? Have you ever developed unusual bruising in the skin around an area of surgery? 2. Have you ever required a blood transfusion? 3. Have you ever bled for a long time or developed a swollen tongue or mouth after cutting or biting your tongue, cheek or lip? What was the longest time it took to stop bleeding from cuts or scrapes? Has bleeding from a cut or scrape ever restarted after stopping completely? 4. How many times have you had teeth pulled and what was the longest time that you bled afterward? Has bleeding ever restarted the day after extraction?

Spontaneous Bleeding 1. Do you develop bruises larger than a silver dollar without remembering when or how you injured yourself? If so, how big was the largest of these bruises? 2. Do you ever have nosebleeds? 3. Do your gums bleed easily? 4. Do you ever have abnormally heavy menstrual periods or spotting between periods? 5. Do you have blood in your urine or stool? Do you ever have black, tarry stools? 6. Have you ever had bleeding into joints or muscles?

Medication History 1. What medication, including aspirin or any other pills or powders for headaches, colds, menstrual cramps, arthritis, joint pains, back aches, or other pains, have you taken within the last week? 2. Do you take medicine to thin the blood or to prevent blood clots? 3. Have you had a medical problem within the past five years requiring a doctor’s care? If so, what is its nature?

Family History 1. Are there any bleeders in the family? 2. Has any blood relative had a problem with unusual bleeding or bruising after surgery? Were blood transfusions required to control this bleeding?

FFP transfusion, the issue of prophylactic repletion of labile clotting factors was not addressed. Prophylactic treatment with DDAVP did not decrease blood loss and transfusion requirements in a randomized study in patients undergoing aortic surgery (130). However, DDAVP can be useful in patients undergoing complex cardiac operations with prolonged cardiopulmonary bypass (131). Recommendations for platelet and labile clotting factor replacement during surgery are best guided by specific laboratory measurement of coagulation deficiency rather than an arbitrary formula (132). The time delay from when the intraoperative microvascular bleeding is first noticed until laboratory measurements to document the particular coagulation disorder are complete can be problematic. If the surgeon’s clinical judgment is confirmed by the laboratory test, additional blood loss and factor depletion has occurred before the appropriate factor replacement products can be made available. A potential solution to this problem would involve improved near-site monitoring of coagulation function. Despite appropriate factor replacement for acquired and congenital coagulation disorders, nonsurgical bleeding

Chapter 7:

can persist and be difficult to treat. A variety of commercially available topical hemostatic agents have been used in this situation. These topical agents are generally derived from bovine collagen or gelatin, or oxidized cellulose. Although these products create a mechanical template on which clot can form, they are limited by a lack of any inherent coagulation mechanism. Fibrin sealant is a potential alternative topical hemostatic agent. Fibrin sealant mimics the final step in the coagulation cascade by combining thrombin and fibrinogen and factor XIII (generally in liquid form) and can be applied directly to a surgical wound or a vascular anastomosis (133,134). Fibrin sealant can be made in the operating room by combining equal volumes of bovine thrombin (with calcium chloride) and cryoprecipitated plasma using separate syringes for each. Commercially prepared fibrin sealant is made of purified, virally inactivated human thrombin and fibrinogen (in some products fibrinolytic inhibitors have been added), is available in Europe, and is undergoing clinical trials in the United States (135–137).

CONGENITAL DISORDERS OF HYPERCOAGULABILITY Resistance to Activated Protein C Resistance to activated protein C is the most common inherited hypercoagulable disorder, affecting approximately 3% to 5% of populations of Western European origin. It is inherited in an autosomal dominant fashion and is due to a single point mutation in the gene coding for factor V, resulting in an Arg506 to Gln amino acid substitution, rendering it ‘‘resistant’’ to inactivation by protein C. Resistance to activated protein C is common in patient who have venous thrombosis, with a prevalence in this group of 20% to 60% (50,51,138–140). Activated protein C resistance is the most common abnormality associated with deep venous thrombosis during pregnancy, and the diagnosis should be diligently sought in this setting. This disorder is also commonly found among patients with recurrent venous thromboembolism (141). The diagnosis can be made using either a plasmabased clotting assay or a DNA assay. The clotting assay is an aPTT with a mixture of patient plasma and factor V–deficient plasma in the presence and absence of added activated protein C. When the added activated protein C does not prolong the aPTT adequately, resistance is suggested. In the DNA-based assay, DNA is extracted from the patient’s blood and amplified using the polymerase chain reaction. A restriction enzyme that recognizes only the normal factor V DNA is added. Normal and abnormal genotypes can then be determined by the examination of the DNA electrophoretic bands. The effect of anticoagulants on the results of hypercoagulability testing can present a point of confusion. The potential for interference with laboratory assays because of therapeutic anticoagulation is generally only an issue for protein C and protein S, the levels of which are decreased by warfarin, because they are vitamin K–dependent proteins. Because a DNA assay is available for resistance to activated protein C, anticoagulation does not interfere with the results. Generally, all factors can be tested for in the presence of heparin, although AT-III levels may be decreased (Fig. 5). The role of resistance to activated protein C in arterial thrombosis has not been determined. In a cohort study of men in the Physician’s Health Study, resistance to activated protein C was found to be a risk factor for venous

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167

Figure 5 Laboratory testing for hypercoagulability. AT-III may be decreased in vivo in patients receiving heparin. Test of APC resistance can be performed if heparin is removed; test plasma should be mixed with factor V–deficient plasma. In an assay for lupus anticoagulant, heparin removed or heparin-insensitive assay should be used. Test is performed with 1:1 mixture of patient’s plasma and normal plasma. Abbreviations: ACA, anticardiolipin antibody; APC, activated protein C; AT-III, antithrombin III. Source: From Ref. 142.

thrombosis but not for myocardial infarction or stroke (143). Another study, however, suggested that resistance to activated protein C might be a risk factor for failure of infrainguinal bypass grafts (144).

Protein S Deficiency Protein S, the vitamin K–dependent cofactor of activated protein C, is also associated with thromboembolic disease when deficiency states exist. The deficiency is generally inherited as an autosomal dominant trait; however, several point mutations have been identified (41,50,145). The clinical manifestations are similar to those seen with deficiency of protein C and AT-III, primarily venous thrombotic events. Arterial thrombotic events can also occur but less commonly than venous thrombosis. About 60% of protein S circulates in inactive form bound to C4b-binding protein (146). The remaining 40% is free and is the active form. Increased plasma levels of C4bbinding protein decrease the levels of free protein S and can influence thrombotic events (147). Because C4b-binding protein is an acute phase reactant that increases during inflammatory states and the postoperative period, relative decreases in free protein S may result, predisposing to thrombotic complications. Levels of total protein S in deficient heterozygotes range from 30% to 65% and levels of free protein S range from 15% to 50% of normal (147). Inherited deficiency states characterized by normal total protein S antigen level, normal or reduced free protein S levels, and diminished protein S activity have also been reported (148,149). Patients with protein S deficiency who have sustained thromboembolic episodes are best managed with lifelong anticoagulation.

Protein C Deficiency Protein C is a vitamin K–dependent enzyme that when activated inhibits factors Va and VIIIa. Protein C deficiency is inherited as an autosomal dominant trait with heterozygotes suffering recurrent venous thromboembolism. The initial thrombotic episode occurs spontaneously in approximately 70% of affected individuals. As with protein S deficiency, the relationship to arterial thrombotic events is unknown.

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Homozygous infants can develop neonatal purpura fulminans. Interestingly, the heterozygote parents infrequently have thrombotic events, suggesting that other factors are involved, which modulate phenotypic expression. As with protein S deficiency states, a number of genetic point mutations have been recognized, which might account for the clinical heterogeneity of this disorder (50,51,150). Laboratory testing is done using a functional assay that measures the ability of activated protein C to inhibit factors Va and VIIIa in a modified aPTT using protein C–deficient plasma that provides the other factors (50,51,142). As with protein S, protein C is a vitamin K–dependent protein, so testing should not be performed while the patient is receiving warfarin therapy. These assays are not influenced by heparin (Fig. 5). Warfarin-induced skin necrosis has occurred in some patients with protein C or protein S deficiency. The clinical and pathologic manifestations are similar to those seen with neonatal purpura fulminans caused by severe protein C deficiency, with skin lesions on the extremities, breasts, trunk, and penis occurring during the first few days of warfarin therapy. The mechanism is thought to be due to a transient hypercoagulable state in which protein C levels decrease faster than factor X levels, as well as a greater effect on hemostatic function from protein C reduction than from factor VII reduction. Because only about one-third of patients with warfarin-induced skin necrosis have an underlying inherited deficiency of protein C (151), heparin is generally administered with warfarin until there is an increase in the PT. Patients with protein C deficiency who have sustained thromboembolism episodes are best managed with lifelong anticoagulation.

AT-III Deficiency Congenital deficiency of AT-III, first described in 1965 (152), has a prevalence of one per 2000 to 5000 and is one of the uncommon hypercoagulable syndromes. Deficiency of AT-III is inherited as an autosomal dominant trait and clinically is characterized by venous thrombosis occurring at an early age. Two-thirds of affected patients have a venous thrombosis by age 35. In the most common form of AT-III deficiency (type I), both the functional and the antigenic levels of AT-III are reduced, resulting from any one of a number of identified mutations (52,53,153,154). Two other types have been identified where the antigenic level of AT-III is normal, but the functional activity is reduced, either because of a defect in the thrombin-binding site (type II) or in the heparin-binding site (type III). Patients with type III AT-III deficiency do not appear to be at increased thrombotic risk unless they are homozygous (142). Patients with AT-III deficiency who have sustained thrombotic episodes are generally treated with lifelong warfarin anticoagulation. Although these patients are often considered to be ‘‘heparin resistant,’’ heparin anticoagulation can be achieved when necessary to acutely treat a thrombotic event. More importantly, AT-III deficiency is the only inherited hypercoagulable disorder for which replacement therapy, comprising concentrates of purified human AT-III, has been approved by the FDA. The concentrates are pasteurized for viral inactivation (115,155). Perioperative replacement therapy with AT-III concentrate is recommended, because 17% to 24% of AT-III–deficient patients undergoing surgery without receiving concentrates develop deep venous thrombosis, even when other forms of prophylaxis are used (52,53,156,157). Despite the commercial availability of the concentrates in the United States since 1990, clinical experience with their perioperative use in

conjunction with anticoagulation has been limited. Successful perioperative use of AT-III concentrates for venous surgery in deficient patients has been described (158).

Hyperhomocysteinemia Homocysteine is an amino acid formed in the metabolism of methionine. Elevated plasma levels of homocysteine can result when there is a deficiency in either one of two enzymes that are involved in cysteine metabolism. A deficiency of cystathione b-synthase prevents adequate transsulfuration of homocysteine. A deficiency of methylenetetrahydrofolate reductase (MTHFR) prevents remethylation of homocysteine to methionine. A number of studies have linked elevated plasma homocysteine levels to an increased risk of premature atherosclerosis and thrombosis (159–166). In the past, much ambiguity has resulted when studies using plasma homocysteine levels as an end point have shown conflicting results regarding the association of homocysteine levels and atherosclerotic risk (167). Recent work has identified a common point mutation in the gene coding for the MTHFR enzyme rendering it thermolabile, resulting in elevated plasma homocysteine levels (168–170). Both homozygotes and heterozygotes have diminished enzyme activity compared to normal, at 30% and 65%, respectively (171). The genomic region of DNA can be amplified using the polymerase chain reaction and then subjected to restriction enzyme analysis, so that genotype can be definitively determined. Populations of Northern European descent have a high prevalence of this mutation, with approximately 10% homozygosity and 40% heterozygosity. It appears that dietary supplementation with folic acid can reduce plasma homocysteine levels in both heterozygotes and homozygotes, which promises a simple and effective therapy for this disorder (170,171). Future studies using these molecular techniques should yield additional insight regarding the role of hyperhomocysteinemia in atherosclerosis and thrombosis, as well as for the potential role of folic acid as a therapeutic agent.

ACQUIRED HYPERCOAGULABLE DISORDERS Antiphospholipid Antibody Syndrome Lupus anticoagulants are antiphospholipid antibodies that have in vitro anticoagulant activity, yet are clinically associated with arterial and venous thrombosis. The constellation of any one of the following clinical manifestations (arterial or venous thrombosis, recurrent abortion, or thrombocytopenia) in the presence of antiphospholid antibodies has been described as the antiphospholipid syndrome (172). When the syndrome occurs in the absence of lupus or other connective tissue disorders, it is referred to as primary antiphospholipid syndrome, and secondary antiphospholipid antibody syndrome when in the presence of lupus or other connective tissue disorders. Drugs such as procainamide, hydralazine, chlorpromazine, quinidine, isoniazid, and methyldopa can also cause antiphospholipid antibodies, with procainamide being most common in the United States (172). When the condition is drug associated, however, there does not appear to be a significant thrombotic risk. The pathogenesis of thrombosis with antiphospholipid antibodies is not completely understood. Proposed mechanisms include platelet activation, inhibition of prostacyclin production, vascular injury, and interference with protein C (172). Alternatively, it is possible that antiphospholipid antibodies are a marker for some other process that is more closely linked with thrombosis. The almost equal tendency for arterial and venous thrombosis with

Chapter 7:

antiphospholipid syndrome distinguishes this disorder from the inherited hypercoagulable conditions where venous thrombosis predominates. Several enzyme-linked immunosorbent assays (ELISAs) for immunoglobulin G (IgG) and immunoglobulin M (IgM) antiphospholipid antibodies are now commercially available and have been standardized (173). The diagnosis of antiphospholipid antibody syndrome can only be confirmed after appropriate laboratory testing on two separate occasions separated by at least 12 weeks (142,174,175). Patients who develop thrombotic complications are generally treated with long-term anticoagulation. Treatment regimens when associated with cerebrovascular thrombosis can also include antiplatelet agents and steroids, although this has not been standardized (172).

HIT (With or Without Thrombosis) Heparin-induced thrombocytopenia (HIT) with or without thrombosis, first recognized in 1973 (176), is associated with morbidity and mortality especially in patients with atherosclerosis, sepsis, and recent surgery (177–179). Recent studies have documented that patients with HIT have antibodies that are directed against complexes of heparin and the heparin-binding cationic protein, PF4, which is secreted from platelet 8 granules and then is bound to platelet and endothelial cell surfaces (180,181). The major factor in the development of HIT (with or without thrombosis) is the formation of antibodies, usually of IgG isotope against the heparin/PF4 complex, which may be localized to the platelet FcgIIa membrane receptor or to other phospholipid surfaces such as heparin sulfates on the endothelial cells. Binding of these antibodies to the complex of heparin and PF4 allows the Fc portion of the IgG molecule to activate platelets through the platelet FcgIIa, which can activate platelet and generate procoagulant membrane microparticles (Fig. 6) (180,181,183–185). Receptor expression can be elevated threefold to fivefold during sepsis or other acute illnesses and returns to normal as the inflammatory process resolves (186). Patients with high levels of receptor expression appear to have the most severe forms of thrombosis with HIT (186). This

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process then initiates thrombosis, which is characteristically rich in platelets, hence the name ‘‘white clot syndrome.’’ Similar to heparin, thrombocytopenia induced from sulfonamides and quinidine cause thrombocytopenia by interacting with the GPIb/IIa and GPIIb/IIIa platelet membrane receptors (180,181,184,187,188). The standard diagnostic test for HIT in most laboratories is the platelet-aggregation test. Although this test is simple and quickly performed, its sensitivity has been questioned. Depending on the reactivity to donor platelets and heparin concentration used in the aggregation test, the sensitivity can range from 29% to 88% (184,189). A more sensitive test appears to be the 14C serotonin release assay (184,190,191). In this test, the release of 14C serotonin from the platelets is measured, rather than the ability of platelets to aggregate, because immune complexes can induce release without causing aggregation. Several laboratories have now developed ELISAs that use heparin/PF4 to detect IgG or IgM antibodies in sera from patients suspected of having HIT (184,192,193). The ELISA for the detection of antiheparin/PF4 antibodies appears to be more sensitive than the 14C serotonin release assay and the platelet aggregation test and has been used clinically to document heparininduced antibodies (184,185). The clinical management of HIT poses many dilemmas, particularly when continued anticoagulation is necessary or desired. Although heparin must be discontinued, few alternatives are readily available. Ideal agents are thrombin-specific inhibitors such as argatroban, hirudin, leprudin, or its analogs. Hirudin is a 65 amino acid polypeptide produced by the salivary gland of the medicinal leech Hirudo medicinalis. Hirudin is the most potent naturally occurring specific inhibitor of thrombin (194–197). Hirudin binds to thrombin at both the N-terminal domain and the C-terminal domain. Natural hirudin, synthetic analogue hirulog, and the recombinant hirudin all contain both of these binding sites. The major indication for leprudin therapy is for the treatment of patients with acute HIT (194–197). Argatroban has also been used successfully as an alternate anticoagulant in patients with HIT. Lowmolecular-weight heparin (LMWH) is now available and

Figure 6 Proposed mechanisms by which heparininduced thrombocytopenia with or without thrombosis occurs. Platelets are activated by thrombin or other agonists and release PF4 from their a-granules. PF4 complexes with heparin on the surface of the platelet. The complex is immunogenic and induces the formation of both IgC and IgM antibodies. The Fc portion of IgG antibodies binds to FcII receptors on platelets and induces further activation and throbocytopenia. FcII receptors are increased by IL-6 and are therefore upregulated in patients with ongoing inflammation. PF4 released from platelets can also bind to heparin sulfate on endothelial cells. IgG or IgM antibodies directed against this complex may cause endothelial cell damage and promote venous or arterial thrombosis. Abbreviations: PF4, platelet factor 4; Ig, immunoglobulin; IL, interleukin. Source: From Ref. 182.

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seems to be less immunogenic than unfractionated heparin. However, 90% of patients with HIT have antibodies that cross-react with LMWH (196,198), making this a poor alternative when continued anticoagulation is necessary. Heparinoid has been used successfully on a compassionate basis to treat HIT (199). Success has also been reported with the use of ancrod, a rapid-acting defibrinating agent. In patients who have venous thromboembolism as a complication of heparin therapy, placement of a Greenfield filter, thrombolytic therapy, and warfarin treatment is useful. In the absence of alternative parenteral anticoagulants, heparin can be considered for use in the HIT patient but only after repeat test results for the antibody are negative. Heparin has been given successfully to patients with a history of HIT and thrombosis who required cardiac bypass (200). In these patients, the interval between the initial and second exposure has usually been one to two months, and heparin has been administered only during surgery, either alone or in the presence of antiplatelet agents such as aspirin. In those situations where heparin absolutely cannot be used, argatroban or heparinoid should be considered under compassionate use.

Malignancy The incidence of thrombosis in patients with malignancy generally ranges between 5% and 15%, but may be as high as 50% with some tumors, notably pancreatic carcinoma (201–206). The highest incidence of thrombotic manifestations is found in patients with acute promyelocytic leukemia, myeloproliferative disorders, primary brain tumors, and mucin-secreting adenocarcinomas of the pancreas, gastrointestinal tract, lung, and ovary. Episodes of thrombosis, particularly migratory superficial thrombophlebitis, may antedate by months the clinical diagnosis of cancer in some patients and may be the first indication of an underlying malignancy. In addition to venous thrombosis, arterial thromboembolism from nonbacterial thrombotic endocarditis may occur. Multiple coagulation abnormalities predisposing to thrombosis have been identified in patients with malignancy. These include thrombocytosis, shortening of the PT and aPTTs, elevation of plasma coagulation factors (fibrinogen, factors V, VIII, IX, and XI), and fibrinogen–fibrin degradation products, shortened platelet survival, decreased AT-III levels, and increased PAI-1 activity. Many of these changes reflect generalized activation of the clotting system resulting in chronic, partially compensated DIC. In addition, macrophages and endothelial cells stimulated by tumor cytokines can express tissue factor. Cytotoxic chemotherapy can also cause the release of thromboplastic substances from tumor cells. In some cases, the chemotherapeutic agents themselves may contribute to thrombosis (201–206).

ANTITHROMBOTIC THERAPY General Considerations Because of its dependency on coagulation reactions resulting in fibrin formation, venous thrombosis is best treated with the anticoagulants heparin and warfarin. Heparin, heparin-like compounds, and warfarin, given in small doses, prevent the onset of venous thrombosis and can therefore be used successfully as prophylaxis of postoperative deep venous thrombosis in high-risk surgical patients. Agents that are pure inhibitors of platelet function, such as aspirin, are much less successful in prophylaxis of

postoperative venous thrombosis. Methods that prevent venous pooling and stasis of blood in the lower extremities are also beneficial in preventing deep vein thrombosis; augmentation of venous emptying by application of intermittent pneumatic compression boots is as effective as anticoagulants (207–211). In addition to preventing the onset of venous thrombosis, anticoagulants inhibit the growth, propagation, and embolization of established thrombi (207–212). In doing so, these agents are the mainstay of therapy for patients with active venous thrombosis in those who are at risk for pulmonary embolism. Aspirin and other antiplatelet agents are not effective in the treatment of active venous thrombosis. Intracardiac thromboemboli are also responsive to anticoagulant therapy. These thrombi are fibrin rich and form under the relatively static flow conditions of dilated chambers, obstructed valve orifices, areas of low shear associated with prosthetic valves, ventricular aneurysm formation, and poor pumping action with impaired chamber emptying secondary to cardiac failure of dysrhythmia. Acute treatment with heparin and long-term treatment with warfarin reduce the incidence of symptomatic emboli stemming from intracardiac thrombi. Antiplatelet agents are effective in preventing thrombogenesis in areas of high shear and disturbed flow in the arterial circulation; this most commonly involves the surface irregularity or stenoses caused by atherosclerotic plaque. Aspirin is the antiplatelet agent in widest use and has been found to be effective in preventing myocardial infarction in patients with unstable angina and stable coronary disease (213); stroke and transient ischemic attacks in patients with cerebral vascular arteriosclerosis, or after carotid endarterectomy; vein graft thrombosis after coronary artery bypass; and prosthetic bypass thrombosis in patients with femoropopliteal reconstruction. Dipyridamole, a pyrimiopyrimidine compound with vasodilator properties, was introduced for the treatment of angina in 1961. The mechanism of action for dipyridamole is not clear. It inhibits phosphodiesterase and could increase platelet cAMP to levels that could inhibit platelet aggregation (214–216). Dypridiamole has often been combined with aspirin and had generally been found to be ineffective in rigorous clinical trials. There is no indication to use this drug, alone or in combination with aspirin, to prevent arterial thrombosis. Although aspirin retards platelet thrombogenesis on the surface of atherosclerotic plaque, there is no evidence that it prevents plaque formation. Ticlopidine and clopidogrel are structurally related thienopyridine derivatives that inhibit ADP-induced platelet aggregation (217–224). After oral administration both drugs inhibit ADP-induced platelet aggregation, even at high concentrations of agonist (217–231). Both drugs are effective in preventing platelet-dependent arterial thromboembolism. In a randomized secondary prevention trial clopidogel versus aspirin in patients at risk of ischemic events (CAPRIE) (232,233), patients were enrolled with a recent history of myocardial infarction, ischemic stroke, or symptomatic peripheral vascular disease. After a mean follow-up of 1.9 years, aspirin decreased vascular outcome events by 5.83% and clopidogrel decreased ischemic events by 5.32% (relative risk reduction of 8.7%, P ¼ 0.043) (232). Fibrinolytic agents include streptokinase, recombinant t-PA, and urokinase; all act by accelerating the conversion of plasminogen to plasmin. These substances can be given systemically or regionally by means of selective infusion through an intra-arterial catheter, and have been found to

Chapter 7:

be most effective in treating patients with acute myocardial infarction. Clinical trials have demonstrated a reduction in infarct size, preservation of ventricular function, and a reduction in mortality. Clinical benefit has been noted less consistently in venous thromboembolism, acute stroke, arterial bypass graft, peripheral arterial bypass graft thrombosis, and peripheral arterial thrombosis. Because fibrinolytic agents dissolve hemostatic clots along with pathologic clots, they are associated with a much higher incidence of bleeding complications than anticoagulants.

THERAPEUTIC AGENTS Anticoagulants Heparin Heparin is a highly sulfated glycosaminoglycan that exhibits an anticoagulant effect through its interaction with AT-III, which then inhibits thrombin and the activated forms of factors XII, XI, X, and IX. The anticoagulant effect of heparin was first described in 1922 and so named because of its hepatic derivation (234). Mast cell synthesis of heparin results in many structurally diverse polysaccharide chains and variable degrees of sulfation (235). Commercially prepared heparin is a heterogeneous mixture of heparin chains and is obtained from porcine intestinal mucosa or bovine lung. Heparin is not absorbed orally and must be administered parenterally or subcutaneously. Heparin action is immediate following intravenous administration and is delayed 20 to 60 minutes after subcutaneous administration. Following intravenous administration, the average half-life is about 90 minutes and can range from 30 to 360 minutes. Clearance is primarily hepatic, with a small potion excreted intact by the kidneys. Recommended dosing uses an initial intravenous bolus (75 U/kg) to ensure rapid anticoagulation, followed by continuous intravenous infusion (10–25 U/kg/hr). Heparin does not cross the placenta and is considered the drug of choice for long-term anticoagulation during pregnancy. Monitoring of heparin administration is most commonly performed using the aPTT. For active thrombosis (venous or arterial), a range of 1.5 to 2.5 times the normal control value is considered therapeutic. Caution is advised when following therapeutic nomograms and algorithms because of the variability of heparin products and individual response. The aPTT should be checked every four to six hours until a steady state infusion dose can be determined. The most common complication of heparin use is bleeding, the incidence of which ranges from 1% to 7% with continuous infusion and from 8% to 14% with intermittent bolus. Heparin can be reversed using protamine sulfate. One milligram of protamine sulfate neutralizes 100 U of heparin. Another significant potential complication is HIT, with or without thrombosis, which was discussed in a previous section. Other complications include osteoporosis from prolonged heparin use and, rarely, allergic reactions.

Warfarin Warfarin is a vitamin K antagonist that exerts its anticoagulant effect through inhibition of synthesis of the vitamin K–dependent factors, prothrombin (II), VII, IX, and X. The name warfarin is an acronym for the patent holder, Wisconsin Alumni Research Foundation, and ‘‘arin’’ for the chemical structure of the 4-hydroxycoumarin ring. Warfarin inhibits the vitamin K–dependent ribosomal

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posttranslational modification of the precursor proteins of the affected clotting factors and proteins C and S. Under normal circumstances, 10 or more glutamic acid residues near the amino-terminus of each precursor protein must be carboxylated, resulting in the formation of the unique amino acid g-carboxyglutamate, which allows the clotting factor proteins to bind calcium during the coagulation cascade (Fig. 7) (235). Warfarin induces hepatic production of partially carboxylated and decarboxylated proteins. Prothrombin molecules with fewer than six g-carboxyglutamic acid residues have markedly reduced activity. Warfarin action is not immediate, because it has no effect on the existing circulating factors. Plasma warfarin is 98% to 99% protein bound to albumin. It is the remaining 1% to 2% free warfarin that exerts the anticoagulant effect. Metabolized warfarin is excreted in the bile, with a plasma half-life that ranges from 20 to 60 hours. Warfarin is administered orally, where it is more than 95% absorbed through the gastrointestinal tract. Dosage is generally initiated at 5 to 10 mg/day until a steady state is reached, at which time a lower dose can be maintained. Monitoring of warfarin therapy has presented problems because of the significant variability in activity of the numerous available thromboplastins available for PT measurement. This problem with nonstandardized thromboplastins is a particular issue in North America. So that warfarin dosage can be standardized in the presence of the many thromboplastins used in the PT, most laboratories report PTresults as the International Normalized Ratio (INR). The system is based on a standardized thromboplastin

Figure 7 Vitamin K metabolism and the mechanism of action of warfarin. Vitamin KH2 serves as a cofactor for a vitamin K–dependent carboxylase that converts glutamic acid residues in precursor coagulation factors to g-carboxyglutamic acid residues. In addition to vitamin KH2, molecular oxygen and carbon dioxide are required. Vitamin KH2 is oxidized to vitamin K epoxide, KO, which is then converted to vitamin K by vitamin K epoxide reductase. Vitamin K reductase reduces vitamin K to its reduced form, vitamin KH2. Warfarin inhibits vitamin K epoxide reductase and, possibly, vitamin K reductase. The decrease in vitamin KH2 limits g-carboxylation of the vitamin K–dependent proteins and interferes with their function. Source: From Ref. 236.

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preparation referred to as the World Health Organization primary international preparation of thromboplastin. This system has been accepted as an international standard for clinical use by most western countries. The INR is calculated as follows: INR ¼ (observed PT/control PT). ISI is the International Sensitivity Index and is a measure of the responsiveness of any given lot of a thromboplastin preparation to that of a standard thromboplastin. For most commercial thromboplastins used in North America, the ISI ranges from 2 to 2.8. The relationship between the PT ratio with different thromboplastins and the INR is illustrated with the nomogram in Fig. 8. The recommended therapeutic range of the INR for given clinical indications is listed in Table 5. Portable devices the size of a glucometer are available that can measure the PT and calculate the INR in seconds using a drop of whole blood. As with heparin, the major complication with warfarin is bleeding. The frequency of this complication can vary considerably and is likely related to the degree and duration of desired anticoagulation, underlying illness, concomitant medications, and patient compliance. The risk of major bleeding is generally in the range of 4% to 5% per treatment year, with major bleeding events occurring at 1% to 2% per year (235). Warfarin-induced skin necrosis can occur and is characterized by skin lesions similar to those of neonatal purpura fulminans. This condition is classically associated with homozygous protein C deficiency, as was previously discussed earlier in that section. Warfarin

Table 5 Effectiveness of Oral Anticoagulant Therapy Condition

Minimal effective

Recommended

a

INR Deep vein thrombosis Prevention Treatment Acute myocardial infarction Prevention of stroke Prevention of recurrence Reduction of mortality Atrial fibrillation Prevention of systemic embolism Cardiac valve replacement Tissue valves Mechanical valves Cerebral embolism Native valvular heart disease

1.5–2.5 2.0–2.3

2.0–3.0b 2.0–3.0

2.0 2.7–4.5 2.7–4.5

2.0–3.0 3.0–4.5b 3.0–4.5b

1.5–2.5

2.0–3.0b

2.0–2.3 1.9–3.6 Not evaluated Not evaluated

2.0–3.0 3.0–4.5

a

For thromboplastin with an ISI of 2.3 the INRs and the corresponding PT ratios follow: INR 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0. PT ratio 1.20, 1.35, 1.49, 1.61, 1.72, 1.83, 1.92, 2.01. b A lower range might be effective. Abbreviations: INR, International Normalized Ratio; PT, prothrombin time; ISI, International Sensitivity Index. Source: Adapted from Ref. 237.

crosses the placenta, where it can cause an embryopathy or fetal bleeding, and therefore should not be used during pregnancy.

Low-Molecular-Weight Heparin

Figure 8 Relation between the PT ratio and the INR for thromboplastin reagents over a range of ISI values. The example shown is for a PT ratio of 1.3 to 11.5 for a thromboplastin preparation with an ISI of 2.3. Abbreviations: INR, International Normalized Ratio; PT, prothrombin time; ISI, International Sensitivity Index. Source: From Ref. 237.

LMWH is produced by chemical or enzymatic depolymerization of heparin molecules and has a molecular weight of 3000 to 6000. Unlike heparin, neither LMWH nor heparinoid is fully reversed by protamine. The anticoagulant effect of LMWH is primarily directed against factor Xa. To neutralize thrombin, heparin must interact with and combine to both AT-III and thrombin (208–210,238). LMWH is unable to bind thrombin and AT-III simultaneously, and therefore cannot accelerate the inactivation of thrombin. The combination of LMWH and AT-III can, however, inactivate factor Xa. The LMWHs produce less prolongation of the aPTT than does standard heparin, because this clotting test depends more on the antithrombin effect than the antifactor Xa effect (238,239). There are several advantages of LMWH over conventional heparin. Bioavailability of LMWH is greater due to lack of binding of LMWH to plasma proteins and endothelial cells. Also, LMWH is not inactivated by P4, as is heparin. LMWH has a longer half-life and a more predictable dose response than heparin, allowing for more convenient outpatient treatment of venous thrombosis using a once- or twice-daily subcutaneous dosage. LMWH also appears to be less immunogenic than conventional heparin. In a recent prospective study of the incidence of HIT with unfractionated heparin and LMWH used as prophylaxis during hip surgery in 655 patients, HIT occurred in 2.7% of recipients of unfractionated heparin and in none of the patients receiving LMWH (240). However, as previously discussed, 90% of HIT patients have antibodies that cross-react with LMWH, making this a poor alternative when continued anticoagulation is necessary in patients with an established diagnosis of HIT.

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Heparinoid

Ancrod

Heparinoids are nonheparin glycosaminoglycans obtained as a by-product of heparin production from porcine intestinal mucosa (241). The anticoagulant effect of heparinoid is directed primarily against factor Xa. Heparinoid is composed of a mixture of dermatan, heparin, and chondroitin sulfates; heparinoid has a very low degree of sulfation and a reduced molecular weight compared to unfractionated heparin. Heparinoid is less likely to bind to platelets (199,241) or to be immunogenic. In the United States, heparinoid has been obtained for compassionate use from Organon, Inc., in West Orange, New Jersey, U.S.A. Because heparinoid contains a small amount of heparin-like substance that would have the capacity to cause HIT, a test for antibody cross-reactivity should be done before substitution of the heparinoid for heparin (198,199). In a recent review of 230 patients who received heparinoid for HIT, 93% of the recipients were judged to have responded in a satisfactory manner (198,199). Only 10% of the sera obtained from patients with HIT showed cross-reactivity with heparinoid, whereas 90% showed cross-reactivity with LMWH.

Another antithrombotic strategy is to deplete fibrinogen concentration and thus impair fibrin formation. This may be achieved by using a number of snake venom enzymes of which only ancrod (extracted from the Malayan pit viper, Agkistrodon rhodostoma) has been used clinically. Ancrod cleaves fibrinopeptide A, but not fibrinopeptide B, from fibrinogen to produce fibrin that is very sensitive to endogenous fibrinolysis. The fibrin formed by the action of ancrod is deposited in the microcirculation, where it is rapidly lysed by endothelial fibrinolytic mechanisms. Ancrod may be given intravenously, subcutaneously, or intramuscularly. Within hours, marked defibrination occurs and is accompanied by a delayed but striking rise in fibrinogen–fibrin degradation products. Hypofibrinogenemia is sustained by daily administration; however, resistance develops because of the elaboration of neutralizing antibodies when repeated injections are given. A potentially important indication for ancrod use may be HIT, for which there is no established treatment at present.

Argatroban Argatroban, a synthetic derivative of L-Arg, is a reversible, direct thrombin inhibitor with a half-life of approximately 20 to 25 minutes. There is no antidote for argatroban. In a phase I trial, argatroban was shown to prolong the aPTT and thrombin time in a dose-dependent fashion (242). In a more recent phase I dose-ranging clinical trial, argatroban was administered to patients with unstable angina (243). Although there were no significant bleeding complications, there was a rebound effect with recurrence of angina following cessation of argatroban. Argatroban has been used successfully as an alternative anticoagulant in patients with HIT, and its use for this indication is currently under investigation (244). Given its short half-life and direct thrombin inhibition, its potential as an alternative to heparin in patients with HIT is encouraging.

Hirudin and Its Analogs Hirudin is an anticoagulant derived from the saliva of the medicinal leech and directly inhibits thrombin. Interest in hirudin as an anticoagulant has increased since its gene was cloned in 1986 with subsequent production by recombinant techniques (181,195,196,245–247). Hirulog is a 20-amino acid polypeptide that consists of three components: an inhibitor of the active site of thrombin, an inhibitor of the fibrinogenbinding site, and a polyglycine spacer that links the other two segments. In normal human volunteers, hirulog has a half-life of 36 minutes. There is no known inhibitor for use as an antidote for hirudin or hirulog. Unlike the heparin/ AT-III complex, hirudin and hirulog inhibit clot-bound thrombin (181,195,196,248) and do not induce thrombocytopenia. The anticoagulant effects and safety of hirulog have been studied in healthy human volunteers (249). There were no significant bleeding complications. No antihirulog antibodies were noted at 7 and 14 days. In addition to use in animal thrombosis models (250,251), hirulog is being tested in clinical trials and has been used successfully in 291 patients undergoing elective coronary angioplasty (252). Hirulog has been used successfully as an anticoagulant in an animal model of carotid endarterectomy in a dose that allowed inhibition of fibrin deposition without significant bleeding (195,196,253). Hirudin has been used as an anticoagulant during coronary artery bypass surgery (195,196,254).

Antiplatelet Agents Aspirin Aspirin acts by acetylating and inhibiting platelet cyclooxygenase, the enzyme that converts arachidonic acid to the endoperoxide intermediates prostaglandin G2 and H2 (8,255). This process inhibits formation of thromboxane A2, and because platelets are anucleate and incapable of replenishing cyclooxygenase, platelets exposed to aspirin are permanently affected. Because of differential effects on platelets and endothelial cells (platelets being more sensitive), a great deal of effort has been devoted to finding the lowest possible dose of aspirin that inhibits platelet thromboxane A2 production and that allows endothelial PTI2 synthesis to continue. There appears to be no difference in the antiplatelet effectiveness between high- and low-dose aspirin (256). A dose as low as 40 mg daily completely inhibits cyclooxygenase activity and has been shown to reduce the incidence of fatal and nonfatal myocardial infarction in patients with unstable angina (257). Whether this dose provides adequate antiplatelet activity in all patients and for a wide spectrum of indications, however, remains uncertain. Another advantage of a lower aspirin dose appears to be less gastrointestinal bleeding, although this advantage might be realized with enteric-coated preparations. Aspirin is rapidly absorbed in the stomach and upper intestine, with peak plasma levels occurring 15 to 20 minutes after ingestion. Absorption from enteric-coated tablets may be delayed; however, reliable and sustained antiplatelet effects are observed after multiple daily doses of such tablets (258). Although aspirin is moderately effective in preventing arterial thromboembolic complications, it is not helpful in halting the progression of atherosclerosis and the development of intimal hyperplasia (259). Aspirin does not prevent platelet adhesion to collagen and subendothelial vWF, and it does not inhibit a-granule secretion in response to platelet agonists (260). Therefore release of growth factors from the a-granule, such as PGDF and transforming growth factor-b, are unaffected by cyclooxygenase inhibitors.

Ticlopidine and Clopidogrel Ticlopidine and clopidogrel inhibit platelet aggregation by altering the platelet membrane and interfering with the membrane–fibrinogen interaction, thereby blocking the

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platelet GPIIv/IIIa receptor (261). Unlike aspirin, ticlopidine and clopidogrel do not interfere with the cyclooxygenase pathway. The antiplatelet effect of ticlopidine is maximal at 24 to 48 hours and is not reversible. It prolongs the bleeding time and has no effect on coagulation assays. In trials studying cerebrovascular disease, ticlopidine appears to be marginally superior to aspirin in preventing stroke and transient ischemic attacks (262,263). The use of ticlopidine during coronary artery stenting appears to be associated with fewer thrombotic complications than aspirin (264). The only known serious adverse effect of ticlopidine appears to be neutropenia, which occurs in less than 1% of patients taking the drug. This condition appears during the first months of therapy and reverses when the drug is discontinued. It is therefore recommended that white blood cell counts be monitored during the first months of treatment. Other adverse effects include diarrhea and skin rash, which may occur in up to 20% of patients. Because of these side effects, a ticlopidine analog, clopidogrel, is being developed. Clopidogrel is administered in doses of 50 to 100 mg daily and reaches a steady state inhibition of ADP-induced aggregation in four to seven days. A major advantage of clopidogrel over ticlopidine is the relative infrequent occurrence of serious side effects (232,233). As mentioned previously, the result of the CAPRIE trials show a significant decrease in atherosclerotic ischemic events in patients treated with clopidogrel when compared to aspirin in patients treated for secondary risk reduction following ischemic atherosclerotic events (232,233).

Dextran Dextran is a polysaccharide that is hydrolyzed and fractionated into polymers of variable molecular weight. The preparations most commonly used as an antiplatelet agent has an average molecular mass of 40,000 kDa (dextran 40). Although the drug was first used as a volume expander, it was subsequently found to have an effect on hemostasis and thrombosis. The principal antithrombotic properties are antiplatelet activity through the reduction of plasma vWF and resulting in a mild defect in platelet adhesion, defective fibrin polymerization and increased clot lysis, and increased blood flow through volume expansion (265,266). Dextran has been shown to be useful in the prevention of venous thromboembolism, but is rarely used for this purpose because it must be administered intravenously and its use is cumbersome (267,268). The use of dextran 40 has also been shown to improve early patency following infrainguinal arterial reconstruction (269). Adverse reactions include pulmonary edema from volume expansion, allergic reactions, and rarely anaphylactic reactions.

c7E3 Fab A new class of potent antiplatelet agents inhibit platelet aggregation by binding the GPIIb/IIIa fibrinogen receptor, causing a defect similar to that found in Glanzmann’s thrombasthenia (16,17,19). One of the most promising of such agents is a monoclonal fragment antigen-binding (Fab) fragment of an IgG antibody, chimeric 7E3 (c7E3), that contains the mouse variable regions and the human constant regions (270). The generic name of c7E3 is abciximab and the trade name is ReoPro. Platelet aggregation is profoundly inhibited by c7E3, both in vitro and in vivo (271). In a study evaluating c7E3 with aspirin and heparin during high-risk coronary angioplasty, there was a significant decrease in thrombotic events compared to the use

of aspirin and heparin alone (272). Patients treated with c7E3 had a twofold increase in bleeding complications, but no increase in cerebral hemorrhage or bleeding-related mortality. Antibody formation against the murine component of c7E3 occurred in 6.5%, but there were no allergic or anaphylactic reactions. The FDA has approved c7E3 for use during high-risk coronary angioplasty and atherectomy. The activating clotting time is prolonged with the use of c7E3 (273), and specific assays to monitor dosage are being developed. The results of additional trials defining the optimal dosage of heparin when administered with c7E3 and evaluating the role of c7E3 in the treatment of other thrombotic disorders are eagerly awaited (274).

SUMMARY Because increasing numbers of routine and complex operations are being performed on patients who have diseases that alter hemostasis, the frequency of abnormal bleeding in surgical patients can be expected to increase. Knowledge of the physiologic principles underlying hemostasis and of derangements that precipitate bleeding is important in modern surgical care. Hemostasis depends on interactions among circulating proteins (coagulation factors and inhibitors), cellular elements (platelets and white blood cells), and vascular endothelium and smooth muscle. In the early stages of hemostasis, platelets rapidly adhere and aggregate at the site of vascular injury and form a platelet plug that temporarily stops blood flow. At the same time, the intrinsic and extrinsic coagulation pathways reactivated, resulting in a fibrin network that fortifies the platelet plug and provides a frame for fibroblastic in-growth and ultimate healing of the injury. The hemostatic response is finely regulated to limit clotting to the site of injury and thereby to maintain vascular patency. Inhibitory mechanisms include the fibrinolytic system, plasma serine protease inhibitors (the most important of which is AT-III), and the antithrombotic properties and functions of endothelial cells. Derangements in hemostatic mechanisms can be both congenital and acquired. In surgical patients, acquired bleeding disorders are far more common than congenital ones. To diagnose and treat such disorders adequately, preoperative assessment of hemostatic competence is mandatory in all surgical problems. The keystone to preoperative evaluation for all bleeding disorders is through history and physical examination.

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163. Fermo I, et al. Prevalence of moderate hyperhomocysteinemia in patients with early-onset venous and arterial occlusive disease. Ann Intern Med 1995; 123:747. 164. Selhub J, et al. Association between homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med 1995; 332:286. 165. den Heijer M, et al. Is hyperhomocysteinemia a risk factor for recurrent venous thrombosis? Lancet 1995; 345:882. 166. Simione P, et al. Hyperhomocysteinemia and deep-vein thrombosis: a case-control study. Thromb Haemost 1996; 76:883. 167. Valentine RJ, et al. Lipoprotein (a), homocysteine, and hypercoagulable states in young men with premature peripheral atherosclerosis: a prospective, controlled analysis. J Vasc Surg 1996; 23:53. 168. Goyette P, et al. Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification. Nat Genet 1994; 7:195. 169. Frosst P, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10:111. 170. Jacques PF, et al. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation 1996; 93:7. 171. Boushey CJ, et al. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA 1995; 274:1049. 172. Alving BM. Lupus anticoagulants, anticardiolipin antibodies, and the antiphospholipid syndrome. In: Loscalzo J, Schafer AI, eds. Thrombosis and Hemorrhage. Boston: Blackwell Scientific Publications, 1994:749. 173. Harris EN, Pierangeli S, Birch D. Anticardiolipin wet workshop report. Fifth International Symposium on Antiphospholipid Antibodies. Am J Clin Pathol 1994; 101:616. 174. Deicher SR, Carman TL, Sheikh, MA, Gomes M. Hypercoagulable syndromes: evaluation and management strategies for acute limb ischemia. Semin Vasc Surg 2001; 14(2):74–85. 175. Kim V, Spandorfer J. Epidemiology of venous thromboembolic disease. Emerg Med Clin North Am 2001; 19(4): 839–859. 176. Rhodes GR, Dixon RH, Silver D. Heparin induced thrombocytopenia with thrombotic and hemorrhagic manifestations. Surg Gynecol Obstet 1973; 136:409. 177. Silver D, Kapsch DN, Tsoi EKM. Heparin-induced thrombocytopenia, thrombosis, and hemorrhage. Ann Surg 1983; 198:301. 178. Laster J, et al. The heparin-induced thrombocytopenia syndrome: an update. Surgery 1987; 102:763. 179. Boshkov LK, et al. Heparin-induced thrombocytopenia and thrombosis: clinical and laboratory studies. Br J Haematol 1993; 84:322. 180. Warkentin TE. Heparin-induced thrombocytopenia. Curr Hematol Rep 2002; 1(1):63–72. 181. Harenberg J, Jorg I, Fenyvesi T. Heparin-induced thrombocytopenia: pathophysiology and new treatment options. Pathophysiol Haemost Thromb 2002; 32(5–6):289–294. 182. Jackson MR, et al. Diagnosis of heparin-induced thrombocytopenia in the vascular surgery patient. Surgery 1997; 131:419. 183. Warkentin TE, Hayward CPM, Boshkov MC, et al. Sera from patients with heparin-induced thrombocytopenia generate plaelet-derived microparticles with procoagulant activity: an explanation for the thrombotic complications of heparininduced thrombocytopenia. Blood 1994; 79:1. 184. Carlsson LE, Santoso S, Baurichter G, et al. Heparin-induced thrombocytopenia: new insights into the impact of FcgammaRIIa-R-H131 polymorphism. Blood 1998; 92:1526. 185. Warkentin TE, Heddle NM. Laboratory diagnosis of immune heparin-induced thrombocytopenia. Curr Hematol Rep 2003; 2(2):148–157. 186. Amiral JA, et al. Pathogenicity of IgA and/or IgM antibodies to heparin-PF4 complexes in patients with heparin-induced thrombocytopenia. Br J Haematol 1995; 92:954.

187. Curtis BR, McFarland JG, Wu G-G, et al. Antibodies in sulfanamide-induced immune thrombocytopenia recognize calcium-dependent epitopes on the glycoprotein Iib/Iia complex. Blood 1994; 84:176. 188. Visentin GP, Newman PJ, Aster RH. Characteristics of quinine- and quinidine-induced antibodies specific for platelet glycoprotein Iib and IIIa. Blood 1991; 77:2668. 189. Chong BH, Burgess J, Ismail F. The clinical usefulness of the platelet aggregation test for the diagnosis of heparin-induced thrombocytopenia. Thromb Haemost 1993; 69:344. 190. Greinacher A, et al. Heparin-associated thrombocytopenia: isolation of the antibody and characterization of a multimolecular PF4-heparin complex as the major antigen. Thromb Haemost 1994; 71:247. 191. Sheridan D, Carter C, Kelton JG. A diagnostic test for heparininduced thrombocytopenia. Blood 1986; 67:27. 192. Amiral J, et al. Platelet factor 4 complexed to heparin is the target for antibodies generated in heparin-induced thrombocytopenia [letter]. Thromb Haemost 1992; 68:95. 193. Aylesworth CL, et al. ELISA for detection of antibodies against the platelet factor 4 (PF4)/heparin complex: methods for standardization. Blood 1995; 86:865a. 194. Markwardt F. The development of hirudin as an antithrombotic drug. Thromb Res 1994; 74:1. 195. Harenberg J, Jorg I, Koch S, Fenyvesi T. Lepirudin for therapeutic use in heparin-induced thrombocytopenia. Hamostaseologie 2004; 24(2):135–143. 196. Jeske WP, Walenga JM. Antithrombotic drugs for the treatment of heparin-induced thrombocytopenia. Methods Mol Med 2004; 93:61–82. 197. Nand S. Hirudin therapy for heparin-associated thrombocytopenia and deep vein thrombosis. Am J Hematol 1993; 43:312. 198. Magnani HN. Heparin-induced thrombocytopenia (HIT): an overview of 230 patients treated with orgaran (Org 10172). Thromb Haemost 1993; 70:554. 199. Ortel TL, et al. Parenteral anticoagulation with the heparinoid Lomoparan (Org 10172) in patients with heparin induced thrombocytopenia and thrombosis. Thromb Haemost 1992; 67:292. 200. Olinger GN, et al. Cardiopulmonary bypass for patients with previously documented heparin-induced platelet aggregation. J Thorac Cardiovasc Surg 1984; 87:673. 201. Dvorak HF. Abnormalities of hemostasis in malignant disease. In: Coleman RW, et al., eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 3rd ed. Philadelphia: JB Lippincott, 1994:1238. 202. Deitcher SR, Gomes MP. Hypercoagulable state testing and malignancy screening following venous thromboembolic events. Vasc Med 2003; 8(1):33–46. 203. Mandala M, Ferretti G, Cremonesi M, Cazzaniga M, Curigliano G, Barnia S. Venous thromboembolism and cancer: new issues for an old topic. Crit Rev Oncol Hematol 2003; 48(1):65–80. 204. Deitcher SR. Cancer-related deep venous thrombosis: clinical importance, treatment challenges, and management strategies. Semin Thromb Hemost 2003; 29(3):247–258. 205. Kakkar AK. An expanding role for antithrombotic therapy in cancer patients. Cancer Treat Rev 2003; 29(suppl 2):23–26. 206. Gomes MP, Deitcher SR. Diagnosis of venous thromboembolic disease in cancer patients. Oncology (Huntingt) 2003; 17(1): 126–135. 207. Clagett GP, et al. Prevention of venous thromboembolism. Chest 1995; 108(4):312S. 208. Stark JE, Kilzer WJ. Venous thromboembolic prophylaxis in hospitalized medical patients. Ann Pharmacother 2004; 38(1): 365–340. 209. Haas S. The present and future of heparin, low molecular weight heparins, pentasaccharide, and hirudin for venous thromboembolism and acute coronary syndromes. Semin Vasc Med 2003; 3(2):139–146. 210. Chang P. New anticoagulants for venous thromboembolic disease. IDrugs 2004; 7(1):50–57.

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239. Hodl R, Klein W. The role of low-molecular-weight heparins in cardiovascular medicine. J Clin Pharm Ther 2003; 28(5): 371–378. 240. Warketin TE, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 1995; 332:1330. 241. Doherty DC, et al. ‘‘Heparin-free’’ cardiopulmonary bypass: first reported use of heparinoid (Org 10172) to provide anticoagulation for cardiopulmonary bypass. Anesthesiology 1990; 73:562. 242. Clarke RJ, et al. Combined administration of aspirin and a specific thrombin inhibitor in man. Circulation 1991; 83:1510. 243. Gold HK, et al. Evidence for a rebound coagulation phenomenon after cessation of a 4-hour infusion of a specific thrombin inhibitor in patients with unstable angina pectoris. J Am Coll Cardiol 1993; 21:1039. 244. Matsuo T, et al. Treatment of heparin-induced thrombocytopenia by use of argatroban, a synthetic thrombin inhibitor. Br J Haematol 1992; 82:627. 245. Sawyer RT. Thrombolytics and anticoagulants from leeches. Biotechnology 1991; 9:513. 246. Maraganore JM, et al. Anticoagulant activity of synthetic hirudin peptides. J Biol Chem 1989; 264(15):8692. 247. Maraganore JM, et al. Design and characterization of hirulogs: a novel class of bivalent peptide inhibitors of thrombin. Biochem 1990; 29:7095. 248. Weitz JI, et al. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 1990; 86:385. 249. Fox I, et al. Anticoagulant activity of HirulogTM, a direct thrombin inhibitor, in humans. Thromb Haemost 1993; 69:157. 250. Yao SK, et al. Thrombin inhibition enhances tissue-type plasminogen activator-induced thrombolysis and delays reocclusion (Part 2). Am J Physiol 1992; 262(2):H374. 251. Klement P, et al. Effects of heparin and hirulog on t-PA induced thrombolysis in a rat model. Fibrinolysis 1990; 4(suppl 3):9. 252. Topol EJ, et al. Use of a direct antithrombin, Hirulog, in place of heparin during coronary angioplasty. Circulation 1993; 87:1622. 253. Jackson MR, et al. Antithrombotic effects of hirulog in a microsurgical carotid endarterectomy model. J Surg Res 1996; 60:15. 254. Riess FC, Potzsch B, Bader R. A case report on the use of recombinant hirudin as an anticoagulant for cardiopulmonary bypass in open heart surgery. Eur J Cardiothorac Surg 1996; 10:386. 255. FitzGerald GA. Mechanisms of platelet activation: Thromboxane A2 as an amplifying signal for other agonists. Am J Cardiol 1991; 68:11B. 256. Hirsh J, et al. Aspirin and other platelet-active drugs. The relationship between dose, effectiveness, and side effects. Chest 1995; 108:247S. 257. Barnett HJM, Eliasziw M, Meldrum HE. Drugs and surgery in the prevention of ischemic stroke. N Engl J Med 1995; 332:238. 258. Jakubowski JA, et al. Cumulative anti-platelet effect of lowdose enteric-coated aspirin. Br J Haematol 1985; 60:635. 259. Clagett GP, Krupski WC. Antithrombotic therapy in peripheral arterial occlusive disease. Chest 1995; 108(4):431S. 260. Rinder CS, et al. Aspirin does not inhibit adenosine diphosphate-induced platelet a-granule release. Blood 1993; 32:505. 261. Di Minno G, et al. Functionally thrombasthenic state in normal platelets following the administration of ticlopidine. J Clin Invest 1985; 75:328. 262. Hass EK, et al. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. N Engl J Med 1989; 321:501. 263. Gent M, et al. The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet 1989; 1:1215.

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264. Goods CM, et al. Comparison of aspirin alone versus aspirin plus ticlopidine after coronary artery stenting. Am J Cardiol 1996; 78:1042. 265. Aberg M, Hedner U, Bergentz SE. Effect of dextran on factor VIII (antihemophilic factor) and platelet function. Ann Surg 1979; 189:182. 266. Aberg M, Bergentz SE, Hedner U. The effect of dextran on the lysability of ex vivo thrombi. Ann Surg 1975; 181:342. 267. Harris WH, et al. Prevention of venous thromboembolism following total hip replacement: warfarin vs dextran 40. JAMA 1972; 220:1319. 268. Clagett GP, Reisch JS. Prevention of venous thromboembolism in general surgical patients. Results of meta-analysis. Ann Surg 1988; 208(2):227. 269. Rutherford RB, et al. The efficacy of dextran 40 in preventing early postoperative thrombus following difficult lower extremity bypass. J Vasc Surg 1984; 1:765.

270. Tcheng JE, et al. Pharmacodynamics of chimeric glycoprotein Iib/IIIa integrin antiplatelet antibody Fab 7E3 in high-risk coronary angioplasty. Circulation 1994; 90:1757. 271. Coller BS, Anderson K, Weisman HF. New antiplatelet agents: platelet GPIIb/IIIa antagonists. Thromb Haemost 1995; 74:302. 272. The EPIC investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med 1994; 330:956. 273. Moliterno DJ, et al. Effect of platelet glycoprotein IIb/IIIa integrin blockade on activated clotting time during percutaneous transluminal coronary angioplasty or directional atherectomy (the EPIC trial). Evaluation of c7E3 Fab in the Prevention of Ischemic Complications Trial. Am J Cardiol 1995; 75:559. 274. Faulds D, Sorkin EM. Abciximab (c7E3 Fab). A review of its pharmacology and therapeutic potential in ischemic heart disease. Drugs 1994; 48:583.

8 Pathophysiology of Shock Ajai K. Malhotra

process of shock. In addition to this toxemic theory of shock, other explanations for the state were also offered during this time (2). The next major step in the understanding of the state of shock occurred when Kieth, in 1919, used the dye dilution method to demonstrate that the shock state was accompanied by hypovolemia (3). The concept of hypovolemia being a major determinant of the shock state, however, did not become established until the classic experiments of Alfred Blalock clearly demonstrated that blood and extracellular fluid losses, in the vicinity of a major injury, were sufficient to cause hypovolemia and shock (4). Wiggers, in the 1940s, developed experimental animal models of progressive hemorrhage leading to hypovolemic shock and described irreversible shock—a state from which animals failed to recover despite complete restoration of blood volume. Furthermore, Wiggers attempted to correlate the concepts of cumulative oxygen debt and death (5). During the mid-20th century, resuscitation from shock, using blood, plasma, and balanced salt solutions, became the primary focus of investigation. It was realized that patients suffering from prolonged and severe hemorrhagic shock could survive, provided they were given large volumes of resuscitation fluids early. The pathophysiology as to why these large volumes were required was elucidated by the work of Shires, who, in a series of experiments, demonstrated that in deep and prolonged hemorrhagic shock, cell membrane function was deranged, resulting in the movement of extracellular fluid into the cells (6). This resulted in a profound extracellular fluid deficit that had to be replenished for the organism to survive. With massive resuscitation, a greater number of patients with even severe hemorrhagic shock survived the initial injury; however, other complications, notably sepsis and multisystem organ failure, started to be recognized as delayed complications of shock and massive volume resuscitation. With improved critical care, the ability to support failing organ systems has improved, but other complications of massive crystalloid resuscitation are being reported. Ironically, current research involving cellular and molecular derangements is increasingly focused on systemic inflammation due to shock and the chemical mediators responsible—akin to the toxemic theory of shock.

Shock: . . . a rude unhinging of the machinery of life . . . Samuel D. Gross, 1870

INTRODUCTION Attempts to define the pathophysiology of shock are as old as the practice of medicine itself. Hippocrates (460–380 B.C.) recognized the state, following traumatic wounds with significant blood loss. He described the Hippocrates facies of a person in the premorbid state from shock, and suggested the use of a tourniquet to control blood loss. Galen (130– 200 A.D.) described ligation of the bleeding vessel to control blood loss, though the technique did not gain widespread acceptance till the work of the French surgeon Ambroise Pare (1510–1590). At about the same time, the groundbreaking work of Andrea Vesalius (1514–1564), and of William Harvey (1578–1657), helped elucidate the anatomy and circulation of the cardiovascular system. The term ‘‘shock’’ itself appeared for the first time in the medical literature in 1743 in an English translation of Henri Francois Le Dran’s (1685–1770) A Treatise, or Reflections Drawn from Experiences with Gunshot Wounds. It referred to a violent physical impact, rather than the physiological changes as a consequence of the impact. The term was used to describe such physiologic sequelae, following major trauma, by George James Guthrie (1785–1856) in his book On Gunshot Wounds of the Extremities, published in 1815. The development of the field of physiology toward the end of the 19th century increased fundamental understanding of the issues involved in shock. George W. Crile (1864–1943) developed animal models of hemorrhagic shock and showed that after hemorrhage the central venous pressure dropped to very low levels. Furthermore, infusion of normal saline resulted in restoration of this pressure and improved survival in his experimental models. He postulated that the increase in central venous pressure, by saline infusion, improved cardiac filling, and thus cardiac output (1). Walter B. Cannon (1872–1945) and William M. Bayliss (1860–1924), two physiologists, made important observations on soldiers injured on the battlefield in World War I. They correlated loss of blood with the development of shock, and also acidosis. Following these observations, they developed animal models of shock caused by injury, and postulated that injured tissue elaborated a toxin that resulted in the state of shock. This concept of traumatic toxemia, prevalent in the early part of the 20th century, was not new because it complemented the centuries-old practice of bloodletting to reverse the

DEFINITION OF SHOCK Shock may be defined as a syndrome in which tissue perfusion is inadequate to meet the metabolic needs of the body. Because the most immediate metabolic nutrient is oxygen, this inadequate perfusion results in tissue hypoxia that has far-reaching effects on the whole organism, individual 181

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organ systems, tissues comprising the individual organ systems, and finally the individual cells. Cellular hypoxia leads to cell injury and the initiation of the inflammatory cascade. In situations where the tissue hypoperfusion is rapidly corrected, cell injury is limited; but if treatment is not provided in an expeditious fashion, the shock state may become irreversible with death of the organism. Thus the shock state should truly be viewed as a continuum from subclinical perfusion deficits to frank organ system dysfunction and death. This concept of shock being an imbalance between the body’s oxygen requirements and the ability of the cardiovascular system to provide oxygen is central to the understanding of the pathophysiology of shock. In some situations, the perfusion measurements may be ‘‘normal’’ or even ‘‘supranormal’’; however, due to a state of systemic inflammation, the body’s oxygen requirements may be significantly increased, and a state of shock may thereby exist.

Oxygen Debt The lack of oxygen observed during shock has led some to look at the state of shock as an oxygen debt owed by the cardiovascular system to the tissues. Oxygen debt is the cumulative difference in the volume of oxygen delivered during the state of hypoperfusion and the volume necessary for the organs to function normally. For shock therapy to be successful, oxygen delivery has to be at a suitable level to not only maintain normal function of the organs, but also repay the debt accumulated during shock. If the shock state is prolonged or deep, the oxygen debt can become so high that the cardiovascular system is unable to deliver enough oxygen to repay the oxygen debt and maintain normal functions, and the organism dies. Animal experiments, and some human studies, have shown a very high level of correlation between oxygen debt accrued during shock and survival with resuscitation. However, interventions to massively increase oxygen delivery during resuscitation to rapidly pay off the debt have failed to show improvement in survival (7).

CARDIOVASCULAR PHYSIOLOGY AND TYPES OF SHOCK The cardiovascular system consists of the heart, which pumps the circulating blood volume through a closed system of channels comprising arteries and arterioles carrying blood to capillary networks in all tissues and venules and veins carrying blood back to the heart. There are three requisites for adequate perfusion: (i) adequate circulating volume—preload—with adequate concentration of hemoglobin to transport oxygen; (ii) adequate power of cardiac contraction—contractility—to pump the circulating volume at an adequate perfusion pressure; and (iii) appropriate tone—afterload—of the vasculature, residing principally in the arterioles, to maintain an adequate perfusion pressure at the tissue level. Unlike a pure mechanical preparation where each of the three variables, preload, contractility, and afterload, may be altered individually, in a biological system, as exists within the body, there is a dynamic interplay between the three variables. As a consequence of this dynamic interplay, if one variable changes, not only is the body perfusion affected directly, but the other two variables too may change in response to the change in the first. This dynamism makes it very difficult at times to evaluate the principal problem causing the state of shock—preload, contractility, or afterload. To partly overcome this difficulty, a thermodynamic model of the cardiovascular system was

proposed by Suga et al. (8–11). A fundamental concept in this model was that the volume of blood delivered by the heart (i.e., cardiac output), and the pressure at which it was delivered were both important determinants of overall perfusion adequacy. These two determinants can be combined to arrive at the mechanical work done by the heart or the power output. A pressure–volume diagram (Fig. 1) can be constructed, provided some key volume and pressure measurements are available, and the exact work done by the heart on the vascular system can be calculated. This pressure–volume diagram not only assesses the work done, but also allows for preload, contractility, and afterload to be evaluated individually and independent of the other two. At point A in the pressure–volume loop (Fig. 1), ventricular filling is initiated with the opening of the atrio-ventricular valves, allowing blood to flow from the atria into the ventricles. In the relaxed state, normal ventricles are very compliant; thus the ventricular volume increases, without significant increase in the ventricular pressure—segment AB in the loop. At point B, ventricular contraction causes an increase in ventricular pressure, forcing the closure of atrioventricular valves. Now, outflow tract (aortic root on the left and pulmonary artery root on the right) pressure is much higher than ventricular pressure, and hence both ventricular outflow valves remain closed. With continued ventricular contraction, ventricular pressure rises, without any change in ventricular volume, because no blood can enter or exit the ventricles—isovolumic contraction: segment BC in the loop. At point C, ventricular pressure rises above the outflow tract pressure, allowing the outflow valves to open. With opening of these valves, there is rapid emptying of the ventricles into the outflow tracts, resulting in decrease in ventricular volume—segment CD in the loop. At point D, the ventricles have emptied, and ventricular systole is ending, resulting in a drop in ventricular pressure to less than the outflow tract pressure, causing the outflow valves to close. With continued ventricular relaxation, ventricular pressure falls, but as the atrio-ventricular valves remain closed, no change in ventricular volume takes place—isovolumic relaxation: segment DA. At point A, the ventricular pressure has fallen

Figure 1 Pressure–volume loop as described by Suga et al. The crosshatched rectangle ABCD represents mechanical work performed by the heart on the vascular system to achieve perfusion. The triangle VoAD represents nonmechanical work performed to re-create ionic electrochemical gradients expended during each contraction cycle. The slope of line VoD represents cardiac contractility, and the slope of line BD represents afterload. The three parameters that define perfusion can be quantified individually independent of the other two by constructing such a pressure–volume loop. Abbreviations: Vo, ventricular unstressed volume; ESV, end systolic volume; EDV, end diastolic volume.

Chapter 8:

to a value less than that of the atrial pressure, allowing the atrio-ventricular valves to open and the cycle to start again at point A. In thermodynamic terms, the area enclosed within the pressure–volume loop ABCD is the mechanical work performed by the heart on the vasculature to achieve perfusion. The loop for the left side represents systemic perfusion. In addition to the mechanical work, there is additional energy expenditure involved in re-establishing electrochemical gradients expended to achieve mechanical work. The point V0 represents ventricular unstressed volume (approximately 5 mL in a normal young heart and approximately 10 mL in a normal older heart). The area enclosed within the triangle, V0AD, represents this nonmechanical energy expenditure. In an ideal situation, the area V0AD should be very small, and area ABCD should be large enough to provide adequate perfusion. Modern monitoring allows for the constructing of pressure–volume loops in patients. As described by Suga et al., the slope of the line V0D represents cardiac contractility and slope of the line BD represents afterload. Additionally, experiments have shown that the contractility, as measured on this loop, is load independent. Hence the pressure– volume loop provides accurate independent quantification of the three parameters upon which cardiac function, and hence perfusion, is dependent—circulating volume on the X-axis, and contractility and afterload as the slopes of the two lines BD and V0D, respectively. This quantification can serve as a guide to therapy because it allows prediction as to which intervention—changes in circulating volume, augmentation of contractility, or manipulation of afterload— is the most likely to improve perfusion (increase area ABCD), with least increase in nonmechanical work (area V0AD).

Types of Shock At a pathophysiologic level, shock may be caused by derangements in one or more of the three parameters that define perfusion—preload, contractility, and afterload. In some situations, the shock is relatively ‘‘pure,’’ and is caused by derangement of only one parameter; however in most clinical situations associated with shock, all three are deranged to a lesser or greater degree. Even in situations where shock is caused by derangement of only one parameter to start with, as the shock state progresses, the other two become secondarily affected. For example, a patient suffering from hemorrhage of a major blood vessel, caused by a single stab wound injury, will develop decreased circulating blood volume—decreased preload—resulting in hypoperfusion or shock. If the bleeding is rapidly controlled and resuscitation provided, the patient will recover. On the other hand, in situations where resuscitation and control of hemorrhage is delayed, the decreased venous return to the heart and poor cardiac perfusion will depress cardiac contractility. Later on, tissues starved of oxygen will cause dilatation of vessels, resulting in changes in afterload. Hence shock initially caused by decreased preload will develop a mixed picture with derangements in contractility and afterload. At times it can be extremely difficult to determine the primary insult that initiated shock and the secondary effects contributing to it. The most commonly accepted classification of shock is presented in Table 1.

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Table 1 Commonly Accepted Classification of Shock, with the Principal Cause of the Hypoperfusion in Parenthesis Hypovolemic shock (loss of preload) Hemorrhagic shock Traumatic shock Cardiogenic shock (loss of cardiac contractility) Neurogenic shock (loss of afterload) Cardiac compressive shock (severe decrease in preload affecting contractility) Septic shock (decreased preload; decreased contractility; deranged afterload)

be caused by loss of blood from the vasculature due to external or internal bleeding—hemorrhagic shock. It may also be caused by nonsanguinous loss of extracellular fluid. This extracellular fluid loss may be external, as seen in diarrhea, vomiting, etc., or internal, as seen in severe inflammatory states as necrotizing pancreatitis. Patients with blunt trauma, with significant blood loss, develop a more severe form of hypovolemic shock—traumatic shock. This is thought to be due to the inflammatory state produced by tissue injury superimposed on the hypovolemic shock due to the hemorrhage.

Cardiogenic Shock Shock due to significant decrease in cardiac contractility causing reduced perfusion is termed ‘‘cardiogenic shock.’’ It is most commonly observed following major myocardial infarction. However, it may also be seen following major blunt trauma to the heart or following viral myocarditis. In late stages of any form of shock, cardiac contractility is affected by cardiac hypoperfusion, and hence a cardiogenic element is often present in the later stages of all forms of shock.

Neurogenic Shock Hypoperfusion as a result of derangement in afterload is termed ‘‘neurogenic shock.’’ It is most commonly observed in cervical spinal cord injury with loss of sympathetic tone to most of the body, resulting in reduction in afterload with decrease in perfusion pressure and shock. Neurogenic shock due to this form of injury, particularly in otherwise young healthy adults, is associated with full and bounding pulse in the face of significant hypotension and bradycardia. The bradycardia is due to loss of sympathetic stimulation to the heart, and the full bounding pulse is due to increased cardiac output in the face of low vascular resistance to cardiac emptying—low afterload. Brief neurogenic shock may also be observed by overactivity of the vagus nerve—vasovagal shock. Any situation that results in major afferent stimulation of the vagus nerve can result in overactivity of the parasympathetic system, suppression of the sympathetic tone resulting in bradycardia, and loss of afterload, with resultant neurogenic shock. Although not considered neurogenic shock in the strictest sense, severe vasoconstriction caused by extraneous administration of sympathomimetic pressor agents can result in tissue hypoperfusion and necrosis; in such situations, a very weak pulse will be observed in the face of ‘‘normal’’ or increased blood pressure.

Hypovolemic Shock

Cardiac Compressive Shock

Any clinical situation causing a reduction in circulating blood volume will result in decreased preload and hypovolemic shock. The decreased circulating volume can

Cardiac compressive shock is a clinical syndrome produced by decreased cardiac filling due to increased pressure within the pericardial or pleural cavities. The increased pressure

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within the pericardium or pleural cavity inhibits venous return to the heart—decreased preload. In the absence of adequate venous return, there is ineffective cardiac contractions—decreased contractility. The situation may be caused by accumulation of fluid or air within the pericardial or pleural cavities. The amount of fluid or air has to be sufficient to cause reduced cardiac filling. In the normal heart, a very small amount of fluid within the pericardial space is enough to embarrass cardiac filling—cardiac tamponade. In the case of the pleural space a fairly large volume of fluid is necessary to produce cardiac compressive shock. A simple pneumothorax does not produce compressive shock. However, if the pneumothorax is of sufficient volume to produce increased intrathoracic pressure—tension pneumothorax— cardiac compressive shock will be seen. Clinically, the condition may be diagnosed by bulging neck veins (absent in hypovolemic patients) and pulsus paradoxus. In addition, if caused by pericardial tamponade, the heart sounds appear distant on auscultation. When caused by tension within the pleural cavity, there is absence of breath sounds on the affected hemithorax, and hyper-resonance if caused by tension pneumothorax and dullness if caused by fluid.

Septic Shock Septic shock is the term used to denote a complex clinical syndrome affecting, to a lesser or greater degree, all three parameters that define perfusion—preload, contractility, and afterload. It is seen in patients with severe systemic sepsis. It is more common in sepsis due to gram-negative organisms, and hence is often referred to as gram-negative or endotoxemic shock. However the syndrome may also be seen with gram-positive septicemia or fungemia. It is initiated by

microbial products acting in concert with inflammatory mediators causing depression in cardiac contractility, and at the same time causing significant vasodilatation—reduced afterload. In addition, the systemic inflammatory response due to systemic sepsis causes capillaries to become leaky, allowing loss of intravascular circulating volume—reduced preload. All three parameters thus affected result in a severe state of shock, associated with a very high mortality. There is also evidence that sepsis leads to the inability of the tissues to adequately utilize whatever oxygen is available, thus exacerbating the tissue hypoxia that is the hallmark of the shock state.

PATHOPHYSIOLOGIC RESPONSE TO SHOCK The causes and types of shock are many. However, in all shock states, tissue perfusion is inadequate to meet the metabolic demands of the body. Consequently, the body’s responses to shock is similar, irrespective of the cause of shock in an individual. The body responds to the state of inadequate perfusion by mounting a neurohumoral response (Fig. 2) and an inflammatory response. Depending upon the type and etiology of shock, one or the other response may predominate, and in addition the individual components of these responses may differ in degree. However, all forms of shock will, to a lesser or greater degree, have both responses, which are primarily geared toward assuring survival of the organism by maintaining perfusion to essential organ systems, often at the cost of less critical body systems. These responses are blunted at the extremes of age, causing infants and older people to have less

Figure 2 Simplified outline of the neural response (left) and the humoral response (right shaded box) observed in a patient developing shock (hypoperfusion). Abbreviations: GH, growth hormone; TSH, thyroid-stimulating hormone; ADH, antidiuretic hormone; ACTH, adrenocorticotropic hormone; ANH, atrial naturitic hormone.

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reserves to deal with shock. Some recent research suggests that there may be some gender differences, particularly in the inflammatory response to shock (12). While in the short term, these responses are essential for survival, in prolonged or severe shock, these same responses may prove deleterious and hasten the death of the organism, thus making the early recognition and prompt treatment of shock essential for good outcomes in a variety of clinical situations associated with shock.

Neurohumoral Response A complex neurohumoral cascade of events is initiated within minutes of developing significant hypoperfusion (Fig. 2). This cascade has been best studied in pure hemorrhagic shock models. It is usually initiated by the lowering of blood pressure as detected by the pressure-sensitive receptors in various parts of the cardiovascular system. However it may also be initiated by pain or other noxious stimuli, by lack of metabolic fuels (e.g., glucose), or by the buildup of metabolic end products [e.g., CO2, or Hþ (acidosis)] (13). The end result of this complex cascade is to (i) increase cardiac output and blood pressure to maintain perfusion; (ii) limit fluid losses to maintain adequate circulating volume; and (iii) allow some degree of regional perfusion autoregulation to limit organ injury. The nervous system responds to lowering of blood pressure by a strong sympathoadrenal discharge in an attempt to improve perfusion. Arterial baroreceptors, located in the carotid sinus and aortic arch, respond immediately to changes in blood pressure, by adjusting the sympathetic tone. The low-pressure atrial stretch receptors are sensitive to both stretch and pressure. The afferent pathways from these peripheral receptors converge in the nucleus tractus solitarius, which in turn causes the vasomotor center to reduce its tonic inhibition of the sympathetic system. The combined effects of these changes is to produce vasoconstriction, increasing afterload and causing the blood pressure to rise, and, at the same time, reduce vascular capacity (arterial and venous), leading to the mobilization of blood from capacitance vessels toward the heart, improving cardiac filling and increasing cardiac output. The cardiac output is further augmented by the sympathetic stimulation of the heart, which causes the heart to contract more vigorously and at a higher rate. Arterial vasoconstriction, in response to the sympathetic discharge, is not uniform. It is more severe in the vascular beds of less vital organs such as the integument, or the splanchnic bed, while limited in the cardiac and cerebral circulations. The end result of this disproportionate vasoconstriction is a redistribution of the limited cardiac output to these more vital organs at the expense of other less important organs. Furthermore, local autoregulatory mechanisms continue to regulate the microperfusion in the heart and brain. Cerebral circulation is particularly sensitive to the buildup of CO2 and Hþ (acid). Similarly, systemic chemoreceptors, primarily located in the aortic arch and carotid body, are sensitive to systemic acidosis and lower the arterial partial pressure of oxygen (14). Simultaneous with the neural response, shock also initiates an endocrine response. The vasomotor center, besides coordinating a strong sympathetic nervous system response with secretion of norepinephrine from nerve endings, also causes secretion of epinephrine from the adrenal medulla, complementing the sympathetic nervous system response (15). In addition, the sympathetic nervous system stimulation causes the glucagon–insulin secretory balance within the

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pancreas to shift toward glucagon (16), and the juxtaglomeruler apparatus in the kidney to secrete renin (17). The atrial stretch receptors, in response to decreased stretch, reduce the secretion of atrial naturitic hormone (ANH). The afferent pathways from the peripheral baro- and chemoreceptors, converging on the nucleus tractus solitarius, cause stimuli to be sent to the hypothalamus. The hypothalamus in turn causes the pituitary gland to secrete adrenocorticotropic hormone (ACTH), antidiuretic hormone (ADH), thyroid-stimulating hormone (TSH), and growth hormone (GH). ACTH stimulates the adrenal cortex to secrete glucocorticoids, while the renin from the juxtaglomerular apparatus, via the elaboration of angiotensin II results in secretion of mineralocorticoids. The secretion of glucagon and glucocorticoids moves the body toward mobilization of fuel stores to supply the heightened energy needs of the organism under severe stress, while the elaboration of ADH and mineralocorticoids, in concert with reduced secretion of ANH, limits loss of fluid from the body to maintain circulating blood volume. The elevated glucose levels observed in early shock, due to lowered insulin levels and insulin resistance from sympathetic discharge, increase the osmolarity of the extracellular compartment allowing intracellular fluid to move out of cells and augment circulating volume (15). The role of TSH and GH are not well defined. TSH may play a permissive role in the sympathetic response, while GH may act in concert with other hormones to increase blood glucose levels.

Systemic Inflammatory Response Over the past two decades there has been a greater understanding of systemic or generalized inflammation. The human body responds to a variety of insults with localized inflammation at the site of the injury. In situations where either the insult is generalized (e.g., prolonged shock), or the magnitude of the localized insult is large (e.g., necrotizing pancreatitis), the inflammation no longer remains localized. In such situations, the inflammatory process becomes generalized, and has been termed ‘‘systemic inflammatory response,’’ and the consequences of this generalized inflammation termed ‘‘systemic inflammatory response syndrome’’ or SIRS. Inflammation is the first step the body initiates in the healing process. However, when the inflammation is generalized, the same processes cause organ dysfunction and can lead to death of the organism. Systemic inflammation is a complex interplay of activation and inhibition of individual components of the three major cascade systems in the body, namely coagulation, complement, and the immune system. The process of shock can be initiated at the time of hypoperfusion, or at the time of resuscitation (ischemia/reperfusion) (18). In its simplest form, the systemic inflammatory response consists of activation of neutrophils in areas of hypoxia with or without reoxygenation. The activated neutrophils express adhesion molecules on their surface, notably CD11a/CD18 (19). Additionally, under the influence of cytokines, generated by a wide variety of hypoxic cells, the endothelial cells and fixed tissue macrophages (e.g., Kupffer cells), express cellular adhesion molecules on their cell membrane surface (20). These adhesion molecules, expressed on the surfaces of neutrophils on the one hand and endothelial cells and fixed tissue macrophages on the other, cause rolling and sticking of the neutrophils, resulting in tight adhesions between the neutrophils and endothelial cells. Finally, chemoattractants (particularly endothelium-produced interleukin-8) induce the neutrophils to emarginate from the capillaries into the

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interstitial spaces (21). Once in the interstitial space, the neutrophils generate free oxygen radicals and tissuedestructive enzymes, resulting in tissue injury. Tissue injury may be delayed till the time of resuscitation (reoxygenation) because free-radical production by neutrophils is most active when oxygen is available. The tissue destruction itself causes more cytokines to be produced, perpetuating the inflammatory process. The state of systemic inflammation involves all major organ systems in the body and causes dysfunction of these systems. As can be expected, the dysfunction is worst in organ systems with abundant capillary networks, such as the lungs, liver, and kidneys. Unless the process is arrested early, organ dysfunction leads to death of the individual.

Organ System Effects The lack of perfusion, the hallmark of shock, affects every living cell in the body, causing far-reaching effects on all body systems. These effects are compounded by the inflammation seen in these organ systems.

Central Nervous System As described above, the central nervous system plays a central role in orchestrating the neuroendocrine response to shock. In addition, there are changes seen within the brain as a consequence of hypoperfusion. Beta endorphins are elaborated by the brain, which may alter the pain response (22). The glucose utilization patterns are altered, with discrete brain stem nuclei increasing glucose utilization (23). There is generalized slowing of brain electrical activity in response to hypotension. This presents clinically in the form of reduced cerebral function, and, at times, with anxiety and restlessness. While most of these changes are reversible, particularly when treatment is provided early, if the shock state is deep and prolonged, some activity may be permanently lost (24). Reflex activity also is depressed. The inability to reverse the loss of reflexes has been suggested to be an early indicator of irreversibility of shock despite achieving a ‘‘normal’’ hemodynamic profile (25). The role of cerebral blood flow (CBF) in causing the observed changes has been studied. CBF is preserved in shock, as is the cerebral oxygen consumption. This is because of preserved cerebral autoregulation and the different response of the cerebral circulation, as opposed to the systemic circulation, to sympathetic stimulation (see above) (26). Even though total CBF is relatively preserved, there are regional differences in the distribution of the flow within the brain. The role of these regional differences in causing the functional changes noted above has not been firmly established, but these differences may contribute to the patchiness of neurologic injury seen after prolonged shock (27). There are, however, limits to cerebral autoregulation of blood flow seen during shock. When the shock state is prolonged, CBF decreases, and brain death follows (26).

the juxtamedullary nephrons (22,28). The flow to these nephrons is important in preserving the hyperosmolarity of the renal medulla, which in turn is essential for tubular concentrating function. When the shock state is prolonged, blood flow to these nephrons is affected as well, resulting in loss of medullary hyperosmolarity. At the cellular level, renal cells respond to circulating catecholamines by increasing glucose production by gluconeogenesis. Late in shock, glucose production falls. It is not clear whether there is any relationship between this altered glucose metabolism and renal function. It has been suggested by some that the changes in glucose production correlate with the energy state of the renal cells, which is important for proper function. At the time the glucose production falls, the energy state of the cells is depleted. The lowered energy state of the cells causes depletion of intracellular adenosine triphosphate (ATP) and intracellular acidosis. This in turn depresses glomerular filtration and concentrating ability of the kidneys. The depressed energy state of the cells has been correlated with renal failure (29). Clinically, this renal failure presents either as oliguric failure with decreased urine output and rising creatinine levels, or nonoliguric renal failure associated with normal or high urine output in the face of rising creatinine levels. It is likely that the two clinical types represent a continuum from the most severe insult resulting in oliguric failure and the less severe insult causing the nonoliguric type of failure.

Heart The role of the cardiovascular system and specifically the heart is well documented as a compensatory response to shock (see above). However, the role of cardiac dysfunction in the progression of the shock state is not as well elucidated. Early in shock, perfusion to the heart is preferentially preserved at the cost of other organs, and the proportion of the cardiac output directed to the heart is increased, with maintenance of cardiac blood flow to near-normal levels. With continued hypoperfusion, these compensatory mechanisms fail, with resultant cardiac dysfunction. Even when the overall blood flow to the heart is ‘‘normal,’’ regional differences in perfusion within the heart exist. Most notably there is evidence of reduction in flow to the endocardium (30). This may play a role in cardiac dysfunction, and may be responsible for the subendocardial hemorrhage and necrosis observed in shock (31). Metabolic defects in myocardial glucose utilization are observed in shock and may be due to abnormal glycolysis secondary to relative myocardial oxygen deficiency. This causes a decrease in intracellular ATP, which has been correlated with survival (31). Lastly, plasma from shocked animals is capable of causing cardiac dysfunction in nonshocked animals, suggesting the presence of a circulating mediator that plays a part in the cardiac dysfunction observed during shock (30).

Lung Kidneys The kidneys are very sensitive to shock, and, in moderate shock, are one of the first organs to fail. Initially, the kidneys respond to hypotension by increasing the tone in the efferent vessels while maintaining or decreasing afferent arterial tone (22). This preserves the glomerular filtration pressure and adequate glomerular filtration. Regional changes in blood flow are observed in early shock. The decreased perfusion is much more pronounced in the superficial cortical region, while there is relative preservation of flow to

Post-traumatic pulmonary insufficiency is a well-recognized consequence of shock. This was initially observed in soldiers injured in Vietnam, and termed the ‘‘Da Nang Lung,’’ later changed to ‘‘Shock lung,’’ and currently called ‘‘Adult respiratory distress syndrome’’ or ARDS. ARDS is a complex syndrome associated with severe diffusion deficit resulting in the inability of the alveoli to transfer oxygen from the inspired gas into the pulmonary capillaries. A variety of cellular and humoral mediators have been implicated in the causation of the syndrome. These mediators cause

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infiltration of neutrophils into the interstitium of the lungs, where they release toxic oxygen radicals and proteolytic enzymes (32). This circumstance results in damage to the alveolar membrane and extravasation of large amount of fluid from the capillaries into the interstitial space. Additionally, the toxic products damage the type I pneumocytes lining the alveoli. The accumulated fluid, in combination with the destruction of pneumocytes, causes a diffusion barrier and hypoxia. This hypoxia, caused by pulmonary dysfunction, compounds the systemic lack of oxygen caused by the shock state. Because the pulmonary failure is often observed two to three days after shock and resuscitation, it remains unclear as to whether the dysfunction is related to the shock state itself or is due to the fluid resuscitation (33). Certain types of resuscitation fluids have been shown to decrease neutrophil sequestration and the amount of fluid that is extravasated in the lungs (34); however, it is unclear whether utilizing those resuscitation regimens will have any beneficial effect on the pulmonary failure (35). In addition to neutrophil infiltration, the lung itself mounts an intense inflammatory response to shock, contributing to the dysfunction (33).

Gastrointestinal Tract The gut is severely affected by hypoperfusion due to shock. Erosion of the mucosa of the stomach and small intestine is well documented (22,36). While in the large majority of patients the erosions are superficial and heal after restoration of blood flow, in some patients the erosions may be deep, and lead to torrential bleeding and death (36). The alteration in splanchnic blood flow, observed in shock, is chiefly due to the body’s compensatory mechanisms diverting limited cardiac output to the heart and brain. This occurs due to intense vasoconstriction of the mesenteric arteries (22,37). Although all vasoconstrictive mediators are involved, the ones most active on the splanchnic circulation are angiotensin II and vasopressin, because the splanchnic vasoconstrictor response to shock is blunted after nephrectomy and hypophysectomy (37,38). The splanchnic vasoconstriction, however, is complex in that there is severe vasoconstriction of arterioles, while at the same time there is dilatation of the mucosal microvasculature, thereby preserving some flow to the mucosa. This vasodilatation in mucosal vessels is believed to be due to the local elaboration of prostaglandins (39,40). A number of investigators have demonstrated that the reduction in splanchnic flow seen during shock often persists despite adequate resuscitation (40–42). This has led some to postulate that microvascular thrombosis and endothelial damage with cell swelling may be an important component of reduced splanchnic flow (38). In some patients, deep and prolonged shock can lead to frank necrosis of parts or the whole of the intestine. Like other areas of the body with large capillary networks, the gut also is prone to neutrophilmediated reperfusion injury (43,44). This injury, probably caused by neutrophil derived oxygen radicals, serves to decrease prostaglandin secretions, compromising mucosal blood flow, and thereby mucosal integrity. The loss of mucosal integrity results in loss of mucosal barrier function, allowing translocation of bacteria and bacterial products across the mucosa into the mesenteric venous beds and lymph nodes (45,46). This translocation of bacteria, observed during shock and resuscitation, has been an area of intense study with some investigators contending that it is responsible for the sepsis and multisystem organ failure

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seen as a delayed consequence of shock. However, although it is clear that gut translocation does occur, whether this translocation has any pathologic consequences is not clear, with most investigators believing that it is probably innocuous. Nonetheless, gut-derived cytokines in response to mucosal injury may still play a significant role in systemic inflammation observed as a consequence of shock (47,48).

Liver The liver is the most metabolically active organ in the body with important roles in maintaining internal homeostasis. It stands to reason that the liver will be affected in shock. Hepatic perfusion is via two different pathways, an arterial pathway through the hepatic arteries and postintestinal venous pathway via the portal vein. The mesenteric flow is severely compromised in shock, and hence the portal flow is reduced. Although there is partial compensation by increased flow in the hepatic arteries, the overall perfusion is decreased and hepatic oxygen demands are not fully met (49–51). Additionally, despite these macrocirculatory adjustments, microcirculatory flow abnormalities occur with derangement of sinusoidal flow (52). Neutrophil infiltration and leukocyte–endothelial cell interactions further compromise sinusoidal flow (53). Reduced sinusoidal perfusion leads to a decrease in intracellular ATP levels (54), and centrilobular hepatic necrosis (55). Clinically, this necrosis manifests itself as an elevation in the hepatic enzyme levels and mild jaundice. In situations where the shock is prolonged, massive hepatic necrosis and fulminant hepatic failure can be seen (55). Metabolically, the cells respond to the increased level of catecholamines, glucagon, and glucocorticoids by increasing glucose production, first by glycogenolysis, and, when glycogen stores have been exhausted, by gluconeogenesis, raising blood glucose levels. In deep and prolonged shock, the cells lose their ability to raise glucose levels, and hypoglycemia is observed (56). This hypoglycemia, seen in prolonged shock, corresponds to mitochondrial dysfunction and impaired oxidative phosphorylation, with decreased hepatic ATP levels and elevated inorganic phosphate levels (57).

Skeletal Muscle Skeletal muscles are not very metabolically active, yet due to the large mass, relative to body weight, metabolic perturbations in the skeletal muscles can have profound effects on the total body metabolism. In patients with shock, skeletal muscles respond to the circulating catecholamines by mobilizing protein stores and providing the liver and kidney the metabolic fuel for gluconeogenesis (22,55). In the absence of adequate oxygen supply, cells all over the body switch from primarily aerobic metabolism to mainly anaerobic metabolism (see later), resulting in an increase in lactate production (54). The skeletal muscle cells contribute the most to the elevated lactate levels seen during shock.

Integument Integumentary circulation is one of the most expendable circulatory beds in the body, and hence when cardiac output is inadequate to meet the needs of the body, this bed is nearly shut down. This absence of perfusion of the skin is responsible for the clinical observation of cold, clammy, and pale skin of patients in shock. The same phenomenon

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was observed by Hippocrates, and described as the Hippocrates facies. While in the short term there is no significant harm to the skin, if the state of shock persists, the absence of perfusion makes skin breakdown at pressure points more likely with resultant pressure sores at these points.

Microcirculatory Effects Microcirculation is the distal-most component of the vasculature, where the exchange of nutrients from the blood to the tissues and the removal of metabolic end products from the tissues to the blood take place. It is an area of intense study, because many believe the transition of shock from a relatively compensated state to a decompensated, and then irreversible state, happens at this level. The microcirculation in shock has been most studied in the skeletal muscle due to accessibility, and the belief that because of the large mass, relative to total body weight, changes here have a much more significant effect on the whole body, as compared to changes in smaller vascular beds. The initial response, as in other beds, is that of intense vasoconstriction under the influence of the sympathetic discharge. If the shock persists, however, there is paradoxical vasodilatation (58,59). The cause of this late vasodilatation, associated with rapid clinical deterioration, is not clearly established. It may be related to buildup of metabolic end products such as CO2 and Hþ (acid) (60). At the capillary level, the response to shock is very heterogeneous (59,61). Some capillaries are constantly perfused, others intermittently, and some, not at all (61,62). The absence of perfusion in some capillaries is thought to be due to endothelial cell swelling, microvascular thrombosis, and leukocyte plugging of the lumen (63,64). Additional arteriovenous channels open up allowing blood to be shunted from the arterioles directly into venules, bypassing the capillaries entirely. The sum total of this microcirculatory derangement is loss of effective capillary surface area, affecting diffusion of nutrients from the blood into tissues and metabolic end products from the tissue into the blood. The buildup of metabolic end products causes derangement in the interstitial milieu, ineffective enzyme systems, and cellular dysfunction. Even after resuscitation, some capillaries fail to ‘‘open up,’’ and this phenomenon is termed the ‘‘no-reflow phenomenon’’ (65). The proportion of capillaries demonstrating the no-reflow phenomenon has been correlated with survival. Thus, the more capillaries adversely affected, the less is the chance of survival.

Role of NO In 1980, several researchers postulated the existence of a chemical mediator that acted at the endothelial level, and was responsible for relaxation of the capillary sphincters, thus controlling microvascular perfusion. This unknown chemical was named the endothelium-derived relaxing factor (66). In 1987, this chemical was identified as nitric oxide (NO) (67). Further research showed that it was derived from L-arginine by a family of enzymes collectively called nitric oxide synthase (NOS). At least three forms of the enzyme have been described. The constitutive form, present in the endothelial cells (ecNOS), is responsible for the baseline production of NO. The best-characterized physiologic role of baseline NO is as a moment-to-moment vasodilator, critical in normal control of blood pressure and flow. A second form of NOS, expressed under the influence of proinflammatory stimuli, and also in prolonged shock, is called inducible NOS (iNOS). NO production by iNOS has been shown to occur in many cell types including

macrophages, hepatocytes, vascular smooth muscle cells, endothelial cells, and fibroblasts. Once induced, iNOS can produce large quantities of NO for hours or days. A third form, found mainly in the central nervous system, is called neural NOS and may be responsible for the differences seen in the systemic and cerebral circulation in response to shock. NO, once generated, has a very short half-life and functions in a paracrine fashion. The biologic actions of NO are principally mediated via the guanylate cyclase/ cyclic guanosine monophosphate pathway. Besides its role in controlling capillary perfusion, the L-arginine–NO pathway may play an important role in regulating the inflammatory state of the cell. The role of the L-arginine–NO pathway in the pathophysiology of shock is an area of intense study, particularly in shock associated with sepsis. In hypovolemic and traumatic shock states, NO levels have been shown to be low in the early phases, probably related to production of inhibitors of ecNOS and also to channeling of L-arginine to alternative pathways by upregulation of other enzyme systems, e.g., arginase (68,69). In prolonged shock and septic shock, NO levels are elevated, probably by upregulation of iNOS (70). This is associated with hypotension and the loss of vasoreactivity to catecholamines. These changes are most pronounced in septic shock but are also seen in other forms of shock. Attempts to improve clinical outcomes by modulating the L-arginine–NO pathway by inhibiting NOS activity to reduce the levels of NO, or conversely by providing NO donors and increasing NO levels, are areas of intense study.

The Cell in Shock The fundamental pathophysiological derangement at the cellular level during shock consists of an alteration in the metabolism, affecting cellular energy production and function. Adequate oxygen availability is crucial for normal cellular function. In the presence of oxygen, aerobic metabolism predominates, with generation of high-energy phosphate bonds—ATP—by sequential glycolysis, tricyclic acid (Kreb’s) cycle, and oxidative phosphorylation (Fig. 3). In the absence of oxygen, due to inadequate perfusion, metabolism shifts to an inefficient anaerobic glycolysis, with inadequate production of ATP and near-complete shutdown of the Kreb’s cycle and oxidative phosphorylation. Not only is the process less efficient, but lactic acid, a by-product of anaerobic metabolism, also builds up in the cell, causing the pH to drop, profoundly affecting essential enzyme systems. Intracellular acidosis can also influence the response of cells to various endogenously produced or exogenously administered circulating hormones or chemicals such as catecholamines or corticosteroids (71). Cellular integrity is dependant upon the protection offered by a functioning and intact cell membrane (72). Enzyme systems within the cell membrane maintain ionic gradients that are responsible for the transmembrane potential difference normally present. One of the most important enzyme systems is Naþ-Kaþ-ATPase. Studies have shown that the cell membrane dysfunction with influx of ions and water can be duplicated by ouabain, which directly inhibits the Naþ-Kaþ-ATPase pump (73). In the shock state, probably due to the depletion of ATP, this important system ceases to function properly resulting in the influx of Naþ into the cell. To maintain osmolar equilibrium, water follows, causing a major volume shift from the extracellular to the intracellular compartment. Additionally, the ionic shift results in significant decrease in the transmembrane

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prolonged shock, and the intracellular accumulation of calcium has been shown to induce many of the changes observed in shocked cells (78). In the above discussion, the microcirculation and the cell have been discussed as separate entities, but in reality they are very intimately related. Changes in the microcirculation are responsible for the cellular derangements due to hypoxia, and conversely, deranged cellular physiology affects the microenvironment of the cell, which in turn influences the microcirculation.

Changes in Body Fluid Compartments

Figure 3 Glucose metabolism in the normally perfused (aerobic) and hypoperfused (anaerobic) state. In the well-perfused state with adequate oxygen availability, metabolism proceeds by sequential glycolysis, Kreb’s cycle, and oxidative phosphorylation to generate high-energy phosphate bonds in the form of adenosine triphosphate. In the hypoperfused state with lack of oxygen at the tissue level there is near complete shutdown of Kreb’s cycle and decoupling of oxidative phosphorylation resulting in fewer high-energy phosphate bonds, and generation of lactic acid as a by-product leading to metabolic acidosis. Abbreviations: ATP, adenosine triphosphate; NADH, nicotinamide adenine dehydrogenase.

potential difference (6,74). There are, however, important differences between cells subjected to the same degree of shock. For example, in skeletal muscle cells, all the mentioned changes are observed, except significant decreases in the ATP levels. It is postulated that the maintenance of ATP levels in muscle cells is from the conversion of creatine phosphate to ATP. In contrast, in hepatocytes, the same degree of shock results in significant depletion of ATP levels, because hepatocytes do not possess alternative sources of high-energy phosphate bonds that can be converted to ATP (54). To explain the inadequacy of NaþKaþ-ATPase in the absence of significant decrease in ATP levels, other mechanisms of cell membrane dysfunction have been postulated. One of the suggested alternative mechanisms for Naþ-Kaþ-ATPase dysfunction is primary damage by endotoxin, complement, or some unidentified toxic product of hypoxic cells (75,76). In addition to the cell membrane dysfunction with loss of transmembrane potential and influx of water and electrolytes into the cell, mitochondrial dysfunction has been implicated as a major component of overall cell dysfunction seen during shock. Mitochondrial dysfunction with uncoupling of oxidative phosphorylation and inadequate ATP production may be directly responsible for the energy depletion observed in the shock state. This is especially true for metabolically active tissues such as the liver. These abnormalities in mitochondrial function can persist for a prolonged period of time even after resuscitation and restoration of substrate has occurred (57,77). Abnormalities of calcium hemostasis are also suggested as a major component of cellular dysfunction during shock. Calcium plays a major role in cellular function: in gluconeogenesis, contraction coupling in excitable cells, protease activation, cell and mitochondrial membrane stability, and coupling of electron and hydrogen ion transport essential for oxidative phosphorylation. In addition, calcium acts as a second messenger for several hormones. A rapid influx of calcium has been shown to occur in cells subjected to

Sixty percent of the body weight in a healthy individual comprises water, with two-thirds being present intracellularly and the rest being extracellular. Three-quarters of the extracellular water is present in the interstitial space, and the rest is intravascular (Fig. 4). In early shock, reduced capillary perfusion results in decreased intracapillary hydrostatic pressure. The decreased hydrostatic pressure causes movement of fluid across the capillary membrane from the interstitial space into the intravascular compartment following Starling forces. Later in shock, there is relative hyperosmolarity of the extracellular compartment, produced by hyperglycemia. In response to this hyperosmolarity, there is movement of fluid from intracellular into the extracellular compartment. Both these changes, transcapillary refill and intra- to extracellular fluid movement, are compensatory mechanisms, augmenting circulating volume and improving cardiac output (Fig. 4). If the shock state persists, however,

Figure 4 Fluid shifts observed during various stages of untreated shock. In the normal person, two-thirds of the body water is present intracellularly. Of the extracellular water, three-fourths is in the interstitial compartment, and the remaining intravascular. With loss of volume from the intravascular compartment during hemorrhagic shock, there is contraction of the intravascular volume (uncompensated shock) leading to reduction in the capillary hydrostatic pressure. With compensation, interstitial fluid moves into the vascular compartment along Starling principles (transcapillary refill). With increased osmolarity of the extracellular compartment, contributed to mostly from hyperglycemia, intracellular fluid moves across cell membrane along osmotic gradients to augment interstitial and intravascular volumes. If the state of shock is prolonged, compensatory mechanisms fail. There is loss of cell membrane potential difference and movement of water and electrolytes across cell membrane resulting in increased intracellular space at the expense of extracellular compartments. — — —, Capillary endothelial lining; ——, cell membrane.

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there is loss of cell membrane potential difference with derangement of ionic gradients and massive shift of fluid from the extracellular compartment into the cells. This intracellular uptake of fluid is the principal site of fluid and electrolyte sequestration seen in prolonged and severe shock (Fig. 4) (6,57,74). In addition, the systemic inflammation induced by prolonged shock results in capillary membrane dysfunction, causing fluid to shift from the intravascular compartment into the interstitium. Once a patient has passed into this phase of shock, for any therapy to be successful, massive volume infusions are required to replenish the extracellular compartment.

Compensated, Decompensated, and Irreversible Shock Wiggers in the mid-20th century performed a series of experiments involving animals with varying degrees of hemorrhagic shock. In his experiments, when animals were bled down to a low blood pressure and maintained in that state, they were relatively fine for a few hours, and completely recovered when the shed blood was returned. This state of shock was termed the ‘‘compensated phase.’’ In this compensated phase of shock, the body’s compensatory mechanisms, especially redistribution of blood flow and increased oxygen extraction, are sufficient to maintain survival. However, if the animals were maintained in shock for a more prolonged period, the animals failed to recover despite reinfusion of all the shed blood. These animals did survive, however, if in addition to the shed blood, they were also given large volumes of balanced salt solution. This state was called the decompensated phase of shock. Finally, if the animals were maintained in the shock state for an even greater length of time, they failed to recover despite reinfusion of all shed blood and infusion of large volumes of salt solution. This phase was termed by Wiggers as ‘‘irreversible shock’’ (6). More recently, these observations have been correlated with derangements at the microcirculatory and cellular level. The decompensated phase of shock occurs at the point when the compensatory mechanisms fail, and fluid shifts from the intravascular compartment to the interstitium across the capillary membrane, and also from the interstitium into the cells across the malfunctioning cellular membrane (6,57,74). The irreversibility of shock, and nonsurvival may be related to the volume of tissue beds that have been occluded for so long that despite resuscitation, too many areas are irretrievable due to microvascular thrombosis, endothelial cell swelling, and leukocyte plugging. While in the nonshocked state, 90% of the capillaries are perfused, shock results in the perfusion of only 30% to 50% of the capillaries. Early in shock, the ability of the organism to compensate and redistribute blood from peripheral beds to vital central organs is dependant on the degree of loss of these capillary beds (61,62). As resuscitation proceeds, arteriolar flow slowly increases with reperfusion of the capillary beds. In survivors, arteriolar flow rates reach 40% to 50% of normal within a few hours. However, in nonsurvivors (irreversible shock), arteriolar flow and consequent capillary reperfusion fails to reach beyond 15% to 20% of normal (65). In concert with these changes, the blood pressure in nonsurvivors fails to reach the levels observed in survivors. At the microcirculatory level, paradoxical dilatation of the precapillary sphincters is observed, with nonresponsiveness to exogenous catecholamines. These later changes are possibly related to upregulation of iNOS, with production of large quantities of NO (70,79).

Investigations into the cause of the no reflow phenomenon seem to implicate endothelial cell dysfunction with swelling, and leukocyte plugging with possible activation and release of toxic products by neutrophils (63,80). In a series of experiments involving animals that were either neutropenic (81) or whose neutrophils were inactivated by a monoclonal antibody directed against the neutrophil adhesion molecule CD18 (82), a higher proportion of animals with absent or nonfunctional neutrophils survived the same degree of shock as compared to normal animals. At autopsy, a significantly higher percentage of no reflow capillaries were noted in the normal (nonsurviving) animals, as compared to the animals with neutropenia, or nonfunctional neutrophils. Because neutrophil-mediated injury is maximum in an oxygen-rich environment, it is unclear how much of the damage is due to mechanical plugging produced by endothelial cell swelling and leukocyte entrapment occurring at the time of shock versus active damage produced by toxic neutrophil products at the time of oxygen abundance seen during resuscitation. Some investigators choose to view shock as a whole-body ischemia reperfusion injury, with neutrophil-mediated organ injury as the most important factor responsible for irreversibility and death (83).

MANAGEMENT CONSIDERATIONS To effectively manage a patient in shock and to reverse the pathophysiology of shock, it is important to be able to (i) diagnose shock by evaluating perfusion adequacy; (ii) treat the state of shock by improving perfusion; (iii) diagnose and treat the cause of shock.

Diagnosis of Shock—Evaluation of Perfusion Shock is a state of perfusion inadequacy, and not merely low blood pressure. In fact, a state of shock (inadequate perfusion) may exist in the face of ‘‘normal’’ blood pressure, while a patient in ‘‘hypotension’’ may have adequate perfusion and not be in shock. A number of relatively simple to fairly complex measures exist to evaluate a patient for adequacy of perfusion. These may broadly be divided into (i) global measures of perfusion adequacy and (ii) organspecific measures of perfusion adequacy. No one measure is perfect and each has its own false negatives and positives, and hence a battery of measures should be taken into consideration when diagnosing shock.

Global Measures of Perfusion Global measures of perfusion are indices that estimate the overall state of perfusion of the body. In situations where these are deranged, a state of shock almost certainly exists. However, if these global measures are within normal limits, there still may be areas in the body where significant hypoperfusion is present.

Lactic Acid The hypoperfusion in shock leads to cellular hypoxia. Cells respond to hypoxia by shifting from aerobic metabolism to anaerobic metabolism, with the generation of lactic acid as a by-product (Fig. 3). Lactic acid is normally cleared by the liver via the Cori cycle to generate bicarbonate. In shock, there is more lactic acid generated, and the liver’s ability to clear this is impaired due to hepatic hypoperfusion. This leads to the accumulation of lactic acid within the body, manifested by elevated serum levels. Elevated lactic acid

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levels signify a global state of hypoperfusion, but like all global measures, normal levels do not rule out localized areas of hypoperfusion. Lactic acid levels may be elevated without hypoperfusion due to some drugs (Metformin), in liver disease due to poor hepatic clearance, and in acute alcohol intoxication. These drawbacks notwithstanding, the lactic acid level remains an excellent global measure of perfusion adequacy, and has been correlated with the degree of shock, and survival. Studies performed on trauma patients have shown that patients with traumatic shock, who rapidly clear lactic acid from the system in response to resuscitation, have a better outcome, as compared to patients who either fail to clear lactic acid, or do so very gradually (84).

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the heart and some other similar organs are suffering from inadequate perfusion and lack of oxygen. Hence MvO2, although invasive, is a very sensitive global measure of perfusion adequacy (86). Modern pulmonary artery catheters are capable of continuously measuring the oxygen saturation in the pulmonary artery, thus providing an excellent realtime assessment of overall perfusion. However, MvO2 may be falsely high, suggesting adequate perfusion even in the presence of shock in patients with advanced liver disease due to opening of cutaneous arteriovenous channels, and also in patients with conditions in which the tissues are unable to extract oxygen from the hemoglobin (septic shock, cyanide poisoning, etc.).

Organ-Specific Measures of Perfusion Base Excess A negative base excess (formerly referred to as base deficit) signifies metabolic acidosis. In shock, there is accumulation of lactic acid as a by-product of anaerobic metabolism, resulting in lactic acidosis that manifests itself as metabolic acidosis and negative base excess. Base excess suffers from the same drawbacks as any other global measure. In addition, base excess may reveal significant metabolic acidosis due to causes other than shock-related hypoperfusion (e.g., renal failure or renal tubular acidosis). Base excess has been extensively studied, particularly in patients with traumatic shock, and is an excellent measure of perfusion adequacy, with good correlation with the degree of shock, and survival (85).

Mixed Venous Oxygen Saturation Hemoglobin molecules present within the red blood cells are the principal mode of oxygen transport within the body. Hemoglobin molecules bind oxygen in the lungs and, in the absence of pulmonary insufficiency, hemoglobin in the blood returning to the heart via the pulmonary veins is fully saturated (100%) with oxygen. At the tissue level, oxygen dissociates from the hemoglobin molecule providing the cells with oxygen. In the nonshocked state of adequate perfusion, the degree of oxygen extraction from the saturated hemoglobin molecule differs in different tissues depending upon the oxygen need. There is very little extraction (approximately 10%) in metabolically inactive tissues such as the skin and fat and the hemoglobin in the venous blood from such tissues remains approximately 90% saturated with oxygen. On the other hand, metabolically active tissues such as the heart muscle extract the maximum possible oxygen (approximately 70%) from the hemoglobin, and the coronary venous hemoglobin oxygen saturation is approximately 30%. When venous blood from all over the body is mixed together, the average oxygen saturation is approximately 75%. This is called the mixed venous oxygen saturation (MvO2) and is measured in blood from the pulmonary artery. The percentage of hemoglobin from which oxygen has been extracted is called the oxygen extraction ratio (normal ¼ 25–30%). In the shock state when the perfusion is inadequate to meet the body’s oxygen requirements, one of the earliest responses by the tissues is to increase extraction from hemoglobin. As a result, there is a decrease in MvO2 and a consequent increase in oxygen extraction ratio. While this compensatory mechanism is available to most tissues to maintain oxygen availability in times of inadequate perfusion, it is not possible in the heart where oxygen extraction is maximum even in the resting state. If the MvO2 falls below 60%, it can be presumed that at least

Due to the drawbacks of global measures, organ-specific measures of perfusion were developed, which evaluate perfusion in specific organs. These measures are mostly utilized for organs that the body considers nonvital, and from where perfusion is diverted away in favor of vital organs such as the heart and brain. The reasoning being that if the body is perfusing these organs well, the overall state of perfusion must be satisfactory.

Integument One of the first vascular beds from where perfusion is redirected away is the integument. Hence one of the earliest organs to show evidence of shock is the skin. On examination, the skin of a patient in shock is cold and clammy. More sophisticated measures have shown changes in cutaneous electrical resistance and changes in tissue oxygen tension measured transcutaneously (87). Although fairly sensitive, cold and clammy skin is not specific to shock, and can be seen in any condition that results in sympathetic stimulation.

Brain In shock, the body preferentially directs limited perfusion toward, rather than away from the brain. Nevertheless, higher brain function is extremely sensitive to even the slightest decrement in perfusion. A patient very early in shock will appear restless, agitated, and oftentimes confused. In severe shock the patient will rapidly lose consciousness. As with the skin, other conditions may produce these same findings.

Mucosal Tonometry Mucosal tonometry measures pH within the lining mucosa of internal organs. As with the skin, in shock, blood flow to the gastrointestinal and genitourinary tracts is severely compromised, resulting in acidosis of the mucous membranes lining these tracts. This fact has been utilized to assess perfusion within these tracts. A number of probes have been developed to measure the pH in different mucosal surfaces. The only technique that has been clinically utilized is gastric tonometry, where a probe attached to the gastric tube measures the pH within the gastric mucosa (88). Others have developed probes to similarly assess the pH in other mucous membranes—urinary bladder, sublingual, etc. While attractive in theory, mucosal pH can be altered by the tissue carbon dioxide levels, and the technique can be quite cumbersome in practice.

Treatment of Shock—Improving Perfusion Once it has been determined that perfusion is inadequate, i.e., a state of shock exists, treatment should be directed

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toward improving perfusion, or reversing the shock state. Among the different types of shock, cardiac compressive shock is an emergency that unless treated immediately can rapidly lead to death. Fortunately, in the majority of instances, cardiac compressive shock can be rapidly diagnosed by a good physical examination. Treatment should immediately achieve decompression of the pericardial or pleural cavities, as the case may be, to rapidly reverse the process and improve perfusion. In all other forms of shock, a systematic approach is essential to elucidate the fundamental derangement—preload, contractility, or afterload—that is responsible for the shock state (Fig. 5). The clinical scenario can provide useful direction as to the most likely derangement. For example, patients with major trauma in most instances would be suffering from hypovolemic shock—reduced preload—due to hemorrhage, while in the presence of high spinal cord injury, neurogenic shock—loss of afterload—is the likely cause. Patients presenting with acute myocardial infarction associated with shock are most likely to have cardiogenic shock— poor contractility—as a cause. However, even in such obvious situations, other derangements should not be ruled out, because a patient presenting in shock following a major motor vehicle collision may have had an acute myocardial infarction that caused the collision.

Evaluation of Preload An adequate circulating volume is essential for adequate cardiac function and perfusion. Adequacy of circulating volume may be assessed clinically by examination for fullness of peripheral veins, auscultation of the chest for rales, examining a chest radiograph for fullness and size of the heart, and the radiolucency of the lung fields. In some situations, the clinical evaluation may be confusing because the variables mentioned are nonspecific and can be affected by other conditions. In such situations, more invasive methods include measurement of the central venous pressure that evaluates cardiac filling on the right side of the heart, and the capillary wedge pressure that evaluates filling on the left side of the heart. However, filling pressures can be affected by the prevailing pressures in the thoracic cavity (e.g., pulmonary and abdominal). Second, the premise of using pressures to evaluate cardiac end-diastolic volume— preload—is that the higher the end-diastolic volume, the higher will be the filling pressures. This premise is based on ‘‘normal’’ pressure–volume relationship of the heart or ‘‘normal’’ ventricular compliance. It is well known that in many disease states, notably sepsis, the ventricular compliance can change from day to day. Hence, filling pressures may give an erroneous estimate of preload. When the clinical picture is confusing, pulmonary artery catheters with

Figure 5 Algorithm outlining the steps in the evaluation and management of shock. Evaluation steps are shown in clear boxes, and action steps in shaded boxes. The callouts to the right show aids used in the suggested evaluation/action.

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rapid response thermisters can be utilized to directly measure cardiac end-diastolic volume. Using these catheters, it is possible to construct the pressure–volume loop and quantitatively measure all parameters of perfusion. Lastly, a small volume challenge may be necessary to establish whether increasing the preload further will be of benefit or not. If by rapidly infusing a bolus of 250 to 500 mL of crystalloid clinical improvement in the perfusion markers is achieved, the patient will benefit from further increases in circulating volume. If however there is no improvement in the perfusion status, the whole clinical situation should be reevaluated to determine the most appropriate intervention. Experimentally, it has been determined that in patients in shock, who have low preload, volume infusion is the most efficient method of improving perfusion—maximum improvement with least cost in terms of increase in cardiac energy needs.

Evaluation of Contractility After determining that the patient has adequate preload, and yet continues to have poor perfusion—remains in shock—evaluation and improvement in cardiac contractility should be the next intervention in the treatment of shock. The best method to quantify cardiac contractility is to place a pulmonary artery catheter with the rapid response thermister and construct a pressure–volume loop. However, even in the absence of such a catheter, a therapeutic trial of an ionotropic agent may provide the required information. If by augmenting the contractility there is improvement in perfusion parameters, then the agent should be continued. Although improving contractility by using such agents results in significant increase in cardiac oxygen requirements, it is more energy efficient than using pressor agents to manipulate afterload. Intensive monitoring is essential to prevent the development of excessive tachycardia because that can lead to a significant increase in cardiac energy requirements, and even precipitate cardiac ischemia.

Evaluation of Afterload In rare situations, after maximizing preload and optimizing cardiac contractility, the patients still remains in shock. In such situations, afterload manipulations are necessary. Increase in afterload is often necessary in neurogenic shock. In other forms of shock, it should be borne in mind that increasing afterload to increase blood pressure, while sometimes required, places a great strain on the heart. Hence increasing afterload by pressor agents should be performed with extreme caution, and for the shortest possible time. It is advisable to have a pulmonary artery catheter in place to ensure that the patient has a high cardiac output, and introduction of a pressor to increase blood pressure will improve perfusion, and not decrease it further. The situation is most often encountered in patients with septic shock; however, afterload manipulation should only be done after ensuring adequate circulating volume and improving cardiac contractility. On the other hand, in some patients, especially older individuals, afterload reduction may be of tremendous benefit. Afterload reduction improves cardiac performance by decreasing the resistance against which the heart has to pump. If the blood pressure is adequate, the circulating volume replenished, and contractility increased, then an agent to reduce afterload may improve perfusion dramatically, while at the same time reducing the cardiac energy requirements. It should be mentioned that the systemic vascular resistance as calculated by regular pulmonary artery

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catheter is very unreliable in quantifying the afterload. This value is derived from the measured cardiac output. Hence if the value is high with a low cardiac output, it cannot be presumed that the low cardiac output is secondary to the high systemic vascular resistance. On the other hand, utilizing the pulmonary artery catheter with rapid response thermister will allow the construction of the pressure–volume loop and the measurement of the afterload, independent of the preload and contractility. This may be invaluable in guiding therapy in patients in whom afterload manipulation is necessary to maintain adequate perfusion.

Treatment of the Cause of Shock The causes of shock are many. As the hypoperfusion of shock is being addressed, a systematic effort should be made to determine the cause of the shock and provide appropriate therapy. The specific therapy for each condition leading to shock is adequately dealt with in other chapters of this book.

THE FUTURE Current therapy of shock involves reversing the deranged physiology brought about by prolonged or severe hypoperfusion leading to tissue hypoxia. One of the areas of research involves developing resuscitation solutions that not only provide circulating volume but at the time also carry oxygen. Such solutions will allow a more rapid correction of the deranged physiology, and possibly improve outcome. Another area of research involves elucidating the cellular and subcellular mechanisms that cause some patients with prolonged or severe shock to pass into a phase of irreversibility. Although the causes and exact point at which an individual passes into the irreversible phase is not clearly established, studies suggest that the transition happens at the microcirculatory level. Some researchers are focusing on therapies to improve the microcirculation while the overall macrocirculatory perfusion is being improved by conventional therapy. Lastly, systemic inflammation initiated by shock contributes very significantly toward organ system failure and death. Therapies are being developed to attenuate the runaway systemic inflammatory response and prevent organ system dysfunction and death.

SUMMARY Shock is a state of perfusion that is inadequate to meet the metabolic needs of the body. It represents a continuum from the relatively compensated state of occult hypoperfusion, to the severe irreversible state where the fundamental functions of the cell are so compromised that no recovery is possible. Because no cell in the body can exist for long without adequate perfusion, even a mild state of shock has far-reaching consequences on every cell in the body, and in turn on the functioning of the organ system comprising those cells. The body responds in a predictable fashion to the state of hypoperfusion by initiating compensatory responses to assure survival of the organism. To adequately treat shock, the state of hypoperfusion has to be recognized. Once recognized, a systematic, sequential pathway should be formulated to correct one or more of the deranged parameters that define perfusion—preload, cardiac contractility, and afterload. At the same time as the shock state is being treated—perfusion being improved—the specific cause of shock should be sought and treated.

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70. Szabo C. Alterations in nitric oxide production in various forms of circulatory shock. New Horiz 1995; 3:2. 71. Mizock BA, Falk JL. Lactic acidosis in critical illness. Crit Care Med 1992; 20:80. 72. Choudhary IH, Sayeed MM, Baue AE. Effect of adenosine triphosphate-magnesium chloride administration n shock. Surgery 1974; 75:220. 73. Williams JA, Winthrow CD, Woodbury DM. Effects of ouabain and diphenylhydantom on transmembrane potentials, intracellular electrolytes, and cell pH of rat muscle and liver in vivo. J Physiol 1971; 212:101. 74. Shires GT III, Peitzman AB, Illner H, et al. Changes in red cell transmembrane potential in hemorrhagic shock. Surg Forum 1981; 32:5. 75. Eastridge BJ, Darlington DN, Evans JA, et al. A circulating shock protein depolarizes cells in hemorrhage and sepsis. Ann Surg 1994; 219:298. 76. Jones R, Carlson DE, Gann DS. A circulating shock protein that depolarizes cells in vitro depresses myocardial contractility and rate in isolated rat hearts. J Trauma 1994; 37:752. 77. Choudhary IH. Cellular mechanisms in shock and ischemia and their correction. Am J Physiol 1983; 245:R117. 78. Smith A, Hayes G, Romaschin A, et al. The role of extracellular calcium in ischemia reperfusion injury in skeletal muscle. J Surg Res 1990; 49:153. 79. Thiermann C, Szabo C, Mitchell JA, et al. Vascular hyporeactivity to vasoconstrictor agents and hemodynamic decompensation in hemorrhagic shock is mediated by nitric oxide. Proc Natl Acad Sci USA 1993; 90:267. 80. Barroso-Aranda J, Schmid-Schonbein GW, Zweifach BW, et al. Granulocytes and no-reflow phenomenon in irreversible hemorrhagic shock. Circ Res 1988; 63:437. 81. Barroso-Aranda J, Schmid-Schonbein GW. Transformation of neutrophils as indicator of irreversibility in hemorrhagic shock. Am J Physiol 1989; 257:H846. 82. Vedder NB, Fouty BW, Winn RK, et al. Role of neutrophils in generalized reperfusion injury associated with resuscitation from shock. Surgery 1989; 106:509. 83. Powell SR, Tortolani AJ. Recent advances in the role of reactive oxygen intermediates in ischemic injury. J Surg Res 1992; 53:417. 84. Abramson D, Scalea T, Hitchcock R, et al. Lactate clearance and survival following injury. J Trauma 1993; 35:584. 85. Rutherford E, Morris J, Reed G, et al. Base deficit stratifies mortality and determines therapy. J Trauma 1992; 33:417. 86. Bishop MH, Shoemaker WC, Appel PL, et al. Prospective randomized trial of survivor values of cardiac index, oxygen delivery, and oxygen consumption as resuscitation endpoints in severe trauma. J Trauma 1995; 38:780. 87. Tremper KK, Shoemaker WC. Transcutaneous oxygen monitoring of critically ill adults with and without low flow shock. Crit Care Med 1981; 9:706. 88. Ivatury RR, Simon RJ, Islam S, et al. A prospective randomized study of endpoints of resuscitation after major trauma: global oxygen transport indices versus organ-specific gastric mucosal pH. J Am Coll Surg 1996; 183:145.

9 Neoplastic Disease: Pathophysiology and Rationale for Treatment Gregory Kennedy and John E. Niederhuber

cell (8). In fact, one group studying H-Ras’ role in the genesis and maintenance of tumors using an inducible murine model of melanoma found the function of Ras to be required for continued cell survival despite the exogenous addition of alternative growth factors (9). This work demonstrates the importance of oncogenic signals in maintaining cellular proliferation and provides hope that functions of the Ras protein may serve as targets for novel therapeutics (10). In fact, many different inhibitors of the Ras protein and the Ras-signaling pathway have been developed and are in clinical trials (10). One such class of drugs is constituted by the farnesyl transferase inhibitors. These drugs work by inhibiting the posttranslational modification of the Ras protein, thereby disrupting its cellular localization. While these drugs have shown great promise in the preclinical phase of their development (11), their use in humans has been somewhat disappointing (10). Another mechanism by which tumor cells frequently achieve autonomous growth is through the modulation of growth factor signals. While most soluble mitogenic growth factors are made by one cell type to stimulate proliferation of another, many cancer cells acquire the ability to synthesize growth factors to which they are responsive, creating positive feedback, often termed ‘‘autocrine stimulation.’’ The idea that tumor cells synthesize, release, and respond to their own growth factors is not novel. A large variety of transformed cells have been reported to produce mitogenic factors, suggesting that this ability of self-stimulation might be important in the establishment and maintenance of transformation. The action of the transforming growth factor peptides is mediated by their distinct membrane receptors, which in turn activate a signaling mechanism eventually leading to a mitogenic response. Such a signaling pathway may be modified by oncogene expression at the receptor or postreceptor levels, as well as by changes in the level of expression of the growth factor itself (12). Indeed, the ability of many oncogenes to render cancer cells independent of growth factors seems to be related to how they alter a signaling pathway, rather than to a primary alteration in the synthesis and release of a specific growth factor. The autocrine action of the effector peptide may be amplified by mechanisms other than an increase in concentration. For example, enhanced cellular responsiveness to a growth factor may also result from a change in the number or affinity of receptors of the growth factor. Thus, very high numbers of epidermal growth factor receptors (EGFrs) are found in squamous carcinoma cells derived from human head and neck cancers (13). Furthermore, different types of sarcomas stained with a monoclonal antibody to EGFr’s demonstrated increased staining in the tumor compared to the stroma (14).

INTRODUCTION Our understanding of both cellular and molecular properties of neoplasia has been significantly enhanced by studies using fresh human tissue and clonogenic tumor cells in tissue culture. In this chapter, we describe basic principles of cancer biology modeled in part from a thoughtful review by Hanahan and Weinberg (1). We have used the six traits of a cancer cell (Table 1) as coined by Hanahan and Weinberg to describe the basic tenets of cancer biology. We also demonstrate through a review of the literature how findings in basic research lead to improved therapies for the treatment of cancer. Finally we summarize basic principles underlying the treatment of cancer. By joining insights from basic research to developments in treatment, we hope to provide rationales for the next generation of cancer therapies.

BASIC CONCEPTS OF CANCER BIOLOGY Self-Sufficiency in Growth Signals The ability to grow autonomously was an early-recognized trait of cancer cells. Researchers identified, in cancer cells, mutations that allow the product of a gene to bypass the normally obligate requirement of somatic cells for external mitogenic signals (2). The identification of these genes was assisted by virologists interested in understanding how certain retroviruses transformed normal avian cells (3,4). Identifying the genes responsible for the transformation of the phenotype induced by infection of cells with retroviruses led to the discovery of mammalian homologs of the viral gene products (5,6). It has been observed over the years that mutations within the cellular proto-oncogenes are a requirement for tumor development and have been found to be common in tumors of all types. For example, it is estimated that up to 20% of all human tumors will have undergone an activating mutation in one of the most famous proto-oncogenes, the Ras gene(s) (7). Such mutations allow the Ras protein to function independently of mitogenic signals, thereby providing a constitutive growth signal to the

Table 1 Six Traits of a Cancer Cell Self-sufficiency in growth signals Insensitivity to growth-inhibitory signals Evasion of programmed cell death Limitless replicative potential Sustained angiogenesis Tissue invasion and metastasis Source: From Ref. 1.

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These types of observations have been furthered by inhibiting the EGFr’s activity with a monoclonal antibody, which resulted in an increased radiosensitivity of squamous cell carcinoma cell lines in vitro (15). Such preclinical observations may have a substantial impact on the treatment of various cancers. Cancer cells can also switch the types of extracellular matrix receptors (integrins) they express, favoring ones that transmit progrowth signals (16,17). In general, cells require anchorage to the extracellular matrix to maintain viability. Integrins can affect viability through the promotion of either cell growth or cell death. For example, integrins can facilitate growth factor–mediated activation of extracellular signal-regulated kinase (ERK), which may be required for cell growth via phosphorylation of the ternary complex factor, which promotes transcription of the immediate-early gene c-Fos (18). On the other hand, loss of attachment to the matrix results in the apoptotic death of many cell types. Mechanisms by which integrins protect cells from apoptosis vary. The integrin a5b1, which binds to fibronectin in the extracellular matrix, protects cells from apoptosis by upregulating the antiapoptotic protein B-cell CLL/lymphoma 2 (Bcl-2) (19). On the other hand, the a5b1 integrin promotes endothelial and melanoma cell survival by the suppression of the p53 pathway and activation of the nuclear factor kappa B transcription factor (20,21). Furthermore, treatment of melanoma M21 cells with antagonists of the integrin a5b3 resulted in their apoptotic death (22). Such observations provide hope that inhibitors of these cell surface proteins may someday prove useful for the treatment of cancer. Tumor growth has traditionally been explored by focusing on isolated genetically deranged cancer cells. While this experimental approach has given us much insight into the biology of cancer, it has ignored any contribution to tumor growth provided by the microenvironment—the apparently normal bystander cells such as fibroblasts, endothelial cells, macrophages, etc. Virtually all cancers are composed of several distinct cell types that appear to communicate via heterotypic signaling. This heterotypic signaling may play a significant role in the initiation of a tumor, as well as in the maintenance of the tumor cell’s continued proliferation. For example, fibroblast cells

constitutively expressing platelet derived growth factor (PDGF) have been shown to induce epithelial tumors when subcutaneously injected into nude mice (23). These findings indicate that successful epithelial tumor cells have the ability to cooperate with their stromal microenvironment, thereby making them more physiologically fit to grow into a tumor. Other studies have found that the initiated cells grown in the presence of stroma isolated from a tumor have a phenotype different from that of the same cells grown in the presence of stroma isolated from normal tissue (24). These observations have been extended by others who have shown that mutations in the tumor suppressor genes p53 and phosphate tensin homolog (PTEN) can be identified in both the tumor and stromal compartments (25); furthermore, these mutations seem to be exclusive of one another. The fact that mutations could be found in these tumor suppressor genes of the stromal cells independent of the epithelial cells is consistent with the stroma contributing through epithelial–stromal cross-talk to tumor development (25). Taken together it is clear that the emphasis formerly placed on isolated tumor cells needs to also include the environment in which the tumor cells reside. Such a shift in paradigm to a ‘‘tissue’’ or ‘‘organ’’ dynamic should result in the identification of new targets for the development of new therapeutic agents.

Insensitivity to Growth-Inhibitory Signals Antiproliferative signals exist to keep the growth of cells in check, thereby preventing tumor formation and achieving tissue homeostasis. These growth-inhibitory signals, like growth-promoting signals, are received by transmembrane receptors coupled to intracellular signaling circuits. To understand fully the mechanism by which antiproliferative signals work, we must first understand the basic cell cycle. The classic cycle of cell division (Fig. 1) can be divided into four ordered and strictly regulated stages: G1 (Gap 1), S (DNA synthesis), G2 (Gap 2), and M (mitosis) (26). Daughter cells generated by mitosis reside in either G1 or G0 (resting or quiescent state) and retain a diploid set of chromosomes. The ultimate molecular regulator of the cell cycle is the retinoblastoma protein (pRb) (27,28). pRb is the classic tumor suppressor protein, the function of which is lost in

Figure 1 A schematic representation of the cell cycle. In the first phase of the cell cycle (G1), the cell is undergoing biochemical changes required for the synthesis of DNA (S). G2 is the second preparatory phase of the cell cycle during which time the cell prepares for mitosis to occur (M). The restriction point of the cell cycle (R) is that point in the cell cycle prior to which mitogenic factors are required for the cell to progress through the cycle. After the restriction point, mitogens are not required for continued progression. G0 is a phase of the cell cycle marked by quiescence. This is a reversible process unless the cell is stimulated to exit the cell cycle permanently commonly through the process of differentiation.

Chapter 9: Neoplastic Disease: Pathophysiology and Rationale for Treatment

patients with retinoblastoma, and was the paradigm for Knudson’s ‘‘two-hit hypothesis’’ (29,30). The essence of this hypothesis is that one mutation within the tumor suppressor gene is inherited with a second ‘‘hit’’ or mutation, resulting in inactivation being required for loss of function. This process is often referred to as loss of heterozygosity or LOH. Tumor suppressor proteins act to regulate growth in a negative manner and are identified when shown to be inactivated by inherited or somatic mutations or through some epigenetic event [for example, promoter methylation (31)] in active cancer cells. Furthermore, the loss of function of a tumor suppressor protein provides a cell with a survival advantage. In the case of pRb, loss of function leads to release of the E2 promoter binding factor (E2F) family of transcription factors, which can then heterodimerize with their binding partners and activate transcription of various E2F-responsive genes, thereby driving the progression of the cell cycle from G1 into the S-phase (32,33). Thus, loss of pRb activity renders cells insensitive to antiproliferative signals that normally would lead to cellular quiescence and arrest of the cell cycle. Antigrowth signals can block proliferation by two distinct mechanisms. The first is characterized by an exit from the cell cycle into a quiescent state. A hallmark of this process of cell cycle exit is reversibility, which can be stimulated by extracellular signals. The process of differentiation is the second mechanism by which proliferation can be blocked. This is a complex, irreversible process. In fact, the genetic events that lead to a state of differentiation are unclear. However, it is clear that tumors can be in various states of differentiation and the inhibition of differentiation plays a role in tumorigenesis. A simplistic way to understand the inhibition of differentiation is to consider a tumor as an aberrant organ initiated by tumorigenic cancer cells that have acquired the capacity for indefinite proliferation through accumulated mutations. This analogy is reminiscent of a normal stem cell giving rise to a normal organ; so we should be able to apply the principles of normal stem cell biology to understand better how tumors develop (34,35). In fact, many observations suggest that analogies between normal stem cells and tumorigenic cells may be appropriate. Both normal stem cells and tumorigenic cells have extensive proliferative potential and the ability to give rise to new tissues. Both tumors and normal tissues are composed of heterogeneous combinations of cells, with different phenotypic characteristics and proliferative potentials (36–39). Because most tumors have a clonal origin (40–43), tumorigenic cancer cells must give rise to phenotypically diverse progeny including cancer cells with indefinite proliferative potential, as well as cancer cells with limited or no proliferative potential. This notion suggests that tumorigenic cancer cells undergo processes that are analogous to the self-renewal and differentiation of normal stem cells. In fact, the hypothesized tumor stem cell population has been identified in breast cancer (44–46). Identification of these populations of cells provides a tantalizing target for the design of new drugs. Therapies that target and efficiently kill populations of pluripotent cells within tumors may ultimately add to the armamentarium of treatment options for some tumors.

Evasion of Programmed Cell Death Apoptosis was initially described by its morphological characteristics, including cell shrinkage, chromatin condensation, and nuclear fragmentation (47–49). The genetic control of

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this process was initially elucidated through elegant studies using Caenorhabditis elegans (50–52), and similar pathways were quickly identified in human cells (53–55). The genedirected nature of apoptosis implies that cell numbers can be regulated by factors that influence cell survival as well as those that control proliferation and differentiation. Moreover, the genetic basis for apoptosis makes it clear that cell death, like any other metabolic ordevelopmental program, can be disrupted by mutation. In fact, the ability to overcome this innate death signal can contribute to carcinogenesis as well as many other human diseases (49). Induction of apoptosis generally involves the detection of a signal—extrinsic or intrinsic—followed by activation of a proteolytic cascade resulting in cell death (Fig. 2) (56–60). The constituents of the pathway can be classified as either sensors or effectors of apoptosis. The role of the sensor molecule is to receive a signal from either extrinsic [Fas ligand expressed on a neighboring cell or the activation of a tumor necrosis factor (TNF)-receptor, for example] or intrinsic sources (through the detection of DNA damage) and transmit this signal into the effector compartment of the pathway. Upon receiving this death signal, the effectors are activated and carry out their duties, ultimately resulting in the characteristic apoptotic changes. The basic effectors of the apoptotic pathway are composed of a group of cysteine proteases, collectively referred to as the caspases. Caspases can be categorized into initiator caspases (caspases 8 and 9) and the effector caspases (for a thorough review on the signaling of apoptosis please see Ref. 60). The initiator caspases receive the signal from the sensors and initiate the proteolytic cascade by processing and activating the effector caspases (61). Some effector caspases cleave and inactivate certain vital cellular proteins such as DNA repair enzymes, lamin, gelsolin, mouse double minute 2 (MDM2) (an inhibitor of p53), and protein kinase Cd (61,62). The apoptotic pathway can be blocked by a number of mechanisms including disruption of the expression of sensors of the apoptotic signal, disruption of the effector pathway, or the expression of genes whose products protect cells from apoptosis by generally unknown mechanisms. For example, the expression of the antiapoptotic protein Bcl-2 can protect cells from death and, when coupled with other proliferative signals, induces tumor formation (63,64). Disruption of the genes that are responsible for the detection of the apoptotic signals can also provide cells with a survival advantage. One example of sensory genes that detect intrinsic signals are the mismatch repair genes, which are responsible for detecting defects in the synthesis of DNA and also for the induction of the repair process (65). The tumor suppressor protein p53 is also involved in maintaining the integrity of the cellular genome and can, therefore, be considered a sensory gene of apoptosis. An example of this function of p53 can be found in cells treated with the drug PALA (N-phophonacetyl-L-aspartate), which is used to select for the amplification of the carbomylphosphate synthase/aspartate carbomyl transferase/ dihidroorotase (CAD) gene, resulting in the depletion of pyrimidine triphosphate pools, the activation of p53, and ultimately in G1 arrest and apoptosis (66). Cells with wild-type p53 do not undergo gene amplification readily. However, cells with mutant p53 entered S phase and were found to have amplified segments of their DNA. The mechanism by which gene amplification is prohibited by p53 remains unclear, but one possibility is that p53 plays a

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Figure 2 Schematic diagram for activation of caspases that lead to apoptosis of mammalian cells. The intrinsic and extrinsic pathways are demonstrated. The extrinsic pathway can be activated by a death receptor engaged by its ligand. For example, the Fas receptor bound to the Fas ligand can activate the extrinsic caspase cascade. Activation of caspase 8 results in the proteolytic cleavage of a number of proteins that contribute to cell death. The intrinsic pathway can be activated by DNA damage, which can activate mitochondrial-mediated apoptosis. The APAF-1 contributes to the activation of caspase 9. Both the intrinsic and extrinsic pathways seem to converge and activate caspase 3. The inhibition of activation of caspase 3 can inhibit apoptosis mediated by both the intrinsic and extrinsic pathways of apoptosis. Abbreviation: APAF-1, apoptosis-activating factor-1.

role in monitoring abnormal recombination intermediates and acts to kill such cells by activating the apoptotic cascade (67,68). Disruption of the extrinsic sensors of the apoptotic pathway can also result in escape of programmed cell death. For example, mutations within the Fas receptor gene have been identified in gastric cancer (69), transitional cell carcinoma of the bladder (70), small cell lung cancer (71), and hematologic malignancies (72,73). Other members of the death receptors, such as the TNF and TNF-related apoptosis-inducing ligand-receptors, have been found to be mutated in human cancers (56,74). Inhibition of the effectors of apoptosis can also result in a decreased sensitivity to apoptosis. Because of the critical roles in development likely served by many of the caspases, genetic loss of function of these proteins is likely rare (75,76). However, disruption of caspase function is a common theme used by infectious agents. For example, baculovirus, a virus infecting insects, encodes a protein called P35, which is a general and very efficient inhibitor of the caspases, making it a potent inhibitor of apoptosis (77–79). Human tumor viruses have also been shown to disrupt the apoptotic machinery by various mechanisms. For example, human papilloma virus, the cause of the vast majority of cases of cervical carcinoma, encodes a protein that inhibits the functions of the tumor suppressor gene p53 by both directly binding to and increasing the degradation of p53 (80–82). Another human tumor virus, Epstein–Barr virus (EBV), has also been shown to inhibit apoptosis, a process that can be reversed by the inhibition of an EBV-protein called Epstein-Barr nuclear antigen-1 (EBNA-1) (83). These findings (83), as well as others (84), hold promise that the therapeutic inhibition of single proteins in cancer cells can result in the initiation of the intrinsic apoptotic program, leading to cell death.

Limitless Replicative Potential When normal cells are placed in cell culture, they will undergo limited cell division under the right conditions. For example, primary B-lymphocytes taken from the peripheral blood of a normal human can be induced to proliferate in the presence of interleukin-4 (IL-4) and CD40 (85,86); these conditions support in seven or more population doublings after which the cells will cease to proliferate. Unlike normal B-cells, most tumor cells are immortal and will grow indefinitely in cell culture. Immortalization of cells is a process that is incompletely understood but likely requires multiple genetic alterations. The best understood process of immortalization involves the in vitro infection of primary B-cells with EBV. When primary B-cells are infected with EBV, the virus expresses a number of genes that are required for the induction and maintenance of proliferation (87,88). These cells will replicate for approximately 30 to 60 population doublings and then undergo a ‘‘blast crisis’’ during which time the majority of cells die (89). The few cells that survive this blast crisis are then referred to as ‘‘immortalized.’’ While it is unclear what genetic events are required for these immortalized cells to arise, some studies have indicated that increased telomerase activity contributes to the immortalization process (90). Human telomerase, hTERT, is a reverse transcriptase that uses an intrinsic RNA as a template for the extension of the G-rich strand of the telomeres, which form a protective cap on the ends of chromosomes (91). It has been postulated that telomere shortening is the ‘‘molecular clock’’ that leads to senescence—the cessation of division of human cells—and that the expression of hTERT overcomes senescence and leads to immortalization of cells in vitro and in tumors in vivo. Much correlative data support this hypothesis (92–94). Direct evidence in support of the

Chapter 9: Neoplastic Disease: Pathophysiology and Rationale for Treatment

hypothesis that the telomere loss plays a causal role in in vitro senescence has come from recent experiments in which telomerase was introduced into normal human cells. Ectopic expression of hTERT in foreskin fibroblasts and retinal epithelial cells, which are telomerase negative, resulted in the maintenance of telomere length, and the life span of the cells was extended by at least 200 population doublings beyond the point at which control cells senesced (95–98). As one would expect, the inhibition of telomerase has also been shown to restrict the life span of primary human fibroblasts (99) and to result in the decreased survival of tumor cells in vitro (92,93,100–102). These results indicate that telomerase may serve as a good target for novel therapies. In fact, the use of telomerase inhibitors as a therapy to treat malignancies is being actively investigated (103). The inhibitors being evaluated are dominant negative hTERT subunits (100,101), peptide nucleic acids and oligonucleotides (102,104,105), and chemical inhibitors (106–109). We anticipate that developing the means to restore mortality to tumor cells in vivo will be studied intensively and would lead to new, useful therapies in the future.

Sustained Angiogenesis The growth of new blood vessels, termed ‘‘angiogenesis,’’ is required for most tumor growth and metastasis. Without new blood vessel formation, tumor clones will be confined within 1 to 1.5 mm diameter (110). Experimental and clinical evidence underpins the notion that neovascularization of a tumor requires a critical number of its cells to have switched to the angiogenic phenotype (110,111). Evidence for this ‘‘angiogenic switch’’ has been derived from three transgenic mouse models that were analyzed throughout multistep tumorigenesis (112). In these animal models, the midstage lesions had developed an angiogenic phenotype prior to the appearance of invasive tumors. The mechanisms by which tumor cells become angiogenic can be categorized as either intrinsic or extrinsic, and both mechanisms result in a shift in the balance between the proangiogenic and antiangiogenic signals. An intrinsic proangiogenic switch implies that some activity within the tumor itself results in the induction of new blood vessel formation. The easiest explanation for how such a switch occurs is through the production of a proangiogenic molecule within the tumor, such as vascular endothelial growth factor (VEGF) (113). Alternatively, transcriptional changes within the tumor cells may result in downregulation of angiogenesis inhibitors such as thrombospondin-1 or b-interferon (113,114). Extrinsic angiogenic signals are derived from host cells recruited by the tumor, such as macrophages, or may be mobilized by the extracellular matrix (115). A variety of proteases can release a basic fibroblast growth factor that is stored in the extracellular matrix (116). Interestingly, essential components of the clotting system can be cleaved into angiogenic inhibitors (117,118). Tumor angiogenesis offers an attractive target for new therapeutics. Two general approaches have been used in the development of antiangiogenic agents: inhibition of proangiogenic factors and therapy with endogenous inhibitors of angiogenesis. More than 10 specific inhibitors of angiogenesis are under development for the treatment of cancer. The agents include antibodies to VEGF (bevacizumab), antibodies to the VEGF-receptor (IMC-IC11), proteins with antiangiogenic activity (angiostatin, endostatin, IL-12, etc.), and a several small molecules (111,119). Many of these small molecules act by blocking VEGF, by blocking its production

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by a tumor cell, by blocking its receptor, or by neutralizing VEGF itself (120–122).

Tissue Invasion and Metastasis Metastasis entails the spread of a primary tumor throughout the body by entering either the blood or lymphatic system. Metastatic tumors arise as a combination of cancer cells and normal supporting cells from the primary tissue. To be successful in the process of metastasis and invasion, most tumor cells must have acquired the first five traits of a cancer cell— they must be self-sufficient in growth signals, be insensitive to growth-inhibitory signals, evade programmed cell death, have limitless replicative potential, and have the ability to sustain angiogenesis. Additional genetic traits that are required for the development of metastasis are at present unknown. Two general models of how metastases develop have been proposed. The prevailing model was proposed over 30 years ago and predicted that metastasis results from selection of a small fraction of cells within the primary tumor that has the ability to metastasize. In support of this hypothesis, murine malignant melanoma cells growing in culture have been found to be heterogeneous in their ability to produce metastatic colonies when injected into a susceptible animal (36). However, cells with greater metastatic potential can be selected for by removing a metastatic focus of tumor from an animal, culturing these cells in vitro, and reinjecting these cells into another animal (123–125). Data such as these are certainly consistent with the conclusion that metastasis is the result of a selection process, but much work still needs to be done in this area to fully understand the complex process of metastasis formation. The second model of metastasis postulates that the capacity to metastasize might be acquired relatively early during multistep tumorigenesis and is intrinsic to the tumor (126). In support of this model, researchers using DNA microarrays recently ascertained the gene expression profiles of a panel of 12 metastatic adenocarcinoma nodules of diverse origins (127). Rigorous data analysis helped in identifying 17 genes that have been described as the metastasis profile. Importantly, this same profile was found in a subset of primary tumors. Patients with primary tumors having this metastases-associated gene-expression program had significantly shorter survival times compared with individuals whose tumors lacked it (127). Others have also shown by genomic screens that gene profiles predictive of metastases can be found in both the metastatic and primary tumors of the same patient (128,129). Findings such as these have many implications. First, if the tendency of a tumor to metastasize is present early on in tumor development, then relatively small primary tumors may already have the ability to give rise to metastatic foci. Second, genetic and biochemical changes that are required for metastases are likely to be the same changes that are required for cells to become tumorigenic (126). A major problem with either of these models of metastasis is that they deal only with the tumor cells and ignore the microenvironment provided by the host. In fact, it has become clear that malignancy is the product of the tumor– host microenvironment (130). The stroma can play a significant role in invasion and metastasis through the production of growth factors or secretion of proteinases that play a role in the angiogenic switch. Therefore, it is quite likely that not only are genetic and biochemical properties of the tumor important for the development of metastases but perhaps equally important are those properties of the host that

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regulate its susceptibility to metastasis formation. This is an exciting area of research that is in its infancy, but future findings could clearly have significant implications for treatment and prognosis.

BIOLOGIC RATIONALE FOR THERAPY Chemotherapy General Considerations The ability to identify antitumor agents has been enhanced by insight into the patterns of growth of normal and neoplastic cells. The most fully characterized portions of the normal cell cycle are the S phase and mitosis. Most of the active chemotherapeutic agents inhibit processes occurring during these two phases of the cell cycle, and these drugs are in general more effective against rapidly dividing cells. Although many classic anticancer treatments such as the alkylating agents are directed at nuclear targets, DNA is also the target for many new anticancer drugs. The synthesis of DNA is a multistep process using various enzyme pathways (131). Anticancer agents have been developed, which, when combined, can inhibit the process at several points simultaneously, thereby enhancing the cytocidal effect. A variety of general strategies can be used, including sequential blockade of different steps in the same biosynthetic pathway, concurrent blockade of different pathways for the synthesis of necessary compounds, complementary inhibition of biochemical processes that may circumvent chemotherapeutic damage, metabolic sensitization of intracellular constituents to chemotherapeutic effects, and the utilization of combined chemotherapy and radiotherapy. Examples of each of these approaches have been described (132,133). Other considerations in the use of chemotherapeutic drugs and the design of chemotherapy regimens include the emergence of drug-resistant cells either by selection of insensitive clones or by the induction of cellular changes that result in drug resistance. There have been many studies related to the origins of chemotherapeutic resistance. It is clear that drug resistance is one of the primary causes of suboptimal outcomes in cancer therapy. Drug resistance in cancer mimics that of antibiotic resistance (134). Limitations in drug delivery via poor absorption, excessive metabolism, environmental changes, or poor penetration to certain sites (organs and tissues) are recognized, and measures to counteract these have been explored. For example, the use of prodrugs or pegylated chemotherapy, organ-specific administration, such as hepatic arterial infusion or intrathecal therapy, hyperoxygenation, and hyperthermia are all strategies aimed at increasing drug-to-target ratio. Resistance at the molecular level may be more difficult to overcome. Certainly, mutation of specific drug targets will result in clinical resistance (135,136). Other molecular changes can also lead to cellular resistance, including alterations in the expression levels of proteins or enzymes responsible for the metabolism of the drug, overexpression of antiapoptotic proteins, and increased expression of DNA repair machinery (137–139). Cells can also develop intrinsic resistance to a broad spectrum of drugs through the action of a membrane protein termed ‘‘P-glycoprotein’’ (140,141). Expression of this protein in cells leads to a multidrug resistance (MDR) phenotype and has been identified to be the cause of resistance to a spectrum of drugs in a number of different cancer types (140). However, at least 48 related human genes have been identified, which encode for proteins that contribute to

the MDR-phenotype (142). Inhibitors of the MDR-genes have been developed and tested but clinical trials thus far have not been promising. In fact, at least two clinical trials have demonstrated no improvement in outcome by the addition of MDR-inhibitors (143,144). Progress in this area of research has been made recently with the advent of newer MDR-inhibitors that appear to be more efficient and less toxic (140). It is likely that these inhibitors will play a role in some specific cancers that clearly overexpress the MDR-inhibitors.

Combination Chemotherapy Optimal chemotherapy requires the use of combinations of drugs because single agents do not cure cancer, with rare exceptions. While the reason for this is not clear, simple mathematics may provide the answer. For example, if tumors are genetically heterogeneous such that 90% of cells are susceptible to one drug and 90% of cells are susceptible to a second drug, the exposure of the cells to both drugs would result in the death of more than 90% of the cells in the tumor. For this reason, combination chemotherapy is now the standard for treatment of many disseminated or metastatic cancers and is curative in some (145). A series of accepted guidelines for combination chemotherapy have been recognized for a number of years: 1. 2. 3. 4. 5.

Select drugs that have been proven effective. Select drugs that have different mechanisms of action. Select drugs that have different spectrums of toxicity. Each drug should be used at maximal dose. Agents with similar dose-limiting toxicities can only be combined safely by reducing doses, resulting in decreased effects. 6. Drug combinations should be administered in the shortest interval between therapy cycles to allow for recovery of normal tissue (146). If these guidelines are followed, dosages that are close to the maximally tolerable dosages for each drug can be used in an intermittent drug treatment schedule designed to optimize the cytotoxic effect of each drug. In the case of hematologic toxicity, especially neutropenia, it is often possible to maintain the dosing schedule and to shorten the period of granulocytopenia by the use of hematopoietic growth factors granulocyte-colony stimulating factor (G-CSF) and granulocyte monocyte-colony stimulating factor (GMCSF) (147). The use of dosage modifications or the use of growth factors should be considered with the therapeutic goals of therapy in mind. If the regimen has potential for cure, every effort should be made to maintain dose and schedule. If palliation is the goal, dose reductions and lengthening of the interval between doses should be considered.

Adjuvant and Neoadjuvant Chemotherapy The use of drugs as adjuvants to surgery or irradiation has led to significant advances in the chemotherapy of cancer (146,148–150). In many instances, the primary localized tumor mass can be removed by surgery or destroyed by irradiation; but even if the diagnosis has been made relatively early, with certain tumors it is quite probable that small, clinically undetectable metastases have already occurred. Even with the considerable advances made in diagnostic techniques, the most common solid tumors (breast, lung, and colon carcinomas) are usually not detectable until the tumor attains a mass of 1 cm in diameter.

Chapter 9: Neoplastic Disease: Pathophysiology and Rationale for Treatment

By this time, approximately 5  108 to 109 cells are present, and the tumor has already doubled in mass about 30 times. Because the chance for cell shedding into the lymphatic system or the blood stream increases with each doubling in tumor mass, there is a significant chance that cells have already metastasized by the time a tumor can be detected. It is not usually practical to eliminate small metastatic foci by surgery or irradiation; thus chemotherapy is usually the treatment of choice in patients at risk for occult metastatic disease. The principles for the use of drugs with surgery or radiotherapy are similar to those for the use of drugs in combination regimens. In general, drugs without a demonstrable activity against advanced tumor when used alone should not be used in adjuvant trials. If combinations of drugs have been shown to be effective in patients with advanced disease, they may be used in the adjuvant setting. Another important consideration is that the drug or the drug combination must be relatively low in general toxicity. Because a significant number of patients may remain free of disease with surgery or radiotherapy alone, the added risk of drug toxicity (and in some cases the induction of secondary malignancies such as leukemia) must be carefully weighed against the potential benefit. The use of an effective drug following surgical or radiation therapy makes sense from a cell kinetic point of view. Experimental evidence derived from the study of murine melanoma cells in vitro led investigators to believe that tumor growth is constant and occurs logarithmically. Using the murine melanoma model, the same investigators demonstrated that cell death induced by a given dose of a chemotherapeutic was independent of the tumor burden, the so-called log-kill hypothesis. While the results of these elegant experiments are very compelling, the principles of murine tumor growth may not be directly applicable to the growth of human tumors. For example, if human tumors responded similarly, one would predict that solid tumors should be more sensitive to chemotherapeutics than has been experienced. In fact, most experimental data is consistent with the conclusion that growth of human solid tumors is not exponential but rather follows Gompertzian kinetics, in which the fraction of cells actively growing is inversely related to the tumor burden. Therefore, Gompertzian growth predicts that when tumor burden is large, the actual fraction of cells growing and being susceptible to a chemotherapy agent is small. Experimental data strongly support the notion that the rate and extent of tumor reduction are related to the growth rate in a population of cells just prior to therapy (151). The difficult problem that continues to confound the curative goal of cancer therapy is the heterogeneity of the tumor cell population. The available models that help gain an insight into the processes underlying this heterogeneity suggest that it exists at the biochemical and pharmacologic level, conferring absolute drug resistance, and at the cell cycle kinetic level, conferring relative drug resistance. All the available models favor the use of combination chemotherapy and the administration of doses of chemotherapy that are as intensive as possible. An important issue that remains is the optimal manner in which to treat a disease such as breast cancer, small cell lung cancer, or lymphoma, for which multiple agents that display some antitumor activity are available. The Goldie–Coldman hypothesis, which mathematically predicts the likelihood that drug-resistant cancer cells are present in a patient at diagnosis (152), favors the use of all active drugs to be

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included in the treatment over the shortest time frame possible. This favors a strict alternating approach. The Norton–Simon approach, which utilizes the concept of Gompertzian growth to explain clinically observed phenomena (151,153), advocates a crossover approach in which each active regimen is used switching to the alternative regimen. Theoretically, this approach accomplishes two important goals. First, it maintains the most dose-intensive administration of each regimen by giving it every cycle, rather than on alternate cycles. Second, it addresses the heterogeneous populations of cells, killing the most sensitive, rapidly growing cells first and then treating the slower-growing, more resistant cells as efficiently as possible. Studies designed to test the various regimens have not been conclusive to date. However, such models provide a framework within which to test new drug regimens. Improvement of chemotherapeutics in the future will require strict attention to such models of tumor growth in addition to the empirical clinical data that have often characterized the approach in the past. A second strategy that is used to treat the micrometastatic disease at the time of diagnosis is neoadjuvant chemotherapy. Neoadjuvant therapy is chemotherapy implemented before surgery in patients with apparently localized disease. The approach has several advantages over the more conventional postoperative adjuvant chemotherapy. It exposes the potential micrometastases to chemotherapy at an earlier stage, it can be an indicator of tumor response (based on in vivo response of the tumor itself), and it may cause significant regression of the primary tumor and perhaps allow for a more conservative surgical procedure (organ/function sparing). Additionally, preoperative chemotherapy may reduce the hypothetical stimulation of tumor cell growth after surgical resection of the primary tumor. The dangers, of course, include ineffectiveness of chemotherapeutic regimens, which may in some cases obscure proper staging of disease or even render a primary tumor unresectable. Some tumors that have been effectively managed using neoadjuvant chemotherapy are soft tissue sarcoma, osteosarcoma, anal cancer, bladder cancer, larynx cancer, esophageal cancer, pancreatic cancer, and locally advanced breast cancer (148).

Radiation Therapy General Considerations Therapeutic radiation is ionizing; it ejects electrons from atoms or molecules with which it interacts. The energy transfer from radiation to tissue by this ionization is immediate. There is now a great deal of evidence that DNA is the target of this ionizing process and the cytotoxic effects of radiation (154–156). The specific lesion believed to be responsible for most radiation-induced cellular death is known as the ‘‘double-strand break.’’ Differences in cellular sensitivity to radiation may be a reflection of the cell’s ability to repair this type of lesion. Not all types of DNA are equally vulnerable to damage. DNA is associated with proteins in a complex threedimensional structure called chromatin. The influence of higher-order DNA structure on its sensitivity to radiationinduced damage is evidenced by the fact that deproteinized DNA is 70 times more susceptible to radiation-induced strand breakage than DNA found in the nucleus (157). Uncoiled DNA is also more susceptible to radiation damage, which means that cells in early S phase are more sensitive to radiation. Experimental data show that cells are more sensitive in early S phase and mitosis than in the late S phase and G2 (158).

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Selection of an optimal time–dosage pattern for treating tumors is a complex problem. It is unlikely that one-time dosage prescription will be optimal for a wide variety of kinetically different tumors located in different anatomic areas. The determination of fraction size, overall treatment time, and total dosage that is best for the control of various tumors constitutes a major, continuing research effort. It is based on several factors such as the inherent radiosensitivity of the tumor and surrounding normal tissues, tumor blood supply, and use of concomitant adjuvant chemotherapy. Although tumor type has a limited effect on inherent radiosensitivity, oxygen has a profound influence on a tumor’s radiation response. It has been known for quite some time that radiation delivered in the presence of oxygen has a more potent biologic effect than in hypoxic conditions (159). Hypoxic cells are 2.5 to 3 times more resistant to radiation than are well-oxygenated cells. There have been many attempts to overcome the hypoxic cell problem, including the use of hyperbaric oxygen, electron affinity compounds that selectively sensitize hypoxic cells, densely ionizing, or high-energy transfer radiation such as neutrons or pi mesons, optimization of the time–dosage schedule to increase reoxygenation between radiation doses, and induction of hyperthermia (160,161). Although the exact mechanism of the effect of oxygen is still speculative, it was noted that other compounds capable of accepting an electron can substitute for oxygen and restore sensitivity to hypoxic cells. These drugs include two thymidine analogs, iododeoxyuridine and bromodeoxyuridine, which increase cellular sensitivity to radiation in direct proportion to their incorporation into DNA by increasing radiation-induced DNA damage and decreasing its repair (162).

eradicated foci of the disease in the CNS, which were not accessible to chemotherapy (163). Treatment of cancer of the anal canal is another excellent example of the clinical benefit of combined chemotherapy and radiotherapy. In fact, it was in the treatment of anal canal squamous cell carcinoma that the use of combined radiotherapy and chemotherapy was first shown to be effective. Standard surgical management of anal canal carcinoma historically involved an abdominoperineal resection, but when local control was achieved with chemoradiotherapy, a conservative local approach, with sphincter preservation, was adopted. With long-term follow-up it has been confirmed that chemoradiation is the preferred therapy for epidermoid carcinoma of the anal canal (164,165). The role of radiation therapy in the local control of cancer is well established (166–171). However, the impact of radiation therapy on survival is less well established. Recently several groups have investigated the role of radiation therapy in the long-term survival of premenopausal and postmenopausal patients with breast cancer (172–174). Trials such as these have established that the addition of radiation therapy to the treatment regimen in certain high-risk patients may improve both disease-free and overall survival. Radiotherapy, chemotherapy, and surgery should be viewed as complementary and not as competitive methods of cancer management. New investigative approaches in radiotherapeutic trials aimed at improving disease control have increased dramatically. It is to be hoped that intelligent integration of improved radiotherapy, along with chemotherapy and surgery, will prove beneficial in the treatment of cancer.

Radiation Oncology

Surgical Oncology

Radiotherapy has three major roles in cancer treatment. It may be used singly as the primary curative method. It may be used as an adjuvant therapy with surgery (either before or after operation) or with chemotherapy, or both. Finally, radiation serves to palliate the symptoms of locally advanced or metastatic disease. As a single method of treatment undertaken with curative intent, radiotherapy is a local or regional form of therapy that is often competitive with surgery. If the probability of cure is equivalent for the two methods, a choice between them is often made on the basis of which carries the lower risk of morbidity. In the case of large tumors, surgery usually has a higher likelihood of tumor cure. However, primary radiotherapy is often used in neoplasms that are technically unresectable or that require excessively mutilating surgery. The combination of radiation with chemotherapy has become the mainstay of treatment for many cancers. Combining these two modalities allows for more conservative management of disease with the supplementation of local therapy with systemic therapy. Radiotherapy may be used in conjunction with a surgery or as an alternative to surgery to treat the primary tumor bed, whereas chemotherapy is used to treat the patient systemically. Adjuvant radiotherapy is of value for the treatment of subclinical disease in ‘‘sanctuary’’ sites not usually accessible to systemic chemotherapy. The best example of this arose from the treatment of acute lymphoblastic leukemia in children. It was clear that, although the disease could be controlled in most parts of the body, relapse in the central nervous system (CNS) was a particular risk. This problem was largely overcome by the addition of prophylactic irradiation that

Surgery is generally recognized as the original cancer therapy and for many years offered the only opportunity for cure. During the past few decades, however, there has been a tremendous advancement in the development of effective nonsurgical methods of treating cancer, and this has greatly changed the role of surgery. Perhaps, one of the most important advances in cancer surgery has been related to an understanding of the biology of cancer growth and metastases. The original concept of a local tumor spreading contiguously to surrounding tissues and to regional lymph nodes led to more and more radical operations. It is now recognized that at the time of cancer diagnosis, some 70% of all solid tumors are already systemic. This understanding of the cancer process has helped the surgeon rethink the role of primary surgery and better define realistic therapeutic goals based on a multimodality approach to treatment. The surgeon is most often the primary physician conducting the evaluation of the patient suspected of having cancer. As the primary physician, the surgeon must assume the responsibility for identifying which patients can be potentially cured by local resection alone and which patients should have adjuvant multimodality treatment. The surgeon must also decide the extent of resectional therapy, balancing the potential for cure through local control with the morbidity of extensive tissue resection. Today, the use of surgery as the sole treatment for a given cancer is rare. Thus the surgeon has a critical role in coordinating a patient’s care and interacting with other specialists. In recent years, the placement of short-term and long-term indwelling central venous catheters has become a relatively common procedure performed on patients with

Chapter 9: Neoplastic Disease: Pathophysiology and Rationale for Treatment

cancer. These catheters provide chronic vascular access for administration of chemotherapy, hematological support, and occasionally nutritional support. The implementation of chronic vascular access has allowed the use of more aggressive treatment involving multiple drugs given over complicated schedules. To meet this need, a number of new implantable catheter systems and drug delivery pumps have been developed. Important developments relating to implantation technique and design have decreased the operative time required to place these devices, and it can usually be done as an outpatient procedure. The surgeon is also called on to handle a variety of surgical emergencies related to the advancing cancer or the use of aggressive therapy. Hemorrhage, sepsis, perforation of viscera, and obstruction of the gastrointestinal tract are examples of problems requiring surgical intervention. These emergencies require a thoughtful and caring physician who understands not only the need to solve the problem at hand but also the delicate balance between helping and harming. The role of the surgical oncologist, or cancer specialist involved in cancer diagnosis and treatment, continues to expand and includes an understanding of the biology of the cancer process, the natural history of specific tumors, the current status of integrated treatment options for each tumor, and the investigative options that may be important to the patient. The role of the surgeon assuming these responsibilities is best defined as that of a member of a multidisciplinary oncology team skilled in various treatment modalities and dedicated to experimental research that can lead to new diagnostic and treatment options (175).

Biologic Therapy We have used the term ‘‘biologic therapy’’ to encompass several different areas. The therapies contained within this term are under investigation to some degree and are at different points in their clinical utility. We have broken this very broad topic into three major groups: immunotherapy, gene therapy, and molecularly directed therapy.

Immunotherapy The effective treatment of cancer through the specific activation of an affected patient’s immune system has been the holy grail of cancer therapy. Any agent that is capable of altering the host–tumor relationship in favor of the host can be considered an immunologic response modifier. Because of the vast information existing in the immunotherapy literature, it is only possible to discuss a few areas that are of exceptional interest. Cytokine Therapy In vivo studies have demonstrated the efficacy of inducing tumor rejection by using immunomodulatory cytokines. Several cytokines are in clinical use today. For example, interferon a-2b has been utilized in the therapy of nodepositive malignant melanoma. Randomized controlled trials of interferon a-2b have demonstrated small but significant improvements in survival of the patients treated with the drug (176). However, such small increases in survival have come at a significant cost, because the morbidity of this cytokine is substantial. In fact, three-quarters of the patients receiving interferon required a dose modification and one quarter of the patients had treatment discontinued due to toxicity. Additionally, there have been two treatmentrelated deaths due to hepatic toxicity. While the beneficial effect of interferon is statistically significant, the toxicity of

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therapy precludes its widespread use in the treatment of malignant melanoma. ILs are hormone-like substances, produced mainly by leukocytes, which have diverse activities on both immunologic and nonimmunologic targets (177). There are at least 12 well-defined ILs, and ongoing research has detected several others (178). IL-2 is Food and Drug Administration approved and has played a critical role in the field of adoptive immunotherapy. IL-2 stimulates the growth and activities of a wide range of cells including natural killer cells, lymphokine-activated killer cells (LAKs), cytotoxic Tlymphocytes, and tumor-infiltrating lymphocytes (TILs). A large number of clinical trials have evaluated the administration of IL-2 alone or in combination with LAKs and TILs (133,179,180). Objective and long-lived responses have been documented in a large proportion of cases, particularly renal cell carcinoma, melanoma, and acute myeloid leukemia (181). Several toxicities associated with IL-2 are generally short lived and resolve within 24 hours of discontinuation of therapy. However, studies indicate that the rate of drugrelated acute mortality is 4% to 5% (177). Use of IL-2 should be restricted to those who are familiar with administration and toxicity. Adoptive Cell Transfer Therapies Adoptive cell transfer therapy is the transfer of cells with antitumor activity to a tumor-bearing host (182). Efforts to identify immune cells with reactivity toward various tumors are ongoing. Lymphocytes present within tumor infiltrates are presumably enriched for effector cells capable of killing the tumor cells (183). However, they appear to have developed a tolerance to the presence of the tumor. These TILs can be enriched by propagating single-cell suspensions from the tumor in IL-2. When isolated and tested in vitro for cytolytic activity against autologous tumor cells, these TILs were found to be 50 to 100 times more potent than IL-2– activated splenocytes (LAKs). A similar superiority to LAKs was also apparent in vivo (184). Adoptive cell transfer therapies provide the opportunity to overcome tolerogenic mechanisms by enabling the selection and activation of highly reactive T-cell subpopulations and by manipulation of the host environment into which the T-cells are introduced. Recently it was demonstrated that treatment with autologous T-cell transfer and high-dose IL-2 therapy after nonmyeloablative lymphodepleting chemotherapy resulted in the rapid growth in vivo of clonal populations of T-cells specific for the melanoma antigen recognized by T-cells (MART-1) melanocyte differentiation antigen, and resulted in the destruction of metastatic tumors and autoimmune attack on normal tissues that expressed the MART-1 antigen (185). Other results have demonstrated transient tumor shrinkage but have no significant objective response (186). While adoptive cell transfer therapy may eventually prove to be useful for the treatment of many different cancers, such a role has yet to be realized. Antibody Therapy The development of antibodies against various membranesignaling proteins, which block the extracellular ligand-binding region of the receptor, has proven to be an important contribution to the management of cancers. The human epidermal growth factor receptor (HER) [erythroblastic leukemia viral oncogene homolog, neuro/glioblastoma derived oncogene homology (avian) (erbB)] family of receptor tyrosine kinases is one of these targets. HERs are transmembrane

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receptors that play a pivotal role in normal cell growth, lineage determination, repair, and functional differentiation (187). These receptors have been demonstrated to be overexpressed in several solid tumor types, including breast, colorectal, esophageal, ovarian, and pancreatic (188). AntiHER2 monoclonal antibodies, trastuzumab and 2C4, have been developed. Traztuzumab acts against HER2-overexpressing tumors, in part, by inducing receptor endocytosis (189). Clinical trials have shown that traztuzumab provides significant clinical benefits as monotherapy (190,191), and improves survival when used in combination with chemotherapy compared with chemotherapy alone in women with HER2-overexpressing metastatic breast tumors (192). 2C4 is a humanized anti-HER2 monoclonal antibody that binds to a different HER2 epitope than does traztuzumab. It functions by inhibiting the heterodimarization of HER2 with other HER family members (193). This results in the inhibition of signaling both in cells with low and high levels of expression of HER2. In vitro and in vivo antitumor activity has been reported in a number of breast and prostate models (193). Clinical trials with 2C4 are currently underway.

Gene Therapy The concept of gene therapy has been around for at least 10 years and remains a very active area of investigation. The idea of introducing genes into tumor cells or into cells that may affect the tumor phenotype and ultimately target a subset of cells for death is tantalizing. However, advancement in this field remains hindered by the problem of cell-specific targeting and effective delivery systems. Despite these major limitations of the technology, we will discuss two potential uses for gene therapy. In the third section we will discuss potential mechanisms of targeting genes to tumor cells. Introduction of Therapeutic Genes Transduction of tumor cells with gene-encoding enzymes that function to convert a nontoxic prodrug into a toxic drug in the vicinity of the tumor cells is under study. The high local concentration of the toxic drug would result in death of tumor cells while limiting general toxicity to the host. Two such strategies involve transduction of the herpes simplex virus thymidine-kinase gene (HSV-tk) or of the cytosine deaminase gene, neither of which occur naturally in mammalian cells. HSV-tk phosphorylates nucleoside analogs, such as acyclovir and ganciclovir, which are not toxic to cells in the unphosphorylated state, and incorporates them into the replicating DNA (194). Even though not all cells are transduced with the gene, several studies have demonstrated killing of nontransduced cells. This observation, referred to as the bystander effect (195,196), is likely due to intracellular transfer of phosphorylated nucleoside via gap junctions. Cytosine deaminase works by deaminating the prodrug 5-flourocytosine to the cytotoxic fluorouracil (197,198). Enzymes such as these, which convert nontoxic prodrugs into toxic agents may prove to be useful in the therapy of cancer. Functional Replacement of Tumor Suppressor Genes As discussed earlier in the chapter, many tumors have lost the function of a tumor suppressor gene, which provides the cells with an overall survival advantage. The replacement of such genes through the introduction of an exogenous genetic template remains very attractive. For example, the human p53 gene is mutated in many human tumors. Transduction of

the wild-type p53 gene can partly reverse the malignant phenotype of tumor cells lacking functional p53 in experimental systems in vitro and in vivo (199). The functional replacement of tumor suppressor genes remains a potentially useful approach to the treatment of cancer. Cell-Specific Targeting The treatment of cancer through the introduction of genes is a natural goal and may eventually prove to be successful. However, this practice is currently severely limited by the process of targeting these therapies to the cells of interest. For example, the introduction of tumor suppressor genes, as discussed above, is theoretically exciting but the overexpression of p53 in all cells would have potentially devastating consequences. Therefore, approaches such as these remain useful in theory until the time they can be targeted to specific groups of cells. One novel approach to this problem has been to use the avian leukosis virus (ALV). ALV cannot infect human cells because they do not express the ALV receptor. However, a soluble version of this receptor has been produced as a fusion with EGF subgroup A avian leukosis virus receptor-EGF (TVA-EGF) (200). Cells expressing the EGF receptor can then be preloaded with this fusion protein and infected with the ALV that has been genetically manipulated to express genes of interest. Similar bridge proteins using VEGF have been developed and have been shown to be effective at rendering VEGF-receptor–expressing cells susceptible to ALV infection (201). The use of these bridge proteins and ALV vectors represent one potential approach for targeting genes to specific groups of cells.

Molecularly Directed Therapy The specific inhibition of signaling pathways by therapeutics is a relatively new field. However, the literature has grown and it is our goal to review two areas we find particularly exciting and to discuss potential applications and limitations. We will first discuss small molecule therapy with emphasis on the highly successful inhibition of BCR-ABL gene by signal transduction inhibitor-571 (STI571). In the second section, we will discuss the inhibition of protein expression by a relatively new technique called RNA-interference or RNAi-571. Small Molecule Therapy The improved understanding of molecular signaling pathways has led to the development of several new targets for cancer therapeutics. Furthermore, improved crystallographic techniques have allowed us to develop small, chemical molecules with specific structures that target these signaling proteins by interacting with their functional domains. Examples of such molecules are accumulating rapidly in the literature but the first such molecule to prove effective was directed against the BCR-Abl protein expressed in most patients with chronic myelogenous leukemia (CML; Fig. 3) (202). This molecule has been shown to have activity in patients with CML and in patients with acute lymphocytic leukemia (ALL), in whom the Philadelphia chromosome is present (203). This type of molecular therapy appears to be very well tolerated with low side effects (204). However, the specific inhibition of proteins will certainly bring a new set of challenges. For example, resistance to these inhibitors has been identified and may involve selection of cells that have mutations in the active site of the breakpoint cluster region/Abelson murine leukemia viral oncogene homolog (BCR/ABL) kinase, which is targeted by the small

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Figure 3 Mechanism of action of STI-571. (A) Depicted is the bcr-abl protein, the expression of which is the result of a chromosomal translocation between chromosomes 9 (c-abl) and 22 (bcr). The abl portion of this protein serves as a protein tyrosine kinase–activating downstream proteins, which ultimately effect cell proliferation. (B) The tyrosinekinase inhibitor STI-571 binds in the ATP-binding pocket of the bcr-abl protein resulting in its displacement and the inhibition of the protein’s functions. STI-571 has demonstrated inhibitory activity against other protein tyrosine kinases. Abbreviation: ATP, adenosine triphosphate.

molecule (135). Despite the challenges likely to be faced, targeted therapy remains one of the most promising and exciting developments in cancer therapy in the last 10 years. RNA Interference RNAi uses short double-stranded RNA (dsRNA) whose sequence matches that of the gene of interest (Fig. 4). Once

in a cell, a dsRNA molecule is cleaved into segments approximately 22 nucleotides long, called short interfering RNAs (siRNAs) (205). siRNAs become bound to the RNAinduced silencing complex, which then also binds any matching mRNA sequence. Once this occurs, the mRNA is degraded, effectively silencing the gene from which it came (205). Until recently, this technology involved the introduction

Figure 4 mRNA degradation mediated by siRNAs. Once in a cell, double-stranded siRNA is bound by the RNA silencing complex and targets matching RNA sequences leading to their destruction. Once this occurs, gene expression is effectively silenced. Abbreviations: mRNA, messenger RNA; siRNA, short-interfering RNA.

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of dsRNA directly into cells. Charged oligonucleotides will not pass through a lipid bilayer, severely limiting the usefulness of RNAi in the treatment of human disease. However, recently developed vector-based strategies that contain stem-loop constructs encoding hairpin RNAs have lead to the intracellular generation of siRNA-like species (206). These constructs have been used to express siRNA stably in cells, resulting in a significant decrease in targeted protein expression (206). They have also been delivered in the context of a retrovirus, making their potential much greater (207–209). Inhibition of protein expression mediated by siRNA has been shown to be an effective means to inhibit the activity of H-ras in ovarian cancer cells and has limited the proliferative capacity of these cells both in vitro and in vivo (209). The utility of RNAi in the therapy of cancer has yet to be demonstrated but this remains a very exciting field of research and will, at the minimum, provide us with a better understanding of the biology of cancer.

SUMMARY The last 30 years have witnessed powerful advances in cancer biology and molecular genetics. These developments in modern biomedical research have shed new light on the processes involved in transformation of normal cells into neoplastic cells, tumor cell proliferation, and the biology of tumor metastasis. Today’s surgeon must have a thorough understanding of these processes and their relationship to therapy to participate as a key member of an integrated, multidisciplinary, oncology research and treatment program. This chapter reviews and highlights the basic concepts of cancer biology and the rationale for the integration of treatment options on the basis of our current understanding of those mechanisms responsible for oncogenesis.

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183. Belldegrun A, Muul LM, Rosenberg SA. Interleukin-2 expanded tumor-infiltrating lymphocytes in human renal cell cancer: isolation, characterization, and antitumor activity. Cancer Res 1988; 48(1):206–214. 184. Spiess PJ, Yang JC, Rosenberg SA. In vivo antitumor activity of tumor-infiltrating lymphocytes expanded in recombinant interleukin-2. J Natl Cancer Inst 1987; 79(5):1067–1075. 185. Dudley ME, Wunderlich JR, Robbins PF, et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 2002; 298(5594): 850–854. 186. Dudley ME, Wunderlich JR, Yang JC, et al. A phase I study of nonmyeloablative chemotherapy and adoptive transfer of autologous tumor antigen-specific T lymphocytes in patients with metastatic melanoma. J Immunother 2002; 25(3):243–251. 187. Kirschbaum MH, Yarden Y. The ErbB/HER family of receptor tyrosine kinases: a potential target for chemoprevention of epithelial neoplasms. J Cell Biochem Suppl 2000; 34:52–60. 188. Arteaga C. Targeting HER1/EGFR: a molecular approach to cancer therapy. Semin Oncol 2003; 30(3 suppl 7):3–14. 189. Yarden Y. Biology of HER2 and its importance in breast cancer. Oncology 2001; 61(suppl 2):1–13. 190. Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 1999; 17(9):2639–2648. 191. Vogel CL, Cobleigh MA, Tripathy D, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 2002; 20(3):719–726. 192. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344(11):783–192. 193. Agus DB, Akita RW, Fox WD, et al. Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell 2002; 2(2):127–137. 194. Moolten FL. Tumor chemosensitivity conferred by inserted herpes thymidine kinase genes: paradigm for a prospective cancer control strategy. Cancer Res 1986; 46(10):5276–5281. 195. Ramesh R, Marrogi AJ, Munshi A, et al. In vivo analysis of the ‘bystander effect’: a cytokine cascade. Exp Hematol 1996; 24(7):829–838. 196. Freeman SM, Abboud CN, Whartenby KA, et al. The ‘‘bystander effect’’: tumor regression when a fraction of the tumor mass is genetically modified. Cancer Res 1993; 53(21):5274–5283.

197. Huber BE, Austin EA, Good SS, et al. In vivo antitumor activity of 5-fluorocytosine on human colorectal carcinoma cells genetically modified to express cytosine deaminase. Cancer Res 1993; 53(19):4619–4626. 198. Huber BE, Austin EA, Richards CA, et al. Metabolism of 5-fluorocytosine to 5-fluorouracil in human colorectal tumor cells transduced with the cytosine deaminase gene: significant antitumor effects when only a small percentage of tumor cells express cytosine deaminase. Proc Natl Acad Sci USA 1994; 91(17):8302–8306. 199. Wills KN, Maneval DC, Menzel P, et al. Development and characterization of recombinant adenoviruses encoding human p53 for gene therapy of cancer. Hum Gene Ther 1994; 5(9):1079–1088. 200. Snitkovsky S, Young JA. Cell-specific viral targeting mediated by a soluble retroviral receptor-ligand fusion protein. Proc Natl Acad Sci USA 1998; 95(12):7063–7068. 201. Snitkovsky S, Niederman TM, Mulligan RC, Young JA. Targeting avian leukosis virus subgroup A vectors by using a TVA-VEGF bridge protein. J Virol 2001; 75(3):1571–1575. 202. Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 1996; 2(5):561–566. 203. Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 2001; 344(14):1038–1042. 204. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001; 344(14):1031–1037. 205. McManus MT, Sharp PA. Gene silencing in mammals by small interfering RNAs. Nat Rev Genet 2002; 3(10) :737–747. 206. Brummelkamp TR, Bernards R, Agami R. A system for stable expression of short interfering RNAs in mammalian cells. Science 2002; 296(5567):550–553. 207. Brummelkamp TR, Bernards R, Agami R. Stable suppression of tumorigenicity by virus-mediated RNA interference. Cancer Cell 2002; 2(3):243–247. 208. Stewart SA, Dykxhoorn DM, Palliser D, et al. Lentivirusdelivered stable gene silencing by RNAi in primary cells. RNA 2003; 9(4):493–501. 209. Yang G, Thompson JA, Fang B, Liu J. Silencing of H-ras gene expression by retrovirus-mediated siRNA decreases transformation efficiency and tumorgrowth in a model of human ovarian cancer. Oncogene 2003; 22(36):5694–5701.

10 The Physiology of Anesthesia and Pain Charles Williams and Denise Lester

six-step gradation in their preoperative health; P1 is a normal, healthy patient and P6 is a brain-dead patient whose organs are being removed for donor purposes (Table 1). While this system functions as a useful quick reference tool, it is also tied to aspects of billing for professional anesthesia services and is a tacit implication of perioperative risks. In general, higher ASA Physical Status classifications are associated with greater preoperative physiologic perturbations and higher perioperative risks of mortality and morbidity. Numerous large single-institution and multi-institution studies have examined anesthesia outcome, but generalizations have been difficult due to differences in inclusion criteria and end points. One study assessed almost one million cases over a one-year period and reported a mortality rate of 1 in 185,000 cases where anesthesia was considered the sole cause of death. Anesthesia was a contributory cause of death in 7 out of 10,000 cases (2). While other studies have reported higher mortality rates, most agree that mortality and morbidity is higher with extremes of age (old and young), higher ASA physical status, and emergent conditions. Underlying disease processes in virtually every organ system can affect anesthetic outcome to some degree, but diseases involving the cardiovascular system have arguably the single greatest impact. Several studies have considered the incidence of fatal and nonfatal cardiac arrests primarily associated with anesthesia and have reported occurrence rates ranging from 1 in 9620 cases (3) to 1 in 14,493 cases (4). Therefore, careful preoperative evaluation of cardiac performance and the identification of potential or active ischemia are warranted. It has been repeatedly shown that if a patient has had a myocardial infarction within the six months prior to undergoing noncardiac surgery, the perioperative reinfarction rate is 5% to 86% (a 1.5 to 10 times higher rate than when the infarction and surgery are separated by more than 6 months) and a mortality rate of 23% to 86% (5). In general, however, anesthesia-related risks have declined markedly over the last 20 years. This has largely been due to two factors. First, developmental advances in the equipment used for the delivery of anesthesia have been produced with the specific goals of eliminating failures, and

INTRODUCTION Although the discipline of anesthesiology has traditionally been focused on delivering safe and effective surgical analgesia and amnesia, more recently it has broadened to include the management of critical care and pain issues. Accordingly, to encompass these extended responsibilities, this chapter is divided into two sections. The first section concerns the physiology of anesthesia and its application toward carrying out operative procedures. This includes the management of intraoperative critical care. The second section deals with surgical pain by discussing current concepts underlying the pathophysiology of pain and how they relate to perioperative care.

THE PHYSIOLOGY OF ANESTHESIA Perioperative changes in a patient’s physiology can be attributed to an interaction between the underlying disease state and coexisting illnesses, the type of anesthesia and the pharmacodynamics of the medications necessary to create acceptable surgical conditions, and the results of the surgical process itself. The choice of the anesthetic technique is unique to each patient and should take these changes into consideration. Lesser considerations include the anesthesiologist’s skill at performing various anesthetic techniques, the patient’s preferences, and cost. The final choice of anesthesia is then made by assessing the patient’s risks of morbidity or mortality associated with a particular anesthetic technique versus the benefits to be gained by the surgery. The risks must be understood and acceptable to the anesthesiologist, the surgeon, and the patient.

PREOPERATIVE DECISIONS An anesthesiologist begins to choose an anesthetic technique by assessing the patient’s health preoperatively. Almost every disease process has anesthetic implications that must be taken into consideration; while an unstable trauma patient has obvious physiologic perturbations, patients with stable, long-standing processes may have more obscure implications. For example, although chronic hypertension and its pharmacologic treatment may appear benign, it can be associated with end-organ damage, autonomic instability, or intravascular volume depletion. The anesthetic implications of other disease states are discussed below. Once all aspects of the patient’s preoperative health are evaluated, a broader categorization can be applied to their condition. The American Society of Anesthesiologists (ASA) hasdevelopedtheASAPhysicalStatusClassificationSystem(1) whereby patients are assigned a classification based upon a

Table 1 The American Society of Anesthesiologists Preoperative Physical Status Classification System P1 A normal, healthy patient P2 A patient with mild systemic disease P3 A patient with severe systemic disease P4 A patient with severe systemic disease that is a constant threat to life P5 A moribund patient who is not expected to survive without the operation P6 A declared brain-dead patient whose organs are being removed for donor purposes Source: From Ref. 1.

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each successive generation of anesthetic drugs is designed to reduce the complications and side effects of its predecessors. It has been suggested, for example, that the use of pulse oximetry and end-tidal capnometry since 1985 has significantly reduced poor outcomes related to ventilatory failure (6,7). Second, anesthesiology, as a professional specialty, has been very effective at learning from its own undesired outcomes. In 1985, the ASA established the ASA Closed Claims Project with the intention of identifying the causes of loss and therefore improving patient safety. To date, thousands of cases have been reviewed and data from their analysis have contributed significantly to the establishment of safe practice standards (8). Regardless of the type of anesthesia chosen or the complexity of the surgical procedure, all patients are carefully monitored intraoperatively. The ASA maintains well-established physiologic monitoring standards for all general, regional, or monitored care anesthetics (Table 2), and require continual evaluation of the patient’s oxygenation, ventilation, circulation, and body temperature (9). Additional monitors can be added if the patient’s preexisting or anticipated surgical condition warrants, including urimetry and various neurophysiologic monitors. Many patients needing surgical intervention also have significant cardiac disease and in these cases, more precise monitoring of cardiopulmonary dynamics is required. In addition to continuous arterial transduction of blood pressure, more direct measurement of cardiac performance can be obtained by pulmonary artery catheterization (Swan–Ganz catheter), noninvasive bioimpedence cardiac output monitors, or transesophageal echocardiography. The latter technique is especially useful in visualizing left ventricular function. Proper intravenous access is critical to the delivery of anesthesia, and if peripheral access is either inadequate or unsatisfactory, central venous access may be required. Such central access can be obtained through the internal jugular or subclavian veins, although sometimes basilic (long-arm) or femoral vein approaches are used. Arterial access for

Table 2 The American Society of Anesthesiologists Standardsa for Basic Anesthetic Monitoring Standard I Qualified anesthesia personnel shall be present in the room throughout the conduct of all general anesthetics, regional anesthetics, and monitored anesthesia care Standard II Oxygenation (i) Oxygen analyzer with a low oxygen concentration limit alarm (ii) Pulse oximetry. Adequate illumination and exposure of the patient are necessary to assess color Ventilation (i) Continual CO2 monitoring. Quantitative monitoring of the volume of expired gas is strongly encouraged (ii) Verify endotracheal tube placement with capnometry. Continual end-tidal CO2 must be employed while intubated or LMA is in place (iii) Continual ventilator disconnection alarm Circulation (i) Electrocardiogram (ii) Arterial blood pressure and heart rate at least every 5 min Body temperature (i) Temperature shall be monitored when clinically significant changes in temperature are intended, anticipated, or suspected a

American Society of Anesthesiologists, last amended October 27, 2004. Abbreviation: LMA, laryngeal mask airway. Source: From Ref. 9.

continual blood pressure monitoring is typically obtained through the radial or dorsalis pedis arteries, but if inaccessible, femoral or brachial artery approaches are also available.

REGIONAL ANESTHESIA Regional anesthesia is based upon a localized blockade of neural conduction created by an appropriately placed injection or infusion of a local anesthetic. These blocks can be categorized into two broad groups: peripheral nerve or plexus blocks and major conduction (neuraxial) blocks. The latter group includes spinal and epidural anesthetics. An anesthesiologist’s choice between regional and general anesthesia relates to the risks of each to the patient and to the ability of a particular block to satisfy surgical requirements. The types of regional blocks most commonly employed are detailed in Tables 3, 4 and 5. A regional technique is often chosen specifically to avoid exposing a patient to the risks of general anesthesia, but regional anesthesia may still present significant risks to a vulnerable patient. This is especially true for neuraxial anesthesia and its accompanying sympathetic blockade. For example, hypotension may be profound in a hypovolemic patient, and patients with ischemic heart disease may experience regional myocardial dysfunction due to hypotension, vasodilatation, and decreased coronary perfusion (10). On the other hand, global systolic ventricular dysfunction or a dilated cardiomyopathy may improve from the reduction in afterload and preload. Despite this, there are few absolute contraindications for regional anesthesia—the strongest being patient refusal. Relative contraindications must be weighed against patient benefit, and include preexisting neurologic disease (medicolegal issues), local or systemic infection, and iatrogenic or induced coagulopathy. Unfortunately, the medications used to produce a regional anesthetic can also present risks. The elimination pharmacokinetics and potency of the local anesthetic influences the onset and duration of the block, and the relative concentration of the anesthetic influences the density of the block. Therefore, an anesthesiologist skilled at regional techniques has a variety of aminoamide (e.g., lidocaine, bupivacaine, prilocaine, and ropivacaine), and aminoester (e.g., cocaine, procaine, and tetracaine) local anesthetics available. Aminoester anesthetics are derivatives of p-aminobenzoic acid, which has a significant allergic potential, but true allergic reactions are extremely rare among the aminoamides. Aminoamides, however, may contain methylparaben, which is a preservative whose chemical structure is similar to p-aminobenzoic acid. Prilocaine produces a dose-dependent methemoglobinemia (11), and bupivacaine (and etidocaine to a lesser extent) may introduce severe cardiac dysrhythmias with intravenous injection (12) that resembles torsades de pointes. It has also been suggested that intrathecal local anesthetics may be neurotoxic. For example, lidocaine has been reported to cause persistent lumbosacral neuropathy after a single intrathecal injection in 1.4 patients out of 1000. Intrathecal lidocaine has also been found to cause transient neurologic symptoms (formerly known as transient radicular irritation, defined as pain or dysesthesia in the buttocks or legs after recovery from spinal anesthesia) in 16% to 33% of patients (13). Systemic toxicity from an accidental intravascular, intrathecal, or excessive dose of local anesthetic involves the cardiovascular system or the central nervous system

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Table 3 Types of Neuraxial Regional Anesthesia and Their Uses Type

Area injected

Major conduction (neuraxial) blocks Spinal anesthesia Subarachnoid space via lumbar puncture below termination of the spinal cord Epidural anesthesia Epidural space outside the ‘‘dura mater’’

Agent injected

Nerves blocked

Indication

Local anesthetic with/without Somatic and visceral sensory Procedures performed in the narcotic by fine needle injection afferent nerves, as well as dermatomes at or below the or catheter placement efferent motor and autonomic mid-abdomen (sympathetic) fibers Local anesthetic and/or narcotic Similar to spinal anesthesia, but Can be used for procedures by catheter placed anywhere more ‘‘segmental’’; less anywhere from the neck to from the cervical to the sacral intense block above and below the sacral area hiatus epidural space the site of injection

(CNS), and often is related to the relative potency of the drug used. While the direct cardiovascular effects of lidocaine are clinically useful in decreasing the rate of depolarization in the fast-conduction tissues of Purkinje fibers and ventricular muscle, dysrhythmias created by bupivacaine toxicity are notoriously difficult to correct. The local anesthetic blood levels required to produce CNS toxicity, however, are much lower than those required to produce cardiovascular collapse; the initial blockade of inhibitory pathways and the stimulation of glutamate release can trigger a progression of symptoms from simple dizziness and disorientation to generalized tonic-clonic convulsions. In experienced hands, regional anesthesia remains a relatively safe alternative to general anesthesia, because the few side effects and complications can usually be managed easily or avoided altogether with prudent patient and block selection. Regional anesthesia, however, may not entirely avoid the risks of general anesthesia. Despite the use of nerve stimulators and various techniques that aid in the confirmation of correct needle location, percutaneous placement of a regional block remains a blind technique and each type of block is associated with varying rates of failure. Any anesthetic plan must therefore also consider the risks of alternative forms of anesthesia should the block fail.

GENERAL ANESTHESIA Patient identification, informed consent, and intravenous access are obtained on all patients regardless of whether general or regional anesthesia is performed. If general anesthesia is chosen, appropriate premedication is then administered, the patient is taken to the operating room, physiologic monitoring is applied, and the patient is preoxygenated. Because the induction of deep anesthesia typically produces respiratory arrest, care must be taken to protect the airway. If the patient has followed fasting guidelines and is not at risk for aspiration (see below), the goal is

to induce general anesthesia quickly and deeply with a shortacting intravenous barbiturate or analog. A mask airway is then established as a fallback point before longer- acting paralytics are administered and maintenance anesthetics are turned on. Once mask ventilation is assured, the patient can be paralyzed and intubated. If the patient is at risk for the aspiration of gastric contents, however, positive pressure ventilation by mask must be avoided so as not to insufflate the stomach and encourage regurgitation. In this case, induction proceeds in rapid sequence with a quick, deep induction of both hypnosis and paralysis, followed by immediate intubation of the airway. To further impede any regurgitated matter from reaching the larynx, external pressure is applied to the cricoid cartilage throughout induction, compressing the more posterior esophagus between the anterior cervical vertebral bodies and the cricoid ring. The immediate administration of a paralytic adds obvious risk to the induction process, but the risk is minimized by sound airway management technique and is acceptable when compared to the mortality and morbidity of aspiration. Maintenance anesthesia is then initiated and a gastric sump (e.g., nasogastric tube) is typically placed to empty the stomach in preparation for emergence at the end of surgery. Maintaining general anesthesia in a surgical patient requires the satisfaction of four components: amnesia, analgesia, hypnosis, and frequently, paralysis. There is currently no single drug that can produce all of these effects, so each is usually addressed individually, and the accompanying changes in the patient’s physiologic state are related to the pharmacodynamics of the drugs used and the patient’s underlying pathologic state. A summary of commonly used amnestics, analgesics, hypnotics, and paralytics is found in Table 6. Patient amnesia and anxiolysis is desirable in the preoperative period, as well as during cases that require only sedation. Historically, central-acting alpha-2 agonists (e.g., clonidine, atropine, and scopolamine) have been used for

Table 4 Types of Peripheral Nerve and Plexus Blocks of the Upper Extremity and Their Uses Type Brachial plexus

Elbow

Wrist

Area injected

Agent injected

Nerves blocked

Indication

Interscalene, supraclavicular, Short-/long-acting local anesthetic Depends upon which branches Operations on shoulder and infraclavicular or axillary injections by fine needle injection or of plexus needed blocked for upper arm block plexus selectively, based catheter placement operation upon operation needs Medial to brachial artery (median Each nerve is blocked with local Both median and radial nerves Operations on forearm and nerve) and lateral to supracondylar anesthetic by fine needle hand ridge (radial nerve) proximal to injection elbow crease Block of median, ulnar, and radial Each nerve is blocked with local Median, ulnar, and radial Operations on hand nerves just proximal to where they anesthetic by fine needle nerves enter hand injection

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Table 5 Types of Peripheral Nerve and Plexus Blocks of the Lower Extremity and Their Uses Type Lumbar plexus

Sciatic nerve

Ankle

Area injected

Agent injected

Nerves blocked

Posterior, translumbar, paravertebral needle is Local anesthetic by fine Femoral, lateral femoral placed adjacent to plexus, but anterior needle injection or catheter cutaneous and obturator approach places needle into the femoral placement nerves nerve sheath Several approaches, but classic approach is Local anesthetic by fine Sciatic nerve, as well as injection deep to the gluteal muscles at the needle injection or catheter branches of the lumbar same time as posterior lumbar plexus block placement plexus Depends upon level of anesthesia needed in Local anesthetic by fine Combinations of saphenous, foot: nerves requiring injection include the needle injection superficial peroneal, deep saphenous, superficial peroneal, deep peroneal, tibial, and sural peroneal, tibial, and sural nerves nerves; all if needed

this purpose, performing as antisialagogues as well. Unfortunately, the unwanted side effects of tachycardia, lower esophageal sphincter relaxation, and CNS toxicity have limited their usefulness, especially in the elderly; so benzodiazepines (e.g., midazolam, lorazepam, and diazepam) are currently preferred. The most popular benzodiazepine, midazolam, has a fast onset (2 to 3 minutes to peak effect), short duration, and reliable anterograde amnesia. Furthermore, amnesia and sedation with midazolam occur in low doses, whereas respiratory depression and hemodynamic instability appear with higher doses. An agonist of the gammaaminobutyric acid type A (GABAA) receptor, the drug’s effects can be reversed by the administration of flumazenil, a competitive, but nonactive binder at the same receptor. Oral diazepam is still occasionally given for adults, and an oral midazolam preparation is now available for pediatric patients. Positive pressure mask ventilation can insufflate the stomach, leading to regurgitation of its contents, and aspiration of this fluid can cause severe pulmonary damage that is directly proportional to its acidity and particulate content. It is therefore important that the stomach is as empty as possible prior to the induction of general anesthesia or the placement of a regional block where the failure of the block may result in general anesthesia. For adults, a fast of at least six hours should elapse for solid foods and two hours for clear liquids. These same guidelines apply for pediatric patients, but if breast milk is the sole means of nutrition, a fast of at least four hours should elapse prior to the conduction of surgery (Table 7) (14). Patients who are at risk for pulmonary aspiration despite following the established guidelines for preoperative fasting (Table 8) may be given antacids and H2 antagonists to raise their gastric pH. In addition, metaclopramide is sometimes used to enhance

Indication Operations on hip and upper leg

Operations on hip and leg

Operations on foot

gastric emptying and decrease gastric fluid volume, but just like nasogastric or orogastric sumps, it does not fully guarantee gastric emptying (15). Although very small doses of opiates are sometimes given immediately preoperatively, they are generally used more aggressively after the airway is protected. Administration during the induction of general anesthesia will establish analgesia prior to incision (preemptive analgesia) and potentially avoid the development of plastic neuronal changes that can lead to increased pain postoperatively (16). While their ability to produce analgesia comes from binding to specific opioid receptors that directly inhibit ascending transmission of nociceptive information from the spinal cord dorsal horn and activate pain control circuits that descend from the midbrain via the rostral ventromedial medulla, these receptors also mediate undesirable side effects. Unfortunately, the side effects increase in both frequency and severity with more potent formulations, and include muscle rigidity, pupil constriction, pruritus (both histamine and nonhistamine mediated), urinary retention, decreased gastric and intestinal motility, and CNS-mediated respiratory depression and bradycardia. With high doses of narcotics, however, deep CNS depression can produce useful general anesthesia; a continuous intravenous infusion of ultra–short-acting remifentanil is often used during neuroanesthesia, and inducing anesthesia with large doses of sufentanil is often preferred for physiologically unstable patients. More frequently, however, general anesthesia is induced and maintained with hypnotic agents. Intravenous boluses of short-acting barbiturates or their analogs (e.g., propofol or etomidate) are commonly used as induction agents and are typically followed by an inhaled vapor (e.g., sevoflorane or isofluorane) administered through a breathing circuit for maintenance. Although an incomplete

Table 6 Drugs Commonly Used in Anesthesia Hypnotics Benzodiazepines Midazolam Diazepam Lorazepam Barbiturates Sodium pentothal Methohexital Other agents Propofol Etomidate Ketamine

Paralytics

Narcotics

Short acting Succinylcholine Rocuronium Mivacurium Intermediate acting Atracurium Vecuronium Long acting Pancuronium Curare

Short acting Remifentanil

Intermediate acting Sufentanil Fentanyl Long acting Meperidine Morphine

Inhalation agents Vapors Isoflurane Sevoflurane Desflurane Halothane Gasses Nitrous oxide

Table 7 Recommended Preoperative Fasting Periods to Reduce the Risk of Pulmonary Aspiration of Gastric Contents Guidelines for preoperative fastinga Material ingested Light meal Nonhuman milk Clear liquids Infant formula Breast milk a

Minimum fasting time 6 hr 6 hr 2 hr 6 hr 4 hr

Applicable to regional and general anesthetics, applicable to all levels of sedation, applicable to all ages. Source: From Ref. 14.

Chapter 10:

Table 8 Factors Influencing the Risks for the Aspiration of Gastric Contents Obesity Pregnancy Gastroparesis (e.g., diabetes, uremia, drugs) Trauma Symptomatic esophageal reflux Failure to complete preoperative NPO recommendations Abbreviation: NPO, nil per os.

anesthetic by itself, nitrous oxide is often added to supplement the hypnotic vapors because of its relatively few side effects. Physiologically, two general rules prevail regarding hypnotic agents. First, with few exceptions, all depress respiratory drive to some degree. Second, all hypnotics, except ketamine and nitrous oxide, are vasodilators and many are additionally cardiac depressants. Propofol, for example, is one of the most destabilizing agents used: its narrow therapeutic index quickly progresses from sedation to apneic general anesthesia and the associated hypotension can be particularly severe in hypovolemic patients. Therefore, only clinicians trained in the use of hypnotics, paralytics, and powerful narcotics should administer these drugs. Paralytics fall into two classes, depolarizing and nondepolarizing agents, and work primarily at the neuromuscular junction. Currently, the only depolarizing agent is succinylcholine, which acts by depolarizing the muscle postjunctional acetylcholine receptors. This triggers muscle fasciculation, and paralysis occurs because the half-life of succinylcholine does not allow muscle repolarization for approximately three minutes. Although succinylcholine has been used successfully since 1952 (17), it can have considerable side effects; under specific circumstances, it can cause significant hyperkalemia, sinus bradycardia, increased intraoccular and intracranial pressures, myalgias, and masseter spasm. Nondepolarizing agents, on the other hand, have few side effects, although some can cause histamine release and others can cause tachycardia. They act as competitive antagonists of acetylcholine at postsynaptic neuromuscular receptors. Reversal of their paralytic effects can be achieved by using medications that block the effects of acetylcholine esterase, which allows junctional concentrations of acetylcholine to rise high enough for it to become the competitive antagonist of the nondepolarizer. The unused nondepolarizing agent can then diffuse away for metabolic removal. Unfortunately, the paralytic reversal process allows acetylcholine levels to rise throughout the body and acetylcholine also mediates the parasympathetic system. Because this can lead to significant bradycardia, the use of paralytic reversal agents typically necessitates the concurrent administration of atropine or glycopyrolate. The choice of depolarizing or nondepolarizing paralytic agents is based upon clinical need—succinylcholine produces a short-acting, fast-onset, dense paralysis, but has side effects that can limit its usefulness. Although they possess far fewer side effects, nondepolarizing agents have considerably slower onsets and longer durations, and are generally much slower to produce a dense motor blockade. Finally, it is important to remember that all paralytic agents work only at the neuromuscular junction, so direct stimulation of muscle tissue by electrocautery will still produce local muscle contraction in a pharmacologically paralyzed patient. From the above discussion, it should be clear that successful airway management is critical if paralytics,

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hypnotics, or potent opioids are administered. If a secure airway is desired, a cuffed and properly sized endotracheal tube provides the most airway protection. Facemasks, laryngeal masks, and jet catheters may be appropriate in certain circumstances, but because they do not seal the airway from the esophagus, the patient remains an aspiration risk. These devices therefore are not considered to provide definitive airways in most situations. On the other hand, pediatric endotracheal tubes seldom have inflatable cuffs, but are still considered definitive. Cuffs unacceptably decrease the available lumen size in small tracheas, promote barotrauma in sensitive lungs, and risk fracturing of the narrowest part of the pediatric airway, the cricoid ring. If sized appropriately, however, the lack of a complete seal between the tracheal wall and the endotracheal tube is acceptably minimized.

CONSCIOUS SEDATION Most hospitals now maintain specific policies regarding the use of anesthetic agents by nonanesthesia personnel for invasive procedures occurring outside of the operating room. This involves achieving a state of moderate sedation described as a drug-induced depression of consciousness during which patients respond purposefully to verbal commands, either alone or accompanied by light tactile stimulation. No interventions are required to maintain a patent airway, spontaneous ventilation is adequate, and cardiovascular function is always maintained (18). Note that reflex withdrawal from a painful stimulus is not a purposeful response. Narcotics and hypnotics used to produce this level of sedation are typically specified in the policy, and paralytics and potent narcotics are not allowed. The most commonly used hypnotic for this purpose is methohexital. An ultra–short-acting barbiturate, its CNS effects are mediated through activation of GABAA receptors and side effects include a depression of respiratory drive, a reduction in cardiac output and blood pressure, and a reflexive tachycardia. With judicious administration, methohexital is capable of producing moderate sedation over a relatively wide range of doses. Propofol, on the other hand, is not recommended for moderate sedation due to its much narrower therapeutic window. The difference between a sedated, spontaneously breathing patient, and an unconscious, apneic patient is often determined by the smallest of propofol doses, and is therefore only recommended for use in intubated patients.

ANESTHETIC IMPLICATIONS OF SELECTED DISEASE STATES As stated above, almost every chronic, underlying disease process has anesthetic implications that must be taken into consideration when assessing patient risk and choosing an anesthetic plan. Two of the most commonly encountered are obesity and diabetes mellitus. In the United States, obesity among adults has risen significantly over the past 20 years. Results from the 1999–2002 National Health and Nutrition Examination Survey (NHANES), as reported by the National Center for Health Statistics, indicate that 30% of American adults 20 years of age or older are obese, and an estimated 65% of American adults are either overweight or obese (19). This prevalence is 16% higher than in a similar study performed

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only eight years earlier, and this increase is not limited to adults. The percentage of young people who are overweight has more than tripled since 1980, and among children and teens, 6 to 19 years old, 16% are considered overweight. Being overweight or obese increases the risk of many secondary diseases such as hypertension, type 2 diabetes, coronary heart disease, stroke, and respiratory conditions, all of which directly impact upon anesthesia risks; a patient who is 30% overweight has a 40% increased chance of dying of heart disease and a 50% increased chance of dying of stroke. The greatest physiologic impact of obesity upon anesthesia revolves around underlying cardiopulmonary derangements. Redundant soft tissue in the upper airway causes obstruction upon the induction of anesthesia and contributes to a difficult tracheal intubation that is already complicated by the high risk of gastric aspiration and the need for rapid airway control. A decreased functional residual capacity that is smaller than closing volumes is worsened by mechanical ventilation and predisposes to hypercapnia and rapid oxygen desaturation from significant atelectasis. Chronic respiratory insufficiency leads to pulmonary hypertension, and combined with a noncompliant left ventricle that is hypertrophied from systemic hypertension, poor myocardial perfusion, and the demand for increased cardiac output, obese patients often require invasive cardiac monitoring intraoperatively and prolonged postoperative intubation. As a result, these patients require extensive preoperative cardiopulmonary evaluation and careful anesthetic planning. The number of documented diabetic patients is enormous and progressively increasing, largely due to the rise in type 2 diabetes that accompanies the weight gain among Americans. In the operating room, tight control of blood glucose level has been shown to be important for the outcome of diabetic patients undergoing cardiopulmonary bypass (20) and during CNS ischemia associated with head injury (21). There otherwise remains little evidence that tight glucose controls benefit any other group of diabetic patients undergoing anesthesia. Instead, the major risks diabetics face during anesthesia comes from the potential end-organ damage created by long-standing disease. Cardiovascular dysfunction and renal insufficiency must be assessed preoperatively, and flexion-extension radiographs are recommended if atlanto-occipital instability is anticipated during intubation. During regional anesthesia, diabetics are more prone to nerve injury, and the peripheral microvascular disease of diabetes may worsen ischemic nerve damage if epinephrine is included in the local anesthetic. Additionally, although rare, intraoperative physical stresses can trigger ketoacidosis or nonketotic hyperosmolar coma in brittle diabetics. There have been numerous regimens advanced for both the preoperative and intraoperative management of insulin and glucose, but as yet, no single method has proven to be superior. Regardless of which regimen is chosen, however, there are several key elements that are important in managing diabetic patients. Clear parameters must be established preoperatively, which define how tightly the patient’s serum glucose is to be managed. For example, type 1 diabetics who produce little or no endogenous insulin are more likely to be candidates for tight control than are type 2 diabetics. Pregnancy, the type of surgical operation, any expected CNS ischemia, or the personal bias of the patient’s primary care physician can all create a disire for tighter intraoperative glucose control. Finally, the frequency of intraoperative serum glucose monitoring must reflect the desired level of glucose control.

ANESTHESIA EMERGENCIES Despite modern equipment, drugs, and techniques, true anesthetic emergencies can occur but are fortunately rare. Often, they are preceded by a progression of warning signs that, if managed in a timely fashion, could have either prevented the emergency or lessened its impact. All anesthesia providers must therefore maintain a high level of vigilance for physiologic changes that may herald a deeper problem. Cardiac arrest, for example, rarely occurs as an isolated event and is caused by harmful dysrhythmias, ionotropic failure, insurmountable afterload, or inadequate filling pressures. These conditions can arise from a wide variety of detectable circumstances that include electrolyte and acid–base disturbances, intravascular volume depletion, myocardial infarction, hypoxemia, tamponade, aortic cross-clamping, pulmonary embolus, and drug effects. When a cardiac arrest does occur in the operating room, the treatment is similar to the steps outlined by the American Heart Association in its Advanced Cardiac Life Support guidelines: proper ventilation should be confirmed and 100% oxygen applied, the circulation should be supported with chest compressions or heart massage, a defibrillator should be applied and used as indicated, consideration should be given to the use of appropriate pharmacological supplementation, and a search should be initiated for any correctable causes of the arrest. Venous air embolism (VAE), on the other hand, typically occurs rapidly with little warning, although its risk of occurrence may be predicted by patient positioning. Any surgery or procedure where the operative site is elevated above the right atrium places the patient at risk for VAE, because veins in this region develop an intravascular pressure that is less than central venous pressure. While this can occur under a variety of circumstances, it is most commonly associated with central line placements, certain gynecologic procedures, and craniotomies. If veins in the elevated site are open to the atmosphere, air will be entrained into the bloodstream and once in the central circulation, air bubbles pass through the right side of the heart and lodge in the pulmonary capillary beds. Here, they interfere with oxygen and carbon dioxide exchange, obstruct pulmonary artery return to the left ventricle (preload), and if severe, cause right-sided heart pressures to rise. If rightsided heart pressures exceed left-sided heart pressures, a patent ‘‘foramen ovale’’ can open, causing a right-to-left cardiac shunt and the possibility that air can pass into the aorta and up the carotid arteries. Precordial Dopplers and transesophageal echocardiograms are sensitive early detectors of VAE, but in the absence of these devices, VAE typically presents with hypotension, oxygen desaturation, hypoxemia, and a falling end-tidal carbon dioxide despite rising arterial levels. There are now several single-lumen, multiple-orifice central venous catheters on the market, which are designed to aspirate air from the right atrium; however, their value is often more diagnostic than therapeutic because presenting symptoms are caused by air that has already passed through the right atrium and into the pulmonarycirculation.Nonetheless,VAEtreatmentisbasedupon preventing the further entrainment of air, minimizing the passage of air to the pulmonary capillary beds, supporting the circulation, and maximizing oxygenation and ventilation (Table 9) until the air is dissolved into the blood. Malignant hyperthermia (MH) is a catastrophic anesthesia emergency that can potentially result in the

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Table 9 The Treatment of Venous Air Embolism

Table 10 The Treatment of Acute Malignant Hyperthermia

Inform the surgeon Administer 100% oxygen Discontinue nitrous oxide Have surgeon flood field with saline or pack wound with saline-soaked sponges to prevent further entrainment Aspirate right atrial VAE catheter, if available Lower surgical site below level of right atrium Place patient in left lateral decubitus position to trap entrained air in right ventricle Support circulation as necessary

Do not administer volatile anesthetics or succinylcholine once MH has been diagnosed or considered Call for additional help Hyperventilate with 100% oxygen Give 2.5 mg/kg of dantrolene sodium for injection. Repeat as often as necessary, titrated to control clinical signs of MH. Continue intravenous dantrolene for at least 24 hr after control of the episode (1 mg/kg q 6 hr) Treat acidosis with bicarbonate—if not promptly reversed by dantrolene Avoid calcium channel blockers: Persistent arrhythmias may be treated with any other standard antiarrhythmics. Most arrhythmias respond to correction of hyperkalemia and acidosis by hyperventilation, dantrolene, and bicarbonate Monitor core temperature Treat hyperkalemia with glucose, insulin, and calcium If hyperthermic or core temperature rises rapidly, cool the subject. Cease cooling efforts when temperature has fallen to 38 C Watch for recrudescence by appropriate monitoring in an intensive care unit for at least 24 hr. Recrudescence occurs in about 25% of MH cases Avoid parenteral potassium, if possible, during ongoing rhabdomyolysis Ensure urine output of at least 2 mL/kg/hr by hydration and diuretics Follow coagulation profile—disseminated intravascular coagulation may occur Measure CKs every 6 hr until decreased. CK may remain elevated for 2 wk if event was severe. After the patient has improved and stabilized, CK should be measured on a declining time basis until it is normal (e.g., every 4 hr during the acute episode to every week during convalescence). This is important because it is elevated normally in some myopathies, and this should be recognized as a part of overall evaluation and treatment

Abbreviation: VAE, venous air embolism.

unexpected death of a healthy patient. It is a sudden dysregulation of skeletal muscle intracellular calcium, triggered by exposure to certain anesthetic agents. These triggering agents include the volatile inhalation anesthetics and succinylcholine. The increase in intracellular calcium levels causes an increased muscle metabolic rate, with accompanying heat production, increased cellular acid content, muscle rigidity, and a leakage of intracellular contents. This then leads to escalating serum potassium levels, cardiac dysrhythmias, and markedly increased serum myoglobin levels with severe rhabdomyolysis. The body temperature rise can be rapid and dramatic: the fever may quickly exceed 110 Fahrenheit.Leftuntreated,cardiacarrest,renalfailure,disseminated intravascular coagulation, internal hemorrhage, liver failure, brain injury, and death may quickly ensue. While MH susceptibility is inherited with an autosomal dominant inheritance pattern, it has also been associated with over 90 genetic mutations (22) and MH-related deaths have been reported even though patients have undergone multiple prior uneventful surgeries. The incidence may be as low as 1 in 65,000 general anesthetics, but may be as high as 1 in 5000 in areas where MH-susceptible families are concentrated, such as Wisconsin, Nebraska, West Virginia, and Michigan in the United States (23). At one time, mortality rates were as high 70%, but with early diagnosis and rapid treatment, the mortality rate is now less than 5%. Worldwide, a number of organizations have been established to provide MH research and support. For example, the Malignant Hyperthermia Association of the United States maintains an informative website, a patient registry, and a toll-free hotline (Box 1) to aid in the diagnosis and treatment of acute MH. Currently, dantrolene sodium is the only specific treatment of MH because it decreases the release of calcium from the storage sites in muscle (the sarcoplasmic reticulum) by binding to calcium channels, but significant physiologic support must also be Box 1 In the United States, Malignant Hyperthermia Association of the United States (MHAUS) Is the Best Source of Information for Health Care Professionals on Malignant Hyperthermia MHAUS 11 East State Street PO Box 1069 Sherburne, New York United States 13460-1069 (607) 674-7901 or (800) 98 MHAUS Web site: www.mhaus.org Hot Line: (800) MH-HYPER or 1-315-464-7079 outside of the U.S.

Abbreviations: CK, creatine kinase; MH, malignant hyperthermia. Source: From Ref. 24.

maintained (Table 10) (24). It is vital that all hospitals, ambulatory care centers, and offices where general anesthesia is administered have a full supply of dantrolene sodium immediately available (Table 11), as well as the facilities to rapidly lower body temperature, test for muscle breakdown, and measure serum acid–base changes, electrolytes, and coagulation (25).

THE PHYSIOLOGY OF PAIN AND ANALGESIA Pain is the perception of an unpleasant sensation that originates from a specific region of the body and is associated with actual or potential tissue damage. In humans, this perception is not simply the afferent conduction of nociception, but includes the highly individual influences of behavioral, cognitive, and sociocultural experiences (26) that can either suppress or intensify pain. While it is this subjective nature to pain that often complicates successful clinical treatment, most approaches to analgesia are nonetheless based upon interruption of nociceptive conduction. Althoughtheanatomic,pharmacologic,andpsychological pathways that conduct and interpret pain are complex, a basic understanding of neurophysiology is essential to pain management. This can be characterized in four parts: transduction, transmission, modulation, and perception.

THE PHYSIOLOGY OF NOCICEPTION Transduction Nociceptors (pain receptors) exist in the skin and deep tissues as the free nerve endings of primary sensory neurons

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Table 11 Contents of a Malignant Hyperthermia Carta 1. Dantrolene sodium for injection—36 vials (each able to be diluted at the time of use with 60 mL sterile water) 2.Sterile water for injection USP (without a bacteriostatic agent) to reconstitute dantrolene—1000 mL 2 3. Sodium bicarbonate (8.4%)—50 mL 5 4. Furosemide 40 mg/amp 4 ampules 5. Dextrose 50%—50 mL vials 2 6. Calcium chloride (10%) 10 mL vial 2 7. Regular insulin 100 units/mL 1 (refrigerated) 8. Lidocaine for injection, 100 mg/5 mL, or 100 mg/10 mL in preloaded syringes (3). Amiodarone is also acceptable 9. Syringes (60 mL 5) to dilute dantrolene 10. Mini-spike1 IV additive pins 2 and Multi-Ad fluid transfer sets 2 (to reconstitute dantrolene) 11. Angiocaths: 16 G, 18 G, 20 G, 2-inch; 22 G, 1-inch; 24 G, 0.75-inch (4 each) (for IV access and arterial line) 12. NG tubes 13. Irrigation tray with piston syringe (1) for NG irrigation 14. Toomy irrigation syringes (60 mL 2) for NG irrigation 15. Microdrip IV set (1) 16. CVP kits 17. Transducer kits for arterial and central venous cannulation 18. A minimum of 3000 mL of refrigerated cold saline solution 19. Large sterile Steri–Drape (for rapid drape of wound) 20. Three-way irrigating foley catheters 21. Urine meter (1) 22. Irrigation tray with piston syringe 23. Large clear plastic bags for ice (4) 24. Small plastic bags for ice (4) 25. Bucket for ice 26. ABG kits (6) 27. Blood specimen tubes for CK, myoglobin, SMA 19, LDH, electrolytes, thyroid studies, PT/PTT, fibrinogen, fibrin split products. CBC, platelets, lactic acid level 28. Urine collection container for myoglobin level 29. Urine hemoglobin dipstick a

All hospitals, ambulatory centers, and offices where general anesthesia is administered must have an malignant hyperthermia cart immediately available. Abbreviations: ABG, arterial blood gas; CBC, complete blood count; CK, creatine kinase; CVP, central venous pressure; IV, intravenous; LDH, lactate dehydrogenase; NG, nasogastric; PT, prothrombin time; PTT, partial thromboplastin time; SMA, serum metabolic assay; USP, United States Pharmacopeia. Source: From Ref. 25.

whose cell bodies are located in the dorsal root and trigeminal ganglia. Mechanical or heat injury results in the release of chemical mediators (autocoids) that trigger a repeated response from local nociceptors in the form of membrane depolarization and a subsequent propagation of afferent signals. There are two major types of nociceptors, codified by conduction rates and their response to specific stimuli. Smalldiameter, thinly myelinated Ad fibers conduct at about 5 to 30 m/s and are activated by thermal or mechanical stimuli. Polymodal C fibers are small-diameter, unmyelinated fibers that conduct at 0.5 to 2 m/s and respond to a wide variety of high-intensity mechanical, chemical, hot (> 45 C), and cold stimuli (27). Stimulation of Ad fibers generally results in sharply localized pricking pain of short duration, and stimulation of C fibers generally produces a poorly localized burning sensation of longer duration (28). Autocoids can arise directly from injured cells (potassium, adenosine triphosphate, acetylcholine, bradykinin, serotonin, prostaglandin E2, and arachidonic acid), released

platelets (serotonin), inflammatory mast cells (histamine), or primary afferent nerve endings (substance P). The release of some mediators also triggers the creation of other chemical mediators. For example, while strongly activating both Ad and C fibers, bradykinin increases the synthesis and release of prostaglandins from nearby cells utilizing the cyclooxygenase metabolism of arachidonic acid. The prostaglandins then sensitize nearby nociceptors that were previously nonresponsive to mechanical stimuli (a phenomenon known as hyperalgesia), probably by lowering nociceptive thresholds. Cyclooxygenase inhibitors such as aspirin and nonsteroidal anti-inflammatory analgesics are effective pain relievers because they block this prostaglandin synthesis and release.

Transmission Nociception is carried by Ad (myelinated) and C (unmyelinated) fibers to the spinal cord via the dorsal roots. Upon entering the cord, axon branches ascend and descend several levels in the tract of Lissauer while collaterals synapse with neurons in the dorsal horns. Nociceptive fibers generally end in the superficial dorsal horn, the marginal zone (Rexed lamina I), and substantia gelatinosa (lamina II), while some Ad fibers penetrate as deep as lamina V. Here, nociceptive afferents connect with either projection neurons that relay signals to the brain or with interneurons that regulate the flow of information to the projection neurons through excitation or inhibition. This convergence of nociception into the dorsal horns is thought to be responsible for referred pain from deep visceral sources that are perceived at the body surface; because a single projection neuron receives input from both sources, higher brain centers cannot distinguish the source. Pain can also arise in the absence of nociceptor activity, often due to peripheral nerve injury and probably related to the hyperactivity of dorsal horn neurons. The burning pain of brachial plexus avulsions or phantom limb pain is such an example. Furthermore, because about 20% of C fibers are sympathetic postganglionic efferents, damaged local nociceptors may be directly activated by sympathetic nonsynaptic electrical cross talk (ephaptic transmission) that produces a severely burning, painful condition called causalgia or reflex sympathetic dystrophy. Nociception is projected to the brain along five ascending spinal pathways: the spinothalamic, spinoreticular, spinocervical, and spinomesencephalic tracts, and the dorsal columns. The spinothalamic tract is the most prominent and has been studied in the most detail; it originates from cord neurons in laminae V-VII and I, crosses the midline, ascends in the anterolateral white matter on the contralateral side, and terminates in the thalamus. The spinoreticular tract is also in the anterolateral white matter of the cord, is both lateral and contralateral, and projects indirectly to the reticular network, thalamus, basal ganglia, and prefrontal and visual cortex. Two major areas of the thalamus receive afferent nociceptive input from spinal projection neurons, the medial and lateral nuclear groups. While many of the neurons in the medial nuclear group (the central lateral nucleus and the intralaminar complex) are exclusively nociceptive, they project widely and suggest a nonspecific role. The lateral nuclear group (the ventrobasal nucleus and the posterior nuclei) also contains neurons that respond exclusively to nociception, but they project to the somatosensory cortex. It is unclear how the cortex processes pain; nociceptive input does not follow any logical topical mapping as does tactile, auditory, or visual information, and clinical studies

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Table 12 Perioperative Physiologic Dysfunction Resulting from Uncontrolled Pain Endocrine system Sympathetic activation Hyperglycemia (elevated glucagon) Accelerated protein breakdown Accelerated nitrogen loss Increased aldosterone secretion Increased cortisol secretion Increased antidiuretic hormone Pulmonary system Decreased functional residual capacity Decreased tidal volume (splinting) Cardiovascular system Increased heart rate Increased blood pressure Increased contractility Increased systemic vascular resistance Renal system Activated rennin-angiotensin system Coagulation Activated coagulation cascade Increased platelet activity Decreased fibrinolysis Immune system Suppressed humoral/cellular immune response Delayed wound healing Gastrointestinal system Inhibited intestinal motility

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been completely proven, it may explain the effectiveness of several clinical modalities. Conceptually, therapeutic pharmacology is directed at blocking these ‘‘gates,’’ and transcutaneous electrical nerve stimulation (TENS) (see below) is thought to relieve pain by stimulating the myelinated dorsal column and peripheral nerve fibers that suppress pain transmission. Price (33) advanced a sequential processing theory as a modification of the Gate Control Theory in which cognitive and contextual appraisal of sensory input have direct causal relationships to affective reactions to pain. Such psychological influences may contribute to cortical modulation of distant nociception.

Perception Human pain perception and pain response are influenced by emotional (affective) components, but the exact nature of this relationship is unclear. For example, does depression in a cancer patient exacerbate pain or does pain exacerbate depression? Pain can induce reflexive or deliberate behavioral changes such as facial grimacing and splinting, and cognition is often altered, notably with chronic and terminal cancer pain, affecting the patient’s ability to cope with their pain. While widely researched in surgical, burn, and cancer pain patients, such psychosocial aspects of pain remain poorly understood, but may represent yet another avenue for therapeutic pain intervention.

PAIN MEASUREMENT have shown that damage to large areas of the cortex does not impair pain detection. Transmission of nociception through the CNS produces a neuroendocrine stress response that involves hypothalamic, pituitary, and adrenal pathways, and results in increased production of cortisol, antidiuretic hormone, glucagon, aldosterone, renin, and angiotension II. The effects include sodium and free water retention, increased blood glucose levels, and a hypermetabolic state that elevates oxygen and substrate consumption (29). In turn, a hypercoagulable state is induced, which may contribute to such postoperative complications as venous graft failure and deep venous thrombosis, and sympathomimetic activation may increase myocardial oxygen consumption, which can precipitate myocardial ischemia in susceptible individuals. Therefore, attenuation of this pathophysiologic neuroendocrine stress response through appropriate pain control may improve related perioperative mortality and morbidity (30,31). A brief summary of perioperative physiologic dysfunction during uncontrolled pain can be found in Table 12.

Modulation The variable nature of the response to pain suggests the existence of a modulatory system within the anatomic pain pathways. Neurophysiological studies have shown that stimulation of low-threshold, myelinated, non-nociceptive spinal cord afferent fibers decreases the response of dorsal horn neurons to afferent unmyelinated nociceptors, and a conduction blockade of these myelinated afferents enhances the response of dorsal horn neurons. Such observations have led Melzack and Wall (32) to propose that reception of nociception at the dorsal horn level is subject to ‘‘gated’’ control (Gate Control Theory) from higher centers via myelinated afferent pathways. Although this theory has not

The subjective nature of pain precludes accurate assessment of a patient’s pain by simple observation; patient reporting is essential. While a number of different methods have been proposed, a visual bar graph with an analog scale is often employed, by which a patient identifies their pain intensity. Typically, the scale is from 0 to 10, where 0 is the absence of pain and 10 is the worst pain the patient can imagine. Frequent and consistently obtained analog pain scores can then be used to quantitatively follow the effectiveness of treatment. The Joint Commission on Accreditation of Healthcare Organizations has recently established standards related to pain management (Table 13). They include recognition of the right of patients to appropriate assessment and management of pain, and a mechanism for screening the presence, nature, and intensity of pain in all patients (34). A visual/ analog scale is a quick and effective means of screening and treating pain in patients, which has been adopted by many hospitals meeting these standards, and is rapidly seeing widespread use in surgical wards.

THE MANAGEMENT OF ACUTE POSTOPERATIVE PAIN In 1992, the U.S. Department of Health and Human Services Agency for Health Care Policy and Research, now known as the Agency for Healthcare Research and Quality (AHRQ), published the Acute Pain Management Clinical Practice Guideline to help surgeons effectively manage acute postoperative pain (35). Over 2.4 million copies of the guideline were printed and distributed, and since then, over 30 additional pain management guidelines have been published by governmental agencies and professional organizations (Table 14). It has been estimated that approximately 23 million patients undergo surgery each year in the United

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Table 13 The Joint Commission on Accreditation of Healthcare Organizations Standards Related to Pain Management Recognize the right of patients to appropriate assessment and management of pain Assess the existence and, if so, the nature and intensity of pain in all patients Record the results of the assessment in a way that facilitates regular reassessment and follow-up Determine and assure staff competency in pain assessment and management, and address pain assessment and management in the orientation of all new staff Establish policies and procedures that support the appropriate prescription or ordering of effective pain medications Educate patients and their families about effective pain management Address patient needs for symptom management in the discharge planning process Ensure that pain does not interfere with a patient’s participation in rehabilitation Incorporate pain management into performance activities (i.e., establish a means of collecting data to monitor the appropriateness and effectiveness of pain management) Source: From Ref. 34.

States alone, and after reviewing over 7000 published reports, the AHRQ concluded that most of these patients still do not get adequate pain relief; these patients continue to feel moderate to severe pain (37). As such, the AHRQ views untreated pain as a patient safety problem (38), and Congress has declared the decade beginning on January 1, 2001 as the Decade of Pain Control and Research. Many of the physiologic responses typically ascribed to perioperative stress, injury, and pain can be reduced or eliminated with appropriate analgesia, and typically, a multimodal approach must be used to fully maximize pain management. For example, while infiltration of incisions with long-acting local anesthetics can produce incisional analgesia intraoperatively, it alone is rarely sufficient for effective overall perioperative pain control. A broad understanding of pain management is therefore necessary, because it allows the surgeon and anesthesiologist to develop pain control plans before surgery and informs the patient what to expect in terms of pain during and after surgery.

Preoperative Assessment Perioperative pain management begins with preoperative planning. A careful assessment of the patient’s medical

history should be obtained, because information about the presence of underlying chronic pain syndromes, medication allergies, or a history of undesirable side effects from narcotics will influence treatment plans. Furthermore, the chronic use of preoperative narcotics or a history of substance abuse may introduce medication tolerances that impact heavily upon intraoperative and postoperative narcotic dosages. Once all information is gathered, postoperative pain control options should be discussed with the patient. It is important to establish a collaborative approach for pain management based upon the patient’s understanding about, and acceptance of, available treatment options (39); patient refusal is a contraindication to any treatment option.

Preemptive Analgesia An intense nociceptive stimulation such as a surgical incision can lead to plastic changes in the CNS (windup), which cause the patient to perceive postoperative pain as more painful than it would have been had the patient not perceived the incision as painful first (40). Numerous clinical studies have shown that if regional anesthesia, epidural opioid analgesia, or, more recently, a nonsteroidal cyclooxygenase-2 inhibitor is administered prior to surgery, postsurgical pain hypersensitivity can be minimized with a subsequent reduction in the requirement for postoperative pain intervention (16,41–44). Such preemptive action may offer prophylaxis from developing certain chronic pain syndromes as well; amputees, for example, are less likely to develop phantom limb pain postoperatively if they receive adequate analgesia prior to surgery. Unfortunately, successful preemptive analgesia remains controversial. Variability in the type and density of analgesia, surgical site, and the timing of administration prior to surgery seem to affect outcome, and because most studies focus only on postoperative pain requirements, there is little evidence that recuperation or long-term outcome is improved (45). Despite this, the concept of preemptive analgesia continues to hold promise for improving postoperative patient comfort.

Systemic Opioids Opioids produce analgesia through direct interaction with opioid receptors in the central, and to a lesser extent, peripheral nervous systems. Most commonly used opioids bind to mu receptor types; activation at the mu1 receptor produces

Table 14 Selected Guidelines for Perioperative Pain Management Guideline title Acute pain management: operative or medical procedures and trauma. AHCPR Publication No. 92-0032 Acute pain management in infants, children, and adolescents: operative and medical procedures. Quick reference guide for clinicians. AHCPR Publication No. 92-0020 (also in 36) Acute pain management in adults: operative procedures. Quick reference guide for clinicians. AHCPR Publication No. 92-0019 Practice guidelines for acute pain management in the perioperative setting Guidelines for the pediatric perioperative anesthesia environment

Release date

Available from

1992

AHRQ Clearinghouse, 1201 East Jefferson Street, Suite 501 Rockville, Maryland 20852 800-368-9295, www.ahrp.gov AHRQ Clearinghouse, 1201 East Jefferson Street, Suite 501 Rockville, Maryland 20852 800-368-9295, www.ahrp.gov

1992

1993

AHRQ Clearinghouse, 1201 East Jefferson Street, Suite 501 Rockville, Maryland 20852 800-368-9295, www.ahrp.gov

April, 1995

American Society of Anesthesiologists, 520 North Northwest Highway Park Ridge, Illinois 60068-2573, www.asahq.org American Academy of Pediatrics, P.O. Box 747 Elk Grove, Illinois 60009-0747, www.aap.org

February, 1999

Abbreviations: AHRQ, Agency for Healthcare Research and Quality; AHCPR, Agency for Health Care Policy and Research.

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supraspinal analgesia, whereas mu2 receptor activation leads to the undesired effects of respiratory depression, bradycardia, nausea, and decreased gastrointestinal motility. Traditionally, until a postoperative patient could tolerate oral narcotics, opioids were largely administered intramuscularly due to the widespread perception that it was the safest way to give narcotics, but apnea and severe oxygen desaturation can still occur with this route of delivery. Also, the pharmacokinetics and pharmacodynamics of opioids administered intramuscularly display a four- to fivefold variation between individual patients, and inadequate analgesia is often the result. Now, intravenous opioids are more commonly employed, typically utilizing a patientcontrolled analgesia (PCA) pump that is triggered when the patient depresses a remote handheld button. These pumps operate on the theory that patients in pain receive analgesic medications in small increments, but only upon demand: if the patient is not in pain, no medication is administered. An internal timer provides a specified lockout interval during which an additional bolus cannot be obtained so that a safe and effective analgesia is provided without the risks of overdose. For patients who require a more constant narcotic serum level, most PCA pumps can be set to additionally deliver a continuous background infusion (basal rate), although this option can introduce more opportunities for overdose and programming error. Agents that are most commonly used for PCA analgesia include morphine (1 mg/mL) given in 0.5 to 2.5 mg increments, meperidine (10 mg/mL) given in 5 to 25 mg increments, and hydromorphone (0.2 mg/mL) given in 0.05 to 0.25 mg increments. Lockout intervals for these drugs should be between 5 and 10 minutes. A more potent but shorter-acting narcotic, fentanyl (10 mcg/mL), can also be used, and is generally given in 10 to 20 mcg increments with a lockout interval of between 3 and 10 minutes. Both the quality and the safety of PCA analgesia have been extensively studied. Although there have been reports of respiratory depression during PCA use, mechanical parameters such as forced expiratory volume in one second, functional residual capacity, and peak flow rates are not different when compared to intramuscular narcotic administration (46). Factors that seem to increase PCA complication risk are advanced age, hypovolemia, large incremental doses, and the use of a basal rate. The quality of PCA analgesia, however, has consistently been shown to be equal or superior to intramuscular narcotic administration: compared with intramuscular narcotic regimens, postoperative pain management with PCA pumps generally uses less total narcotics and produces higher patient and nurse satisfaction levels (47). Sudden cessation of opioid medications after continued therapy may lead to the development of abstinence syndromes. Physiologic dependence (tolerance) can develop after only five days of therapy, and opioid withdrawal can result in tachycardia, lacrimation, yawning, nausea, hypertension, restlessness, and insomnia.

Intra- and Postoperative Intraspinal and Epidural Analgesia Local anesthetics infused through a properly placed epidural or intrathecal catheter produce satisfactory intraoperative regional anesthesia for a variety of conditions, and although long-term use of intrathecal catheters pose unacceptable infection risks, epidural catheters are often left in place for extended postoperative periods to maintain analgesia.

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Surgical doses of local anesthetics, however, are impractical postoperatively because of the unwanted side effects of hypotension, dense sensory and motor blocks, nausea, and urinary retention; so epidural opioids are commonly employed. When comparing epidural versus intramuscular analgesic regimens, patients utilizing the epidural route have been shown to use up to seven times less narcotic, have superior analgesia, ambulate sooner, have fewer pulmonary complications, have earlier return of bowel function, and be discharged from the hospital earlier (48). Furthermore, highrisk surgical patients receiving combined epidural/general anesthesia and postoperative epidural opioids have lower overall complication and infection rates, shorter times to extubation, and significantly lower hospital costs than those receiving postoperative intramuscular or intravenous opioids (49). Despite these advantages, however, there are risks associated with the use of intraspinal and epidural opioids. As with the intramuscular and intravenous route, severe respiratory depression and CO2 narcosis can develop, as well as pruritus, urinary retention, and nausea. These side effects can be effectively managed, but treatment begins with vigilant monitoring of the patient. While intensive care facilities are well suited for this, step-down units or conventional surgical wards where the nursing staff has been specially educated in the care of patients with epidural catheters can also be effectively employed. In many institutions, the use of neuraxial techniques such as epidural and spinal anesthesia has been declining with the increasing use of low-molecular-weight heparin for thromboprophylaxis. Spinal hematoma is relatively rare; although it defies study by a prospective randomized study or laboratory model, there are multiple case reports and clinical series documenting its occurrence. As a result, in 2002, a Consensus Conference of the American Society of Regional Anesthesia and Pain Medicine formally recognized spinal hematoma as a definite risk during spinal and epidural anesthesia in patients receiving antithrombotic therapy (44). The patient’s coagulation status must be optimized at the time of needle placement, and anticoagulation must be carefully monitored during any epidural catheterization. Furthermore, indwelling catheters should not be removed in the presence of therapeutic anticoagulation, because this appears to significantly increase the risk of potentially devastating spinal hematoma (50).

Other Regional Techniques A variety of surgical neural blockades can be continued postoperatively for pain management. For example, while single injections of long-acting local anesthetics into the axillary sheath, femoral sheath, lumbar plexus, or sciatic nerve produce blocks that are dense enough to allow surgery, they can also provide postoperative analgesia for up to 24 hours. Insertion of catheters into these sites for continuous analgesia and sympathetic blockade may be particularly advantageous after implantation surgery or for maintaining a normal range of motion following joint surgery. In addition, interpleural catheters, correctly placed following thoracic surgery provide unilateral analgesia without apparent sensory block, presumably from multiple intercostal nerve blocks (51).

Nonpharmacologic Modalities Cognitive modalities such as distraction, relaxation, and hypnosis have been successfully utilized as adjuncts to other analgesic interventions in the perioperative period. While

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having the ability to improve overall patient satisfaction without producing limiting side effects, it should be noted that randomized controlled trials have produced conflicting results on efficacy; further study is needed to clarify their exact role in the management of postoperative pain. Physical modalities such as TENS may be beneficial adjuncts in the treatment of postoperative pain or in relieving discomfort associated with positioning during surgery and immobilization. TENS produces electroanalgesia through the spinal cord–gating mechanism (see above), and has been shown to be effective over incision sites and for thoracotomy, post–cesarean section, total hip replacement, knee replacement, shoulder pain, lumbar spine surgery, and cholecystectomy (52,53). Unfortunately, it is contraindicated in patients with cognitive impairment and should not be used near demand-type cardiac pacemakers, over a pregnant uterus, carotid sinuses, and laryngeal or pharyngeal muscles, or around the eye. There are few random controlled trials of needle acupuncture in the management of postoperative pain, but a recent Consensus Statement from the National Institutes of Health suggests that it may be considered a treatment option (54). For example, acupuncture has been shown to provide effective pain relief and improved range of motion following ablation and axillary lymphadenectomy in patients with breast cancer (55). While there can be unfortunate side effects, most complications can be avoided by the use of licensed, certified practitioners and Food and Drug Administration–approved single-use needles.

Acute Pain Services Acute Pain Services began to appear in 1988. Today, although few small hospitals have them, approximately 34% to 44% of hospitals in Europe (56,57) and most major institutions in the United States (58) have organized Acute Pain Services. Typically anesthesiology based, they are often multidisciplinary and are designed to create a framework in which postoperative pain can be managed more effectively. To date, there have been no high-quality, systematic review of the benefits, costs, and comparative outcomes, but large-scale observational studies of Acute Pain Services indicate that they can improve postoperative pain without endangering patient safety (59).

SUMMARY The major advances that have occurred in surgery over the past 50 years would not have been possible without similar advances in the field of anesthesiology. The ability to regionally anesthetize various parts of the body without necessarily having to induce general anesthesia has broadened the scope of operative surgery and enabled even high-risk patients to undergo needed procedures with an acceptable morbidity and mortality. Thus, choosing the anesthetic technique and the corresponding pharmacologic agents needed to achieve the best anesthetic result can now be individualized for the patient’s specific needs. Factors contributing to these selections include the part of the body requiring surgery, the patient’s health status, the patient’s particular preferences, and the skill of the anesthesiologist. Working together, the patient, surgeon, and anesthesiologist can tailor the approach to anesthesia so that it optimizes the patient’s desires and safety while allowing the surgeon to successfully complete the operation.

Equal advances have occurred in our understanding of the physiology of pain. Although the complexity of nociception continues to present unique challenges, much of the process has now been deciphered, and innovative strategies are continually being developed to interrupt the transduction, transmission, modulation, and perception of pain. These strategies, both pharmacologically and nonpharmacologically mediated, can now be combined to effectively manage the cause and severity of pain, even in the most difficult of circumstances.

REFERENCES 1. American Society of Anesthesiologists. The ASA Physical Status Classification System. www.asahq.org/clinicalinfo.htm. 2. Buck N, Devlin HB, Lunn JL. Report of a confidential enquiry into perioperative deaths. Nuffield Provincial Hospitals Trust, London: The King’s Fund Publishing House, 1987. 3. Keenan RL, Boyan CP. Cardiac arrest due to anesthesia. JAMA 1985; 253:2373. 4. Newland MC, Ellis SJ, Lydiatt CA, et al. Anesthetic-related cardiac arrest and its mortality: a report covering 72,959 anesthetics over 10 years from a US teaching hospital. Anesthesiology 2002; 97:108. 5. Shah KB, Kleinman BS, Sami H, et al. Reevaluation of perioperative myocardial infarction in patients with prior myocardial infarction undergoing noncardiac operations. Anesth Analg 1990; 71:231. 6. Keenan RL, Boyan CP. Decreasing frequency of anesthetic cardiac arrests. J Clin Anesth 1991; 3:354–357. 7. Eichhorn JH. Effect of monitoring standards on anesthesia outcome. Int Anesth Clin 1993; 31(3):181–190. 8. American Society of Anesthesiologists. The ASA Closed Claims Project. www.asaclosedclaims.org. 9. American Society of Anesthesiologists. Standards for Basic Anesthetic Monitoring. Last amended on October 27, 2004. www.asahq.org/clinicalinfo.htm. 10. Saada M, Duval AM, Bounet F, et al. Abnormalities in myocardial segmented wall motion during lumbar epidural anesthesia. Anesthesiology 1989; 71:26–32. 11. Lund PC, Cwik JC. Propitocaine (citanest) and methemoglobinemia. Anesthesiology 1965; 26:569–571. 12. Reiz S, Nath S. Cardiotoxicity of local anaesthetic agents. Br J Anaesth 1986; 58:736–746. 13. Auroy Y, Benhamou D, Bargues L, et al. Major complications of regional anesthesia in France: The SOS Regional Anesthesia Hotline Service. Anesthesiology 2002; 97:1274–1280. 14. American Society of Anesthesiologists. Task Force on preoperative fasting and the use of pharmacologic agents to reduce the risk of pulmonary aspiration. Practice guidelines for preoperative fasting and the use of pharmacologic agents to reduce the risk of pulmonary aspiration: application to healthy patients undergoing elective procedures. Last modified October 7, 2002. www.asahq.org/clinicalinfo.htm. 15. White PF. Pharmacologic and clinical aspects of preoperative medication. Anesth and Anal 1986; 65:963–974. 16. Moiniche S, Kehlet H, Dahl JB. A qualitative and quantitative systematic review of preemptive analgesia for postoperative pain relief. Anesthesiology 2002; 96(3):725–741. 17. Foldes FF, McNall PG, Borrego-Hinojosa JM. Succinylcholine, a new approach to muscular relaxation in anesthesiology. N Engl J Med 1952; 247:596–600. 18. American Society of Anesthesiologists. Practice guidelines for sedation and analgesia by non-anesthesiologists. An updated report by the American Society of Anesthesiologists Task Force on sedation and analgesia by non-anesthesiologists. Approved by the House of Delegates on October 25, 1995. Last amended on October 17, 2001. www.asahq.org/clinicalinfo.htm. 19. National Center for Health Statistics, Centers for Disease Control and Prevention, U.S. Department of Health and Human Services.

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21. 22.

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28. 29.

30.

31. 32. 33. 34.

35.

36.

37.

38.

Prevalence of overweight and obesity among adults: United States, 1999–2002. Results from the 1999–2002 National Health and Nutrition Examination Survey (NHANES). http://www.cdc.gov/ nchs/products/pubs/pubd/hestats/obese/obse99.htm. Lanier WL. Glucose management during cardiopulmonary bypass: cardiovascular and neurologic implications. Anesth Analg 1991; 72:423. Lam AM, et al. Hyperglycemia and neurological outcome in patients with head injury. J Neruosurg 1991; 75:545. Jurkatt-Rott K, McCarthy T, Lehmann-Horn F. Genetics and pathogenesis of malignant hyperthermia. Muscle Nerve 2000; 23:4–17. Malignant Hyperthermia Association of the United States. What is malignant hyperthermia? An MHAUS online brochure. Last updated August 31, 2004. http://www.mhaus.org/index.cfm/fuseaction/OnlineBrochures.List.cfm. Malignant Hyperthermia Association of the United States. Clinical update—managing MH. An MHAUS online brochure. Last updated July 1, 2005. http://www.mhaus.org/index.cfm/ fuseaction/OnlineBrochures.List.cfm. Malignant Hyperthermia Association of the United States. Drugs, equipment, and dantrolene—managing MH. An MHAUS online brochure. Last updated October 1, 2004. http://www.mhaus. org/index.cfm/fuseaction/OnlineBrochures.List.cfm. McGuire DB. The multidimensional phenomenon of cancer pain. In: McGuire DB, Yarbro CH, eds. Cancer Pain Management. Philadelphia: Saunders, 1987:1–20. Jessell TM, Kelly DD. Pain and analgesia. In: Kandel ER, Schwartz JH, Jessell TM, eds. Principles of Neural Science. 3rd ed. East Norwalk, Connecticut: Appleton & Lange, 1991:386. Sorkin LS. Pain pathways and spinal modulation. Anesthes Clinic North Amer 1989; 7:17. Kehlet H. Modification of responses to surgery by neural blockade. In: Cousins MJ, Bridenbaugh PO, eds. Neural Blockade in Clinical Anesthesia Management of Pain. 3rd ed. Philadelphia: Lippincott-Raven Publishers, 1998. Liu S, Carpenter RL, Neal JM. Epidural anesthesia and analgesia. Their role in postoperative outcome. Anesthesiology 1995; 82:1474. Wu CL, Fleisher LA. Outcomes research in regional anesthesia and analgesia. Anesth Analg 2000; 91:1232. Melzak R, Wall PD. Pain mechanisms: a new theory. Science 1965; 150:971–979. Price DD. Psychological and Neural Mechanisms of Pain. New York: Raven, 1988. Joint Commission of Accreditation of Healthcare Organizations. Comprehensive Accreditation Manual for Hospitals. Oakbrook Terrace, Illinois: Joint Commission of Accreditation of Healthcare Organizations, 2001. Acute Pain Management: Operative or Medical Procedures and Trauma. Clinical Practice Guideline. Publication No. AHCPR 92-0032. Rockville, MD: Agency for Health Care Policy and Research, Public Health Service, U.S. Department of Health and Human Services, 1992. Acute pain management in infants, children, and adolescents: operative and medical procedures. Quick reference guide for clinicians. J Pain Symptom Manage 1992; 7:229–242. Acute Pain Management: Operative or Medical Procedures and Trauma. Clinical Practice Guideline. Panel findings. Carr DB, Jacox A, co-chairs. Agency for Healthcare Research and Quality, Public Health Service, U.S. Department of Health and Human Services, released 1994. Brownfield E. Pain management. In: Evidence Report/Technology Assessment, No. 42. Making Health Care Safer: A Critical Analysis of Patient Safety Practices. Contract No. 290-97-0013, Publication No. 01-E058. Agency for Healthcare Research and Quality, Public Health Service, U.S. Department of Health and Human Services, 1997.

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39. Owen H, McMillan V, Rogowski D. Post-operative pain therapy: a survey of patients’ expectations and their experiences. Pain 1990; 41(3):303–307. 40. Woolf CJ. Evidence for a central component of postinjury pain hypersensitivity. Nature 1983; 308:386–388. 41. Bekker A, Cooper PR, Frempong-Boadu A, Errico T, Lebovits A. Evaluation of preoperative administration of the cyclooxygenase-2 inhibitor rofecoxib for the treatment of postoperative pain after lumbar disc surgery. Neurosurgery 2002; 50(50): 1053–1057. 42. Carr DB, Sternlicht A, Carabuena JM, Wurm WH, Robelen G. Efficacy and safety of pre-emptive levobupivicaine in elective shoulder surgery. Reg Anesth Pain Med 2000; 25(suppl):20. 43. Katz J, Clairoux M. Kavangh BP, et al. Pre-emptive lumbar anesthesia reduces postoperative pain and patient-controlled morphine consumption after lower abdominal surgery. Pain 1994; 59:395–403. 44. Gottschalk A, Smith DS, Jobes DR, et al. Preemptive epidural analgesia and recovery from radical prostatectomy. JAMA 1998; 279:1076–1082. 45. Hogan QH. No preemptive analgesia: is that so bad? Anesthesiology 2002; 96:526–527. 46. Welchew EA. On-demand analgesia. A double-blind comparison of on-demand intravenous fentanyl with regular intramuscular morphine. Anaesthesia 1983; 38:19. 47. White PF, Parker RK. Use of patient-controlled analgesia for management of acute pain. JAMA 1988; 259:243. 48. Rawal N, Sjostrand U, Christoffersson E, et al. Comparison of intramuscular and epidural morphine for postoperative analgesia in the grossly obese: influence on postoperative ambulation and pulmonary function. Anesth Analg 1984; 63:583. 49. Yeager MP, Glass DD, Neff RK, Brinck-Johnsen T. Epidural anesthesia and analgesia in high-risk surgical patients. Anesthesiology 1988; 68:925. 50. American Society of Regional Anesthesia and Pain Medicine. Regional anesthesia in the anticoagulated patient—defining the risks. Developed from American Society of Regional Anesthesia and Pain Medicine Consensus Conference during the Annual Spring Meeting on Regional Anesthesia, 2002. http://www. asra.com/items_of_interest/consensus_statements. 51. Baxter AD, Jennings FO, Harris RS, Flynn JF. Continuous intercostals blockade after cardiac surgery. Br J Anaesth 1987; 59:162. 52. Hamza MA, White PF, Ahmen HE, Ghoname EA. Effect of the frequency of transcutaneous electrical nerve stimulation on the postoperative opioid analgesic requirement and recovery profile. Anesthesiology 1999; 91(5):1232–1238. 53. Bruzga R, Speer K. Challenges of rehabilitation after shoulder surgery. Clin Sports Med 1999; 18(4):769–793. 54. National Institutes of Health. Acupuncture, NIH consensus statement, Nov 3–5, 1997. 55. He JP, Friedrich M, Ertan AK, Muller K, Schmidt W. Pain-relief and movement improvement by acupuncture after ablation and axillary lymphadenectomy in patients with mammary cancer. Clin Exp Obstet Gynecol 1999; 26(2):81–84. 56. Bardiau FM, Braeckman MM, Seidel L, Albert A, Boogaerts JG. Effectiveness of an acute pain service inception in a general hospital. J Clin Anesth 1999; 11:583–589. 57. Hall PA, Bowden MI. Introducing an acute pain service. Br J Hosp Med 1996; 55:15–17. 58. Ready LB. How many acute pain services are there in the US and who is managing patient-controlled analgesia? Anesth 1995; 82:322. 59. Acute pain services. In: Markowitz AJ, ed. Evidence Report/ Technology Assessment, No. 43, Making Health Care Safer: A Critical Analysis of Patient Safety Practices. Contract No. 29097-0013, Publication No. 01-E058. Agency for Healthcare Research and Quality, Public Health Service, U.S. Department of Health and Human Services, 1997.

11 Sepsis and the Syndrome of Multiple Organ Failure Lena M. Napolitano

and/or clinical utility of the diagnosis of sepsis (5). The primary consensus points of this conference were as follows:

INTRODUCTION Sepsis is the leading cause of morbidity and mortality in critically ill patients in most intensive care units. Sepsis is recognized as the systemic response to infection, and connotes a clinical syndrome that may occur in any age group, in markedly different patient populations, and in response to a multitude of microbial pathogens from multiple different anatomical sites within the human body. It may range in severity from mild systemic inflammation without significant chemical consequences to multisystem organ failure and septic shock with an exceedingly high mortality rate. This chapter is an update of the understanding of the relationship between sepsis and multiple organ dysfunction and failure, the underlying pathophysiology and outcomes of both, and contemporary strategies for the prevention and treatment of sepsis and multiple organ dysfunction syndrome.

&

&

&

&

&

The current concepts of sepsis, severe sepsis, and septic shock seem to be robust definitions and should remain as described 10 years ago. Current definitions do not allow for precise staging of the host response to infection. Signs and symptoms of sepsis are more varied than the initial criteria established in 1991. A list of these signs and symptoms, for the diagnosis of sepsis is presented. The future lies in developing a staging system that will characterize progression of sepsis. A new system, predisposition, infection, response, and organ dysfunction (PIRO), is proposed for characterizing and staging the host response to infection.

This new conceptual framework for understanding sepsis, which was developed, called the PIRO concept, is a classification scheme that could stratify patients on the basis of their predisposing conditions, the nature and extent of the insult (in the case of sepsis and infection), the nature and magnitude of the host response, and the degree of concomitant organ dysfunction (Table 2). This has been conceptually modeled from the TNM classification (tumor size, nodal spread, and metastases) that has been successfully

SEPSIS: DEFINITIONS In 1991, the American College of Chest Physicians and the Society of Critical Care Medicine convened a consensus conference to more accurately define sepsis (1,2). The term ‘‘systemic inflammatory response syndrome’’ (SIRS) was defined as a clinical response arising from a nonspecific insult such as infection, trauma, thermal injury, or sterile inflammatory processes such as pancreatitis. This clinical response included fever or hypothermia, tachycardia, tachypnea, and leukocytosis or leukopenia (Table 1). SIRS is characterized by two or more of these clinical manifestations. ‘‘Sepsis’’ was defined as SIRS with a presumed or confirmed infectious process. Sepsis can progress to ‘‘severe sepsis,’’ which was defined as sepsis with organ dysfunction or evidence of hypoperfusion or hypotension. ‘‘Septic shock’’ was defined as sepsis-induced hypotension, persisting despite adequate fluid resuscitation, along with the presence of hypoperfusion abnormalities or organ dysfunction. While consensus definitions of sepsis have proven to be of great value, the lack of uniformity in interpretation of these definitions continues to be problematic for clinicians and basic researchers alike (3). A recent European Society of Intensive Care Medicine and Society of Critical Care Medicine physician attitudinal survey revealed that 71% of responders cited no common definition of sepsis (4), despite the previously published consensus conference criteria for sepsis, severe sepsis, and septic shock. In 2001, an International Sepsis Definitions Conference was convened to review the strengths and weaknesses of the current definitions of sepsis and related conditions, identify ways to improve the current definitions, and identify methodologies for increasing the accuracy, reliability,

Table 1 Definitions of SIRS, Sepsis, and Severe Sepsis Term

Definition

SIRS

A clinical response arising from a nonspecific insult, including
2 of the following: Temperature
38 C or 36 C Heart rate
90 beats/min Respirations
20/min White blood cell count
12,000/mm3 or 4000/mm3 or > 10% neutrophils SIRS with a presumed or confirmed infectious process Sepsis with
1 sign of organ failure: Cardiovascular (refractory hypotension) Renal Respiratory Hepatic Hematologic Central nervous system Metabolic acidosis Sepsis-induced hypotension, despite adequate fluid resuscitation, with presence of perfusion abnormalities

Sepsis Severe sepsis

Septic shock

Abbreviation: SIRS, systemic inflammatory response syndrome. Source: From Ref. 1.

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Table 2 The PIRO System for Staging Sepsis Domain

Present

Predisposition

Premorbid illness with reduced probability of short-term survival. Cultural or religious beliefs, age, sex

Insult, infection

Culture and sensitivity of infecting pathogens; detection of disease amenable to source control SIRS, other signs of sepsis, shock, CRP

Response

Organ dysfunction

Organ dysfunction as number of failing organs or composite score (e.g., MODS, SOFA, LODS, PEMOD, PELOD)

Future Genetic polymorphisms in components of inflammatory response (e.g., TLR, TNF, IL-1, CD 14); enhanced understanding of specific interactions between pathogens and host diseases Assay of microbial products (LPS, mannan, bacterial DNA); gene transcript profiles Nonspecific markers of activated inflammation (e.g., PCT or IL-6) or impaired host responsiveness (e.g., HLA-DR); specific detection of target of therapy (e.g., protein C, TNF, PAF) Dynamic measures of cellular response to insult—apoptosis, cytopathic hypoxia, cell stress

Rationale In the present, premorbid factors impact on the potential attributable morbidity and mortality of an acute insult; deleterious consequences of insult heavily dependent on genetic predisposition (future) Specific therapies directed against inciting insult require demonstration and characterization of that insult Both mortality risk and potential to respond to therapy vary with nonspecific measures of disease severity (e.g., shock); specific mediator-targeted therapy is predicated on the presence and activity of mediator Response to preemptive therapy (e.g., targeting microorganism or early mediator) not possible if damage already present; therapies targeting the injurious cellular process require that it be present

Abbreviations: TLR, Toll-like receptor; TNF, tumor necrosis factor; IL, interleukin; LPS, lipopolysaccharide; SIRS, systemic inflammatory response syndrome; CRP, C-reactive protein; PCT, procalcitonin; HLA-DR, human leukocyte: antigen-DR; PAF, platelet-activating factor; MODS, multiple organ dysfunction syndrome; SOFA, sepsis-related organ failure assessment; LODS, logistic organ dysfunction system; PEMOD, pediatric multiple organ dysfunction; PELOD, pediatric logistic organ dysfunction; PIRO, predisposition, infection, response, and organ dysfunction. Source: From Ref. 5.

used in defining treatment and prognostic indicators in clinical oncology. PIRO was introduced as a hypothesisgenerating model for future research, and extensive testing will be necessary before it can be considered ready for routine application in clinical practice. Advances in sepsis research will require better markers to delineate more homogenous subsets of patients within a highly heterogenous group of critically ill patients. A roundtable meeting on biomarkers in sepsis was held in 2000 to develop a taxonomy of markers relevant to clinical research in sepsis (6). A ‘‘marker’’ is a measure that identifies a biological state or that predicts the presence or severity of a pathologic process or disease. More than 80 putative markers of sepsis have been described (Table 3). Virtually all of the putative sepsis markers can be classified as prognostic markers, because they identify patient groups at increased risk for mortality. None of these markers has yet shown utility in stratifying patients with respect to therapy (i.e., diagnostic markers) or in titrating that therapy (i.e., response markers). For instance, elevation in the serum concentration of procalcitonin (PCT) has been associated with systemic infection and sepsis in a number of human studies. This association has led to the proposed use of PCT as a novel biomarker of bacterial sepsis. A recent systematic health technology assessment of PCT as a diagnostic test for sepsis was performed (7) to answer a specific and important question—can PCT accurately distinguish sepsis in patients with SIRS who have a suspected infection? Likelihood ratios were calculated from published data. The published evidence did not support a general claim that PCT is a useful decision support tool for diagnosing sepsis in patients who have SIRS. PCT had a slightly better ability to exclude the diagnosis of sepsis. The role for using PCT testing in the intensive care unit (ICU) will likely continue to evolve along with our understanding and definition of sepsis. Similarly, C-reactive protein (CRP), an acute-phase protein released by the liver after the onset of inflammation or tissue damage, has been evaluated as a marker of

infection and sepsis in critically ill patients (8). Blood concentrations of CRP have been documented to increase rapidly in response to infection, trauma, ischemia, burns, and other inflammatory conditions. Serum CRP concentrations are increased in patients with sepsis, and a recent study documented that the combination of CRP > 50 mg/L with clinical criteria for SIRS was an independent predictor of infection in critically ill patients. Elevated CRP concentrations on ICU admission have also been documented to correlate with mortality and organ failure in critically ill patients (9). A new method to help assess the presence or absence of infection in critically ill patients was recently developed (10). The infection probability score (IPS) was developed using routinely available variables in a cohort of 353 critically ill patients at risk for infection and sepsis, and was validated in another set of patients (n ¼ 140). The resulting IPS consists of six different variables and ranged from 0 to 26 points (0–2 for temperature, 0–12 for heart rate, 0–1 for respiratory rate, 0–3 for white blood cell count, 0–6 for CRP, and 0–2 for sequential organ failure assessment score). The best predictors for infection were heart rate and CRP, whereas respiratory rate was found to have the poorest predictive value. The cutoff value for the IPS was 14 points, with a positive predictive value of 53.6% and a negative predictive value of 89.5%. Model performance was very good (Hosmer–Lemeshow statistic, P ¼ 0.918), and the areas under receiver operating characteristic curves were 0.820 for the developmental set and 0.873 for the validation set. Patients with a score 85 years old). Mortality was 28.6%, or 215,000 deaths nationally, and also increased with age, from 10% in children to 38.4% in those >85 years old. Women had lower age-specific incidence and mortality, but the difference in mortality was explained by differences in underlying disease and the site of infection. The average costs per case were $22,100, with annual total costs of $16.7 billion nationally. Costs were higher in infants, nonsurvivors, ICU patients, surgical patients, and patients with more organ failure. This study documented that severe sepsis is a common, expensive, and frequently fatal condition, with as many deaths annually as those from acute myocardial infarction. It is especially common in the elderly and is likely to increase substantially as the U.S. population ages. European studies have also examined the incidence, risk factors, and outcomes of severe sepsis and septic shock. The French ICU Group for Severe Sepsis conducted a large inception cohort study from a two-month prospective survey of 11,828 consecutive admissions to 170 adult ICUs of public hospitals in France (15). This study documented that 742 patients had documented infection and severe sepsis, confirming severe sepsis rates of 6.3 per 100 ICU admissions. The 28-day mortality rate was 56% in patients with severe sepsis. Major determinants of both early (< 3 days) and secondary deaths in the whole cohort were the Simplified Acute Physiology Score (SAPS) II and the number of acute organ system failures. Other risk factors for early death included a low arterial blood pH (< 7.33, P < 0.001) and shock (P ¼ 0.03), whereas secondary deaths were associated with the admission category (P < 0.001), a rapidly or ultimately fatal underlying disease (P < 0.001), a preexisting liver (P ¼ 0.01) or cardiovascular (P ¼ 0.002) insufficiency, hypothermia (P ¼ 0.02), thrombocytopenia (P ¼ 0.01), and multiple sources of infection (P ¼ 0.02). In patients with documented sepsis, bacteremia was associated with early mortality (P ¼ 0.03). This study was important, in that it determined that only three of four patients presenting with clinically suspected severe sepsis in France had documented infection. Review of the control arms of recent sepsis trials also documents a variable mortality rate of sepsis, dependent on the number of patients enrolled with SIRS and presumed infection, severe sepsis, and septic shock in each trial

(Fig. 1). Variability in sepsis mortality rates in the control arm of these trials is also likely related to variability in treatment of sepsis in the individual institutions (16,17). A recent retrospective cohort study (18) examined long-term mortality among patients with severe sepsis. All persons with bacterial or fungal infections and acute organ dysfunction (severe sepsis) who were hospitalized between January 1, 1991, and August 31, 2000 (n ¼ 16,019) were studied using a large, integrated, geographically diverse, U.S. health-insurance claims database covering three million lives annually. All patients were followed from the date of hospitalization with severe sepsis (index admission) to August 31, 2000, disenrollment from the health plan, or death, whichever occurred first. Most patients (81.2%) were >65 years of age; 53.4% were men. Mortality was 21.2% for the index admission, and increased to 51.4% at one year, and 74.2% at five years. This study demonstrated that mortality rates are high in patients with severe sepsis, during the period of acute illness as well as long-term mortality rates up to five years post-hospitalization. In October 2002, the Centers for Medicare and Medicaid Services established new ICD-9 codes for sepsis (Table 4) (19). Prior to this, the only ICD-9 code for sepsis was ‘‘septicemia.’’ As medical practitioners caring for SIRS and sepsis patients utilize these new codes, additional information will be captured regarding the accurate incidence and outcome of patients with sepsis and severe sepsis in the United States.

PATHOPHYSIOLOGY OF SEPSIS Despite advances in both antibiotic therapy and supportive care, the mortality rate due to severe sepsis has only slightly improved in the past several decades. The pathophysiology of organ failure and death in patients with sepsis remains elusive. With increased understanding of the pathophysiology of sepsis, particularly the intricate interplay between activation of coagulation and inflammation, novel therapeutic agents that may improve clinical outcomes are being researched and developed. The pathophysiology and current treatment of severe sepsis are reviewed. The prevailing theory has been that sepsis represents an uncontrolled inflammatory response or hyperinflammation manifest as the SIRS. But more recent data document a subsequent state of severe immunosuppression or hypoimmune state in sepsis (20). We have come to realize that,

Chapter 11: Sepsis and the Syndrome of Multiple Organ Failure

Table 4 New ICD-9 Codes for Sepsis ICD-9 code 995.90 995.91 995.92 995.93 995.94

Diagnosis SIRS, unspecified SIRS due to infectious process without organ dysfunction SIRS due to infectious process with organ dysfunction (severe sepsis) SIRS due to noninfectious process without organ dysfunction SIRS due to noninfectious process with organ dysfunction

Abbreviations: ICD, International Classification of Diseases; SIRS, systemic inflammatory response syndrome.

Immune Status Hypoimmune Normal Hyperimmune

initially, sepsis may be characterized by increases in inflammatory mediators; but as sepsis persists, there is a shift toward an anti-inflammatory immunosuppressive state (Fig. 2). The term ‘‘compensatory anti-inflammatory response syndrome (CARS)’’ has been used to define immunologically those patients with sepsis syndromes, who are manifesting predominantly a pattern of macrophage deactivation, reduced antigen presentation, and T-cell anergy. Intact innate and acquired immune responses are essential for defeating systemic microbial infections in sepsis (17).

Healthy person with meningococcemia Elderly patient with malnutrition and diverticulitis Patient with diabetes, chronic renal failure, and pneumonia

Recovery

Death 1

2

3

4 Days

5

6

7

8

Figure 2 Immunologic response of three hypothetical patients with sepsis. The individual response is determined by many factors, including the virulence of the organism, the size of the inoculum, and the patient’s coexisting conditions, age, and polymorphisms in genes for cytokines. The initial immune response is hyperinflammatory, but the response rapidly progresses to hypoinflammatory. A secondary bump in the hyperimmune state can occur during the hospital course with secondary infections. In the hypothetical healthy person who has contracted a serious meningococcal infection, there is an initial robust hyperinflammatory response. This patient would have extremely high plasma concentrations of TNF-a and other inflammatory cytokines. Death may occur due to a hyperinflammatory state, and antiinflammatory treatments may improve the likelihood of survival. If infection resolves rapidly, there is only a minimal hypoimmune state. In the hypothetical elderly malnourished person with diverticulitis, the initial response is limited, and, if infection persists, a prolonged hypoinflammatory response develops, followed by either recovery or death. In the hypothetical patient with diabetes, chronic renal failure, and pneumonia, the initial response is blunted, and there is prolonged depression of immune function, culminating in death. Abbreviation: TNF, tumor necrosis factor. Source: From Ref. 14.

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The orchestration of diverse cell types, including macrophages, monocytes, dendritic cells, and lymphocytes, is critical in the physiologic response to infection and sepsis (Fig. 3). One mechanism of immune suppression in sepsis is related to the activation of CD4 T-cells to secrete cytokines with anti-inflammatory (type 2 helper T-cell, Th2) properties, including interleukin-4 (IL-4) and IL-10. Activated CD4 T-cells can also secrete cytokines with inflammatory (type 1 helper T-cell, Thl) properties, including tumor necrosis factor-a (TNF-a), interferon-g, and IL-2. Reversal of the Th2 response has been documented in some studies to improve survival in sepsis (21,22). Additional studies have demonstrated that the level of IL-10 is increased in patients with sepsis, and that this level predicts mortality (23,24). Sepsis caused by gram-negative bacteria and that caused by gram-positive bacteria often manifest similar clinical features. A recent study (25) investigated plasma proinflammatory cytokine profiles in patients with sepsis due to gram-positive and gram-negative bacteria and studied the cytokine production and differential gene regulation of leukocytes stimulated ex vivo with Escherichia coli lipopolysaccharide (LPS) or heat-killed Staphylococcus aureus. Concentrations of TNF-a, IL-1 receptor antagonist (IL-IRa), IL-8, IL-10, IL-18-binding protein, PCT, and protein C in plasma did not differ between patients with sepsis due to gram-negative and gram-positive bacteria. However, plasma IL-lb, IL-6, and IL-18 concentrations were significantly higher in patients with sepsis due to gram-positive bacteria. Ex vivo stimulation of whole blood with heat-killed S. aureus markedly increased IL-lb and IL-18 levels more than E. coli LPS stimulation. Microarray analysis revealed at least 359 cross-validated probe sets (genes) significant at the P < 0.001 level whose expression discriminated among gram-negative organism–stimulated, gram-positive organism– stimulated, and unstimulated whole-blood leukocytes. The host inflammatory responses to gram-negative and grampositive stimuli not only share some common response elements, but also exhibit distinct patterns of cytokine appearance and leukocyte gene expression. The role of apoptotic cell death in sepsis is of great interest. Apoptosis is a programmed form of cell suicide in which executioner proteins known as caspases initiate enzymatic pathways that culminate in disruption of mitochondrial function, cleavage of DNA, cell shrinkage, and membrane changes that mark the cell for phagocytosis. Three recent reviews (26–28) focused on advances in our understanding of the mechanisms of cell death in sepsis, the types of cells that are dying, and the consequences on immunity. Extensive apoptotic death results in immune cell depletion and may compromise the ability of the patient to eradicate the primary infection and predispose to secondary nosocomial infections. Peripheral circulating lymphocyte apoptosis is also increased in patients with sepsis and correlates with the severity of the disease (29). In addition, recent evidence indicates that uptake of apoptotic cells impairs the immune function of surviving cells and contributes to immunosuppression. Furthermore, significantly increased apoptosis of splenic dendritic cells was identified in an animal model of sepsis (30). Dendritic cells are a phenotypically diverse group of antigen-presenting cells that have unique capabilities to regulate the activity and survival and B- and T-lymphocytes. Proper functioning of dendritic cells is essential to the host’s control of invading pathogens (Fig. 3). This profound loss of dendritic cells by caspase 3–mediated apoptosis may significantly compromise B- and T-cell function and impair the ability

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Figure 3 The response to pathogens in sepsis, involving ‘‘cross talk’’ among many immune cells, including macrophages, dendritic cells, and CD4 T-cells. Macrophages and dendritic cells are activated by the ingestion of bacteria and by stimulation through cytokines (e.g., interferon) secreted by CD4 T-cells. Alternatively, CD4 T-cells that have an anti-inflammatory profile (Th2) secrete IL-10 that suppresses macrophage activation. CD4 T-cells become activated by stimulation through macrophages or dendritic cells. For example, macrophages and dendritic cells secrete IL-12, which activates CD4 T-cells to secrete inflammatory (Th1) cytokines. Depending on numerous factors (e.g., the type of organism and the site of infection), macrophages and dendritic cells will respond by inducing either inflammatory or anti-inflammatory cytokines or causing a global reduction in cytokine production (anergy). Macrophages or dendritic cells that have previously ingested necrotic cells will induce an inflammatory cytokine profile (Th1). Ingestion of apoptotic cells can induce either an anti-inflammatory cytokine profile or anergy. A plus sign indicates upregulation, and a minus sign indicates downregulation; in cases where both a plus sign and a minus sign appear, either upregulation or downregulation may occur, depending on a variety of factors. Abbreviations: IL, interleukin; Th1, type 1 helper T-cells; Th2, type 2 helper T-cells. Source: From Ref. 20.

of the host to survive sepsis. This new understanding of the complex pathophysiology of sepsis may lead to novel therapeutic approaches, including pharmacological agents that block apoptosis. Recent studies in animal models of sepsis with increased lymphocyte apoptosis have shown that inhibition of apoptosis increases survival. Transgenic mice overexpressing Bcl-2 were protected from lethality secondary to generalized peritonitis (31). Similarly, treatment of mice with a broadacting caspase inhibitor protected mice from sepsis-induced mortality (32). These studies provide strong evidence that

lymphocyte apopotosis plays a critical role in sepsis, indicating a potentially new therapeutic approach for the treatment of sepsis.

GENETIC VARIABILITY IN SEPSIS It has recently been identified that genetic differences may be important markers or determinants of clinical outcomes, including nosocomial infection and severe sepsis (33). This is a complex area of investigation in humans, and relies on identification of particular genetic markers (DNA

Chapter 11: Sepsis and the Syndrome of Multiple Organ Failure

sequences) and the association with risk for sepsis and ultimate outcome in sepsis. The genetic risk for pneumonia, sepsis, and other serious infections is generally unrecognized or underestimated. Sepsis is caused by the immune response to infection and is manifest by pain, fever, and edema as the result of the activation of coagulation and inflammatory responses. In severe cases, sepsis leads to organ dysfunction and failure and ultimately death. Most patients with infection do not develop severe sepsis and septic shock, and yet those that do have a significantly increased risk of death. Genetic and environmental variables may influence why one patient with infection gets sicker than the other. For example, people may be programmed to respond to infection in different ways; some with aggressive immune responses that may be able to eradicate infection before it manifests itself in physical symptoms, while others may have less aggressive immune systems that allow them to get sick more often. The discovery of various common genetic polymorphisms in genes that control the inflammatory response (e.g., TNF) has lent credence to this hypothesis (34). Yet discovery of the actual relationship between risks of infection or severe sepsis and individual genotypes will require larger, more rigorously designed studies. Genetic epidemiologic studies suggest a strong genetic influence on the outcome from sepsis, and genetics may explain the wide variation in the individual response to infection that has long puzzled clinicians. Several candidate genes have been identified as important in the inflammatory response and investigated in case-controlled studies, including the TNF-a and TNF-b genes, positioned next to each other within the cluster of human leukocyte antigen class III genes on chromosome 6. Other candidate genes for sepsis and septic shock include the IL-1 receptor antagonist gene, the heat shock protein gene, the IL-6 gene, the IL-10 gene, the CD14 gene, the Toll-like receptor (TLR)-4 gene, and the TLR-2 gene, to name a few. A recent comprehensive review (35) summarized the evidence for a genetic susceptibility to development of sepsis and death from sepsis, discussed the candidate genes likely to be involved in the pathogenesis of sepsis, and reviewed the potential for targeted therapy of sepsis and septic shock based on genetic variability. Although the strongest evidence for a genetic risk comes from an adoptee study, most evidence for a genetic role in infection involves association studies that compare the incidence of specific mutations in a population with infection to a control population (36). Investigators have studied polymorphisms in or near genes that code for proteins that participate in the inflammatory response. Most positive association studies have examined genes for important inflammatory molecules such as TNF, the IL-1 family, IL-10, and angiotensin-converting enzyme as well as molecules important in antigen recognition, such as the mannose-binding lectin, CD14, and TLRs. Single nucleotide polymorphisms in regulatory regions may affect trans cription of inflammation-related genes such as TNF-a, ILs, and cell surface receptors, in ways that contribute to an increased risk for sepsis. Naturally occurring genetic differences in the TNF-a promotor have been documented as markers for the development of severe sepsis in trauma. A recent study (37) examined the risk for severe sepsis and for death associated with polymorphism in the TNF-a promoter by multivariate analysis. One hundred fifty-two patients had a 24% incidence of severe sepsis and a 13% case fatality rate.

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The A-allele was most common at the 308 position (n ¼ 35). A-allele carriage at this location was associated with an adjusted odds ratio of 4.6 (95% confidence interval, 1.9–10.9) for severe sepsis and of 2.1 (95% confidence interval, 0.6–7.3) for death. This study documented a clear association between the A-allele at the 308 position in the TNF-a promoter and increased risk for severe sepsis and possibly for death after trauma. Gender differences in TNF-b polymorphisms were prospectively examined in 201 patients (68 women and 133 men) with severe sepsis (38). The genotype distribution of patients homozygous for TNFB1 and heterozygous or homozygous for TNFB2 was comparable between men and women with severe sepsis. In women, no difference in survival rate was found between the different genotypes, while mortality rate was significantly increased in men homozygous for TNFB2 compared with the other genotypes (P < 0.05; P < 0.01). Overall, survival rate was higher for women (P < 0.05), but was not significantly different between men and women with respect to genotypes (P ¼ 0.07 for TNFB2/B2). Poor prognosis of surgical sepsis was associated with male gender and the genomic marker TNF-b Ncol polymorphism in this study. Genomic polymorphism within the IL-1 family cytokines is also associated with outcome in sepsis. The allele frequencies and genotype distribution of IL-la, IL-lb, and IL-1Ra gene polymorphism have also been examined in septic patients (39). The allele frequencies of IL-1 receptor antagonist RN2 and genotype RN2/2 were increased in 60 septic patients compared with normal controls (P < 0.01 and 0.05, respectively). Allele frequencies or genotype distribution of interleukin-1-alpha and interleukin-1-beta gene polymorphism did not differ between septic patients and normal controls. In addition, genotypes A2/2, B2/2, and KN2/2 were associated with a significantly higher mortality rate (70–80%) in septic patients. Patients with any two of the three alleles (i.e., A2, B2, and RN2) suffered from much more severe sepsis (as measured by the acute physiology and chronic health evaluation II (APACHE II) and multiple organ dysfunction syndrome score) and a higher mortality rate (55–65%), whereas septic patients with genotypes A1/1, B1/1, or RN1/1 showed a much lower mortality rate (0–13%). Allele IL-1RN2, but not IL-1A or IL-1B gene polymorphism, was associated with susceptibility to sepsis. Alleles A2, B2, and RN2 might be important high-risk genetic markers for sepsis. A recent study (40) determined the functionality of identified polymorphisms in the promoter and upstream regions of the IL-10 gene in terms of release of IL-10 from LPS-stimulated whole blood from healthy volunteers, and evaluated the relationship of IL-10 polymorphisms to IL-10 release, development of sepsis, and mortality in critically ill patients. A total of 132 healthy volunteers plus 67 consecutive critically ill patients were recruited within 24 hours of admission to the ICU, regardless of diagnosis. Stimulated IL-10 release in critically ill patients was significantly lower than in healthy subjects (P < 0.0001). In addition, in the patients who developed sepsis, IL-10 release at admission to the ICU was significantly lower than in patients who did not subsequently develop sepsis [median (range) 1.47 (0.13– 6.90) ng/mL compared with 4.93 (0.03–16.80) ng/mL, P ¼ 0.001]. The A allele of the single nucleotide polymorphism at 592 base pairs was associated with lower IL-10 release and higher mortality in critically ill patients. Other polymorphisms were not linked to IL-10 release, sepsis, or mortality.

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Contrasting findings regarding IL-10 were reported in a recent study of patients (n ¼ 61) with pneumococcal infection (41). IL-10 allele G homozygous patients (for the biallelic IL-10–1082 promoter) had the highest risk for septic shock (odds ratio of 6.1; 95% confidence interval, 1.4–27.2; corrected P ¼ 0.024). The whole blood LPS-stimulated IL-10 release was highest in IL-10 G homozygous patients (P ¼ 0.04). In contrast to the prior study, this IL-10 polymorphism, associated with high IL-10 inducibility, was associated with worse outcome of pneumococcal infection, possibly via induced immunosuppression and impaired bacterial clearance. A genetic component to risk of sepsis and resultant complications clearly exists. Confirmation of these findings and associations with other genetic polymorphisms await large-scale population studies and further validation of the physiologic significance of the variant alleles.

TREATMENT STRATEGIES IN SEPSIS Standard therapy for sepsis and severe sepsis includes source control, antibiotics, aggressive resuscitation and hemodynamic support, and nutrition and supportive therapy for other organ dysfunctions.

Source Control Optimal management of infection and sepsis encompasses the important concept of ‘‘source control,’’ i.e., control of the source of the infection. Decisive implementation of optimal source control measures includes the drainage of abscesses and collections of infected fluid, the debridement of necrotic infected tissue, and the use of definitive measures to prevent further contamination. Source control in pneumonia, for example, may require endotracheal intubation for adequate clearance of purulent tracheal secretions. In complicated pneumonia, source control may require tube thoracostomy for a parapneumonic empyema. Source control is a particularly important concept in the treatment of abdominal sepsis (42) and surgical sepsis (43). The current clinical management of surgical patients with sepsis is governed by two principles: control of the source of infection and supportive management of the patient until recovery. Intra-abdominal infections are a common source of sepsis, and are an important cause of morbidity and mortality in the ICU. Outcome in abdominal sepsis is dependent on timely and accurate diagnosis, early adequate source control, and vigorous resuscitation and antibiotic support. In May 1997, a panel of surgeon-investigators met to discuss the clinical importance and research implications of controlling the source of abdominal infections (44). It was concluded that source control is critical to therapeutic success, and that antimicrobial therapy and other adjunctive interventions will fail if the source of infection is not controlled by drainage resection, exteriorization, or other means. The definitions of drainage source control varied dependent on the type and location of infection. All participants agreed that failure to consider the adequacy of source control of infection has limited the value of most clinical trials of therapeutic anti-infective agents. Besides recognizing source control as an essential goal of patient care, there is considerable need for further investigative work to define, record, and stratify the adequacy of source control in clinical trials of therapeutic agents for abdominal infections.

Evaluation of the adequacy of source control in the critically ill patient can be difficult (45). As with other modes of anti-infective therapy, effective source control measures are expected to result in clinical improvement, reflected in the resolution of clinical signs of sepsis or systemic inflammation, bacteriological resolution, and resolution of organ dysfunction and ultimately survival. Adequacy of source control can be determined by radiographic evidence (i.e., drainage of an abscess and resolution of pneumonia infiltrate), repeated surgical evaluation (i.e., adequacy of debridement of necrotizing soft-tissue infections until there is evidence of healthy granulation tissue throughout the wound), and microbiologic eradication of infection (i.e., blood cultures negative after an episode of bacteremia). The appropriate interventions to determine the adequacy of source control are dictated by the clinical circumstances and the site and source of infection. The general principles that guide the use of source control techniques in the management of the patient with severe sepsis or septic shock are fundamental to effective sepsis treatment.

Systemic Antibiotics Systemic antibiotic therapy is a fundamental component of the standard therapy of sepsis. Antibiotics are essential to the treatment of bacterial sepsis, because they reduce the bacterial burden. The adequacy of initial empirical antimicrobial treatment, therefore, is crucial in terms of successful outcome. Unfortunately, many studies have documented high rates of inadequate initial antibiotic therapy in infection and sepsis, ranging from 20% to 70% (46–50). These studies have also confirmed increased mortality associated with inadequate antimicrobial therapy in the treatment of nosocomial infections, including pneumonia and bacteremia. Inadequate antimicrobial therapy has also been associated with increased mortality in sepsis. The incidence and outcome associated with inadequate antibiotic therapy was recently examined in the Monoclonal Anti-TNF: A Randomized Controlled Sepsis (MONARCS) trial, which enrolled patients with suspected sepsis (51). The study enrolled 2634 patients, 91% of whom received adequate antibiotic therapy. The mortality rate among patients given adequate antibiotic treatment was 33% versus 43% among patients given inadequate treatment (P < 0.001). This study concluded that adequate antibiotic therapy resulted in a significant decrease in the crude mortality rate among patients suspected of sepsis. Similarly, a prospective observational study of 107 septic shock patients documented that 89% of patients received adequate antimicrobial therapy, but 11% did not (52). Inadequate antimicrobial therapy was associated with a 39% excess of mortality. A de-escalation (removal of a nonpivotal antibiotic that was not necessary based on microbiologic cultures) of the empiric antimicrobial therapy was possible in 64% of patients. A recent study (53) evaluated the impact of adequate empirical antibiotic therapy on in-hospital mortality rate, after controlling for confounding variables, in a cohort of patients (n ¼ 406) admitted to the ICU with sepsis. The impact of adequate empirical antibiotic therapy on early (less than three days), 28-day, and 60-day mortality rates also was assessed. Microbiological documentation of sepsis was obtained in 67% of the patients. At ICU admission, sepsis was present in 105 patients (25.9%), severe sepsis in 116 (28.6%), and septic shock in 185 (45.6%). By multivariate analysis, predictors of in-hospital mortality were sepsisrelated organ failure assessment (SOFA) score at ICU

Chapter 11: Sepsis and the Syndrome of Multiple Organ Failure

admission [odds ratio (OR), 1.29], the increase in SOFA score over the first three days in the ICU (OR, 1.40), respiratory failure within the first 24 hours in the ICU (OR, 3.12), and inadequate empirical antimicrobial therapy in patients with ‘‘nonsurgical sepsis’’ (OR, 8.14). Adequate empirical antimicrobial therapy in ‘‘surgical sepsis’’ (OR, 0.37) and urologic sepsis (OR, 0.14) was a protective factor. Regarding early mortality (less than three days), factors associated with fatality were immunosuppression (OR, 4.57), chronic cardiac failure (OR, 9.83) renal failure within the first 24 hours in the unit (OR, 8.63), and respiratory failure within the first 24 hours in the ICU (OR, 12.35). Fungal infection (OR, 47.32) and previous antibiotic therapy within the last month (OR, 2.23) were independent variables related to administration of inadequate antibiotic therapy. This study clearly determined that in patients admitted to the ICU for sepsis, the adequacy of initial empirical antimicrobial treatment was an independent predictor of in-hospital mortality. The incidence and effect of inappropriate initial antimicrobial therapy on the prognosis of patients with sepsis who were enrolled in a clinical trial of an immunomodulating agent conducted in 108 hospitals in North America and Europe was recently examined (54). Initial antimicrobial choice and results of microbiologic cultures were studied in 904 patients who had microbiologically confirmed severe sepsis or early, septic shock. If a patient did not receive at least one antimicrobial agent to which the causative microorganisms were susceptible within 24 hours from the diagnosis of severe sepsis, then the initial antimicrobial treatment was considered to be inappropriate. A propensity score that adjusted for factors associated with inappropriate antimicrobial treatment was calculated and included in multivariable models to adjust for confounding. A total of 468 patients (52%) had documented bloodstream infection, and 211 patients (23%) received inappropriate initial antimicrobial therapy. Characteristics associated with inappropriate treatment were study enrollment in Europe, admission to surgery, nosocomial infection, infection with multiresistant microorganisms, and fungal or polymicrobial infection (all P< 0.05). The 28-day mortality was 24% (168/693) for patients in the adequately treated group versus 39% (82/211) for patients receiving inappropriate initial antimicrobial therapy (P< 0.001). After adjusting for comorbid conditions, severity of illness, site of infection, and the propensity score, inappropriate antimicrobial therapy was independently associated with increased mortality (OR, 1.8; 95% confidence interval: 1.2–2.6). In this large cohort of patients with microbiologically confirmed severe sepsis, appropriate initial antimicrobial therapy was an important determinant of survival. One important factor contributing to the high incidence of inadequate initial antimicrobial therapy in sepsis is the increasing incidence of antibiotic-resistant organisms as the etiology of infection and sepsis. In critical care, particularly problematic pathogens include methicillinresistant S. aureus and multidrug-resistant Pseudomonas species. A number of studies in sepsis have documented that, for most pathogens, resistance contributes to significant increases in mortality (55). This has been clearly demonstrated in bacteremia, including community- and hospital-acquired infection, and with bacteremia caused by vancomycin-resistant enterococci, methicillin-resistant staphylococci, and extended-spectrum–producing gramnegative bacteria. Significant mortality increases have also been documented with antibiotic-resistant pathogens as the

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etiology of ventilator-associated pneumonia and serious infections requiring admission to intensive care. There is now convincing evidence and consensus that initiation of broad-spectrum antimicrobial therapy to cover the likely pathogens including multi-drug resistant pathogens pending culture results is mandatory in sepsis to minimize adverse outcomes. De-escalation of this therapy from broad-spectrum initial coverage to targeted antimicrobial therapy after results of cultures and susceptibility tests become available is a necessary component of this strategy, in order to minimize unnecessary use of broad-spectrum antibiotics and possibly promote further bacterial resistance.

Resuscitation and Hemodynamic Support Early aggressive fluid resuscitation is a standard component of sepsis therapy and should be the initial step in hemodynamic support of patients with septic shock (56). The goal of fluid resuscitation in sepsis is restoration of tissue perfusion and normalization of oxidative metabolism. Increasing cardiac output and oxygen delivery is dependent on expansion of blood and plasma volume. Intravascular volume can be repleted through the use of packed red cells, crystalloid solutions, and colloid solutions. Fluid infusion is best initiated with boluses titrated to clinical endpoints of heart rate, urine output, and blood pressure. If a central venous pressure is available, levels of 8–12 mmHg should be maintained. Patients who do not respond rapidly to initial fluid boluses or those with poor physiologic reserve should be considered for invasive hemodynamic monitoring. If fluid therapy alone fails to restore adequate arterial pressure and organ perfusion, therapy with vasopressor agents should be initiated. Potential vasopressor agents include dopamine, norepinephrine, epinephrine, or phenylephrine. Dopamine and norepinephrine are both effective for increasing arterial blood pressure, although norepinephrine may be a more effective vasopressor in some patients. An important study (prospective, double-blind, randomized) compared dopamine and norepinephrine for the treatment of hyperdynamic septic shock (57). At the doses tested, norepinephrine was found to be more effective and reliable than dopamine to reverse the abnormalities of hyperdynamic septic shock. In the great majority of the study patients, norepinephrine was able to increase mean perfusion pressure without apparent adverse effect on peripheral blood flow or on renal blood flow, and at the same time, resulted in increased oxygen uptake. Furthermore, it has been documented that the use of epinephrine in sepsis may be associated with increased tachyarrhythmias and potential vasoconstriction of the splanchnic circulation resulting in gut hypoperfusion. A study in 20 patients with septic shock (58) examined the effects of dopamine, norepinephrine, and epinephrine on the splanchnic perfusion in septic shock by measurement of changes in splanchnic circulation (indocyanine green dilution and hepatic vein catheter) and gastric mucosal pCO2 (gas tonometry). This study documented that dopamine and norepinephrine had similar systemic hemodynamic effects, but epinephrine resulted in impaired splanchnic circulation in severe septic shock. When adequately fluid resuscitated, most septic patients are hyperdynamic, but myocardial contractility, as assessed by ejection fraction, is impaired (59). Serial radionuclide cine angiographic and hemodynamic evaluations were done on 20 patients with documented septic shock. Although all patients had a normal or elevated cardiac index, 10 patients (50% of the study cohort) had moderate

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to severe depression of their ejection fraction with values below 0.40. The mean initial ejection fraction for the survivors was 0.32 0.04, and their mean end-systolic and end-diastolic ventricular volumes were substantially increased with a normal stroke volume. The survivors’ serial scans showed a gradual return to normal ejection fraction and ventricular volume by 10 days after the onset of shock. Some patients, especially those with preexisting cardiac dysfunction, may have decreased cardiac output and may require inotropic agents such as dobutamine, dopamine, and epinephrine. Dobutamine is the first choice for patients with low cardiac index and/or low mixed venous oxygen saturation and an adequate mean arterial blood pressure, following fluid resuscitation. Based on the principles outlined above, a simple clinical strategy for resuscitation and hemodynamic stabilization in sepsis and septic shock has been established (Fig. 4). A more aggressive approach to resuscitation in sepsis and septic shock has recently been evaluated. Goal-directed therapy has been used for severe sepsis and septic shock in the ICU. This approach involves adjustments of cardiac preload, afterload, and contractility to balance oxygen delivery with oxygen demand. A recent study (61) evaluated the efficacy of early goal-directed therapy (EGDT) (Fig. 5) before admission to the ICU. Patients who arrived at an urban emergency department with severe sepsis or septic shock (n ¼ 263) were randomized to receive either six hours of

Central venous and arterial catheterization

CVP or FTc

CVP < 8 mm Hg or FTc < 330 msec

500-mL bolus of NS or LR every 30 min prn

CVP 8–12 mm Hg or FTc 330–360 msec

MAP

< 65 mm Hg Norepinephrine (adjustable dosage) ± vasopressin 0.04 U/min (fixed dosage)

EGDT or standard therapy (as a control) before admission to the ICU. Clinicians who subsequently assumed the care of the patients were blinded to the treatment assignment. In-hospital mortality (the primary efficacy outcome), end points with respect to resuscitation, and APACHE II scores were obtained serially for 72 hours and compared between the study groups. There were no significant differences between the groups with respect to base-line characteristics. Inhospital mortality was 30.5% in the group assigned to EGDT, as compared with 46.5% in the group assigned to standard therapy (P ¼ 0.009). During the interval from 7 to 72 hours, the patients assigned to EGDT had a significantly higher mean central venous oxygen saturation, a lower lactate concentration, a lower base deficit, and a higher pH than the patients assigned to standard therapy (P < 0.02 for all comparisons). During the same period, mean APACHE II scores were significantly lower, indicating less severe organ dysfunction, in the patients assigned to EGDT than in those assigned to standard therapy (13.0 6.3 vs. 15.9 6.4, P 65

New Strategies for the Treatment of Sepsis CI and ScvO2 or SvO2

CI < 2.0 and ScvO2 or SvO2 < 70% Dobutamine 5 µg/kg/min (adjustable dosage)

CI > 2.0 and ScvO2 or SvO2 < 70%

Goals achieved

Figure 4 Resuscitiation and hemodynamic stabilization strategy in sepsis and septic shock. Abbreviations: CVP, central venous pressure; FTc, flow time corrected; NS, normal saline or 0.9% sodium chloride; LR, lactated Ringer’s solution; MAP, mean arterial pressure; CI, cardiac index; SCVO2, central venous oxygen saturation; SVO2, mixed venous oxygen saturation. Source: From Ref. 60.

Considerable progress has been made in the past few years in the development of therapeutic interventions that can reduce mortality in sepsis. However, encouraging physicians to put the results of new studies into practice is not always simple. A report from a recent roundtable convened to provide guidance for clinicians on the integration and implementation of new interventions for treatment of sepsis was recently published (63). Five topics were selected that have been shown in randomized, controlled trials to reduce mortality in sepsis: limiting the tidal volume in acute lung injury or acute respiratory distress syndrome, EGDT, use of drotrecogin alfa (activated), use of moderate doses of steroids, and tight control of blood sugar. Each new intervention has a place in the management of patients with sepsis. Furthermore, and importantly, the therapies are not mutually exclusive; many patients will need a combination of several treatment strategies. Optimal patient selection and timing

Chapter 11: Sepsis and the Syndrome of Multiple Organ Failure

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Supplemental oxygen ± endotracheal intubation and mechanical ventilation

Central venous and arterial catheterization

Sedation, paralysis (if intubated), or both

25 and minimal risk for bleeding) with severe sepsis and septic shock.

Hemofiltration in Sepsis Hemofiltration, especially early hemofiltration, has emerged as a therapeutic modality for early renal dysfunction and renal failure in sepsis, acute respiratory distress syndrome (ARDS), multiple organ failure, and patients with severe metabolic abnormalities (107). Newer devices for hemofiltration have made continuous renal replacement therapy very easy. Extracorporeal therapies designed to remove substances from the circulation now include hemodialysis, hemofiltration, hemoadsorption, plasma filtration, cell-based therapies, and combinations of any of the above. In recent years, there have been considerable advances in our understanding and technical capabilities, but consensus over the optimal way and under what conditions to use these therapies does not exist. There is significant controversy regarding whether hemofiltration in septic patients without renal dysfunction or renal failure is associated with any improvement in ultimate outcome (108). One potential mechanism for the efficacy of hemofiltration may be improved hemostatic changes, similar to the mechanism for activated protein C treatment in sepsis. One study in 40 patients with SIRS-associated renal failure documented a significant reduction in PAI type 1 activity in patients receiving continuous renal replacement therapy (109). Hemofiltration induces fibrinolysis, allows clot breakdown, and prevents microthrombosis, similar to the underlying mechanism for activated protein C. Proapoptotic molecules are generated during sepsis, which may be responsible for alteration of organ function in sepsis, and removal of systemic apoptotic activity may

affect recovery from sepsis. These proapoptotic factors can be eliminated by dialytic membranes with the removal rate maximized by using super high-flux dialysers that may represent a compromise between hemofiltration and plasmafiltration membranes (110). Another potential mechanism is related to clearance of inflammatory mediators. Continuous veno-venous hemofiltration with high permeability hemofilters is a novel approach in the adjuvant therapy of septic patients. High-permeability hemofilters are characterized by an increased pore size that facilitates the filtration of inflammatory mediators. A recent study (111) documented that high-permeability hemofiltration restores peripheral blood mononuclear cell proliferation in septic patients probably by eliminating immunomodulatory mediators. This may represent a new renal replacement therapy able to modulate monocyte function in sepsis. Some studies show that hemofiltration may have some beneficial effects in sepsis, such as shortened length of stay (112–114). Yet, the prospective clinical studies investigating hemofiltration in sepsis have been so small that translating them into overall improved survival has been difficult. The ‘‘Acute Dialysis Quality Initiative’’ (115) was established to perform an evidence-based appraisal and set of consensus recommendations to standardize care and direct further research in this area. The results of previous consensus conferences are available online (www.ADQI.net). Three prospective randomized controlled trials of extracorporeal blood therapy for SIRS/Sepsis and not for renal replacement therapy have been conducted. The first was a small multicenter trial of 30 patients randomized to plasmafiltration or conventional treatment (112). Plasmafiltration was performed by hollow fiber plasma filter continuously for 34 hours. This study showed no difference in mortality or organ failure. The concentration of several mediators was decreased. This study was not sufficiently powered to detect clinically important differences. The second study was a small single-center trial of 24 septic patients without renal failure randomized to continuous venovenous hemofiltration (CVVH) (2 L/hr of ultrafiltrate) or conventional treatment. This study showed no effects of CVVH on organ failure, survival, or concentration of several immune mediators (113). This study was not sufficiently powered to detect clinically meaningful differences in survival. Finally, the third trial was a larger single-center trial of 106 patients with severe sepsis/septic shock randomized to conventional treatment or plasmapheresis. In this study, plasmapheresis was performed by intermittent continuous flow centrifugation. This study showed that patients treated with plasmapheresis had a 33.3% mortality, while the control group had a 53.8% mortality (P ¼ 0.049 Fisher’s exact test) (114). Together with the existing literature, these three studies suggest that CVVH at 2 L/hr may not be useful in SIRS/Sepsis in the absence of acute renal failure, but the studies had insufficient sample size. The studies of plasmapheresis in SIRS/Sepsis have so far been inconsistent in their findings, making evaluation difficult. However, it remains possible that plasmapheresis might offer a clinical benefit, and larger multicenter studies of this modality of extracorporeal blood treatment in SIRS/Sepsis should be considered. The consensus recommendation of the ADQI group was that in SIRS/Sepsis without acute renal failure, standard-dose continuous renal replacement therapy is unlikely to provide benefit over standard therapy and is a poor candidate for future studies. Other methods of

Chapter 11: Sepsis and the Syndrome of Multiple Organ Failure

extracorporeal blood treatment including high-volume hemofiltration, plasma therapies, and hemoadsorption are perhaps more promising but relatively untested, and they should undergo further study. Plasma therapies should be further explored to determine the importance of such technical aspects as plasmafiltration versus centrifugation, continuous versus intermittent therapy, timing, intensity, and type of replacement fluid. The existing preliminary data are sufficiently strong to recommend further investigation in the treatment of SIRS/Sepsis in appropriately designed and powered prospective randomized clinical trials.

Failed Strategies for the Treatment of Sepsis There is no question that excessive production of inflammatory mediators during invasive infection plays a key role in the pathogenesis of septic shock. However, novel therapies directed at modifying the inflammatory response in severe sepsis and septic shock have, up to now, not proven beneficial (17,116,117). Drotrecogin alfa (activated), activated protein C, is the first biological modifier that has been shown, in a phase III randomized controlled trial, to be of benefit in the treatment of severe sepsis. However, novel treatments have so far failed to live up to the expectations following extensive and promising in vitro and in vivo

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animal studies, and following promising phase I and II clinical trials. Natanson et al. (17) carefully scrutinized the results of 21 nonglucocorticoid mediator-specific anti-inflammatory agents in sepsis and septic shock (Fig. 7). The combined results of all 21 of these sepsis trials demonstrated consistent, small, statistically significant beneficial effect (OR, 1.11, 95% constant interval, 1.02–1.20, P ¼ 0.02). Further examination of only the double-blind trials (n ¼ 16), which theoretically have less potential for bias than single-blind studies (n ¼ 5), documented the same small but significant beneficial effect (OR, 1.11; 95% constant interval, 1.01–1.21, P ¼ 0.02). Also important to realize, however, is that significant differences in mortality rates were identified in the control arms of these sepsis trials (Fig. 1). The reasons for these significant differences in 28-day all-cause mortality rates of septic patients must be carefully scrutinized. A recent metaregression analysis (118,119) of these preclinical and clinical trials in combination with prospective confirmatory studies demonstrated that risk of death as assessed by control group mortality rate significantly altered the treatment effect of these agents in both humans and animals. While anti-inflammatory agents were very beneficial in groups with high control mortality rates, they were ineffective or harmful in groups with low control

Number of Patients Enrolled 500 1000 1500 2000 Control

Therapy/Type of agent

Treated

Odds Ratio

BAY x 1351/TNF-MAb

P-55/sTNFr BAY x 1351/TNF-MAb Antril/IL-1ra Antril/IL-1ra Odds Ratio BN52021/PAFra

Clinical Trial

BAY x 1351/TNF-MAb CPO-127/Anti-Bradykinin

95% Confidence Interval

P-55/s TNFr Ibuprofen/Anti-Prostaglandin MAK 195FTNF-MAb BN 52021/PAFra CPO-127/Anti-Bradykinin P-80/s TNFr MAK 195F/TNF-MAb Antril/IL-1ra CB0006/TNF-MAb CDP571/TNF-MAb MAK 195F/TNF-MAb Ibuproten/Anti-Prostaglandin Ibuprofen/ Anti-Prostaglandin

0.125 0.25 0.5 0.67 1 0.5 2.0 4.0 8.0 Increasing Harm Increasing Benefit No Effect Odds Ratio

Figure 7 Survival odds ratios and 95% confidence intervals for 21 clinical trials of nonglucocorticoid mediator– specific anti-inflammatory agents. The 21 trials are ranked in order by the total number of patients enrolled. The larger clinical trials enrolling >250 patients had similar small beneficial effects. The smaller trials enrolling 250 patients were equally likely to show beneficial or harmful trends. The results of these smaller trials are not inconsistent with the larger trials, as can be seen by the overlap of the 95% confidence intervals. Rather, the estimate of the drug’s treated effect in smaller trials is less accurate because of sampling error. Two of these trials had treatment effects at specific doses of the agents used that were significant outliers (P ¼ 0.016, data not shown). The p-80 sTNFr in high and medium doses and the P-55 sTNF in very low doses produced harmful effects (combined, P ¼ 0.009). Excluding patients treated with the high and medium doses of the P-80 sTNFr and very low doses of the P-55 sTNFr (the groups that constitute significant outliers) results in a small, but even more significant, increase in the odds of surviving for patients treated with mediator–specific anti-inflammatory therapies. Abbreviations: IL-1ra, interleukin-1 receptor antagonist; PAFra, platelet-activating factor receptor antagonist; sTNFr, soluble tumor necrosis factor receptor. Source: From Ref. 17.

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mortality rates. Thus, variation in the risk of death due to sepsis provides a basis for the marked difference in the efficacy of these anti-inflammatory agents in preclinical and clinical trials over the last decade. In contrast to mediatorspecific anti-inflammatory agents, glucocorticoids and activated protein C have recently demonstrated significant beneficial effects in individual clinical trials. However, glucocorticoids were studied only in patients with vasopressor-dependent septic shock, which is associated with a high control mortality rate (i.e., 61%) similar to the level at which mediator-specific agents would have been expected to be markedly beneficial. Furthermore, consistent with earlier findings for mediator-specific anti-inflammatory agents, analysis of the activated protein C study also demonstrated a relationship between risk of death and effect of treatment. Developing better methods to define high-risk septic populations for treatment with anti-inflammatory agents will increase the efficacy of this therapeutic approach and minimize its potential for harm. Similar to the anti-inflammatory studies in sepsis, anticoagulant therapies have produced mixed results regarding efficacy (improved survival) in sepsis. Once again, it is clear that coagulation abnormalities are in part responsible for the physiologic derangements of the sepsis syndrome. A metaanalysis (120) of clinical trials of anticoagulants in sepsis was recently performed and included 11 studies that satisfied the inclusion criteria. Collectively, these studies enrolled 4690 patients (range of 29–2314) and examined three agents: antithrombin III (2659 patients), tissue factor pathway inhibitor (210 patients), and activated protein C (1821 patients). The OR (with 95% CI) for effect on mortality for these agents, relative to control treatment, was 0.8692 (0.7519–1.006). Weighted linear regression analysis was consistent with a control group mortality–dependent effect for these agents (P ¼ 0.02). Only five of the studies reported bleeding complications. Pooling the results of these five studies (4376 patients) resulted in an OR (with 95% CI) of 1.70 (1.40–2.07) relative to control treatment for bleeding risk. This meta-analysis concluded that anticoagulants as adjuvant therapy do not appear to improve outcome in sepsis and are associated with a significant risk of bleeding complications. As stated above for anti-inflammatory strategies, treatment effect of the anticoagulant therapies was dependent upon disease severity, suggesting that the safety and efficacy of these agents may be enhanced by refinement in techniques of clinical stratification. Another confounding variable in the design of sepsis trials is lack of control of basic treatment strategies in sepsis, such as adequate source control, adequate early aggressive fluid resuscitation, and adequate systemic antibiotic therapy. It is common knowledge that in many of the sepsis trials, patients were treated with inappropriate antibiotics with initial empiric therapy based on subsequent culture results, and these patients had worse outcome. These uncontrolled variables may have obscured the potential efficacy of the numerous immunomodulatory strategies tested in severe sepsis and septic shock. By standardizing protocols and reducing these uncontrolled variables, research in septic shock can be more precisely targeted and evaluated in improving patient outcomes (121). Additional recent prospective randomized controlled studies in severe sepsis and septic shock have documented the lack of efficacy of tissue factor pathway inhibitor (122) and antienterobacteriaceae monoclonal antibody (123). The use of the nonselective nitric oxide inhibitor (NG-methylL-arginine hydrochloride) in septic shock was associated

with increased 28-day mortality (59% vs. 49%, P < 0.001), due to a higher portion of cardiovascular deaths, despite a lower incidence of deaths caused by multiple organ failure (124). A number of different strategies are currently being investigated in preclinical and early clinical trials for the treatment of patients with sepsis and septic shock. These can be broadly divided into three groups: strategies aimed at bacterial targets, strategies aimed at disorders of immune regulation in the host, and, finally, other novel strategies based on modifying host response (125). Which, if any, of these will prove successful in large clinical trials is unknown. Nevertheless, changes in trial design and improved methodology to focus on septic patients at high risk of death, and control of the many confounding variables identified in prior studies should result in more meaningful and positive results for the future.

MULTIPLE ORGAN DYSFUNCTION AND FAILURE: DEFINITIONS Advances in intensive care have allowed many critically ill patients to survive their initial insult. These patients may later demonstrate multiple organ dysfunction and failure, the genesis of which appears to be the body’s reaction to critical illness, manifested by an imbalance and failure of inflammatory and immune system homeostasis. The manifestation of multiple organ dysfunction syndrome in the critically ill has been termed MODS. MODS mortality is high and remains a leading cause of death in ICUs. The understanding of the pathophysiology of severe sepsis and MODS has moved from a focus on inflammation to include an understanding of the associated anti-inflammatory responses. Loss of homeostasis can manifest as malignant inflammation or immune paralysis. Increased emphasis is emerging on the role of loss of immune homeostasis and disordered coagulation as a cause of organ injury and dysfunction. MODS is a common but poorly understood complication of critical illness (126–128). MODS is associated with significant morbidity and mortality in critical illness and trauma and is commonly associated with nosocomial infectious complications. About half of the patients who succumb to septic shock die of multiple organ system failure (129). A MODS severity score is useful to standardize reports in order to improve the understanding of the course of disease. Furthermore, the MODS scoring systems allow scientific evaluation of the impact of new treatments on outcome, including organ failure. Two severity scores are commonly utilized for MODS, including the Marshall MODS score (Table 5) (128), and the Sequential Organ Failure Assessment (SOFA) score (Table 6) (130).

INCIDENCE AND OUTCOME OF MODS Critically ill patients who develop MODS (one or more organ system failures) have increased mortality compared to critically ill patients without MODS. This has been documented for medical, surgical, and trauma critically ill patients. A number of studies have identified, however, that there has been a significant improvement in survival in patients with MODS over the last three decades (131,132). An early, large prospective, multicenter inception cohort study of 60 ICUs in the United States, including over 20,000 ICU patients, compared the outcomes for patients with one or more organ system failures treated in 1988 to 1990 with those outcomes from 1979 to 1982, documented

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Table 5 The MODS Score (Marshall MODS Score) MODS score Variables Respiratory: PaO2/FiO2 ratio Renal: Serum creatinine Hepatic: Serum bilirubin Cardiovascular: Pulse-adjusted HR Hematologic: Platelet count Neurologic: Glasgow coma score

0

1

2

3

4

>300 100 20 10.0

226–300 101–200 21–60 10.1–15.0

151–225 210–350 61–120 15.1–20.0

76–150 351–500 121–240 20.1–30.0

75 >500 >240 >30.0

>120 15

81–120 13–14

51–80 10–12

21–50 7–9

20 6

PaO2/FiO2 ratio is calculated with reference to the use or mode of mechanical ventilation, and without reference to the use or level of positive end-expiratory pressure. The serum creatinine concentration is measured in mmol/L, without reference to the use of dialysis. The serum bilirubin concentration is measured in mmol/L. The PAR is calculated as the product of the HR multiplied by the ratio of the RAP to the MAP: PAR ¼ HR  RAP/MAP. The platelet count is measured in platelets/mL 10-3. The Glasgow Coma Score is preferably calculated by the patient’s nurse, and is scored conservatively (for the patient receiving sedation or muscle relaxants, normal function is assumed, unless there is evidence of intrinsically altered mentation). Abbreviations: PAR, pressure-adjusted heart rate; HR, heart rate; RAP, right atrial (central venous) pressure; MAP, mean arterial pressure; MODS, multiple organ dysfunction syndrome. Source: From Ref. 128.

patients in ICUs. The incidence and overall outcome did not significantly change over the eight-year study period, but there was a significant improvement in survival for patients with persistent severe organ system failure. A recent study (132) examined the current incidence and mortality of organ failure in a homogenous population of critically ill trauma patients (n ¼ 869). All trauma patients admitted to the ICU at an urban Level I trauma center were prospectively studied. Patients were evaluated for the presence of organ failure using initial definitions proposed by Knaus and co-workers (131) and by Fry et al. (133). Newer definitions of organ failure incorporating organ dysfunction and severity-of-illness scores were also obtained in all patients in an attempt to predict outcome. These included lung injury scores (acute respiratory distress syndrome scores), APACHE II and III scores, injury severity score (ISS), and multiple organ dysfunction scores. Single organ failure occurred in 163 patients (18.7%) and multiple organ failure occurred in 44 patients (5.1%). All single organ failure was caused by respiratory failure. Respiratory failure

risk factors for developing organ system failure, and investigated the relationship of these factors to hospital survival (131). The incidence of organ system failure (48%) among patients treated in 1988 to 1990 was similar (44%) to the occurrence rate in patients in 1979 to 1982; and an identical proportion (14%) developed multiple organ system failure. There was a significant (P< 0.0003) improvement in hospital mortality for patients with three or more organ system failures on day 4 or later of organ system failure. However, overall hospital mortality rates from multiple organ system failure were not different over this eight-year period. The most important predictor of hospital mortality was the severity of physiologic disturbance on the initial day of failure. Discrimination of patients by risk of hospital mortality was better using the prognostic scoring system on day 1 of organ system failure (receiver operating characteristic curve ¼ 0.88) than using a model based on the number of organ system failures (receiver operating characteristic curve ¼ 0.68). This pivotal study documented that organ system failure remains a major contributor to death in

Table 6 The SOFA Score SOFA score Variables Respiration: PaO2/FiO2 Coagulation: Platelets, 103/mL Liver: Bilirubin mg/dL mmol/L Cardiovascular: Hypotension

CNS: Glasgow coma score Renal: Creatinine Mg/dL mmol a

1

2

3

4 a

300 204 Dopamine >15, or epinephrine >0.1, or norepinephrine >0.1c 5 >440

With respiratory support. MAP. c Adrenergic agents administered for at least 1 hr (dosages are in mg/kg/min). Abbreviations: SOFA, Sequential Organ Failure Assessment; CNS, central nervous system; MAP, mean arterial pressure. b

7 days were more commonly transfused (63.0%) compared with patients with ICU length of stay < 7 days (33.4%, P< 0.0001). Mean pretransfusion hemoglobin was 8.6 þ 1.7 g/dL in this U.S. study. The number of RBC transfusions a patient received during the study was independently associated with longer ICU and hospital lengths of stay and an increase in mortality. A large prospective, multicenter trial (Transfusion Requirements in Critical Care Trial, TRICC) by the Canadian Critical Care Trials Group (152) documented that a restrictive transfusion strategy (hemoglobin maintained between 7 and 9 g/dL) was as effective as a liberal transfusion strategy (hemoglobin maintained between 10 and 12 g/dL). In this trial, 838 critically ill patients were randomized to a restrictive or liberal transfusion strategy. Although the 30-day mortality rates were similar in the two groups, the hospital mortality rate was significantly lower in the restrictive-strategy group (22.3% vs. 28.1%, P ¼ 0.05). Mortality rates were also significantly lower with the restrictive transfusion strategy among patients who were less acutely ill (APACHE II score of < 20, 8.7% in restrictive group vs. 16.1% in liberal group; P ¼ 0.03) and among patients who were less than 55 years of age (5.7% vs. 13.0%, respectively; P ¼ 0.02). This study documented that a restrictive strategy of RBC transfusion in critically ill patients was at least as effective as and possibly superior to a liberal transfusion strategy, with the possible exception of patients with acute myocardial infarction and unstable angina. Efforts to reduce blood transfusion rates in the ICU are warranted, and blood transfusion should be reserved for physiologic indications. Alternatives to allogeneic blood transfusion are currently under preclinical and clinical investigation. These include the use of the new generation of hemoglobin-based oxygen carriers (153) from both human and bovine source and recombinant human hemoglobin expressed in E. coli for treatment of acute blood loss and the use of recombinant human erythropoietin for the treatment of ICU-acquired anemia (154).

SUMMARY Sepsis and the multiple organ failure that often results there from is frequently the cause of death in critically ill and severely injured patients. With increasing understanding of the linkage between these two events and the pathogens and mediators responsible for this relationship, strategies have evolved that have favorly impacted the lethal outcome as commonly observed in the past in patients developing

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sepsis. The foregoing chapter has attempted to provide stateof-the-art knowledge concerning the evolution of sepsis into organ failure and contemporary management to decrease the associated morbidity and all too frequent mortality.

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85. Holmes CL, Patel BM, Russell JA, Walley KR. Physiology of vasopressin relevant to management of septic shock. Crit Care Rev Chest 2001; 120:989–1002. 86. Landry DW, Levin HR, Gallant EM, et al. Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation 1997; 95:1122–1125. 87. Landry DW, Levin HR, Gallant EM, et al. Vasopressin pressor hypersensitivity in vasodilatory septic shock. Crit Care Med 1997; 25:1279–1282. 88. Sharshar T, Blanchard A, Paillard M, Raphael JC, Gajdos P, Annane D. Circulating vasopressin levels in septic shock. Crit Care Med 2003; 31(6):1752–1758. 89. Malay MB, Ashton RC Jr, Landry DW, et al. Low-dose vasopressin in the treatment of vasodilatory septic shock. J Trauma 1999; 47:699–703. 90. Holmes CL, Walley KR, Chittock DR, et al. The effects of vasopressin on hemodynamics and renal function in severe septic shock: a case series. Intensive Care Med 2001; 27:1416–1421. 91. Dunser M, Luckner G, Mayr A, et al. The effects of vasopressin on systemic hemodynamics in catecholamine-resistant septic and postcardiotomy shock: a retrospective analysis. Anesth Analg 2001; 93:7–13. 92. Patel BM, Chittock DR, Russell JA, et al. Beneficial effects of short-term vasopressin infusion during severe septic shock. Anesthesiology 2002; 96: 576–582. 93. Klinzing S, Simon M, Reinhart K, Bredle DL, Meier-Hellmann A. High-dose vasopressin is not superior to norepinephrine in septic shock. Crit Care Med 2003; 31(11):2646–2650. 94. Gando S, Nanzaki S, Kemmotsu O. Disseminated intravascular coagulation and sustained SIRS predicts organ dysfunction after trauma: application of clinical decision analysis. Ann Surg 1999; 229(1):121–127. 95. Gando S, Kameue T, Matsuda N, et al. Combined activation of coagulation and inflammation has an important role in multiple organ dysfunction and poor outcome after severe trauma. Thromb Haemost 2002; 88(6):943–949. 96. Levi M, Keller TT, van Gorp E, ten Cate H. Infection and inflammation and the coagulation system. Cardiovasc Res 2003; 60(1):26–39. 97. Boehme MW, Deng Y, Raeth U, et al. Release of thrombomodulin from endothelial cells by concerted action of TNF-alpha and neutrophils: in vivo and in vitro studies. Immunology 1996; 87:134–140. 98. Fourrier F, Chopin C, Goudemand J, et al. Septic shock, multiple organ failure, and disseminated intravascular coagulation: compared patterns of antithrombin HI, protein C, and protein S deficiencies. Chest 1992; 101:816–823. 99. Lorente JA, Garcia-Frade LJ, Landin L, et al. Time course of hemostatic abnormalities in sepsis and its relation to outcome. Chest 1993; 103:1536–1542. 100. Boldt J, Papsdorf M, Rothe A, Kumie B, Piper S. Changes of the hemostatic network in critically ill patients—is there a difference between sepsis, trauma, and neurosurgery patients? Crit Care Med 2000; 28:445–450. 101. Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344:699–709. 102. Bernard GR, Macias WL, Joyce DE, Williams MD, Bailey J, Vincent JL. Safety assessment of drotrecogin alfa (activated) in the treatment of adult patients with severe sepsis. Crit Care 2003; 7(2):155–163 (Epub 2003, Feb 28). 103. Vincent JL, Angus DC, Artigas A, et al. Effects of drotrecogin alfa (activated) on organ dysfunction in the PROWESS trial. Crit Care Med 2003; 31(3):834–840. 104. Dhainaut JF, Laterre PF, Janes JM, et al. Drotrecogin alfa (activated) in the treatment of severe sepsis patients with multiple organ dysfunction: data from the PROWESS trial. Intensive Care Med 2003 (Epub ahead of print). 105. Doig CJ, Laupland KB, Zygun DA, Manns BJ. The epidemiology of severe sepsis syndrome and its treatment with recombinant human activated protein C. Expert Opin Pharmacother 2003; 4(10):1789–1799.

106. Angus DC, Linde-Zwirble WT, Clermont G, et al. PROWESS Investigators. Cost-effectiveness of drotrecogin alfa (activated) in the treatment of severe sepsis. Crit Care Med 2003; 31(1):1–11. 107. Napolitano LM. Hemofiltration in sepsis: additional supportive evidence. Crit Care Med 2001; 29(7):1485–1487. 108. Honore PM, Matson JR. Hemofiltration, adsorption, sieving and the challenge of sepsis therapy design. Crit Care 2002; 6(5):394–396 (Epub 2002 Sep 04). 109. Garcia-Fernandez N, Lavilla FJ, Rocha E, Purroy A. Haemostatic changes in systemic inflammatory response syndrome during continuous renal replacement therapy. J Nephrol 2000; 13(4):282–289. 110. Bordoni V, Bolgan I, Brendolan A, et al. Caspase-3 and -8 activation and cytokine removal with a novel cellulose triacetate super-permeable membrane in an in vitro sepsis model. Int J Artif Organs 2003; 26(10):897–905. 111. Morgera S, Haase M, Rocktaschei J, et al. High permeability haemofiltration improves peripheral blood mononuclear cell proliferation in septic patients with acute renal failure. Nephrol Dial Transplant 2003; 18(12):2570–2576. 112. Reeves J, Butt W, Shann F, et al. Continuous plasmafiltration in sepsis syndrome. Crit Care Med 1999; 27:2096–2104. 113. Cole L, Bellomo R, Hart G, et al. A phase II randomized, controlled trial of continuous hemofiltration in sepsis. Crit Care Med 2002; 30:100–106. 114. Busund R, Koukline V, Utrobin U, Nedashkovsky E. Plasmapheresis in severe sepsis and septic shock: a prospective, randomized, controlled trial. Intensive Care Med 2002; 28: 1434–1439. 115. Kellum JA, Bellomo R, Mehta R, Ronco C. Blood purification in non-renal critical illness. Blood Purif 2003; 21(1):6–13. 116. Napolitano LM, Faist E, Wichmann MW, Coimbra R. Immune dysfunction in trauma. Trauma Care in the New Millennium. Surg Clin N Am 1999; 79(6):1385–1416. 117. Dellinger RP, Parrillo JE. Mediator modulation therapy of severe sepsis and septic shock: does it work? Crit Care Med 2004; 32(1):282–286 [Editorial]. 118. Eichacker PQ, Parent C, Kalil A, et al. Risk and the efficacy of antiinflammatory agents: retrospective and confirmatory studies of sepsis. Am J Respir Crit Care Med 2002; 166(9): 1197–1205. 119. Minneci P, Deans K, Natanson C, Eichacker PQ. Increasing the efficacy of anti-inflammatory agents used in the treatment of sepsis. Eur J Clin Microbiol Infect Dis 2003; 22(1):1–9 (Epub 2003 Jan 28). 120. Freeman BD, Zehnbauer BA, Buchman TG. A meta-analysis of controlled trials of anticoagulant therapies in patients with sepsis. Shock 2003; 20(1):5–9. 121. Nasraway SA. The problems and challenges of immunotherapy in sepsis. Chest 2003; 123(suppl 5):451S–459S. 122. Abraham E, Reinhart K, Opal S, et al. OPTIMIST Trial Study Group. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA 2003; 290(2):238–247. 123. Albertson TE, Panacek EA, MacArthur RD, et al. MAB-T88 Sepsis Study Group. Multicenter evaluation of a human monoclonal antibody to Enterobacteriaceae common antigen in patients with Gram-negative sepsis. Crit Care Med 2003; 31(2):419–427. 124. Lopez A, Lorente JA, Steingrub J, et al. Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in patients with septic shock. Crit Care Med 2004; 32:21–30. 125. Cohen J. Recent developments in the identification of novel therapeutic targets for the treatment of patients with sepsis and septic shock. Scand J Infect Dis 2003; 35(9):690–696. 126. Khadaroo RG, Marshall JC. ARDS and the multiple organ dysfunction syndrome. Common mechanisms of a common systemic process. Crit Care Clin 2002; 18(1):127–141. 127. Marshall JC. Inflammation, coagulopathy, and the pathogenesis of multiple organ dysfunction syndrome. Crit Care Med 2001; 29(suppl 7):S99–S106.

Chapter 11: Sepsis and the Syndrome of Multiple Organ Failure 128. Marshall JC. Multiple organ dysfunction score: reliable descriptor of a complex clinical outcome. Crit Care Med 1995; 23(10):1638–1652. 129. Parrillo JE, Parker MM, Natanson C, et al. Septic shock in humans: advances in the understanding of pathogenesis, cardiovascular dysfunction and therapy. Ann Intern Med 1990; 113:227–242. 130. Vincent JL, Moreno R, Takala J, et al. The SOFA score to describe organ dysfunction/failure: on behalf of the Working Group on Sepsis-related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 1996; 22:707–710. 131. Zimmerman JE, Knaus WA, Wagner DP, Sun X, Hakim RB, Nystrom PO. A comparison of risks and outcomes for patients with organ system failure: 1982–1990. Crit Care Med 1996; 24(10):1633–1641. 132. Durham RM, Moran JJ, Mazuski JE, Shapiro MJ, Baue AE, Flint LM. Multiple organ failure in trauma patients. J Trauma 2003; 55(4):608–616. 133. Fry DE, Pearlstein L, Fulton RL, Polk HC Jr. Multiple system organ failure. The role of uncontrolled infection. Arch Surg 1980; 115(2):136–140. 134. Flaatten H, Gjerde S, Guttormsen AB, et al. Outcome after acute respiratory failure is more dependent on dysfunction in other vital organs than on the severity of the respiratory failure. Crit Care 2003; 7(4):R72 (Epub 2003 Jul 09). 135. Brun-Buisson C, Minelli C, Bertolini G, et al. Epidemiology and outcome of acute lung injury in European intensive care units results from the ALIVE study. Intensive Care Med 2003 (Epub ahead of print). 136. Barie PS, Hydo LJ. Epidemiology of multiple organ dysfunction syndrome in critical surgical illness. Surg Infect 2000; 1(3):173–186. 137. Maier R. Pathogenesis of MODS–Endotoxin, inflammatory cells and their mediators: cytokines and reactive oxygen species. Surg Infect 2000; 1(3):197–205. 138. Cobb JP, Buchman TG, Karl IE, Hotchkiss RS. Molecular biology of MODS: injury, adaptation and apoptosis. Surg Infect 2000; 1(3):207–213. 139. Rotstein OD. Pathogenesis of MODS: gut origin, protection and decontamination. Surg Infect 2000; 1(3):217–225. 140. Brealey D, Singer M. Mitochondrial dysfunction in sepsis. Curr Infect Dis Rep 2003; 5(5):365–371. 141. Biffl WL, Moore EE, Haenel JB. Nutrition support of the trauma patient. Nutrition 2002; 18(11–;12):960–965.

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142. Yanagawa T, Bunn F, Roberts I, Wentz R, Pierro A. Nutritional support for head-injured patients. Cochrane Database Syst Rev 2002; 3:CD001530. 143. Bastian L, Weimann A. Immunonutrition in patients after multiple trauma. Br J Nutr 2002; 87(suppl 1):S133–S134. 144. Heyland DK, Novak F, Drover JW, Jain M, Su X, Suchner U. Should immunonutrition become routine in critically ill patients? A systematic review of the evidence. JAMA 2001; 286(8):944–953. 145. Nathens AB, Neff MJ, Jurkovich GJ, et al. Randomized, prospective trial of antioxidant supplementation in critically ill surgical patients. Ann Surg 2002; 236(6):814–822. 146. Moore FA, Moore EE, Sauaia A. Blood transfusion: an independent risk factor for postinjury multiple organ failure. Arch Surg 1997; 132(6):620–625. 147. Malone DL, Dunne J, Tracy JK, Putnam AT, Scalea TM, Napolitano LM. Blood transfusion, independent of shock severity, is associated with worse outcome in trauma. J Trauma 2003; 54(5):898–907. 148. Claridge JA, Sawyer RG, Schulman AM, McLemore EC, Young JS. Blood transfusions correlate with infections in trauma patients in a dose-dependent manner. Am Surg 2002; 68(7):566–572. 149. Hill GE, Frawley WH, Griffith KE, Forestner JE, Minei JP. Allogeneic blood transfusion increases the risk of postoperative bacterial infection: a meta-analysis. J Trauma 2003; 54: 908–914. 150. Vincent JL, Baron JF, Reinhart K, et al. ABC (Anemia and Blood Transfusion in Critical Care) Investigators. Anemia and blood transfusion in critically ill patients. JAMA 2002; 288(12):1499–1507. 151. Corwin HL, Gettinger A, Pearl RG, et al. The CRIT Study: anemia and blood transfusion in the critically ill-current clinical practice in the United States. Crit Care Med 2004; 32(1): 39–52. 152. Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med 1999; 340(6):409–417. 153. Moore EE. Blood substitutes: the future is now. J Am Coll Surg 2003; 196(1):1–17. 154. Corwin HL, Gettinger A, Pearl RG, et al. Efficacy of recombinant human erythropoietin in critically ill patients: a randomized controlled trial. JAMA 2002; 288:2827–2835.

12 Application of Cellular and Molecular Biology in Modern Surgical Practice Huiping Zhou and Jian-Ying Wang

the other is the ‘‘macromolecule class’’ such as proteins and nucleic acids (4). All living cells, without any known exception, store their hereditary information in DNA molecules. The genome is the entire DNA content of a cell. The eukaryotic genome is made up of two distinct components: nuclear genome and mitochondrial genome. The nuclear genomes are divided into two or more linear DNA molecules. The basic structures of all eukaryotic nuclear genomes are similar, but the size is very different in various organisms. The human nuclear genome is divided into 24 linear DNA molecules, which comprises approximately 3
109 base pairs (bp). The mitochondrial genome is a circular DNA molecule of 16,569 bp (1,5). A gene is a segment of DNA (or, in a few cases, RNA such as in viruses) that encodes the information required to produce a functional RNA. A messenger RNA (mRNA) is a transcript of a protein-coding gene and can be translated into protein. Each protein-coding gene encodes one specific protein. The noncoding genes are transcribed into structural RNA molecules such as ribosomal RNA (rRNA) or transfer RNA (tRNA). The eukaryotic genes are not precisely colinear with their proteins. The length of human genes is usually much longer than that of mRNA sequences. The expressed (or coding) sequences of most genes are named exons and are usually interrupted by intervening introns or other sequences that do not encode any amino acid sequences for the polypeptide products and must be spliced out during transcription (5). The existence of splicing makes it possible that some eukaryotic genes can be spliced in different ways and transcribed into different mature mRNA molecules. This process is called ‘‘differential splicing.’’ Therefore, organisms can use differential splicing to produce different forms of a given protein, depending on various cell types or different stages of development. In general, one gene makes one protein, but it has been realized that some eukaryotic genes are able to produce several different versions of the protein (1). The human genome was originally predicted as having 50,000 to over 140,000 genes. However, recent completion of the human genome sequence has clearly revealed that the human genome only contains approximately 26,000 to 38,000 genes, which are far fewer than the earlier molecular predictions (5,6). The coding regions of these genes take up only 3% of the genome (1,3). All of the cells in the adult human body have their own copy or copies of the genome except a few cell types that lack nuclei in their fully differentiated state, such as red blood cells. It is clear that the diversity of cell types and functions reflects patterns of different gene expression.

INTRODUCTION During the last two decades, there has been a great explosion in new knowledge and technology regarding cellular and molecular biology. One of the most important achievements in this field is the successful completion of the Human Genome Project in 2003. The identification and sequencing of the entire human genome is revolutionizing our surgical practice. These advances will rapidly transform our traditional surgical care to modern surgical practice that is based on cellular and molecular approaches for prevention, diagnosis, and treatment of human surgical diseases. There are several excellent textbooks available (1–5), in which the information about core knowledge of advanced cellular and molecular biology is presented in detail. The goal of this chapter is to present an overview of basic concepts and common techniques of cellular and molecular biology and also to highlight its potential application in the modern surgical practice.

BASIC GENETIC MECHANISMS Cells and Human Genome There are millions of living species on earth today. Each species possesses a genome that contains all of the biological information required to reproduce itself faithfully. The structural and functional units of all living organisms are cells. The human body contains more than 1014 cells with different types and functions (1). As the smallest irreducible units of life, cells share the same machinery for their functions. Two important functions of living cells are (i) to store, reproduce, and transmit information, and (ii) to enhance the rate of chemical reactions, a property referred to as catalysis (2). Although there are significant differences among various cell types, all of the living cells share common structural features. They all have a nucleus or nucleoid, in which the genome is stored and replicated, the plasma membrane, which is composed of enormous lipids and proteins, and the cytoplasm, which contains an aqueous solution, suspended particles, and organelles. Cells with a nuclear membrane (or nuclear envelope) are named eukaryotes, while cells without a nuclear envelope are called prokaryotes (Fig. 1). Eukaryotic cells also have a number of other membrane-bound compartments, which are absent in prokaryotes, such as endoplasmic reticulum, mitochondrion, lysosomes, and Golgi apparatus (3). Cells are very small, but chemically very sophisticated in general. The simplest cells contain more than 2500 different molecules. There are two large classes of molecules in every cell. One is the ‘‘small molecule class’’ such as sugars, amino acids, fatty acids, and nucleotides; 253

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Figure 1 Cells of eukaryotes (A) and prokaryotes (B). Eukaryotic cells are characterized by their membrane-bound organelles such as nucleus, endoplasmic reticulum, mitochondrion, and Golgi. The nuclear body of the eukaryotic cell is bounded by a nuclear membrane and is called a nucleus. The prokaryotic cells are much smaller and simpler than eukaryotic cells and lack characteristics of subcellular membrane-enclosed organelles. The prokaryotic cells do not have a nucleus and the nuclear body is called a nucleoid. Some prokaryotic cells have external whiplike flagella for locomotion.

DNA and Chromosomes DNA is the most important substance of life. It carries the hereditary information that determines the structures of RNAs and proteins. The only known functions of DNA are the storage and transmission of biological information. The DNA molecules consist of two antiparallel nucleotide strands with complementary nucleotide sequences that are held together principally by hydrogen bonds and basestacking interactions to form a right-hand double helix (7). Each nucleotide contains a phosphate group, a sugar moiety, and a base (either purine or pyrimidine) (Fig. 2). These two nucleotide strands are composed of four different nucleotides that are linked together by phosphodiester bonds

Figure 2 The chemical structures of DNA nucleotide (A) and the bases of nucleic acids (B). A DNA nucleotide consists of a nitrogencontaining base, five-carbon sugar, and one or more phosphate groups. The base is attached to a ribose ring, which is in turn bonded to a phosphate group. Principal bases of nucleic acids include adenine (A), guanine (G), thymine (T), cytosine (C), and uracil (U).

between the base and the phosphate group. These linkages are always the same, with the phosphate group connecting the 50 -carbon atom of one deoxyribose residue to the 30 -carbon atom of the deoxyribose in the adjacent nucleotide. Each nucleotide strand has a 50 -end with a free hydroxyl or phosphate group at the 50 -carbon of a sugar and a 30 -end with a free hydroxyl group at the 30 -carbon of a sugar (Fig. 3). The sugar–phosphate backbones are on the outside of the double helix, and the bases project inward toward each other. The complementary strands have opposite polarity and their bases must be paired. The adenine (A) must be paired with thymine (T) by two

Figure 3 Phosphodiester linkage of DNA backbone. The regular phosphodiester bonds between sugar and phosphate groups form the backbone of DNA. The phosphate group is always connecting the 50 -carbon atom of one deoxyribose residue to the 30 -carbon atom of the deoxyribose in the adjacent nucleotide.

Chapter 12: Application of Cellular and Molecular Biology in Modern Surgical Practice

Figure 4 The base paring of two DNA strands. In the double helix, two polynucleotides, running in antiparallel directions, are wound around one another and held together by hydrogen bonds between base pairs. Sequence of four bases, including adenine (A), guanine (G), thymine (T), cytosine (C), determines the specificity of genetic information. The bases face inward from the sugar–phosphate backbone and form pairs with complementary bases on the opposing strand.

hydrogen bonds, while the cytosine (C) must be paired with guanine (G) by three hydrogen bonds (Fig. 4). Each of these base pairs possesses a symmetry that permits it to be inserted into the double helix in two ways (A ¼ T and T ¼ A; G ¼ C and C ¼ G). DNA molecules are the largest macromolecules in the cell and are normally packaged into structures known as chromosomes. Most prokaryotic cells have a single chromosome, but eukaryotic cells usually contain multiple chromosomes. Each chromosome contains one linear DNA molecule. Human beings are diploid organisms and carry 46 chromosomes in total, including two copies of 22 different autosomes and two sex chromosomes, XX for females or XY for males. One copy of chromosomes is inherited from the mother and one is inherited from the father (1–5). The total length of chromosomal DNA in the nucleus of a human cell is about 105 times the diameter of a typical cell. The chromosomal DNA is folded and compacted with a number of specific proteins called histones to form chromatin. Histones are small basic proteins, which bind to DNA primarily through ionic bonds between the negatively charged phosphate groups of DNA and the positively charged side groups of arginine and lysine. There are two types of chromatin: euchromatin and heterochromatin. Euchromatin is compacted during the division but decondenses at the interphase, and it is genetically active. Heterochromatin is highly compacted and remains condensed throughout the cell cycle, which is genetically inactive. The DNA folding is essential for packaging the long DNA molecules in an orderly way in the nucleus. The packaging of chromosome DNA not only facilitates DNA replication and segregation but also affects the activity of genes (1,2).

DNA Replication, Repair, and Recombination With the discovery of the DNA double helical structure by James Watson and Francis Crick in 1953, it was possible to

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understand how genes could be faithfully duplicated prior to cell division. Fundamental properties of the DNA replication process are essentially identical in all organisms. The DNA replication is semiconservative. Each DNA strand serves as a template for the synthesis of a new strand by DNA polymerases and results in the production of two identical daughter DNA molecules, each containing one original and one newly replicated strand (4). DNA replication begins at a large number of sites in the genome, which are called the origins of replication, and usually precedes bidirectionally along the DNA molecule. A new strand of DNA is always synthesized in the 50 to 30 direction. Because the two strands are antiparallel, the template strand is read from 30 end to 50 end. The leading strand is continuously synthesized in the same direction as the replication fork movement. The other strand (called ‘‘lagging strand’’) is synthesized discontinuously in short pieces, which are called Okazaki fragments, in the direction opposite to the direction of fork movement (Fig. 5). The nick is sealed by DNA ligase. The fidelity of DNA replication is extremely important, and any mistake results in the change of DNA sequences in a daughter strand, which is named mutation. The mutation rate of DNA replication is extremely low, about 1 nucleotide change per 109 nucleotide replication. The DNA polymerases not only have base selection activity but also have 30 ! 50 exonuclease (or proofreading) activity. Both activities account for the high degree of fidelity in replication. The additional accuracy accounts for the repair systems after replication. The DNA molecules in a cell are irreplaceable. Many processes can damage the DNA structures and result in mutations. The most frequent chemical reactions to induce DNA damages in cells are depurination and deamination. Ultraviolet radiation also damages the DNA by covalently linking two adjacent pyrimidine bases (C or T). The gene mutations represent changes in the sequence of bases, through either the replacement of one base pair with another (substitution mutation) or the addition and/or deletion of one or more base pairs (insertion or deletion mutation).

Figure 5 The structure of a DNA replication fork. The DNA replication is semiconservative, and a new DNA strand is always synthesized in the 50 !30 direction. Only the leading strand can begin at the 30 end of the template DNA and grow continuously as the replication fork moves along the template DNA. The other strand must grow discontinuously by synthesizing a series of short DNA molecules, called Okazaki fragments, in the opposite direction. These Okazaki fragments are ligated together by the action of an enzyme called DNA ligase.

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The mutations that result in incorrect substitutions of amino acids are termed ‘‘missense mutation.’’ The missense mutation may affect the structure and function of a protein. If the mutations result in the replacement of an amino acid codon with a stop codon, they are called nonsense mutation. Nonsense mutation usually leads to the early termination of protein synthesis. If the addition or deletion of one or multiple base pairs leads to the open reading frame shift, it is called frameshift mutation. The frameshift mutation will lead to the introduction of different amino acids or a stop codon. Both the amino acid sequence and the length will be different from the original protein (Fig. 6). If the mutation occurs in the nonessential DNA or has no effect on the gene function, it is called silent mutation. However, most mutations are deleterious. If these damages are uncorrected when DNA is replicated, most of them will lead to deletion or substitution of one or more base pairs in the newly synthesized DNA strand (1,5,8). The human genome is constantly injured by many endogenous and exogenous agents. It is estimated that a human cell accumulates thousands of injuries every day. Maintenance of genetic stability requires not only the accuracy of DNA replication but also the presence of repair systems, which are essential to DNA integrity. Correction of the mutations in DNA sequences is called DNA repair (1–5). The double helical structure of DNA molecule is critical to the safe storage of genetic information and ideally suited for DNA repair. Because both strands contain the same genetic information, the damage in one strand can be readily removed and correctly replaced by using the complementary strand as template. There are multiple repair systems in the cell; most of them use the undamaged strand as a template to repair the damaged strand. The five major repair systems in most cells are (i) direct repair systems—fill in nicks and

correct some types of nucleotide modification without excision of nucleotides; (ii) base excision repair systems—repair many types of damaged nucleotides by removal of a damaged nucleotide followed by resynthesis of DNA to fill the gap; (iii) nucleotide excision repair systems—similar to base excision repair and are used to correct more extensive types of damages; (iv) mismatch repair systems—correct errors of DNA replication; and (v) recombinant repair systems—mend double-strand breaks. All of the repair systems require a number of specific enzymes to correct or excise the damaged sequences and replace them. Recent studies have shown that the gene mutations and deficiency of DNA repair systems are strongly related to a variety of serious human diseases such as cancers (1–5,9). Although genetic stability is very important for survival, there must be a balance between genetic stability and genetic variation for evolution to proceed in response to environmental change. The chromosomal DNA sequences can be occasionally rearranged. The rearrangements of DNA sequences are carried out by genetic recombinations, which include general recombination, site-specific recombination, and DNA transposition (1,4). The general recombination is also called homologous recombination. The genetic exchanges occur between any two chromosomes (or segments of the same chromosome) that have homologous DNA sequences. These rearrangements usually do not change the order of the genes on the chromosomes. The general recombination is essential for the repair of several types of DNA damages and accurate chromosome segregation during meiosis, and also provides genetic diversity in a population. The site-specific recombination only occurs at the specific DNA sequences. Specialized nucleotide sequences can move between two different positions in a single chromosome or between two different chromosomes, which alters gene order and adds new information into the genome. The DNA transposition is distinct from both the general recombination and the site-specific recombination. This process involves a small segment of DNA (called transposon), which is able to move or hop from one location on a chromosome to another on the same or different chromosome. The movement of a transposon does not require sequence homology. The most studied example of transposition is the generation of complete immunoglobulin genes (1). In general, genetic recombination plays an important role in the evolution of cells and organisms, which includes DNA repair, regulation of gene expression, and maintenance of genetic diversity.

How Cells Read the Genome: From DNA to Protein

Figure 6 Different types of mutations. (A) Missense mutation: a single base change results in the incorporation of a different amino acid. (B) Nonsense mutation: a single base change results in the incoporation of a stop codon. (C) Frameshift mutation: a single base deletion results in the incorporation of different amino acids.

Most of the biological activities of the cell are carried out by proteins. The structure and the biological function of a protein are determined by the order and number of amino acids of the polypeptide, while the amino acid sequence of the polypeptide is determined by the DNA sequence of the corresponding gene. Most of the genes in eukaryotic cells are located in the nucleus, while protein synthesis occurs in the ribosomes, which are located in the cytoplasm. Therefore, the DNA itself does not directly guide the protein synthesis. To transfer the genetic information from nucleus to ribosomes, the nucleotide sequence of the gene is first copied to an intermediate molecule, RNA, which is also a linear polymer of nucleotides. The primary structures of RNA and DNA molecules are very similar and thus make it possible such that DNA can transfer its genetic information to

Chapter 12: Application of Cellular and Molecular Biology in Modern Surgical Practice

RNA. The major differences between DNA and RNA are that the sugar molecule in the backbone of RNA molecules is ribose instead of deoxyribose, and uracil (U) is used to pair with adenine (A) instead of thymine (T). RNA is the only macromolecule known to store and transmit genetic information from the nucleus to the cytoplasm. The RNA is synthesized from DNA with a base sequence complementary to one of the DNA strands by a process called transcription. There are three major kinds of RNA transcripts including rRNA, mRNA, and tRNA. rRNAs are the most abundant in the cell, and more than 80% of total cellular RNA is found in ribosomes. rRNAs function as a framework to which ribosomal proteins are bound. mRNA only constitutes 4% of the total cellular RNA and is used as a template to direct the synthesis of the protein through a process called translation. Most of the mRNA molecules have a short half-life and are immediately destroyed after directing the synthesis of a protein (5). As shown in Figure 7, a mature eukaryotic mRNA molecule contains a 50 -end leader sequence capped with a 7-methyl-guanosine during transcription, a coding sequence and a 30 -end poly (A) tail added after transcription. The 50 -cap structure is critical for initiation of protein synthesis and protects the pre-mRNA from being degraded by enzymes, while the 30 -poly (A) tail is important for the stability of mature mRNA. tRNAs function as an interpreter and read the information in the mRNA and transfer the appropriate amino acid to the growing polypeptide during the protein synthesis. All tRNAs have the same cloverleaf structure with an amino acid attachment site. There is at least one tRNA molecule for each amino acid, although many amino acids have more than one tRNA molecule (10).

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It has been well established that every three nucleotide residues of mRNA encode one amino acid. The groups of nucleotides that code for an amino acid are called codons. Each codon can specify only one amino acid. There are four different nucleotides, which constitute 64 different types of codons. Because there are only 20 different types of amino acids, many amino acids must be specified by more than one codon. The rules by which the nucleotide sequence of the mRNA is translated to amino acid sequence of a protein are called the genetic code, which was completely deciphered in 1966 (5). Among the 64 codons, 61 codons are used to code for specific amino acids. The other three codons do not specify the incorporation of any amino acid but code for the termination of polypeptide synthesis, and are named stop codons. Another special codon is AUG. In addition to coding for methionine, AUG also functions as a start codon to signal the beginning of the polypeptide synthesis in all cells (Table 1). The sequence of nucleotides that runs from a start codon to a termination codon is referred as a reading frame. Most RNAs can only be read in one frame (4). The synthesis of protein is the most complex biosynthetic process, which requires the mRNA as template and hundreds of different macromolecules to cooperate together. To form a functional protein, the newly synthesized polypeptide chain must fold up into its unique three-dimensional confirmation, modified by other enzymes, and conjugated with any small-molecule cofactors required for its activity. Thus, the flow of genetic information in cells is DNA ! mRNA ! protein (Fig. 8).

Control of Gene Expression

Figure 7 mRNA processing in eukaryotic cells. The transcription of DNA into mRNA begins by the binding of the RNA polymerase to a site upstream of the gene called promoter. Once the polymerase is bond to the promoter, it moves along the DNA, making a single mRNA copy from only one strand of the DNA double helix. During transcription, methyl caps are added at the 50 -end of the pre-mRNA. After transcription, the introns are excised and a poly(A) tail is added at the 30 end to produce a mature mRNA molecule. Abbreviation: mRNA, messenger RNA.

Basically, all the cells in a human body contain exactly the same genetic information. However, the structure and function of different cell types are totally unrelated. Not all genes are expressed in every type of cell. Instead, each cell type only expresses a certain subset of its genes to make the proteins that are necessary for its specific functions. For example, the hemoglobins are only expressed in red blood cells. This does not mean that other types of cells do not have the gene for hemoglobin. The generation of cellular diversity is known as differentiation. The cells have the ability to change the pattern of gene expression by activating or repressing certain genes, and regulating the levels of their proteins based on both their needs during development and various physiological responses. The cell-type specific gene expression is precisely regulated and controlled by numerous factors at different levels (11). There are two major ways through which cells control the differential expression of various genes. The first mechanism is transcriptional control, which regulates the rates in which specific mRNA molecules are transcribed off their DNA templates via various molecular signals. The second mechanism is translational control, which determines the rates in which mRNAs are translated into polypeptides. For most cells, the primary control of gene expression is at the level of transcription. Transcription is initiated by the binding of the RNA polymerase to the promoter, which is located at the upstream of the gene, and followed by the moving of RNA polymerase along the DNA and synthesizing single-strand mRNA. The newly synthesized mRNA molecule is further modified before it is exported from the nucleus to the cytoplasm where it is translated into protein (Fig. 8). The gene expression is controlled by either regulating the ability of the RNA polymerase to bind to

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Table 1 The Genetic Code 2nd base in codon

U

A

G

C

A

G

Phe UUU Phe UUC Leu UUA Leu UUG Leu CUU Leu CUC Leu CUA Leu CUG Ile AUU Ile AUC Ile AUA Met AUG Val GUU Val GUC Val GUA Val GUG

Ser UCU Ser UCC Ser UCA Ser UCG Pro CCU Pro CCC Pro CCA Pro CCG Thr ACU Thr ACC Thr ACA Thr ACG Ala GCU Ala GCC Ala GCA Ala GCG

Tyr UAU Tyr UAC Stop UAA Stop UGG His CAU His CAC Gln CAA Gln CAG Asn AAU Asn AAC Lys AAA Lys AAG Asp GAU Asp GAC Glu GAA Glu GAG

Cys UGU Cys UGC Stop UGA Trp UGG Arg CGU Arg CGC Arg CGA Arg CGG Ser AGU Ser AGC Arg AGA Arg AGG Gly GGU Gly GGC Gly GGA Gly GGG

U C A G U C A G U C A G U C A G

3rd base in codon

1st base in codon

C

U

The RNA is constructed from four types of nucleotides, there are 64 possible triplet codons (4
4
4). Three of these possible codons specify the termination of the polypeptide chain. They are called ‘‘stop codons.’’ The rest of 61 codons specify only 20 different amino acids. Most of the amino acids are represented by more than one codon. In addition to specifying for methionine, AUG also serves as a ‘‘start’’ signal for protein synthesis. Abbreviations: A, adenine; G, guanine; C, cytosine; U, uracil.

the promoter or regulating the ability of the RNA polymerase to transcribe the gene. In eukaryotic cells, regulation of the transcription initiation is the most widespread form of gene control. There are many regulatory proteins (called transcription factors), which are assembled in a particular order and bind to very specific DNA sequences (called regulatory elements) located upstream or downstream of the gene to regulate the process of transcription (Fig. 9). These regulatory elements are cell-type specific or tissue-type specific, and they only activate the genes in certain cells or tissues at a given time and determine which gene is

Figure 8 From DNA to protein. The genetic information in DNA is read out by transcription into mRNA in the nucleus. After processing, the mature mRNA is exported to the cytosol, where it is used to guide the protein synthesis. Abbreviation: mRNA, messenger RNA.

transcribed into RNA molecules. For example, MyoD is a muscle-specific transcription activator that is essential to myogenesis and is only found in muscle tissue. Many transcriptional factors are able to form dimers, either homodimers or heterodimers, and then bind to specific DNA sequences. Under most circumstances, the homodimers and heterodimers bind to distinct DNA sequences. For example, c-Jun/c-Jun homodimers bind to the well-known AP-1 regulatory site and c-Fos/c-Fos homodimers do not recognize this AP-1 site, whereas the c-Jun/c-Fos heterodimers bind to the AP-1 with much higher affinity than the c-Jun/c-Jun homodimers. These regulatory proteins function in various combinations to control gene expression and generate many different cell types during development. It has been clear that eukaryotic genes are interrupted by introns that must be spliced out during RNA processing. The processing of mature RNA molecules determines how many proteins are generated from the same primary RNA transcript, and also are regulated by many different factors in different cells (4). There are many steps for the synthesis of protein from DNA. In general, every step required for gene expression could be controlled. Although gene transcription is the predominant step of regulation for most genes, posttranscriptional regulations are also crucial for many genes under various physiological and pathological conditions. The stability of mRNA determines the rate of degradation, and is regulated by proteins that bind to the 50 - or 30 -untranslated regions of mRNA. The mature mRNA molecules are synthesized in the nucleus and must be transported into the cytoplasm for translation by ribosome complex. The RNA transport determines which mRNA is exported and when it is exported, and this process is also tightly regulated. In addition to the transcriptional and posttranscriptional regulations, control of the translation and the post-translation also regulates the activity of gene expression by determining the frequency of translation, and modulates the protein activity through various modifications.

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Figure 9 The structure of a gene. The entire functional unit of the gene includes a regulatory region and a transcription region. The regulatory region contains promoter, response element, and enhancer, while the transcription region consists of coding DNA sequences (exon) and noncoding DNA sequences (intron).

Genetic Polymorphism Genetic polymorphism is the difference in DNA sequence among individuals, groups, and populations, which include single nucleotide polymorphism (SNP), sequence repeats, insertions, deletions, and recombinations (1–5). Genomic variation is responsible for diversity in the human species. A genetic polymorphism is related to the different phenotypes such as different colors of eyes, skin, and hair. Genetic polymorphisms result from chance processes, or are induced by external agents such as viruses and radiation. The disease-associated or external agents inducing DNA sequence changes are called genetic mutations, which are a kind of genetic polymorphism. An SNP is a single base mutation in DNA, which is the simplest form and most common source of genetic polymorphism in the human genome (approximately 90% of all human DNA polymorphisms). Most of the SNPs (approximately 66%) result from a ‘‘transition’’ substitution between purines or pyrimidines. The rest of the SNPs are from a ‘‘transversion’’ substitution between purine and pyrimidine. The distribution of SNPs is not uniform in the human genome. If the SNP occurs in a coding region of a gene, it may have two different effects on the corresponding proteins. The mutation may or may not cause any change in the amino acid sequence. If the SNP occurs in regulatory regions of the gene, it affects the expression of the gene. The observable properties of the individual are called phenotype, which is developed under the combined influences of the individual’s genotype and the effects of environmental factors. Genotype is the genetic constitution of an individual, with respect to a single trait or a larger set of traits. The particular pattern of sequential SNPs (or alleles) on a single chromosome is called haplotype. Several studies have indicated that SNP haplotypes are more useful than genotypes in association-based studies for the analysis of candidate genes and gene regions. There are also cases in which disease susceptibility is related to the presence or absence of a known haplotype. The haplotype patterns are usually specific to populations; the haplotype mapping will reveal the association of certain diseases with the specific populations. The most important applications of the SNP-related research are gene–disease association studies and drug– target validation. Even though most diseases are influenced by multiple genes and various environmental factors, the SNP mapping identifies the individual genes responsible for a number of diseases such as Huntington’s disease and cystic fibrosis. Some recent studies have demonstrated that DNA sequence differences in the promoter of PRKCB1 contribute to diabetic nephropathy susceptibility in type-I diabetes mellitus. Pharmacogenetics mostly relies on the associations between the specific genetic marker such as SNPs, either alone or arranged in a specific linear order on a certain chromosomal region (haplotypes), and a particular

response to drugs. Numerous associations have been reported between selected genotypes and specific responses to cardiovascular drugs. Studies of the correlation between patients’ genotype and their sensitivity to different drugs have greatly advanced drug design and development. Analysis of an individual haplotype also provides valuable information for genetic predisposition to a particular health condition, determining the risk to certain diseases and confirmation of genetic disease diagnosis (12).

CELLULAR AND MOLECULAR BIOLOGICAL TECHNOLOGY: FROM RECOMBINANT DNA TO TRANSGENIC ANIMALS Cell Isolation and Growth in Culture Most of the tissues in human bodies contain a mixture of cell types. To study the structures and functions of an individual type of cell, it is necessary to obtain a pure population of one type of cells. The initial step is to rupture the extracellular matrix that holds the cells together and obtain a mixture of cell suspension. The most typical way is through digestion of the tissue sample with proteolytic enzymes such as collagenase and trypsin. Several techniques have been developed to isolate a single type of cells from a mixture of cell suspension (1–5). The ‘‘first’’ basic technique is based on the different physical properties such as densities and sizes of different types of cells. For example, white blood cells and red blood cells have very different densities and can easily be separated by centrifugation; and coronary endothelial cells and smooth muscle cells can be isolated by mesh sizing and centrifugation (13). Some cells adhere strongly to a glass or plastic surface and can be separated from those cells having low tendency to adhere. Another approach is based on the specific binding of the surface molecules of a single cell type in a tissue to immobilized antibodies. The bound cells can be recovered by enzyme digestion or gentle shaking. The ‘‘second’’ technique is laser capture microdissection. Selected cells are carefully dissected from thin tissue slices using a laser beam. This method can be used to isolate a single cell from a tissue sample. The third and most advanced technique is using a fluorescence-activated cell sorter (FACS), an instrument based on flow cytometry, to select different cells. The cells are sorted out from thousands of other cells by measuring the light they scatter or the fluorescence they emit as they pass single-file through a laser beam both by the fluorescent tagging of cell surface molecules and by the insertion of fluorescent genetic markers. Single cell sorting as a refinement of flow cytometric or FACS has been used for the selection and isolation of individual cells, for microscopy, for culture, and, more recently, for genetic analysis by single cell polymerase chain reaction (PCR; see discussion below) (14,15).

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Most of the cells isolated from animal tissues are grown in a tissue-culture dish using appropriate culture medium. The requirements for different cells to grow in vitro are distinct. Usually, the cultures prepared directly from tissues are called primary cultures, which can be further subcultured and made to proliferate. Isolation and in vitro culture of single type of cells make it possible to study their specific functions. Most vertebrate cells will stop dividing after a limited number of divisions in culture. It is difficult to construct the stable cell line from normal human cells. Most of the stable human cell lines are generated from tumor cells, which proliferate indefinitely and express at least some of the special characteristics of the original normal cells (1). The most important breakthrough in cell culture is the establishment of human embryonic stem (ES) cell lines. There are four essential processes during the development of an embryo, which are controlled by selective gene expression: cell proliferation, cell specialization, cell interactions, and cell movement. Human ES cells can proliferate indefinitely. Because ES cells retain the ability to control gene expression, they have the ability to develop into any kind of tissue of the body, which can then be potentially used to replace or repair damaged tissues in the human (16). Additionally, two different cells can be fused together to form hybrid cells in culture. The most important application of a hybrid cell line is the production of monoclonal antibodies (7). The procedure was established through the pioneering efforts of Kohler and Milstein in the 1970s (17). The antibody-producing B lymphocytes are fused with a specialized myeloma cell line that no longer produces its own antibody, but continuously reproduces. The fused cells are called hybridomas and have the properties of both parent cells. They propagate rapidly in culture like myeloma cells, and simultaneously produce antibodies specified by the B lymphocyte. They provide a permanent and stable source of monoclonal antibodies that have been widely used for biomedical research, clinical diagnosis, and therapy.

Fractionation of Cells A typical mammalian cell is made of several functional organelles. Cell biology provides the means required for the analysis of the composition and properties of purified cellular elements. Subcellular fractionation is an approach universal across all cell types and tissues. The intracellular organelles and proteins can be purified and analyzed by various biochemical techniques. The initial step in subcellular fractionation is to break the cell membrane, which is done by osmotic shock, sonication, grinding in a high-speed blender, or homogenization. The components of the cell homogenate, which differ greatly in size and density, are simply separated by centrifugation. Most fractionation procedures start with differential centrifugation (also called differential-velocity centrifugation) at increasingly higher speeds. The cellular components are partially separated by their different sedimentation rates. Each pellet fraction of differential centrifugation is further purified by equilibrium density-gradient centrifugation, which separates cellular components according to their density. The partially purified organelle fraction is layered on top of a dense nonionic substance with increasing gradient (sucrose or glycerol) and centrifuged at high speed for several hours. This method can be used to separate lysosomes, mitochondria, and peroxisomes. Some cell fractions still contain more

than one type of organelle even after differential and equilibrium density-gradient centrifugation. These fractions are further purified by immunological methods using specific antibodies for organelle-specific proteins. This method is particularly useful for separating organelles that have a similar size and density (1–5).

DNA Isolation, Cloning, and Sequencing Recombinant DNA techniques have brought about a revolution in our understanding of fundamental biological processes, provided new tools for studying the structures and functions of proteins, and dramatically advanced the methods for diagnosis and treatment of various human genetic diseases, and along with the development of genetically engineered pharmaceutical products. The first specific restriction nuclease, HindII, was discovered by Hamilton Smith in 1970. Since that time, it has been greatly successful for molecular biologists to manipulate large DNA molecules (7). To date, several hundred restriction nucleases have been isolated from various bacterial strains, and more than 150 different specific cleavage sites have been identified. These enzymes recognize the specific sequences of four to eight nucleotides in DNA, and cut the DNA molecule into various fragments, either with the blunt end or with the cohesive end, which are easily rejoined together with other DNA fragments which have blunt ends or the same cohesive ends. These restriction nucleases opened a new direction to develop extremely useful methods of DNA sequencing and recombinant techniques (7,18). DNA cloning refers to isolation and amplification of a specific gene sequence. To isolate the specific gene, the first step is to construct a DNA library, which includes, at least, one fragment of DNA that contains the gene of interest. The most common vectors used to construct the DNA library are plasmids and phages, which replicate rapidly in bacterial cells. There are two types of DNA libraries, which have different usages, namely genomic DNA library and complementary DNA (cDNA) library. Genomic DNA library is constructed by the digestion of the entire genome with the specific restriction nuclease and cloning each fragment into a cosmid vector, which is derived from plasmids and l-phages. A cosmid is able to carry a much larger segment of foreign DNA than that of plasmid and phage vector, and facilitates the genomic cloning. The cDNA library is constructed by reverse transcription of mRNA isolated from the cell or tissue into the cDNA and cloning of the entire collection of cDNA into the vector, plasmid, or phage (7). Both the genomic DNA and the cDNA library are screened to isolate the clones carrying the desired DNA sequence by using specific nucleic acid probes. Many genes of receptors and enzymes are cloned by using this method. It has been shown that the nucleotide sequence is not always available for screening libraries. The alternative method to identify specific cDNA is to look for its gene product in bacteria or assay for the function of the protein after cloning the cDNA into appropriate expression vectors. More recently, the eukaryotic expression cloning is also used to isolate genes by functional assay in mammalian cells. For example, the receptor for erythropoietin (EPO) was cloned by assaying the high-affinity EPO-binding site on the cell surface (19). Once an individual vector containing the cDNA of interest is obtained, the next step is to determine the nucleotide sequence that encodes the protein of interest. Based on the DNA sequence, the amino acid sequence of the protein can be predicted. The modern history of DNA sequencing began in 1977, when Sanger reported his method for

Chapter 12: Application of Cellular and Molecular Biology in Modern Surgical Practice

determining the nucleotide sequence by chain-terminating nucleotide analogs (20). Since then, many improvements have been made. By using fluorescent dye–labeled nucleotides, the DNA sequence is read by a computer (21). DNA sequencing is now completely automated. In contrast to only being able to sequence 1000 bp a day in the bestequipped laboratory in the mid-1980s, the sequence centers of the Human Genome Project sequence 1000 bp a second presently. The success of the Human Genome Project is largely due to the development of high-throughput DNA sequencing methods (6). In the early 1980s, the major problem in studying and analyzing genes was the low copy numbers of the target genes in a complex genome. The invention of the PCR technique revolutionized molecular genetics and enables us to easily produce enormous numbers of copies of the specified DNA sequence being studied, to directly clone the specific gene from genomic DNA or mRNA isolated from cells or tissues without the construction of cDNA libraries, and manipulate the gene sequence. The principle of PCR technique is illustrated in Figure 10. The PCR method is extremely sensitive and able to detect a single DNA molecule in the sample. It has been used to diagnose genetic diseases, to detect very low levels of viral infection such as HIV infection, and to identify the genetic ‘‘fingerprint.’’

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Advances in the field of recombinant DNA have dramatically accelerated the pace of basic biomedical research and biopharmaceutical development (22). Gene manipulation has become one of the important basic approaches to new drug design since the early 1990s. The isolation, cloning, and expression of genes in vitro make it possible to manufacture biological agents with therapeutic value on a large scale. This technology is especially attractive when the sources for the isolation of biopharmaceutical agents are scarce, the isolation and purification are difficult, or the only available source is likely to be contaminated with infectious or immunogenic agents. The first recombinant DNA-produced therapeutic protein on the market was human insulin, which is now approved for treatment of insulin-dependent diabetes. Presently, there are more than 50 FDA-approved biopharmaceutical agents and/or indications for use in United States.

Analyses of Protein Structure and Function Most of the biological functions of living cells are performed by proteins. Understanding how proteins function helps us define how cells work under physiological and pathological conditions. The functions of the specific protein are determined by its structure. Based on the amino acid sequence, the secondary structure is predicted in regard to a-helices

Figure 10 Amplification of DNA using the PCR. The DNA from a selected region of a gene is amplified by using two specific synthetic DNA oligonucleotides (called primers). The primers are complementary to the sequences that flank the target region on each strand. The standard cycle of PCR includes three steps: denature of template DNA, annealing of primers, and extension of new strands. This process is repeated for as many as 30 to 60 cycles to produce a large numbers of identical DNA fragments of interest. Abbreviation: PCR, polymerase chain reaction.

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and b-sheets. However, the three-dimensional structure is difficult to predict. The major technique used to determine the three-dimensional structure of macromolecules such as proteins, at atomic resolution, is X-ray crystallography (1). In order for the object to be seen, its size needs to be at least half the wavelength of the light being used to see it. Using visible light, it is never possible to see atoms even under the most powerful of microscopes, because visible light has a wavelength much longer than the distance between atoms. X-rays are the form of electromagnetic radiation with a wavelength on the order of bond lengths. When X-rays pass through a crystal sample of the protein, the diffraction pattern is created by the atoms of the sample, which is interpreted mathematically into the actual location of atoms in the crystal sample by a computer. Therefore, the threedimensional structure of the protein can be deduced. To perform X-ray crystallography, it is necessary to grow crystals with appropriate size. If the protein has difficultly forming crystals, such as membrane proteins, an alternative method is Nuclear Magnetic Resonance (NMR) spectroscopy (23). NMR is the phenomenon that occurs when the nuclei of certain atoms are immersed in a static magnetic field and exposed to a second oscillating magnetic field. Some nuclei experience this phenomenon, and others do not, depending upon whether they possess a property called magnetic moment or spin. NMR spectroscopy employs the use of the NMR phenomenon to study physical, chemical, and biological properties of matter. It is routinely used by chemists to study chemical structure using simple one-dimensional techniques. Two-dimensional techniques are used to determine the structure of more complicated molecules. These techniques are replacing X-ray crystallography for the determination of protein structure. NMR spectroscopy only requires a small volume of concentrated protein. Because this study is performed in solution, it provides the dynamic information of the protein. During the last decade, the databases of protein and nucleic acid sequences have dramatically proliferated. Based on sequence similarity, the function of the gene is predicted by the available information of other characterized genes. Proteins having similar amino acid sequences or structures usually have similar biological functions. To identify the function of the new protein, the first step is to search the databases such as BLAST and FASTA for similar sequences, which usually provide valuable information for predicting the structure and function of the protein. Recombinant DNA techniques are able to replace or add the DNA fragment in a gene. Two different genes can be ligated together to express fusion proteins, which is a useful method in studying protein function and tracking proteins in living cells. The common strategy is to tag the protein with an epitope such as six-histidine, HA, FLAG, and Myc or with the well-characterized marker proteins including glutathione S-transferase, which are recognized by commercially available antibodies. These tagged proteins are easily purified by immunoprecipitation or affinity chromatography, and monitored by using the fluorescence- or dye-labeled secondary antibody. For tracking the proteins in living cells, the most useful tool is the green fluorescent protein (GFP). Once the target protein is fused with GFP, the movement of the protein is simply monitored by fluorescence microscopy. There are several GFP derivatives of different colors, which are used together with GFP to monitor the protein–protein interactions. Most proteins must form a complex with other proteins or molecules to perform their biological functions.

Identification of their partners facilitates the characterization of their biological roles. There are several methods available to study the protein–protein interactions. Protein affinity chromatography is used to isolate the interacting proteins. However, the simplest method for identifying the interacting proteins is the coimmunoprecipitation in which a specific antibody is used to bind the target protein; the immunocomplex is precipitated by using an affinity reagent attached to a solid matrix such as protein A/G-conjugated agarose. The proteins that physically interact with the target protein are also precipitated out of the solution, and their identity is further determined by western blot analysis or other suitable method. Recently, two powerful techniques, the two-hybrid system and phage display system, have been developed to simultaneously isolate the interacting proteins and the genes that encode them (24,25). To understand how the protein interacts with its partners, it is necessary to study the dynamics of protein association. The interactions between proteins can be monitored in real time using surface plasmon resonance, which has been used to characterize ligand–receptor coupling, DNA–protein binding, and antibody–antigen binding (26).

Studying Gene Expression and Function Structure and function of the protein is determined by its gene. When and/or where the gene is expressed reflects its biological functions in the cell or organism. Expression of the specific gene is tightly regulated and controlled by regulatory sequences in the noncoding region of the gene. The easiest way to examine how the gene expression is regulated is to replace the coding sequence of the specific gene with a reporter gene such as b-galactosidase or GFP. Once the recombinant DNA is transfected into cells, expression of the reporter gene is easy to detect by measuring enzyme activity or fluorescence. Regulation of the reporter gene expression is controlled by the same regulatory sequences that regulate original gene expression (1–3). Expression of the gene is the process by which the DNA sequence of the gene is transcribed and the mRNA is further translated into the protein. Expression pattern of the specific gene in different tissues and cells can be determined by hybridization techniques such as northern blotting analysis and in situ hybridization. Invention of DNA microarrays has revolutionized the way to monitor the gene expression. In contrast to monitoring a single gene at a time, DNA microarrays are able to simultaneously monitor the expression of thousands of genes and provide a powerful tool to potentially identify and quantify levels of gene expression for all genes at the same time (27). As mentioned earlier, searching the databases for the homologous genes is used to predict the gene function based on the information from other identified genes. However, we still need specific tools to confirm what exactly the gene does in cells. To understand how the gene is expressed and what biological function it has in the cell or organism, the most effective way is to interrupt expression of the gene and to monitor the changes in cellular functions. This can be done by replacing the normal gene with a mutant gene or inactivating the target gene. During last decade, the ‘‘antisense’’ approach has been widely used to block the synthesis of the protein by artificially providing complementary single-strand antisense nucleic acid corresponding to the target gene. However, the antisense molecules are not stable and difficult to deliver effectively to target tissues (28,29). To avoid the degradation of the antisense RNA, a stable

Chapter 12: Application of Cellular and Molecular Biology in Modern Surgical Practice

synthetic RNA analogue, morpholino-RNA, is used (30). More recently, the RNA interference (RNAi) technique has been rapidly advanced. RNAi is the process of sequencespecific and post-transcriptional gene silencing in the cells initiated by double-stranded RNA that is homologous in the sequence to the silenced gene. The RNAi was originally observed in plants, fungi, and C. elegans (31). Elbashir et al. have demonstrated that chemically synthesized 21-nt small interfering RNA (siRNA) duplexes specifically suppress the expression of endogenous and heterologous genes in different mammalian cell lines, including human 293 and Hela cells (32–34). The discoveries of siRNA-mediated RNAi in different eukaryotic species and plants suggest a highly conserved mechanism in nature. The specific pathways and mechanisms of RNAi in mammalian cells are currently under intense investigation (35). The basic mechanism of siRNA-mediated RNAi is illustrated in Figure 11. The siRNA approach provides a new effective tool for studying gene function in mammalian cells, and it has a great potential to develop the gene-specific therapeutics.

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Transgenic Animals The development and application of transgenic technologies have made a serious impact on our understanding of complex biological mechanisms during the last decade. Application of transgenic animals in various in vivo studies has increased dramatically, and has greatly advanced our knowledge regarding biological functions of various novel proteins under physiological and pathological conditions (36). A transgenic animal is one in which its genome has been permanently modified by gene insertion, gene deletion, or gene replacement. There are two methods that are widely used to produce transgenic mice. The first method is the employment of transforming ES cells with the desired DNA in tissue culture. ES cells are harvested from the inner cell mass of mouse blastocysts. They are grown in culture and retain their full potential to produce all the cells of mature animals when they are reintroduced into a mouse blastocyst, and then the blastocyst is introduced into the uterus of a pseudopregnant female. The target gene is modified in ES cells by using homologous recombination. The second method involves injecting the desired gene into the pronucleus of a fertilized mouse egg. The transgenic animals that carry foreign genes provide the important information for regulation and function of the specific genes being studied. If the replacement gene is nonfunctional or the functional gene is deleted, the transgenic animals with a deleted or inactivated gene are called ‘‘knockout’’ animals. By using knockout mice, the biological functions of many mammalian genes have been dissected. Under various biological circumstances, knockout mice are not affected by their deficiency, because the mouse genome has sufficient redundancy to compensate for a single missing pair of alleles. Most genes are also pleiotropic; they are expressed in different tissues in different ways and at different times during development (1,11,36). The past decade has witnessed a spectacular explosion in both the development and the use of transgenic technologies. Transgenic animals are used not only to aid our fundamental understanding of biological mechanisms, but also to facilitate the development of a range of various disease models. Information obtained from transgenic approaches is now truly beginning to impact our knowledge regarding human diseases. Some of the most exciting model systems relevant to neurodegenerative disease and cancer are allowing the radical development of new therapies in vivo. Transgenic sheep and chickens are produced that express foreign proteins in their milk or in the ‘‘white’’ of eggs. These animals provide a valuable source for producing therapeutic proteins (1–5).

THE MOLECULAR ORGANIZATION OF THE CELLS Cell Signaling

Figure 11 The mechanism of siRNA-mediated RNAi in mammalian cells. The synthetic dsRNA is transfected into the cells. These siRNAs are assembled into endoribonuclease-containing complexes known as RISCs. After unwinding, the antisense strands of the siRNAs base pair with a short region of the target mRNA and result in degradation of the target mRNA. Abbreviations: dsRNA, double stranded RNA; siRNA, small interfering RNA; RNAi, RNA interference; RISC, RNA-induced silencing complex.

There are more than 200 different types of cells in the human body. Each cell is constantly exposed to hundreds of different signals from its environment. The intercellular communication network coordinates the growth, differentiation, and metabolism of various cells. Cells communicate with each other by either direct interactions or various extracellular signaling molecules. Normal functions of different cellular signaling pathways are essential to the health of the human body. The process by which various signals alter the physiology of a cell is called transduction. Many diseases such as cancer result from dysfunctions or imbalance of cell-signaling transduction (2).

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Cell-signaling occurs via the initial interaction of two or more molecules. There are a variety of signaling molecules such as amino acids, peptides, proteins, nucleotides, and lipids, which are involved in the cell-to-cell communication. These molecules are synthesized and released from the signaling cells and then act on the specific target cells. Binding of the signaling molecule (ligand) to the specific protein (receptor) on the target cells triggers a cascade of intracellular signals that affect behavior of the target cells. Based on the distance between signaling molecules and their targets, intracellular signaling molecules are classified into four types: endocrine, paracrine, autocrine, and contactdependent signaling (Fig. 12). In endocrine signaling, the signaling molecules secreted from endocrine cells, known as hormones, enter the systemic circulation and then bind to the specific receptors on the target cells at remote sites. In paracrine signaling, the transmitters released from paracrine cells bind to receptors on adjacent cells to exert their biologic functions such as neurotransmitters. The action of paracrine transmitters is rapid and short compared to endocrine signaling. In autocrine signaling, the signaling molecules are released and act on the other cells of the same type as well as themselves. Many cells secrete growth factors that stimulate their own growth and proliferation. This is the major signaling mechanism of cancer cells. Another form of signaling is the contact-dependent signaling. Many signaling molecules remain bound to the cell surface of the signaling cells and interact directly with the receptors on the adjacent cells. Some signaling molecules are produced by different types of cells and act in more than one type of cell-to-cell signaling. For example, cholecystokinin (CCK) is secreted into the bloodstream by endocrine cells of the upper small intestine. However, CCK is also present in the nerves of the gastrointestinal tract and brain. Epidermal growth factor (EGF) is a membrane-bound protein hormone, which directly binds to the receptors on the adjacent cells. The EGF molecule is also released from the membrane by protease cleavage. The secreted EGF acts on distant cells as an endocrine-signaling molecule (4,37).

The cellular response to a particular signaling molecule depends on its binding to the specific receptors, which are the cell surface receptors, nucleus receptors, or cytosolic receptors. Different cell types have different receptors for the same ligand, and even the same receptor triggers different biological responses to the same ligand in different types of cells. On the other hand, different receptors induce the same cellular response in certain cell types. For example, activation of glucagon or epinephrine receptors in liver cells induces degradation of glucagon and increases the level of blood glucose. Some extracellular hydrophobic hormones such as steroids, thyroxine, and retinoic acid interact with intracellular receptors by diffusing across the plasma membrane, while some small signaling molecules such as nitric oxide and carbon monoxide directly regulate the activities of the intracellular enzymes. However, most of the extracellular signaling molecules are hydrophilic and bind to the cell surface receptors of the target cells to modulate cellular responses. The three major classes of cell surface receptors are G protein–coupled receptors (GPCRs), enzyme-linked receptors, and ion-channel receptors (2,4,11). GPCRs represent a major class of signal transduction proteins that transduce extracellular signals to the cell interior through the activation of heterotrimeric guanine nucleotide–binding proteins (G proteins). G proteins contain three subunits—a, b, and g. When G protein is activated, the Ga subunit binds guanosine triphosphate (GTP) and dissociates from bg subunits. The Ga subunit has intrinsic GTPase activity, which hydrolyzes GTP to guanosine diphosphate (GDP). Once the GTP is hydrolyzed to GDP, the GDP-bound Ga subunit will reassociate with bg subunits. It has been demonstrated that the GTPase activity of the a subunit is regulated by regulator of G protein signaling proteins, which function as a-subunit–specific GTPase-activating proteins and play an important role in shutting-off G protein–mediated responses. Receptor occupation promotes interaction between the receptor and the G protein on the interior surface of the membrane. This induces the exchange of GDP for GTP on the G protein a subunit and dissociation of

Figure 12 General pathways of cell communication. (A) Endocrine signaling. It depends on endocrine cells, which secrete hormones into the bloodstream that are then distributed widely throughout the body. (B) Paracrine signaling. It depends on signals that are released into the extracellular space and act locally on neighboring cells. (C) Autocrine signaling. A group of identical cells produces a higher concentration of a secreted signal than does a signal cell. When this signal binds back to a receptor on the same cell type, it encourages the cells to respond coordinately as a group. (D) Contact-dependent signaling. This signaling pathway requires cells to be in direct membrane–membrane contact. Many of the same types of signaling molecules are used in all of four signaling pathways and critical differences lie in the speed and selectivity with which the signals are delivered to their targets.

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Figure 13 The structure of seven transmembrane G protein– coupled receptors. Most of the GPCRs belong to the seven transmembrane superfamily of transmenbrane receptors. A typical GPCR possesses seven transmembrane helices, which contain roughly 20 to 25 amino acids. Upon binding of the specific ligands on one side of the membrane, these receptors activate G proteins on the other side. Activated GPCRs further initiate a cascade of events regulating cell proliferation, cell survival, and cell migration.

the a subunit from the bg heterodimer. Depending on its isoform, the GTP-a subunit complex mediates intracellular signaling either indirectly by acting on effector molecules such as adenylyl cyclase and phospholipase C (PLC) or directly by regulating the activity of ion channels or kinases (38). More than 2000 GPCRs have been reported since bovine opsin was cloned in 1983 and the b-adrenergic receptor in 1986. They are classified into over 100 subfamilies according to the sequence homology, ligand structures, and receptor functions. The ligands for the GPCRs include ions, organic odorants, amines, peptides, proteins, lipids, nucleotides, and photons. The GPCRs can be single- or multitransmembrane proteins. Most of the GPCRs are seven transmembrane proteins, which have a similar structure (Fig. 13). The GPCRs contain an extracellular N-terminal segment, seven transmembrane segments (TMs), three extracellular loops, three intracellular loops, and a C-terminal segment. Each of the seven TMs is generally composed of 20–35 amino acids. However, the lengths of N-terminal segments, loops, and C-terminal segments at different receptors are substantially variable. Although the majority of GPCRs mediate signal transduction via G proteins, some of these receptors are also capable of sending signals via a number of other signal molecules, including Jak2 kinase, PLCg, or protein kinase C. Differences in agonists and effectors provide an early hint of the remarkable diversity of situations in which GPCRs are employed to select, amplify, and transmit signals from the external environment to elicit cellular responses and modify functions (39–42). These receptors play an important physiological role, and their dysfunctions are involved in the pathogenesis of various diseases. GPCRs are also the most common targets for drug development at present. It has been estimated that more than half of all modern drugs target the GPCR-signaling pathway, and the effects of more than 30% of the top 100 marketed drugs are mediated directly or indirectly through an activation or blockade of GPCR-mediated receptors (43). Enzyme-linked receptors are the second major type of cell-surface receptors, which are activated by extracellular signaling proteins and promote cell proliferation, differentiation, and survival. Similar to GPCRs, enzyme-linked receptors also are transmembrane proteins, but only span the plasma membrane once. The ligand-binding domain is located on the outer surface of the plasma membrane. The intracellular domain has the intrinsic enzyme activity or is coupled to intracellular enzymes. Based on the type of enzymatic activity during signal transduction, they are classified into five subtypes: (i) tyrosine kinase receptors such as insulin-like growth factor, platelet-derived growth factor,

EGF, and fibroblast growth factor receptors, which phosphorylate the specific tyrosine residues on the intracellular signaling proteins; (ii) tyrosine kinase–associated receptors, which are associated with tyrosine kinase proteins; (iii) receptor-like tyrosine phosphatases, which remove phosphate groups from tyrosine of specific signaling proteins; (iv) receptor serine/threonine kinases such as transforming growth factor beta and bone morphogenetic proteins, which phosphorylate the specific serine or threonine to transduce the intracellular signals; and (v) receptor guanylate cyclases such as natriuretic peptide receptors, which catalyze the production of cyclic GMP in the cytosol. The activation of enzyme-linked receptors is essential for a variety of biological functions (2). Ion-channel receptors are the simplest signal transducers and form holes or pores in the plasma membrane and open or close in response to the ligand binding or changes in transmembrane potential. The ion channels are selective for the ions that pass through and generally allow passage of either anions or cations, but not both. The way through which the ion passes through channels is passive in general. There are three types of ion-channels: (i) ligand-gated ion channels, which transfer the chemical signal to electrical signal, such as nicotinic acetylcholine receptor; (ii) voltagegated ion channels such as voltage-gated Naþ channels, voltage-gated Kþ channels, and voltage-gated Ca2þ channels, which are responsible for the generation of action potentials in electrically excitable cells; and (iii) mechanically gated channels. The ion channels transduce a signal by either changing the cytosolic concentration of an ion such as Ca2þ or altering transmembrane electrical potential (2).

Cell Proliferation and the Cell Cycle The ability of cells to grow and divide underlies the propagation of life. The cell cycle is the ‘‘program’’ for cell growth and cell division (proliferation). There are four phases of the cell cycle: G1 (and G0), S, G2, and M (Fig. 14). The G1 phase is characterized by gene expression and protein synthesis, which enables the cell to produce all the necessary proteins for DNA synthesis, and primes the cell to enter the S phase. This is the only phase of the cell cycle that is regulated primarily by extracellular stimuli. The length of G1 phase depends on the extracellular conditions and signals. During the S phase, the cell replicates its DNA once, which allows the cell to divide into two daughter cells, each with a complete copy of DNA. Before the cells do this, they need to enter the third phase of the cell cycle: the G2 phase. The G2 phase provides additional time for cells to synthesize

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Figure 14 The phases of the cell cycle in mammalian cells. The cell grows continuously and the cell cycle consists of four phases: G1 (first gap) phase, S (DNA synthesis) phase, G2 (second gap) phase, and M (mitosis) phase. Progression through the cell cycle is highly regulated by a conserved family of serine/threonine protein kinases that are composed of a regulatory subunit (the cyclins) and a catalytic subunit (the cyclindependent kinases). During the cell cycle progression, both G1 to S phase transition and G2 to M phase transition are critical checkpoints.

proteins and primes them to be able to divide. During the G2 phase, the cell monitors the faithful completion of S phase. Once this is complete, the cell finally enters the fourth and final phase of the cell cycle: the M phase. At the M phase, the cell divides (called cytokinesis) into two daughter cells. The newly divided cells can either start the cycle again by entering G1 phase or become quiescent by entering G0 (2). The cell cycle is primarily regulated at two checkpoints, the G1/S and the G2/M transitions, which are tightly controlled by heterodimeric proteins composed of the catalytic subunit and the regulatory subunit that determine substrate specificity (44). The protein kinase activity of the catalytic subunits depends on the formation of heterodimeric complex with various cyclins, which are called cyclin-dependent kinases (CDKs). The cyclin–CDK complexes phosphorylate many other proteins, which regulate DNA replication and mitosis. Different cyclin–CDK complexes choreograph the passage of cells through the different phases. There are four classes of cyclins that bind to CDKs at different stages of the cell cycle: G1/S-cyclins, S-cyclins, M-cyclins, and G-cyclins. The activities of CDKs are regulated by extracellular stimuli through cyclin binding, phosphorylation, dephosphorylation, and the binding to CDK inhibitors (45). The rate of cell proliferation is mainly determined by the relative proportion of cycling cells versus quiescent cells. Uncontrolled or inappropriate cell growth and proliferation contribute to the development of cancers (46,47).

Cell Migration Cell migration is an important process that is involved in a variety of normal and pathological events, including embryo development, wound healing, and the abnormal and life-threatening movement of cancer cells. The ability of cells to adapt a variety of shapes and to carry out coordinated and directed movements is a complex process that is regulated through multiple signaling pathways. Cell migration is the result of a series of coordinated cellular events, including lamellipodial extension and retraction, cortical transport of myosin and actin, contraction of transverse fibers, and tail retraction (26). Understanding the signals that start, direct, and stop cell migration is one of the central questions of modern biology, and the current knowledge regarding the regulation and control of cell

motility is reviewed and presented in detail in several textbooks (1–5).

Apoptosis All cells have a limited lifespan. There are two forms of cell death. Cell death caused by external factors such as mechanical damage and injurious agents is called necrosis, which is characterized by swelling, leaking of cell contents, and inflammation of surrounding tissues. Cells are also induced to commit suicide, which is called programmed cell death or apoptosis. Apoptosis is a genetically regulated form of programmed cell death defined by distinct morphological and biochemical features. These features include membrane blebbing, chromatin condensation, cell shrinkage, DNA fragmentation, release of cytochrome c, and apoptotic body formation (48). Apoptosis is an important physiologic process and regulates tissue homeostasis by balance in cell number between newly divided and surviving cells. Defects of apoptosis are implicated in many diseases such as hyperplasia and cancers (49). Two major classes of proteins involved in regulation of apoptosis are the Bcl-2 family and the caspase family (50,51). The Bcl-2 proteins were initially isolated from human follicular lymphoma cells and comprising both proapoptotic and antiapoptotic members, which are the major intracellular regulators of apoptosis. There are more than a dozen kinds of proteins that have been identified as the members of Bcl-2 family such as Bcl-2, BclXL, Bax, Bak, and Bad. All members possess at least one of four conserved motifs known as Bcl-2 homology domains (BH1 to BH4), which control the ability of these proteins to dimerize and act as a checkpoint upstream of caspases and mitochondrial dysfunction (48,52). Caspases as essential mediators of apoptosis are highly specific proteases that cleave proteins exclusively at aspartic acid residues and regulate proteolysis during the apoptotic cell death. The substrate specificity of these proteins is determined by the sequence of three amino acids before the aspartate residue (53). There are three different pathways by which cells commit suicide through apoptosis. The first is the intrinsic or mitochondrial pathway, which is triggered by internal signals. In healthy cells, the internal damage results in the release of cytochrome c and Apaf-1 protein, which are normally bound to Bcl-2 on the outer membranes of mitochondria. The released cytochrome c and Apaf-1 bind to molecules of caspase-9, which sequentially activate other caspases and results in the degradation of chromosomal DNA, digestion of structural proteins in the cytoplasm, and phagocytosis of the cell. The second pathway is known as the death receptor pathway that is triggered by external signals. This pathway is particularly important in the immune system. The death receptors such as Fas/CD95 and tumor necrosis factor receptor are integral membrane proteins with their receptor domains exposed on the surface of the cell and a conserved protein–protein interaction module (called death domain) in the cytoplasm. Binding of the complementary death activators transmits the signal to the cytoplasm that leads to activation of caspase-8, which initiates a cascade of other caspase activation and results in the phagocytosis of the cell. The third pathway is mediated by apoptosis-inducing factor (AIF), which is the protein normally located in the intermembrane space of mitochondria. This pathway is usually triggered by dangerous reactive oxygen species such as hydrogen peroxide, hypochlorite ion, and hydroxyl radical and superoxide anion. The released

Chapter 12: Application of Cellular and Molecular Biology in Modern Surgical Practice

AIF binds to the DNA in the nucleus and results in the destruction of DNA, leading to cell death (2). In summary, apoptosis is a central regulator of tissue homeostasis in multicellular organisms. Cells that are no longer needed or are a threat to the body are destroyed by apoptosis. Apoptosis is mediated by proteolytic enzymes called caspases that cause cell death by cleaving specific proteins in the cytoplasm and nucleus. The activation of caspases is initiated by either extracellular or intracellular death signals, and is regulated by members of the Bcl-2 and IAP protein families. Disruption of apoptosis is responsible for a variety of diseases such as autoimmune diseases and cancers.

Gut Mucosal Wounds and Healing Gastrointestinal mucosal wounds and injury occur in circumstances commonly encountered in daily life, from mild physical trauma during digestion to localized damage from the ingestion of alcohol, aspirin, and/or nonsteroidal anti-inflammatory compounds, or from Helicobacter pylori infection. Acute mucosal injury also occurs in critical illnesses including various surgical conditions such as trauma, thermal injury, shock, and sepsis. After injury, the mucosal tissue exhibits a spectrum of responses. In an acute response to injury, damaged cells are sloughed, and remaining viable cells from areas adjacent to or just beneath the injured surface migrate to cover the denuded area. This early restitution is independent of cell proliferation and appears to be an initial host response to prevent noxious agents from causing deeper tissue damage (54). In contrast to this rapid repair process, deeper damage and chronic ulcers manifest long-term complex responses that require de novo mRNA and protein synthesis and cell replication. Altered gene regulation in response to wounding or ulceration results in an increase in cell proliferation to replace lost cells (52). Over the last decade, considerable progress has been made in understanding the roles of early primary response genes in events responsible for the process of cell renewal during ulcer and wound healing in the gastrointestinal mucosa and other tissues. Most of these early primary response genes belong to the family of proto-oncogenes and are responsible for control of the cell cycle. Because the expression of these early primary response genes is rapid and transient following injury or when normal quiescent cells are exposed to mitogenic substances, they have been thought to act as mediators linking short-term signals, immediately after cell surface stimulation, to proliferation by regulating the activation of specific genes. These early primary response genes such as proto-oncogenes code for sequence-specific DNA binding nuclear proteins with a potential to influence directly the expression of specific genes at the transcriptional level. Therefore, activation of early primary response gene expression plays important roles in healing following the wounding of the gastrointestinal mucosa and other tissues. Normal cells respond to wounding by altering rapidly the expression of various genes whose products are central to cell migration and proliferation. In the early response following injury, the increased synthesis of transcription factors is critical to the modulation of expression of cell-type specific or developmentally regulated genes (55,56). This provides a pathway for controlling the expression of a gene whose product is infrequently required under physiological conditions. The process of transcription is a fundamental element in gene expression and is an attractive control point for the regulation of gene activation. The region immediately upstream of the transcribed sequence contains two

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types of elements: (i) sequences involved in the process of transcription itself and (ii) sequences found in genes transcribed in a particular tissue or in response to a specific signal. These tissue- and stimulus-specific sequences are implicated in selective cellular responses to wounding and to growth factors or cytokines. Transcription factors are regulated to become active only in the appropriate cell type or in response to the appropriate stimulus. One of the mechanisms responsible for the control of transcription factor activity is the regulation of the synthesis and degradation of the factor itself. The other is the regulation of the activity of the pre-existing factor. Although low basal expression of the nuclear protooncogenes c-fos, c-jun, and c-myc is observed in most cells, their expression is rapidly and transiently induced following wounding in vivo as well as in vitro (55,56). The products of these proto-oncogenes are nuclear transcription factors that bind to specific DNA sequences in the vicinity of target genes, leading to the activation of ‘‘second responsive genes’’ in generative tissues following injury. Recently, CDK4 and p21 were identified as target genes of c-myc. This is significant because c-myc activation stimulates expression of the CDK4 gene, but represses the p21 promoter activity, providing a direct link between c-myc and cell-cycle regulation. In addition to AP-1 and c-myc, there are additional cis-acting elements, including the serum responsive element of SP1/SP2, the NF-kB binding site, and the AP-2 activation site, which also may be involved in the process of wound healing. These elements are recognized by transcription factors distinct from AP-1 and c-myc, but their activity is modulated by exposure to phorbol esters or other protein kinase C activators.

NOVEL TREATMENT STRATEGIES IN MODERN SURGICAL CARE Gene Therapy Gene therapy is an exciting and powerful tool that offers new opportunities for potential treatment and prevention of a wide array of diseases (57–59). Instead of giving a patient a traditional chemical drug to treat or control the symptoms of a genetic disorder, gene therapy is directed at actually treating the basic problem by altering the genetic makeup of the patient’s cells through the use of targeted and relatively nontoxic therapy, which can identify, disable, and destroy sick cells. For example, the gene therapy for cancers involves the manipulation of intracellular DNA to control or kill malignant cells. Cancer gene therapy has the potential to provide highly selective and curative cancer treatment without systemic toxicity, depending on our understanding of tumor biology, methods for gene delivery to specific cell types, and strategies to regulate the levels and duration of gene expression. In order for the transgene to work in patients, the gene of interest must be inserted into a vector adjacent to a promoter that induces transcription. Then the construct is packaged and delivered to a specific target cell, transcribed, and expressed in a concentration high enough to have an effect. Typically, the transfer of transgene constructs into living cells is accomplished by using viral or nonviral vectors. Viral vectors are used in the majority of gene therapy studies because of their higher efficiency of gene transfer compared to nonviral techniques. Viral vectors for gene therapy may be RNA- or DNA- virus based. To date, the RNA viruses include the retroviruses such as murine leukemia virus and mouse

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mammary tumor virus, the lentiviruses derived from human immunodeficiency virus, and the spumaviruses. The DNA viruses include adenovirus, adeno-associated viruses, vaccinia virus, and herpes simplex virus. Because viral vectors are designed to be replication deficient, they cannot spread outside the transfected target cells. However, some viral vectors are replication competent or replication attenuated, permitting viral replication in permissive cells.The selection of the viral vectors for the gene therapy of particular tissues or diseases is based on (i) their maximum permissible transgene size, (ii) transfection efficiency and maximum viral titer attainable, (iii) tendency to provoke inflammatory and immune response, (iv) persistence of gene expression and ability to transduce nondividing cells, and (v) target cell specificity and impact on the host genome. Several nonviral gene transfer systems are currently available to introduce a new genetic material into mammalian cells (60). These methods include the direct tissue injection of DNA, the transfection across the cell membrane using liposomes, peptide delivery systems, and polymer vectors. Although various nonviral gene transfer approaches are nontoxic and nonimmunogenic, their efficiency of gene transfer is lower than that achieved by using viral vectors. ‘‘Naked’’ DNA vectors (plasmids) are unsuitable for systemic administration because they are rapidly degraded by serum nucleases. However, direct injection of DNA vectors into specific tissues such as muscle and the gut mucosa can produce transient low levels of gene expression. Cationic liposomes are positively charged lipid bilayers that form vesicles with negatively charged DNA vectors on the external surface and are also able to package large transgenes, but the efficiency gene transfer is low. DNA–protein complexes are developed by using naturally occurring or synthetic peptides as gene delivery systems. The DNA-binding peptides coupled to cell-specific ligands allow receptor-mediated targeting of the peptide/DNA complexes to specific cells types. Hybrid vectors that combined both viral and synthetic approaches have also been devised and are currently under extensive investigation. It has been shown that DNA complexed to polylysine or DEAE-dextran–conjugated adenovirus improves gene transfer efficiency dramatically. The current in vivo trials for gene therapy face several challenging questions, although a number of in vitro experiments have shown great promise. These difficult issues include patient safety, vector design, improvement of in vivo gene delivery, transfer efficiency, and gene regulation after cellular transduction.

Cell Therapy Cell therapy provides an alternative approach that overcomes some of the shortcomings of gene therapy. Cell therapy is a new concept to repair diseased organs by using genetically modified cell grafts that are initially transfected ex vivo with excellent long-term efficiency, and then transplanted to the targeted organs (57,61–63). Cell therapy is subdivided into two principally different approaches: (i) implantation of isolated cells and (ii) implantation of in vitro engineered tissue constructs. Generally, cell therapy is applied for the treatment of a variety of diseases at three different levels: (i) to replace absent or malfunctioning cells, (ii) to modify the biological functions of targeted organs by using cell grafts genetically engineered to express specific proteins, and (iii) to modify the targeted organ environment by local secretion of specific recombinant proteins.

During the past two decades, several attempts have been made in order to find a new strategy to treat diseased organs such as injured spinal cords, heart failure, cancers, and diabetes in experimental animals, which provide a novel therapeutic approach for some critical illnesses in humans. Cell therapy is one of these new therapeutic strategies to restore the normal functions of injured organs by transplantation of the appropriate cell populations. To do so, cell therapy requires the following steps: (i) establish the proper cell sources for transplantation, (ii) in vitro assessment of the phenotypic structural and functional properties of the cell grafts, (iii) establish transplantation strategies to deliver the cells to the desired locations, and (iv) achieve the desired in vivo effect by assuring the survival of the cell grafts, their integration and interactions with host tissue, and their proper function. A critical limitation for the development of cell replacement strategies is the limitation of cell sources for humans. One solution to this cell-sourcing problem is to use the recently described human ES cell lines (57). These unique cell lines are able to be propagated in vitro in the undifferentiated state in large quantities and to be coaxed to differentiate to a plurality of cell lineages. It has been shown, for example, that ES cells cultured in the specific differentiating system are not limited to the generation of isolated cardiac cells, but rather a functional cardiac syncytium is generated with a stable pacemaker activity and electrical propagation that also respond to adrenergic and cholinergic stimuli. There is no doubt that application of ES cells is of great value for future cell therapy strategies, although a number of ethical, psychological, and legal implications are envisioned and will need to be addressed.

Oncologic Surgery The significant advances in cellular and molecular biology, especially the Human Genome Project, will have farreaching effects on diagnostic studies, treatment, and counseling of cancer patients and their family members. Microarray technology using DNA ‘‘chips’’ provides one of the most promising approaches to large-scale studies of genetic variations and detection of gene mutations and gene expression for cancer patients and high-risk populations (64). DNA chips generally consist of a thin slice of glass or silicone about the size of a postage stamp on which threads of synthetic nucleic acids are arrayed, and thousands of gene expression can be determined on a single DNA chip. For example, microarray technology has been applied to detect HIV sequence variation, p53 gene mutation in breast tissue, and expression of cytochrome P-450. This new technology is also used to make genomic comparisons across species, genetic recombination, large-scale analysis of gene copy number and expression, and protein expression in cancers. Based on cellular and molecular evidence for potential development of various cancers in high-risk groups, surgeons are going to play a critical role in both genetic assessment and ultimate therapy. There are several successful applications in this new area. For example, the new finding regarding the association between mutations of the ret proto-oncogene and hereditary medulary thyroid carcinoma allows surgeons to identify patients in whom medulary thyroid cancer will eventually develop. In addition, clinical molecular evidence by genetic screening for mutations of the ret proto-oncogene in patients with the multiple endocrine neoplasia type-II syndrome allows prophylactic thyroidectomy to be performed at an earlier stage of the disease process than does traditional biochemical screening. Other

Chapter 12: Application of Cellular and Molecular Biology in Modern Surgical Practice

application of cellular and molecular biology in modern surgical practice is to test patients with familial adenomatous polyposis in which the timing and extent of therapy are dependent on exact location of the adenomatous polyposis coli mutations. Furthermore, although it is still controversial, some patients will receive early surgical treatment based on identification of the mutations of the breast cancer susceptibility genes such as BRCA-1 and BRCA-2. There is no doubt that surgical cancer treatment protocols will be improved significantly because more information becomes known regarding mutations of these genes and the clinical implications of these mutations.

Tissue Engineering and Transplantation Although remarkable advances have been made in organ transplantation over the past two decades, the most significant limitation is the availability of suitable organs. There is an increasing concern that the level of organ and tissue demand cannot be met by organ donation alone. It has been proposed for many years that xenotransplantation is a possible solution to the problem of organ availability and suitability. Although several critical studies have been carried out to elucidate the possibility of using xenotransplanted organs and short-term successes have been reported, there have been no long-term survivors using these techniques. Based on information from the fields of genomics and structural biology, it is possible that scientists will be able to genetically engineer tissues and animals to potentially have more specific combinations of human antigens. Animals can be developed whose immune systems are engineered to more closely resemble that of humans, thus decreasing the dependence on organ donors. The current progress of cellular and molecular biology, especially the successful cloning of sheep and cattle, also offers another possibility to address the organ donation problem by the potential for organ cloning. Recently, this concept and possibility has received a considerable amount of attention. Although the issue of whole animal cloning is fascinating, the growing field of stem cell biology is the greatest hope for transplant patients. Based on the characterization of human stem cells and the information gathered from the Human Genome Project, scientists are already able to develop organ-cloning techniques that will most assuredly revolutionize the field of transplantation in the future. Human ES cells have the ability to divide without limitation and give rise to many types of differentiated and specialized tissues with a specific purpose. It is anticipated that scientists will genetically engineer tissues for the purpose of human organ transplantation by the identification of human ES cells and the potential modification of these cells via gene therapy.

SUMMARY This chapter provides an overview of the tremendous advances that have been made in cellular and molecular biology over the past two decades and the impact this knowledge has had and which will continue to have on the management of surgical disease. It is which anticipated that application of this information will become even more extensive during the next decade and that many of the diseases currently treated by surgical manipulation will lend themselves either partially or completely to alteration of fundamental molecular processes within cells. As such, it is mandatory that the modern surgeon be aware of this knowledge explosion and how advances in

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molecular biology can be employed to more effectively treat surgical disease.

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44. Woo RA, Poon RY. Cyclin-dependent kinases and S phase control in mammalian cells. Cell Cycle 2003; 2:316–324. 45. Fischer PM. Recent advances and new directions in the discovery and development of cyclin-dependent kinase inhibitors. Curr Opin Drug Discov Devel 2001; 4:623–634. 46. Vermeulen K, Berneman ZN, Van Bockstaele DR. Cell cycle and apoptosis. Cell Prolif 2003; 36:165–175. 47. Vermeulen K, Van Bockstaele DR, Berneman ZN. The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell Prolif 2003; 36:131–149. 48. Otsuki Y, Li Z, Shibata MA. Apoptotic detection methods— from morphology to gene. Prog Histochem Cytochem 2003; 38: 275–339. 49. Nicholson DW, Thornberry NA. Apoptosis–life and death decisions. Science 2003; 299:214–215. 50. Wolf BB, Green DR. Suicidal tendencies: apoptotic cell death by caspase family proteinases. J Biol Chem 1999; 274:20049–20052. 51. Adams JM, Cory S. The Bcl-2 protein family: arbiters of cell survival. Science 1998; 281:1322–1326. 52. Wang JY. Expression of early primary response genes in healing of gastrointestinal mucosal injury. In: Cho CH, Wang JY, eds. Gastrointestinal Mucosal Repair and Experimental Therapeutics. Switzerland: S Karger AG, 2002:82–100. 53. Thornberry NA. Caspases: key mediators of apoptosis. Chem Biol 1998; 5:R97–R103. 54. Silen W, Ito S. Mechanisms for rapid-epithelialization of the gastric mucosal surface. Annu Rev Physiol 1985; 47:217–229. 55. Wang JY, Johnson LR. Expression of proto-oncogenes c-fos and c-myc in healing of gastric mucosal stress ulcers. Am J Physiol Gastrointest Liver Physiol 1994; 266:G878–G886. 56. Makino R, Hagashi K, Sugimura T. c-myc transcript is induced in rat liver at very early stage of regeneration or by cycloheximide treatment. Nature 1984; 310:697–698. 57. Hochedlinger K, Jaenisch R. Nuclear transplantation, embryonic stem cells, and the potential for cell therapy. N Engl J Med 2003; 349:275–286. 58. Fink D, Mata M, Glorioso JC. Cell and gene therapy in the treatment of pain. Ad Drug Deliv Rev 2003; 55:1055–1064. 59. Hughes RM. Strategies for cancer gene therapy. J Surg Oncol 2004; 85:28–35. 60. Baltzer A, Lieberman JR. Regional gene therapy to enhance bone repair. Gene Ther 2004; 11:344–360. 61. Menasche P. Cell therapy of heart failure. C R Biol 2002; 325: 731–738. 62. Gepstein L, Feld Y, Yankelson L. Somatic gene and cell therapy strategies for the treatment of cardiac arrhythmias. Am J Physiol Heart Circ Physiol 2004; 286:H815–H822. 63. Ramon-Cuete A, Santos-Benito FF. Cell therapy to repair injured spinal cords: olfactory ensheathing glia transplantation. Restor Neurol Neurosci 2001; 19:149–156. 64. Khan J, Bittner ML, Chen Y. DNA microarray technology: the anticipated impact on the study of human disease. Biochim Biophys Acta 1999; 1423:M17–M28.

13 Physiologic Principles in Preparing Patients for Surgery Henry J. Schiller, Kara C. Kort, and Lelan F. Sillin

than 70 has been implicated as a risk factor for postoperative cardiac complications (1). Ideally, patients should be kept nil per os (NPO) for eight hours prior to an anesthetic to minimize the risk of aspiration. They should be well hydrated, and electrolytes should be within normal limits. Any active infection should be identified and treated preoperatively.

INTRODUCTION Surgery can be considered ‘‘controlled trauma’’ that predictably alters the patient’s normal physiology. These physiologic derangements may be more severe, and less well tolerated, in patients with concurrent illnesses such as coronary artery disease or chronic obstructive pulmonary disease (COPD). The potential benefits of an operative procedure must be balanced against the potential risks of the procedure and the risks and benefits of management alternatives. It is imperative that the surgeon be able to recognize those features that may increase a patient’s expected morbidity or mortality and to modify the perioperative management and operative plan accordingly. Just as ‘‘an ounce of prevention is better than a pound of cure,’’ anticipating the patient’s expected clinical course provides a better outcome than reacting to what may have been a preventable complication. An optimal outcome in surgery requires a thoughtful diagnostic workup, careful perioperative care, appropriate surgical procedure, and conscientious follow-up. Preoperative care remains an integral part of surgical care and is the ultimate responsibility of the surgeon. While preparing a patient for surgery may become routine, it is better to understand the physiologic principles involved rather than simply issuing ‘‘standard orders’’ by rote. A thoughtful evaluation based on a thorough knowledge of the natural history of the disease process involved, associated medical conditions, and the physiologic changes produced by them are essential for assessing the risk of treatment options and engaging in appropriate management of the patient’s problems.

Surgical Consent The surgeon must speak with the patient candidly about the proposed surgery. The patient should be given an explanation of the disease process, its expected course, and the indications for surgery. This should include a clear discussion of therapeutic alternatives. In discussing the specifics of the procedure, the patient should be informed of the expected rates of mortality and morbidity. Although it is unnecessary and counterproductive to intentionally frighten the patient, the surgeon has the medical, legal, and moral responsibility to inform the patient of potential complications or adverse outcomes. This is best done in the presence of a family member or another witness to prevent later misunderstandings. The risk of bleeding should be specifically discussed with the patient, and specific consent for the transfusion of blood products must be obtained. It is also desirable to obtain advance directives from the patient, in the event the patient is unable to participate in medical decisionmaking later in the course of the disease. Finally, the patient should be told what to expect postoperatively, including the tubes and lines one is likely to have in place, the amount of pain one is likely to experience despite analgesia, and regimens one is likely to undergo. Clear and honest communication increases the patient’s confidence in the care he or she is receiving and will serve to strengthen the patient–physician relationship.

GENERAL ASPECTS OF PREOPERATIVE PREPARATION

Nutrition

A thorough history and physical examination should be performed along with a pertinent review of systems. All preoperative medications should be known, and allergies should be especially noted. Operative notes and pathology reports from prior surgical procedures frequently prove enlightening. One may obtain a general impression of the patient’s physical condition by physical examination. Often a patient may pass or fail the ‘‘look test.’’ Important features to note are the patient’s apparent nutritional status and body habitus. Simple observations may give clues to clinically important conditions; for example, breathlessness, a barrel chest, clubbing, and cyanosis may indicate COPD. Patients in distress generally display an easily recognizable picture of vigilant anxiety. A patient’s functional status should also be assessed, because this may provide an important indication of underlying cardiac disease. Age greater

A patient’s nutritional stores may be rapidly depleted by perioperative fasting and dietary restrictions. Moreover, the patient who is poorly nourished at the outset has fewer reserves and tolerates fasting poorly. Although fluid and electrolyte losses from recent emesis or diarrhea are easily documented, there is no specific laboratory measure for malnutrition. A serum albumin of less than 3.5 mg/dL may give a crude indication of malnutrition, but its long serum half-life (18 days) makes it relatively insensitive to acute perturbations in nutrition. Serum proteins with shorter circulating half-lives, such as retinol-binding protein, prealbumin, and fibrinogen, are also acute phase proteins and therefore may be artifactually elevated by recent infection or inflammation. Ultimately, history (weight loss, dietary habits, etc.), physical examination, and 271

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anthropometrics (e.g., triceps skinfold) should be used in concert with serum protein levels to determine a patient’s nutritional reserve. In general, patients weighing 80% or less of ideal body weight or patients with recent, profound weight loss (greater than 10% ideal body weight) should be considered for preoperative hyperalimentation (2,3). Enteral nutrition should be used in patients with a functioning gastrointestinal tract. Preoperative total parenteral nutrition should be given for at least 10 days preoperatively in malnourished patients. Consideration should be given for perioperative total parenteral nutrition even in wellnourished patients who will require bowel rest for more than five to seven days (3).

Obesity Obesity, an all too common disorder in industrialized nations, provides additional physiologic stress including increased work of breathing and a requirement for a higher cardiac output. Comorbidities often seen in obese patients include respiratory insufficiency, coronary artery disease, hypertension, and diabetes mellitus (4). Although the precise definitions of obesity and morbid obesity vary, in general, a patient weighing more than 130% of his or her ideal body weight is at increased risk for perioperative complications such as atelectasis, pneumonia, respiratory failure, deep venous thrombosis (DVT), or wound complications (5). In patients undergoing bariatric surgery, hypertension and sleep apnea have been identified as independent risk factors for postoperative complications (6). There is usually little that can be done preoperatively to remedy obesity. Attention must therefore be directed toward the prevention of expected postoperative complications. Preoperative incentive spirometry, DVT prophylaxis, skin care, and early mobilization postoperatively may help decrease the risk of complications.

Integument The integument is the largest organ of the body. The skin plays an invaluable role both as a barrier to conserve body heat and water and as a barrier to prevent infection from potential environmental pathogens. Trauma, or burns, that lead to major skin loss may predispose to hypovolemia from fluid loss and hypothermia from heat loss. Such patients must receive fluid resuscitation and must be kept warm. Percent skin loss may be determined by the ‘‘rule of nines’’ (7) so that an estimate of the patient’s fluid requirements may be calculated by the Parkland formula (8). Relatively minor skin trauma may predispose to infection by providing a portal of entry for resident skin flora. Skin harbors a resident microbial flora and therefore represents not only a barrier to infection, which will be compromised by a surgical incision, but also a source of microbes with which to contaminate the surgical wound. For this reason, the skin ought to be scrubbed for surgery with povidone-iodine, hexachlorophene, or chlorhexidine (9). This provides both mechanical cleansing to remove contaminants and debris and topical antiseptics to further decrease bacterial counts in the surgical field. Shaving the patient the night before surgery increases the incidence of wound infection compared to shaving just prior to the surgical incision (9). This is doubtlessly due to compromise of the skin’s microbial barrier function by microabrasions and nicks. Depilatory agents may be used in place of shaving, although risk of hypersensitivity reactions to these agents remains. Ideally, abrasions, rashes, eruptions, and furuncles are treated prior to operation, particularly in

situations in which prosthetics are to be implanted. In the event this is not possible, incisions should be planned to avoid these areas. Preoperative antibiotics possessing grampositive coverage may be given for prophylaxis.

Antibiotic Prophylaxis The incidence of postsurgical infection ranges from 2.8% to 7.6%, making it the second most common nosocomial infection, after catheter-related urinary tract infection (10). These range from simple skin infections to major sepsis, and they may have a profound impact on patient outcome and cost of care. Preexisting infections should be treated prior to elective operation to minimize the risk of postoperative infection. Prophylactic antibiotics administered perioperatively are clearly beneficial (10,11). Conversely, prophylactic antibiotics administered after the skin incision is made do not achieve the desired effect and may be detrimental to both the patient and the institution by promoting the overgrowth of antibiotic-resistant bacteria. Surgical procedures are classified as clean, clean contaminated, contaminated, or dirty. Clean cases involve no entry into the respiratory, gastrointestinal, or genitourinary tract and have no break in sterile technique. The incidence of postsurgical infection is only 2% to 5%, which decreases to 0.8% with perioperative antibiotic prophylaxis (12). Because clean surgical cases comprise approximately 75% of all procedures, unless the patient has additional risk factors for infection (Box 1), antibiotics are withheld because of the low incidence of infection. The benefit of prophylactic antibiotics is difficult to demonstrate. Clean contaminated cases involve entry into the respiratory, gastrointestinal, or genitourinary tract without gross contamination of the surgical field. The incidence of postsurgical infection is 8% to 10%, which decreases to 1.3% with antibiotic prophylaxis. Contaminated wounds include open traumatic wounds, major breaks in sterile technique, or significant spillage from the gastrointestinal tract. In these wounds, the incidence of postsurgical infection is 20%, which decreases to 10.2% with antibiotic prophylaxis. Dirty cases involve fields with established infection and carry a 40% incidence of wound infection. Therapeutic, rather than prophylactic, antibiotic coverage is indicated for these cases (12,13). Prophylactic antibiotic coverage should be chosen according to the organisms most likely to cause infection. In general, first-generation cephalosporins (i.e., cefazolin) have been used because of their broad gram-positive and Box 1 Factors Increasing the Risk of Postoperative Infection Duration of operation greater than 2 hours Emergency surgery Advanced age Placement of prosthetic material Medical conditions Preexisting infection Malignancy Diabetes mellitus Obesity Malnutrition Steroid usage Immunoincompetence Local vascular disease Source: From Ref. 13.

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Table 1 Bowel Preparation for Elective Colonic Surgery Preoperative day 3 2

1

0

Traditional preparation

Polyethylene glycol

Clear liquid diet Bisacodyl capsule orally at 6 P.M. Clear liquid diet Magnesium citrate 6% sodium, 296 mL orally at 10 A.M., 2 P.M., and 6 P.M. Cleansing enemas until clear rectal effluent Clear liquid diet Magnesium citrate 6% sodium, 296 mL orally at 10 A.M. and 2 P.M. Neomycin sulfate and erythromycin base, 1 g each orally at 1 P.M., 2 P.M., and 11 P.M. NPO after midnight Rectal evacuation at 7 A.M. Cefoxitin or cefotetan, intravenous perioperative administration

Regular diet as desired Regular diet as desired

Light breakfast as desired before 8 A.M. Polyethylene glycol 1 L hr orally
5 hr or until clear rectal effluent Neomycin sulfate and erythromycin base, 1 g each orally at 1 P.M., 2 P.M., and 11 P.M. NPO after midnight Rectal evacuation at 7 A.M. Cefoxitin or cefotetan, intravenous perioperative administration

Abbreviation: NPO, nil per os. Source: From Ref. 16.

gram-negative coverage, their long half-life, low cost, and low toxicity. It is important to obtain adequate tissue levels prior to operation. Repeated doses should be administered during lengthy procedures (14). Providing prophylactic antibiotic coverage beyond 24 to 48 hours is of no benefit and increases the risk of colonization or infection by antibiotic-resistant bacterial strains (15). Colonic surgery usually requires more significant preoperative regimens (Table 1). The colon contains the highest bacterial concentrations of any location in the body. The flora includes both aerobes and anaerobes. Although the latter predominate, some of the aerobes are particularly virulent (i.e., Escherichia coli). Consequently, postoperative infections are the major source of morbidity in colonic surgery. Although it is not possible to actually sterilize the colon, significant reduction in colonic flora can be achieved. A combination of mechanical colonic lavage preparation and oral nonabsorbable antibiotics prior to surgery is required to decrease infection rates (17). The standard prophylactic regimen still remains a combination of oral neomycin and oral erythromycin. Mechanical cleansing is achieved either with the traditional three-day preparation using bisacodyl, magnesium citrate, and cleansing enemas or a one-day preparation using a large volume of orally administered polyethylene glycolelectrolyte lavage solution. One-day preparations have been found to be efficacious, safe, and relatively well tolerated preoperatively, in addition to minimizing dietary alterations and reducing preoperative hospitalization (16). Systemic intravenous antibiotics are often added to this regimen (i.e., cefoxitin or cefotetan); however, it remains controversial as to whether this provides any benefit over mechanical preparation with oral antibiotics (10,17,18).

SPECIFIC ASPECTS OF PREOPERATIVE PREPARATION Risks of Pulmonary Disease Patients should be questioned regarding smoking history, chronic cough or sputum production, wheezing, or shortness of breath. Any history of chronic lung disease, pneumonia, chest injury, occupational exposures, or requirement for intubation should be obtained. Current exercise tolerance and medication use, particularly use of bronchodilators and corticosteroids, give an indication as

to the severity of pulmonary disease. The physical examination should document body habitus, respiratory rate and effort, the presence and quality of breath sounds, the anteroposterior diameter of the chest, cyanosis, and clubbing. Patients over the age of 40 or patients with a history of cigarette smoking or pulmonary disease should receive a preoperative chest X-ray examination. Patients undergoing pulmonary resection should have formal pulmonary function testing, including spirometry, room air arterial blood gas determination, and split-lung perfusion testing. ‘‘Formal pulmonary function testing has not been shown to be superior to history and physical examination in predicting postoperative pulmonary complications in abdominal and nonresective thoracic surgery (19–21). While forced vital capacity (FVC) of less than 1.5 L/min, preoperative hypercapnea of 45 mmHg or more and a forced expiratory time of nine seconds or more predict postoperative pulmonary complications, so do age of 65 years or greater, smoking of 40 pack years or more and a body mass index of 30 or more (22).’’ General anesthesia leads to depression of respiratory drive, particularly in response to hypercarbia and hypoxia. Tidal volume (TV), functional residual capacity (FRC), and thoracic volume decrease as the diaphragm loses tone and moves cephalad. The resulting atelectasis and preferential ventilation of the nondependent regions of the lungs leads to ventilation-perfusion mismatch, thereby increasing shunt fraction (21). High abdominal incisions, thoracotomy incisions, and median sternotomy predispose toward postoperative pulmonary complications. Pain and muscular splinting lead to inhibition of coughing, and a decrease in TV high abdominal incisions result in ‘‘diaphragmatic dysfunction’’ such that ventilation is more dependent on chest excursion (23). Forced expiratory volume in one second (FEV1) and vital capacity decrease from 25% to 50%, and the FRC decreases (24). Cardiac surgery may result in dysfunction of the left hemidiaphragm, probably from left phrenic nerve injury incurred either during dissection of the left internal mammary artery at the thoracic inlet or by cold injury during slush cooling of the heart (25). These predispose the patient to mucous plugging, atelectasis, and ultimately pneumonia. Although laparoscopic surgery largely avoids the muscle splinting seen with high abdominal incisions, absorption of carbon dioxide from the pneumoperitoneum

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occurs, predisposing to intraoperative hypercarbia and acidosis (23,26). Smokers and patients with chronic lung disease are at increased risk for these postoperative pulmonary complications. Smoking eventually leads to COPD, but even smokers with normal pulmonary function tests (PFTs) face an increased risk of pulmonary complication. Smoking both stimulates mucous secretion and impairs the mucociliary apparatus necessary to efficiently clear these secretions. Carbon monoxide found in cigarette smoke binds hemoglobin in preference to oxygen, thereby decreasing oxygen-carrying capacity. Moreover, cigarette smoking increases airway irritability, which may lead to perioperative bronchospasm and small airway dysfunction. Current smokers undergoing surgery can expect up to a 33% rate of pulmonary complications (mucus plugging, atelectasis, pneumonia, pleural effusion, or pneumothorax). Cessation of smoking for at least two months preoperatively decreases this rate to 14.5%, and cessation of smoking for more than six months decreases the rate of pulmonary complications to that of patients who have never smoked. ‘‘Paradoxically, cessation of smoking within a month of a planned surgery may increase the risk of pulmonary complications by 14-fold (27,28). Smoking has also been noted to increase wound-healing complications in surgical patients (29,30).’’ Patients with chronic pulmonary disease either have a restrictive or an obstructive pattern. Restrictive diseases are generally characterized by a decreased FVC and total lung capacity (TLC), whereas obstructive diseases are characterized by a decrease in the ratio of FEVI/FVC. Patients with COPD such as emphysema and chronic bronchitis have an increased FRC and TLC but may have a decreased TV. Consequently, a greater respiratory rate is required to maintain an adequate minute ventilation. Carbon dioxide retention indicates severe disease. The presence of these chronic pulmonary diseases can be determined by history and physical examination. Subtle decrements in pulmonary function and the severity of overt pulmonary disease may be measured objectively by formal PFTs, including clinical spirometry and arterial blood gas determination. In abdominal and nonresective thoracic surgery, PFTs are used to assess risk for postoperative pulmonary complications and to identify those patients likely to require specialized postoperative respiratory therapy or even postoperative mechanical ventilation. ‘‘In general, formal PFTs are not superior to a detailed history and physical examination for this purpose, although an FVC of less than 1.5 L/min, an FEVI of less than 1 L/min, and a PCO2 of 45 mmHg or more do predict postoperative pulmonary complications (19–22).’’ Clinical spirometry, split perfusion lung scanning, and preoperative arterial blood gas determinations do correlate with postoperative respiratory insufficiency and mortality in patients undergoing pulmonary resection. In general, the predicted FEVI postresection should exceed 800 mL (31). ‘‘Patients preparing for general anesthesia should cease smoking at least two months beforehand (32).’’ Moreover, they should be educated preoperatively regarding the importance of deep breathing and coughing. Those with preexisting pulmonary disease should receive preoperative bronchodilator therapy with either beta-adrenergic agonists or ipratroprium bromide (an atropine derivative) (24). Patients already receiving theophylline preparations should continue them. Aminophylline should not be administered prophylactically because the toxic-to-therapeutic index is small (24). Patients with steroid-dependent COPD should receive stress-dose steroids perioperatively. Elective

operation should be avoided in patients with active pulmonary infections, and prophylactic antibiotics with activity against Haemophilus influenzae and Streptococcus pneumoniae may be administered in those with chronic lung disease to suppress endogenous bronchial flora (24). High-risk patients should additionally receive postural drainage and chest physiotherapy. Epidural analgesia may improve the diaphragmatic dysfunction seen with high abdominal incisions (23), while pleural catheter analgesia may improve the respiratory mechanics after thoracotomy (33).

Risks of Cardiovascular Disease The cardiac history should detail exercise tolerance and symptoms of angina, dyspnea, orthopnea, paroxysmal nocturnal dyspnea, fatigue, palpitations, and syncope. Any history of myocardial infarction, congestive heart failure, valvular heart disease, or arrhythmia should be elicited. Examiners should listen for murmurs, clicks, extra heart sounds (S3 and S4), rales, and bruits. Blood pressure, heart rate, and pulses should be noted, as should the presence of jugulovenous distension, peripheral edema, and hepatomegaly. The results of previous cardiac testing should be reviewed. During operation, the cardiovascular system is stressed both by anesthetic agents and by fluid shifts. The inhalation agents are generally myocardial depressants (32). Loss of vascular tone during general, spinal, or epidural anesthesia may provoke hypotension, particularly in the hypovolemic patient. Postanesthetic recovery of vascular tone may result in fluid overload. Hypothermia results in vasoconstriction, and rewarming is associated with vasodilation and consequent hypotension. Longer procedures have greater evaporative fluid and heat losses, and more extensive procedures promote greater fluid loss into the ‘‘third space.’’ The hypotension seen with induction of anesthesia can be minimized by adequate preoperative hydration. Patients requiring preoperative bowel preparation or those receiving chronic diuretic therapy may require additional fluids because of baseline volume contraction.

Hemodynamic Monitoring Basic hemodynamic monitoring is performed noninvasively with pulse and blood pressure determinations. Urine output is followed as a crude indicator of visceral perfusion. Invasive monitoring is reserved for the hemodynamically unstable patient or those with underlying cardiac disease such as congestive heart failure, recent myocardial infarction, or significant coronary artery disease. It is also useful when urine output cannot be used as an indicator of visceral perfusion, such as in patients with end-stage renal disease (ESRD) or with diabetes insipidus. The benefits derived from invasive monitoring must always be weighed against the complications, which generally include infection, thrombosis, and hemorrhage. Percutaneous arterial catheters are used in patients requiring instantaneous, continuous blood pressure monitoring or for those requiring repeated arterial blood sampling. The catheters are usually placed in the radial artery after ensuring adequate ulnar artery collateral flow to the palmar arch by the modified Allen’s test. Central venous catheters measure pressure in the superior vena cava. This equals right ventricular pressure at the end of diastole and therefore gives an approximation of right ventricular end-diastolic volume (right ventricular preload) in the normal, compliant heart. This is useful in patients with preserved myocardial function, who may

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experience large fluid shifts during operation. Central venous catheters are generally inserted into either the internal jugular or the subclavian vein, although insertion into the femoral vein is also acceptable. Percutaneous insertion into the left internal jugular vein places the patient at risk for thoracic duct injury. Inadvertent arterial cannulation is risked at all insertion sites but is particularly worrisome in the subclavian position, where direct arterial compression for hemostasis is not generally possible. The subclavian approach also places the patient at risk for pneumothorax. The Swan–Ganz, or pulmonary artery, catheter provides a better indication of left-sided cardiac function. The proximal port provides a central venous pressure. The distal port provides pulmonary artery pressures and the pulmonary capillary wedge pressure, which, in the absence of severe mitral stenosis, equals left ventricular end-diastolic pressure, giving an indication of left ventricular preload. Cardiac output may also be measured by thermodilution. These values, along with blood pressure, hemoglobin concentration, and saturation may be used to calculate systemic vascular resistance, pulmonary vascular resistance, stroke work, oxygen delivery, and oxygen consumption. Complications of pulmonary artery catheter insertion are the same as those seen in central venous catheter insertion. In addition, the patient is at risk for ventricular arrhythmias, right bundle branch block, valvular injury, cardiac perforation, and pulmonary artery rupture. Moreover, catheter sepsis, endocarditis, venous thrombosis, and pulmonary infarction may develop over time. Therefore pulmonary artery catheterization should be performed only for specific indications. Specific indications for preoperative pulmonary artery catheterization include the following (34–36). 1. 2. 3.

High risk for myocardial ischemia Refractory congestive heart failure Symptomatic valvular heart disease

A prospective randomized study by Berlauk et al. (35) examined the utility of preoperative pulmonary artery catheterization in patients undergoing peripheral vascular surgery, who lacked the above indications. Patients receiving pulmonary artery catheters were optimized to the following end points: pulmonary capillary wedge pressure  8 mmHg, < 15 mmHg; cardiac index  2.8 L/min/m2; and systemic vascular resistance  1100 dyne sec cm5 (Fig. 1). The death rate was decreased from 9.5% in the control group to 1.5% in the pulmonary artery catheter group, and the overall rate of complications (intraoperative arrhythmia, tachycardia or hypotension, postoperative cardiac morbidity, or early graft thrombosis) decreased from 42.9% to 16.2%. Pulmonary artery catheterization more than 12 hours preoperatively offered no advantage to that performed immediately preoperatively. Although these patients lacked specific indications for pulmonary artery catheter insertion, patients with peripheral vascular disease are known to be at high risk for cardiac complications (37,38).

Coronary Artery Disease The cardiovascular effects of anesthesia, along with fluid shifts, may stress those patients with coronary artery disease beyond their ability to respond appropriately. Perioperative myocardial infarction and/or death may result. Myocardial ischemia will, and infarction may, occur when the myocardial oxygen demand exceeds the myocardial oxygen supply. Patients with fixed coronary artery stenoses depend on maintaining coronary artery perfusion pressure above a

Figure 1 Algorithm for preoperative cardiovascular tune-up. CV measurements were repeated after each intervention. Inotropes: dobutamine or dopamine. Vasodilators: nitroglycerin or nitroprusside. Measurement units are mmHg for pressure, dyne sec cm5 for resistance, and L/min/m2 for CI. Abbreviations: CI, cardiac index; CV, cardiovascular; PAWP, pulmonary artery wedge pressure; SVR, systemic vascular resistance. Source: From Ref. 35.

critical level to prevent ischemia. In these patients, hypotension decreases coronary artery perfusion pressure. A reduction in mean arterial pressure of just 6% may provoke myocardial ischemia (39). Coronary artery blood flow is dependent both on wall tension and diastolic filling time. In the failing ventricle, increasing preload (end-diastolic pressure) increases wall tension, thereby decreasing coronary perfusion. Tachycardia decreases diastolic filling time, also decreasing coronary perfusion (40). In hypertensive patients, myocardial oxygen demand is increased, which may provoke ischemia and infarction (40). Recent myocardial infarction increases the risk of reinfarction and death in the noncardiac surgery patient. In one study, a general anesthetic administered within three months of myocardial infarction resulted in a reinfarction rate of 37%. The rate decreased to 16% from three to six months after infarction to just 6% after six months, with an overall mortality of 50% in the reinfarcted patients (41). In the emergent setting, aggressive cardiac management with invasive hemodynamic monitoring can reduce the risk of reinfarction to approximately 6% in patients suffering myocardial infarction

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within the previous six months (42). While it was previously recommended that a patient not undergo elective surgery within six months of suffering myocardial infarction, more recent recommendations from the American Heart Association allow stratification of risk during convalescence. In the absence of residual myocardium at risk by stress testing, the risk of reinfarction is low, and the patient should be able to undergo elective surgery after waiting four to six weeks (36). In 1996, the American College of Cardiology and the American Heart Association first published guidelines for perioperative cardiovascular evaluation of patients undergoing noncardiac surgery, which were subsequently updated in 2002 (36). These recommendations provide clinical markers of increased perioperative cardiovascular risk (Table 2) and estimates of functional capacity (Table 3) and stratify the cardiac risk of various noncardiac surgical procedures (Table 4). These factors are then incorporated into an algorithm to determine which patients require further cardiac evaluation prior to undergoing surgery (Fig. 2). Moreover, the use of beta-blockers for patients at risk for coronary artery disease has been shown to reduce perioperative cardiovascular complications and mortality for up to two years after surgery and should be administered preoperatively and continued postoperatively (44).

Congestive Heart Failure Left ventricular dysfunction eventually leads to cardiac pump failure. Compensatory mechanisms include ventricular dilation and hypertrophy. As the ejection fraction Table 2 Clinical Predictors of Increased Perioperative Cardiovascular Risk (Myocardial Infarction, Heart Failure, Death) Major Unstable coronary syndromes Acute or recent MI with evidence of important ischemic risk by clinical symptoms or noninvasive study Unstable or severe angina (Canadian class III or IV) Decompensated heart failure Significant arrhythmias High-grade atrioventricular block Symptomatic ventricular arrthythmias in the presence of underlying heart disease Suptaventricular arrhythmias with uncontrolled ventricular rate Severe valvular disease Intermediate Mild angina pectoris (Candian class I or II) Previous MI by history or pathological Q waves Compensated or prior heart failure Diabetes mellitus (particularly insulin-dependent) Renal insufficiency Minor Advanced age Abnormal ECG (left ventricular hypertrophy, left bundle branch block, ST-T abnormalities) Rhythm other than sinus (e.g., atrial fibrillation) Low functional capacity (e.g., inability to climb one flight of stairs with a bag of groceries) History of stroke Uncontrolled systemic hypertension The American College of Cardiology National Database defines recent MI as that occurring between 7 days and less than or equal to 30 days and acute MI as that occuring within 7 days. May include stable angina in patients who are usually sedentary. Abbreviations: MI, myocardial infarction; ECG, electrocardiogram. Source: From Refs. 36, 43.

Table 3 Estimated Energy Requirements for Various Activities 1 MET

4 METs

Greater than 10 METs

Can you take care of yourself? Eat, dress, or use the toilet? Walk indoors around the house? Walk a block or two on level groung at 2 to 3 mph or 3.2 to 4.8 km/h? Do light work around the house, such as dusting or washing dishes? Climb a flight of stairs or walk up a hill? Walk on level ground at 4 mph or 6.4 km/ h? Run a Short distance? Do heavy work around the house, such as scrubbling floors or lifting or moving heavy furniture? Participate in moderate activities such as golf, bowling, dancing, doubles tennis, or throwing a baseball or football? Participate in strenuous sports such as swimming, singles tennis, football, basketball, or skiling?

Adapted from the Duke Activity Status Index and AHA Exercise Standards. Abbreviation: MET, metabolic equivalent. Source: From Ref. 36.

decreases, end-systolic and end-diastolic volumes increase. This increases both end-diastolic and end-systolic ventricular pressures, resulting in increased wall stress, and increased myocardial oxygen consumption. As ventricular compliance decreases, cardiac output increasingly depends on diastolic filling time. Thus tachycardia is poorly tolerated (45,46). The overall five-year mortality in patients with congestive heart failure is 50% (47). Predictors of mortality include poor functional capacity, high pulmonary capillary wedge pressure, low stroke work index, spontaneous ventricular arrhythmias, and elevated plasma levels of norepinephrine and renin (46). Congestive heart failure is a risk factor for perioperative mortality (36). Treatment consists of preload reduction with sodium restriction and diuretics. Digitalis improves myocardial contractility (45). Afterload reduction with isosorbide dinitrate and hydralazine improves cardiac output and reduces long-term mortality (48). Angiotensinconverting enzyme (ACE) inhibitors improve cardiac function, probably by both afterload reduction and interruption of the sodium and water retention characteristic of congestive heart failure (49). ACE inhibitors also reduce long-term mortality (49). Beta-blockers may also be appropriate in patients without refractory heart failure (50). Table 4 Cardiac Riska Stratification for Noncardiac Surgical Procedures High (reported cardiac risk often greater than 5%) Emergent major operations, particularly in the elderly Aortic and other major vascular surgery Peripheral vascular surgery Anticipated prolonged surgical procedures associated with large fluid shifts and/or blood loss Intermediate (reported cardiac risk generally less than 5%) Carotid endarterectomy Head and neck surgery Intraperitoneal and intrathoracic surgery Orthopedic surgery Prostate surgery Low (reported cardiac risk generally less than 1%) Endoscopic procedures Superficial procedure Cataract surgery Breast surgery a

Combined incidence of cardiac death and nonfatal myocardial infarction. Do not generally require further preoperative cardiac testing. Source: From Ref. 36.

Chapter 13: Physiologic Principles in Preparing Patients for Surgery

STEP 1

STEP 2

Emergency

Need for noncardiac surgery Urgent or elective surgery

No Yes

Coronary revascularization within 5 yr? No

STEP 3

Postoperative risk stratification and risk factor management

Operating room

surgery

277

Recurrent symptoms or signs?

Yes

Recent coronary angiogram Favorable result and or stress test? no change in symptoms Unfavorable result or

Yes

Recent coronary evaluation No

Operating room

change in symptoms

Clinical predictors

STEP 5 STEP 4 Consider delay or cancel noncardiac surgery

Consider coronary angiography

Medical management and risk factor modification

Subsequent care dictated by findings and treatment results

STEP 6

Clinical predictors

Functional capacity

Minor or no clinical predictors ‡

Intermediate clinical predictors †

Major clinical predictors**

Go to step 7

Go to step 6

Major Clinical Predictors**

. Unstable coronary syndromes . Decompensated CHF . Significant arrhythmias . Severe valvular disease

Intermediate clinical predictors †

Intermediate Clinical Predictors †

. Mild angina pectoris . Prior MI . Compensated or

Moderate or excellent (>4 METS)

Poor (4 METS)

Poor (75%) should be evaluated for carotid endarterectomy prior to undergoing spinal or general anesthesia for an elective procedure (72).

Risks of Liver Disease Preoperative evaluation and management of the patient with liver disease is a challenging problem. The liver is involved in numerous metabolic and synthetic processes including amino acid, carbohydrate, and lipid metabolism, excretion of bilirubin, and maintenance of glucose homeostasis. Predicting how a patient will respond not only to surgery but also to the effects of anesthesia can be extremely difficult. The evaluation of the patient with overt liver disease must include the cause of the disease (i.e., alcoholic cirrhosis and hepatitis), the chronicity of the disease, and the degree of hepatocellular injury based on both clinical findings and laboratory abnormalities. The magnitude of the surgery to be performed and the type of anesthesia to be administered must also be considered. Patients without overt liver disease but with abnormal liver function test results may require further workup.

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Box 2 Cardiac Conditions Associated with Endocarditis Endocarditis prophylaxis recommended High-risk category Prosthetic cardiac valves, including bioprosthetic and homograft valves History of bacterial endocarditis Complex cyanotic congenital heart disease (e.g., single ventricle states, transposition of the great arteries, and tetralogy of Fallot) Surgically constructed systemic pulmonary shunts or conduits Moderate-risk category Most other congenital cardiac malformations (other than those mentioned above and below) Acquired valvar dysfunction (e.g., rheumatic heart disease) Hypertrophic cardiomyopathy Mitral valve prolapse with valvar regurgitation and/or thickened leaflets Endocarditis prophylaxis not recommended Negligible-risk category (no greater risk than the general population) Isolated secundum atrial septal defect Surgical repair of atrial septal defect, ventricular septal defect, or patent ductus arteriosus (without residual beyond 6 months) History of coronary artery bypass graft surgery Mitral valve prolapse without valvar regurgitation Physiologic, functional, or innocent heart murmurs History of Kawasaki disease without valvar dysfunction History of rheumatic fever without valvar dysfunction Cardiac pacemakers (intravascular and epicardial) and implanted defibrillators Source: From Ref. 71.

Hepatic Dysfunction Due to Anesthetic Agents Anesthetic agents may exacerbate hepatic dysfunction. Although none of the currently used anesthetic agents are directly hepatotoxic, these agents, whether inhalational, spinal, or epidural, reduce hepatic blood flow by 30% to 50% (73,74). Patients with completely normal liver function can develop asymptomatic elevations in transaminases. Those with known hepatic disease may develop clinically apparent impairment (75). Moreover, impaired liver function may include impaired drug metabolism, thereby prolonging the action of anesthetic agents, sedatives, narcotic analgesics, or induction agents. These agents must be carefully administered with appropriate dosing. Sedative effects and hepatic encephalopathy must be closely monitored (73). Liver disease may lead to coagulopathy by several mechanisms. Hepatic disease can be associated with decreased synthesis and function of coagulation proteins, especially the vitamin K–dependent clotting factors (75). Vitamin K deficiency is common particularly in patients with cholestatic disorders or those receiving antibiotics to suppress endogenous gut flora (76). Liver disease may lead to qualitative or quantitative platelet abnormalities including the splenic sequestration seen with portal hypertension. Coagulation factors must be checked preoperatively in any patient with known or suspected liver disease. Patients with obstructive jaundice should receive parenteral vitamin K preoperatively. Failure of vitamin K to correct a prolonged PT indicates severe hepatocellular function (75,76). In this case, fresh frozen plasma must be used to achieve an adequate PT for surgery. Bleeding time should be obtained in

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Box 3 Dental Procedures and Endocarditis Prophylaxis

Box 4 Other Procedures and Endocarditis Prophylaxis

Endocarditis prophylaxis recommendeda Dental extractions Periodontal procedures including surgery, scaling and root planing, probing, and recall maintenance Dental implant placement and reimplantation of avulsed teeth Endodontic (root canal) instrumentation or surgery only beyond the apex Subgingival placement of antibiotic fibers or strips. Initial placement of orthodontic bands but not brackets Intraligamentary local anesthetic injections Prophylactic cleaning of teeth or implants where bleeding is anticipated

Endocarditis prophylaxis recommended Respiratory tract Tonsillectomy and/or adenoidectomy Surgical operations that involve respiratory mucosa Bronchoscopy with a rigid bronchoscope Gastrointestinal tracta Sclerotherapy for esophageal varices Esophageal stricture dilation Endoscopic retrograde cholangiography with biliary obstruction Biliary tract surgery Surgical operations that involve intestinal mucosa Genitourinary tract Prostatic surgery Cystoscopy Urethral dilation

Endocarditis prophylaxis not recommended Restorative dentistryb (operative and prosthodontic) with or without retraction cordc Local anesthetic injections (nonintraligamentary) Intracanal endodontic treatment; post placement and buildup Placement of rubber dams Postoperative suture removal Placement of removable prosthodontic or orthodontic appliances Taking of oral impressions Fluoride treatments Taking of oral radiographs Orthodontic appliance adjustment Shedding of primary teeth

Endocarditis prophylaxis not recommended Respiratory tract Endotracheal intubation Bronchoscopy with a flexible bronchoscope with or without biopsyb Tympanostomy tube insertion Gastrointestinal tract Transesophageal echocardiographyb Endoscopy with or without gastrointestinal biopsyb Genitourinary tract Vaginal hysterectomyb Vaginal deliveryb Cesarean section In uninfected tissue: Urethral catheterization Uterine dilatation and curettage Therapeutic abortion Sterilization procedures Insertion or removal of intrauterine devices Other Cardiac catheterization, including balloon angioplasty Implanted cardiac pacemakers, implanted defibrillators, and coronary stents Incision or biopsy of surgically scrubbed skin Circumcision

a

Prophylaxis is recommended for patients with high- and moderate-risk cardiac conditions. b This includes restoration of decayed teeth (filling cavities) and replacement of missing teeth. c Clinical judgment may indicate antibiotic use in selected circumstances that may present with significant bleeding. Source: From Ref. 71.

all patients with less than 100,000 platelets/mm3 and platelet transfusions considered in patients with elevated bleeding times and/or less than 50,000 platelets/mm3 (75,76). Obviously, purely elective surgery should be postponed in the patient with severe acute hepatic disease. Supportive care during the acute phase reduces operative risk. Operative considerations for specific hepatic disorders are discussed briefly in the following sections.

Acute Viral Hepatitis Acute viral hepatitis increases operative morbidity and mortality (77). Laboratory abnormalities seen in these patients include moderate-to-marked elevations in serum transaminase levels and mild elevations in alkaline phosphatase. Jaundice may or may not be present. The specific serologic diagnosis of the viral agent can usually be made (73). If possible, laparotomy should be avoided in the setting of acute viral hepatitis. The increased availability of accurate serologic testing and radiologic and endoscopic diagnostic procedures usually establishes the diagnosis of hepatitis, thereby obviating the need for surgery (73,76).

a

Prophylaxis is recommended for high-risk patients; optional for mediumrisk patients. b Prophylaxis is optional for high-risk patients. Source: From Ref. 71.

elective surgery is not contraindicated, a period of abstinence may be beneficial by avoiding the symptoms of postoperative alcohol withdrawal. Acute alcoholic hepatitis is more severe than acute viral hepatitis. Several studies have shown significantly increased morbidity and mortality of surgery in patients with alcoholic hepatitis (78,79). Diagnosis should be made by percutaneous liver biopsy. Elective surgery is contraindicated in this group of patients and should be postponed until laboratory and clinical parameters are normal.

Alcoholic Liver Disease Alcoholic liver disease can range from fatty liver (hepatic steatosis) to the more severe acute alcoholic hepatitis to cirrhosis. The patient with alcoholic fatty liver is not at increased risk for operative complications (73,76). Mild elevations in transaminase and alkaline phosphatase may be seen and diagnosis confirmed by liver biopsy. Although

Chronic Hepatitis Chronic hepatitis refers to a group of disorders characterized by chronic inflammation of the liver, persisting for at least three to six months (73). Chronic hepatitis is usually divided into chronic persistent form and chronic active form. Patients with chronic persistent hepatitis are usually

Chapter 13: Physiologic Principles in Preparing Patients for Surgery

281

Table 5 Prophylactic Regimens for Dental, Oral, Respiratory Tract, or Esophageal Procedures Situation Standard general prophylaxis Unable to take oral medications Allergic to penicillin

Allergic to penicillin and unable to take oral medications

Regimena

Agent Amoxicillin Ampicillin Clindamycin Or Cephalexinb or cefadroxilb Or Azithromycin or clarithromycin Clindamycin Or Cefazolinb

Adults: 2 g; children: 50 mg/kg orally 1 hr before procedure Adults: 2 g IM or IV; children: 50 mg/kg IM or IV within 30 min before procedure Adults: 500 mg; children: 20 mg/kg orally 1 hr before procedure Adults: 2 g; children: 50 mg/kg orally 1 hr before procedure Adults: 500 mg; children: 15 mg/kg orally 1 hr before procedure Adults: 600 mg/children: 20 mg/kg IV within 30 min before procedure Adults: 1 g; children: 25 mg/kg IM or IV within 30 min before procedure

a

Total children’s dose should not exceed adult dose. b Cephalosporins should not be used in individuals with immediate-type hypersensitivity reaction (urticaria, angioedema, or anaphylaxis) to penicillins. Abbreviations: IM, intramuscular; IV, intravenous. Source: From Ref. 71.

asymptomatic with only mild laboratory abnormalities. This form is not considered a contraindication to elective surgery and these patients tolerate operation well (73,80). Chronic active hepatitis is a more ominous disorder, which, unlike chronic persistent hepatitis, may progress to cirrhosis. Mild, asymptomatic anicteric patients with chronic active hepatitis tolerate elective surgery well (80), whereas symptomatic patients with jaundice and significantly elevated serum liver function test levels have increased perioperative mortality. Elective operation is contraindicated in these cases (81).

Cirrhosis The Child-Turcotte classification is a well-known system that attempts to correlate the severity of cirrhosis (and therefore the hepatic reserve) with expected operative mortality (82). It grades the degree of ascites, encephalopathy, malnutrition, hyperbilirubinemia, and hypoalbuminemia in the cirrhotic patient. Although the classification was originally intended to evaluate patients undergoing portacaval

shunting, it has since been generalized to nonshunt surgery. Patients are classified (A, B, and C) according to the severity of hepatic insufficiency. Mortality rates of 0% to 10%, 4% to 31%, and 19% to 76% are quoted for classes A, B, and C, respectively, for portacaval shunts and nonshunt operations. In general, patients in Child class A tolerate surgery well, whereas patients in Child class C have a prohibitive operative mortality, thereby contraindicating elective surgery. Patients in Child class B must be assessed individually (Box 5). The preoperative preparation of the cirrhotic patient should include evaluation of the metabolic alterations including hyponatremia, hypoalbuminemia, glucose intolerance, and possible oxygen desaturation (73). Although these abnormalities may not be completely correctable preoperatively, they should be closely monitored both during and after operation. In addition, coagulation parameters must be evaluated and corrected preoperatively. Nutritional status should be optimized preoperatively when possible. Unfortunately, routine liver function biochemical

Table 6 Prophylactic Regimens for Genitourinary/Gastrointestinal (Excluding Esophageal) Procedures Situation

Agentsa

High-risk patients

Ampicillin plus gentamicin

High-risk patients allergic to ampicillin/amoxicillin

Vancomycin plus gentamicin

Moderate-risk patients

Amoxicillin or ampicillin

Moderate-risk patients allergic to ampicillin/amoxicillin

Vancomycin

a

Total children’s dose should not exceed adult dose. No second dose of vancomycin. Abbreviations: IM, intramuscular; IV, intravenous. Source: From Ref. 71.

b

Regimentb Adults: ampicillin 2 g IM or IV plus gentamicin 1.5 mg/kg (not to exceed 120 mg) within 30 min of starting procedure; 6 hrs later, ampicillin 1 g IM/IV or amoxicillin 1 g orally Children: ampicillin 50 mg/kg IM or IV (not to exceed 2 g) plus gentamicin 1.5 mg/kg within 30 min of starting procedure; 6 hrs later, ampicillin 25 mg/kg IM/IV or amoxicillin 25 mg/kg orally Adults: vancomycin 1 g IV over 1–2 hrs plus gentamicin 1.5 mg/kg IV/IM (not to exceed 120 mg); complete injection/infusion within 30 min of starting procedure Children: vancomycin 20 mg/kg IV over 1–2 hrs plus gentamicin 1.5 mg/kg IV/IM; complete injection/infusion within 30 min of starting procedure Adults: amoxicillin 2 g orally 1 hr before procedure, or ampicillin 2 g IM/IV within 30 min of starting procedure Children: amoxicillin 50 mg/kg orally 1 hr before procedure, or ampicillin 50 mg/kg IM/IV within 30 min of starting procedure Adults: vancomycin 1.0 g IV over 1–2 hrs; complete infusion within 30 min of starting procedure Children: vancomycin 20 mg/kg IV over 1–2 hrs; complete infusion within 30 min of starting procedure

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Box 5 Relative Hepatologic Contraindications for Elective Surgery Active, acute viral hepatitis Active, acute alcoholic hepatitis Fulminant hepatitis Icteric, symptomatic chronic active hepatitis Contemplated ileostomy or colostomy in a cirrhotic Contemplated abdominal surgery in OLT candidate PT greater than 3 seconds prolonged (despite vitamin K) Child C cirrhotic Abbreviations: OLT, orthotopic liver transplantation; PT, prothrombin time. Source: From Ref. 76.

tests (serum aminotransferase and alkaline phosphatase) tend to correlate poorly with the actual degree of hepatic impairment (73). With the availability and routine use of preoperative laboratory tests, the surgeon may encounter patients with unsuspected abnormal results from liver ‘‘function’’ tests while preparing for elective surgery. Although medical consultation may be obtained in these instances, the surgeon should be aware of the necessary further preoperative evaluation of these patients. History of recent drug use, past hepatitis or jaundice, blood transfusions, and general symptoms of liver disease, such as malaise, fatigue, and arthralgia, are important to elicit (83). Physical examination should include potential evaluation for the signs of chronic liver disease, such as cutaneous spider angiomata, parotid swelling, gynecomastia, palmar erythema, Dupuytren’s contractures, organomegaly, ascites, encephalopathy, and poor nutritional status. A serum albumin level and a coagulation profile to assess the functional ability of the liver complement serum levels of bilirubin, alkaline phosphatase, serum glutamic-oxaloacetic transaminase, serum glutamate pyruvate transaminase, and lactate dehydrogenase in assessing injury of the liver (83). Clearly patients with underlying liver disease are at increased surgical risk. Essential preoperative preparation of these patients must include correction of coagulopathy and electrolyte abnormalities (hypokalemia and hyponatremia), and control of ascites, hepatic encephalopathy, and infection (83). Specifically, the PT should be corrected to within three seconds of control, preferably with vitamin K. Massive ascites may require paracentesis preoperatively (83).

Risks of Kidney Disease The kidney performs several important functions, including filtration and elimination of nitrogenous wastes and regulation of fluid volume, electrolyte concentrations, acid–base balance, and blood pressure, and certain endocrine functions. Moreover, urine output in the patient with normal renal function provides an important, albeit indirect, indication of visceral perfusion. Impairment of renal function generally increases both the risk of operation and the incidence of postoperative complications (84–86). Despite the kidney’s many functions, renal insufficiency or failure in the surgical patient presents clinically as either oliguria or a rising serum creatinine level. Patients with preexisting renal disease may have hypertension, hypoalbuminemia, lethargy, or anorexia (87). Acute renal failure can be defined as a recent increase of serum creatinine of at least 0.5 mg/dL and reflects the inability of the kidneys to adequately eliminate nitrogenous wastes (88). Renal creatinine clearance is used to estimate the glomerular filtration

rate (GFR). The minimal obligatory urine volume output for an adult is 0.5 mg/kg/hr (1.0 mg/kg/hr in children), although nonoliguric renal failure may be present with seemingly adequate urine volumes. Chronic renal insufficiency predisposes the patient to further renal injury from either hypoperfusion or nephrotoxins (89). Acute renal failure is due either to prerenal, postrenal, or intrarenal lesions. Prerenal azotemia results from renal hypoperfusion; although this azotemia is reversible, it will progress to ischemic acute tubular necrosis (ATN) with continued hypoperfusion (88). Homeostatic mechanisms maintain renal blood flow and GFR in the presence of hypovolemia or hypotension. The oliguria and azotemia seen in the prerenal state represents autoregulation with reabsorption of sodium and water to maintain or expand the effective circulating volume (88). Causes of prerenal azotemia include hypovolemia, sepsis, neurogenic shock, congestive heart failure, and hepatorenal failure (90). Whereas sodium and water reabsorption with circulating volume expansion is an appropriate response with a low effective circulating volume, it is an inappropriate response in congestive heart failure, which is characterized by an excessive circulating volume (fluid overload). Restoration of renal perfusion reverses prerenal azotemia. This requires volume administration in hypovolemia, and diuresis in congestive heart failure. Generally, the diagnosis of prerenal azotemia is supported by a high blood urea nitrogen/creatinine ratio (> 20:1), a low urine sodium (UNa < 20), or a low fractional excretion of sodium (FENa < 1%) (88,89). Intrarenal acute renal failure may occur from a number of diseases, including the glomerulonephritides; but the most common form encountered in the surgical patient is ATN. ATN results from injury to the renal tubular epithelium, which is responsible for maintaining selective permeability to water and other solutes in ultrafiltrate, as well as for active transport of electrolytes, as is seen in the loop of Henle. Injury may result from hypoperfusion and ischemia or from any number of nephrotoxins. ATN may lead to either oliguric (< 400 mL/day) renal failure or nonoliguric renal failure. The renal injury resulting in nonoliguric ATN is less severe than that resulting in the oliguric form (88). The causes of ischemic ATN are the same as those resulting in prerenal azotemia, although the insult is more severe. Hypovolemic shock, septic shock, neurogenic shock and congestive heart failure, or cardiogenic shock may result in ATN. Generally, ischemic ATN follows a recognizable period of profound hypotension (88). The progression from prerenal azotemia to ATN represents a continuum; often restoration of renal perfusion restores some degree of renal function, representing the tubules of those nephrons that have not yet succumbed to ischemia. The diagnosis of ATN is supported by the presence of tubular casts on urinalysis, a high UNa (> 40) and a high FENa (> 4%) (87,89). Toxins leading to ATN include heme pigments (from myoglobin and hemoglobin), drugs (aminoglycoside antibiotics), and radiographic contrast agents. With rhabdomyolysis, myoglobin released into the circulation is filtered across the glomerulus. It precipitates in the lumen of the renal tubule; under acidic conditions, the heme moiety dissociates from the protein component and is taken up and metabolized by the tubular epithelium, to which it is ultimately toxic. Hemoglobinuria following massive hemolysis, as in transfusion reactions, causes ATN in an analogous fashion. ATN is prevented by maintaining

Chapter 13: Physiologic Principles in Preparing Patients for Surgery

high urine flow rates and alkalinizing the urine to prevent dissociation of the heme pigment from the globin. Aminoglycosides and radiographic contrast agents may both cause ATN in a dose-dependent fashion, possibly by direct toxicity to the tubular epithelium. These agents potentiate the injury incurred by ischemia or other nephrotoxins and are particularly toxic in the face of preexisting renal insufficiency. Obstructive jaundice results in postoperative ATN in approximately 16% to 18% of patients. The mortality rate of renal failure in this setting correlates with serum bilirubin levels (91). Obstructive jaundice causes a decrease in total peripheral resistance, either because of peripheral vasodilation or an impairment of the vasoconstrictor response to pressor agents. This leads to a decrease in the effective plasma volume and explains the exaggerated hypotensive response seen with hemorrhage (91,92). Moreover, obstructive jaundice also decreases renal blood flow (91,92). The postoperative renal failure seen with obstructive jaundice may simply represent an ischemic ATN related to impaired hemodynamic responses and resultant hypotension, although endotoxin may also play a role. Bile salts bind and inactivate endotoxin, thereby preventing its absorption from the gut lumen (92). The absence of bile salts in the gut lumen, as seen with obstructive jaundice, results in endotoxemia. This may explain the systemic and intrarenal hemodynamic effects seen with obstructive jaundice (91,92). The use of oral bile salts appears to prevent endotoxemia (83). Preoperative external biliary drainage has not been shown to be effective in decreasing the incidence of postoperative renal failure (92). Current recommendations include preoperative hydration, avoidance of nephrotoxic agents, preoperative administration of mannitol (500 mL of 10% mannitol infused for a period of one to two hours prior to operation), and oral administration of bile salts preoperatively (sodium deoxycholate 500 mg every eight hours for 48 hours) (92). The perioperative use of low-dose dopamine (3 mg/kg/min) appears not to be of benefit (93). Postrenal azotemia results from obstructive uropathy (85,88). This commonly results from urethral obstruction, either caused by prostatic hypertrophy (in men) or Foley catheter blockage. Unilateral ureteric obstruction does not generally result in azotemia, because the contralateral kidney compensates by hyperfiltration (90). If the obstruction is relieved early, postrenal azotemia is reversible. Persistent obstruction results in irreversible renal injury (94). Foley catheterization usually excludes bladder outlet obstruction, although the Foley catheter itself may be occluded by blood clots or fibrinous exudate. Renal ultrasonography is useful to rule out ureteric obstruction (95). Chronic renal failure may result from any number of causes, including atherosclerosis, diabetes, hypertension, glomerulonephritis, ischemia, or exposure to nephrotoxins (90). It must be recognized that these patients may lack the ability to concentrate or dilute their urine in response to fluid shifts or electrolyte disturbances (96). Therefore fluid balance and electrolyte concentrations must be monitored meticulously. Excessive administration of potassium, magnesium, and phosphate should be avoided. Dosages of drugs that undergo renal excretion should be decreased according to the patient’s estimated GFR. Exposure to nephrotoxins should be avoided. Chronic renal failure may also be associated with anemia, which should be corrected preoperatively (96,97). Risk factors for the development of perioperative renal failure include preexisting renal insufficiency, diabetes

283

mellitus, advanced age, jaundice, and aortic or cardiac surgery (85,98). To preserve renal function, patients should be well hydrated prior to surgery and prior to the administration of potentially nephrotoxic agents. Fluid shifts and electrolyte loads should be minimized. Hypotension should be avoided. Invasive hemodynamic monitoring with pulmonary artery catheterization should be considered both in patients requiring cardiac optimization and in those undergoing surgery in which large fluid shifts can be anticipated. In the presence of oliguria, postrenal factors should be excluded, urine output should be carefully monitored, and prerenal factors (either hypovolemia or inadequate cardiac function) should be corrected (96,97). Patients with ESRD requiring dialysis have an increased risk for perioperative morbidity and mortality (86,99). These patients have a high incidence of associated diseases, including diabetes mellitus, hypertension, and coronary artery disease. Complications include hyperkalemia, sepsis, hemorrhage, cardiac dysfunction, and hemodynamic instability (86). Anemia is common because of decreased erythropoietin production. A hematocrit less than 25% should be corrected, either electively with recombinant human erythropoietin or emergently with blood transfusion (96,100). The qualitative platelet dysfunction may be due to circulating guanidinosuccinic and hydroxyphenolic acids, which inhibit platelet factor 3 activity (101). Dialysis improves platelet function, as will administration of cryoprecipitate, 1-deamino-8-d-arginine vasopressin (DDAVP), or conjugated estrogens. Platelet transfusions are used for significant hemorrhage (101). Ideally, the patient with ESRD should receive dialysis within 24 hours of operation (97). Excessive hydration should be avoided. In patients with significant coronary artery disease, invasive hemodynamic monitoring should be considered.

Risks of Endocrine Disease Diabetes Mellitus Diabetes mellitus is a common disorder or carbohydrate metabolism with an estimated prevalence of between 2% and 5% in the United States (102). The hyperglycemia associated with diabetes results from either a deficiency of insulin (type I) or a resistance to its action (type II). Complications from diabetes mellitus are common and include diabetic retinopathy, nephropathy, neuropathy, and an accelerated atherosclerosis. Diabetic sensory neuropathy usually has a ‘‘stocking and glove’’ distribution. Diabetic autonomic neuropathy may lead to postural hypotension, arrhythmias, gastroparesis, and urinary retention. Diabetes is the most common cause of blindness in the United States and is responsible for more than 25% of new cases of ESRD, and for more than 50% of all lower extremity amputations (103). As a result of the expected long-term sequelae of diabetes mellitus, approximately 50% of all diabetic patients eventually require surgery (104). Because of the high incidence of coronary artery disease and renal dysfunction in this population, the expected perioperative morbidity and mortality in the diabetic patient are higher than that of the nondiabetic patient (102). Furthermore, defects in wound healing and the immune system condemn the diabetic patient to a higher rate of wound complications (105–107). Although no prospective study demonstrates an improved surgical outcome in the euglycemic as opposed to the hyperglycemic patient (108), hyperglycemia may lead to profound fluid and electrolyte depletion, altered immune function, and impaired wound healing (105– 107,109). Adequate insulin administration corrects the defects in granulocyte and fibroblast function seen with

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hyperglycemia (110). Intuitively, it would seem that perioperative glycemic control should minimize surgical risk. Achieving glycemic control may be challenging because of the diabetogenic response elicited by the stress of surgery, anesthesia, and inflammation (108). Part of the response to stress is an increased release of the counter-regulatory hormones (epinephrine, glucagon, cortisol, and growth factor), each of which either directly or indirectly stimulate glucose production (108). In addition, these hormones are primarily catabolic, thereby promoting significant lipolysis and ketogenesis (108).

Preoperative Assessment Prior to operation, the patient’s type of diabetes should be determined and the patient’s regimen for glycemic control should be clearly ascertained. The adequacy of recent glycemic control may be determined by reviewing blood glucose records and by obtaining a glycosylated hemoglobin level. Patients taking oral hypoglycemics should be screened for episodes of profound hypoglycemia, which is a common complication of these medications. Complications of diabetes should be identified preoperatively as well. Thus a thorough assessment of cardiovascular status and a determination of renal function (screening serum creatinine) are necessary, as is identification of any diabetic sensory or autonomic neuropathy.

Insulin and Fluid Administration Plasma glucose levels should be tightly controlled perioperatively, avoiding hypoglycemia and hyperglycemia. The stress response to infection, inflammation, and surgery increases plasma glucose levels. Even moderate elevations in plasma glucose levels may result in glycosuria and therefore an osmotic diuresis. Although this may lead to volume depletion and electrolyte disturbances in non– insulin-dependent patients, it may progress to overt diabetic ketoacidosis in those who are insulin dependent (108). If diabetic ketoacidosis is present, operation must be postponed until the patient’s fluid volume is restored and the pH, electrolyte, and glucose levels are corrected (102). Preoperatively, the insulin dose must be adjusted for the fasting patient. All diabetic patients, both insulin dependent and non–insulin dependent, should receive insulin therapy during surgery (111). Indications for insulin therapy are summarized in the Box 6. A number of acceptable regimens for administration have been described, and no single regimen has been proved to be superior (111). A common regimen used for insulin-dependent patients is to give fasting patients one-half of their usual morning dose of intermediate-acting insulin subcutaneously on the morning of operation. The serum glucose is then checked every two to four hours and supplemental intermediate-acting insulin is administered according to a sliding scale dosage. This is continued until the patients can eat normally and resume their usual regimen. Subcutaneous administration of insulin may result in erratic absorption and unpredictable serum levels, particularly with the hemodynamic changes seen perioperatively (108,112–114). Intravenous administration of insulin offers the theoretic advantage of more predictable serum levels of insulin. Table 7 provides a guideline for perioperative intravenous insulin administration. Although fixed-rate insulin infusions offer no proven advantage over subcutaneous administration (109,113), variable-rate infusions may be more useful to stabilize glucose levels (115). Continuous

Box 6 Indications for Insulin Therapy During an Operation Always All patients taking insulin—both insulin-dependent diabetes mellitus and NIDDM Patients with NIDDM treated with diet, oral hypoglycemic agents, or both, but having chronic hyperglycemia (FBG > 10 mmol/L and glycosylated Hb > 0.1) Variable Patients with NIDDM treated with diet, oral hypoglycemic agents, or both, under good control Current FBG  10 mmol/L Glycosylated Hb 0.08–0.1 Duration of operation less than 2 hrs Use of glucose solutions not planned Abbreviations: FBG, fasting blood glucose; Hb, hemoglobin; NIDDM, noninsulin-dependent diabetes mellitus. Source: From Ref. 111.

intravenous insulin infusion is clearly superior to other methods when used intraoperatively (116), although this unfortunately remains an underutilized technique (117). If continuous intravenous insulin infusion is used, it generally is continued until the patient begins to eat (108,118). Preoperative intravenous fluids should provide dextrose to prevent hypoglycemia and the accumulation of ketones and free fatty acids. Five percent dextrose should be added to maintenance intravenous fluids, generally halfnormal saline, running at roughly 1 mL/kg/hr for adults. Because lactate is a gluconeogenic precursor, lactated Ringer’s solution administered at a high infusion rate may produce hyperglycemia (119). Thus additional fluid requirements should be met with dextrose-free solutions.

Cortisol Metabolic Dysfunction Cortisol is synthesized, stored, and secreted from cells of the adrenal cortex. Release is controlled primarily by the anterior pituitary hormone adrenocorticotropic hormone (ACTH). Cortisol influences the metabolism of glucose, amino acids, and fatty acids and potentiates the actions of glucagon and epinephrine in the liver. Cortisol secretion, in response to increased ACTH production, is increased by acute stress including fever, pain, hemorrhage, and operative trauma. The glucocorticoid activity of cortisol maintains the responsiveness of small vessels to catecholamines, thereby maintaining vascular tone. Moreover, glucocorticoids influence the distribution of total body water to maintain intravascular volume (120,121). Insufficient cortisol release in response to stress may be life threatening. It may result from primary adrenal gland insufficiency (addisonian crisis) or from suppression of the hypothalamic-pituitary-adrenal cortical axis, as is seen with chronic steroid therapy. Signs and symptoms of chronic adrenal insufficiency are nonspecific and include weakness, nausea, fever, weight loss, lethargy, and even delirium. Hyponatremia and hyperkalemia result from mineralocorticoid (aldosterone) deficiency. Hypoglycemia may reflect glucocorticoid deficiency leading to diminished hepatic gluconeogenesis, even with elevated levels of glucagon and epinephrine. Hypercalcemia is also seen, and blood count differentials may reveal eosinophilia (121). Acute adrenal insufficiency presents clinically as hypotension with a high cardiac output and a

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Table 7 Algorithm Guidelines for Perioperative Diabetes Management of Separate Insulin and Glucose Infusions Insulin Regular, 25 U, in 250 mL normal saline (1 U/10 mL) Infuse insulin intravenously from an infusion pump; flush 50 mL through line before connecting to patient; piggyback this line to the perioperative maintenance fluids infusion line Monitor blood glucose levels hourly during operation and every 2–4 hr before and after operation once stable Perioperative maintenance fluids must contain dextrose (5%) Do the initial blood glucose measurement ‘‘stat’’ in the clinical laboratory Blood glucose mmol/L 4.4 4.5–5.5 5.6–7.8 7.9–10 10.1–12.2 12.3–14.4 14.5–16.6 16.7–18.9 > 18.9

Insulin mg/dL

U/hr

mL/hr

Fluids (mL/hr)

 80 81–100 101–140 141–180 181–220 221–260 261–300 301–340 > 341

0 0.5 1 1.5 2 2.5 3 4 5

0 5 10 15 20 25 30 40 50

125 125 125 125 125 100 100 100 100

Blood glucose  4.4 mmol/L, bolus with 50% dextrose in water (25 mL); once blood glucose > 4.4 mmol/L, restart insulin infusion and recheck in 30 min. Decreased insulin needs patients treated with diet, oral agents, or < 50 U insulin per day. Increased insulin needs sepsis, steroid therapy (renal transplantation), coronary artery bypass. If high-dose insulin is anticipated, a more concentrated insulin solution should be prepared to avoid excessive fluid intake. Source: From Ref. 111.

low systemic vascular resistance that is resistant to pressors but responds to glucocorticoid administration (122). Although circulatory collapse caused by adrenal insufficiency is a decidedly uncommon complication of surgery (0.01–0.7% of cases) (123), patients at risk should be identified to receive perioperative stress doses of glucocorticoids. The functional status of the hypothalamicpituitary-adrenal cortical axis should be assessed for patients receiving chronic glucocorticoid therapy, particularly if they show signs of Cushing’s syndrome. While a plasma cortisol level of greater than 500 nmol/L is suggestive of adequate adrenal function, the 30-minute ACTH stimulation test provides an accurate screening test for adrenal dysfunction (123). Recommended stress doses of steroids typically consist of 50 to 100 mg of hydrocortisone given intravenously every six to eight hours, followed by a steroid taper (122). In a recent review, Salem et al. (123) recommended basing glucocorticoid dosing on the magnitude of surgical stress. They recommended the following dosing guidelines: Minor surgical stress: 25 milligrams of hydrocortisone equivalent per day for 1 day Moderate surgical stress: 50–75 milligrams of hydrocortisone equivalent per day for 1 to 2 days Major surgical stress: 100–150 milligrams of hydrocortisone equivalent per day for 2 to 3 days These doses may be continued for postoperative complications that extend the stress response. Patients already receiving baseline glucocorticoid therapy in excess of these recommended stress doses probably do not require additional perioperative coverage.

Pheochromocytoma Pheochromocytomas are rare endocrine tumors of neural crest cells in the adrenal medulla or sympathetic ganglia that secrete catecholamines, often in dangerously high concentrations.

While the majority are located within the adrenal glands, approximately 6% are ectopic. Ten percent of pheochromocytomas may be bilateral (124), and 8% to 10% are malignant (125). These tumors account for hypertension in less than 0.1% of all patients, but they are estimated to cause the deaths of approximately 1000 Americans each year (126). Preoperative preparation of patients known to have this tumor is of major importance if the risks of excess catecholamine release such as malignant hypertension, stroke, myocardial infarction, or death are to be reduced. Suspicion of a pheochromocytoma should be heightened in a patient with unexplained episodic or sustained hypertension, headache, palpitations, and excessive sweating (127) precipitated by stimuli such as stress, exercise, or sexual activity. Other less common symptoms include nervousness and anxiety, tremor, nausea with or without vomiting, weakness, and weight loss. In those patients known to have a pheochromocytoma, preoperative localization is essential to safe, rapid surgical management. Occasionally, pheochromocytomas are found intraoperatively during an unrelated procedure or in females during pregnancy or parturition. In these situations, blood pressure and fluid management becomes critical. Determination of the 24-hour urinary catecholamine levels with or without epinephrine–norepinephrine fractionation (124) is used to confirm the diagnosis. Ninety-eight percent of patients with a pheochromocytoma have an elevated serum or urinary catecholamine level (128). Plasma catecholamine levels greater than 2000 pg/mL are considered diagnostic of a pheochromocytoma. Epinephrine–norepinephrine fractionation has been successfully used in those patients with normal total catecholamine levels, in whom pheochromocytoma is strongly suspected. An epinephrine fraction of greater than 20% correlates with a pheochromocytoma. Pheochromocytomas 1 cm in size or greater are best localized by computed tomography (CT) scan (124,125). If CT scan fails to demonstrate the lesion, selective arteriography should be performed (125). Ultrasound or magnetic resonance imaging may be helpful in pregnant patients.

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Metaiodobenzylguanidine scintigraphy is most useful for extra-adrenal, recurrent, or metastatic disease (128). Surgical excision is the treatment for pheochromocytomas and should be performed before other elective procedures. Appropriate preoperative preparation reduces the morbidity and mortality associated with possible catecholamine release during induction of anesthesia or surgical manipulation of the tumor. Preoperative alpha-adrenergic blockade serves to re-expand plasma volume, control hypertension, and minimize blood pressure fluctuations intraoperatively. Phenoxybenzamine, 10 to 20 mg three to four times daily for 7 to 10 days before operation, blocks both postsynaptic (alpha1-) and presynaptic (alpha2-) adrenergic receptors (125). More recently, prazosin, a selective alpha1-blocker, has been used (2–5 mg twice daily) (125), which provides acceptable alpha-adrenergic blockade with fewer side effects (124). Preoperative beta-blockade is not routinely necessary in the absence of tachyarrhythmias. Should arrhythmias arise intraoperatively, intravenous propranolol can be administered (124,125). Beta-blockade should never be administered prior to alpha-blockade, because it may induce a pressor response, causing severe hypertension.

Thyroid Dysfunction The normally functioning thyroid gland synthesizes, stores, and releases the thyroid hormones thyroxine (T4) and triiodothyronine (T3). These regulate many aspects of cellular metabolism, including oxygen consumption and heat production, as well as potentiate the effects of the sympathetic nervous system. Release of these hormones into the circulation is mediated by thyroid-stimulating hormone (TSH) produced by the pituitary gland, which itself is regulated by a classic negative feedback system (129). Thyroid hormone concentrations can be altered either as a result of primary thyroid dysfunction or the physiologic disturbances mediated by the body’s stress response. Major operative trauma or injury impairs the normal peripheral conversion of T4 to T3, in part due to a rise in serum cortisol. Both circulating T3 level and the total T4 concentration are reduced, but without the expected rise in TSH concentrations. Presumably, total T4 concentration is decreased with injury, whereas free T4 levels remain normal (129). Hyperthyroidism, or thyrotoxicosis, results from excessive release of thyroid hormone and is associated with signs and symptoms of heat intolerance, sweating, palpitations, increased appetite, weight loss, and fatigue. More worrisome signs are tachycardia, atrial fibrillation, heart failure, and myopathy, which may develop in some patients. Thyrotoxicosis must be both recognized and treated prior to operation. Euthyroidism is the goal of preoperative treatment in order to avoid thyroid storm, which may be precipitated by the stress of anesthesia or surgery. Thyrotoxicosis is usually corrected preoperatively with a combination of antithyroid medication (methimazole or propylthiouracil) to inhibit thyroid hormone synthesis and exogenous thyroxine to counteract the trophic effects of TSH, thereby decreasing the vascularity of the gland (130). Beta-blockade is now standard therapy to control tachycardia and the hypertension perioperatively. Propranolol has been widely used, titrating the dose to maintain the pulse rate less than 80 to 100 beats/min. More recently, selective beta1-blocking agents such as metoprolol have been used to avoid bronchospasm in patients with reactive airway disease. The exclusive use of beta1-blockade to

control thyrotoxicosis perioperatively has been advocated to avoid the low, but finite, incidence of agranulocytosis seen with the antithyroid agents. A prospective randomized trial compared the use of metoprolol to antithyroid agents for control of hyperthyroidism in patients undergoing thyroid surgery. There were no anesthetic or cardiovascular complications in either group; nor was any difference in consistency or vascularity of the gland noted (131). Hypothyroidism is relatively common, occurring in approximately 2% of the adult female population (132). Signs and symptoms include cool dry skin, ‘‘puffy’’ features, cold intolerance, constipation, hoarseness, dry hair, brittle nails, nonpitting edema, slowed reflexes, and bradycardia. Hemodynamically, hypothyroidism is characterized by a low cardiac index, decreased stroke volume, decreased vascular volume, and an increased systemic vascular resistance (133,134). Up to 30% of untreated patients may have pericardial effusions (135). Hypothyroid-induced hypertension (136) and defects in lipid metabolism predispose these patients toward atherosclerosis. The diagnosis of primary hypothyroidism is confirmed by low serum T4 levels and elevated TSH levels. Surgical complications in patients with hypothyroidism include intraoperative hypotension and altered drug metabolism. Gastrointestinal and neuropsychiatric complications are more prevalent, but the risk of infection, operative bleeding, perioperative arrhythmias, hypothermia, and hyponatremia is not increased. Moreover, hypothyroidism predisposes toward heart failure during cardiac surgery (137). The hypothyroidism should be corrected toward euthyroidism prior to elective surgery, although this may be difficult in the patient with preexisting atherosclerotic coronary artery disease. The chronotropic and inotropic effects of thyroid hormone increase myocardial oxygen consumption, potentially leading to myocardial ischemia. Empiric recommendations exist for hormone replacement in patients with hypothyroidism and known or suspected ischemic heart disease. L-Thyroxine is started at a low dose of 25 mg/day and increased in 12.5 to 25 mg increments at four- to six-week intervals. Although the dose is usually reduced if worsening myocardial ischemia is evident, alternatively, beta-blocking agents may be added (132). Myocardial revascularization is indicated in patients unable to tolerate thyroid replacement (132).

RISKS OF HEMATOLOGIC DISEASE Appropriate management of the surgical patient with a known hematologic disorder is extremely important to avoid potentially disastrous complications. More subtle, but no less important, is the workup of the patient in whom a hematologic abnormality is discovered incidentally on routine preoperative testing.

Anemia Preparation of the anemic patient involves consideration not only of the degree of anemia but also the cause of the anemia and how this may affect the patient’s perioperative course (138). The common assertion that the preoperative hemoglobin level should be at least 10 g/dL to avoid complications is not supported in the literature (138). An otherwise healthy patient undergoing minor surgery should tolerate a hemoglobin level of 7 to 8 g/dL. A patient with significant COPD requiring general anesthesia should have a hemoglobin level of at least 10 g/dL even for minor

Chapter 13: Physiologic Principles in Preparing Patients for Surgery

surgery. In general, if significant blood loss is likely or if the general health status of the patient is questionable, the hemoglobin level should be kept around 10 g/dL (139). Workup of the anemia should proceed prior to surgery, because this may uncover a condition (i.e., occult malignancy) that would alter the operative plan (140). Infection from blood transfusion involves a small, but finite, risk. With this in mind it becomes reasonable to determine a ‘‘safe’’ level of hemoglobin on an individual basis taking into consideration patient volume status, cause and chronicity of anemia, age, underlying cardiovascular disease, type of surgery, and anticipated blood loss (138). Postoperatively, mild-to-moderate anemia has not been shown to have an adverse effect on wound healing (141). History, physical examination, and a few routine laboratory tests can usually determine the cause of the anemia. Table 8 shows which tests are helpful in determining the various causes. The surgical patients with sickle cell anemia may have significant comorbidities in addition to anemia, including cardiomyopathy, congestive heart failure, chronic pulmonary disease, renal insufficiency, nephrotic syndrome, chronic liver disease, and other organ dysfunction. These patients usually have normal or increased blood volume and generally tolerate chronic hemoglobin levels of 6 to 9 g/dL without difficulty. Transfusions in these patients are not routinely necessary simply to increase oxygen-carrying capacity, nor are they considered necessary for most surgical procedures (138). For major surgery in which hypoxia, hypotension, or acidosis are likely to occur, exchange transfusions to reduce the hemoglobin S fraction to approximately 20% to 30% of total hemoglobin may be beneficial (142). The patient with an immunohemolytic anemia must be clearly identified and referred to the blood bank far in advance of surgery, because finding compatible crossmatched blood may be extremely difficult, if not impossible, in the event of hemorrhage (140).

Polycythemia Polycythemia or erythrocytosis can be classified as relative or absolute. Relative erythrocytosis is the result of reduced plasma volume. Absolute erythrocytosis is further classified as either primary or secondary. Primary erythrocytosis or polycythemia vera is a neoplastic disorder characterized by increased red blood cell mass, splenomegaly, thrombosis, and leukocytosis. Secondary polycythemia can be physiologically appropriate in association with pulmonary disease, cardiac disease, or high altitudes. Polycythemia may be physiologically inappropriate as seen in patients with renal

287

cysts or tumors of the kidney, liver, uterus, and posterior fossa (138). Patients with polycythemia vera and its associated high hematocrit are known to have increased surgical morbidity and mortality likely caused by the increased risk of thromboembolic events (143,144). Once the cause of the erythrocytosis has been determined, phlebotomy is used to decrease the hematocrit to an acceptable level. Phlebotomy is usually performed by removing 350 to 500 mL of blood every other day until the appropriate hematocrit is reached. Lesser amounts (200–300 mL) should be removed each time in the elderly or those patients with cardiac disease (138). In primary polycythemia vera, the hematocrit should be decreased to less than 45% prior to surgery (138). In patients with physiologically inappropriate erythrocytoses, the hematocrit should be reduced to at least 45% to 50% as well. In cases in which erythrocytosis is physiologically appropriate, one must weigh the risk of thromboembolic events against the risk of decreasing the oxygen-carrying capacity in a patient with cardiac or pulmonary compromise. For these patients, reducing the hematocrit to approximately 50% to 60% is suggested (145).

Disorders of White Blood Cells Abnormalities in white blood cell count, either leukopenia or leukocytosis, are usually associated with an underlying disease. As a result, the perioperative risks often are related to the underlying disorder. Leukocytosis may be seen with infections, neoplasms, or leukemia. Leukopenia may be seen with radiation, chemotherapy, or overwhelming infection (138). An absolute neutrophil count of less than 1000/mL is associated with a higher incidence of bacterial infections (140). Elective surgery should probably be postponed in the face of severe leukopenia. If urgent operation is required, the patient should be aggressively monitored for infection (138,140).

Platelet Disorders Platelet dysfunction must be characterized as either quantitative or qualitative. The patient with thrombocytopenia but without a qualitative platelet function defect has abnormal bleeding related to the platelet count. In general, excessive bleeding, even with severe trauma, is rare with a platelet count greater than 100,000/mL. Platelet counts greater than 50,000/mL are considered adequate for most surgical procedures. Higher counts are usually preferable for most cardiac, neurologic, and some ophthalmologic surgery (138,140). In addition, bleeding risk must be considered in any patient with fever, infection, sepsis, or anemia regardless of the platelet count (138,140).

Table 8 Laboratory Tests to Determine the Cause of Anemia Laboratory value Reticulocyte count Mean corpuscular volume Mean corpuscular volume Red blood cell

Source: From Ref. 138.

Abnormality High Low High with low reticulocyte count Low with low reticulocyte count Low with normal mean corpuscular volume (normocytic anemia)

Further tests to consider

Possible diagnosis

Hemolysis Decreased red blood cell production Macrocytic anemia secondary to vitamin B12, or B12 and folate levels, liver function tests, thyroid function tests, bone marrow folate deficiency, liver disease, hypothyroidism, examination or primary marrow disorders Serum iron, total iron-binding capacity, ferritin Iron deficiency, chronic malignant or inflammatory disease, thalassemia minor level, hemoglobin A2 Renal function tests, Coombs’ test, erythrocyte Uremia, chronic disease, hemolysis, or bone sedimentation rate, lactate dehydrogenase, marrow depression bilirubin

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Part One: General Considerations

Evaluation of thrombocytopenia should identify the cause as being related to either decreased production, sequestration, or increased destruction. Patients with primary production problems such as those secondary to neoplasms, aplastic anemia, or chemotherapeutic agents tend to show erythrocyte and leukocyte abnormalities as well (138). Thrombocytopenia resulting from sequestration is seen with hypersplenism with or without splenomegaly. An accompanying anemia and leukopenia is seen with a normal marrow (138). Thrombocytopenia secondary to increased platelet destruction can be seen with the use of certain drugs, infection, idiopathic thrombocytopenia purpura (ITP), or disseminated intravascular coagulation (DIC) (138). Drug-associated platelet dysfunction such as that seen with salicylates usually corrects within one week following discontinuation of the drug. Some drugs have a more prolonged effect and so repeated count and function should be obtained prior to proceeding with operation. Elective surgery should be postponed until the platelet defect is characterized and the underlying disorder is treated (140,146). A low platelet count due to increased platelet destruction is unlikely to be improved by platelet transfusion. For nonelective surgery, if pathologic bleeding occurs, or if no therapy is available for the underlying disorder, platelet transfusion is appropriate (140,146). In general, one unit of platelets will raise a platelet count by approximately 5000 to 10,000/mL. For platelet consumption and bleeding due to DIC, the underlying cause must be treated and the patient should be transfused with platelet concentrates and fresh frozen plasma (138). Although the normal lifespan of newly produced platelets is approximately 8 to 10 days, the expected lifespan of transfused platelets is between several hours and three days (140). A posttransfusion platelet count is necessary before proceeding with surgery (138,140). Steroids are the initial therapy for ITP. When a response is seen, splenectomy can be considered with the planned operative procedure. For patients not responding to steroids, splenectomy should be performed prior to elective surgery in an attempt to improve platelet counts. Preoperative intravenous gamma globulin should be given to patients unresponsive to steroid or splenectomy (138).

Coagulation Defects Adequate hemostasis is crucial to successful surgery. The history and physical examination are the most valuable screens for potential coagulation defects. However, as technology advances and more screening tests become available to the physician, one must consider which tests are appropriate. Several studies have looked at how useful and

accurate some of these screening tests are and which ones, based on the history and surgery to be performed, should be obtained preoperatively (146). History should focus on any excessive bleeding with previous surgery, trauma or tooth extraction, drug use, renal or liver disease or any family history of bleeding disorders (138). Physical examination should focus on petechiae, ecchymoses, jaundice, or hepatosplenomegaly (138). Although history and physical examination are vital, laboratory screening tests are necessary for several reasons. They may protect against the failure to elicit an adequate history preoperatively. Some patients may not provide a reliable history. The patient may have a coagulation abnormality that causes bleeding only after surgery (e.g., factor XI deficiency), and the patient may never have had a surgical procedure. Moreover, a patient having undergone previous surgery may have only recently developed a coagulopathy (146). A preoperative screening questionnaire is recommended to identify the patient at risk (Box 7). Patients undergoing minor surgery with no suspicious bleeding history require no further studies (138,146). PT, activated partial thromboplastin time (aPTT), and a platelet count should be assessed in patients having a major operation with no evidence of a bleeding history (147). A bleeding time should also be obtained in any patient with a suspicious or suggestive history, who will be undergoing major surgery. This is particularly important in cardiac bypass surgery or prostate surgery where hemostasis could be further impaired or in any type of surgery in which excessive bleeding could be catastrophic (neurosurgery or ophthalmologic surgery) (138). In general, the aPTT evaluates the intrinsic pathway of the coagulation cascade, whereas the PT evaluates the extrinsic and common pathway. Prolongation of the aPTT can be caused by a deficiency of factor XI, antibodies against a specific coagulation factor, by von Willebrand’s disease (factor VIII RWF deficiency), or by a deficiency of factor VIII or IX (hemophilia A or B) in males (138). Lupus anticoagulant causes an artifactual prolongation of the aPTT but actually leads to a hypercoagulable state. Prolongation of the PT can be seen with factor VII deficiency, vitamin K deficiency, or liver disease. A prolongation of both the PT and aPTT is seen with liver disease, DIC, or vitamin K deficiency (138,140). Patients with known hemophilia A (factor VIII deficiency) can be treated specifically with factor VIII concentrate. Patients with severe hemophilia undergoing major surgery should receive 40 U/kg of factor VIII concentrate immediately before surgery (138,140). Postoperatively, the

Box 7 Preoperative Hemostatic Evaluation Have you ever bled for a long time or developed a swollen tongue or mouth after cutting or biting your tongue, cheek, or lip? Do you develop bruises larger than a silver dollar without being able to remember when or how you injured yourself? If so, how big was the largest of these bruises? How many times have you had teeth pulled, and what was the longest time that you bled after an extraction? Has bleeding ever started up again the day after an extraction? What operations have you had, including minor surgery such as skin biopsies? Was bleeding after surgery ever hard to stop? Have you ever developed unusual bruising in the skin around an area of surgery or injury? Have you had a medical problem within the past 5 yr requiring a doctor’s care? If so, what was its nature? What medications, including aspirin or any other remedies for headaches, colds, menstrual cramps, or other pains, have you taken within the past 7 to 9 days? Has any blood relative had a problem with unusual bruising or bleeding after surgery? Were blood transfusions required to control this bleeding? Source: From Ref. 146.

Chapter 13: Physiologic Principles in Preparing Patients for Surgery

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bleeding correlates with the efficacy of a particular prophylaxis regimen. It is therefore important to stratify the risk of VTE (Table 9), as well as identify the appropriate prophylaxis regimen for each level of risk (Tables 9 and 10) (149).’’

dose is tapered according to the surgery performed, continuing longer for more major procedures. Patients with minor hemophilia undergoing major operative procedures can also be managed with cryoprecipitate that contains factor VIII. In addition, DDAVP can be used in mild hemophilia to raise factor VIII levels to the normal range (138). Patients with known hemophilia B (factor IX deficiency) can be treated similarly to those with hemophilia A. Factor IX concentrate is available; however, it contains activated clotting factors, and therefore the patient must be carefully monitored for thrombotic complications. Preoperative preparation of the patient with von Willebrand’s disease includes the use of DDAVP. A test dose is given preoperatively to evaluate response. Cryoprecipitate should be used for major surgical procedures (138). Liver disease can cause coagulation abnormalities by several mechanisms. The treatment and workup of coagulation problems associated with hepatic disease were discussed earlier in the chapter.

HIV INFECTION AND AIDS Patients infected with the human immunodeficiency virus (HIV), both those who have asymptomatic HIV and those who have progressed to the acquired immunodeficiency syndrome (AIDS), have a greater risk of morbidity and mortality, presumably because of their immunosuppression (150–156). The diagnosis of AIDS requires a positive HIV serology and the presence of either opportunistic infections, opportunistic tumors, neurologic complications resulting in encephalopathy, CD4þ T-lymphocyte percentage of less than 14%, or an absolute CD4þ count of less than 200/mm3 (154). Patients with end-stage AIDS can be expected to have a very poor outcome with surgical intervention, and so only conservative, palliative care should be offered to these patients. The difficulty remains, however, in identifying those HIV-positive and non–end-stage AIDS patients who may benefit from surgical intervention. ‘‘In general, HIV-positive patients on retroviral therapy are presenting for surgery in better condition than in the past, and have acceptable long-term results even after cardiac surgery (155).’’ HIV infection, even in the absence of AIDS, appears to impair wound healing. Safavi et al. (150) presented a series of 48 HIV-positive patients undergoing anorectal surgery. Whereas essentially 100% of the wounds would be expected to heal in healthy patients, Safavi et al. found that only 69% of the wounds in HIV-positive patients healed. In patients with AIDS, only 26% of the wounds healed. CD4þ counts did not correlate with the outcome. ‘‘In HIV-positive patients undergoing resection of anal condylomata, low CD4þ counts did correlate with recurrence (156).’’

PROPHYLAXIS AGAINST THROMBOEMBOLISM Surgical patients are at risk for developing venous thromboembolism (VTE) on the basis of Virchow’s triad (stasis, endothelial damage, and hypercoagulable state). The patient is at high risk of developing DVT while immobilized on the operating table. Effective prophylaxis regimens include the use of sequential compression devices on the lower extremities during surgery and the administration of subcutaneous heparin injections (5000 units every 8 to 12 hours), starting two hours prior to surgery (148,149). ‘‘More recently, low-molecular-weight heparins (LMWHs) have been shown to be efficacious for thromboembolism prophylaxis in both orthopedic and general surgical patients. The use of LMWHs has also been noted to cause fewer wound hematomas than the use of unfractionated heparin (148). The American College of Chest Physicians provides guidelines for prophylaxis against VTE (149). In general, risk of

Table 9 Stratification of Risk for Venous Thromboembolism in Surgical Patients (For Definition of Prevention Strategies, See Regimens to Prevent Venous Thromboembolism.) Level of risk, examples Low risk Minor surgery in patinets < 40 yrs with no additional risk factors Moderate risk Minor surgery in patients with additional risk factors nonmajor surgery in patients aged 40–60 yrs with no additional risk factors; major surgery in patients < 40 yrs with no additional risk factors High risk Nonmajor surgery in patients > 60 yrs or with additional risk factors major surgery in patients > 40 yrs or with additional risk factors Higher risk Major surgery in patients > 40 yrs plus prior history of VTE, cancer, or molecular hyperocagulable state; hip or knee arthroplasty lip fracture surgery major trauma; or spinal cord injury

Calf DVT(%)

Proximal DVT(%)

Clinical PE(%)

Fatal PE(%)

2

0.4

0.2

0.002

No specific measures Aggressive mobilization

10–20

2–4

1–2

0.1–0.4

LDUH q12H, LMWH, ES, or IPC

20–40

4–8

2–4

0.4–1.0

LDUH q8h, LMWH, or IPC

40–80

10–20

4–10

0.2–5

Successful prevention strategies

LMWH, orlal anticoagulating, IPC/ ES þ LDUH/LMWH, or ADH

Abbreviations: DVT, deep venous thrombosis; VTE, venous thromboembolism; LDUH, low-dose unfractionated heparin; LMWH, low-molecular-weight heparin; IPC, intermittent pneumatic compression device; ES, elastic stockings; ADH, antidiuretic hormone. Source: From Refs. 60, 74, 149.

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Table 10 Treatment Regimens to Prevent Venous Thromboembolism Method LDUH ADH LMWH and heparnoidsa

Perioperative warfarin IPC/ES

Description Heparin 5000 U SC, given q8–12h starting 1–2 hrs before operation Heparin SC, given q8h starting at approximately 3500 U SC and adjusted by500 U SC per dose, to maintain a midinterval aPTT at high normal values General surgery moderate risk: Dalteparin, 2500 U SC 1–2 hrs before surgery and once daily postop Enoxaparin, 20 mg SC, 1–2 hrs before surgery and once daily postop Nadroparin, 2850 U SC 2–4 hrs before surgery and once daily postop Trinzaparin, 3500 U SC 2 hrs before surgery and once daily postop General surgery high risk: Dalteparin, 5000 U SC 8–12 hrs before surgery and once daily postop Danaparold, 750 U SC 1–4 hrs before surgery and q12h postop Enoxaparin, 40 mg SC, 1–4 hrs preop and once dialy postop Enoxaparin, 30 mg SC, q12h starting 8–12 hrs postop Orthopedic surgery Dalteparin, 5000 U SC 8–12 hrs preop and once daily starting 12–24 hrs postop Dalteparin, 2500 U SC 6–8 hrs postop then 5000 U SC once daily Danaparoid, 750 U SC 1–4 hrs prop and q12h postop Enoxaparin, 30 mg SC q12h starting 12–24 hrs postop Enoxaparin, 40 mg SC once daily starting 10–12 hrs preop Nadroparin, 38 U/kg SC 12 hrs preop 12 hrs postop and once daily on postop days 1, 2, and 3; then increase to 57 U/kg SC once daily Trinzaparin, 75 U/kg SC once daily starting 12–24 hrs postop Tinzaparin, 4500 U SC 12 hrs preop and once daily postop Major Trauma Enoxaparin, 30 mg SC q12h starting 12–36 hrs postinjury if hemostatically stable Acute spinal cord injury Enoxaparin, 30 mg SC q12h Medical conditions Dalteparin, 2500 U SC once daily Danaparold, 750 U SC q12h Enoxaparin, 40 mg SC once daily Nadroparin 2850 U SC once dialy Start daily dose with approximately 5–10 mg the day of or the day after surgery adjust the dose for a target INR of 25 (range 2–3) Start immediately before operation; and continue until fully ambulatory

a

Dosage expressed in anti-Xa units (for enoxaparin, 1 mg ¼ 100 anti-Xa units). Abbreviations: ADH, antidiuretic hormone; LDVH, low-dose unfractionated heparin; LMWH, low-molecular-weight heparin; ES, elastic stockings; IPC, intermittent pneumatic compression device; aPTT, activated partial thromboplastin time; Postop, postoperative; SC, subcutaneous. Source: From Ref. 149.

Patients with AIDS, undergoing emergent laparotomy, including appendectomy, have an expected perioperative mortality of 12% and an expected morbidity of 26% (151,152). The presence of opportunistic infections, lack of ongoing prophylactic treatment for AIDS-related disease, and ongoing sepsis at laparotomy correlate with increased morbidity and mortality (152). Binderow et al. (153) tried to predict outcome in 10 HIV-positive patients and 25 patients with AIDS, undergoing major abdominal surgery, excluding appendectomy. The perioperative mortality for the group with AIDS was 33% compared to 10% for the HIV-positive group. Perioperative mortality correlated with serum albumin, which was significantly different in survivors (3.9 g/L) versus nonsurvivors (2.8 g/L). Total and differential white blood cell counts do not seem to correlate with outcome (151–153). Based on the available studies (150–154,156) HIVpositive patients are more likely to benefit from surgery than patients with AIDS. Relatively minor procedures, such as for vascular access, or lymph node biopsy are well tolerated without undue morbidity (154). Ideally, HIV-positive patients and patients with AIDS undergoing elective surgery should be well nourished and free of opportunistic infection at the time of operation.

SUMMARY The physiologic derangements accompanying surgery may, at times, exceed the patient’s physiologic reserve, resulting in significant morbidity and mortality. It is the responsibility of the surgeon to balance the potential risks and benefits of an operative procedure with the management alternatives to provide the patient with an optimal outcome. A thorough history and physical examination not only define the surgical disease process of interest but also identify associated comorbidities. Knowledge of the disease processes involved allows stratification of risk and the determination of the appropriate course of therapy. Ultimately, a thoughtful approach to the preoperative preparation of the surgical patient serves to minimize morbidity and mortality.

REFERENCES 1. Detsky AS, et al. Cardiac assessment for patients undergoing noncardiac surgery; a multifactorial clinical risk index. Arch Intern Med 1986; 16:2131.

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52. Epstein M. Hypertension as a risk factor for progression of chronic renal disease. Blood Press1994; (suppl 1):23. 53. Lip GY, Gammage MD, Beevers DG. Hypertension and the heart. Br Med Bull 1994; 50(2):299. 54. Lithell H. Pathogenesis and prevalence of atherosclerosis in hypertensive patients. Am J Hypertens 1994; 7(2):2S. 55. Shaper AG, Wannamethee G, Walker M. Physical activity, hypertension and risk of heart attack in men without evidence of ischaemic heart disease. Hum Hypertens 1994; 8(1):3. 56. Devereux RB, et al. Left ventricular hypertrophy associated with hypertension and its relevance as a risk factor for complications. J Cardiovasc Pharmacol 1993; 21(suppl 2):S38. 57. Schwartzkopff B, et al. Heart failure on the basis of hypertension. Circulation 1993; 87(suppl 5):IV66. 58. Moser M. Effect of diuretics on morbidity and mortality in the treatment of hypertension. Cardiology 1994; 84(suppl 2):27. 59. Allman KG, et al. Resistant hypertension and preoperative silent myocardial ischaemia in surgical patients. Br J Anaesth 1994; 73:574. 60. Sideris DA. High blood pressure and ventricular arrhythmias. Eur Heart J 1993; 14:1548. 61. Gifford RW, Manger WM, Bravo EL. Pheochromocytoma. Endocrinol Metab Clin North Am 1994; 23(2):387. 62. Rackley CE. Valvular heart disease. In: Wyngaarden JB, Smith LH, eds. Cecil Textbook of Medicine. 17th ed. WB Saunders: Philadelphia, 1985. 63. Braunwauld E. Valvular heart disease. In: Braunwauld E, ed. Heart Disease: A Textbook of Cardiovascular Medicine. 4th ed. Philadelphia: WB Saunders, 1992. 64. Leavitt JI, Coats MH, Falk RH. Effects of exercise on transmittal gradient and pulmonary artery pressure in patients with mitral stenosis or a prosthetic mitral valve: A Doppler Echocardiographic Study. J Am Coll Cardiol 1991; 17:1520. 65. Thomas SJ, Lowenstein E. Anesthetic management of the patient with valvular heart disease. Int Anesthesiol Clin 1979; 17(1):67. 66. Danielsen R, Nordrehaug JE, Vi-Mo H. Clinical and haemodynamic features in relation to severity of aortic stenosis in adults. Eur Heart J 1991; 12:791. 67. Driscoll DJ, et al. Cardiorespiratory responses to exercise of patients with aortic stenosis, pulmonary stenosis and ventricular septal defect. Circulation 1993; 87(suppl I):1–102. 68. Kennedy KD, et al. Natural history of moderate aortic stenosis. J Am Coll Cardiol 1991; 17(2):313. 69. Turpie AGG. Preventing thromboembolism in patients with prosthetic heart valves. Cardiol Clin 1994; 12(3):487. 70. Madura JA, Rookstool M, Wease G. The management of patients on chronic coumadin therapy undergoing subsequent surgical procedures. Am Surg 1994; 60:542. 71. Dajani AS, et al. Prevention of bacterial endocarditis. JAMA 1997; 277:1794. 72. Callow AD, Trachtenberg JD. Diagnosis and surgical management of asymptomatic carotid stenosis. In: Ernst CB, Stanley JC, eds. Current Therapy in Vascular Surgery. 3rd ed. St. Louis: Mosby, 1995. 73. Freidman LS, Maddrey WC. Surgery in the patient with liver disease. Med Clin North Am 1987; 2(3):453. 74. Ngai SH. Current concepts in anesthesiology. N Engl J Med 1980; 302:564. 75. Kelly DA, Tuddenham EGD. Haemostatic problems in liver disease. Gut 1986; 27:339. 76. Gholson CF, Provenza JM, Bacon BR. Hepatologic considerations in patients with parenchymal liver disease undergoing surgery. Am J Gastroenterol 1990; 85(5):487. 77. Harville DD, Summerskill WH. Surgery in acute hepatitis. JAMA 1963; 1984:257. 78. Greenwood SM, Lefler CT, Minkowitz S. The increased mortality rate of open liver biopsy in alcoholic hepatitis. Surg Gynecol Obstet 1972; 134:600. 79. Powell Jackson P, Greenway B, Williams R. Adverse effects of laparotomy in patients with unsuspected liver disease. Br J Surg 1982; 69:449.

80. Runyan BA. Surgical procedures are tolerated well by patients with asymptomatic chronic hepatitis. J Clin Gastroenterol 1986; 8:542. 81. Hargrove MD. Chronic active hepatitis: possible adverse effects of exploratory laparotomy. Surgery 1970; 68:771. 82. Child CG, Turcotte JG. Surgery and portal hypertension. In: Child CG, ed. The Liver and Portal Hypertension. Philadelphia: WB Saunders, 1964. 83. Conn M. Preoperative evaluation of the patient with liver disease. Mt Sinai J Med 1991; 58(1):75. 84. Schepens MA, et al. Risk assessment of acute renal failure after thoracoabdominal aortic aneurysm surgery. Ann Surg 1994; 219(4):400. 85. Novis BK, et al. Association of preoperative risk factors with postoperative acute renal failure. Anesth Analg 1994; 78:143. 86. Pinson CW, et al. Surgery in long-term dialysis patients: experience with more than 300 cases. Am J Surg 1986; 151:567. 87. Rose BD. Diagnostic approach to the patient with renal disease. In: Rose BD, ed. Pathophysiology of Renal Disease. New York: McGraw-Hill, 1987. 88. Rose BD. Acute renal failure-prerenal disease versus acute tubular necrosis. In: Rose BD, ed. Pathophysiology of Renal Disease. New York: McGraw-Hill, 1987. 89. Kellen M, et al. Predictive and diagnostic tests of renal failure: a review. Anesth Analg 1994; 78:134. 90. Rose BD, Brenner BM. Mechanisms of progression of renal disease. In: Rose BD, ed. Pathophysiology of Renal Disease. New York: McGraw-Hill, 1987. 91. Coratelli P, Passavanti C. Pathophysiology of renal failure in obstructive jaundice. Miner Electrolyte Metab 1990; 16:61. 92. Wait RB, Kahng KU. Renal failure complicating obstructive jaundice. Am J Surg 1989; 157:256. 93. Parks RW, et al. Prospective study of postoperative function in obstructive jaundice and the effect of perioperative dopamine. Br J Surg 1994; 81:437. 94. Turka LA. Urinary tract obstruction. In: Rose BD, ed. Pathophysiology of Renal Disease. New York: McGraw-Hill, 1987. 95. Webb JA, et al. Can ultrasound and computed tomography replace high-dose urography in patients with impaired renal function? Q J Med 1984; 53:411. 96. Burke JF, Francos GC. Surgery in the patient with acute or chronic renal failure. Med Clin North Am 1987; 71(3):489. 97. Muller MC. Anesthesia for the patient with renal dysfunction. Int Anesthesiol Clin 1984; 22(1):169. 98. Kellerman PS. Perioperative care of the renal patient. Arch Intern Med 1994; 154:1674. 99. Solomonson MD, Johnson ME, Ilstrup D. Risk factors in patients having surgery to create an arteriovenous fistula. Anesth Analg 1994; 79:694. 100. Ziccardi VB, et al. Management of the oral and maxillofacial surgery patient with end-stage renal disease. J Oral Maxillofac Surg 1992; 50:1207. 101. Bick RL. Acquired platelet function defects. Hematol Oncol Clin North Am 1992; 6(6):1203. 102. Edelson GW, Fachnie JD, Whitehouse FW. Perioperative management of diabetes. Henry Ford Hosp Med J 1990; 38(4):262. 103. Feingold KR, et al. Diabetes mellitus. In: Andreoli TE et al., eds. Cecil Essentials of Medicine. 2nd ed. Philadelphia: WB Saunders, 1990. 104. Root HE. Preoperative care of the diabetic patient. Postgrad Med 1966; 40:439. 105. Goodson WH III, Hunt TK. Wound healing and the diabetic patient. Surg Gynecol Obstet 1979; 149:600. 106. Goodson WH III, Hunt TK. Deficient collagen formation by obese mice in a standard wound model. Am J Surg 1979; 138:692. 107. Gottrup F, Adreassen TT. Healing of incisional wounds in stomach and duodenum: the influence of experimental diabetes. J Surg Res 1981; 313:61. 108. Hirsch IB, McGill JB. Role of insulin in management of surgical patients with diabetes mellitus. Diabetes Care 1990; 13:980.

Chapter 13: Physiologic Principles in Preparing Patients for Surgery 109. Taitelman U, Reese EA, Bessman AN. Insulin in the management of the diabetic surgical patient. JAMA 1977; 237:658. 110. McMurry JF. Wound healing with diabetes mellitus better glucose control for better wound healing in diabetes. Surg Clin North Am 1984; 64(4):769. 111. Gavin LA. Management of diabetes mellitus during surgery. West J Med 1989; 151:525. 112. Galloway JA, et al. Factors influencing the absorption, serum insulin concentration, and blood glucose responses after injections of regular insulin and various insulin mixtures. Diabetes Care 1981; 4:366. 113. Hildebrand P, Sestoft L, Nielson SL. The absorption of subcutaneously injected short-acting soluble insulin: influence of injection technique and concentration. Diabetes Care 1983; 6:459. 114. Goldberg NJ, et al. Insulin therapy in the diabetic surgical patient: metabolic and hormone response to low-dose insulin infusion. Diabetes Care 1981; 4:279. 115. Watts NB, et al. Postoperative management of diabetes mellitus: steady state glucose control with bedside algorithm for insulin adjustment. Diabetes Care 1987; 10:722. 116. Pezzarossa A, et al. Perioperative management of diabetic subjects: subcutaneous versus intravenous insulin administration during glucose-potassium infusion. Diabetes Care 1988; 11:52. 117. Farkas-Hirsch R, Boyle PJ, Hirsch IB. Glycemic control in the surgical patient with IDDM [abstract]. Diabetes 1989; 38(suppl 2):39A. 118. Alberti KGMM, Marshall SM. Diabetes and surgery. In: Alberti KGMM, Krall LP, eds. The Diabetes Annual. New York: Elsevier, 1988:248. 119. Felig P, et al. Blood glucose and gluconeogenesis in fasting man. Arch Intern Med 1969; 123:293. 120. Fritz I, Levine R. Action of adrenal cortical steroids and norepinephrine on vascular responses of stress in adrenalectomized rats. Am J Physiol 1951; 165:456. 121. Knowlton AL. Adrenal insufficiency in the intensive care setting. J Intens Care Med 1989; 4:35. 122. Claussen MS, Landercasper J, Cogbill TH. Acute adrenal insufficiency presenting as shock after trauma and surgery: three cases and review of the literature. J Trauma 1992; 32(1):94. 123. Salem M, et al. Perioperative glucocorticoid coverage: a reassessment 42 years after emergence of a problem. Ann Surg 1994; 219(4): 416. 124. Havlik RJ, Cahow E, Kinder BK. Advances in the diagnosis and treatment of pheochromocytoma. Arch Surg 1988; 123:626. 125. Bravo EL, Gifford RW Jr. Pheochromocytoma: diagnosis, location and management. N Engl J Med 1984; 311:1298. 126. Hauptman JB, Modlinger RS, Ertel NH. Pheochromocytoma resistant to alpha-adrenergic blockade. Arch Intern Med 1983; 143:2321. 127. Hull CJ. Pheochromocytoma diagnosis, preoperative preparation and anaesthetic management. Br J Anaesth 1986; 58:1453. 128. Malone MJ, et al. Preoperative and surgical management of pheochromocytoma. Urol Clin North Am 1989; 16(3):567. 129. Gann DS, Foster AH. Endocrine and metabolic responses to injury. In: Schwartz SI, ed. Principles of Surgery. 6th ed. New York: McGraw-Hill, 1994. 130. Heimann P, Martinson J. Surgical treatment of thyrotoxicosis: results of 272 operations with special reference to preoperative treatment with antithyroid drugs and L-thyroxine. Br J Surg 1975; 62:683. 131. Alderberth A, Stenstrom G, Hasselgren PO. The selective betalblocking agent metoprolol compared with antithyroid

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PART TWO: The Alimentary Tract ESOPHAGUS AND STOMACH

14 Physiologic Dysfunction of the Esophagus Nahid Hamoui and Peter F. Crookes

vertebral bodies. The cricopharyngeus muscle, which functionally represents the UES, is at the level of C7 at rest and C6 during a swallow. Superiorly are the pharyngeal constrictors, and the cervical esophagus becomes the thoracic esophagus at the level of the thoracic inlet. The trachea is anterior, the carotid sheaths are lateral, and in the grooves between the trachea and esophagus on either side lie the recurrent laryngeal nerves, which innervate the vocal cord mechanism. In the chest, the esophagus enters at the thoracic inlet and lies on the vertebral bodies before moving slightly to the left in the lower chest to pass through the esophageal hiatus. In its upper part, it is crossed by the azygos vein on the right, and it is closely related to the thoracic duct in the lower mediastinum. The entire length of the esophagus may be accessed from the right side of the chest, but access to the cardia is restricted by the liver. The left side of the chest provides direct access to the lower esophagus and cardia, but it is hard to reach the upper esophagus because it is behind the aortic arch. The lower esophagus is visible in the abdomen only after incising the peritoneum and the tissue binding the esophagus to the arch of the crura. Underneath this peritoneum is a fine-curved white line, the phrenoesophageal membrane. When this is incised, it can be pushed off the esophagus to separate it from the crura. The junction of the esophagus and stomach is marked by an anterior pad of fat. The anterior vagus nerve is closely applied to the anterior aspect of the esophagus, and the posterior vagus lies in the mediastinum behind and to the right of the esophagus.

INTRODUCTION The gastrointestinal (GI) tract can be thought of as a long tube subdivided into a series of compartments with unique pH and enzymatic environments, each being separated from the next by a sphincter. Food residue is pumped through a valve into a receptacle, where chemical changes occur, before it is pumped into a more distal compartment. The most proximal is the mouth, where the tongue and pharyngeal muscles pump food through the upper esophageal sphincter (UES) into the proximal esophagus. Food is then pumped through another valve, the lower esophageal sphincter (LES), into the reservoir portion of the stomach, where the pH is strongly acidic, and subsequently pumped by the antrum through the pylorus into another receptacle, the duodenum. In the duodenum the pH is again alkaline, facilitating the action of trypsin and carboxypeptidases, and the residue is further influenced by enzymes from the small bowel itself, before being pumped through another valve, the ileocecal valve, into the cecum, a reservoir portion of the colon. In the colon, fluids and electrolytes are adjusted and the residue is pumped by the descending colon through the anal sphincter to the exterior. The esophagus is the most proximal portion of this system of importance to the surgeon. Its function is simpler to understand and study than most other portions of the GI tract. The esophagus functionally consists of a UES, whose function is largely to protect the airway from contamination by ingested solids and liquids, a tubular portion termed the ‘‘esophageal body,’’ whose function is to propel food into the stomach, and an LES, whose function is to protect the esophageal mucosa from contamination by gastric juice in the face of substantial changes in intragastric pressure or intra-abdominal pressure, while still permitting belching of air when necessary. Diseases of the esophagus can be classified as benign and malignant, and benign disease can be further distinguished as structural and functional. Structural diseases, characterized by anatomical alterations such as hernias, strictures, tumors, or diverticula, generally represent more advanced and life-threatening situations, and are most readily identified on imaging or endoscopic studies. Functional diseases are less commonly a threat to life, but substantially affect quality of life (QoL). The major tools to study esophageal function are esophageal manometry and 24-hour pH monitoring.

Physiology Food is taken into the mouth where it is chewed and lubricated. Swallowing is initiated voluntarily by posterior movement of the tongue against the hard palate, pinching off a bolus and transferring it to the pharynx. Thereafter it is entirely a reflex action. Several mechanisms combine to ensure safe delivery of the bolus into the esophagus. Breathing is temporarily halted. Contraction of the tensor veli palati muscle occludes the nasopharynx, preventing the pressure generated by the tongue from being dissipated through the nose. The larynx is pulled upwards and forwards by the action of the strap muscles of the neck, chiefly the mylohyoid and thyrohyoid muscles. This not only causes the epiglottis to lie more horizontally, but physically opens the UES. The cricopharyngeus muscle relaxes in concert with contraction of the pharyngeal constrictors. The wave of peristalsis generated by this activity passes down the esophagus. The strap muscles then relax, the larynx returns to its normal location, and the cricopharyngeus muscle resumes its normal tone. This whole process, occurring in skeletal muscle, is rapid, taking less than a second to complete.

ANATOMY AND PHYSIOLOGY Surgical Anatomy The esophagus spans three areas often treated by three different surgical specialists: ENT, thoracic, and general surgeons. In the neck, it lies immediately adjacent to the 295

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Within the esophageal body, lubricated food is then propelled distally by peristalsis. A wave of circular muscle contraction, preceded by longitudinal muscle relaxation, passes down the esophagus at about 3 cm/sec. The amplitude of the circular muscle contraction is sufficient to occlude the bolus and propel it distally in a manner analogous to the way in which a surgical drain is ‘‘stripped’’ between finger and thumb to empty its contained secretions. The circular muscle at the gastroesophageal junction (GEJ) has the special property of tonic contraction producing a resting tone of about 15 mmHg. This is the physiologic basis of the LES. It is innervated by cholinergic fibers of both excitatory and inhibitory types. Relaxation of the LES is mediated by stimulating the inhibitory neurons, which secrete vasoactive intestinal polypeptide (VIP) and cause the release of nitrous oxide. Relaxation is induced by swallowing, and begins at the onset of the swallow. The LES pressure reaches a nadir as the peristaltic wave reaches the distal esophagus, and then undergoes a postrelaxation contraction. The LES too opens in response to gastric distention and also undergoes periods of transient loss of tone, often termed ‘‘transient LES relaxations’’ (TLESRs), which may be neurally mediated or be the result of effacement of the LES in the presence of gastric distention.

SYMPTOMS OF ESOPHAGEAL DISEASE It is common to characterize symptoms arising from esophageal disease as either typical or atypical. Typical symptoms, namely heartburn, regurgitation, or dysphagia, immediately suggest the esophagus as their source and prompt esophageal evaluation. Atypical symptoms initially suggest another system. Chest pain is likely to be referred to a cardiologist and the patient will likely undergo a series of more or less invasive studies before heart disease is excluded. Cough, asthma, and recurrent pneumonia are generally referred to a pulmonologist, and patients reporting hoarseness are typically referred to an ENT surgeon.

Typical Symptoms Heartburn, sometimes called pyrosis, is a burning retrosternal discomfort often coming on 30 to 90 minutes after meals and often relieved by antacids and abolished by strong acid suppressants. The patient will often point with the spread fingers spanning the sternum (the ‘‘open hand’’ sign). In the early stages, it occurs only after an unusually rich, voluminous, or late meal. In severe cases, it is provoked even by drinking water, by lying down, or by bending over. Whether it is a daily or only an occasional occurrence, it tends to be milder when the stomach is empty rather than when it is full. Regurgitation is most frequently used to mean the sudden, effortless appearance of gastric contents in the throat or mouth. It may be isolated or occur with a belch, in which case it is sometimes described as a ‘‘hot belch’’ or ‘‘acid belch.’’ Some patients can produce it almost at will, when it is called rumination. This learned disorder is a form of reflux disease, but must be distinguished from bulimia, which is a behavioral disorder characterized by voluntary initiation of vomiting, consciously or unconsciously, in an attempt to lose weight. Regurgitation is also used to describe the forceful ejection of esophageal contents. It occurs most often in achalasia, when the dilated esophagus has a substantial capacity. If more is eaten than can be passed into the stomach, the

patient will eventually be forced to regurgitate, in which case the material tastes bland rather than acidic, indicating that it has never entered the stomach. In this respect it differs from vomiting. The need to regurgitate often comes on suddenly even if the precipitating factors are predictable, as observed by many patients who report that on entering a restaurant they instinctively choose a table near the restroom. Patients sometimes speak of ‘‘bringing up foam’’ especially in the postoperative period. This indicates relative obstruction to esophageal outflow. It may happen after a tight anastomosis or antireflux procedure, or a gastric bypass. Saliva is not emptied from the esophagus and when the patient drinks liquid, it displaces the saliva proximally, causing it to be regurgitated. Dysphagia is a term used to describe any sensation associated with difficulty in passing food from the mouth to the stomach. It actually includes two quite distinct symptoms. Oropharyngeal dysphagia, sometimes called ‘‘transfer’’ dysphagia, describes difficulty getting food from the mouth into the esophagus. This is how the lay person interprets the phrase ‘‘difficulty in swallowing’’ and it tends to be associated with coughing and choking while actually swallowing. Soft solids cause less trouble than liquids or tough solids. In contrast, esophageal or ‘‘transport’’ dysphagia, describes difficulty in passing food down the esophagus into the stomach. Patients with this symptom may deny difficulty in swallowing, but report that food sticks or ‘‘hangs up’’ in the lower chest. Coughing in this situation occurs after eating, not during the act of swallowing. It is broadly true that mechanical obstructions such as stricture or tumor initially cause this symptom only with solids, with liquid transport being unaffected. Difficulty in transporting both solids and liquids generally indicates a motility disorder. One further principle relates the location of the sensation to the location of the lesion. In general, symptoms are never felt distal to the site of the lesion. They are felt at the site of the lesion or referred proximally. As a consequence, the sensation of food sticking in the neck may be from a lesion at that site but could also be from a more distal lesion. In contrast, a sense of food hanging up in the lower chest usually corresponds to a lesion in that site and will not be caused by a problem in the cervical esophagus. Odynophagia or pain on swallowing is typical of esophagitis in the proximal esophagus, typically from nonreflux causes, such as infections and caustic ingestion.

Atypical Symptoms Chest pain resembling angina may be the result of either reflux or a motor disorder of the esophagus, and the patient describes it as a pressure or heaviness, often pointing with the closed fist. It may radiate to the back, jaw, or neck. The serious implications of this symptom in the patients’ mind often overshadow any connection it may have with eating (1). Cough may occur in several ways. Spasms of coughing during eating suggests dysfunction of the UES, such as may occur in any of the above-mentioned neurological conditions, but may also represent a tracheoesophageal fistula where a high esophageal tumor or penetrating esophageal ulcer erodes into the trachea or bronchus. Esophageal problems frequently cause cough on lying down, particularly Zenker’s diverticulum, and any condition such as achalasia where the esophagus cannot empty properly. Patients with underlying gastroesophageal reflux disease (GERD),

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especially with a large hiatal hernia and a defective LES, commonly wake up coughing at night (2). Asthma suggests GERD when it is nonallergic and occurs for the first time in middle age. The patient with a chronic cough and a normal chest X-ray, a common scenario for the primary care physician, most likely has one of three common conditions: postnasal drip, GERD, or asthma, and in many of those diagnosed with asthma, the etiology will be GERD (3,4). Recurrent pneumonia is a rare occurrence in an otherwise healthy person with a normal immune system. When it occurs, think of aspiration. It may be due to GERD or a neuromuscular disease such as stroke or Parkinson’s disease, which impairs laryngeal protection. Hoarseness may be caused by GERD, in which case, it typically is worse in the mornings, whereas hoarseness, which worsens with voice use, as in teachers or singers, suggests primary laryngeal disease or improper use. It may also have a neurological cause from a generalized disease or from an intrathoracic tumor compressing the recurrent laryngeal nerve. Globus sensation, formerly called globus hystericus, is the sense of something sticking in the throat, in the absence of an anatomical explanation. It is occasionally caused by reflux disease, but is most often regarded as a conversion disorder (5).

Important Nonesophageal Symptoms Some symptoms are important because they actually point away from the esophagus, and yet are frequently misinterpreted. It is important for the surgeon not to be pressurized into operating on a patient because of a symptom misinterpreted as being due to reflux. Nausea is rarely a symptom of esophageal disease. It typically indicates gastric dysfunction and even if associated with heartburn, it is not likely to be improved by antireflux surgery. Halitosis is often thought by lay people and even physicians to originate in the stomach. It may be confused with the sensation of retasting or resmelling food after belching. True halitosis, which is noticed by observers and not the patient, results from overgrowth of bacteria on the posterior tongue with release of volatile sulfur compounds, and the treatment is maintaining oral hygiene, not antireflux therapy. Metallic or acid taste in the mouth is not caused by reflux. It may be due to excessive salivation, sometimes called water brash, which may precede vomiting.

PHYSICAL EXAMINATION Because of the location of the esophagus, it is very rare to find abnormalities detectable on physical exam. Signs of advanced metastatic esophageal cancer include palpable supraclavicular nodes, hoarseness from recurrent laryngeal nerve involvement, signs of superior vena cava syndrome, jaundice or hepatomegaly from liver metastases, and ascites from peritoneal involvement. Patients whose dysphagia has a neuromuscular basis are often easy to recognize at a glance. Dysphonia (soft voice) and dysarthria (inability to articulate) are immediately obvious. Easily recognizable patterns are present for Parkinson’s disease (shuffling gait, pill rolling tremor, dysphonia, and emotionless expression), myasthenia gravis (ptosis, fatigability), amyotrophic lateral sclerosis (dysarthria, muscle wasting with fasciculation), myotonic dystrophy (characteristic cadaverous fascies,

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frontal balding, and slow relaxation of contracted muscles), and dermatomyositis (characteristic heliotrope rash on the dorsum of the hands and fingers). Occasionally calluses on the knuckles of the index and middle fingers are observed, and are a sign that the patient makes herself vomit by putting the fingers down the throat.

INVESTIGATIONS Four major modes of investigation dominate the study of esophageal disease, two primarily directed toward identifying structural lesions (endoscopy and contrast radiography) and two toward uncovering functional disturbances (esophageal manometry and 24-hour esophageal pH monitoring). Understanding these four tests is fundamental to intelligent analysis of esophageal diseases.

Barium Radiology Contrast radiology of the esophagus has been used for almost a century, but it still remains one of the most valuable sources of both structural and functional information. In specialized units, the examination is carried out with a strict protocol to yield the maximum information (6). Patients at high risk of aspiration, including those recovering from esophageal surgery, or whose symptoms are localized to the oropharyngeal region, are studied in the upright position. All others have the esophagus examined while lying horizontal, usually prone, and turned to the side to separate the esophagus from the vertebral column. It is easier to assess the efficacy of peristalsis when the effect of gravity is removed. A sequence of five swallows of barium is given. In normal subjects, three or more of these five swallows will be transported by a stripping peristaltic wave that empties the esophagus. This is primary peristalsis. A secondary peristaltic wave is stimulated by esophageal distention. Segmental spasm due to simultaneous contractions in the esophageal body are typical of diffuse esophageal spasm. Radiologists sometimes describe the appearance of repetitive, nonperistaltic, simultaneous contractions as ‘‘tertiary peristalsis’’ even though they are not peristaltic. A typical study is shown in Figure 1. The presence of a stricture, tumor, or hiatal hernia or diverticulum is generally easy to identify. It is useful to measure the diameter of the esophagus. The normal esophagus is rarely larger than 2.5 cm in diameter, and any esophagus wider than 3 cm strongly suggests achalasia. Other obstructions such as a tight Nissen fundoplication or lap band, or stricture or cancer, do not produce such gross esophageal dilation. A Nissen fundoplication is visible as a soft tissue density in the cardia with a narrow channel through it: it should be below the diaphragm. If it is not so, then it implies that the fundoplication has herniated. If there are gastric folds above the soft tissue density, a slipped Nissen is present. To study cricopharyngeal dysphagia or recurrent aspiration, an examination termed a ‘‘modified barium swallow’’ is often carried out in consultation with a speech pathologist, who will administer not just liquid barium, but liquids of different viscosities, including thin barium, thick barium, applesauce, and cookies impregnated with barium (7). Typical findings in these patients are ineffective movement of the tongue and palate, nonocclusive contraction of the pharynx, retention of barium in the recesses of the pharynx (vallecula and pyriform sinuses) and spillover of the barium into the laryngeal vestibule, which may or may not produce coughing, and frank aspiration down into the trachea.

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Figure 1 Normal barium esophagogram (A) A–P view and (B) lateral view.

Endoscopy Endoscopy should be thought of as the physical examination of the esophagus. It is generally the first investigation recommended in elucidating a patient’s symptoms, unless the presentation is dominated by dysphagia, in which case it is generally wise to obtain a ‘‘road map’’ by first performing a barium swallow. It will detect gross structural alterations such as hernia and cancers and strictures and diverticula, visualize Barrett’s epithelium, and permit biopsy of lesions, and therapeutic measures such as dilation of strictures, insertion of stents, and removal of foreign bodies. Surgeons who operate on the upper GI tract should be expert endoscopists, because gastroenterologists are frequently unfamiliar with the anatomic details of such procedures as gastric pull-up, colon interposition, Roux Y gastric bypass, duodenal switch, partial or total fundoplications, and other frequently performed contemporary operations.

Safety Modern flexible videoendoscopes provide excellent mucosal visualization over most of the esophagus. They carry low risk of perforation or hemorrhage when merely inspecting, but dilating achalasia or an esophageal stricture, or injecting esophageal varices, increases the risk by 3- to 10-fold (8). The major risks are perforation, hemorrhage, aspiration, and oversedation and side effects of sedative medication. When perforation occurs, it tends to be at or just proximal to the site of the pathology, which is commonly at the distal end. The use of dilators, or the large endoscopic ultrasound scope, substantially increases the risk of perforation. The rigid endoscope is rarely used in modern practice except by ENT surgeons. It is more likely than flexible endoscopy to cause perforation, especially in the cervical esophagus. However it remains a valuable instrument in emergency situation because suction is better, grasping forceps are stronger, and sharp or angled foreign bodies can be more safely grasped and withdrawn into the scope. The degree of sedation required is generally called ‘‘conscious sedation,’’ though many patients are not at all conscious. Administering a combination of an opiate

(meperidine or fentanyl) and a short-acting benzodiazepine such as midazolam in small incremental doses is the most common technique. Propofol is an excellent alternative but in most hospitals it must be administered by an anesthesiologist. Oxygen must be administered by nasal cannulae, and pulse, blood pressure, and oxygen saturation must be monitored continuously and recorded every five minutes. It is wise to spray the pharynx with local anesthetic. The patient is then turned on to his left side to allow gastric juice to pool in the fundus away from the cardia and hence reduce the risk of aspiration. A mouth guard is inserted before the patient becomes too drowsy to cooperate. The technique of endoscopy is now well described and is only briefly summarized here. The major principle is to advance the scope with gentleness and under vision. Lock the smaller (left–right) control so that the scope tip only curves in one plane. Turn the larger, outer wheel clockwise to flex the tip of the scope. This will give an image on the screen in the correct orientation with the tongue at the bottom and the uvula at the top. Advance the scope over the tongue, keeping the tip rotated until the epiglottis is reached. Unflex the tip a little to go behind the epiglottis and observe the cords: the anterior junction will be at the bottom of the screen, and the two diverging arytenoids will be near the top. Unflex the scope slightly to go behind the arytenoids. The cricopharyngeus is identified by the slight bunching of folds behind the vocal cords. Gentle pressure and insufflation of air generally causes it to relax and then the scope will be in the proximal esophagus. The presence of any saliva or food residue is noted. The normal squamocolumnar junction, sometimes called the Z-line, is generally seen about 35 to 37 cm from the incisor teeth in females and 37 to 40 cm in males. The GEJ is defined as the top of the rugal folds. The crura of the diaphragm are usually easily seen as a pinching-off point when the patient sniffs or breathes deeply. In normal subjects, these three landmarks are within a centimeter of one another. If the squamocolumnar junction is significantly more proximal than the GEJ, then Barrett’s esophagus is present. If the GEJ is two or more centimeters proximal to the crura, then a hiatal hernia is present.

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Mucosal abnormalities can be esophagitis, classified according to the type and size of erosions present, or Barrett’s esophagus, recognized as extension of the salmon-orange–colored columnar mucosa into the tubular esophagus. Esophagitis is diagnosed by visual appearance on endoscopy, not on biopsy, but Barrett’s esophagus must be confirmed by finding intestinal metaplasia on biopsy. A lot of information can be obtained by retroflexing the scope, i.e., curving the tip so that it looks up the lesser curve toward the cardia, visualizing the scope itself coming through the cardia. The appearance of the GEJ has been graded by Hill into four categories, which are roughly correlated with the competency of the valve, with Hill Grade I being normal (near complete frenulum, minimal opening in response to distention), Grade II showing some effacement of the frenulum or flap valve, Grade III showing loss of the frenulum and frequent prolonged periods of GEJ opening, and Grade IV indicating a fixed hiatal hernia (Fig. 2) (9). The upper esophagus and pharynx is best examined as the scope is withdrawn. Look for an ‘‘inlet patch’’ of columnar mucosa just below the cricopharyngeus. Sometimes these small areas of columnar mucosa contain parietal cells and secrete acid, and may be responsible for laryngeal symptoms (10). Take the opportunity to inspect the vocal cords as the scope is withdrawn out of the pharynx. Redness, edema, or ulceration may denote reflux laryngitis and a paralyzed cord is easily identified.

Esophageal Histology Endoscopic examination of the esophagus permits the biopsy of mucosal lesions and strictures, and frequently yields useful information even if the mucosa appears visually normal. Esophageal mucosal biopsy can be technically awkward because the forceps are in the same axis as the mucosa, rather than perpendicular. One useful technique is to place the open biopsy forceps adjacent to the area to be biopsied, and apply strong suction and then close the forceps. Insufflation will then confirm that the correct tissue has been grasped. This is especially useful in biopsying Barrett’s esophagus, where multiple biopsies around the circumference are needed. The histological details of individual disease processes are discussed in the relevant sections later in this chapter.

Figure 2 Retroflexed view of the GEJ, showing large hernia extending up into the chest (Hill Grade IV). Abbreviation: GEJ, gastroesophageal junction.

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Other Common Imaging Techniques Chest Radiography The information that can be derived from a chest X-ray should not be overlooked. In the emergency situation, look for pneumothorax, pleural effusion, mediastinal, and soft tissue emphysema. A large hiatal hernia presents as a retrocardiac soft tissue shadow with a horizontal air–fluid level, and a dilated esophagus in achalasia will be seen as a curved longitudinal shadow along the left heart border. These features when present act as pointers to referral for a more focused investigation of the esophagus.

Computed Tomography Computed tomography (CT) of the chest shows the esophagus in cross section and is particularly useful in staging malignancies. Generally, the esophagus is observed as collapsed tube containing minimal contrast or air, just anterior to the vertebral bodies. Tumors cause wall thickening and, when advanced, are seen as a bulky mass, and adjacent lymphadenopathy may be observed. If the esophagus appears dilated and contains fluid, perhaps with a fluid level, the most likely diagnosis is achalasia. In the emergency situation, CT scanning can reveal mediastinal, periesophageal air in patients with perforation.

Esophageal Motility The functions of the esophagus are entirely motor. The pharynx contracts and the UES opens. The esophageal body sequentially contracts, causing a stripping wave to pass down the esophagus, propelling its contents distally. The LES begins to relax at the onset of the swallow, and its pressure reaches a nadir as the bolus is propelled into the stomach. The relaxation is followed by a contraction and resumption of resting tone. Any uncleared bolus within the esophageal body stimulates a secondary peristaltic wave. At times, the LES undergoes periods of opening not associated with swallowing. This is most common after gaseous distention of the stomach, for example, after ingestion of carbonated beverages, and is the mechanism of belching. These periods of sphincter opening are often termed ‘‘TLESRs’’ and are the principal steps in the mechanism of episodes of reflux in normal subjects and in many patients with reflux. They are more common after meals, in the upright position, and rarely occur when lying down (11). All of the above functions are identified by esophageal motility testing. Typically, a catheter with pressure sensors 5 cm apart is passed through the anesthetized nostril into the esophagus, and advanced until all the sensors are in the stomach. This is recognizable by the presence of small (2–3 mmHg) elevations of pressure with each breath. The catheter is then drawn back slowly in 1 cm increments. As the most proximal sensor approaches the cardia, these pressure elevations with respiration become much more marked, because the sensor is being squeezed by the crura at each breath, but the pressure returns to normal between breaths. Pulling more proximally brings the sensor into the LES itself, characterized by elevation of the resting pressure off the gastric baseline, but still augmented by respiration. Further withdrawal leads to the point where inspiration causes the pressure to decrease. This point, the respiratory inversion point (RIP), is functionally the point of attachment of the phrenoesophageal membrane. The portion of the LES distal to the RIP is the intra-abdominal portion, and it responds to changes in intra-abdominal pressure. The portion of the LES proximal to the RIP is the intrathoracic portion (Fig. 3). The

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Figure 3 Manometric tracing of a transducer being pulled through the LES showing the resting pressure, the overall length, and the abdominal length. Abbreviation: LES, lower esophageal sphincter.

best estimate of LES pressure is controversial. The absolute method of measurement is not critical provided the same method is used in normal controls as in patients. Our preference is to measure in mid-inspiration at the RIP. It is vital when interpreting values from other laboratories that the method of interpretation is known. From the pressure tracing in each sensor, a value for the pressure, the overall length, and the intra-abdominal length of the LES will be obtained. The final result is the average of the readings from the individual sensors. The LES can be conceived of as a sequence of resistors connected in series. The length over which its pressure is applied contributes to protection from reflux, because the LES length is reduced with gastric distention, predisposing the patient to reflux. The overall length of the LES is easily calculated as the distance from the distal end to the proximal end of the LES, the final result being an average of the lengths calculated by each transducer on the catheter. Independently of the overall length, the portion of the LES within the abdomen, i.e., between the distal end and the RIP, is important in protecting against fluctuations in intra-abdominal pressure. Loss of this intra-abdominal length predisposes to reflux when the intra-abdominal pressure rises, for example, on straining or bending over. It is a characteristic feature of large hiatal hernias that the intraabdominal length of the LES is reduced. The three important components of the LES are pressure, overall length, and abdominal length (Table 1). A patient who is defective in any one of these parameters is said to have a structurally defective sphincter (12). In health, the LES is surrounded by the crura of the diaphragm. The contraction of the crural diaphragm appears

Table 1 Normal Values for Resting Parameters of the Lower Esophageal Sphincter Based on Study of 50 Normal Subjects in Our Laboratory Parameter Resting pressure Overall length Abdominal length

Mean

Normal range

13.8 mmHg 3.7 cm 2.2 cm

6–27 mmHg 2–5 cm 1–4 cm

to augment the effect of the intrinsic sphincter, and has led to the popularization of the ‘‘two-sphincter’’ hypothesis of reflux protection. However, the relative importance of the diaphragmatic contribution is still debated, but it is undeniable that when a hiatal hernia is present, these two components are separated rather than superimposed, and the crura lose their ability to protect the esophagus from reflux caused by increases in intra-abdominal pressure. The resting tone of the sphincter is maximal in the fasting state. Physical distention of the upper stomach and release of cholecystokinins and other peptides cause the pressure and length to be reduced. Consequently if a defective sphincter is identified in the motility laboratory with the patient in a fasting state, it can only get worse after a meal.

LES Relaxation The dynamic function of the LES is relaxation. This is important in two situations: one when it relaxes too readily, permitting reflux, and the other when it does not relax enough, as in achalasia. Clinically, LES relaxation is measured when the pressure sensor is positioned within the LES and 5 cc boluses of water are given. As swallowing is initiated, the LES begins to relax, and it reaches its nadir as the bolus reaches the distal esophagus (Fig. 4). Failure of relaxation is the hallmark of achalasia but may also be seen after an excessively tight fundoplication or laparoscopic gastric banding or a small infiltrating tumor of the cardia.

Esophageal Body Function The esophageal body contracts in response to a swallow by generating a wave of contraction of the circular muscle, which passes down the esophagus at a rate of 2 to 4 cm/sec. This is termed ‘‘primary peristalsis’’ (Fig. 5). Secondary peristalsis occurs in response to esophageal distention, for example, residual portions of a recently swallowed bolus or reflux of gas from the fundus into the esophagus. It can be produced experimentally by inflating a balloon in the esophagus. ‘‘Tertiary peristalsis’’ is a misnomer and is a term used by radiologists to describe the prolonged simultaneous

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Figure 4 Manometric tracing of LES relaxation in response to a swallow. Abbreviation: LES, lower esophageal sphincter.

contractions of the esophagus long after a swallow has passed, and is seen in diffuse esophageal spasm. Because of the helical arrangement of the circular muscle fibers of the esophagus, such prolonged contractions can produce the small outpouchings of the lumen, called pseudodiverticula, an appearance sometimes described as ‘‘corkscrew esophagus’’ or ‘‘rosary beading.’’ To transport a bolus, peristalsis must have two qualities: strength and organization. The strength or amplitude of the contraction must be sufficient to occlude the lumen and force the bolus distally, not just indent it. If we consider the analogy of stripping a Jackson-Pratt drain, a defective amplitude corresponds to the situation where the finger and thumb are not squeezed sufficiently strongly, and thus the contained serum or clot is not pushed into the bulb. Similarly, the wave will not transport a bolus if it is not organized sequentially from top to bottom. If the esophagus contracts simultaneously at all points along its length, no net

movement of the bolus will occur. This would be rather like squeezing the Jackson-Pratt tubing with both hands all at once rather than starting at the exit from the skin and squeezing toward the bulb. Amplitude is a property of the muscle and is impaired in diseases that injure or replace the muscle, such as scleroderma or longstanding reflux disease. Bolus transport is seriously impaired if the amplitude of contractions in the distal esophagus falls below 30 mmHg (13). In contrast, organization of peristalsis is a neurologic phenomenon and is impaired in diseases such as diffuse esophageal spasm or achalasia.

Upper Esophageal Sphincter The pharynx and UES are the last areas to be studied during a motility examination. Although the familiar coupling of proximal pump contraction and valve relaxation operates in this area, it is harder to study because it is composed of skeletal muscle and responds much more rapidly than

Figure 5 Manometric tracing of a primary peristaltic wave.

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smooth muscle. In addition, the UES moves cranially about 2 cm with each swallow, and the typical transducer may miss the event if it is not positioned accurately. Usually a specialized catheter with more closely spaced transducers is used to make motility recordings. The key elements in the study are to have a transducer in the pharynx and one in the most proximal part of the UES. As the pharynx contracts, the UES opens. Opening of the UES is augmented by the corresponding movement of the larynx and hyoid. They move both upwards and anteriorly, pulling the UES open. This is reflected in the initial rapid drop to subatmospheric pressure, seen on the UES tracing. If the UES transducer is not positioned at the top of the UES, the upward movement of the UES relative to the transducer will cause it to record intraesophageal pressure during the swallow, giving an illusion of relaxation. Outflow resistance can be inferred if the UES does not relax adequately. Indirect evidence of impaired relaxation is seen when the bolus is flowing through the sphincter. The hump or shoulder in the pharyngeal tracings represents the pressure of the bolus immediately prior to the closure of the lumen at the tail of the bolus. The higher this pressure, the greater the resistance to flow (14).

Ambulatory (24-Hour) Esophageal pH Monitoring Reflux is an episodic phenomenon. Recognition of this was the stimulus to develop a method for monitoring the intraesophageal pH for a prolonged period. It was first reported in a clinically useful form in 1974, and the criteria for defining the presence or absence of abnormal reflux have not been improved upon (15). In most cases, a pH sensor, usually of antimony, on a fine (7 Fr) catheter is passed through the nose into the esophagus and positioned 5 cm above the manometrically determined upper border of the LES. The traditional technique is being replaced by a wireless system where a capsule containing a pH sensor and a small battery-powered transmitter is deployed in the esophagus. It dislodges spontaneously two to five days later and is passed in the stool. Early studies show that results are broadly comparable to that obtained with a conventional catheter, but normal ranges are slightly different (16). It is becoming popular to place it transorally at the time of endoscopy, where it is positioned 6 cm above the endoscopically determined squamocolumnar junction. This is convenient, because the patient is already sedated and avoids the need to pass a bulky capsule through the nostril, but may be less accurate. Esophageal acid exposure is generally expressed in terms of the fraction of the monitored period during which acid was detected. The esophagus normally has a pH in the range 5 to 7, whereas the stomach pH is between 1 and 1.5. The most common threshold chosen is pH 4. Very few circumstances other than presence of refluxed gastric acid cause esophageal pH to drop below pH 4. This is also the level at which pepsin ceases to be active. Pepsin is a proteolytic enzyme most active in the range 2 to 3, and its activity is effectively zero at pH 4. For practical purposes, a threshold of pH 4 is the definition of reflux. A typical recording over a 24-hour period is shown graphically in Figure 6. The simplest way to quantify esophageal acid exposure is to express the total time below pH 4 as a percentage of the total monitored time. It is generally about 2% in normal subjects, and the upper limit of normal is 4%. Other features of the pH record, including total number of episodes, percentage of time below pH 4 in the supine position as well as the upright position, duration of the longest episode,

Figure 6 Typical 24-hour esophageal pH record showing episodes of reflux mostly in the upright position.

and number of episodes longer than five minutes in duration, can be combined into a composite score (Table 2). This score, because it takes account of the slight differences between normal ranges for males and females, gives a value independent of sex and appears to be superior to discriminate between normal and abnormal reflux. It may be important to detect reflux of gastric contents more proximally in the esophagus, for example, when laryngeal symptoms predominate and there is minimal heartburn. Normal episodes of acid reflux rarely reach above mid-esophagus. The intrathoracic pressure is maximally negative in mid-thorax, and in the more proximal esophagus, the pressure rises until in the pharynx it is equal to atmospheric. Reflux has to be very severe before it reaches all the way up to the pharynx, and more than 1% of the total monitored period is regarded as pathologic. To study the proximal acid exposure, a catheter with two electrodes 15 cm apart is used, the distal one being 5 cm, and the upper one 20 cm, above the LES (17).

Monitoring of Bile Reflux Nonacidic components of gastric juice may also be injurious. This has led to the development of devices to detect duodenal contents by identifying bilirubin. The bilirubin sensor (Bilitec) has a tiny spectrophotometer at the end of a catheter, which can detect the yellow light emitted by bilirubin. The intensity of the scattered light is proportional to the concentration of bilirubin. It is important to note that bilirubin is itself not the injurious agent, but merely acts as a marker for the presence of duodenal juice. A threshold of detectability is set and the time when bilirubin was detected Table 2 Mean and Upper Limit of Normal for the Typical Parameters of 24 Hours Esophageal pH Recording Parameter

Mean

Upper limit of normal

% time below pH 4 (total) % time below pH 4 (upright) % time below pH 4 (supine) # reflux episodes below pH 4 # reflux episodes > 5 min Duration of longest episode Composite score

1.5 2.2 0.6 19.0 0.8 6.7 6.0

4.5 8.4 3.5 47 3.5 19.8 14.7

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impedance as the swallowed liquid is transported down the esophagus. The direction of flow—whether antegrade as in swallowing or retrograde as in reflux—is easily determined from the tracings (Fig. 8). The method can be used to identify whether or not the bolus was actually transported, can detect reflux independent of acidity, and determine the proximal extent of the reflux (21). As it becomes more widely available it will have the capacity to provide the same functional information as the videoesophagogram.

Other Tests of Esophageal and Gastric Function Gastric Emptying

Figure 7 Record of simultaneous monitoring of presence of esophageal bilirubin and esophageal pH.

Gastric emptying is measured by ingesting a radiolabeled meal and scanning the stomach with a gamma camera. The decrease in counts with time in the region of interest is a measure of rate at which food empties from the stomach. The time taken for the radioactivity to drop by 50% is the most commonly used measure of gastric emptying (t1/2) and is generally less than 90 minutes.

Gastric Acid Secretion

above that is recorded and expressed as a percentage of the monitored period (Fig. 7) (18,19).

Multilevel Intraluminal Impedance A novel method of assessing intraesophageal events has been developed using changes in intraluminal impedance to mark swallowing and reflux events (20). Impedance can be thought of as resistance to current flow between two electrodes, and in the esophagus, impedance is increased when the catheters are lying in air, for example in belching, and reduced when conducting liquid is present in the esophagus. A swallow causes a momentary rise in impedance as a small quantity of air is swallowed first, followed by a drop in

Occasionally it may be necessary to assess vagal function in the stomach. This is typically when a patient has symptoms after a fundoplication, which are difficult to interpret. The question of whether or not the vagal nerves were injured by the operation is then an important one. Normally functioning vagi may be stimulated by sham feeding, i.e., the patient chews a tasty meal, but spits it out rather than swallow it. This stimulates the cephalic phase of gastric secretion and is vagally mediated. The older test using insulin-induced hypoglycemia has been abandoned because of risks of extreme hypoglycemia. If the vagi are intact, there will be an increase in the stimulated acid output above basal acid output. It has been reported that detecting an increase in serum pancreatic polypeptide following a sham feed may reliably detect functioning vagal nerves. This is a much more attractive option because it avoids the need for intubation of the stomach (22,23).

Figure 8 Simultaneous manometry (lower four tracings) and multilevel intraluminal impedance (upper four tracings) in a patient showing four swallows. Note that the abrupt decline in impedance indicates the passage of the bolus, and that recovery to the previous level indicates that the bolus has passed.

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ESOPHAGEAL DISEASES Gastroesophageal Reflux Disease GERD is the most common esophageal disease in Western society (24). Its prevalence is hard to estimate because largescale studies rely solely on symptoms. Despite the limitations of such studies, it is clear that heartburn is very common in Western populations, where 30% of the surveyed population use antacids once a month, and 7% report daily heartburn.

Physiology of GERD It is important to understand that GERD is not a disease caused by too much acid. With rare exceptions, acid secretion is normal in GERD. Nor is it caused by Helicobacter pylori. Large epidemiologic studies have revealed that H. pylori, especially the cagþ strain, is actually less prevalent in severe GERD, and that eradication of H. pylori does not improve, or may even worsen GERD (25). It has been hypothesized that the steady reduction of H. pylori infection in Western society is causally associated with the rising incidence of GERD in the same societies. Excessive reflux of gastric juice occurs because of dysfunction of the LES mechanism. This intuitive concept is still the most important factor in the pathogenesis of GERD. However, once an episode of reflux has occurred, a clearance mechanism is activated: swallowing occurs, causing peristaltic clearance of the majority of the bolus (‘‘volume’’ clearance), and acid remaining in contact with the mucosa is neutralized by the buffering effect of saliva (‘‘chemical clearance’’). It can easily be understood that ineffective peristalsis and defective salivation, such as after head and neck irradiation, both permit a given reflux episode to inflict additional epithelial damage. Fundamental to understanding management of GERD is appreciation of the mechanical factors that prevent reflux in health (12). The intra-abdominal pressure is positive with respect to the atmosphere, but the intrathoracic pressure is negative. This gradient increases with inspiration. Were it not for the physiologic barrier between the stomach and esophagus, reflux would be promoted by every breath. The nature of the barrier has been the subject of investigation for 50 years since its discovery manometrically in 1955. The LES can fail in two ways: (i) the resting parameters of pressure and length can be reduced, a situation described as a structurally defective sphincter and which is easily measurable in the esophageal motility laboratory, or (ii) it can undergo periods of loss of tone (TLESRs). Many TLESRs are not associated with reflux, but in symptomatic patients, the proportion of TLESRs associated with reflux is increased (26). Both of these mechanisms are important. In early disease, when the symptoms are intermittent and provoked by large or rich meals causing gastric distention, episodic loss of tone predominates. In severe disease, permanent reduction of LES length and tone is present, and further deterioration occurs with eating. Several recent observations are relevant in this regard. Consumption of carbonated beverages produces a reduction in the length and pressure of the LES in many subjects. The large and increasing amount of soda consumed by Western populations has been correlated with the increasing incidence of GERD in these communities. It is undeniable that dietary substances that cause reduction in LES pressure and/or delay gastric emptying—such as fat, onions, coffee, chocolate, and alcohol—are commonly consumed by Western populations, and the average portion size has significantly increased in the past generation.

Hiatal Hernia The relationship between hiatal hernia and GERD is complex. Following the seminal report of Allison in 1951, hiatal herniation was assumed to be the cause of the disease and surgical approaches were focused on anatomic reduction of the hernia (27). With the discovery of the LES, the role of hiatal hernia was de-emphasized (28). It is now clear that both factors are independently important (29). Much of the confusion results from the subjectivity of hiatal hernia detection. By convention, sliding hiatal hernia, in which the fundus and GEJ is displaced proximally above the diaphragm in the same axis as the esophagus, is termed ‘‘type I.’’ In type II hernia, the GEJ remains anchored below the crura, but the fundus rolls up alongside the esophagus, hence the term ‘‘paraesophageal hiatal hernia.’’ Type III hernias are large hernias combining both features, and the most extreme case of all, where the entire stomach is drawn up into the chest, is sometimes called type IV or intrathoracic stomach. Type I hernias are by far the most common. They are classified according to the distance between the GEJ and the crura, and are categorized as small (2–3 cm), moderate (3–5 cm), or large (>5 cm). Small type I hernias are extremely common and of limited clinical significance, being present in at least 30% of asymptomatic normal subjects. Moderate and larger hernias have a clearer relationship to reflux disease. They are rare in children and commoner in older subjects, and appear to be the result of attenuation of the phrenoesophageal membrane and other connective tissue structures binding the distal esophagus beneath the diaphragm. Larger hernias tend to be associated with more advanced disease, causing more severe heartburn and extraesophageal manifestations, as well as greater degrees of esophageal injury such as esophagitis and Barrett’s esophagus (30). The mechanisms by which hiatal hernia cause or aggravate reflux disease include (i) physical distraction of the phrenoesophageal membrane leading to attenuation of the function of the LES, (ii) impairment of esophageal emptying, and (iii) phenomenon of ‘‘rereflux’’ where acid in the supradiaphragmatic pouch is propelled back up into the esophagus under the influence of negative intrathoracic pressure (31). Patterns of Acid Reflux The use of pH monitoring has allowed a number of different patterns of reflux to be distinguished. Normal subjects may have 40 or more episodes of reflux daily, but they are brief, and rapidly cleared, and tend to occur after meals. The earliest form of reflux disease is an exacerbation of this phenomenon. Increased numbers of reflux episodes may occur, but in early disease, they tend to be confined to the upright period, with reflux at night being rare. Severe disease is characterized by reflux both day and night (Fig. 9). Supine reflux episodes are longer because esophageal clearance is no longer aided by gravity, and because there is less swallowing and less saliva transported down the esophagus to neutralize the acid. The acid contact time is therefore longer, and more likely to induce esophagitis. It has recently been observed that after a meal, there is a small ‘‘pocket’’ of unbuffered acid within the stomach just below the cardia, and that after a meal, the squamous mucosa of the distal esophagus is exposed to this acid (32). This very distal acid is not detected by conventional probes 5 cm above the LES. In fact, acid exposure immediately above the GEJ is about six times that measured in the conventional position (33). This phenomenon has been recently dubbed ‘‘short-segment reflux’’ and may explain

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Figure 9 Twenty-four hour esophageal pH monitoring showing severe gastroesophageal reflux in both upright and supine period.

why short-segment Barrett’s esophagus is several times more common than long-segment Barrett’s esophagus.

Clinical Spectrum of GERD GERD may present with symptoms of the disease process itself or with complications. Time and skill are necessary to elicit the exact nature of the patient’s symptoms. Patients reporting heartburn and regurgitation are immediately suspected of having GERD and are frequently started on strong acid suppression by primary care physicians. For reasons indicated in the section on symptomatology, patients’ descriptions are often imprecise. A dramatic response to proton pump inhibitors (PPIs) is a useful, though not absolute, diagnostic feature. Dysphagia in the context of reflux disease may be due to a stricture, to diffuse muscular damage leading to loss of motility, or to the development of adenocarcinoma in Barrett’s esophagus. When GERD causes coughing, wheezing, recurrent pneumonia, or hoarseness, the patient may be referred initially to another specialist before GERD is suspected. Patients being considered for lung transplantation are often evaluated for reflux if the underlying disease is not clearly understood, as in idiopathic pulmonary fibrosis. The other important atypical presentation of GERD is central chest pain, initially suggesting a cardiac problem. This usually prompts a cardiac workup, which, when negative, will lead to consideration of esophageal disease. In about 50% of patients with chest pain but a normal coronary angiogram, the cause is related to the esophagus, and most commonly is GERD (34).

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Tissue Injury in GERD Acid and pepsin in the esophagus not only stimulate nerve endings to produce heartburn, but cause cellular damage. The extent and character of the damage is roughly correlated with the degree of acid reflux. It is intuitive that injury from GERD should be concentrated in the most distal esophagus, in contrast with the damage inflicted by ingested agents, which is more severe proximally. Esophagitis is a visual diagnosis based on endoscopic appearance. It has been graded by many systems, of which the most common in use are the Los Angeles system and the new Savary-Miller classification (35,36). Although the details vary slightly, both systems agree that some form of focal erosion is necessary for the diagnosis of esophagitis (Table 3). Mere erythema is not only subjective but can be an artifact of the image-generating system of modern videoendosscopes. In mild disease, the changes are limited to a single mucosal fold, whereas more severe disease shows multiple and even confluent erosions, with the most severe disease being totally circumferential (Fig. 10). The natural history of esophagitis is reasonably well worked out. The important fact to grasp is that for most patients it is a lifelong disease. Prior to the widespread availability of strong acid suppression, a patient found to have esophagitis for the first time had a 50% chance of remaining at that stage, a 25% chance of reverting to a lesser grade, and about a 25% chance of progressing to a more severe grade in the long term. In contemporary practice, most patients can have healing maintained, even if the dose of medications needs to be escalated. But once it is present, it rarely goes away without treatment. Histologic markers of reflux disease are well worked out for erosive disease. The mucosa is characterized by loss of surface epithelium and presence of acute and chronic inflammatory cells in the submucosa. An increasing number of patients are found to have no erosive changes despite prominent symptoms. This situation, called nonerosive (or normal endoscopy) reflux disease or NERD, is increasingly detected, and may reflect a lower threshold to perform endoscopy, as well as the effect of chronic PPI use. In this patient group are some who are undoubtedly true refluxers, but whose mucosa is healed. They may be diluted by other patients whose symptoms are not due to reflux at all. There have been attempts to improve the specificity of diagnosis by histology, most notably by Ismail-Beghi, where the height of the rete pegs in squamous mucosa and the depth of the germinal cell layer were reported to be more sensitive (37). These criteria are too nonspecific to be of much diagnostic value. Histologic Changes of GERD The esophagus is lined by stratified squamous mucosa, and the stomach by columnar mucosa containing parietal cells

Table 3 Two Common Classifications for Describing Endoscopic Appearance of Esophagitis Los Angeles Grade A

Mucosal break
5 mm in length

Savary Miller Grade 1

Los Angeles Grade B

Mucosal break > 5 mm

Savary Miller Grade 2

Los Angeles Grade C

Mucosal break continuous between > 2 mucosal folds Mucosal break  75% of esophageal circumference

Savary Miller Grade 3

Los Angeles Grade D

Savary Miller Grade 4

One or more non confluent lesion with erythema and edema Confluent erosive and edematous lesions not covering the complete esophageal circumference The lesion covers the complete esophageal circumference Esophageal ulcer, Barrett’s epithelium, strictures, and other chronic mucosal lesions

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Figure 10 Endoscopic appearance of moderately severe esophagitis (Grade 2).

esophagitis are not known. There is clearly a genetic component, highlighted by the predominance in males (sevenfold increased incidence) and whites compared with AfricanAmericans or Latinos. However, the increased incidence in the past 30 years suggests an environmental basis. Dietary factors may play a role, and there is also concern that the relative alkalinization of the stomach, brought about by the chronic use of acid suppressants, may permit colonization of the stomach with bacteria that have the capacity to degrade bile salts. Deconjugated bile salts can produce carcinogens that may be refluxed with the gastric juice. The genetic events that lead to metaplasia and subsequently neoplasia take a very long time to produce visible changes. At some point the process may be irreversible, and this is the explanation for why cancer can develop even after successful abolition of reflux. However, it must be pointed out that most esophageal carcinomas, which develop after antireflux surgery, do so in the first few years after surgery: late cancers usually indicate that the surgical procedure has ceased to be an effective antireflux barrier. Data from studies in the 1980s before the development of modern antireflux surgery are therefore of limited relevance.

Treatment of GERD termed ‘‘oxyntic mucosa.’’ The point of transition between these two is visible endoscopically as the Z-line, which winds circumferentially around the esophagogastric junction. It is usually a sharply visible demarcation. Historically it has been assumed that there is a junctional band of columnar epithelium termed ‘‘cardiac mucosa’’ where there are only mucus glands and no parietal cells. Whether cardiac mucosa is a normal phenomenon or an acquired condition secondary to reflux is controversial, but recent studies of adult and pediatric autopsy material clearly indicate that cardiac mucosa is absent or barely detectable (< 1 mm) at birth and increases throughout life (38,39). When present, it nearly always contains inflammatory cells and is called carditis. If this carditis is associated with widespread inflammation of the fundic mucosa, it is related to H. pylori in the stomach. However, in the absence of generalized inflammation in the stomach, the presence of carditis appears to be an early indicator of reflux disease. In excised specimens removed for reasons not related to reflux, such as upper esophageal tumors, the tissue deep to this mucosa contains submucosal glands, indicating that it has arisen from the esophagus. Proof of association with early GERD is hard to obtain because the pH probes are placed 5 to 6 cm above this area and hence may not detect reflux. It is hypothesized that the healthy squamocolumnar junction is in the region of the LES and is thus largely protected from gastric juice: but in the presence of gastric dilation, it becomes exposed to gastric juice for longer periods and hence undergoes columnar metaplasia. Extension of this process up into the esophagus will follow if the LES deteriorates; it is recognized that there is an inverse relationship between the efficacy of the LES and extent of columnar mucosa. The process then undergoes another key step, namely the development of intestinalization of the columnar mucosa. Histologically this is characterized by the presence of goblet cells. The resulting epithelium is termed ‘‘intestinal’’ or ‘‘specialized’’ epithelium, and it is this epithelium that has the capacity to undergo further transformation to malignancy. Although it appears that the only etiologic factor is GERD, the features of reflux, which cause one person to develop specialized epithelium and another to have simple

The goal of treatment is relief of symptoms and prevention, or reversal, of complications. Uncomplicated reflux disease generally responds well to both medical and surgical treatment. It is customary, especially in the primary care setting, to recommend lifestyle changes as an aid to symptom control. These include losing weight, sleeping with the head of the bed elevated, avoiding tight clothing, and making dietary changes. The dietary changes involve the avoidance of large meals, late meals, and meals rich in fat or containing items such as chocolate, onions, spices, and tomatoes, and cessation of alcohol and tobacco intake. However meritorious dietary strictures may be in their own right, patients rarely comply with them. Acid suppression may be helped in the short term by taking antacids or H2 receptor antagonists (H2RA), all of which are readily available over the counter. The relief tends to be short lived and only of value when symptoms are mild or intermittent. Physiology of Acid Suppression It is not widely appreciated that esophageal damage is not primarily a direct result of acid: rather, the acid acts to facilitate the action of pepsin. Because pepsin cannot be reduced directly, reduction of acid secretion by the parietal cells of the stomach is the only practical way to render refluxed gastric contents less damaging. The parietal cells secrete hydrogen ions (protons) into the gastric lumen in response to various stimuli, of which the three most significant are acetylcholine, gastrin, and histamine. Reducing these stimuli to the parietal cells was the logic behind vagotomy, antrectomy, administration of and H2RA drugs. Each factor is relatively minor in isolation, and though the degree of acid suppression produced by any one of these measures is sufficient to heal peptic ulcers, it is quite inadequate for the treatment of reflux disease. The development of drugs that irreversibly bind the Naþ-Kþ-Hþ pump in the luminal border of the parietal cell marked a new phase in the medical management of peptic diseases. These drugs, commonly called proton pump inhibitors (PPIs), irreversibly bind to the pump when it is in an active condition, and because the lifespan of the gastric mucosa is one to two days, the drug needs to be administered daily.

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With the introduction of PPIs, it was possible to produce really profound suppression of gastric acid, and patients for the first time could appreciate freedom from heartburn. Many randomized trials comparing H2RAs with PPIs showed the clear superiority of the symptom control and healing of esophagitis produced by PPIs. Most studies of PPIs have as their end point the control of heartburn and healing of esophagitis. In the past decade, several features of PPI treatment have become clear. It works best in the maximally stimulated stomach. If taken without food, the only pumps actively inhibited are the few actually functioning at the time. Subsequent food intake will then stimulate acid as before. It is best to take the pills with food. In addition, it has become clear that many patients require twice daily dosing to maintain the pH elevation in the stomach. Some patients have recovery of acid secretion during the night, the so-called nocturnal acid breakthrough. This is best suppressed by adding an H2RA at bedtime. Although PPIs generally produce excellent relief of heartburn, other symptoms related to the physical process of reflux, such as regurgitation and laryngeal and respiratory symptoms, do not respond so dramatically. Outcome Measures The classical outcome measures in treatment of benign disease are control of symptoms and prevention of complications. In recent years, there has been emphasis on QoL studies using structured validated questionnaires such as the Short Form 36 or a more specific GI QoL. In addition, economic considerations are increasingly factored into treatment algorithms, especially by large health maintenance organizations. The overall costs of treating a common disease by expensive medications or surgery are very high. Comparison of Medical and Surgical Treatment In practice, the choice of treatment is too often determined by the physician’s bias, because there is good support in the literature from uncontrolled series for the efficacy of both medical and surgical treatment. When surgery was compared with the medical treatment available in the 1970s and 1980s in randomized controlled trials, it was shown to be superior. There are very few randomized controlled trials comparing modern medical and modern surgical treatment. Recent trials comparing contemporary laparoscopic Nissen fundoplication, and PPI therapy have shown smaller, but still significant, advantages for surgery. The best data come from Sweden, where the long-term freedom from symptoms was superior after surgery than after PPI treatment (40). The difference between medical and surgical outcomes was reduced if the medically treated patients were allowed to increase the dose of PPI. A much publicized trial by Spechler et al. from the Veterans Administration (VA) initially reported much better subjective and objective results when surgery was compared with use of H2 blockers and antacids. When these patients were followed up 10 years later, the differences had disappeared; many of the surgical patients were back on medication and there was actually a higher death rate among surgical patients from heart disease. However, the unique social spectrum sampled by this VA study makes it difficult to apply to the average patient with GERD (41). It will always be difficult to perform an acceptable clinical trial because the quality of surgery is difficult to standardize, and medical recommendations vary with time. Consequently, the results of any such trial tend to be disputed by the time it is published.

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It is much more logical to realize that both forms of treatment have strengths and to tailor the treatment to the disease. Some features of the disease are known to predict advancement or the development of complications: they include the following: young age; marked anatomic disruption (large hiatal hernia); erosive esophagitis at first presentation; reflux at night (supine reflux); and defective LES. Numerous publications attest to the predictive effect of these factors. In a recent study of the outcome of laparoscopic fundoplication in our department, three major factors emerged in multivariate analysis: positive 24-hour pH score, typical symptoms, and a good response to medical treatment. If all three factors were present, 97% of patients were pleased. If none of the factors was present, success was less than 50% (42). Surgical treatment, as well as giving superior durability of symptom control, has also been shown to provide superior protection against tissue injury: strictures need fewer dilations and esophagitis is more reliably healed. However, the issue of protection against malignant change in Barrett’s esophagus is discussed below. It is quite erroneous to suggest that only patients who fail to be controlled by medical treatment should be referred for surgery. Given the efficacy of contemporary medical treatment, patients who do not respond with marked symptom improvement to PPI drugs probably do not have GERD. A good response to strong acid suppression is one of the major predictors of a good outcome of fundoplication. The reason to recommend surgery for such patients is that extraesophageal manifestations tend to dominate the picture even when heartburn is well controlled by PPIs. In addition patients come to resent the need to take pills regularly, and the costs of repeated prescriptions, office visits, and frequent endoscopy. These are substantially reduced after successful surgery. Studies of QoL have repeatedly shown that surgical treatment results in superior improvement in QoL than does medical treatment (43,44). Both medical treatment and surgical treatment are expensive, but the costs of surgery are up-front, whereas the costs of medical treatment are spread out over the rest of the patient’s lifetime. Undoubtedly, some medically treated patients will develop complications and require more interventions such as endoscopy. Equally, there will be a certain percentage of long-term surgical failure, in the region of 10% to 15%, requiring additional medical treatment, endoscopies, and possibly revisional surgery. It is remarkably difficult to estimate actual costs, because most studies simply report the hospital charges; but the costs of medical treatment tend to exceed those of surgery in about 5 to 10 years. Endoscopic Antireflux Procedures The last few years have witnessed the development of attempts to restore competence to the GEJ by an intervention using the endoscope. There are currently four methods approved by the Food and Drug Administration. The Stretta procedure uses radiofrequency energy to produce a series of small lesions in the submucosa and muscular layer of the LES and cardia, causing collagen contraction and tightening. The Enteryx procedure involves injection of an inert polymer into the submucosa of the distal esophagus to create a bulking effect. However, recent complications such as aortoesophageal fistula have led to its withdrawal. The EndoCinch technique involves inserting a stitch to bunch up the GEJ. Finally, the endoscopic plicator is inserted down an overtube and places a staple into the GEJ with the aim of reinforcing the angle of His.

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The results of these four methods are all remarkably similar. There is little measurable change in the characteristics of the LES, and acid exposure in the esophagus is reduced by about half. It is rare for acid exposure to be restored to normal. Approximately 50% of patients are able to discontinue the use of PPI drugs. Symptomatic improvement despite significant reduction of acid exposure may be the result of sensory denervation produced by the procedure. Patients most likely to respond are those without a significant hiatal hernia and those with relatively mild disease. It seems intuitive that the relatively minor alterations produced by these endoscopic methods are unlikely to be of benefit in the face of significant anatomical alteration (45). Endoscopic antireflux procedures are relatively safe, but a few deaths have been reported. One was from accidental injection of polymer through the wall of the esophagus into the aorta in an elderly patient, with the production of an aortoesophageal fistula. Other deaths have resulted from unrecognized perforation of the esophagus, probably because the apparent simplicity of the procedure led to complacency in follow-up and insufficient attention was paid to the complaint of chest pain the night following the procedure. Physiology of Surgical Control of Gastroesophageal Reflux. The range of operations commonly used to treat uncomplicated reflux has narrowed down to a small number. Common to all methods are restoration of the distal esophagus into the abdominal cavity, repair of the hiatal hernia, and wrapping of the fundus of the stomach around the distal esophagus, termed fundoplication. In a Nissen fundoplication, the fundus completely encircles the esophagus and the two lips are sutured to each other to create a 360 wrap. Incomplete fundoplications are usually reserved for patients with profound defects in peristalsis, especially achalasia, because they have a lesser tendency to produce obstruction. There are two types, the anterior Dor hemifundoplication and the posterior hemifundoplication described by Toupet, and are further considered in the section on achalasia. Other procedures such as the Belsey procedure, which was essentially a 270 fundoplication performed through the left chest with extensive esophageal mobilization and formal subdiaphragmatic fixation of the wrap, are rarely performed except as salvage procedures or in cases of marked esophageal shortening. Similarly, the Hill posterior gastropexy, despite the excellent results reported by its originator, has not gained wide acceptance. The mechanism of action of fundoplication is still debated. It prevents the shortening of the LES, induced by gastric distention after a meal. When intragastric pressure rises, it is transmitted to the portion of the distal (wrapped) esophagus, causing it to collapse, rather in the manner of a Heimlich valve. Both partial and total fundoplications reduce the frequency of TLESRs. Both accentuate the angle of His, making the LES less liable to be opened as the stomach dilates. These actions are not absolute, and partial fundoplications have less effect than total fundoplication. Choice of Procedure. At one end of the spectrum are surgeons who perform Nissen fundoplication on all patients with GERD, and at the other are those who have tried to tailor the selection of procedure to the characteristics of each patient. In the past decade, there had been broad consensus that GERD roughly follows the ‘‘80/20’’ rule of many disease processes: 80% of patients cause only 20% of the trouble, but 20% of the patients cause 80% of the trouble. The 80% include those with uncomplicated reflux disease,

small hiatal hernias without esophageal shortening, and adequate esophageal motility and are good operative candidates. They are well managed by laparoscopic Nissen fundoplication and this operation is now well established in the armamentarium of community surgeons. The 20% are those patients with such features as esophageal shortening, fixed hiatal hernias, ineffective esophageal motility, and atypical symptoms, and those after a failed previous repair and they may require other procedures, including open transabdominal repair, a transthoracic approach to permit greater esophageal mobilization, the possible addition of a Collis gastroplasty, and, when all else fails, near total gastrectomy with Roux-en-Y diversion, or even esophageal replacement. Technique of Nissen Fundoplication (46). The operation is usually performed with the patient in the modified lithotomy position, with the surgeon standing between the patient’s legs. Increasingly surgeons are performing the procedure with the patient supine, probably because the increasing use of laparoscopic gastric bypass has enhanced familiarity with the approach. In either case, it is important to support the patient to avoid slipping when the table is tilted to the head-up position. Five ports are used: the camera is inserted at or just to the left of the midline six inches below the xiphoid, and pneumoperitoneum established. The patient is then tilted into steep reverse Trendelenburg position and additional ports are inserted under direct vision as follows: the port for the liver retractor is inserted either laterally on the right subcostal position, or at the xiphoid, to elevate the left lateral segment off the lesser omentum and cardia. The liver retractor is fixed by a self-retaining ‘‘iron-intern’’ retractor and once in position does not need to be moved for the remainder of the case. Then a right and left subcostal port is inserted for the surgeon’s left and right hands and a left lateral port for traction on the stomach. The steps of the operation are as follows: Esophageal Mobilization. Identification of the clear area of the lesser omentum (pars flaccida), which is opened to gain entrance to the lesser sac is described below (Fig. 11). The more opaque portion of the lesser omentum above the hepatic branch of the vagus nerve is also opened, and the edge of the right crus identified. The fat is dissected off the right crus to reveal a sulcus between the crus and the right margin of the esophagus. This is separated to mobilize the right and posterior margins of the distal esophagus. If the dissection is too close to the esophageal wall, the right (posterior)

Figure 11 Initial retraction for exposure of the esophageal hiatus. A fan retractor elevates the left lateral segment of the liver. A Babcock clamp retracts the esophageal fat pad.

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vagus nerve may be injured. The dissection is kept close to the crus and the vagus will remain safe in the periesophageal fat. The tissue overlying the esophagus at the apex of the right crus can be elevated off the esophagus and transected: the anterior vagus nerve is closely adherent to the esophagus and will be safely out of the way. Using a Babcock forceps to pull the fundus down and to the right, the left crus can be identified and the tissue binding it to the cardia and the angle of His can be incised (Fig. 12). A sulcus can be similarly identified on the left side of the esophagus. By working alternately from the right and left side, it will be possible to elevate the esophagus out of the crural tunnel and pass a grasper behind the esophagus over the left crus to emerge in the left upper quadrant, taking care to avoid the spleen. This grasper is then used to pull a Penrose drain behind the esophagus. The Penrose is secured with an Endoloop and all subsequent traction on the distal esophagus is made using this sling. The dissection of the crura is complete when the right and left crura are seen to meet in a V at the bottom of the operative field, and when several centimeters of distal esophagus are freely mobilized within the abdomen. Fundic Mobilization. The fundus is then mobilized by dividing the short gastric arteries with the Harmonic scalpel or Ligasure device. The left lateral Babcock is released from the Penrose sling and used to hold away the greater omentum beginning one-third of the way down the greater curve and proceeding upwards toward the cardia (Fig. 13). The most critical vessels to divide, to ensure adequate mobility of the fundus, are the high and medial vessels binding the cardia to the pancreas. This step is what permits the fundus to be brought behind the esophagus without twisting, and division of the easily accessible vessels on the upper greater curve is only necessary to permit access to these deeper vessels. The dissection is complete when the surgeon can see the caudate lobe from the left side of the cardia and GEJ. Several randomized controlled trials have attempted to study the value of fundic mobilization, without finding a clear advantage. One trial even reported that the symptomatic outcome was worse when the fundus was mobilized. However, it is not clear from the operative descriptions if the mobilization actually included the critical step of liberating the back of the fundus. Crural Repair. In the early days of laparoscopic Nissen, this step was often omitted, leading to an unacceptable

Figure 12 Dissection of the left crus and the angle of His.

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Figure 13 Retraction of the gastrosplenic omentum in preparation for division of the short gastric vessels.

risk of wrap migration with hernia recurrence (47). The repair is normally performed from behind the esophagus. A sequence of interrupted nonabsorbable sutures, e.g., O-Ethibond, are inserted into the crura (Fig. 14). Care must be taken not to injure the aorta in suturing the left eras, or the vena cava on the right. A figure-of-8 formation may be employed but risks getting the threads tangled. The resulting aperture should be snug but not tight. When the hernia is large, or has a paraesophageal component, the crura may be attenuated and widely separated. Simple suture then creates a risk of recurrence, a feature of many laparoscopic series. Many surgeons have attempted to reinforce the repair by some kind of prosthetic patch, such as Marlex mesh, in a manner similar to that for inguinal hernia repair. Fears that it would lead to esophageal erosion have not been borne out in practice, and the preponderance of evidence suggests that it is beneficial in reducing recurrence in large hernias where the crura are flimsy (48). Creation of the Wrap. To bring the fundus behind the esophagus, a silk marking stitch is inserted on the posterior fundus at a point measured from the GEJ for 6 cm along the circumference and then 6 cm perpendicular to a tangent at that point. This is the optimal point to form the posterior lip of the fundoplication. This suture is grasped from the right side and the fundus pulled through behind the esophagus (Fig. 15). A portion of anterior fundus is then grasped and

Figure 14 (Left): Closure of the crura with interrupted 2-0 silk. (Right): Penrose drain around esophagus to facilitate exposure of the crura for closure.

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Figure 16 Fixation of the fundoplication with a single horizontal mattress suture of 2-0 Prolene reinforced by Teflon pledgets. The 60 FG bougie passed just before the wrap is sutured ensures a floppy fundoplication. The inset shows the correct orientation of the wrap. Figure 15 Creation of the fundoplication. The posterior portion of the mobilized fundus is grasped by the Babcock forceps and pulled behind the esophagus.

moved to the right to meet the posterior lip in the right lateral position. The posterior lip should remain in this location without retracting to the left. A large (56 or 60 Fr) Maloney bougie is then passed with extreme care by the anesthesiologist. There is level 1 evidence that the use of such a bougie reduces postoperative dysphagia. Nevertheless it can be dangerous, especially if there is esophagitis or a stricture, and the esophagus and bougie must be thoroughly lubricated. When the bougie is safely in the stomach, the fundoplication appears tighter and some additional manipulation may be required to ensure that it sits without tension. The anterior and posterior lips are then united by a nonabsorbable suture to create a short wrap of 1.5 cm. Generally, we use a single-pledgeted horizontal mattress suture of 2/0 Prolene, which passes through both lips of the fundus as well as the esophageal wall (Fig. 16). Two additional sutures unite the fundic lips, one above and one below this, but they do not incorporate the esophageal wall. Many surgeons prefer to use three simple nonabsorbable sutures to avoid the occasional risk of erosion of the pledgets. Some surgeons reconstitute the phrenoesophageal membrane by suturing the arch of the crura to the distal esophagus above the wrap to reduce the chance of the wrap migrating upwards. To prevent the possibility of inadvertently wrapping the fundus round the proximal stomach instead of the distal esophagus, some surgeons deliberately pass the wrap between the posterior vagus nerve and the esophagus. The posterior vagus nerve is so tightly bound to the upper stomach that it acts as a barrier to wrong placement or future migration. When the operation is done through an open laparotomy, the steps are identical. Exposure is gained by retracting the sternum and costal margin with retractors fixed to a transverse bar at the level of the nipples, the so-called upper hand. Postoperative care is generally simple: the nasogastric tube is removed the next day, and, in fact, many surgeons no

longer use one. Oral liquids are administered the next day, and the patient is usually ready for discharge on the second postoperative day. A subset of fit, motivated, and younger patients who live locally may be discharged on the first day, or even the day of surgery. For such patients, many programs employ an intense regimen of early mobilization, liberal use of local anesthesia in the port sites, and liberal use of intravenous ketoralac (Toradol) in the early postoperative period, and early postoperative review in the office. Patients can drink liquids slowly but will experience difficulty if more than a small quantity is taken at a time. Patients should be able to take soft food in a few days and it is recommended that they avoid bread and meat for the first month, and that all medications be taken in crushed or liquid form. Carbonated beverages should be avoided. Most patients lose 10 to 15 pounds in the first few months, but the weight is generally regained within a year. The crural repair is dependent on a few sutures through muscle and the patient should not lift heavy objects or do vigorous manual labor for about six weeks. Most can return to a sedentary job one to two weeks after discharge. Postoperatively, after major dysphagia has resolved, it is common for patients to notice increased flatulence and looseness of bowel movements. This is so common that patients should be warned about the possibility. Patients will be unable to belch from the stomach, though small eructations of air trapped in the esophagus may occur. It is also hard to vomit, especially in the first year. Although abdominal bloating is often described, it is almost equally common in patients with GERD before surgery, and is rarely a problem unless the wrap is too tight or the patient has the habit of air swallowing. Perioperative Complications of Nissen Fundoplication for Uncomplicated Reflux. The most dreaded intraoperative complications are perforation of the esophagus or the back of the fundus, most commonly caused by dissecting the back of the GEJ without clear vision (49). Maladroit passage of the bougie may also cause perforation, for example, if the Penrose sling has not been relaxed and the bougie develops a ‘‘knuckle,’’ which splits the esophageal wall. If recognized

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promptly and repaired accurately, the eventual good outcome is generally unaffected. If unrecognized, then the patient presents with unusually severe abdominal or shoulder pain or signs of sepsis a few days postoperatively, sometimes after discharge. It is important to be vigilant and consider the possibility of perforation in any patient reporting unusual pain, fever, or tachycardia after discharge. Hemorrhage most commonly comes from liver damage inflicted by the liver retractor. It also may occur from the short gastric arteries or from splenic injury, and is generally controllable locally. If it affects the ability to see safely, it can often be controlled by a 4  4 gauze sponge inserted down the left upper trocar. Pressure with the sponge for a few minutes generally allows the bleeding point to be seen and controlled. Hemostatic agents such as fibrin glue are helpful in this situation. Vagal injury is occasionally blamed for postoperative gastric discomfort. Recent evidence using a sham feed to stimulate vagally mediated pancreatic polypeptide release suggests that some degree of vagal injury is very common (40%) early after Nissen fundoplication, but that it is not relevant to postoperative symptoms (23). Postoperative Complications. Complications discovered postoperatively may include an excessively tight wrap. This may present with total dysphagia, causing regurgitation of saliva, often described as foam. A barium swallow will resemble achalasia with dilation of the entire esophagus, a fluid level, and minimal passage of barium into the stomach. In most cases, the simplest solution is to return the patient to the operating room (OR). The problem may be an excessively tight crural closure, when release of the uppermost suture may solve the problem, or the wrap may have been too tight or twisted and it must be redone. If done within one to two days, it is generally not difficult. One reported cause of late dysphagia is excessive perihiatal fibrous scarring. This has even been reported in cases where the crura were not sutured, and is thought to be due to excessive use of electrocautery in the esophageal dissection (50). There are several reports of reherniation in the early postoperative period, possibly related to retching and vomiting, and if discovered within the first few days, laparoscopic rerepair is not generally difficult. If discovered late, then it is advisable to wait several months before attempting a repair. It is possible that for many patients, recurrent hiatal herniations may have actually occurred early but may not have been discovered. Early radiologic investigation of symptoms in the immediate postoperative period may identify this situation but laparoscopic reexploration is still relatively easy (51). A super-competent wrap may cause the so-called gasbloat syndrome, characterized by resonant abdominal distention coupled with the inability to burp. This may happen if the patient is a habitual air swallower, and it may improve as edema resolves and the patient adapts, no longer having to swallow as much because there is no longer any acid stimulating the esophagus. In severe cases, it may be necessary to insert a nasogastric tube, or even a percutaneous endoscopic gastrostomy (PEG). Occasionally, such patients are so chronically unhappy that the only solution is to dismantle the fundoplication and perhaps convert to a partial wrap.

Complicated GERD The complications of GERD are caused by tissue injury that produces an overlapping group of abnormalities

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including esophagitis, stricture, Barrett’s esophagus, and esophageal shortening. Esophagitis Esophagitis is an endoscopic diagnosis based on the visual appearance of mucosal erosions classified according to either the Los Angeles or the modified Savary-Miller systems. When the muscosa is visually normal, esophagitis is not present, regardless of the presence of inflammatory cells on mucosal biopsy. With the widespread use of PPI medications, it is possible to heal esophagitis in more than 90% of patients, and a normal endoscopy may cause the physician to underestimate the severity of the disease. This emphasizes the need for objective measurement of esophageal acid exposure. Stricture An esophageal stricture is a circumferential narrowing of the esophageal lumen, sufficient to prevent the passage of a 12 mm endoscope. When caused by reflux, it occurs just above the GEJ. GERD was formerly the most common cause of esophageal strictures in the pre-PPI era. Such strictures are now relatively rare. The esophageal strictures seen in practice are now most commonly anastomotic strictures or the result of pill or other caustic ingestion. Many pills, including over-the-counter preparations such as iron, calcium, and vitamin supplements, have been implicated in the creation of esophageal ulcers and strictures. Amongst prescribed medications, the antiosteoporosis agent Fosamax and nonsteroidal anti-inflammatory drugs (NSAIDs) are the worst offenders. Strictures present with dysphagia for solids and are readily visualized on both radiological and endoscopic studies. When seen for the first time, it is important to biopsy the stricture to ensure that it is not a malignancy. Benign strictures generally respond well to dilation. All dilations carry the risk of esophageal perforation. However, the use of through-the-scope balloon dilators has rendered dilation a much safer procedure, because the shearing forces produced by passage of a bougie are not present, and the procedure can be preformed under direct vision. Very tight or tortuous strictures should be dilated in a fluoroscopy suite, a guide wire passed under radiologic control, and Savary bougies passed over the wire. It is important to keep the wire still as the bougie is advanced, to use great gentleness, and to dilate only a small number of steps at any one sitting. When a size 36-Fr bougie has been passed, it should be possible to pass the scope through the stricture, and pass the guide wire under direct vision thereafter. In a tight stricture, no more than three graded bougies should be passed in one session. After dilation, the process that produced the stricture must then be controlled. A reflux stricture represents a failure of medical treatment and is likely to be best served by Nissen fundoplication, if the patient is a good operative risk and peristalsis is adequate. Strictures tend to occur in frail elderly patients who take a lot of other medications, and they are at higher risk of pill injury superimposed on a reflux stricture. Good pharmacologic control of acid secretion is especially important in this population. Undilatable strictures, or strictures that can be physically dilated but produce no symptomatic improvement, fall into the category sometimes called global esophageal failure and may require esophageal replacement (52). Schatzki’s Ring A specific type of stricture presents as a thin shelf at the squamocolumnar junction in association with a hiatal

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Figure 17 Typical appearance of Schatzki ring. Note the coexistent hiatal hernia.

hernia (Fig. 17). Its association with symptoms of GERD is variable, perhaps because it may represent a very localized response to excessive acid in the distal esophagus, and the localized fibrosis acts rather like an endogenous antireflux device, preventing further effacement of the sphincter and limiting reflux. It characteristically presents with intermittent dysphagia for solid foods. It responds well to dilation, but if improvement of the dysphagia is accompanied by the development of heartburn, the patient should be studied for other evidence of GERD and treated accordingly (53,54). Barrett’s Esophagus In the past decade, Barrett’s esophagus has emerged as the most significant complication of GERD. Improved symptom control by PPI use and reduction in the incidence of stricture is partly responsible. But an absolute increase has also occurred, bringing with it a parallel increase in esophageal adenocarcinoma (55). The cause of this changing epidemiologic pattern is still debated, but important environmental shifts in most Western countries include a reduction in the prevalence of H. pylori infection, and an increase in dietary fat and even carbonated beverage consumption, all of which are known to increase reflux in other situations. A cause and effect relationship has also been proposed between the widespread use of acid suppressant medications and the increasing incidence of esophageal adenocarcinoma, because the two phenomena have increased in parallel since in 1970s. There are theoretical grounds to indicate that prolonged acid reduction in the stomach leads to bacterial colonization,

which can then deconjugate bile salts, which reflux back into the stomach and esophagus. This hypothesis is still speculative at present. However, one common thread in the plethora of theories of the pathogenesis of Barrett’s esophagus appears to be the addition of duodenal-gastric reflux, sometimes called bile reflux, into the esophagus. Many studies using the Bilitec probe or continuous aspiration of esophageal secretions have confirmed that in Barrett’s esophagus, there are higher concentrations of bile salts than in uncomplicated reflux. The problem in interpreting these studies is that Barrett’s esophagus is also associated with the greatest acid reflux as well, and the presence of bile may simply be a nonspecific marker for severity. There seems to be general agreement that there is more bile in the refluxate of patients with Barrett’s than in patients with GERD but without Barrett’s (56). Bile salts have been shown to be mitogenic in other situations, such as in the colon. Regardless of the etiology of the mucosal transformation, Barrett’s esophagus tends to be associated with the most advanced stages of reflux disease: most patients have hiatal hernia, reduced LES length and pressure, reduced peristaltic amplitude in the distal esophagus, and markedly elevated acid exposure on 24-hour pH monitoring. Barrett’s esophagus is characterized endoscopically by the presence of velvety orange–red mucosa lining the tubular esophagus and histologically by the presence of columnar epithelium with intestinal metaplasila (Fig. 18). The visual appearance at endoscopy can sometimes be confused with herniation of normal gastric mucosa above the crura, and, in the past, Barrett’s esophagus was only diagnosed if the columnar mucosa extended 2 cm or more above the esophagogastric junction. The histologic hallmark of Barrett’s esophagus is the presence of ‘‘specialized’’ columnar epithelium, which shows features of intestinal metaplasia, easily recognized by the presence of goblet cells. These features may be seen in biopsies of specimens less than 2 cm above the esophagogastric junction, sometimes called short-segment Barrett’s esophagus (57). Shortsegment Barrett’s esophagus often appears as a small tongue of columnar epithelium extending above the Z-line into the lower esophagus. Barrett’s esophagus may exist on its own or may itself be complicated by ulceration, stricture, dysplasia, and malignant change. Ulceration typically occurs at the upper limit of the specialized mucosa, at the squamocolumnar junction. Barrett’s ulcers resemble duodenal ulcers in having the tendency to penetrate deeply, and to

Figure 18 Endoscopic appearance of Barrett’s esophagus.

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heal with stricture formation. Thus strictures in Barrett’s esophagus represent the site of a former ulcer, and, for this reason, are typically much higher than conventional peptic strictures, which occur at the GEJ. Malignant transformation of specialized epithelium generally progresses through a sequence of steps that include low-grade dysplasia, high-grade dysplasia, and invasive carcinoma. Irregular biopsy intervals during follow-up and sampling error prevent the sequence from being recorded in every patient, and the rate of transformation is very variable. The risk of malignant transformation in a given patient is hard to determine, though population estimates based on retrospective studies vary from less than 1 per 50 patient years to 1 per 440 patient years. The development of esophageal cancer via the metaplasia-dysplasia-carcinoma sequence is characterized by the accumulation of multiple genetic and epigenetic modifications. Many of these events affect cell growth through modulating the cell cycle, apoptosis, cell signaling, and cell adhesion. These genetic mutations may be useful in the future to identify those patients, with Barrett’s esophagus, at highest risk of developing adenocarcinoma. The early genetic changes detected in the progression of Barrett’s are loss of the p16 gene, loss of the p53 gene, cyclin D1 overexpression, and losses of the APC, Rb, and DCC loci, and aneuploidy (58). However, there appears to be no simple sequence of genetic mutations in the metaplasia-dysplasia-carcinoma path, making it difficult to use these mutations as markers of progressive disease. The environmental influences that initiate these genetic events in the cell are also unknown. Treatment specific to Barrett’s esophagus is controversial. In general, neither medical nor surgical treatment of underlying GERD produces disappearance of the Barrett’s epithelium, though its extent may be reduced, and squamous epithelium may overgrow the metaplastic epithelium, without replacing it. Many gastroenterologists doubt that the mere presence of Barrett’s epithelium requires any additional treatment beyond routine PPI treatment for underlying GERD. However, this policy underestimates the severity of the disease and underplays the effect of symptoms other than heartburn. While it is true that there is no conclusive proof that more total reflux control, as produced by fundoplication, can prevent cancer, there is strong evidence from several studies that dysplasia and progression to cancer are very rare after effective Nissen fundoplication. Most cancers, which do develop after fundoplication, either occur relatively early (within the first three years) or after the Nissen has become defective (59,60). However, in the absence of conclusive evidence, it is still recommended that patients with Barrett’s undergo regular endoscopic surveillance after antireflux surgery. Ablation of Barrett’s Mucosa. Removal of the abnormal epithelium has been intensively studied in the past decade. The two major methods in current use are the thermal technique in which thermal energy is directed from a heating electrode [multipolar electrocautery (MPEC)] and photodynamic therapy in which a sensitizing agent known as a protoporphyrin is given systemically and ultraviolet (UV) light is directed into the distal esophagus. The sensitizing agent is preferentially taken up into the abnormal mucosa, and absorption of the UV light is concentrated in that segment. The cardinal problem is that most methods of removing the mucosa also cause damage to the submucosa, producing a more scarred and ulcerated lesion that will at best heal with a stricture (61).

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Removal of Barrett’s mucosa with these methods is variable, and buried islands of glandular mucosa frequently remain after squamous mucosa regenerates. Consequently, they have been reserved for high-risk patients and those with dysplasia. However, a newer method using closely spaced rings to deliver radiofrequency energy on the outside of an inflatable intraesophageal balloon (Barrx) has shown great potential, because the depth of injury can be precisely controlled. This accomplishes the twin goals of total mucosal removal without damaging the underlying submucosa, permitting healing to occur without stricture. Early results with this method are extremely promising. Surveillance in Barrett’s Esophagus. The rationale for regular surveillance is that if a cancer develops, it will be found at an early stage and will be more amenable to curative treatment. It has been clearly shown that cancers discovered in the course of regular surveillance are highly curable (90% five-year survival), in contrast with cancers discovered after the patient presents with dysphagia, when 10% to 30% fiveyear survival is the rule. The approved protocol is to take biopsies from four quadrants of the circumference every 2 cm of Barrett’s mucosa (62,63). In the absence of dysplasia, surveillance is recommended every two years, and more frequently if dysplasia is identified. The features of low-grade dysplasia have much in common with reactive changes associated with active inflammation, and when diagnosed, the patient should have a course of really intensive acid suppression and then undergo repeat biopsy after 6 to 12 weeks. In many cases, the dysplasia will not be detected on this repeat biopsy, suggesting that it was mistaken on the first occasion. High-grade dysplasia is synonymous with carcinoma in situ, but is generally not diagnosed until confirmed by a second pathologist experienced in this area (64). The treatment of high-grade dysplasia is discussed in the section on esophageal carcinoma. Special Situations Esophageal Shortening. Most experienced esophageal surgeons recognize the situation where the GEJ is fixed higher in the crural tunnel or the mediastinum and it cannot be brought down below the diaphragm without tension. Preoperatively, it is more common in the presence of a large (> 5 cm) hiatal hernia, especially if fixed or associated with an esophageal stricture, in which case the shoulders of the supradiaphragmatic pouch will be sloping rather like a chardonnay bottle, rather than horizontal like a cabernet bottle. The appearance is caused by transmural scarring pulling the stomach upwards, and is the radiologic hallmark of a fixed or irreducible hernia. This is a difficult situation to deal with. If an unsuspected short esophagus is discovered intraoperatively, the options are to perform some kind of Collis gastroplasty and, create a neoesophagus that will then lie in the abdomen and can be wrapped by remaining fundus, the so-called Collis–Nissen operation. If shortening is detected at laparoscopy, a similar Collis gastroplasty may be performed by inserting the GIA stapler via the right fourth intercostal space and bringing it out in the hiatus, where it is at the correct angle, parallel to the esophagus. The fundoplication can then be completed by wrapping the fundus around the neoesophagus (65). Other solutions are to complete as much of the dissection as possible through the abdomen, close, and then turn the patient left side up and perform a thoracotomy through the sixth or seventh intercostal space. This will allow more extensive esophageal mobilization up to

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the aortic arch, and more esophageal length can be obtained by dividing the direct branches from the aorta and the bronchial arteries, as well as some of branches of the vagal plexus near the hilum of the left lung. Once enough length has been obtained, a transthoracic Nissen may be performed and the crura closed. This approach imposes a longer hospital stay, the need for intercostal tube underwater seal, and the risk of persistent post-thoracotomy pain later on. If adequate length cannot be obtained, a Collis gastroplasty is easily carried out with a GIA stapler and the remaining fundus wrapped around this segment. The initial results of these procedures tend to be very pleasing but the continued secretion of acid mucosa above the wrap leads to long-term failure in a significant proportion (66). The Hypomotile Esophagus. A patient with severe GERD and poor esophageal motility may have secondary, refluxinduced damage, or may have an underlying disease such as scleroderma in which the muscle of the distal esophagus is gradually replaced and peristalsis is lost (Fig. 19). Having to deal with such a case after a fundoplication has gone wrong emphasizes the need to assess esophageal motility before operating. Scleroderma and achalasia misdiagnosed as GERD are the two serious diagnoses that should not be missed. Most other forms of nonspecific motor disorder will respond well to Nissen fundoplication, provided the amplitude of peristalsis is greater than 20 mmHg in the lower esophagus. The paradox of this situation is that the cases that have the worst peristalsis and the highest risk of post-Nissen dysphagia are the very patients in whom the maximal reflux protection provided by the Nissen is most desirable (67,68). When there is very poor amplitude, it often coexists with esophageal shortening, and such cases are best approached through the chest. In the comparatively rare situation of a hypomotile esophagus with normal esophageal length, a laparoscopic partial fundoplication is an acceptable solution.

GERD in Morbidly Obese Patients. It is undeniable that a fundoplication, whether open or laparoscopic, is more difficult in obese patients, and there is some evidence that the outcome of fundoplication is less satisfactory (69). Other surgeons have found no difference in outcome (70). Patients with both GERD and morbid obesity may well be candidates for a primarily bariatric operation, because both Roux-en-Y gastric bypass and the adjustable gastric band have been found to reduce GERD. Consideration should be given to offering gastric bypass to such patients. Key to the selection will be a history of repeated failure of dietary and other conservative measures to achieve or sustain weight loss. Such patients are more than ready to accept the limitations imposed by a bariatric operation, and the freedom from reflux symptoms is a welcome bonus. However, an obese patient presenting primarily with reflux symptoms, who is not troubled by her weight and has made no concerted effort to lose weight, is probably an unsuitable candidate for bariatric surgery and likely to be intolerant of the dietary restrictions it would produce. Such a patient should be counseled about weight loss by nonsurgical means prior to scheduling antireflux surgery, because even short-term weight loss will improve the exposure and make the liver easier to retract. Reflux Causing End-Stage Lung Disease. In tertiary referral centers with large transplant programs, surgeons may be asked to consider antireflux surgery in potential lung transplant recipients. It is wise to confirm or exclude GERD in all potential lung transplant recipients where the lung pathology is not clearly understood. Diagnoses such as ‘‘idiopathic pulmonary fibrosis’’ or ‘‘usual interstitial pneumonitis’’ are commonly caused by GERD, and examination of the excised lungs sometimes reveals particles of vegetable matter that have presumably been aspirated (71). In contrast, when the disease is known, as in cystic fibrosis, reflux is unlikely to be a contributing factor.

Figure 19 Motility tracing of a patient with scleroderma, showing low-amplitude ineffective peristaltic contractions in the esophageal body.

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The characteristic features of reflux-induced lung disease are that heartburn and regurgitation are relatively minor symptoms, and may be absent, because the presentation is dominated by more serious or worrying symptoms such as extreme dyspnea. The esophageal mucosa often looks normal at endoscopy. The only satisfactory way to rule out GERD is by 24-hour pH monitoring. When reflux is found, it makes sense to perform surgery prior to lung transplant. Some degree of gastroparesis may be induced by the perihilar dissection, causing vagal injury and exacerbating preexisting reflux. Fundoplication is not especially difficult, but prolonged CO2 insufflation will lead to hypercarbia and the patient may need to remain intubated overnight to restore the pCO2 to its baseline level. Failed Antireflux Surgery. As the numbers of patients undergoing surgery for GERD increases, it is inevitable that patients with an unsatisfactory result will be referred to surgeons, especially in larger referral centers. The common patterns are either recurrence of the former symptoms or the development of new symptoms, such as dysphagia or abdominal pain, bloating, flatulence, or diarrhea. Up to 30% of patients after Nissen fundoplication will be found to be back on PPI therapy after surgery. When these patients are studied, less than one-third actually have any evidence of recurrent reflux (72). In the remainder, it has been prescribed by a primary care physician or gastroenterologist as empiric treatment. This practice is to be deplored, but it continues to fuel the unsubstantiated claim that fundoplication is only a short-term solution. Common patterns include recurrence of the hiatal hernia, breakdown of the fundoplication, a slipped Nissen fundoplication, and excessively tight fundoplication. These will present with recurrent heartburn and regurgitation or pulmonary symptoms, and worse or new-onset dysphagia. Abdominal symptoms such as bloating may be due to vagal denervation. A patient with a failed Nissen fundoplication requires a thorough workup to elucidate the cause of failure and plan remedial surgery if necessary. Barium esophagogram and upper endoscopy will establish if the fundoplication is intact or disrupted, if the wrap has migrated above the diaphragm, or if it is around the proximal stomach (slipped Nissen). The appearance of a herniated Nissen on endoscopy is characteristic, and easily distinguished from a correctly sited Nissen fundoplication (Fig. 20). Manometry will confirm if there is outflow obstruction by the presence of elevated LES pressure with failure to relax on swallowing,

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and if there is peristaltic failure. Recurrent reflux can be diagnosed by 24-hour pH monitoring. The original operative report and preoperative evaluation should be reviewed where possible, because this will give a clue to the presence of underlying esophageal disease. It was common in the past to perform most revisional surgery transthoracically. They are increasingly performed through the abdomen, and in many experienced centers, laparoscopic revisions are routine. Whether open or laparoscopic, it must be emphasized that revisional antireflux operations are much more difficult than primary procedures and there is a greater incidence of inadvertent gastric or esophageal perforation and vagal injury (73). If the cause of failure can be identified, a repeat operation can be expected to give a good result in 80% of cases. Third-time revisions are more problematic. A good result may still be obtained if a clear cause of failure can be identified and corrected. However, it is often the case that the distal esophagus and fundus are encased in dense scar tissue, and liberating the fundus in such circumstances results in a rather traumatized area with the creation of gastrotomy or esophageal perforation, and the vagus nerves are almost inevitably transected. These cases are usually best managed by near-total gastrectomy or by esophageal replacement with a colon interposition in a specialist referral center. Nonreflux Esophagitis. Cases of esophagitis due to causes other than reflux will occasionally present to a surgeon. Typically, there is more intense odynophagia than heartburn, and acid suppression is not of benefit. Infectious etiologies predominate, most often in the immunocompromised patient such as those with HIV/AIDS or on chemotherapy for malignancy elsewhere. The most common varieties are Candida, often easily recognizable by the presence of typical thrush lesion in the throat and white cheesy exudates on the esophageal mucosa, and viral causes such as herpes and cytomegalovirus, which present as punched-out ulcers throughout the esophagus (Fig. 21). These are treated by attacking the underlying cause and providing purely symptomatic relief by avoiding provocative or irritant foods. A second important cause is the toxicity of ingested caustic agents or pills, as described in the section on strictures. One recently described form of esophagitis in both children and adults is characterized by a narrow-caliber esophagus, sometimes with a series of circumferential ridges in the mucosa on endoscopy, described as ‘‘feline’’ esophagus. The characteristic on histology is the presence of eosinophils (> 20 per high power field) and for this

Figure 20 Endoscopic appearance of (A) correctly sited Nissen fundoplication and (B) herniated wrap, where the fundoplication can be seen passing up through the hiatus.

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diverticulum develops, because it appears to be due to an outpouching of the mucosa through a defect just above the nonrelaxing sphincter (Fig. 22). A Zenker’s diverticulum frequently presents with the coughing and choking typical of incomplete UES relaxation, but in addition the physical presence of the diverticulum allows the accumulation of food and saliva, which then causes coughing and regurgitation, when the patient lies down.

Treatment of Zenker’s Diverticulum

Figure 21 Endoscopic appearance of viral esophagitis.

reason it is known as eosinophilic esophagitis (74). The dominant symptom is dysphagia, and there is broad agreement that dilation tends to cause a long spiral tear in the mucosa, associated with severe chest pain. Frank perforation, however, is rare. It may have an autoimmune or allergic etiology and has been found to respond to leukotriene inhibitors.

Although often occurring in elderly, high-risk patients with other comorbidities, symptomatic Zenker’s diverticulum is so disabling that treatment is required, and only surgical treatment offers any prospect of improvement. The conventional approach is to perform cricomyotomy, which corrects the underlying physiologic defect, and the treatment of the actual diverticulum then depends on its size. A small diverticulum is generally taken up into the mucosa and requires no other treatment. Moderate-sized diverticula, once dissected out, can be suspended from the anterior longitudinal ligament, avoiding the need for actually opening the diverticulum. The largest (> 6 cm) should be excised, generally using a GIA stapler with a bougie in the esophagus to protect it from excessive narrowing. If a cricomyotomy is not performed, merely excising the diverticulum is likely to lead to

ESOPHAGEAL MOTOR DISORDERS Esophageal motor disorders primarily affect either the pharyngoesophageal segment or the esophageal body and LES. Although they are rare, there is increasing recognition that they can be a source of considerable morbidity and even mortality, which can result from either aspiration or complications of endoscopic treatment. Motor disorders affecting the UES present with difficulty in swallowing, choking, and coughing during eating, and most commonly result from a more general neurological cause, either vascular or degenerative. Some information can be obtained from a carefully performed videoesophagogram or modified barium swallow to detect aspiration and observe the movement of the epiglottis, larynx, and pharynx during swallowing. Treatment generally focuses on speech and swallowing therapy to teach airway protection, and provision of a PEG may be necessary to maintain nutrition. Exercises taught by therapists include teaching the patient to hold the breath, and deliberately to swallow twice in quick succession before breathing again. A special subgroup of usually elderly patients may present with dysphagia and choking due to defective UES relaxation. This appears to be localized to the cricopharyngeus muscle, because age-related metabolic deficiencies in the mitochondria of this frequently exercised skeletal muscle eventually cause fibrotic changes in the muscle, which then becomes stiff and loses compliance. This can be identified manometrically as impaired UES relaxation in the face of normal pharyngeal contraction. The typical findings are elevated residual pressure in the UES during a swallow, and indirectly, the presence of an elevated intrabolus pressure, because this is the manometric equivalent of impaired UES opening. Radiologically, there is an indentation or bar in the barium column when swallowing. Not all cricopharyngeal bars are symptomatic, but if it occupies more than 60% of the circumference of the esophageal lumen at that point, it is likely to cause serious symptoms. This physiologic situation is the underlying reason that Zenker’s

Figure 22 Typical appearance of Zenker’s diverticulum. Note the narrow opening of the UES with the origin of the diverticulum proximal to it. Abbreviation: UES, upper esophageal sphincter.

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failure of the staple line with a long-term salivary fistula, and even if it does heal, the diverticulum is likely to recur because the underlying condition, which produced it, was not corrected.

Cricomyotomy for Other Pharyngoesophageal Disorders Patients with degenerative or vascular neurologic conditions affecting the swallowing mechanism occasionally benefit from cricomyotomy if the pharyngeal muscles are sufficiently strong and coordinated to propel a bolus into the hypopharynx (14). This can be fairly easily established by detailed manometry, but a simple clinical guide to the adequacy of more proximal oropharyngeal dysfunction is to listen to the patient speak. Dysarthria, if present, indicates severe proximal involvement of the tongue and palate, and cricomyotomy is unlikely to be beneficial.

Technique of Cricopharyngeal Myotomy It should be remembered that patients requiring cricopharyngeal myotomy are often elderly, with arthritis of the cervical spine, and many are on anticoagulation. Oral anticoagulants must be stopped a week ahead of time and the patient maintained on heparin until it is safe to restart it. Sometimes the edema that accompanies the operative exposure makes swallowing worse before it improves it, and such patients may require assisted nutrition for a few weeks until they are able to eat comfortably and without coughing and choking. Such patients often benefit from a concomitant PEG insertion because it is rather worrying to perform it in the postoperative period if it should prove necessary. Exposure of the cervical esophagus is a fundamental skill that is also applicable to performing esophagectomy, repair of perforations, or creation of esophagostomy (Fig. 23). The patient is positioned supine with a roll between the shoulders, the neck slightly extended, the head resting on a donut, and the chin turned very slightly to the right. The skin is prepped to the level of the ear lobe. An incision is made along the anterior border of the left sternocleidomastoid muscle and deepened down through the

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platysma. The omohyoid muscle is seen crossing the neck obliquely and is divided. The strap muscles are divided just above their attachments to the manubrium. This allows the space to be opened between the larynx and trachea and thyroid medially and the carotid sheath laterally. By opening this space, the finger can easily reach the cervical spine and mobilize the posterior wall of the esophagus from the hyoid bone down into the mediastinum. The cervical esophagus is then easily identified in this paravertebral position. Care should be taken not to retract the larynx and trachea medially with a metal retractor: the recurrent laryngeal nerve is in the groove between the trachea and the esophagus and is easily traumatized. It is easiest to begin the myotomy on normal cervical esophagus well below the level of the larynx and divide first the longitudinal and then the circular muscle. Once the plane between the circular muscle and submucosa is reached, it is relatively easy to carry the myotomy down into the upper thoracic esophagus, and upwards, dividing the thick circular muscle of the cricopharyngeus, and carrying the incision upwards on to the pharyngeal constrictors. Excessive cautery should be avoided, because this could cause a small area of necrosis and lead to delayed perforation. Postoperative hematoma is a bothersome complication that will delay the patient’s functional recovery for several weeks. Every effort should be made to obtain perfect hemostasis, if necessary by tilting the patient head down to identify small bleeders and applying a topical agent such as fibrin glue. The platysma and skin should be closed precisely to avoid puckering because it will subsequently cause difficulty shaving.

Transoral Treatment of Zenker’s Diverticulum The modern treatment of moderate-sized Zenker’s diverticulum involves the passage of a specially designed rigid scope, and then a modified GIA type stapler so that one limb is in the diverticulum and the other in the esophageal lumen. When the gun is fired, the UES is automatically transected and the mucosa stapled, and the diverticulum is incorporated into the esophageal lumen. It can be performed as an outpatient procedure and avoids many of the risks, including recurrent nerve palsy, associated with open cricopharyngeal myotomy (75).

Recurrent Nerve Paralysis

Figure 23 Initial exposure for cricomyotomy via a left neck incision.

Damage to the recurrent laryngeal nerve in the neck is a known risk of any cervical esophageal operation. Anatomic variations of the course of the recurrent nerve are more common on the right, which is one reason why most esophageal mobilization is approached from the left side. Temporary injury may be caused by retraction or nearby cautery, and actual transection of the nerve is a risk if the anterior surface of the esophagus is mobilized, because the nerve lies in the groove between the anterior wall of the esophagus and the posterior wall of the trachea. The mobilization of the cervical esophagus for esophagectomy is more extensive and in its distal portion it is often done bluntly, and the incidence of nerve injury is correspondingly higher. Regardless of the cause, the effect of the injury is serious. Severe hoarseness will be present immediately afterwards, and swallowing is more difficult and aspiration is common. But the most severe functional problem is inability to cough effectively. The cough is instantly recognizable as a hollow ‘‘bovine’’ sound, and should immediately focus attention on airway protection and chest physical therapy.

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Treatment of the condition depends on whether recovery is expected. If the nerve was clearly seen and protected, it may be assumed that recovery will occur in a few weeks. Functional improvement in the voice and in coughing mechanics may be produced by injecting the affected cord to increase its bulk and permit the healthy vocal cord to oppose it more easily. Injection may be with glycerol, which is the shortest acting, with liquid fat, or with Teflon paste. If the nerve is known to be permanently injured, a thyroplasty operation may be performed. In this procedure, the thyroid cartilage is opened and the affected cord medialized by inserting a piece of nonabsorbable material such as Gore-Tex between the cord and the ala of the thyroid cartilage.

Motor Disorders of the Esophageal Body and LES Esophageal motor disorders affecting the esophageal body usually present with dysphagia and chest pain. Unlike mechanical obstruction, which presents with difficulty in eating solids, esophageal motor disorders classically present with dysphagia for both liquids and solids. They are diagnosed primarily by esophageal manometry. Endoscopy is often normal, and the disordered transit identified on barium studies is not sufficiently quantitative to categorize the disorder. Precise diagnosis is difficult for several reasons: the causes of most of the abnormalities are not known, many manometric abnormalities have no apparent physiologic consequences, and even when the manometric abnormality is corrected, the symptom may not resolve. Further, the symptoms can also be mimicked by other disease processes, most notably angina. Historically, there have been four named esophageal motor disorders: achalasia, diffuse esophageal spasm, nutcracker esophagus, and hypertensive LES, and a fifth category termed nonspecific esophageal motor disorder (NEMD), which is an umbrella term to describe tracings that are clearly abnormal but which do not fall into one of the above named categories (76).

up food finely. When under pressure to eat quickly, the symptoms get worse and they frequently prefer to eat in isolation rather than in company. With progression of the disease, most patients also develop regurgitation. Generally, it occurs during or at the end of a meal, and the material tastes bland rather than sour or bitter. It can also occur at night, causing staining of the pillow, and at times may wake the patient from sleep because of coughing or choking. Regurgitation may lead to avoidance of eating in company, and, sometimes, social isolation. Patients may be told that their symptoms are due to stress and may be taking antidepressive or anxiolytic medication. Chest pain also occurs in some patients, and may lead to the disease being confused with GERD. Most patients with achalasia have some weight loss, although this is not always the case, and the disease has been diagnosed even in the context of morbid obesity. The diagnosis is most commonly suspected on barium swallow. The classic findings of achalasia are a dilated esophagus with an air–fluid level and a smooth, tapered ‘‘bird’s beak’’ appearance representing the poorly relaxing LES (Fig. 24). In the early stages of the disease, the diameter of the esophagus may be normal. The late stage of achalasia is characterized by a tortuous, sigmoid esophagus, and an epiphrenic diverticulum may develop (Fig. 25). Because the esophagus empties only when the hydrostatic pressure of the fluid column overcomes the LES pressure, air remains

Achalasia Achalasia is the best known primary motility disorder of the esophagus. The cause is unknown, although degenerative, autoimmune, and infectious etiologies have been hypothesized (77). Pathologic examination shows an inflammatory response in the esophageal myenteric plexus, resulting in a selective loss of postganglionic inhibitory neurons containing nitric oxide and vasoactive intestinal peptide. Unopposed cholinergic stimulation leads to high basal LES pressures and inadequate relaxation of the sphincter. Inhibitory influences are also necessary for normal peristalsis. There is also some experimental evidence that obstruction at the GEJ may produce a condition with the radiologic and manometric features of achalasia. This corresponds to the clinical situation where features of achalasia develop in response to an infiltrating tumor of the cardia or after a tight Nissen fundoplication or placement of an adjustable gastric band. This evidence suggests that in some situations, the increased outflow resistance is a primary phenomenon and the degeneration of the esophageal body is secondary (78–80). Chagas’ disease, which is caused by infection with the parasite Trypanosoma cruzi, can also cause an achalasia-like syndrome in the esophagus. Patients with achalasia often present with dysphagia for solids and liquids. Careful questioning may be necessary to elicit this symptom. Patients may deny dysphagia, but may have developed methods of compensating for it, such as avoiding certain foods, eating slowly, or cutting

Figure 24 Barium study of patient with achalasia showing bird’s beak appearance of lower esophagus.

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neoplasm, which causes this pseudoachalasia, is an infiltrating tumor of the cardia, which can only be seen when the endoscope is retroflexed. Patients who appear to have extrinsic compression of the esophagus should be referred for more definitive imaging via endoscopic ultrasonography, or CT. Manometry is the key test by which to establish the diagnosis of achalasia (Fig. 26). The classic features on stationary manometry are as follows: 1. 2. 3. 4.

Figure 25 Barium study of advanced achalasia with sigmoid deformity and esophageal dilation with air–fluid level.

in the esophagus above the fluid, and hence there may be no visible gastric air bubble on upright chest X-ray. Upper endoscopy will often confirm findings reflected on barium studies, such as retained food and esophageal dilation. It is important to perform endoscopy to rule out a neoplasm of the esophagus, stomach, or mediastinum, all of which can cause symptoms that mimic achalasia. The most common

Elevated LES pressure Incomplete LES relaxation Absence of esophageal body peristalsis Positive intraesophageal body pressure

The resting LES pressure is usually raised, but can be normal in as many as 50% of patients. It is never low in untreated achalasia. Some abnormality of LES relaxation is seen in all patients: in 70% to 80% it is absent or incomplete, and in the remainder the relaxations are complete, but are of short duration (usually less than 6 seconds) and are functionally inadequate. In classic achalasia, the esophageal body is aperistaltic and intraesophageal pressure is positive, reflecting resistance to outflow. On swallowing, an isobaric low-pressure wave is usually seen simultaneously in all levels in the esophagus, representing the pressure generated by the pharynx being transmitted to the esophageal body. However, some patients may have normal or even high-amplitude simultaneous contractions in the esophageal body. This has led to description of a subgroup termed ‘‘vigorous achalasia.’’ It is not clear whether this is a separate disease or if it represents a stage in the evolution of classic achalasia. No treatment for achalasia can restore peristalsis or normal LES relaxation. Thus, every treatment option is designed to reduce the pressure gradient across the LES, thus facilitating esophageal emptying by gravity. The mainstay of long-term treatment centers round pneumatic dilation and surgical myotomy, but endoscopic injection of botulinum toxin into the LES and even some oral medications are occasionally recommended.

Figure 26 Classic manometric tracing of achalasia patient showing isobaric waves in response to a swallow, and positive intraesophageal body pressure.

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Smooth muscle relaxants including sublingual isosorbide dinitrate or calcium channel blockers can be taken prophylactically before meals, or as necessary for pain or dysphagia. These drugs provide variable relief of symptoms, and their effectiveness tends to decrease with time and their side effects such as headache and hypotension are intolerable. Botulinum toxin inhibits the calciumdependent release of acetylcholine from nerve terminals, thus countering the effect of the selective loss of inhibitory neurotransmitters. When injected directly into the LES at endoscopy, it is initially effective in relieving symptoms in about 85% of patients. The treatment is conceptually very attractive because the risk of perforation is very low, but symptoms recur in most patients within six months, possibly because of regeneration of the affected receptors. In addition, it is possible that myotomy may be more difficult after injection because of submucosal scar. Older patients and those with vigorous achalasia are more likely to have a sustained response (81). Because of its short duration of action, botulinum toxin injection has largely been abandoned except in high-risk patients. Thus, the two major treatments for achalasia remain pneumatic dilation and surgical myotomy. Pneumatic dilation involves placing a balloon over a guide wire so as to straddle the LES, which is then inflated to a pressure adequate to tear the muscle fibers of the sphincter. It is best performed in the fluoroscopy suite and the inflation is continued until the ‘‘waist’’ in the balloon is eliminated. The most commonly used dilators are the Rigiflex polyethylene balloons (Microvasive, Boston, Massachusetts, U.S.A.), which come in three diameter sizes ranging from 3 to 4 cm. The procedure can be done on an outpatient basis and has minimal recovery time. The attractions of convenience have to be balanced against the risk of perforation (up to 2% in modern series) and a response rate that is somewhat poorer than that of surgical treatment, especially in younger patients (82). Approximately 30% of patients will require subsequent dilations. Surgical myotomy was traditionally performed by either an open abdominal or thoracic approach. The development of thoracoscopic myotomy was a steppingstone to laparoscopic myotomy, which is currently the most commonly performed operation for achalasia (83). The approach to the operation is similar to a laparoscopic Nissen, except that circumferential mobilization of the esophagus is not necessary. The anterior aspect of the esophagus is dissected free from the left crus, and then the muscle fibers of the LES are divided proximally 4 to 5 cm until the esophageal body is clearly reached. The myotomy is carried 1 to 2 cm onto the stomach. A partial fundoplication is performed to prevent reflux. The Dor approach is currently preferred over a posterior wrap (Toupet) because it avoids the need to perform circumferential mobilization of the esophagus. It is not known why a Dor fundoplication appears to be superior for reflux protection in achalasia, but the posterior fundoplication is better for primary reflux disease (84). It is most likely because the underlying pathophysiology of postmyotomy reflux in achalasia is different from that of conventional GERD, which tends to be associated with hiatal hernia and some degree of esophageal shortening. Some surgeons have suggested that a partial wrap is unnecessary; however, this approach risks performing an inadequate myotomy through fear of causing reflux (85). The laparoscopic Heller myotomy with a Dor wrap can thus be considered the gold standard for surgical treatment of achalasia. Good to excellent results are reported in 80% to 100% of patients. The main

complication is uncontrolled gastroesophageal reflux, which occurs in about 10% of patients (86). Regardless of the mode of treatment, patients usually dramatically improve symptomatically in the first few months. If symptoms alone are used as an end point, both myotomy and dilation appear to yield excellent results in 70% to 90% of patients. Objective studies are hard to obtain, especially if they involve passing tubes. One simple semiquantitative study is the use of a timed barium swallow, in which the height of the barium column is measured one minute and five minutes after swallowing a defined amount of barium, to quantify esophageal emptying (87). Advanced and Recurrent Disease In end-stage achalasia, patients may not be able to empty the esophagus even after myotomy. A very dilated esophagus eventually develops a sigmoid deformity because it is fixed at either end. When this occurs, there is a dependent loop of esophagus, which resembles a drain beneath a kitchen sink. There are recent reports of cases where laparoscopic myotomy was performed in such patients with a good outcome (88). Most experienced surgeons have found that myotomy is unlikely to be successful for such patients and recommend esophagectomy. Transhiatal esophagectomy may be hazardous in this group of patients because blood vessels supplying the enlarged esophagus are likely to be dilated, and transthoracic esophagectomy may be safer. The etiology of failed myotomy depends somewhat on the time course in which the patient becomes symptomatic. Early failure (within one year after operation) is more likely to be the result of an error in technique, and repeat myotomy is more likely to be helpful. Dysphagia that occurs more than one year after surgery is most likely due to reflux stricture. Often, the only treatment that can be offered to the patient at this point is esophagectomy. Patients with morbid obesity may develop achalasia, although this is rare. Presentation is usually atypical in that regurgitation and respiratory symptoms are often more predominant than dysphagia. Care should be taken not to perform a bariatric procedure that may exacerbate resistance at the LES, such as laparoscopic banding or gastric bypass with Roux-en-Y. We have successfully combined Heller myotomy with biliopancreatic diversion/duodenal switch for several of these patients (89).

Other Motility Disorders Diffuse esophageal spasm presents most commonly with recurrent chest pain and dysphagia. The chest pain is not exertional, but can be confused with cardiac angina in that it may respond to nitroglycerin. Dysphagia is nonprogressive, associated with both liquids and solids, and can be precipitated by stress, liquids of extreme temperatures, or rapid eating. The cause is unknown. Patients have been shown to be hypersensitive to cholinergic and pentagastrin stimulation; it has also been suggested that gastroesophageal reflux and stressful events can produce spasm (90). Enhanced sensitivity may be mediated by a defect in neural inhibition related to decreased availability of nitric oxide. However, unlike achalasia, there are no specific histologic features in the myenteric plexus in patients with diffuse esophageal spasm (91). Radiographic studies may be normal in patients with diffuse esophageal spasm, or may show tertiary contractions with segmentation of the esophagus, known as ‘‘corkscrew esophagus.’’ Ambulatory 24-hour pH monitoring may show associated GERD in 20% to 50% of patients (92). Diffuse

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Figure 27 Typical manometric tracing of a patient with diffuse esophageal spasm.

esophageal spasm is defined manometrically by the presence of simultaneous contractions in 20% or more wet swallows, with an amplitude exceeding 30 mmHg (Fig. 27). However, this definition is somewhat arbitrary and is often debated. Other manometric findings found less consistently include long-duration contractions, repetitive waves, spontaneous non–swallow-induced contractions, and abnormalities of LES pressure or relaxation (93,94). Diffuse esophageal spasm is a benign disease in that it rarely causes nutritional problems and does not lead to lifethreatening complications. For this reason, symptom control is the major goal of treatment. Some patients may respond to reassurance that symptoms have an esophageal origin and are not cardiac in nature. Gastroesophageal reflux should be treated. Long-acting nitrates, calcium channel blockers, anticholinergics, and Sildenafil have all been used to treat this condition; although they can decrease high-amplitude contractions, they do not consistently relieve chest pain (95–98). Antidepressant medications can improve symptoms, although they do not affect esophageal motility (99). Pneumatic dilation and botulinum toxin have also been used to treat patients with complaints of severe dysphagia, as has long surgical myotomy (100–102). Surgery is more effective in relieving dysphagia than chest pain (103). Nutcracker esophagus is a hypercontractile disorder in which esophageal contraction amplitude in the distal esophagus exceeds two standard deviations above the mean of normal individuals (generally > 180 mmHg). Peristalsis is normally transmitted. If the resting pressure of the LES is above the normal range, hypertensive LES is present. These two abnormalities often coexist, suggesting that they may represent a spectrum of hypercontractile esophagus. Radiography and endoscopy are usually normal. Patients with coexisting GER may be identified on 24-hour pH testing. Unlike achalasia, the neural basis for the abnormality is not known. The relationship between symptoms and manometric abnormalities is unclear. Chest pain is not predictably relieved after reduction of contraction amplitude by either

medications or myotomy; therefore, treatment results are unpredictable. However there are encouraging reports of the use of Sildenafil. The one feature that appears to carry unequivocal benefit is treatment of associated GER. ‘‘Hypocontractile esophagus,’’ or ineffective esophageal motility, is a term recently coined to describe patients with either low-amplitude (< 30 mmHg) peristaltic or simultaneous contractions in the distal esophagus or failed peristalsis in which the wave does not propagate throughout the length of the esophagus. It is the one subcategory of NEMDs of clinical significance. Many patients with ineffective esophageal motility have GER, often associated with respiratory or ear, nose, and throat complaints (104,105). Similar motility abnormalities may also be found in patients with scleroderma, which causes vascular obliteration and secondary fibrosis, leading to damage of esophageal smooth muscle and its innervation (106). Other connective tissue diseases that can less frequently cause ineffective esophageal motility are mixed connective tissue disease, rheumatoid arthritis, and systemic lupus. No drug is currently available, which reliably increases peristaltic amplitude. Treatment of ineffective esophageal motility is therefore limited to control of associated GER.

ESOPHAGEAL EMERGENCIES Four common emergencies affecting the esophagus may present to the surgeon: hemorrhage, perforation, caustic ingestion, and food or foreign body impaction. Common to all is the need for skillful endoscopic assessment, the potential to cause or exacerbate injury by injudicious manipulation, and the ever present need to protect the airway. Variceal hemorrhage is discussed in Chapter 20. Nonvariceal hemorrhage may originate from diffuse mucosal inflammation, most commonly severe reflux esophagitis. Peptic ulcers of the esophagus, now a rarity but formerly a common complication of Barrett’s esophagus, tend to be deep and penetrate into major vessels feeding the distal

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esophagus. A rare cause of massive esophageal bleeding is aortoesophageal fistula, which is caused by a thoracic aortic aneurysm eroding into the esophagus. If the underlying condition is known, passing a Sengstaken–Blakemore tube to produce tamponade while the patient is prepared for the OR has been found to be successful by a few isolated reports. Focal bleeding from primary esophageal lesions responds to local endoscopic measures, and diffuse bleeding is best managed medically by aggressively suppressing acid. Caustic ingestion is now rare in the United States as the hazards of ingested cleaning agents have become more widely known. Accidental ingestion still occasionally occurs in children. Most cases are suicidal in their intent and are characterized by severe corrosive injury to the mouth, pharynx, airway, and esophagus. Strong alkali is more damaging than strong acid, because the acid causes coagulative necrosis, which limits further damage. Alkali produces liquefactive necrosis allowing deeper penetration. Total necrosis of the stomach and even adjacent organs such as the trachea and the transverse colon may occur. The priorities are to protect the airway, to replace fluid losses and maintain the circulation, and to provide adequate broad-spectrum antibiotic coverage because of the wide range of organisms found within the esophagus. Attempts to induce emesis are harmful because the caustic agent does further damage in the process of vomiting. After resuscitation, the extent of the injury is assessed. Traditional teaching used to advocate endoscopy only as far as the major lesion, because of fears of exacerbating the injury, but this advice stemmed from the era of rigid endoscopy, and the modern narrow-caliber flexible endoscopy may be safely used if handled with skill and gentleness. It is important to avoid excessive air insufflation, not to advance where the lumen cannot be seen, and to avoid tight curvatures of the scope tip. There is value in assessing the extent of damage to the stomach and pylorus, because it may be necessary in future even to perform a PEG or to use the stomach as an esophageal substitute, and if it is necrotic, it may need to be excised (107). Exploration is likely to be necessary if the patient is very toxic and shocked despite resuscitation. A blunt esophagectomy may be performed by exposing the esophagus in the abdomen and then exposing the cervical esophagus, and stripping using the varicose vein stripper. The proximal end is brought out as a cervical esophagostomy. If the stomach is healthy it is retained and a gastrostomy is created. Subsequent reconstruction is best delayed for several months because the scarring process continues for months and tends to proceed proximally. If an anastomosis is created, it may subsequently develop a very dense stricture. The most difficult lesions to reconstruct are those involving the pharynx and pyriform sinuses. A colopharyngeal anastomosis may function well if one pyriform sinus is preserved, but if both are fibrosed, it almost invariably leads to intolerable aspiration (108). In this situation it is likely that the patient will have to choose between being able to speak but not eat, or eat but not speak. Adequate and safe alimentation can be restored only by a pharyngolaryngectomy with an end tracheostomy. For milder degrees of injury, resection will not be required, but strictures are likely to develop. Systemic steroids have been found to be of no value in preventing or limiting the extent of a stricture (109). Esophageal perforations are of two types, spontaneous (Boerhaave’s syndrome) and endoscopic. The latter are more common, but generally less severe because the examination is done when the stomach is empty and it may be detected very shortly afterwards. In either case,

the typical symptom is severe chest pain and there may be circulatory collapse and subcutaneous emphysema in the neck. Extraesophageal air may be seen on chest X-ray (Fig. 28). Once the diagnosis of perforation is made, it is generally advisable to get a gastrografin swallow to establish its location, because this will determine the surgical approach. Perforations close to the cardia can be managed via the abdomen, but most will require a thoracotomy. A small subset of perforations may be managed nonoperatively by keeping the patient nil per os, providing adequate hydration, antibiotics, and nutrition for five to seven days. Cases suitable for this approach have perforations that are small, not associated with systemic sepsis, and where the swallowed contrast is seen to drain back into the esophagus and not lie in an undrained mediastinal cavity (110). All others should be repaired, and the key factor in determining the outcome is the delay between the event and the repair. If delayed more than 24 hours, the tissues may be so edematous and distorted that repair is very likely to break down, and such a case may do better by diverting the esophagus in the neck. There is increasing recognition that the mucosa remains strong even if the surrounding muscle is flimsy and degenerate. It may even be necessary to extend the apparent length of the perforation to ensure that the apex of the mucosal rent is identified and sutured accurately. If such a repair is attempted, the suture line should be buttressed with a flap of pleura or better still, intercostal muscle. Food impaction occurs in the presence of esophageal strictures and presents with total inability to swallow anything. Well-meaning bystanders often attempt to give the patient more to drink, exacerbating the distress and risking aspiration. The patient will tend to regurgitate saliva. This is a true emergency and is best managed by immediate endoscopy. The use of meat tenderizers is not recommended, because they are as likely to digest the esophagus as the impacted food (111). Usually it is a piece of meat, and it can be removed with rat-tooth forceps or sometimes pushed into the stomach with gentleness.

Figure 28 Chest X-ray showing subcutaneous emphysema in a patient with esophageal perforation. The arrow points to periesophageal air above the left clavicle and this is sometimes the earliest sign of perforation on plain X-ray.

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Irregular foreign bodies swallowed by children and psychiatrically disturbed or edentulous adults are more hazardous, and sometimes damage is inflicted by maladroit attempts at removal. The range of objects is very large, and includes batteries, dentures, and sharp objects such as pins, nails, and broken glass. Many of these can be removed by the use of an overtube or a rigid endoscope. The object is pulled back into the scope and the whole assembly then removed.

significant risk factor is Barrett’s esophagus (113,114). The incidence in Western countries is about 4 per 100,000 in the United States and 8 per 100,000 in the United Kingdom. In patients known to have Barrett’s, the risk has been estimated at about 0.5% patient per year, as discussed in the previous section on Barrett’s esophagus. There is strong evidence that the increase is real and not due to greater detection rates or reclassification of tumors of the upper stomach and cardia, as these are also increasing (115).

ESOPHAGEAL TUMORS Leiomyoma

Presentation

The only benign tumor of any significance is the esophageal leiomyoma. It is often discovered incidentally when a barium study or endoscopy is carried out for some other symptom. Occasionally, vague chest pain or dysphagia for solids may be reported. The characteristic appearance is a nonobstructing, smooth indentation covered by normal mucosa. Biopsy is useless; it rarely gets deeper than the mucosa, and if it does, it will render the excision more difficult because there will be an area of adherence to the mucosa, which may lead to a perforation when the lesion is removed surgically. Fine-needle aspiration may be performed, and the tissue characterized by special stains. Typical leiomyomas are positive for desmin and smooth muscle actin, and negative for CD34 and CD117. Unlike similar stromal tumors more distally in the GI tract, which are frequently positive for CD117, esophageal leiomyomas have a low propensity to recur and are adequately treated by being enucleated (112). It may be done by thoracotomy or thoracoscopy, but in either case taking care not to injure the vagal nerves as the esophagus is mobilized. Tumors less than 8 cm can be safely enucleated in this way, and the muscle wall is generally reapproximated to prevent subsequent diverticulum formation. The functional results are excellent and recurrence is extremely rare.

Esophageal cancer is a disease affecting patients of advancing age, with dysphagia and weight loss being by far the most common symptoms at the time of diagnosis. In a few patients dysphagia does not occur, and symptoms arise from invasion of the primary tumor into adjacent structures or from metastases. Unfortunately, when dysphagia does occur, it is usually late in the natural history of the disease. As a result, the dysphagia becomes severe enough to motivate the patient to seek medical advice only when a large proportion of the esophageal circumference is infiltrated with cancer. Increasingly, however, the diagnosis is being made on endoscopy as part of a surveillance program of patients known to have Barrett’s esophagus, in which case the tumors are usually detected at an early stage. Clinically, the diagnosis can be suspected on barium esophagogram, in which an ulcerating, irregular lesion is usually seen (Fig. 29). Endoscopy will show a friable mass, and biopsies are easily obtained. Difficulties can occur with esophageal strictures, where biopsies are hard to obtain, and in presumed achalasia, where a small infiltrating tumor of

Cancer of the Esophagus Esophageal carcinomas are of two types, squamous carcinoma and adenocarcinoma, which although differing profoundly in epidemiology, etiologic factors, relative incidence, and response to radiation therapy, present a similar clinical picture and are treated similarly from the surgeon’s point of view. The surgeon’s options depend more on the location and stage of the tumor than the histologic type. Squamous carcinoma accounts for most of esophageal carcinomas worldwide, but in the West it has been overtaken by adenocarcinoma as the leading type of esophageal cancer. Its incidence is highly variable, ranging from around 2 per 100,000 in the United States to 160 per 100,000 in highrisk areas of South Africa and the Hunan province of China. The environmental factors responsible for these sharply localized high incidences have not been conclusively identified, although both additives from local foodstuffs (nitroso compounds in pickled vegetables and smoked meats) and deficiencies (zinc and molybdenum) have been suggested. In the United States, smoking and alcohol consumption are strongly linked with squamous carcinoma and it most commonly occurs in African-Americans. Other definite associations link squamous carcinoma with long-standing achalasia, lye strictures, tylosis (an autosomal dominant disorder characterized by hyperkeratosis of the palms), and human papilloma virus. Adenocarcinoma of the esophagus is now the fastest increasing cancer in the Western world, and the only

Figure 29 Barium esophagogram in a patient with a large esophageal carcinoma demonstrating the ‘‘apple core’’ appearance.

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the cardia may produce manometric and radiologic features indistinguishable from those of achalasia. The tumor may only be seen when the scope is retroflexed and the cardia is viewed from below.

Staging Esophageal cancer is classified according to the 2002 American Joint Committee on Cancer tumor-node-metastasis (TNM) classification system, which depends on the depth of penetration of the primary tumor and the presence of lymph node or distant metastases. In practice, the T-stage is commonly classified as either intramucosal, intramural, or transmural (Fig. 30). Of patients presenting with dysphagia, up to 50% have unresectable or metastatic disease at the time of presentation. Some idea of advanced spread can be obtained from clinical examination and features of the esophagogram or on endoscopy (tumors > 8 cm in length). Staging requires other imaging techniques to assess lesser degrees of spread. CT scanning is widely used but is not accurate in staging small tumors. Magnetic resonance imaging (MRI) has not been shown to have any advantage over CT scanning in this regard. Patients with smaller tumors may benefit from further evaluation with endoscopic ultrasonography (Fig. 31). This technique is able to predict the depth of tumor invasion in 80% to 90% of patients and the extent of lymph node involvement by metastatic disease in 70% to 80% of patients (116). Lymph nodes can also be sampled using ultrasonographically guided fine-needle aspiration. Positron-emission tomography with fluorodeoxyglucose F18 can also be used to identify disease that has spread to regional lymph nodes. The increasing detection of earlier tumors has concentrated attention on the early spread of esophageal cancer. Tumors confined to the mucosa (T1) have a very low incidence of positive lymph nodes, and any involved nodes tend to be close to the tumor. In contrast, once the tumor extends into the submucosa, the incidence of involved lymph nodes increases to 50% (117). The rich submucosal plexus of esophageal lymphatics presents little barrier to the spread of tumor (Fig. 32).

Figure 30 Schematic representation of depth of penetration of tumors.

Figure 31 Appearance of an early esophageal carcinoma on endoscopic ultrasonography. The normal layers of the esophagus are clearly visible.

New proposals for staging have emerged because of the increasing prevalence of adenocarcinoma in the region of the cardia. It may be hard to determine if a tumor that straddles the GEJ originated in the distal esophagus or the proximal stomach. The current TNM staging system presents difficulty in interpreting lymph node metastases in cancers straddling the GEJ. If they are viewed as esophageal cancers, then positive nodes at the celiac axis would be viewed as distant metastatic disease. It is more logical to view the nodal status of these patients based on the numbers of lymph nodes involved rather than their location (118). Siewert et al. have proposed the following classification: Type I carcinomas arise from the distal esophagus, usually in a segment of Barrett’s epithelium, and may infiltrate the GEJ from above, type II carcinomas appear to arise from

Figure 32 Lymphatic drainage of the esophagus.

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the true junction of the esophagus and stomach, and type III carcinomas are subcardial gastric cancers that infiltrate the GEJ from below. Based on this classification, they propose that type II cancers should be treated with total gastrectomy and transhiatal resection of the distal esophagus (119). The goal of treatment in esophageal carcinoma may be either curative or palliative. The factors that govern whether a curative or palliative operation should be done are based on the location of the tumor, the age and fitness of the patient, and the stage of the disease.

Principles of Curative Surgery In esophageal cancer where the tumor can be completely removed, leaving no residual disease (R0 resection), the patient has the potential for long-term cure. The ability to perform R0 resection depends on the stage of the tumor and the physiologic fitness of the patient. By combining the endoscopic, histologic, and CT scan characteristics of the lesions, tumors may be classified as follows: High-Grade Dysplasia in Barrett’s Esophagus Convention wisdom has recommended subtotal esophagectomy for high-grade dysplasia, provided the diagnosis is confirmed by a knowledgeable pathologist. Even with careful preoperative endoscopy, on average, 40% of such excised specimens will have small intramucosal tumors detected (120). However, there is some evidence that patients can coexist with high-grade dysplasia for a considerable time, often many years. This allows for several endoscopies at three-month intervals to solidify the diagnosis, especially in elderly patients in whom conventional esophagectomy carries a high risk. If small intramuscoal tumors are detected on biopsy of Barrett’s with high-grade dysplasia, the risk of lymph node spread will determine whether or not en bloc esophagectomy is necessary. The most critical factor is the visual appearance of the mucosa. If there is no visible focal lesion on endoscopy, the chance of involved lymph nodes is very small, and a limited esophagectomy may be safely

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recommended. In this situation we perform vagal-sparing esophagectomy. Technique of Vagal-Sparing Esophagectomy (121) Through an upper midline abdominal incision, the right and left vagal nerves are identified and isolated. A limited, highly selective proximal gastric vagotomy is performed along the upper 4 cm of the lesser curve. The stomach is divided just below the GEJ. A left neck incision is then made and the esophagus is divided at the level of the thoracic inlet. The proximal staple line of the gastric division is then opened and a vein stripper passed up the esophagus into the neck wound and secured. The stripper is then pulled back into the abdomen, inverting the esophagus as it transverses the posterior mediastinum. This strips the branches of the esophageal plexus off the longitudinal muscle of the esophagus, preserving the esophageal plexus along with the proximal vagal nerves and the distal vagal trunks. The transverse colon is then used to reestablish intestinal continuity. This operation has been shown to preserve vagal function and prevent postoperative dumping and diarrhea, as well as result in improved meal capacity. In contrast to the situation where there is no visible lesion on endoscopy, the presence of a visible ulcer or tumor makes it likely that lymph node spread has already occurred, and en bloc esophagectomy is recommended. En bloc resection implies removal of a tissue block surrounded on all sides by normal tissue and requires a subtotal esophagectomy and a two-thirds gastrectomy in continuity with a block of tissue containing the following nodal groups: subcarinal, inferior paraesophageal, left gastric, celiac, hepatic, and splenic artery nodes. The dissection is limited anteriorly by the pericardium, laterally by the left and right mediastinal pleura, and posteriorly by the intercostal arteries, aorta, and anterior vertebral ligaments. The proximal margin is the carina, the inferior margin is the celiac axis and common hepatic artery, and the lateral margins are the mediastinal pleura and a collar of diaphragmatic muscle around the esophageal hiatus (Fig. 33). The resection

Figure 33 Extent of resection in en bloc esophagectomy. (A) Thoracic resection, (B) abdominal resection.

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is done through three incisions in the following order. First, exploration of the abdomen is performed through an upper midline incision and the porta hepatic and subpancreatic nodes are examined by biopsy. If no metastases are identified, the incision is closed, and an en bloc dissection of the esophagus through a right posterolateral thoracotomy is performed with mobilization of the esophagus above the aortic arch. The thoracotomy is closed, the patient repositioned in the supine position, and the upper midline abdominal incision reopened to permit en bloc dissection of the stomach and associated lymph nodes. The spleen and the splenic artery with its associated lymph nodes are removed by dissecting them off the superior border of the pancreas. A left neck incision is made to allow proximal division of the esophagus. The mobilized esophagus is removed transhiatally, and the stomach is divided at the incisura angularis. GI continuity is reestablished with a left colon interposition. In our experience, operative mortality of an en bloc esophagectomy is 6% and five-year survival is 52% (Fig. 34) (122). More advanced tumors presenting with dysphagia are less likely to be resectable for cure. In adenocarcinoma of the distal esophagus, the most common kind in current Western practice, it is simplest to perform transhiatal esophagectomy and make a conduit out of the stomach, preserving the right gastric and right gastroepiploic arteries. The excision is performed by mobilizing the distal esophagus, taking a rim of diaphragm and mediastinal tissue, and bluntly by using the fingers of the surgeon’s right hand to detach the esophagus from its surroundings. Usually some tough branches of the vagus nerve to the esophagus must be sharply divided. The esophagus is mobilized in the neck, and the operator makes contact with the operator from below to free the esophagus from the pleura laterally and the trachea and left main bronchus anteriorly. This approach is more dangerous in tumors of the middle or upper thoracic esophagus, because of the risk of injury to the tracheobronchial tree. For this reason, we prefer to perform right thoracotomy to establish a safe excision in more proximal tumors. In tumors of the cervical esophagus, the thoracic esophagus is removed by blunt dissection through a cervical

and upper abdominal incision. A simultaneous en bloc bilateral neck dissection is performed, sparing the jugular veins on both sides. A total laryngectomy in combination with esophagectorny is usually necessary. The stomach is pulled up through the esophageal bed, and a permanent tracheostomy stoma is constructed. More limited tumors may be excised without sacrificing the larynx, and continuity established using a forearm skin flap based on the radial artery. It is constructed into a tube and sutured between the pharynx and the esophagus at the root of the neck, and the artery and vein of the skin flap anastomosed to the external carotid artery and internal jugular vein, respectively. Choice and Technique of Esophageal Reconstruction After excising the cancer, continuity is generally restored either by using the stomach or the left colon as a conduit. The so-called gastric pull-up is created by dividing the omentum from the greater curve of the stomach, preserving the right gastroepiploic artery. Care is taken as the fundus is detached from the spleen to preserve as much tissue as possible. On the lesser curve side, the right gastric artery is preserved, and the left gastric artery divided at its junction with the celiac, taking all the lymph node tissue with the specimen. A wedge of stomach on the lesser curve is excised with the specimen. A pyloroplasty is generally performed to guard against aspiration of the contents of a nonemptying gastric tube. The mobilized gastric tube is sutured to a large funnel-shaped esophageal prosthesis such as a Mousseau-Barbin tube or even a very large chest tube, which is then passed up the posterior mediastinum to emerge in the neck incision, where an anastomosis is easily made with a single layer of interrupted monofilament sutures with the knots on the inside. The left colon is also a satisfactory esophageal substitute (123). It is created by mobilizing the colon completely and dividing the middle colic artery close to its origin from the superior mesenteric, preserving the Y-shaped branching pattern, which maintains the marginal artery. This works well because the marginal artery closely follows the line of the colon, allowing it to be straightened out. The proximal end of the graft is sutured to the cervical esophagus and the colon divided without transecting the mesocolon, to preserve blood supply. The distal end of the transposed segment is anastomosed to the stomach, either end to end to the antrum if the proximal stomach is excised, or to the posterior aspect of the fundus if the vagi have been preserved. If the reconstruction is done as a delayed procedure, for example, after perforation or caustic injury, the posterior mediastinal route is not accessible, and a substernal tunnel can be created. It is usually necessary to excise the distal left clavicle and the left side of the manubrium to create more room and avoid constriction and angulation of the conduit.

Adjuvant Therapy

Figure 34 Survival after en bloc EBE vs. THE for cancer. Abbreviations: EBE, esophagectomy; THE, transhiatal esophagectomy.

Because of the overall poor prognosis of patients with esophageal cancer, there has been much interest in multimodal therapy involving different combinations of surgery, radiation, and chemotherapy. Preoperative chemotherapy or radiation therapy in isolation has been found to confer no benefit. Currently neoadjuvant therapy—chemotherapy or radiation given before resection—has shown the most promise, with several phase II trials suggesting improved locoregional control and survival (124,125). However, phase III trials have not conclusively demonstrated improved

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survival, although they do suggest benefit for complete pathologic responders (126). The so-called multimodal therapy, involving preoperative chemotherapy and radiation therapy in doses up to 4000 Gray, has been shown in only one trial to have some survival benefit (127). On the basis of this single trial, multimodal therapy has been touted as being the standard of care. However the benefits were slight, the surgical excisions performed were not oncologically sound, and the graphical representation of the survival curves did not correspond to those reported in the text. Another recent trial of preoperative chemotherapy reported a median survival benefit of 512 days in the chemotherapy group compared to 405 days after surgery alone. All other trials of neoadjuvant therapy reported to date do not show an overall survival benefit. It is common to point out that some patients apparently respond to preoperative therapy so well that no viable tumor is found in the excised specimen. These patients have a greatly improved survival (80% at five years) compared with those having only a partial response or no response at all. At present there is no reliable method to predict response to chemotherapy, but analysis of the expression of genes relevant to the mode of action of chemotherapy may be helpful. Patients demonstrating lower levels of thymidylate synthase respond better to chemotherapeutic agents such as 5-Fluorouracil (128). Consequently, analysis of gene expression may permit the response to chemotherapeutic agents to be identified, and will allow the chemotherapy regimen to be tailored to the patient’s tumor.

Management of the Patient after Esophagectomy Esophagectomy is a major undertaking, whether for benign or malignant disease, and should ideally be carried out in specialist centers. There is good evidence that the results of esophagectomy are related to the caseload. In centers performing five or fewer esophagectomies per year, the mortality is steeply increased (129,130). The reasons for the improved outcome in high-volume centers are complex and are not just due to better standardized surgical technique: anesthesia, postoperative intensive care, and nursing and respiratory care all need to be optimized to obtain the best results. Early recognition and definitive management of complications, when they do occur, is better in experienced centers. The major complications that follow esophagectomy are leakage of the anastomosis, ischemia of the transposed stomach or colon, and aspiration pneumonia. The manifestations of these complications may be subtle, and include not only tachycardia, fever, leukocytosis, hypoxia, and metabolic acidosis, but also mild elevations of glucose, BUN, and creatinine, thrombocytopenia, and the new onset of atrial fibrillation. In the intensive care unit, it is vital to have good central venous access and a working nasogastric tube and to nurse the patient with the head of the bed elevated 30 . This is one of the few remaining areas in surgery where the nasogastric tube is vital, and until the conduit drains adequately the patient is at risk of aspiration from a stagnant stomach or colon interposition. The development of any these nonspecific signs of sepsis should prompt a proactive search for a source, and it is especially valuable to be able to endoscope the patient in the early postoperative period to check the integrity of the anastomosis and the health of the conduit. Frankly necrotic mucosa is occasionally seen, but relative ischemia is characterized by the presence of an exudate that does not wash off. After the early perioperative period has passed, patients still remain at risk for aspiration pneumonia. The

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relative merits of the stomach compared with the colon as the ideal esophageal substitute have been debated for years. Most surgeons perform gastric pull-up because it is quicker, is simpler, and requires only one anastomosis rather than three, and recovery is probably quicker. With prolonged survival, however, the disadvantages of the gastric pull-up emerge, including proximal esophagitis of the squamouslined remnant of the upper esophagus and even the development of Barrett’s esophagus. The function of the colon interposition seems to improve with time, and hence it is more suitable for the treatment of benign disease. Many of the abdominal symptoms following esophagectomy may actually be caused by the effect of vagotomy on the intestinal tract, and hence the operation of vagal-sparing esophagectomy is clearly superior from the functional point of view.

Palliative Therapy If the patient’s condition is considered incurable on preoperative or intraoperative evaluation, the severity of dysphagia or other incapacitating symptoms are assessed. Dysphagia for even semisolids is an indication for palliative resection. It is well documented that a transhiatal esophageal resection and reconstruction with esophagogastrostomy offers the best palliation, provided that the patient is physiologically fit. It allows the patient to eat without dysphagia and prevents the local complications of perforation, hemorrhage, fistula formation, and incapacitating pain. Tumors may be unresectable because of distant metastases or because of direct invasion of the aorta, spine, or heart in distal tumors, and in squamous tumors of the mid-esophagus, the trachea and bronchi are frequently invaded. Further, the patient’s general condition may be too poor to justify an extensive surgical procedure. In this situation, relief of dysphagia requires reestablishing a conduit through which food may pass. Most malignant strictures can be intubated using the flexible endoscope under sedation. Self-expanding metal stents are now available for this purpose, and have a lower complication rate than polyvinyl tubes. However, esophageal perforation, reflux of gastric contents, obstruction of the tube by tumor or food, and stent migration can still occur. The median survival after insertion of an esophageal tube for carcinoma is two to four months, but the benefit to the patient is well worth the risk, particularly in those who are unable to swallow even saliva. Other methods of establishing a lumen in unresectable esophageal cancers are laser ablation or electrocoagulation. The former carries few complications but requires frequent repetition to maintain patency, while the latter is useful only in circumferential tumors and requires fluoroscopy to position the heating electrode.

Chemoprevention of Esophageal Cancer Adenocarcinoma could theoretically be prevented if all reflux were stopped before the development of Barrett’s esophagus. Because there is no way to accomplish this, attention has focused on other steps within the sequence from metaplasia to neoplasia. This is the rationale for the use of cyclooxygenase-2 (COX-2) inhibitors in the chemoprevention of cancer. The COX-2 enzyme, which is induced at sites of inflammation, is involved in arachidonic acid metabolism. Because arachidonic acid is a potent inducer of apoptosis, COX-2 inhibitors promote apoptosis. Regular use of aspirin has been found to reduce the incidence of colon cancer, and there are strong grounds for expecting that esophageal cancer may be similarly reduced by NSAID use. However, withdrawal of selective COX-2 inhibitors such as rofecoxib and

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celecoxib has recently tempered enthusiasm for this approach. The value of regular aspirin in preventing the transformation of Barrett’s esophagus to esophageal cancer is being investigated in a large-scale trial based in the United Kingdom.

SUMMARY While often thought of as a tube to transport food from the mouth to the stomach, the esophagus is a dynamic organ whose presence becomes most noticed when it is affected by one of three disorders: a motility disease, gastroesophageal reflux, or neoplasia. Of these, reflux is by far the most common and afflicts millions of patients each year. While symptoms may vary from patient to patient, the hallmark associated with reflux is ‘‘heart-burn,’’ secondary to the mucosal irritant effects elicited by the refluxing gastroduodenal secretions. Fortunately, a variety of treatment options are available to manage this disorder. For most patients, effective management can be induced initially with acid suppression utilizing a proton pump inhibitor. For patients refractory to this therapy or whose symptomatology overrides what was initially efficacious, surgical intervention with Nissen fundoplication has proved to be a durable alternative. The most life-threatening complication of reflux disease is Barrett’s esophagus because of its premalignant potential. When Barrett’s mucosa becomes severely dysplastic, esophagectomy is currently the best treatment option to provide cure for this in situ cancer. Of the motor disturbances affecting the esophagus, Zenker’s diverticulum and achalasia are the most commonly encountered. Depending on size, a surgical myotomy is often all that is needed to manage Zenker’s disease. While dilatation of the obstructed esophagus can provide long-term management for achalasia, the most durable therapeutic option is again surgical myotomy. The most lethal problem affecting the esophagus is carcinoma. Both squamous and adenocarcinoma can occur, with the occurrence of the latter histologic variety being on the increase, possibly due to the reflux of bile and pancreatic juice. The adenocarcinoma most commonly develops in the Barrett’s mucosa, which undergoes severe dysplastic changes. If detected early enough, curability is possible. In contrast, squamous cell carcinoma is for the most part an incurable disease because ‘‘early detection’’ is so uncommonly encountered. In patients with this problem, palliation with attempts to improve swallowing is often the only treatment that can be offered.

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71. Tsai P, Peters J, Johnson W, Cohen R, Starnes V. Laparoscopic fundoplication 1 month prior to lung transplantation. Surg Endosc 1996; 10:668–670. 72. Lord RV, Kaminski A, Oberg S, et al. Absence of gastroesophageal reflux disease in a majority of patients taking acid suppression medications after Nissen fundoplication. J Gastrointest Surg 2002; 6:3–9. 73. Papasavas PK, Yeaney WW, Landreneau RJ, et al. Reoperative laparoscopic fundoplication for the treatment of failed fundoplication. J Thorac Cardiovasc Surg 2004; 128:509–516. 74. Noel RJ, Putnam PE, Rothenberg ME. Eosinophilic esophagitis. N Engl J Med 2004; 351(9):940–941. 75. van Overbeek JJ. Pathogenesis and methods of treatment of Zenker’s diverticulum. Ann Otol Rhinol Laryngol 2003; 112: 583–593. 76. Spechler SJ, Castell DO. Classification of oesophageal motility abnormalities. Gut 2001; 49:145–151. 77. Paterson WG. Etiology and pathogenesis of achalasia. Gastrointest Endosc Clin N Am 2001; 11:249–266, vi. 78. Awad ZT, Selima MA, Filipi CJ. Pseudoachalasia as a late complication of gastric wrap performed for morbid obesity: report of a case. Surg Today 2002; 32:906–909. 79. Stylopoulos N, Bunker CJ, Rattner DW. Development of achalasia secondary to laparoscopic Nissen fundoplication. J Gastrointest Surg 2002; 6:368–376. 80. Wiesner W, Hauser M, Schob O, Weber M, Hauser RS. Pseudo-achalasia following laparoscopically placed adjustable gastric banding. Obes Surg 2001; 11:513–518. 81. Neubrand M, Scheurlen C, Schepke M, Sauerbruch T. Longterm results and prognostic factors in the treatment of achalasia with botulinum toxin. Endoscopy 2002; 34:519–523. 82. Eckardt VF, Gockel I, Bernhard G. Pneumatic dilation for achalasia: late results of a prospective follow up investigation. Gut 2004; 53:629–633. 83. Patti MG, Pellegrini CA, Horgan S, et al. Minimally invasive surgery for achalasia: an 8-year experience with 168 patient. Ann Surg 1999; 230:587–593. 84. Wiechmann RJ, Ferguson MK, Naunheim KS, et al. Videoassisted surgical management of achalasia of the esophagus. J Thorac Cardiovasc Surg 1999; 118:916–923. 85. Richards WO, Torquati A, Holzman MD, et al. Heller myotomy versus Heller myotomy with Dor fundoplication for achalasia: a prospective randomized double-blind clinical trial. Ann Surg 2004; 240:405–412. 86. Zaninotto G, Costantini M, Molena D, et al. Treatment of esophageal achalasia with laparoscopic Heller myotomy and Dor partial anterior fundoplication: prospective evaluation of 100 consecutive patients. J Gastrointest Surg 2000; 4: 282–289. 87. de Oliveira JM, Birgisson S, Doinoff C, et al. Timed barium swallow: a simple technique for evaluating esophageal emptying in patients with achalasia. AJR 1997; 169:473–479. 88. Mineo TC, Pompeo E. Long-term outcome of Heller myotomy in achalasie sigmoid esophagus. J Thorac Cardiovasc Surg 2004; 128:402–407. 89. Almogy G, Anthone GJ, Crookes PF. Achalasia in the context of morbid obesity: a rare but important association. Obes Surg 2003; 13:896–900. 90. Anderson KO, Dalton CB, Bradley LA, Richter JE. Stress induces alterations of esophageal pressures in healthy volunteers and non-cardiac chest pain patients. Dig Dis Sci 1989; 34:83–91. 91. Champion JK, Delise N, Hunt T. Myenteric plexus in spastic motility disorders. J Gastrointest Surg 2001; 5:514–516. 92. Peters LJ, Mass LC, Petty D, et al. Spontaneous non-cardiac chest pain: evaluation by 24 hour ambulatory esophageal motility and pH monitoring. Gastroenterology 1988; 94:878–886. 93. Richter JE, Castell DO. Diffuse esophageal spasm: a reappraisal. Ann Intern Med 1984; 100:242–245. 94. DiMarino Al Jr, Cohen S. Characteristics of lower esophageal function in symptomatic diffuse esophageal spasm. Gastroenterology 1997; 66:1–6.

95. Orlando RC, Bozymski EM. Clinical and manometric effects of nitroglycerin in diffuse esophageal spasm. N Engl J Med 1973; 289:23–25. 96. Davies HA, Lewis MJ, Rhodes J, Henderson AH. Trial of nifedipine for prevention of esophageal spasm. Digestion 1987; 36:81–83. 97. Hongo M, Traube M, McCallum RW. Comparison of effects of nifedipine, probantheline bromide, and the combination on esophageal motor function in normal volunteers. Dig Dis Sci 1984; 29:300–305. 98. Eherer AJ, Schwetz I, Hammer HF, et al. Effect of sildenafil on oesophageal motor function in health subjects and patients with oesophageal motor disorders. Gut 2002; 50:758–764. 99. Cannon RO, Quyyumi AA, Mincemoyer R, et al. Imipramine in patients with chest pain despite normal coronary angiograms. N Engl J Med 1994; 330:1411–1417. 100. Ebert EC, Ouyang A, Wright SH, Cohen S. Pneumatic dilation in patients with symptomatic diffuse esophageal spasm and lower esophageal sphincter dysfunction. Dig Dis Sci 1983; 28:481–485. 101. Fishman VM, Parkman HP, Schiano TD, et al. Symptomatic improvement in achalasia after botulinum toxin of the lower esophageal sphincter. Am J Gastroenterol 1996; 91:1724–1730. 102. Henderson RD, Ryder D, Marryatt G. Extended esophageal myotomy and short total fundoplication hernia repair in diffuse esophageal spasm: five-year review in 34 patients. Ann Thorac Surg 1987; 43:25–31. 103. Eypasch EP, DeMeester TR, Klingman RR, Stein HJ. Physiologic assessment and surgical management of diffuse esophageal spasm. J Thorac Cardiovasc Surg 1992; 104:859–868. 104. Leite LP, Johnston BT, Barrett J, et al. Ineffective esophageal motility (IEM): the primary finding in patients with nonspecific esophageal motility disorder. Dig Dis Sci 1997; 42: 1853–1858. 105. Fouad YM, Katz PO, Hatlebakk JG, Castell DO. Ineffective esophageal motility: the most common motility abnormality in patients with GERD-associated respiratory symptoms. Am J Gastroenterol 1999; 94(6):1464–1467. 106. Lock G, Holstege A, Lang B, Scholmerich J. Gastrointestinal manifestations of progressive systemic sclerosis. Am J Gastroenterol 1997; 92:763–771. 107. Estrera A, Taylor W, Mills LJ, Platt MR. Corrosive burns of the esophagus and stomach: a recommendation for an aggressive surgical approach. Ann Thorac Surg 1986; 41:276–283. 108. Tran Ba Huy P, Celerier M. Management of severe caustic stenosis of the hypopharynx and esophagus by ileocolic transposition via suprahyoid or transepiglottic approach. Analysis of 18 cases. Ann Surg 1988; 207:439–445. 109. Anderson KD, Rouse TM, Randolph JG. A controlled trial of corticosteroids in children with corrosive injury of the esophagus. N Engl J Med 1990; 323:637–640. 110. Cameron JL, Keffer RF, Hendrix TR, Mehigan DG, Baker RR. Selective non-operative management of contained intra-thoracic esophageal perforations. Ann Thorac Surg 1979; 27: 404–408. 111. Hall ML, Huseby JS. Hemorrhagic pulmonary edema associated with meat tenderizer treatment for esophageal meat impaction. Chest 1988; 94:640–642. 112. Lee LS, Singhal S, Brinster CJ, et al. Current management of esophageal leiomyoma. J Am Coll Surg 2004; 198: 136–146. 113. Bollschweiler E, Wolfgarten E, Gutschow C, Holscher AH. Demographic variations in the rising incidence of esophageal adenocarcinoma in white males. Cancer 2000; 92:549–555. 114. Lagergren J. Adenocarcinoma of oesophagus: what exactly is the size of the problem and who is at risk? Gut 2005; 54:i1–i5. 115. Pohl H, Welch HG. The role of overdiagnosis and reclassification in the marked increase of esophageal adenocarcinoma incidence. J Natl Can Inst 2005; 97:142–146. 116. Van Dam J. Endosonographic evaluation of the patient with esophageal cancer. Chest 1997; 112(suppl):184S–190S. 117. Nigro JJ, Hagen JA, DeMeester TR, et al. Prevalence and location of nodal metastases in distal esophageal adenocarcinoma

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confined to the wall: implications or therapy. J Thorac Cardiovasc Surg 1999; 117:16–25. Hardwick RH, Williams GT. Staging of oesophageal adenocarcinoma. Br J Surg 2002; 89:1076–1077. Siewert JR, Stein HJ, Fink U. Surgical resection for cancer of the cardia. Semin Surg Oncol 1999; 17:125–131. Heitmeiller RF, Redmond M, Hamilton SR. Barrett’s esophagus with high-grade dysplasia: an indication for prophylactic esophagectomy. Ann Surg 1996; 224:66–71. Banki F, Mason R, DeMeester SR, et al. Vagal-sparing esophagectomy: a more physiologic alternative. Ann Surg 2002; 236:324–336. Hagen JA, DeMeester SR, Peters JH, Chandrasoma P, DeMeester T. Curative resection for esophageal adenocarcinoma: analysis of 100 en bloc esophagectomies. Ann Surg 2001; 234:520–531. DeMeester TR, Johansson K-E, Franze I, et al. Indications, surgical technique, and long-term functional results of colon interposition or bypass. Ann Surg 1988; 208:460–474. Stewart JR, Hoff SJ, Johnson DH, et al. Improved survival with neoadjuvant therapy and resection for adenocarcinoma of the esophagus. Ann Surg 1993; 218:571–576.

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125. Ferguson MK, Reeder LB, Hoffman PC, Haraf DJ, Drinkard LC, Vokes EE I. Intensive multimodality therapy for carcinoma of the esophagus and gastroesophageal junction. Ann Surg Oncol 1995; 2:101–106. 126. Visser BC, Venook AP, Patti MG. Adjuvant and neoadjuvant therapy for esophageal cancer: a critical reappraisal. Surg Oncol 2003; 12:1–7. 127. Walsh TN, Noonan N, Hollywood D, Kelly A, Keeling N, Hennessy TPJ. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 1996; 335:462–467. 128. Harpole DH, Moore M, Herndon JE, et al. The prognostic value of molecular marker analysis in patients treated with trimodality therapy for esophageal cancer. Clin Cancer Res 2001; 7:562–569. 129. Patti MG, Corvera CU, Glasgow RE, Way LW. A hospital’s annual rate of esophagectomy influences the operative mortality rate. J Gastrointest Surg 1998; 2:186–192. 130. Dimick JB, Pronovost PJ, Cowan JA, Lipsett PA. Surgical volume and quality of care for esophageal resection: do high-volume hospitals have fewer complications? Ann Thorac Surg 2003; 75:337–341.

15 Gastric Physiology and Acid-Peptic Disorders Kenneth S. Helmer and David W. Mercer

primitive stomach now becomes the ventral surface, and the original right side becomes the dorsal surface. Similarly, the cranial portion, which develops into the fundus, moves to the left and inferiorly, while the caudal region, which develops into the pyloric antrum, moves to the right and superiorly. This rotation, which begins at around 28 days and extends to about 48 days, gives the stomach its final position, which is almost transverse to the long axis of the body. This explains why the anterior wall of the stomach is supplied by the left vagus nerve and the posterior wall supplied by the right vagus nerve (1). Figures 1 and 2 demonstrate early embryologic development and rotation.

INTRODUCTION The gastrointestinal (GI) system is a boundary between the external world and the internal environment of the human body. The stomach plays an important role in the GI system, not only by helping to protect the internal environment from outside pathogens by the bactericidal activity of gastric acid, but also in preparing food for digestion and absorption of nutrients. The stomach functions to act as a reservoir for food by accommodating large quantities of ingested food through receptive relaxation. Through contraction and relaxation of the stomach musculature the stomach mixes and liquefies food with gastric juice, which partially digests food and emulsifies fats. Although simplified here, an intricate and complex relationship between exocrine, endocrine, paracrine, and neurocrine pathways are involved. The aim of this chapter is to summarize these complex interactions as well as to illustrate the physiologic anatomy as it relates to surgical diseases.

Gastric Anatomy Divisions The stomach is generally divided into four anatomic regions as shown in Figure 3. Although these divisions are useful to the surgeon in describing anatomical resections, they do not necessarily denote histological, secretory, or muscular physiology of the stomach. The most proximal portion of the stomach is the cardia, which is just distal to the gastroesophageal (GE) junction. The cardia contains mucous cells and attaches the stomach to the esophagus. The fundus is the portion of the proximal stomach, which is the most superior and extends above the GE junction. The fundus is bounded superiorly by the diaphragm and laterally by the spleen. The angle of His is an anatomic angle, which the fundus forms with the left margin of the esophagus. The body of the stomach is also the largest portion and is contained between the relatively straight lesser curvature on the right and the longer greater curvature on the left. The body is also referred to as the corpus. The angularis incisura is an abrupt angle along the lesser curvature that directs the distal stomach to the right. This angle designates where the body of the stomach ends and the antrum begins. It can also be identified grossly by the confluence of vasculature along the lesser curvature at the angle. The pylorus, which resides in the distal antrum, connects the stomach to the proximal duodenum. The pyloric opening is surrounded by a thickened ring of gastric circular muscle, which constitutes the pyloric sphincter.

NORMAL PHYSIOLOGY Stomach Embryology During the fourth week of gestation, the primitive gut forms as the dorsal part of the yolk sac is incorporated into the embryo. The epithelia at the cranial and caudal ends of the tract develop into the ectoderm of the primitive mouth (stomodeum) and primitive anal pit (proctodeum), respectively. The epithelium and glands of the digestive tract are formed by the endoderm of the primitive gut, while the splanchnic mesenchyme, which surrounds the endoderm, forms the muscular tissue, connective tissue, and other layers comprising the wall of the digestive tract. The foregut goes on to develop into the adult derivatives of the primitive pharynx, lower respiratory system, esophagus, stomach, duodenum (proximal to the common bile duct), liver, biliary system, and pancreas. The artery of the foregut develops into the celiac artery, which supplies these structures except the pharynx derivatives, respiratory tract, and proximal esophagus. The stomach begins as a simple tubular structure in the distal part of the foregut and dilatation during the middle of the fourth week designates the future site of the stomach. The stomach initially enlarges in a ventrodorsal fashion in the median plane. The greater curvature of the stomach, which is demarcated as the dorsal plane, grows faster than the ventral plane (lesser curvature). As this takes place, the stomach slowly rotates 90
in a clockwise direction around its longitudinal axis. This rotation explains the unique axis of the stomach. The lesser curvature (ventral border) moves to the right and the greater curvature (dorsal border) to the left, which effectively changes the stomach’s ventral–dorsal designation. The original left side of the

Blood Supply The stomach receives the majority of blood from the right and left gastric and right and left gastroepiploic arteries. The majority of the blood supply originates from the celiac artery. Additionally, blood may also be supplied by the inferior phrenic arteries and short gastric arteries from the spleen. Figure 4 demonstrates the arterial supply of the stomach. The left and right gastric arteries supply the 333

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the left toward the gastric cardia, giving off esophageal and hepatic branches before turning to the right and running along the lesser curvature of the stomach within the lesser omentum. It runs from superior to inferior and anastomoses with the right gastric artery. An aberrant left hepatic artery may originate from the left gastric artery approximately 15% to 20% of the time. This is important because, if present, proximal ligation of the left gastric artery may result in left-sided hepatic ischemia, because occasionally an aberrant left hepatic artery is the only arterial blood supply to the left hepatic lobe. The right gastric artery is a branch-off from the common hepatic artery and runs to the pylorus and then upward along the lesser curvature of the stomach. Occasionally, the gastroduodenal artery may supply the right gastric artery. The left and right gastroepiploic arteries supply the greater curvature of the stomach. The left gastroepiploic artery runs to the right along the greater curvature of the stomach and is supplied by the splenic artery. The right gastroepiploic artery also runs to the left along the greater curvature and anastomoses with the left gastroepiploic artery. It is supplied by the gastroduodenal artery and also supplies the greater omentum. The short gastric arteries also supply the greater curvature and they are branches of the splenic artery. Fortunately, because of the superiorly extensive anastomotic connections between the four major arteries supplying the stomach, gastric viability can be preserved after ligation of all but one primary artery. This anastomotic network of arteries is advantageous to the surgeon performing gastric resection and reconstruction. Furthermore, in instances of celiac artery occlusion, gastric blood supply may be maintained by the superior mesenteric artery via collaterals from the pancreaticoduodenal arcade. Unfortunately for the patient, the rich anastomosis also means that gastric hemorrhage is not amenable to ligation of gastric arteries. The venous drainage of the stomach generally parallels the arterial supply. The left gastric (coronary) and right gastric veins usually drain into the portal vein. The right gastroepiploic vein drains into the superior mesenteric vein and the left gastroepiploic vein drains into the splenic vein.

Lymphatic Drainage

Figure 1 Drawings illustrating development and rotation of the stomach and formation of the omental bursa (lesser sac) and greater omentum. (A) About 28 days. (B) About 35 days. (C) About 40 days. (D) About 48 days. Source: From Ref. 1, with permission of Elsevier.

lesser curvature of the stomach. The left gastric artery is the first and smallest branch of the celiac trunk. However, it is the largest artery to the stomach. It runs upward and to

The lymphatic drainage of the stomach generally parallels the gastric venous return. Figure 5 demonstrates lymphatic drainage. The antral portion of the greater curvature (Zone I) drains to the subpyloric and omental nodal group. Lymph from the proximal greater curvature (Zone II) traverses through the pancreaticosplenic nodes to the left gastroepiploic and splenic group of nodes. The lymph from the superior portion of the lesser curvature (Zone III) drains into the superior gastric group of lymph nodes surrounding the left gastric artery and subsequently into the left gastric, paracardial, and celiac nodes. The suprapyloric lymph nodes (Zone IV) drain the distal or antral portion of the lesser curvature. Drainage from all of these lymphatic basins subsequently drains into the celiac group of lymph nodes before traversing into the thoracic duct. Because of the extensive intramural and extramural communication of the lymphatic system of the human stomach, gastric cancer metastasis may drain to any of the nodal basins regardless of cancer location within the stomach. As a consequence, there is frequently microscopic evidence of malignant cells many centimeters from a primary cancer site, and malignant cells are frequently identified in the tissue margin of resection.

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Figure 2 Diagrams illustrating development of the stomach and its mesenteries, and formation of the omental bursa (lesser sac). (A) Five weeks development. (B) Transverse section showing clefts in the dorsal mesogastrium. (C) Later stage after coalescence of the clefts to form the omental bursa. (D) Transverse section showing the initial appearance of the omental bursa. (E) The dorsal mesentery has elongated and the omental bursa has enlarged. (F and G) Transverse and longitudinal sections, respectively, showing elongation of the dorsal mesogastrium and expansion of the omental bursa. (H) Six weeks, showing the greater omentum and expansion of the omental bursa. (I and J) Transverse and longitudinal sections, respectively, showing the inferior recess of the omental bursa and the omental (epiploic) foramen. Source: From Ref. 1, with permission of Elsevier.

Innervation The stomach’s innervation consists of an extrinsic system and an intrinsic system. The extrinsic innervation of the stomach consists of parasympathetic, sympathetic, and a nonadrenergic, noncholinergic (NANC) system. The intrinsic nervous system is made of primarily networks formed by submucosal and myenteric plexuses, which are also termed as the ‘‘enteric nervous system.’’ Together this multi-integrated network of communication is referred to as part of the autonomic nervous system. We have no conscious control over this system and are mostly unaware of its activity. The parasympathetic nervous system of the stomach is innervated via the vagus nerve. The vagus nerve originates in the vagal nucleus in the floor of the fourth ventricle and descends through the neck in the carotid sheath before aligning alongside the esophagus in the thorax. Prior to traversing the diaphragm, the vagal nerves form a periesophageal plexus by dividing into several branches. These branches

then coalesce into the left and right vagal trunks before passing through the esophageal hiatus of the diaphragm, as shown in Figure 6. The left vagus nerve traverses anterior to the esophagus and the right vagus traverses posteriorly. This is secondary to the 90
rotation of the stomach during gestation, as described previously. The left vagus gives off a hepatic branch, which innervates the liver and the biliary system. After giving off this branch, the vagus traverses anteriorly along and innervates the lesser curvature of the stomach. Here it is called the anterior nerve of Latarjet. The right or posterior vagus nerve branches into a division to the celiac plexus and another to the posterior aspect of the lesser curvature. The ‘‘criminal’’ nerve of Grassi is the first branch of the right vagus nerve and, if left undivided during vagotomy, is a potential etiology of recurrent gastric ulcers. The majority (> 90%) of vagal fibers are afferent and carry information from the GI tract to the central nervous system (CNS). Efferent fibers originate in the dorsal nucleus of the medulla and synapse with postsynaptic neurons in the

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Figure 3 Schematic of the anatomical regions of the stomach.

myenteric and submucosal plexuses in the gastric wall. The efferent fibers directly innervate smooth muscle and epithelial cells. The vagus nerve mainly functions to influence gastric motor function, especially the accommodation reflex, and gastric secretion. Acetylcholine is the major neurotransmitter of the vagus nerve, but nitric oxide (NO) has also recently been shown to act as a neurotransmitter as well. The sympathetic nervous system of the stomach originates from the spinal segments T5–T10. The afferent fibers pass directly from the stomach to the dorsal spinal roots without any synapse. Afferent fibers are responsible for the sense of pain from the stomach. Efferent fibers pass from the spinal nerve roots via gray rami communicantes and synapse at the prevertebral ganglia. Presynaptic fibers then pass through the greater splanchnic fibers to the celiac plexus. Here they synapse again with postsynaptic sympathetics. These fibers travel alongside the arterial system of celiac origin. Sympathetic neurons release adrenergic as well as cholinergic neurotransmitters.

Figure 4 Gastric arterial supply. Source: Adapted from Ref. 2.

Figure 5 Lymphatic drainage of the stomach. There are four zones of drainage. Zone I (inferior gastric) drains lymph into the subpyloric and omental nodes. Zone II (splenic) drains into the pancreaticosplenic nodes. Zone III (superior gastric) drains lymph into the superior gastric nodes. Zone IV (hepatic) drains into the suprapyloric gastric nodes.

A third and newly identified innervation of the stomach is via a NANC pathway within the myenteric plexus, which is mediated by NO together with vasoactive intestinal polypeptide (VIP) as a parallel cotransmitter (3). Studies in animals have demonstrated that NO has been identified as a major inhibitory NANC neurotransmitter in the GI tract and stomach (4). NO is synthesized by the

Figure 6 Schematic of the vagus nerve and its divisions in the thorax and abdomen. Left and right vagus nerves coalesce above the hiatus to form the anterior and posterior vagal trunks. Other configurations exist. Source: Adapted from Ref. 2.

Chapter 15: Gastric Physiology and Acid-Peptic Disorders

activation of neuronal NO synthase (nNOS) in the myenteric plexus. It has been demonstrated in animals that NO released in response to nerve stimulation of the myenteric plexus causes relaxation of the smooth muscle and appears to regulate the accommodation reflex of the fundus. Research suggests that nitric oxide synthase (NOS) expression in the gastric myenteric plexus is also controlled by the vagal nerve and nicotinic synapses because truncal vagotomy and administration of hexamethonium significantly reduced NANC relaxation, the catalytic activity of NOS, the number of NOS-immunoreactive cells, and the density of NOS-immunoreactive bands and NOS mRNA bands obtained from gastric tissue. This may be secondary to the Ca2þ-dependent protein kinase C pathway, which appears to upregulate nNOS mRNA expression and nNOS synthesis in the gastric myenteric plexus (5). Previous studies in animals have also shown that NOS inhibitors delay gastric emptying. The reduction of nNOS expression, associated with impaired local production of NO, may be responsible for motility disorders in the GI tract and motility disorders after vagotomy. It appears that extrinsic denervation may upregulate nNOS expression, resulting in enhanced muscular relaxation and disturbed peristalsis. Furthermore, NO from the neuronal form of NOS appears to play a significant role in relaxation of the pyloric and lower esophageal sphincters (6). The intrinsic innervation of the stomach consists of a submucosal plexus that is located between the muscularis mucosae and the circular muscle. This plexus is also termed Meissner’s plexus. The myenteric plexus, also called Auerbach’s plexus, lies between the longitudinal and circular muscles, or the muscularis externa. Together, the intrinsic nervous system of the stomach functions to relay information to and from the extrinsic nervous system and also to relay information within the stomach. Because of the rich synaptic connections within the stomach, local reflex responses and information can be forwarded from one part of the stomach to another without any involvement of the extrinsic system. The stomach has a network of interstitial cells of Cajal (ICCs) associated with the Auerbach’s plexus, as well as intramuscular ICC. Recently, these cells have been shown to play an important role in neural transmission (7). ICCs are critical for slow-wave generation, making ICC the pacemaker cells of the gut, allowing rhythmic peristaltic motor patterns in the mid and distal stomach. There are two types of ICCs within the stomach. The first are spindle-shaped cells within the circular and longitudinal muscle layers from the fundus to the distal antrum. These intramuscular ICCs are closely associated with inhibitory and excitatory nerves. They appear to serve as mediators between enteric nerves and smooth muscle cells. They also appear to mediate slow-wave activity. Intramuscular ICCs have been found to have close association with enteric neurons that release NO, acetylcholine, and substance P. The second type of ICCs have highly branching networks within the myenteric (Auerbach’s) plexus between the longitudinal and circular muscle layers of the corpus and antrum. These ICCs function in pacemaker generation by generating slow-wave activity (7). Cholinergic, serotonergic, NANC, and peptidergic neurons are present within the intrinsic nervous system of the stomach, which are the neural fibers of Auerbach’s and Meissner’s autonomic plexus. The neuropeptides identified that regulate gastric physiology include acetylcholine, serotonin, substance P, calcitonin-gene–related peptide, bombesin, NO, VIP, cholecystokinin (CCK), and somatostatin.

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Peritoneal Reflections and Omentum The dorsal mesentery attaches the stomach to the dorsal wall of the abdominal cavity, and after being carried to the left during rotation of the stomach forms a recess between the posterior wall of the stomach and the posterior abdominal wall, called the omental bursa or lesser sac of peritoneum. This bursa communicates with the main part of the peritoneal cavity through a small opening called the epiploic (omental) foramen, which is posterior to the free edge of the lesser omentum in the adult. The dorsal mesentery further develops to become the greater omentum. The ventral mesentery develops into the lesser omentum and attaches the lesser curvature of the stomach and the proximal 2 cm of the duodenum to the liver via the hepatogastric and hepatoduodenal ligaments. The omentum is a large sheet of fatty mesentery that plays a protective role in the abdomen by walling off inflammatory processes or visceral perforations, thereby preventing peritonitis, as well as serving as a depository for tumor metastases. It is often called the ‘‘watchdog’’ of the abdomen. The greater omentum surgically is divided into two parts: the true greater omentum, which hangs freely into the peritoneal cavity from the transverse colon, and the gastrocolic ligament, which connects the greater curvature of the stomach and the transverse colon. The lesser omentum is a double layer of peritoneum extending from the porta hepatis of the liver to the lesser curvature of the stomach and the first portion of the duodenum. The lesser omentum is important surgically because it contains the left and right gastric vessels, which run between its two layers, and its right free margin contains the hepatic artery, bile duct, and portal vein. The lesser omentum consists of the hepatogastric and hepatoduodenal ligaments and forms the anterior wall of the lesser sac of the peritoneal cavity. The anatomy of the peritoneal ligaments that are attached to the stomach are important because, not only must they be transected during resection of the stomach, but also because of the vasculature that may be present within them. As mentioned above, the hepatogastric ligament attaches the stomach to the liver along the lesser curvature. The gastrosplenic (lienogastric) ligament extends from the left portion of the greater curvature of the stomach to the hilum of the spleen. It contains the short gastric vessels and the left gastroepiploic vessels. The gastrophrenic ligament runs from the upper portion of the greater curvature of the stomach to the diaphragm. The gastrocolic ligament extends from the greater curvature of the stomach to the transverse colon as mentioned above. Figure 7 demonstrates the mesenteric attachments of the stomach.

Gastric Morphology The luminal surface of the stomach is covered in large infoldings, which are called rugae. Rugae consist of mucosa and submucosa that are most prominent in the proximal stomach and extend longitudinally toward the antrum. Rugae allow the stomach to distend to accommodate a meal as well as increase the epithelial surface area. The mucosa interacts with the luminal milieu and contains most of the glandular digestive and endocrine cells of the stomach. The mucosal layer consists of epithelium, lamina propria, and muscularis mucosa. The lamina propria is a thin connective tissue layer that contains the blood supply, lymphatics, and nerves to support the surface epithelium. The submucosa is adjacent to the muscularis mucosa and is the strongest layer of the gastric

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Figure 8 Transverse cross section of the layers of the gastric wall.

Figure 7 Schematic of the mesenteric attachments of the stomach.

wall because of its collagen-rich layer of connective tissue. The submucosa is a very vascular layer of the gastric wall. Here there is a rich anastomosis of arterial and venous collaterals as well as lymphatics. The Meissner’s plexus of autonomic nerves also resides in the submucosa. The muscularis mucosa consists of low-density smooth muscle cells. Auerbach’s myenteric plexus resides within the muscularis externa, which is the next layer of the gastric wall. The muscularis externa consists of three muscular sublayers—inner oblique, middle circular, and outer longitudinal. The middle circular layer becomes thicker at the pylorus and functions as a true anatomic sphincter. The longitudinal layer of the muscularis can be separated into two different categories: a longitudinal layer that is common with the esophagus and ends in the corpus, and a longitudinal layer that originates in the corpus and spreads into the duodenum. Figure 8 depicts the transverse section of the gastric wall.

Gastric Microscopic Organization The gastric mucosa consists of a multitude of cells that vary according to the region in the stomach in which they are found and also vary by depth within the mucosa. The superficial epithelial lining of the mucosa consists of columnar glandular epithelia. These surface epithelial cells are mucin secreting and have basal nuclei, with mucin-containing granules in the apical region. The apex has short microvilli and a thin apical coating of glycocalyx. These cells also exist deep within the gastric pits where they are coined ‘‘neck cells.’’ Neck cells have a lower content of mucin granules and increased mitosis. Neck cells are also thought to be the progenitor cells that give rise to the surface epithelium, as well as the cells of the gastric glands. The gastric cardia contains mostly mucinous cells, which are indistinguishable from the neck cells of the gastric pits. The mucinous neck cells throughout the pits function to maintain a thin layer of mucous gel that covers the gastric mucosa. The gastric

pits themselves drain several gastric glands. The fundus and body of the stomach contain mucin-secreting surface epithelia and neck cells, parietal cells, chief cells, and few neuroendocrine cells. Parietal cells are recognized by their abundant mitochondria, which stain brightly pink on hematoxylin and eosin preparations and are found in greatest numbers in the body of the stomach. The high content of mitochondria is indicative of the high energy requirements of gastric acid secretion. The neck and base of the gastric pits contain parietal cells and chief cells, which stain purple because of their large basophilic zymogen granules. The antrum not only contains mucinous cells, but also neuroendocrine cells such as gastrin (G) cells or somatostatin (D) cells. The neuroendocrine cells can be classified as either open or closed. Endocrine cells that have their microvilli in direct contact with gastric luminal contents are considered open type. Chemical and pH sensors on the microvilli likely stimulate the cell to secrete their prestored peptides. Closed-type endocrine cells do not contact the lumen and likely function by sensing the interstitial milieu. For example, G-cells and D-cells in the antrum are open-type cells and appear to sense the luminal concentration of acid and digesting meal. They respond by releasing gastrin or somatostatin, respectively. In contrast, D-cells in the fundus and body are of the closed type and intimately interact with parietal cells through their microvilli. Enterochromaffin cells, which secrete serotonin and other peptides, and enterochromaffin-like (ECL) cells, which secrete histamine, are also located within the mucosa. Gastric pits within the stomach further increase the epithelial surface area and also differ by region, as does the glandular epithelium. In the cardia, the pits are short and the glands are branched. The fundus and body contain more tubular glands and long gastric pits. The antrum again has branched glands and shorter pits. Biopsy specimens taken from human stomachs show that the content of epithelial cells consists of 13% parietal cells, 44% chief cells, 40% mucus cells, and 3% endocrine cells. Figure 9 demonstrates the basic histology of a gastric pit.

GASTRIC PHYSIOLOGY Both neural and hormonal mediators regulate the function of gastric relaxation, motility, and gastric secretion. Neural

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and emptying. Pre- and postprandial gastric motility are separate entities and are explained in more detail below.

Fasting (Preprandial) Gastric Motility

Figure 9 The gastric pit. Schematic of the histologic cell types of the stomach. Abbreviations: G, gastric; ECL, enterochromaffin-like.

The electrical activity of the stomach functions to clear the gastric lumen of indigestible food particles, digestive secretions, and sloughed-off cells via interdigestive motor cycles that occur every 90 to 120 minutes. These motor cycles are termed the migrating myoelectric complex (MMC) and begin with the depolarization of pacemaker cells located high on the greater curvature of the body of the stomach. These pacemaker cells are a collection of specialized smooth muscle cells that generate cyclic pacemaker potentials, which propagate in a circumferential and antegrade fashion toward the pylorus. These slow waves of potential are initiated at three cycles per minute and are capable of depolarizing smooth muscle cells, thereby producing action potentials that are associated with gastric muscle contractions. Each cycle of MMC is made up of four phases of electrical activity. Phase I is the quiescent phase where slow wave potentials are present, but they neither depolarize smooth muscle cells nor produce action potentials. Phase I of the MMC has no gastric contractions, but only increased gastric tone. Phase II consists of slow wave potentials with irregular depolarization of smooth muscle cells, or motor spikes, which cause occasional gastric contractions. In Phase III of the MMC, regular motor spike activity is associated with the slow waves, causing forceful gastric contractions every 15 to 20 seconds, which sweeps intraluminal contents toward the pylorus to clear the stomach. The brief recovery period prior to the next MMC cycle is Phase IV (9,10).

Postprandial Gastric Motility regulation is accomplished by an intricate network of adrenergic, cholinergic, and NANC neural pathways. Hormonal and peptide interactions are accomplished through one of three pathways: endocrine, paracrine, or neurocrine. The exocrine function of the stomach also plays a role in gastric secretion. All of these pathways of gastric physiology are intertwined and the precise action of a target cell depends on the relative balance of mediators acting upon it.

Neural/Electrical Regulation Motility The neuromuscular apparatus of the stomach functions to store an ingested meal, prepare it for digestion through mixing and trituration, and deliver it to the duodenum in usable quantities (emptying). This is accomplished through neural mechanisms and myogenic potentials, which regulate the electrical and motor activity of the organ. Extrinsic neural controls are mediated through the adrenergic (sympathetic) and cholinergic (parasympathetic-vagal) pathways. The myenteric plexus mediates the intrinsic neural pathway, which is termed the NANC pathway and is mediated through the release of NO from the nNOS at the nerve terminal (4,6,8). The myogenic pathway involves action potentials generated by the excitatory membranes of smooth muscle cells, and results in muscle contraction. Similar to action potentials within neurons, when the cell membrane resting potential exceeds its threshold value, an action potential is generated, which results in smooth muscle contraction. The gastric pacemaker cells of Cajal regulate this process. The electrical and motor activities of the stomach are responsible for gastric relaxation, mixing, trituration,

The fasting cycle of the stomach is disrupted when feeding occurs. When feeding begins, the function of the stomach switches to accommodate the meal, begin digestion, and deliver appropriate volumes and sizes of a meal into the duodenum. During a swallow, the proximal stomach relaxes at the same time that the lower esophageal sphincter relaxes in order to accept the food bolus (receptive relaxation). After the bolus enters the stomach, further relaxation is stimulated to accommodate the meal (accommodation reflex). The intraluminal pressure then returns slowly to basal levels, which are essentially equal to the intra-abdominal pressure. This process facilitates the stomach to receive volumes as high as 1500 mL without significant increases in pressure. The relaxation of the stomach is mediated by the vagovagal reflex, which feeds information via vagal afferents to the CNS and back to the gastric smooth muscle via vagal efferents. Vagotomy can abolish this reflex so that higher intragastric pressures are present in the presence of a meal. For this reason, vagotomy is often associated with a feeling of early satiety by patients (11–14). Gastric emptying of liquids is thought to be controlled by the proximal stomach via low-amplitude tonic contractions of the fundus, which creates a pressure gradient between the stomach and duodenum and facilitates emptying of liquids. In contrast, solids are mixed with gastric juice and broken down into digestible amounts prior to emptying. This is accomplished through repetitive forceful ring contractions from the mid body and antrum, which propel food particles against a closed pylorus, compressing them, with subsequent retropulsion of solids and liquids back again, which assures mixing of food particles. Food is thereby thoroughly mixed with gastric juice, liquefied, partially digested,

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and fats emulsified. Pacemaker cells in the mid-stomach initiate these forceful contractions by initiating membrane potentials and subsequent action potentials of the smooth muscle cells. Contractions occur every three to five minutes and last from 2 to 20 seconds. Furthermore, the contractions increase in both velocity and speed as they travel distally toward the pylorus, as demonstrated in Figure 10. As the peristaltic contractions increase in speed they actually overtake the majority of gastric contents ahead of the wave, propelling a small amount of contents into the duodenum while the majority of contents are retropulsed back because the force of the contraction wave closes the distal antrum. Breakdown of food particles in this manner ensures that food particles less than 1 mm in size will be emptied into the duodenum. The length of time that the food remains in the stomach varies considerably depending on many factors. In general liquids empty faster than solids. The T12 of gastric emptying for water is approximately 10 to 20 minutes and depends on the tone of the proximal stomach. Gastric emptying of solids varies from one to four hours and depends on the ease of liquefaction as well as the intensity of peristaltic contractions. Again, flow of food into the duodenum to change into chyme occurs as particles less than 1 mm become suspended in the gastric effluent. The content of a meal also determines the rate of emptying. Generally, the emptying rate for carbohydrates is greater than that for proteins, which is greater than that for fats. The enterogastric reflex consists of neural and hormone-mediated reflexes that regulate gastric motor activity. Psychic stimuli, pain, taste, or smell can alter gastric motility and emptying through vagal cholinergic and adrenergic sympathetic fibers. Receptors in the duodenum are also sensitive to changes in osmolarity, pH, lipid content, or stretching of the duodenal wall and inhibit gastric emptying through neural and hormonal mechanisms. For example, increased osmolarity and acidity of chyme have feedback inhibition on gastric emptying. Peptides that inhibit gastric motility and emptying include CCK, secretin, glucagon, vasoactive inhibitory peptide, and gastric inhibitory polypeptide. Figure 11 demonstrates the enterogastric reflex.

Figure 10 Schematic of postprandial gastric motility. Measurements of gastric intraluminal pressures demonstrate that as gastric contractions move distally toward the pylorus, the force of contraction increases. The letters correspond to location in the stomach.

Figure 11 The enterogastric reflex. The accommodation reflex and stimulation of gastric motility have differential pathways, which vary between the proximal and distal stomach. Source: From Ref. 1, with permission of Elsevier.

Hormonal/Peptide Regulation Gastrin Gastrin was the second true hormone to be identified in 1905, because of its ability to stimulate acid secretion. The name gastrin literally means ‘‘to stimulate the stomach.’’ Although its existence was controversial for the next 43 years, gastrin is now known as a major hormonal regulator of acid secretion. Gastrin is produced by the G-cells of the antral mucosa and exists as three distinct gastrin peptides: G-34 (big gastrin), G-17 (little gastrin), and G-14 (minigastrin). All of these molecular forms of gastrin are found in both antral tissue and in the circulation, and exist in both sulfated (gastrin II) and unsulfated forms (gastrin I). A pentapeptide at the carboxyl terminus of gastrin confers biological activity. G-17 accounts for about 90% of gastrin released from the antral mucosa. However, in the circulation, G-34 predominates because its half-life is about five times that of G-17 (15–17). Endogenous and exogenous gastrins regulate gastric acid secretion and do so through interactions with gastrin receptors on the parietal cell. However, the effects of gastrin may also be regulated via release of histamine (see below) from ECL cells. Evidence for this is suggested by the finding that H2-receptor antagonists significantly blunt gastrin-stimulated acid secretion from parietal cells. However, on a molar basis, gastrin is 1500 times more potent than histamine in stimulating acid secretion (18–20). Gastrin also displays considerable trophic effects on parietal and ECL cells. In the Zollinger–Ellison syndrome (ZES), high levels of circulating gastrin cause marked hypertrophy of the rugae of the proximal stomach. In fact, hypergastrinemia from any cause can lead to mucosal hypertrophy and hyperplasia of parietal cells as well as an increase in the number of ECL cells, and rarely is associated with the development of gastric carcinoid tumors (21). Although acid secretion and trophic effects are the major physiologic actions of gastrin, at pharmacologic doses, gastrin also

Chapter 15: Gastric Physiology and Acid-Peptic Disorders

Table 1 Causes of Hypergastrinemia Ulcerogenic causes Antral G-cell hyperplasia or hyperfunction Retained excluded antrum Zollinger–Ellison syndrome Gastric outlet obstruction Short-gut syndrome

Nonulcerogenic causes Antisecretory agents (PPIs) Atrophic gastritis Pernicious anemia Acid-reducing procedure (vagotomy) Helicobacter pylori infection Chronic renal failure

Abbreviation: PPIs, proton-pump inhibitors.

stimulates pepsinogen, intrinsic factor, and pancreatic enzyme secretion, increases lower esophageal sphincter pressure, stimulates intestinal and gallbladder motility, and renders the stomach less susceptible to injury from luminal irritants. The release of gastrin is regulated by luminal peptides and amino acids contained within a meal. These are the most potent stimulators of gastrin release. Other mediators of gastrin release include gastric distention, vagal stimulation, vagotomy, calcium, and prolonged luminal alkalinization. An important feedback inhibition of gastrin release is acidification of the gastric luminal contents to below pH 3. Somatostatin (see below) is another potent inhibitor of gastrin release, and in the antrum, gastrin and somatostatin release are inversely proportional and functionally linked. Hypergastrinemia can occur when there is inhibition of acid secretion. It can occur with administration of antisecretory agents such as H2-receptor antagonists or proton-pump inhibitors (PPIs), or following surgical procedures such as vagotomy or retained gastric antrum after gastrectomy. Disease states that are associated with hypergastrinemia are separated into those that are ulcerogenic (excess acid secretion) and those that are nonulcerogenic (normal or low acid secretion). Table 1 lists common causes of chronic hypergastrinemia. Gastrin gene knockout mice have demonstrated that maturation of parietal and ECL cells was disturbed and also that the number of parietal cells was reduced. However, there was no general atrophy of the gastric mucosa. Genetic lack of gastrin also impaired basal acid secretion and almost completely inhibited histamine- and acetylcholine-induced gastric acid secretion. Furthermore, achlorhydria from lack of gastrin allowed for bacterial overgrowth in the stomachs of the gastrin knockout mice, consistent with the important role the stomach plays in helping to protect the internal environment from outside pathogens by the bactericidal activity of gastric acid (22).

Somatostatin Somatostatin was originally isolated from the hypothalamus and known as growth hormone release inhibitory factor. However, the majority of somatostatin is found in the GI system and is an inhibitor of insulin, glucagon, and gastrin release, as well as an inhibitor of gastric acid secretion. In the stomach, it is produced by D-cells in the antrum and fundus, and also is released by nerve endings; therefore it functions as a paracrine and neurocrine factor. Somatostatin exists endogenously as either somatostatin-14 or somatostatin-28. The primary actions of somatostatin within the stomach are via a paracrine effect wherein D-cells release somatostatin in the vicinity of parietal cells and G-cells, thereby inhibiting them from gastric acid secretion and gastrin release, respectively. Inhibition of gastric acid secretion occurs by either directly inhibiting the parietal cell or by indirectly inhibiting acid secretion through inhibition of

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gastrin release and downregulation of histamine release from ECL cells. Stimulation for somatostatin release in the stomach is mainly via antral acidification, while vagal activation inhibits its release (23–28).

Vasoactive Intestinal Polypeptide VIP is a 27–amino acid peptide that has many of the effects of secretin, gastric inhibitory polypeptide, and glucagon. VIP is released mainly by nerves around the gastroesophageal and pyloric sphincters and mediates the relaxation of GI smooth muscle. Both vagal stimulation and gastric distention mediate VIP release. VIP may inhibit gastric acid secretion, but its main functions are as an inhibitory neurotransmitter that causes relaxation of the lower esophageal sphincter, proximal stomach, and antral smooth muscle (29). NO mediates, together with VIP as a parallel cotransmitter, the NANC neurotransmission of the proximal stomach, which functions to produce gastric relaxation upon food intake (3,4,30).

Gastrin-Releasing Peptide Bombesin, a potent acid and gastrin-stimulating peptide, was first identified from extracts of the frog, Bombina bombina (31,32). Gastrin-releasing peptide (GRP) is a structurally similar mammalian peptide that stimulates gastric acid secretion through binding to receptors on G-cells and subsequently stimulating release of gastrin. GRP is primarily found at nerve endings in the acid- and gastrin-secreting portions of the stomach, and is an important mediator of vagally stimulated gastrin release. Also, bombesin plays a role in gastroprotection primarily by stimulating the release of endogenous gastrin (33). There is also recent evidence that GRP and bombesin-like peptides may play an important role in the control of food intake and obesity by suppressing the drive to feed. Knockout mice for the bombesin receptor subtype-3 demonstrated a phenotype that displayed hyperphagia and obesity (34,35).

Histamine Histamine is not a peptide, but is found within acidic granules of ECL cells and resident mast-like cells within the lamina propria. Histamine plays an important role in parietal cell acid secretion as it potentiates the actions of gastrin and acetylcholine. In fact, administration of H2-receptor antagonists, such as cimetidine, almost completely abolishes gastrin- and acetylcholine-induced gastric acid secretion by the parietal cell. This suggests that histamine plays an intermediary role in gastric acid secretion. The release of histamine is stimulated by gastrin, acetylcholine, and epinephrine through specific receptor–ligand interactions on the ECL cell. The ECL cell also has somatostatin receptors, which act to inhibit gastrin-stimulated histamine release (36,37).

Ghrelin Ghrelin is a 28–amino acid peptide predominantly produced by endocrine cells of the oxyntic mucosa of the stomach, with substantially lower amounts derived from the bowel, pancreas, and other organs. Removal of the acid-producing part of the stomach decreases circulating ghrelin by 80%. Ghrelin appears to be under endocrine and metabolic control, has a diurnal rhythm, and likely plays a major role in the neuroendocrine and metabolic response to changes in nutritional status, and may be a major anabolic hormone. Ghrelin displays a strong growth hormone-releasing action,

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which is mediated by the activation of growth hormone secretagogue receptor type 1a. Human studies have shown a dose-dependent stimulation of growth hormone release with exogenous administration of ghrelin. Although the most significant response to ghrelin is growth hormone release, exogenous administration also causes increases in prolactin, adrenocorticotropin hormone, cortisol, and aldosterone through mechanisms that are as yet unclear (38). Recent studies have reported ghrelin to affect the insulinsignaling system, implicating ghrelin in glucose homeostasis (39,40). Two studies have demonstrated that ghrelin administration reduces insulin secretion (41), and that ghrelin has powerful effects on islet cells, suggesting that endogenous ghrelin may contribute to the physiological control of insulin and glucagon release (42). In studies of human volunteers by Wren et al., intravenous ghrelin administration was shown to enhance appetite and increase food intake (43). Interestingly, in patients who have undergone a gastric bypass, Cummings et al. have demonstrated that ghrelin levels are 77% lower than levels in matched obese controls. Furthermore, the decrease in ghrelin levels after gastric bypass surgery is not seen with other forms of antiobesity surgery (44). This suggests that ghrelin may be responsive to the normal flow of nutrients across the stomach. Other studies have also suggested this because ghrelin levels are decreased by inducing gastric distention with 50% dextrose, but not by gastric distention with saline, which further suggests a role for gastric chemosensory afferents in ghrelin secretion. However, the mechanisms underlying suppression of ghrelin in gastric bypass surgery are still unknown. Several other studies have also suggested that ghrelin leads to a switch toward glycolysis and away from fatty acid oxidation, which would favor fat deposition (45). Tschop et al. showed that it leads to an increase in fat mass through an increase in adiposity in the rodent (46). Although it appears that ghrelin may be upregulated in times of negative energy balance and downregulated in times of positive energy balance, the role of ghrelin in energy metabolism is still unclear. However, it may come to have a role in the treatment and prevention of obesity. Defective ghrelin signaling from the stomach could contribute to abnormalities in energy balance, growth, and associated GI and neuroendocrine functions (47).

Exocrine Regulation The stomach secretes approximately 3 L of gastric juice a day. Physiologically active components of gastric juice are pepsinogens, mucus, hydrochloric acid, and intrinsic factor. Gastric juice is secreted in the tubular glands or gastric pits by parietal cells, chief cells, and mucus cells. Gastric juice also contains constituents of swallowed saliva and duodenal refluxate. At all rates of secretion, gastric juice is essentially isotonic to plasma. However, the rate of secretion causes different ionic compositions. Basal rates of secretion form the gastric juice, which is primarily a solution consisting of NaCl with lesser amounts of Hþ and Kþ. With the stimulation of acid secretion, the concentration of Hþ increases and Naþ decreases. Therefore at maximal rates of acid secretion, the gastric juice consists of mainly HCl with small amounts of Naþ and Kþ. However, even at basal rates of acid secretion the fluid is very acidic. Hþ concentration may range from 10 mEq/L basally up to 150 mEq/L at peak rates. Differences in ionic composition are secondary to two different phases of secretion. Nonparietal cell secretion contains primarily NaCl with Kþ and HCO3 present in amounts approximately

equal to their concentrations in plasma. With stimulation of acid secretion, the parietal cell secretes a solution across a concentration gradient, which is composed of approximately 150 mEq/L HCl with 10 to 20 mEq/L of KCl. At all rates of secretion, however, gastric juice is essentially a mixture of these two components. In patients who lose significant volumes of gastric juice, either by nasogastric decompression or vomiting for example, knowledge of these components is important to guide the replacement of these electrolytes. Gastric acid is important in the process of early digestion. It functions to begin the digestive process as well as protect the GI system from ingested bacteria because the acid is bacteriostatic. Acid also is necessary for the conversion of inactive pepsinogen into the active enzyme pepsin, which begins digestion of dietary protein. Mucus secretion in the stomach serves not only as a protective barrier against intraluminal acid, but also as a physical lubricant to protect the epithelial layer from ingested material. Mucus and bicarbonate within the mucous secretions act to buffer the luminal surface epithelium from HCl and maintain neutral pH of the solution that is in contact with this layer. Intrinsic factor binds vitamin B12 to allow absorption of vitamin B12 in the ileum.

Pepsinogen Pepsinogen is a proenzyme that has a molecular weight of 42,500 kDa and is stored and secreted by chief cells and mucus cells. At an intraluminal pH < 5, pepsinogen is cleaved into pepsin, which is the physiologically active protein. Pepsin then acts to autocatalyze the conversion of more pepsinogen to pepsin as well as to digest proteins preferably at sites where tyrosine or phenylalanine follow toward the carboxyterminal of the peptide chain. Two types of pepsinogens are secreted. Group I pepsinogens are secreted by chief cells and by mucus cells located in the oxyntic acid–secreting portion of the stomach. Group II pepsinogens are secreted by mucus cells, not only in the oxyntic gland mucosa of the acid-secreting portion of the stomach, but also in the antrum and proximal duodenum. Group II pepsinogens are active over a wider range of pH values than Group I pepsinogens, which become inactivated at pH > 5 (48,49). Most of the pepsinogen secretion is during the cephalic and gastric phases (see below) of acid secretion and is through vagal stimulation. Hence, acetylcholine is the strongest stimulator of pepsin secretion. Acid is not only necessary for the cleavage of pepsinogens, but also stimulates pepsinogen secretion by triggering a cholinergic reflex, which stimulates chief cells. Acid also increases secretin release from the duodenum, which further enhances pepsinogen secretion. Cholinomimetic drugs and CCK may also stimulate its secretion. Atropine and vagotomy are potent inhibitors of pepsin secretion (50).

Intrinsic Factor Intrinsic factor is a mucoprotein with a molecular weight of 60 kDa that is secreted by the parietal cell. Intrinsic factor is the only secretory product of the stomach necessary for life because it combines with vitamin B12 to form a complex, which is required for the absorption of the vitamin by an active process in the terminal ileum. The secretion of intrinsic factor parallels gastric acid secretion, but is not necessarily linked to acid secretion, because administration of PPIs does not block the absorption of labeled vitamin B12. The absence of intrinsic factor leads to pernicious anemia, a disease associated with achlorhydria and the absence of

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parietal cells. Because the liver stores vitamin B12 for a number of years, the manifestations of this disease usually occur several years after the disease process has begun. Patients with pernicious anemia or total gastrectomy require vitamin B12 supplementation (51–54).

Gastric Acid Secretion The acid secretory process is regulated by the parietal cell and is a process of active transport that requires the consumption of adenosine triphosphate (ATP). The hydrogen/potassiumadenosinetriphosphatase (Hþ/Kþ-ATPase) within the parietal cell is an ATP-driven proton pump, which transports Hþ ions into the lumen of the gastric pits in exchange for Kþ ions. Cl also follows hydrogen into the lumen by passive diffusion. For every Hþ ion that is secreted, one HCO3 ion is transported out of the basolateral membrane in exchange for passive diffusion of a Cl ion into the parietal cell. The HCO3 is formed with the aid of the catalyst carbonic anhydrase from CO2 and OH, which is accumulated within the cell. The Kþ, which is required for the Hþ/Kþ-ATPase, is supplied by accumulation of Kþ into the parietal cell from the basolateral membrane with the aid of an active Naþ/Kþ-ATPase. Kþ pumped into the parietal cell by the Naþ/Kþ-ATPase is then passed luminally via passive diffusion through a Kþ channel. The Kþ therefore is being recycled. Furthermore, insertion of the potassium and chloride channels into the luminal membrane is essential to acid secretion (55,56). The cellular processes that demonstrate production and secretion of HCl are demonstrated in Figure 12. The ultrastructure of the parietal cell is unique to the stomach and is designed to allow for the secretion of HCl against a large concentration gradient. The parietal cells can secrete HCl in concentrations up to 160 mEq/L and secrete up to 2 L/day. This solution can have a pH of less than 1, and because the pH of blood is 7.4, this means that the parietal cell requires large amounts of energy in the form of ATP to fuel acid secretion. This ATP energy is supplied by large concentrations of mitochondria. The parietal cell for this reason has the largest concentration of mitochondria of any cell in the body. The Hþ/Kþ-ATPase is the final common pathway for gastric acid secretion by the parietal cell and is composed of a catalytic alpha subunit and a glycoprotein beta subunit. During the nonsecreting state, gastric parietal cells store the Hþ/Kþ-ATPase subunits within intracellular tubular and vesicular membranes called tubulovesicles. While attached to the tubulovesicular membranes, the alpha and beta subunits of the Hþ/Kþ-ATPase are stored separately. The secretory canaliculus in a resting parietal cell is closed to the gastric lumen, but with stimulation of acid secretion these canaliculi fuse with the tubulovesicular membrane, expand, and open into the gastric lumen. Furthermore, the microvilli of the secretory canaliculus increase greatly in number and length, so that the surface area for secretion increases greatly. Following removal of the stimulus for acid secretion, the secretory canaliculus rearranges and collapses losing its luminal connection, and the Hþ/Kþ-ATPase heterodimer disassembles and returns to the cytoplasmic tubulovesicles (57–60). This entire process is referred to as the membrane recycling hypothesis (61). An example of this complex morphologic transformation is shown in Figure 13. The degree of acid secretion by the parietal cells depends on the overall influence of acid secretory and inhibitory pathways. Basal and stimulated gastric acid

Figure 12 HCl secretion of the parietal cell. The proton pump (H/KATPase) actively secretes hydrogen ions in exchange for potassium. Kþ passively returns to the gastric lumen via Kþ channels, which must be activated for Hþ secretion to occur. Cl also passively diffuses into the lumen. For every Hþ secreted into the lumen, one HCO3 ion passively enters the bloodstream in exchange for Cl. Abbreviation: H/K-ATPase, hydrogen/ potassium-adenosinetriphosphatase.

secretions are ultimately regulated by the Hþ/Kþ-ATPase, but three stimuli regulate its function. Acetylcholine, gastrin, and histamine all account for stimulation of acid secretion by the parietal cell (20,62–64). Acetylcholine is released from the vagus nerve and parasympathetic ganglion cells and is the principal neurotransmitter regulating acid secretion. Acetylcholine from vagal fibers not only directly stimulates the parietal cell, but also indirectly stimulates it by innervating G-cells and ECL cells, stimulating them to release gastrin and histamine, respectively (63). Release of gastrin by G-cells has direct hormonal effects on the parietal cell and also stimulates histamine release. The ECL cells release histamine, which has a paracrine-like effect on the parietal cell. Histamine plays a central role in the regulation of acid secretion because it potentiates the effects of gastrin and acetylcholine. Similarly, potentiation also exists between gastrin and acetylcholine. These effects of potentiation can be demonstrated by the fact that H2-receptor antagonists also block secretory responses to acetylcholine and gastrin. Likewise, atropine blocks histamine and gastrinstimulated acid secretion. Thus, not only does the degree of acid secretion depend on the sum of its stimulators, but potentiation also allows for small amounts of secretory stimuli to produce near maximal effects. The ability of the

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Figure 14 Vagal control of gastric acid secretion and potentiation by histamine and gastrin. Psychic stimuli during the cephalic phase stimulates acid secretion via Ach either directly by activating Ach receptors on the parietal cell or by stimulating G-cells or ECL cells to release gastrin and histamine, respectively. Luminal stimulants such as distention or peptides also stimulate acid secretion via vagal afferents. Synaptic connections exist in the myenteric and submucosal plexus. Abbreviations: Ach, acetylcholine; ECL, enterochromaffin-like.

Figure 13 Electron micrograph demonstrating parietal cell conformational differences between an unstimulated and histamine-stimulated parietal cell. C, chief cell; M, mitochondria; N, nucleus; T, tubulovesicles; S, secretory membranes; arrow represents lumen of secretory canaliculus. Original magnification 7500. Source: Adapted from Ref. 57, with permission from the American Gastroenterological Association.

parietal cell to allow for potentiation is a result of having different second messenger systems for acid secretion. Acetylcholine, which binds to the M3 subtype of the muscarinic receptor, stimulates the formation of inositol triphosphate (IP3) and the subsequent release of intracellular calcium. Histamine binding to histamine receptors, which are G-protein coupled receptors, stimulates adenylate cyclase, resulting in increases in intracellular cyclic adenosine monophosphate (AMP) levels. The second messenger system for gastrin is intracellular calcium, which increases after gastrin interaction with its receptor. Gastrin receptors belong to the

CCK receptor family, are classical G-proteins, and are classified as either type A or type B. The type A CCK receptors have affinity for sulfated CCK analogs and a low affinity for gastrin. Type B CCK receptors have a high affinity for both gastrin and CCK and are the receptors responsible for increasing acid secretion. Figure 14 is a schematic of vagal acid stimulatory pathways and interaction of histamine and gastrin. In the absence of a stimulus for acid secretion, basal acid secretion is 10 to 20 mEq/L, is approximately 10% of maximal acid output, and has a circadian variation with night-time acid secretion being greater than that at daytime. Basal acid secretion appears to be regulated via a combination of cholinergic and histaminergic signals because vagotomy or atropine reduce basal acid secretion by approximately 75% to 90% and H2 receptor antagonists reduce it by approximately 90%. However, stimulation of gastric secretion is more complex and is described as consisting of three interrelated and concurrent phases: cephalic, gastric, and intestinal.

Cephalic Phase The cephalic phase (Fig. 15A) is also considered to be the psychic-neural phase of gastric secretion. This phase originates with the thought, sight, smell, or taste of food, and can be conditioned with the anticipation of a meal.

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Figure 15 Differential influences on gastric acid stimulation. (A) Psychic or neural influences on acid secretion are via vagal inputs, directly or indirectly via stimulation by gastrin or histamine. (B) Local gastric influences are via mechanical distention or chemical stimulation. (C) The intestinal phase of acid secretion begins when chyme enters the duodenum. Source: From Ref. 1, with permission of Elsevier.

Emotions such as aggression may stimulate secretion, while fear inhibits it. Also hypoglycemia may stimulate this reflex arc. While the exact mechanisms of how the afferent limbs of sight, smell, taste, and emotions or thoughts stimulate secretion are still to be fully elucidated, several higher centers in the brain have been identified and include the dorsal vagal complex, nucleus tractus solitarius, and dorsal motor nucleus and may involve the release of thyrotropin-releasing hormone. The efferent limb of the cephalic reflex is the vagus nerve. Besides directly activating the parietal cell via acetylcholine that binds to muscarinic receptors, the vagus indirectly activates secretion via stimulation of histamine and gastrin release. Indirect stimulation may be through acetylcholine or other mediators because although atropine attenuates the direct effects on the parietal cell, it does not block the release of gastrin during this phase. It appears that gastrin release via the vagus is mediated by acetylcholine as well as GRP. Although the secretory response in the cephalic phase is greater than that in the other phases, it accounts for approximately only 30% of the total volume of gastric acid produced because of the short duration of reflex. The entire cephalic phase can be blocked by vagotomy (65).

Gastric Phase When food enters the stomach, the gastric phase (Fig. 15B) of secretion begins. When the gastric contents reach the antrum, mechanical stretching and chemical stimulation (peptides, amino acids, calcium, ethanol, etc.) cause release of gastrin. Endocrine release of gastrin from antral G-cells into the bloodstream stimulates acid secretion. Protein components of a meal, particularly the aromatic amino acids phenylalanine and tryptophan, stimulate gastrin release. This release of gastrin is not blocked by vagotomy or atropine, but is blocked by acidification of the antral mucosa to below pH 3. Food also causes acid secretion via mechanical distention. Gastric distention activates

mechanoreceptors or stretch receptors in the stomach, which initiate both an intramural reflex that stimulates parietal cells directly via acetylcholine, and an extramural or vagovagal reflex that stimulates parietal cells directly via acetylcholine and stimulates gastrin release via GRP, and subsequent parietal cell stimulation indirectly. The vagovagal extramural reflex is identical to the cephalic phase and may be abolished by vagotomy. The entire gastric phase accounts for most (60–70%) of meal-stimulated acid output with mechanical distention accounting for approximately 30% to 40% of the response (65).

Intestinal Phase Entry of chyme into the duodenum begins the intestinal phase (Fig. 15C) of gastric secretion. Although the intestinal phase is poorly understood, it is believed that stretching of the intestinal wall and the absorbed amino acids stimulate gastric secretion. A stimulatory peptide hormone, now called enterooxyntin, released from the small bowel may mediate this phase. Although gastrin is found in the intestinal mucosa it is not released under normal conditions in humans. A low pH and fat in duodenal chyme inhibit acid secretion and this appears to be mediated via secretin, gastric inhibitory peptide, or somatostatin. The intestinal phase of gastric secretion appears to be designed to allow the quantity and composition of the chyme leaving the stomach to meet the requirements for digestion within the small intestine. With regard to acid secretion, the intestinal phase only accounts for 10% of the response to a meal (65).

Gastric Mucosal Barrier Gastric Mucus and Bicarbonate The presence of intraluminal gastric acid and its injurious effects warrants a protective mechanism to prevent the stomach from autodigestion. This is accomplished, in part,

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by secretion of a gelatinous layer containing proteins, glycoproteins, mucopolysaccharide, and bicarbonate, which lines the superficial gastric epithelium to form a barrier between luminal contents and gastric mucosal cells. This mucuscontaining barrier is dynamic and constantly replenished by the surface epithelium. It functions as a buffer, neutralizing intraluminal acid to maintain a more physiologic pH at the mucosal surface. Furthermore, bile salts, pepsin, lysolecithin, and other luminal irritants, including those ingested, are retarded by the gel mucus layer. Release of mucus from vacuoles is stimulated by cholinergic activity as well as by the intraluminal application of acetylcholine and prostaglandins (66). Inhibition of mucus secretion is caused by agents that inhibit cyclooxygenase (COX), such as aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) (67). The mucus layer by itself is incapable of attenuating proton mobility and maintaining a neutral pH at the mucosal surface. Therefore, the mucosal barrier maintains an aqueous, alkaline layer on the mucosal surface by trapping bicarbonate secreted by mucosal cells located in the acid-secreting and antral portions of the stomach. This barrier maintains a steep pH gradient across it, which ranges from a pH of 2 on the luminal side to a pH of 7 on the epithelial side. Acid secretion is much greater than bicarbonate secretion and data suggests that transport of protons via channels away from the epithelial surface may serve to maintain this bicarbonate-rich layer (68). Recent evidence further suggests that prostaglandins produced by the constitutive isoform of COX also appear to play a large role in the secretion of bicarbonate and maintenance of the mucus layer (69). In addition, the increased utilization of NSAIDs by patients suggests a connection between nonselective COX inhibition and ulcer disease in humans (70,71). It also appears that the release of NO from the neuronal isoform of NOS contained within the superficial gastric epithelial cells functions as an important mediator in maintaining the gastric mucosal barrier (72). Furthermore, nonselective NOS inhibition has been shown to decrease gastric mucosal prostaglandin E2 release and aggravate gastric injury caused by luminal irritants (72–74). It also appears that low levels of NO released by constitutive NOS maintain gastric mucosal integrity and are gastroprotective, while high levels of unregulated NO release from inducible nitric oxide synthase (iNOS) contributes to gastric injury. It has also been shown that exogenous low-dose NO administration is gastroprotective while high-dose exogenous NO administration causes gastric injury (72,75).

Epithelial Barrier Not only is the mucosal barrier responsible for protection of the gastric mucosa, but an intact layer of surface epithelium also provides protection. Gastric surface epithelial cell membranes, tight junctions, and cellular renewal play a significant role in gastric defense. In normal gastric mucosa, there is a potential difference across the mucosa, which is the result of active transport maintained by the activity of the Na/K-ATPase, which pumps chloride into the lumen in exchange for sodium. Loss of this transmucosal electrical potential difference coincides with increased permeability of the epithelium, which predisposes the surface epithelium to further damage as protons flux into the mucosa in exchange for an efflux of sodium, proteins, water, and glucose into the lumen. Luminal irritants such as aspirin, NSAIDs, ethanol, bile salts, pepsins, Helicobacter pylori, and lysolecithin can damage the epithelial layer and cause changes in its

permeability. Fortunately, the gastric surface epithelium replaces itself faster than any other epithelial surface in the body. The turnover rate for surface epithelium is approximately every three days. Mucous neck cells, which are found between the gastric pit and gland, migrate luminally and become surface epithelium. This migration of cells functions to replace injured surface epithelium and represents a component of epithelial defense against injury. A more rapid defense mechanism of the epithelium is called restitution or re-epithelialization. This process occurs during superficial gastric injury and consists of the migration of epithelial cells across denuded or superficially injured areas (76–78). Repair in this fashion is rapid and occurs within 60 minutes. Restitution does not require cell division, but it does require an intact muscularis mucosae.

Gastric Mucosal Blood Flow Gastric mucosal blood flow also plays a major role in gastroprotection (73,79,80). Blood flow not only ensures the proper delivery of oxygen and nutrients to the gastric mucosa, but also ensures prompt removal of any protons that may have traversed the epithelial barrier. Because the gastric mucosa is vulnerable to injury when the pH falls below 4, prompt removal of hydrogen ions by the rich network of capillaries represents another defense mechanism. Furthermore, blood flow functions to remove any toxic oxidative radicals that may be liberated during times of stress or from ischemia and reperfusion. Low pH and oxygen-derived free radicals may injure the gastric mucosa by causing derangements in cellular membranes or subcellular organelles, or by compromising various enzymatic functions. Hypoperfusion of the gastric mucosa also causes a relative anaerobic state secondary to depletion of ATP, which is necessary for aerobic metabolism. Depletion of ATP further compromises enzymatic functions, especially functions of the Na/K and H/KATPases. Given the rich blood supply of the stomach, it tolerates most reductions in blood flow reasonably well. However, when gastric mucosal blood flow is reduced by 40% of normal values, gastric injury may occur (81). When blood flow is reduced by more than 70%, marked mucosal injury results, and the presence of luminal irritants or acid greatly exacerbates injury (81). Locally produced NO and prostaglandins represent potent vasodilators in the gastric mucosa that serve to enhance mucosal blood flow in the face of a damaging luminal insult and thereby limit the extent of gastric injury (80,82,83).

ABNORMAL PHYSIOLOGY Stress Gastritis Stress gastritis remains an important clinical concern especially in the intensive care unit (ICU) setting. Although improvements in ICU care, recent advances in the understanding of the pathophysiology of gastritis, and the availability of more potent antisecretory agents have decreased the incidence of this problem, life-threatening gastric bleeding from stress ulcerations can still occur (84). Stress gastritis is typically seen in critically ill patients and appears to be associated with alterations in gastric mucosal defense and barrier function. The presence of gastric acid is also a predisposing factor, although acid secretion is not necessarily increased. These lesions are associated with a number of clinical predisposing conditions, including multiple traumatic injuries, endotoxemia or sepsis, shock, cardiac dysfunction, and multiple organ failure (84). Other terms used

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to describe this condition include stress erosive gastritis, hemorrhagic gastritis, and hemorrhagic erosive gastritis. Stress ulcerations are characterized by their endoscopic appearance and typically change over time. When they appear within the first 24 hours after a stressor or injury, they are referred to as acute stress gastritis. In this setting, the gastritis is characterized by multiple superficial erosions in discrete areas of the gastric mucosa, with or without focal hemorrhage or an adherent clot. These lesions typically begin in the proximal or acid-secreting portion of the stomach and appear microscopically as small wedgeshaped mucosal hemorrhages with coagulation necrosis of the superficial mucosal cells. If acute stress gastritis lesions progress, they can erode into the submucosa and the underlying vasculature to cause frank hemorrhage. When these lesions progress to ulceration, or if clot organization or an inflammatory exudate develops, the lesions are classified as the late form of acute stress gastritis. This usually occurs 24 to 72 hours after a stressor or injury (84). These late lesions have extension of hemorrhage, inflammatory cell infiltration, and coagulation necrosis into the muscularis mucosa layers of the stomach when viewed microscopically. In addition, they appear identical to that of regenerating mucosa around a healing gastric ulcer.

Pathophysiology Recent experimental observations have identified a number of factors that appear to contribute to stress erosive gastritis. However, the precise mechanisms responsible for the development of this condition still remain to be fully elucidated. The common theme for its development appears to be dysfunctional intrinsic gastric mucosal defense mechanisms as opposed to an increase in acid secretion. However, stressinduced gastric lesions do appear to require the presence of acid. Stress gastritis lesions are most commonly found in critically ill patients, and by definition they occur after physical trauma, shock, sepsis, hemorrhagic shock, renal failure, respiratory failure, prolonged intubation, head trauma, or severe burns. The factors that appear to predispose to the development of gastritis from the above injuries or physiologic changes include reduced gastric mucosal blood flow, a reduction in mucus or bicarbonate secretion, or a reduction in endogenous NO or prostaglandin secretion (75,80,82,85). Another common factor is the development of mucosal ischemia such as that seen when hypoxia, sepsis, or organ failure occurs. In this setting, mucosal ischemia is thought to cause a breakdown of normal defense mechanisms. As a result, luminal acid is then able to damage the more susceptible mucosa by increased back-diffusion of hydrogen ions into the mucosa (86,87). That such back-diffusion of protons occur with gastric barrier disruption has been confirmed experimentally (88). It is also thought that this back-diffusion might elicit histamine release with vasodilatation and eventual bleeding if there is erosion into the mucosa (89). Although the diffusion of protons into the gastric mucosa is thought to be partly responsible for the development of gastritis lesions, there is little evidence to suggest that this-back diffusion is caused by increased gastric acid secretion. In fact, it has been shown in animal models that during endotoxemia and ischemia-reperfusion, basal and pentagastrin-stimulated acid secretion is decreased (72,90,91). Nevertheless, the presence of luminal acid still appears to be a prerequisite for gastritis to occur. Moreover, complete neutralization of luminal acid or treatment with antisecretory agents precludes the development of stress gastritis (92).

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Stress gastritis lesions occur in several clinical settings. The first setting occurs in patients who experience some form of major stress. Included in this category are patients with severe illnesses or multiple organ failure, polytrauma, sepsis, hemorrhagic shock, or ischemia-reperfusion injuries. When lesions occur in this setting, there is a possibility for significant hemorrhage if the erosion extends into the larger submucosal vessels. Hemorrhagic bleeding from these forms of stress erosions can be life threatening and may require urgent endoscopy or surgical intervention. Mucosal ischemia with production of damaging free radicals is thought to be a predominant factor responsible for causing derangements in the intrinsic gastric mucosal defense system. Alternatively, in rat models of endotoxemia, a reduction in NO from the constitutive isoform of NOS and excessive NO production from the inducible isoform of NOS cause injury to the cytoskeletal components within cells of the gastric epithelium, rendering the stomach more susceptible to injury from luminal irritants (72). Defects in cyclooxygenase metabolism have also been proposed as a possible etiologic factor (93). The second clinical scenario is not necessarily related to a defect in mucosal defense, but rather related to elevated levels of serum gastrin and secondary increases in acid secretion. These lesions are most commonly seen in patients who have sustained head trauma, with acute injury to the CNS, the so-called ‘‘Cushing’s ulcer.’’ These lesions are characteristically deeper than other acute erosions and are more likely to erode through the stomach. Often the Cushing’s ulcer presents as a single ulcerative focus that can develop in the stomach or duodenum. The third scenario is the ‘‘Curling’s ulcer,’’ which occurs in patients with extensive burns. This variety frequently extends from the stomach into the duodenum and may be demonstrable only there, in contrast to most forms of stress ulcers, which are more commonly confined to the proximal stomach. Despite the potential for hemorrhage, the incidence of this life-threatening problem has significantly diminished in recent years, presumably due to improvements in our ability to manage critically ill patients and our ability to identify and prophylactically treat patients at risk. Risk factors for developing hemorrhagic gastritis include the presence of adult respiratory distress syndrome, multiple trauma (especially head trauma), prolonged intubation, major burns over 35% of the body surface area, oliguric renal failure, large transfusion requirements, hypotension, sepsis, hepatic obstruction, prolonged surgical procedures, and sepsis from any source as predisposing factors. In addition, there has been a direct correlation between acute upper GI hemorrhage and the severity of underlying critical illness (94).

Presentation and Diagnosis The predominant clinical sign of gastritis is painless upper GI bleeding. More than 50% of patients develop their stress gastritis within one to two days following a traumatic event. The clinical signs may present in a delayed fashion because the erosive lesions must erode into the submucosal vessels for bleeding to occur. Typically, gastric bleeding from gastritis is slow and intermittent and may only be detectable by a few flecks of blood in the nasogastric tube or by an unexplained drop in the hemoglobin levels. Similarly, heme-positive stool may be detected on rectal examination, although melena and hematochezia are rare. If hemorrhage occurs, endoscopy must be performed to differentiate stress gastritis from other sources of GI hemorrhage and to

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potentially provide endoscopic therapy. Upper endoscopy is diagnostic in greater than 90% of patients and is the diagnostic modality of choice (95). If the development of upper GI bleeding from gastritis is not identified and treated appropriately, profound hemorrhage can develop, accompanied by hematemesis and hemorrhagic shock.

and all bleeding points are secured, the incidence of rebleeding is low (85,101). In contrast, some surgeons prefer to perform a partial gastrectomy in combination with vagotomy. However, the only indication for total gastrectomy is in the rare patient who presents with life-threatening hemorrhage refractory to other forms of therapy.

Therapy

Prophylaxis

Any patient who presents with significant upper GI bleeding requires prompt fluid resuscitation, with correction of any coagulation or platelet abnormalities as well as the administration of blood if it is required. The initial treatment should consist of saline lavage of the stomach through a nasogastric tube to remove blood and clots that may prolong bleeding through fibrinolysis. Placement of a nasogastric tube also helps to prevent gastric distention, which could stimulate gastrin release and cause a secondary increase in gastric acid secretion. Nasogastric decompression and/or gastric lavage also removes gastric acid, bile, and pancreatic juice that may have refluxed back into the stomach, all of which may potentially further exacerbate gastric mucosal injury. This approach ceases upper GI hemorrhage from gastritis in over 80% of patients and allows visualization during endoscopy (96–98). Once bleeding has ceased as demonstrated by clear nasogastric tube aspirates, the intraluminal gastric pH should be maintained at greater than 5.0 with antisecretory agents. The mainstay of treatment is with a PPI. Alternatively, histamine receptor antagonists, with or without the combination of an antacid, can also be used. Furthermore, sepsis must be treated with appropriate antimicrobials in conjunction with control of the infectious source. While endoscopy is useful to determine the etiology of upper GI bleeding, there is little evidence to suggest that endoscopic treatment with electrocautery or heater probe coagulation has any benefits in the therapy of bleeding from acute stress gastritis. Another treatment modality is the selective infusion of vasopressin into the splanchnic circulation via the left gastric artery because some studies suggest that it may be effective at controlling acute bleeding (99,100). If vasopressin instillation is instituted, it is administered by continuous infusion through a catheter at a rate of 0.2 to 0.4 IU/min for a maximum of 48 to 72 hours. Vasopressin should not be used in patients with underlying cardiac or liver disease. However, while vasopressin may decrease blood loss, it has not been shown to result in improved survival (100). Because of the extensive submucosal plexus of arterial vessels within the stomach, interventional radiology using angiography techniques has also been tried, but for the most part is unsuccessful. Surgical intervention is not usually required for acute stress gastritis. However, if there is recurrent or persistent bleeding that requires more that six units of blood, surgery may be indicated. If surgery is attempted, one approach is through a long anterior gastrotomy in the proximal stomach because most lesions of stress gastritis are found in this region. The gastric lumen is then cleared of blood and the specific bleeding points identified. Bleeding areas are managed with figure of eight stitches taken deep within the gastric wall. Any actively bleeding site needs to be secured by suture. Most superficial gastric erosions are not actively bleeding at the time of surgery and therefore do not usually require ligature unless a blood vessel is seen at the base. After completing the operation by closing the anterior gastrotomy, a truncal vagotomy and pyloroplasty should be performed to reduce acid secretion. If the surgeon is diligent

In light of the high mortality rates associated with acute gastritis in patients who develop massive upper GI hemorrhage, prophylaxis is recommended for high-risk ICU patients. In patients at risk, treatment of any metabolic derangements, underlying organ dysfunction, or untreated sepsis needs to be initiated. This includes resuscitation to correct any perfusion deficits from shock and administration of antibiotics and source control for sepsis. Ventilatory support should be optimized in addition to correcting any systemic acid–base abnormalities. Furthermore, nutritional support is mandatory, preferably via the enteral route, because it is associated with fewer infectious complications (102). In addition to the aforementioned modalities to optimize patient care, prophylactic therapy should be given to those patients at high risk. The patients at risk for stress gastritis in the intensive care setting appear to be patients with respiratory failure who require mechanical ventilation or who have hypotension, sepsis, or an underlying coagulopathy (103). Prophylactic therapy is usually aimed at neutralizing or preventing acid secretion. In the past, antacids were administered as prophylaxis for stress gastritis and had an efficacy of 96%. This usually required hourly administration of antacids via the nasogastric tube and intraluminal gastric pH was maintained above 3.5. For most patients, attempts were made to maintain the pH above 5.0 as more than 99.9% of acid is neutralized and pepsin is inactivated. Several controlled prospective trials have demonstrated that titration of gastric pH with antacids is effective at preventing GI bleeding in patients at risk for stress gastritis in the ICU setting (104–107). H2 receptor antagonists have also been used as prophylactic agents to prevent stress ulceration. However, there does not appear to be any advantage to prevention of acute stress gastritis when comparing antacids versus H2 blockers (108). Nevertheless, H2receptor antagonists have about a 97% efficacy when used as medical prophylaxis for stress gastritis (108). Sucralfate is another agent that has been employed for prophylaxis against stress gastritis and is extremely efficacious in the 90% to 97% range. It may be given in a dose of 1 g every six hours and may be just as effective as antacids or H2 receptor antagonists (105,109). Furthermore, this form of prophylaxis has the added benefit of allowing the stomach to maintain its normal pH and thus prevent bacterial overgrowth. This latter effect may be beneficial because several studies have suggested that gastric luminal alkalinization predisposes the stomach to bacterial overgrowth and subsequent nosocomial pneumonia (110,111), although a review of the published literature does not necessarily support this (112). Lastly, exogenous prostaglandins have also been tried as stress gastritis prophylaxis agents. However, their efficacy appears to be less than that of the other agents.

Peptic Ulcer Disease Epidemiology Peptic ulcer disease remains one of the most prevalent and costly GI diseases. In the United States, the annual incidence

Chapter 15: Gastric Physiology and Acid-Peptic Disorders

of active ulcer (gastric ulcer and duodenal ulcer) is about 1.8% or roughly 500,000 thousand new cases per year. In addition, there are approximately 4,000,000 ulcer recurrences yearly (113). In the last two decades, elective admissions have decreased dramatically, while admissions for complications related to ulcer disease have shown little change (114). Each year, it is estimated that three to four million patients are seen by a physician for diagnosis and treatment of peptic ulcer disease, and an additional three to four million patients are self-medicating. Furthermore, it is estimated that over 130,000 operations are performed yearly for peptic ulcer disease, and approximately 9000 patients die from complications related to their peptic ulcer disease. While hospitalization rates for duodenal ulcers have decreased, they have remained relatively stable for gastric ulcer (113,115,116). However, admissions for bleeding gastric ulcers have increased over the last several years and they are more likely to occur in elderly patients (113,117,118). This increase in the occurrence of gastric ulcers complicated by bleeding is also associated with an increase in NSAID ingestion. Interestingly, the incidence in peptic ulcer has increased in women in the United States while it has decreased in men (113). It is speculated that the increase in the number of women with peptic ulcer disease is in part due to an increase in the prevalence of smoking and an increase in NSAID ingestion. The most common cause of death in patients with peptic ulcer disease is bleeding in patients who have major medical problems or are over the age of 65 (113,116,118). In patients with peptic ulcer disease that presents with upper GI bleeding, approximately 80% of these bleeds are selflimited. However, there is approximately a 10% incidence of mortality (113,116,118). The national American Society for Gastrointestinal Endoscopy (ASGE) survey on upper GI bleeding demonstrated that mortality increases with age, rebleeding, and with comorbid conditions. In patients under 60 years of age the mortality was 8.7%. For those over 60, the mortality was 13.4%. Recurrent bleeding increases the mortality rate to approximately 30% to 44%. For patients with no comorbid conditions, the mortality rate was 2.5%. However, with three significant comorbid conditions the mortality rate increased to 15%, and with six comorbid conditions the mortality rate rose to 67%. Other factors of an adverse outcome from upper GI hemorrhage are a visible vessel on endoscopy, oozing of bright red blood, and fresh blood clot at the base of the ulcer. Pumping or oozing lesions had a significantly greater need for surgical management and were associated with a higher mortality, 24% and 16%, respectively (119,120). Perhaps the most drastic change in our understanding of peptic ulcer disease is the identification of H. pylori and the realization that peptic ulcer disease is in reality an infectious disease. Human gastric bacteria were first discovered in the early 1900s. In the 1920s, urease was erroneously thought to be produced by humans and to be protective. In the 1950s, these previously observed bacteria were dismissed as contaminates. However, in the 1970s, gastric bacteria were rediscovered and found to be associated with inflammation. Twelve years later, the first successful culture of the organism was accomplished by Marshall and Warren, who named it Campylobacter pyloridis (121). Then, in 1987, it was reported that eradication of the organism reduced duodenal ulcer recurrence (122). Following reclassification of the organism to H. pylori in 1989, the National Institutes of Health (NIH) convened a consensus panel that issued guidelines for management of ulcer disease, taking H. pylori into account. Consequently, any treatment plan for peptic

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ulcer disease, both medical and surgical, requires that H. pylori be considered. The association between H. pylori and peptic ulcer disease is discussed in more detail in the section on ‘‘Pathogenesis.’’ Despite our advances in medical therapy to inhibit acid secretion and to eradicate H. pylori, surgery remains important in managing patients suffering from peptic ulcer disease. Over the last two decades, there has been an increase in emergency operations performed for complications of peptic ulcers while the number of operations for elective indications has decreased markedly (113). Moreover, there is a high recurrence rate for peptic ulcerations following discontinuation of medical therapy. As a result, there is a renewed interest in operative management of patients with peptic ulcer disease, although the indications for surgery have not changed (bleeding, perforation, obstruction, intractability, etc.). However, the type of operation performed for peptic ulcer disease has changed in the H. pylori era (123–125). While some of the earliest surgical procedures for peptic ulcer disease usually involved some type of gastrectomy, later operations involved denervating the parietal cell secreting mass with some sort of vagotomy (see below). However, recent studies indicate that vagotomy may not even be necessary in some situations such as perforation of the duodenum, provided that H. pylori is eradicated (124).

Location and Type of Ulcer Peptic ulcer disease can be divided into gastric and duodenal ulcers. Both types tend to occur near mucosal junctions. Duodenal ulcers usually occur at the duodenal-pyloric junction, whereas gastric ulcers tend to occur at the oxynticantral junction, the antral-pyloric junction, or the esophagogastric junction. By definition, an ulcer extends through the muscularis mucosa, in contrast to an erosion, which is superficial to the muscularis mucosa. Duodenal ulcer disease usually occurs in the first portion of the duodenum just beyond the pyloric sphincter (i.e., duodenal bulb). It is almost always associated with the secretion of acid and pepsin in conjunction with either H. pylori infection or the ingestion of NSAIDs (126). Occasionally, it may occur in more distal parts of the duodenum if caused by the ZES (see below). In comparison, gastric ulcer may present in four forms (Fig. 16). Type 1 gastric ulcers are most common, accounting for about 60% to 70% of the total. These are typically located on the lesser curvature at or proximal to the incisura, near the junction of the oxyntic and antral mucosa. Most are associated with diffuse antral gastritis or multifocal atrophic gastritis. Type 2 gastric ulcers (about 15%) occur in the exact location as the Type 1 lesion, but are associated with either active or chronic duodenal ulcer disease. Type 3 gastric ulcers (20%) are usually located within 2 cm of the pylorus. The fourth type of gastric ulcer is located in the proximal stomach or in the cardia and is rare in the United States and Europe but common in Latin America. Types 2 and 3 gastric ulcers appear to behave more like duodenal ulcers in that they are associated with excess acid secretion. In contrast, Type 1 and Type 4 gastric ulcers are usually not associated with excess acid secretion. Moreover, gastric cancers may ulcerate and resemble gastric ulcers. Furthermore, ulcers may be caused by nonacid conditions or other peptic disorders such as Crohn’s disease, pancreatic rests, syphilis, Candida, or malignant diseases such as Kaposi’s sarcoma, lymphoma, carcinoma, or pancreatic carcinoma.

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Figure 16 Location of gastric ulcers. Type 1 gastric ulcers are located in the gastric body usually within the lesser curvature. Type 2 ulcers are Type 1 ulcers associated with a duodenal ulcer. Type 3 ulcers are located within the prepyloric gastric antrum. Type 4 gastric ulcers are located high on the lesser curvature near the cardia.

Pathogenesis H. pylori Infection H. pylori is believed to be associated with approximately 90% of duodenal ulcers and approximately 75% of gastric ulcers. The organism was first identified and isolated by Marshall and Warren (121). They were also the first to appreciate the relationship between H. pylori infection and gastritis. The organism is a helical-shaped gram-negative rod with four to six flagellae and is found within gastric epithelium or within sites of gastric metaplasia in the esophagus, duodenum, rectum, or Meckel’s diverticulum. H. pylori is usually only found in gastric epithelium because the epithelium expresses specific adherence receptors that are recognized by the bacterium (127,128). Its pathogenicity is related to the production of endotoxin and other toxic products that cause local tissue injury, production of urease, local mucosal immune responses, or increased gastrin levels with an associated increase in acid secretion. The virulence factors that are most often implicated in H. pylori–induced mucosal injury are CagA and VacA cytotoxins, ammonia, protease, lipase, and urease enzymes (129–131). H. pylori– induced release of proinflammatory mediators and cytokines such as NO via iNOS, COX-2, tumor necrosis factor-a, gamma interferon, interleukin (IL)-1b, IL-4, IL-6, IL-8, IL-10, endothelin-1, and nuclear factor-kappa beta have also been implicated in mucosal injury, apoptosis, and gastric cancer (132–137). Other injurious effects of H. pylori are related to its ability to induce apoptosis and abrogate cell-cycle progression and cellular proliferation (134,135). Locally produced toxic mediators include breakdown products of urease (i.e., ammonia), cytotoxins, mucinase, which degrades mucus and glycoproteins, phospholipases, which damage mucus and epithelial cells, and platelet activating factor, which causes microcirculation thrombosis and mucosal injury (129,131). H. pylori production of chemotactic factors also causes a local inflammatory reaction with infiltration and recruitment of neutrophilic polymorphonuclear cells, lymphocytes, plasma cells, macrophages, and eosinophils, and later with the development and recruitment of specifically committed cells [lymphocytes sensitized to H. pylori antigens and B-cells producing immunoglobulin

(Ig) (IgA, IgG, and possibly IgE antibodies)] against a variety of H. pylori surface and flagellar proteins. Subsequently, there is formation of lymphoid follicles, which are not normally present in the gastric mucosa (138,139). In patients with H. pylori infection and duodenal ulcer disease, basal and stimulated gastrin levels are significantly increased (140–144). Some data suggest that the mechanism responsible for increased gastrin levels is the H. pylori infection that causes a reduction in antral D-cells (141). A reduction in D-cells leads to a reduction in somatostatin synthesis, which causes an increase in gastrin synthesis due to disinhibition of antral G-cells (i.e., loss of tonic somatostatin inhibition) (141). Other mechanisms suggested for changes in these gut hormones are from ammonia produced by H. pylori and monochloramine, the effect on somatostatin receptor subtype-2, the action of lipopolysaccharide from H. pylori on somatostatin receptors, infiltration of inflammatory cells and release of inflammatory mediators, and diversity of bacterial strains (140). Regardless of the mechanisms, eradication of H. pylori leads to an increase in antral D-cells, with an increase in somatostatin synthesis and a concomitant decrease in gastrin levels (141,145). While H. pylori infection appears to cause a reduction in antral D-cells, with a reduction in somatostatin and a concomitant increase in serum gastrin levels, there is not necessarily an increase in gastric acid secretion. Although H. pylori–infected patients with duodenal ulcers do have a marked increase in acid secretion, H. pylori–positive healthy volunteers have a small increase or no increase in acid secretion when compared to H. pylori–negative volunteers (142). In addition, other studies suggest that increased acid secretion in duodenal ulcer patients is a result of increased parietal cell mass that is independent of, or not related to, H. pylori infection (142,145). Peptic ulcers are also strongly associated with antral gastritis. Even before identification of H. pylori, it was known that almost all peptic ulcer patients had histologic evidence of antral gastritis. However, it is now well recognized that most cases of histologic gastritis are due to H. pylori infection. In fact, the only patients with gastric ulcers and no gastritis are those ingesting aspirin or other NSAIDs. In one study the occurrence of antral inflammation, atrophy, and intestinal metaplasia did not differ between patients with H. pylori– negative and H. pylori–positive ulcers, but activity of gastritis was more common in H. pylori–positive than in H. pylori– negative patients (94.9% vs. 47.1%, respectively) (147). H. pylori–negative peptic ulcer disease was independently associated with older age, bile reflux, the use of nonsteroidal anti-inflammatory analgesics, and intestinal metaplasia, while H. pylori–positive peptic ulcer disease was associated with active inflammation of the antral mucosa and tendency to ulcer recurrence (147). In most cases, the infection tends to be confined initially to the antrum with a resultant antral inflammatory reaction. Further evidence supporting a causal role for H. pylori in histologic gastritis is the finding that eradication of H. pylori improves gastric histology, although gastritis does not necessarily equate with symptoms of dyspepsia (148). H. pylori represents a chronic infection found worldwide. Once a person is infected, usually in childhood, it is probably for life because spontaneous remission is rare. There also tends to be an inverse relationship between infection and the socioeconomic status. The reasons for this remain poorly understood, but may be due to factors such as sanitary conditions, familial clustering, and crowding. The etiology of transmission is still elusive although a fecal–oral or oral–oral

Chapter 15: Gastric Physiology and Acid-Peptic Disorders

route has been suggested because there is a strong relationship between children and familial crowding and H. pylori infection, which suggests person-to-person transmission. In fact, several studies have documented familial clustering of H. pylori infection, demonstrating that H. pylori in one household member is associated with a greater chance of infection in other members (149–151). In another study, H. pylori infection was most common in the lowest socioeconomic class (85%), intermediate in the middle class (52%), and lowest in the highest class (11%) (152). The odds ratio for H. pylori infection comparing the highest childhood crowding index with the lowest crowding was 4.5 (95% confidence interval of 3.3–5.7), indicating a marked and significant effect of childhood crowding on H. pylori infection (152). These data provide strong evidence that the infection is transmitted by a person-to-person route and that the infection is commonly acquired early in life. H. pylori infection is associated with a number of common upper GI disorders. It is virtually always present in the setting of active chronic gastritis and is present in the majority of duodenal and gastric ulcer patients. In several studies H. pylori was found in 75% to 95% of duodenal ulcers and 70% of gastric ulcers (153,154). Noninfected gastric ulcer patients tend to be NSAID users. There is a less strong association with nonulcer dyspepsia, which is probably in the range of about 50%. In addition, a substantial number of gastric cancer patients show evidence of past H. pylori infection. There is also a strong association between mucosalassociated lymphoid tissue (MALT) lymphoma and H. pylori infection. Interestingly, regression of these lymphomas has been demonstrated following eradication of the organism and therefore H. pylori eradication should be attempted before chemotherapy (155). Limited data are available to estimate the lifetime risk of developing an ulcer in patients with H. pylori infection. However, Sullen et al. from Australia performed a serologic study with a mean period of evaluation of 18 years. During this time frame, 15% of H. pylori–positive subjects developed verified duodenal ulcer as compared to 3% of seronegative individuals (156). Another study by Sipponen et al. evaluated patients after 10 years in Scandinavia. This study was related to the presence or absence of histologic gastritis at the time of their initial assessments. Because H. pylori causes most cases of histologic gastritis, this observation was used as a marker for H. pylori infection. In this study, 11% of the patients with histologic gastritis developed peptic ulcer disease over a 10-year period as compared with only 1% of those without gastritis (157). It should also be noted that the incidence of ulcers in these two studies may have been underestimated as many patients with asymptomatic or minimally symptomatic ulcers may not have presented for medical evaluation. However, another factor implicating a causative role for H. pylori in ulcer formation is that eradication of H. pylori dramatically reduces ulcer recurrence (158,159). Although ulcers are easily cured using a variety of medications, they tend to recur if H. pylori is not eradicated or acid-lowering surgery is not performed. However, a large number of prospective trials now document that patients with H. pylori infection and ulcer disease who have documented eradication of the organism, virtually never (< 2%) develop recurrent ulcers (154,160,161) and the rate of reinfection with H. pylori is less than 5% (154,161,162). If H. pylori is not eradicated after treatment, a significant number (50–75%) may have an ulcer recurrence by one year (159,163–166); however, in the presence of antiulcer

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maintenance therapy with acid inhibitors, this rate decreases to approximately 25% at 12 months (164,166). In this latter group, in those patients who do develop recurrent ulcers, they are usually associated with NSAID utilization. In the Cochrane Database Review of recurrent bleeding from peptic ulcer disease after treatment, seven studies with a total of 578 patients demonstrated that the mean percentage of rebleeding with H. pylori eradication therapy was 2.9%, and without H. pylori eradication therapy, in groups without subsequent long-term maintenance antisecretory therapy, it was 20% (167). In three other studies with a total of 470 patients, the mean percentage of rebleeding in H. pylori eradication therapy group was 1.6%, and in noneradication therapy group with long-term maintenance anti-secretory therapy it was 5.6% (167). Nonsteroidal Anti-Inflammatory Drugs After H. pylori infection, ingestion of NSAIDs is the most common cause of peptic ulcer disease. As previously mentioned, hospitalizations for bleeding upper GI lesions are increasing along with increased NSAID use. Most of the increased NSAID utilization has occurred in women above the age of 50, which is also the group with the increase in bleeding gastric ulcers (168). The increased risk of bleeding has been documented in placebo-controlled trials with chronic aspirin utilization for prevention of recurrent heart attack or stroke (169). Furthermore, the increased risk of bleeding and ulcerations is proportional to the daily dosage of NSAID (170). Consequently, the ingestion of NSAIDs remains an important factor in ulcer pathogenesis, especially in relationship to the development of complications and death (170). The role of NSAIDs in peptic ulcer disease becomes even more meaningful if one considers the fact that roughly three million people in the United States take NSAIDs daily and about 1 in 10 patients taking daily NSAIDs have an acute ulcer. In addition, 2% to 4% of NSAID users have GI complications each year and greater than 3000 deaths and over 25,000 hospitalizations per year are attributable to NSAID-induced GI complications. Moreover, when compared to the general population, NSAIDs increase the risk of GI complications approximately 2- to 10-fold (170). NSAID ingestion not only causes acute gastroduodenal injury, but also is associated with chronic gastroduodenal injury. This risk of mucosal injury and/or ulceration is roughly proportional to the anti-inflammatory effect associated with each NSAID (170). While acute epigastric pain is common during the acute phase, it does not necessarily correlate with mucosal lesions. However, the presence of chronic epigastric pain is more suggestive of ulceration. The acute gastroduodenal lesions typically appear within one to two weeks of ingestion of the NSAIDs and range from mucosal hyperemia to superficial gastric erosions. In contrast, chronic injury typically occurs after one month and may be seen in the stomach as erosions or ulcerations in the gastric antrum or in the duodenum. Again, ulcer risk is dose related and the acute mucosal response does not necessarily predict subsequent ulcer risk. In comparison to H. pylori ulcers, which are more frequently found in the duodenum, NSAID-induced ulcers are more frequently found in the stomach. H. pylori ulcers are also nearly always associated with chronic active gastritis, whereas gastritis is not frequently found with an NSAID-induced ulcer, occurring only about 25% of the time. In addition, when NSAID use is discontinued, the ulcers usually do not recur, whereas with H. pylori–related ulcers, there is a 50% to 80% recurrence rate in one year unless the organism is eradicated with therapy (154).

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Acid There is a linear relationship between maximal acid output and parietal cell number. However, gastric acid secretory rates are altered in patients with upper GI diseases. Basal acid secretion is normally in the 1 to 8 mmol/hr rate and the response to pentagastrin ranges from 6 to 40 mmol/hr. In Types 1 and 4 gastric ulcers, basal as well as pentagastrin-stimulated acid output is decreased. In contrast, gastric secretory rates are increased in patients with duodenal ulcers and gastrinoma. In fact, an adequate level of acid secretion is a prerequisite for duodenal ulcers and their presence is rare in patients who have a maximal acid output of less than 12 to 15 mmol/hr. For Types 1 and 4 gastric ulcers, which are not associated with excessive acid secretion, acid acts as an important cofactor, exacerbating the underlying ulcer damage and retarding the ability of the stomach to heal. For patients with Type 2 or 3 gastric ulcers, gastric acid hypersecretion does seem to be more common, and consequently they behave more like duodenal ulcers. Duodenal Ulcer Pathophysiology Duodenal ulcer is a disease of multiple etiologies. Its development usually requires acid and pepsin secretion in combination with either infection with H. pylori or ingestion of NSAIDs. In addition, these patients have a variety of secretory abnormalities (Table 2) (171). The more common secretory abnormalities relate to decreased bicarbonate secretion, increased nocturnal acid secretion, increased duodenal acid load, and increased daytime acid secretion. There is also a strong correlation between parietal cell number and maximal acid output. Interestingly, mean parietal cell number is increased in duodenal ulcers patients but not in gastric ulcer patients (172). However, at least two-thirds of duodenal ulcer patients and gastric ulcer patients fall within the normal range. Additionally, there is considerable overlap in gastric acid secretion between duodenal ulcer patients and normal patients without ulcer disease. Because the overlap between duodenal ulcer patients and normal subjects is so great, acid secretory testing is of little value in establishing a diagnosis of duodenal ulcer. Nevertheless, subjects with maximal acid secretion less than 10 mmol/hr are unlikely to develop or have duodenal ulcer disease. Gastric Ulcer Pathophysiology Gastric ulcers can occur anywhere in the stomach, although they usually present on the lesser curvature near the incisura angularis as shown in Figure 16. Approximately 60% of ulcers are located in this location and are classified as Type 1 gastric ulcers. These ulcers generally are not associated with excessive acid secretion and usually have low to normal acid output. Most occur within 1.5 cm of the histologic transition zone between the fundic and antral Table 2 Frequency of Duodenal Ulcer Secretory Abnormalities Decreased duodenal bicarbonate secretion (70%) Increased nocturnal acid secretion (70%) Increased duodenal acid load (65%) Increased daytime acid secretion (50%) Increased pentagastrin-stimulated maximal acid output (40%) Increased sensitivity to gastrin (35%) Increased basal gastrin (35%) Increased gastric emptying (30%) Decreased pH inhibition of gastrin release (25%) Increased postprandial gastrin release (25%)

Table 3 Conditions Associated with Gastric Ulceration Age > 40 Female > male (2:1) Aspirin/NSAIDs Abnormalities in acid–pepsin secretion Gastric stasis Delayed gastric emptying Burns Head trauma

Duodenal ulcer Duodenal gastric reflux of bile Gastritis Helicobacter pylori Tobacco Alcohol Corticosteroids Infection/sepsis

Abbreviation: NSAIDs, nonsteroidal anti-inflammatory drugs.

mucosa. In contrast, Type 2 gastric ulcers are located in the body of the stomach in the same location as a Type 1, but occur in combination with a duodenal ulcer. These types of ulcers usually are associated with excess acid secretion. Type 3 gastric ulcers are prepyloric ulcers and account for about 20% of the lesions. These ulcers also behave like duodenal ulcers and are associated with hypersecretion of gastric acid. Type 4 gastric ulcers occur high on the lesser curvature near the GE junction. The incidence of Type 4 gastric ulcers is less than 10% and they are not associated with excessive acid secretion. Lastly, some ulcers may appear on the greater curvature of the stomach but the incidence is less than 5% (173,174). The peak incidence of gastric ulcers occurrence is between 55 and 65 years of age; they rarely develop before the age of 40. They are more likely to occur in the lower than in the higher social economic classes and are slightly more common in the nonwhite than the white population. The exact pathogenesis of a benign gastric ulcer remains unknown. Some conditions that may predispose to gastric ulceration are shown in Table 3. With respect to acid and pepsin secretion, the presence of acid appears to be essential to the production of gastric ulcers; however the total secretory output appears to be less important. Nevertheless, it is noteworthy that rapid healing follows antacid therapy, antisecretory therapy, or vagotomy, even when the lesion-bearing portion of the stomach is left intact, because in the presence of gastric mucosal damage, acid is ulcerogenic even when present in normal or less than normal amounts.

Clinical Manifestations Duodenal Ulcer Abdominal Pain. The most common symptom associated with duodenal ulcer disease is well-localized mid-epigastric abdominal pain. The pain is usually tolerable and frequently relieved by food. The pain may also be episodic, seasonal in the spring and fall, or it may relapse during periods of emotional stress. For these reasons and because it is relieved, many patients do not seek medical attention until they have had the disease for many years. The presence of constant pain suggests that there is deeper penetration of the ulcer and referral of pain to the back is usually a sign of penetration into the pancreas. Diffuse peritoneal irritation is usually a sign of free perforation. Perforation. About 5% of the time, a penetrating ulcer will penetrate through the duodenum into the free peritoneal cavity to elicit a chemical peritonitis. The patient can typically recall the exact time of onset of abdominal pain that is frequently accompanied by fever, tachycardia, dehydration, and ileus. Abdominal examination reveals exquisite tenderness, rigidity, and rebound. A hallmark of free perforation

Chapter 15: Gastric Physiology and Acid-Peptic Disorders

is the demonstration of free air underneath the diaphragm on an upright chest radiograph. This complication of duodenal ulcer disease represents a surgical emergency. Once the diagnosis is made, operation should be performed in an expeditious fashion following appropriate fluid resuscitation. Bleeding. The most common cause of death in patients with peptic ulcer disease is bleeding in patients who have major medical problems or are over the age of 65 (116,118). Because the duodenum has an abundant blood supply and the gastroduodenal artery lies directly posterior to the duodenum bulb, GI bleeding from a duodenal ulcer is fairly common. Fortunately, most of the ulcers are superficial or are located in portions of the duodenum that are not adjacent to the large gastroduodenal artery or its branches. Consequently, most duodenal ulcers present with only minor bleeding episodes that are detected by the presence of melenotic or guaiac-positive stool. Bleeding duodenal ulcers account for about 25% of all upper GI bleeding patients who present to the hospital. Obstruction. Acute inflammation of the duodenum may also lead to a functional gastric outlet obstruction manifested by delayed gastric emptying, anorexia, or nausea accompanied by vomiting. In cases of prolonged vomiting, patients may become dehydrated and develop a hypochloremic hypokalemic metabolic alkalosis secondary to loss of gastric juice rich in hydrogen, chloride, and potassium ions. In this setting, fluid resuscitation requires replacement of the chloride and potassium deficiencies, in addition to nasogastric suction for relief of the obstructed stomach. In addition to acute inflammation, chronic inflammation of the duodenum may lead to recurrent episodes of healing followed by repair and scarring with, ultimately, fibrosis and stenosis of the duodenal lumen. In this situation, the obstruction is accompanied by painless vomiting of large volumes of gastric contents with similar metabolic abnormalities as seen in the acute situation. The stomach can become massively dilated in this setting and it rapidly loses its muscular tone. Marked weight loss and malnutrition are also common in this situation. Gastric Ulcer Gastric ulcers represent a clinical challenge in that it is often impossible to differentiate between gastric carcinoma and benign ulcers. Like duodenal ulcers, gastric ulcers are also characterized by recurrent episodes of quiescence and relapse. Surgical intervention is required in 8% to 20% of those patients developing complications from their gastric ulcer disease. The most frequent complication of gastric ulceration, however, is perforation. Most perforations occur along the anterior aspect of the lesser curvature. In general, larger ulcers are associated with more morbidity and higher mortality rates. Hemorrhage occurs approximately 35% to 40% of the time at some point during the course of gastric ulceration. Usually, patients who develop significant bleeding from their gastric ulcers are older, less likely to stop bleeding, and have a higher morbidity and mortality than patients bleeding from duodenal ulcers. Hemorrhage is most frequently observed in patients with Type 2 and Type 3 gastric ulcers. Similar to that in duodenal ulcers, gastric outlet obstruction can also occur in patients with Type 2 or Type 3 gastric ulcers. However, one must carefully differentiate between benign obstruction and obstruction secondary to antral carcinoma. On occasion, benign ulcers have also been found to result in spontaneous gastrocolic fistulas.

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Zollinger–Ellison Syndrome ZES is a disease caused by a tumor, known as gastrinoma, because it continuously releases gastrin into the circulation. Such tumors are usually located either in the pancreas or duodenum, or in the regional lymph nodes adjacent to these organs. As many as 90% of these tumors are found in the socalled gastrinoma triangle, bounded superiorly by the point where the cystic duct joins the common duct, inferiorly by the junction of the inferior margin of the second and third parts of the duodenum, and left laterally by the junction of the head and neck of the pancreas. Not only does the excessive amount of gastrin released by these tumors stimulate gastric acid hypersecretion, but it also stimulates parietal cell hyperplasia, which potentiates their acid-secretory capacity (175). The clinical triad of this syndrome consists of gastric acid hypersecretion, severe peptic ulcer disease, and a non–beta islet cell tumor. These gastrinomas usually occur sporadically (75%), are multiple about 50% of the time but roughly 25% are associated with multiple endocrine neoplasia type 1 (MEN1) syndrome. In the past, most gastrinomas were found to be malignant, but the advent of better and earlier screening has lead to the discovery of more benign neoplasms. However, up to 66% of gastrinomas are still found to be malignant (176,177). Hypergastrinemia associated with ZES accounts for most, if not all, of the clinical symptoms experienced by patients. Abdominal pain and peptic ulcer disease are the hallmarks of the syndrome and typically occur in more that 80% of patients. About one half of patients also exhibit diarrhea secondary to increased gastric acid secretion. Weight loss and steatorrhea also occur secondary to decreased duodenal/jejunal pH and the inactivation of lipase. Esophagitis from gastroesophageal reflux is also common. Endoscopy frequently demonstrates prominent gastric rugal folds, reflecting the trophic effect of hypergastrinemia on the gastric fundus, in addition to evidence of peptic ulcer disease. Gastrinoma and ZES should always be considered and ruled out in patients who have recurrent or intractable peptic ulcer disease despite eradication of H. pylori and appropriate antisecretory therapy; multiple or atypically located ulcers; peptic ulcer disease associated with significant diarrhea; peptic ulcer disease associated with symptoms of MEN1 such as hyperparathyroidism or in kindreds of MEN1 patients; large gastric rugae on endoscopy; or in those patients with other pancreatic endocrine tumors. Similarly, patients undergoing elective surgical intervention for peptic ulcer disease should have the possibility of gastrinoma included in their preoperative evaluation. Provocative tests are usually not required to establish the diagnosis of ZES, because fasting and stimulated plasma gastrin levels are usually elevated. Most patients with gastrinoma have elevated fasting serum gastrin levels ( > 200 pg/mL), and values greater than 1000 pg/mL may be diagnostic. However, hypergastrinemia may be present in other disease states. Basal acid output of greater than 15 mEq/hr (or > 5 mEq/hr in those with previous antiulcer surgery) supports this diagnosis. The secretin test is the most sensitive and specific provocative test for gastrinoma and aids in the differentiation between gastrinomas and other causes of ulcerogenic hypergastrinemia (Table 1). Serum gastrin samples are measured before and after intravenous administration of secretin (2 U/kg), at five-minutes intervals for 30 minutes. An increase in the serum gastrin level of greater than 200 pg/mL above basal levels is specific for gastrinoma versus other causes of hypergastrinemia, which do not demonstrate this response (177).

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After diagnosis of gastrinoma, acid suppression therapy should be initiated, preferably with a proton-pump inhibitor. Medical management is indicated preoperatively and in patients with metastatic and/or unresectable gastrinoma. Localization of the gastrinoma should be performed before undertaking an operative intervention. Noninvasive methods include computed tomography scanning, magnetic resonance imaging, endoscopic ultrasound, and 111In-octreotide scintigraphy (somatostatin receptor imaging). Invasive modalities may be used if noninvasive methods fail to localize the tumor. These include selective visceral angiography, percutaneous transhepatic portal venous sampling for gastrin, and the selective arterial secretin stimulation test (176,177). In patients with resectable gastrinomas, surgical resection should be performed that includes tumor resection from the duodenum, pancreas, or regional lymph nodes. Total gastrectomy is rarely indicated, and is reserved for patients who are noncompliant with acid suppression therapy or when the tumor cannot be localized.

Diagnosis History and physical examination are probably of limited value in distinguishing between gastric and duodenal ulceration. Routine laboratory studies include a complete blood count, liver chemistries, serum creatinine, and calcium levels. A serum gastrin level should also be obtained in patients with ulcers that are refractory to medical therapy or require surgery. An upright chest radiograph is usually performed for ruling out perforation. The two principal means of diagnosing peptic ulcers are upper GI radiographs and fiberoptic endoscopy. Contrast radiography is less expensive and most (90%) can be diagnosed accurately. However, about 5% of ulcers that appear radiographically benign are malignant. As endoscopy is becoming more cost-effective, many clinicians are now using this modality as the sole method for diagnosis. H. pylori testing should also be done in all patients with suspected peptic ulcer disease. H. pylori Testing Diagnostic tests for H. pylori are divided into noninvasive and invasive tests. Noninvasive tests do not require endoscopy whereas invasive tests do and require a sample of gastric mucosa. The noninvasive tests available are serology and the carbon-labeled urea breath test. The invasive tests available are the rapid urease test, histology, and culture. Serology. Serology can be used to diagnose H. pylori because H. pylori infection elicits a local as well as a systemic IgG-mediated immune response. Serology is the diagnostic test of choice when endoscopy is not indicated and has about 90% sensitivity and specificity associated with it (178–180). Because antibody titers can remain high for a year or more, the serology test should not be used to assess eradication following therapy. However, two studies have shown that a decrease in antibody titers of 25% at six months does correlate with eradication of H. pylori, with a sensitivity greater than 75% and a specificity of greater than 95% (179,180). Urea Breath Test. Another noninvasive test used for diagnosing H. pylori is the carbon-labeled urea breath test. This test is based on the ability of H. pylori to hydrolyze urea. Its sensitivity and specificity are both greater than 95% (181). The test is performed by having the patient ingest carbon isotope–labeled urea, using either C14 or C13. If C13 is used, mass spectrometry is required, whereas C14 does not,

but is associated with a low level of radiation exposure. Following ingestion of the carbon isotope, urea will be metabolized to ammonia and labeled bicarbonate if H. pylori infection is present. The labeled bicarbonate is excreted in the breath as labeled carbon dioxide, which is then quantified. The urea breath test is less expensive than endoscopy and samples the entire stomach. False negatives can occur if the test is done too soon after treatment, so it is usually best to test four weeks after therapy is finished. The urea breath test is the method of choice to document eradication (182). Rapid Urease Assay. The method of choice to diagnose H. pylori if endoscopy is employed is the rapid urease test. This test is also based on the ability of H. pylori to hydrolyze urea. The enzyme urease catalyzes degradation of urea to ammonia and bicarbonate, creating an alkaline environment that can be detected by a pH indicator. Mucosal biopsies are placed into a liquid or solid medium containing urea and a pH indicator. Sensitivity is approximately 90% and specificity is 98%, and the results are available within hours (183–185). Histology. Endoscopy can also be performed to obtain biopsy samples of gastric mucosa followed by histologic visualization of H. pylori. H. pylori is identified by its appearance and colonization sites with routine hematoxylin and eosin stains or with special stains such as silver, Giemsa, or Genta, for improved visibility. Sensitivity is about 95% and specificity 99%. This test is widely available and affords the clinician the ability to assess the severity of gastritis as well as to confirm the presence or absence of the organism. Culture. Culturing of gastric mucosa obtained at endoscopy can also be performed to diagnose H. pylori. The sensitivity is approximately 80% and specificity is 100%. However, it requires laboratory expertise and diagnosis requires up to three to five days. Nevertheless, it does provide the opportunity to perform antibiotic sensitivity testing on isolates should the need arise. H. pylori Testing Summary In summary, it is not necessary to perform endoscopy to diagnose H. pylori. Serology is the test of choice for initial diagnosis when endoscopy is not required. If, however, endoscopy is to be performed, the rapid urease assay or histology are both excellent options, but the cost advantage lies with the rapid urease assay. To document eradication after treatment, the urea breath test is the method of choice, but again should not be performed until four weeks after therapy ends. If the breath test is unavailable, endoscopy may be performed in selected patients such as those with bleeding ulcers or other complications of their peptic ulcer disease. Upper GI Radiography A relatively safe method of diagnosing peptic ulcer disease is by upper GI radiography. Upper GI radiography requires the patient to swallow barium and then radiographs are obtained, which outline the intraluminal cavity of the stomach and duodenum. Demonstration of an ulcer is performed by visualizing an ulcer crater, which is usually round or oval, that disrupts the intact gastric or duodenal mucosa. The study is useful to determine location and depth of penetration of the ulcer as well as the extent of deformation and fibrosis. The limiting factor of barium swallow in upper GI radiography is that it is technician dependent and also requires the diagnostic skills of a radiologist, which may

Chapter 15: Gastric Physiology and Acid-Peptic Disorders

be physician dependent. When air is included in the upper GI barium radiograph (double-contrast study), the sensitivity of detecting ulcer craters can be increased to 80% to 90% from 50% when air is not included (single-contrast study). The location of a gastric ulcer is of little predictive value in establishing malignancy because benign and malignant ulcers can occur anywhere in the stomach. However, the size of the gastric ulcer may have some predictive value in that larger lesions are more likely to be malignant than smaller ones. In addition, the finding of an ulcer with an associated mass; interrupted, fused, or nodular mucosal folds approaching the margin of the crater; or an ulcer with irregular filling defects in the ulcer crater is suggestive of a malignancy. Fiberoptic Endoscopy Endoscopy is the most reliable method of diagnosing a gastric ulcer, with an accuracy of over 97%. In addition, if multiple biopsies and brushings for cytology are performed, the probability of diagnosing a malignancy is also in excess of 97%. In general, benign ulcers have smoother, more regular, rounded edges with a flat smooth ulcer base. Malignancy is more often associated with a mass that may protrude into the lumen or have folds surrounding the ulcer crater that are nodular, clubbed, fused, or stop short of the ulcer margin. Again, multiple biopsy specimens are necessary for any of these ulcers because ruling out a malignancy is mandatory. Clinical symptoms or signs that may prompt early endoscopic evaluation include major weight loss, symptoms of gastric outlet obstruction, a palpable abdominal mass, guaiac-positive stool, or blood-loss anemia. In addition to providing diagnostic abilities, endoscopy provides the ability to sample tissue for H. pylori testing and may also be used for therapeutic purposes in the setting of GI bleeding (see treatment of bleeding below) or in the therapy of obstruction (see the following section).

Treatment Medical Management The use of medicinal products for the treatment of symptoms of disturbances in gastric physiology has a long history in all cultures. Recent advances in understanding molecular mechanisms have given us the opportunity to not only understand peptic ulcer disease, but also regulate the cellular mechanisms that cause ulcer disease. We now have an arsenal of therapeutic interventions that allow us to target several different areas related to peptic ulceration. Antagonists of histamine, gastrin, and acetylcholine receptors; PPIs; and agents that alter mucosal defenses all have the potential to make an impact on ulcer reduction and prevention. Recently, treatment of H. pylori, cessation of NSAIDs use, inhibition of acid secretion, buffering of gastric acidity, and understanding of the mucosal barrier have all played a significant role in the treatment of ulceration. Alterations in patient lifestyles also play a significant role in ulcer healing. Cessation of cigarette smoking and tobacco use should be emphasized to the patient, as tobacco has been shown to delay ulcer healing. If possible, the use of COX inhibitors such as aspirin and NSAIDs should also be avoided. In those patients for whom anti-inflammatory drugs are needed, the physician should consider the use of the more selective COX-2 inhibitors, which are associated with a lower incidence of ulceration. The ingestion of alcohol and coffee should also be moderated because they damage the mucosa and stimulate acid secretion, respectively.

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Antacids. Antacids have the benefit of being able to quickly buffer acid and raise the pH of the gastric fluid. They reduce gastric acidity by reacting with hydrochloric acid, forming a salt and water to inhibit peptic activity by raising the pH. Increasing pH also secondarily inhibits pepsin activity. Antacids differ greatly in their buffering ability, absorption, taste, and side effects. They are most effective when ingested one hour after a meal. If taken on an empty stomach, the antacids are emptied rapidly and have only a transient buffering effect. However, if taken after meals, they are retained in the stomach and exert their buffering action for longer periods of time. The minimum dose of antacids required to produce optimal healing rates represents only a few tablets or liquid doses of antacids per day, usually in doses of 200 to 1000 mmol/day. This dosage level produces minimal side effects and results in approximately 80% ulcer healing at one month. The mechanism for ulcer healing at lower doses is not clear because gastric acidity is only neutralized for brief periods. Historically, antacids have been used for prophylaxis and treatment of gastritis, as well as for treatment of gastric and duodenal ulcers. When used as prophylaxis against stress gastritis in critically ill patients, antacids are as efficacious as H2-receptor antagonists in protection against bleeding. Similarly, antacids are as effective as H2-receptor antagonists in the healing of gastric and duodenal ulcers. Magnesium antacids tend to be the best buffers, but can cause significant diarrhea by a cathartic action. In contrast, aluminum acids precipitate with phosphorous and can occasionally result in hypophosphatemia and sometimes constipation. Consequently, while antacids may heal duodenal ulcers with an efficacy comparable to that observed with H2-receptor antagonists, the frequent dosing schedule and side effects of antacids have caused a decline in their use in favor of more selective inhibitors of acid secretion. H2-Receptor Antagonists. H2-receptor antagonists were the first class of selective acid inhibitors to be developed. They function by reversibly binding to the histamine receptor of the parietal cell by mimicking the imidazole ring of histamine, which the histamine receptor recognizes. Variations in the ring structure and side chains have allowed for the development of several generations of H2-receptor antagonists, which all differ in their potency and half-life. These variations allow for longer duration as well as for decreased side effects. The older generation of H2-receptor antagonists, such as cimetidine and ranitidine, has the undesirable side effects of metabolism in the liver by the hepatic microsomal enzyme system. Because these older drugs undergo hepatic metabolism, they have the ability to increase serum levels and pharmacologic effects of medications that also rely on hepatic metabolism. Historically, continuous intravenous infusion of H2-receptor antagonists has been shown to produce more uniform acid inhibition than intermittent administration, but newer generations of these drugs are just as effective owing to greater potency and longer half-lives (186). The fluctuating effects of intermittently administered older H2-receptor antagonists are probably caused by the relatively short half-life of these agents, which ranges from 1.5 to 3 hours. Split-dose, evening and nighttime therapy are all effective, but again continuous intravenous infusion produces the most uniform acid inhibition. Many randomized controlled trials indicate that all H2-receptor antagonists result in gastric and duodenal ulcer healing rates of 70% to 80% after four weeks and 80% to 90% after eight weeks of therapy (187–191). However, in patients

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who are infected with H. pylori, cessation of H2-receptor antagonists without treating H. pylori results in significant ulcer recurrence within a year (192). Proton-Pump Inhibitors. The final common pathway for all stimulation of gastric acid secretion is the H/K-ATPase of the parietal cells. Therefore, it is not surprising that antagonists for the proton pump have been developed. PPIs, of which omeprazole is the classic prototype, are a class of benzimidazoles which covalently bond to the catalytic alpha subunit of the H/K-ATPase, thereby permanently inhibiting gastric acid secretion of any given parietal cell affected. Because the proton pump is the final common pathway for all acid secretion, inhibition by PPIs negates all acid secretion from affected parietal cells from all types of acid stimulation. Basal acid secretion, meal-stimulated acid secretion, and secretagogue-stimulated acid secretion are all suppressed. Therefore, PPIs are the most potent class of acid-inhibiting agents and provide more consistent inhibition. Furthermore, inhibition of acid secretion is of longer duration with this class of agents because binding to the proton pump is irreversible. Generally, inhibition lasts for longer than 18 hours. To resume acid secretion, new proton pumps must be synthesized. PPIs are weak bases, which require an acidic environment to become ionized and activated (193,194). Usually a pH of less than three is needed for this activation to occur. PPIs that are taken by the oral route require acidic gastric luminal fluid to become activated. Consequently, antacids and H2-receptor antagonists should not be used in conjunction with PPIs. As a result, various oral preparations have been developed, which limit intragastric degradation and promote systemic absorption and increased bioavailability. Newer agents have also been developed, which may be administered intravenously and subsequently have improved bioavailability. The properties of PPIs allow for the advantage of selectivity of gastric parietal cells over other forms of acid-reducing agents. Specifically, PPIs are very selective to binding to the parietal cell H/K-ATPase and also require an acidic environment to become activated, which allows for the accumulation of PPIs within the acidic environment of the parietal cell secretory canaliculus. Another advantage of PPIs is that they have less interaction with the hepatic microsomal enzyme system and therefore have less effect on metabolism of other medications (193,194). One concern about the use of PPIs is that such significant inhibition of acid secretion causes secretion of gastrin. Hypergastrenemia has been observed with use of these agents, as well as ECL cell hyperplasia (193,194). However, concerns about these side effects do not appear to be clinically relevant in comparison to the necessary treatment of ulcer disease. Currently, five PPIs are approved by the Food and Drug Administration. These are omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole. The newer agents have been developed subsequent to omeprazole and offer several advantages, particularly with respect to quicker onset of action, and reduced potential for pharmacokinetic variation and drug interactions. All of the PPIs appear to have similar efficacy in relation to healing of peptic ulcer disease. PPIs also appear to have a more rapid healing of ulcers than other forms of medical treatment. In relation to H2-receptor antagonists, PPIs have a 14% advantage at two weeks and a 9% advantage at four weeks when compared to cimetidine. Also improvement of symptoms is more quickly achieved with these agents. They also

produce more rapid healing of ulcers than the standard H2-receptor antagonists. Three meta-analyses of over 1000 patients in more than 30 randomized studies have demonstrated a gastric and duodenal ulcer healing rate of 85% at four weeks and 96% at eight weeks (195–197). Antacids and H2-receptor antagonists should not be used in combination with PPIs because these agents require an acidic environment within the gastric lumen in order to become activated and bind to the proton pump at the secretory canaliculus. The utilization of antacids or H2-receptor antagonists in combination with PPIs could have deleterious effects by promoting an alkaline environment and thereby preventing activation of the PPI. The medical management of ZES is another indication for the use of PPIs. Sucralfate. Sucralfate is an additional agent that has been evaluated and used for prophylaxis against stress gastritis as well as peptic ulcer disease. Sucralfate is the aluminum salt of sucrose octasulfate. For sucralfate to be activated, it needs to be in an environment of acidic pH. At a pH below 3.5, sucralfate polymerizes into a viscous gel that has the ability to coat the ulcer and adhere to the gastroduodenal mucosa. Although the exact mechanism of sucralfate is still debated, some of its mechanisms of action appear to be by providing a protective barrier through inhibiting the actions of pepsin, binding bile salts, and increasing the production of mucosal prostaglandins, bicarbonate, and mucus, and microvascular blood flow. Sucralfate has also been shown to bind epidermal growth factor, delivering it to the gastroduodenal mucosal layer. Studies in animals and humans have also demonstrated that sucralfate stimulates the proliferation of epithelium at ulcer margins. Because sucralfate has no systemic absorption, it has a benefit of not interacting with the metabolism of other medications. Likewise, sucralfate is recommended for the treatment of peptic ulcer in pregnancy or in those patients who need long-term antiulcer therapy. Gastric and duodenal ulcer healing after four to six weeks of treatment with sucralfate (1 g q.i.d.) is superior to placebo and comparable to H2-receptor antagonists such as cimetidine (198,199). Similar healing rates have been reported with twice daily dosing (2 g b.i.d. 30 minutes before breakfast and at bedtime). At least one study has also shown that sucralfate is as efficacious as maximal H2-blocker therapy for gastric stress ulceration prophylaxis and would save approximately $30,000/ICU bed/yr in patient charges versus H2-receptor antagonists (109). Treatment of H. pylori Infection. There are three major goals for treating patients with ulcer disease. First, symptoms need to be relieved. Second, the ulcer needs to be healed, and third, one must prevent recurrence. Antisecretory agents with acid suppression have traditionally achieved the first two goals. With NSAID-related ulcers, discontinuation of NSAIDs achieves the third goal. However in the setting of non-NSAID ulcers, which are usually secondary to H. pylori, eradication of H. pylori can also almost completely prevent recurrence of ulcers. For duodenal ulcers, the recurrence rate following successful healing is roughly 72% if no additional therapy is employed. If H2-receptor antagonists are used as maintenance therapy, patients still have a 25% recurrence rate (153). However, if H. pylori is eradicated, only 2% of the patients have an ulcer recurrence (153,161). The gold standard in the past for eradicating H. pylori was triple therapy in combination with a bismuth-based therapy for two weeks. However, various triple regimens for H. pylori eradication have emerged. Most of these employ

Chapter 15: Gastric Physiology and Acid-Peptic Disorders

a PPI in combination with antibiotics such as metronidazole, chlorythromycin, or amoxicillin. These regimens are one to two weeks in duration, have the advantage of not containing bismuth, and are only given twice a day. Some of these triple regimens are currently available in a packet such as Helidac and are taken anywhere from 7 to 10 days to 2 weeks. Eradication rates for these new triple regimens are in the 80% to 95% range. For acute ulcers, all three drugs are given for one week, followed by two additional weeks of a PPI alone, or treatment for four to six weeks with a full-dose H2-receptor antagonist. In February of 1994, the NIH convened a consensus conference on H. pylori in peptic ulcer disease. At this conference, a number of recommendations were made (Table 4) (200). All patients with gastric or duodenal ulcers who were infected with H. pylori should be treated, regardless of whether first presentation or recurrence. H. pylori–infected ulcer patients receiving maintenance treatment or with a history of complicated or refractory disease should also be treated. They added that there was no reason to consider routine detection or treatment in the absence of ulcers and concluded that NSAID use should not alter treatment. The NSAID should be discontinued if possible, but if H. pylori is present, H. pylori should be treated. For patients with complications such as bleeding or perforation, documentation of eradication was imperative. Again, this is most easily performed with a urea breath test. Although not recommended by NIH, it is also appropriate to treat H. pylori– positive patients with MALT lymphoma for the previously mentioned reasons. Nevertheless some controversial treatment issues still exist. In nonulcer dyspepsia, the infected patient who insists upon eradication of H. pylori needs to be advised of the benefits or lack of benefits H. pylori eradication might have because it is unlikely that eradication will improve symptoms, and it is possible that it will contribute to the emergence of antibiotic resistance. It is also important to remember that the success of therapy for H. pylori depends upon the correct use of the regimens. One cannot substitute ampicillin for amoxicillin and one cannot substitute doxycycline for tetracycline. Appropriate dosages need to be used, the recommended frequency of administration adhered to, and the duration of drug therapy enforced (200). For treatment of active NSAID ulcers, it is best to discontinue the NSAID if at all possible, while the ulcer is being treated. If patients must continue their NSAIDs, cotherapy with misoprostol, a prostaglandin analogue,

Table 4 NIH Concensus Panel Treatment Recommendations for Helicobacter pylori 1. Patients with active peptic ulcer disease who are H. pylori positive a. Use of NSAIDs should not alter treatment. b. Document eradication in those with complications. 2. Ulcer patients in remission who are H. pylori positive, including patients on maintenance H2-receptor antagonist therapy. 3. H. pylori positive–patients with MALT lymphoma. 4. Controversial issues in H. pylori positive–patients. a. First-degree relatives of gastric cancer patients. b. Immigrants from countries with high prevalence of gastric cancer. c. Individuals with gastric cancer precursor lesions (intestinal metaplasia). d. Nonulcer dyspepsia patients who insist upon eradication (benefit vs. risk). e. Patients on long-term antisecretory therapy for reflux disease. Abbreviations: NIH, National Institutes of Health; NSAIDs, non steroidal antiinflammatory drugs; MALT, mucosal-associated lymphoid tissue.

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might be of benefit (201,202). Testing should be performed for H. pylori and if present treatment administered. For patients with gastric ulcers, PPIs have been shown to be more effective that H2-receptor antagonists in patients taking NSAIDs (201,202). Approach to the Patient Bleeding from Peptic Ulcer Disease. Approximately 80% of upper GI bleeds are selflimited. The overall mortality of 8% to 10% for those who continue to bleed or in whom bleeding recurs has not changed dramatically over the last several decades despite an older and probably sicker patient population. The initial step in management is adequate initial and ongoing resuscitation. Following resuscitation, endoscopy is performed to assess the cause and severity of the bleed, which will dictate the required intensity of therapy and predict the risk of further bleeding and/or death. Several factors are associated with continued or recurrent bleeding and increase the risk of mortality. Most studies have demonstrated that mortality increases with age such as the ASGE study, which found a mortality of 8.7% for patients 60 years old or less and 13.4% for those above 60 years (119,120). The severity of the initial bleed is also an adverse prognostic factor and this might include the presence of shock, a high transfusion requirement, or bright red blood in the nasogastric tube or in the stool (119,120). Interestingly, recurrent bleeding increased the mortality rate from 7% to a range of 30% to 40% (119,120,167). The onset of bleeding in a hospital was also associated with a higher mortality rate (33%) compared to those who bled outside of the hospital or prior to admission (7%). In the ASGE study, the absence of any concomitant disease was associated with a mortality rate of 2.5%. If there were three concomitant diseases, the mortality rate rose to 14.6%. With six concomitant diseases, the mortality rate rose to 66.7% (119,120). Stigmata of recent hemorrhage from peptic ulcers also represent an adverse prognostic sign. These stigmata included a visible vessel on endoscopy, oozing of bright red blood, and fresh or old blood clot at the base of the ulcer (119,120). When a visible vessel was seen, it was associated with a 50% rebleeding rate, while other signs were associated with a lower rebleeding rate of about 8% (119,120). In the ASGE study, pumping or oozing lesions had a significantly greater mortality (16%) and need for surgery (24%), when compared to those with clot or no blood (mortality 6.7%, surgery 11%) (119,120). In addition, patients undergoing emergency surgery had a 30% mortality rate compared to 10% for those undergoing elective surgery (119,120). Mortality also rises with increased severity of bleeding, which correlates with transfusion requirement. If no units are transfused, the mortality rate is approximately 2%, for one to three units, approximately 5%, for four to six units, approximately 12%, for seven to nine units, approximately 15%, and when more than 10 units are used, the mortality rate rises to approximately 35% (119,120). A pumping or oozing lesion in the ASGE study was associated with a transfusion requirement greater than five units (37.6%), which was significantly different when compared to patients who had a clot or no blood on the lesion (119,120). In the latter group, only 20% required more than five units of blood. The risk of rebleeding in a patient with no active bleeding and overlying clot varies from 8% to 30%. The visible vessel is regarded as the one stigma of recent hemorrhage that is associated with the highest incidence of rebleeding. In patients with a visible vessel, rebleeding occurred in 56% of patients compared to 8% in those with oozing and 0% in with no stigmata of recent

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hemorrhage (119,120). Mortality was also limited to those patients with visible vessels. Endoscopy remains the investigation of choice for patients with upper GI bleeding from peptic ulcer disease. Bleeding can be controlled with a variety of modalities, including thermotherapy (heater probe, multipolar or bipolar electrocoagulation) as well as injection of ethanol or epinephrine solutions. After bleeding is controlled, long-term medical therapy includes antisecretory agents usually in the form of a PPI plus testing for H. pylori, with treatment if positive. If H. pylori is present, documentation of eradication should be performed following therapy. If the bleeding continues or recurs, surgery may be indicated, and this will be discussed under duodenal and gastric ulcer disease individually. Surgical Procedure for Peptic Ulcer and Its Complications Indications for surgery in peptic ulcer cases are intractability, hemorrhage, perforation, and obstruction. Elective surgery for intractability is becoming more and more rare as medical therapy becomes more effective. The recognition of H. pylori and its eradication suggest that the intractability indication for surgery may apply only to patients in whom the organism cannot be eradicated or who cannot be taken off NSAIDs. In contrast to uncomplicated ulcers, the incidence of ulcers with complications requiring surgery does not seem to have diminished, and therefore familiarity with the various methods for treating bleeding, perforation, and obstruction is essential. The surgical options are shown in Figure 17. Specific recommendations are depicted in Table 5. One goal of ulcer surgery is to prevent gastric acid secretion. Subtotal gastrectomy was considered optimal management for duodenal and gastric ulcers until Dragstedt’s description of vagotomy and its impact on ulcer healing and recurrence (203). As described below, there are three levels of vagotomy that can be performed and these are shown in Figure 17. Vagotomy decreases peak acid

output by approximately 50%, while vagotomy plus antrectomy, which removes the gastrin-secreting portion of the stomach, decreases peak acid output by approximately 85%. Truncal Vagotomy. As shown in Figure 17, truncal vagotomy is performed by division of the left and right vagus nerves above the hepatic and celiac branches just above the GE junction. Most surgeons employ some form of drainage procedure in combination with truncal vagotomy. Usually it is combined with a Heineke-Mikulicz pyloroplasty, although when the duodenal bulb is scarred, a Finney’s pyloroplasty or Jaboulay gastroduodenostomy may be necessary. From a technical standpoint, truncal vagotomy with pyloroplasty represents an uncomplicated procedure that can be performed quickly. Highly Selective Vagotomy (Parietal Cell Vagotomy). The highly selective vagotomy is also called the parietal cell vagotomy or the proximal gastric vagotomy. This procedure was developed after recognition that truncal vagotomy in combination with a drainage procedure or gastric resection adversely affected the pyloral antral pump function. This procedure divides only the vagus nerves supplying the acid-producing portion of the stomach gastric within the corpus and fundus. This procedure preserves the vagal innervation of the gastric antrum so that there is no need for routine drainage procedures (Fig. 17). Consequently, there are fewer postoperative complications. Ideally, two or three branches to the antrum and pylorus should be preserved. The ‘‘criminal nerve of Grassi’’ represents a very proximal branch of the posterior trunk of the vagus and great attention needs to be taken to avoid missing this branch in the division process because it predisposes for ulcer recurrence if left intact. The recurrence rates following highly selective vagotomy are variable and depend on the skill of the operator and the duration of follow-up. Lengthy longitudinal follow-up is

Figure 17 Surgical approaches to treat peptic ulcer disease.

Chapter 15: Gastric Physiology and Acid-Peptic Disorders

Table 5 Surgical Treatment Recommendations for Complications Related to Peptic Ulcer Disease 1. Duodenal ulcer a. Intractable—parietal cell vagotomy b. Bleeding—truncal vagotomy with pyloroplasty and oversewing of bleeding vessel c. Perforation—patch closure with treatment for Helicobacter pylori d. Obstruction—rule out malignancy and parietal cell vagotomy with gastrojejunostomy 2. Gastric ulcer a. Intractable—Type 1—distal gastrectomy with Billroth I. Type 2 or Type 3—distal gastrectomy with truncal vagotomy b. Bleeding—Type 1—distal gastrectomy with Billroth I—Type 2 or Type 3—distal gastrectomy in combination with truncal vagotomy c. Perforated—Type 1—stable, distal gastrectomy with Billroth I; unstable; biopsy, patch, and treatment for H. pylori—Type 2 and Type 3—patch closure with treatment for H. pylori d. Obstruction—rule out malignancy and parietal cell vagotomy with gastrojejunostomy e. Type 4 depends on ulcer size, distance from the GE junction and degree of surrounding inflammation. See text f. Giant gastric ulcers—distal gastrectomy with vagotomy reserved for Type 2 and Type 3 gastric ulcers Abbreviation: GE, gastroesophageal.

necessary to evaluate the results of this procedure because of the consistently reported rise in recurrent ulceration with time. Recurrence rates of 10% to 15% are reported for this procedure when performed by skilled surgeons (204–206). These compare very favorably with or are even slightly higher than those reported after truncal vagotomy in combination with pyloroplasty. However, truncal vagotomy with pyloroplasty is more commonly associated with postvagotomy dumping syndrome and postvagotomy diarrhea. The moderate ulcer recurrence rate with highly selective vagotomy is considered acceptable by many surgeons because recurrences in this scenario are usually responsive to medical therapy with PPIs. Interestingly, when the results of this procedure are broken down by the preoperative ulcer site, there appears to be strong data suggesting that prepyloric ulcers are more likely to be associated with recurrence than duodenal ulcers for unclear reasons (207,208). As a result, it may not be the procedure of choice for prepyloric ulcers. Truncal Vagotomy and Antrectomy. The most common indications for antrectomy or distal gastrectomy are gastric ulcer and large benign gastric tumors. Relative contraindications include cirrhosis, extensive scarring of the proximal duodenum, which leaves a difficult or tenuous duodenal closure, and previous operations on the proximal duodenum, such as choledochoduodenostomy. When done in combination with truncal vagotomy, the recurrence rate for ulceration after truncal vagotomy and antrectomy is approximately 0% to 2% (209,210). However, this low recurrence rate needs to be balanced against postgastrectomy and postvagotomy syndromes, which rarely occur following highly selective vagotomy, but appear in 20% of the patients undergoing this procedure. As shown in Figure 17, GI continuity after distal gastrectomy can be accomplished by either a gastroduodenostomy (Billroth I) or gastrojejunostomy (Billroth II). For benign diseases, gastroduodenostomy is usually favored because it avoids the problem of retained antrum syndrome, duodenal stump leak, and afferent loop obstruction associated with gastrojejunostomy following resection. If the duodenum is significantly scarred,

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gastroduodenostomy may be technically more difficult necessitating gastrojejunostomy. If a gastrojejunostomy is performed, the loop of jejunum chosen for anastomosis is usually brought through the transverse mesocolon in a retrocolic fashion rather than in front of the transverse colon in an antecolic fashion. The retrocolic anastomosis minimizes the length of the afferent limb and decreases the likelihood of twisting or kinking, which could potentially lead to afferent loop obstruction and predispose to the devastating complication of a duodenal stump leak. Although vagotomy and antrectomy are clearly effective at managing ulcerations, they are used infrequently today in the treatment of patients with peptic ulcer disease, as described below. In general, operations of lesser magnitude are performed more frequently in the H. pylori era. The overall mortality rate for antrectomy is about 2% but is obviously higher in patients with comorbid conditions such as insulin-dependent diabetes or immunosupression. Approximately 20% of patients develop some form of postgastrectomy and/or postvagotomy complications. Subtotal Gastrectomy. Subtotal gastrectomy is rarely performed today for treatment of patients with peptic ulcer disease. It is usually reserved for patients with underlying malignancies or patients who have developed recurrent ulcerations following truncal vagotomy and antrectomy. The latter scenario assumes that medical therapy has been unable to heal the recurrent ulcer and that ZES has been ruled out. Following subtotal gastrectomy, restoration of GI continuity can be accomplished with either a Billroth II anastomosis or via a Roux-en-Y gastrojejunostomy. Laparoscopic Procedures. Not surprisingly, since the advent of laparoscopic cholecystectomy, many surgeons have applied minimally invasive surgical approaches to gastric surgery. Both parietal cell vagotomy and posterior truncal vagotomy with anterior seromyotomy (Taylor procedure) can be accomplished laparoscopically and represent effective antiulcer operations. However, long-term results are still unavailable for comparison with those of the openly performed procedures. Dumping syndrome and postvagotomy diarrhea have similar incidence rates to that observed after open highly selective vagotomy. Major concerns regarding this operation relate primarily to its efficacy in the prevention of recurrent ulcers. Because incomplete innervation predisposes patients to recurrent ulcerations following highly selective vagotomy, anterior seromyotomy might place patients at risk for recurrence due to failure to completely denervate the parietal cell mass. Laparoscopic approaches can also be used for repair of simple perforations by omental patching and offer clear advantages as opposed to the formal laparotomy required in open procedures (211). Surgical Indications Surgical therapy serves several purposes. It salvages patients from life-threatening complications associated with perforation, hemorrhage, and gastric outlet obstruction. It provides cure for the disease in the form of protection from recurrence, and it rules out the potential for malignancy in the case of gastric ulcerations. The indications for surgery are intractable abdominal pain, bleeding, perforation, and obstruction. For all ulcers being considered for elective surgery, antisecretory agents should probably be discontinued for about 72 hours prior to operation to allow gastric acidity

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to return to normal levels, which minimizes bacterial overgrowth and the extent of contamination. Intractable Duodenal Ulcer. Intractability implies failure of an ulcer to heal after an initial trial of 12 weeks of therapy or a relapse in patients once therapy has been discontinued. Although rarely seen today, intractable duodenal ulcer should be treated by parietal cell vagotomy. While this can be performed openly, many prefer a laparoscopic approach. The laparoscopic technology available to us today allows us to perform parietal cell vagotomy in exactly the same way it is performed openly and probably provides better visualization. Proximal gastric vagotomy is associated with a morbidity of less than 1% and a mortality of less than 0.5%. Unfortunately, the recurrence rate is roughly 5% to 25% (212–214). Some surgeons prefer a Taylor procedure in which the posterior truncal vagotomy is performed laparoscopically and then an endoscopic GI stapler is used to perform a seromyotomy across the anterior portion of the stomach to divide all the vagal fibers coursing through the seromuscular layer. Although some are concerned about dividing vagal innervation to the celiac ganglion and to the rest of the viscera, there is considerable evidence that preserving vagal innervation of the celiac axis and small bowel does little to reduce the side effects of vagotomy. Thus, the Taylor procedure appears to be equivalent to parietal cell vagotomy and the side effects are not any greater. Taylor has published data that suggest that anterior lesser curve seromyotomy and posterior truncal vagotomy result in acid suppression that is similar in magnitude to that achieved following highly selective vagotomy or truncal vagotomy with drainage (215,216). Gastric emptying following the Taylor procedure is also similar to that of highly selective vagotomy (increased emptying of liquids and normal emptying of solids), and dumping and diarrhea are less than that observed following truncal vagotomy and drainage (216). Intractable Gastric Ulcer. Type 1 Gastric Ulcer. For Type 1 gastric ulcers, malignancy remains a major concern and excision of the ulcer is mandatory. Distal gastrectomy is probably the best operation in this clinical situation. Reestablishment of intestinal continuity can be performed with a Billroth I or Billroth II, but again, a Billroth I is the preferred choice, providing malignancy has been ruled out. The morbidity associated with a distal gastrectomy without vagotomy and Billroth I reconstruction is approximately 3% to 5% for elective treatment of Type 1 gastric ulcers. Mortality ranges from 1% to 2% and is associated with recurrence rate of less than 2%. It is important to remember, however, that the presentation of a nonhealing gastric ulcer in the H. pylori era should raise serious concerns about the presence of underlying malignancy. If malignancy is encountered, a subtotal gastrectomy with a Billroth II gastrojejunostomy or Roux-en-Y gastrojejunostomy should be performed. Vagotomy is usually not necessary for the Type 1 gastric ulcer because it is not dependent upon gastric acid. Although technically more difficult, a parietal cell vagotomy with wedge excision of the ulcer could also be performed. However, because intractable peptic ulcer disease is so uncommon, it is important to insure that adequate time has elapsed and appropriate therapy has been administered to allow healing of the ulcer to occur. This includes confirmation that H. pylori has been eradicated and that NSAIDs have been eliminated as a potential cause. Most patients with a Type 1 gastric ulcer should in fact heal following appropriate medical therapy.

Type 2 or Type 3 Gastric Ulcers. If Type 2 or 3 gastric ulcers have not healed and H. pylori has been eradicated, a distal gastrectomy in combination with vagotomy should be performed. Several studies suggest that patients undergoing highly selective vagotomy for Type 2 or Type 3 gastric ulcers have a worse outcome than those undergoing resection (205,206). The type of vagotomy performed in combination with the resection can be either a selective or truncal vagotomy. However, there are still some who advocate performing a laparoscopic parietal cell vagotomy and reserve resection for those who develop ulcer recurrence. Management of Type 4 gastric ulcers will be discussed separately. Bleeding Duodenal Ulcers. As a result of aggressive endoscopic management, there has been a significant reduction in the number of patients who require surgery to control their bleeding. The patients who come to surgery are usually sicker, more elderly, and more likely to have complications. Laine and Peterson demonstrated that you can treat endoscopically at least one recurrence of bleeding, with no increase in mortality and morbidity and have long-term control of hemorrhage in approximately half of the patients (217). However, these patients need to be observed closely and treatment with endoscopy needs to be as prompt and aggressive as possible. Although the therapeutic endoscopist is able to stop the bleeding and is confident that the bleeding can be managed endoscopically, the patient still requires therapy with a PPI and must undergo therapy for H. pylori after testing, including documentation of eradication after treatment. For those patients who continue to bleed, or who are referred by the endoscopist, the duodenal bleeding is usually controlled by opening the duodenum and oversewing the ulcer with a U stitch to stop bleeding from either the pancreaticoduodenal artery or gastroduodenal artery. After obtaining control of the bleeding an acid-reducing procedure is performed. As most of these patients are elderly, have bled a lot, and have some degree of hypotension, the more time consuming parietal cell vagotomy is usually not indicated. Instead, a truncal vagotomy with pyloroplasty is performed. Although not proven, there are some who advocate opening the duodenum, ligating the gastroduodenal vessel, closing the duodenum, and then eradicating H. pylori. The clear exception to this would be if the patient had received therapy in the past for H. pylori and failed or if the patient was known to be H. pylori negative. In this situation, an acid-reducing procedure is clearly indicated. Most surgeons would not perform any type of gastrectomy for a bleeding duodenal ulcer. Bleeding Gastric Ulcers. For bleeding Type 1 gastric ulcers, a distal gastrectomy with Billroth I anastomosis is usually performed. Some have advocated adding vagotomy for patients who continue to be on NSAIDs, although the data on this is likewise unclear. However, even if patients need to stay on NSAIDs, they should be given misoprostol, a prostaglandin analog, because it has been found to have a 40% reduction in serious GI complications in those patients who have to stay on NSAIDs (218). For Type 2 and Type 3 gastric ulcers, distal gastrectomy in combination with vagotomy is indicated. Perforated Duodenal Ulcers. For perforated duodenal ulcers, simple patching followed by eradication of H. pylori is indicated. However, this assumes that the patient is H. pylori positive and will be compliant with therapy to eradicate H. pylori. If the patient is known to be H. pylori negative,

Chapter 15: Gastric Physiology and Acid-Peptic Disorders

then an acid-reducing procedure (i.e., truncal vagotomy with pyloroplasty or parietal cell vagotomy) should be performed (124). Patch closure of the duodenum can be performed either laparoscopically or openly (211,219). In some cases, patients present with a sealed perforation. One of the first studies assessing this group of patients came out of Hong Kong, where a series of patients were treated prospectively and successfully with nonoperative management (220). These patients were hemodynamically stable and without signs of toxicity. Unfortunately, the patients who failed were the ones in whom it would be most desirable to use nonoperative management (i.e., the elderly and the very ill). In this situation, upper GI radiography must be performed to confirm that the ulcer is indeed sealed as suggested by Burn and Donovan (221). Nonoperative therapy in this situation would include treatment for H. pylori and acid suppression. For all perforated duodenal ulcer patients who are H. pylori positive, documentation of H. pylori eradication with a urea breath test is mandatory, and it is paramount that the patients are compliant with their medications to treat H. pylori regardless of whether they are managed surgically or nonoperatively. Perforated Gastric Ulcer. For perforated Type 1 gastric ulcers that occur in hemodynamically stable patients, distal gastrectomy with Billroth I reanastomosis is indicated. However, simple patching of the gastric ulcer, testing for H. pylori, and treatment if positive, can also be considered. However, the risk of malignancy needs to be ruled out and therefore biopsy of the ulcer bed also needs to be performed. In addition, even if initial biopsies are negative, documentation of healing needs to be undertaken at a later date with repeat endoscopy and rebiopsying of the ulcer if it has not healed. Adding vagotomy for perforated Type 1 gastric ulcers is unlikely to be of any value. Because Type 2 and Type 3 gastric ulcers behave like duodenal ulcers, they can be simply treated with patch closure followed by treatment for H. pylori, provided the gastric ulcer is biopsied. Again, this assumes that patients are H. pylori positive. Gastric Outlet Obstruction. Gastric outlet obstruction is more common with duodenal and Type 3 gastric ulcers, but can occur in patients with a Type 2 ulcer. Obstruction is an unusual presentation for Type 1 gastric ulcers and its presence should suggest an occult malignancy. All patients with gastric outlet obstruction require preoperative nasogastric decompression for several days, correction of fluid and electrolyte imbalances, antisecretory therapy, and endoscopy with biopsies prior to surgical intervention. The first principle is to categorize the patient as either acutely or chronically obstructed. If the patient is acutely obstructed, the patient should be treated nonoperatively with nasogastric decompression, intravenous fluid, nutritional support as needed, and acid-suppressive therapy. H. pylori should be tested for and treated. On the other hand, if the patient has chronic gastric outlet obstruction, as might be the case from a chronic duodenal ulcer with fibrosis, operative therapy is usually indicated to open up the gastric outlet. In addition, an acid-reducing procedure is necessary. The preferred procedure for those patients presenting with a gastric outlet obstruction is parietal cell vagotomy with a gastrojejunostomy. Gastrectomy can be done if technically feasible. Alternatively, gastrojejunostomy with truncal vagotomy is also an option and technically much easier. The physiologic argument for doing the parietal cell vagotomy with a gastrojejunostomy as opposed to truncal vagotomy, is that it

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maintains innervation to the chronically obstructed antrum. As a result, the patient may have fewer chronic emptying problems than if you perform truncal vagotomy. The only randomized trial examining the management of operation for gastric outlet obstructions was done by Csendes et al. (222). He found that gastroduodenostomy in conjunction with a highly selective vagotomy yielded the poorest results of the three operations, in terms of symptomatic relief, the other two being selective vagotomy with antrectomy and highly selective vagotomy with gastroenterostomy. Endoscopic balloon dilatation has also been tried in this situation, although those who benefit from this procedure are likely those with acute gastric outlet obstruction and not those with chronic gastric outlet obstruction (223). These patients also require therapy for H. pylori. Type 4 Gastric Ulcers. The Type 4 gastric ulcer presents a difficult management problem (224). The surgical treatment depends upon the ulcer size, the distance from the GE junction, and the degree of surrounding inflammation. Whenever possible, the ulcer should be excised. The most aggressive approach would be to perform a distal gastrectomy including a small portion of the esophageal wall and ulcer with a Roux-en-Y esophagogastrojejunostomy to restore intestinal continuity. For Type 4 gastric ulcers that are located 2 to 5 cm from the GE junction, a distal gastrectomy with a vertical extension of the resection to include the lesser curvature with the ulcer can be performed. After resection, bowel continuity is restored with an end-to-end gastroduodenostomy. Some have even advocated leaving the ulcer in place or locally excising it in conjunction with the truncal vagotomy and pyloroplasty. Giant Gastric Ulcers. Giant gastric ulcers are defined as ulcers with a diameter of 3 cm or greater. They are usually found on the lesser curvature and only 4% occur along the greater curvature. It is not uncommon for these ulcers to penetrate into contiguous structures such as the spleen, pancreas, liver, or transverse colon, and be falsely diagnosed as unresectable malignancy, despite normal biopsy results. The incidence of malignancy probably ranges from 6% to 30% and increases with the size of the ulcer. Giant gastric ulcers have a high likelihood of developing complications (i.e., perforation, bleeding, etc.), and therefore early operation is thought to be the treatment of choice. The operation of choice is resection including the ulcer bed, with vagotomy reserved for Type 2 and Type 3 gastric ulcers. In the high-risk patient with significant underlying comorbid conditions, a local excision combined with vagotomy and pyloroplasty may be considered; otherwise resection has the highest chance for successful outcome. Postoperative Complications Associated with Peptic Ulcer Disease Management. The overall mortality rate for vagotomy and pyloroplasty or a vagotomy with antrectomy is about 1% or less, whereas for highly selective vagotomy it is around 0.05%. Postoperative complications include bleeding, infection, and delayed gastric emptying, which can occur in roughly 5% of patients following vagotomy and pyloroplasty or vagotomy and antrectomy. Highly selective vagotomy has the lowest rate of associated complications, which occur in only about 1% of patients. In addition to these early complications, gastric surgery results in a number of physiologic derangements due to loss of reservoir function, interruption of the pyloric sphincter mechanism, and the type of gastric reconstruction and from vagal nerve transection.

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These disorders are collectively referred to as postgastrectomy syndromes. Although the physiologic derangements account for the majority of symptoms, there are also some psychological elements associated with the disease process, which remain poorly understood. Approximately 25% of the patients who undergo surgery for peptic ulcer disease subsequently develop some degree of postgastrectomy syndrome, although this frequency is much lower in patients who underwent highly selective vagotomy. Fortunately, only about 1% of them become permanently disabled from their symptoms. When these postgastrectomy symptoms develop, it becomes more apparent that every attempt should be made to avoid reoperation because many of these patients lack a clearly mechanical or physiological defect, and because many of the problems persist despite reoperation. If reoperation is attempted, it should not be performed until an adequate trial of conservative therapy has been administered and for an adequate period of time. A detailed discussion of these postgastrectomy syndromes can be found in the Chapter on Alterations in Gastrointestinal Function Secondary to Previous Operation.

SUMMARY The stomach is the first organ to participate in the digestive process following the ingestion of a meal. Upon receiving food, it acts as a giant reservoir by accommodating large quantities through a process known as receptive relaxation. It then becomes a mixing bowl in which repetitive contraction and relaxation of the gastric musculature enables churning and food liquification in an environment of acid and pepsin secretion, so that the resultant gastric chyme, which consists of partially digested protein and emulsified fat, is ready for further processing after discharge into the proximal duodenum. These actions are all accomplished through an intricate and complex relationship involving exocrine, endocrine, paracrine, and neurocrine pathways. Under most circumstances, the balance among these various physiologic processing units is exquisitely controlled, so that the resultant acid chyme is not damaging to the lining of the stomach or the first portion of the duodenum. Occasionally, this balance is perturbed by bacterial infestation with H. pylori, excessive use of mucosal damaging agents such as NSAIDs or an endocrinopathy like ZES. The result of all of these aberrations is an inability of the gastric and/or duodenal mucosa to resist the damaging effects of the stomach’s secreted acid and pepsin. Fortunately, major breakthroughs in our understanding of acidpeptic disorders over the past two to three decades has enabled effective management of many of these diseases and even cure in some. In contrast to 30 years ago, when surgical intervention with vagal denervation and various degrees of gastric resection were the only means of controlling acid/peptic disorders, most patients can now live meaningful lives that are productive and pain free using a variety of nonoperative treatment strategies.

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192. Palmer RH, Frank WO, Karlstadt R. Maintenance therapy of duodenal ulcer with H2-receptor antagonists—a meta-analysis. Aliment Pharmacol Ther 1990; 4:283–294. 193. Der G. An overview of proton pump inhibitors. Gastroenterol Nurs 2003; 26:182–190. 194. Robinson M, Horn J. Clinical pharmacology of proton pump inhibitors: what the practising physician needs to know. Drugs 2003; 63:2739–2754. 195. Bamberg P, Caswell CM, Frame MH, Lam SK, Wong EC. A meta-analysis comparing the efficacy of omeprazole with H2-receptor antagonists for acute treatment of duodenal ulcer in Asian patients. J Gastroenterol Hepatol 1992; 7:577–585. 196. Eriksson S, Langstrom G, Rikner L, Carlsson R, Naesdal J. Omeprazole and H2-receptor antagonists in the acute treatment of duodenal ulcer, gastric ulcer and reflux oesophagitis: a meta-analysis. Eur J Gastroenterol Hepatol 1995; 7:467–475. 197. Poynard T, Lemaire M, Agostini H. Meta-analysis of randomized clinical trials comparing lansoprazole with ranitidine or famotidine in the treatment of acute duodenal ulcer. Eur J Gastroenterol Hepatol 1995; 7:661–665. 198. Rey JF, Legras B, Verdier A, Vicari F, Gorget C. Comparative study of sucralfate versus cimetidine in the treatment of acute gastroduodenal ulcer. Randomized trial with 667 patients. Am J Med 1989; 86:116–121. 199. Pop P, Nikkels RE, Thys O, Dorrestein GC. Comparison of sucralfate and cimetidine in the treatment of duodenal and gastric ulcers. A multicenter study. Scand J Gastroenterol Suppl 1983; 83:43–47. 200. Summary of the NIH consensus. Helicobacter pylori in peptic ulcer disease. Md Med J 1994; 43:923–924. 201. Hooper L, Brown TJ, Elliott R, Payne K, Roberts C, Symmons D. The effectiveness of five strategies for the prevention of gastrointestinal toxicity induced by non-steroidal anti-inflammatory drugs: systematic review. BMJ 2004; 329:948. 202. Rostom A, Dube C, Wells G, et al. Prevention of NSAIDinduced gastroduodenal ulcers. Cochrane Database Syst Rev 2002:CD002296. 203. Dragstedt LR. Gastric vagotomy in the treatment of peptic ulcer. Postgrad Med 1951; 10:482–490. 204. Chan VM, Reznick RK, O’Rourke K, Kitchens JM, Lossing AG, Detsky AS. Meta-analysis of highly selective vagotomy versus truncal vagotomy and pyloroplasty in the surgical treatment of uncomplicated duodenal ulcer. Can J Surg 1994; 37: 457–464. 205. Ihasz M, Batorfi J, Balint A, et al. Long-term clinical results of highly selective vagotomy performed between 1980 and 1990. Surg Today 1996; 26:546–551. 206. Enskog L, Rydberg B, Adami HO, Enander LK, Ingvar C. Clinical results 1–10 years after highly selective vagotomy in 306 patients with prepyloric and duodenal ulcer disease. Br J Surg 1986; 73:357–360. 207. Popiela T, Turczynowski W, Karcz D, Legutko J, Zajac A. Longterm results of highly selective vagotomy in the treatment of duodenal ulcer patients using the intra-operative endoscopic congo red test to identify the parietal cell antrum-corpus borderline. Hepatogastroenterology 1993; 40:267–271. 208. Adami HO, Enander LK, Enskog L, Ingvar C, Rydberg B. Recurrences 1 to 10 years after highly selective vagotomy in prepyloric and duodenal ulcer disease. Frequency, pattern, and predictors. Ann Surg 1984; 199:393–399. 209. Hubert JP Jr, Kiernan PD, Beahrs OH, ReMine WH. Truncal vagotomy and resection in the treatment of duodenal ulcer. Mayo Clin Proc 1980; 55:19–24. 210. Koo J, Lam SK, Chan P, et al. Proximal gastric vagotomy, truncal vagotomy with drainage, and truncal vagotomy with antrectomy for chronic duodenal ulcer. A prospective, randomized controlled trial. Ann Surg 1983; 197:265–271. 211. Siu WT, Leong HT, Law BK, et al. Laparoscopic repair for perforated peptic ulcer: a randomized controlled trial. Ann Surg 2002; 235:313–319. 212. Donahue PE, Bombeck CT, Condon RE, Nyhus LM. Proximal gastric vagotomy versus selective vagotomy with antrectomy:

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SMALL AND LARGE INTESTINE

16 Physiology of Digestion and Absorption Bobby S. Glickman and Jon S. Thompson

There are important regional differences in fluid and electrolyte absorption in the gut. These are related to gradients in mucosal resistance, absorptive mechanisms, and cellular transporters. The jejunum absorbs water isosmotically secondary to Na-coupled nutrient absorption. The ileum absorbs NaCl and secretes bicarbonate, also isosmotically. Generally the small bowel absorbs large volumes of fluid along with nutrient solutes, but does not concentrate the intestinal luminal contents. The colon is capable of absorbing sodium against a concentration gradient resulting in the formation of a compact stool. Interestingly, just as fluid fluxes (secretion and absorption) vary along the length of the gut, there is also variation within the microscopic realm of the individual villi and crypts. Enterocytes, similar to other transport epithelia, have distinct apical (luminal) and basolateral (serosal) membranes, tight intercellular junctions, a sodium pump in the basolateral membrane, and a negative intracellular potential difference. As enterocytes mature and migrate from the crypt base to the villus tip, they express proteins favoring absorption versus secretion. Transport molecules such as sodium channels, sodium nutrient carriers, and sodium– hydrogen exchange (NHE) -3 have a greater density in villus cells, whereas the cystic fibrosis transmembrane regulator (CFTR), which is responsible for Cl secretion, is more dense at the base of the crypt. Thus, in general, net absorption occurs in the villi, while net secretion occurs in the crypts. As a consequence, intestinal diseases, which primarily affect the villi shift the balance of fluid transport in favor of secretory diarrhea (1). To be absorbed, solutes first must traverse the unstirred layer of water and mucous adjacent to the epithelium. The depth of the unstirred layer varies along the length of the gut and will influence the rate at which particularly large lipid-soluble molecules are absorbed. The depth of the layer is influenced by luminal contents and peristalsis. Two major routes for absorption of fluids and electrolytes across the epithelium of the intestine exist. One route is between the enterocytes, despite the ‘‘relatively’’ tight junctions, and the other is directly across the lipid bilayer membrane of the enterocytes via diffusion, carriers, or channels. The relative importance of these two pathways and others is currently being reevaluated. Paracellular permeability is a dynamic mechanism influenced by, primarily, the apical zona occludens, which can be altered by various agonists and cellular characteristics such as the volume. Water, low-molecular-weight solutes, and ions use this pathway, flowing passively along electrochemical and osmotic gradients. The paracellular route lacks directional specificity, and movement may occur into or out of the lumen depending on relative concentrations as long as the pathways are open. The tight junctions are

INTRODUCTION The gastrointestinal (GI) tract has the sole responsibility for extracting fuel from the environment along with the physical building blocks and chemicals necessary to build and run the machinery of the body. The normal human diet comprises approximately 2 L of water admixed with 400 g of carbohydrate, 100 g of protein, and 60 to 100 g of fat. The digestive process proceeds in the stomach by mechanical, acid, and enzymatic activity resulting in chyme production. The resultant slurry is introduced to the duodenum under the control of hormones sensitive to volume, osmolality, and acidity. The role of the small intestine, then, is to absorb ingested water, electrolytes, and nutrients as well as to absorb the additional water, electrolytes, and enzymes secreted by the intestinal tract for the digestive process. This occurs sequentially along the small intestine involving intraluminal, mucosal, and intracellular processes and differs significantly for the various nutrients. Assimilation of nutrients is a complex process that we are better appreciating at the molecular level through ongoing investigation. The physicochemical steps of digestion have been well characterized along with much of the membrane events resulting in absorption. Secretion and motility are intimately related to digestion and absorption with regulation via the intrinsic and extrinsic innervation of the GI tract and interdependence of the mesenteric vasculature, lymphatics, and regulatory polypeptides. Despite the complexity, digestion and absorption are very efficient processes that result in the delivery of 1 L of effluent containing less than 5% of ingested nutrient to the large intestine. Still, many states of dysregulation are poorly understood along with overall governing mechanisms coordinating the elements of normal digestion and absorption. While some technical triumphs such as intestinal transplantation have become a reality, other processes as ubiquitous as postoperative ileus remain incompletely understood and with few treatment options. This chapter presents the current understanding of the digestion and absorption of dietary contents.

FLUID AND ELECTROLYTE SECRETION AND ABSORPTION The average adult produces approximately 100 to 200 mL of stool water per day. Considering that the gut normally handles 10 L of fluid daily (1–2 L exogenous intake and the rest endogenous secretions), this organ exhibits a highly efficient mechanism for conserving salt and water. Changes in intestinal absorption and secretion of fluid and electrolytes may result in increased stool water and hence diarrhea. 369

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‘‘tighter’’ in moving distally from jejunum to colon allowing Na and water absorption against a gradient. Water movement occurs in response to osmotic gradients. Sodium is the principal ion driving absorptive flows, whereas active chloride secretion promotes the movement of water into the intestinal lumen. Nutrients have a crucial role in determining water transport. Carbohydrate malabsorption causes luminal retention of considerable osmotic force, while absorption of sugars and amino acids enhances water absorption. Sodium transport in the enterocyte is not only a major determinant of water flux but is also coupled to nutrient absorption through specific carriers (Fig. 1). The enterocyte actively pumps large amounts of sodium [using adenosine triphosphate (ATP) as energy] out of its own cytoplasm and into the underlying mucosal interstitium to be cleared away in equilibrium with the bloodstream. The pumps responsible for this process are located on the basal and lateral portions of the columnar enterocytes. This creates a relatively low concentration of cytosolic Na, so that the apical (i.e., brush border or luminal) portion of the enterocyte membrane can absorb Na along a favorable (‘‘downhill’’) electrochemical and diffusion gradient. Within this paradigm

are three basic mechanisms of Na entry across the apical membrane: (i) solute-coupled Na transport (e.g., to drive the uptake of amino acids and glucose), (ii) Cl-coupled Na transport (analogous to other solutes but for accumulation of intracellular Cl), and (iii) electrogenic sodium absorption independent of other solutes but facilitating water absorption. In all cases, the Na absorbed across the apical membrane is extruded across the basolateral membrane by the ATP-powered Na pump (1). Solute-coupled Na absorption allows for the accumulation of nutrients such as amino acids and glucose against a concentration gradient through linkage to ‘‘downhill’’ Na movement. This mechanism is influenced by luminal paracrine and systemic factors. A variety of transmembrane proteins act as carriers to shuttle the sodium ion, along with the cotransported molecule and surrounding water molecules, into the cellular space. The most prominent of these is labeled SGLT1. This 664 amino acid protein on the apical membrane is found exclusively in the small intestine, primarily in villus tip enterocytes. This transporter is responsible for half of the daily water reuptake in the intestine (2). Solute-coupled Na absorption is the mechanism of oral rehydration therapy used worldwide for cholera and related

Figure 1 Schematic depiction of Na-coupled nutrient and water transport across the intestinal brush border epithelium. Small open circles depict water molecules surrounding solutes. These water molecules are cotransported with the corresponding solute. The engine is the basolateral adenosine triphosphate–dependent Na pump, which expels Na from the cell and produces adenosine diphosphate as the spent fuel. Source: Illustration by Dr. Thompson.

Chapter 16: Physiology of Digestion and Absorption

endemics. The administration of oral solutions of dilute glucose or amino acids in combination with sodium allows water to be reclaimed as it follows these solutes across the membranes and between the ‘‘tight’’ junctions leaving the lumen (3). For every molecule of glucose absorbed, two molecules of Na and 225 molecules of water are absorbed as well (4,5). In fact, tight junctions are dilated by intraluminal glucose (6). The Cl-coupled Na absorption is more complex than the other solute-coupled transport systems. In fact, two distinct transporters work in concert to accomplish the task. One transporter exchanges Na for H (NHE), while the other exchanges Cl for HCO3. The net effect is the uptake of NaCl and export of a proton and HCO3, which effectively combine to form water and CO2 in the lumen (7,8). pH responses likely coordinate the two activities. Several NHEs have been identified. NHE-1 is localized to the basolateral membrane and regulates cell volume and pH. NHE-3 is an apical transporter found in villus cells, upregulated by glucocorticoids, and linked to growth factors. Na absorption that is not coupled to a solute or chloride is electrogenic because it involves net transfer of positive charge. Unlike the coupled transport systems that involve specialized protein carriers, this type of Na transport occurs through selective channels in the membrane that allow the passage of Na, but exclude other cations and anions. This absorptive pathway is most readily apparent in the distal colon and can be stimulated by mineralocorticoids and blocked by the diuretic amiloride. This mechanism accounts for the majority of sodium absorption between meals. Cl, the principal ion governing secretion, accumulates within intestinal cells above its electrochemical equilibrium. The permeability (conductance) of the apical membrane for Cl determines the rate of the anion’s movement across this membrane. The Cl conductance is controlled by several intracellular mediators: cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), inositol triphosphate, and calcium. Stimuli (e.g., cholera toxin, which raises cAMP or Escherichia coli, which raises cGMP) that increase any of these factors cause active Cl secretion and, secondarily, movement of water into the intestinal lumen. In addition to increasing the Cl conductance of the apical membrane, these mediators also block the Na–Cl cotransport system. This antiabsorptive effect favors fluid accumulation within the intestinal lumen and an increase in diarrhea. However, these agents have no effect on Na absorption coupled to solutes such as sugars or amino acids. The therapeutic implications of this observation have led to oral rehydration therapy. Defective Cl secretion can produce the opposite problem. The protein product of the cystic fibrosis (CF) gene, cystic fibrosis transmembrane conductance regulator (CFTR), is an apical transmembrane protein found in many tissues, notably respiratory and intestinal epithelia (9). CFTR is activated by intracellular cAMP and protein kinase A to open and allow Cl to move down its concentration gradient into the intestinal lumen; Na and water follow. In CF, a missense mutation leads to defective Cl secretion and consequently dehydrated secretions. In the GI tract, this may lead to obstruction of the intestinal lumen or pancreatic duct (10). In addition to the complex array of solute and nutrient transporters, which carry water to and fro across the brush border, water movement may be facilitated by specialized proteins known as aquaporins, which function as water channels (11). However, despite much recent attention, no direct

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evidence has shown a significant role for an aquaporin in intestinal transport of water or solutes in human physiology.

OVERVIEW OF DIGESTION Fundamentals The digestive process is both mechanical and chemical. Mastication occurs in the mouth along with the introduction of salivary amylase and lipase. After transport by deglutition and muscular propulsion through the esophagus, mechanical mixing and churning continue in the acidic environment of the stomach. Pepsin contributes to early protein breakdown within the stomach. The duodenum receives the acidic chyme via the pylorus, and pancreatic bicarbonate neutralizes the contents. Pancreatic enzymes continue the digestion of fats, carbohydrates, and proteins as described below. Bile salts are introduced simultaneously and potentiate lipid digestion and transport across the unstirred water layer. Absorption at various levels is schematically shown in Table 1. As transit continues through the small bowel, large volumes of fluid are exchanged, and brush border enzymes complement the luminal pancreatic enzymes and bile salts to complete digestion. The colon has some absorptive capacity but primarily processes the fecal waste into a convenient form.

Pancreatic Enzymes Detailed discussion of the exocrine pancreas is covered in chapter by Joehl on pancreas. For the purpose of understanding digestion of the nutrients in our food, a brief survey of the relevant enzymes is helpful. As in the salivary glands, the pancreas produces amylase in great abundance, which will cleave dietary starch (amylopectin) into three types of small subunits, which undergo final digestion by nonpancreatic enzymes attached to the intestinal brush border. The pancreas also secretes numerous proteases including trypsin, chymotrypsin, elastase, and carboxypeptidase. These enzymes cleave proteins into much smaller subunits of individual amino acids as well as dipeptides and tripeptides. These forms then undergo direct absorption or further cleavage at the brush border. Finally, dietary fat is digested under the influence of three additional pancreatic enzymes and a coenzyme: lipase (and colipase), phospholipase A2 and cholesterol esterase. Naturally, the acid-buffering Table 1 Nutrient Absorption Specificity at Different Sites in the Intestine Duodenum Carbohydrate Fat Protein Bile salts Minerals Copper Iron Calcium Magnesium Phosphorus Sodium Zinc Vitamins A, D, E, K B1 B12

þþ þþ þþ

Jejunum þþþ þþþ þþþ

Ileum

Terminal ileum

þ þ þ þþþ

þþ þþþ þþ þ þ þ

þ þþ þþþ þþþ þþþ þþþ þþ

þ þþ þþ þþ þþþ

þ þ

þþþ þþþ

þ þþ þþþ

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bicarbonate secretion from the pancreas also facilitates efficient function of these enzymes.

Biliary Secretions and Enterohepatic Circulation The products of enzymatic digestion of dietary fat remain relatively water insoluble. Bile salts provide the mechanism for bringing cholesterol, monoglycerides, fatty acids, and phospholipids into solution by forming micelles. The structure of bile salts is similar to cholesterol and, in fact, results from cholesterol modification. In addition to several alterations in stereochemistry, saturation, and side groups in the ring, the tail of the molecule is carboxylated to an acid form. This acid form is then conjugated with glycine or taurine to form the final bile salt. Conjugation prevents undesired reabsorption of the bile salt until it encounters specific receptors in the terminal ileum and increases its solubility. It is through this ileal reabsorption that bile salts are transported back to the liver, a process known as enterohepatic circulation (see below). Bile salts are detergents; like all detergents they are amphophiles, possessing both hydrophilic and hydrophobic regions. Placed in an aqueous solution, bile salts spontaneously form into a particular three-dimensional arrangement called a micelle, in which the hydrophilic regions of the molecules are directed outward and the hydrophobic regions inward, thereby shielded from the aqueous environment. Diglycerides and triglycerides are too bulky to be packaged in these micelles and must await lipase hydrolysis. Fat-soluble vitamins are also included in micelles. A bile salt pool of 2 g cycles through the enterohepatic circulation six times daily. Only 0.5 g is lost in the stool daily to be replaced by synthesis. There are two different mechanisms of bile acid absorption. Passive diffusion occurs throughout, while active carrier-mediated transport is limited to the terminal ileum. The ileal bile acid transport system comprises the active mechanism for reclaiming bile salts. The system has four key components. First, a basolateral Na-K ATPase generates a sodium gradient across the cell membrane. Second, this Na gradient drives a Na-coupled bile acid symporter, which carries the bile acid into the terminal ileal enterocyte. Third, a bile acid–binding protein within the cytoplasm reduces the activity of the bile acid to prevent injury to the cell and its organelles. Finally, a basolateral anion exchanger exports the conserved bile acid for portal circulation and eventual reuptake and excretion by the liver (12). Disruption of the enterohepatic circulation may result in malabsorption and/or diarrhea. Ileal resection or dysfunction (e.g., Crohn’s disease) blocks the reabsorption of bile acids. Even with small resections of the ileum ( < 100 cm), the passage of bile acids into the colon is increased. The dihydroxy bile acids are potent cathartics; they alter intestinal permeability and stimulate active electrolyte secretion (13). Because there is considerable hepatic synthetic reserve, the increased fecal loss is compensated for by increased production. Therefore steatorrhea is mild, and the diarrhea that occurs is caused by the secretory effect of bile salts on the colon. With larger ileal resections ( > 100 cm), the liver can no longer produce enough bile acid to compensate for the fecal loss. Bile salt secretion drops significantly, and the steatorrhea becomes more severe ( > 20 g/day of fat) because of inadequate micelle formation in the small bowel. Diarrhea results in this setting from the increase in colonic long-chain fatty acids, which like bile salts, stimulate secretion. The enterohepatic circulation may be significantly altered by medications or in certain specific clinical settings. Cholestyramine, for example, functions as a binding resin

and sequesters bile acids. Thus, diarrhea associated with unabsorbed bile acids can be treated. Ursodeoxycholic acid, naturally occurring in bear bile and used in cholestatic diseases and for prophylaxis of cholelithiasis, is itself a hydrophilic bile acid. Oral administration of ursodeoxycholic acid competitively inhibits the ileal absorption of endogenous hydrophobic bile acids such as chenodeoxycholic and deoxycholic acid. Ursodeoxycholate becomes the major component of the bile salt pool. The consequences are diverse, including resolution of cholestasis. Ursodeoxycholic acid is unlikely to cause diarrhea because it has only one alpha-hydroxyl group. Bacterial overgrowth may impact the enterohepatic circulation by causing deconjugation of bile acids. The resultant unconjugated bile acid forms are less soluble, and fat absorption may be impaired by limited micellar formation.

PROTEIN ABSORPTION Dietary protein accounts for 10% to 15% of calories and 70% of intestinal protein load; the remainder consists of secreted enzymes and sloughed cells. Protein digestion begins with denaturation by gastric acid. Pepsinogen, secreted by gastric chief cells, is converted to pepsin in this same acidic environment. Pepsin begins the breakdown of denatured proteins into polypeptide subunits. However, pepsin is not essential for normal protein digestion or absorption. Individuals who do not synthesize pepsin (e.g., because of pernicious anemia or gastrectomy) still absorb protein efficiently (14,15). The presence of amino acids in the duodenal lumen liberates cholecystokinin, which then stimulates the release of pancreatic enzymes. Most protein digestion occurs in the upper small bowel by the action of pancreatic proteases (Fig. 2). These proteases are secreted as proenzymes from the pancreas and are activated in the duodenum by the mucosal enzyme enterokinase and pancreatic trypsin. Protein is digested, by the secreted pancreatic endopeptidases and exopeptidases, to amino acids and small peptides. The endopeptidases (trypsin, chymotrypsin, and elastase) hydrolyze bonds in the interior of polypeptides. The resulting polypeptides of varying lengths are further digested by the exopeptidases. The pancreatic carboxypeptidases hydrolyze terminal amino acids from the carboxyl end of peptides, whereas aminopeptidases produced by intestinal cells hydrolyze the terminal amino acids from the amino end of peptides. Finally, dipeptidases on the epithelial brush border liberate individual amino acids from their substrate. Following enzymatic digestion, one-third of amino acids are absorbed as free amino acids, while the majority is absorbed in the form of dipeptides and tripeptides. These oligopeptides then undergo breakdown to free amino acids within the enterocyte. This intracellular hydrolysis occurs for 90% of absorbed oligopeptides. The transporter responsible for this uptake of small peptides, hPEPT1, two or three amino acids in length, has been identified. It works by cotransporting a proton along a favorable electrochemical gradient in concert with the peptide absorption (Fig. 3). The electrochemical gradient is generated by a separate but related antiport exchanger (NHE3), which expels hydrogen and allows entry of sodium (along its favorable gradient). Many medications taken orally (e.g., beta-lactams and angiotensin-converting enzymeinhibitors) also mimic these forms and are absorbed by the same mechanisms. Bacterial enterotoxins (e.g., E. coli) or medications (e.g., the potassium sparing diuretic amiloride) can

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Sequence of protein digestion Proteins

Polypeptides

Oligopeptides > FAAs

FAAs> Oligopeptides

FAAs

H S

S S

H S

Apical FAA transporters Oligopeptide transporters Brush border peptidases

Basolateral FAA transporters

Figure 2 Intraluminal and mucosal processing of peptides and amino acids. The sequence of protein digestion and peptide transport across the intestinal epithelium is shown. Many proteins contain several polypeptide subunits that associate closely by both noncovalent forces and covalent disulfide bonds. Disulfide bonds are broken allowing separation of peptide subunits in concert with denaturation to permit access for peptidases. Oligopeptides are transported by hPEPT1. The details of hPEPT1 function are seen in Figure 3. Free amino acids are transported by a variety of luminal and basolateral carriers. These are detailed in Tables 2 and 3. Source: Illustration by Dr. Thompson.

Na NHE3

Intact Oligopeptide H h Pep T1 oligopeptide

Free Amonia Acids Di and tri pepticlasses

Figure 3 Schematic function of the oligopeptide transporter hPEPT1. Most absorbed oligopeptides are subject to intracellular hydrolysis to free amino acids prior to metabolism or export. Source: Illustration by Dr. Thompson.

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inhibit NHE3, with resultant potential for decreased transport of peptides or peptidomimetic medications (16). Oligopeptides are primarily absorbed in the jejunum. Oligopeptide absorption by hPEPT1 is more robust and efficient than free amino acid absorption. Recognition of the oligopeptide transport pathway is essential for rational design of enteral feeding formulas. For example, an elemental type diet rich in di and tripeptides is more readily absorbed than one biased toward free amino acids. Consequently, the optimal formula for elemental nutrition will contain mostly oligopeptides instead of free amino acids. Free amino acids are generally absorbed in the ileum. Free amino acid transport across both the luminal and the basolateral membranes is quite complex. Each of these membranes utilizes transport proteins, which carry distinct or overlapping groups of free amino acids. The two membranes utilize distinct groups of carrier proteins. The luminal membrane harbors at least seven classes of transport proteins. Five of these transporters are dependent on the transmembrane Na gradient and two are independent. Table 2 lists the transporters and their substrates. Similarly, the basolateral membrane harbors at least five transporters of free amino acids. These are listed in Table 3. Amino acids (particularly glutamine) are also a significant energy source for enterocytes. About 10% of absorbed amino acids are utilized this way. Glutamine has been extensively studied for a possible therapeutic effect in many intestinal diseases as well as sepsis with multiorgan failure. Unfortunately there is limited evidence to support this role.

CARBOHYDRATE ABSORPTION Carbohydrate consumption accounts for the predominant form of caloric intake in most diets. Starch is a polysaccharide or complex carbohydrate and accounts for about one-third of total calories (two-thirds of carbohydrate calories) in a western diet. Amylopectin is the predominant form of starch followed by amylose. Disaccharides account for most of the remaining dietary carbohydrate. Sucrose (glucose–fructose), or table sugar, and lactose (glucose– galactose) from milk products are the main dietary disaccharides. Sucrose and lactose account for about 30% and 10% of dietary carbohydrate, respectively. Carbohydrates are absorbed as simple monosaccharides, following the necessary enzymatic degradation within the intestinal lumen and at the brush border cell surface. Glycogen is a

Table 3 Free Amino Acid Transporters Localized to the Basolateral Membrane of the Intestinal Epithelium Transporter Na gradient dependent . . . A ASC Na gradient independent . . . asc L yþ

Substrate Dipolar a-amino acids, imino acids Alanine, serine, cystine Alanine, serine, cystine Alanine, serine, glutamine, cystine Basic amino acids (lysine, arginine, ornithine)

minor component of the diet, but is the body’s major form of carbohydrate storage. Dietary fiber is a nondigestible polymeric form of glucose such as cellulose, hemicellulose, and pectin as well as oligosaccharide forms (raffinose and stachyose) found in legumes such as beans and lentils. Human beings lack the enzyme necessary for the hydrolysis of the particular linkages between the individual monosaccharide subunits. Unabsorbed dietary fiber not only increases fecal bulk, but also influences absorption of other nutrients. Fiber delays absorption of sugars and fat reducing the insulin response to a meal and lowers cholesterol levels by binding bile salts. Starch, the major form of dietary carbohydrate, is a polymer of glucose with a molecular weight of 100,000 or greater; i.e., one molecule of starch usually has more than 500 glucose subunits. The linkage between the glucose moieties determines the type of starch and its enzymatic degradation. Such types are classified by the spatial configuration of the glucosidic bond (alpha and beta) and the carbon atoms involved in the linkage (1,4 or 1,6). Amylose is a straight chain of alpha-1,4–linked glucoses. The most common form of dietary starch is the branched starch amylopectin, which consists of alpha-1,4 chains and branch points created by alpha-1,6 linkages at every 20 to 25 residues (Fig. 4). Glycogen is a branched starch like amylopectin, but it has a greater frequency of alpha-1,6 linkages. Digestion of starch begins in the mouth with the help of salivary amylase, but comes to a rapid halt in the acid environment of the stomach. Carbohydrate digestion is completed in the upper small bowel (primarily jejunum) and consists of two phases: intraluminal breakdown of starch and brush border hydrolysis of oligosaccharides

Table 2 Free Amino Acid Transporters Localized to the Luminal Surface of the Intestinal Epithelium Transporter Na gradient dependent . . . B B0,þ IMINO B X
AG Na gradient independent . . . b0,þ yþ

Substrate Dipolar a-amino acids Dipolar a-amino acids, basic amino acids, cystine Imino acids (proline, hydroxyproline) B-amino acids Acidic amino acids (aspartate, glutamate) Dipolar a-amino acids, basic amino acids, cystine Basic amino acids

Figure 4 Alpha-amylopectin and its final hydrolytic products are shown with glucose molecules (circles) joined by alpha-1,4 (horizontal) links or alpha-1,6 (vertical) links. Source: From Ref. 17.

Chapter 16: Physiology of Digestion and Absorption

(Fig. 5). Unlike oligopeptides, oligosaccharides require digestion to sugars for absorption. Pancreatic alpha-amylase is primarily responsible for intraluminal digestion of starch. Because it is secreted in great excess, clinically significant amylase deficiency is extremely rare, even in cases of severe pancreatic insufficiency. Alpha-amylase is active only at the interior alpha-1,4 bonds of starch. It cannot hydrolyze 1,6 links, 1,4 links next to branch points, or the terminal glucose–glucose links. Therefore the final products of amylase digestion are the disaccharide maltose, the trisaccharide maltotriose, and alpha-limit dextrins (i.e., larger oligosaccharides of 5–10 glucose units containing the branch points). Human amylase is inactive against beta-links; therefore cellulose, which is made up entirely of beta-1,4 links, is not digested. Maltose, maltotriose, and alpha-limit dextrins, along with dietary disaccharides, are broken down into simple sugars (monosaccharides) by specific brush border enzymes (18). These include the enzymes beta-galactosidase (lactase), glycoamylase, sucrase, isomaltase, and alpha-dextrinase (19). The sucrase and isomaltase subunits are cleaved from a single larger proenzyme by trypsin or elastin after transport to the brush border (20). The concentration of these brush border enzymes is greatest in the villus cells of the jejunum and upper ileum (21,22). The enzymatic function is present in abundance, and the absorption of the monosaccharides (glucose, galactose, and fructose) is the limiting factor. These sugars can accumulate in the lumen and inhibit the corresponding disaccharidase. The hydrolytic capacity of the brush border enzymes provides an excess of monosaccharides for the transport carrier. The exception to this is lactose absorption, where the hydrolytic capacity of lactase is rate limiting. In many parts of the world, lactase-phylorizin hydrolase activity declines early in life. Genetically programmed downregulation of the lactase gene is detectable in children from the second year of life independent of dietary content. When clinically symptomatic, lactase deficiency may be treated by dietary modification or lactase enzyme supplementation. A complex regulatory mechanism appears to coordinate the activity of the brush border enzymes and the corresponding transport proteins (23). Glucose and galactose are transported across the luminal membrane of the cell by a family of carrier proteins that couple the movement of sugar to sodium, SGLT1 (24). This transport mechanism is similar to Na-coupled amino acid absorption. In the later stages of absorption, intraluminal concentrations of sugars may decrease; however, because of the Na coupling, active transport of sugars against a concentration gradient can occur. A mutation in the sodium–glucose cotransporter gene (SGLT1) is an

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autosomal recessive trait producing severe diarrhea in newborn infants. A prompt clinical response is seen with treatment by elimination of lactose, glucose, and galactose from the diet (25). In contrast to the Na-coupled SGLT1, transport of glucose and galactose across the brush border, a group of carriers called GLUT (GLUT, glucose transport), mediates nonactive transport of substrates by facilitative diffusion. There are six GLUT species. Originally named for ‘‘glucose transporter,’’ this designation is somewhat misleading because fructose and galactose may be carried by certain species. Fructose absorption into the cell occurs by facilitated diffusion through GLUT 5. Although usually absorbed completely, fructose absorption capacity is limited. Because it is not concentrated against a gradient, unabsorbed fructose may serve as an osmotic load-drawing fluid into the isosmotic jejunum. This nutrient, present in soda, candy, fruit, and fruit juices as a sweetener, may result in bloating, abdominal pain, and diarrhea or excess flatulence. Analogous to lactose or sorbitol intolerance, fructose intolerance may explain these symptoms in susceptible individuals (26). The overall design of carbohydrate absorption is to deliver maximal amounts of calories while introducing the least possible osmotic force into the duodenum and jejunum, where carbohydrates are primarily absorbed. A molecule of starch and a molecule of glucose have the same osmotic effect but vastly different caloric value. Intraluminal digestion of starch stops at the oligosaccharide stage, limiting the osmotic effect. The rapid absorption of monosaccharides into the intestine after action by brush border enzymes minimizes the potential for drawing fluid into the jejunum and duodenum. Under normal conditions this system is extremely effective; when disrupted, malabsorption may be compounded by osmotic diarrhea. The enterocyte is not only responsible for nutrient uptake across its brush border but also delivery of the nutrient across the basolateral membrane to be available for systemic distribution. Once delivered into the cytosol, glucose can exit the cell across the basolateral membrane by two distinct mechanisms. Facilitated diffusion by glucose transporters (e.g., GLUT2) had long been thought to be the only significant pathway for glucose egress from the enterocyte; however, recent evidence demonstrates a second pathway of significant capacity. This route involves exocytosis of glucose packaged in vesicles (27). This newly recognized pathway may have significance in the genetic disease Fanconi–Bickel syndrome where mutant GLUT2 transporters result in glycogen storage and transport derangements (28). Fructose and galactose are exported from the enterocyte primarily by GLUT2 as well.

Figure 5 Carbohydrate digestion and absorption. The principal intraluminal event is starch digestion by amylase (left side of figure). The resulting maltose, maltotriose, and alpha-limit dextrins are broken down further by brush border enzymes, as are the disaccharides (crosshatched area). Specific active transport systems, coupled to Na, exist for glucose and galactose. Fructose is absorbed by facilitated diffusion. Source: Courtesy of G. Roddey, MD and J. H. Sellin, MD, from Chapter 18 of the Second Edition.

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FAT ABSORPTION Fat accounts for about 40% of caloric intake. Most fat (90%) is in the form of triglycerides, which consist of a glycerol backbone (three carbons long) and three fatty acids protruding like spokes. The fatty acids occur in varying lengths (i.e., number of consecutive carbon groups), and those of medium chain length (6–10 carbon units) are absorbed differently from the longer chains after enzymatic separation from the glycerol backbone. The next most common moiety in the diet is phospholipid, which is similar to triglycerides but one of the carbons on the glycerol backbone is linked to a polar phosphate moiety instead of a nonpolar fatty acid. Phospholipids are primarily present as the fundamental building block of cellular membranes (lipid bilayer). The strategy of lipid absorption essentially is designed to overcome the insolubility of nonpolar compounds in an aqueous medium. Absorption of a typical triglyceride containing longchain fatty acid branches is complex, requiring several steps (Fig. 6). Two of the side branches must be cleaved by the intraluminal enzymes, lipase and colipase. This leaves two free long-chain fatty acids and a long chain monoglyceride (one of the fatty acid branches still attached to the glycerol backbone). These subunits are then solubilized by bile salt micelles. The micelles facilitate delivery of the lipid products across the unstirred water layer and then the lipid bilayer of the enterocyte brush border. The micelle probably dissociates at the apical membrane during absorption. The bile salts and some cholesterol from any given micelle generally returns to the luminal phase for another round of emulsification after securing transport for the previous fatty acid cargo into the cell. Meanwhile, fatty acids, cholesterol, and monoglycerides can then permeate through the lipid regions of the apical membrane into the cell interior. In the absence of adequate bile salts, small droplets of hydrolyzed lipid products may permeate the unstirred water layer to reach the absorptive brush border. Diffusion into the cell by this route is favored chemically by the acidic microenvironment of the unstirred layer, which enhances solubility of the lipid molecules as they cross the bilayer cell membrane. Short- and medium-chain fatty acids traverse the brush border mainly by simple diffusion, while long-chain fatty acids enjoy dedicated carriers (FATP, fatty acid transport proteins). FATP 4 appears to be the major transporter (29–31). This molecule may be a target for antiobesity drug development. Once inside the enterocyte, fatty acid–binding proteins (FABPs) mediate transport to the endoplasmic reticulum for resynthesis of triglycerides. These FABPs prevent

their cargo from straying and joining unintended membranes and organelles prior to processing (32–34). Most of the fat in the diet is absorbed in the duodenum and proximal jejunum. Cells at the villus tip are primarily involved. The bile acids are recovered downstream in the terminal ileum after their emulsifying duties are complete. Unlike amino acids and sugars, lipids do not require a specific transmembrane carrier protein. Interestingly, once inside the epithelial cell, the lipid subunits are reassembled into triglycerides and cholesterol esters. Through a series of enzymatic steps in the endoplasmic reticulum, triglycerides are reformed and then accumulate within the Golgi apparatus. However, before exiting across the basolateral membrane of the cell, the triglycerides must be suitably packaged for transport in lymph. This process is chylomicron formation. Chylomicrons are large spheres (1000–5000 A) with a core of hydrophobic lipids, primarily triglycerides, which also include cholesterol, cholesterol esters, fat-soluble vitamins, and trace fats. The surface is covered by phospholipids and specialized apolipoproteins. Although these apolipoproteins cover less than a quarter of the surface and account for about 1% of the mass, they are essential for chylomicron formation and transport. These proteins are made in the intestine; their rate of synthesis appears to be stimulated by fat absorption. Congenital absence of a certain apolipoprotein (abetalipoproteinemia) prevents the exit step of chylomicrons across the basolateral membrane of the cell (35). Once in the subepithelial space, chylomicrons enter the central lacteal of the villus and the intestinal lymphatic system. Because of their size, they cannot pass through the relatively tight junctions of the capillaries and are therefore excluded from the portal system. The function of colipase is to expose the triglyceride target by displacing bile acids, while the lipase enzyme executes the hydrolytic cleavage reaction liberating the subunits as described. Without colipase, lipase function would be inhibited (36). Lipase has two sources: lingual (which is acid resistant) and pancreatic (which is present in great excess). Phospholipid digestion occurs similarly, but the pancreatic enzyme responsible is phospholipase A2. All of these processes are pH dependent, and thus pancreatic exocrine function is critical for the absorption of fat from the perspective of bicarbonate and enzyme secretion. Orlistat is an inhibitor of pancreatic and other lipases. It may be used in obesity to limit intestinal fat absorption (37,38). Cholesterol esterase is an enzyme responsible for cholesterol hydrolysis. This enzyme cleaves the esterified cholesterol molecule into its free lipophilic form, which then incorporates into the core of a micelle. One dietary source of fat comes replete with its

Figure 6 Fat digestion and absorption. Dietary fats, TG, and CE are emulsified to form fat droplets within the intestinal lumen. These droplets undergo a physiochemical transformation into a viscous isotrophic phase. At this stage, the TG is digested by pancreatic lipase. The resultant FFA and monoglyceride (MG), along with cholesterol (C), form mixed micelles with bile salts. The micelle then diffuses to the apical membrane. There are no brush border enzymes or specific membrane transport systems for fat absorption. Abbreviations: TG, triglycerides; CE, cholesterol esters; FFA, free fatty acids; MG, monoglyceride. Source: Courtesy of G. Roddey, MD and J. H. Sellin, MD, from Chapter 18 of the Second Edition.

Chapter 16: Physiology of Digestion and Absorption

own digestive enzyme. Human, but not bovine, milk contains a nonspecific lipase that is acid resistant, and therefore serves as an intestinal lipase for breast-fed infants with immature endogenous lipase production. Medium-chain triglycerides can be absorbed intact by the portal venous circulation. Alternatively, these same medium-chain triglycerides are readily hydrolyzed by lipase, and the fatty acid subunits are also absorbed directly into the portal circulation rather than the lymphatics. Consequently, medium-chain triglycerides can be theoretically used to advantage in the management of chylous ascites or chylothorax by supplying lipids via a route not dependent on lymph transport. Medium-chain triglycerides may also be absorbed more efficiently than other lipids in malabsorptive disorders. Short-chain fatty acids are produced during bacterial degradation of complex carbohydrates and proteins in the colon. These acids are absorbed similarly, and intracellular pH is balanced by the Na–H exchanger. Short-chain fatty acid uptake may provide an additional caloric source in patients with the short bowel syndrome (39).

VITAMINS AND MINERALS The fat-soluble vitamins (i.e., A, D, E, and K) are hydrolyzed, dissolved, and absorbed via bile salt dissolution similar to dietary fat. Both vitamin A (retinol) and beta carotene, the major dietary precursor of vitamin A, are absorbed by passive diffusion, as is vitamin D. Vitamin D (actually a precursor of the active metabolite forms) is derived primarily not only from endogenous sources through a sterol precursor but also from dietary sources. Vitamin E is ingested as alpha-tocopherol acetate prior to hydrolysis and micellar absorption. It is absorbed by passive diffusion in the small intestine. Dietary vitamin K is absorbed analogously, but is also formed endogenously in the colon as a bacterial product where it can be absorbed by colonocytes. Dietary (vegetable derived) vitamin K1 is absorbed through a carrier-mediated process in the small intestine facilitated by bile salts. Endogenous (bacteria derived) vitamin K2 is absorbed passively in the ileum and colon (40,41). The water-soluble B vitamins are absorbed by a variety of mechanisms. The smaller vitamins such as pyridoxine are absorbed by passive diffusion. Specific sodium-dependent active transport processes occur for thiamine, riboflavin, pantothenic acid, and biotin. Thiamine and riboflavin require energy-dependent phosphorylation and active transport. Vitamin B12 requires initial binding to salivary R proteins following liberation from foodstuff by gastric acid. Next the cobalamin is again liberated in the duodenum by pancreatic enzymes before its binding to intrinsic factor. Intrinsic factor is secreted by gastric parietal cells. Intrinsic factor protects the cobalamin molecule from degradation, and facilitates uptake by specific receptors in the terminal ileum. Cobalamin is a biologically precious molecule primarily extracted from meat. Human beings store enough reserve for several years, but deficiency ultimately results in megaloblastic anemia and neuropathy. Gastric or ileal resection or disease, gastric bypass, dietary insufficiency (vegetarian), or pancreatic insufficiency may each result in depletion of vitamin B12. After enterocyte uptake in the terminal ileum, cobalamin is complexed with transcobalamin for circulatory distribution. Vitamin C is best absorbed in the ileum, but its overall efficiency is low as a result of easy saturation of receptors. The receptors are active transport proteins that couple vitamin C absorption to Na gradients analogous to protein

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and carbohydrate uptake. Because of the easy saturation of its receptors, large doses of vitamin C are poorly absorbed. Folic acid consists of a pteroic acid moiety linked to l-glutamate. Most dietary folate is in a conjugated form, with a chain of several glutamates (polyglutamate folates). Absorption of folate depends on hydrolysis of the glutamic acid chain and subsequent transfer of the monoglutamyl product across the intestinal epithelium. The glutamic acid chain appears to be resistant to pancreatic digestive enzymes and is most likely broken down by brush border enzymes, which liberate free folic acid and amino acids. Polyglutamate folate, as such, is not absorbed (42). The rate-limiting step in folate absorption is entry across the apical membrane of the enterocyte. At low luminal concentrations of folate, a saturable, anion-exchange mechanism of facilitated diffusion exists. At high-luminal concentrations, passive diffusion becomes evident. Alterations in pH affect the rate of intestinal uptake of folate; the optimum is pH 6.5. The epithelial cells reduce methylate folate, releasing methyltetrahydrofolate into the portal blood. In addition to small bowel folate absorption, the colon has receptors for folate transport at the luminal level as well as the basolateral membrane to facilitate uptake and passage into the systemic circulation (43). A common transmembrane protein transporter has been identified in the absorption of many divalent cations including iron, zinc, manganese, cobalt, cadmium, copper, nickel, and lead. It has been named divalent cation transporter 1 and is richly expressed in the duodenum (44). Iron levels modulate expression of this transporter. Zinc appears to be both absorbed and secreted in the small intestine with only 5% to 10% of ingested zinc being absorbed. There is enterohepatic circulation with maximal absorption in the ileum. The rare condition acrodermatitis enteropathica results from a defect in the absorption of zinc caused by a mutation in the brush border zinc transport protein (45). Copper absorption occurs primarily in the stomach and duodenum by a receptor-mediated saturable process. Copper is secreted in bile. Magnesium appears to be absorbed passively in the distal small intestine. Phosphate is absorbed throughout the small intestine by active and passive mechanisms (46). Most dietary iron is complexed in the organic heme molecules of hemoglobin and myoglobin. Iron salts are less readily absorbed than these organic moieties. Ferric iron (Fe2þ) is more readily absorbed than ferrous iron (Fe3þ); thus, in the intestine, ferric iron is reduced to ferrous iron by ferrireductase or gastric acid, ascorbic acid, and certain amino acids. Phosphates and fiber may reduce iron availability. Hereditary hemochromatosis is an autosomal recessive trait characterized by hyperabsorption of iron. Mechanisms for iron excretion from the body are limited (i.e., iron is hard to get rid of once absorbed); so homeostasis is achieved by regulating the uptake to closely match requirements. Hemochromatosis is excessive uptake relative to the iron stores. A mutation in the causative gene, HFE, disturbs the enterocyte’s ability to limit absorption of luminal iron based on body stores, possibly reflected by transferring saturation (47,48). Calcium is absorbed actively in the duodenum by a transporter protein as well as passively by paracellular diffusion throughout the small intestine. Calbindin, a member of the calmodulin superfamily, is a protein that buffers the intracellular space from calcium flux. This prevents intracellular calcium from inappropriately triggering the vast machinery of kinases that are stimulated by free calcium. Calbindin also may function as a calcium sensor to regulate absorption in the intestine (49). Vitamin D enhances this

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process, when stores are low, by upregulating calbindin, basolateral calcium (ATP dependent) pumps, and brush border permeability (50–53). Calcium is primarily absorbed in the small intestine as detailed, but colonocytes also have the capacity for carrier-mediated uptake. The absorbed calcium is subsequently exchanged for Na at the basolateral membrane to facilitate exit from the cell and systemic distribution (43).

REGULATION Regulation of the GI tract is very complex and includes influences from peptide hormones, neurotransmitters from an intrinsic and extrinsic autonomic nervous system, lymphatics, and circulation. The mucosa of the GI tract produces numerous hormones. Although their functions in GI regulation are only partly understood, Table 4 lists their known effects (54–56). In addition to those listed, two newer peptides have been described including orphanin in the colon and xenin in the duodenum with their effects being investigated (57). Furthermore, ubiquitous substances including acetycholine, serotonin, histamine, and nitric oxide all have complex and varied effects on intestinal regulation with regard to motility, secretion and permeability, and blood flow. They are produced throughout the GI tract, and their effects are site specific and a subject of active investigation (57). Motility of the GI tract accomplishes distal propulsion of contents as well as segmentation and mixing. The wall of the GI tract is home to an extrinsic neuronal complex (parasympathetic and sympathetic) and an intrinsic network of modified smooth muscle cells that function as a syncitium analogous to the cardiac Purkinge cell–conducting system. These interstitial cells of Cajal are responsible for the migrating motor complex (MC) which sweeps the GI tract free of debris periodically between meals. These cells have been described as the pacesetters of the intestine.

Intestinal lymphatics perform a dual function in reticuloendothelial processing and lipid absorption. The GI tract comprises the largest reservoir of lymphocytes in the body, which not only reflects an important immune and barrier function, but also a mechanism for pathophysiology in disease states. Enterocytes may participate in antigen presentation to these lymphocytes. This may be a mechanism of the phenomenon of oral tolerance in which rejection of antigens is downregulated following their oral administration. Circulatory derangements including ischemia or portal hypertension may disrupt normal performance of the gut. Portal hypertension can be viewed as a dysregulation of intestinohepatic blood flow resulting froma combinationof obstructed outflow and (counterintuitively) increased splanchnic inflow. Disturbances in motility and bacterial overgrowth in the small intestine may occur in cirrhotic patients (58).

DIARRHEA AND MALABSORPTION Alterations in the normal physiology of digestion and absorption can be manifest by the clinical findings of malabsorption and diarrhea. Malabsorption means that a nutrient in the diet is passing through the GI tract incompletely absorbed such that clinical features of weight loss, steatorrhea, flatulence, or a specific nutritional deficiency state results. Diarrhea is the abnormal passage of loose or liquid stool more frequently than three times daily or greater than 200 mL in volume. Diarrhea may be a prominent feature of malabsorption, but malabsorption may be present without diarrhea. Alternatively, diarrhea may be present in the absence of malabsorption (59). Malabsorption may be described mechanistically by the level of digestive derangement: luminal, mucosal, or removal. Luminal malabsorption includes failure of the digestive enzymes or their associated media to hydrolyze or otherwise prepare the ingested nutrients for transport

Table 4 Gastrointestinal Hormones and Intestinal Physiology Polypeptide Bombesin (gastrin releasing peptide) CCK

Ghrelin Glucagon-like peptide 1 Glucagon-like peptide 2 Gastric inhibitory peptide Gastrin

Motilin Neurotensin Pancreatic polypeptide Peptide YY Secretin Somatostatin Vasoactive intestinal peptide

Effects Universal ‘‘on’’ switch; stimulates release of acid and all GI hormones except secretin Stimulates intestinal motility, pancreatic enzyme secretion, gallbladder contraction, sphincter of Oddi relaxation; delays gastric emptying Stimulates growth hormone release, appetite Stimulates insulin release; inhibits intestinal motility, glucagon release, and gastric acid Enterotrophic Inhibits gastrin release; pepsinogen; stimulates insulin release Gastric acid, pepsinogen and pancreatic secretion; gastric mucosal growth; intestinal motility; decreased intestinal fluid absorption Stimulates interdigestive motility and possibly MMC Inhibits gastric secretion, promotes pancreatic and intestinal secretion and motility; enterotrophic Inhibits pancreatic secretion; stimulates GI motility Inhibits GI motility, secretion, appetite Stimulates bile flow, pancreatic water and bicarbonate secretion; inhibits gastrin and GI transit Universal ‘‘off’’ switch; inhibits GI motility, secretion, hormonal release Vasodilator; promotes pancreatic and intestinal secretion; inhibits gastric acid

Abbreviations: CCK, cholecystokinin; GI, gastrointestinal; MMC, migrating motor complex.

Stimulants

Source

Vagus nerve

Small bowel

Lumenal amino acids and lipids

Duodenum, jejunum

Starvation, hypoglycemia Lumenal glucose and fat

Stomach Ileum (L cells)

Nutrient ingestion Lumenal nutrients

Ileum and colon (L cells) Duodenum, jejunum (K cells) Antrum, duodenum (G cells)

Peptides, amino acids, antral distention, bombesin vagal and adrenergic stimulation Fasting, gastric distention, fat Lumenal fat Protein Lumenal fat, CCK Lumenal acid, fat, and bile Lumenal nutrients, CCK Vagus nerve

Duodenum, jejunum Ileum (N cells) Pancreas Ileum, colon Duodenum, jejunum (S cells) Duodenum, jejunum (I cells) Intestinal neurons

Chapter 16: Physiology of Digestion and Absorption

across the brush border. The differential diagnosis includes gastrectomy, Zollinger–Ellison syndrome, pancreatic insufficiency, bacterial overgrowth, and bile acid insufficiency. Mucosal malabsorption indicates a loss of the mucosal surface area or inadequacy of the mucosal surface in the terminal stage of digestion or transport of ingested nutrients. Potential diagnoses include short bowel syndrome, radiation enteritis, lactose deficiency, and celiac sprue. Malabsorption at the removal phase occurs with failure to export nutrients from the enterocyte effectively for distribution by the portal venous or lacteal routes. Causative disorders may include mesenteric vascular insufficiency and lymphatic obstruction. Evaluation for malabsorption includes confirmation of malabsorbed nutrients, determining the potential mechanism as described above, and then making a specific diagnosis. Broadly, malabsorption can be investigated by evaluation of the stool for the malabsorbed nutrient or its metabolite or by breath tests to detect the bacterial degradation of the malabsorbed nutrient. Fecal fat, rather than carbohydrate or protein, is used as a sensitive indicator of malabsorption for two fundamental reasons: successful fat absorption requires the pancreas, biliary system, and intestinal mucosa and therefore reflects the normal functioning of all three components. Additionally, a correlation exists between unabsorbed dietary fat and fecal fat, whereas unabsorbed carbohydrate and protein are rapidly degraded by bacteria. Once a mechanism and specific diagnosis are determined, appropriate treatment is instituted. Nutritional support may be required during the evaluation period. Diarrhea can be classified by following mechanisms: osmotic, secretory, exudative, and hypermotility. Multiple mechanisms may be contributory in a single patient (17). Fecal incontinence or urgency can be mistaken for diarrhea. Osmotic diarrhea is primarily seen in malabsorption, where the malabsorbed nutrient or its degradation products contribute to luminal fluid retention. Magnesium-containing laxatives work in the same way. Dietary restrictions may be necessary. Secretory diarrhea is produced by the action of toxic or irritating substances on the intestinal mucosa. Increased electrolyte loss is seen and oral rehydration therapy may be employed. Cholera toxin has multiple effects, but most prominently, secretory diarrhea. Bile acid dysregulation following cholecystectomy may irritate the colonic mucosa. Though rare, neuroendocrine tumors such as VIPoma, gastrinoma, and carcinoid should be considered. Exudative diarrhea results from the loss of blood protein or mucous from inflammation and ulceration or infection of the mucosa. Causes include Clostridium difficile, bacterial enterocolitis, radiation proctitis, chemotherapeutics, colorectal neoplasm, and inflammatory bowel disease. Immunocompromised hosts may suffer diarrhea related to opportunistic infections or the underlying cause such as HIV. Treatment is determined by the specific cause. Increased motility alone with decreased intestinal transit time may also produce diarrhea. Vagotomy may produce this disturbance. However, the other types of diarrhea mentioned above are often associated with rapid transit, so that this is a common contributor to all types of diarrhea.

SUMMARY The efficient absorption and digestion of nutrients require the integration of a series of complex events occuring within

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the intestinal lumen, at the epithelial border and within the enterocyte. Fat absorption requires emulsification and solubilization by micelles within the intestinal lumen before absorption across the epithelium. Products of carbohydrate and protein digestion require specific transport carriers at the apical border of the intestinal epithelium. The absorption of water occurs secondary to the active transport of ions. Sodium is the major ion determining osmotic gradients favorable for water absorption while chloride is the driving force for secretion. All of these processes are regulated under the influence of peptide hormones, neurotransmitters, lymphatics, and the circulation. Diarrhea and malabsorption are the major clinical manifestations of impaired digestion and absorption. Clinical management requires a symptomatic approach to clarify the cause of diarrhea or malabsorption, which then can be managed appropriately. While many of the basic physiologic processes involved in digestion and absorption have been known for almost a century, we continue to make further advances in our understanding, which should improve our clinical management.

REFERENCES 1. Sellin J. Intestinal electrolyte absorption and secretion. In: Sleisenger M, Fordtran JS, eds. Gastrointestinal Disease. 6th. Philadelphia: WB Saunders, 1998:1451–1471. 2. Meinild AK, Klaerke D, Loo DD, Wright EM, Zeuthen T. The human Naþ/glucose cotransporter is a molecular water pump. J Physiol 1998; 508:15–21. 3. Leiper JB. Intestinal water absorption—implications for the formulation of rehydration solutions. Int J Sports Med 1998; 19(suppl 2):S129–S132. 4. Loo DDF, Zeuthen T, Chandy G, et al. Cotransport of water by the Naþ/glucose transporter. Proc Natl Acad Sci USA 1996; 93:13367–13370. 5. Madara JL, Pappenheimer JR. Structural basis for physiological regulation of paracellular pathways in intestinal epithelia. J Membr Biol 1987; 100:149–164. 6. Pappenheimer JR. Physiological regulation of transepithelial impedance in the intestinal mucosa of rats and hamsters. J Membr Biol 1987; 100:137–148. 7. Fordtran JS, Rector FC, Carter NW. Mechanisms of sodium absorption in the human small intestine. J Clin Invest 1968; 47:884. 8. Liedtke CM, Hopfer U. Mechanism of Cl translocation across small intestinal brush border membrane. Am J Physiol 1982; 243:G263. 9. Anderson MP, Sheppard DN, Berger HA, Welsh MJ. Chloride channels in the apical membrane of normal and cystic fibrosis airway and intestinal epithelia. (Part 1). Am J Physiol 1992; 263:L1–L14. 10. Fuller CM, Benos DJ. CFTR! (Part 1). Am J Physiol 1992; 263:C267–C286. 11. King LS, Agre P. Pathophysiology of the aquaporin water channels. Annu Rev Physiol 1996; 58:619–648. 12. Hofmann AF. Intestinal absorption of bile acids and biliary constituents. In: Johnson RL, ed. Physiology of the Gastrointestinal Tract. 3rd ed. New York: Raven Press, 1994:1850. 13. Heubi JE. Bile acid-induced diarrhea. In: Lebenthal E, Duffey M, eds. A Textbook of Secretory Diarrhea. New York: Raven Press, 1990. 14. Matthews DM, Adibi SA. Peptide absorption. Gastroenterology 1976; 71:151. 15. Sleisenger MH, Kim YS. Protein digestion and absorption. N Engl J Med 1979; 300:659. 16. Thwaites DT, Kennedy DJ, Raldua D, et al. H/dipeptide absorption across the human intestinal epithelium is controlled indirectly via a functional Na/H exchanger. Gastroentrology 2002; 122:1322–1333.

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17. Gray GM. Carbohydrate digestion and absorption. N Engl J Med 1975; 292:1225. 18. Alpers DH, Seetharam B. Physiology of diseases involving intestinal brush-border proteins. N Engl J Med 1977; 296:1047. 19. Takenoshita M, Yabune M, Katsura H, et al. Low sucrase activity in the small intestine of a senesence-accelerated strain of mouse, SAMP1. Biosci Biotechnol Biochem 1998; 62: 965–969. 20. Brasitus TA, Stirin MD. Absorption and cellular actions of vitamin D. In: Johnson LR, ed. Physiology of the Gastrointestinal Tract. 3rd ed. New York: Raven Press, 1994:1935. 21. Triadrou N, Bataille J, Schmitz J. Longitudinal study of the human intestinal brush border membrane proteins. Gastroenterology 1983; 85:1326. 22. Rosensweig NS, Herman RH. Control of jejunal sucrase and maltase activity by dietary sucrose or fructose in man. J Clin Invest 1967; 46:186. 23. Kimmich GA, Randles J. Evidence for an intestinal Naþ: sugar transport coupling stoichiometry of 2.0. Biochim Biophys Acta 1980; 596:439. 24. Wright EM, Turk E, Martin MG. Molecular basis for glucosegalactose malabsorption. Cell Biochem Biophys 2002; 36: 115–121. 25. Choi YK, Johlin FC Jr, Summers RW, Jackson M, Rao SS. Fructose intolerance: an under-recognized problem. Am J Gastroenterol 2003; 98:1348–1353. 26. Santer R, Hillebrand G, Steinmann B, Schaub J. Intestinal glucose transport: evidence for a membrane traffic-based pathway in humans. Gastroenterology 2003; 124:34–39. 27. Santer R, Groth S, Kinner M, et al. The mutation spectrum of the facilitative glucose transporter gene SLCA2 (GLUT2) in patients with Fanconi-Bickel syndrome. Hum Genet 2002; 110:21–29. 28. Hirsch D, Stahl A, Lodish HF. A family of fatty acid transporters conserved from mycobacterium to man. Proc Natl Acad Sci USA 1998; 95:8625–8629. 29. Schaffer JE, Lodish HF. Expression cloning and characterization of a novel adipocyte long chain fatty acid transport protein (see comments). Cell 1994; 79:427–436. 30. Stahl A, Hirsch DJ, Gimeno RE, et al. Identification of the major intestinal fatty acid transport protein. Mol Cell 1999; 4:299–308. 31. Kaikaus RM, Bass NM, Ockner RK. Functions of fatty acid binding proteins. Experientia 1990; 46:617–630. 32. Luxon BA. Inhibition of binding to fatty acid binding protein reduces the intracellular transport of fatty acids. Am J Physiol 1996; 271:G113–G120. 33. Luxon BA, Milliano MT. Cytoplasmic transport of fatty acids in rat enterocytes: role of binding to fatty acid-binding protein. Am J Physiol 1999; 277:G361–G366. 34. Tso P. Intestinal lipid absorption. In: Johnson LR, ed. Physiology of the Gastrointestinal Tract. 3rd ed. New York: Raven Press, 1999:1867–1907. 35. Gaskin KJ, Durie PR, Hill RE, Lee LM, Forstner GG. Colipase and maximally activated pancreatic lipase in normal subjects and patients with steatorrhea. J Clin Invest 1982; 69:427. 36. Hollander PA, Elbein SC, Hirsch IB, et al. Role of orlistat in the treatment of obese patients with type 2 diabetes. A 1-year randomized double-blind study. Diabetes Care 1998; 21:1288–1294. 37. McNeely W, Benfield P. Orlistat. Drugs 1998; 56:241–249. 38. Gonda T, Maouyo D, Rees SE, Montrose MH. Regulation of intracellular pH gradients by identified Na/H exchanger

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17 Circulation and Vascular Disorders of the Splanchnic Vascular Bed Stuart I. Myers and Patricia A. Lowry

directly out of the arteriole into the venule without being carried to the tips of the villi. Thus, as much as 80% of blood flow bypasses the tip of the villus in this manner and will not be available for metabolic functions of the villi (Fig. 3) (4). The celiac axis supplies the foregut structures primarily below the diaphragm (Fig. 4). The celiac axis originates from the anterior surface of the aorta at the level of T12. It is usually between 1 and 1.5 cm in length. After coursing through the crura of the diaphragm, it divides into the splenic, left gastric, and common hepatic arteries. The bifurcation of this major trunk occurs at the superior border of the pancreas. The SMA is the main supplier of intestinal blood flow from the duodenum–jejunum junction to the mid-transverse colon. The SMA originates from the anterior surface of the aorta 1.5 cm below the celiac axis. Its course is inferior to the pancreas where it divides into multiple branches that supply the lower portion of the pancreas, the small bowel, and the proximal two-thirds of the colon. The first three branches of the SMA are important from both a clinical and theoretical point of view. The inferior pancreaticoduodenal artery originates from the SMA and may be either a single trunk or a pair of vessels. If there is a single trunk, it divides very soon after its origin into an anterior and posterior branch. These supply the anterior and posterior inferior portions of the head of the pancreas. In addition, branches supply the third portion of the duodenum. These vessels course in a superior direction and anastomose directly, with their superior counterparts originating from the hepatic artery. The middle colic artery is the second branch of the SMA. The middle colic artery courses in the transverse mesocolon and sends branches to supply the transverse colon. There is, in addition, a branch that courses toward the left colon and anastomoses with the left colic artery. There are direct communications between the middle colic artery and the right colic artery via the marginal artery, which courses in the mesentery of the transverse and right colon. There is likewise a second anastomotic branch to the left colic complex via this marginal artery. The right colic artery is the third branch of the SMA and this courses in the right colonic mesentery, supplying the right colon with anastomotic branches via the marginal artery to both the middle colic artery and the ileocolic artery. The remainder of the SMA is virtually an end vessel with segmental branches going to the jejunum and ileum. The SMA terminates in the ileocolic branch, which supplies the terminal ileum, cecum, and appendix. It has a small communicating vessel, as just described, coursing along the marginal artery and anastomosing with the right colic artery (7,8). The inferior mesenteric artery (IMA) supplies the hindgut from mid-transverse colon to the rectum and is

INTRODUCTION The blood vessels of the gastrointestinal (GI) system are part of a more extensive system called the splanchnic circulation. The splanchnic circulation includes the gut, pancreas, liver, and spleen. Splanchnic blood flow courses through the gut, spleen, and pancreas and then flows immediately into the hepatic circulation by way of the portal vein. Blood then flows through minute liver sinusoids and re-enters the systemic circulation via the hepatic veins. This complex secondary flow of blood allows the reticuloendothelial system of the sinusoids to remove harmful bacteria and other substances that could potentially enter the systemic circulation. Maintenance of an adequate blood supply to the intestines is important in insuring normal intestinal homeostasis. Splanchnic blood flow is influenced by several factors including the status of the normal systemic circulation, the degree of collateral blood flow, and the exposure to exogenous and endogenous neuro-humoral factors. Maintenance of normal splanchnic blood flow is important in preserving intestinal motility, absorption of nutrients, and immune function. This chapter will examine the anatomy and physiology of intestinal blood flow and will then examine the pathophysiology of the clinical disorders that result from altered intestinal blood flow.

NORMAL ANATOMY AND COLLATERAL CIRCULATION The intestines are supplied by a series of parallel circulations via the branches of the superior mesenteric artery (SMA) and the inferior mesenteric arteries. The collateral circulation is extensive and involves flow originating from the celiac axis as well (Fig. 1). On entering the wall of the gut, the arteries divide into branches that circle the gut in both directions, with the distal vessels meeting on the antimesenteric border of the intestine. Smaller arteries then penetrate the intestinal wall and supply the major distributing plexus within the submucosa (2). The intestinal arteries begin as first-order arterioles (1A). 1A vessels penetrate both muscle layers and course along the outer surface of the submucosa, giving rise to second-order arterioles (2A). Third-order arterioles (3A) pass from the submucosa directly into the tips of the mucosal villi. At the tip of the villi, they then divide into an arcade of vessels that feed the net-like subepithelial capillary system located on all sides of the villus (Fig. 2). Arterial flow and venous flow in the villus are in opposite direction and the vessels lie in close proximity. Because of this unusual ‘‘countercurrent vascular arrangement,’’ blood diffuses 381

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(A) CELIAC A.

SMA

LEFT COLIC A.

MIDDLE COLIC A. INF. MES. A.

COMMON ILIAC A.

SUP. HEMORRHOIDAL A.

DEEP CIRCUMFLEX A. INT. ILIAC A.

(B)

CELIAC A. SUP. MES. A.

INTERCOSTAL A.

INF. MES. A.

LUMBAR A. ILIO-LUMBAR A. CIRCUMFLEX ILIAC A.

COMMON ILIAC A. INT. ILIAC A.

EXT. ILIAC A.

INF. EPIGASTRIC A.

Figure 1 (A) Components of the viscerosystemic collateral circulation. This figure represents direction of flow through the splanchnic vascular bed to compensate for chronic occlusion of the infrarenal aorta. The arrows denote direction of flow. (B) Components of the systemic–systemic collateral flow. These are systemic collateral flow routes that may develop during chronic infrarenal aortic occlusion. Abbreviation: SMA, superior mesenteric artery. Source: From Ref. 1.

Figure 2 Outline of the intestinal microvasculature emphasizing blood supply with the inflow (A1), transitional (A2), and premucosal (A3) arteriolar structure, as well as outflow (V1) and transitional (V2) venules. Source: From Ref. 3.

Figure 3 Microvasculature of the villus, showing a countercurrent arrangement of blood flow in the arterioles and venules. Source: From Ref. 5.

the smallest of the three major vessels supplying the abdominal viscera. It originates from the anterior surface of the abdominal aorta 4 cm above the bifurcation. This vessel is very short, rarely exceeding 1 cm in length. The IMA divides into three branches, which supply the left colon, sigmoid colon, and superior portion of the rectum (Fig. 5). The left colic artery is the superior branch of the IMA. It courses upward along the descending colon and supplies it by segmental branches. It communicates with the marginal artery and, in addition, has a larger branch that connects directly with a branch of the middle colic artery in the mesentery of the colon. The sigmoidal arteries comprise the middle segmental distribution of the IMA, and there are usually three of them. They extend to the sigmoid colon and supply it in a segmental manner. These branches anastomose with the marginal artery along the colonic border. The superior rectal artery is the lower segment of the inferior mesenteric arterial system and supplies the superior portion of the rectum. It is the terminus of the IMA and anastomoses with the sigmoidal branches via the marginal artery. In addition, the superior rectal artery connects with the inferior and middle rectal arteries via a rich plexus in the wall of the rectum. The blood supply of the lower portion of the rectum originates from the internal iliac system. It comprises two paired vessels, the middle and inferior rectal arteries. The middle rectal arteries originate directly from the internal iliac arteries and course medially to the rectum through the lateral rectal attachments in the pelvis. They are very small vessels, measuring no more than 1 mm in diameter. They supply the middle portion of the rectum and anastomose with the superior rectal artery and inferior rectal

Chapter 17: Circulation and Vascular Disorders of the Splanchnic Vascular Bed

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Figure 4 Artist’s conception of the surgical anatomy of the celiac axis and its three major branches. Some detail of collateral circulation and adjacent viscera is included. Source: From Ref. 6.

artery through the rich arterial plexus in the rectal wall. The inferior rectal artery is a terminal branch of the pudendal artery, which originates from the internal iliac artery. The pudendal artery passes through Alcock’s canal and extends into the perineal area. Here it gives off a branch to the rectum, which is a significant artery, usually measuring over 1 mm in diameter. This artery supplies the lower portion of the rectum and the anal canal. In addition, it may carry the bulk of the blood supply to the anal sphincter (Fig. 5) (7,8). There are four important anastomotic pathways that are constant and play a major role in the collateral circulation of the abdominal viscera: the left inferior phrenic artery,

the pancreaticoduodenal arcade, the left colic–middle colic arterial anastomosis, and the internal iliac artery system. The paired inferior phrenic arteries are the first parietal branches of the abdominal aorta. The inferior phrenic artery commonly originates between the diaphragmatic crura and courses the dome of the diaphragm where they divide into anterior and posterior branches. The posterior branches anastomose with intercostals arteries. The anterior branches anastomose with twigs of the contralateral artery, the musculophrenic artery, the pericardiophrenic artery, and the internal thoracic artery and can also communicate with the hepatic artery.

Figure 5 Artist’s conception representing the superior and inferior mesenteric arteries as well as the renal arteries, with adjacent viscera. Source: From Ref. 6.

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The pancreaticoduodenal arcade is a constant collateral channel joining the celiac axis and superior mesenteric arterial systems. Although the primary function of these vessels is to supply the pancreas and second and third portions of the duodenum, they can function as an anastomotic pathway between the two major upper abdominal vessels. It is interesting to note that the blood may run either cephalad or caudad in this system, depending upon the site of occlusion (Fig. 6). The left colic branch of the IMA sends a direct communicating branch to the the middle colic branch of the SMA. With occlusion of either the SMA or the IMA, this collateral channel will enlarge to carry the blood supply toward the area of occlusion. The internal iliac vessels supply the middle rectal and inferior rectal arteries. These anastomose by a rich arterial plexus within the wall of the rectum and anal area. The internal iliac arteries are particularly important at the time of abdominal aortic resection. The IMA is frequently sacrificed during aortic aneurysm repair. The internal iliac then becomes an important source of blood flow to the rectum and distal sigmoid colon (Figs. 7 and 8) (7,8). Additional collateral flow is provided to the gut via an extensive microscopic endogenous collateral network of vessels. As described above, small arteries penetrate the intestinal wall on the antimesenteric border, which divides into extensive submucosal vascular plexi, which provide a rich subepithelial capillary network within each villus at the cellular level. This plexus is much more extensive in the small bowel than in the colon, rendering the small intestine more resistant to ischemia. The physiologic control

Figure 7 Superior mesenteric–IMA anastomosis. An inferior mesenteric arteriogram demonstrates the anastomosis between the left colic artery (large closed arrow) and the middle colic branch (large open arrow) of the SMA. This is the arc of Riolan. The marginal artery of Drummond (small arrows) is seen adjacent to the mesenteric border of the descending colon. Abbreviations: IMA, inferior mesenteric artery; SMA, superior mesenteric artery. Source: From Ref. 10.

of microvascular intestinal blood flow is not unlike other vascular beds. The intestinal microvasculature is a circuit composed of a series of resistance arterioles, precapillary sphincters, capillaries, postcapillary sphincters, and the venous capacitance vessels. The most important determinant of blood flow control is the resistance arterioles (7,8). Venous blood collects in small venules, which form a system of venous arcades within the mesentery. These arcades join to form veins that correspond to the named arteries within the mesentery. These veins then drain into the inferior and superior mesenteric veins (SMVs) that join to form the portal vein. The extensive venous arcades within the mesentery provide an extensive venous collateral network for the small and large intestine (8).

PHYSIOLOGY OF INTESTINAL CIRCULATION

Figure 6 Celiac-SMA anastomosis. A superior mesenteric arteriogram of a patient with stenosis of the proximal hepatic artery demonstrates enlarged inferior pancreatoduodenal arcades (small arrow) filling the gastroduodenal (large arrows) and proper hepatic arteries. Abbreviation: SMA, superior mesenteric artery. Source: From Ref. 9.

Intestinal blood flow is affected by a variety of neurohumoral, local, and functional factors. Of prime importance is the sympathetic nervous system, which via a-adrenergic receptors maintains resting splanchnic arteriolar tone. The splanchnic bed receives up to 30% of the total cardiac output at rest, with 70% or more of the flow, which perfuses the mucosal–submucosal layers. Over the past several decades several hypotheses have evolved to describe three major areas of circulatory determinants for the regulation of intestinal blood flow. These include extrinsic factors (sympathetic and parasympathetic nervous system), intrinsic factors (local metabolic vs. myogenic), and humoral factors (circulating or

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Table 1 Endogenous and Exogenous Vasoactive Mediators of the Splanchnic Circulation Constrictor Sympathetic tone (adrenergic) Parasympathetic tone (cholinergic) PO2 PCO2 pH Metabolites (Kþ, lactate, adenosine) Angiotensin I, II, III Activated complement (C5a) Antidiuretic hormone Calcium Endothelin-1 Epinephrine LTs Motilin Neuromedin U Neuropeptide Y Norepinephrine (high dose) Oxytocin PeptideYY PAF Prostaglandin B2, D2, F2a, H2 Serotonin TxA2 Vasopressin

Figure 8 Arteriogram of a patient with occlusion of the SMA. The prominent meandering artery shows that collateral channels have been present for some time and that the occlusion is not acute. The arrows show the direction of flow from the IMA to the SMA. Abbreviations: IMA, inferior mesenteric artery; SMA, superior mesenteric artery. Source: From Refs. 11, 11a.

local vasoactive or neurohumoral agents) (12–17). The reader should be reminded that the factors that contribute to the regulation of splanchnic blood flow are similar to those regulating other vascular beds. A list of potential vasoactive mediators of the splanchnic circulation is presented in Table 1.

Intrinsic Factors Regulating GI Blood Flow The splanchnic vascular bed, similar to other vascular beds, has the capacity for the return of normal blood flow over a wide variety of perfusion pressure to maintain adequate blood flow to the intestines. This autoregulation of blood flow implies that when the vascular bed is exposed to an increase in arterial blood pressure, the initial increase in blood flow to the vascular bed decreases to the normal level. The converse occurs with a decrease in arterial blood pressure. Two views have been proposed to explain this acute autoregulation mechanism: the metabolic theory and the myogenic theory.

Metabolic Theory The metabolic hypothesis of intrinsic regulation states that any pathologic situation that creates a negative imbalance between oxygen supply and demand raises the local concentrations of tissue metabolites, such as Hþ and Kþ, hyperosmolarity of the blood, the number of adenosine nucleotides, and the concentration of carbon dioxide,

Vasodilator Sympathetic tone Parasympathetic tone PO2 PCO2 pH Metabolites Acetylcholine Activated complement (C3a, C5a) Adenosine Adrenomedullin Bradykinin Calcitonin gene-related peptide Cholecystokinin Dopamine Gastric inhibitory peptide Gastrin Glucagon Glucocorticoids Glucose-dependent insulinotropic peptide Histamine Insulin Kalikrein Magnesium Neuromedin N Neurotensin NO Nitroglycerin Norepinephrine (low dose) Opiates Pituitary adenylate cyclase– activating Polypeptide Prostaglandin I2, E2 Secretin Serotonin (low dose) Sodium Substance P Thrombin Thyrotropin-releasing factor Uridine triphosphate VIP Xenin Xenopsin

Abbreviations: LTs, leukotrienes; PAF, platelet-activating factor; TxA2, thromboxane A2; NO, nitric oxide; VIP, vasoactive intestinal peptide.

causing local acidosis, which contributes to the control of local blood flow. Conversely, if excess blood flow occurs, excess metabolic nutrients will cause blood vessels to constrict, returning blood flow to normal. The metabolic theory therefore states that it is oxygen delivery, rather than blood flow, that regulates the intestinal circulation.

Myogenic Theory (15) The myogenic theory is based on the experimental observation that the stretch of a blood vessel will lead to smooth muscle cell contraction. Thus a high level of vessel stretch will cause a reactive vasoconstriction. Conversely at low pressures, the smooth muscle cells relax and blood flow thus increases. The myogenic theory thus assumes that vascular resistance is proportional to arteriolar transmural pressure, requiring the existence of arteriolar tension receptors. An

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acute decrease in perfusion pressure is compensated for by local regulatory mechanisms, so that flow reduction is proportionately less than the reduction in perfusion pressure, allowing maintenance of constant intestinal capillary pressure and transcapillary fluid exchange (15–17).

Mechanism for Dilating Large Upstream Arteries The myogenic and metabolic theories describe local mechanisms for preserving normal blood flow at the microvascular level. The endothelial cells of the larger arteries upstream from the microvascular vessels can synthesize several vasoactive substances that can affect contraction or vasodilation. One such substance is nitric oxide (NO). Rapid blood flow through a larger arteriole or artery causes shear stress and increases endothelial synthesis and release of NO, causing the artery to dilate and increase blood flow (12).

Intrinsic Paracrine Vasoactive Substances That Contribute to the Regulation of Splanchnic Blood Flow Endogenous NO has also been proposed to contribute to the regulation of microvascular blood flow in the GI tract. Evidence indicates that NO may be an important mediator of vascular tone in the GI tract, in particular gastric mucosal blood flow. Kubes et al. have shown that basal NO production is important in minimizing mucosal and microvascular barrier dysfunction following intestinal ischemia-reperfusion (IR) injury. Although the specific mechanisms are unknown, NO may be acting as an antioxidant and as an inhibitor of neutrophil adhesion to vascular endothelium and migration from blood vessels (18–22). Prostaglandins (PGs) have been shown to have both potent vasodilatory and vasoconstrictive actions in the splanchnic vascular bed. The major vasodilators are prostacyclin (PGI2) and PGE2, and the major vasoconstrictor (and agonist of platelet aggregation) is thromboxane A2 (TxA2). PGs have been shown to be synthesized throughout GI tract. Thus, the entire GI tract could serve as a source for locally vasoactive PGs. PG synthesis in the resting intestine favored the vasodilator PGs as cyclooxygenase (COX) inhibition decreased blood flow to the intestine. The importance of resting intestinal vasodilator PGs was further shown by experiments utilizing exogenous TxA2 to constrict the splanchnic vascular bed. In this study, splanchnic vascular vasoconstriction by exogenous TxA2 was potentiated by endogenous prostanoid inhibition by indomethacin [10 mg/kg intravenous (IV) inhibits endogenous vasodilators PGI2 and PGE2]. This finding suggested that synthesis of splanchnic vasodilator PGs is an important compensatory mechanism in the maintenance of blood flow (23–35). Leukotrienes (LTs) are another group of potent vasoactive metabolic products of arachidonic acid metabolism synthesized by the enzyme 5-lipoxygenase. The cysteinyl LTs [leukotriene C4 (LTC4), leukotriene D4(LTD4), and leukotriene E4(LTE4)] and the dehydroxylated LTB4 have been studied in normal and shock states. Injection of cysteinyl LTs caused systemic reactions that are similar to signs and symptoms associated with shock. These systemic effects are intense bronchoconstriction, increased vascular permeability, mucous formation, and coronary and splanchnic vasoconstriction (36–38).

Parasympathetic nerve stimulation leads to increasing blood flow to the stomach and lower colon (39). Activation of muscarinic receptors on the endothelium leads to a release of NO, which diffuses to the vascular smooth muscle and causes relaxation and vasodilation. In contrast, sympathetic nerve stimulation has a direct effect on the entire GI tract to cause vasoconstriction, primarily by activation of a-adrenergic receptors. Sympathetic fibers are distributed to all levels of the arteries except precapillary sphincters and the metarterioles (39). Thus, the greatest effect of sympathetic nerve stimulation is on the small arteries and arterioles. Stimulation of these fibers leads to the release of norepinephrine, vasoconstriction of the precapillary resistance vessels, and decreased blood flow. However, as seen elsewhere in the body, reduction of blood flow is associated with disproportionate vasoconstriction in the postcapillary capillary venous beds that make up the capacitance vessels. Within minutes of initial vasoconstriction, blood flow rises to nearly normal levels. The most reasonable explanation appears to be differential a and b adrenergic stimuli. A reactive hyperemic response generally follows the cessation of sympathetic stimulation, concluding this triphasic response to splanchnic sympathetic activity. Adrenergic stimuli also change intestinal motility, wall tension, and absorption and secretion, all of which have a profound effect on regional and local blood flow (39–41). Understanding the role of circulating GI hormones on the regulation of splanchnic blood flow continues to be a challenge. Most observations of the role of these hormones depend on the animal model used, experimental conditions, and the animal species utilized. Despite these challenges, some brief generalizations can be presented to the reader. Angiotensin II (AII) and vasopressin appear to be important physiological vasoconstrictors and redistribute flow from the muscle and mucosa to the submucosal layer (42). Cholecystokinin and secretin increase mucosal blood flow by activation of specific receptors on vascular smooth muscle cells. Enteroglucagon-like peptide, found in epithelial ‘‘L’’ type cells, is released following a meal and may contribute to the hyperemic response. Gastrin (or pentagastrin), in addition to increasing gastric acid secretion, increases gastric mucosal blood flow and has a questionable effect on proximal small-intestinal blood flow. Glucagon was shown to be a potent intestinal vasodilator in the cat (43). Somatostatin is a relatively selective vasoconstrictor of the upper GI circulation at pharmacologic doses. Substance P, a vasoactive intestinal peptide (VIP), and gastric inhibitory polypeptide all tend to be vasodilators at pharmacologic doses but not physiologic levels. Neurotensin is found in neuronal cells and its vasodilator effects are limited to the muscular layer. Motilin reduces mucosal blood flow. VIP, a neurocrine and paracrine mediator, is associated with the nerves supplying most of the intestinal vessels. These VIP-associated vessels are more pronounced in the mucosa and thus VIP is associated more with increase of blood flow to the mucosal layer. Peptide YY redistributes blood flow from the muscularis to the mucosa and submucosa Substance P is often associated with 5-HT and is located on nervous tissues. These fibers nervate layers of the vessel but Substance P appears to act most directly on the smooth muscle cells (44–47).

Extrinsic Factors That Regulate GI Blood Flow

REPERFUSION INJURY OF THE INTESTINE Clinical Relevance

The sympathetic and parasympathetic nervous systems make up the extrinsic component of intestinal blood flow.

There can be little doubt regarding the clinical relevance of ischemia and reperfusion injury to clinical medicine. The

Chapter 17: Circulation and Vascular Disorders of the Splanchnic Vascular Bed

reactivity of the splanchnic vascular bed to circulating and local paracrine vasoconstrictors and the sensitivity of the intestinal mucosa to reduced oxygen and nutrient delivery make it particularly susceptible to hypoperfusion with subsequent reperfusion injury. Intestinal reperfusion injury may occur following relief of arterial occlusion (e.g., during vascular surgical procedures or traumatic injury) or the restoration of systemic perfusion in patients suffering hypovolemic or cardiogenic shock (Fig. 9). The clinical manifestations of intestinal IR injury are dependent upon the duration and severity of the underlying ischemia. The mucosa is most susceptible to this injury and hence mucosal necrosis and sloughing with subsequent hemorrhage may be a manifestation of relatively early injury. In general, massive hemorrhage is a relatively uncommon presentation for this injury. Severe injury may be

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associated with transmural necrosis of the intestinal wall, perforation, and peritonitis. More chronic ischemic states may be associated with the development of an ischemic stricture, with subsequent intestinal obstruction. Of interest, even relatively minimal periods of ischemia (e.g., one hour) may be associated with altered intestinal epithelial integrity (18). This has been postulated to be an important factor in the pathogenesis of the systemic inflammatory response syndrome and multiple organ failure in critically ill patients (49). A study by Paterson et al. suggested an association between skeletal muscle reperfusion and noncardiogenic pulmonary edema in patients undergoing repair of abdominal aortic aneurysms (AAAs) (50). Others have demonstrated that the most common cause of death following repair of AAAs is multiple organ failure syndrome (51).

Intestinal Morphology Clinically Important Causes of Intestinal Reperfusion Injury ................................... PRESPLANCHNIC HEART/CENTRAL CIRCULATORY SYSTEM (Nonocclusive mesenteric ischemia) Reduced Cardiac Output Hypovolemia Hemorrhage Cardiac tamponade Cardiac failure Dialysis Anesthesia Sepsis Hypoplastic left heart syndrome

The significance of reperfusion to tissue injury is evidenced by observations that the histologic injury and physiologic dysfunction of reperfused tissue is greater than that associated with an equivalent period of ischemia alone. This was demonstrated in the intestine by Parks and Granger in a study in which the histologic evidence of mucosal injury was significantly greater following three hours of ischemia and one hour of reperfusion than that associated with four hours of ischemia alone (52). As is shown in Figure 10, the principal morphologic site of intestinal reperfusion injury is the mucosa, with epithelial sloughing from the villi, mucosal edema, neutrophil infiltration, and hemorrhage into the lumen (52,54). This histologic picture has been well characterized with grading scales proposed by Mangino et al. and Chiu et al. (54,55).

Intestinal Pathophysiology SPLANCHNIC MACROVASCULAR OCCLUSION (Superior mesenteric artery) In situ thrombosis (atherosclerosis) Embolic disease Operative procedures Trauma Compression MICROVASCULAR OCCLUSION (Arteriolar, precapillary, postcapillary sphincters) Drugs Digitalis Cyclosporine Anesthetic agents Halothane Reperfusion injury Sympathetic nerve stimulation Norepinephrine POSTSPLANCHNIC MESENTERIC VENOUS THROMBOSIS Hypercoagulable syndromes Digitalis Cirrhosis Sympathetic nerve stimulation Norepinephrine

Figure 9 List of clinically important causes of intestinal reperfusion injury. Source: From Ref. 48.

Intestinal reperfusion injury is characterized by severely impaired splanchnic microvascular and epithelial function. Reperfusion-induced microvascular dysfunction has been characterized by the appearance of edema and hemorrhage within the mucosa, the extravasation of plasma proteins, and reduction of splanchnic blood flow. Altered microvascular permeability has been quantitated utilizing labeled plasma proteins (21) and determination of the osmotic reflection coefficient (56). Each of these parameters as well as the histologic findings has suggested an increased leakiness of the microvasculature for fluid and macromolecules upon reperfusion. Altered epithelial permeability has been quantitated by measuring the blood-to-lumen movement of 51Cr-labeled ethylenediaminetetraacetic acid (51Cr-EDTA) (18,20,21). Normally the IV administration of 51Cr-EDTA results in almost instantaneous equilibration across the vasculature into the interstitium; however, its movement across the epithelium is greatly restricted. After even a relatively brief period of ischemia (e.g., one hour), reperfusion has been shown to cause a sevenfold rise in the concentration of 51Cr-EDTA within the lumen of the bowel when compared with controls (18), a finding consistent with the morphologic picture of epithelial cell loss and villus injury. The effect of intestinal reperfusion on splanchnic blood flow has been examined using radiolabeled microspheres and flow probes in models of SMA occlusion (57) and hemorrhage and resuscitation (58). As early as 15 minutes following reperfusion, intestinal blood flow is severely reduced, a finding that persists throughout reperfusion

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Figure 10 (A) Representative photomicrograph of ileum from a sham-operated time-matched rat undergoing laparotomy, with isolation of the SMA without occlusion. Note that the villus epithelium is intact and there is no evidence of edema or neutrophil infiltration (hematoxylin-eosin X 100). (B) Representative photomicrograph of ileum of a rat undergoing 120 minutes of intestinal ischemia and 60 minutes of reperfusion. In this example the SMA was occluded with a microvascular clip; release of the clip allowed reperfusion. Mucosal injury is characterized by epithelial sloughing from the villi, mucosal edema, neutrophil infiltration, and hemorrhage into the lumen (hematoxylin-eosin X 100). Abbreviation: SMA, superior mesenteric artery. Source: From Ref. 53.

(57,58). This progressive loss of tissue perfusion has also been demonstrated in models of skeletal muscle reperfusion (59) and has been termed the ‘‘no-reflow phenomenon’’ and likely relates to the generation of oxygen-derived free radicals (ODFRs), neutrophil sequestration, inhibition of prostacyclin, and, perhaps, NO release.

Mediators of Reperfusion-Induced Tissue Injury Reperfusion of ischemic intestine induces the release of a variety of proinflammatory mediators that exacerbate the local intestinal injury and lead to the generation of paracrine proinflammatory and vasoactive substances in remote organs. Many of these substances serve to direct, amplify, and disseminate the inflammatory response. For example, in addition to directly injuring tissue through the peroxidation of plasma membranes, ODFRs have been shown to be important chemotactic substances for neutrophils contributing to the activation of complement and are at least in part responsible for the impairment of the compensatory release of the potent vasodilator PGI2. These relationships highlight the redundancy in these proinflammatory systems [e.g., neutrophil chemotaxis may be related to local superoxide, TxA2 platelet-activating factor (PAF), and LTB4 release, and complement activation]. Several of the most important mediators are described below in detail.

Eicosanoids PGs are synthesized by the entire GI tract (26). Depending upon the specific mediator, prostanoids have been shown to have potent vasodilator (PGI2 and PGE2) and vasoconstrictor effects (TxA2) in the splanchnic vascular bed. Furthermore, these agents also appear to have important proinflammatory (TxA2) effects. PG synthesis in the resting intestine favors the vasodilator PGs, as evidenced by the observation that COX inhibition decreases blood flow to the intestine (28–30). Furthermore, cyclo-oxgenase inhibition was found in an isolated, perfused intestine preparation to significantly potentiate the vasoconstrictor effects of exogenous TxA2 administration (29). These studies suggest that

the paracrine release of the vasodilator PGs (PGE2 and PGI2) is an important autoregulatory mechanism in the maintenance of normal splanchnic blood flow. Humoral factors that have been shown to contribute to the regulation of splanchnic blood flow include angiotensin, norepinephrine, kinins, and eicosanoids. Using a swine cardiac tamponade model of hypovolemic shock, Bailey et al. (60) demonstrated that diminished perfusion of the splanchnic vascular bed was disproportionate to the reduction in cardiac output during hypovolemic shock. The exaggerated splanchnic hypoperfusion was related to the sensitivity of the splanchnic microvasculature to elevated circulating AII levels (60). Several investigators have demonstrated that AII and norepinephrine induce the release of PGI2 and PGE2 from the perfused rat splanchnic vasculature, suggesting that these potent vasodilators may antagonize the vasoconstrictor influences of AII, sympathetic nerve stimulation, and norepinephrine (24,61,62). These important studies suggested that splanchnic vasoconstriction might occur as a consequence of both increased exogenous factors, which cause vasoconstriction (AII, norepinephrine, sympathetic nerve stimulation), and the loss of endogenous splanchnic vasodilators. One must not totally exclude a role for vasoconstrictor eicosanoids in mediating splanchnic vasoconstriction. Exogenous LTC4 and TxA2 have been shown to be potent vasoconstrictors of the splanchnic vascular bed. Furthermore, Mangino et al. (53) demonstrated that following intestinal ischemia and reperfusion, LTC4 and TxA2 release was increased by more than 300%. The effect of vasoactive eicosanoids and inflammatory mediators on splanchnic blood flow during intestinal IR is outlined in Figure 11. A series of studies have shown that PGI2 is the predominant eicosanoid released by the in vitro perfused splanchnic vascular bed [termed the splanchnic vessel þ splanchnic intestine (SVþSI) preparation] and the in vitro perfused SVs (termed the SV preparation). Perfusing both preparations with a hypoxic Krebs–Henseleit buffer decreased in vitro SV þ SI PGI2 release but did not alter thromboxane B2 or PGE2 release or SV PGI2 release (31).

Chapter 17: Circulation and Vascular Disorders of the Splanchnic Vascular Bed

Figure 11 Postulated mechanism by which ODFRs are formed during intestinal IR injury. Events occurring during ischemia are indicated by dashed lines. Reported mechanisms by which ODFRs induce tissue injury are shown in the bottom right corner. Abbreviations: TxA2, thromboxane; LTB4, leukotriene; PAF, platelet activating factor; TNF, tumor necrosis factor; IL, interleukin; LTC4, leukotriene; ODFRs, oxygen-derived free radicals; IR, ischemia-reperfusion; LPS, lipopolysaccharide. Source: From Ref. 63.

These studies showed that there were two important sources of splanchnic PGI2 synthesis and release, the SVs and the intestine itself. The next group of studies was designed to specifically determine the role of exogenous AII during hypoxiainduced splanchnic vasoconstriction. Exogenous AII stimulated a dose-related increase in PGI2 release from both SV þ SI and SV preparations. Hypoxic perfusion significantly decreased SV and not (SV þ SI) PGI2 release (64). These studies further confirmed that both the SVs and the intestine were likely sources of both basal and AII-stimulated PG synthesis. Basal (not AII-stimulated) intestinal (SV þ SI) PGI2 synthesis was more vulnerable to hypoxia than that of the SV preparation (vessels). This is thought to be related to the sensitivity of the mucosa to the effects of hypoxia, particularly given the high metabolic activity and usually largest percentage of blood flow that is attributed to the mucosa (30,31,62). SV AII-stimulated PG synthesis was more sensitive to hypoxia than the SV þ SI. Decreased SV PGI2 release may thus be of importance in AII-mediated splanchnic vasoconstriction seen in shock. A series of studies examined the effects of acute hemorrhage on endogenous splanchnic PGI2 synthesis and release. Acute hemorrhage to a mean arterial pressure of 30 mmHg for 30 minutes (without reperfusion) severely reduces splanchnic blood flow (58) and induces a threefold increase in the release of PGI2 from the splanchnic vascular bed (31,64,65). It was postulated that the reduced PGI2 release seen following prolonged intestinal ischemia was due to a hypoxic environment similar to that seen during the perfusion of the isolated, perfused intestine with unoxygenated Krebs–Henseleit buffer (31,64,65). More recent studies have examined the enzymatic mechanisms by which hemorrhage induces the release of PGI2 from the splanchnic vascular bed. Inhibition of protein synthesis by administering cycloheximide to the isolated, perfused intestine of animals sustaining acute hemorrhage abolished the exaggerated PGI2 release associated with this

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model (66). Western blot analysis of protein from the SMA, aorta and ileal mucosa, and muscularis/serosa for prostacyclin synthase (PS) and COX demonstrated a twofold increase in both of these enzymes within the ileal muscularis/serosa and a 50% increase in PS within the aorta and SMA (33). Together these data suggest that the increased release of PGI2 from the splanchnic bed following acute hemorrhage is dependent upon new protein synthesis and that the location of the increased enzyme content is the ileal muscularis/ serosa (COX and PS) and the aorta and SMA (PS). In contrast to animals sustaining acute hemorrhage alone, hemorrhage followed by reperfusion (the infusion of shed blood) was found to abolish the compensatory increased splanchnic release of PGI2 and hence worsen splanchnic hypoperfusion (34,35,67). Subsequent studies showed that the reperfusion-induced decrease in splanchnic PGI2 synthesis and SMA blood flow were restored to control levels by treatment with superoxide dismutase, a scavenger of ODFRs (67,68). These studies supported the notion that ODFRs were involved in the regulation of splanchnic PGI2 synthesis following acute hemorrhage and shock followed by reperfusion (SK þ R). These studies were the first to show that ODFRs contribute to the regulation of prostacyclin synthesis in the whole organ, supporting earlier studies by Egan et al. who demonstrated similar findings in cell-free systems (68,69). Recent studies have examined the effect of allopurinol and pentoxifylline on splanchnic PGI2 release following intestinal reperfusion injury (70). In these experiments, the SMA of rats was occluded for 20 minutes with a microvascular clip; release of the clip allowed reperfusion for 30 minutes. Treatment of the animals with pentoxifylline protected splanchnic PGI2 release whereas pretreatment with allopurinol, a xanthine oxidase inhibitor (71), had no demonstrable effect on the release of prostacyclin. Although this study did not specifically examine the mechanism of pentoxifylline protection of splanchnic PGI2 release following severe splanchnic IR injury, previous reports have shown that pentoxifylline increased tissue oxygenation, increased oxygen consumption, decreased leukocyte adhesiveness, and increased intestinal microvascular blood flow (72–75). Pentoxifylline has been proposed to improve intestinal microvascular blood flow by decreasing leukocyte ‘‘plugging’’ of microvasculature. This hypothesis was supported by in vitro studies demonstrating that pentoxifylline increased leukocyte deformability, decreased leukocyte adherence, enhanced chemotaxis, and blocked the action of inflammatory cytokines on leukocyte function (76–80). Several investigators have also demonstrated that pentoxifylline inhibits cytokine [tumor necrosis factor (TNF), interleukin-1]-induced neutrophil activation, thus preventing lysosomal degranulation, superoxide production and neutrophil adhesion to endothelium (80). Although the exact mechanism by which pentoxifylline protects endogenous splanchnic PGI2 release following intestinal IR injury is unknown, one can postulate that maintaining splanchnic microcirculatory flow during periods of ischemic or hemorrhagic shock is a worthy goal that, if achieved, may prevent intestinal barrier failure and its sequelae.

Oxygen-Derived Free Radicals Intestinal reperfusion injury has been associated with ODFRs (e.g., O2
, H2O2, and OH
) since the early 1980s (24,31). This work has been summarized by Granger et al. (81) and is illustrated in Figure 12. It is postulated that during ischemia, adenosine triphosphate (ATP) is catabolized to

ISCHEMIA

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ATP

AMP

Adenosine

Inosine

Xanthine Dehydrogenase Fe 2+ Fe3+

Hypoxanthine

Xanthine Oxidase

SOD Xanthine + O 2H2O2

OH-+ OH-

O2

REPERFUSION Peroxidation of membrane phospholipids DNA strand breakage Degradation of hyaluronic acid Altered intracellular metabolism reduced ATP production disrupted intracellular Ca homeostasis Neutrophil chemotaxis Complement activation Inhibition of Prostacyclin release Increase Thromboxane release Inactivation of constitutively released nitric oxide Formation of peroxy nitrite upon reaction with nitric oxide

hypoxanthine, which accumulates within the ischemic intestine. Simultaneously, xanthine dehydrogenase is converted to xanthine oxidase, which upon reperfusion (with the reintroduction of molecular oxygen) catalyzes the formation of xanthine from hypoxanthine. Superoxide anion (O2
) is produced as a by-product of this reaction and may then be converted to hydrogen peroxide (H2O2) and hydroxyl radicals. The evidence supporting a role for xanthine oxidase– generated ODFRs in the local intestinal reperfusion injury has been summarized by Zimmerman et al. (83) and includes the following observations: (i) The intestinal mucosa is a rich source of xanthine oxidase. (ii) During intestinal ischemia, xanthine dehydrogenase is rapidly converted to xanthine oxidase (e.g., within the first hour of ischemia there is a six- to eightfold increase in xanthine oxidase). (iii) During intestinal ischemia there is a 10- to 20-fold increase in the concentration of hypoxanthine. (iv) Inhibitors of xanthine oxidase attenuate reperfusioninduced changes in intestinal microvascular permeability and mucosal injury. (v) Protease inhibitors, which prevent the conversion of xanthine dehydrogenase to xanthine oxidase, protect against reperfusion-induced intestinal injury. (vi) The intra-arterial infusion of hypoxanthine and xanthine oxidase increases vascular permeability in normal bowel to the same extent as observed in the postischemic intestine (an effect prevented by superoxide dismutase). (vii) Pretreatment with allopurinol (an inhibitor of xanthine oxidase) prevents the increased spontaneous chemiluminescence (an index of oxidant production) observed following reperfusion of the ischemic intestine. The mechanisms by which reperfusion-induced ODFR generation alter intestinal microvascular and epithelial integrity include the peroxidation of microvascular plasma membrane components

Figure 12 Hypothesis for events contributing to reduced splanchnic perfusion following intestinal IR injury. IR injury induces splanchnic vasoconstriction through two simultaneous actions, through the splanchnic vascular bed and through the systemic circulation. IR induces local splanchnic production of ODFRs, which originate from either the splanchnic bed or activated neutrophils. ODFRs downregulate endogenous splanchnic vasodilator synthesis (NO and PGI2). Neutrophils, activated by IR or potent circulating factors such as TxA2, LTB4, PAF, TNF, or a variety of cytokines, may contribute to splanchnic ischemia by microcirculatory plugging and release of potent vasoconstrictors such as TxA2 or LTC4. IR injury upregulates production of cytokines, PAF, etc., and activated complement. The net result is neutrophil activation, which contributes to production of ODFRs, and microcirculatory plugging, which can occur in the splanchnic bed or distal visceral beds such as the kidney, lung, heart, etc. Abbreviations: ATP, adenosine triphosphate; AMP, adenosine monophosphate; ODFRs, oxygenderived free radicals; IR, ischemia-reperfusion; PAF, platelet-activating factor; TxA2, thromboxane A2; TNF, tumor necrosis factor; LTB4, leukotriene B4; NO, nitric oxide; SOD, superoxide dismutase; PGI2, prosta cyclin I2. Source: From Ref. 82.

(84), degradation of hyaluronic acid (84), DNA strand breakage (85) and altered intracellular metabolism with reduced ATP production (86), and disrupted intracellular calcium homeostasis (87). These effects may alter microvascular integrity by impairing endothelial cell function and viability and disrupting the integrity of the interstitial matrix and capillary basement membrane (84–87). The role of endothelials cells, is likely to be particularly significant because they are considered to be an important endogenous source of ODFR production during IR injury (88). Furthermore, immunolocalization studies have demonstrated that hypoxia increases the activity of xanthine oxidase in cultured endothelial cells (88). In addition to directly mediating tissue injury, ODFRs may be particularly important in orchestrating the local inflammatory response. Granulocyte activation and adherence to the microvasculature is linked to the formation of reactive oxygen metabolites. Evidence for this includes the observation that scavengers of O2
and H2O2 inhibit reperfusion-induced splanchnic leukosequestration and neutrophil–endothelial cell adherence (83,89,90). The mechanism by which this occurs is unclear although O2
–mediated inactivation of NO (the constitutive release of which acts as an important endothelium-derived antiadhesion molecule) has been postulated (22). Other potential mechanisms involve H2O2-mediated generation of PAF (91) and complement activation with the formation of the potent anaphylatoxins C3a and C5a (92,93). Reactive oxygen intermediates may also contribute to reperfusion injury by altering the function and integrity of normal autoregulatory mechanisms in the intestinal microvasculature. As alluded to previously, O2
may inactivate NO with subsequent vasoconstriction, neutrophil and platelet

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adherence, and enhanced microvascular permeability (22,94,95). Furthermore, previous studies in our laboratory have demonstrated that the compensatory release of PGI2 by the ischemic intestine is inhibited by ODFRs upon reperfusion (35,67)—an event corresponding temporally to a marked reduction in splanchnic perfusion (35,57,58,67).

Neutrophils Within minutes of intestinal reperfusion, neutrophils are sequestered in the splanchnic, pulmonary, and hepatic microvascular beds. Activated neutrophils are thought to play an important role in the altered intestinal mucosal permeability (96) and microvascular dysfunction (56) associated with reperfusion injury. Evidence for this relationship has been derived from studies in which depletion of neutrophil numbers [with antineutrophil serum (56,96) or cytotoxic agents (58)] or inhibition of neutrophil–endothelial cell adherence [with specific monoclonal antibodies against adherence receptor glycoproteins (56,96)] was shown to protect the mucosal epithelium and microvascular membrane from reperfusion injury. These studies suggest that neutrophil infiltration is a cause, rather than an effect, of reperfusioninduced microvascular injury in the intestine (56). There are several mechanisms by which the sequestered neutrophils may mediate reperfusion-induced tissue injury. The large size and poor deformability of activated neutrophils, coupled with their ability to establish receptormediated adhesive interactions with the endothelium, may contribute to the capacity of these cells to obstruct the microcirculation during IR (59,97). Furthermore, previous studies have related neutrophils activated during hemorrhage resuscitation to inhibition of the release of the potent vasodilator PGI2 by the splanchnic bed (58). The activation of neutrophils and their emigration through the microvascular endothelium are also associated with the generation of a variety of cytotoxic substances including ODFRs, proteases, cationic proteins, and collagenase, which may disrupt microvascular barrier integrity. The mechanisms by which neutrophils are activated during IR have been examined by a variety of investigators. Reperfusion-induced neutrophil infiltration and tissue injury has been related to xanthine oxidase activation and the generation of O2
, H2O2, and the hydroxyl radical (89,90,98). The activation of complement with the generation of the anaphylatoxins C3a and C5a (92,93), the local release of PAF (99), impaired endothelial NO release (22) and local generation of LTB4 and TxA2 (83) also likely contribute to neutrophil–endothelial cell interaction with subsequent emigration and neutrophil-mediated tissue injury.

Complement Intestinal reperfusion injury induces the activation of the alternate and classical complement cascades, with the generation of C3a and C5a (93,100). Complement activation has also been associated with other models of local tissue injury including skeletal muscle reperfusion (101) and thermal cutaneous injury (93). Hill et al. related the local intestinal reperfusion injury to the activation of complement in an experiment in which soluble complement receptor 1 was found to attenuate histologic evidence of the injury. One mechanism by which this appeared to occur was by inhibiting the sequestration of neutrophils into the intestine (100). Other potential mechanisms by which activated complement fragments may contribute to the local intestinal reperfusion injury include the formation of a membrane attack complex (C5b-9) with direct injury to the microvascular

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endothelium and complement-mediated release of TxA2 and other proinflammatory vasoactive substances.

Nitric Oxide A variety of investigators have examined the role of NO in maintaining splanchnic microvascular function in normal and pathologic states (including intestinal reperfusion injury) (18,20,21). Studies by Kubes and coworkers have demonstrated in normal intestine that inhibition of the constitutive release of NO increases splanchnic vascular resistance, enhances microvascular permeability, and promotes neutrophil–endothelial cell interaction (22,94,95). Inhibition of the endothelial isoform of NO synthase [e.g., with NGnitro-L-arginine (L-NAME)] has been shown to markedly exacerbate reperfusion-induced intestinal microvascular permeability (20,21). In one series of studies, L-NAME caused a threefold increase in reperfusion-induced protein extravasation and a twofold increase in mucosal permeability over that associated with reperfusion injury alone (18,21). In this study, the infusion of exogenous sources of NO attenuated reperfusion-induced changes in microvascular and mucosal permeability but failed to significantly improve splanchnic blood flow, suggesting that the beneficial effect of NO in this model is not limited to its role as a potent vasodilator. As discussed earlier, the constitutive release of NO by the endothelium also has important effects on neutrophil– endothelial cell interaction (22,102), which may be of particular significance given the well-recognized effect of IR on neutrophil activation and recruitment (22,77). The nonselective inhibition of NO synthase with NG-monomethyl-Larginine or L-NAME has been shown to increase neutrophil adhesion to postcapillary venules more than 15-fold and neutrophil emigration more than threefold; an effect thought to be mediated through the leukocyte adhesion glycoprotein CD11/CD18 (95). Gaboury et al. suggested that the antiadhesive action of NO might be a result of its ability to inactivate the superoxide radical (22). This mechanism of action may be of particular importance in ODFR injury because the superoxide radical is thought to be involved in the neutrophil sequestration characteristic of this injury (89,90). Lastly, NO may directly affect microvascular permeability by an early (< 10 minutes) neutrophil-independent effect. Inhibition of NO release with L-NAME increases microvascular leakage of protein even prior to neutrophil adherence and emigration in the postcapillary venule (95). The mechanism by which this occurs appears to be complex, involving cyclic guanosine monophosphate, PAF, and alterations in the endothelial cell cytoskeleton (95). These data suggest that inhibition of the constitutive release of NO by L-NAME may directly enhance reperfusion-induced splanchnic microvascular permeability.

Remote Organ Injury Following Intestinal IR Intestinal IR incites a generalized inflammatory response characterized by the appearance of activated complement fragments, neutrophils, eicosanoids, endotoxin, and cytokines within the circulation (103–106). Many of these substances serve to direct, amplify, and disseminate the inflammatory response as is outlined in Table 1. This generalized inflammatory state culminates in injury to the lungs, liver, heart, and kidneys (103). An in-depth discussion of the pathophysiology of remote organ injury following intestinal IR is beyond the scope of this chapter and the reader is provided with references to examine this important area of pathophysiology (Fig. 11) (103–106).

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Clinical Syndromes That Provide Insight into Intestinal IR Injury There are a number of examples of clinical conditions associated with intestinal reperfusion injury, which provide clinical relevance for the many laboratory studies examining the local and remote consequences of this condition. Furthermore, examination of these clinical conditions allows greater insight into the pathophysiology of intestinal reperfusion injury, particularly because it relates to the balance between vasoactive paracrine and circulating mediators. This section will concentrate on presenting clinical conditions not commonly associated with intestinal IR. A comprehensive list of presplanchnic, splanchnic, and postsplanchnic causes of intestinal reperfusion injury is shown in Figure 9. The most common causes of mesenteric ischemia are presplanchnic in location and have been termed ‘‘nonocclusive mesenteric ischemia’’ (NOMI). The principal physiologic abnormality is reduced cardiac output, which may be the consequence of reduced preload, impaired contractility, or increased afterload. Hypovolemia due to hemorrhage, third-space fluid losses, diarrhea, vomiting, and hemodialysis is an extremely common cause of NOMI. Several studies have related hemodialysis to the development of NOMI. In one study, 9% of deaths of patients undergoing chronic hemodialysis deaths were due to NOMI. Furthermore, of those patients that developed NOMI, 75% died (107). The treatment of these patients includes prompt reversal of the hypotension, papaverine infusion, and subsequent avoidance of hypotension during dialysis (108). Another common cause of NOMI is impaired cardiac contractility that is associated with acute myocardial infarction, congestive heart failure, or cardiac arrest. Gaussorgues et al. related cardiac failure to mesenteric ischemia and altered intestinal integrity by documenting the presence of enteric bacteria within the bloodstream following cardiac arrest (109). In this study, 13 of 33 patients sustaining cardiac arrest (average duration 18 11 minutes) and undergoing cardiopulmonary resuscitation (average duration 6 4 minutes) were bacteremic within 12 hours of their cardiac arrest. In every case but one, the organism was a normal constituent of the enteric flora. Furthermore, all of these patients with enteric flora within their bloodstream died. This study provides further evidence supporting the hypothesis of bacterial translocation due to altered intestinal integrity following low flow states such as cardiac arrest (109). Lastly, Hebra et al. reported on 387 patients studied with hypoplastic left heart syndrome, of whom nearly 10% developed acute mesenteric ischemia at an average age of 17.5 5.4 weeks. Nearly 80% of these patients had documented low flow state with hypotension before the development of NOMI. The mortality rate for this group of patients was greater than 80% (110). This study provides clinical correlation for the experimental work previously described in pigs by Bulkely and coworkers (111,112). Several studies have demonstrated the importance of maintaining a balance of endogenous splanchnic vasodilators to counterbalance the normal constant adrenergic stimulus of norepinephrine release. Commonly used medications can alter this delicate balance either from normal usage or abuse. Petti et al. reported one case of a 19-year-old patient who presented with isolated NOMI following an overdose of the b-blocker propranolol. The splanchnic ischemia present in this patient was thought to be mediated by the unopposed a-adrenergic activity of the splanchnic adrenergic nervous system (113). Digitalis has also been shown to cause

splanchnic vasoconstriction with resultant increased splanchnic vascular resistance. The mode of action of digitalis in the splanchnic vascular bed is hypothesized to be mediated by increased vascular smooth muscle tone of splanchnic resistance and capacitance vessels and by increasing a-adrenergic tone (114). A study in normal volunteers showed that the decrease in splanchnic blood flow found following digitalis administration could be blocked by diltiazem, a calcium channel blocker (115). Calcium mediation of splanchnic vasoconstriction is not limited to digitalis. A more recent study in animals by Rego et al. showed a similar mechanism of action for cyclosporine-induced splanchnic vasoconstriction. Cyclosporine potentiation of isolated rat mesenteric arterial vasoconstriction was shown to be mediated by transmembrane calcium transport and exaggerated release of calcium, which could be blocked by use of calcium channel blockers (116).

Summary of Intestinal IR Injury From the material presented in the foregoing discussion, one can formulate a hypothesis encompassing intestinal IR injury. Intestinal IR injury (from any injury model) results in the local production of ODFRs that induce downregulation of endogenous splanchnic vasodilators and as a result, decreased splanchnic blood flow, loss of intestinal barrier function, and activation of neutrophils, complement, and other potent inflammatory mediators. The activated neutrophils, complement, and inflammatory mediators alter distant organ function by the interaction of the distant organ with neutrophil-mediated ODFR release, LTB4, or other neutrophil-derived factors. Circulating activated neutrophils interact with all distant organs (and the intestine) with varied effects on local autocrine factors, which contribute to altered organ function. The combination of microcirculation ‘‘plugging’’ by the activated neutrophils and the release of potent vasoactive compounds both contribute to organ dysfunction.

CLINICAL EVALUATION OF INTESTINAL BLOOD FLOW The diagnosis of acute mesenteric ischemia still relies on the clinician having a high index of suspicion for this disease. The incidence of acute mesenteric ischemia is 1% of admissions to tertiary medical centers but continues to rise due to increased awareness of this disease. The presentation of the patient with acute abdominal pain over the age of 50 and with cardiac arrhythmias, long-standing congestive heart failure, recent myocardial infarction, or hypotension should raise the awareness of the clinician. In all reported series, acute abdominal pain is the most common presenting symptom, which is usually out of proportion to the physical findings. Over the past several decades, various laboratory parameters have been examined with regard to specificity for acute mesenteric ischemia. Leukocytosis above 15,000 cells/mm3 is present in 75% of these patients. Approximately 50% of these patients present with a metabolic acidosis. The finding of an acid–base disturbance implies a serious systemic illness, and no study has proved that either an acidosis or a base deficit is a reliable predictor of intestinal ischemia. Elevated serum levels of amylase, alkaline phosphatase, lactate dehydrogenase, aspartate transferase, D-lactate, phosphate, and creatinine kinase and its isoenzymes have all proven to be nonspecific with regard to the diagnosis of acute mesenteric ischemia. All of these

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laboratory tests when positive may be more of an indication of advanced disease or of other GI emergencies (117–123). Several techniques do hold promise in aiding the diagnosing of acute mesenteric ischemia. Analysis of peritoneal fluid and tonometric analysis of intraluminal pH of the different areas of the GI tract may in the future provide insight into the diagnosis of acute mesenteric ischemia. The limitation of these or any other tests used to diagnose acute mesenteric ischemia is the delay of time, which can adversely affect survival in these acutely ill patients (124–127). The use of Duplex scanning and Doppler flowmetry has been examined in these patients. Duplex sonography can aid in the diagnosis of acute mesenteric venous thrombosis of the SMV and portal veins. However Duplex scanning can only identify a lesion in the origin of major splanchnic arteries and cannot identify more distal mesenteric arterial pathology. The Duplex scan can therefore be used as a screening measure while the patients awaits transport to angiography suite or the operating room. Further description of the use of the Duplex scan and the radiologic evaluation of patients with acute mesenteric ischemia is described in the next section (13).

RADIOLOGIC EVALUATION OF PATIENTS WITH ACUTE MESENTERIC ISCHEMIA If the clinician suspects the diagnosis of acute mesenteric ischemia, rapid early arteriography is considered the next step. Arteriography is the only diagnostic modality that been shown to improve survival before infarction and prior to laparotomy if it can be performed without delay. Although the radiologic techniques listed below can be useful in the diagnosis of acute mesenteric syndromes, the clinician must consider the critical factor of time delay until definitive treatment is obtained with the potential of each modality to provide significant information to help in the diagnosis and treatment of these severely ill patients.

Plain Films The results of plain radiography are nonspecific and have a very low sensitivity in patients presenting with acute mesenteric ischemia (128,129). The most common finding is a nonspecific ileus pattern with dilated fluid-filled loops of bowel, but findings can also be minimal. Other findings that can be found on plain radiologic films include thickening of the bowel wall secondary to submucosal hemorrhage (thumbprinting) and separation of bowel loops caused by mucosal thickening, intramural gas, and mesenteric or portal venous gas. These findings when present usually indicate advanced disease (Fig. 13A) (129,131,132).

Ultrasound The findings identified by ultrasound are nonspecific for acute mesenteric ischemia. These include distended bowel loops, decreased peristalsis, ileus and peritoneal fluid collections. Flow abnormalities or the presence of thrombi within the origin of the mesenteric vessels increase the diagnostic accuracy (133,134). The presence of intramural gas and fluid collections are signs of necrosis of the intestinal wall (133). Ultrasound examination can demonstrate thrombosed mesenteric vessels that appear as tubular dilated structures filled with echogenic material. Duplex and color Doppler sonography can identify absence of flow and complete occlusion of the mesenteric vessels; however this technique cannot

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reliably exclude peripherally located thromboemboli. Use of ultrasound has several major limitations that one must appreciate. These include the lack of patient cooperation, air-filled distended bowel loops, which can obscure the acoustic window, and the lack of skill and inexperience on the part of the person performing the ultrasound study (135). Ultrasound has also been shown to be a poor correlation between flow parameters and the severity of the intestinal ischemia (136,137). One must consider the added time delay of patients being evaluated with ultrasound with obtaining definitive diagnosis and treatment.

Angiography The use of angiography continues to be the most reliable method for diagnosing acute mesenteric ischemia. The main advantage of angiography over all other methods is twofold. First, one can make a rapid diagnosis of the origin of the acute mesenteric ischemia. The sensitivity of angiography for diagnosis of acute mesenteric ischemia approaches 90% (128,130). The findings of an abrupt cutoff of the vessel without evidence of collateral flow are considered diagnostic of an acute thromboembolic event. Second, angiography allows immediate therapy with either fibrinolytic agents or vasodilating agents. The disadvantages and risks of angiography include risk from the use of an invasive procedure (bleeding, femoral artery injury or occlusion, distal emboli, false aneurysm formation, arterial to venous fistula, etc.), nephrotoxicity of the dye, time delay from surgery treatment, and the cost. In the diagnosis of mesenteric thrombosis, the SMA origin is most commonly involved; but all three mesenteric vessels can be involved. Acute emboli typically lodge within several centimeters of the origin of the SMA. SMA emboli can also lodge at the orifice of the middle colic artery or at the origin of the right colic and ileocolic arteries. SMA emboli have a high association with other peripheral embolic events (Figs. 14 and 15) (13). The SMA is the most commonly symptomatic mesenteric vessel affected by NOMI. The angiographic findings associated with NOMI include segmental mesenteric arterial constriction, alternating areas of narrowing and dilatation of SMA branches, and spasm of the arcades. Both anteroposterior and lateral arteriographic views are necessary to adequately evaluate the arterial tree and accurately exclude mesenteric thrombosis. The selective infusion of vasodilating agents (0.5 to 1.0 mg/min papaverine) has been advocated to maintain intestinal perfusion in both the occlusive and nonocclusive forms of acute mesenteric ischemia. The selective infusion of vasodilators in patients diagnosed with NOMI prior to bowel infarction may relieve the arterial spasm and prevent the need for operative intervention (Figs. 16 and 17). Use of thrombolysis with and without angioplasty has been reported in several small series. In one series, over a threeyear period, 10 patients who presented with acute SMA emboli, normal abdominal examination, and normal abdominal plain films were treated with thrombolytic therapy. Seven of the 10 patients had successful clot lysis and did not require surgical treatment (141).

Barium Studies Barium studies should not be attempted in patients with acute mesenteric syndrome because the barium interferes with angiography and in the presence of bowel perforation can initiate an intense inflammatory reaction in the peritoneal cavity. Barium enema is occasionally performed in patients with atypical presentation of abdominal pain,

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Figure 13 A 60-year-old man with a history of mycoardial infarction, weakness, hypotension, fever, and acute abdominal pain. (A) Plain film of the abdomen shows distended loops of small bowel and some gas in the stomach and right colon. (B) An emergency superior mesenteric angiogram shows no evidence of vasoconstriction. The arcades in the right colon are prominent. (C and D) A barium enema shows extensive submucosal edema of the descending colon to the splenic flexure, manifested by thumbprinting; this is diagnostic of ischemic colitis. The patient resolved all symptoms over several days of conservative treatment and appropriate resuscitation. Follow-up barium enema showed no abnormality. Source: From Ref. 130.

when acute mesenteric ischemia is not suspected. Radiologic findings of acute ischemia include thumbprinting, bowel dilatation, thickened folds, ulceration, stasis of the barium, and effacement of the mucosal pattern (134,142). Upper GI tract barium studies in patients with acute mesenteric ischemia can demonstrate thickened folds, ulcerations, stasis of barium in the affected bowel, and stenosis (Fig. 13) (134,142–144).

Computed Tomography The early reports of computed tomography (CT) accuracy using first- and second-generation scanners were not favorable (41,134). The introduction of spiral CT and rapid bolus injection of contrast markedly improved the capability of CT to identify the bowel wall and and mesenteric vessels. CT sensitivity in the diagnosis of acute mesenteric ischemia

has ranged from 64% to 82% (128,134). CT finding specific for acute mesenteric ischemia includes splanchnic vascular occlusion, intramural gas, lack of bowel wall enhancement, and infarcts of the kidney, liver, and spleen (129,145). CT cannot detect early reversible mesenteric ischemia and cannot be used for treatment. Recent advances in CT development have resulted in the multidetector row CT, which combines multiple rows of detectors, faster gantry rotation, and narrow collimation (146). This technique can provide more detailed anatomic information about the intestine and mesenteric vessels. Use of three-dimensional (3D) volume rendering and maximum intensity projection imaging will be able to display the mesenteric vessels in a manner similar to conventional angiography (146). In a recent study, use of the biphasic CT with mesenteric CT angiography showed that the finding of any one of pneumatosis

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Figure 14 Example of a SMA embolus. (A) Plain film shows no definite abnormality. There is normal distribution of gas in the stomach and small bowel. (B) A superior mesenteric arteriogram shows a filling defect in the main portion of the SMA; the arrow indicates the location of the embolus. Abbreviation: SMA, superior mesenteric artery. Source: From Ref. 138.

intestinalis, venous gas, SMA occlusion, celiac and IMA occlusion with distal SMA disease, or arterial embolism was 100% specific but only 73% sensitive in diagnosing acute mesenteric ischemia. A finding of bowel wall thickening in addition to focal lack of bowel wall enhancement, solid organ infarction, or venous thrombosis was 50% sensitive and 94% specific. Use of either of these criteria or the diagnosis showed a sensitivity of 96% and a specificity of 94% (147). Figure 18 depicts a CT scan performed for a patient with advanced intestinal ischemia with probable bowel wall necrosis.

Magnetic Resonance Angiography

Figure 15 Example of an acute SMA thrombosis. The lateral projection of the abdominal aortogram shows occlusion of the SMA (arrow) within the first centimeter of the origin. There is intense vasoconstriction of the celiac and renal arteries. Abbreviation: SMA, superior mesenteric artery. Source: From Ref. 138.

Magnetic resonance angiography (MRA), over the past decade, has evolved from a research tool to a clinical diagnostic modality. Because of the urgent need for treatment of acute mesenteric ischemia, MRA is only rarely utilized. Vascular visualization with MR has been greatly improved by the introduction of 3D gadolinium-enhanced MRA. MRA was shown in an experimental model to have similar sensitivity and specificity to digital subtraction angiography. MRA can show in situ thrombosis of the SMA, as well as visualization of collateral vessels. MRA is far less sensitive in identifying emboli that are more peripheral in the mesenteric bed. Dual-phase contrast-enhanced (CE) 3D MRA has been shown to be highly accurate in the diagnosis of SMV and portal vein thrombosis. MRA has as established role for chronic mesenteric ischemia (149). Despite the advances in CT and MRA, these modalities are of value in diagnosis but cannot, like conventional angiography, provide therapeutic benefit. Therefore conventional angiography remains the gold standard for the evaluation of acute mesenteric ischemia.

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Figure 16 NOMI with reversal. Seventy-four-yearold-man had congestive heart failure and pulmonary edema. Treatment with diuretics and digitalis. On the fourth day, the patient developed diffuse abdominal pain and abdominal distention. (A) Plain abdominal radiography shows pattern of nonspecific distention of the colon and small bowel, which is consistent with but not diagnostic of mesenteric ischemia. (B) Selective superior mesenteric angiogram, arterial phase, demonstrates diffuse abdominal spasm and impaired visualization of the intestinal arcade. (C) Selective SMA angiogram following a 16-hour therapeutic papaverine infusion demonstrates reversal of the vasoconstriction with the reappearance of the intestinal arcades. Abbreviations: NOMI, nonocclusive mesenteric ischemia; SMA, superior mesenteric artery. Source: From Ref. 139.

INTRAOPERATIVE ASSESSMENT OF INTESTINAL VIABILITY The intraoperative assessment of bowel viability is an important component of the operative treatment of acute mesenteric syndromes and is of importance in the immediate survival of the patients and ultimately the long-term outcome of those patients who survive the acute insult. The

three major techniques that are utilized for intraoperative assessment of bowel viability are clinical judgment, use of the pencil-like sterile Doppler ultrasonic flow probe, and use of fluorescein and inspection under Wood’s lamp. Other techniques (such as laser doppler flowmetry and pulse oximetry) have been used, but are not as well accepted (13). Clinical assessment of bowel viability includes detecting pulsation in the arcades, color of the bowel, peristalsis,

Figure 17 Diagrammatic representation of intestinal vasoconstriction before and after reversal as seen in Figure 16B and C. Source: From Ref. 140.

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Figure 18 CT scan showing gas (arrow) in the portal veins (A) and gas (arrows) in the wall of the mesentery, and mesenteric vessels (B). Pneumatosis is a late sign of ischemic injury, connotes bowel necrosis, and mandates exploration. Abbreviation: CT, computed tomography. Source: From Ref. 148.

and bleeding from the cut edges. The clinical assessment of bowel viability depends on the experience of the surgeon and the obvious absence of these entities in the infarcted bowel. The surgeon first removes the infracted or necrotic bowel. Next, warmed, moist packs are applied to the bowel of questionable viability and adequate time (15–30 minutes) allowed to pass before further bowel resection is performed. For areas of continued questionable bowel viability secondlook procedures are performed 24 to 48 hours after the first laparotomy, followed by repeat laparotomy and further bowel resection, if needed. The downside to the second-look operation is the potential of exposing the patient to additional anesthetic and metabolic stress during the time prior to the second laparotomy. Clinical assessment is often complemented by the use of the pencil sterile Doppler probe. The small pencil-shaped probe is first tested on the larger vessels such as the abdominal aorta. The Doppler probe is gently applied to the antimesenteric border of the bowel wall and to discrete mesenteric flow. Obtaining a pulsatile arterial signal is an indication of blood flow to that particular bowel segment; however one must be aware that this technique only indicates presence or absence of flow and does not quantify the amount (150,151). This technique has scientific support based on several animal models and clinical series (152). One obvious limitation is the lack of sensitivity in small, patchy areas of questionable bowel viability in the presence of inadequate bowel wall blood flow (150–154). The second technique used in combination with clinical assessment to assess intraoperative bowel viability is the fluorescein dye technique. Fluorescein dye is an organic compound that enters viable intestine within minutes of IV injection. Fluorescein emits a gold-green fluorescence when it is exposed to ultraviolet light in the range of 3600 to 4000 nm. Two ampules (1000 mg) are injected over 60 seconds intravenously. The operating room lights are turned off and the bowel exposed to a Wood’s lamp (3600 nm). The gold-green fluorescence provides evidence of viable intestine whereas the absence of fluorescence demonstrates nonviable intestine. This technique has a 96% sensitivity and a 95% specificity for arterial ischemic syndromes (13,155–157). The dye itself can cause nausea and vomiting and, rarely, anaphylaxis (156). Unfortunately the dye presence has a long half-life and repeat use can only be done after 48 hours. Several series have described the sensitivity as 100% and the specificity to be 100% whereas the figures were 50% and 58%, respectively, for Doppler ultrasonography. In this study, clinical judgment had a sensitivity and specificity of 82% and 91% (154–158).

These data really support the combined use of clinical judgment and the use of the Doppler and/or the fluorescein techniques.

DISEASES THAT AFFECT THE VISCERAL VESSELS Occlusive disease of the visceral vessels can be divided into acute and chronic presentations and can affect either the arterial or the venous visceral vessels. Separate categories of disease will be presented, as well as descriptions of presentations following disease of each visceral artery. Acute visceral syndromes include acute emboli, in situ thrombosis of the visceral arteries, NOMI, and mesenteric venous thrombosis. A major difficulty with treatment of the acute visceral syndromes is the nonspecific presentation of the patients. The patients commonly present early in the disease with abdominal pain out of proportion to the abdominal examination. This presentation can occur in up to 90% of these patients, but not in all patients. The presentation of abdominal crisis, spontaneous bowel evacuation, and significant cardiac disease has been described as Bergan’s Triad for this disorder. Affected patients are often younger, with no prior intestinal angina symptoms (13,159–163). A majority of these patients who present with acute mesenteric disease are elderly and over 70% present over the age of 60. Nausea, vomiting, and diarrhea may be present but these are not consistent findings. Bowel sounds may be hyperactive in the early stages of the disease and disappear later following necrosis of the bowel. The patients’ temperature may be normal in the early stages of the disease to markedly elevated following bowel necrosis. Patients who present with acute mesenteric ischemia may present with melena or occult blood in up to 75% of patients. A pre-existing history of myocardial infarction and/or atrial fibrillation may indicate acute emboli as the etiology of mesenteric ischemia, whereas a preexisting history of chronic mesenteric ischemia can indicate the etiology as being in situ thrombosis. The most consistent laboratory finding is the immediate elevation of the white blood count. This elevation ranges from 16,000 to 35,000 cells/mm3. The presentation of the patients can range from severe abdominal pain to one of shock due to sepsis or volume depletion due to bowel perforation or necrosis. It should be emphasized that there are no consistent symptoms or physical findings in the presentation of patients with acute mesenteric ischemia. Development of peritoneal signs (abdominal tenderness, rebound, etc.) unfortunately usually indicates progression of the disease to bowel infarction and increased mortality. To minimize morbidity and

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mortality, the patients who present with acute mesenteric ischemia require rapid diagnosis, stabilization and correction of medical and metabolic problems, and use of invasive cardiovascular monitoring prior to and during definitive treatment of the underlying pathology (13,159–163).

Acute Diseases That Affect the Visceral Vessels Acute Embolus More than 95% of all emboli involving major abdominal visceral arteries originate from the heart and the aortic wall but unusual emboli include those from bronchogenic carcinoma, atrial myxoma, aortic or mitral valvular prostheses, and the proximal aortic wall (164). Paradoxical embolization in which the embolus arises in the peripheral venous system can occur but is quite rare. Acute mesenteric emboli can constitute up to 50% of all acute mesenteric syndromes (13,159–164). These patients normally do not have an antecedent history of chronic visceral angina but do have a history of preexisting cardiac disease such as atrial fibrillation (up to 70%), myocardial infarction, rheumatic heart disease arterial emboli. The majority of acute emboli to the mesenteric arteries affect the SMA, with a total of 5% of all peripheral arterial emboli affecting this vessel. This may be secondary to the acute angle of the SMA takeoff from the aorta, which allows easy entry of the embolus (Figs. 14 and 15). The celiac axis is not as affected by symptomatic acute emboli as the SMA. The may be due to either the right angle origin of the vessel from its takeoff from the aortic wall, or because of the excellent collateral flow of the celiac axis. An embolus to the celiac axis would most likely lodge at the trifurcation and allow adequate collateral flow from the SMA via the gastroduodenal branches to supply the entire distribution of the hepatic, left gastric, and splenic arteries. In contrast, emboli to the SMA usually comes to rest beyond the origin of the middle colic artery. Distal to the origin of the inferior pancreaticoduodenal arteries and the middle colic artery, the SMA narrows. At this area in the SMA there is little chance for collateral blood flow and the presentation of the patient will most likely be acute with small bowel necrosis. The distribution of emboli to the branches of the SMA are as follows: the middle colic artery (55%), right colic artery (16%), ileocolic artery (7%), or smaller peripheral branches (4%). Emboli involving the IMA are uncommon; however, they have been seen after manipulation of an atherosclerotic aorta. This may cause atherosclerotic debris to be broken off with subsequent embolization and infarction of the sigmoid colon (13,159–165).

Atherosclerosis Atherosclerosis may cause obliteration of the visceral arteries either secondary to aneurysmal formation or by simple occlusion secondary to the accumulation of atherosclerotic plaques. Derrick et al. (1959) accurately described the common distribution of atherosclerotic occlusive disease within the abdominal visceral arteries (166). They demonstrated that the common site of occlusion and plaque formation was within the first several centimeters from the origin of these vessels. The main channels beyond this point are most often spared from significant atherosclerotic deposition. Reiner et al. demonstrated that although uncommon, localized areas of bowel infarction can be due to areas of occlusive disease distal to the main arterial trunks (Figs. 7 and 8) (167) and, although uncommon, they may account for a localized area of infarction. In situ thrombosis of an underlying atherosclerotic plaque can occur in the SMA, celiac trunk, or IMA (in that

order of frequency). In situ thrombosis of an underlying atherosclerotic plaque comprises 44% to 82% of all acute mesenteric ischemic events. In contrast to patients who present with acute mesenteric embolic disease, from 50% to 70% patients with in situ thrombosis present with a history of weight loss, diarrhea, abdominal pain, or the diagnosis of an abdominal bruit. The overall mortality rate associated with acute in situ thromboses averages 80%, with some series having almost two-thirds of these patients undergoing laparotomy and or massive bowel resections because of extensive intestinal necrosis. The clinical presentation and amount of bowel resection required is determined by the site of in situ thrombosis and the extent of collateral flow. Complete atherosclerotic obstruction of the visceral vessels is not infrequently encountered in asymptomatic patients undergoing angiography for other pathology. The presence of collateral systems may allow more time before evolution of bowel necrosis or may contribute to a clinical presentation that is less severe than for embolus. Nevertheless, patients presenting with abdominal pain, again out of proportion to clinical findings, with a concomitant history of cardiovascular disease should alert the clinician to consider in situ thrombosis in the differential diagnosis (13,128,130,134,159–167).

Operative Interruption of Visceral Vessels Involvement of the SMA by neoplasm of the pancreas is one indication of nonoperability. Therefore, it seems unlikely that there would be justification for ligation of the SMA during resection of the pancreas. In the event that ligation should become necessary, the interruption must be proximal to the inferior pancreaticoduodenal branches to allow adequate collateral circulation from the celiac axis. Revascularization would seem prudent in the event that the SMA must be sacrificed. This could be done by reimplantation or with a bypass graft and would ensure adequate blood supply to the superior mesenteric distribution. During a 95% pancreatectomy for chronic relapsing pancreatitis, at least one branch of the pancreaticoduodenal arcade must be preserved in the course of extensive pancreatectomy (168). This must be done to ensure adequate blood supply to the duodenum. The blood supply to the duodenum and distal common bile duct originates as segmental branches from the pancreaticoduodenal arcade. Consequently, it is imperative at the time of a 95% pancreatectomy that one of these branches be preserved as it courses along the medial border of the duodenum in order to ensure adequate viability of the duodenum and distal common bile duct. Intestinal ischemia is an infrequent but serious complication of abdominal aortic surgery. The reported incidence of significant colon ischemia varies between 0.2% and 10%, with mortality rates averaging 50% to 75% (13,159–170). In a recent large clinical review of 2137 patients, the overall incidence of clinically significant ischemia was 1.1% (171). Intestinal ischemia is seen five times less frequently after surgery for occlusive disease versus AAA repair (13,159–172). In patients with aortic occlusive disease, the IMA is usually occluded with resulting rich collateral blood flow to the left colon. In aneurysmal disease, ischemia of the left colon may follow intraoperative ligation of the IMA if collateral circulation is compromised by coexistent SMA disease, by previous bowel resection, or by congenital interruption or absence of collateral routes. Congenital anatomy that predisposes to this problem include an aberrant takeoff of the middle colic artery (usually from the right colic artery) in 20% of cases andthe absence of the marginal artery of Drummond at the splenic flexure in 7%

Chapter 17: Circulation and Vascular Disorders of the Splanchnic Vascular Bed

(173). Other factors increasing risk of left colon ischemia following repair of AAAs include prolonged cross clamp time, reoperative graft procedures, ruptured aneurysms, the presence of hypoxemia, hypotension, arrhythmias and operative colonic trauma, and digitalis toxicity (13,171– 173). The internal iliac artery is another potential source of collateral flow to the left colon. The internal iliac artery can be diseased by an atherosclerotic or aneurysmal disease that can limit its capability of providing collateral flow to the IMA. An aortoiliac steal syndrome has been described after simultaneous aortic reconstructions and lumbar sympathectomies, resulting in a 40% to 70% decrease in IMA flow (13,171–174). Although infrequent, iatrogenic injury to the IMA can cause massive small bowel necrosis when it serves as the major collateral to the small bowel via the meandering mesenteric artery. If incomplete collateral flow to the IMA (little retrograde backflow) and left colon ischemia is suspected during aortic surgery, or if the IMA shows large ascending collateral vessels on preoperative angiographic examination, one can preserve antegrade IMA flow by end-to-side aortic anastomosis (Carrel button technique) or by use of an interposition vein graft (169,175). Postoperative patients who develop bloody diarrhea or watery guaiac-positive stools 48 to 72 hours after surgery should be suspected of developing intestinal ischemia. These patients can present with symptoms ranging from mild abdominal pain to septic shock. These patients should undergo immediate sigmoidoscopy. The presence of subclinical mucosal ischemia has been reported in 4% to 7% of patients (13,169–175). If sigmoidoscopy reveals hemorrhagic ulcerations and mucosal edema with friability, the patient will require resection of all compromised colon, and end-colostomy with distal Hartmann’s procedure. Patients with more benign findings on sigmoidoscopy can be conservatively followed with repeat sigmoidoscopy 24 to 48 hours later.

Nonocclusive Mesenteric Ischemia NOMI accounts for 20% to 50% of all mesenteric infarctions in which autopsy data are included (13,60,159–167, 176). NOMI has increased in incidence as our capability of treating increasing ill patients in the intensive care unit setting has evolved. NOMI almost always involves the distribution of the SMA and usually is the result of a redistribution of cardiac output combined with an SMA stenosis (one-third of patients). The decrease in mesenteric perfusion pressure is accompanied by splanchnic vasoconstriction initiated by myogenic mechanisms. The increased release of renal AII appears to be one of the mediators that contribute to the splanchnic vasoconstriction. The intense splanchnic vasoconstriction contributes to thrombus formation in the microvasculature with significant reduction in intestinal blood flow. In hypotensive patients, both endogenously released catecholamines and/or exogenous catecholamines further constrict the splanchnic microcirculation, with subsequent local thrombus formation, capillary sludging and hemoconcentration, and finally bowel ischemia and necrosis. Patients who are not treated in a timely manner suffer a mortality rate approaching 100% (13,60,159–167,176). Any pathologic condition that can lower the cardiac output can be associated with NOMI. These include congestive heart failure, arrhythmias, cardiopulmonary bypass, cardiogenic or septic shock, administration of vasopressors and IV calcium, major thermal injuries, and pancreatitis. In particular, one should be wary of patients treated with

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digitalis, which is a potent in vitro contractor of arterial and venous smooth muscle in the gut, which simultaneously decreases splanchnic blood flow and oxygen consumption. As many as 83% of patients who present with NOMI are receiving digitalis at the time of diagnosis. The diagnosis is most commonly made in patients who are admitted to the hospital with the associated conditions listed above. The patients develop abdominal pain and evidence of a low cardiac output. The differential diagnosis includes acute cholecystitis, appendicitis, and bowel obstruction. The absence of abdominal pain in this condition is far more frequent than in occlusive mesenteric ischemia. Plain abdominal films often show only fluid-filled bowel loops. Emergent angiography is indicated and can distinguish NOMI from the occlusive syndromes and there may be a failure to visualize mesenteric vascular arcades or intramural vessels (Figs. 16 and 17). The initial treatment of this syndrome is the use of intra-arterial infusion of vasodilators (papaverine, glucagon, PGs, etc.) with concomitant aggressive attempts to normalize intravascular volume and cardiac hemodynamics. If the patients do not develop signs or symptoms of intestinal ischemia or necrosis, conservative therapy is warranted. Operative intervention and anesthesia only serve to further contribute to continued arterial spasm. Repeat angiography is then performed to document improvement or resolution of the arterial spasm. If the patient does not improve or deteriorates (suspect bowel necrosis) a laparotomy should be performed. Massive fluid replacement, cardiac support, and a continuous epidural block to decrease splanchnic vasoconstriction have been recommended after operation (13,60,159–167,176).

Mesenteric Venous Thrombosis Mesenteric venous thrombosis is the least common of the mesenteric ischemic syndromes, occurring in 5% or fewer of reported cases. Mesenteric venous thrombosis occurs in patients with predisposing conditions such as abdominal trauma, peritonitis, abdominal inflammation, abdominal trauma, portal hypertension, intra-abdominal tumors, adhesions, volvulus, decompression sickness, sickle-cell disease, polycythemia vera, coagulopathies (especially antithrombin in deficiencies and protein C and S deficiency), pregnancy, recent splenectomy, and the use of oral contraceptives. More than 40% of patients have had previous deep vein thrombophlebitis of the lower extremity. The reported age range is from 11 months to 89 years, but most series report an average age of approximately 50 years (13,159–167,177–179). Patients who present with acute mesenteric venous thrombosis have involvement of the major named veins, whereas patients with a less acute (or subacute presentation) more commonly have thrombosis of the of the smaller mesenteric veins. Patients with acute mesenteric venous thrombosis usually present with severe abdominal pain, tenderness, distention, positive fecal occult blood, and decreased bowel sounds. Experimental evidence shows that increasing venous pressure is associated with a myogenic cell–mediated reflex constriction of the arterioles, leading to more severe ischemia. The combination of increased venous pressure and arteriolar vasoconstriction contributes to massive bowel edema, cyanosis of the bowel wall, and eventually bowel necrosis. In contrast, patients presenting with subacute mesenteric venous thrombosis present with vague abdominal pain, nausea, and feelings of lassitude, which can last from days to weeks prior to examination. The pathology of the more subacute mesenteric venous

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thrombosis is thought to be thrombosis of small venules, which does not progress to involvement of the larger named veins. Progression of the venous thrombosis to involve the larger vein can lead to a progression of the symptoms as stated above (177–179). The laboratory analysis of patients with mesenteric venous thrombosis are quite nonspecific and include leukocytosis, hemoconcentration, and copious, bloody peritoneal transudate. Plain film examinations of patients with the subacute presentation are nonspecific. Findings of rigid, thickwalled segments of edematous bowel in which a small gas collection remains fixed in a straight or curved lumen on different radiographs usually implies infarcted intestine. As with acute arterial mesenteric ischemia, early selective angiography can be diagnostic, showing thrombus in the SMV, a delay in filling during the arterial phase, small artery spasm, poor emptying of arteries, failure of venous systems (including the portal vein) to opacify, reflux of contrast medium into the artery, and often opacification of thickened bowel wall as a result of transudation of contrast medium (128–131,133,134). In contrast to radiologic evaluation of patients with acute arterial mesenteric ischemia, other diagnostic modalities have been utilized with success in patients suspected of having mesenteric venous thrombosis [Ultrasound, CT, and magnetic resonance imaging (MRI)] (135– 137,141–147,149). A CE CT scan can establish a diagnosis in more than 90% of patients with mesenteric venous thrombosis and MRI has the advantage of avoiding exposure of the patient to ionizing radiation. Patients suspected of mesenteric venous thrombosis are the one group of mesenteric ischemic syndromes who benefit from early and aggressive anticoagulation and if presenting before bowel necrosis may benefit from a trial of thrombolytic therapy (13,128,134,160).

Management: The Preoperative, Operative and Postoperative Management Preoperative Management The patient at risk for acute mesenteric syndromes needs to be rapidly identified by history and presenting symptoms and signs. The patient is immediately treated with aggressive resuscitation to correct metabolic abnormalities and restore fluid volume. The resuscitation may require aggressive cardiovascular monitoring. Because of their constrictor effects on splanchnic blood flow, vasopressors and digitalis compounds should be avoided whenever possible. Antibiotic coverage is recommended when surgery is anticipated, and broad-spectrum coverage is the rule (13,159–167). Beside routine laboratory analysis, electrocardiograph (EKG), chest X-ray (CXR), and plain film of the abdomen should be obtained. This evaluation should be minimized in terms of time and the patient should, as rapidly as possible, undergo angiographic analysis of all three major splanchnic trunks to minimize bowel ischemia and necrosis. Some authorities recommend halving the usual dose of contrast medium because of these patients’ tenuous fluid balance and to avoid renal failure (128,134). Occlusion of the SMA or one of its branches with arterial spasm and a lack of collaterals (as seen with acute thrombosis) is frequently demonstrated. The splanchnic vasoconstriction seen with SMA embolization is well documented and its persistence after embolectomy may be a reason for the frequent inability to restore adequate blood flow and for the frequent late reocclusions of distal vessels. Because of this distal vasospasm, arterial vasodilators are selectively administered by

most radiologists (13,128,134,159–167). Tolazoline is used in an initial 25 mg bolus because of its rapid effect; further angiographic exposures are taken to ascertain this effect. If vasodilation is noted, a continuous intra-arterial infusion of papaverine is begun at 30 to 60 mg/hr. Glucagon at a rate of 1 g/kg/min has also been shown to improve blood flow when administered parenterally. Tolazoline is neither as safe nor as efficacious as papaverine for continuous infusion. The clinical and angiographic responses to vasodilator therapy determine the duration of the papaverine infusion, which is usually continued for 12 to 24 hours. Patients who demonstrate collateral flow and do not show signs or symptoms of severe bowel ischemia or necrosis may be candidates for thrombolytic therapy of emboli or in situ thrombotic clot and subsequent angioplasty of underlying atherosclerotic plaque. Differentiation between arterial thrombus and embolus can be difficult, and these patients should be treated for SMA embolus. The simultaneous obstruction of both celiac and superior mesenteric vessels by in situ thrombosis is usually ameliorated by restoring blood flow through just one of the involved vessels.

Interventional Management Embolus Following rapid resuscitation and demonstration of an SMA embolus by arteriography, the patient should be rapidly transported for operative management. The skin preparation in the operating room should include both legs in case autogenous vein graft or patch is required. Formal open exploratory laparotomy is performed. The bowel is rapidly assessed and arterial reconstruction is performed for any question of bowel viability. The SMA is identified by dissection through the base of the small bowel mesentery. The patient is given a bolus of heparin if it has not been started prior to arrival to the operating room. Following obtaining proximal and distal control of the SMA, a linear or transverse arteriotomy is made. The linear arteriotomy is preferred because this allows easy distal extension of the arteriotomy, if needed at the time of exploration. The formal embolectomy is performed with the use of the Fogarty catheters to remove all blood clots. Because of the small size of the SMA, a vein patch is preferred for closure of the arteriotomy. Successful removal of the clot and restoration of the SMA blood flow is confirmed by the presence of a palpable pulse and triphasic Doppler blood flow in the SMA distal to the embolectomy and the presence of arterial pulsations in the bowel mesentery. One must now observe the entire GI tract for 15 to 30 minutes to assess the need for bowel resection. The waiting period will allow the surgeon to more correctly assess which bowel requires resection and which bowel may reverse the ischemic process and be preserved. The bowel that presents with a dark or dusky appearance may be viable and be able to be preserved. Several adjunctive measures to observation are utilized to help the surgeon decide which areas of questionable viability can be preserved. These measures include fluorescein injection and Doppler ultrasonography, or a combination of the two can be used to help the surgeon decide which bowel is viable and can be preserved or which bowel is not viable and requires resection. The morbidity and mortality following treatment of acute mesenteric ischemia due to embolus is related to the amount of bowel resected, with resections of more than 50% approaching a 90% mortality. The bowel that continues to be questionable following treatment is further assessed with the use of a ‘‘second-look’’ operation within 24 hours. This decision is made at the time of the

Chapter 17: Circulation and Vascular Disorders of the Splanchnic Vascular Bed

original laprotomy. Patients may also require repeat angiography and/or postoperative continuation of intra-arterial papaverine to further minimize morbidity and mortality (13,159–165,180). One must weigh the relative risks of the continued use of anticoagulants in patients treated with acute mesenteric ischemia following SMA embolus. The use of systemic anticoagulation can lead to complications of intra-abdominal bleeding. However, the risk of postoperative thrombosis of the SMA and its branches remains a risk in patients not treated with systemic anticoagulation. The use of anticoagulation is thus dependent on the clinical picture and the experience of the treating surgeon. For example, one would not use systemic anticoagulation in patients who progress to multiple organ failure and disseminated intravascular coagulation. In general, to minimize bleeding risk yet decrease the incidence of late postoperative thromboses, most clinicians recommend some anticoagulation 48 hours after the operation. In patients awaiting a second-look procedure, low-molecular-weight dextran has been cited for both its plasma volumeexpansion qualities and its antithrombotic properties. The duration of anticoagulation varies widely among patients. Thrombolytic therapy should only be used in patients without evidence of bowel necrosis (13,159–165). The postoperative course of these patients is usually quite difficult. The patients can be exposed to shock-like syndromes due to sepsis, hypovolemia, or cardiogenic mechanisms. The patients can suffer from overt sepsis, GI bleeding, acute renal failure, pulmonary insufficiency, and myocardial dysfunction, all of which may progress to multiple organ dysfunction syndrome. The patient should be treated in an intensive care setting with use of invasive cardiovascular monitoring. Stable postoperative patients who develop unexplained acidosis, sepsis of unexplained origin, and refractory cardiovascular instability all suggest continuing bowel necrosis and may necessitate a second-look procedure. Treatment of patients who present with minor emboli is different than those presenting with major emboli and bowel necrosis. Minor SMA emboli are defined as those limited to the branches of the SMA or to the SMA distal to the origin of the ileocolic artery. Patients with minor emboli and without peritoneal signs are managed conservatively with papaverine infusion with or without anticoagulation and clinical observation. If patients develop evidence of bowel necrosis or peritoneal signs, prompt exploration is undertaken. Rarely patients who present with major emboli without peritoneal signs can be treated conservatively. These patients tend to have excellent collateral flow with perfusion distal to the embolus and are thus treated as patients who present with minor emboli (13,159–165). Acute Mesenteric Thrombosis The initial approach to operative treatment of patients with mesenteric thrombosis is similar to that of treatment of the patient with acute SMA embolus. The patient is treated with rapid resuscitation and is rapidly transported to the operating room. The skin preparation in the operating room should include both legs for harvesting vein for a graft. These patients present with thrombus formation in the presence of a stenotic atherosclerotic plaque. Restoration of blood flow to the mesenteric artery in question will require removal of the blood clot and treatment of the underlying atherosclerotic lesion. Antegrade bypass to the SMA or celiac artery is preferred with use of autologous vein graft in the presence of bowel necrosis and

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infarction (13,159–165,181). Although successful thromboendarterectomy has been reported, most current authors favor venous graft or prosthetic bypass of the affected segment, with the aorta or right iliac artery as the inflow vessel (181–183). Reimplantation, if performed, is accomplished by transecting the artery distal to its disease and anastamosing directly to the aorta. The postoperative care is similar to that for acute mesenteric ischemia due to embolus. The postoperative course of these patients can be quite challenging. These patients have the added mortality and morbidity due to the systemic nature of the atherosclerotic disease, which can affect the coronary, cerebrovascular, renal, and extremity vascular beds. Because of the reperfusion of the acute intestinal ischemia, the patients can be exposed to shock-like syndromes due to sepsis, hypovolemia, or cardiogenic mechanisms. The patients can suffer individual visceral organ failure or progressive failure of multiple visceral organs. The patients are monitored closely in an intensive care setting with use of invasive cardiovascular monitoring. Unexplained acidosis, sepsis of unexplained origin, and refractory cardiovascular instability in stable postoperative patients all suggest continuing bowel necrosis and may necessitate a second-look procedure. Increasing numbers of patients who present with mesenteric thrombosis due to underlying atherosclerotic plaque have been treated with thrombolysis and percutaneous balloon angioplasties of the SMA or celiac arteries (128,134,141,184). This interventional approach may help decrease morbidity and mortality in the elderly complex patients but can only be performed in patients without evidence of bowel necrosis or infarction. Acute Mesenteric Ischemia After Aortic Surgery If incomplete collateral flow to the IMA (little retrograde backflow) and left colon ischemia is suspected during aortic surgery, or if the IMA shows large ascending collateral vessels on preoperative angiographic examination, one can preserve antegrade IMA flow by end-to-side aortic anastomosis (Carrel button technique) or by use of an interposition vein graft. Postoperative patients who develop bloody diarrhea or watery guaiac-positive stools 48 to 72 hours after surgery should be suspected of developing intestinal ischemia. These patients can present with symptoms ranging from mild abdominal pain to septic shock. These patients should undergo immediate sigmoidoscopy. The presence of subclinical mucosal ischemia has been reported in 4% to 7% of patients. If sigmoidoscopy reveals hemorrhagic ulcerations and mucosal edema with friability, the patient will require resection of all compromised colon, and end-colostomy with distal Hartmann’s procedure. Patients with more benign findings on sigmoidoscopy can be conservatively followed with repeat sigmoidoscopy 24 to 48 hours later. Small bowel ischemia is treated similarly in an aggressive fashion, although sigmoidoscopic findings may only reveal melena (13,159–165,169,175). Mesenteric Venous Thrombosis Patients suspected of mesenteric venous thrombosis are the one group with mesenteric ischemic syndromes who benefit with early and aggressive anticoagulation and if presenting before bowel necrosis may benefit from a trial of thrombolytic therapy and thrombolytic therapy. The majority of patients will require emergent surgery following an attempt to identify location and extent of venous clot (136). Immediately prior to abdominal exploration, the patients are treated with aggressive fluid resuscitation, anticoagulation with IV heparin, and systemic antibiotics.

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The surgeon removes all nonviable bowel and performs venous thrombectomy of the SMA to remove the thrombus. If the surgery is successful, the patients will require systemic oral anticoagulation with warfarin compounds for a minimum of six months after surgery. If the patient has an identified underlying coagulation disorder, then systemic oral anticoagulation is continued for life. Only the nonviable bowel needs to be resected because the combination of heparin therapy and second-look operations has been shown to limit the extent of bowel resection. Untreated, the mortality rate for acute mesenteric venous thrombosis is close to 100% whereas aggressive use of early exploration and anticoagulation has decreased the operative mortality rate below 15% with heparin therapy. Early and late rethrombosis is unfortunately common. Early rethrombosis is seen in about one-quarter of cases and carries a higher mortality rate of 60% to 80%. Some surgeons routinely advocate second-look procedures because of this high rethrombosis rate (13,159–165,177–179). Chronic Intestinal Ischemia The syndrome of chronic mesenteric ischemia was first described by Schnitzler in 1901 and Warburg in 1905 (185,186). Klein, in 1921, was the first to compare the pain of chronic mesenteric ischemia to the pain caused by intermittent claudication (187). In 1936, Dunphy was the first investigator to suggest that the symptoms of chronic mesenteric ischemia were a possible harbinger to the in situ thrombosis of one or more of the major visceral vessels, with subsequent development of intestinal gangrene (188). In Klein’s classic review, he described three possible outcomes to the gradual occlusion of the visceral arteries. The first possible outcome is the establishment of adequate collateral blood flow. The second possible outcome is intestinal infarction with a high incidence of mortality. The third possible outcome is obstruction of the visceral vessel without intestinal necrosis due to collateral blood flow that is adequate to meet minimal needs of intestinal viability but is not enough to meet the postprandial demands of increased blood flow, and the presentation of chronic intestinal ischemia (187). Patients who present with chronic intestinal angina are usually in the sixth decade of life and present with all the standard risk factors of systemic atherosclerosis. Most are heavy smokers, but unlike atherosclerotic syndromes, this has increased incidence in female patients (outnumber males in the ratio 3:1) (13,169,189–191). Patients with chronic mesenteric ischemia present with postprandial pain, weight loss, and diarrhea (13,169,189–191). The pain is usually generalized in the upper abdomen and may be referred to the back (182). Because the splanchnic bed has extensive collateral blood flow, most patients with chronic intestinal angina have involvement of at least two of the three major mesenteric vessels (188,189). The abdominal pain occurs from 15 minutes to 1 hour following a meal, is usually periumbilical, and can last up to three hours. Weight loss is usually significant as patients develop a fear of eating, diarrhea presents in one third of patients and these may have occult blood. Physical examination is nonspecific and an abdominal bruit may be present in 50% of these patients. The presentation of abdominal pain and weight loss may lead these patients to be evaluated for a variety of clinical diagnoses, especially for a GI neoplasm (13,189–192). Although not common, there are instances when involvement of one mesenteric vessel can cause symptoms of intestinal angina. Dunbar (193) and Rob (182,194)

described the clinical entity of celiac trunk compression in which patients present with postprandial upper abdominal pain and associated weight loss. Unlike patients with classic chronic mesenteric ischemia, patients with celiac compression usually do not have associated diarrhea; however they do readily restrict their food intake. Drapanas and Bron suggested that symptoms caused by celiac compression syndrome may be due a steal of blood from the SMA system to supply the distribution of the celiac axis (195). Reiner et al. suggested that occlusive disease in the pancreaticoduodenal arcade could prevent adequate collateral circulation to the celiac axis from the SMA system, thus providing another possible explanation for the symptoms due to celiac compression (167). Communications between the inferior and superior pancreaticoduodenal artery is uncommon, occurring in less than 1% of cadavers (196). Less frequently, the stenosis results from compression of the celiac axis by a celiac ganglion or arcuate ligament of the diaphragm, compression from an expanding or dissecting aortic aneurysm, or thromboangiitis obliterans or periarteritis nodosa. Duplex scan can be used as a screening tool to identify patients with significant occlusive disease at the origin of the celiac and superior mesenteric arteries (197–200). Over the past 15 years, numerous studies have shown that duplex ultrasound is an accurate screening test for proximal stenosis or occlusion of the celiac and superior mesenteric arteries. Moneta et al. have shown that a peak systolic velocity greater than 275 cm/sec is highly specific for significant SMA stenosis (198). Perko and Zwolak et al. have suggested that the use of end-diastolic velocity greater than 45 cm/sec is more accurate than use of peak systolic velocity (199,200). Gentile et al. have also reported blunting of the normal differences in peak systolic velocities between fasting and postprandial states (201). The duplex ultrasound thus has been shown to be accurate in both diagnosing proximal celiac and SMA stenosis and in assessing the physiologic significance of these stenoses. The reader should understand that the use of the duplex ultrasound in assessing the proximal celiac and superior mesenteric vessels is highly technician dependent. More recently, experience has been gained with MRA and CT angiography (197,202–209). CE MR has benefited from improved gradient technology, which allows ultrafast volume acquisitions with computer-assisted muliplane reformatting or volume rendering (202–204). This technique has been shown to correlate very well with conventional angiography and to be reproducible from observer to observer (202,205,206). An obvious advantage of MR compared to CT angiography is that it is safe for use in patients with compromised renal function. Spiral CT and more recent multidetector row CT produce better data on the abdominal aorta and all of its branches. The newer computer reconstruction techniques allow accurate measurement of arterial stenoses (197,207,208). Either Duplex ultrasound or MR or CT angiography should still be viewed as screening test to avoid unnecessary angiograms (197). If reconstruction is considered an arteriogram should be performed (Fig. 19). One must be sure that lateral as well as A–P views of the aorta are obtained to accurately assess the celiac artery and SMA arteries. Oblique views are necessary to evaluate the origin of the IMA. Routine selective catheterization of the visceral arteries provides information on the severity of the stenoses and the blood supply. Collateral vessels are usually best visualized on the anterioposterior projections. Select catheterization of the celiac artery can provide data on the length of SMA occlusions. The IMA should

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Figure 19 Chronic mesenteric ischemia. A 61-year-old female patient with a five-year history of postprandial pain. (A) Mid-arterial phase aortogram shows a large, prominent IMA. (B) Late-phase arterial study shows the SMA (arrow) being filled in a retrograde fashion by collaterals from the IMA. It also shows late filling of the hepatic and splenic branches of the celiac artery. (C) Lateral view shows marked stenosis of the origin of the celiac artery (arrow). Abbreviations: IMA, inferior mesenteric artery; SMA, superior mesenteric artery. Source: From Ref. 210.

not undergo selective catheterization because this artery may be the sole arterial supply to the entire intestine and dissection of the IMA can lead to necrosis of the entire GI tract (197). The most common angiographic finding is significant stenoses of both the celiac artery and the SMA (85% of patients), in the presence of large collateral vessels (189,197,211). Patients who present with intestinal angina and weight loss and who demonstrate significant stenoses of the mesenteric vessels are considered for interventional repair. Intervention approach may either be by the use of angioplasty and stent or direct operative repair with either transaortic endarterectomy or bypass grafting. If celiac and SMA stenoses are found in an appropriately symptomatic patient, the literature favors revascularization of the SMA first by percutaneous angiography and then by stent placement. The celiac is a tortuous vessel that may require a staged approach (197). In cases of failed SMA percutaneous transluminal angioplasty, the celiac artery is approached. The use of thrombolytic agents has been suggested by several authors prior to passing a catheter across a symptomatic lesion (212,213). More recent reports have shown that stent placement in visceral arteries should be performed to both achieve successful recanalization of the artery and treat procedure-related dissection (197,212–215). Long-term prospective studies examining the use of angioplasty and stent technology in the treatment of chronic mesenteric ischemia will be required to determine long-term efficacy of this approach. Comparison to open operative surgical approaches will also require randomized study in the future to provide comparison of long-term efficacy and short- and long-term complications (197). Operative repair can be achieved either by bypass grafting or endarterectomy techniques (13,180,189,191,216–221).

There are advantages and disadvantages of either technique and the type of operative repair depends on the surgeon’s experience. Bypass grafting can utilize either autogenous greater saphenous vein or polyethylene terephthalate fabric (Dacron) grafts. Dacron grafts are preferred due to their resistance to kinking and better results. Use of autogenous greater saphenous vein is necessary in the presence of severe intestinal ischemia or spillage of bowel contents. Revascularization of more than one mesenteric vessel provides the best long-term result, with relief of pain (in 90% of patients), regaining of lost weight (75%), and improvement of malabsorption (13,191,216–221).

MISCELLANEOUS DISEASES THAT AFFECT THE VISCERA Occlusion or disruption of the blood supply to the abdominal viscera can occur by traumatic disruption, thrombosis secondary to trauma, external compression, or obliteration of the lumen.

Trauma Abdominal vascular injuries accounted for 2% of all vascular injuries during World War II, the Korean War, and the Vietnam War. Abdominal vascular injuries were highly lethal, with most patients dying before being treated. Those patients who survived long enough for implementation of treatment mostly had iliac artery injuries (222). In contrast, the civilian experience has greatly differed from the military experience. The incidence of abdominal vascular injuries due to penetrating trauma is approximately 10% to 20% and the incidence of abdominal vascular injuries due to

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blunt injury is approximately 5% to 10% (222–225). Several authors have suggested that the short time required for hospitalization and the lower wounding power of civilian handguns are responsible for the higher incidence of abdominal vascular trauma, in civilian practices (222–225). Zone I injuries involve the suprames colon, inframesocolon, suprarenal and infrarenal arteries, SMA and the celiac vessels. Zone II injuries involve the renal vessels. Zone III injuries involve the iliac vessels. These complex injuries require an excellent knowledge of anatomy, resuscitation, and prevention of hypothermia, use of intraoperative maneuvers suck as the Mattox maneuver, experience with vascular reconstruction, and appropriate use of different bypass graft materials. The reader is referred to several excellent reviews of this interesting, complex, and challenging area of diagnosis and treatment of complex abdominal vascular injuries (222–225).

External Compression Syndromes The celiac artery compression syndrome is an example of external compression of the celiac artery by the median arcuate ligament as described by Harjola and Dunbar et al. or compression by the celiac ganglia as described by Rob (182,193,194,226). Neoplasms may cause occlusion of major visceral arteries by either external compression or direct invasion. The celiac artery compression syndrome presents as postprandial pain and often as positional abdominal pain in the epigastrium associated with an epigastric bruit, nausea, and weight loss. The histopathologic findings of the celiac artery show a process of chronic celiac artery compression and significant intimal thickening (227). Younger women are often more affected than men (169,228). The variable anatomic positions of the celiac axis and median arcuate ligament may indeed lead to an anterior compression of the celiac axis, especially during expiration and various postural changes (Figs. 20 and 21). Duplex ultrasonography can be used to screen patients who are suspected of this celiac artery compression syndrome. Lateral aortic views obtained during angiographic analysis will show eccentric compression of the celiac trunk along its superior border, with caudal displacement confirming the clinical diagnosis. Despite confirming the clinical impression of celiac artery compression syndrome by arteriography, data from several reviews demonstrate that the diagnosis of celiac artery compression syndrome is quite controversial. In a series of 50 patients who were diagnosed with a symptomatic celiac artery compression syndrome, 24% were found to have at least a 50% stenosis of the celiac axis (231). Another review of 330 patients who were identified as having a symptomatic celiac artery compression syndrome by arteriography only demonstrated abdominal pain in 30% and weight loss in only 50% of these patients (228). Long-term follow-up following operative repair of symptomatic celiac artery compression syndrome reported recurrence rates of symptoms of over 50% (13,228,231– 234). Several authors have hypothesized that the symptoms related to celiac compression may be due in some cases to external pulsatile compression of the celiac plexus by the celiac artery. Several options are considered for surgical repair. For those patients whose syndrome is felt to be secondary to median arcuate ligament compression of the celiac artery, division of the ligament should be curative. For those patients whose symptoms are secondary to celiac compression from the celiac ganglion, ganglionectomy is indicated. For either etiology, bypass of the obstruction or patch angioplasty has been described (13,169,234).

Figure 20 Celiac artery compression. This is a lateral projection of an abdominal aortogram demonstrating extrinsic compression upon the superior aspect of the celiac axis. There is poststenotic dilatation distally. The SMA is normal. Abbreviation: SMA, superior mesenteric artery. Source: From Ref. 229.

A different type of external compression is one where the SMA compresses the duodenum. The symptoms are similar to chronic mesenteric ischemia but vomiting is obviously prominent due to the duodenal obstruction. The etiology of this syndrome is compression of the duodenum between the SMA (or major SMA branches) and the aorta and vertebral bodies. The SMA leaves the aorta at rather an acute angle under which lie the third and fourth portions of the duodenum. The syndrome is named after Wilkies, who described this entity in 1927. The majority of the patients are young females and commonly have other problems such as requiring complete bed rest and body cast, scoliosis, acute weight loss, and anorexia nervosa (13,235–238). Radiologic diagnosis is achieved using cineradiography, which classically demonstrates a ‘‘to-and-fro of the duodenal contents’’ proximal to the crossing of the SMA (236). A significant number of patients also have concomitant peptic ulcer disease (15%). Surgical treatment is limited to symptomatic patients with positive radiologic findings as described above. Surgical treatment consists of division of the ligament of Treitz; however duodenojejunostomy may be required in chronic cases.

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Figure 21 Lateral aortogram in a patient with typical celiac compression syndrome. The degree of narrowing is increased markedly in full expiration. Source: From Ref. 230.

Inflammatory Lesions Inflammatory lesions that involve the splanchnic arteries are quite rare; however, a review of the more common lesions is important to provide the reader with data to develop an appropriate index of suspicion to diagnose patients who present with these diseases. Vasculitis can affect all levels of vessel in the splanchnic circulation, resulting in mesenteric ischemia, paralytic ileus, submucosal edema and hemorrhage, bowel stricture, or perforation. Vasculitis may involve primarily large vessels (Takayasu arteritis, giant cell arteritis, etc.), medium-sized vessels (polyarteritis nodosa, Kawasaki disease, primary granulomatous central nervous system vasculitis, etc.), or the small vessels (Henoch–Schonlein syndrome, systemic lupus erythematosis, rheumatoid vasculitis, Behcet syndrome, Wegener granulomatosis, Churg–Strauss syndrome). A reference for an excellent review of the radiologic findings of the mesenteric vasculitides is provided for the reader (239–241). The diseases that affect the larger vessels may present in a similar manner as acute emboli, thrombosis unless the patient has other systemic symptoms associated with the underlying vasculitis. Tuberculosis and collagen vascular diseases may produce an arteritis that causes secondary occlusive disease in the branches of the abdominal aorta. The lesions can involve the first several centimeters of the vessel at its origin from the aorta or involve the medium or small arterioles and thus may cause a variety of symptoms, including intestinal infarction. There is no adequate collateral blood supply to the small arterioles of the small intestine and involvement of these vessels almost invariably results in necrosis. Table 2 lists the collagen vascular diseases that most commonly affect the GI tract. The data presents the areas of major involvement and only those symptoms produced by involvement with the vessels supplying the GI tract. Thromboangiitis obliterans (Buerger’s disease) should be classified under inflammatory lesions but will be considered separately. This disease occurs in very young people

and is most often associated with the excessive use of tobacco. The usual site of this disease is the medium-sized arteries of the extremities. Figures 22 and 23 demonstrate typical changes found in patients undergoing angiography for Buerger’s disease. Fewer than a dozen verified cases of intestinal Buerger’s disease have been reported. Mesenteric vessel involvement by Buerger’s disease is unusual in that concomitant involvement of the peripheral vascular bed has not been reported. The site of involvement, similar to that of the collagen vascular diseases reported in Table 2, are the medium and small arteries of the splanchnic bed, which can result in small-intestinal perforation (40%), bowel necrosis, dysmotility and obstruction and death (40% mortality) (13,239,244–246).

Cocaine-Associated Mesenteric Ischemia In recent years, several publications have documented the association of cocaine abuse with acute and chronic mesenteric ischemia (247–250). The majority of patients of either sex present at less than 35 years of age and can present with intestinal ischemia that ranges from chronic visceral ischemia to bowel infarction. Myers et al. reported two cases of young women with a two-year IV cocaine abuse, who presented with severe chronic mesenteric ischemia. Both patients demonstrated celiac and SMA occlusions on diagnostic angiography and both were managed successfully with visceral revascularization (247). A subsequent follow-up study showed that the pathology in these two patients revealed total arterial obstruction by luminal thrombus with recanalization (250). The conclusion of these studies is that mesenteric ischemia should be considered in the differential diagnosis of acute and chronic abdominal pain in cocaine consumers (247–250). The use of crack cocaine during pregnancy exposes both the mother and the fetus to the potent vasoconstrictive actions of cocaine. Fetal activity of plasma cholinesterase, the enzyme responsible for detoxification of cocaine, is quite low (251). Therefore prolonged maternal cocaine abuse

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Table 2 GI Manifestations of Rheumatalogic Diseases Diagnosis

Pathology

Symptoms affecting mesenteric vessels

GI involvement

Antiphospholipid Antibody syndrome

Vasculitis

Small intestine, esophagus, colon

Behecet’s disease Churg–Strauss syndrome Cogan’s syndrome

Systemic vasculitis Necrotizing granulomatous vasculitis Aortitis, vasculitis

SMA vasculitis, SMA aneurysm SMA, small intestine Aorta, SMA

Giant cell arteritis Henoch–Schonlein purpura

Large vessel arteritis Immunoglobulin A-mediated immune Affecting small vessel

Aorta (10%), SMA Intestine, colon, esophagus, pancreas gallbladder

Inflammatory muscle disorders

Vasculopathy, small vessel involvement

Small intestine, esophagus

Kawasaki disease

Vasculitis

Coronary, SMA

Polyarteritis nodosa

Vasculitis of medium and small vessels

Small bowel

Rheumatoid arthritis

Small artery vasculitis

Ileum, colon, esophagus

Sjogren’s syndrome Systemic lupus erythmatosis

Mononuclear cell infiltration Deposition of pathogenic antibodies and immune complexes

Small intestine, colon Entire GI tract

Systemic sclerosis

Inflammatory vasculitis

Entire GI tract

Takayasu arteritis

Large vessel arteritis

Aorta, branches of aorta

Wegener’s granulomatosis

Necrotizing vasculitis granulomatous inflammation

Small intestine, colon

Vascular thromboses, thrombocytopenia, intestinal ischemia Intestinal ischemia and infarction Intestinal mucosal ischemia AAA, abdominal pain, nausea and vomiting after a meal Intestinal gangrene Abdominal pain, nonthrombocytopenic purpura, arthritis, ulceration of bowel mucosa, bowel infarction, gastric and bowel perforation, pancreatitis, appendicitis, cholecystitis, intususseption Abnormal GI peristalsis, reduced GI motility, hiatal hernia, intestinal ischemia, necrosis or perforation, 10% incidence of malignancy within 1 yr Abdominal pain, small bowel obstruction secondary to with stricture Abdominal pain, SI ischemia, perforation (5%), bowel infarction (1.4%), ulceration (6%) Ileal or colonic ischemia, diminished esophageal peristalsis, profuse diarrhea, flatulence, weight loss Jejunitis, sigmoiditis Esophageal ulceration and perforation, intestinal dysmotility, vasculitis and malabsorption, venous thrombosis and intestinal ischemia, aneurysmal disease Dysphagia, dyspepsia, small-intestinal dysmotility, pneumatosis intestinalis Abdominal pain, nausea, diarrhea, saccular aneurysms Intestinal perforation and ulceration

Abbreviations: AAA, abdominal aortic aneurysm; GI, gastrointestinal; SMA, superior mesenteric artery; SI, splanchnic intestine.

exposes the fetus to increased serum levels of cocaine. Fetal and neonatal exposure to cocaine can lead to prolonged ischemia of the intestine, integument, cardiovascular system, and the brain (252–255). Several case reports have described neonatal intestinal ischemia with bowel perforation secondary to maternal cocaine abuse (256–258).

SUMMARY The mesenteric vascular bed receives and distributes 10% to 15% of the cardiac output. GI functions of motility and digestion are dependent on adequate blood flow, which is distributed and regulated by both intrinsic and extrinsic mechanisms. Extrinsic control of mesenteric blood flow is due to the sympathetic and parasympathetic nervous system, circulating GI hormones, and vasoactive factors released from around the body. The intrinsic mechanisms regulating mesenteric blood flow are due to both myogenic

and metabolic regulatory systems. Pathophysiologic mechanisms that imbalance this complex interaction of extrinsic and intrinsic control of mesenteric blood flow produce a broad spectrum of disorders that can be difficult to diagnose and treat successfully. The diagnosis of acute mesenteric syndromes is dependent on the clinician having a high index of suspicion for this disease, which will then lead to rapid resuscitation and diagnosis. The use of diagnostic techniques of Duplex scan, Doppler flowmeter, and CT scan is only indicated when they do not add a time delay to transfer either to the angiography suite or to the operating suite. Angiography remains the gold standard in diagnosing acute mesenteric ischemia and can also be therapeutic in cases of NOMI or in those cases identified before bowel necrosis, which can be treated with lysis and angioplasty. The current data support the combined use of clinical judgment and the Doppler and/or the fluorescein techniques for intraoperative assessment of bowel viability. Aggressive

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Figure 22 (A and B) Brachial angiogram shows a hypoplastic ulnar artery (white arrows), persistence of the interosseous artery (large black arrows), and occlusion of the distal radial artery at the level of the wrist (white arrow), with extensive but small collaterals (small black arrows). There is no reconstruction of the palmar arches. The arterial branches of the palm and fingers are severely narrowed. Source: From Ref. 242.

Figure 23 (A and B) Absence of both palmar arches, multiple areas of arterial narrowing (large white arrows), obstructions (black arrows), and pruning of the digital arteries (small white arrows). Source: From Ref. 243.

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diagnosis and treatment is the only means to reduce the high morbidity and mortality associated with each of these pathologic disorders of mesenteric blood flow. Identification of patients at risk for development of acute mesenteric ischemia (patients with chronic mesenteric ischemia, etc.) is one more means to try and decrease the high complication rates seen with acute mesenteric ischemia.

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18 Inflammatory Disorders of the Small Bowel and Colon Douglas J. Turner and Barbara L. Bass

pathogenesis of CD, the NOD variants seem to account for less than 20% of all cases. The evidence of a genetic predisposition is less strong for UC than for CD. However, there is evidence of association with some DR2 alleles of the human leukocyte antigen region as well as some areas on chromosomes 3, 7, and 12. Specific genetic factors also impact on the severity of the disease in UC, as well as its response to steroids and its extraintestinal manifestations (4,5).

INTRODUCTION The intestinal tract is the site of a number of inflammatory disorders that vary considerably in underlying pathogenesis, pattern of presentation, and severity. This chapter summarizes the more important inflammatory processes involving the small bowel and colon, emphasizing the underlying physiologic dysfunction associated with each, and the means by which physiologic function may be restored or improved through surgical intervention.

Infection Because of the clinical and pathologic similarities to chronic dysentery, infectious agents have been suspected in IBD since the earliest reports. There is frequently a temporal relationship between the onset of IBD and antecedent enteric infection. There are also striking similarities in histologic appearance between CD and tuberculus enteritis, as noted initially by Crohn when describing the disease in 1932 (6). Accordingly, Mycobacterium paratuberculosis has been the object of much recent interest as a causative agent. This agent has been cultured from several patients with CD, and some CD patients have antibody titers against mycobacterial antigens (7,8). DNA polymerase chain reaction studies have identified mycobacterial antigens in intestinal mucosa; however it has not been found to be specific for CD (7). An alternative hypothesis, prompted by the discovery of viral antigens in the mucosa of CD patients, suggests that chronic measles (paramyxovirus) infection may lead to a chronic vasculitis that leads to repeated mucosal injury (9). This has not been confirmed by other investigators, as has been the case with myriad other pathogenic microbes that have been proposed as etiologic agents of IBD. Clinical experience argues against infection per se, as IBD does not respond to antibiotic therapy (except for management of infections complications), whereas it does improve with immunosuppressive medications. However, intestinal microflora may be a factor in IBD either through an, as yet, undiscovered pathogen or also through antigenic stimuli. Certain bacterial proteins have shown cross-reactivity with host proteins, suggesting that this mimicry may induce an autoimmune response (10). In experimental models, administration of bacterial products has also been shown to initiate colitis. The amelioration of IBD activity following diversion of the fecal stream may be due, in part, to the removal of bacterial infections or antigenic stimuli (11).

INFLAMMATORY BOWEL DISEASE Inflammatory bowel disease (IBD) encompasses a broad spectrum of idiopathic relapsing inflammatory conditions affecting the intestinal tract; the two most common are Crohn’s disease (CD) and ulcerative colitis (UC). The prevalence for each of these conditions ranges from 5 to 100 cases/100,000 population. The incidence of CD is gradually increasing, whereas that of UC has been stable over the last three decades. Both of these diseases show a bimodal peak in the age of onset, with peaks in the third and seventh decades of life. Despite substantial expansion of our understanding of these conditions over the past 20 years, the exact pathogenesis of these entities remains uncertain.

Pathogenesis Genetics A role of genetic predisposition in IBD is supported by heritable patterns of disease. Genetic factors appear to be more important in CD than UC. Monozygotic twins are more likely to have IBD than dizygotic twins, and about 15% of all IBD patients have a first degree relative with confirmed diagnosis of IBD. Epidemiological studies of race and ethnicity have shown certain populations (e.g., Ashkenazic Jews and whites) to have high prevalence rates of IBD. Environmental factors are clearly operative as well, as demonstrated by the decreased risk of developing IBD after immigration to different countries. Recently, a specific genetic susceptibility locus has been mapped for CD to the IBD1 site on chromosome 16 (1). Further, recent genome scans of affected pairs have yielded multiple areas on several chromosomes (6, 12, and 14 among others) that are possible loci for disease association (2). One relevant gene, the NOD2 gene, has been described in association with CD (3), and appears to encode for a protein that both associates with bacterial lipopolysaccharide and is involved in apoptotic cell death (1). Although this protein appears to play a major role in the

Host Defenses A number of immunologic abnormalities have been detected in IBD (Table 1) (12). The number of factors, the multiple effects ascribed to each, and the counter-regulatory relationships that exist among them make isolating a single 415

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Table 1 Immunologic Abnormalities in IBD Factors increased Serum IgA1 Mucosal IgG, IgG:IgA ratio pANCA (UC) Major histocompatibility complex class II antigen expression by enterocytes Mucosal IL-1, IL-6, IL-8 Serum IL-2, IL-6, IL-10 Soluble IL-2 receptor Mucosal CD8þ (cytotoxic) T-cells TNF-a CD14þ macrophages CD44v3 and v6 colonocyte surface antigen (UC) Mucosal substance P (UC) LP T-cell response to IL-2 LP T-cells (CD) Mucosal PGE2 and LTB4 Serum intercellular adhesion molecule-1 Tropomyosin Mucosal permeability (CD) IL-2 receptor Transferrin receptor 4F2 antigen

Factors decreased Dimeric, secretory IgA T-cell response to IL-2 Mucosal IL-2, IL-4, interferon-g Monocyte IL-4 responsiveness Mucosal mucin (UC) Mucosal CD4þ (helper) T-cells Mucosal vasoactive intestinal peptide (UC) Mucosal substance P (CD)

Abbreviations: IBD, inflammatory bowel disease; Ig, immunoglobin; IL, interleukin; LP, lamina propria; pANCA, perinuclear antineutrophil cytoplasmic antibody; PGE2, prostaglandin E2; LTB4, leukotrieae B4; UC, ulcerative colitis; CD, Crohn’s disease; TNF, tumor necrosis factor.

element as the causative factor in IBD a daunting task. Indeed, the vast number of irregularities identified, to date, is not unexpected for IBD, but rather predictable given the ongoing inflammation characteristic of IBD. Nevertheless, a number of factors suggest a central role for the mucosal immune system in IBD pathophysiology. In UC, enterocytes have been shown to inappropriately express class II major histocompatibility antigens that regulate T-cell activity. Recent attention in UC has focused on autoantibodies targeted against a 40 kDa antigen on the colonic epithelial cells, which appears to be related to tropomyosin, as well as against perinuclear antineutrophil cytoplasmic antibody (pANCA) (10). In some reports, as many as 70% of patients with UC express pANCAs (13). Although evidence confirming a specific role for pANCA has not been found, it has recently allowed identification of a subgroup of CD patients who demonstrate increased colonic disease activity (14), as well as a subgroup of UC patients more likely to demonstrate biliary manifestations of IBD (13). Cross-reactivity with pANCA has allowed the identification of ocular and biliary antigens that may play a role in extraintestinal manifestations of IBD (15). CD has repeatedly been shown to be associated with proliferation of helper T-cells (8). Both UC and CD show increased expression of B-cells, T-cells, and several cytokines as shown in Table 1. One clear mediator in human CD is tumor necrosis factor (TNF)-a, and several clinical trials have demonstrated chimeric anti–TNF-a to be an effective agent, leading to its use in the clinical setting (16).

Dietary and Environmental Factors Diet has been implicated as a possible etiologic factor because of its importance in determining the local environment of

the gastrointestinal tract. The ‘‘Western’’ diet (or its deficiencies) is also implicated, due to the striking increase of IBD seen in the Western industrialized world. No specific food item including caffeine, cow’s milk, eggs, refined sugars, and wheat, among the many suspected, has been proven responsible. Psychological factors inducing stress and depression have been shown to associate with IBD (17). Of the many environmental factors proposed to play a role, only tobacco has proved significant. Smoking appears to have a protective effect on UC, while it appears to serve as a risk factor for CD; in patients with CD, smoking rates are twice the rate of the general population (18).

Clinical Presentation UC can often be differentiated from CD on the basis of the history and physical examination. UC is best characterized by the acute onset of abdominal pain, diarrhea, hematochezia, and tenesmus. The severity of symptoms corresponds to the extent of the disease. The abdominal examination may be unremarkable in the patient with UC unless toxic megacolon is present. In contrast, the clinical manifestations of CD may be highly variable due to the potential for diffuse and sporadic involvement of any area of the gastrointestinal tract. The disease typically presents in an insidious manner, often coming to medical attention only after a complication has developed. Chronic abdominal pain, nonbloody diarrhea, and signs of systemic toxicity such as fever, malaise, and cachexia are its cardinal features. Signs of obstruction or an inflammatory mass may be present in addition to perianal disease. Both forms of IBD may be associated with extraintestinal manifestations, more commonly UC. The pathologic features that have been used to distinguish the two forms of IBD are shown in Figure 1. Approximately 10% to 15% of patients, specifically those with severe colitis, have conditions that cannot be characterized at presentation as a specific form of IBD. Such ‘‘indeterminate’’ colitis eventually defines itself on long-term follow-up, based on patterns of disease progression. For all

Figure 1 Pathologic features of IBD. Abbreviation: IBD, inflammatory bowel disease.

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conditions, exclusion of infectious enteritis by a thorough travel and exposure history, as well as with stool and serologic studies, is of critical importance at initial diagnosis. Other laboratory studies are not specific for IBD, but may help identify correctable electrolyte or hematologic abnormalities. Acute-phase factors (C-reactive protein, sedimentation rate, etc.) are frequently monitored despite the lack of correlation with clinically or endoscopically determined disease severity. Monitoring of visceral protein levels (albumin, prealbumin, transferrin, etc.) in these chronically ill patients allows the assessment of nutritional status. Colonoscopy can generally differentiate the two processes and rule out other causes of colitis, although examination and biopsy specimen interpretations are more accurate in the healing or quiescent stage. Once the diagnosis has been established, endoscopy should be employed cautiously, especially during flare-ups, when the risk of complication is high. Because the small bowel is less accessible to endoscopy, the diagnosis of small bowel CD is dependent on small bowel radiographic contrast studies, which can best demonstrate mucosal lesions as well as delineate the number, location, and degree of stricturing and fistulization (Figs. 2–5). Computed tomography (CT) is particularly useful in cases with abscess formation but may also reveal inflammatory masses and luminal obstruction.

Management Medical Therapy Anti-inflammatory therapy, beginning in the 1930s with sulfasalazine (SASP), has been the mainstay of medical management (8). The SASP molecule links 5-aminosalicyclic acid (5-ASA), responsible for the drug’s therapeutic effects, with sulfapyridine, which was initially thought to act as an antibiotic but which is now known to serve essentially as a carrier. SASP’s use is limited by allergic and dosedependent side effects, attributed to the sulfa component, and by limited efficacy in severe UC and small intestinal CD. The exact mechanism of action is unknown, but the drug has been shown to inhibit a number of proinflammatory processes active in IBD, including release of interleukin (IL)-1 and other cytokines, mucosal antibody synthesis,

Figure 2 Crohn’s ileitis. Characteristic transmural inflammation of the terminal ileum with fibrosis of the intestinal wall. Note the abrupt cessation of the disease at the ileocecal valve and completely normal appearance of the cecal mucosa and wall. Source: From Ref. 19.

Figure 3 Crohn’s ileitis. Upper gastrointestinal and small bowel followthrough contrast study showing multiple long strictures distributed through many feet of small bowel, the characteristic pattern of skip lesions seen in this disease. Surgical management of skip lesions is dependent on their proximity and localization to a single region of the small bowel. Clusters of strictures are best managed by segmental resection, whereas diffuse skip-lesion strictures are optimally managed with stricturoplasty. Source: From Ref. 20.

arachidonic acid metabolism, and oxygen radical production. An intriguing recent report suggests that long-term 5-ASA use may be protective against the development of cancer (22). Mesalamine, the unbound 5-ASA moiety, and

Figure 4 Photomicrograph of biopsy specimen from a patient with UC. Moderate dysplasia with loss of polarity and proliferation of epithelial cells is noted (original magnification
260). Abbreviation: UC, ulcerative colitis. Source: From Ref. 21.

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Figure 5 UC. Barium enema of a patient with panulcerative colitis, revealing the cobblestone texture of the colonic mucosa and loss of haustral markings that give rise to the ‘‘lead pipe’’ appearance of the colon. Abbreviation: UC, ulcerative colitis. Source: From Ref. 20.

olasalazine, a 5-ASA dimer, are newer, costlier formulations; they have fewer side effects than SASP, but their efficacy is probably only equivalent. Because patients are able to tolerate higher doses, and because the bioavailability of 5-ASA is higher in the small bowel, mesalamine appears particularly well suited to management of small intestinal CD. Additionally, although there has been no demonstrated benefit of maintenance therapy with SASP in CD after resection, a number of trials have shown reduced recurrence with high-dose mesalamine (23). Moderate to severe exacerbations of IBD are treated with systemic glucocorticoids, which exert their therapeutic effects through nonspecific inhibition of inflammation and immune function. Enema preparations (for both 5-ASA and steroids) can be used effectively as topical agents in distal UC. Until the advent of small intestine–active 5-ASA agents, symptomatic small bowel CD necessitated the use of systemic steroids. There is no benefit to continued maintenance therapy with steroids after remission has been induced or after surgical resection. Steroid dependence warrants consideration of either alternative modes of therapy or surgical intervention because of the severe dose- and duration-related side effects associated with long-term steroid use. The need for alternatives to glucocorticoids for severe disease has led to the use of immunosuppressant therapy for IBD, adapted from the organ transplant experience. Two purine analogs, azathioprine and its metabolite 6-mercaptopurine, have been the most extensively and successfully used (24). Their mechanism of action in IBD has not been determined, but it is likely that their specific inhibition of T-cell and natural killer cell function and proliferation plays an important part. Their major benefit in

IBD management has been their steroid-sparing effect and their ability to maintain remission. They have also been shown to be effective in the therapy of perianal and fistulous CD. One drawback is their delayed onset of activity, often requiring three to six months for improvement to become apparent. Neutropenia is the major dose-limiting side effect, and close monitoring of the complete blood count is essential. Although controversial, recent data implies that IBD patients on azathioprine are not at increased risk of lymphoma as are patients on long-term immunosuppression with solid organ transplants (25). The folate inhibitor, methotrexate, has been used extensively as an anti-inflammatory agent in rheumatoid diseases, and has been used to maintain long-term remission and steroid-sparing effects particularly for CD. Toxicities upon the bone marrow, liver, and lungs limit its usage. Cyclosporine, a selective inhibitor of IL-2 synthesis, has also shown some benefit for select patients with severe disease, although the data is conflicting and the potential toxicities (especially nephrotoxicity) are severe. There is little role for antibiotics in UC except for the perioperative period. On the other hand, patients with CD often require antibiotics for perforating disease (phlegmons and abscesses). Metronidazole and ciprofloxacin have both been shown to be effective in moderate CD, particularly those with an active colonic component (26,27). Newer agents include a variety of therapies that target TNF. The most widely utilized medication in this category is infliximab (Remicade), a human–murine chimeric monoclonal antibody against TNF-a. Infusion of infliximab in initial reports showed that a single infusion generated as high as an 81% response rate and 48% remission rate (28). Further trials of this agent have demonstrated its safety; side effects include acute infusion reactions in approximately 20% of patients, most commonly in patients who have had prior infusions and developed antichimeric antibodies (1,29). Both CD and UC patients are at increased risk for the development of adenocarcinoma; although the far greater risk is for colorectal adenocarcinoma in patients with UC. Although the same predisposing genetic alterations necessary for the progression from normal to adenomatous to malignant cell phenotype that has been shown to take place in sporadic colorectal cancer have been confirmed in UC, the cause of the increased risk and more rapid progression is unknown (30). Cancer screening for patients with UC presupposes that colonoscopy can identify premalignant areas of dysplasia. Most protocols call for patients with long-standing (longer than seven years) pancolitis to undergo colonoscopy every other year. Multiple biopsy samples are obtained to identify dysplastic mucosa. The benefit of such surveillance programs has been questioned from a cost-analysis perspective because of the extraordinary number of colonoscopies and biopsies required to identify the 12% of patients with UC who are likely to have cancer develop. Others have criticized programs for their shortcomings, noting that as many as 42% of patients are found to have an invasive cancer when colectomy is carried out for dysplasia and as many as a third of these cancers are locally advanced or metastatic at the time of surgery (31). Nevertheless, with the lack of alternatives, surveillance represents the best option for most patients.

Surgical Therapy Surgical management of IBD is often viewed as a last resort. In UC, this tendency is largely a result of cultural aversion to ileostomy, which was at one time the only alternative to continued medical management. Delayed surgical

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intervention in CD is probably a reaction to the aggressive resectional approaches common in the past, which were based on the misguided notion that the disease could be eradicated and all too frequently created short bowel syndrome and parenteral nutrition dependency. The evolution of the ileoanal pouch procedure into an acceptable alternative to ileostomy for UC and the development of more deliberate bowel preserving surgical approaches to CD have radically altered current management and improved outcomes. Surgical removal of the diseased colonic mucosa cures UC and eliminates the risk of carcinoma. Nevertheless, because the disease runs a variable course, surgery is reserved for the more aggressive patterns of UC. In order of frequency, the indications for surgery in UC are intractability, steroid dependence or intolerance, cancer prophylaxis (for patients with mucosal dysplasia) or cancer resection, fulminant presentation (toxic megacolon), perforation, and hemorrhage. An operation is required during the first year after diagnosis in as many as 30% of patients with severe colitis. The overall rates of colectomy vary widely, between 25% and 80%, at 25 years follow-up (32). The need for colectomy varies according to extent and severity of the disease. The likelihood of requiring surgery is six times greater for patients with pancolitis than for those with isolated proctitis, but approximately 15% to 20% of patients with initially limited distal disease have eventually progressed to more extensive colitis. Early operation is usually necessary because of the aggressive nature of the disease. Patients come to surgery later in the course of the disease either for intractable, recurrent disease or because of the risk for development or actual presence of cancer. The choice of reconstructive method for UC is dictated by the clinical setting. Use of partial colon resection in any situation, other than an emergency, has been largely abandoned, on grounds that it leaves diseased tissue behind. When sepsis, hemorrhage, or toxic megacolon is present, or the possibility of advanced cancer exists, an abdominal colectomy and end-ileostomy with either a Hartmann pouch or a mucous fistula are performed. This strategy allows a restorative procedure at a later time. In the elective case, patient choice, moderated by consideration of age and body habitus, plays a large role. Many opt for restorative proctocolectomy, with removal of the distal rectal mucosa and the creation of an ileal reservoir with an ileoanal anastomosis. Some surgeons opt to render the pouch nonfunctional with the use of a temporary diverting ileostomy, to avoid early postoperative septic and anastomotic complications, although single-stage procedures with no diverting ileostomy can be safely performed in carefully selected patients (33,34). The morbidity of the pouch procedure (in its numerous configurations) compares favorably with that associated with proctocolectomy and ileostomy, although the requirement for multiple surgical procedures is clear. Idiopathic pouch inflammation, known as pouchitis, occurs in 20% to 30% of patients following restorative proctocolectomy (35,36). Pouchitis is unrelated to misdiagnosed CD and is rarely observed in patients undergoing pouch creation for familial polyposis. This syndrome provides further evidence of an underlying disorder in the regulatory mechanisms of inflammation in these patients. Many patients with pouchitis harbor pANCAs. In a small minority of patients, pouchitis is aggressive, necessitating long-term medical therapy or even pouch excision. Most cases, however, respond to short courses of metronidazole or quinolones and nonsteroidal anti-inflammatory drugs.

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Operation does not affect the natural history of CD; indeed, asymptomatic microscopic recurrence is found in 70% to 80% of patients at one year (37). For this reason, surgical therapy is directed toward correcting complications and removing gross disease, not attaining negative microscopic margins of resection. Obstructing strictures, symptomatic internal fistulas, external fistulas, abscess formation from perforation, and persistent perianal disease are usual indications. Surgery should not be deferred indefinitely during multiple trials of ineffective medical therapy. This strategy risks worsening the nutritional condition of these patients and may lead to life-threatening complications from medical therapies. Surgery should be considered for chronic, unremitting symptoms when medical therapy has not affected prompt or durable remission. Preoperative definition of the intestinal anatomy is essential to identify concurrent areas of disease, particularly with respect to strictures. Equally important is the radiographic definition of fistulous connections, which are generally but not exclusively found proximal to strictures. A major advance in the management of these patients has been the development of radiologically directed percutaneous drainage techniques. Used as temporizing measures to relieve the septic complications of abscess formation, these techniques allow nutritional optimization by parenteral route in these ill patients in preparation for definitive surgical intervention. Endoscopy may be necessary when enterocolonic fistulas are identified, to rule out colonic CD and the need for more extensive resection. Limiting resection to grossly normal margins at dominant stricture sites or at points of fistulization, rather than to microscopically normal margins, has been shown to be safe and preserves functional tissue (38,39). To avoid excessive resection and risk of short bowel syndrome, simple or multiple ‘‘strictureplasties’’ may be used to release stenotic regions when multiple areas of small bowel are involved (40). Experience with strictureplasty in ileocolonic anastomotic strictures and colonic strictures is largely anecdotal and requires further evaluation. Resection remains the primary mode of treatment for colonic disease, and the benefits of proctocolectomy with ileostomy versus ileorectal anastomosis continue to be debated.

APPENDICITIS Inflammation of the appendix is the most common acute surgical disease in North America. Long recognized as a potentially lethal entity, early reports of right lower quadrant disease refer to ‘‘perityphlitis,’’ a process ascribed to acute pathology of the appendix in a classic article by Fitz in 1886 (41). Appendicitis may occur at any age, but has a peak incidence in the 10- to 19-year-old age group, which corresponds to the increased lymphoid tissue found in appendices of patients in this age group. During the last half century, the rate of appendicitis appears to be declining (42). The vermiform appendix is a worm-like appendage of the cecum found at the confluence of the three taeniae coli. The appendiceal artery, a branch of the ileocolic artery, provides the arterial blood supply to the appendix, which courses through its distinct mesentery. The narrow orifice of the appendix predisposes the lumen to obstruction from either luminal or mural processes, both of which are causally linked to appendiceal inflammation. Although obstruction of the appendiceal lumen as the primary etiology of appendicitis has been debated, research starting with that of Wangensteen and Bowers (43) in the 1930s

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provides experimental and clinical support for this pathophysiologic mechanism. The most common cause of obstruction is a fecalith, a concretion of luminal contents impacted at the orifice of the appendiceal lumen. Fecaliths are common, being present in approximately 30% of patients without appendicitis. They are nonetheless, likely involved in the pathogenesis of appendicitis for as many as 90% of cases of gangrenous appendicitis are found to have an associated fecalith (44). Less common causes of appendiceal obstruction include lymphoid hyperplasia, foreign bodies, intestinal worms, and neoplasms. The most common neoplasm of the appendix associated with appendicitis is the carcinoid tumor. Appendicitis associated with an adenocarcinoma or metastatic disease to the appendix has been reported rarely. Although the precise mechanism by which luminal obstruction can result in appendiceal inflammation has not been determined, the following sequence is frequently described. Continued secretion of mucus and fluid from the appendiceal mucosa after luminal obstruction causes mural distention. The increased wall distention and tension elicit visceral afferent nerve stimulation, which is clinically manifested as vague, periumbilical abdominal pain. As the distension continues, lymphatic and capillary obstruction ensues, and resident bacteria multiply, further worsening the hydrostatic pressure. As venous pressure is overcome, the mucosa becomes leaky, and inflammation progresses to the serosa, initiating somatic nerve stimulation and parietal pain sensation localized to the right lower quadrant. Left untreated, venous thrombosis and arterial thrombosis follow, with consequent ischemia, eventually leading to gangrene and perforation. The classic clinical presentation of appendicitis begins with vague periumbilical abdominal pain, which subsequently localizes to the right lower quadrant over the next 12 to 48 hours. Localization, however, may vary in cases where the tip of the appendix is retrocecal, intrapelvic, or elevated by the uterus during pregnancy. Anorexia, nausea, and vomiting are frequently reported, and altered bowel habits may be noted. Low-grade fever and mild leukocytosis, along with a urinalysis showing a few leukocytes and erythrocytes presumably due to inflammation of the adjacent right ureter, may be present. Physical examination typically reveals right lower quadrant tenderness with guarding, depending on the degree of inflammation present. If a mass is present, advanced disease associated with a large appendiceal phlegmon or abscess is likely. Unfortunately, clinical findings and the course of the disease are often variable and subtle. Delay in diagnosis and treatment is common, particularly in infants, young children, and elderly persons. Delay in appropriate treatment is associated with progression of appendicitis to gangrene and appendiceal abscess. Morbidity increases with delay of therapy. While mortality from appendicitis is rare, it does occur and is typically associated with a delay in diagnosis. Mortality risk is highest for elderly, immunecompromised, and infant patients. The variability in presentation of acute appendicitis, both in clinical course and physical findings, and the potentially dire consequences of misdiagnosis have prompted efforts to develop a more definitive laboratory test or management algorithm. Multiple studies have investigated the value of leukocyte counts, C-reactive protein, phospholipase A2, and sedimentation rate (45). Clinical algorithms that selectively use abdominal radiography, ultrasonography, or CT scan with or without gastrointestinal contrast studies

have also been investigated. Despite many such studies, no diagnostic algorithm has yet proved able to provide exceptional predictive value, and clinical assessment and judgment remain the diagnostic tools of choice. Diagnostic algorithms are often region or institution specific, based largely on the availability of emergency imaging and local emergency room physicians and surgical preferences (46). Prompt diagnosis and appendectomy remain the mainstay in treating appendicitis and preventing complications. As described by McBurney (47), a right lower quadrant incision with delivery of the appendix and amputation at its base is the standard of care for acute appendicitis (Fig. 6). If perforation is noted, adequate irrigation of the operative area and pelvis is added to the procedure, and wound closure is delayed. Laparoscopic appendectomy is an equally successful approach. Additionally, laparoscopy offers the opportunity to confirm the diagnosis and examine the lower abdomen and pelvis for other pathology, using a minimally invasive approach. This modality may have particular value when diagnostic uncertainty is heightened, particularly in female patients. Several reports have noted less postoperative pain, shorter hospitalizations, and superior cosmetic results with this modality. Although laparoscopic appendectomy is a safe procedure for uncomplicated appendicitis, its use in complicated appendicitis can be technically challenging (49). Perioperative antibiotics are indicated to decrease the incidence of wound infection in acute appendicitis.

Figure 6 Technique of appendectomy. (A) Common incisions for the open appendectomy technique. (B) Delivery of the appendix. (C) Ligation and division of the mesoappendix. (D) Ligation of the base of the appendix. (E) Residual stump without inversion. (F) Removal of the appendix with ligation. (G) Inversion of ligated stump. Source: From Ref. 48.

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Therapeutic antibiotics are required for right lower quadrant peritonitis secondary to appendiceal perforation. Infrequently, patients may present with ‘‘missed appendicitis,’’ with the primary manifestation of a right lower quadrant abscess. Such abscesses can be managed with percutaneous drainage followed by interval appendectomy two to three months later (47).

MECKEL’S DIVERTICULUM ‘‘Meckel’s diverticulum is frequently suspected, often looked for and seldom found.’’ So stated Mayo (50) regarding this congenital abnormality of the small intestine. A true diverticulum, a Meckel’s diverticulum, involves all layers of the small intestine, and is the result of a remnant of the omphalomesenteric duct. In utero, this duct connects the primitive gut to the yolk sac and normally obliterates by seven to eight weeks of gestation. Failure of obliteration can result either in an ileoumbilical fistula, a cystic remnant along the duct, a fibrous band, or, most commonly, a Meckel’s diverticulum. These diverticuli are usually found within 90 cm of the ileocecal value; however, at least 180 cm of bowel proximal to the ileocecal value should be evaluated prior to excluding a Meckel’s diverticulum (51). The blood supply to the diverticulum is from a remnant of the vitelline artery, which arises from the superior mesenteric artery and may or may not have its own mesentery. There is about a 2% (range 0.14–2.45%) incidence of this anomaly in the general population. Asymptomatic lesions are equally described in both sexes; however, symptomatic cases are described three times as frequently in men. There is an association between Meckel’s diverticulum and certain congenital anomalies, including cleft palate, bicornuate uterus, and annular pancreas. There is also an increased incidence in CD (6–18%), but the explanation for this is unknown (52). As many as 50% of Meckel’s diverticuli contain ectopic gastrointestinal mucosal tissue. Parietal cell–rich acid-secreting mucosa is most commonly present, but less frequently pancreatic tissue, Brunner’s glands, colonic mucosa, or hepatobiliary tissue is identified. Inflammatory conditions may arise from acid secretion and ulceration of the adjacent ileal mucosa, which may lead to gastrointestinal hemorrhage. Obstruction of the orifice of the diverticulum by fecal matter, foreign bodies, or neoplastic tissue may elicit an inflammatory cycle similar to appendicitis. Carcinoids and adenocarcinomas have been rarely found in diverticuli. In adults, the most common complication of Meckel’s diverticulum is mechanical small bowel obstruction. Multiple patterns of obstruction have been described, including intussusception into the terminal ileum and right colon, volvulus of the attached small bowel around the fibrous mesenteric band, and internal herniation. Local inflammatory changes, with peptic ulceration and scarring, can also progress to lesions that cause obstruction. Incarceration of a Meckel’s diverticulum in an abdominal hernia has been described and is referred to as a Littre’s hernia. Although first described for incarceration within a femoral hernia, this term is now generally applied to any hernia with an incarceratedMeckel’sdiverticulum.Thecomplicationsassociatedwith Meckel’s diverticulum vary with the age of the patient. The pediatric population most commonly has painless hematochezia, whereas the adult population is more likely to show symptoms referable to diverticular inflammation or bowel obstruction. Because this anomaly is relatively rare, accurate diagnosis is often not established until laparotomy.

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The presence of ectopic gastric mucosa in some Meckel’s diverticuli has allowed the development of a noninvasive imaging procedure. Diverticuli containing functional gastric mucosa selectively take up 99m(Tc) pertechnetate after intravenous injection. This gamma-emitting isotope can then be detected with external cameras. At least 1.8 cm2 of ectopic gastric mucosa must be present to be detected with this scan. The accuracy of the scan in children approaches 90%; in the adult population, however, sensitivity is 62.5% and specificity is only 9% (53). Surgical management of symptomatic Meckel’s diverticulum requires surgical segmental small bowel resection to remove all ectopic tissue and adjacent inflamed or ulcerated areas. The incidental finding of Meckel’s diverticulum presents less clear indications for excision. Lesions with a narrow orifice, an associated palpable mass, a fibrous band, or a vitelline vessel without a mesentery should be resected. The incidental Meckel’s diverticulum with any of these features that is free of signs of inflammation or scarring can be safely managed with simple excision from the antimesenteric surface of the small bowel, without segmental small bowel resection. This simplified approach is easily accomplished with a gastrointestinal stapling device. The risk of morbidity after elective, incidental excision has been reported to be 2%, compared with a 7% risk of morbidity after operation for symptomatic lesions. Meckel’s diverticuli without these findings should likely be left undisturbed (54).

JEJUNOILEAL DIVERTICULI Diverticuli of the jejunum and ileum are rarely associated with clinical manifestations. Although such diverticuli are noted in 4.6% of the population at autopsy, they are described on only 0.5% to 2.3% of small bowel contrast studies (55,56). These pseudodiverticuli are formed by herniation of the small bowel mucosa into the mesenteric fat at the sites where the vasa recta penetrate the bowel wall. The diverticuli, often multiple, are more frequently found in the proximal jejunum, probably because of the larger size of the vasa recta in this area of the small bowel, and are often not apparent on routine abdominal exploration, because they are concealed within the mesenteric fat. They are thought to be acquired diverticuli; it is theorized that increased intraluminal pressure, possibly associated with abnormal peristaltic action, may be responsible for their development. Although these diverticuli are frequently clinically silent, clinical syndromes that may be associated with small bowel diverticuli include malabsorption, hemorrhage, inflammation, and obstruction. Extensive regions of small bowel diverticulosis may be associated with abnormal small bowel motility, with consequent stasis and bacterial overgrowth. A secondary malabsorption syndrome characterized by crampy abdominal pain, anemia, and diarrhea may ensue. Hemorrhage is rarely associated with these lesions, but they have been described as a cause of recurrent occult gastrointestinal hemorrhage. Obstruction of the orifice of the diverticulum with inspissated luminal material can result in acute inflammation, which may progress to peritonitis and perforation. Asymptomatic lesions, or those identified incidentally on upper gastrointestinal tract small bowel follow-through series, do not require surgical intervention. Lesions associated with acute inflammation or hemorrhage require emergency operation with segmental small bowel resection.

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COLONIC DIVERTICULAR DISEASE Colonic diverticulosis is a common acquired structural disorder of the colon. Although it was first described in the 18th century, the pathologic significance of this disorder was not fully appreciated until the early 20th century. This condition has increased in frequency during the last 80 years in conjunction with an aging population; autopsy prevalence rates of 5% were noted in the early 1900s, while prevalent rates of 50% are now reported. Approximately 30% of all persons older than 45 years have diverticulosis, and as many as 70% of people older than 85 years have this condition. The condition is manifested equally among men and women. The pathogenesis of colonic diverticuli remains unclear, although two factors seem to be operative in their development: weakness in the colonic wall and intraluminal pressure gradients. Intraluminal pressure recordings demonstrate a process termed segmentation, which allows small segments of the bowel to develop relatively high pressures. Patients with diverticulosis have similar resting pressures, but generate markedly increased pressures with contraction. Diverticuli are most frequently identified in the sigmoid colon, the region where the highest pressures are generated (Fig. 7). The structural feature that is predisposed to diverticular development is the point where the vasa recta enter the bowel through the muscular wall. These perforating vessels cause weakness in the colon wall and are the sites where diverticuli form. The association of diverticular disease with increasing age may be explained by the decreased collagen synthesis and increased elastin content of the submucosa of the colon in elderly persons. Muscular thickening of the colonic wall, a condition termed myochosis, is present in younger people of the Western population at risk for disease. This muscular abnormality constricts the lumen of the colon and leads to higher intraluminal pressures; it is thought to be the precursor of diverticulosis (58). A low-residue diet typical of Western populations is associated with the risk of diverticulosis (59). Diverticulosis is not present in African populations, where a high-residue

Figure 7 Diverticulosis of the colon. Cross section of the colon depicting the sites where diverticuli form. Note that the antimesenteric portion is spared. Diverticuli originate at the site where the blood vessel penetrates the colonic wall. Source: From Ref. 57.

diet is the norm. Population-shift studies have shown that Japanese immigrants, who have a low incidence of diverticulosis before immigration, acquire the same risk as the native U.S. population after adopting the low-residue regional diet of their new environment. As many as 25% of patients with diverticulosis develop a complication of this condition. Acute diverticulitis is the most common manifestation. Diverticulitis is caused by the obstruction of the orifice of the diverticulum by fecal material, with consequent bacterial overgrowth, inflammation, and eventual transmural inflammation and peritonitis. Advanced complications may be manifested by free or localized perforation, abscess formation, fistulization to adjacent viscera or the skin, and acute colonic obstruction. Bleeding is rarely associated with acute diverticulitis, although it is a well-described complication of diverticulosis. Acute diverticulitis is characterized by the gradual onset of crampy left lower quadrant pain. Altered bowel habits, including diarrhea or constipation, may be reported. More advanced disease is associated with fever, leukocytosis, and distinct left lower quadrant peritonitis. An abdominal CT scan to identify pericolonic inflammation and mesenteric streaking, with or without associated abscess, is the most sensitive radiographic study to identify acute diverticulitis. Contrast enemas and sigmoidoscopy are contraindicated, and plain abdominal films are of value only to rule out free perforation. Mild cases of diverticulitis, not associated with paralytic ileus, can be treated with oral antibiotics on an outpatient basis. However, patients with fever, leukocytosis, or left lower quadrant peritonitis require hospitalization for intravenous antibiotic administration. Prompt evaluation with CT scan allows percutaneous drainage of localized abscess cavities preparatory to delayed elective segmental colonic resection. Patients with diffuse peritonitis and those for whom initial nonoperative therapeutic measures fail should proceed to urgent laparotomy. Surgical management is dictated by the operative findings (60). If preoperative mechanical bowel preparation is possible, a one-stage procedure with resection and primary anastomosis is indicated. All involved bowel should be resected, particularly including the entire sigmoid colon. The distal margin of resection should be defined by the region in the upper rectum, where the taeniae coli splay apart to become a confluent muscular layer. Patients with acute perforation, localized undrained abscess, or peritonitis should be treated with a two-stage procedure, with initial segmental resection of the inflamed bowel, descending colostomy, and a Hartman’s rectal pouch. Rarely, the inflammatory process in the sigmoid colon is so severe as to warrant the older three-stage approach to this disease, in which a transverse colostomy to divert fecal stream is performed at the initial setting, prior to subsequent sigmoid resection after the acute inflammatory process resolves and later closure of the colostomy. Elective surgical resection is generally recommended for patients younger than 40 years who have had one attack of diverticulitis severe enough to warrant hospitalization. Judgment regarding elective surgical management for older patients is based on medical comorbidities and suitability of the patient for elective colonic resection. Patients who have had a single attack of diverticulitis have a risk of recurrent disease exceeding 50%. For surgeons experienced with the technique, laparoscopic or hand-assisted minimally invasive approaches are appropriate options for patients undergoing sigmoid resection for diverticulitis.

Chapter 18: Inflammatory Disorders of the Small Bowel and Colon

CLOSTRIDIUM DIFFICILE COLITIS With the advent of broad-spectrum antibiotics and their frequent use, the incidence of pseudomembranous colitis caused by C. difficile infection is increasing. C. difficile colitis is characterized by diarrhea and colorectal mucosal inflammation. Original descriptions of this clinical scenario date to the 19th century in patients undergoing intestinal surgery for obstruction or ischemia; this observation, combined with occasional contemporary reports of C. difficile colitis in immunocompromised patients, attests to the possibility that the condition may develop in the absence of antibiotic use. Nevertheless, the disease today is closely associated with antibiotic therapy (61,62). Enteral medications appear to be slightly more likely to lead to disease than parenteral antibiotics, although frequency of use of parenteral agents in surgery makes them a common cause in this subset of patients. Agents most frequently implicated are cephalosporins, clindamycin, and lincomycin, but associations have been made with nearly all antibiotics except aminoglycosides, nitroimidazols, and monobactams. Prolonged antibiotic use is most often involved, but a single dose of systemic therapy can lead to C. difficile colitis. C. difficile is most likely a minor component of the normal flora, although it is rarely cultured in individuals without symptoms. The organism can be transmitted from patient to patient by health care carriers and instruments, and nosocomial epidemics are well documented (63). Once the organism is present, antibiotic-induced alterations in the normal colonic microflora may give C. difficile the proliferative advantage that leads to clinical disease. Of the various products that the bacterium secretes, two are toxins. Toxin A is weakly cytotoxic but elicits an inflammatory response characterized by vasodilation and hemorrhage (64). Toxin B is released from the cell membrane on lysis and is the basis for commercially available cytotoxic assays. Both toxins are necessary for clinical disease. C. difficile colitis represents one of the more common and costly nosocomial infections in surgical patients. A high index of suspicion is critical to allow a prompt therapeutic response. Watery diarrhea is the hallmark of the disease. Blood may be present in the stool but is rare. Abdominal pain and low-grade fevers are characteristic but not specific in patients after abdominal operations. Mortality as great as 40% is documented for untreated patients; it drops to less than 10% with recognition and institution of appropriate measures. Stool cultures for the organism and stool assay for the C. difficile cytotoxin (toxin B) are diagnostic and readily available in most institutions. Although culture is the most sensitive test, cytotoxin assay is more specific (65). The presence of leukocytes in the stool can be a more rapid, if less sensitive and specific, diagnostic aid. When the diagnosis is uncertain, endoscopy can be helpful. The rectum and left colon are involved in 75% of patients, with the right colon affected infrequently. Endoscopy reveals scattered patches of white plaque (the pseudomembranes) interspersed between normal appearing mucosa. Histologically, plaques are made up of fibrin, mucus, sloughed epithelial cells, and neutrophils. In the absence of pseudomembranes, the microscopic appearance can be difficult to differentiate from that of ischemic colitis. Most patients show clinical improvement when the offending antibiotic is removed, although diarrhea may persist for more than a month. Relapses occur and carriers without symptoms pose a risk to the community. Therefore, even mild cases should be treated. Treatment consists of

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institution of C. difficile-specific therapy; the agents of choice are oral vancomycin and metronidazole. Although vancomycin may have a slight therapeutic advantage, its greater cost and the recent development of vancomycin resistant Enterococcus species mandate that its use be reserved for severe cases or metronidazole-resistant C. difficile colitis. Parenteral metronidazole can be used in patients unable to take oral medication; higher therapeutic doses are needed, however, and therapeutic failures are more common. If continued antibiotic treatment is essential for treatment of concomitant disease, antibiotics not commonly linked to C. difficile colitis, such as penicillin, ampicillin, aminoglycosides, erythromycin, or tetracycline, should be used if possible. Surgery may be required in fulminant cases associated with toxic megacolon or perforation. C. difficile colitis is most likely to progress to megacolon and systemic sepsis in immune-compromised patients, particularly those with solid organ transplants. Marked systemic sepsis, extreme leukocytosis, and colonic distention and ileus are the hallmarks of toxic megacolon. Prompt surgical resection of the total abdominal colon with ileostomy and Hartman’s pouch is appropriate. At the time of exploration, transmural necrosis may not be evident on gross external examination of the colon, nonetheless total abdominal colectomy should be performed (66).

RADIATION ENTERITIS The beneficial effects of radiation on tumors became evident shortly after Roentgen invented his X-ray device 100 years ago. The harmful effects on normal tissue were reported soon thereafter, but it was not until the development of megavoltage external-beam radiation in the 1950s, which expanded the therapeutic role of irradiation, that intestinal damage began to be widely reported (67). Despite efforts to limit injury by minimizing the radiation field and optimizing the dose administered, an increased incidence of gastrointestinal complications has been reported (68). The increase is probably caused by the increased use of this modality for pelvic malignancies as well as improved long-term patient survival. The synchronous administration of chemotherapy during radiation therapy to enhance radiosensitivity of the tumor may also lead to an increase in the incidence of radiation enteritis. The acute effects of radiation are defined in experimental in vivo models (69,70). Radiation energy induces its tumoricidal effects by denaturing DNA and forming oxygen free radicals. The sensitivity of normal tissue varies according to the proliferative rate of the cellular components. The alimentary tract, particularly the small bowel, is exquisitely sensitive to radiation because of the high rate of proliferation found throughout the intestinal epithelium. Mitotic activity in the crypts of the small intestine stops within hours after radiation exposure to single radiation doses of 500 to 1000 cGy (rads). Cell necrosis peaks at six to eight hours. Conventional understanding proposed a proliferative burst during the next 24 hours by the remaining viable crypt cells. However, it is more likely that initial repair occurs by restitution, with flattening of the villi as residual cells spread out to cover the denuded areas of the epithelium. A leukocyte infiltrate is often present. The changes are associated with nausea, vomiting, and diarrhea. The diarrhea results in part from malabsorption of nutrients and bile salts and can be ameliorated by cholestyramine (71). Restitution from a single small-dose injury is complete

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by day 3, whereas after a course of treatment, histologic recovery requires two weeks. Symptomatic recovery may take as long as six months. With larger doses (1500 cGy) and a proportionately larger cell kill, the re-epithelialization process is incomplete, the intestinal barrier function is lost, and septic death often results. Clinically, acute radiation enteritis is usually self-limited and responds to symptomatic therapy and conservative management. Whereas acute injury is limited to the mucosa, chronic radiation enteritis involves the full thickness of the intestinal wall. It is seen six months to many years after exposure, generally correlates with the severity of the acute injury, and occurs through unknown mechanisms (72). The most prominent and consistent histologic feature is obliterative sclerosis and intimal hyperplasia of the submucosal arterioles. This obstruction to blood flow likely results in ischemia and is responsible for the mucosal ulceration and atrophy typically associated with it. Inflammatory cells infiltrate the lamina propria, and the muscularis mucosa is hyperplastic and fibrotic. The normal appearance of the muscularis propria is preserved. Serositis, with infiltration by fibroblasts and inflammatory cells, is universally present. These changes are generally progressive. Patients with chronic injury generally show acute signs of partial bowel obstruction superimposed on a history of chronic diarrhea and malabsorption. Because many have a prior history of abdominal surgery, cancer, or both, differentiating between radiation enteritis and tumor recurrence or adhesions may be difficult. Contrast upper and lower gastrointestinal tract series may be helpful, although findings must be differentiated clinically from other processes, primarily CD and ischemia. Such series also help define the location and extent of fistulous tracts and strictures, thereby guiding the operative approach. Most cases respond, at least initially, to conservative management with institution of bowel rest followed by a low-residue diet. As many as 40% of patients receiving radiation treatments have symptoms severe enough to require medical intervention at some point, and 2% to 5% require operative management. Fistula and stricture are the major indications for operation. Surgical intervention is hampered by the extensive serositis and dense vascular adhesions commonly encountered. Conservative measures such as proximal enterostomy and enteroenteral bypasses may be the most appropriate approach. Resection with reanastomosis can be safely carried out when the segment involved can be mobilized and the ends to be anastomosed are grossly normal in appearance. Because of the progressive nature and difficult management once the disease is established, prevention is the key. Careful targeting of the radiation field, optimization of the dose, and distension of the bladder during treatments minimize the risk of intestinal injury, although a relationship between amount of bowel exposed in the radiation field and surgical complications is not always evident (73). A number of intraoperative techniques have been suggested to prevent small bowel from dropping into the pelvis after such radical procedures as hysterectomy, exenteration, and abdominoperineal resection. These include reperitonealization of the pelvis, placement of omental, and absorbable mesh slings across the pelvic brim, and insertion of salineor silicone-filled pouches in the pelvic space. The efficacy of these measures remains unproven. Numerous pharmacologic agents have been shown to ameliorate acute experimental radiation injury, including elemental diets, prostaglandins, epidermal growth factor, glutamine, and sucralfate, but proof of clinical benefit is lacking for all

but the last, and none have been shown to alter the course of chronic radiation enteritis.

SUMMARY A large number of inflammatory disorders may adversely influence the normal physiology of the small bowel and colon. The inflammatory disorders of surgical significance include appendicitis, Meckel’s diverticulitis, diverticular disease of the colon (and on occasion jejunum and ileum), CD, and UC. Other diseases that may require surgical intervention in selected situations include C. difficile colitis and radiation enteritis. The impact that these disease processes have on intestinal function varies considerably in terms of disability and long-term sequelae. An understanding of the physiologic derangements associated with each inflammatory disorder forms the basis for correction and for those surgical procedures that must be used to restore intestinal function to normal.

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LIVER, BILIARY TRACT, PANCREAS, AND SPLEEN

19 Hepatic Physiology Jose M. Prince and Timothy R. Billiar

when the liver primordium emerges from the ventral aspect of the distal foregut at approximately 18 days. By week 16, the architectural organization of the liver is well developed (5). Hepatogenesis proceeds from two anlages, the hepatic diverticulum and the septum transversum. The septum transversum is the mesenchymal plate that partially divides the embryonic thoracic and abdominal cavities. The development of the hepatic diverticulum at the future duodenum requires the formation of the definitive endoderm during gastrulation. Endodermal patterning yields a population of liver progenitor cells called hepatoblasts (Fig. 1) (6,7). Arising cranially from the hepatic diverticulum, the hepatoblasts form sheets and cords within the septum transversum, which are arranged along the vitelline veins as they enter from the yolk sac. Ultimately, the vitelline veins fuse to form the portal vein. The hepatoblasts differentiate into hepatocytes and cholangiocytes (8). The caudal development of the hepatic diverticulum forms the extrahepatic biliary system, including the gall bladder. As hepatogenesis progresses, the enlarging liver makes contact with the superior and inferior coverings that delimit the septum transversum and begins to split them apart. The inferior serosal membrane covers almost the entire surface of the liver as the visceral peritoneum; however, at the superior pole, the liver makes direct contact with the developing central tendon of the diaphragm, avoiding the peritoneal investiture and is identified surgically as the bare area of the liver. The margins of the bare area are surrounded by the reflection, or fold, of the peritoneum from the inferior surface of the diaphragm onto the surface of the liver, forming the coronary ligament (encircling the bare area like a crown). Of note, the direct contact between the liver and the diaphragm in the bare area permits the formation of vascular anastomoses between hepatic portal vessels and the systemic veins of the diaphragm. Surgical mobilization of the liver during operation is based on identifying and dividing the ligamentous attachments of the liver formed during development. A narrow ventral mesentery attaches the liver to the ventral body wall and differentiates into the membranous falciform ligament. The umbilical vein is carried within the free caudal margin of this membrane. The ventral mesentery also gives rise to the lesser omentum, a translucent membrane between the liver and the stomach, which may be identified as having two principal components: the hepatoduodenal ligament and the hepatogastric ligament. The hepatoduodenal ligament consists of the caudal border of the lesser omentum, which connects the liver to the developing stomach. Within the hepatoduodenal ligament are contained the portal vein, the proper hepatic artery, and the extrahepatic biliary ducts (hepatic, cystic, and common bile ducts).

INTRODUCTION From the earliest times of recorded history, the liver has enjoyed special attention and fascination. In ancient Mesopotamia, the cradle of civilization, sorcerers and physicians would perform divination rituals in order to discover the sin committed by a person, which rendered them ill. This was often accomplished by hepatascopy in which the liver of a sacrified animal, such as a sheep, would be carefully examined in an effort to determine the tribute demanded by the gods for the transgression. The underlying idea was that the liver was the collecting point of blood and therefore the seat of life (1). By carefully examining its topical anatomy, the intentions of the gods could be discerned. According to the world’s oldest medical record, a Sumerian clay tablet dating from 2150 B.C., the responsibilities of the treating physicians were to wash wounds, make poultices, and apply bandages; the physicians in ancient Babylon may have been the first to be regulated by law because a description in the Hammurabic code describing their pay scale and obligations stated, ‘‘if a physician performs a major operation on a lord . . . and has caused the lord’s death . . . they shall cut off his hand’’ (2). Such penalties were derived from divination rituals using hepatoscopy. It is little wonder that the liver has enjoyed a high place of preeminence down through the centuries. Even today, it is associated with continuing mystery. How does it regenerate itself when large portions are resected? When many other organs are expendable why are its functions so crucial that life itself depends on its health? While many of its mysteries have been unraveled, the liver continues to be an unusual organ demanding great respect. This chapter attempts to explain its complex anatomy and physiology and why it is so important if homeostasis is to be insured for the entire human organism.

EMBRYOLOGY Accounting for 5% of the body weight of a newborn infant, it is not surprising that the liver develops into the most massive organ in the fetus. In fact, the liver produces most of the prominence of the newborn abdomen (3,4). A careful understanding of the process by which the liver forms, known as hepatogenesis, provides the operating surgeon with the functional understanding necessary to fully grasp the surgical anatomy of this organ. For this to be fully appreciated, one must have a thorough knowledge of the birth of this organ. Over the last several decades, great advances have been made in identifying the important genes whose expression dictates the initiation of cellular differentiation into the complex 3-D structure of the liver. It all commences 427

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(A) Competence

(B) Specification

(C) Morphogenesis

ventral foregut endoderm

Pre-cardiac mesodem

cardiac mesodem

hepatic genes activated

vascularized liver

septum transversum mesenchyme

As its name implies, the hepatogastric ligament is the region of the lesser omentum between the liver and the stomach. During the sixth week, the abdominal foregut rotates to the right, directing the liver to its adult anatomic location in the right upper quadrant of the abdomen. As a result of this rotation, the lesser omentum reduces the communication between the lesser and greater sacs of the peritoneal cavity to a narrow canal, the epiploic foramen of Winslow (9).

Circulatory System Hepatogenesis is carefully coordinated with vascular development. Angioblasts, the precursors to endothelial cells, are found between the thickening hepatic endoderm and the surrounding septum transversum mesenchyme prior to hepatocyte invasion of the septum transversum. These early endothelial cells intermingle with the hepatoblasts as they form into a liver bud and provide crucial growth stimulus to the hepatic bud (10). During the 5th week of gestation, initial advances into the hepatic cords form channels originating from the vitelline veins to form primitive sinusoids, a dense network of anatomizing venous spaces. In the adult liver, these sinusoids will be lined with a fenestrated endothelium that exposes the hepatocytes to the contents of the blood as it flows from the portal vein and hepatic artery to the hepatic veins. The primitive embryonic venous system is divided into three bilaterally symmetrical drainage systems of which two play critical roles in the development of the hepatic vasculature. The vitelline system collects deoxygenated blood from the gastrointestinal tract; whereas, the umbilical system carries oxygenated blood from the placenta. The right and left vitelline veins emerge from the yolk sac; however, by the third month, the left vitelline vein has completely disappeared and united with the right vitelline vein to form the portal vein. The portal vein enters the enlarging hepatic mass through the porta hepatis, or hilum of the liver, establishing the pathways for the portal tracts and intrahepatic branching of portal veins with associated mesenchymal tissue (11). The superior portion of the right vitelline vein ultimately becomes the terminal segment of the inferior vena cava (IVC). Within the growing liver, a single oblique channel amongst the sinusoids, the ductus venosus, becomes dominant and drains into the IVC. During fetal life, the ductus venosus receives the oxygenated blood from the umbilical system and shunts it directly to the heart (9). In contrast to the vitelline veins, the right umbilical vein will disappear with the left umbilical vein persisting. The hepatic artery is derived from the celiac axis, and arterial sprouts grow into the liver from the hilum along the portal tracts.

Figure 1 Phases of hepatogenesis. Endodermal patterning results in the activation of hepatic genes with subsequent liver differentiation into the septum transversum mesenchyme. Source: From Ref. 7.

Proper development of the complex sinusoidal vasculature during hepatogenesis is essential for the liver to perform its role as a site for hematopoiesis by midgestation. During fetal life, the liver is the prominent site of hematopoiesis and up to 60% of the liver mass consists of blood cells (12). As early as the 4th week, foci of hematopoietic cells derived from the mesenchyme of the septum transversum begin to produce blood cells. This intense and diffuse production of blood between hepatoblasts and within the portal tracts continues until 24 weeks of gestation. After 25 to 28 weeks, the hematopoetic cells begin to form islands, and by the 36th week, hematopoeisis exists only as scattered islands in the parenchyma as other sites in the body increasingly bear the burden of hematopoeisis.

Biliary System At the same time as the liver parenchyma develops, both the intrahepatic and extrahepatic biliary ducts form. By week 7, a double layer of cells develops around the portal tract. Peripheral biliary tubular structures form between these two layers of cells. Over the next several weeks, these structures remodel to form terminal bile ducts by week 11. From this point onwards, the maturation of the intrahepatic biliary tree occurs from the hilum outwards and continues past birth for several months. Bile acid synthesis begins at 5 to 9 weeks, with bile secretion identified by 12 weeks (13). The extrahepatic and intrahepatic biliary tree maintain patency and continuity throughout gestation, ensuring a passage to the alimentary canal for the bile (5).

HISTOLOGY The microarchitectural determination of what constitutes the functional liver unit has been debated since 1833. Classically, the liver comprises 1 to 2 mm diameter hexagonal hepatic lobules oriented around the terminal tributaries of the hepatic vein or central veins. Hepatocytes radiate as cords of cells from the central vein, with hepatocytes abutting the portal tract referred to as the limiting plate. Upon microscopic evaluation, hepatocytes tend to be uninucleate, diploid cells with minimal variation in overall cellular dimensions, though the nuclei may vary in size, number, and ploidy. Between the cords of hepatocytes are vascular sinusoids that bathe the cells on two sides with well-mixed portal venous and hepatic arterial blood, representing 25% of the cardiac output of the body. The terminology developed to discuss hepatic lobular anatomy persists in the practice of liver pathology, with pathologists describing injury patterns by location as being centrilobular, mid-zonal, or periportal (14).

Chapter 19: Hepatic Physiology

Alternatively, the hepatic acinar structure of the liver has been advanced by some authors as a more accurate depiction of the ‘‘metabolic lobule.’’ Triangular in shape, the acinus has at its base the terminal branches of the hepatic artery and the portal vein, with the terminal hepatic venule (i.e., the central vein) occupying the apex of the acinus (Fig. 2). The parenchyma of the hepatic acinus is divided into three zones based upon distance from the blood supply. The concept of zonal distribution accurately represents a lobular gradient of hepatic enzymes, oxygen concentration, and metabolic substrates, which corresponds with many forms of hepatic injury (16). In addition to the parenchymal hepatocytes, a number of nonparenchymal cells constitute key populations of cells that are essential to proper functioning of the liver as an organ. Endothelial cells lining the suinusoids define an extrasinusoidal space of Disse, into which the microvilli of the liver protrude. The large pores, or fenestrations (almost 1 mm), present between the endothelial cells permit substances in the plasma, including large proteins such as albumin, to move freely into the space of Disse. Within the space of Disse, hepatic stellate cells (formerly called Ito cells) can be found. They contribute to the storage and metabolism of vitamin A and to collagen production in the normal and fibrotic liver. They are an important source of the key hepatocyte mitogen, hepatocyte growth factor (HGF) (17). Scattered Kupffer cells of the monocyte–phagocyte system populate the luminal face of the endothelial cells, accounting for 31% of sinusoidal cells. These Kupffer cells provide a rich source of cytokines for signaling within the liver after injury and, as will be discuss later, play a critical role in fighting infections (18).

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beneath the armor provided by the right lower ribs and their cartilage, though the liver may abut the abdominal wall in the epigastrium of a healthy person. Beneath the ribs, the upper extent of the liver should be considered to be as high as the 5th rib at the level of the nipple line. The normal inferior extent of the liver can often be palpated along the costal margin in the thin upright patient, though patients with hepatic congestion and enlargement may present with a liver palpable all the way to the right lower quadrant. When supine, the liver gravitates backwards; whereas, with deep inspiration, the diaphragm forces descent of the liver below the costal margin. The gallbladder fundus projects toward the lateral aspect of the right rectus muscle at the level of the 9th rib (19–21).

Internal Surface Anatomy The spongy, reddish brown liver is surrounded by a capsule of strong connective tissue, called Glisson’s capsule. The liver has a soft consistency that is easily friable. The liver is divided into right and left lobes by a line that extends from the gallbadder fossa to the IVC, called Cantlie’s line. The left lobe of the liver is further divided into lateral and medial segments by the falciform ligament. As described above, the embryologic development of the liver determines the topographic anatomy of the liver, which is defined on initial surgical exploration principally by its five ligamentous attachments. Additionally, adjacent organs leave their impression on the liver surface, including the stomach, the right kidney, the transverse colon, and the diaphragm. There are no visible surface markings that define the hepatic segmental anatomy described below.

Functional Anatomy ANATOMY As the largest abdominal organ and the largest gland in the body, the liver accounts for about 2% of the body weight in adults (about 1.5 kg). During routine physical examination or in the rapid evaluation of a trauma patient, it is important for the surgeon to understand the location of the liver relative to patient position and external anatomy. On physical examination, the majority of the liver is protected

Figure 2 Diagram comparing the hepatic acinus with zones 1, 2, and 3 to the hepatic lobule (dotted line). Portal tract contains portal venule (v), hepatic arteriole (a), and hepatic duct (d), terminal hepatic venule (t). Source: From Ref. 15.

Since 1954, Couinaud’s liver segment classification has become the standard basis for liver surgery (Fig. 3). In this system, autonomously functioning units of the liver are defined by avascular planes based upon the interface of the portal venous anatomy with the hepatic veins (23). Segments 1 through 4 represent the classic left lobe of the liver; whereas, segments 5 through 8 correspond to the right lobe of the liver. The middle hepatic vein separates the right and left lobes of the liver as it passes in the interlobar fissure. Segment 1, the caudate lobe, lies anterior and to the left of the IVC. Segments 2 and 3, the left lateral segments, and segment 4 constitute the remainder of the classical left lobe. The right hepatic vein, the longest vein in the liver, runs in the right intersegmental fissure and divides the right lobe of the liver into anterior (segments 5 and 8) and posterior (segments 6 and 7) components. The portal elements further divide the anterior and posterior components into their respective segments (Fig. 4) (24). Based on this segmental anatomy of the liver, complex hepatic resections have been developed to a degree of sophistication that forms the basis of living related donor transplantation (26). In dealing with malignancy in the liver, the cardinal rules of hepatic resection mandate that all tumor be resected with sufficient hepatic parenchyma preserved to sustain life without disrupting the vascular, venous, and biliary drainage of the remaining liver (27).

Vascular Anatomy The portal venous, hepatic arterial, and biliary systems run together within the intrasegmental parts of the hepatic parenchyma. The portal venous system provides approximately 75% of the hepatic inflow, with the remaining 25%

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Figure 3 The functional division of the liver and of the liver segments according to Couinaud’s nomenclature: (A) as seen in the patient; (B) in the ex vivo position. Source: From Ref. 22.

supplied by the hepatic artery; however, the hepatic arterial flow provides about 50% to 75% of the oxygen to the liver. Commonly arising from the celiac artery, the common hepatic artery provides systemic arterial blood to the liver.

Figure 4 Schematic representation of the functional anatomy of the liver. There are three main hepatic veins lying within the liver scissurae and dividing the liver into four sectors, each receiving a portal pedicle. The hepatic veins and portal pedicles are intertwined as are the fingers of two hands. Source: From Ref. 25.

Occasionally, the common hepatic artery may arise from the superior mesenteric artery. The common hepatic artery divides into left and right branches, but the origins of these arteries can vary frequently. In the most common variations, the left hepatic branch originates from the left gastric artery (25%) or the right hepatic branch arises from the superior mesentery artery (17%). The division between left and right hepatic arteries generally occurs to the left of the hepatic hilum. As it courses laterally, the right hepatic artery crosses behind the common hepatic duct in 80% of people. Variations in the hepatic arterial system are almost as common as the ‘‘normal’’ condition that is found in only 55% of the population (28). The portal vein is hidden in the hepatoduodenal ligament behind the extrahepatic bile ducts and hepatic artery. The portal vein divides at the hepatic hilum into the left and the shorter right branch. The right branch divides anteriorly to supply segments 5 and 8 via ascending and descending branches, respectively. The right portal vein posterior branch curves posterolaterally and divides for segments 6 and 7. The left portal vein courses transversely for 3 to 5 cm in the hilum and then curves left and anteriorly to the base of the umbilical fissure. The left portal venous system anatomy is rather constant, with segment 2 provided with a solitary vein and segment 3 having up to three veins (29). Variations in the portal vein tend to involve the right portal vein system with a trifurcation found in 10% to 15% of livers or a right anterior portal vein originating from the left portal vein. Rarely, the entire left portal vein may be absent (30). The portal venous system is valveless, permitting retrograde diversion of flow in the setting of obstruction resulting in portal hypertension. Portal hypertension may be categorized as suprahepatic, intrahepatic, or prehepatic. In the setting of suprahepatic and intrahepatic portal hypertension, ascites formation may be precipitated by the increased sinusoidal pressure that leads to increased passage of fluid into the space of Disse. Ultimately, hepatic lymph drainage capacity is exceeded and in combination with a low oncotic pressure, the patient develops ascites (31). For example, hepatic venous obstruction, as occurs with heart failure or hepatic vein thrombosis, results in increased pressure in the sinusoids causing portal venous system hypertension. Blood flow may even be reversed in acute settings in the portal veins. The absence of valves, which permits this flow reversal, allows surgeons to cannulate smaller omental or mesenteric vessels to measure portal vein pressure intraoperatively. In chronic conditions resulting in portal hypertension, the augmentation of the extrahepatic communications between the portal venous system and the systemic venous system provides an important alternate flow of blood for the portal blood to the right side of the heart. Four principal sites of portosystemic anastamoses are (i) distal esophagus/proximal stomach, (ii) umbilical/ periumbilical veins, (iii) superior/inferior and middle hemorrhoidal veins, and (iv) retroperitoneal veins (32). The venous drainage of the liver consists of three main hepatic veins that drain into the suprahepatic IVC and a variety of accessory hepatic veins that drain into the retrohepatic vena cava. The main hepatic veins flow in the interlobar or intersegmentar fissures. The right hepatic vein is single in 94% of cases and drains segments 5, 6, and 7. Following Cantlie’s line, the middle hepatic vein forms a common trunk with the left hepatic vein in 85% of people and drains the central liver (segments 4, 5, and 8) (33). The left hepatic vein drains segments 2 and 3 (sometimes 4) and generally joins the middle hepatic vein prior to

Chapter 19: Hepatic Physiology

arriving at the IVC. The caudate lobe is drained mainly on the left by a single vein in half of all livers.

Biliary Anatomy Understanding the variations in the biliary anatomy is critical to proceeding safely with liver and gallbladder surgery. The gallbladder can vary in size and position, sometimes being buried deep within the liver parenchyma. It can be double or septated, or can have its own mesenterium. The delicate blood supply of the extrahepatic bile ducts is provided by as many as seven arteries that may form distinct anastamotic patterns around the ducts. Typically, the distal, or retroduodenal, bile duct is supplied by the posterior superior pancreaticoduodenal artery, and the right hepatic artery provides the blood supply to the middle part. The gallbladder and cystic duct have a rich network, but the right and left hepatic ducts have a sparse network. Most commonly, the cystic artery is a single artery originating from the right hepatic artery. At times, two cystic arteries may be present. Venous drainage of the gallbladder is into the portal system of adjacent liver segments 4 and 5, with important implications for the spread of gallbladder pathology into the liver parenchyma (30).

HEPATIC FUNCTIONS (TABLE 1) Blood Reservoir Large quantities of blood can be stored in the liver. The liver is an expandable organ in which the normal blood volume of about 450 mL (10% of total body blood volume) can be increased to hold up to an additional 1 L of blood. Cardiac failure is a common clinical scenario requiring this adaptive response by the liver. In the setting of acute hemorrhage, the liver may provide as much as 300 mL of blood to compensate for the bleeding (34).

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systemic circulation as a result of the ruthless efficiency of the Kupffer cells in phagocytosing the foreign intruders. A 90% hepatectomy, however, results in bacteremia within two hours in rats. Kupffer cells, macrophages derived from blood mononuclear cells, inhabit the hepatic sinusoids and comprise between 70% and 90% of the reticuoendothelial system (35). The Kupffer cells also prevent endotoxins from entering the systemic circulation (36). In addition to their role in filtering the blood, the Kupffer cells play an important role in intercellular signaling and cytokine release in response to various forms of hepatic injury and disease (37).

Hemostasis The liver parenchyma produces almost all of the enzymes necessary for the coagulation cascade (38). Fibrinogen, prothrombin, Factor V, and Factor VII are amongst the important factors produced by the liver. In addition to the parenchyma, the endothelial cells and macrophages found in the liver produce some of the coagulation factors. Macrophages produce Factor VIII:C and plasminogen activator inhibitor-2, whereas, endothelial cells generate tissue plasminogen activator, von Willebrand factor, and thrombomodulin. The liver produces all the vitamin K–dependent coagulation factors, which include prothrombin and Factors VII, IX, and X. Vitamin K is a fat-soluble vitamin absorbed from the small intestine through the action of bile (39). Inadequate biliary production and excretion from liver disease can result in vitamin K insufficiency, which results in a coagulopathic state. In fact, liver disease in general is associated with a hemorrhagic diathesis caused by a number of factors including impaired synthesis of the coagulation factors (Table 2) (40).

Toxin Elimination

Blood that passes through the intestinal capillaries picks up a large number of bacteria from the intestines. In fact, blood cultures performed on portal venous samples will often grow colonic bacilli; whereas, systemic blood samples will rarely grow bacterial colonies. Less than 1% of the bacteria that arrive at the liver via the portal vein will enter

In addition to cleansing the blood of macroscopic bacteria, the liver filters the blood and chemically modifies a variety of toxins, drugs, and hormones. These biotransformation and detoxification reactions are numerous. Many tend to involve the P-450–dependent microsomal mixed function oxidase system (42). In principle, the liver attempts to modify endogenous or exogenous substances to either inactivate the substance directly or render it more suitable for elimination from the body by biliary or urinary excretion. Liver diseases may manifest a failure of this hepatic function

Table 1 Hepatic Functions

Table 2 Effect of Liver Disease on Hemostasis

Filtration (Kupffer cell of reticuloendothelial system) Capture and process incoming substrates and bacteria Maintenance of metabolic homeostasis Fundamental mechanisms Capture Intracellular metabolism Storage Release Modulation of metabolic substrates Carbohydrates: glucose, fructose, galactose Lipids: fatty acids, glycerol, cholesterol Amino acids: protein synthesis and degradation Specific protein synthesis Secretory proteins: albumin, acute phase reactants, carrier proteins Coagulation proteins: clotting proteins, anticoagulants, proteins, fibrinolytic proteins Lipid phase metabolism Drug metabolism Bile formation

Decreased synthesis of proteins Coagulation: Factors XII, IX, VII, V, and II; fibrinogen, prekallikrein, kininogen Anticoagulant: proteins C and S, antithrombin III Profibrinolytic: plasminogen Antifibrinolytic: 2–antiplasmin, Cl–inhibitor, 2–macro–globulin, histidine-rich glycoprotein Synthesis of abnormal proteins Vitamin K–dependent factors Factor VIII and von Willebrand’s factor Fibrinogen Decreased clearance function Activated coagulation factors Plasminogen activators Thrombin antithrombin III complexes Abnormalities of platelets Disseminated intravascular coagulation Lipoproteins

Blood Cleansing

Source: From Ref. 41.

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as an increased sensitivity to certain drugs such as sedatives or opiates or may enhance the biologic action of endogenous hormones, evidenced by the feminizing effects of chronic liver disease. Unfortunately, a healthy liver can suffer injury as a result of a drug reaction. In fact this accounts for 50% of the cases of acute liver failure in the United States, 75% of which result in liver transplantation or death (43). Acetaminophen, the most common agent responsible for acute liver failure, causes hepatocyte injury in a dose-related manner. Therapy with N-acetylcysteine repletes glutathione levels and may prevent injury if started within the first 24 hours after ingestion (44). One particularly important hepatic detoxification pathway is that involving the elimination of the ammonium ion (Fig. 5). Utlilizing the Krebs–Henseleit cycle, the ammonium ion is converted to urea via a series of intermediates in a process that involves both the mitochondria and the cytosol of the hepatocytes (46). This pathway of ammonium fixation is irreversible. Glutamate, formed from ammonium ion and alpha-ketoglutarate, serves as the principal NH2 donor. Carbamoyl-phosphate synthetase I represents the ratecontrolling step in urea synthesis (47). Two-thirds of the ammonia entering the portal vein is converted to urea and the remainder into glutamine. Unlike urea synthesis, glutamine synthesis for detoxification is a reversible process.

Iron Storage The normal iron content of the body is about 4 g including about 1 g of storage iron kept mostly in the liver (48). Iron absorbed from the small intestine is transported in the plasma as transferrin. Transferrin may release its iron to any tissue, but hepatocytes in particular accept excess iron present in the blood. In the cytoplasm of the hepatocytes, iron binds with apoferritin to form ferritin, the storage form of iron. Individuals with hereditary hemochromatosis

Figure 5 The urea cycle. Source: From Ref. 45.

suffer from a chronic iron overload syndrome that results in excessive iron storage in the liver and subsequent hepatic injury and fibrosis (49).

METABOLIC HOMEOSTASIS The liver functions as a complex chemical factory organizing, conducting, and regulating a multitude of chemical reactions that sustain our lives. Throughout their productive life, the hepatic cells maintain a high rate of metabolism in which they share substrates and energy from one metabolic system to another. We shall focus our discussion on the key metabolic processes that are especially important in understanding the integrated physiology of the surgical patient.

Carbohydrate Metabolism In carbohydrate metabolism, the liver plays an important role in maintaining a normal blood glucose concentration by changing glucose production, altering glycogen storage, and converting galactose and fructose to glucose. With key components of the body, such as brain tissue and red blood corpuscles being obligate consumers of glucose, production of glucose must be maintained, despite iatrogenic, physiologic, or pathologic challenges. The liver produces glucose as a result of two main processes, gluconeogenesis and glycogenolysis (Fig. 6). Hepatic glucose production and utilization involves the movement of substrates through a series of major cycles involving a sequence of intricate reactions, each catalyzed by an enzyme. Ultimately, all of the reactions result in glucose transport into or out of the hepatocyte. In the fed state or when hormonal conditions (i.e., high insulin, low glucagon) favor hepatocyte glucose uptake, glucose enters hepatocytes as a result of facilitated diffusion through constitutively active glucose transporters, primarily GLUT-2 (51). Conversely, when the hormonal conditions that favor gluconeogenesis exist (i.e., low insulin, high glucagon, and fasting state), hepatocytes release glucose into the extracellular space. The ability of hepatocytes to respond in these two manners depends upon regulation of the enzyme glucokinase (hexokinase IV), which rapidly phosphorylates intracellular glucose (52). This keeps glucose levels from building up inside the hepatocyte and maintains a concentration gradient across the cell membrane. Diabetes, in which hepatocyte glucose utilization is unbalanced and glucose is released from the cells as a result of unrestrained gluconeogenesis, serves as a good example (53). In this setting, glucokinase mRNA levels are very low and the glucokinase gene is inactive. As a result, glucokinase activity is reduced, a low rate of glucose phosphorylation exists, intracellular glucose accumulates, and glucose is exported by facilitated diffusion. Injection of insulin in the diabetic state increases glucokinase gene transcription and mRNA levels within 30 to 60 minutes, leading to increased glucokinase activity (54,55). The insulinmediated increase in glucokinase activity results in increased glucose phosphorylation, decreasing the intracellular glucose pool and favoring glucose entry into the hepatocyte along a downhill gradient. Although insulin regulates glucokinase activity in hepatocytes, insulin plays almost no role in glucose transport into hepatocytes. By contrast, in peripheral tissues such as muscle, insulin signaling leads to increased glucose transporter levels (GLUT-4) in the cell membrane and increased glucose uptake (56). Independent of the glucose concentration, glucagon inhibits

Chapter 19: Hepatic Physiology

Figure 6 Glycolysis–gluconeogenesis. These reactions are entirely cytoplasmic and, in response to mass action, readily reversible. Reversibility permits glycolysis and gluconeogenesis in the same cellular compartment. Mass action is determined by importation of substrate under the influence of insulin (glycolysis and glycogen synthesis), facilitated exit from the pathway (pyruvate entry into mitochondria for the Krebs cycle), or the entry of products (lactate or amino acids) that promote gluconeogenesis, an event also regulated by glucagon. The location of the rate-limiting enzymatic pathways for both glycolysis and gluconeogenesis are identified. Source: Adapted from Ref. 50.

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for only 12 hours, with the peripheral tissues requiring 180 g/day (120 g for the brain). During fasting and starvation, the liver coordinates a complex process of metabolic adaptation. During the initial phase of fasting, the liver produces glucose from its glycogen stores by the process of glycogenolysis. As hepatic glycogen stores become exhausted in the first 24 hours, gluconeogenesis becomes increasingly more important and alternative substrates begin to replace glucose as the source of fuel throughout the body. During the initial 48 hours, serum glucagon levels increase while insulin levels decrease to about half their normal level. This increase in the plasma glucagon/insulin ratio stimulates hepatic gluconeogenesis, glycogenolysis, synthesis of ketone bodies, and free fatty acid (FFA) mobilization from adipose tissue (59,61). The liver then turns to other sources outside of itself to provide the necessary substrates for gluconeogenesis. The main gluconeogenic precursors are amino acids released from muscle, lactate, and glycerol (62). In the fasting state, lactate accounts for 50% of the gluconeogenic substrates and an even greater component during exercise. At baseline, lactate is produced by the anaerobic glycolysis of red blood cells, platelets, and the renal medulla; however, tissues in which pyruvate oxidation capacity is exceeded (e.g., exercising muscle) by a high rate of glycolysis produce lactate. In the Cori cycle, when the muscle metabolizes glucose only to lactate, the liver converts this lactate to glucose, which the muscle can once again convert to lactate for energy (63). The adaptation to starvation can be so successful that obese individuals have been treated clinically for over 200 days of total fasting without serious complications (64). Additional sources of glucose include the digestion of sucrose and lactose in the small intestine to yield glucose, fructose, and galactose. Both the fructose and galactose enter the portal system where the majority is removed by the first passage of blood through the liver. In the hepatocytes, fructose and galactose are metabolized into substrates for glycolysis or glycogen synthesis. Fructose utilization is not insulin dependent.

Lipid Metabolism glucokinase and overrides the stimulatory effect of insulin (55). Additonally, glucokinase activity may be modulated by a glucokinase regulatory protein that competitively inhibits glucose binding (57). Intracellular signaling by second messenger cascades initiated by these hormones results in altered levels of cyclic adenosine monophosphate, calcium, and phospatidylinositol 3-kinase (58). Ultimately, the overall flow of metabolites depends upon the underlying hormonal state of the patient, which regulates the key hepatic enzymes that alter the balance, resulting in glucose uptake or release by the hepatocytes. The process of hepatocyte glucose metabolism is regulated by a variety of acute and chronic regulatory mechanisms (59). After a meal in response to the increase in blood glucose concentration, hepatocytes convert glucose to glycogen for storage. Glycogen synthase catalyzes the key step of glycogen synthesis. The activity of glycogen synthase is regulated by its phosphorylation state and by phosphorylated glucose levels (56). The total hepatic glycogen stores may be as much as 80 g. By contrast, the muscles contain 400 g of glycogen but unlike the liver, the muscle cells are unable to secrete glucose (60). The 80 g of hepatic glycogen stores are sufficient to supply the fuel needs of the body

There are three major classes of complex lipids: triglycerides, cholesterol, and phospholipids. The largest energy reservoir in the human body is stored as triglyceride in adipose tissue. These triglyceride stores are hydrolyzed to FFAs and glycerol by a hormone-sensitive lipase (65). The FFAs enter the circulation where they associate with albumin during transport. The FFAs can then be oxidized to water and carbon dioxide through the citric acid cycle and generate tremendous amounts of energy. Although some lipid metabolism can occur in all cells of the body, certain aspects of lipid metabolism occur principally in the liver. The liver has a high capacity to remove FFAs from the circulation. Once in the hepatocytes, the liver has the capacity to maintain a high rate of FFA oxidation to supply energy above and beyond its need, which can be utilized by the other organs in the body. Unlike in other organs, FFAs can be esterified back into tryglycerides or be oxidized to ketone bodies (e.g., acetoacetate and b-hydroxybutyrate) in the liver. During periods of starvation, the brain and muscle can utilize these ketone bodies as an additional source of energy. During fed periods when insulin levels are high and glucagon is low, the liver synthesizes fat from carbohydrates and proteins, which is then transported by lipoproteins to adipose tissue for storage.

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The liver is a principal site for lipoprotein formation. These lipoproteins are water-soluble macromolecular complexes of lipids and one or more specific proteins, called apoproteins. These complexes form pseudomicelles with the nonpolar lipids in the center of the complex and the more polar lipids and apoproteins forming the external surface. The apoprotein component of the lipoproteins targets the complex for delivery to specific tissues in the body. In general, the lipoproteins contain cholesterol, triglycerides, phospholipids, cholesteryl esters, and apoproteins. In humans, six major classes of plasma lipoproteins are commonly defined by their density, particle size, apoprotein content, and electrophoretic mobility (66). Chylomicrons are generated by the small intestine to carry dietary triglycerides and cholesterol. Endothelial cells of the vascular system enrich the cholesterol content of these chylomicrons by hydrolyzing the triglycerides with lipoprotein lipase (LPL). These chylomicron remnants are then rapidly cleared by the liver. The liver in turn synthesizes very low-density lipoproteins (VLDLs) to export the cholesterol and triglycerides generated by the liver. The VLDL is then subjected to hydrolysis of its triglyceride content by LPL and a distinct hepatic LPL to yield intermediate-density lipoproteins and low-density lipoproteins (LDLs) (67). The LDLs serve as the major cholesterol transport carriers in the plasma. Finally, the liver, in addition to other sources, generates high-density lipoproteins (HDLs), which associate with much of the cholesteryl esters as a result of the action of lecithin-cholesterol acytransferase. In reverse cholesterol transport, HDLs acquire cholesterol from the peripheral tissues and transfer them back to the liver as cholesteryl esters for excretion. Almost 80% of the cholesterol synthesized by the liver is converted to bile salts and secreted into the bile. Both the cholesterol and phospholipids carried by the lipoproteins are used by the cells of the body for a variety of uses including the formation of cellular membranes and intracellular structures (68).

Protein Metabolism Without a liver, the body might be able to adjust carbohydrate and fat metabolism and still survive; however, without the liver performing its critical role in protein metabolism, the patient cannot survive more than a few days at best. Proteins obtained from our diet are utilized by the liver for the synthesis of nonessential amino acids, purines, pyrmidines, and other nitrogen-containing compounds. The most significant functions of the liver in protein metabolism include (i) deamination of amino acids, (ii) urea formation for ammonia removal, (iii) synthesis of plasma proteins, and (iv) interconversions between the amino acids and other important metabolic compounds (Fig. 7). The vast majority of deamination, a necessary step in the processing of amino acids for energy, occurs in the liver. In carbohydrate and fat metabolism, complete oxidation results in the by-products of carbon dioxide and water, which are eliminated by respiration and urination. By contrast, protein metabolism results in the hydrolysis of proteins into bipolar amino acids whose oxidation results in HCO3 and NH4þ (ammonium). The nitrogenous waste may be cleared by a variety of mechanisms. The liver removes the waste product of this deamination, ammonia, from the body by forming urea through the urea cycle as previously described. Furthermore, additional ammonia produced by enteric bacteria and by the intestines is processed into urea by the liver. Although carbamoyl-phosphate synthetase is the rate-controlling enzyme of the urea cycle, the liver glutaminase in the periportal hepatocytes has the unique characteristic of being activated by its product, which results in a feed-forward effect on hepatic urea synthesis (70). Glutamine synthesis is the most important alternative pathway for ammonia detoxification and can be carried out in a number of tissues including perivenous hepatocytes. In fact, glutamine constitutes 50% of the free amino acid pool in the body (71). Normally, ammonia levels are maintained in a narrow range by hepatic ureagenesis and muscle glutamine synthesis.

Figure 7 Amino acid interconversion relies on cytoplasmic transamination, whereas metabolism of the carbon skeleton of the amino acid proceeds in the mitochondria. Most intermediates of the Krebs cycle can readily diffuse from the double convoluted membrane of the mitochondrion to participate in cytoplasmic intermediary metabolism. Source: From Ref. 69.

Chapter 19: Hepatic Physiology

Without hepatic urea generation in liver failure, the rising plasma concentration of ammonia reflects the presence of hepatic encephalopathy, which may result in hepatic coma and death (72). In cirrhosis, portosystemic shunts can greatly decrease blood flow to the liver, limiting the plasma exposed to the liver for ammonia elimination, resulting in increased systemic ammonia levels (73,74). These shunts can account for up to 50% of the portal flow (75). Perhaps as important as ammonia metabolism is the fact that the bicarbonate produced by oxidation of proteins must be eliminated to regulate systemic pH. Thus, urea synthesis removes not only toxic ammonium ions, but also equimolar amounts of bicarbonate. Adjustments in hepatic urea synthesis are important in pH homeostasis, highlighting another important interrelated function of the liver (76). After a meal rich in protein, the liver extracts the vast majority of the amino acids entering into the portal circulation. An important exception to note involves the branched-chain amino acids (BCAA), leucine, isoleucine, and valine. These BCAA are used primarily by the skeletal muscle (74). Because they do not require hepatic processing, attempts have been made to evaluate the use of BCAA in hepatic failure to reduce hepatic encephalopathy (77–79). Insulin release after a protein-rich meal facilitates the uptake of amino acids into muscle and fat and inhibits protein breakdown. Both the liver and muscle interconvert amino acids and release them into the circulation. The nonessential amino acids are oxidized in the liver and muscle, but the essential amino acids are primarily consumed in the liver. Excess dietary amino acids cannot be stored in the body. Some of the amino acids are used for gluconeogenesis, others for nonessential amino acid synthesis or protein synthesis. Except for the imunoglobulins, the vast majority of the major plasma proteins are produced by the liver. Serum albumin, the most abundant serum protein, is produced exclusively in the liver (80). Albumin production can account for up to 15% of all the total hepatic proteins synthesized. In addition to housekeeping protein production, the liver constantly responds to the needs of the body. Activation of the systemic inflammatory response results in a burst of protein synthesis, such as that of C-reactive protein and fibrinogen, in response to signaling by interleukin (IL)-6. These acute phase proteins generally serve to limit tissue damage and facilitate microbial clearance by inhibiting protesases, opsonizing bacteria, binding heavy metals, and modifying the immune response (81,82). The production of each of the proteins synthesized by the liver is controlled by specific regulatory mechanisms. In general, the plasma concentrations of specific proteins after acute liver injury depends upon the kinetics of synthesis and the turnover rate of the particular protein. For example, clotting factors (plasma half-time of hours to days) are more likely to be depressed initially by acute liver injury, than longer-lived proteins such as albumin (3 weeks).

Biliary Metabolism The formation of bile by the liver and the function of the bile salts in the digestive system are discussed in other sections of this book. We will briefly review the basic aspects of bile formation important in understanding liver physiology. Red blood corpuscles have a life span averaging 120 days (83). Senescent erythrocytes are degraded by the mononuclear phagocytic cells of the liver, spleen, and bone marrow. The heme moiety from the hemoglobin within these corpuscles accounts for about 70% of the bilirubin formed by the

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breakdown of heme. The rate-limiting step for bilirubin formation is the conversion of heme to biliverdin. Biliverdin, a nontoxic, water-soluble compound, is then converted to water-insoluble, nonpolar bilirubin. This unconjugated bilirubin diffuses across biologic membranes, crossing the blood–brain barrier, the placenta, and the gallbladder epithelium. As a result, unconjugated bilirubin is excreted in bile in only trace amounts. Unconjugated bilirubin is transported in the circulation reversibly bound to albumin until delivery to the liver, where it is esterified with glucuronic acid, increasing the water solubility of the compound. The conjugated bilirubin glucuronides are then secreted by an energy-dependent process into the bile canaliculi for transport to the gallbladder and intestines. Within the terminal ileum and colon, the conjugated bilirubin is converted once again to an unconjugated bilirubin. This time, the unconjugated bilirubin is modified into urobilinogens and related products. A small portion is oxidized to urobilin, providing some of the brown pigment that gives stool its normal color. In normal adults, 95% of circulating bilirubin is unconjugated. Unconjugated bilirubin exposed to light causes the formation of photoisomers and lumirubin, which can be excreted by the liver without conjugation. This process provides the physiologic foundation for the treatment of neonatal hyperbilirubinemia with phototherapy (84).

PATHOPHYSIOLOGY Understanding the clinical manifestations and diagnostic approaches to treating patients with deranged liver function is critical to the preoperative assessment that in many cases predetermines the successful outcome of surgical intervention in liver diseases. Patients with liver disease are burdened with a greater risk for surgical and anesthesia complications (85). A careful history and physical examination prior to surgery should be performed to screen patients for liver disease (Table 3). Risk factors to inquire about include prior blood transfusions, tattoos, intravenous illicit drug use, alcohol consumption, sexually transmitted diseases, family history of liver disease, and current medications. Physical examination should evaluate the patient for the presence of jaundice, ascites or increased abdominal girth, gynecomastia, spider telangiectasias, palmar erythema, splenomegaly, or testicular atrophy. Should liver disease be identified or known preoperatively, an assessment of the surgical risk must be made by the surgeon and discussed with the patient. This assessment must consider the nature and urgency of the procedure, the severity of the liver disease, and the presence of comorbid medical conditions. Many studies have identified a variety of risk factors with the type of surgery perhaps being the Table 3 Preoperative Surgical Evaluation of Patients Should Include Screening for Some of These Common Findings Identifiable by a Careful History and Physical Examination History Blood transfusions Tattoos Intravenous illegal drug use Alcohol consumption Sexually transmitted diseases Family history of liver disease Current medications

Physical examination Jaundice Ascites or increased abdominal girth Spider telangiectasias Palmar erythema Splenomegaly Gynecomastia Testicular atrophy

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most important (86). Emergency surgery carries a higher morbidity and mortality than elective procedures. When comparing different surgical sites, abdominal surgery reduces hepatic arterial blood flow to a greater degree than extraabdominal procedures through a reflex systemic hypotension from dilation of capacitance vessels when traction is applied to the viscera (87). Within the abdomen, cholecystectomy, gastric operations, and colectomy have traditionally been associated with a greater mortality in patients with decompensated cirrhosis (88–92). With the advances in minimally invasive surgery over the last decade, a laparoscopic approach may be feasible in the setting of compensated cirrhosis and may improve outcomes in the future (93,94). In general, cardiac surgery in the face of cirrhosis presents the patient with a high risk of death (95). As we have discussed in this chapter, the liver performs a great number of critical functions for the body; thus it is not surprising that a malfunctioning or failing liver should expose patients to a greater risk of death and complications with surgery. A very useful system for assessing the risk of surgery in patients with chronic liver disease is the Child–Pugh classification schema (Table 4). A number of retrospective studies demonstrate that perioperative morbidity and mortality correlate well with this classification of cirrhosis (98,99). Each component of the system evaluates a different aspect of hepatic function. Albumin and prothrombin measure the synthetic function of the liver. Bilirubin levels reflect the capacity of the liver to process metabolities. Ascites accumulation reflects the presence of portal venous hypertension and the alterations in plasma oncotic pressure. Lastly, the presence of hepatic encephalopathy heralds an inability of the liver to clear toxins from the circulation. Patients with significant hepatic dysfunction, undergoing abdominal surgery, can have mortality rates as high as 82% for Child C (100). Other classification systems that utilize different parameters have been evaluated and are used at some centers. The Acute Physiology and Chronic Health Evaluation III score has been shown to predict survival in cirrhotic patients admitted to an intensive care unit (101). Recently, the model for end-stage liver disease scale, MELD, has replaced the Child–Pugh classification for liver transplant allocation (102). Hepatic encephalopathy befalls patients with both chronic and acute liver failure. In acute liver failure, patients suffer from a rapid decline in mentation with increased intracranial pressure, which may lead to death. Chronic liver disease results in impaired memory, poor reaction times, sensory Table 4 Pugh’s Modification of Child’s Classification Clinical and biochemical measurements Encephalopathy (96) Ascites Bilirubin (mg/100 mL) Albumin (g/L) PT (second prolonged) Child’s A ¼ 5–6 points (mortality ¼ 3–10%) Child’s B ¼ 7–9 points (mortality ¼ 10–30%) Child’s C ¼ 10–15 points (mortality ¼ 50–80%)

Points scored for increasing abnormality 1

2

3

None Absent 1–2 >35 1–4

1 and 2 Slight 2–3 28–35 4–6

3 and 4 Moderate >3 6

Abbreviation: PT, prothrombin time. Source: From Ref. 97.

and motor dysfunction, and maybe even coma. These changes are fully reversible with the improvement of liver function. The precise pathogenesis remains unclear. Since 1893, when members of Pavlov’s group described ‘‘the meat intoxication syndrome,’’ ammonia has been judged an important factor in the development of hepatic encephalopathy. Ammonia and other toxins are not metabolized properly by the liver in patients with hepatic encephalopathy, resulting in alterations in the blood–brain barrier, cerebral neurotransmission, and cerebral energy metabolism (103,104).

DIAGNOSTIC TESTING Clinical evaluation of the patient with liver disease normally includes a variety of assays to assist the surgeon with making the initial diagnosis, following patient progress, and determining prognosis. Not surprisingly, with the liver performing such a complex variety of tasks for the body, laboratory tests of liver function and disease may not accurately reflect the actual state of the organ. Thus, the surgeon must combine a variety of tests performed over a range of time and interpret the test results within the context of each individual patient. As we discussed in the prior section, assessing the extent of liver disease remains invaluable in planning the operation, ensuring sufficient hepatic reserves, and counseling the patient. We will briefly review the most common tests performed in clinical practice, often called the liver function tests (105). This nomenclature is misleading, because most of these tests do not actually measure how the liver is functioning. In considering these laboratory assays, they can best be divided into two broad categories: (i) true hepatic function assays and (ii) screening tests of hepatobiliary disease.

Hepatic Function Tests Synthesis Albumin The critical role of protein synthesis of the liver can be evaluated by determining the serum level of proteins synthesized by the liver. For this reason, serum albumin levels may provide insight into the protein synthetic capacity of the liver over a period of several weeks. The half-life of albumin in the serum is approximately 21 days, with 4% of the total albumin pool being degraded daily. The liver synthesizes about 200 mg/kg of albumin daily in a healthy person. The serum albumin level reflects a balance between synthesis and loss (80). Hypoalbuminemia is not specific for the functional state of the liver because low albumin levels might represent a decreased synthetic capacity by the liver, protein malnutrition, increased extracellular volume, or increased protein loss as occurs in the nephrotic renal syndrome. This example emphasizes an important aspect of the clinical decision, which surgeons face when evaluating patients with hepatic disease, namely a single test result that is often uninterpretable in isolation of other results in the context of the individual patient. Surgical patients often have depressed albumin synthesis as a result of the inflammatory signaling mediated by inhibitory substances such as tumor necrosis factor and IL-1 (106,107). Prothrombin Time Another important tests of hepatic synthesis is the measurement of the prothrombin time (PT). As previously discussed, the liver is the major site for generation of the coagulation proteins. The PT measures the rate at which

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prothrombin in titrated plasma is converted to thrombin. This test depends not only on the plasma levels of prothrombin, but also on the proteins involved in the extrinsic pathway of the coagulation cascade, such as fibrinogen and Factors V, VII, and IX. The plasma half-life of these factors is usually less than one day, causing a rapid change in the PT with changes in hepatic synthetic function. A prolonged PT is not specific for liver disease, but may correlate with prognosis in some hepatic conditions when congenital and acquired coagulopathies have been eliminated from the differential diagnosis. In general, when the PT is prolonged due to vitamin K deficiency, the parenteral adminstration of vitamin K will rapidly rectify the situation. In the setting of parenchymal liver disease, vitamin K supplementation is ineffective. The degree of prolongation of the prothromin time correlates with prognosis in some conditions. In acute viral, toxic, or alcoholic hepatitis, a prolongation of more than five seconds may signal a more fulminant course of disease. A PT greater than 100 seconds may be an indication for liver transplantation (108,109).

Screening Tests Hepatocyte Cellular Injury Hepatocytes contain thousands of enzymes within their toolbox to perform the tasks assigned to the liver by the body. These enzymes are normally intracellular, but are released when the hepatocytes are injured. The most commonly assayed enzymes are the aminotransferases, aspartate aminotransferase (AST) and alanine aminotransferase (ALT). AST and ALT catalyze the transfer of alpha-amino groups from aspartate and alanine, respectively, to ketoglutarate, yielding pyruvate and oxaloacetate. Neither enzyme is exclusively found in the liver, though ALT is present in highest concentration in the liver and is more specific for liver disease than AST. ALT is localized to the cytoplasm; whereas, AST is found within the cytoplasm and the mitochondria of the cells. AST is cleared more rapidly than ALT. The highest elevations occur in conditions associated with extensive hepatocellular necrosis, such as viral hepatitis, ischemic shock, and acute toxic injury; however, the extent of liver cell necrosis correlates poorly with the magnitude of elevation. Furthermore, the absolute elevation offers little prognostic value. In caring for patients with alcoholic hepatitis, the transaminase levels will rarely go over 200 to 300 IU/L (110–112). In addition to AST and ALT, a variety of hepatic enzymes have been evaluated for diagnostic purposes and have been found to be inferior to the aminotransferases. Lactose dehydrogenase, isocitrate dehydrogenase, and sorbitol dehydrogenase are cytoplasmic enzymes found in hepatocytes and in a number of tissues throughout the body (113,114). They have limited diagnostic usefulness. Glutamate dehydrogenase is a mitochondrial enzyme with a high concentration in centrilobular hepatocytes; however, measurement is rarely performed clinically (115).

Biliary Injury Alkaline phosphatases (ALP) are present in many tissues in the body, but the serum levels usually reflect the hepatic and bone isozymes. ALP catalyzes the release of orthophosphate from ester substrates at alkaline pH. Although a variety of nonhepatic conditions may cause an elevation in ALP levels, the source may be easily identified based upon the clinical picture. If necessary, further laboratory tests can be performed to differentiate the isoenzyme; however, the more common clinical practice involves the addition of a second

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confirmatory assay such as 5’-nuleotidase, leucine aminopeptidase, or gamma-glutamyl transpeptidase (GGTP). Of these tests, GGTP has become the most common adjunctive assay because the GGTP level is not elevated in bone disease. Thus, an elevated ALP in the setting of an elevated GGTP suggests a hepatobiliary origin for the ALP. Large elevations of ALP of 3 to 10 times normal usually indicate obstruction of bile flow in the biliary tree, with the highest elevations generally seen with extrahepatic obstruction. The ALP may be the only clinically identified alteration seen in patients with bile duct strictures or lesions obstructing only one lobe or segment, and for this reason it is a fairly sensitive screening test for hepatic malignancy. Of course, the ALP assay is not a perfect screening test because one-third of the patients with isolated ALP elevations have no evidence of hepatobiliary disease (105).

Metabolite and Drug Clearance This group of tests measures the capacity of the liver to clear exogenous and endogenous substances from the circulation. As described previously, the metabolism of hemoglobin results in the production of bilirubin, which is processed by the liver for excretion into the gut. Hepatic injury may result in a decreased capacity of the liver to conjugate bile and other drugs, resulting in hyperbilirubinemia. Hyperbilirubinemia may result from a variety of other causes including excessive hemolysis, genetic defects in bilirubin processing, or excretory dysfunction. Although, bilirubin measurements, both conjugated and unconjugated fractions, are the most commonly assessed endogenous marker of metabolite and drug clearance, other assays have been developed, which rely upon the capacity of the liver to clear an exogenous drug or dye. The use of indocyanine green and bromsulphalein dyes, galactose and lidocaine administration, and various breath tests (aminopyrine/caffeine) have all been evaluated, but they have seen little general clinical use (116–118).

Immunologic Tests A number of specific tests have been developed to identify infectious and inflammatory conditions that affect the liver. Viral hepatitis caused by hepatitis A, B, C, D, or E viruses can be assayed in the serum. Other infectious causes can be pursued, such as cytomegalovirus, Epstein–Barr virus, or amebic infections (119,120). In the setting of autoimmune disorders, the presence of antimitochondrial (primary biliary cirrhosis), smooth muscle (sclerosing cholangitis), or antinuclear antibody can be determined (121). Alpha fetoprotein and carcinoembryonic antigen levels may prove useful in evaluating patients with neoplasms.

Liver Biopsy Liver biopsy is the gold standard diagnostic test in alcoholic liver disease and cirrhosis, short of explanting the entire liver. Liver biopsy may be performed via a blind percutaneous approach, transjugular, ultrasound or radiographically directed, or a laparoscopic biopsy (122). In the setting of acute hepatitis or acute cholestatic jaundice, the histologic changes are nonspecific and the biopsy is mainly for prognostic purposes. With cirrhosis, the liver biopsy may demonstrate not only the presence of cirrhosis, but perhaps the etiology as well, such as hereditary hemochromatosis, alpha-1 antitrypsin deficiency, or Wilson’s disease. Although the risk of death from a liver biopsy is low (0.04%), a significant concern associated with the procedure is the possibility of sampling

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error in which the histology of the biopsy may not be a true representation of the current state of the pathology (123).

Radiographic Evaluation A complete review of all the radiologic tests available to assess the liver is beyond the scope of this chapter. Ultrasound provides a useful noninvasive method of evaluating the parenchyma, the biliary system, and the vascular supply of the liver; however, ultrasound evaluation is hampered by operator variability and lower accuracy in hepatic lesion detection (124). Intraoperative ultrasound facilitates the identification of lesions that might not be palpable or visualized during a laparoscopic procedure. Increasing speed and quality of computed tomography (CT) scanning has continued to improve the anatomic picture and utility of this study in the preoperative evaluation of patients for hepatic resection. Lesions less than 5 mm in diameter can now be identified and, in some cases, characterized. Liver CT evaluation can be performed using dual or triple phase imaging. Because most tumors of the liver have only a hepatic arterial blood supply, the hepatic arterial phase of the CT detects hypervascular lesions (such as hepatocellular carcinoma). Improved detection of liver lesions can be obtained by angiographically assisted CT scans. In the setting of trauma, CT scanning has become the gold standard modality for detecting solid organ injury in the hemodynamically stable patient and has demonstrated a high sensitivity and specificity for liver lacerations. In addition to CT scanning, magnetic resonance imaging (MRI) of the liver has proved very specific for both focal and diffuse liver diseases (125,126). Many of the advances in both CT and MRI scanning are based on significant improvements in the computer hardware and software available to enhance and manipulate the radiographic images (127,128).

REGENERATION Incorporated into the tale of Prometheus in Greek mythology, hepatic regeneration remains a fascinating area of active scientific exploration. In the myth, Prometheus is punished by the gods for giving men the knowledge of fire by having him chained to a stone. Daily a great bird eats his liver, only to have it regrow overnight to be ready for another meal. In actuality, the regenerative process does not happen overnight, but instead involves a complex process of self-renewal. Most organs in the adult human are unable to increase cell numbers after injury, but instead some are able to respond with cellular hypertrophy (129). The liver does not actually regenerate in the true sense as depicted in the legend of Prometheus. A new lobe does not regrow after partial hepatectomy. Partial hepatectomy results in the initiation of DNA synthesis in the remaining liver cells and a return by the liver to its optimal mass relative to the body (130). This capacity is unlimited, occurring after multiple resections. There are three phases in liver regeneration: (i) initiation, (ii) proliferation, and (iii) termination. The liver initiates regeneration three days after a resection and returns to its original size after about six months. Liver function has usually returned to normal two to three weeks after partial hepatectomy (129). Many advances have been made in identifying the genetic and molecular signals that regulate the growth factors and cytokines important in liver regeneration, many of which are elaborated by the Kupffer cells and hepatic stellate cells

(131). In particular, HGF plays an important role in the signaling responsible for regeneration (132). Epidermal growth factor (EGF) and transforming growth factor-alpha (TGFalpha) are also strong mitogens for primary hepatocytes (129). Hepatic oval ‘‘stem’’ cells are increasingly identified as participants in some forms of hepatic regeneration. These small cells have an oval nucleus and are bipotential cells with the capacity to differentiate into both hepatocytes and bile ductular cells. The oval cells are believed to reside in the canals of Hering and in extrahepatic sites, in particular the bone marrow (133). Oval cells express receptors for HGF, EGF, and TGF-alpha. The mechanisms by which these cells are activated and differentiate to participate in hepatic regeneration are not well understood and are the subject of intense investigation (134).

FUTURE Only 40 years ago, patients with end-stage liver disease had no surgical therapy available to them. Organ transplantation, once the stuff of science fiction, has become almost routine. With the advent of the orthotopic liver transplant, the possibility of surviving once unsurvivable conditions has become a reality. The one-year survival is almost 90% and a threeyear survival of 80% can be achieved at many leading medical centers. Despite increasing utilization of marginal donors and living related donor transplantation, waiting lists persist in the United States, with more than 1500 patients dying while awaiting transplant in 2003 (Based on OPTN data as on January 1, 2005). A variety of new approaches and some new twists on old approaches continue to be pioneered. Split liver transplantation allows for the right lobe of the liver to be transplanted into an adult while the left lobe is given to a pediatric recipient. Unfortunately, this technique results in increased graft failure and biliary complications. Domino transplantation has also been used to increase the organ pool by transplanting the explanted liver from a recipient with familial amyloidosis to a second recipient. Living donor transplantation has significantly increased the pool of donors, with 500 adult-to-adult transplants performed in the United States in 2001. In addition to whole organ transplants, isolated hepatocyte transplantation has been used as a bridge to transplantation in patients with fulminant hepatic failure and to treat inherited metabolic disorders (135). For similar indications, extracorporeal liver perfusion has been attempted over the last four decades using human, pig, baboon, and cow livers (136). At present, a number of institutions are in the process of developing artificial bioreactors within which to grow hepatocytes to perform a version of hemodialysis as a bridge to transplant for patients in fulminant hepatic failure. Finally, modifications in the porcine genome continue to be pursued in hopes of lowering the immunologic barriers to xenotransplantation. Ultimately, finding an adequate long-term nonbiologic replacement for the liver remains inconceivable given the more than 5000 functions performed by the organ.

SUMMARY Among the many organs required for human existence, the liver is especially unique not only because it is critical to life itself, but also because of its unusual ability to heal and regenerate itself when injured. It is the only organ in the

Chapter 19: Hepatic Physiology

body where protein, lipid, and carbohydrate metabolism come together for metabolic coordination and homeostasis; if it fails in carrying out these responsibilities eventual death is the end result from complications resulting from its failure to carry out its life-giving functions. In contrast to the kidney in which absent organ function can be substituted by hemodialysis, it is unlikely that a mechanical device will ever be developed, which can successfully take over the literally thousands of intrinsic functions carried out by the liver. Thus, as reverenced by the ancients of old, the liver truly is an organ of wonder and fascination.

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20 Portal Hypertension Alexander S. Rosemurgy and Emmanuel E. Zervos

pancreas. Conventionally, the common hepatic artery arises off the celiac axis, and, in short order, becomes the proper hepatic artery beyond the origin of the gastroduodenal artery, and then the left and right hepatic arteries. It is not uncommon to have an accessory or replaced right hepatic artery arising from the superior mesenteric artery, which travels to the liver anterior and lateral to the portal vein. Figure 1 shows normal portal anatomy.

INTRODUCTION Normal portal pressure is near 10 to 12 mmHg, with a gradient of near 0 to 4 mmHg between portal vein and the inferior vena cava (IVC). While the term ‘‘portal hypertension’’ denotes an increased pressure in the portal vein, it is generally reserved for occasions when the portal vein–IVC gradient is increased beyond 10 to 12 mmHg. There are a host of reasons why portal hypertension can develop. Some of the causes of portal hypertension are much more innocuous than others. For example, extrahepatic compression or obstruction of the portal vein can lead to portal hypertension, without concomitant hepatocellular dysfunction. Conversely, hepatic injury with subsequent fibrosis, as with cirrhosis, can lead to portal hypertension in the setting of impaired hepatic function. Therapies applied to portal hypertension will have varying outcomes depending on underlying liver function. Thus, knowing the cause of portal hypertension is essential in assigning risks of therapy and in predicting outcomes after therapy. Causes of portal hypertension are noted in Table 1. Particular note is made of the sinusoidal causes of portal hypertension, because they are notoriously associated with impaired hepatic function.

VARICEAL HEMORRHAGE Presentation and Early Care There are several reasons why someone with portal hypertension will present for care. Portal hypertension may exist, but not be the cause of presentation. Rather, patients with portal hypertension might present because of impaired hepatic function, ascites, encephalopathy, or quality-of-life issues. Portal hypertension may result in gastrointestinal bleeding, which can be very sensational. As pressures in the portal system increase, small, otherwise nondescript, veins arising along the portal vein and its branches become low-resistance outflow collaterals. These veins become conduits through which portal blood flows out of and away from the hypertensive portal system toward the relatively lower-pressure central venous system. While much focus is on the area of the esophagus,

ANATOMY The liver has two sources of vascular inflow: hepatic arterial inflow and portal venous inflow. The majority (60% to 70%) of hepatic blood flow is from the portal venous system. Conversely, the majority (60–70%) of oxygen delivery to the liver comes from the hepatic artery, because the portal vein has relatively lower oxygen saturation. The portal venous system drains the spleen, the colon, the small bowel, the pancreas, the duodenum, and the gallbladder. Before entering the hepatoduodenal ligament, the portal vein travels along the undersurface of the

coronary vein portal vein

Table 1 Causes of Portal Hypertension

Splenic vein

Presinusoidal Extrahepatic Congenital Trauma Malignancy

Intrahepatic Schistosomaisis Congenital hepatic fibrosis Primary biliary cirrhosis

inferior mesenteric vein

Sinusoidal Cirrhosis

Postsinusoidal Budd Chiari Veno-occlusive disease

superior mesenteric vein

Hypercoagulable state Umbilical sepsis

Figure 1 Normal portal anatomy.

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esophagogastric junction, and stomach, collateralization of veins from the portal system occurs in clinically important forms in several locations (Table 2). Because of systemic– portal venous collateralization in patients with portal hypertension, varicose veins (i.e., varices) can and will arise, an example being the superior hemorrhoidal veins. Other sites where the interface between the portal system and the systemic venous system is particularly important are at enterostomy (e.g., ileostomy and colostomy) sites (Fig. 2). Most commonly, patients with portal hypertension, which presents as bleeding will present with bleeding arising from varices along the esophagus, esophagogastric junction, or stomach. Bleeding from varices can be slow or massive. Thereby, blood loss can be occult in patients presenting with anemia, or it can be massive and sensational, in patients vomiting blood and in extremis. For the purpose of this chapter, we will focus on rapid blood loss, though principles put forth in this chapter are applicable to all patients. When patients present with variceal bleeding, many activities important in care must occur at once. Airway management is of paramount importance, as patients undergo the ‘‘ABC’s of resuscitation.’’ If patients are not adequately oxygenating or ventilating, orotracheal intubation should be undertaken without delay. As well, if encephalopathy or other cause of depression of mentation exists, the airway should be protected by orotracheal intubation. Secure intravenous access must be obtained; central venous access is not a priority at this time. Resuscitation must be initiated immediately, with uncrossed matched blood given, if necessary. The immediate end point of resuscitation is stabilization of blood pressure. Subsequently, measures of organ perfusion, such as urinary output, become paramount and, later yet, concerns with over-resuscitation require attention. If patients are over-resuscitated, many adverse events can occur. Obviously, over-resuscitation can lead to acute pulmonary edema and other complications, but the issue in these patients is the impact of over-resuscitation on portal pressure. If a healthy patient without portal hypertension is over-resuscitated, then central venous pressure could be pushed to 20 mmHg. With this, and a portal vein–IVC pressure gradient of 6 mmHg, portal pressures are pushed to 26 mmHg. Generally, this has no sequela, because there are no varices. For a patient with portal hypertension, over-resuscitation, which elevates the central venous Table 2 Sites of Communication Between Portal Venous and Systemic Circulation Along the stomach, gastroesophageal junction, and esophagus In the cephalad retroperitoneum about the pancreas, duodenum, and root of the mesentery Retroperitoneal collaterals between the intestines and retroperitoneum, especially laterally, particularly involving the colon, particularly at the hepatic flexure and splenic flexure Between the superior (portal) and inferior (systemic) hemorrhoidal veins Veins about the bladder, especially anteriorly (space of Retzius) At the site of a colostomy, ileostomy, gastrostomy, or other stoma At the umbilicus, where the umbilical vein (which connects to the left branch of the portal vein) communicates with cutaneous veins (systemic venous system) leading to the appearance of caput medusa (large dilated superficial veins in the subcutaneous tissue on the abdominal wall) Between the spleen and the diaphragm In adhesions involving the intra-abdominal viscera and the retroperitoneum

Figure 2 Colostomy in a patient with portal hypertension (note varices around stoma).

pressure to 20 mmHg, has important implications. For this patient, with a portal vein–IVC gradient of 16 mmHg, portal pressures are raised to 36 mmHg and varices are distended, promoting ongoing bleeding. Promotion of ongoing bleeding can be the unfortunate and unintended consequence of over-resuscitation. Given that under-resuscitation is the concern with early therapy, central venous pressure monitoring is not necessary until later, after blood pressure has stabilized and time permits. Pharmacotherapy should be utilized as a first step after the ‘‘ABC’s of resuscitation.’’ Octreotide has become the drug of choice to reduce portal venous inflow and, thereby, portal pressures. If bleeding can be controlled with Octreotide, time would permit further evaluation and care. If bleeding continues out of control, further intervention must be undertaken immediately. Endoscopy can have major role in the diagnosis and treatment of major variceal bleeding. If bleeding continues despite Octreotide therapy, endoscopy should be undertaken to identify the source of bleeding, and, if possible, control it. Patients with cirrhosis and portal hypertension, and who experience gastrointestinal hemorrhage, have a high probability of bleeding from sites other than varices. High on the list of sites of nonvariceal bleeding is duodenal ulcer disease. Other potential sites of bleeding include sites of gastric ulcer disease, distal esophageal disease, including reflux esophagitis or Mallory–Weis tears, and esophagogastroduodenal malignancy. Endoscopy can identify sites of nonvariceal bleeding, unless bleeding is so rapid that the esophagus, stomach, and duodenum cannot be cleared of blood and blood clots. If profuse bleeding does not allow application of endoscopy, a balloon-tipped tube passed per os into the stomach should be utilized to control exsanguinating presumptive variceal hemorrhage. The Sengstaken–Blakemore (SB) tube is commonly utilized (Fig. 3). Before being used, a nasogastric-type tube should be tied to the SB tube proximal to the esophageal balloon. The application of the nasogastric-type tube will prevent accumulation of oropharyngeal secretions in the proximal esophagus.

Chapter 20:

Figure 3 SB tube in situ. Abbreviation: SB, Sengstaken–Blakemore.

The SB tube is passed per os into the stomach. If time permits, an X-ray is obtained to document position of the SB tube in the stomach. If time and circumstances do not permit, air should be pushed down the gastric lavage port. Auscultation of the abdominal wall over the stomach can confirm placement of the SB tube into stomach with some security. At this point, the gastric balloon is in place with 250 cc of air, and the SB tube is pulled back with one pound of pressure. To accomplish this, we use a 500 cc bag of crystalloid hoisted over a pulley on an orthopedic frame, which is always available in the emergency department or ICU. If bleeding continues, the esophageal balloon is inflated to 30 mmHg pressure. The SB tube can be left in place with balloons inflated for 48 hours. Beyond this, ulcerations brought on by the inflated balloons are an ever-increasing concern. Control of bleeding by the SB tube allows resuscitation to continue uncompromised by ongoing blood loss, correction of coagulopathy, treatment of comorbidities, support of drug/ alcohol dependency, purging of the gastrointestinal tract (GI) of blood, and attention to issues of general health. If, after the application of pharmacologic therapy, bleeding ameliorates and endoscopy can be undertaken, specific therapy for bleeding can be undertaken. Bleeding due to variceal sources can be addressed with endoscopic variceal sclerotherapy (EVS) or banding (EVB). While EVS and EVB are effective, their use is often determined by the endoscopist’s preference. In general, EVB is preferred for smaller, more isolated varices. Unfortunately, only varices limited to the esophagus or the first few centimeters of the proximal stomach are amenable to or candidates for EVS or EVB. Complications of EVS or EVB are thankfully uncommon. Ulcerations at sites of therapy are not uncommon, but uncommonly, the ulcers can bleed. Bleeding at sites of ulceration can be massive and will require site-specific care (endoscopic injection, thermal energy, or balloon tamponade) and possibly portal decompression. Late stricture formation is also possible, but uncommon. The biggest risk of EVS or EVB is failure to control variceal bleeding. Such a failure will require definitive therapy, to be discussed, possibly after temporary balloon tamponade. While successful endoscopic therapy will result in cessation of bleeding, ultimately the goal of endoscopic therapy

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is obliteration of esophageal and very proximal gastric varices. This may require several sessions of EVS or EVB even after cessation of bleeding. Longer-term, surveillance endoscopy will be required to ensure obliteration of varices. Failure of endoscopic therapy must be defined prior to initiation of EVS or EVB. Generally, failure of endoscopic therapy is defined as the inability to control variceal bleeding, finding varices most amenable to endoscopic therapy (e.g., gastric varices or portal gastropathy), or the inability to obliterate esophageal varices over time. Gastric varices require a special mention. While they may develop as venous outflow conduits from the portal vein confluence, along the wall of the stomach, they may not develop into vascular structures of any size. Conventionally, gastric varices are thought of as large tortuous vessels in the gastric wall. They may, however, develop as small extensive venous channels in the gastric wall, giving the stomach lining the appearance of velvet saturated with blood. This latter appearance of gastric varices is often referred to as ‘‘portal gastropathy’’ or ‘‘gastritis’’ of portal hypertension. The former term denotes the appearance the stomach lining can acquire in portal hypertension, while the latter recognizes the impairment of gastric function, which can occur with portal hypertension. In general, the early evaluation and care of patients with portal hypertension is best defined by the axiom ‘‘hope for the best, but prepare for the worst.’’ Keep blood products on hand; keep an SB tube at the bedside. Utilize pharmacotherapy and endoscopic therapy early. Prepare for the possibility that more definitive therapy may be necessary.

Assessing Hepatic Function When patients present with variceal hemorrhage due to portal hypertension and cirrhosis, an important part of the evaluation process is assessment of liver function. This assessment is undertaken through many routes. Both clinical and laboratory assessment are important. At the bedside, much can be said about a patient’s liver function. Generally muscular wasting, though possibly due to lifestyle, is consistent with poor liver function. As well, ascites, cutaneous spider angiomas, a ‘‘ruddy’’ complexion, encephalopathy (to whatever degree), extensive bruising, and jaundice or icterus are manifestations of the extensive hepatic impairment that can be apparent clinically. Laboratory testing can also document hepatic impairment. Hepatic synthetic ability can be determined through serum cholesterol and albumin, though both are acute phase reactants and will decrease notably with stress. Prothrombin time (PT) is a measure of the intrinsic clotting mechanism and is dependent upon hepatic synthesis. Bleeding can notably impact PT through consumption and loss. Hepatic detoxification can be measured through serum bilirubin levels. Elevated levels, particularly of the unconjugated form, of bilirubin are indicative of hepatic impairment. Impaired detoxification will impact drug metabolism, as with narcotics, numerous anesthetic agents, and Tylenol; but this will not aid in assessment of liver function. Platelet counts are depressed in patients with cirrhosis and portal hypertension, particularly with bleeding. High portal pressures and/or splenic vein occlusion will lead to splenic sequestration of platelets and, thereby, thrombocytopenia. Bleeding will add to this through platelet loss and consumption. Taken together, clinical and laboratory testing and assessment of liver function can be used to stratify hepatic reserve. Differences between hepatic function and

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Table 3 Child–Turcotte Hepatic Risk Classification A Bilirubin Albumin Encephalopathy Ascites Nutrition (muscle mass)

3.5 None None Normal

B 2–3 3–3.5 Controlled Controlled Fair

Table 4 Pugh Modification of Child’s Classification C >3 3 Refractory >6 Dense 6 hr flatulence, dyspepsia not related suggests cholecystitis (vs. colic) to stones Mild-to-moderate gallbladder Febrile, usually 4 mg/dL or amylase >1000 U/L suspect CBD stone

Physical findings

Laboratory findings

Diagnostic tests (see Table 55-4 for details) Natural history

Treatment

Ultrasonography OCG; Meltzer-Lyon test

Ultrasonography; hepatobiliary scintigraphy (DISIDA, HIDA scans); abdominal CT

Choledocholithiasis

Cholangitis

Intermittent obstruction of CBD

Impacted stone in CBD causing bile stasis; bacterial superinfection of stagnant bile; early bacteremia Often asymptomatic; Charcot’s triad (pain, symptoms (when jaundice, fever) present in present) indistinguishable 70%; may be mild, from biliary colic symptoms; transient pain often predisposes to cholangitis accompanied by chills; and acute pancreatitis mental confusion lethargy, and delirium suggestive of bacteremia Often completely normal Fever in 95%, RUQ tender in examination result if 90%; jaundice in 80%; obstruction intermittent; peritoneal signs in 15%; jaundice with pain hypotension with mental suggestive of stones; confusion in 15% painless jaundice and suggestive of gram-negative palpable gallbladder sepsis suggestive of malignancy Elevated serum bilirubin and Leukocytosis in 80%; normal alkaline phosphatase levels WBC count with left shift seen with CBD obstruction; may be only hematologic serum bilirubin level finding in 20%; serum >10 mg/dL suggestive of bilirubin level >2 mg/dL in malignant obstruction or 80%, but when 200 mg/dL LDH > 350 IU/dL SGOT > 250 IU/dL

During initial 48 hr Hematocrit fall > 10% BUN elevation > 5 mg/dL Ca2þ fall to < 8 mg/dL Arterial pO2 < 60 mmHg Base deficit > 4 mEq/L Fluid sequestration > 6 L

Abbreviations: BUN, blood urea nitrogen; LDH, lactate dehydrogenase; SGOT, serum glutamic-oxaloacetic transaminase.

pancreas then completely resolve within 18 days after the onset of pancreatitis when compared to control groups (51). The fasting hyperglycemia and hyperglucagonemia resolve with the pancreatitis. Elevated concentrations of glucagon and glucose normalize within 18 to 21 days after resolution of pancreatitis (52).

Scarring/Fibrosis Pancreatic fibrosis is a central histologic response after pancreatitis (53). There is transient collagen deposition with acinar necrosis in acute pancreatitis, while in chronic pancreatitis, there is permanent and disorganized pancreatic fibrosis and parenchymal cell atrophy. Fibrosis serves as a deterrent to future organ regeneration and contributes to endocrine and exocrine dysfunction of the gland. Although this is a well-recognized process, the mechanisms of fibrogenesis are poorly understood. There is evidence that differentiation and proliferation of pancreatic myofibroblast or ‘‘stellate’’ cells may be responsible for an increase in extracellular matrix (ECM) production as in hepatic fibrosis and cirrhosis (54,55). In normal pancreas, quiescent pancreatic stellate cells (PSCs) can be identified by staining for the cytoskeletal protein desmin, a stellate cell selective marker (56). PSCs are found in a periacinar location, with long cytoplasmic processes encircling the base of pancreatic acini (56). In vitro studies with cultured PSCs have revealed that the cells store vitamin A in the form of lipid droplets in the cytoplasm, a feature similar to that described for hepatic stellate cells (56). During pancreatic injury, PSCs are activated and transform into a myofibroblastic phenotype that exhibits positive staining for the cytoskeletal protein, a smooth muscle actin (a-SMA) (51), and secrete increased amounts of collagen as previously described in hepatic stellate cells during liver injury. Proinflammatory cytokines such as TNF-a, IL-1, and IL-6 and reactive oxygen species activate PSCs as evidenced by increased a-SMA expression (57). During regeneration from cerulein-induced pancreatitis, the expression of transforming growth factor-b (TGF-b) is enhanced in acinar and stellate cells of rat pancreas (58,59) and in patients with acute or chronic pancreatitis (60,61). TGF-b protein will increase twofold after 24 to 48 hours and return to normal seven days after insult (62). TGF-b mRNA expression will peak two or three days after an experimental stimulus (59,62). TGF-b is a key regulator of ECM production and myofibroblast proliferation. The expression of procollagen type I mRNA was markedly increased and correlated with the level of TGF-b mRNA (63). Culturing PSC with increasing concentrations of TGF-b raises collagen protein synthesis and inhibits matrix metalloproteinase (MMP)-3 and MMP-9 (64). TGFb–neutralizing antibodies when injected into rats during regeneration from cerulein pancreatitis significantly reduce collagen types I and III protein and mRNA (65). The stellate cells express TGF-b in an autocrine stimulatory loop and enhance fibrosis not only by increased production but also decreased degradation of collagen. Platelets aggregate in injured sites of the pancreas and release growth factors that propoagate fibrosis. Platelets are an early source of TGF-b and platelet-derived growth factor (PDGF), which also can stimulate stellate cell proliferation (66,67) and increased collagen synthesis (56). The signaling pathways involved in PSC stimulation included the extracellular signal-regulated kinases as well as the activation of the activator protein complex (67). PSCs have the capacity to respond to cytokines known to be upregulated in acute pancreatitis. PSCs have the

Chapter 22:

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potential to be actively involved in both the recovery phase and the progression of the disease. During a self-limited attack of acute pancreatitis, cytokine-activated PSCs may participate in tissue repair by regulating ECM deposition in the gland (57). During repeated attacks of pancreatitis, PSCs may attain a persistently activated state with increased collagen synthesis leading to fibrosis. Tissue repair is a process regulated by a balance between synthesis and degradation of the ECM. ECM degradation is performed by a family of proteolytic enzymes known as MMPs. These MMPs are zinc-bound proteases that degrade at least one component of the ECM, and are bound and inhibited by tissue inhibitors of metalloproteinases. The MMPs are secreted in a latent proenzyme form and are activated by other proteases such as trypsin and a chymotrypsin. MMPs degrade a variety of ECM constituents; MMP-1 degrades collagen types I and III, whereas MMP-2 degrades collagen type IV and fibronectin (68). Imbalance in ECM homeostasis occurs not only from increased production but also decreased degradation through an overall decrease in the action of MMPs (69). Expression of the active form of MMP-9 and the activity of MMP-9 and MMP-2 have been shown to decrease initially in a rat model of pancreatitis induced with cerulein (69). MMP-2 may then play a role in resolution of the fibrotic cascade as well. If monitored one week after the inciting event, MMP-1 and MMP-2 mRNA and protein levels will rise and play a role in preventing uncontrolled deposition of ECM (51,59).

known trophic effects on rodent pancreatic growth (80). The CCK-B receptor binds both gastrin and CCK with equal affinity. It is a G-protein–coupled receptor that activates phospholipase C, phosphatidylinositol hydrolysis, release of intracellular calcium, and the phosphorylation of protein kinase C (81). The trophic effects of gastrin and its receptor remain controversial. The adult rat pancreas has less gastrin receptor present (79). When a transgenic mouse constitutively expressed gastrin receptors in the exocrine pancreas, the expression of the gastrin receptor correlated with a significant increase in pancreas weight (82). The rodent studies of exogenous gastrin as a trophic factor are conflicting: some suggest a trophic effect on pancreatic growth (83,84), whereas others have failed to detect an effect (85,86). IL-10, a potent anti-inflammatory cytokine, limits the severity of acute pancreatitis (87,88). IL-10 can be produced by multiple cell lines and has inhibitory effects on T-cell function and stimulatory effects on B-lymphocytes, augmenting the secretion of immunoglobulins (89). It downregulates TGF-b release by inflammatory cells on stimulation (90). IL-10 has been shown to reduce acinar necrosis, parenchymal infiltration by polymorphonuclear cells and macrophages, and release of inflammatory cytokines (91,92). After repeated induction of acute pancreatitis in mice, endogenous IL-10 limits fibrogensis, collagen deposition, and TGF-b expression. IL-10 knockout mice display a dramatic decrease in acinar cell proliferation and higher levels of activated stellate cells (93).

Regeneration/Growth

TREATMENTS

After the acute injury, a regeneration or repair phase of the pancreas is characterized by the decrease of inflammatory cell infiltrate and of the release of proinflammatory mediators (70). A proliferation of acinar cells occurs as soon as 72 hours, after a cerulein-induced acute pancreatitis in rats, and persists for at least one week (50,70). The extracellular factors and intracellular events that induce pancreatic acinar cell proliferation in the regenerating pancreas are incompletely characterized and are an area of active interest. The mitogen-activated protein kinase (MAPK) activation and expression of cell cycle regulatory proteins play a role in the molecular mechanisms of pancreatic regeneration. The gut hormone, CCK, is a potent trophic factor of the pancreas (71). CCK activations of tyrosine kinases, phosphatidylinositol 3-kinase, and phospholipase D have been reported as early events (72–74), along with stimulation of MAPK cascades (75). Pancreatectomy is known to cause islet cell hypertrophy and also is seen in type II diabetes. Genetic profiling has demonstrated specific gene activation (76). Complexes containing a cyclin and a cyclin-dependent kinase (cdk) orchestrate progression through the cell cycle. Cyclin D family members are found in early G1 phase and cyclin E with Cdk2 in late G1. Sustained activation of p42/p44 MAPKs and Cdk2 along with the overexpression of cyclins D1 and E and reduction of cyclin inhibitors occurs after pancreatectomy, and are factors in signaling during pancreas regeneration (77). The activity of certain genes in the rat pancreas, after subtotal pancreatectomy, has been examined to give further insight into the repression and stimulation of certain genes during regeneration. The oncogenes c-myc and H-ras were overexpressed within 48 hours after resection, as measured by corresponding mRNA concentrations (78). CCK receptors in the gastrointestinal tract have been classified into two subsets, CCK-A and CCK-B (gastrin) receptors (79). The CCK-A receptor and its ligand CCK have

Pain, either persistent or episodic, usually requires treatment. Abstinence from alcohol or other causative agents, administering analgesic medications and performing nerve blocks, are necessary. Nonoperative management is the preferred initial management. Clinical outcomes have improved only to the extent that critical care has evolved in recent years. Derangements in other organ systems indicate severe disease and the need for aggressive intensive care unit management. Aggressive fluid and electrolyte resuscitation should be undertaken to prevent hypovolemia and prerenal azotemia. Serial monitoring of electrolytes and serum glucose is necessary to direct fluid resuscitation. Supplemental oxygen should be administered, and mechanical ventilation instituted in the event of respiratory insufficiency. Invasive monitoring may be necessary in the event of clinical deterioration. Antibiotic prophylaxis has been proposed for all patients with severe acute pancreatitis to prevent subsequent infection. Early studies of prophylactic intravenous antibiotics in the treatment of unselected patients with acute pancreatitis failed to show any effect on morbidity and mortality (94,95). Later studies recognized the importance of pancreatic tissue concentrations of antibiotics after intravenous infusion (96). One study found that early pancreatic infection in severe experimental pancreatitis was reduced with an antibiotic (imipenem) that was concentrated in pancreatic tissue (97), and these results correlated with a multicenter randomized clinical trial (98). The typical organisms found in pancreatic infections are enteric species. Multiple organisms are frequent. Antibiotic prophylaxis is now an accepted practice to reduce incidence of infected necrosis. It can alter the bacteriology of secondary pancreatic infection from predominantly gram-negative coliforms to gram-positive organisms (99). Imipenem and the fluoroquinolones have been the most successful, both because of their

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broad spectrum and their penetration into pancreatic tissues. However, in a randomized, prospective trial, patients treated with perfloxacin had an incidence of infected necrosis that was significantly higher than that among patients receiving imipenem (34% vs. 10%) (100). At the present time, intravenous administration of imipenem–cilastatin is recommended. Therapy should begin as soon as the diagnosis of acute necrotizing pancreatitis is made and should continue for at least two to four weeks. The role of surgical intervention is largely limited to (i) cholecystectomy and the clearance of stones from the biliary tree early in gallstone pancreatitis and (ii) debridement of dead tissues and drainage of infection for significant deterioration or sepsis associated with infected pancreatic necrosis. Infection should be suspected when symptoms persist, despite medical treatment. At that time, a constrastenhanced CT scan should be performed. Poor enhancement of the pancreatic tissue indicates pancreatic necrosis. Contrast-enhanced abdominal CT is the gold standard for the noninvasive diagnosis of pancreatic necrosis, with an accuracy of more than 90% when there is more than 30% glandular necrosis (101). The lack of normal contrast enhancement may be better detected several days after initial clinical presentation. Without improvement in the patient’s condition, this area should be aspirated percutaneously, gram stained, and cultured. If infection is present, an operation is indicated. Percutaneous drainage is inadequate. If infection is not present, the CT scan and aspiration are repeated at weekly intervals. Generally, sterile pancreatic necrosis can be safely managed without debridement, whereas infected necrosis should be removed. Deterioration in the patient’s condition, however, may necessitate earlier aspiration or operation, and should not be delayed because infection has not been proven. At operation, the lesser sac is entered, the fluid is drained, and the necrotic pancreas is debrided. Large sump drains are placed for postoperative lavage and drainage. A feeding jejunostomy tube is also placed in most of these critically ill patients. To meet increased metabolic demands and to ‘‘rest’’ the pancreas, total parenteral nutrition (TPN) administered through a central venous catheter is frequently used in patients with severe pancreatitis. This does not limit the course of disease and is associated with increased cost and infectious complications when compared to enteral feeding (102). In two recent randomized, prospective studies, patients with severe acute pancreatitis received either TPN or enteral feeding through a nasoenteric feeding tube placed beyond the ligament of Treitz. Enteral feeding was well tolerated, had no adverse clinical effects, and resulted in significantly fewer total and infectious complications (103,104). Oral intake can be resumed as soon as patients will tolerate it. However, until the associated ileus resolves, the patient should be given nothing by mouth. Somatostatin reduces pancreatic secretion by 70% in healthy patients. In animal models, somatostatin analogs increase DNA synthesis and protein content after induction of pancreatitis, and thus accelerate pancreatic repair and regeneration (105). To date, a sufficiently large trial has not been published to support the use of somatostatin in acute pancreatitis. However, a meta-analysis of controlled trials did suggest a survival advantage (45). The role of exogenous enzymes, CCK antagonists, and somatostatin in chronic pancreatitis remains uncertain, and further study is needed before widespread application is recommended. As it became clear in the early 1990s that pancreatitis was associated with the appearance of inflammatory

cytokines, many postulated that cytokine antagonism would be beneficial. The first study was published by Guice et al. in 1991 using serum from rabbits exposed to murine TNF (anti-TNF antiserum) as a potential TNF antagonist (106). Early results were disappointing. Subsequent work used species-specific anti-TNF antibodies to show the importance of this cytokine to pancreatitis progression. Pretreatment with anti-TNF antibodies attenuated the expected rise of serum TNF, glucose, and amylase (107). The blockade of TNF decreased pancreatic edema, necrosis, and inflammation, while decreasing mortality by more than half (108–110). Similarly, the inhibition of IL-1 activity also prevents the development of severe pancreatitis. Administration of an IL-1 receptor antagonist limited the degree of pancreatic inflammation (111). An IL-1 receptor antagonist inhibits IL-1 from activating surface receptors on target cells (112). Norman et al. have also shown a reduction in mortality from acute pancreatitis with delayed anti IL-1 therapy (113,114). Pretreatment with PAF-antibodies appears to ameliorate the severity of acute pancreatitis (115). Pharmacological inhibition of PSC activation may have the potential to become a new therapeutic approach for the treatment of chronic pancreatitis. Previous development strategies aimed at preventing pancreatic fibrosis have been hampered by incomplete knowledge of the molecular processes that underlie PSC activation. Trapidil, a drug that acts as a competitive antagonist of PDGF and developed as a coronary vasodilator, reduced PDGF-stimulated PSC growth in a dose-dependent manner (67). Nitric oxide (NO) is a potent vasodilator. Its use in acute pancreatitis remains controversial. Some studies have concluded that NO may be harmful (116), while others found that NO administration in established acute pancreatitis benefits both the acute inflammatory process and the associated pulmonary injury (117). These beneficial effects may be due to an inhibitory effect on neutrophil migration and improved pancreatic perfusion. Experimental acute pancreatitis can be modified by the early use of free radical scavengers or antioxidants (118), for superoxide dismutase decreased the arterial vasocontriction and leukocyte adherence associated with experimental acute pancreatitis (119). Use of antiprotease agents such as aprotinin or gabexate mesilate has been disappointing and is not currently supported (96).

Treatment of Chronic Pancreatitis Acute and chronic pancreatitis are distinguished from each other on the basis of structural and functional criteria. The morphologic changes of chronic pancreatitis include varying degrees of edema, and acute inflammation superimposed on a background of chronic changes that include fibrosis, inflammation, and loss of exocrine tissue. Repeated insult and inflammatory cycles result in irreversible parenchymal destruction, which can lead to (53) persistent abdominal pain as well as endocrine and/or exocrine insufficiency. Serum amylase and lipase concentrations may be normal or slightly elevated, particularly if the gland is already compromised by extensive fibrosis. Calcium deposition can be noted primarily in the head of the pancreas and may be seen in up to 30% of plain abdominal radiographs of these patients. A CT scan or ultrasonography may demonstrate the shrunken, constricted, and calcified pancreas characteristic of the disease. The hypersecretion of protein from acinar cells in the absence of increased fluid or bicarbonate secretion from duct cells

Chapter 22:

Normal Exocrine Function and Inflammatory Diseases of the Pancreas

is characteristic of chronic pancreatitis. Precipitates of proteinaceous material are observed in intercalated and canalicular ducts. Infiltration of the interstitium by inflammatory cells is followed by the deposition of fibrous tissue within and between lobules (53). Endoscopic retrograde cholangio-pancreatography (ERCP) is the gold-standard imaging procedure for the diagnosis of chronic pancreatitis and planning treatment. Fibrosis of the ducts is common and causes intermittent narrowing and dilatation giving the ‘‘chain of lakes’’ appearance on ERCP. Ductal changes on endoscopy can be classified as mild, moderate, or severe. Surgical or endoscopic decompression and ductal drainage may be necessary but does not improve the exocrine or endocrine dysfunction. Endoscopically placed stents or endoprostheses can provide short-term symptom relief, although most of the data reported on their use is from short-term, nonrandomized studies (120,121). Stents can be used for relatively short periods, and the response to drainage can be used to identify patients most likely to benefit from surgical drainage. Chronic pancreatitis produces a depressed insulin and C-peptide response to oral or intravenous glucose, and reduced responsiveness to intravenous arginine, alanine, or glucagon. Insulin-dependent diabetes mellitus occurs in about 40% of patients with chronic pancreatitis. Glucagon responses to arginine, alanine, and insulin-induced hypoglycemia are often suppressed. Abnormal release of pancreatic polypeptide, gastric inhibitory peptide, and motilin has been reported (122). In chronic pancreatitis, exocrine insufficiency may lead to CCK-mediated stimulation of the pancreas. Fat malabsorption and steatorrhea from pancreatic insufficiency occur, when stimulated lipase decreases to less than 10% of normal. Fecal fat can be measured usually over 72 hours during ingestion of a diet containing 70 to 100 g of fat per day. Values greater than 7% of ingested fat in the stool are abnormal. Attempts at mitigating this process include administration of digestive enzymes, CCK receptor antagonists, or somatostatin. Treatment of malabsorption requires delivery of pancreatic enzymes in active form to the duodenum. Gastric acidity serves to inactivate the enzymes when given orally. Large amounts of pancreatic enzymes are given with meals along with histamine-2 receptor antagonists to facilitate delivery.

Medical Treatment Treatment is directed toward the relief of pain and the management of malabsorption and diabetes. Early in the disease, abdominal pain may occur only in association with recurrent episodes of inflammation. With progression, the pain becomes more frequent and each episode lasts longer, so that patients may experience discomfort daily or even continuously. Patients may consume alcohol in an attempt to relieve the discomfort, and many of them also become addicted to narcotics. Every effort should be made to eliminate the use of alcohol. Many of these patients lose weight because eating provokes pain and they voluntarily reduce their food intake. Because carbohydrates are better absorbed than proteins and fats, patients should be given diets with liberal amounts of carbohydrates, as much protein as possible and only as much fat as can be tolerated. Pancreatic enzymes should be provided in an amount that supplies approximately 30,000 lipase units with each meal. In some patients, low gastric pH destroys the lipase before it mixes with chyme. Gastric acid antisecretory drugs should be

477

Table 4 Indications for Surgery in Chronic Pancreatitis Chronic pain that is refractory to nonsurgical treatment Effects of fibrosis on neighboring structures Symptomatic duodenal obstruction Persistent common bile duct obstruction Splenic vein obstruction with portal hypertension and bleeding varices Symptomatic colonic obstruction Effects of ductal disruption Persistent or symptomatic pseudocyst Pancreatic fistula unresponsive to medical therapy Pancreatic ascites unresponsive to medical therapy Suspected pancreatic cancer

prescribed to raise the gastric pH. An alternative is to change the enzyme preparation to one that is enterically coated.

Indications for Surgical Therapy The indications for surgical therapy for chronic pancreatitis are listed in Table 4. In the United States, the vast majority of referrals for surgery are for the management of chronic pain (123). Varying degrees of common duct, duodenal, and vascular obstruction are often present in patients with advanced pancreatic fibrosis, who are referred for surgery because of pain. In the well-documented series of 448 patients operated on at the University of Ulm primarily for the indication of pain, approximately 50% had a common bile duct stenosis, and approximately 25% had some degree of duodenal narrowing (124). Two surgical approaches have been used (i) drainage operations to relieve ductal obstruction or (ii) resection to remove diseased pancreatic tissue, and are listed in Table 5. Patients with a dilated duct (>7 mm) are usually candidates for a drainage procedure; if the duct is narrow, resection is preferred. Ductal anatomy is defined with CT scanning and ERCP.

Drainage Procedure With the longitudinal pancreaticojejunostomy (Puestow procedure), an incision is made through the anterior wall of the main pancreatic duct for its entire length (Fig. 6). A Roux-en-Y limb of jejunum is sutured to the opened pancreas along its length to drain the gland directly into the small intestine. The early results after longitudinal pancreaticojejunostomy are good: 65% to 80% of patients experience initial pain relief. With longer follow-up, however, there is a gradual decline in the percentage of patients who remain pain-free. Consequently, about one-third of patients who undergo this procedure remain pain free, about one-third have early improvement but experience return of pain, and about one-third have an inadequate initial response and continued pain. The Puestow procedure Table 5 Surgical Procedures for the Treatment of Pain in Chronic Pancreatitis Duct drainage procedure Longitudinal pancreaticojejunostomy (Puestow procedure) Pure resection procedures Distal pancreatectomy Pancreaticoduodenectomy (Whipple procedure) Total pancreatectomy with islet cell autotransplantation Combined duct drainage-resection procedures Longitudinal pancreaticojejunostomy with partial pancreatic head resection (Frey procedure) Duodenum-preserving partial resection of the pancreatic head (Beger procedure)

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Figure 6 (A) Longitudinal incision of the main pancreatic duct in preparation for lateral pancreaticojejunostomy (Peustow procedure): the most frequently used drainage procedure for chronic pancreatitis. (B) A Roux-en-Y limb of jejunum is sutured to the opened pancreatic duct along its length. Source: From Refs. 13, 125.

reduces the elevated interstitial pressure in these patients, and has been associated with a return of pancreatic blood flow (126). Unfortunately, ductal drainage operations have little impact on the degree of malabsorption. Therefore, surgery should not be performed to promote improvement in pancreatic function.

Resection After resection, pain is relieved in about 85% of cases; however, the relief is more durable than after a drainage procedure and more likely to be permanent (Fig. 7). Diabetes requiring insulin for its management is a likely occurrence after major pancreatic resections. Resections of the tail of the pancreas of 40% or less usually do not worsen pancreatic insufficiency. Resections of 50% to 80% of the distal pancreas produce significant steatorrhea in at least 20% of patients. Diabetes mellitus also worsens in up to 30% of patients. In patients undergoing 80% to 95% distal resections, 50% have worsening of both steatorrhea and diabetes. Distal resections

Figure 7 Surgical resection for chronic pancreatitis. (A) Distal resection of the pancreas with pancreaticojejunostomy. (B) Subtotal pancreatectomy. Source: From Ref. 125.

do not alter gastric emptying and the mixing of food with pancreatic juice. Pancreaticoduodenectomy alters both. At least half of all patients have troublesome steatorrhea after this operation. Diabetes worsens in about 10% of patients (Fig. 8). When total pancreatectomy is performed, all patients require insulin and pancreatic enzyme replacement. Furthermore, hypoglycemic episodes are more common in this group, probably due to the absence of pancreatic glucagon. The development of better methods for isolating human pancreatic islets has now made total pancreatectomy, with islet autotransplantation an option in the treatment of chronic pancreatitis. The largest experience has been in Minneapolis (127), where islet autografts were performed in 48 patients, and 75% experienced complete pain relief.

Combined Duct Drainage and Resection Procedures Failures of duct drainage procedures have often been ascribed to inadequate drainage of the head of the pancreas. Frey has pointed out the technical difficulties associated

Figure 8 Pancreaticoduodenectomy (Whipple procedure). (A) Preoperative anatomic relationships. (B) Postoperative reconstruction showing pancreatic, biliary, and gastric anastomoses. A cholecystectomy and bilateral truncal vagotomy are also part of the procedure. In many cases, the distal stomach and pylorus can be preserved, and vagotomy is then unnecessary.

Chapter 22:

Normal Exocrine Function and Inflammatory Diseases of the Pancreas

with achieving an adequate decompression of the duct of Wirsung in the head of the pancreas, particularly when the head is enlarged (128). Two procedures, the Frey procedure and the Beger procedure, have been designed as combined duct drainage and resection procedures to resect most of the pancreatic head without the high rate of morbidity associated with traditional pancreaticoduodenectomy and with less disruption of upper abdominal anatomy and physiology. In the Frey procedure, the majority of the head of the pancreas is removed piecemeal, resulting in a ‘‘coring-out’’ of the head, leaving a thin remnant of pancreatic head along the duodenal sweep, around the distal common bile duct, and around the portal and superior mesenteric veins. Then routine longitudinal decompression of the pancreatic duct is utilized. Izbicki et al. compared the Frey procedure with the traditional Whipple procedure in a prospective trial (129). The Frey procedure appeared to be as effective as a traditional pancreaticoduodenectomy in terms of pain relief, but was associated with less perioperative morbidity and a better quality of life. The Beger procedure is a subtotal resection of the pancreatic head that leaves a small remnant of pancreas along the common bile duct. It is a technically challenging procedure and has not been widely adopted despite its outstanding results. The Frey procedure and the Beger procedure were compared in a randomized trial (130). At a mean follow-up of 1.5 years, a decrease of 95% and 94% in the pain score after the Beger and Frey procedures and an increase of 67% in the overall quality-of-life index in both groups were observed.

6.

7.

8.

9.

10.

11. 12.

13.

14.

15.

SUMMARY 16.

In acute pancreatitis, a number of inciting factors have been identified, but the final common pathway leading to autodigestion and its systemic manifestations has not yet been identified. Uncomplicated acute pancreatitis is a self-limited disease, and usually resolves without altered digestive function or permanent damage to other organ systems. Recovery is generally complete, and does not recur if the cause is removed. Chronic pancreatitis is associated with permanent damage to the gland. Digestive and endocrine functions are altered according to the degree of glandular damage. This loss of function is usually permanent and in many cases progressive. Patients with chronic pancreatitis may also have recurrent episodes of acute pancreatitis. Surgery has a role in the palliation of refractory pain.

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Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen requires both Ca2þ and protein kinase C as messengers. Am J Physiol 1999; 277(3 Pt 1):G678–G686. Steinle AU, Weidenbach H, Wagner M, Adler G, Schmid RM. NF-kappaB/Rel activation in cerulein pancreatitis. Gastroenterology 1999; 116(2):420–430. Ethridge RT, Hashimoto K, Chung DH, Ehlers RA, Rajaraman S, Evers BM. Selective inhibition of NF-kappaB attenuates the severity of cerulein-induced acute pancreatitis. J Am Coll Surg 2002; 195(4):497–505. Balthazar EJ, Robinson DL, Megibow AJ, Ranson JH. Acute pancreatitis: value of CT in establishing prognosis. Radiology 1990; 174(2):331–336. Carey LC. Extra-abdominal manifestations of acute pancreatitis. Surgery 1979; 86(2):337–342. Kaye MD. Pleuropulmonary complications of pancreatitis. Thorax 1968; 23(3):297–306. Halmagyi DF, Karis JH, Stenning FG, Varga D. Pulmonary hypertension in acute hemorrhagic pancreatitis. Surgery 1974; 76(4):637–642. Berry AR, Taylor TV, Davies GC. Pulmonary function and fibrinogen metabolism in acute pancreatitis. Br J Surg 1981; 68(12):870–873. Bradley EL III, Hall JR, Lutz J, Hamner L, Lattouf O. Hemodynamic consequences of severe pancreatitis. Ann Surg 1983; 198(2):130–133. Dubick MA, Conteas CN, Billy HT, Majumdar AP, Geokas MC. Raised serum concentrations of pancreatic enzymes in cigarette smokers. Gut 1987; 28(3):330–335. Toyama MT, Ashley SW, Reber HA. Pathophysiologic basis of management. In: Howard JM, Idezuki Y, Ihse I, Prinz RA, eds. Surgical Diseases of the Pancreas. Baltimore: Williams & Wilkins, 1998:199–205. Drew SI, Joffe B, Vinik A, Seftel H, Singer F. The first 24 hours of acute pancreatitis. Changes in biochemical and endocrine homeostasis in patients with pancreatitis compared with those in control subjects undergoing stress for reasons other than pancreatitis. Am J Med 1978; 64(5):795–803. Pezzilli R, Billi P, Miglioli M, Gullo L. Serum amylase and lipase concentrations and lipase/amylase ratio in assessment of etiology and severity of acute pancreatitis. Dig Dis Sci 1993; 38(7):1265–1269. Ranson JH, Rifkind KM, Roses DF, Fink SD, Eng K, Spencer FC. Prognostic signs and the role of operative management in acute pancreatitis. Surg Gynecol Obstet 1974; 139(1):69–81. Wilson C, Heath DI, Imrie CW. Prediction of outcome in acute pancreatitis: a comparative study of APACHE II, clinical assessment and multiple factor scoring systems. Br J Surg 1990; 77(11):1260–1264. Dominguez-Munoz JE, Carballo F, Garcia MJ, et al. Monitoring of serum proteinase—antiproteinase balance and systemic inflammatory response in prognostic evaluation of acute pancreatitis. Results of a prospective multicenter study. Dig Dis Sci 1993; 38(3):507–513. Heath DI, Cruickshank A, Gudgeon M, Jehanli A, Shenkin A, Imrie CW. Role of interleukin-6 in mediating the acute phase protein response and potential as an early means of severity assessment in acute pancreatitis. Gut 1993; 34(1):41–45. Galloway SW, Kingsnorth AN. Reduction in circulating levels of CD4-positive lymphocytes in acute pancreatitis: relationship to endotoxin, interleukin 6 and disease severity. Br J Surg 1994; 81(2):312. Pezzilli R, Billi P, Miniero R, et al. Serum interleukin-6, interleukin-8, and beta 2-microglobulin in early assessment of severity of acute pancreatitis. Comparison with serum C-reactive protein. Dig Dis Sci 1995; 40(11):2341–2348. Inagaki T, Hoshino M, Hayakawa T, et al. Interleukin-6 is a useful marker for early prediction of the severity of acute pancreatitis. Pancreas 1997; 14(1):1–8. Elsasser HP, Adler G, Kern HF. Fibroblast structure and function during regeneration from hormone-induced acute pancreatitis in the rat. Pancreas 1989; 4(2):169–178.

51. Yokota T, Denham W, Murayama K, Pelham C, Joehl R, Bell RH Jr. Pancreatic stellate cell activation and MMP production in experimental pancreatic fibrosis. J Surg Res 2002; 104(2): 106–111. 52. Solomon SS, Duckworth WC, Jallepalli P, Bobal MA, Iyer R. The glucose intolerance of acute pancreatitis: hormonal response to arginine. Diabetes 1980; 29(1):22–26. 53. Satake K, Yamamoto T, Umeyama K. A serial histologic study of the healing process after relapsing edematous acute pancreatitis in the rat. Surg Gynecol Obstet 1987; 165(2): 148–152. 54. Bachem MG, Schneider E, Gross H, et al. Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology 1998; 115(2):421–432. 55. Apte MV, Haber PS, Applegate TL, et al. Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture. Gut 1998; 43(1):128–133. 56. Apte MV, Haber PS, Darby SJ, et al. Pancreatic stellate cells are activated by proinflammatory cytokines: implications for pancreatic fibrogenesis. Gut 1999; 44(4):534–541. 57. Mews P, Phillips P, Fahmy R, et al. Pancreatic stellate cells respond to inflammatory cytokines: potential role in chronic pancreatitis. Gut 2002; 50(4):535–541. 58. Gress T, Muller-Pillasch F, Elsasser HP, et al. Enhancement of transforming growth factor beta 1 expression in the rat pancreas during regeneration from caerulein-induced pancreatitis. Eur J Clin Invest 1994; 24(10):679–685. 59. Kihara Y, Tashiro M, Nakamura H, Yamaguchi T, Yoshikawa H, Otsuki M. Role of TGF-beta1, extracellular matrix, and matrix metalloproteinase in the healing process of the pancreas after induction of acute necrotizing pancreatitis using arginine in rats. Pancreas 2001; 23(3):288–295. 60. di Mola FF, Friess H, Martignoni ME, et al. Connective tissue growth factor is a regulator for fibrosis in human chronic pancreatitis. Ann Surg 1999; 230(1):63–71. 61. di Mola FF, Friess H, Riesle E, et al. Connective tissue growth factor is involved in pancreatic repair and tissue remodeling in human and rat acute necrotizing pancreatitis. Ann Surg 2002; 235(1):60–67. 62. Muller-Pillasch F, Menke A, Yamaguchi H, et al. TGFbeta and the extracellular matrix in pancreatitis. Hepatogastroenterology 1999; 46(29):2751–2756. 63. Friess H, Lu Z, Riesle E, et al. Enhanced expression of TGFbetas and their receptors in human acute pancreatitis. Ann Surg 1998; 227(1):95–104. 64. Shek FW, Benyon RC, Walker FM, et al. Expression of transforming growth factor-beta 1 by pancreatic stellate cells and its implications for matrix secretion and turnover in chronic pancreatitis. Am J Pathol 2002; 160(5):1787–1798. 65. Menke A, Yamaguchi H, Gress TM, Adler G. Extracellular matrix is reduced by inhibition of transforming growth factor beta1 in pancreatitis in the rat. Gastroenterology 1997; 113(1):295–303. 66. Luttenberger T, Schmid-Kotsas A, Menke A, et al. Plateletderived growth factors stimulate proliferation and extracellular matrix synthesis of pancreatic stellate cells: implications in pathogenesis of pancreas fibrosis. Lab Invest 2000; 80(1):47–55. 67. Jaster R, Sparmann G, Emmrich J, Liebe S. Extracellular signal regulated kinases are key mediators of mitogenic signals in rat pancreatic stellate cells. Gut 2002; 51(4):579–584. 68. Baramova E, Foidart JM. Matrix metalloproteinase family. Cell Biol Int 1995; 19(3):239–242. 69. Ng EK, Barent BL, Smith GS, Joehl RJ, Murayama KM. Decreased type IV collagenase activity in experimental pancreatic fibrosis. J Surg Res 2001; 96(1):6–9. 70. Elsasser HP, Adler G, Kern HF. Time course and cellular source of pancreatic regeneration following acute pancreatitis in the rat. Pancreas 1986; 1(5):421–429. 71. Pap A, Boros L, Hajnal F. Essential role of cholecystokinin in pancreatic regeneration after 60% distal resection in rats. Pancreas 1991; 6(4):412–418.

Chapter 22:

Normal Exocrine Function and Inflammatory Diseases of the Pancreas

72. Rivard N, Lebel D, Laine J, Morisset J. Regulation of pancreatic tyrosine kinase and phosphatase activities by cholecystokinin and somatostatin. Am J Physiol 1994; 266(6 Pt 1): G1130–G1138. 73. Rivard N, Rydzewska G, Lods JS, Martinez J, Morisset J. Pancreas growth, tyrosine kinase, PtdIns 3-kinase, and PLD involve high-affinity CCK-receptor occupation. Am J Physiol 1994; 266(1 Pt 1):G62–G70. 74. Rivard N, Rydzewska G, Morisset J. Cholecystokinin-induced pancreatic growth involves the high-affinity CCK receptor and concomitant activation of tyrosine kinase and phospholipase D. Ann NY Acad Sci 1994; 713:422–423. 75. Dabrowski A, Detjen KM, Logsdon CD, Williams JA. Stimulation of both CCK-A and CCK-B receptors activates MAP kinases in AR42J and receptor-transfected CHO cells. Digestion 1997; 58(4):361–367. 76. Lim HW, Lee JE, Shin SJ, et al. Identification of differentially expressed mRNA during pancreas regeneration of rat by mRNA differential display. Biochem Biophys Res Commun 2002; 299(5):806–812. 77. Morisset J, Aliaga JC, Calvo EL, Bourassa J, Rivard N. Expression and modulation of p42/p44 MAPKs and cell cycle regulatory proteins in rat pancreas regeneration. Am J Physiol 1999; 277(5 Pt 1):G953–G959. 78. Calvo EL, Dusetti NJ, Cadenas MB, Dagorn JC, Iovanna JL. Changes in gene expression during pancreatic regeneration: activation of c-myc and H-ras oncogenes in the rat pancreas. Pancreas 1991; 6(2):150–156. 79. Zhou W, Povoski SP, Bell RH Jr. Characterization of cholecystokinin receptors and messenger RNA expression in rat pancreas: evidence for expression of cholecystokinin-A receptors but not cholecystokinin-B (gastrin) receptors. J Surg Res 1995; 58(3):281–289. 80. Povoski SP, Zhou W, Longnecker DS, Jensen RT, Mantey SA, Bell RH Jr. Stimulation of in vivo pancreatic growth in the rat is mediated specifically by way of cholecystokinin-A receptors. Gastroenterology 1994; 107(4):1135–1146. 81. Tsunoda Y, Takeda H, Otaki T, Asaka M, Nakagaki I, Sasaki S. Intracellular Ca2þ shift and signal transduction from the tubulovesicular portion of gastric parietal cells during gastrin stimulation or Ca2þ ionophore treatment: comparison between luminescent and fluorescent probes, and electron probe X-ray microanalyzer. Biochem Cell Biol 1988; 66(4): 279–287. 82. Yen TW, Sandgren EP, Liggitt HD, et al. The gastrin receptor promotes pancreatic growth in transgenic mice. Pancreas 2002; 24(2):121–129. 83. Dembinski AB, Johnson LR. Stimulation of pancreatic growth by secretin, caerulein, and pentagastrin. Endocrinology 1980; 106(1):323–328. 84. Balas D, Senegas-Balas F, Pradayrol L, Vayssette J, Bertrand C, Ribet A. Long-term comparative effect of cholecystokinin and gastrin on mouse stomach, antrum, intestine, and exocrine pancreas. Am J Anat 1985; 174(1):27–43. 85. Chen D, Nylander AG, Norlen P, Hakanson R. Gastrin does not stimulate growth of the rat pancreas. Scand J Gastroenterol 1996; 31(4):404–410. 86. Ryberg B, Axelson J, Hakanson R, Sundler F, Mattsson H. Trophic effects of continuous infusion of [Leu15]-gastrin-17 in the rat. Gastroenterology 1990; 98(1):33–38. 87. Kusske AM, Rongione AJ, Ashley SW, McFadden DW, Reber HA. Interleukin-10 prevents death in lethal necrotizing pancreatitis in mice. Surgery 1996; 120(2):284–288; discussion 289. 88. Rongione AJ, Kusske AM, Kwan K, Ashley SW, Reber HA, McFadden DW. Interleukin 10 reduces the severity of acute pancreatitis in rats. Gastroenterology 1997; 112(3):960–967. 89. Selzman CH, Shames BD, Miller SA, et al. Therapeutic implications of interleukin-10 in surgical disease. Shock 1998; 10(5):309–318. 90. Rongione AJ, Kusske AM, Ashley SW, Reber HA, McFadden DW. Interleukin-10 prevents early cytokine release in severe

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111. Norman J, Franz M, Fabri PJ, Gower WR. Decreased severity of experimental acute pancreatitis by pre or post treatment with interleukin-1 receptor antagonist. Gastroenterology 1994; 106:A311. 112. Tanaka N, Murata A, Uda K, et al. Interleukin-1 receptor antagonist modifies the changes in vital organs induced by acute necrotizing pancreatitis in a rat experimental model. Crit Care Med 1995; 23(5):901–908. 113. Norman J, Franz M, Messina J, et al. Interleukin-1 receptor antagonist decreases severity of experimental acute pancreatitis. Surgery 1995; 117(6):648–655. 114. Norman JG, Franz MG, Fink GS, et al. Decreased mortality of severe acute pancreatitis after proximal cytokine blockade. Ann Surg 1995; 221(6):625–631; discussion 631–624. 115. Konturek SJ, Dembinski A, Konturek PJ, et al. Role of platelet activating factor in pathogenesis of acute pancreatitis in rats. Gut 1992; 33(9):1268–1274. 116. Dabrowski A, Gabryelewicz A. Nitric oxide contributes to multiorgan oxidative stress in acute experimental pancreatitis. Scand J Gastroenterol 1994; 29(10):943–948. 117. Closa D, Hotter G, Prats N, et al. Prostanoid generation in early stages of acute pancreatitis: a role for nitric oxide. Inflammation 1994; 18(5):469–480. 118. Sanfey H, Bulkley GB, Cameron JL. The role of oxygenderived free radicals in the pathogenesis of acute pancreatitis. Ann Surg 1984; 200(4):405–413. 119. Kusterer K, Poschmann T, Friedemann A, Enghofer M, Zendler S, Usadel KH. Arterial constriction, ischemiareperfusion, and leukocyte adherence in acute pancreatitis. Am J Physiol 1993; 265(1 Pt 1):G165–G171. 120. Geenen JE, Rolny P. Endoscopic therapy of acute and chronic pancreatitis. Gastrointest Endosc 1991; 37(3):377–382.

121. Cremer M, Deviere J, Delhaye M, Baize M, Vandermeeren A. Stenting in severe chronic pancreatitis: results of mediumterm follow-up in seventy-six patients. Endoscopy 1991; 23(3):171–176. 122. Nealon WH, Townsend CM Jr, Thompson JC. The time course of beta cell dysfunction in chronic ethanol-induced pancreatitis: a prospective analysis. Surgery 1988; 104(6):1074–1079. 123. Bell RH Jr. Surgical options in the patient with chronic pancreatitis. Curr Gastroenterol Rep 2000; 2(2):146–151. 124. Beger HG, Schlosser W, Siech M, Poch B. The surgical management of chronic pancreatitis: duodenum-preserving pancreatectomy. Adv Surg 1999; 32:87–104. 125. Way L. Current Surgical Diagnosis and Treatment. Los Altos: Lange Medical Books, 1985. 126. Wedgwood KR, Farmer RC, Reber HA. A model of hemorrhagic pancreatitis in cats—role of 16,16-dimethyl prostaglandin E2. Gastroenterology 1986; 90(1):32–39. 127. Wahoff DC, Papalois BE, Najarian JS, et al. Autologous islet transplantation to prevent diabetes after pancreatic resection. Ann Surg 1995; 222(4):562–575; discussion 575–579. 128. Frey CF. The surgical management of chronic pancreatitis: the Frey procedure. Adv Surg 1999; 32:41–85. 129. Izbicki JR, Bloechle C, Broering DC, Knoefel WT, Kuechler T, Broelsch CE. Extended drainage versus resection in surgery for chronic pancreatitis: a prospective randomized trial comparing the longitudinal pancreaticojejunostomy combined with local pancreatic head excision with the pylorus-preserving pancreatoduodenectomy. Ann Surg 1998; 228(6):771–779. 130. Izbicki JR, Bloechle C, Knoefel WT, Kuechler T, Binmoeller KF, Broelsch CE. Duodenum-preserving resection of the head of the pancreas in chronic pancreatitis. A prospective, randomized trial. Ann Surg 1995; 221(4):350–358.

23 The Jaundiced Patient Attila Nakeeb and Henry A. Pitt

into bile. Unconjugated bilirubin is transported across the sinusoidal membrane of the hepatocyte into the cytoplasm. Once inside the hepatocyte, unconjugated bilirubin is again bound by a cytoplasmic protein, in this case a glutathione S-transferase. The microsomal enzyme uridine diphosphate glucuronyl transferase then conjugates the insoluble unconjugated bilirubin with glucuronic acid to form the water-soluble conjugated forms, bilirubin monoglucuronide (15%) and bilirubin diglucuronide (85%). Conjugated bilirubin is then excreted from the hepatocyte into the bile canaliculus by an active transport mechanism. Excretion into bile is the rate-limiting step in bilirubin metabolism. After excretion, bile flows through the biliary ductal–collecting system, may or may not be stored in the gallbladder, and enters the duodenum. In the terminal ileum and colon, bilirubin is converted by bacterial enzymes into urobilinogen. About 10% to 20% of the urobilinogen is then reabsorbed from the intestine into the portal circulation, creating an enterohepatic circulation. This recycled urobilinogen may be reexcreted either into the bile by the liver or into urine by the kidney. The remaining urobilinogen in the intestine is converted to fecobilinogen, which gives stool its characteristic brown color. Normal bilirubin metabolism can be summarized as a series of steps including (i) production, (ii) uptake by the hepatocyte, (iii) conjugation, (iv) excretion into bile ducts, and (v) delivery to the intestine. Jaundice can result from defects in any of these steps of bilirubin metabolism.

INTRODUCTION The evaluation and management of the jaundiced patient is a common problem facing the general surgeon. Jaundice, or icterus, refers to a yellow staining of the skin, mucous membranes, and body fluids by bilirubin. Serum bilirubin concentration is normally between 0.5 and 1.3 mg/dL, and jaundice usually becomes clinically apparent when the serum bilirubin concentration exceeds 2.0 mg/dL. During the past century, significant advances have been made in our understanding of the pathophysiology, diagnosis, and management of the jaundiced patient. Biochemists have elucidated normal bilirubin metabolism and have described specific defects that result in different clinical syndromes. The development of diagnostic imaging techniques such as ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), percutaneous and endoscopic cholangiography, endoscopic US (EUS), and staging laparoscopy have dramatically changed the current diagnostic approach to the jaundiced patient. Many of these techniques have led to newer therapeutic options to relieve biliary obstruction. Similarly, advances have been made in perioperative and operative managements that have resulted in improved operative survival of the jaundiced patient. Before discussing the various diagnostic and therapeutic modalities available for the management of the jaundiced patient, normal and abnormal bilirubin metabolism will be reviewed, a classification system of jaundice will be presented, and the multiple pathophysiologic effects of jaundice will be explained.

CLASSIFICATION OF JAUNDICE Numerous systems for the classification of jaundice have been proposed based on factors such as pathogenic mechanisms, disease processes, and treatment regimens. However, the most widely accepted classification system is one that relates jaundice to an alteration in normal bilirubin metabolism. In this system, jaundice may result from (i) increased production of bilirubin, (ii) impaired uptake of bilirubin, (iii) impaired conjugation of bilirubin, (iv) impaired transport or excretion of bilirubin into the bile canaliculus, or (v) obstruction of the intrahepatic or extrahepatic biliary tree (Table 1). Overproduction, impaired uptake, and impaired conjugation of bilirubin all lead to a predominately unconjugated hyperbilirubinemia. Impaired transport and excretion or biliary ductal obstruction results in hyperbilirubinemia that is primarily conjugated. Some patients have multiple defects in normal metabolism. For example, a patient with biliary obstruction from tumor may develop secondary hepatocellular dysfunction. Therefore, these classification systems may be simplifications of more complex disease processes.

BILIRUBIN METABOLISM In adults, between 250 and 350 mg of bilirubin is produced each day. Approximately 80% to 85% of this bilirubin is derived from the destruction of senescent red blood cells by the reticuloendothelial system. The remaining 15% to 20% comes from the breakdown of nonhemoglobin proteins such as myoglobin and the cytochromes. The metabolism of bilirubin is reviewed in Figure 1. In reticuloendothelial cells, the microsomal enzyme heme oxygenase cleaves heme into biliverdin. Biliverdin is then reduced to bilirubin by the cytosolic enzyme biliverdin reductase before being released into the circulation. In this unconjugated form, bilirubin is water insoluble and is transported to the liver, tightly bound to albumin. The liver removes unconjugated bilirubin and other organic anions bound to albumin from plasma. After the bilirubin–albumin complex enters the sinusoidal circulation of the liver, three distinct metabolic phases are recognized: (i) hepatocyte uptake, (ii) conjugation, and (iii) excretion 483

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is a congenital defect that results in unconjugated hyperbilirubinemia because of reduced bilirubin glucuronyl transferase levels within hepatocytes. The bilirubin level fluctuates depending on the clinical state but rarely exceeds 3.0 mg/dL. In the Crigler–Najjar syndromes, there is either a complete absence of glucuronyl transferase activity (type I) or a marked decrease in glucuronyl transferase activity (type II). Type I disease is usually fatal within the first year of life.

Impaired Transport or Excretion Impairment of bilirubin transport or excretion into the bile canaliculus results in intrahepatic cholestasis or ‘‘medical’’ jaundice. Hepatitis—viral, alcoholic, or drug induced—is the most common cause of intrahepatic cholestasis. Drugs such as the ‘‘statins,’’ oral contraceptives, and anabolic steroids also may cause a defect in the excretion of bilirubin. Genetic defects in the hepatic excretion of bilirubin and other organic anions across the hepatocyte membrane exist in both the Dubin–Johnson and Rotor syndromes. In the Dubin–Johnson syndrome, pigments accumulate within hepatocytes, causing the liver to turn black. The Rotor syndrome has a similar defect in hepatic storage of bilirubin, except that no pigment accumulates within the liver parenchyma. Figure 1 Schematic representation of normal bilirubin metabolism. Abbreviations: GT, glucuronyl transferase; BMG, bilirubin monoglucuronide; BDG, bilirubin diglucuronide; EHC, enterohepatic circulation.

Increased Production Overproduction of bilirubin can result from either congenital or acquired hemolysis. Hereditary causes include spherocytosis, thalassemia, and sickle cell disease. Acquired causes of hemolysis include sepsis, burns, infections, drugs, transfusion reactions, and acquired autoimmune diseases. When the capacity of the liver to remove bilirubin from the circulation is exceeded, unconjugated hyperbilirubinemia occurs. The total bilirubin level in hemolysis rarely exceeds 4 to 5 mg/dL. However, if underlying hepatocellular dysfunction is also present, much higher bilirubin levels may occur.

Biliary Obstruction Jaundice due to biliary obstruction is often referred to as ‘‘surgical’’ jaundice. With biliary obstruction, hyperbilirubinemia is primarily conjugated, but unconjugated bilirubin is often also moderately elevated. Common causes of surgical jaundice are depicted in Table 1, and will be the primary focus of the remainder of this chapter.

PATHOPHYSIOLOGY OF JAUNDICE Biliary obstruction produces local effects on the bile ducts that lead to derangements of hepatic function and, ultimately, to widespread systemic effects. Patients who are jaundiced have an increased risk of developing hepatic dysfunction, renal failure, cardiovascular impairments, nutritional deficiencies, bleeding problems, infections, and wound complications, and of dying after surgery.

Impaired Uptake and Conjugation

Hepatobiliary

Impaired uptake of unconjugated bilirubin by hepatocytes can be caused by drugs, prolonged fasting, and sepsis and following viral hepatitis. Neonatal jaundice results from an immaturity of the hepatic conjugating and transport system. This problem occurs between the second and fifth days of life, and usually disappears by two weeks, as the enzyme systems mature. Gilbert’s syndrome is the most common cause of unconjugated nonhemolytic hyperbilirubinemia and affects between 2.5% and 7% of the population. Gilbert’s syndrome

The biliary system normally has a low pressure (5–10 cm H2O). In the setting of complete or partial biliary obstruction, biliary pressure can approach 30 cmH2O (1). As biliary pressure increases, the tight junctions between hepatocytes and bile duct cells are disrupted, resulting in an increase in bile duct and canalicular permeability. Bile contents can freely reflux into liver sinusoids, causing a marked inflammatory response in the portal triads. In patients with long-standing obstruction, intrahepatic bile ductule proliferation occurs and can lead to the development of biliary cirrhosis.

Table 1 Classification of Jaundice Defect in bilirubin metabolism Increased production Impaired hepatocyte uptake Reduced conjugation Impaired transport and excretion Biliary obstruction

Predominant hyperbilirubinemia Unconjugated Unconjugated Unconjugated Conjugated Conjugated

Examples Congenital hemoglobinopathies, hemolysis, multiple transfusions, sepsis, burns Gilbert’s disease, drug induced Neonatal jaundice, Crigler–Najjar syndrome Hepatitis, cirrhosis, Dubin–Johnson syndrome, Rotor syndrome Choledocholithiasis, benign strictures, chronic pancreatitis, sclerosing cholangitis, periampullary cancer, cholangiocarcinoma

Chapter 23: The Jaundiced Patient

Extrahepatic biliary obstruction and jaundice also can alter important secretory, metabolic, and synthetic functions of the liver. When biliary pressure rises above 20 cmH2O, hepatic bile secretion is diminished and hepatocytes cannot excrete efficiently against the high ductal pressure. As a result, excretory products of the hepatocytes reflux directly into the vascular system leading to systemic toxicity. Jaundiced patients have a decreased capacity to excrete drugs, such as antibiotics, that are normally secreted into bile (2). The increased concentration of bile acids associated with obstructive jaundice results in inhibition of the hepatic cytochrome P450 enzymes and, therefore, in a decrease in the rate of oxidative metabolism in the liver. In addition, bile acids in abnormally high concentrations can induce apoptosis (programmed cell death) in hepatocytes (3). The synthetic function of the hepatocyte is also decreased with obstructive jaundice, as evidenced by decreased plasma levels of albumin, clotting factors, and secretory immunoglobulins. The Kupffer cell is a tissue macrophage that is the predominant cell type of the hepatic reticuloendothelial system. Normally, infectious agents, damaged blood cells, cellular debris, fibrin degradation products, and endotoxin that are absorbed or formed in the portal circulation are effectively filtered by Kupffer cells and removed from the systemic circulation. Kupffer cells also play an interactive role with hepatocytes, modulating synthesis of hepatic proteins. Obstructive jaundice has been shown to have profound effects on Kupffer cells, including decreased endocytosis, phagocytosis, clearance of bacteria and endotoxin, and expression of the major histocompatibility complex class II antigen and a subsequent diminished ability to process antigen (4–6). In addition, biliary obstruction has been shown to increase levels of proinflammatory cytokines, including tumor necrosis factor a and interleukin-6. Several authors have reported impairment of both macro- and microvascular perfusion of the liver in obstructive jaundice. Intravital fluorescence microscopy has shown a significant increase in the number of nonperfused sinusoids after three days of extrahepatic cholestasis. In perfused sinusoids, a 35% decrease in the mean diameter and a 25% decrease in flow velocity were noted (7).

Cardiovascular In addition to hepatic dysfunction, obstructive jaundice is known to cause severe hemodynamic and cardiac disturbances. Experimental animals with obstructive jaundice tend to be hypotensive and exhibit an exaggerated hypotensive response to hemorrhage. Studies in experimental animals have demonstrated that bile duct–ligated animals have (i) decreased cardiac contractility, (ii) reduced left ventricular pressures, (iii) impaired response to b-agonist drugs such as isoproterenol and norepinephrine, and (iv) decreased peripheral vascular resistance (8–10). In a study of nine patients with obstructive or cholestatic jaundice, Lumlertgul et al. (11) have shown a significantly blunted response in left ventricular ejection fraction compared to normal volunteers, following the infusion of the positive inotrope dobutamine. Recently, Padillo et al. (12) have shown a negative correlation between serum bilirubin and left ventricular systolic work in 13 patients with biliary obstruction and no previous history of heart, lung, or kidney disease. Moreover, successful internal biliary drainage in their patients was associated with a significant increase in cardiac output, compliance, and contractility. The combination of depressed cardiac function and decreased total peripheral resistance most likely makes the jaundiced

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patient more susceptible to the development of postoperative shock than nonjaundiced patients.

Renal The association between jaundice and postoperative renal failure has been known for many years. The reported incidence of postoperative acute renal failure approaches 10%. Moreover, the mortality rate in jaundiced patients developing renal failure has been reported to be as high as 70% (13). Important factors that may play a role in the development of renal failure in obstructive jaundice include (i) depressed cardiac function, (ii) hypovolemia, and (iii) endotoxemia. The decreased cardiac function associated with obstructive jaundice leads to a decrease in renal perfusion. Moreover, it has been postulated that this decreased cardiac output results in stretching of the atrium and an increase in production of the hormone atrial natriuretic peptide (ANP). ANP is known to cause natriuresis, to counter the action of water- and sodium-retaining hormones, to inhibit the thirst mechanism and produce peripheral vasodilatation. Plasma levels of ANP have been shown to be increased in both experimental animals and patients with extrahepatic biliary obstruction (12,14). In addition to the direct effects of jaundice on the heart and peripheral vasculature discussed above, the increased serum levels of bile acids associated with obstructive jaundice have a direct diuretic and natriuretic effect on the kidney, resulting in significant extracellular volume depletion and hypovolemia. In dogs, the infusion of bile into the renal artery results in increased urine flow, natriuresis, and kaliuresis. This diuretic effect may be mediated by increased prostaglandin E2–production by the kidney (15). The third factor in the development of renal failure is endotoxemia. Approximately 50% of patients with obstructive jaundice (16,17) have endotoxin in their peripheral blood. This phenomenon may be the result of a lack of bile salts in the gut lumen that normally prevent absorption of endotoxins and inhibit anaerobic bacterial growth as well as the decreased hepatic clearance of endotoxin by Kupffer cells. Endotoxin also causes renal vasoconstriction and redistribution of renal blood flow away from the cortex and disturbances in coagulation including the activation of complement, macrophages, leukocytes, and platelets (16). As a result, glomerular and peritubular fibrin is deposited. This factor, in combination with reduced renal cortical blood flow, results in the tubular and cortical necrosis observed in jaundiced patients with renal failure. Mechanisms of the pathophysiology of renal failure in obstructive jaundice are summarized in Figure 2.

Coagulation Disturbances of blood coagulation are also commonly present in jaundiced patients. The most frequently observed clotting defect in patients with biliary obstruction is prolongation of the prothrombin time (PT). This problem results from impaired vitamin K absorption from the gut, secondary to a lack of intestinal bile. This coagulopathy is usually reversible by the parenteral administration of vitamin K. Decreased bile levels in the small intestine may also result in diminished absorption of other fat-soluble vitamins and fats, which results in weight loss and loss of calcium. This latter factor, as well as the above-mentioned increase in circulating endotoxin, may further contribute to clotting abnormalities. In experimental animals, endotoxin affects factors XI and XII and causes platelet and direct endothelial damage

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Obstructive Jaundice

Systemic Bile Salts Gut Bile Salts

Kupffer Cell Clearance

Clearance of Cardiotoxins?

Endotoxemia

Cardiovascular System

LV Function

ANP and Hypodypsia

ANP and Cytokines

Plasma Volume

Peripheral Resistance

Blood Pressure

Systemic Bilirubin

Renal System

Coagulation System

Prostaglandins and Cytokines

Peritubular Fibrin Deposition

Altered Intrarenal Hemodynamics

Direct Parenchyma Toxicity

Renal Vascular Resistance Renal Permeability

Figure 2 Mechanism of renal dysfunction in jaundice. Abbreviations: LV, left ventricular; ANP, atrial natriuretic peptide.

Renal Impairment or Acute Renal Failure

(16). Moreover, endotoxin release in jaundiced patients results in a low-grade disseminated intravascular coagulation (DIC) with increased fibrin degradation products. Hunt (18) has shown that jaundiced patients with circulating endotoxin or increased fibrin degradation product levels before surgery are at increased risk for hemorrhagic complications. In addition to problems with endotoxemia, cirrhotic patients may have even more complicated clotting abnormalities, such as problems with thrombocytopenia from hypersplenism and fibrinolysis.

Immune System Surgery in the jaundiced patient is associated with a significant rate of postoperative septic complications. Jaundiced patients have a number of defects in cellular immunity that make them more prone to infection. Cainzos et al. (19) have demonstrated an association between jaundice and altered delayed type hypersensitivity. Only 16% of 118 jaundiced patients were immunocompetent compared to 76% of 59 healthy controls when tested with a battery of seven skin antigens. Several authors have shown impaired T-cell proliferation (20), decreased neutrophil chemotaxis (21), and defective bacterial phagocytosis (22) following bile duct ligation in rats. As mentioned earlier, the ability of the reticuloendothelial system, specifically liver Kupffer cells, to clear bacteria and endotoxin from the circulation is also reduced in obstructive jaundice. The absence of bile from the intestinal tract also plays a role in the infectious complications seen in patients with obstructive jaundice. Bacterial translocation from the gut has been shown to be increased in the setting of bile duct obstruction (23). Obstruction causes a disruption of the enterohepatic circulation and results in the loss of the emulsifying antiendotoxin effect of bile acids. Therefore, a larger pool of endotoxin is available within the intestine for absorption into the portal circulation. The combination of a lack of bile in the intestine and the impairment of cellular

immunity and reticuloendothelial cell function most likely results in the observed increase in septic and infectious complications in the jaundiced patient.

Wound Healing Delayed wound healing and a high incidence of wound dehiscence and incisional hernias have been observed in patients undergoing surgery for the relief of obstructive jaundice. Patients with obstructive jaundice have decreased activity of the enzyme propylhydroxylase in their skin. Propylhydroxylase is necessary for the incorporation of proline amino acid residues into collagen, and its activity has been used as a measure of collagen synthesis. Grande et al. (24) measured skin propylhydroxylase activity in 95 patients with extrahepatic bile duct obstruction and 123 nonjaundiced control patients undergoing cholecystectomy. The jaundiced patients had only 11% of the skin propylhydroxylase activity of the controls. In the subgroup of patients that had jaundice secondary to malignancy, the propylhydroxylase activity was less than 7% of that in controls. With relief of obstruction, the activity increased to 22% of that in controls. Interestingly, in patients with jaundice secondary to benign obstruction, the activity increased to 100% of that in controls.

Other Factors Other problems that face jaundiced patients are anorexia, weight loss, and resultant malnutrition. Appetite is adversely influenced by the lack of bile salts in the intestinal tract. In addition, patients with pancreatic or periampullary malignant lesions may have partial duodenal obstruction or abnormal gastric emptying, perhaps secondary to tumor infiltration of the celiac nerve plexus. Patients with pancreatic or ampullary tumors may also have pancreatic endocrine and exocrine insufficiency. This latter problem may further compound other nutritional defects that, in turn, may multiply the immune deficits of the jaundiced patient.

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a benign biliary stricture or retained common duct stones. A history of biliary colic points toward choledocholithiasis. Pancreatic cancer, on the other hand, is more likely to present with progressive, painless jaundice and weight loss. The presence of fever, chills, and upper abdominal pain in addition to jaundice (Charcot’s triad) is suggestive of cholangitis, which occurs more often in patients with choledocholithiasis than in those with malignant obstruction. On physical examination, the abdomen should be carefully palpated. A small liver may be discovered in severe cirrhosis or hepatitis. A tender liver edge may be found in hepatitis, congestive heart failure, or alcoholic hepatitis. A palpable, nontender gallbladder may be noted in pancreatic or ampullary carcinoma (Courvoisier’s sign). A tender gallbladder, on the other hand, may be palpated in choledocholithiasis with associated cholecystitis. The signs of cirrhosis (i.e., ascites, spider angioma, or periumbilical venous enlargement) should also be noted.

In recent years, it has become clear that the many physiologic derangements that occur with obstructive jaundice take a long time to reverse. For example, Koyama et al. (25) have shown that hepatic mitochondrial function does not return to normal even seven weeks after relief of obstruction. This same prolonged effect of obstructive jaundice has been noted with lymphocyte, polymorphonuclear, and Kupffer cell function. Therefore, even patients who have had temporary relief of biliary obstruction via percutaneous or endoscopic stents are likely to remain at risk for the development of significant complications following surgery.

DIAGNOSTIC APPROACH When confronted with a patient with jaundice, the objective of the physician is to identify any potentially treatable causes. The most important distinction to be made is whether the jaundice is caused by intrahepatic cholestasis or extrahepatic obstruction. Fortunately, the distinction between ‘‘medical’’ and ‘‘surgical’’ jaundice can be made relatively easily with a careful history, physical examination, review of serum chemistries, and radiological evaluation. An algorithm for the evaluation of the jaundiced patient is shown in Figure 3. The following discussion will present an approach to the jaundiced patient that will allow for an accurate diagnosis to be made without subjecting the patient to needless risk, discomfort, or expense.

Biochemical Evaluation Along with the history and physical examination, biochemical evaluation is an integral part of the initial workup of the jaundiced patient. Hyperbilirubinemia is the sine qua non of jaundice, and the level of bilirubin can indicate the severity of the disease process. Moreover, bilirubin levels can be used to follow disease progression. The routine laboratory tests that should be performed on all jaundiced patients include direct (conjugated) and indirect (unconjugated) bilirubin, alkaline phosphatase, serum transaminases, and amylase determinations (Table 2). Patients with hemolysis have an increase in the indirect (unconjugated) fraction of bilirubin, whereas the direct (conjugated) bilirubin level is normal. As stated previously, the total bilirubin concentration in hemolysis rarely exceeds 4 to 5 mg/dL. Bilirubin is absent in the urine of patients with hemolysis, because indirect bilirubin is not excreted by the kidney.

Clinical Evaluation The first and most important step in the workup of the jaundiced patient is to obtain a careful history. Important historical points to consider include occupational exposures, travel history, prior blood transfusions, and alcohol consumption and a complete review of all medications. Previous surgery, especially biliary, raises the suspicion of

Jaundice

Indirect hyperbilirubinemia

Hemolysis workup

History, physical exam, laboratory tests

Direct hyperbilirubinemia

Suspect extrahepatic disorder

Suspect intrahepatic disease Medical workup

Surgical workup

Suspect stone disease

CT scan

Ultrasound CBD stones

Suspect malignancy

Hepatitis screen, observation, liver biopsy

Dilated ducts

No CBD stones

Suspect proximal obstruction

Suspect distal obstruction

EUS MRCP

EUS

ERCP+ES

LC

LC + LCBDE

ERCP

PTC

ERCP

Figure 3 Algorithm for the evaluation of jaundice. Abbreviations: CBD, common bile duct; CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; ES, endoscopic sphincterotomy; EUS, endoscopic ultrasound; MRCP, magnetic resonance cholangiopancreatography; PTC, percutaneous transhepatic cholangiography; LC, laparoscopic cholecystectomy; LCBDE, laparoscopic common bile duct exploration.

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Table 2 Laboratory Tests in the Diagnosis of Jaundice Serum bilirubin Cause of jaundice Hemolysis Hepatocellular dysfunction Intrahepatic cholestasis Extrahepatic obstruction

Conjugated

Unconjugated

Serum alkaline phosphatase

$ "" """ """

""" "" "" ""

$ " "" """

Urine Serum transaminases

Bilirubin

Urobilinogen

$ """ "" "

0 "" """ """

"" " 0 or # 0 or #

0 ¼ none; # ¼ decreased; $ ¼ no change; " ¼ mild elevation; "" ¼ moderate elevation; """ ¼ marked elevation.

The amino acid transaminases aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are serum markers for hepatocyte damage. AST is found in liver, heart, kidney, skeletal muscle, and brain tissue. ALT is found predominantly within hepatocytes, making ALT more specific for identifying liver injury. In cases of hepatic parenchymal disease, broad derangements of liver function tests are seen. The concentrations of both conjugated and unconjugated fractions of bilirubin are increased. With the increased level of conjugated bilirubin in the serum, bilirubinuria develops. In patients with acute hepatitis, serum ALT and AST are markedly elevated. In contrast, alkaline phosphatase and bilirubin levels in these patients may be only slightly elevated. As in hepatitis, the serum transaminases are elevated in alcoholic liver disease, with serum AST levels usually being greater than twice serum ALT levels. In the cirrhotic patient, serum bilirubin levels increase in proportion to the degree of parenchymal damage. Albumin and the coagulation factors V, VII, IX, and X, prothrombin, and fibrinogen are all synthesized in the liver. Therefore, the measurement of serum albumin levels and PT may be helpful in assessing the degree of parenchymal liver injury. In extrahepatic obstruction, the fraction of direct bilirubin is increased along with a moderate increase in indirect bilirubin. The highest elevations of bilirubin are usually found in patients with malignant extrahepatic obstruction where bilirubin levels may exceed 20 mg/dL. With malignant obstruction, the alkaline phosphatase is also elevated to the same degree. Other liver function tests are usually normal or only slightly elevated, and the amylase concentration is usually normal. Common bile duct stones, on the other hand, rarely cause an increased bilirubin level greater than 10 to 12 mg/dL. With choledocholithiasis, alkaline phosphatase is also usually elevated to a moderate degree. As a gallstone passes through and momentarily obstructs the ampulla of Vater, serum transaminase levels may transiently rise. In this setting, hyperamylasemia may also develop. If longstanding extrahepatic obstruction is present, liver damage and fibrosis can occur, thus resulting in a combined intra- and extrahepatic biochemical profile. Serum alkaline phosphatase is often a more sensitive indicator of obstruction and may be elevated when the bilirubin level is normal. This circumstance occurs most commonly with incomplete or partial obstruction. However, increased levels of alkaline phosphatase activity may also result from bone disease. If this possibility is suspected, serum 50 -nucleotidase or serum g-glutamyl transpeptidase levels should be measured, because both of these parallel changes in alkaline phosphatase from a hepatobiliary source and are not found in bone. By obtaining a careful history, performing a physical examination, and interpreting laboratory tests, an experienced clinician can usually accurately differentiate intrahepatic diseases from extrahepatic obstruction. O’Connor et al.

(26) reported that the accuracies in diagnosing extrahepatic obstruction by clinical evaluation, CT, US, and biliary scintigraphy were 84%, 81%, 78%, and 68%, respectively. This analysis suggests that clinical evaluation is comparable to noninvasive radiological tests in the detection of extrahepatic biliary obstruction. However, although the sensitivity of clinical examination in this study was 95%, the specificity was only 76%. Thus, nearly one-fourth of patients diagnosed as having extrahepatic obstructive disease will actually have hepatocellular disease. Therefore, although the history and physical examination are vital in evaluating the patient with jaundice, further tests are usually essential to diagnose the specific cause of jaundice.

Radiologic Evaluation The goals of the radiologic evaluation of the jaundiced patient include: (i) the confirmation of clinically suspected extrahepatic biliary obstruction by the demonstration of a dilated biliary tree, (ii) the identification of the cause and site of extrahepatic biliary obstruction, and (iii) the selection of patients in whom surgical or interventional radiologic or endoscopic treatment is indicated.

Abdominal Plain Films The likelihood of a plain abdominal X-ray film providing diagnostic information in the jaundiced patient is low. Abdominal X-ray may reveal gallstones, a calcified gallbladder wall, or the outline of a distended gallbladder. Approximately 15% to 20% of gallstones are radiopaque and can be visualized by radiography. However, cholangiography will still be necessary to determine whether common duct stones are present and to rule out other causes of jaundice such as hepatic parenchymal disease or an obstructing tumor.

Ultrasonography Transabdominal US is commonly performed as the initial screening procedure in the jaundiced patient. US is noninvasive, inexpensive, and widely available. Dilated intrahepatic bile ducts are a reliable sign of extrahepatic biliary obstruction, and most series report that US can detect dilatation of the intrahepatic or proximal extrahepatic bile ducts with at least an 80% accuracy rate (27,28). The normal extrahepatic bile duct diameter is less than 10 mm, and normal intrahepatic duct diameter is less than 4 mm. Dilated ducts are easily detectable by ultrasonography and often can be identified before the onset of clinical jaundice. Failure of ultrasonography to detect dilated ducts usually indicates an intrahepatic source of jaundice. However, the absence of ductal dilatation does not entirely rule out extrahepatic obstruction. In intermittent or partial obstruction, the intrahepatic biliary tree may not be dilated. Likewise, in long-standing obstruction, especially if secondary biliary fibrosis or cirrhosis is present, dilated ducts may not be seen.

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Table 3 Comparison Between US and CT in the Diagnosis of the Jaundiced Patient Criterion Identification of ductal dilatation Identification of cause of obstruction Patient selection Other factors

US

CT

80–85% 35–40% Thin patients, pregnancy, suspected choledocholithiasis Less expensive, no radiation

> 90% 40–80% Obese patients, bowel gas, suspected malignancy More expensive, radiation

Abbreviations: CT, computed tomography; US, ultrasound.

In these cases, where extrahepatic obstruction is suspected despite a negative US, cholangiography may be necessary. US can differentiate between extrahepatic obstruction and hepatocellular causes of jaundice in up to 96% of cases (29). Unfortunately, US is limited in its ability to identify the cause and exact location of an obstructing lesion. The anatomic level of the obstruction can be estimated in up to half of the patients. The cause of the obstruction is evident in a far lower proportion. This low yield in determining the cause of obstruction is caused by a failure to visualize the entire common bile duct, especially the distal third, and an inconsistency in the ability of US to detect common duct stones. The distal end of the bile duct is frequently obscured by duodenal or colonic gas. Studies indicate that US successfully identifies the presence of common bile duct stones in at most 70% of patients. Therefore, although US is a valuable initial step in the evaluation of the jaundiced patient, further diagnostic studies such as CT or cholangiography are usually necessary to identify the cause and exact location of the obstruction.

Computed Tomography CT can also be used to differentiate intrahepatic disease with nondilated ducts from extrahepatic obstruction. CT is more than 90% accurate in detecting the presence of ductal dilation (Table 3). This slightly higher success rate compared to US is because CT provides better definition of

anatomic structures and can use contrast media to enhance delineations (Fig. 4A). The accuracy of CT in determining the site and cause of obstruction is controversial, with rates ranging between 30% and 96% (27,30). This wide range of reported accuracy of CT in diagnosing the cause and anatomic location of an obstructing lesion results primarily from differences in the reported ability of CT to detect obstructing common bile duct stones. CT shows the common bile duct in cross-section instead of longitudinally, and small stones in the common bile duct may not be identified. In addition, CT scanning, especially with newer spiral techniques and three-dimensional reconstructions (Fig. 4B), can also provide highly accurate information regarding retroperitoneal extension, vascular invasion, and spread to the liver in malignant causes of biliary obstruction. In summary, CT and US have similar value in the diagnosis of biliary ductal dilation. CT may be the preferred initial screening procedure in obese patients, or in patients with suspected malignancy. Most authorities agree that CT is slightly more accurate than US in detecting the nature and anatomic level of obstruction. CT also has the advantage of routinely being able to visualize the pancreas and, therefore, is probably the screening procedure of choice if a periampullary tumor is suspected. On the other hand, US is less expensive, is more widely available, and does not

Figure 4 (A) CT of a patient demonstrating dilation primarily on the left, but also of the right hepatic duct. (B) Three-dimensional CT vascular reconstruction. Abbreviations: LGA, left gastric artery; CHA, common hepatic artery; GDA, gastroduodenal artery; PHA, proper hepatic artery; LHA, left hepatic artery; RHA, right hepatic artery; CT, computed tomography.

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expose the patient to radiation. Therefore, US should be performed initially if stone disease is suspected.

Magnetic Resonance Imaging Over the past decade, MRI has become a powerful noninvasive technique for the evaluation of obstructive jaundice. Magnetic resonance cholangiopancreatography (MRCP) is performed with T2-weighted sequences that depict the biliary tract and pancreatic ducts as a high-signal intensity or bright structure without the use of contrast material, instrumentation, or ionizing radiation (Fig. 5). MRCP is frequently used for the noninvasive diagnosis of common bile duct stones. Recent studies with state-of-the-art techniques yield sensitivities of 90% to 100%, specificities of 92% to 100%, positive predictive values of 93% to 100%, and negative predictive values of 96% to 100% in the setting of suspected choledocholithiasis (31). Patients found to have stones can then go on to have stone extraction through endoscopic retrograde cholangiopancreatography (ERCP) or surgery. MRCP can also be helpful in the diagnosis of biliary strictures. Lopera et al. (32) studied 29 patients with malignant hilar biliary strictures with MRCP and percutaneous transhepatic cholangiography (PTC), and showed that MRCP was able to accurately predict biliary tract morphology in 96% of patients. Early strictures that have not yet caused biliary dilatation may be missed by MRCP, because the ducts are not distended with contrast. Advantages of MRI and MRCP in the evaluation of the jaundiced patient include the ability to visualize the proximal and distal extension of tumor within the bile ducts and to evaluate the liver, pancreas, and associated blood vessels for local tumor invasion or metastasis.

Endoscopic Ultrasound EUS is a relatively new modality that is beginning to play a significant role in the evaluation of the jaundiced patient. EUS can diagnose the most common causes of extrahepatic

Figure 5 A magnetic resonance cholangiogram showing a nondilated biliary tree and a moderately dilated proximal pancreatic duct.

biliary obstruction such as choledocholithiasis and pancreaticobiliary malignancies (Fig. 6) with the same or with better accuracy than direct cholangiography or ERCP. EUS is a semi-invasive test that can be performed with a very low rate of complications (less than 0.1%) (33). Several authors have shown that EUS can be used for the diagnosis of common bile duct stones, with a sensitivity between 92% and 100% and a specificity between 95% and 100%. The negative predictive value for EUS is more than 97% (34). Therefore, when EUS is negative for common duct stones, ERCP or intraoperative cholangiography can be avoided. EUS is the most sensitive modality for the diagnosis of pancreatic carcinoma. The strengths of EUS techniques for pancreatic cancer are clarification of small lesions (< 2 cm) when CT findings are questionable or negative, detection of malignant lymphadenopathy, and the ability to perform EUS-guided fine needle aspiration (FNA) for definitive diagnosis and staging. The accuracy of EUS without FNA averages 85% for T stage and 70% for N stage disease. The combination of EUS and FNA has a sensitivity of 93% and a specificity of 100% for T stage and an accuracy of 88% for N stage (35).

Biliary Scintigraphy Technetium-99m labeled iminodiacetic acid derivatives (HIDA, DISIDA, and P1PIDA) are injected intravenously, rapidly extracted from the blood, and excreted into the bile. These radionuclide scans provide functional information about the liver’s ability to excrete radiolabelled substances into a nonobstructed biliary tree. Biliary scintigraphy is useful in the workup of neonatal jaundice, the detection of bile leaks, and the diagnosis of acute cholecystitis. Cholescintigraphy also provides a method to noninvasively evaluate the patency and function of biliary–enteric anastomoses and for studying the kinetics of bile flow in patients suspected of having disorders of biliary motility. Biliary scintigraphy plays only a limited role in the evaluation of a patient with jaundice. The technique has been shown to be useful in the diagnosis of complete common bile duct obstruction. Any appearance of the

Figure 6 Endoscopic ultrasound showing a mass in the head of the pancreas adjacent to the portal vein. Abbreviations: GB, gallbladder; PD, pancreatic duct; PV, portal vein; PANC, pancreas.

Chapter 23: The Jaundiced Patient

nucleotide in the gastrointestinal (GI) tract indicates patency of bile flow into the duodenum. However, other available noninvasive tests such as US, CT, and MRI have generally been shown to be more accurate and, therefore, are preferred.

Percutaneous Transhepatic Cholangiography Direct cholangiography is indicated if dilated bile ducts are visualized on US or CT, or if the clinical suspicion of extrahepatic biliary obstruction remains high despite a negative noninvasive imaging. Direct cholangiography may be performed percutaneously or endoscopically. PTC involves the cannulation of intrahepatic bile ducts with a thin, flexible Chiba needle under radiographic control, followed by the injection of contrast material to outline the bile ducts. PTC is successful in differentiating intrahepatic from extrahepatic obstruction in up to 96% of cases (36). Percutaneous cholangiography is highly accurate in defining the site and cause of extrahepatic obstruction (Fig. 7). PTC can define the site of an obstructing lesion in approximately 95% of patients, and the cause of the obstruction in nearly 90% of cases (37). Diagnostic cholangiography can also be combined with a series of therapeutic maneuvers such as the insertion of biliary stents or endoprostheses, percutaneous stone extraction, biliary dilation, and cholangioscopy. In addition, cholangiography provides an

Figure 7 A transhepatic cholangiogram showing a benign postoperative stricture (note multiple surgical clips near the bifurcation of the common hepatic duct).

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anatomical road map of the biliary tree that is useful during surgical procedures. The success rate of entering a bile duct during PTC increases with the experience of the radiologist. In patients with dilated intrahepatic ducts, PTC is nearly 100% successful. In patients with nondilated bile ducts, the success rate is approximately 70%. Although PTC is an invasive procedure, it has an acceptably low complication rate (38). The major complication rate of transhepatic cholangiography at most centers is less than 5%. The most commonly reported complications include hemorrhage (2.5%), sepsis (2.5%), bile peritonitis (1.8%), and pneumothorax or empyema (1.8%). The procedure-related mortality rate is approximately 0.5%. Even with more frequent passes of the needle (i.e., as many as 15 attempts), no increase in the complication rate has been reported. Thus, in the management of the jaundiced patient, the advantages of PTC are the ability to (i) establish a diagnosis, (ii) determine the site and cause of obstruction, and (iii) provide specific anatomic detail.

Endoscopic Retrograde Cholangiography Endoscopic retrograde cholangiography (ERC) is the other option for direct visualization of the biliary system (Fig. 8). The technique of ERC requires a skilled endoscopist

Figure 8 Endoscopic retrograde cholangiopancreatography showing a dilated extrahepatic biliary tree from a common duct stone and a normal pancreatic duct.

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Table 4 Comparison of Percutaneous Transhepatic Cholangiography and Endoscopic Retrograde Cholangiography Criterion Success rate Identification of cause of obstruction Complications Mortality Expense Skill required Patient selection

Transhepatic cholangiography > 90% with dilated ducts, 70% with nondilated ducts 90–100% 5% (range 3–10%) 0.2–0.9% Less Less Proximal lesions, altered gastroduodenal anatomy, failed endoscopic cholangiography

who is capable of cannulating the sphincter of Oddi with a side-viewing duodenoscope and then filling the biliary tree with contrast material in a retrograde fashion. The success rate of ERC is approximately 85% to 90% and improves with the experience of the endoscopist. ERC is able to define the site and cause of extrahepatic obstructive jaundice in 75% to 90% of patients (27,39). As in PTC, the complication and mortality rates of ERC are acceptably low. A complication rate of less than 3% and a mortality rate of less than 0.1% can be expected (40,41). The two major complications of the procedure are sepsis and acute pancreatitis. Prophylactic antibiotics should be administered before the procedure if biliary obstruction is suspected. In the jaundiced patient identified as having dilated ducts on US or CT, direct cholangiography by either PTC or ERC is the next procedure to be used (Table 4). PTC is less expensive, is more widely available, requires less expertise than ERC, and has a higher success rate if dilated ducts are present. In patients with total biliary obstruction, PTC provides the surgeon with information about the proximal biliary tree, whereas ERC frequently can only delineate the anatomy of the distal bile duct. PTC is the preferred procedure if therapeutic manipulations such as biliary drainage, balloon dilation, or endoprosthesis placement are necessary for hilar bile duct lesions. ERC may be difficult or impossible to perform in patients with ampullary stenosis or in those who have altered GI anatomy secondary to previous surgery. However, in several instances ERC is preferable to PTC. Percutaneous cholangiography is contraindicated in patients with an uncorrectable coagulopathy or with significant ascites. ERC allows for endoscopic visualization of the upper GI tract and ampullary region. Therefore, lesions can be biopsied and varices identified during the course of an ERC. Moreover, cannulation and injection with contrast of the pancreatic duct is often helpful in patients suspected of having pancreatic cancer. In patients with postcholecystectomy symptoms or sphincter of Oddi dyskinesia, ERC enables visualization and cannulation of the ampulla and manometric pressure recordings. As with PTC, therapeutic manipulations such as endoscopic sphincterotomy (ES) and stenting may be carried out in conjunction with ERC. In summary, the method of direct cholangiography that is chosen, either PTC or ERC, is individualized in each case. In certain situations such as totally obstructing proximal lesions, PTC may be the procedure of choice. On the other hand, when noninvasive studies suggest periampullary or pancreatic pathology, ERC provides additional useful information. The choice between these two procedures may ultimately be decided by the expertise of the radiologists and endoscopists at an individual institution.

Endoscopic cholangiography 80–90% with either dilated or nondilated ducts 75–90% 5% (range 2–7%) 0.1–0.2% More More Distal lesions, pancreatic pathology, coagulopathy, ascites, failed transhepatic cholangiography

Liver Biopsy The development of US and CT has made percutaneous liver biopsy unnecessary in most cases of jaundice caused by extrahepatic obstruction. However, numerous indications for liver biopsy remain. If clinical and laboratory data indicate intrahepatic cholestasis and if dilated bile ducts are not present on US or CT scans, a liver biopsy is usually the next test. Liver biopsy may be useful if diagnostic studies are negative or equivocal, or if parenchymal disease is suspected along with extrahepatic obstruction. A liver biopsy can aid in the diagnosis of intrahepatic cholestasis, storage diseases, unexplained hepatomegaly, and liver infections. Among the cholestatic causes of jaundice in which a liver biopsy may be helpful are hepatitis, cirrhosis, drug-induced cholestasis, primary biliary cirrhosis, and sclerosing cholangitis. Other indications for percutaneous liver biopsy are diseases such as amyloidosis, glycogen storage disease, and liver infections such as tuberculosis, histoplasmosis, and coccidiomycosis. Liver biopsy is a relatively safe procedure. In reviews of very large series of liver biopsies, mortality rates of 0.01% to 0.02% and a serious complication rate of 0.2% to 0.4% have been reported. The most frequent complications of liver biopsy are hemorrhage and bacteremia. This latter problem occurs most frequently in patients with chronic bile duct infections. Percutaneous liver biopsy is contraindicated if the patient is uncooperative or if an uncorrectable coagulation defect is present. If the patient has a prolonged PT or partial thromboplastin time (PTT) or a diminished platelet count, attempts should be made to correct these abnormalities with vitamin K, fresh frozen plasma, or specific component therapy. If the coagulopathy persists and liver biopsy is essential, laparoscopic or open liver biopsy must be considered.

PATIENT MANAGEMENT Once it has been determined that extrahepatic biliary obstruction is the cause of jaundice, a surgeon should become intimately involved in the management of the jaundiced patient. Extrahepatic biliary obstruction, or ‘‘surgical’’ jaundice, may be the result of either benign or malignant disease processes. Jaundice from benign lesions can be caused by congenital defects, by complications of gallstone disease, and from inflammatory or traumatic strictures of the bile duct. Malignant causes of extrahepatic biliary obstruction include cholangiocarcinomas, gallbladder cancers, and cancers of the head of the pancreas, ampulla, or duodenum. Prior to a discussion of the management of common causes of ‘‘surgical’’ jaundice, important issues in the general management of the jaundiced patient will be described.

Chapter 23: The Jaundiced Patient

Assessment of Risk In the past, the only option for the relief of obstructive jaundice had been operative. However, with the development of therapeutic techniques such as percutaneous and endoscopic stenting, balloon dilatation, and ES, many nonoperative options for the relief of obstructive jaundice are now available. The surgeon must determine the safest and most efficacious form of therapy for each individual patient, as well as adequately prepare them for surgery or nonoperative therapeutic interventions. In an effort to determine which patients undergoing biliary surgery were at greatest risk, Pitt et al. (42) analyzed 15 clinical and laboratory parameters in 155 consecutive patients. These authors found that eight factors (advanced age, malignant obstruction, anemia, leukocytosis, hyperbilirubinemia, increased alkaline phosphatase, increased creatinine, and hypoalbuminemia) were associated with an increased risk of death following surgery. Subsequent analyses by Hunt (18), Blarney et al. (43), and Dixon et al. (44) have also confirmed these findings. In these analyses the most consistent predictors of outcome were shown to be the presence of malignancy, elevated serum bilirubin, hypoalbuminemia, and increased serum creatinine. In a 1987 report, Little (45) defined a mortality index that employs albumin, creatinine, and a cholangitis score (Table 5) to predict which patients with jaundice are at increased risk. In a prospective study of 40 patients, Little’s mortality index was 100% accurate in predicting outcome. Thus, the assessment of nutritional status, renal function, and sepsis may be the most important factors to consider when attempting to determine who should or should not be an operative candidate.

Management Issues Patients with obstructive jaundice and those with hepatocellular disease severe enough to cause jaundice are prone to develop many secondary problems. Jaundiced patients are at increased risk for the development of renal failure, GI bleeding, infections, and wound complications (see section ‘‘Pathophysiology of Jaundice’’). Cardiac, pulmonary, and renal function must be considered in every patient undergoing major abdominal surgery. In addition, special attention must be focused on the jaundiced patient’s nutritional status, coagulability, immune function, and presence or absence of biliary sepsis. Patients with chronic liver disease and cirrhosis may also develop ascites and encephalopathy, which may require specific treatment.

Cardiopulmonary In assessing cardiopulmonary status, the patient’s age, history of recent myocardial infarction, presence of congestive heart failure, significant valvular aortic stenosis, or a disturbance of normal cardiac rhythm have all been Table 5 Little’s Mortality Index Mortality index ¼ 0.0016
serum creatinine (mM/L)  0.0227
albumin (g/L) þ 0.0641
cholangitis score þ 0.6935 Cholangitis score: 0 if afebrile 1 if temperature 37.5 C without rigors 3 if > 37.5 C with rigors, RUQ pain 4 if fever with shock and/or mental changes (obtundation) An index of 0.4 or greater is associated with a high risk of death. Abbreviation: RUQ, right upper quadrant.

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correlated with increased operative risk (46). In addition, patients with severe pulmonary disease may not be candidates for extensive abdominal surgery.

Renal Jaundiced patients, especially those with cirrhosis and cholangitis, are at increased risk of developing renal insufficiency. The maintenance of adequate blood volume and the correction of dehydration are extremely important if renal complications are to be avoided. However, fluid management can be quite complex in jaundiced patients. These patients may benefit from invasive hemodynamic monitoring with central venous catheters and, in some cases, pulmonary artery catheters to assist in assessing intravascular volume. Certain oral bile salts have been shown to be efficacious in preventing the development of postoperative renal dysfunction. In a study by Evans et al. (47), two of nine jaundiced patients not receiving oral sodium taurocholate before surgery developed acute renal failure. Creatinine clearance in these patients decreased from a mean value of 85 to 55 mL/min. In contrast, none of the nine jaundiced patients treated before surgery with oral bile salts developed renal failure, with the mean creatinine clearance increasing from 79 to 99 mL/min. In a study by Cahill (17), 54% of 24 jaundiced patients not given oral bile salts before surgery were found to have systemic endotoxemia, which was associated with renal impairment in two-thirds of the cases. In comparison, none of eight jaundiced patients given 500 mg of sodium deoxycholate every eight hours for 48 hours before surgery had portal or systemic endotoxemia. Moreover, none of these eight patients had evidence of renal impairment.

Nutrition Malnutrition is a significant risk factor for surgery in the setting of obstructive jaundice. Halliday et al. (48) noted that patients who died in the postoperative period following surgery for obstructive jaundice had a significant reduction in body weight, mid-arm circumference, total body potassium, and reactivity to skin test antigens. In a study from Italy (49), enteral hyperalimentation was found to significantly decrease operative morbidity and mortality in a group of patients treated with 20 days of preoperative percutaneous biliary drainage. Although most patients with benign biliary problems are adequately nourished, various degrees of malnutrition are frequently present in patients with malignant obstruction. Therefore, patients with malignant obstructive jaundice should be evaluated for evidence of malnutrition and nutritional support instituted if necessary.

Coagulation Patients with obstructive jaundice, cholangitis, or cirrhosis are all prone to excessive intraoperative bleeding. The most common clotting defect in patients with obstructive jaundice is prolongation of the PT, which is usually reversible by the administration of parenteral vitamin K. Patients with severe jaundice and/or cholangitis may also develop DIC, which may require infusion of platelets and fresh frozen plasma. Reversal of DIC also requires control of the underlying sepsis, which usually includes biliary drainage and systemic antibiotics. In cirrhotic patients, clotting abnormalities may be more complicated and include (i) thrombocytopenia secondary to hypersplenism, (ii) prolongation of PTand PTT, and (iii) fibrinolysis. Vitamin K should be administered if the PT is prolonged. If no effect is seen and/or the PTT is also prolonged, fresh

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frozen plasma should be given. Thrombocytopenia can usually be managed by intraoperative platelet infusions. If the patient has a shortened clot lysis time and hypofibrinogenemia, epsilonaminocaproic acid may be indicated.

Pruritus Pruritus is often a distressing problem in the jaundiced patient. The exact cause of pruritus remains obscure, but increased bile salts, histamines, and central nervous system opiate receptors have been implicated (50). In some patients, relief from itching can be obtained by bile salt–binding agents such as cholestyramine. Various sedatives and antihistamines can also provide relief of itching in jaundiced patients. However, relief of biliary obstruction remains the most effective method for managing this problem.

Cholangitis Biliary sepsis has also been identified as a major risk factor in the jaundiced patient. Cholangitis occurs when there is partial or complete obstruction of the bile duct, resulting in increased intraluminal pressure, and infected bile behind the obstruction. Patients with cholangitis present with right upper quadrant (RUQ) abdominal pain, fever, and jaundice (Charcot’s triad). Patients with ‘‘toxic’’ cholangitis, Charcot’s triad plus shock and mental confusion (Reynold’s pentad), have significant mortality with appropriate antibiotic therapy alone and, therefore, require emergent biliary decompression. Gigot et al. (51) identified seven prognostic factors that are indications for urgent biliary decompression. These factors included: (i) acute renal failure, (ii) liver abscesses, (iii) cirrhosis, (iv) high malignant stricture, (v) PTC, (vi) female gender, and (vii) advanced age. However, emergent surgical treatment is associated with significant morbidity and mortality. Therefore, both percutaneous and endoscopic biliary drainage have been proposed as effective therapy for the 5% to 10% of patients with cholangitis who are unresponsive to conservative therapy. Lai et al. (52) have shown in a series of 82 patients with severe acute cholangitis that endoscopic drainage is associated with a lower morbidity, 34% versus 66%, and mortality, 10% versus 32%, than operative drainage.

Antibiotic Coverage Because of the depressed immune system that accompanies jaundice, adequate antibiotic coverage needs to be provided for the treatment of cholangitis and prior to any manipulation of the biliary tree. Under normal conditions, bile, the biliary tree, and the liver are sterile. However, biliary stasis, obstruction, biliary–enteric anastomoses, and foreign bodies predispose the biliary system to infection. The organisms most commonly isolated from the biliary tree include Escherichia coli, Klebsiella pneumonia, Enterococcus, and, with increasing frequency, the anaerobe Bacteroides fragilis. Approximately two-thirds of patients with bactobilia will have gram-negative aerobes, and 25% to 30% will have enterococcus in their bile. Anaerobes are found in the bile of older patients, those with cholangitis, and those with complex biliary problems and indwelling tubes (53). Four factors must be considered when choosing antibiotics for the jaundiced patient. These properties include: (i) the antibacterial spectrum of the antibiotic, (ii) serum and liver concentrations, (iii) biliary excretion, and (iv) toxicity. In acute cholangitis, gram-negative aerobes play a major role and are well covered by the second or third generation

cephalosporins, aminoglycosides, ureidopenicillins, carbapenems, and the fluoroquinolones. Ureidopenicillins, such as piperacillin, offer the advantage of gram-positive coverage, including enterococci, and of anaerobic coverage. When combined with a beta-lactamase inhibitor such as tazobactam, piperacillin offers extended and improved coverage against organisms with acquired resistance. Most fluoroquinolones like ciprofloxacin do not cover the anaerobes, and should be used in combination with an agent with anaerobic coverage (i.e., metronidazole). Pseudomonas has been recovered with increased frequency in patients with cholangitis, particularly those with chronic indwelling stents, and should be covered in severely ill patients. Both mezlocillin and piperacillin have performed as well as combination therapy including an aminoglycoside in prospective randomized trials in patients with cholangitis. In patients with biliary obstruction and cholangitis, serum levels of antibiotics are more important than biliary excretion levels. The biliary excretion of antibiotics is significantly reduced in the setting of biliary obstruction, making it difficult to achieve high bile levels of antibiotics in the situations where they are most needed. Therefore, antibacterial specificity and toxicity should be the most important factors to consider in the selection of antibiotic therapy. Prophylactic antibiotics should be administered in all patients undergoing operative or nonoperative manipulations of the biliary tree including cholangiography and sphincterotomy. Meijer et al. (54) published a meta-analysis of 42 controlled clinical trials of antibiotic prophylaxis in biliary tract surgery. They demonstrated that patients undergoing prophylactic antibiotic therapy had a 9% lower incidence of infection. The authors also concluded that second and third generation cephalosporins were no more effective in preventing infection than first generation cephalosporins. Therefore, in uncomplicated cases, a broad spectrum first generation cephalosporin usually provides adequate coverage for prophylaxis.

Preoperative Drainage The preoperative relief of jaundice and the reversal of its systemic effects by either endoscopic or transhepatic biliary decompression has been proposed as a method to decrease the risk of surgery in jaundiced patients. However, several prospective randomized studies have shown that the routine use of preoperative biliary drainage does not reduce operative morbidity or mortality in patients with obstructive jaundice. In addition, a recent meta-analysis also concluded that preoperative biliary drainage increased rather than decreased overall complications (from surgery and the drainage procedure), and provided no benefit in terms of reduced mortality or decreased hospital stay (55). In fact, several studies have documented a higher incidence of infectious complications (wound infection and pancreatic fistula) and even mortality in patients undergoing pancreatic or biliary tract resection after preoperative biliary decompression (55,56). Lai et al. (57) have also documented similar results when endoscopic drainage has been used to decompress the biliary tree preoperatively. Several other studies (58–60) have confirmed these findings (Table 6). Moreover, preoperative biliary tract drainage has been shown to significantly lengthen the hospital stay for these patients. Thus, although retrospective analyses suggested that preoperative drainage might be beneficial, prospective, randomized studies have not supported this finding. A criticism of these prospective studies is that the duration of preoperative drainage (10–18 days) may not have

Chapter 23: The Jaundiced Patient

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Table 6 Results of Randomized Trials Comparing Preoperative Biliary Drainage Postoperative mortality (%) Authors Hatfield et al. (58) McPherson et al. (59) Pitt et al. (60) Lai et al. (57)

No. of patients

Type of drainage

No drainage

Preoperative drainage

55 65 75 85

Transhepatic Transhepatic Transhepatic Endoscopic

15 19 5 14

14 32 8 15

been long enough to reverse the multiple metabolic and immunologic abnormalities associated with severe obstructive jaundice. Both animal and human studies demonstrate that the recovery of various metabolic and immune functions require at least six weeks after the relief of biliary obstruction (61–64). Similarly, animal studies strongly suggest that return of bile to the intestinal tract has significant advantages over external biliary drainage (65). Although the data suggest that preoperative biliary drainage may not be of any benefit in the routine patient, this maneuver may have some value in selected patients with advanced malnutrition, biliary sepsis, and hilar malignancies requiring liver resection. Preoperatively placed catheters are also of value in the operating room during difficult biliary dissections as well as in aiding in the placement of long-term transhepatic stents.

BENIGN DISEASE Choledocholithiasis The most common benign cause of obstructive jaundice is choledocholithiasis. The incidence of stones in the bile ducts of patients undergoing laparoscopic cholecystectomy is approximately 5% to 10%, and the incidence of retained bile duct stones following cholecystectomy and common bile duct exploration (CBDE) has been 5% to 10%. The most common symptoms of choledocholithiasis are pain, jaundice, and fever. Biliary colic results from intermittent obstruction of the cystic or common duct. With choledocholithiasis, serum bilirubin levels usually range from 2 to 8 mg/dL, with a mean of approximately 5 mg/dL. Fever and chills result from the cholangitis that often accompanies choledocholithiasis. Positive bile cultures are found in almost 90% of patients with primary bile duct stones. Patients with common duct stones require treatment to prevent the complications of choledocholithiasis. These complications include cholangitis, liver abscesses, secondary biliary cirrhosis, and pancreatitis. Prior to the development of endoscopic and laparoscopic techniques, open cholecystectomy with CBDE was the treatment of choice for choledocholithiasis. However, in the era of laparoscopic cholecystectomy and ES, the management of choledocholithiasis has become more controversial. The options for treatment now include: (i) preoperative ERCP and sphincterotomy followed by laparoscopic cholecystectomy, (ii) open cholecystectomy and open CBDE, (iii) laparoscopic cholecystectomy with laparoscopic CBDE, or (iv) laparoscopic cholecystectomy and postoperative ERCP and sphincterotomy. ES is accepted as a valuable technique in the management of choledocholithiasis in patients who previously have undergone cholecystectomy. ES is a relatively safe and effective procedure for the removal of common duct stones and can achieve a clearance rate of almost 90% (66). In recent series, procedure-related mortality occurs in less than 1%

of patients, with major postprocedure morbidity averaging 8% (Table 7). The long-term complication rate is 13% and includes sphincter stenosis and recurrent stones (67). Until recently, the option for the management of choledocholithiasis discovered intraoperatively was either postoperative ERCP or open bile duct exploration. With the development of new equipment and techniques for laparoscopic common duct exploration, open surgery and sphincterotomy may be avoidable. Laparoscopic duct exploration can be accomplished by intubating the cystic duct or by creating a choledochotomy. In the transcystic duct approach, the cystic duct is dilated, and common duct stones can be retrieved with a basket under fluoroscopic guidance or direct vision using a flexible choledochoscope. Laparoscopic choledochotomy is technically more challenging, but has the advantage of being able to extract larger impacted stones and to retrieve stones from the common hepatic duct. The success rate for laparoscopic CBDE is approximately 85%. In addition, prospective randomized trial has shown that laparoscopic CBDE at the time of laparoscopic cholecystectomy is as effective as ERC at achieving stone clearance (68). The procedure-related complication rates are similar with both approaches, but the laparoscopic bile duct exploration is associated with a significantly shorter length of stay (Table 8). As surgeons gain more experience with laparoscopic techniques and appropriate equipment becomes available, more patients may be able to undergo laparoscopic bile duct exploration for the management of choledocholithiasis.

Bile Duct Strictures Benign bile duct strictures can be caused by pancreatitis, primary sclerosing cholangitis, acute cholangitis, autoimmune disorders, or following either blunt or penetrating abdominal trauma. However, the vast majority of benign strictures follow iatrogenic bile duct injury, most commonly during laparoscopic cholecystectomy. The majority Table 7 Mortality, Morbidity, and Late Complications of Endoscopic Sphincterotomy Complications Mortality Major morbidity Hemorrhage Pancreatitis Cholangitis/impaction Duodenal perforation Emergency surgery Unsuccessful procedure Late complications Gallbladder problems Recurrent stones Sphincter stenosis

Mean (%)

Range (%)

1.1 8.2 2.8 2.7 1.8 1 1.5 9.8

0.4–1.7 4.4–8.7 1.8–5 0.6–3.3 0.8–2.3 0.2–1.5 0.4–2.4 3.4–14

14.9 5.9 3

14.7–15.2 2.8–20.5 0.8–3.7

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Table 8 Laparoscopic Bile Duct Exploration vs. Postoperative ERC for Bile Duct Stones

Lap CBDE Post op ERC þ ES

N

Primary duct clearance (%)

Secondary duct clearance (%)

Morbidity (%)

Mean hospital length of stay (days)

40 40

75 75

100 93

18 15

1.0 3.5

Abbreviations: CBDE, common bile duct exploration; ERC þ ES, endoscopic retrograde cholangiography plus endoscopic sphincterotomy. Source: From Ref. 68.

of injuries are recognized intraoperatively or during the early postoperative period, and with appropriate management, the long-term results are acceptable. However, with unrecognized or inappropriately managed biliary strictures, recurrent cholangitis, secondary biliary cirrhosis, and portal hypertension may eventually develop. The exact incidence of bile duct injury during open cholecystectomy has been estimated at 0.1% to 0.2%. With the advent of laparoscopic cholecystectomy, this rate has increased to approximately 0.3% to 0.5%. Factors such as acute inflammation, anatomical variants, excessive bleeding, obesity, lack of adequate assistance, and the surgeon’s experience have been associated with bile duct injuries during laparoscopic cholecystectomy. Bile duct strictures can also occur at sites of previous biliary–enteric anastomoses. Ischemia of the anastomosis from excessive dissection of the duct prior to anastomosis is a likely cause of these strictures. The clinical presentation of postoperative strictures is variable, with nearly 80% being identified within one year of the initial operation. Patients developing strictures early after cholecystectomy usually present either with progressive elevations in serum bilirubin and alkaline phosphatase or with bile leaks, whereas patients presenting months or years after surgery often present with cholangitis. Excessive pain in the early postoperative period may also be an indication that bile is leaking. The diagnostic evaluation in the jaundiced patient with a suspected bile duct injury begins with an abdominal CT scan or US. This evaluation will demonstrate the presence of intrahepatic and extrahepatic ductal dilation. These studies also can provide some anatomic information about the level of the injury, whether the ductal system to one segment or lobe is affected or whether the entire intrahepatic ductal system is involved. In patients with intrahepatic ductal dilation from a biliary stricture, PTC and placement of a transhepatic stent will decompress the biliary tree, relieve the jaundice, and define the proximal extent of the injury, which is critical in determining the appropriate treatment. Prior to the definitive management of benign bile duct strictures, adequate control of biliary sepsis by either endoscopic or transhepatic biliary drainage and optimal nutritional status are important. Once these goals have been accomplished, three options for the management of the stricture include: (i) surgical excision with reconstruction, (ii) percutaneous balloon dilatation, and (iii) endoscopic dilatation and stenting. The goal of surgical therapy is to re-establish the flow of bile from the liver to the proximal intestine and to prevent the formation of a recurrent stricture. These goals are best achieved by the creation of a Roux-en-Y biliary–enteric anastomosis (Fig. 9). Principles to be observed in the surgical repair of bile duct strictures include complete resection of the stricture, trimming back of the proximal bile duct to expose healthy biliary mucosa, and the creation of a

tension free mucosa-to-mucosa anastomosis to a 40 to 60 cm Roux-en-Y jejunal limb (69). Acceptable results are achieved in the majority of patients undergoing operative repair of bile duct stricture or injury. The operative mortality associated with repair of a bile duct injury has been less than 1% in several large series, and common complications have included cholangitis, subhepatic or subphrenic abscess, bile leak, and hemobilia. Long-term follow-up is necessary to fully evaluate the results of either operative or nonoperative bile duct injury management. Restenosis of a biliary–enteric anastomosis can manifest itself many years following operative repair. Two-thirds of recurrences, however, will become symptomatic within two years after repair. In one large series, 91% of patients were free of jaundice and cholangitis after undergoing operative repair of a laparoscopic bile duct injury (70). Several factors may influence the eventual success of biliary reconstruction for bile duct injuries. More proximal strictures (at or proximal to the hepatic duct bifurcation) have a lower success rate, when compared with distal strictures (distal to the hepatic duct bifurcation). Percutaneous balloon dilation and stenting also has a significantly lower success rate (64%) than operative repair.

Figure 9 Postoperative cholangiogram showing bilateral Roux-en-Y hepaticojejunostomies in a patient with a bile duct injury secondary to laparoscopic cholecystectomy.

Chapter 23: The Jaundiced Patient

Nonoperative options for the management of a benign bile duct strictures are percutaneous and endoscopic balloon dilatation and stenting. Both techniques involve intubating the biliary system, from above in the case of percutaneous dilatation and from below with endoscopic dilatation, crossing the stricture with a guidewire under fluoroscopic guidance, inflating an angioplasty-type balloon to dilate the stricture, and then stenting the lesion. With both techniques, patients often require multiple stricture dilatations. Results for both procedures are similar with success rates ranging between 55% to 87% for percutaneous dilatations, and 53% to 96% for endoscopic dilatation (71). The complication rate for transhepatic dilatation ranges between 20% and 30% and includes cholangitis, bleeding, and bile leaks. The mortality rate is 1%. The complications associated with endoscopic balloon dilatation are similar to that reported for ES, with cholangitis, pancreatitis, bleeding, and perforation of the duodenum occurring in 8% to 10% of patients. When analyzing data on the efficacy of nonoperative stricture management, the length of follow-up is very important. Surgical experience has demonstrated that recurrence of strictures may occur many years after treatment. In a report from the Johns Hopkins Hospital, Pitt et al. (72) compared the results of operative stricture repair with Roux-en-Y hepaticojejunostomy and long-term stenting in 25 patients, with percutaneous balloon dilatation in 20 patients. Eighty-eight percent of patients managed surgically had a successful outcome at 57 months, whereas only 55% of patients managed with dilatation had a good outcome at 59 months. Therefore, the authors recommended that surgical therapy should be offered to young, healthy patients, and that nonoperative therapy be reserved for patients who have a prohibitive operative risk or have a short life expectancy.

MALIGNANT DISEASE Periampullary Carcinoma Periampullary cancers are a group of malignant neoplasms that cause jaundice by obstructing the distal common bile duct. Adenocarcinoma of the head of the pancreas accounts for 50% to 60% of all periampullary cancers, whereas carcinoma of the ampulla of Vater (20–30%), distal bile duct (10–15%), and duodenum (10%) account for the rest. Patients usually present with jaundice, acholic stools, dark urine, pruritus, and weight loss. The presence of a palpable nontender gallbladder in a jaundiced patient suggests neoplastic obstruction of the distal common bile duct. Serum bilirubin levels are usually higher than those seen with benign biliary obstruction and may exceed 20 mg/dL. The best available tumor markers are carcinoembryonic antigen and carbohydrate antigen (CA) 19–9. A CA-19–9 value greater than 200 in the absence of jaundice is 95% accurate in predicting malignancy. CA-19–9 levels should be obtained preoperatively and followed postoperatively as an indication of recurrent tumor. Postresection increase in these tumor markers often precede the radiographic demonstration of recurrent malignancy. Patients who are suspected of having a periampullary neoplasm should undergo thin section dynamic contrast–enhanced CT scanning. The CT scan can document dilated intrahepatic and extrahepatic bile ducts and localize a periampullary mass. The presence of a dilated distal pancreatic duct in addition to a dilated distal bile duct suggests pancreatic cancer. The CT scan can also demon-

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strate local tumor extension, involvement of contiguous structures, distant metastasis, or invasion of the mesenteric and portal vessels. MRI offers no advantage over CT in the diagnoses of periampullary cancers. However, EUS can play a role in the preoperative staging of periampullary neoplasms. The main uses for EUS are for the detection of small pancreatic lesions (< 2 cm) and for detecting lymph node and vascular involvement. EUS is not effective in assessing metastatic disease to the liver. In patients that require a tissue diagnosis (poor operative candidates or patients undergoing neoadjuvant therapy), EUS-guided FNA can be used to acquire tissue samples for cytologic analysis. Traditionally, the next step in the evaluation of the jaundiced patient has been ERCP. The endoscopic approach allows for the visualization of the duodenum and ampulla, and biopsies can be performed if necessary. In addition, ERCP allows for direct imaging of the pancreatic duct. The sensitivity of ERCP for the diagnosis of pancreatic cancer approaches 90%. The finding of a long irregular stricture in an otherwise normal pancreatic duct is highly suggestive of a pancreatic cancer. Although ERCP is reliable in confirming the clinical suspicion of pancreatic cancer, it should not be used routinely. Diagnostic ERCP should be reserved for patients with presumed periampullary cancer and obstructive jaundice in whom no mass is demonstrated on CT scanning, the symptomatic but nonjaundiced patient without an obvious pancreatic mass, or the patient with chronic pancreatitis in whom the development of a pancreatic mass is suspected based on clinical determination or the development of jaundice. Routine preoperative biliary drainage should be avoided, and its use limited to patients with biliary sepsis secondary to cholangitis and in patients with major nutritional deficiency states and high-grade biliary obstructions. As mentioned earlier, several randomized prospective trials have shown that routine preoperative biliary decompression does not reduce operative mortality and may prolong hospital stay. Surgical resection offers the only chance for long-term survival from periampullary malignancies. The operative management of periampullary cancer consists of two phases: first, assessing tumor resectability and then, if the tumor is resectable, completing a pancreaticoduodenectomy. After opening the abdomen, a careful search for tumor outside the limits of a pancreaticoduodenal resection should be carried out. The liver, omentum, and peritoneal surfaces are inspected and palpated, and suspicious lesions biopsied and submitted for frozen section analysis. Regional lymph nodes are next evaluated for the presence of tumor involvement. Tumor present in the periaortic lymph nodes of the celiac axis indicates that the tumor is beyond the limits of normal resection. However, the presence of tumor-bearing lymph nodes that normally would be incorporated within the resection specimen do not constitute a contraindication to resection. Once distant metastases have been excluded, an assessment is made as to whether the primary tumor is resectable. Local factors that preclude pancreaticoduodenal resection include retroperitoneal extension of the tumor to involve the inferior vena cava or aorta, or direct involvement or encasement of the superior mesenteric artery, superior mesenteric vein, or portal vein. If no contraindication to resection is present, either a pylorus-preserving pancreaticoduodenectomy or a classic Whipple procedure can be performed. Palliative surgery for periampullary cancer is appropriate in patients with unresectable disease discovered at

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Nonoperative methods of palliation should be considered in patients in whom preoperative staging suggests distant metastatic disease or a locally unresectable tumor, patients who are not candidates for operative intervention, or in patients not expected to survive for more than three months. Long-term survival for periampullary cancers is dependent on the type of cancer, stage, and resection status. Data from The Johns Hopkins Hospital in 242 patients undergoing pancreaticoduodenectomy for periampullary carcinoma shows a five-year actual survival of 15% for pancreatic primaries, 27% for distal bile duct primaries, 39% for ampulla primaries, and 59% for duodenal primaries (81). Patients with unresected tumors have an expected survival between six and nine months.

exploration or in good-risk patients in whom tumor-related symptoms are poorly alleviated through nonoperative means. Palliative surgery is designed to (i) relieve biliary obstruction, (ii) prevent gastric outlet obstruction, and (iii) palliate tumor-associated pain. Recent studies (73,74) have shown that surgical palliation of jaundice with either a choledocho- or hepaticojejunostomy can be accomplished safely, with a mortality rate less than 3%, an overall morbidity rate of 30% to 40%, and a recurrent jaundice rate of 3%. In patients without symptoms of gastric outlet obstruction, a debate has existed as to whether or not to perform a prophylactic gastric bypass at the time of biliary bypass. Surgeons that do not perform prophylactic bypass feel that it needlessly increases postoperative length of stay and can be associated with delayed gastric emptying and increased morbidity and mortality. However, data from a recent prospective randomized trial of prophylactic gastrojejunostomy in patients with unresectable cancer does not support this view (75). In this study, 44 patients were randomized to a gastrojejunostomy, and 43 did not undergo gastric bypass. No mortality occurred in either group. In addition, no differences existed in either the complication rate or the postoperative length of stay. However, 19% of the nonbypassed patients developed late duodenal obstruction (P < 0.05). Therefore, prophylactic gastrojejunostomy should be performed in patients undergoing surgical palliation for unresectable periampullary carcinoma. The management of pain in patients dying of carcinoma of the pancreas is one of the most important aspects of their care. In a prospective randomized trial, Lillemoe et al. (76) have demonstrated that the intraoperative injection of 50% alcohol into the celiac plexus at the time of surgery can significantly reduce and prevent the development of pain in patients with unresectable cancer. In patients with malignant obstruction of the biliary tract, the placement of endoscopic or percutaneous biliary stents have been proposed as alternatives to surgical palliation. Four prospective randomized trials comparing nonoperative biliary stenting with surgical biliary bypass for malignant obstructive jaundice have been published (77–80). As Table 9 demonstrates, both operative and nonoperative techniques are equally effective in relieving jaundice. Nonoperative therapy, however, was associated with a lower complication rate and shorter initial hospital stays. Advocates of surgical palliation criticize these studies on two counts. First, the 30-day hospital mortality rate for the surgical arms of these studies was high, ranging from 14% to 24%, compared to more recent series, with mortality rates of 2% to 8%. The second reason that surgical palliation is favored by some authors is that nonoperative palliation is frequently associated with the late complications of recurrent jaundice and gastric-outlet obstruction.

Cholangiocarcinoma Cholangiocarcinoma can occur in any portion of the biliary tree. A clinically useful classification system of cholangiocarcinoma divides them into intrahepatic, perihilar, distal, and diffuse types (82). The intrahepatic tumors are managed similarly to primary liver tumors, and the distal cholangiocarcinomas are managed with pancreaticoduodenectomy. The perihilar, or Klatskin, tumors comprise 60% to 80% of all cholangiocarcinomas and are the most difficult to manage. Over 90% of cholangiocarcinomas present with jaundice. Serum bilirubin in cases of malignant jaundice can be markedly elevated, attaining levels between 20 and 30 mg/dL. The radiological evaluation of patients with cholangiocarcinoma should delineate the overall extent of the tumor including involvement of the bile ducts, liver, portal vessels, and distant metastases. The initial radiographic studies consist of either abdominal US or CT scanning. Intrahepatic cholangiocarcinomas are easily visualized on CT scans; however, perihilar and distal tumors are often difficult to visualize on US and standard CT scan. A hilar cholangiocarcinoma will give a picture of a dilated intrahepatic biliary tree and a normal or collapsed gallbladder and extrahepatic biliary tree. Distal tumors will lead to dilation of the gallbladder and both the intra- and extrahepatic biliary tree. After documentation of bile duct dilation, biliary anatomy has been traditionally defined cholangiographically through either the percutaneous transhepatic or the endoscopic retrograde routes. The most proximal extent of the tumor is the most important feature in determining resectability in patients with perihilar tumors, and the percutaneous route is favored in these patients because it defines the proximal extent of tumor involvement most reliably. Recently, magnetic resonance cholangiography (MRC) has documented diagnostic accuracy comparable to percutaneous and endoscopic cholangiography. Curative treatment of patients with cholangiocarcinoma is only possible with complete resection. The

Table 9 Results of Operative vs. Nonoperative Palliation of Malignant Obstructive Jaundice Jaundice relief (%) Author Bornman et al. (77) Shepard et al. (78) Andersen et al. (79) Smith et al. (80) 

Mortality (%)

Complications (%)

Recurrent jaundice (%)

Late duodenal obstruction (%)

N

Stent

Surg

Stent

Surg

Stent

Surg

Stent

Surg

Stent

Surg

Stent

50 48 50 201

Transhepatic Endoscopic Endoscopic Endoscopic

76 92 88 91

84 82 96 92

20 20 24 14

8 9 20 3

32 56 20 29

28 30 36 11

16 0 – 2

38 30 – 36

0 4 0 7

14 9 0 17

P 50% surface area or expanding; ruptured subcapsular, or parenchymal hematoma Intraparenchymal hematoma > 5 cm or expanding > 3 cm parenchymal depth or involving trabecular vessels Laceration involving segmental or hilar vessels producing major devascularization ( > 25% of spleen) Completely shattered spleen Hilar vascular injury, which devascularizes spleen

Source: From Ref. 116.

Angiography Although angiography is not routinely used in the management of splenic injury, it remains both a diagnostic and an interventional adjunct tool available to the trauma surgeon. It may be performed when a major vessel injury is suspected on CT scan or ultrasound or in order to localize an ongoing bleed. In a 1995-study, Sclafani et al. suggested that arteriography could help in a more ‘‘clever’’ choice of plan of management. Their study found a good correlation between the absence of contrast material extravasation (‘‘contrast blush’’) on angiography of the spleen and the success of nonsurgical treatment (113,118). Extravasation, whether discovered by CT scan or angiography, is thus an indication for surgical approach or for selective embolization in stable patients. This latter procedure, which can be done with coils or gelfoam pledgets, has been successful in the treatment of more than 75% of patients with contrast blush in the spleen, thus increasing the number of patients managed nonoperatively (113,118,119). The percentage of success of nonoperative management can be even higher if splenic artery pseudoaneurysms are identified and embolized during the same procedure (119).

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the extent of organ disruption, and (iii) the excessive appearance in medical literature of the term ‘‘nontherapeutic laparotomy’’ where laparotomies performed on the basis of clinical presentation and peritoneal lavage revealed only minimal splenic injury that could not justify its removal. Nonoperative management of splenic injury is now the standard of care in the pediatric population and is reported to be successful in about 97% of patients (120). The success of nonoperative therapy with children was extended to the adult population with more than 65% of adult trauma cases successfully managed without laparotomy (120,121). This approach was of great importance in decreasing the morbidity and mortality associated with nontherapeutic laparotomies and the potential devastating effects of splenectomy on the immune system. Support for the nonoperative choice has increased significantly in the last 10 to 15 years, and the choice of adult trauma patients that will be managed nonsurgically became more liberal. In fact, the question today in the practice of surgical trauma of the spleen is not whether nonoperative choice is successful but whether the right patient is being selected. An impressive number of articles regarding indications and contraindications for nonoperative management exists and presents conflicting data; thus, the surgeon must be critical in selecting guidelines for the management of splenic trauma. According to the practice guidelines of the EAST, ‘‘there are class II and mostly class III data to suggest that nonoperative management of blunt hepatic and/or splenic injuries in a hemodynamically stable patient is reasonable’’ (113). With current literature, hemodynamic instability, tentatively defined as systolic blood pressure below 85 mmHg or pulse rate above 125 beats per minute, is the most reliable predictor of the failure of nonsurgical approach. Extravasation of contrast material on CT scanning (contrast blush) suggests active hemorrhage and is a strong indication for operative choice (Fig. 6) (113,122). Those patients who were treated conservatively despite this finding were consistently at a greater risk for failure of their nonsurgical management (115,123). Although higher grades of splenic injuries (like grade IV or V injury on the AAST Organ Injury Scale)(Fig. 7) or the

Management Nonoperative Approach Management of splenic injury has evolved to a great extent over the last three decades. During the early 1970s, a positive DPL was a clear indication for an exploratory laparotomy because one might miss an ongoing hemorrhage or other intra-abdominal injuries. The traditional teaching in academic hospitals was that once the spleen is injured, a splenectomy is guaranteed because this ‘‘nonvital’’ organ can rebleed and endanger the life of the patient. Later in the 20th century, surgeons, especially pediatric surgeons, started to be more selective in their choice of patients to undergo laparotomy or splenectomy. Factors which led to the concept of nonoperative management of splenic injuries include (i) the repetitive reporting and description of serious and fatal infections in patients who underwent splenectomy, especially children, (ii) the rapid advance of radiologic techniques, especially ultrasonography and CT, and their help in discovering and delineating

Figure 6 CT scan of a patient with splenic trauma showing contrast material extravasation (contrast blush). Abbreviation: CT, computed tomography. Source: From Ref. 122.

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Splenic Salvage Techniques

Figure 7 Grade V splenic injury in a patient with blunt abdominal trauma. Source: Courtesy of A. Hirshberg MD, Ben Taub General Hospital, Houston, Texas, U.S.A.

presence of hemoperitoneum may be associated with a higher risk of failure (121), these alone are not considered contraindications to nonoperative approach (113), and a significant number of retrospective studies succeeded in demonstrating acceptable rates of success with nonsurgical treatment (124). Nonetheless, in a recent prospective study published by Velmahos et al. (125), 206 patients with abdominal trauma were followed and higher rates of failure of nonoperative treatment were recorded. The failure rate for nonsurgical management of splenic injury was higher (34%) than that of hepatic injury (17%). The same study also suggests that positive ultrasonographic findings in a hemodynamically stable patient, significant hemoperitoneum (>300 mL), and the need for transfusions are independent predictors of the failure of nonoperative choice. The presence of splenic injury along with these three factors predicted nonsurgical treatment failure in 96% of the patients (125). The need for further prospective investigations to delineate indications for nonoperative approach in stable patients with severe splenic injury and/or hemoperitoneum cannot be overemphasized. According to recent investigations, previously existent splenic pathology, neurologic impairment (altered mental status), and older age (>55 years) are not contraindications to nonoperative management as previously thought, and the success rates in these specific groups compares well to the rest of the nonoperatively managed trauma population (121,126,127). Nonoperative approach is associated with some complications, especially when applied to extensive high-grade splenic injuries. Delayed splenic rupture is a potentially lethal complication and includes a missed primary splenic rupture or a true secondary rupture not present upon review of the initial CT scan. This true rupture could be due to an increase in osmotic pressure accompanying the lysis of the clot or due to the expansion of a subcapsular hematoma (127). Other potential complications include formation of arteriovenous fistulae, arterial pseudoaneurysms, splenic abscesses, and splenic pseudocysts.

Attempts at repairing the spleen began as a result of the recognition of its immunologic role and the potential morbidities and mortalities associated with splenectomy, most important of which being the serious overwhelming postsplenectomy sepsis. Moreover, it was noted that the empty abdominal space created after the performance of a splenectomy rapidly fills with blood clots, creating a suitable niche for bacterial infection and subsequent abscess formation. A nine-year experience at an urban trauma center revealed that splenorrhaphy, or splenic repair, was possible in slightly less than one half of patients (128). Splenic salvage is now performed less often because of the recognition of the success of nonoperative management. In general, splenic repair should be attempted, instead of a total splenectomy, whenever feasible. Hemodynamic instability, serious multiple organ injury, or major lacerations that involve the hilum prelude splenic salvage and should lead to splenectomy. If the patient requires more than two units of blood intraoperatively, or the salvage procedure requires a long operative time (>40 minutes), the risk of transfusion or procedure-related complications may outweigh the risk of postsplenectomy sepsis, and total splenectomy becomes a better choice. The risk of bleeding with splenic repair, if done properly, is minimal and does not exceed 1% (128,129). A full mobilization of the spleen from its anatomic bed to the abdominal incision wound is necessary by division of the splenic ligaments and the peritoneal attachments (Fig. 8). This is one of the most important steps of the procedure, and should be done carefully in order to avoid putting traction on the spleen and risking rupture of the splenic capsule. The tail of the pancreas should be visualized at all times in order to avoid its injury. Once the spleen is free and completely under vision, the surgeon should inspect it and decide what mode of repair would be most suitable. Compression of the splenic artery, as it courses in the tail of the pancreas or at the hilum, helps in adequate control of bleeding in order to evaluate the situation. Removal of blood clots, ligation of bleeding vessels, and debridement of fragmented, loose, or nonviable tissue are essential. Superficial injuries or injuries of low grades on the AAST scale can be successfully treated with cauterization, argon beam laser, or by application of one of the several hemostatic agents available. These include gelfoam, microcrystalline collagen, topical thrombin sponges, fibrin glue, and oxidized cellulose. Among these, fibrin glue has been reported to result in excellent hemostatic results with minimal recurrent or persistent bleeding (130). Deeper injuries of the spleen will need suturing (splenorrhaphy), partial splenectomy, or mesh wrapping. The use of 3–0 Prolene interrupted suturing should be done along the capsule and tied without putting too much traction or shearing forces on the spleen. With the capsule of an elderly patient being usually weaker, Teflon or collagen pledgets should be used as a platform over which the sutures are placed. This gives the surgeon a wider margin of error and prevents excessive injury to the splenic capsule. If nonviable parenchymal tissue has been debrided, the omentum can be used as a bridge between the two sides of the splenic parenchyma and the sutures taken on either side of that bridge (Fig. 8A). Tamponade of the spleen with mesh wrapping is an effective option that can be applied for higher grades of splenic injury, especially when there are multiple splenic lacerations or tears. This mesh is usually composed of

Chapter 24: The Spleen

biodegradable polyglycolic acid or polyglactin and should be wrapped around the full body of the spleen (Fig. 8B). In case of failure of suturing, or if a defined segment(s) of the spleen is injured, partial splenectomy can be attempted. This is possibly due to the segmental anatomy of the spleen and the division of the splenic artery into different branches before entering the hilum. Arteries that supply this designed segment or even adjacent segments can be ligated before resection of the segment as an attempt to minimize fluid loss (Fig. 8C). Surgeons are encouraged to save a part of the resected spleen in case autotransplantation is considered. This latter procedure, which can be done following splenorrhaphy or partial or total splenectomy, involves cutting 1- to 2-mm slices of splenic parenchyma and implanting them in different areas of the abdomen. Larger sizes are less viable and often rapidly undergo necrosis. The omental pouch has been found in animal studies to be the best site to perform this autotransplantation. This technique is based on the assumption that ‘‘splenosis’’ or functional remnant splenic tissue might help prevent postsplenectomy infections. In fact, some splenic phagocytic function is preserved with autotransplantation and the levels of IgM commonly return to normal. Decreases in the amount of Howell–Jolly bodies and pitted RBCs are also reported (131). Whether this implanted splenic tissue actually helps in decreasing the risk of postsplenectomy sepsis or not is more controversial. The current data is not solid or convincing enough to suggest less susceptibility to overwhelming postsplenectomy infection (OPSI). Moreover, some studies suggest that more than 40% of the initial splenic mass is needed in order to significantly preserve splenic function (132), and that implantation of up to 80% of the splenic tissue is necessary to provide optimum survival in case of bacteremic sepsis (133). This could make partial splenectomy with good arterial preservation a more practical option than splenic autotransplantation. Splenectomy is reserved for those patients who fail salvage trials and for those who initially present with severe

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hemodynamic instability or serious injuries like a shuttered or avulsed spleen. The trauma surgeon should not hesitate to shift to the option of splenectomy whenever nonsurgical or salvage attempts seem to be failing.

Follow-Up Evaluations Several studies were published to establish the need for radiologic follow-up of abdominal trauma patients, especially those treated nonoperatively. However, an agreement on follow-up treatment has not been reached and the need for randomized clinical trials to help elucidate the benefit of follow-up CT scans or ultrasounds is increasing. This is mainly due to the benefits of nonsurgical treatment being challenged by the delayed complications not previously known when splenectomy was the standard of care. Some of these complications, as discussed previously, can be managed nonsurgically with interventional radiology, which encouraged many physicians to practice regular follow-up imaging (127). As an example, Davis et al. strongly recommend follow-up CT scans and suggest that 74% of contrast blush incidences and a large number of pseudoaneurysms are detected on these follow-up images and thus can be managed accordingly (119). According to the EAST Work Group, there is no evidence-based data that suggest a benefit from serial CT scanning without clinical indications (113). Moreover, there is no scientific evidence to suggest that bed rest or restricted activity is beneficial for the patients managed nonsurgically, but evidence of healing must be present before the patient is advised to resume regular activities, including contact sports (113). The time needed for the spleen to recover was evaluated in a study published in 2001 and demonstrated that the healing time is largely dependent on the AAST grade of injury. For example, 88% of grade II injuries healed within 64 days, while 77% of grade IV injuries needed 81 days to heal (134). Therefore, a period of three months is a reasonable time for patients to resume regular or sports-related activity.

Figure 8 Injured spleen mobilized into the abdominal incision. Splenic salvage techniques include: (A) omental bridging of debrided splenic parenchyma with the placement of interrupted sutures; (B) polyglactin mesh tamponade for multiple splenic lacerations; (C) partial splenectomy after segmental artery ligation.

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SPLENECTOMY Preoperative Preparation The surgeon must be aware of the specific condition of the patient and all the complications of the entity that caused the splenic disease. The need for transfusion of platelets should be assessed and addressed preoperatively. If the platelet count is above 25,000/mL and the platelet function is normal, there is rarely a need for such a transfusion. Patients with ITP and severe thrombocytopenia may require the use of agents such as IVIG, which help in elevating the platelets counts to relatively safe levels. Prophylactic antibiotics may be administered for those patients who suffer from immunosppression secondary to their primary disease or to the mode of therapy they already received. Preoperative vaccination is an important step of the preparation of patients for an elective splenectomy. However, an urgent splenectomy, as in the case of trauma, rarely offers such an opportunity. The most important of the vaccines, preferably given several weeks before the operation, is the pnemococcal vaccine. Additional vaccines are the H. influenzae B and the meningococcal vaccines, which should be given when possible, especially for high-risk groups. The importance of these vaccines and the best timing of their administration pre- and postoperatively (which will be discussed in a latter section of this chapter) are derived from the potential seriousness of postsplenectomy infections, especially with encapsulated bacteria.

Open Splenectomy Several incisions are possible in order to access the spleen including upper midline, left subcostal, and even thoracoabdominal incisions. A search for accessory spleens is performed first. The spleen is then mobilized by dividing the splenorenal, splenophrenic, and splenocolic ligaments. Intact ligaments may hinder control of any unexpected bleeding if ligation of splenic vessels is attempted before division of the ligaments. The spleen is moved anteriorly and out of the abdomen. The gastrosplenic ligament may then be divided with particular attention to the short gastric vessels that must be identified and ligated without running the risk of injuring the gastric wall. The splenic artery and vein are then separately ligated, while the tail of the pancreas is constantly under vision. The best place to ligate these vessels may be next to their entry into the splenic parenchyma in order to avoid pancreatic injury. The spleen is then removed medially, the short gastric vessels and the vessels around the tail of the pancreas checked for hemostasis, and the abdomen closed. Alternatively, in cases of massive splenomegaly, the splenic vessels can be accessed and ligated through the lesser sac, resulting in the shrinking of the spleen to a certain extent and decreasing the risk of bleeding. A drain is usually not advised because it increases the risk of intraperitoneal infection. If a drain is placed, it should be of the closed suction type and should be removed as soon as the surgeon feels confident that no persistent bleeding is present.

Laparoscopic Splenectomy LS is today’s procedure of choice for elective splenectomies. Several recent reports confirmed that LS has comparable postoperative results to open splenectomy along with the advantages of a minimally invasive technique. These include less mean blood loss, earlier tolerance of regular diet, less postoperative pain with significantly less need for intravenous narcotics, shorter hospital stay, and better cosmetic results. The laparoscopic approach is successful

in both children and adults and is particularly effective for the removal of normal-sized spleens like those found in patients with ITP. Application of LS in cases of massive splenomegaly is also feasible and has been described. The use of hand-assisted laparoscopic surgery for very large spleens is probably helpful because it offers the advantages of a minimally invasive procedure in the presence of a giant spleen (135). Splenic embolization with fragments of sterile sponge gelatin that ablate a large proportion of the arterial supply of the spleen is occasionally needed before LS to decrease blood loss (Fig. 9); however, ablation of more than 70% of the splenic vasculature has been proposed for optimal results (12). A study performed in 1998 suggested that this technique is mostly useful in spleens with a length between 20 and 30 cm only, while those patients with shorter and longer spleens do not benefit from preoperative splenic embolization (136). The patient is placed in the right lateral position, and four trocars are placed along the left costal margin while the port for the camera is placed more inferiorly. The sequence of intraoperative steps to be followed laparoscopically is similar to that already described in the open technique. By the end of the procedure, the spleen is placed in a special extraction bag, fragmented, and carefully retrieved in pieces from a trocar site. Disadvantages of LS include a longer operative time than open splenectomy and the possibility of conversion to the open technique. Nevertheless, this operative time difference has been found to be related to the learning curve of the surgeon, and both the operative time and the rate of conversion were found to decrease significantly after the surgeon performs the first 10 to 20 operations (137). Application of robotics technology has been tried in gastrointestinal procedures and in LS specifically, and has shown significant promise. The advantages of the robot-assisted technique include filtering of the surgeon’s hand tremor and transforming the large-scale hand motion into small movements of the robotic arm (138,139).

Accessory Splenectomy Some cases of relapsing hematologic disorders, especially in patients with ITP, have been suggested to be due to an undetected accessory spleen at the time of initial surgery. Due to difficulty in locating accessory spleens at reoperation, detection of splenic tissue preoperatively is advised. This can be done with the use of technetium-99 sulfur colloid or, in the case of ITP, with indium 111 platelet-labeled radionuclide studies. If splenic tissue is detected, accessory splenectomy is necessary (34). These accessory spleens, found in 15% to 30% of the population with recurrent ITP, are most commonly located in the area of the previous spleen; however, a search for them in more distant sites is recommended as well (Table 1). Preoperative injection of radiolabeled platelets in patients with ITP along with the intraoperative use of a sterile hand-held gamma probe is very helpful in the localization of accessory splenic tissue and in the confirmation of its complete excision. Several reports of successful remission of relapsing or persistent ITP are present in literature, some of which suggesting a remission rate as high as 66% after accessory splenectomy (34).

Complications of Splenectomy In addition to the complications potentially seen after any gastrointestinal operation such as intraoperative blood loss, pulmonary lower lobe atelactasis, postoperative ileus, and

Chapter 24: The Spleen

Figure 9 Angiographic embolization. (A) Pre-embolization splenic vessels (B) postembolization with gelfoam pledgets distally and coils proximally. Source: Courtesy of C. Whigham MD, Ben Taub General Hospital, Houston, Texas, U.S.A.

wound infection, splenectomy has been associated with some serious sequelae such as postoperative sepsis and thrombocytosis. Moreover, intraoperative iatrogenic injury to the pancreas may result in pancreatitis, pancreatic pseudocyst, or pancreatic fistula. In addition, injuring the stomach may lead to abscess or gastric fistula formation.

Thrombocytosis Platelet levels increase in the first one to three weeks after splenectomy. These levels can reach as high as 2,000,000/mL, especially in patients with myeloproliferative disorders. Although the relationship between this thrombocytosis and thrombotic events has not been demonstrated (140), the seriousness of any potential thromboembolic phenomenon like deep venous thrombosis or pulmonary embolism is sufficient to warrant an antiplatelet agent such as aspirin, when the platelet counts reach levels higher than 1,000,000/mL. In a study by Pimpl in 1989, a review of 37,012 autopsies of patients, who underwent splenectomies, was performed. The risk of pulmonary embolism as a cause of death was found to be higher than in control autopsies (141). The causal relationship between this increased incidence of embolism and the presence of thrombocytosis has not been demonstrated.

Overwhelming Postsplenectomy Infection As repeatedly mentioned in earlier sections, patients who undergo splenectomy are at an increased risk for fulminant sepsis due to encapsulated bacteria, mostly S. pneumoniae. This entity, called OPSI, changed the view of the spleen as a dispensable organ in the mid-20th century. Although OPSI can occur in any asplenic patient, its incidence is highest among the pediatric population and in those patients who undergo splenectomy for hematologic and oncologic disorders, and lowest for the adults who undergo splenectomy for trauma. It is especially prevalent in patients with thalassemia major and Hodgkin’s lymphoma (12,143,144). The risk of postsplenectomy sepsis is particularly high during the first two postoperative years (144), but this risk persists indefinitely with a lifetime prevalence estimated to be between 1% and 5% (12,143). Mortality from OPSI exceeds 50%, and mortalities as high as 80% have been described in pnemococcal infections. Survivors often struggle for a long period of time in the intensive care unit. Pathogens. The pathogens responsible for this entity are mainly S. pneumoniae, H. influenzae, and N. meningitidis.

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E. coli, Pseudomonas and group B streptococcus are less commonly involved. Capnocytophaga canimorsus has also been reported as a rare cause of OPSI, classically occurring after dog scratches or dog bites (145). The asplenic patient is also at an increased risk for parasitic infections like malaria and babesiosis. In fact, one-third of clinical human babesiosis, a protozoan disease similar to malaria, occurs in asplenic patients (146). This parasitic infection, which presents as a flu-like illness in normal people, progresses to a fulminant parasitemia and to lethal respiratory distress and hemolytic anemia in an asplenic patient (900, 902). Still, more emphasis is placed on S. pneumoniae, as it is responsible for more than 70% of fulminant sepsis described in literature (143). Clinical presentation. Patients with OPSI present with signs and symptoms of an upper respiratory tract infection, but rapidly thereafter manifest high-grade fever, chills, vomiting, petechiae, purpura, and hypotension. Some patients are reported to present with an acute abdomen picture (145). The patient’s neurologic status deteriorates quickly from an altered sensorium to coma, and, not uncommonly, death. Investigation. Laboratory studies in OPSI show a picture similar to that of disseminated intravascular coagulation, with depleted complement levels, fibrinogen, and platelets. Leukocytosis may be present, but most patients will have granulocytopenia instead. Acute renal failure and acute adrenal failure (Waterhouse–Friderichsen syndrome) can occur and are due to intraorgan hemorrhage and necrosis. Peripheral smear often shows bacteria; blood cultures are positive in the absence of prophylactic antibiotic intake. Management. As soon as the diagnosis of postsplenectomy sepsis is suspected, empiric broad-spectrum antibiotics should be administrated intravenously, and the patient should be monitored closely in the hospital. Fluid therapy should be combined with inotropes for a better response in case of hemodynamic instability. Ventilatory support is generally needed because of the frequent association of this entity with hypoxemia, respiratory distress and neurologic impairment. High-dose penicillin is the standard antibiotic for OPSI. In areas with increased incidence of pneumococcal resistance, however, the preferred empiric antibiotics are high-dose vancomycin and ceftriaxone given simultaneously. IVIG are under investigations but showed significant success in animal studies (147). Prevention. The best way to prevent postsplenectomy infection and sepsis is by avoiding splenectomy when possible, or by performing one of the splenic salvage techniques described previously in this chapter. Weighing the risk– benefit ratio associated with total splenectomy is necessary, but the fear of OPSI should not be a deterrent to performing the procedure when needed. Immunization with polyvalent pneumococcal, meningococcal polysaccharide, and conjugate H. influenzae vaccines is essential and has been proven to decrease the risk of OPSI. In the case of an elective splenectomy, the vaccines should be administered 14 days preoperatively for the best results. This is not always possible, as in the case of trauma, at which time postoperative vaccination becomes crucial. The timing of postoperative vaccination is a matter of controversy. Two studies published in 1998 and 2002 compared serum antibody titers of patients vaccinated on the 1st, 7th, 14th, and 28th day postoperatively. These studies found similar antibody levels irrespective of the day of vaccination, but the functional activity of these antibodies was significantly more elevated in those patients vaccinated 14 days postoperatively (148,149). Therefore, delaying immunization until two weeks postoperatively is currently recommended

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to enhance the response to the vaccine. In the presence of hypovolemic shock, prior to splenectomy, immediate vaccination within 24 hours may be more beneficial (150). Revaccination within two to six years is well tolerated and seems reasonable to keep an adequate antibody level and provide protection against encapsulated bacteria (151). A poor antibody level response after pneumococcal polysaccharide vaccine in patients with hematological disorders, such as HL, suggests an increased risk of pneumococcal infection despite repetitive re-vaccinations (152). Chemoprophylaxis of splenectomized pediatric patients with daily penicillin is widely practiced and is reported to result in a marked decrease in the incidence of postsplenectomy infections. Antibiotic prophylaxis in adults is more controversial and is recommended currently for high-risk groups like those with immunocompromised states or hematologic malignancies. Because the risk of OPSI is present indefinitely, and because the pneumococcal resistance to penicillin is increasing rapidly, the duration of chemoprophylaxis is questionable and should be addressed in future studies. Finally, patients should be instructed of the risk of lethal sepsis with splenectomy, and should be able to recognize early signs of an infection. They should be keep antibiotics (amoxicillin) with them and start an adequate regimen in case of fever or other infectious signs, even before examination by a physician. A medical-alert bracelet indicating the patient’s asplenic status can be lifesaving in case of an emergency.

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OTHER CONDITIONS

25 Gastrointestinal Hemorrhage Kevin Bruen and Leigh Neumayer

Baseline labs including hematocrit and coagulation factors should be sent with the assumption that the hematocrit may be considerably lower than the initially obtained value. If necessary, blood products should be infused as the resuscitative effort continues. Midway along the spectrum is the patient who is not in extremis, but may still have signs of hemodynamic compromise. A history of intermittent hematemesis suggests an upper GI source, while hematochezia, or bright red blood per rectum, suggests a lower intestinal source. It should be noted, however, that up to 18% of patients presenting with suspected lower GI hemorrhage will in fact have an upper GI source (2). Duodenal ulcer is the most common cause in this case, followed by a gastric ulcer (4). Conversely, melena,a although classically regarded as an upper GI source, may in fact be from the lower intestine. Symptoms of weakness, dizziness, or presyncope may be reported. Orthostatic blood pressures can be taken knowing that a drop in blood pressure of 20 mmHg or an increase in pulse by 20 indicates significant blood loss. At the other end of the spectrum is the patient with chronic or occult blood loss. The history may lack obvious visualization of blood loss; however, the patient may also complain of weakness and symptoms of orthostasis. Often, the patient is referred for evaluation of GI bleeding after being found to have anemia or positive fecal occult blood cards. These individuals will most likely be seen in the outpatient setting. A systemic approach to the evaluation of these patients should also be employed with upper and lower endoscopy followed by consideration of examining the small bowel. Once the patient has been hemodynamically stabilized, the next goal is to determine the source of bleeding (Fig. 1). Upper and lower intestinal bleeding is classically delineated by that which occurs above and below the ligament of Treitz, respectively. Placement of a nasogastric tube is a reasonable first step. Suctioning of gross blood immediately confirms an upper GI source. Clear, nonbilious fluid makes a gastric source less likely; however, it does not rule out a lesion beyond the pylorus in the duodenum. Bilious aspirate without evidence of blood most frequently suggests a lower GI source. Analyzing nasogastric aspirate may be of questionable utility however. The incidence of an upper GI bleed in the setting of clear aspirate is still 20% (5). The vast majority of patients with suspected upper GI hemorrhage based on history or an observed account will undergo upper endoscopy for confirmation. Gastric lavage ice-cold solutions are no longer utilized; however, warm solutions maybe of benefit to clear the GI tract prior to endoscopy.

INTRODUCTION Gastrointestinal (GI) hemorrhage is a centuries-old problem that continues to be significant today. The incidence of GI hemorrhage remains constant at 100 per 100,000 hospitalizations per year from upper sources and 20.5 per 100,000 from lower sources (1,2). A more elderly population with multiple comorbidities is thought to be a major contributing factor. With the advent of evidence-based medicine, there has been increased awareness and demand for proven approaches in medicine. GI bleeding is no exception, and there has been a relative increase in the number of studies analyzing treatment approaches. A recent review of the literature reveals efforts to standardize the care of these patients to obtain better outcomes and to more efficiently utilize resources. There have been several developments in recent years with regard to diagnosing and managing GI hemorrhage. Endoscopy is a proven modality for the evaluation of upper GI bleeding. A recent study of cost and length of hospital stay in patients with GI hemorrhage found that early endoscopy and protocol-driven decision-making in patient care decreases length of stay and cost (3). Advances in diagnostic and therapeutic interventional radiology techniques have also increased the effectiveness of evaluating and treating GI hemorrhage with fewer complications. Establishing evaluative measures to determine early on which patients require aggressive care and which can be managed as outpatients has also been studied. Capsule endoscopy in which the entire length of the intestine is imaged by swallowing a microcamera that transmits images has become a reality. Knowledge of this development and others is an important step toward obtaining better patient outcomes.

INITIAL EVALUATION AND MANAGEMENT The physiology of GI hemorrhage can be categorized into two distinct entities: the physiology of hypovolemia and the physiology of the underlying etiology of the bleed. The initial assessment of the patient focuses on evaluating and establishing hemodynamic stability prior to embarking on a search for the bleeding source. The patient with a GI hemorrhage presents somewhere along a spectrum. At one end of the spectrum and most concerning is the patient with gross hematemesis, melena, and hemodynamic instability. This presentation should place into motion a cascade of actions not unfamiliar to the surgeon. The ABCs of airway, breathing, and circulation should be evaluated and established. The patient with gross hematemesis may require a controlled intubation to avoid aspiration and to secure the airway prior to anticipated endoscopy. Two large bore IVs should be placed and aggressive fluid resuscitation with crystalloid initiated while blood is typed and crossed.

a

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A black, tarry stool that results from blood having been digested as it passes through the GI tract.

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Gastrointestinal Hemorrhage

Table 1 Addenbrooke’s Pre-Endoscopic Stratification for Risk of Mortality and Need for Urgent Treatment in Patients with Acute Upper GI Hemorrhage Risk group

Nasogastric tube

High Nonbilious,

Bloody fluid

Nonbloody fluid

Possible UGI Source

UGI source

Bilious, nonbloody fluid

Probably LGI source

UGI endoscopy

Diagnostic

Nondiagnostic

Massive hemorrhage Appropriate Treatment

Selective visceral angiography

No source identified

Intermediate

RBC scan repeat UGI endosopy

Figure 1 Diagnostic steps in the evaluation of acute gastrointestinal hemorrhage.

Risk stratification has been an area of investigation in several recent studies. Risk factors for increased mortality include increased age and medical comorbidities (6). Patient history, vital signs, and physical examination all have a role in predicting the potential severity of a GI hemorrhage. One study looking at patients with lower-intestinal bleed identified several factors as predictors of having a severe bleed (transfusion of more than two units of blood in 24 hours, a drop in hematocrit of 20%, continued bleeding after 24 hours of hemodynamic stability, or readmission within one week). Specifically, a patient with a HR >100, systolic blood pressure lower than 115, and a history of syncope has a relative risk of nearly three times or greater of meeting the criteria for a severe bleed (7). Risk stratification can also be used to predict rebleeding and mortality. Rebleeding is of particular interest due to the fact that 25% of patients with a peptic ulcer source, who rebleed do not survive (8). A study from the United Kingdom classified patients with upper GI sources into high, medium, or low risk upon admission (9). The highest single factor present determined risk stratification (Table 1). Following a total of 1349 consecutive patients over a three-year period, the two-week mortality was 12%, 3%, and 0% in high-, medium-, and low-risk groups, respectively. Incidence of rebleeding in each of the groups was 44%, 2.3%, and 0%. Multiple logistical regression was then utilized to determine risk factors predictive of mortality. Perhaps as anticipated, systolic blood pressure less than 100, persistent tachycardia, age greater than 60, coagulopathy, abnormal liver function tests, and the presence of another comorbidity all increased the odds of mortality. The study criteria draw attention to the key portions of the work-up and can be used as a guide to direct resource priority and utilization. Patients with absence of any of the listed risk factors (low-risk classification—76 patients in this study) can be managed as outpatients. In an era of staffing and bed shortages, the study supports the utilization of intensive care unit (ICU) beds for highest risk patients. The initial evaluation of hematemesis is by upper endoscopy. Endoscopy has been shown to decrease mortality

Low

Variable Recurrent bleeding (any of: resting tachycardia and supine hypotension with no obvious cause; further fresh blood hematemesis; ruddy melena; falling hemoglobin concentration more than could be explained by hemodilution) Persistent tachycardia (pulse >100 beats/min despite resuscitation) History of esophageal varices Systolic blood pressure 17 sec) Thrombocytopenia (platelet count 20 mmHg on negative chronotropes (e.g., beta blockers) Age >60 Hemoglobin 28 units/wk or >10 units in the previous 24 hr) NSAIDs (current or recent NSAID or aspirin) Previous gastrointestinal bleed or peptic ulceration Abnormal liver biochemistry (transaminases, alkaline phosphatase, or bilirubin) Postural hypotension >10 mmHg (sitting or standing compared with supine) Systolic blood pressure >20 mmHg below patient’s normal (if known) None of the aforementioned factors

Note: Patients stratified into highest risk group for which at least one risk factor was present. Abbreviations: GI, gastrointestinal; NSAIDs, nonsteroidal anti-inflammatory drugs. Source: From Ref. 9.

from acute bleeding as well as length of stay (3,10). A community-based study looking at early endoscopy within 24 hours of admission decreased the odds of surgery or rebleeding in all patients (OR ¼ 0.70) and most significantly in patients considered at highest risk (OR ¼ 0.20). Length of stay was also decreased by 30% (11). Another study employing endoscopy within 12 hours of presentation randomized low risk patients to hospital admission or discharge with outpatient follow-up. The incidence of rebleeding in the two groups was 2%. The cost of outpatient management strategy was $340 compared to $3940 with in-hospital admission (12).

UPPER INTESTINAL BLEEDING Etiology Esophageal Varices Esophageal varices are a common and significant complication of liver disease and cirrhosis. Approximately 40% of patients with cirrhosis develop varices with an estimated mortality rate of 30% to 50% (13,14). Ascites, telangiectasias, gynecomastia, splenomegaly, and hepatic synthetic dysfunction are all suggestive of cirrhosis. Overall, esophageal hemorrhage accounts for 14% of cases of upper GI hemorrhage (Table 2). The esophagus and its blood supply may be divided into three regions—cervical, thoracic, and abdominal. The cervical esophagus is supplied by branches of the inferior

Chapter 25: Gastrointestinal Hemorrhage

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Table 2 Causes of Acute Upper GI Bleeding Common Duodenal ulcers Gastric ulcers Gastritis Duodenitis Esophagitis Mallory–Weiss tear Cirrhosis-associated lesions Esophageal varices Gastric varices Portal gastropathy Anastomotic (marginal ulcer) Angiodysplasia Dieulafoy lesion

Uncommon Duodenal Crohn’s disease Leiomyoma Hemobilia Gastric polyps Aortoenteric fistula Polypectomy bleeding Malignancy Esophageal squamous cell cancer Esophageal adenocarcinoma Gastric adenocarcinoma Gastric lymphoma Gastric Kaposi’s sarcoma Gastric antral vascular ectasia

Abbreviation: GI, gastrointestinal. Source: From Ref. 15.

thyroid artery. The venous return follows in similar fashion via the inferior thyroid vein. The thoracic esophagus receives branches from the descending aorta, bronchial arteries, and intercostals. A venous plexus lines the esophagus, with drainage to the azygous, hemiazygous, and accessory azygous veins. The abdominal portion of the esophagus receives its blood from the left gastric and inferior phrenic arteries. The venous return empties into the left gastric vein. The left gastric vein is the only vein draining the esophagus, which communicates with the portal vein instead of the systemic circulation. This anatomical fact leads to the development of esophageal varices in the presence of portal hypertension. The typical presentation of an esophageal bleed is hematemesis. Aggressive resuscitation including securing an airway is critical. Urgent endoscopy is necessary following resuscitation. Varices typically have an appearance of serpiginous, longitudinally oriented gray projections (15). Active bleeding, clots, red discoloration, or blisters are all suggestive of recent bleeding (15). It should be noted, however, that approximately 50% of bleeding episodes in the patient with cirrhosis are not related to varices. Management of variceal bleeding has improved in recent years. Early endoscopy and medical management with agents such as octreotide have reduced mortality to 15% (in hospital and up to 6 weeks postbleed) (16). Although vasopressin has traditionally been used in the past to reduce portal pressure, other pharmaceutical agents have been found to be as effective without the cardiovascular side effects. For example, terlipressin, an analogue of vasopressin, is the only agent to have demonstrated a mortality benefit and similar effectiveness as endoscopy (17). Both 0.2 and 1 mg every four hours have been studied with 80% and 90% success rates, respectively, at controlling bleeding by day 2 of hemorrhage. The higher dosing regimen was also found to decrease the need for blood products without an increased incidence of side effects (18). Balloon tamponade using a triple lumen tube with gastric esophageal balloons has been used as a temporizing measure in acute hemorrhage. Following X-ray confirmation of balloon placement, the gastric balloon is inflated with 150 to 200 cc of normal saline. If bleeding continues, the esophageal balloon may also be inflated with 40 to 60 mmHg pressure. The balloon should be deflated every two hours to allow adequate esophageal perfusion. Balloon tamponade has been shown to be effective in approximately

Figure 2 Esophageal banding is an effective technique in primary prevention, as well as in actively bleeding varices.

90% of patients. It is however a temporizing measure with rebleeding in two-thirds of patients upon deflation. Unfortunately, balloon tamponade has also been associated with aspiration pneumonia, esophageal necrosis, and rupture. Acute endoscopic therapeutic options include banding, sclerotherapy, injection with epinephrine or a combination of techniques. Sclerotherapy has been shown to be effective, stopping 96% of initial bleeding episodes (19,20). Interestingly, a recent meta-analysis comparing sclerotherapy to vasopressin, somatostatin, octreotide, or terlipressin found no advantage for sclerotherapy over medical management with any of the aforementioned agents. This study took into account 12 trials and looked at a number of measures including failure to control bleeding, rebleeding, transfusion, and mortality (21). Banding causes thrombosis and has been shown to be more effective than sclerotherapy for long-term results (22). Band ligation is also frequently used as a second-line treatment being performed every one to two weeks until varices are obliterated (Fig. 2). Combination therapy with medical and endoscopic techniques is most frequently used in current practice. Meta-analysis reviewing a number of techniques and pharmaceutical agents has found that an overall small benefit is gained in obtaining initial hemostasis (relative risk 1.1) and five-day hemostasis (relative risk l.28) using combination therapy (23). Propranolol has been used for many years as primary prophylaxis and still persists today as the initial standard treatment for esophageal varices (24). Band ligation has been advocated as an alternative to propranolol for primary prophylaxis and has been demonstrated to be as effective and without side effects (25). Long-term treatment options also include transjugular intrahepatic portosystemic shunting (TIPS) and portocaval shunts. In retrospective studies, TIPS has been shown to reduce long-term mortality when compared to sclerotherapy and band ligation alone (26). Unfortunately, the complication rate of TIPS is high with two-year mortality and shunt failure rates approaching 50% (27).

Mallory–Weiss Tear A tear in the mucosa near the gastroesophageal junction may be a direct result of vomiting or retching. The process

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Figure 3 The Mallory–Weiss tear is located at the gastroesophageal (GE) junction located on the gastric side of GE junction made visible here with retroflexing of the endoscope.

of vomiting originates in several centrally located sites including the medulla and chemotrigger zone located on the floor of the fourth ventricle. Sensory input from a number of sources may trigger the vomiting reflex. Anatomically, the process of vomiting begins in the duodenum. A reverse wave of peristalsis occurs with subsequent contraction of the abdominal musculature raising the pressures at the distal esophagus. The pressure may reach a difference of up to 200 mmHg between the distal esophagus pressure and the negative pressure of the thorax. The subsequent force directed against the distal esophagus creates a Mallory–Weiss tear. Such lesions make up 6% of all upper GI bleeding sources (28). The classic presentation is a patient with a history of alcohol abuse, who forcefully vomits and subsequently develops hematemesis. Endoscopy typically reveals a linear mucosal tear oriented longitudinally, most commonly located on the gastric side of the gastroesophageal (GE) junction (Fig. 3) (15). Frequently, bleeding from these lesions has already ceased upon presentation for medical care. Studies comparing medical and endoscopic treatment with either banding ligation/hemiclip application or epinephrine injection suggest that unless there is active bleeding, medical therapy is as effective as endoscopic intervention (29).

over a 50-month period, gastric ulcers made up 32% of episodes and duodenal ulcers contributed 28% (28). It is estimated that approximately 20% of patients with peptic ulcer disease experience bleeding at some point during the course of the disease. Presentation is typically with either hematemesis or melena. However, as previously discussed, hematochezia may also be seen initially. The gastroduodenal artery is located posterior to the duodenum and is frequently the source of bleeding (Fig. 4). A major risk factor for ulcer formation is nonsteroidal anti-inflammatory drugs (NSAIDs). Each year, over 70 million prescription drugs and 30 billion over-the-counter preparations are sold (31). NSAIDs have long been known to be a risk factor for GI hemorrhage. A recent meta-analysis using a combination of data from randomized controlled, case controlled, and cohort studies found a 2.5 to 5.5 times increased relative risk of GI bleeding with concurrent NSAID use. The association of Helicobacter pylori, a bacteria implicated in the etiology of peptic ulcer disease, with GI hemorrhage has recently been called into question. A case–control study confirmed previous studies demonstrating that the incidence of H. pylori infection was actually lower in patients with hemorrhage and most likely not a risk factor for bleeding (32). Eradication of H. pylori however has been shown to decrease the rate of rebleeding (33). The use of lansoprazole following H. pylori eradication in patients who continue to require aspirin therapy has been found to reduce the risk of recurrent complication from 15% to 1.5% (34). The interaction of H. pylori disease and NSAIDs has also been evaluated. While untreated H. pylori infection contributes to the risk of upper GI hemorrhage in those individuals starting NSAID therapy, in those who have a history of long-term NSAID usage, the greatest risk is attributed to the NSAID use (35). GI injury arises from the imbalance of acid production and an altered gastric mucosal barrier. Studies have found an equal incidence of disease due to enteric-coated formulations suggesting that the systemic effects of decreased prostaglandin synthesis are primarily responsible. Selective cyclo-oxygenase-2 inhibitors (Cox-2 inhibitors) have been developed to work as anti-inflammatory agents while maintaining prostaglandin synthesis. A large population cohort study including over 40,000 patients compared the incidence of disease due to traditional NSAIDs to that due to diclofenac plus misoprostol, rofecoxib, and celecoxib. Misoprostol is a prostaglandin analogue preparation, while rofecoxib and celecoxib are Cox-2 inhibitors. The study

Dieulafoy Lesion The Dieulafoy lesion is a relatively rare cause of upper GI hemorrhage representing a dilated superficial vessel located just below the mucosa. Most lesions are located on the lesser curvature of the stomach near the GE junction as a prominent pigmented vessel without evidence of ulceration (30). The etiology is unknown. These lesions typically present with significant hematochezia without hematemesis. Combination therapy with epinephrine injection and bipolar coagulation as well as marking the lesion with India ink in the event that rebleeding requires repeat endoscopy or surgery has been advocated (4).

Peptic Ulcer Disease Peptic ulcer disease makes up nearly 60% of upper GI bleeds. In one inner city series analyzing patients presenting

Figure 4 Duodenal ulcer with large overlying clot.

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found no increased risk of upper GI hemorrhage compared to an unopposed cohort with the use of celecoxib. There was an increased relative risk of 4.4 for traditional NSAIDs, 3.2 for diclofenac plus misoprostol, and 1.9 for rofecoxib compared to celecoxib (36). Initial medical treatment for suspected peptic ulcer hemorrhage includes starting a proton pump inhibitor (PPI), such as omeprazole. Misoprostol has been found to be beneficial in healing peptic ulcers, however less effective and less well tolerated than omeprazole (37). H2-receptor antagonists and, more recently, PPI have been shown to promote healing of peptic ulcers. The ASTRONAUT Trial— Acid Suppression Trial: Ranitidine versus Omeprazole for NSAID Associated Ulcer Treatment—found 80% healing of peptic ulcers with 20 or 40 mg of omeprazole orally daily compared to 63% with 150 mg of ranitidine twice daily (38). PPIs have also been show to have a benefit over H2 blockers in preventing rebleeding after successful coagulation. In a randomized, placebo, double-blinded study, omeprazole was found to decrease the incidence of rebleeding and the need for surgery in patients with a nonbleeding, visible vessel or an adherent clot. PPIs were not however found to be beneficial in patients with vessels that had arterial spurting or oozing (39). A cost analysis looking at IV omeprazole found hospital costs to be less by avoiding one episode of rebleeding after endoscopic treatment (40). Morgan found that continuous IV pantoprazole was more effective than bolus therapy alone in preventing rebleeding, suggesting greatest effect with a bolus of 80 mg followed by 8 mg/hr infusion over three days (41). However, there has not been a demonstrated effect on mortality (42). Another study looking at oral omeprazole following endoscopic therapy found omeprazole to reduce the number of rebleeding episodes by 50% (43). A bleeding ulcer may appear in several forms upon endoscopic visualization. The ulcer may be obvious and acutely bleeding, or on the contrary difficult to identify. Different variations on the theme exist and are classified by Forrest classifications. These include actively spurting vessel (la); actively bleeding, nonspurting vessel (Ib); visible nonbleeding vessel (IIa) (Fig. 5); nonbleeding ulcer with overlying clot (IIb); ulcer with black base (IIc); and ulcer

with clean base (III). Studies have also demonstrated that the greatest risk factor for rebleeding is based on Forrest classification (44). Actively bleeding vessels have a 88% chance of rebleeding and visible vessels have a 40% to 50% chance of rebleeding, while those with adherent clot a 30% chance (Table 3) (4,45). Other risk factors included ulcer size and site, hematemesis upon presentation, cirrhosis, hypotension, and recent surgery (44). Endoscopy with therapeutic intervention has been shown to decrease mortality and the need for surgery (46). Obtaining adequate visualization may be difficult at times; however, erythromycin, which enhances gastric emptying, has been found to provide a clearer view during endoscopy when given 20 minutes prior to the procedure. The need for second-look endoscopy is also found to be reduced from 33% down to 12% (47). There are two primary modes of thermal therapy used today—electrocoagulation and heater probes. In multipolar or bipolar electrocoagulation, electrical current runs between three adjacent bipolar microelectrodes creating heat with subsequent coagulation of tissue proteins and vessel constriction (4). Heater probes work similarly, consisting of a hollow aluminum cylinder and coil. Small, randomized studies have found heater probes favorable to hemoclips in achieving hemostasis (48). Laser and argon plasma coagulation are also frequently used as thermal modalities. For the actively bleeding vessel, combining bipolar or heater probe techniques with epinephrine is recommended, while in the nonbleeding visible vessel, bipolar or heater probe therapy is sufficient (4,49). Removal of clot from a nonbleeding ulcer with precedent treatment involving injection with epinephrine followed by heater probe or bipolar electrocoagulation has been shown to reduce the risk of rebleeding to zero compared to 35% with medical therapy alone (50). Oozing ulcers typically have a rebleeding rate of 10% to 27% and can be reduced to 5% with epinephrine or thermal probe. Finally, clean-based ulcers have a 5% risk of bleeding and patients with this disorder have been managed successfully as outpatients (4,45,51). Once initial bleeding is controlled, debate exists whether second-look endoscopy is a cost and clinically effective strategy. Using probability estimates from current literature, a decision analysis calculated second-look endoscopy in high-risk patients only as most effective and least expensive (52). Massive bleeding from duodenal ulcer disease, perhaps more so than any other source of bleeding and especially with failure of endoscopy, is often times best managed with surgical intervention. In a study of 738 patients admitted for Table 3 Prevalence and Rebleeding Rate of Various Stigmata of Ulcer Hemorrhage in the CURE Study of 200 Consecutive Patients Admitted to an ICU Stigmata Active arterial bleeding Nonbleeding visible vessel Nonbleeding clot Oozing bleeding without stigmata Nonbleeding flat spots Clean ulcer base a

Figure 5 Gastric ulcers with a visible nonbleeding vessel (Forrest classification IIa) have a 50% chance of rebleeding without endoscopic intervention.

Prevalence (%) Rebleeding ratea (%) 12 22 10 14 10 32

88 50 33 10 7 3

Rebleeding refers to clinically significant rebleeding with the transfusion of additional units of packed red blood cells beyond those for the initial resuscitation in patients receiving medical therapy without endoscopic hemostasis. Abbreviation: ICU, intensive care unit. Source: From Ref. 4.

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acute bleeding peptic ulcers, 32 patients required surgery. Twenty-five patients failed epinephrine or polidocanol injection (3.4%), six had gastric or duodenal perforation from endoscopy (0.8%), and one developed gastric necrosis. The overall mortality rate of gastric ulcer bleeding is 10% (8). Classical indications have included a six-unit blood loss in 24-hour period and persistent blood loss with hemodynamic instability. Early surgical intervention has been advocated following initial endoscopic hemostasis and in one small series reduced mortality to 0% (53). Considering the present era of medical management of peptic ulcer disease and reservation of surgery for unstable patients, it has been argued that surgery should be focused and expedient. Bleeding gastric ulcers can be excised with a limited resection. Hemorrhage from a duodenal ulcer is controlled by placing sutures in the ulcer base, ligating the gastroduodenal artery source. The risk/benefit of spending additional time performing a vagotomy procedure in a critically ill patient is controversial.

Stress Gastritis Stress gastritis is not uncommon in the ICU setting, and is typically characterized by multiple, acute, shallow gastric ulcers. Stress ulcers are formed from a complex pathophysiology that involves tissue ischemia and reperfusion injury (54). The two most significant risk factors include mechanical ventilation and coagulopathy (55). Prophylaxis with either PPI or H2 blockers has been shown to prevent the incidence of GI bleeding in both patient populations (56). There is however debate as to whether PPIs are superior to H2 blockers. Studies have suggested that while maintaining a pH > 4 preserves gastric mucosa, a pH > 6, which can only be achieved through the use of PPIs, may further decrease the risk of bleeding (54).

Other Sources of Upper GI Bleeding Angiodysplasia accounts for 4% of upper GI bleeds and is associated with renal failure and aortic stenosis (57,58). These lesions are superficial dilated vessels most frequently located on the stomach and duodenum. On endoscopy, angiodysplasia appears as a network of vascular structures consisting of 2 to 8 mm diameter individual lesions with a starburst pattern (15). Coagulation with thermal techniques is highly effective. Hemobilia is defined as bleeding into the biliary tract. A number of oncologic, traumatic, infectious, and vascular etiologies exist. A recent literature review of 222 cases identified two-thirds of causes to be iatrogenic (59). The majority of cases are diagnosed by angiography with medical therapy and embolization utilized as initial treatment. Overall mortality is 5%. Splenic artery aneurysms are typically incidental findings on angiography. Splenic artery pseudoaneurysm has been reported to occur in up to 10% of patients with pancreatitis (60). There have been case reports of rupture into the stomach presenting as severe upper GI hemorrhage (61). Aortoenteric fistula may present as a result of abdominal aortic aneurysm, or following aneurysm repair with grafting (62). The incidence of both circumstances is considerably low. Patients classically present with a history of a sentinel bleeding, abdominal pain, fever, and a pulsatile mass on physical examination. Endoscopy and computed tomography (CT) scanning have been used successfully in evaluation. Fatal exsanguination occurs if not recognized. Clinical suspicion with prompt surgical intervention has been advocated as the key to patient survival (63).

The advent of laparoscopic gastric bypass surgery has introduced another post-surgical cause of bleeding. In a series of 155 patients, on whom Roux-en-y reconstruction was performed, five developed postoperative bleeding. Two of these patients required surgical intervention and in both cases, bleeding was identified at the staple line (64). Late hemorrhage following gastric bypass has also been studied. Braley reports four cases occurring at an average of 15.5 years after surgery, who presented with massive hemorrhage. Initial work-up included endoscopy, nuclear scan, and arteriography. Intraoperative endoscopy of the gastric remnant was performed followed by subtotal gastrectomy with three out of the four bleeding sources in the resected gastric remnant and duodenum (65).

LOWER INTESTINAL BLEEDING Lower intestinal bleeding makes up 25% of all GI hemorrhages and typically presents with hematochezia. Darker stools, although usually associated with an upper GI source of bleeding, can certainly occur with lower GI bleeding as well. A large based population study found the incidence of lower intestinal bleeding to be 24/100,000 for males and 17/100,000 for females. The rate increases over 200fold in the third to ninth decades of life (2). The most common etiologies were diverticulosis 41.6%, colorectal malignancy 9%, and ischemic colitis 8.7% (Table 4). Other causes of bleeding having an incidence of approximately 5% each include rectal ulcers, post-polypectomy bleed, colonic angiomas, or radiation telangiectasis (4). Overall mortality in this study of 219 patients with lower GI bleeding was 5% (2). The same guidelines for initial evaluation, as previously discussed, which include obtaining adequate IV access and initiating fluid resuscitation, are recommended. The patient’s presentation may give insight into the cause of bleeding. Diverticulosis frequently presents with brisk bleeding, whereas ulcerative colitis or infectious colitis are associated with constitutional symptoms and bloody diarrhea. NSAIDs may cause ulcerations, and warfarin may precipitate bleeding from already present pathology. Individuals who recently underwent colonoscopy and polypectomy may also present with bleeding.

Table 4 Causes of Lower Intestinal Hemorrhage Diverticulosis Colon cancer Polyps/postpolypectomy Ischemic colitis Arteriovenous malformations Inflammatory bowel disease Ulcerative colitis Chron’s disease Infectious colitis E. coli Salmonella Shigella Yersinia Vibrio Campylobacter Chlamydia Clostridium difficile Abbreviations: CMV, inflammatory drug.

cytomegalovirus;

HIV associated CMV Kaposi’s sarcoma Radiation colitis NSAID-induced ulcer Coagulopathy Anorectal Hemorrhoids Fistula Fissure Rectal ulcers Rectal cancer

NSAID,

nonsteroidal

anti-

Chapter 25: Gastrointestinal Hemorrhage

Evaluation Colonoscopy The decision to utilize, as well as the timing of, colonoscopy has been a subject of debate. The presence of severe bleeding in which visualization would be difficult is a frequently cited reason for not pursuing urgent colonoscopy. A retrospective review of 90 patients (urgent colonoscopy was performed in 39) found a definitive source in only three patients, a probable source in 26 patients, and no source in the remaining 10 patients (66). Other researchers have found urgent colonoscopy as the initial evaluative method of choice, allowing for immediate intervention and decreasing the need for surgery (67). Oral preparation to purge blood and clots is safe and increases the rate of successful localization. In one prospective study, urgent colonoscopy was performed after upper endoscopy and oral purge in a series of patients with ongoing severe hematochezia. A colonic source was found 74% of the time, and an upper GI source was found 11% of the time. The remaining 15% were classified as having either a presumed small intestine or an undiagnosed source (68). Another recent retrospective review of 345 patients identified a bleeding site in nearly 90% of cases (69). Early utilization of colonoscopy has also been found to decrease the length of hospital stay by identifying and discharging patients without evidence of active bleeding (Fig. 6) (70).

Arteriography In patients with hemorrhage that is severe, not amenable to or following unsuccessful colonoscopy, arteriography should be considered. Arteriography is able to detect bleeding at a minimum of 0.5 mL/min with optimal visualization at a rate of 1 mL/min (71). It has frequently been used preoperatively to mark the source of hemorrhage via injection of methylene blue. Interventional techniques allow placement of embolic coil or local infusion of vasopressin. Vasopressin is given at a rate of 0.2 units/min once the catheter is positioned in a distal vessel near the source and may be increased up to 0.4 units/min to control bleeding. If successful, the infusion is continued for 12 to 24 hours followed by a 24-hour taper. Unfortunately, this technique is associated with a rebleeding

Lower Gastrointestinal Hemorrhage

Nasogastric tube Rule out UGI source Proctoscopy Rule out rectal source Continued massive

Low rate or

hemorrhage

intermittent hemorrhage

Angiography Diagnostic

Nondiagnostic

Colonscopy Nondiagnostic

Diagnostic

Figure 6 Diagnostic steps in the evaluation of lower gastrointestinal hemorrhage.

533

rate of approximately 50%. Vasopressin is also not without side effects, the most significant being coronary vasoconstriction. Concurrent intravenous nitroglycerin therefore may be required. Updated studies using super-selective embolization with coils have recently been published. One series obtained initial hemostasis in all 27 patients. Subsequently, six patients developed rebleeding and two patients developed colonic ischemia (72). Another series controlled initial bleeding sources in all 10 patients, two of whom subsequently rebled (73).

Nucleotide Scan Nucleotide scan uses 99mTc sulfur colloid or 99mTc-tagged red blood cells to find occult sources of bleeding. The modality is frequently performed when colonoscopy is negative, and is more sensitive than arteriography, detecting bleeding at a rate of 0.l cc/min (74). A positive scan is identified by extravasation, pooling, or configuration to the bowel lumen. The accuracy in localizing colonic bleeding using nucleotide scans has been reported as 75% (75). Other studies, however, report less-impressive figures of 24.4% using Tc sulfur colloid and 27.5% using Tc RBC (76). Peristalsis in part also accounts for the difficulty in localizing the site of bleeding (71). Increasing the duration of scan has been shown to increase the detection rate and may account for study discrepancies.

Helical CT Helical CT scanning has recently been evaluated in a small series. Nineteen of 26 patients evaluated by colonoscopy, enteroscopy, or surgery had an accurate diagnosis with helical CT. Additionally, four of five small bowel hemorrhages and 10 of 14 colonic sources were identified. Overall, the primary diagnosis was made by CT in 10 of 19 patients (74).

Etiology Diverticulosis Diverticulosis is an out-pouching of the mucosa and submucosa as the vasa recta penetrate the circular muscular layer. Recent theories suggest a component of taenia coli elastosis with sigmoid shortening and diverticulum formation (77). The descending colon is the most common site of diverticulosis with right-sided lesions seen more frequently in younger patients. Diverticular disease is estimated to affect 30% to 60% of the general population; however, only 5% of patients will have GI hemorrhage (78). In 75% of patients, bleeding will stop spontaneously (79). Findings with colonoscopy of recent bleeding may include a visible or actively bleeding diverticulum or adherent clot (Fig. 7). Local injection with epinephrine, bipolar electrocoagulation, or both have been found to stop active bleeding with a very low incidence of rebleeding (67). AVM Arteriovenous malformations (AVMs) are a result of the failure of the precapillary sphincters entering the intestinal capillary bed. An increase in blood flow subsequently occurs with potential for rupture into the adjacent mucosal tissue. Bleeding is typically intermittent, causing a chronic anemic state. Endoscopic therapy consists of coagulation via colonoscopy and may require several treatments to treat multiple sites (4). Segmental resection of multiple lesions unamendable to endoscopic therapy is also a treatment option.

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Tumors Adenocarcinoma causes bleeding through ulcerative erosion during colonic invasion and is responsible for 9% of lower bleeding causes (2). Presentation is typically of occult blood loss or anemia and rarely of acute bleed. Colonoscopy is diagnostic and is utilized in biopsy of polyps and ulcers. The incidence of severe bleeding requiring hospitalization following polpectomy is 0.2% (83). Other Causes Other causes of lower GI bleeding include anorectal sources, coagulopathy, HIV, and NSAIDs. Evaluation of the anus and rectum is the first step in the patient with hematochezia. Hemorrhoids, rectal ulcers, fissure, and fistulas are all common causes of rectal bleeding. In younger patients in whom definitive rectal pathology is not identified, sigmoidoscopy is utilized. A study looking at the yield of colonoscopy in 1766 subjects found that there was no evidence of cancer beyond the length of a sigmoidoscope in subjects less than 40 years old. The study also found that 7% of patients in this age category had a proximal lesion that accounted for their bleeding (84). It is however recommended that all patients older than 40 years undergo full colonoscopy. Bleeding or anemia in the setting of anticoagulation therapy raises the question of a proximal lesion and not simply drug induced. GI bleeding in HIV patients is most frequently associated with CMV infection, followed by idiopathic colonic ulcers and intestinal Kaposi’s sarcoma (85). Finally, ASA and NSAIDs, although classically associated with peptic ulcer disease, are also known to cause similar ulcerative lesions in the colon (31).

Treatment

Figure 7 (A–C) Bleeding diverticulum located in the sigmoid colon. Endoscopic treatment with bipolar electrocoagulation is performed with resulting hemostasis.

Colitis Several etiologies of colitis exist, including ischemia, infection, radiation, and inflammatory bowel disease. Ischemic colitis represents 9% of causes of lower GI bleeding (2). The entity is seen in the elderly and affects the watershed areas of the colon. Infectious causes of colitis include E. coli, Salmonella, Shigella, Yersinia, Vibrio, Campylobacter, Chlamydia, and Clostridium difficile (80). Cytomegalovirus (CMV) is known to cause an infectious colitis in patients with HIV infection (81). Colonoscopy’s role is that of biopsy rather than specific therapeutic intervention. Radiation therapy causes the formation of colonic telangiectasias that are susceptible to bleeding. Ulcerative colitis and Crohn’s disease rarely present with major acute hemorrhage accounting for 0.1% and 1.2% of admissions for these disease entities, respectively (82). Recurrent bleeding is an indication for surgical resection.

Surgery in lower intestinal bleeding is not infrequently used as a procedure of last resort. Historically, colectomy procedures have been associated with poor outcomes. Mortality rates have ranged from 30% to 75% with blind segmental colectomy having the highest rebleeding and mortality (86). Ideally, a localization study should be performed to direct colonic resection. Emergent surgery is an option when other diagnostic modalities fail or in those patients who would not survive the delay for catheter-based intervention. Once the decision is made to proceed with surgery, total abdominal colectomy is the recommended procedure. Baker in his series found a mortality of 6%, compared to 15% with limited resection (87). Differences in outcome compared to previous studies with higher mortality rates are most likely due to patient selection, bleeding severity, and other comorbidities.

Small Intestine Bleeding When both upper endoscopy and colonoscopy fail to reveal a source of bleeding, the possibility of a small intestine source should be considered. Vascular lesions are the most common cause including AVM, vascular ectasia, hemangiomas, and hemangiodysplasias. Other causes include small bowel tumors such as leiomyomas, lymphomas, Crohn’s disease, Meckel’s diverticulum, and jejunal diverticulum.

Evaluation Push Enteroscopy Evaluation of the small intestine is a diagnostic challenge, and several options exist. Previously, radiographic upper GI barium study with small bowel follow-through was frequently used, primarily aimed at identifying a bleeding

Chapter 25: Gastrointestinal Hemorrhage

mass lesion. The sensitivity of this technique, however, has been reported at only 10% and thus, it no longer serves a role in modern-day management. Push enteroscopy is the continuation of the upper endoscopy beyond the ligament of Treitz. It can be used to assess the small bowel into the distal jejunum. The main advantage is the ability to see a larger portion of the intestine; however, the ileum is typically out of reach during evaluation. In addition to small intestine length, the presence of rugal folds contributes to the difficulty in identifying a hemorrhagic source; however, if found, the option does exist for therapeutic intervention. Intraoperative Enteroscopy Intraoperative enteroscopy is another technique to evaluate the small intestine. The technique utilizes a pediatric enteroscope advanced orally or via an enterotomy. The scope is passed rostrally and caudally to evaluate for the source of bleeding. One series identified 16 of 20 small intestine bleeding sources, which were subsequently managed with small bowel resection. The rebleeding rate, however, was 30%, and two of the patients with negative examination subsequently died of massive hemorrhage (88). This incidence of rebleeding is similar to that in other studies with the majority of rebleeding lesions being AVMs (89). Capsule Endoscopy The advent of capsule endoscopy is a sign of the everevolving medical technology. The capsule is a small camera that can be swallowed by the patient and that serially takes images along its voyage through the GI tract. This technique allows the entire tract—including the distal jejunum and the ileum—to be visualized. The first prospective trial of its use followed 32 patients with chronic bleeding evaluated using conventional modalities including small bowel followthrough, scintigraphy, arteriography, push endoscopy, and capsule endoscopy. Conventional methods were diagnostic in 16% of cases, push endoscopy in 28%, and capsule endoscopy in 66% (90).

OCCULT BLEEDING Occult bleeding refers to blood loss in a patient with anemia or guiac positive stools. Obscure bleeding is a term used in reference to an unknown bleeding source in a patient with known GI hemorrhage. A number of techniques including arteriography and tagged red blood cell scans are available as previously discussed. The work-up for occult bleeding is common to all patients presenting with GI hemorrhage and includes history, physical examination, and ultimately endoscopy (Table 5). The differential diagnosis of occult bleeding is extensive. These may be divided into two classifications—those associated with positive fecal occult testing and those with iron-deficiency anemia (Table 5). History and physical examination may reveal clues as to the possible source. Several associations are implicit, such as a history of NSAIDs or weight loss associated with cancer in an older patient. Blue rubber nevus syndrome may present in a younger patient with cutaneous hemangiomas, while oral mucosal and extremity hemangiomas may be found in a patient with hereditary hemorrhagic telangiectasia (91). Family history may reveal a history of polyposis syndromes, also associated with occult bleeding. Endoscopy should be the next step in evaluation. The initial choice of colonoscopy or endoscopy is frequently

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Table 5 Causes of Occult GI Bleeding Positive FOBT Upper GI lesions Esophagitis Peptic ulcer disease Gastritis/erosions Duodenitis/ erosions Angiodysplasia Esophageal or gastric varices Gastric cancer

Gastric or duodenal polyps

Colonic lesions Colon polyps Colon cancer Angiodysplasia Colonic ulcers

Iron deficiency anemia Upper GI lesions Esophagitis Peptic ulcer disease Gastritis/erosions Duodenitis Angiodysplasia Portalhypertensive gastropathy Gastric or esophageal cancer Gastric or duodenal polyps Celiac sprue Crohn’s disease Gastric/duodenal lymphoma Partial gastrectomy GAVE

Colonic lesions Colon polyps Colon cancer Angiodysplasia Colonic ulcers Colitis/IBD Parasitic infestation Hemorrhoids

Diverticular disease

Abbreviations: IBD, inflammatory bowel disease; GAVE, gastric antral vascular ectasia; GI, gastrointestinal. Source: From Ref. 91.

based on symptoms. In an elderly patient, searching for a source of cancer is of priority. The positive predictive value of fecal occult testing for colon cancer is only 7%, leaving a number of other possibilities (92). However, colon polyps and cancer are associated with bleeding 70% of the time (92). Examination of the upper GI tract will also frequently reveal a source. Studies have found the majority of lesions via esophagogastroduodenoscopy (EGD). One of the many studies categorizing sources of occult bleeding examined 248 patients with positive fecal occult blood test (FOBT) and found a lower bleeding source in 54 patients and an upper source in 71 patients (93). Negative upper and lower endoscopy presents a dilemma to the clinician. Repeat upper endoscopy in particular identifies initially missed lesions in 30% to 75% of cases. Most frequently, Cameron’s ulcer located in hiatial hernias, peptic ulcer disease, and vascular ectasia are subsequently found (91). The decision to proceed with further evaluation should be based on the severity and the recurrence of anemia. When colonoscopy and upper endoscopy are negative in patients with anemia, 83% will respond to iron therapy alone (94). In those patients with significant persistent losses, the small bowel is considered next for evaluation. Push enteroscopy is most frequently utilized in the setting of occult bleeding. As previously discussed, the technique uses an endoscope advanced past the ligament of Treitz. Success in identifying a lesion occurs 50% of the time, with AVMs being the most common lesion (89). Push enteroscopy has also been advocated as the initial test rather than EGD alone in occult bleeding, increasing the diagnostic yield from 41% to 67% while saving time to diagnosis and perhaps cost (95). Finally, capsule endoscopy is also becoming more readily available with success rates of identifying an occult bleeding source 76% of the time (96). Despite a best effort, many

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patients will continue to bleed from an unidentified source. These patients should have regular follow-up to monitor hemoglobin levels and to offer reassurance.

SUMMARY GI hemorrhage continues to be responsible for as many as 2% of all hospital admissions, with an overall mortality rate approaching 5% to 12%. Bleeding proximal to the ligament of Treitz is termed ‘‘upper GI hemorrhage,’’ while that distal to this anatomic site is referred to as lower GI hemorrhage. Endoscopy provides the mainstay of identifying the source of bleeding for suspected upper tract hemorrhage, while a combination of maneuvers, including endoscopy, radionuclide scanning, and arteriography, may prove necessary to pinpoint the source of bleeding from a lower tract site. Capsule endoscopy is emerging as an important diagnostic aid for bleeding arising from the small intestine, a region of the gut that heretofore was difficult to evaluate. Fortunately, GI tract hemorrhage can be managed without operative intervention in the vast majority of patients using various endoscopic and/or angiographic techniques. In the small subset of patients requiring surgery, the underlying cause will dictate the specific procedure required. In the unusual patient in whom the source of bleeding remains occult, continued surveillance ultimately identifies the underlying cause in the majority of individuals. Appropriate therapy can then be employed based on the natural history of this cause.

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26 The Anatomy, Physiology, and Differential Diagnosis of Acute Abdominal Pain Kathryn A. Richardson, Ryan M. Wolfort, and Richard H. Turnage

The pain is more intense and more precisely localized than visceral pain. It is lateralized because only one side of the nervous system innervates a given part of the parietal peritoneum. The pain is exacerbated by movement or coughing, and hence patients will usually lie still in an attempt to limit their pain.

INTRODUCTION Abdominal pain is the principal symptom of most acute abdominal diseases. In particular, the acute onset of severe abdominal pain in a patient who was previously well suggests a disease of surgical importance, especially if the pain has persisted for six hours or more. The term ‘‘acute abdomen’’ is often applied to such cases; however, this term should not be equated with the need for operation. It does, however, necessitate ‘‘a serious and thorough attempt at diagnosis’’ (1). The onset of severe abdominal pain is caused by ischemia, inflammation of an abdominal organ or tissue, or acute distention of a hollow smooth muscle-lined structure such as the ureter or intestine or by stretching of the peritoneum or the capsule of a solid organ. This chapter relates the anatomy and physiology of acute abdominal pain to the clinical presentation of patients with diseases commonly associated with this symptom. Furthermore, the influence of extremes of age, immunosuppression with steroids or acquired immunodeficiency syndrome (AIDS), and spinal cord injury on the clinical presentation of patients with acute abdominal diseases is reviewed.

Referred Pain Referred pain occurs when pain is perceived in an area of the body remote from its site of origin. It is intense, sharp, and perceived to be superficial in nature. Referred pain occurs as the visceral stimulus intensifies. Well-known examples of referred pain are shown in Figure 2A and include shoulder pain upon inflammation of the diaphragm, scapular pain associated with acute biliary tract disease, or testicular or labial pain caused by retroperitoneal inflammation. Referred pain is caused by the convergence of visceral afferent neurons innervating an injured or inflamed organ, with somatic afferent fibers arising from a different anatomic region. This convergence occurs at the level of second-order neurons at the same level in the spinal cord as illustrated in Figure 2B.

TYPES OF ABDOMINAL PAIN

ANATOMY AND PHYSIOLOGY OF ABDOMINAL PAIN Visceral and Somatoparietal Nociceptors

Abdominal pain may be categorized as visceral, somatoparietal, or referred based on distinct clinical features and the underlying neuroanatomy.

The neuroreceptors involved in nociception are the peripheral ends of two distinct types of afferent nerve fibers: A-delta fibers and C-fibers.

Visceral Pain

A-Delta Fibers

Visceral pain is caused by stimulation of visceral nociceptors by inflammation, distention, or ischemia. The pain is dull and poorly localized to the epigastrium, periumbilical region, or the lower mid-abdomen depending upon the dermatomal distribution of the nerves supplying the diseased organ. This is illustrated in Figure 1. The pain is poorly localized because the innervation of most viscera is multisegmental and contains fewer nerve receptors than highly sensitive organs such as the skin. It is perceived in the midline because the abdominal organs transmit sensory afferents to both sides of the spinal cord. Visceral pain is often described as cramping, burning, or gnawing and may be accompanied by secondary autonomic effects such as sweating, restlessness, nausea, vomiting, perspiration, and pallor. The patient may move about in an effort to lessen the discomfort.

The A-delta fibers are myelinated nerves that are 3 to 4 mm in diameter and transmit signals at a rate of 6 to 30 m/sec. They are primarily distributed in skin and muscle. A-delta fibers mediate the sharp, sudden, and well-localized pain that follows acute injury or inflammation. These fibers transmit somatoparietal pain sensation from the anterior and lateral abdominal walls to the central nervous system via spinal nerves from segments T7 through L1. Somatoparietal pain from the posterior abdominal wall is transmitted to the central nervous system via spinal nerves from segments L2 to L5. The pain is precisely localized by the specific spinal level (T7–L1) and the side of activated A-delta fibers (right or left).

C-Fibers C-fibers are unmyelinated nerves that are primarily involved in the transmission of visceral pain in association with the autonomic nervous system. These fibers are more slowly transmitting than the A-delta fibers (0.5–2 m/sec)

Somatoparietal Pain Somatoparietal pain is due to stimulation of somatic sensory spinal nerves innervating the parietal peritoneum (T7–L1). 539

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to provide sensory innervation to the hypogastrium and lower anterior abdominal wall. The iliohypogastric nerve runs parallel to the 12th thoracic nerve to pierce the transversus abdominis muscle near the iliac crest. After coursing between the transversus abdominis and the internal oblique muscle for a short distance, the nerve pierces the latter to travel under the external oblique fascia toward the external inguinal ring. It emerges through the superior crus of the external inguinal ring to provide sensory innervation to the anterior abdominal wall in the hypogastrium. The ilioinguinal nerve courses parallel to the iliohypogastric but closer to the iliac crest. Unlike the iliohypogastric, the ilioinguinal nerve courses with the spermatic cord to emerge from the external inguinal ring with its terminal branches providing sensory innervation to the skin of the inguinal region and the scrotum or labium.

Peripheral Neural Pathways for Visceral Pain

Figure 1 Anatomic locations where visceral abdominal pain is perceived. The location in which visceral pain is perceived is related to the embryologic site of origin of the organ from which the pain stimulus emanates. Activation of nociceptors in the foregut (stomach, duodenum, liver, spleen, and gallbladder) causes the perception of pain in the epigastrium (T5–T9). Stimulation of nociceptors in the midgut (small intestine, appendix, and right colon) causes the perception of pain in the periumbilical region (T8–L1). Pain stimuli from the hindgut-derived organs (left colon and proximal rectum) is perceived in the hypogastrium (T12–L1).

and produce a sensation of pain that is dull, burning, and poorly localized. The sensation of pain mediated by these fibers is also more gradual in onset and longer in duration than the sensation transmitted by A-delta fibers. C-fibers are located in the walls of hollow viscera, mesentery, parietal peritoneum, and the capsule of solid organs. In addition to transmitting the sensation of pain to the central nervous system, stimulation of C-fibers activates local regulatory reflexes mediated by the enteric nervous system and long spinal reflexes mediated by the autonomic nervous system.

Peripheral Neural Pathways for Somatoparietal Pain The 7th to 12th thoracic nerves follow a curvilinear course in the intercostal spaces to emerge from under the costal cartilages and lower ribs. From here, they course medially between the internal oblique and the transversus abdominis muscles to reach the anterior midline. The seventh and eighth thoracic nerves course horizontally or slightly upward to reach the epigastrium whereas the lower nerves follow an increasingly caudal trajectory. As these nerves course medially, they provide motor branches to the abdominal wall musculature and sensory branches to the anterolateral abdominal wall. The anterior ramus of the 10th thoracic nerve reaches the skin at the level of the umbilicus, and the 12th thoracic nerve provides sensory innervation to the skin of the hypogastrium. The anatomic course of the nerves innervating the abdominal wall as well as the corresponding dermatomes are shown in Figure 3A and B. The ilioinguinal and iliohypogastric nerves arise from the anterior rami of the 12th thoracic and first lumbar nerves

The visceral afferent fibers transmitting nociception from the abdominal viscera to the central nervous system follow the distribution of the autonomic nervous system, principally the sympathetic nervous system. Only the middle and upper esophagus and the pelvic organs receive visceral sensory afferents along parasympathetic nerves. The sensory innervation of abdominal organs is related to the embryologic site of origin of the organ. Pain originating in structures derived from the embryonic foregut is perceived in the epigastrium, pain originating in midgut-derived structures is felt in the periumbilical region, and pain originating in structures derived from the embryonic hindgut is perceived in the hypogastrium. The relationship between the site of visceral pain and the embryologic origin of the injured or diseased organ is shown in Table 1 and Figure 1.

Central Neuroanatomy of Visceral and Somatoparietal Pain The sensory afferent nerves from both the abdominal viscera and the abdominal wall enter the spinal cord through the posterior nerve root. The cell bodies for the visceral and somatoparietal afferent nerves are located in the dorsal root ganglia of the spinal nerves. The relationship between the splanchnic and spinal nerves and the corresponding dorsal root ganglion is illustrated in Figure 4. Upon entering the spinal cord, the visceral afferent fibers branch into the dorsal horn and into Lissauer’s tract over several spinal segments before terminating on the dorsal horn cells in Rexed lamina V. Somatic nerves also enter the spinal cord through the dorsal nerve root and branch to synapse with second-order neurons in lamina I. From the dorsal horn, second-order neurons either transmit nociceptive impulses to other neurons (i.e., interneurons or relay cells) or transmit nociceptive impulses via fibers that cross through the anterior commissure to ascend the spinal cord in the contralateral spinothalamic and spinoreticular tract. Ultimately, these fibers project to the thalamic nuclei and the reticular formation nuclei of the pons and medulla. The pons sends third-order neurons to the somatosensory cortex, where the discriminative aspects of pain are perceived. The medulla sends neurons to the limbic system and frontal cortex, where the emotional aspects of pain are interpreted and the associated phenomena of nausea, vomiting, and other physiologic responses are precipitated. Afferent pain impulses are modified by inhibitory neuronal pathways within the dorsal horns of the spinal cord. These inhibitory neurons originate in the mesencephalon,

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Figure 2 The surface anatomy (A) and neuroanatomy (B) of referred abdominal pain is perceived. The location of the referred abdominal pain is based on the convergence of visceral afferent neurons innervating an injured or inflamed organ 1 with somatic afferent fibers arising from the anatomic region in which the referred pain is perceived 3. These visceral and somatic afferent neurons synapse with second-order neurons in the spinal cord 2 and the brain interprets the pain to be somatic in origin and localizes it to the shoulder. Source: From Refs. 2, 3.

periventricular gray matter, and caudate nucleus and descend within the spinal cord to the level of the substantia gelatinosa where they release endogenous opioids and enkephalins, which inhibit ascending nociceptive pain impulses. Inhibitory interneurons also act upon the cell bodies of nerves in Rexed lamina V of the dorsal horn, which receive impulses from both somatic and visceral afferent nerve fibers. Together, these inhibitory pathways allow cerebral modification of afferent pain impulses.

PATHOPHYSIOLOGIC STIMULI FOR SOMATIC AND VISCERAL NOCICEPTORS Somatoparietal nociceptors respond to sudden increases in tissue pressure, the cutting or tearing of tissue, and acute changes in tissue temperature or pH (such as that associated with inflammation). The principal mechanical stimulus for visceral nociceptors is a sudden change in the geometry of the bowel or capsule of a solid organ. This may occur by distention of an acutely obstructed intestine, ureter or fallopian tube, or the stretching of Glisson’s capsule in patients with acute hepatitis or congestive heart failure. Unlike somatoparietal nociceptors, the cutting, tearing, or crushing of abdominal viscera does not stimulate visceral sensory afferents. Visceral nociceptors also respond to chemical stimuli, particularly those associated with inflammation and ischemia. It is postulated that these proinflammatory states induce the release of vasoactive substances (i.e., bradykinin, histamine, serotonin, and eicosanoids), gastrointestinal neurotransmitters and hormones (i.e., substance P and calcitonin-gene–related peptide), and various end products of metabolism (i.e., potassium and hydrogen ions),

which then stimulate visceral afferent sensory neurons. These substances may also potentiate the effects of mechanical stimuli by lowering the threshold for a given mechanical stimulus to excite the C-fiber nociceptor.

EVALUATION OF PATIENTS WITH ACUTE ABDOMINAL PAIN The acute onset of severe abdominal pain necessitates prompt diagnosis. In some cases, the clinical findings are so compelling that there is little doubt as to the etiology, much less the course of action. In others, the precise diagnosis is not readily apparent. In these instances, an earnest effort, based upon a thorough history and physical examination, must be made to determine the cause of the patient’s symptoms. An orderly and systematic approach to diagnosis will facilitate the development of a relevant differential diagnosis and guide the appropriate use of laboratory and imaging studies. The components of the differ ential diagnosis should be considered according to those conditions that are most common and those that present the greatest threat to the patient’s life.

History The goal of the clinician’s examination is to recognize the subtle signs and symptoms of abdominal diseases early in their evolution, well prior to the development of peritonitis. An accurate, detailed history provides the initial, and perhaps most important, step toward elucidating the cause of the patient’s abdominal pain. In large part, an accurate differential diagnosis may be based upon the location and

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Figure 3 (A) The anatomic course of the thoracic (T7–12) and lumbar (L1–L2) spinal nerves that provide somatoparietal pain sensation to the abdominal wall. The thoracic and lumbar spinal nerves follow a curvilinear course around the torso to provide motor innervation to the flat muscles of the abdominal wall and sensory innervation to the skin, muscle, and parietal peritoneum of the anterolateral abdominal wall. (B) The dermatomes providing sensation to the abdominal wall originate from the seventh thoracic nerve to the second lumbar nerve. The seventh thoracic nerve innervates the epigastrium, the 10th thoracic nerve innervates the region of the umbilicus, and the 12th thoracic and first lumbar nerves provide sensory innervation to the hypogastrium. There is considerable overlap between these dermatomes such that division of one of the nerves alone to a given dermatome will result in minimal deficit. Source: From Refs. 4, 5.

character of the patient’s pain and the chronologic relationship between the pain and other symptoms.

Chronology and Pattern of Abdominal Pain It is important to understand the evolution of the patient’s illness from the moment of onset until the time of examination. Patients with significant abdominal pain will often be able to precisely time the onset of their symptoms. The awakening from a sound sleep by the onset of acute abdominal pain is almost always of great significance. Pain that is sudden in onset, severe, and well localized frequently results from an acute intra-abdominal ischemic or inflammatory process that will require surgical management. In these instances, the pain does not abate with time but retains its severe character as is illustrated by ‘‘Line A’’ in Figure 5. In some instances, the patient will collapse at the onset of their pain. Examples of these conditions include perforation of a duodenal or gastric ulcer, ruptured ectopic pregnancy, ruptured abdominal or splanchnic artery aneurysm, and acute mesenteric ischemia. Other patients will present with a more gradual onset and evolution of their abdominal pain as illustrated by ‘‘Line B’’ in Figure 5. Patients with acute appendicitis will often present with an early vague periumbilical visceral pain followed by localization of severe somatoparietal pain at McBurney’s point. This gradual evolution of pain and associated symptoms is also apparent in cases of acute cholecystitis, acute pancreatitis, and acute diverticulitis.

Obstruction of a hollow viscus such as the small intestine or the ureter causes colicky or cramping pain that is best described by a crescendo–decrescendo pattern with relative freedom from pain between cramps; a pattern illustrated by ‘‘Line C’’ in Figure 5. The change of colicky visceral pain to a constant somatoparietal pattern in patients with intestinal obstruction strongly suggests infarction of the obstructed intestine. The pain caused by obstruction of the cystic duct in cases of biliary ‘‘colic’’ is steady and not paroxysmal, and hence the term ‘‘biliary colic’’ is a misnomer. In this instance, the lack of a dense muscular wall and hence strong steady contractions prevent the cramping associated with obstruction of other hollow viscera.

Location of Abdominal Pain Precise localization of the patient’s abdominal pain is extremely valuable in developing an accurate differential diagnosis. Even patients with severe diffuse pain can often identify a site of greatest discomfort or the site from which the pain originates. The patient may also be able to differentiate the initial medially located, vague visceral pain from the subsequent sharp, well-localized somatoparietal pain. It is important to recall the common sites in which visceral and referred pain from injured or inflamed organs are perceived (Figs. 1 and 2). Understanding the normal anatomic location of various organs, as well as their aberrant locations, may be

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Table 1 Relationship Between the Site of Visceral Pain and the Embryonic Origin of the Diseased or Injured Organ Embryonic site of origin

Surface location

Dermatomal distribution and nerves

Foregut

Epigastrium

T5–T9 spinal levels, celiac plexus, greater splanchnic nerves

Midgut

Periumbilical

T8–L1 spinal levels, lesser and least splanchnic nerves

Hindgut

Hypogastrium

Urogenital system and gonads

Hypogastrium

T11–L1 and S3–S5 spinal levels, inferior mesenteric plexus, lowest splanchnic nerve, hypogastric plexus T10–L 2 spinal levels

Intra-abdominal organs Esophagus, stomach, duodenum, spleen, liver, gall bladder, portion of the pancreas Jejunum, ileum, appendix, cecum, ascending colon, and the right half of the transverse colon Distal half of the transverse colon, descending colon, sigmoid colon and rectum Kidneys, ureter, bladder, uterus, vagina, gonads

Representative diseases Peptic ulcer disease, biliary colic, acute pancreatitis SBO, acute appendicitis, Meckel’s diverticulitis Acute diverticulitis, ischemic colitis, ulcerative colitis Acute salpingitis, pyelonephritis, ureteral colic

Abbreviation: SBO, small bowel obstruction.

suggestive of the organ from which somatoparietal pain impulses originate. Common causes of pain in each of the regions of the abdomen are shown in Figure 6E. It should be recalled that the flow of fluid within the peritoneal cavity is governed by various ligaments or mesenteries, which subdivide the peritoneal cavity into interconnected compartments or spaces. This results in well-defined pathways by which fluid flows within the peritoneal cavity (Fig. 7). From this knowledge, it is understandable how the acrid fluid of a perforated duodenal ulcer may flow down the right paracolic gutter to inflame the parietal peritoneum in the right lower abdomen and cause symptoms suggestive of acute appendicitis. Furthermore, peritoneal fluid normally flows from the pelvis superiorly toward lymphatic channels within the

Figure 4 The sensory afferent nerves from both the abdominal viscera and the anterolateral abdominal wall enter the spinal cord through the posterior nerve root. The cell bodies for both the visceral and the somatoparietal afferent nerves are located in the posterior root ganglion. Source: From Ref. 6.

inferior surface of the diaphragm. Thus infections originating in the pelvis may cause symptoms in other parts of the abdomen, e.g., the right upper abdominal pain associated with Fitz-Hugh-Curtis syndrome from acute salpingitis.

Aggravating and Alleviating Factors The factors that exacerbate or relieve a patient’s pain may provide additional, supportive information to that gleaned from review of the character and location of the pain. Patients with peritonitis will often relate that any sudden movement will exacerbate their pain, such as that produced by coughing. These patients will often lie motionless on the examining table in an attempt to minimize their discomfort. Patients with acute pancreatitis will relate a lessening of their discomfort upon assuming an upright, or even bent over, posture.

Figure 5 Patterns of acute abdominal pain. (A) This unremitting severe pain pattern is characteristic of perforation of the duodenum or stomach from ulcer disease, ruptured ectopic pregnancy, and ruptured visceral artery aneurysm or abdominal aortic aneurysm. (B) The pattern of pain associated with acute pancreatitis, acute cholecystitis, and acute appendicitis is more gradual in onset and evolution. (C) This crescendo–decrescendo pattern of severe pain with intervening periods of absence of pain is characteristic of the colicky pain of simple small intestinal obstruction and obstruction of the ureter by a calculus. (D) Many uncomplicated conditions are associated with the gradual onset and spontaneous resolution of abdominal pain such as acute gastroenteritis.

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Figure 6 Common diagnoses associated with pain and localized tenderness in the right upper quadrant (A), the left upper quadrant (B), the right lower quadrant (C), and the left lower quadrant (D), and diffuse, generalized abdominal pain and tenderness (E). These diagnoses are grouped according to the organ or organ system in which they occur. Abbreviations: SMA, superior mesenteric artery; SMV, superior mesenteric vein.

Chapter 26: The Anatomy, Physiology, and Differential Diagnosis of Acute Abdominal Pain

Figure 7 Intraperitoneal circulation of fluid from the pelvis toward the lymphatic channels in the inferior surface of the diaphragm. From these pathways it is apparent how an infection within the pelvis, such as acute salpingitis, may spread to involve the peri-hepatic spaces to cause FitzHugh-Curtis syndrome. Fluid may also move from superior locations toward the pelvis in response to gravity. For example, the acrid fluid of a perforated duodenal ulcer may spread down the right paracolic gutter to present as peritonitis in the right lower abdomen. Source: From Ref. 7.

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with a pelvic abscess from perforated appendicitis may present with diarrhea and tenesmus. The failure to pass flatus is an important symptom in patients suspected of having intestinal obstruction. However, it should be noted that patients with a partial small intestinal obstruction, or a high-grade colonic obstruction, may present with a profuse watery diarrhea that is likely to mislead the uninformed examiner who believes that any bowel motions exclude the possibility of obstruction. It is the failure to pass flatus in these cases that supports the diagnosis of intestinal obstruction. Patients with severe abdominal inflammatory conditions may have a fever but the presence of rigors and high fever (103–104 F), particularly early in the course of a patient’s illness, is uncommon. It is of utmost importance to inquire about the menstrual history of premenopausal women presenting with acute abdominal pain. The precise date of the last period must be determined and any irregularity noted. The symptoms associated with a ruptured follicular cyst (Mittelschmerz) usually occur at midcycle whereas rupture of a corpus luteum cyst occurs at the time of the menses. Patients with a tubal pregnancy will almost invariably report some menstrual irregularity in the weeks preceding the onset of their pain.

Past Medical History and Family and Social History

Associated Symptoms It is unusual for abdominal pain to be the only symptom of an acute abdominal disease of surgical importance. Information regarding constitutional symptoms (e.g., fever, chills, and weight loss), digestive function (e.g., anorexia, nausea, vomiting, flatus, diarrhea, and constipation), jaundice, dysuria, menstruation, and pregnancy must be obtained. It is of particular importance to elucidate the temporal relationship between these symptoms and the onset of the patient’s pain. Forexample, patients with acute appendicitis will nearly always develop nausea and vomiting after the onset of their abdominal pain. In fact, the diagnosis of acute appendicitis would be unlikely in those instances in which nausea and vomiting preceded the development of pain. The presence of anorexia and the character and volume of the emesis should be noted. As alluded to earlier, activation of visceral nociceptors is often associated with autonomic effects including vomiting. Even patients with acute obstruction of the ureter or the cystic duct by a stone will have early and sudden emesis of bilious or clear fluid; a similar phenomenon occurs in patients with acute ovarian torsion. In patients with intestinal obstruction, the character of the emesis changes over time from bilious fluid early to a brownish, feculent fluid later in the evolution of this disease. The emesis of patients with proximal small intestinal obstruction is frequent, copious, and early in onset after the development of the patient’s pain, and whereas patients with more distally located obstructions will have less frequent emesis. Anorexia is a more constant symptom than vomiting in patients with acute abdominal diseases. The acute loss of appetite is always significant, especially when accompanied by the development of abdominal pain. An acute change in bowel habits is also likely to be of significance in patients presenting with acute abdominal pain. Patients

Careful review of the patient’s chronic or previous medical problems will often shed light on the current situation. Previous history of partial small bowel obstruction (SBO), renal calculi, or inflammatory bowel disease should alert the clinician to the possibility of a recurrence of their disease. Medication use, both prescriptive and over the counter, must be ascertained, particularly given the association between nonsteroidal anti-inflammatory drug use and ulcer disease. A careful review of the patient’s family history may yield important information regarding the cause of their abdominal pain, particularly in children. Sickle cell disease in people of African descent is a good example. The patient’s social history, especially the use of illicit drugs, may be important in determining the etiology of their disease. For example, cocaine use is associated with ischemic perforation of the intestine.

Physical Examination A thorough physical examination is of paramount importance in developing an accurate differential diagnosis and determining the presence of peritonitis and the need for urgent or emergent operation. The physical findings must be interpreted in the context of the patient’s medical history. For example, elderly or immunocompromised patients will often lack clear physical signs of peritonitis, even in the presence of a perforated bowel (a topic considered subsequently).

Systemic Examination The physical examination begins by observing the patient’s general appearance, posture, position in bed, degree of discomfort, and facial expression. A patient lying still in bed with hips and knees flexed, and reluctant to move with a distressed facial expression suggests the presence of peritonitis whereas those patients who writhe about in bed seeking a comfortable position are more likely to have colic from an obstructed ureter or intestine or acute mesenteric ischemia.

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The patient’s heart rate, ventilatory rate, temperature, and blood pressure should be measured; tachycardia and tachypnea may result from pain, sepsis, or hypovolemia. An irregularly irregular pulse, suggestive of atrial fibrillation, should greatly heighten one’s suspicion that the patient’s abdominal pain is due to an embolus to the superior mesenteric artery (SMA) with resultant acute mesenteric ischemia. Noteworthily, a normal pulse rate does not preclude the presence of significant abdominal diseases. Careful auscultation of the lungs may provide evidence of lower lobe pneumonia, an important extra-abdominal cause of abdominal pain. Examination of the extremities may demonstrate mottling of the skin of the lower extremities, consistent with poor tissue perfusion from hypovolemia or septic shock.

Abdominal Examination Examination of the abdomen begins by the examiner asking the patient to precisely locate the site of greatest discomfort. The tendency to immediately palpate this region must be avoided; gentleness is essential to a successful examination. The clinician proceeds from the least painful maneuver initially to that of greatest discomfort. Examination of the abdomen begins with inspection for evidence of chronic diseases (e.g., cirrhosis with ascites and dilated periumbilical veins) or abdominal distention suggestive of a distal intestinal obstruction. Previous laparotomy incision sites and hernias must be noted and recently incarcerated hernias should be viewed with particular concern because of their association with strangulated intestinal obstruction. Auscultation of the abdomen in patients with peritonitis will demonstrate diminished bowel sounds consistent with the associated paralytic ileus. Patients with early small intestinal obstruction may have characteristic ‘‘rushes and tinkles.’’ Noteworthily, rarely if ever, are the auscultatory findings so compelling as to be diagnostic of a particular abdominal disease. Percussion and palpation of the abdomen should proceed from the quadrant of the abdomen farthest from the area of greatest tenderness. Gentle percussion will readily distinguish between tympanitic gas-filled dilated loops of obstructed bowel and the shifting dullness of ascites. Percussion of the abdomen will also localize the point of maximal tenderness and often provide the first physical evidence of localized or diffuse peritonitis. The presence (or absence) of voluntary or involuntary guarding (i.e., muscular rigidity) and the specific site of maximal tenderness upon gentle palpation should be elicited. This does not require deep palpation and should be done in such a way as to minimize discomfort to the patient. Extension of the inflammatory process to involve the parietal peritoneum is associated with voluntary guarding, in its earliest stages, and involuntary guarding as the process progresses. It is rare for a patient to have peritonitis without at least some detectable tenderness upon palpation of the abdomen or, in those cases in which the inflamed organ is within the pelvis, tenderness upon rectal or pelvic examination. The most common scenario is localized tenderness with or without voluntary guarding. The presence of diffuse involuntary guarding (or a rigid or ‘‘board-like’’ abdomen) suggests perforation of the stomach, duodenum, or colon. Peritonitis may also be detected by eliciting focal abdominal pain by gently shaking the bed, striking the patient’s heel or asking the patient to breathe deeply or to cough.

Intra-abdominal or retroperitoneal masses may be palpable in patients without significant guarding. The presence of a pulsatile mid-abdominal mass and back pain suggests a ruptured abdominal aortic aneurysm. Also, inflammatory masses may be appreciated in some patients with acute appendicitis or acute cholecystitis, although often voluntary guarding at the site of peritoneal inflammation precludes identification of the mass. ‘‘Rebound’’ pain may be elicited by pressing the fingers gently but deeply over an inflamed focus within the abdomen after which the pressure is suddenly released. This maneuver is associated with sudden and, sometimes, severe pain on the ‘‘rebound.’’ Like Silen, ‘‘we do not recommend the performance of this test, for it elicits no more than can be ascertained by careful, gentle pressure and may cause unexpected and unnecessary pain’’ (1). Inflammation in the region of the psoas muscle, as may occur in patients with retrocecal appendicitis, causes pain during contraction or passive stretching of this muscle. This sign may be elicited by placing the patient in a supine position and flexing the right hip against resistance. Alternatively, the so-called psoas sign may be induced by placing the patient in the left lateral decubitus position with the examiner passively extending the right hip. Inflammation involving the fascia of the obturator internus muscle within the pelvis causes pain upon internal and external rotation of the flexed right hip, the so-called obturator sign.

Genital, Rectal, and Pelvic Examinations Examination of patients with acute abdominal pain is incomplete without digital examination of the pelvis and rectum. These techniques will identify pelvic inflammation that may not be apparent upon examination of the anterior abdominal wall. For example, patients with acute appendicitis in whom the appendix lies in the pelvis will often have minimal tenderness upon palpation of the anterior abdominal wall but will frequently have tenderness on rectal and pelvic examination. Similarly, patients with tuboovarian inflammation will often have tenderness limited to the pelvis and hence demonstrable only by pelvic or rectal examination.

Laboratory Tests Laboratory tests are obtained to narrow the differential diagnosis and to identify acute and chronic medical problems that may represent a threat to the patient’s welfare or otherwise alter the treatment plan. These tests should be obtained only after a thorough history and physical examination have been performed. Tests commonly utilized include a complete blood count with a differential count of the leukocytes and determination of serum electrolytes, blood urea nitrogen, creatinine, and glucose concentrations. A urine or serum pregnancy test should be performed in all women of reproductive age. Serum liver function tests (e.g., serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and bilirubin) as well as serum amylase determination are obtained, particularly in patients with upper abdominal or right-sided abdominal pain. A serum albumin should be obtained in patients with historical or physical evidence of chronic disease such as cirrhosis. Lastly, an electrocardiogram should be obtained on middle-aged and older men and women presenting with abdominal pain to detect myocardial ischemia or infarction. Inferior wall myocardial infarction is an important cause of acute upper abdominal pain because of the risk it presents to the patient’s life if not detected.

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It must be noted that ‘‘overreliance on laboratory tests . . . will very often mislead the clinician, especially if the history and physical examination are less than diligent and complete’’ (1). For example, patients with acute appendicitis will often have a normal white blood cell (WBC) count and differential, especially early in the course of their disease, i.e., at the very time one wishes to detect it. Similarly, patients with acute intra-abdominal or retroperitoneal hemorrhage will initially have a normal blood hemoglobin level because of the acute nature of their bleeding.

Imaging Studies Similar to laboratory tests, diagnostic imaging studies are performed to narrow the differential diagnosis and to identify acute and chronic medical problems. An upright chest radiograph (posterior–anterior and lateral views) should be performed to exclude thoracic causes of acute abdominal pain, especially lower lobe pneumonia. In addition, these images will readily demonstrate the presence of pneumoperitoneum. Abdominal radiographs (supine and upright) are commonly obtained on patients presenting with acute abdominal pain. Although they are diagnostic in a minority of cases, they may provide corroborating evidence of abdominal diseases such as an appendicolith in patients with appendicitis, ‘‘sentinel’’ loops of dilated, gas-filled bowel in patients with acute pancreatitis, or an ileus in patients with peritonitis. In patients with intestinal obstruction, these images will be diagnostic. Ultrasonography (US) is a particularly important diagnostic tool in patients suspected of having biliary, hepatic, or pelvic diseases. The sensitivity and specificity of US to detect various diseases presenting with acute abdominal pain are shown in Table 2. Sonography, particularly with Doppler, is also very accurate in detecting aortic aneurysms, and less accurate in detecting visceral artery aneurysms. US is limited by its dependence upon the skill of the physician performing and interpreting the examination as well as the frequent occurrence of ileus (and hence gas-filled loops of bowel) in patients with abdominal diseases. Computed tomography (CT) of the abdomen and pelvis with enteral and parenteral contrast is the most versatile diagnostic tool for evaluating patients with acute abdominal pain. CT, utilizing the lung windows, will detect pneumoperitoneum with great sensitivity. CT has also been shown to have an excellent sensitivity and specificity for detecting acute inflammation associated with acute appendicitis, acute diverticulitis, acute pancreatitis, and acute cholecystitis. CT will detect with great accuracy the presence of both aortic Table 2 The Sensitivity and Specificity of Ultrasonography in Detecting Common Abdominal Diseases Presenting with Acute Abdominal Pain

Cholelithiasis (biliary colic) Acute cholecystitis Acute appendicitis Abdominal aortic aneurysm Ovarian torsion Acute salpingitis Ruptured ectopic pregnancy

Sensitivity (%)

Specificity (%)

References

88–100

92–95

8,9

94 55 100 92–95 92–95 92–95

78 95 100 97–98 97–98 97–98

9 10 11 12 12 12

aneurysms and visceral artery aneurysms. Lastly, recent studies have shown that CT is quite accurate in detecting the presence of small intestinal obstruction in equivocal cases. The sensitivity and specificity of CT in detecting various abdominal diseases presenting with acute abdominal pain are shown in Table 3. It should be emphasized that although CT is a valuable adjunct to the clinical history and physical examination, it does little to change the therapeutic algorithm in patients with the signs and symptoms of diffuse peritonitis, uncomplicated acute appendicitis, or even intestinal obstruction.

PROTOTYPICAL EXAMPLES OF ACUTE ABDOMINAL PAIN As alluded to earlier, acute abdominal pain is caused by inflammation, ischemia, and distention of hollow viscera or the capsule of solid organs. This section describes the clinical findings of patients with acute appendicitis, intestinal obstruction, and acute mesenteric ischemia as prototypes for the presentation of acute abdominal pain in the setting of inflammation, visceral ischemia, and obstruction.

Acute Appendicitis as a Prototype for Pain Due to Inflammation Acute appendicitis represents a spectrum of acute inflammatory changes ranging from simple acute inflammation to transmural necrosis and perforation. The earliest visible findings of appendicitis are prominent serosal blood vessels and edema of the appendiceal wall. As the disease progresses, the appendix becomes distended and covered with a fibrinopurulent exudate. Microscopically, acute appendicitis is characterized by a neutrophilic infiltrate of the muscularis propria with inflammation and ulceration of the mucosa, edema, and microabscesses within the appendiceal wall. Thrombosis of intramural blood vessels leads to focal gangrene and ultimately disintegration of the appendiceal wall. Transmural necrosis causes perforation with local abscess formation or, less commonly, diffuse peritonitis.

History Patients with acute appendicitis initially describe a vague periumbilical or epigastric discomfort. This initial visceral pain, often characterized as an ‘‘upset stomach’’ or a vague cramping or gnawing pain, is due to distention and localized inflammation of the appendix. Patients in whom the appendix is located behind the cecum or the terminal ileum Table 3 The Sensitivity and Specificity of Computed Tomography in Detecting Common Abdominal Diseases Presenting with Acute Abdominal Pain

Acute appendicitis Abdominal aortic aneurysm Ruptured abdominal aortic aneurysm Acute diverticulitis Small bowel obstruction Acute mesenteric ischemia

Sensitivity (%)

Specificity (%)

87–100 100

83–99 100

References 13 14

79–88

79–88

14

85–95 90–100 50–73

79–98 57–71 94–100

15–17 18,19 20

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may lack this epigastric or periumbilical pain and present initially with pain localized to the right iliac region. Over the next few hours, patients may experience mild nausea and may have a few episodes of emesis. Nausea and anorexia are so common in patients with acute appendicitis that the presence of hunger should raise a question regarding the diagnosis. If vomiting is a predominant symptom or if vomiting precedes the development of abdominal pain, the diagnosis of acute appendicitis should be questioned. Patients will often report an elevated body temperature; however, high fevers with rigors are uncommon and suggest perforation or another disease. Over the next 12 to 24 hours, the pain increases in intensity and is accompanied by a noticeable shift in the location to the right lower abdomen. This localization of abdominal pain is an important diagnostic feature that occurs in more than 80% of patients with acute appendicitis (21). This somatoparietal pain, which results from extension of the inflammatory process to involve the parietal peritoneum, is more intense and more precisely localized than the initial visceral periumbilical or epigastric pain. Older patients often lack this classic migration of pain from the periumbilical region to the right lower quadrant. Also right lower quadrant abdominal pain may be delayed in onset, or even absent, in patients with an inflamed pelvic appendix. Only about 50% to 60% of patients with acute appendicitis will have typical symptoms. Patients with symptoms for more than 24 to 48 hours have an increased incidence of perforation with associated morbidity.

Physical Examination Patients with acute appendicitis often appear ill and will usually be lying relatively still with their legs flexed at the knee and hip. The heart rate is usually normal or only slightly elevated. Tachycardia, when present, suggests perforation or significant intravascular volume depletion. The temperature is usually normal or only slightly elevated. A body temperature much greater than 100.5 F suggests a gangrenous appendix and if the initial symptom of the illness is a high fever (i.e., 103 F or 104 F), or if fever precedes the development of abdominal pain, a diagnosis other than acute appendicitis should be considered. Although absent in the early stages of the disease, localized tenderness over the site of the appendix is an important diagnostic feature. Often this can be demonstrated by light percussion of the abdomen. Palpation may also demonstrate tenderness at McBurney’s point (i.e., the junction of the lateral and middle thirds of a line drawn between the umbilicus and the right anterior superior iliac spine) with voluntary and, in advanced cases, involuntary guarding. Gently rocking the bed or striking the heel of the foot will reproduce or exacerbate this discomfort. Patients with early appendicitis in whom the acute inflammatory process has yet to involve the parietal peritoneum will often lack the abdominal wall tenderness and guarding characteristic of more advanced disease. Similarly, patients with a retrocecal appendix as well as those patients in whom the appendix lies within the pelvis may also lack the tenderness and guarding of the abdominal wall musculature. In instances of retrocecal appendicitis, a ‘‘psoas sign’’ may be elicited and in those patients in whom the appendix is located deep within the pelvis, evidence of inflammation involving the obturator internus fascia may be manifested by an ‘‘obturator sign’’ as described earlier. Silen notes that ‘‘whatever the constellation of signs and symptoms, the

clinical diagnosis of acute appendicitis cannot be made unless tenderness (no matter how slight) can be demonstrated in some location’’ (1).

Laboratory Tests and Imaging Studies There are no laboratory tests with which to secure the diagnosis of acute appendicitis; the principal value of these tests comes from excluding other causes of acute abdominal pain. Most patients with appendicitis will have a modest leukocytosis with 11,000 to 17,000 cells per cubic millimeter; the differential cell count may reveal an elevated percentage of granulocytes. It must be noted that many patients with acute appendicitis will have a normal WBC count and differential. Because the diagnosis of acute appendicitis can be reliably based on a characteristic clinical presentation in as many as 50% of cases, there is little support for routine radiographic imaging of all patients suspected of having acute appendicitis. However, in those cases in which the clinical presentation is confusing, US and CT may be extremely valuable. In particular, these studies have nearly supplanted diagnostic strategies of admission, observation, and serial examination of patients suspected to have acute appendicitis but with atypical examinations. A CT of a patient with acute appendicitis is shown in Figure 8; this image demonstrates a distended appendix with peri-appendiceal and peri-cecal fat stranding consistent with acute inflammation.

Acute Mesenteric Embolus as a Prototype for Pain Due to Intestinal Ischemia Pathophysiology The sudden occlusion of the SMA by an embolus causes 30% to 50% of cases of acute mesenteric arterial ischemia (22,23). About half of these emboli lodge in the SMA just distal to the proximal jejunal and middle colic branches, 35% break apart and embolize distally into the splanchnic vasculature, and

Figure 8 Computed tomography of the abdomen in a patient with acute appendicitis. The white arrow points to the distended appendix and the stippled arrow points to the peri-appendiceal inflammation marked by stranding in the mesentery of the cecum and peri-appendiceal tissues. Source: Courtesy of Maureen Heldman, Dept. of Radiology, LSU Health Sciences Center, Shreveport, Louisiana, U.S.A.

Chapter 26: The Anatomy, Physiology, and Differential Diagnosis of Acute Abdominal Pain

15% lodge at the ostium (24). When the mean arterial pressure in the SMA is less than 70 mmHg, there is a linear relationship between tissue perfusion and mean arterial pressure during which time tissue viability is maintained through increased oxygen extraction. Below 40 mmHg this mechanism fails, and the bowel becomes progressively more ischemic as anaerobic metabolism replaces aerobic. At this point, the degree of tissue injury is directly related to the duration and anatomic extent of ischemia (25). Structural injury to the villi occurs, with as little as 15 minutes of ischemia; three hours of ischemia causes sloughing of the intestinal mucosa. Restoration of blood flow at this point leads to the regeneration of a new epithelium from crypt cells (26); however, six hours of ischemia leads to transmural necrosis, progressing to perforation and sepsis. Numerous proinflammatory mediators are involved in the pathophysiology of this injury, particularly neutrophils, oxygen-derived free radicals, cytokines, and eicosanoids. Visceral C-fibers are sensitive to many of these proinflammatory and vasoactive substances as well as the metabolic end products of anaerobic metabolism that accumulate in the splanchnic microvascular beds during ischemia. These metabolic and proinflammatory mediators may also lower the pain threshold for mechanical stimuli, a phenomenon of importance because acute mesenteric ischemia often causes vigorous peristaltic activity, which diminishes to inactivity as the period of ischemia increases.

History The ‘‘classic’’ symptoms of patients with an SMA embolus are the sudden onset of excruciating periumbilical pain with bowel evacuation that becomes bloody with time. The onset is usually dramatic given the sudden nature of the event and the lack of preestablished arterial collaterals. Silen warns that often ‘‘early symptoms are present and are relatively mild in 50% of cases for three to four days before medical attention is sought’’ (1). In most cases, emboli originate from a left atrial or ventricular mural thrombus in patients with a history of heart disease such as congestive heart failure, endocarditis, recent myocardial infarction, or cardiac arrhythmias, particularly atrial fibrillation. This association of SMA embolus with acute or chronic cardiac conditions, especially atrial fibrillation and recent myocardial infarction, is so great that a patient with these conditions presenting with the acute onset of severe abdominal pain must be thought to have an SMA embolus until proven otherwise.

Physical Examination Early in the course of the illness, the abdomen of patients with SMA embolus is soft, nontender, and nondistended. In fact, the association of these mild physical findings with severe pain, out of proportion to the examination, is a hallmark of this illness. As the disease progresses, the abdomen becomes distended. Prominent tenderness and rigidity are absent until very late in the course of the disease. Fever, leukocytosis, hypotension, and tachycardia are late (too late!) manifestations of this disease.

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they lack the sensitivity and specificity to be helpful in the evaluation of patients suspected of having SMA embolus. Early in the course of the disease, plain abdominal radiographs are normal whereas in advanced cases, there may be dilated loops of small intestine consistent with an ileus and the appearance of ‘‘thumbprinting’’ of the small intestine and right colon due to marked edema within the bowel wall. CT will show only nonspecific signs of bowel ischemia including bowel wall edema, luminal dilation, and stranding within the mesentery. Less common, but more ominous, findings of intestinal necrosis include intramural gas and mesenteric or portal venous gas. Patient movement, overlying bowel gas from the associated ileus, and complex anatomy limit the efficacy of duplex US in the evaluation of patients suspected of having an SMA embolus. Arteriography is the only certain means of diagnosing an SMA embolus preoperatively during which it will usually demonstrate a rounded filling defect with nearly complete obstruction to arterial flow. This diagnostic study will differentiate those patients with nonocclusive mesenteric ischemia from those with a structural lesion amenable to operative repair. Patients with obvious peritonitis should undergo immediate laparotomy without prior arteriography.

Small Intestinal Obstruction as a Prototype for Pain Due to Obstruction Pathogenesis Mechanical obstruction to the normal flow of intestinal contents through the gastrointestinal tract may be categorized by the degree of obstruction (i.e., partial or complete), the absence or presence of ischemia (simple or strangulated), and the site of obstruction (i.e., small intestine or colon). The most common cause of mechanical SBO is intraabdominal adhesions following laparotomy; other important causes include hernias and neoplasms. Early after the onset of acute small intestinal obstruction, there are periods of intense intestinal myoelectric activity and peristalsis manifested clinically by colicky mid-abdominal visceral-type pain. The frequency of these contractions is inversely related to the distance from the ligament of Treitz, with more proximal jejunal obstructions having a greater frequency of peristalsis. As the duration of obstruction increases, the intestinal myoelectric activity diminishes and the interdigestive migrating myoelectrical complex pattern is replaced by ineffectual and seemingly disorganized clusters of contractions (27–29). Proximal to the obstruction, the bowel becomes distended as large amounts of fluid and swallowed air accumulate within the lumen. Impaired mucosal water and electrolyte absorption and enhanced secretion cause the net movement of isotonic fluid from the vasculature into the intestinal lumen (30). This phenomenon, in combination with losses from vomiting and reduced oral intake, causes profound intravascular volume depletion that is manifested clinically by tachycardia, tachypnea, oliguria, and, in advanced cases, hypotension.

History Laboratory Tests and Imaging Studies On admission to the hospital, most patients with acute mesenteric ischemia will have a leukocytosis and about 50% will have metabolic acidosis (23). Elevated levels of serum phosphate and amylase are often noted; however,

Patients with SBO typically present with the acute onset of periumbilical cramping pain, vomiting, obstipation, and abdominal distention. The colicky abdominal pain characteristic of SBO is visceral in nature and its location reflects the midgut embryologic origin of the small intestine.

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Typically, patients with proximal obstruction will describe paroxysms of periumbilical pain occurring at four- to fiveminute intervals whereas patients with more distal obstructions will experience paroxysms of pain less frequently. With increasing time, the cramping colicky pain subsides as the motility in the distended intestine is inhibited. The development of continuous, severe pain strongly suggests ischemia of the obstructed intestine. Closed-loop obstructions, which are associated with a high rate of strangulation, present with the sudden onset of severe unremitting periumbilical pain. Proximal obstructions are associated with profuse vomiting and severe, frequent cramping pain with minimal abdominal distention whereas patients with more distally located obstructions have less frequent vomiting, more abdominal distention, and a greater period of time between paroxysms of pain. The emesis of patients with SBO is usually feculent because of the increased bacterial count in the lumen of the obstructed gut. Although obstipation is an important symptom of intestinal obstruction, patients with partial obstruction may continue to pass flatus and stool. Even patients with complete SBO will evacuate the intestine distal to the point of obstruction. The duration of obstruction is best judged by the time lapsed since the passage of flatus because the transit time of swallowed air is much less than that of solid or liquid intestinal contents.

Physical Examination The systemic manifestations of intestinal obstruction are related to hypovolemia and the systemic response to inflammation (i.e., tachycardia, tachypnea, altered mental status, oliguria, and hypotension). The latter findings, particularly when unresponsive to volume repletion, strongly suggest the presence of intestinal ischemia and necrosis. Auscultation of the abdomen will usually demonstrate periods of high-pitched or musical bowel sounds that correspond to cramping abdominal pain separated by intervals of relative quiet. Borborygmi may be audible in these patients and may correspond with paroxysms of cramping pain. With prolonged obstruction, bowel sounds may be absent. Palpation of the abdomen of patients with simple intestinal obstruction will usually demonstrate minimal tenderness and no guarding. Significant tenderness and guarding, especially if localized, strongly suggests strangulated obstruction. Patients with closed-loop obstructions will often have pain that is out of proportion to the physical findings, much like that of patients with acute mesenteric ischemia. A tender mass at the site of an inguinal, femoral, or umbilical hernia suggests that this is the cause of the obstruction; erythema of the overlying skin suggests intestinal ischemia.

Laboratory Tests and Imaging Studies Patients with SBO will often have a slight leukocytosis on their complete blood count. Neutrophilia with a predominance of immature cellular forms is more common in patients with strangulated obstruction than in patients with simple obstruction; however, the predictive value of this parameter is too low to be useful as a sole determinant of strangulation. Serum electrolyte abnormalities (especially involving sodium, potassium, and chloride), acid–base disturbances (especially metabolic acidosis secondary to intravascular volume depletion), and altered renal function are common in patients with intestinal obstruction. Serum levels of amylase, lipase, lactate dehydrogenase, phosphate, and potassium may be elevated in patients with strangulated bowel; however, these parameters lack sufficient predictive value to allow differentiation between simple and strangulated obstruction at a stage prior to frank intestinal necrosis and peritonitis. Plain abdominal radiographs taken with the patient in the supine position and in the upright (or lateral decubitus) position will usually confirm the diagnosis of intestinal obstruction, localize the site of obstruction to the small intestine or colon, and provide evidence of the degree of obstruction. Noteworthily, up to 30% of patients with SBO will have equivocal or normal abdominal radiographs. False negative studies are particularly likely in patients with proximal or closed-loop obstructions. In these patients, abdominal CT scanning with enteral and intravenous contrast will usually differentiate mechanical obstruction from paralytic ileus and helps in determining the site and degree of obstruction.

ABDOMINAL PAIN IN SPECIAL PATIENT GROUPS This section describes the effect of age, immunosuppression with corticosteroids and AIDS, and spinal cord injury on the clinical features of acute abdominal diseases as well as the relative frequency of various diseases within the differential diagnosis of acute abdominal pain.

The Effect of Age on the Presentation of Patients with Acute Abdominal Disease A patient’s age significantly influences the relative frequency with which various diseases occur in patients presenting with acute abdominal pain. The influence of age on the differential diagnosis of acute abdominal pain is shown in Table 4. The most common causes of severe abdominal pain in young children include gastroenteritis, intussusception, pyelonephritis, and midgut volvulus; although appendicitis occurs in this age group, it is uncommon. Acute appendicitis becomes an important cause of severe abdominal pain in children greater than four years of age. Abdominal trauma from child abuse,

Table 4 Causes of Acute Abdominal Pain in Various Age Groups Less than 3 years of age Gastroenteritis Intussusception Pyelonephritis Midgut volvulus

4–11 years Gastroenteritis Appendicitis Abdominal trauma from child abuse Mesenteric lymphadenitis Urinary tract infection

Source: From Refs. 2, 31–36.

12–18 years Appendicitis Gastroenteritis Mittelschmerz Acute salpingitis Ovarian torsion Ruptured ectopic pregnancy

18–65 years Nonspecific abdominal pain Appendicitis Acute biliary disease

Greater than 66 years Biliary tract disease Nonspecific abdominal pain Malignancy Bowel obstruction Peptic ulcer disease Incarcerated hernias Appendicitis

Chapter 26: The Anatomy, Physiology, and Differential Diagnosis of Acute Abdominal Pain

with resultant intra-abdominal injury, is also an important cause of severe abdominal pain during childhood. As young girls enter adolescence, gynecologic causes of abdominal pain become prominent, with Mittelschmerz, acute salpingitis, ovarian torsion, and ectopic pregnancy assuming a prominent role in the differential diagnosis. During adulthood, nonspecific abdominal pain is a common cause of abdominal pain as are appendicitis, biliary tract disease, and urinary tract diseases (31,37,38). The most common causes of severe abdominal pain in the elderly are biliary tract diseases, nonspecific abdominal pain, and malignancies. Appendicitis occurs but to a lesser extent than in younger individuals. The very young and very old tend to present with more advanced and complicated disease than do patients in the middle years. In a survey of nearly 3400 children undergoing appendectomy, the median rate of perforation for children between the ages of 0 and 4 years was 66% compared with 37% for children 5 to 17 years of age (39). The rate of perforated appendicitis averages 10% in young and middle-aged adults (2) and nearly 70% in the elderly (40). At least in part, the high rate of advanced and complicated acute abdominal disease in the very young and the elderly comes from the difficulty in recognizing the clinical manifestations of these diseases in these populations. In very young children with acute appendicitis, vomiting, lethargy, and irritability are important symptoms whereas localized right lower abdominal tenderness is detected in less than 50% of young children (41). In contrast to adults, diarrhea is a relatively common finding in young children with acute appendicitis. In one study, one-third of all children less than three years of age with acute appendicitis presented with diarrhea (42). In older children, the clinical presentation of acute appendicitis is similar to that of adults and includes abdominal pain and tenderness, anorexia, nausea and vomiting, fever, and leukocytosis. Most older patients with acute appendicitis will have abdominal pain and right lower quadrant tenderness upon presentation to the hospital; however, more than half of these patients will have had symptoms for more than 48 hours—an observation consistent with the nearly 70% rate of perforation and 40% rate of intra-abdominal abscess formation (40). The difficulty in correctly diagnosing the cause of acute abdominal pain in elderly patients at the initial examination is corroborated by a study that reported the sensitivity and specificity of the diagnosis at the time of admission to be 68% and 76%, respectively, for patients older than 65 years of age and 82% and 86% for younger patients (43).

The Effect of Immunosuppression on the Presentation of Patients with Abdominal Disease Suppression of an individual’s immune function by chronic diseases such as AIDS or exogenous agents such as corticosteroids alters the clinical presentation of patients with acute abdominal conditions and introduces a variety of unusual diseases into the differential diagnosis.

Steroids Exogenous corticosteroids suppress the inflammatory cascades activated by tissue injury by inhibiting the release of arachidonic acid (and hence numerous proinflammatory eicosanoids) and cytokines (including interleukin-1 and interleukin-2). These agents also decrease leukocyte adherence, chemotaxis, and hence recruitment into sites of tissue injury and profoundly reduce the inflammation, collagen

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synthesis, and wound contraction associated with the healing of injured tissues (44). Patients receiving exogenous corticosteroids who develop localized or generalized peritonitis will often lack the usual signs and symptoms of such inflammation. The absence of significant abdominal pain, tenderness, and fever in patients with acute abdominal diseases, even gastrointestinal perforation, who are receiving steroid therapy significantly delays appropriate diagnosis and operative management and contributes to the significant mortality risks associated with these diseases (45). The mechanism by which steroid therapy attenuates the clinical features of acute abdominal diseases is unclear. However it is postulated that by inhibiting the release of various proinflammatory substances such as prostaglandins and cytokines, corticosteroids reduce the stimulus for visceral nociception (46). The use of corticosteroids in patients is associated with a much higher incidence of intestinal perforation and peritonitis when compared with the general population (45,47,48). Furthermore, corticosteroid use is an important risk factor for dehiscence of intestinal anastomoses in a retrospective analysis of 754 patients (49).

AIDS Abdominal pain is a frequent complaint of patients with AIDS; however, in most instances, this pain is self-limiting and is not clinically significant. Severe acute abdominal pain, usually in combination with other gastrointestinal symptoms, occurs in about 12% to 15% of patients with AIDS (50,51). Others have estimated that severe gastrointestinal symptoms of AIDS occur in as many as 50% of patients (52). In most cases, this pain is related to HIV infection and its associated opportunistic infections and neoplasms (51). Examples of these HIV-related diseases and symptom complexes are shown in Table 5 and Figure 9. Although these diseases are important causes of severe abdominal pain in patients with AIDS, the efficacy of current therapy with protease inhibitors and antiretroviral medications (highly active antiretroviral treatment) has increased the relative frequency of common causes of acute abdominal pain in the general population, such as appendicitis, acute cholecystitis, and acute diverticulitis. Common causes of HIV-specific severe abdominal pain include non-Hodgkin’s lymphoma, which may obstruct the gastrointestinal tract or cause distention of the hepatic or splenic capsule secondary to infiltration of these organs by this tumor. Perforation of the gastrointestinal tract may result from cytomegalovirus (CMV)-induced vasculitis causing submucosal thrombosis with mucosal ischemia, ulceration, and eventually transmural necrosis (54). Infectious enteritis, with CMV, Mycobacterium avium, or cryptosporidium is a particularly common cause of severe abdominal pain and diarrhea in patients with AIDS. Primary peritonitis (i.e., peritonitis in the absence of gastrointestinal perforation) is well described in patients with AIDS, the cause of which includes numerous infectious agents including histoplasmosis, tuberculosis, M. avium, and toxoplasmosis. Lastly, pancreatitis is a frequent cause of abdominal pain in patients with AIDS and results most often from drugs (e.g., dideoxyinoside, pentamidine, trimethoprim-sulfamethoxazole) and infections with CMV, mycobacteria, and Cryptococcus. The clinical presentation of acute abdominal diseases in patients with AIDS is similar to that of the general population with a few exceptions. It is not unusual for these patients to develop an acute disease process, such as acute

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Table 5 Causes of Abdominal Pain in Patients with AIDS Organ Stomach Gastritis Ulcer Obstruction Mass Small intestine Enteritis Obstruction Perforation Colon Colitis Obstruction Perforation Appendicitis Liver, spleen Infiltration Biliary tract Cholecystitis Papillary stenosis Pancreas Inflammation Tumor Mesentery, peritoneum

Etiology CMV, cryptosporidium, Helicobacter pylori CMV Cryptosporidium, CMV, lymphoma Lymphoma, Kaposi’s sarcoma, CMV Cryptosporidium, CMV, Mycobacterium avium Lymphoma, Kaposi’s sarcoma CMV, lymphoma CMV, enteric bacteria, herpes simplex virus Lymphoma, Kaposi’s sarcoma, intussusception CMV, lymphoma, Herpes simplex virus Kaposi’s sarcoma, cryptosporidium, CMV Lymphoma, CMV, M. avium CMV, cryptosporidium, microsporidium CMV, cryptosporidium, Kaposi’s sarcoma CMV, Kaposi’s sarcoma, pentamidine, didanosine Lymphoma, Kaposi’s sarcoma M. avium, cryptococcus, Kaposi’s sarcoma, lymphoma, histoplasmosis, tuberculosis, coccidioidomycosis, toxoplasmosis

Abbreviation: CMV, cytomegalovirus. Source: From Ref. 53.

appendicitis, in the setting of chronic abdominal pain and low-grade fevers. Flum et al. noted that 91% of their patients with AIDS and acute appendicitis had the combination of right lower-quadrant abdominal pain and tenderness (55). Patients with AIDS may also lack the systemic leukocytosis that is associated with many severe acute abdominal

conditions, including complicated appendicitis (54,55). The diagnostic strategies and indication for operation in patients with AIDS who develop severe acute abdominal pain are the same as for patients without HIV infection. CT is of particular value in determining the presence of intestinal perforation with secondary peritonitis as well as the local inflammation characteristic of acute appendicitis.

The Effect of Spinal Cord Injury on the Presentation of Patients with Abdominal Disease Acute abdominal diseases are an important cause of death of spinal cord–injured patients. The mortality rate for acute abdominal diseases in patients with spinal cord injuries is 10% to 15%. This high mortality rate is similar to that of immunocompromised or elderly patients and is attributable to delays in identification and treatment of the various abdominal conditions, especially perforation of the bowel (56–58). As alluded to earlier, the most common symptom of patients with acute abdominal diseases is pain. Unfortunately, patients with spinal cord injuries may or may not have this important symptom. The presentation of acute abdominal diseases in spinal cord–injured patients is dependent upon the neurologic level and completeness of the injury as well as the degree of continuity of the reflex arc below the level of the injury (59). Normal somatic sensation to the anterolateral abdominal wall originates from T7 to L1; hence, patients with complete spinal cord lesions above T7 will have no somatoparietal sensation in the abdominal wall (57). Painful stimuli from the abdominal viscera reach the spinal cord via the thoracic sympathetic, splancnhnic, hypogastric, or pelvic nerves, with the sympathetic outflow from most of the viscera originating from the T5 level or below (60). The visceral sensory fibers of the rectum and bladder are carried via the S2 to S4 parasympathetic system. Patients with injury above the level of the splanchnic outflow tract at T6 are referred to as having ‘‘high’’ spinal cord injuries, whereas those patients with injuries below this level are regarded as having ‘‘low’’ cord lesions (59). Patients with

Figure 9 Common clinical presentations and related diagnoses in patients with AIDS. Of note: Because antiretroviral treatment strategies have become more successful, AIDS-specific diseases have declined in the differential diagnosis of abdominal pain in this population and the diseases present in the general population have assumed a greater position. Abbreviation: CMV, cytomegalovirus.

Chapter 26: The Anatomy, Physiology, and Differential Diagnosis of Acute Abdominal Pain

high cord injuries have a loss of sensory, motor, and reflex functions within the viscera and abdominal wall (61). In these instances, patients with an acute intra-abdominal process may present with increased spasticity (often generalized and including abdominal musculature), vague abdominal pain, referred shoulder tip pain, altered bowel function with abdominal distension, nausea and vomiting, autonomic dysreflexia and/or a feeling ‘‘that there is something wrong’’ (57,59,61,62). Patients with spinal cord injuries below the level of the splanchnic outflow tract (i.e., T6) are much likely to manifest an acute abdominal disease with abdominal pain than are patients with high cord injuries (56,59,62). Activation of visceral nociceptors by distention of hollow viscera or inflammation may cause spinal reflex sweating and increased spasticity of the limbs, sphincters, or adjacent abdominal muscles. This autonomic dysreflexia is a problem unique to patients with a spinal cord injury at the T6 level and above. In one study, autonomic dysreflexia was present in 84% of the patients with high spinal cord lesions (58). The inability of inexperienced clinicians to recognize subtle symptoms of acute abdominal disease is felt to be an important cause of delays in diagnosis and therapy and hence negative outcomes. Juler and Eltoral report that often the only clue to the presence of significant abdominal diseases is a change in the degree of spasticity (59). Longo et al. have suggested that any deviation from a normal lifestyle in a patient with a spinal cord lesion should alert the clinician to the possibility of serious abdominal diseases (63). It is of interest and importance that laboratory tests and imaging studies are often not diagnostic in patients with spinal cord injuries. Many spinal cord–injured patients will have a urinary tract infection, pressure sores, or respiratory illnesses, which complicates interpretation of the patient’s vague symptoms. Furthermore, several studies have demonstrated that as many as 33% to 50% of patients with spinal cord injuries will not mount a leukocytosis in the presence of significant abdominal diseases. These investigators also noted that standard abdominal imaging studies such as abdominal radiographs, US, or CT suggested the correct diagnosis in only 62% to 77% of patients with acute abdomen diseases (56,62).

SUMMARY The clinical condition characterized by the acute onset of abdominal pain, usually in association with other findings such as nausea, vomiting, anorexia, and abdominal distention, has been given the designation ‘‘acute abdomen.’’ Both intra-abdominal and extra-abdominal pathologic lesions can be responsible for this condition, many of which have lifethreatening potential. Such being the case, the underlying diagnosis must be promptly made and appropriate treatment measures expeditiously instituted. To accomplish these goals in the most judicious fashion, the treating physician must obtain an accurate database and be able to extrapolate these data within a fund of knowledge encompassing the anatomy, embryology, neurophysiology, and natural history of each potential cause. This database is derived from the history and physical findings, supported by the various laboratory tests and radiologic studies obtained. The differential diagnosis of the acute abdomen can be challenging, even to the most astute physician, but is ultimately successful when approached from this frame of reference.

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REFERENCES 1. Silen W. Cope’s Early Diagnosis of the Acute Abdomen. 20th ed. New York: Oxford Press, 2000. 2. Glasgow RE, Mulvihill SJ. Abdominal pain, including the acute abdomen. In: Feldman M, Friedman LS, Sleisinger MH, eds. Sleisenger & Fordtran’s Gastrointestinal and Liver Disease: Pathophysiology/Diagnosis/Management. Philadelphia: Saunders, 2002:71. 3. Cheung LY, Ballinger WF. Manifestations and diagnosis of gastrointestinal disease. In: Hardy JD, ed. Hardy’s Textbook of Surgery. Philadelphia: JB Lippincott, 1983. 4. Anson BJ, McVay CB. Surgical Anatomy. 5th ed. Philadelphia: WB Saunders, 1971:467. 5. Anderson JE. Grant’s Atlas of Anatomy. 7th ed. Baltimore: Williams & Wilkins Co., 1978:5–42. 6. Currie DJ. Abdominal Pain. New York: Hemisphere Publishing, 1979. 7. Anson BJ, McVay CB. Surgical Anatomy. 5th ed. Philadelphia: WB Saunders, 1971:594. 8. Fang R, Pilcher JA, Putnam AT, Smith T, Smith DL. Accuracy of surgeon-performed gall bladder ultrasound. Am J Surg 1999; 178:475. 9. Trowbridge RL, Rutkowski NK, Shojania KG. Does this patient have acute cholecystitis? JAMA 2003; 289:80. 10. Franke C, Bohner H, Yang Q. Ultrasonography for diagnosis of acute appendicitis: results of a prospective multicenter trial. World J Surg 1999; 23:141. 11. LaRoy LL, Cormier PJ, Matalan TA. Imaging of abdominal aortic aneurysms. Am J Roentgenol 1989; 152:785–792. 12. Frederick JL, et al. Routine use of vaginal ultrasonography in the preoperative evaluation of gynecological patients. J Reprod Medicine 1991; 36:779. 13. Sarosi GA Jr, Turnage RH. Appendicitis. In: Feldman M, Friedman LS, Sleisenger MH, eds. Sleisenger & Fordtran’s Gastrointestinal and Liver Disease: Pathophysiology/Diagnosis/ Management. Philadelphia: Saunders, 2002:2089. 14. Adam DJ, Bradbury AW, Stuart WP, et al. The value of computed tomography in the assessment of suspected ruptured abdominal aortic aneurysm. J Vasc Surg 1998; 27:431. 15. Ferzoco LB, Raptopoulos V, Silen W. Acute diverticulitis. NEJM 1998; 338:1521. 16. Halligan S, Saunders B. Imaging diverticular disease. Best Pract Res Clin Gastroenterol 2002; 16:595. 17. Ambrosetti P, Jenny A, Becker C, Terrier TF, Morel P. Acute left colonic diverticulitis–compared performance of computed tomography and water-soluble contrast enema: prospective evaluation of 420 patients. Dis Colon Rectum 2000; 43:1363. 18. Peck JJ, Milleson T, Phelan J. The role of computed tomography with contrast and small bowel obstruction in the management of small bowel obstruction. Am J Surg 1999; 177:375. 19. Daneshmand S, Hedley CG, Stain SC. The utility and reliability of CT scan in the diagnosis of small bowel obstruction. Am Surg 1999; 65:922. 20. Kirkpatrick ID. Biphasic CT with mesenteric CT angiography in the evaluation of acute mesenteric ischemia: initial experience. Radiology 2003; 229:91. 21. Wagner JM, McKinney WP, Carpenter JL. Does this patient have appendicitis? JAMA 1996; 276:1589. 22. Bradbury AW, Brittenden J, McBride K, Ruckley CV. Mesenteric ischaemia: a multidisciplinary approach. Br J Surg 1995; 82:1446. 23. Kaleya RN, Boley SJ. Acute mesenteric ischemia. Crit Care Clin 1995; 2:479. 24. Batellier J, Kieny R. Superior mesenteric artery embolism: eighty-two cases. Ann Vasc Surg 1990; 4:112. 25. Udassin R, Vromen A, Haskel Y. The time sequence of injury and recovery following transient reversible intestinal ischemia. J Surg Res 1994; 56:221. 26. Kummerlen C, Seiler N, Galluser M, et al. Polyamines and the recovery of intestinal morphology and function after ischemic damage in rats. Digestion 1994; 55:168.

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27. Camilleri M. Jejunal manometry in distal subacute mechanical obstruction: significance of prolonged simultaneous contractions. Gut 1989; 30:468. 28. Frank JW, Sarr MG, Camiller M. Use of gastroduodenal motility to differentiate mechanical and functional intestinal obstruction: an analysis of clinical outcome. Am J Gastroenterol 1994; 89:339. 29. Summers RW, Yanda R, Prihodaq M, et al. Acute intestinal obstruction: an electromyographic study in dogs. Gastroenterology 1983; 85:1301. 30. Shields R. The absorption and secretion of fluid and electrolytes by the obstructed bowel. Br J Surg 1965; 52:774. 31. Miettinen P, Pasanen P, Lahtinen J, Alhava E. Acute abdominal pain in adults. Ann Chir Gynaecol 1996; 85:5. 32. Moir CR. Abdominal pain in infants and children. Mayo Clin Proc 1996; 71:984. 33. Hatch E. The acute abdomen in children. Pediatr Clin North Am 1985; 32:1151. 34. Neblett WW, Pietsch JB, Holcomb GW. Acute abdominal conditions in children and adolescents. Surg Clin North Am 1988; 68:415. 35. Bugliosi TF, Meloy TD, Vukov LF. Acute abdominal pain in the elderly. Ann Emerg Med 1990; 19:1383. 36. Bender J. Approach to the acute abdomen. Med Clin North Am 1989; 73:1413. 37. Hawthorn IE. Abdominal pain as a cause of acute admission to hospital. J R Coll Surg Edinburgh 1992; 39:389. 38. Caterino S, Cavallini M, Meli C, et al. Acute abdominal pain in emergency surgery. Clinical epidemiologic study of 450 patients. Ann Ital Chir 1997; 68:807. 39. Newman K, Ponsky T, Kittle K, et al. Appendicitis 2000: variability in practice, outcomes, and resource utilization at thirty pediatric hospitals. J Pediatric Surg 2003; 38:372. 40. Hui TT, Major KM, Avital I, Hiatt JR, Margulies DR. Outcome of elderly patients with appendicitis: effect of computed tomography and laparoscopy. Arch Surg 2002; 137:995. 41. Rothrock SG, Pagane J. Acute appendicitis in children: emergency department diagnosis and management. Ann Emerg Med 2000; 36:39. 42. Horwitz JR, Gursoy M, Jaksic T, et al. Importance of diarrhea as a presenting symptom of appendicitis in very young children. Am J Surg 1997; 173:80. 43. Kizer KW, Vassar MJ. Emergency department diagnosis of abdominal disorders in the elderly. Am J Emerg Med 1998; 16:357. 44. Levenson SM, Demetriou AA. Metabolic factors. In: Cohen IK, Diegelmann RF, Lindblad WJ, eds. Wound Healing, Biochemical and Clinical Aspects. Saunders: Philadelphia, 1992:248. 45. Menegaux F, Chenard X, Wechsler B, Boutin Z, Chigot JP. Diffuse peritonitis in steroid-treated patients. Dig Surg 1998; 15:247. 46. Parham P. Elements of the immune system and their roles in defense. In: The Immune System. 1st ed. London: Elvesier Science, 2000:16–20.

47. Wolfe F, Hawley DJ. The comparative risk and predictors of adverse gastrointestinal events in rheumatoid arthritis and osteoarthritis: a prospective 13 year study of 2131 patients. J Rheumatol 2000; 27:1668. 48. Weiner HL, Rezai AR, Cooper PR. Sigmoid diverticular perforation in neurosurgical patients receiving high-dose corticosteroids. Neurosurgery 1993; 33:40. 49. Golub R, Golub RW, Cantu R Jr, Stein HD. A multivariate analysis of factors contributing to leakage of intestinal anastomoses. J Am Coll Surg 1997; 184:364. 50. Barone JE, Gingold BS, Arvanitis ML, et al. Abdominal pain in patients with acquired immune deficiency syndrome Ann Surg 1986; 204:619. 51. Parente F, Cernuschi M, Antinori S, et al. Severe abdominal pain in patients with AIDS: frequency, clinical aspects, causes and outcome. Scand J Gastroenterol 1994; 29:511. 52. Fauci AS, Masur H, Gelman EP, et al. Gastrointestinal manifestations of the acquired immune deficiency syndrome: an update. Ann Intern Med 1985; 102:800. 53. Wilcox CM. Gastrointestinal consequences of infection with human immunodeficiency virus. In: Feldman M, Friedman LS, Sleisinger MH, eds. Sleisenger & Fordtran’s Gastrointestinal and Liver Disease: Pathophysiology/Diagnosis/ Management. Philadelphia: Saunders, 2002:487. 54. Mueller GP, Williams RA. Surgical infections in AIDS patients. Am J Surg 1995; 169:34S. 55. Flum DR, Steinberg SD, Sarkis AY, Wallack MK. Appendicitis in patients with acquired immunodeficiency syndrome. J Am Coll Surg 1997; 184:481. 56. Neumayer LA, Bull DA, Mohr JD, Putnam CW. The acutely affected abdomen in paraplegic spinal cord injury patients. Ann Surg 1990; 212:561. 57. Sheridan R. Diagnosis of the acute abdomen in the neurologically stable spinal-cord injury patient. J Clin Gastroenterol 1992; 15:325. 58. Strauther GR, Longo WE, Virgo KS, Johnson FE. Appendicitis in patients with previous spinal cord injury. Am J Surg 1999; 178:403. 59. Juler GL, Eltoral IM. The acute abdomen in spinal cord injury patients. Paraplegia 1985; 23:118. 60. McMinn RMH. Introduction to regional anatomy. In: McMinn RMH, ed. Last’s Anatomy. Regional and Applied. 9th ed. Edinburgh: Churchill Livingstone, 1994. 61. Bar-On Z, Ohry A. The acute abdomen in spinal cord injury individuals. Paraplegia 1995; 33:704. 62. Miller BJ, Geraghty TJ, Wong C-H, Hall DF, Cohen JR. Outcome of the acute abdomen in patients with previous spinal cord injury. ANZ J Surgery 2001; 71:407. 63. Longo WE, Ballantyne GH, Modlin IM. Colorectal disease in spinal cord patients. An occult diagnosis. Dis Colon Rectum 1990; 33:131.

27 Neoplastic Disorders of the Gastrointestinal Tract Carlos A. Murillo, Kenneth J. Woodside, Lindsey N. Jackson, and B. Mark Evers

with specific K-ras mutations (7–9), although mutant K-ras inactivation in advanced colorectal carcinoma cells does result in decreased malignant activity (10).

INTRODUCTION Collectively, cancers of the gastrointestinal (GI) tract represent a common problem worldwide. Incidence of cancers along the longitudinal axis of the GI tract is variable, with adenocarcinomas of the colon and rectum representing the third most frequent cause of cancer deaths in men and women in the United States, whereas cancers of the small bowel are rare. On the other hand, gastric cancers have decreased in frequency in the United States over the last century; however, they remain a common problem in certain parts of the world such as Asia. This chapter will discuss cancers arising in the GI tract and particularly focus on the pathophysiology and molecular biology contributing to the development of these cancers.

Growth Factor Receptors HER2/neu/c-erb-B2 mutations are found in gastric cancers. The HER2/c-erb-B2 oncogene is the human homolog of the rat neuroblastoma neu oncogene, which closely resembles the EGF receptor (1). In gastric cancer, gene amplification of c-erb-B2 results in overexpression and abnormal cell growth, and probably results in increased metastatic potential and invasiveness (11–13). The hepatocyte growth factor (HGF) receptor is encoded by the c-met proto-oncogene. Overexpression or mutation of this tyrosine kinase receptor is also noted in gastric tumors (14,15). In addition, stromal production of HGF may further promote tumor growth (16–18). b-Catenin and Wnt Pathway Recently, alterations in b-catenin, a molecule involved in cytoskeleton anchoring, and other Wnt pathway members (Fig. 2) have been explored in GI and other carcinomas as well as in familial adenomatous polyposis (FAP) patients (20–24). While the exact mechanism is still somewhat unclear, accumulation of b-catenin seems to result in increased malignant potential, probably through downstream mediators such as c-myc or cyclin D (19,24,25).

CELLULAR AND MOLECULAR BIOLOGY OF GI CANCERS Oncogenes and Tumor Suppressor Proteins Oncogenes Oncogenes are mutant versions of normal genes, called proto-oncogenes, involved in cellular growth and proliferations. Typically, these genes are abnormally activated growth factors [transforming growth factor-b (TGF-b), insulin-like growth factor, and epidermal growth factor (EGF), Wnt] or their receptors (HER2/neu/c-erb-B2 and c-met), intracellular signaling molecules (K-ras), or transcription factors (c-myc, b-catenin). Tumor suppressor genes, in contrast, normally inhibit cellular growth and act as a counterbalance to proto-oncogenes (Fig. 1). As such, oncogenes can produce phenotypic changes with mutation of only one copy, while tumor suppressor genes usually require mutation or loss of expression of both copies for malignant transformation to occur (2). Typically, multiple mutations of different types are acquired over time, resulting in malignant conversion; single gene mutations are not adequate for tumorigenesis.

Tumor Suppressor Proteins Adenomatous Polyposis Coli Studies of familial colorectal cancer syndromes have been instrumental in identifying a number of genetic defects that contribute to the pathogenesis of this disease process. The adenomatous polyposis coli (APC) gene has been demonstrated as an important tumor suppressor protein for the development of colorectal cancers. FAP occurs as a consequence of inherited mutation of the APC gene and then subsequent mutation or loss of the remaining normal copy. Mutations of the APC gene appear to be one of the earliest changes in sporadic tumor development as well, and possibly an initiating event in a majority of nonfamilial cases. APC is located on chromosome 5p21 and encodes a protein of up to 2843 residues (26,27). The APC protein is expressed in the cytoplasm of a number of tissues, and contains sequences similar to intermediate filament proteins such as myosin and keratin. The vast majority of APC mutations in sporadic and FAP cancers result in truncated proteins. About half of the mutations involve a region spanning less than 10% of the gene. While both wild-type and mutant forms are cytoplasmic, mutant proteins are soluble whereas wild-type proteins are not. Moreover, it appears that certain mutant versions may interfere with the function of the normal

K-ras One of the better-described oncogenes is K-ras. K-ras mutations are found in about 40% of primary colorectal carcinomas (3,4) and 85% of pancreatic cancers (5). K-ras and the related family members N-ras and H-ras are G proteins found on the inner surface of the plasma membrane and are involved in the control of cell differentiation and proliferation (5,6). Point mutations at certain codons result in loss of the ability to convert guanosine triphosphate to guanosine diphosphate. These mutated G proteins constitutively transmit proliferation signals. In patients with colorectal carcinoma, variable results are noted when attempting to correlate tumor aggressiveness 555

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Figure 1 Normal regulation of cellular proliferation depends upon equilibration between the growth-promoting influence exerted by proto-oncogenes and the growth-inhibiting activity of tumor suppressor genes. Cancer occurs as a consequence of the uncontrolled cellular proliferation that follows disruption of this balance through genetic alterations that activate oncogenes and inactivate tumor suppressor genes. Source: From Ref. 1.

protein in cells heterozygous for the mutation by formation of partially insoluble aggregates in a dominant-negative fashion (28). The protein product of the APC gene associates with a- and b-catenins, which are cadherin-binding proteins (29). b-Catenins bind directly to APC, and a-catenins bind directly to b-catenins and are associated with APC. These catenins then bind directly to E-cadherin, a protein associated with cell–cell adhesions, forming adherens junctions. Thus, mutant APC genes may contribute to abnormal cell signaling and promote cancer formation (20,30). APC has also been associated with cytoplasmic microtubule assembly. Proteins within cells with APC mutations have been documented to lack a carboxy terminal structure that mediates microtubule assembly. Mutant APC proteins also serve to bind to wild-type proteins, and inactivate the wild-type proteins in a dominant-negative fashion and prevent microtubule attachment (29). The APC protein appears to play an integral role in cell–cell adhesion and indirectly in the transcription of genes during development. By sequestering b-catenin, APC prevents it from associating with E-cadherin through a- and g-catenin (plakoglobulin); E-cadherin has an extracellular domain that protrudes from the cell surface and participates in cell-to-cell adhesion by binding to E-cadherins, which extend from neighboring cells (29,31). A small region of exon 15 of the APC gene is designated as the mutation cluster region, because it is

Figure 2 Oncogenes and tumor suppressors in the wnt signaling pathway. Source: From Ref. 19.

the site for 60% of all sequence mutations within the APC gene (32). p53 The p53 tumor suppressor gene, located on chromosome 17, is involved in approximately half of all colorectal carcinomas, making it the most common tumor suppressor protein (33). The p53 gene encodes for a phosphoprotein that affects the cell cycle by arresting cells in the G1 phase of the cell cycle, thus allowing for repairs of DNA strands before the S phase of the cell cycle (34). Mutations of the p53 gene are missense mutations producing altered function proteins rather than silent, truncated proteins. The loss of the p53 gene is probably the key event that allows progression of a severely dysplastic adenoma into a carcinoma (Fig. 3) (36). Mutations of the p53 gene are thought to be lateoccurring events in the sequence progression of carcinoma formation and are more common in invasive cancers (37). Functional p53 exists in the cell as a tetramer; alterations at the interface conjoining the subunits disable the protein (38). Interestingly, p53 is a tumor suppressor gene, and certain mutant forms have the capacity to behave like oncogenes. Certain mutant forms of p53 require only one mutated allele to abrogate p53 function, because p53 mutants have the additional property of increased stability in the cell compared with the wild-type protein. Consequently, because they are not as easily broken down, the mutant protein tends to accumulate in the cell (39). In cells containing a p53 mutation, elevated concentrations of the p53 product can often be detected (40). Deleted in Colon Cancer Deleted in colon cancer (DCC) is a tumor suppressor gene of 29 exons spanning over a million base pairs on the long arm of chromosome 18 (18q) (41). It encodes at 1447-amino acid transmembrane protein whose extracellular domain resembles the neural cell adhesion molecule family of proteins (42). DCC probably participates in signaling pathways that control cell proliferation and differentiation, a finding that is further supported by the fact that many mature epithelial cells express DCC in a restricted fashion limited to the proliferative compartment. Recent studies have raised doubts concerning the role of DCC, thus suggesting that, although DCC appears to play a role in neural development, it is likely not the tumor suppressor from 18q that was thought to promote colorectal carcinoma (43,44). Loss of heterozygosity in 18q occurs in more than 70% of colorectal cancers, and the altered region includes the DCC locus in over 90% of carcinomas with 18q allelic loss. Studies comparing the incidence of DCC allelic loss among adenomas and carcinomas indicate that loss in this region is a relatively late event in the progression of cancer (45). There has also been evidence to suggest that tumors with allelic

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Figure 4 The PI3K pathway. Abbreviations: PTEN, phosphatash and tension; p85/p110, PI3K heterodimer; P, phosphorylation site; PIP2, phosphatidylinositol 4,5-phosphate; PIP3, phosphatidylinositol 3,4,5-phosphate; PDK, phosphatidylinositide-dependent kinase; GSK-3, glycogen synthase kinase-3; FKHR-L1, forkhead transcription factor; BAD, Bcl-2 antagonist of cell death; TNF-a, tumor necrosis factor-a. Source: From Ref. 53.

Figure 3 Colorectal carcinogenesis. Abbreviations: APC, adenomatous polyposis coli; DCC, deleted in colon cancer. Source: From Ref. 35.

loss at 18q metastasize more readily and behave more aggressively (46). Thus, DCC mutations may be of prognostic value. Recent observations on the function of DCC in intracellular signaling have provided a renewed interest in the potential contribution of DCC in the activation of colorectal cancer. In particular, studies suggest that when engaged by netrin ligands, DCC may activate downstream signaling pathways (47). Moreover, in cancers where netrin is absent or at low levels, DCC can promote apoptosis (47). Finally, recent functional studies have shown that inhibition of cell death induced by DCC in the mouse intestine leads to tumor formation. DPC4/SMAD4 Another candidate tumor suppressor gene is called DPC4 (deleted in pancreatic carcinoma), also known as SMAD4. Similar to DCC, DPC4/SMAD4 is located on chromosome 18q (48). Germline DPC4 mutations have been noted in a subset of patients with juvenile polyposis syndrome. DPC4 mutations have been noted in only approximately 10% to 15% of colorectal carcinomas and much less frequently in other GI tumors such as gastric cancers (49). Based on the frequencies of mutations in DPC4, this gene appears not to be a primary tumor suppressor gene targeted for inactivation by 18q loss of heterozygosity in colorectal

cancer (49). Nevertheless, inactivation of this gene is likely to have an important role in the tumor process, because it encodes a protein that functions to transduce TGF-b growth regulatory signals, and TGF-b has significant growth inhibitory effects on colonic epithelial cells (50). Phosphatase and Tensin Phosphatase and tensin (PTEN) homolog deleted on chromosome 10 (p10), also called MMAC1 or TEP1, is a tumor suppressor gene identified on human chromosome 10q23 (51). PTEN plays a major role in cell cycle arrest and apoptosis, as well as other cellular processes such as cell adhesion, migration, and differentiation (52). Disruption of PTEN in mice results in early embryonic lethality, whereas animals heterozygous for this allele develop a broad array of tumors including intestinal tumors. Recent studies show that the phosphatidylinositol-3 kinase (PI3K) product is a critical target of PTEN, by directly dephosphorylating the D3-phosphate group of the lipid second messenger (PI3, 4, 5-triphosphate), thus suggesting that PTEN can serve as a negative regulator of the signaling events mediated by PI3K (Fig. 4) (54). Although heterozygous PTEN mice are viable, they show hyperplastic-dysplastic changes and spontaneous tumor formation in various tissues including the colon (55). In humans, PTEN germline mutations have been found in autosomal-dominant cancer syndromes with overlapping clinical features: Cowden disease and Bannayan–Zonana syndrome (56). Even though each of these syndromes manifests distinct phenotypes such as thyroid carcinoma, breast cancers, meningiomas, or macrocephaly, they are all characterized by multiple hamartomas in the intestine.

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p16 p16 is a tumor suppressor gene found at chromosome 9p21 (57). It is transcribed from the CDK N2a gene that also encodes the p19 Ark protein; the two products are obtained through alternative splicing of RNA (58). Like p53, it functions to inhibit cell cycle progression in the presence of genetic mutation at critical junctions, thus controlling neoplastic growth. It is thought that the p16 product suppresses tumors by inhibiting CDK/cyclin phosphorylation of the retinoblastoma (Rb)/E2F complex (59). The downstream effect of the normal p16 protein activity is the inhibition of transcription of genes that are responsible for growth and differentiation through hyperphosphorylated Rb protein. p16 is known to act in a regulatory feedback circuit with CDK-4, D-type cyclins, and Rb protein (60). The p16 gene appears to be inactivated through three basic mechanisms: point mutation with loss of heterozygosity within CDK N2a, homozygous deletion, and through methylation of the prime motor region (59). p16 mutations have been described in both diffuse and intestinal type gastric cancers.

Mismatch Repair Genes In about 80% of patients with hereditary nonpolyposis colorectal carcinoma (HNPCC), the propensity toward development of colorectal tumors results from an inherited mutation in one or more DNA mismatch repair genes (61). Loss of function of these genes leads to replication errors accumulating at a rate of 1000-fold in normal cells for each cell cycle, consequently resulting in the acceleration of cancer progression (62). The mismatch repair genes specific to HNPCC and sporadic cases of colorectal cancer target specific point mutations and microsatellite repeats. Cells with this type of error are said to be replication error–positive (RERþ) and to possess microsatellite instability (MSI). The most common genes affected are MSH2 and MLH1, followed by PMS1, PMS2, and MSH6 (62). In addition, one candidate tumor suppressor gene that is found to be consistently associated with RERþ colorectal neoplasms is the gene encoding the type 2 TGF-b receptor (63). Colorectal neoplasms with this mutation have a growth advantage that is clearly not a by-product of the generalized instability in these tumors. TGF-bR2 may play an important role in mediating differentiation and apoptosis of gut epithelial cells.

Stromal Influences Angiogenesis Angiogenesis, the process of new capillary formation (Fig. 5), is required for tumor growth and metastasis. Initially, small tumors may survive on established blood supply. However, as a tumor grows larger, metabolic demand requires microvessel ingrowth and neovascularization to supply nutrients and oxygen. These tumors induce phenotypic changes in vascular endothelial cells, initiating a new blood supply and allowing more rapid growth (65). This vascular ingrowth is associated with, but probably disproportionate to, the normal microvessel formation stimulated by hypoxia (66–68). Conversely, when blood supply does not keep up with metabolic demand, central necrosis or apoptosis, a common finding in larger tumors, may result (69,70). Intuitively, these tumors also have increased metastatic potential, as the process of angiogenesis involves enzymatic alteration of the basement membrane, cell migration, and proliferation.

Figure 5 The process of tumor angiogenesis. In a complex series of events, angiogenic factors provide a signal for quiescent mature blood vessels to develop new vascular sprouts that subsequently undergo remodeling and maturation. Source: From Ref. 64.

A number of cytokines have been implicated in angiogenesis, including TGF-b1, vascular endothelial growth factor (VEGF), HGF, and small molecules such as platelet activating factor and nitric oxide (NO). TGF-b1 regulates multiple processes from malignant transformation and immunomodulation to microvessel formation and matrix remodeling with multiple layers of regulation. VEGF, in contrast, is a direct-acting angiogenic hormone that is required for endothelial cell survival in new blood vessels, and is associated with tumor progression (71–73). Furthermore, malignant transformation has been associated with increased VEGF expression (74,75). The resulting increase in VEGF results in increased expression of growth factor receptors and matrix metalloproteinases (MMP). Vascular permeability increases and MMP-induced degradation of the extracellular matrix allows endothelial cell migration and proliferation, resulting in vascular budding and microvessel formation (Fig. 6) (65). Bevacizumab, a humanized monoclonal anti-VEGF antibody, has shown increased response rates and survival times when used with irinotecan, 5-fluorouracil (5-FU), and leucovorin (77,78), and is the first VEGF-related agent approved by the Food and Drug Administration for use in metastatic colorectal cancer. There are three VEGF receptors (VEGF-R), all of which are transmembrane tyrosine kinase receptors. VEGF-R1 activation promotes endothelial cell migration but not proliferation, while VEGF-R2 activation is required for endothelial cell differentiation and development (79–81). VEGF-R3 binds

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Figure 6 Tumor angiogenesis is mediated by factors secreted from tumor cells or infiltrating stromal cells. Source: From Ref. 76.

other members of the VEGF family. Although VEGF-R1 has a higher affinity for VEGF than VEGF-R2, in endothelial cells overexpressing VEGF-R1, VEGF induces receptor phosphorylation, but not mitogenesis (65), suggesting that VEGF-R2 is the more likely candidate for therapeutic intervention. A number of tyrosine kinase inhibitors have entered clinical trials in an attempt to exploit the necessity of VEGF for microvessel ingrowth (Table 1) (82). Furthermore, VEGF-R2 binding is enhanced by the presence of its coreceptor, neuropilin-1 (83). A soluble neuropilin-1 has been shown to have antitumor activity in a rat prostate carcinoma model (84).

Epithelial–Mesenchymal Crosstalk Carcinogenesis is a multicellular process, where alterations in the surrounding microenvironment are part of tumor progression. Surrounding stromal cells have recently gained attention for their role in the proliferation and progression of epithelial carcinoma cells (85–88). Increased expression of proangiogenic factors, such as TGF-b and VEGF, and factors involved in extracellular matrix remodeling, such as multiple endocrine neoplasia type-1 (MMP-1), tissue inhibitors of MMPs (TIMP-1), and plasminogen activator inhibitor type-1 (PAI-1) and, again, TGF-b, have been noted in colonic carcinoma (Fig. 7) (85,87,89). In addition, proinflammatory cytokines such as interleukin-8 (IL-8) are also upregulated

Table 1 Tyrosine Kinase Inhibitors in Clinical Trials Inhibitor PTK787/ZK222584 AZD6474 CP-547, 632 SU11248

Target VEGF-R1 and VEGF-R2 VEGF-R2, EGF-R VEGF-R2, EGF-R, PDGF-R VEGF-R1 and VEGF-R2, PDGF-R, Flt-3

Clinical trial phase 3 2 2 3

Abbreviations: EGF-R, epidermal growth factor receptor; Flt-3, fms-like tyrosine kinase 3; PDGF-R, platelet-derived growth factor receptor; VEGFR1, vascular endothelial growth factor receptor 1; VEGF-R2, VEGF receptor 2. Source: From Ref. 82.

Figure 7 Immunohistochemical analysis for proteins related to angiogenesis, invasion, and metastasis. Representative immunohistochemical sections are shown for VEGF, TIMP-1, and PAI-1. Paired sections of normal mucosa and colon cancer from the same patients are displayed (magnification, 400
). Abbreviation: VEGF, vascular endothelial growth factor. Source: From Ref. 89.

(89), which have angiogenic and mitogenic properties (90). Also, stromal cells may exhibit enhanced proliferation (89), suggesting that the active role these cells play in carcinogenesis results in abnormal growth of both the tumor and the stroma.

Inflammatory Components Contributing to GI Cancers Inflammation and GI Cancers The link between chronic inflammation and cancer was first reported by the French surgeon Jean Nicholas Marjolin who, in 1828, described the occurrence of squamous cell carcinoma in a post-traumatic, chronically inflamed wound (91). In 1863, Rudolf Virchow identified leukocytes in tumor stroma and suggested that malignancy originated at sites of chronic inflammation, challenging the popular opinion that lymphoreticular infiltrate was simply a reaction to the neoplastic process (90). The occurrence of cancers arising after prolonged inflammation has been described in every organ system of the body. Many of these cancers are attributable to infectious, mechanical, or chemical agents that elicit a chronic immune response. Recent evidence implicates a role for such an inflammatory response in the development of GI cancer. While the overall incidence of gastric cancer in the United States has significantly decreased over the past 50 years, gastric cancer remains the second most common cancer-related mortality in developing countries (92). The single most identifiable factor contributing to the development of gastric adenocarcinomas, particularly the intestinal

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decrease the risk of developing colorectal cancer in IBD patients, (ii) the risk of colorectal cancer increases with duration of illness, and (iii) the risk of colorectal cancer increases with severity of inflammation (94). Other differences in colorectal cancer development in patients with IBD include a younger age at tumor development, mucinous or signet ring histology, higher incidence of two or more primary tumors, and more proximal distribution of tumors (94).

Chronic Inflammation and the Tumor Microenvironment

Figure 8 The relationship between chronic Helicobacter pylori infection and gastric cancer. Abbreviation: NO, nitric oxide. Source: From Ref. 94.

type, which generally involves the distal stomach (93), is chronic infection with the bacterium Helicobacter pylori (H. pylori), which has led to its recent classification as a class I carcinogen by the World Health Organization (WHO) (92). Case-controlled studies have estimated an approximately 2- to 17-fold increased risk of patients seropositive for H. pylori to develop gastric cancer when compared with seronegative patients (Fig. 8) (95). Inflammatory bowel disease (IBD), including both ulcerative colitis (UC) and Crohn’s disease, has a wellestablished association with the development of colorectal cancer. In contrast to conditions such as FAP and HNPCC, which have a well-defined genetic basis and follow an ‘‘adenoma–carcinoma’’ sequence of development, it appears that chronic inflammation predisposes to the development of colorectal cancer in the setting of IBD, following an ‘‘inflammation-dysplasia-carcinoma’’ model (Fig. 9) (94,96). This is supported by the following facts: (i) anti-inflammatory agents

The chronic inflammatory response represents a fine balance between active inflammation, repair, and destruction that occurs in response to a persistent stimulus over a prolonged period of time. Activation of leukocytes in response to such an ongoing stimulus leads to the production of chemokines, cytokines, and reactive oxygen species (ROS), resulting in accumulated tissue destruction and subsequent attempts at healing via remodeling, angiogenesis, and connective tissue replacement. Accumulation of cellular damage with loss of cell cycle control mechanisms is thought to be the final common pathway leading to tumor initiation (91,97). Tumor stroma is far more likely to contribute to tumor growth, invasion, and immunosuppression than it is to mount an effective antitumor response. Gastric and colorectal cancer stroma shares a common composition of macrophages, dendritic cells, lymphocytes, fibroblasts, connective tissue, and a fibrin-gel matrix (98). Examination of tumor cells and surrounding stroma has demonstrated that a mitogenic relationship exists between the two, whereby tumor cells express receptors for mediators produced by stromal elements (98). Of the stromal elements, the tumor-associated macrophages are the chief effectors of chronic inflammation in the pathogenesis of gastric and colorectal cancer, producing a large array of inflammatory mediators. These inflammatory mediators include growth and angiogenic factors (PDGF, TGF-b, and EGF), cytokines and chemokines [IL-1, IL-8,

Figure 9 Proposed model of how inflammation-associated with colitis promotes the development of colonic dysplasia and cancer. Abbreviation: MMR, mismatch repair. Source: From Ref. 96.

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and tumor necrosis factor-a (TNF-a)], and proteolytic enzymes (proteases, elastase, collagenase, hydrolases, phosphatases, matrix metalloproteinase-9, and lipases) that degrade the extracellular matrix, promoting invasiveness, and cytotoxic agents which likely contribute to host cell genomic damage and promote carcinogenesis, such as ROS, hydrogen peroxide (H2O2), and NO (91,97,99). Macrophages also produce migration inhibitory factor (MIF), which contributes to mononuclear cell immobilization at the site of active, chronic inflammation; however, MIF also has the dual role of suppressing transcriptional activation of the tumor suppressor gene p53, which may also contribute to carcinogenesis (91,97,100). H2O2, a by-product of macrophage activation, has the ability to activate the nuclear factor-kB (NF-kB) pathway, leading to translocation of the activated complex to the nucleus, where it acts as a transcription factor for products inhibiting apoptosis (100). TNF-a also activates the NF-kB complex, effectively inhibiting apoptosis (100). TNF-a, IL-1, and IL-6, produced by activated leukocytes, are major mediators of inflammation and tumorigenesis (101–103). Together they induce production of adhesion molecules, growth factors, eicosanoids, NO, and chemotactic and angiogenic factors such as VEGF, and upregulate pathways that subsequently inhibit apoptosis, thus supporting tumor initiation, growth, and invasion. Receptors are found both on stromal elements and tumor cells, suggesting both autocrine and paracrine local effects (91,98). Experimental deletion of selected cytokines and chemokines in animal models confers resistance to carcinogenesis, supporting their role in the development of cancer (104,105). Neoplasia developing in the setting of chronic inflammation is a multihit process, resulting from the accumulation of genetic mutations (Fig. 10). These mutations may largely be due to the effects of ROS such as superoxide anions, H2O2, hydroxyl and hydroperoxyl radicals, and reactive nitrogen species such as NO, collectively known as reactive oxygen and nitrogen species (RONS), that are elaborated by activated inflammatory cells (91,106). The toxic effects of RONS include DNA strand breaks, mismatches, mutations, and the formation of adducts with DNA (100,107). NO is specifically responsible for the nitrosylation of proteins involved in apoptosis, such as caspases-3, -8, and -9, resulting in inactivation and prevention of cell death in response to injury (107). H2O2 is capable of damaging the protein complexes responsible for DNA mismatch repair, resulting in inactivation and accumulation of sequence errors (106).

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Signaling Pathways Linking Inflammation and GI Cancer Many derangements in cell signaling occur during the transformation of a normal cell to a malignant phenotype. It is useful to identify cell-signaling pathways that may inhibit apoptosis and promote tumor growth, which are similarly upregulated in multiple cancer cell lines. Three prominent pathways include cyclooxygenase-2 (COX-2), NF-kB, and PI3K pathways. COX-2, also known as prostaglandin G/H synthase, is the rate-limiting enzyme catalyzing the conversion of arachidonic acid to a variety of inflammatory and physiological mediators, including prostaglandins and thromboxane. The COX-2 isoform of this enzyme belongs to a class of genes known as immediate early or early growth response genes inducible by inflammatory cytokines and growth factors, including IL-1 and TNF-a, and its products are predominantly proinflammatory prostaglandins and eicosanoids involved in regulation of the immune response (Fig. 11) (109). COX-2 is not normally expressed in the human intestine, but its activity is significantly elevated in the majority of human colorectal and gastric cancers (110). A significant and early COX-2 overexpression is associated with UC, both in inflamed and in noninflamed mucosa, and with UCassociated dysplasia and neoplasia (110). This has led to interest in defining its specific mechanism of action in chronic inflammation and neoplasia to determine if its inhibition may act as an adjunct to current chemotherapy. Large epidemiologic studies have demonstrated a 30% to 50% reduction in adenomatous polyp formation, incident disease, and death from colorectal cancer by inhibiting COX-2 activity with nonsteroidal anti-inflammatory medications (111). NF-kB is a ubiquitously expressed transcription factor that plays a pivotal role in cellular responses to environmental changes, such as stress, inflammation, and infection. NF-kB is activated in response to infectious agents or cytokines, including TNF-a, IL-1, ROS, and lipopolysaccharide (112). Its products include growth factors, cytokines, cell adhesion molecules, immunoreceptors, and cell survival proteins, making it an important and complex regulator of the immune response (112,113). Constitutive activation of NF-kB has been described in inflammatory conditions such as gastritis and IBD, as well as many solid tumors, including GI cancers. The activation of NF-kB by proinflammatory stimuli and its ability to inhibit apoptosis have led to the assumption that the NF-kB pathway provides a mechanistic link between inflammation and cancer (114).

Figure 10 Inflammation and the landscape theory. Chronic inflammation, as seen in inflammatory bowel disease, causes damage of stromal cells, and subsequent healing allows these damaged cells to be exposed to growth factors. This combination of cell damage and proliferation may lead to the development of an abnormal microenvironment, where stromal elements encourage the production of transformed cells. Abbreviations: COX-2, cyclooxygenase-2; NF-kB, nuclear factor kB; ROS, reactive oxygen species. Source: From Ref. 100.

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Figure 11 COX-2–derived PGE2 promotes tumor development. Abbreviations: COX-2, cyclooxygenase-2: VEGF, vascular endothelical growth factor. Source: From Ref. 108.

Another pathway playing a critical role in the balance between cell survival and apoptosis is the PI3K pathway. PI3K, a ubiquitous lipid kinase activated by a wide variety of extracellular stimuli, including inflammatory cytokines (e.g., TNF-a) and growth factors, is involved in the regulation of diverse cellular processes such as cell growth and survival, actin cytoskeletal rearrangement, membrane ruffling, and vesicular trafficking (115); therefore, signaling through this pathway plays a pivotal role in the regulation of cellular growth, transformation, and tumorigenesis. Increased PI3K activity has been identified in as many as 86% of human colorectal cancers, with increasing activity correlating with increasing tumorigenic potential of the cancer cell lines examined (115,116). The promotion of cell survival by PI3K and its subsequent contribution to tumorigenesis is thought to occur via the inhibition of proapoptotic signals and the induction of survival signals (116).

Hormone and Hormone Receptors The receptors for GI hormones are cell surface G protein– coupled receptors (117). These receptors regulate a number of cellular processes including growth, differentiation, and development. The binding of GI hormones to their G protein–coupled receptors can result in a varied cellular response through complex activation of the hormone– receptor complex (118). In a manner analogous to other hormone responsive tumors such as breast cancers and prostate cancers, GI cancers can also possess receptors for various intestinal hormones, and the binding of these hormones to their receptors can lead to increased growth of these cancers. Experimental studies have shown that colorectal and gastric cancers that possess receptors for selected GI hormones are responsive to the effects of these hormones, resulting in enhanced proliferation (119). GI hormones are cellular messengers that regulate intracellular signaling within intestinal tract cells affecting secretion, motility, absorption, digestion, and cell proliferation (120). GI hormones are produced and secreted by endocrine cells located throughout the GI mucosa and pancreas. Although these hormones were initially discovered as solely endocrine in nature, recent studies have demonstrated that these hormones can act in either a paracrine or autocrine fashion (120). GI hormones that have been shown to play a role in the growth of gastric or colorectal cancers include gastrin, bombesin/gastrin-releasing peptide, and neurotensin (120). In addition, the hormone,

somatostatin, has been shown to inhibit the proliferation of various GI cancers through both direct and indirect mechanisms (121,122). Although the amount of proliferation contributed by GI hormones on tumor growth may be relatively small, the identification of GI cancers with these receptors may be important in streamlining chemotherapy to include agents that block these receptors, which, in conjunction with other standard chemotherapeutic agents, may be useful in selected cancers.

NEOPLASTIC DISEASES OF THE STOMACH, SMALL BOWEL, AND COLORECTUM Gastric Neoplasms The majority of gastric neoplasms are malignant, with 90% to 95% of these cases identified as adenocarcinomas (123). Other malignant neoplasms include lymphomas and sarcomas. Benign gastric neoplasms include leiomyomas and lipomas.

Benign Gastric Tumors Gastric polyps are usually an incidental finding on endoscopy and are detected in approximately 2% to 3% of upper GI endoscopies (124). Hyperplastic polyps are among the most frequently observed polyps; these polyps are usually small and benign. Adenomatous polyps have a risk for malignancy that is associated with size; the greater the size, the more likely an invasive cancer is present (125). Resection is required for polyps, either by endoscopic polypectomy or, if too large, gastric resection. Other benign conditions of the stomach include leiomyomas, which are smooth muscle tumors of benign origin, lipomas, and ectopic pancreas.

Adenocarcinoma of the Stomach Incidence/Epidemiology Adenocarcinoma of the stomach is the second most common cancer worldwide, when specific geographic variations are included (126). Notably, higher rates are noted in Japan and in some parts of South America, whereas lower rates occur in Western Europe and the United States (127,128). In the United States, gastric adenocarcinoma is the 10th most common cancer, with an incidence that has been decreasing over the last 70 years (129). Gastric cancer is twice as common in men as in women, and is higher among

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African-American men than Caucasian men. As with other cancers, the incidence increases with age, peaking in the seventh decade. Other factors, which contribute to gastric adenocarcinoma, include environmental exposure as well as other cultural or genetic factors. Although adenocarcinoma localized to the distal stomach has declined, the incidence in other more proximal sites, including the gastric cardia, have increased, possibly as a result of differences in pathogenic factors. Etiology Diet has been postulated to play a role in the geographic differences noted in gastric adenocarcinoma. Diets low in animal protein and fat, high in complex carbohydrates, high in salted meats and fish, and high in nitrates or H. pylori in the drinking water are associated with an increased risk for gastric adenocarcinoma (130). In contrast, the consumption of raw vegetables, fruits, and high-fiber foods is associated with a lower risk of gastric cancer. Other factors associated with an increased risk of gastric adenocarcinoma include low socioeconomic status (except in Japan), cigarette smoking, male gender, and H. pylori infection. The presence of immunoglobulin G antibodies to H. pylori appears to correlate with the local incidence and mortality rates of gastric cancer (131). Infection with the cagA strain produces a greater mucosal inflammation than cagAnegative strains and results in a greater risk of gastric cancer (132). Host genetic factors also play a role in development, as noted by increased risk of hypochlorhydria induced by H. pylori associated with increased IL-1 gene cluster polymorphisms, thus resulting in increased gastric cancer (133). Therefore, the familial clustering of H. pylori infection associated with inherited genetic polymorphisms linked to hypochlorhydria may explain the increased risk in individuals of certain families (134). Pernicious anemia is associated with an increased risk for developing gastric adenocarcinoma (135,136). This condition represents an autoimmune gastritis of the oxyntic mucosa and increases the risk of gastric cancer as a result of increased chronic inflammation. The presence of adenomatous gastric polyps carries a distinct risk for the development of gastric adenocarcinoma in the polyp. Similar to polyps in the colon, increasing size of the polyp is associated with increased risk of invasive cancer (125). Several genetic alterations have been reported to occur in gastric adenocarcinomas and include the overexpression of the c-met proto-oncogene (the receptor for the HGF) and the K-sam and c-erb-B2 oncogenes (Fig. 12). Inactivation of the tumor suppressor genes, p53 and p16, have been noted in both diffuse- and intestinal-type cancers, whereas APC gene mutations tend to be more frequent in the intestinal-type gastric cancers (138–140). In addition, a reduction or loss of the cell adhesion molecule, E-cadherin, is noted in about 50% of diffuse-type gastric cancers and MSI is noted in approximately 20% to 30% of intestinal-type cancers (133,138,141). Pathology The most useful and widely used classification system for gastric adenocarcinomas divides those cancers into two types: intestinal and diffuse (123,142). The intestinal type arises in the setting of precancerous conditions such as gastric atrophy or intestinal metaplasia; men are more commonly affected than women, and the incidence of intestinal type increases with age. This variant is well differentiated,

Figure 12 A model for the progression of molecular lesions in gastric cancer. The two histological subtypes of gastric adenocarcinoma, diffuse and intestinal gastric cancer, originate from different combinations of molecular lesions. Abbreviations: APC, adenomatous polyposis coli; DCC, deleted colon cancer; TGF-b, transforming growth factor-b. Source: From Ref. 137.

with a tendency to form glands, and metastatic spread is generally hematogenous to distant organs. The intestinal type is typically noted in the distal stomach with ulcerations; this form is declining in incidence in the United States (143). In contrast, the diffuse type involves widespread thickening of the stomach, especially in the cardia and often affects younger patients. It often presents as linitis plastica, a particularly virulent form of gastric cancer characterized by nondistensible and thickened stomach walls. In addition, the diffuse form of gastric cancer is composed of signet ring cells (123). The route of spread is generally by transmural extension and through lymphatic invasion. This form is more common in women, affects a slightly younger age group, and is associated with blood type A, suggesting a genetic etiology (142). Clinical Manifestations The symptoms associated with gastric adenocarcinoma can be relatively nonspecific and, therefore, may not be diagnosed at an early stage. Early symptoms include epigastric discomfort and indigestion, which may be mistaken for gastritis or peptic ulcer. More advanced disease presents with weight loss, anorexia, fatigue, or vomiting. Proximal tumors can present as dysphagia with involvement of the GE junction. More distal cancers may present as a gastric outlet obstruction. Diffuse mural involvement, such as that which occurs with linitis plastica, may result in early satiety (144,145). Clinically significant GI bleeding is rare, but as many as 15% of patients may develop hematemesis and 40% of patients are anemic (146). Classic physical findings associated with very advanced gastric cancers and metastatic spread include a palpable abdominal mass, a palpable supraclavicular (Virchow’s) or periumbilical (Sister Mary Joseph’s) lymph node, peritoneal metastasis palpable by

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rectal examination (Blumer’s shelf), or a palpable ovarian mass (Krukenberg’s tumor) (147). Diagnosis Once suspected, gastric adenocarcinoma may be diagnosed by a barium upper GI contrast study or, preferably, upper GI endoscopy with biopsy and cytology, which approaches a diagnostic accuracy of 90% to 95% (148). Once identified, the staging of gastric cancer is performed by endoscopic ultrasound (EUS), which provides a staging accuracy of approximately 75% (149). Staging by computed tomography (CT) scan provides complementary information regarding lymphadenopathy and extragastric organ involvement. Treatment Surgical treatment remains the only hope for cure. It is estimated that surgical resection for cure is possible in only 25% to 30% of the cases (150). If the tumor is confined to the distal stomach, subtotal gastrectomy is performed, with resection of surrounding lymph nodes. In contrast, tumors in the more proximal stomach require total gastrectomy. The role of extended lymphadenectomy in combination with the primary resection remains controversial. The various types of surgical procedures that are employed to manage gastric cancer are shown in Figure 13. The routes of lymphatic spread are shown in Figure 14. Gastric adenocarcinomas are partially responsive to chemotherapy. Single-agent treatment with 5-FU, doxorubicin, mitomycin C, or cisplatin provides a response rate of approximately 20% to 30% (153,154). When used in combination, response rates of 35% to 50% can be obtained. Radiation therapy is relatively ineffective and is used in only special cases for predominately palliative reasons (155). Prognosis Overall, the five-year survival rate of gastric adenocarcinoma is less than 10% (156). Prognostic factors include anatomic location and nodal status. That is, distal gastric cancers without lymph node involvement have a better prognosis than proximal gastric cancers with or without lymph node involvement. Other prognostic factors include depth of penetration and tumor cell aneuploidy. Linitis plastica and infiltrating lesions are associated with an overall worse prognosis. The TMN system of classifying gastric carcinoma emphasizes the extent of spread through the gastric wall and the presence or absence of regional lymph node involvement (Fig. 15). It is the major system of staging this disease in the United States.

Gastric Lymphoma The stomach is the most common site for lymphomas of the GI system. However, they are still relatively infrequent, accounting for less than 15% of gastric malignancies (123). Patients often present with vague symptoms including epigastric pain, early satiety, and fatigue; more than half of patients present with anemia. Similar to adenocarcinoma, lymphomas occur in an older age group, with more cases noted in men (158). The majority of gastric lymphomas are non-Hodgkin’s lymphomas, with the most common histologic diagnosis of diffuse large B-cell lymphoma followed by extranodal marginal cell lymphoma [mucosa-associated lymphoid tissue (MALT)] (Table 2). MALT lymphomas are strongly associated with H. pylori infection (Fig. 16) (159).

Figure 13 Surgical options for treatment of gastric adenocarcinoma. (A) Subtotal gastrectomy with gastrojejunal reconstruction. (B) Total gastrectomy followed by esophagojejunostomy. (C) Esophagogastrectomy with intrathoracic or cervical reconstruction. Source: From Ref. 151.

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TNM Classification of Carcinoma of the Stomach

Category

Criteria

PRIMARY TUMOR (T) TX Primary tumor cannot be assessed T0 No evidence of primary tumor Tis Carcinoma in situ: intraepithelial tumor without invasion of the lamina propria T1 Tumor invades lamina propria or submucosa T2 Tumor invades muscularis propria or subserosa . T2a Tumor invades muscularis propria T2b Tumor invades subserosa T3 Tumor penetrates serosa (visceral peritoneum) without invasion of adjacent structures T4 Tumor invades adjacent structures

Figure 14 Routes of lymphatic spread for carcinoma of stomach. Source: From Ref. 152.

Gastric lymphomas usually arise as ulcers or as exophytic masses. Diagnosis may be obtained by upper GI endoscopy or upper GI barium studies. Proper staging of gastric lymphoma involves endoscopic ultrasonography, chest and abdominal CT scans, and, in some cases, bone marrow biopsy. The treatment of diffuse large B-cell lymphoma of the stomach is with combination chemotherapy with or without radiotherapy. Five-year survival rates of 40% to 60% have been reported using this treatment modality. For MALT lesions, the eradication of H. pylori infection appears to induce regression of the tumor. However, longer-term studies are required before this can be substantiated (158,161).

Gastric Sarcomas Leiomyosarcomas constitute about 1% of all gastric cancers and usually occur as an intramural mass with central ulceration. Symptoms can include bleeding accompanied by a palpable mass. Surgical resection results in a five-year survival rate of about 50% (162).

Neoplasms of the Small Intestine Incidence/Epidemiology Small bowel neoplasms are exceedingly rare, constituting only 5% of all GI neoplasms and only 1% to 2% of all malignant tumors of the GI tract (163). The mean age at onset is approximately 59 years and, similar to other cancers, there appears to be a geographic distribution, with the highest cancer rates among the Maori of New Zealand and ethnic Hawaiians (164). Numerous risk factors and associated conditions have been described with relation to small bowel neoplasms and include patients with FAP, HNPCC, Peutz– Jeghers syndrome, Crohn’s disease, gluten-sensitive enteropathy (i.e., celiac sprue), and biliary diversion (e.g., previous cholecystectomy). Controversial factors that may contribute to small bowel cancers include smoking, heavy alcohol consumption, and consumption of red meat or salt-cured foods. Although the molecular genetics of small bowel neoplasms

REGIONAL LYMPH NODES (N) NX Regional lymph node(s) cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in 1 to 6 regional lymph nodes N2 Metastasis in 7 to 15 regional lymph nodes N3 Metastasis in more than 15 regional lymph nodes DISTANT METASTASIS (M) MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis STAGE GROUPING Stage 0 Tis Stage 1A Tl Stage IB Tl T2a/b Stage II Tl T2a/b T3 Stage III T2a/b T3 T4 Stage IIIB T3 Stage IV T4 Tl-3 Any T

N0 N0 N1 N0 N2 N1 N0 N2 N1 N0 N2 N1_3 N3 Any N

M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1

Figure 15 TNM classification of carcinoma of the stomach. Source: From Ref. 157.

have not been entirely characterized, similar to colorectal cancers, mutations of the K-ras gene are commonly found (165). Allelic losses, particularly involving tumor suppressor genes, APC, p53, DCC, and DPC4 (SMAD4) genes, have been noted in some small bowel cancers (166–168).

Pathology Benign neoplasms of the small bowel account for the majority of small bowel neoplasms. These benign lesions include adenomas, leiomyomas, lipomas, and angiomas (169).

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Table 2 Frequency of Organ Involvement GI lymphoma Diffuse large cell lymphoma MALT lymphoma Burkitt’s lymphoma Peripheral T-cell lymphoma Mantle cell lymphoma Follicular lymphoma

Stomach 55 40 3 0 95%). These cells contain few intracellular organelles and appear to be relatively metabolically inert, allowing for maximal oxygen delivery with minimal energetic demand. These cells also function to reabsorb pathologic accumulation of alveolar fluid (4). In contrast, type II alveolar cells are sparsely interspersed cuboidal cells with an abundance of intracellular organelles and are metabolically active. These cells produce surfactant and can regenerate the epithelium by differentiating into type I cells. Surfactant is a lipoprotein complex containing large amounts of saturated lecithins and other proteins and serves two main functions. Surfactant reduces surface tension at the air–tissue interface of the lung, reducing inhalational work. It also stabilizes the alveoli, thereby contributing to the general compliance of the lung. Surfactant also has an immunoprotective role. Two surfactant proteins, SP-A and SP-D, have been described to have a host of immune functions, including pathogen opsonization, regulation of inflammatory mediators, and even direct antimicrobial activity by increasing membrane permeability (5,6). The capillary endothelial cell makes up the other half of the blood–air interface. The endothelial cells are water permeable, but impermeable to macromolecules. They are metabolically active and secrete prostaglandins, and can deactivate bioactive compounds such as histamine and serotonin. The alveolar epithelium and capillary endothelium are supported by a thin interstitium, composed of a proteoglycan matrix embedded with elastin and collagen, which is produced by fibroblasts. Elastin can stretch to 130% of its length while retaining recoil properties and is the prime determinant of the mechanical properties of the lung. Its loss, as seen in patients with emphysema, leads to hyperexpansion and loss of elastic recoil. Stimulation of fibroblasts during disease processes can lead to severe pathology such as pulmonary fibrosis or acute respiratory distress syndrome (ARDS). Interspersed in the interstitium are alveolar macrophages, which provide a further layer of immunologic defense. They appear to be derived from a pluripotential cell—possibly circulating monocytes, which remain dormant until needed for differentiation. Alveolar macrophages actively engulf bacteria and inert particles and experimentally have been demonstrated to clear 95% of aerosolized bacteria within four hours of exposure (7).

The Chest Wall and Diaphragm Bony Thorax The chest wall is supported by the 12 thoracic vertebrae and the associated ribs. Movement of the ribs during forced respiration changes the dimension of the thorax facilitating inspiration and expiration. Movement of the upper six ribs during respiration has been likened to that of a waterpump handle, increasing the anterior–posterior dimension. Movement of the 7th through 10th ribs has been likened to that of a water bucket handle, increasing the lateral thoracic dimension.

Muscles of Respiration The diaphragm is the chief muscle of inspiration. Concentric contraction of its muscle fibers lowers the central tendon from the level of the nipples to the costal margin, greatly increasing the thoracic vertical dimension. Between the ribs are the external, internal, and innermost intercostal muscles.

Contraction of the interchondral intercostal muscles rotates the ribs upward, while contraction of the interosseous intercostal muscles rotates the ribs downward. Contraction of the neck muscles and other chest wall muscles (scalenes, sternocleidomastoid, pectoral muscles, etc.) can also contribute to movement of the ribs and changes in thoracic dimension during active respiration. Additionally, contraction of the abdominal wall muscles compresses the abdomen, pushing the diaphragm upward and augmenting active expiration.

Pleura The parietal pleura lines the inner chest wall, while the visceral pleura lines the lungs. The two pleurae are continuous with each other, joining at the lung hilum. The space between the parietal and visceral pleura is normally only a potential space containing a few milliliters of serous fluid. It can become abnormally enlarged in conditions such as pneumothorax, pleural effusion, hemothorax, and empyema.

Lung Volumes and Pulmonary Function Tests The inspiratory–expiratory cycle can be divided into four lung volumes (Fig. 2). The tidal volume (TV) is the volume of air inspired during a normal breath. The inspiratory reserve volume (IRV) is the volume of air, beyond the TV, that can be inspired with maximal inspiratory effort. The expiratory reserve volume (ERV) is the volume of air that can be expelled with maximal effort following a normal passive exhalation. The residual volume (RV) is the volume that still remains in the lung following maximal expiration. These volumes can also be grouped into four standard capacities. The total lung capacity is the total volume of air in the lung at maximum inhalation and is equal to the sum of all four volumes (TV þ IRV þ ERV þ RV). The vital capacity (VC) is the maximal amount of air that can be moved in one breath and is equal to the sum of TV þ IRV þ ERV. The functional residual capacity (FRC) is the volume that remains in the lung after normal passive exhalation and is equal to the sum of ERV þ RV. The inspiratory capacity is the maximal amount of air that can be inhaled after a normal passive exhalation and is equal to the sum of TV þ IRV. Although whole body plethysmography is considered the gold standard in the measurement of lung volumes and capacities, it is not clinically practical to use. Lung volumes and capacities that do not include RV are easily measured with a spirometer. Measurements with a spirometer are also performed over time. The simple and clinically useful measures of pulmonary function obtained with spirometry include the forced expiratory volume in one second (FEV1) and the forced vital capacity (FVC). Normal values can vary based on sex, age, and height. A

Figure 2 Spirometry. Abbreviations: ERV, expiratory reserve volume; FRC, functional residual capacity; IC, inspiratory capacity; RV, residual volume; TLC, total lung capacity; TV, tidal volume; VC, vital capacity. Source: From Ref. 8.

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Table 1 FEV1 and FVC in Normal and Diseased Lungs Normal lung

Obstructive lung disease

Restrictive lung disease

FVC ¼ normal FEV1 ¼ normal FEV1/FVC > 75% FVC ¼ normal or decreased FEV1 ¼ decreased FEV1/FVC < 75% FVC ¼ decreased FEV1 ¼ decreased FEV1/FVC > 75%

Figure 3 Themechanicalwork required to overcome the compliance of the respiratory system (triangular area) and the airway resistance (curved loop) during lung inspiration. The total work is the sum of the two. Source: From Ref. 11.

Abbreviations: FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity.

normal 70-kg adult male will have an FEV1 of about 4 L and an FVC of about 5 L. The ratio of FEV1 to FVC can be used to define normal, restrictive, and obstructive patterns of lung function. Normal healthy individuals have an FEV1/FVC of 80%. FEV1 is determined in part by airway resistance, which is increased with various diseases such as asthma and chronic bronchitis, and pulmonary irritants such as smoke. With increased airway obstruction, FEV1 will fall by a much greater level relative to the FVC and the ratio will drop. With restrictive patterns of lung disease, there will also be a reduction in FVC, but not as large a drop in FEV1, and the ratio may be normal or even elevated (Table 1). Genetics and environmental factors can also affect pulmonary function tests (PFTs). Spirometry and genomic scanning of individuals enrolled in the Original and Offspring Cohort Framingham studies demonstrated loci on chromosomes 4, 6, and 21 that strongly influence FEV1 and FVC (9). Diets high in vitamin C have also been associated with a lower age–related decrease in FEV1 (10).

Mechanics of Respiration Air movement into and out of the lungs is driven by changes in thoracic pressure. Thoracic pressure is created by a balance between the elastic nature of the lungs, the respiratory muscles, and the chest wall. During quiet respiration (near FRC), inspiration is active, while expiration is passive. At the end of a normal passive exhalation, the atmospheric and alveolar air pressures are equal, and there is no pressure gradient for gas movement. The respiratory muscles are relaxed and the inward elastic contractive force of the lungs equals the outward expansive force of the chest wall. Active contraction of expiratory muscles, as described above, can further enhance expiration by compressing the thoracic cavity. Active contraction of inspiratory muscles increases the thoracic volume, lowering intrathoracic pressure and causing inward movement of air. At end-inspiration, potential energy has been stored into the tissues and elastic recoil drives expiration. In the compression and expansion of gas, work (W) is defined by the product of pressure (P) and volume (V), where W ¼ PV Pressure volume loops (Fig. 3) during respiration can be constructed, and the total area represented by TV multiplied by dP (the change in intrapleural pressure) is proportional to the work of breathing. Normally, the work of breathing represents 2% to 3% of resting oxygen consumption. Lung compliance and airway resistance are the principal determinants of respiratory work. Compliance (C) is

defined by the change in volume (V) produced by a change in pressure (P) where, C ¼ dV=dP Using the same pressure volume loops, the compliance of the lung is equal to the slope of the line from the beginning to the end of inspiration. Total compliance is the sum of chest wall and lung compliance. Generally, chest wall compliance remains fairly constant, and clinically significant changes in compliance are due to changes in lung compliance.

Perfusion The lungs have a dual blood supply: the pulmonary vasculature and the bronchial vasculature. Systemic venous blood returning to the heart is mixed with cardiac venous blood (via the coronary sinus and thebesian veins) with an oxygen saturation of 68% to 76% normally. The entire output of the right ventricle is then ejected into the pulmonary artery. The pulmonary artery branches into lobar, then segmental branches corresponding to the bronchopulmonary segments (Fig. 4). The pulmonary arterial vessels are thinner and less muscular than systemic vessels, resulting in a distensible, low-pressure, low-resistance circuit. Normal pulmonary blood pressure is approximately one-fifth of systemic circulation (15–30/6–12 mmHg). After passage through the pulmonary capillaries, blood is then returned by right and left, superior and inferior pulmonary veins. In contrast, the bronchial arteries receive 1% to 2% of the cardiac output from the left ventricle, with an oxygen saturation of 100% because they arise from the aorta. Some bronchial arteries will bypass the capillary network and drain directly into the pulmonary venous system, contributing to physiologic shunting. Distribution of blood flow within the lung is not uniform. Gravity and alveolar pressure influence regional lung perfusion. West described three zones of perfusion in an upright individual from cranial to caudal relating PA, Pa, and PV (Fig. 5). When moving from the lung apices to the bases, hydrostatic pressure in the blood vessels increases while the alveolar pressure remains constant. Thus the vessels in the dependent portions of the lungs are at higher pressures and receive greater blood flow. In zone 1, near the lung apices, the alveolar pressure, PA, may exceed both Pa and PV, preventing blood flow, and thus creating dead space (areas of ventilation but no perfusion). This does not occur normally, but can occur if the Pa pressures are abnormally low (such as in hypovolemia) or if the PA is abnormally high

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Figure 4 Pulmonary artery segmental anatomy. Source: From Ref. 12.

(such as in mechanical ventilation). In contrast, reduced blood flow can be seen at the base of the lung as well if pulmonary venous pressures (PV) are abnormally high, as in left heart failure (3). Blood flow is also affected by the local alveolar oxygen tension. Local hypoxia produces pulmonary vasoconstriction, which is further potentiated by hypercapnia and acidosis. Functionally, hypoxic pulmonary vasoconstriction helps match pulmonary blood flow to alveolar ventilation by shifting blood flow to alveoli with higher oxygen levels (which is locally related to the alveolar ventilation).

Carbon dioxide is about 25 times more soluble than oxygen. CO2 is then rapidly converted to bicarbonate and approximately 90% of carbon dioxide is transported as bicarbonate. The remaining fraction is transported as dissolved carbon dioxide and protein-bound carbamino compounds. Only a small gradient is required to facilitate carbon dioxide uptake from peripheral tissues and elimination at the alveolus [normal venous partial pressure of CO2 (PCO2 ) of 46 mmHg; and arterial PCO2 ¼ alveolar PCO2 of 40 mmHg—Fig. 6]. At steady state, CO2 production is directly proportional to the product of alveolar ventilation (VA) and the PCO2 , where

Ventilation Ventilation refers to the movement of gases between the lungs and the atmosphere. Not all of the gases taken in participate in gas exchange at the alveolar capillary membrane. As described above anatomic dead space ventilation occurs within the conducting airways that do not participate in gas exchange. Additional physiologic dead space ventilation occurs in alveoli that are underperfused and thus not able to fully participate in gas exchange. The volume of gas that reaches the alveoli and is able to participate in gas exchange is referred to as alveolar ventilation.

VCO2 ðCO2 productionÞ
VA  PCO2 Therefore, if CO2 production is relatively constant, VA is inversely proportional to PCO2 . Practically, this can be used to predict how changes in minute ventilation, VE (assuming a relatively small effect from dead space ventilation), will affect PCO2 . For example, changing a patient with a minute ventilation of 10 L/min and an arterial PCO2 of 40 mmHg to a VE 8 L/min would be expected to change the arterial PCO2 to 50 mmHg (10  40/8).

ZONE 1 PA > Pa > PV

ZONE 2 Pa > PA > PV

Alveolar PA Pa Arterial

PV Distance Venous

ZONE 3 Pa > PV > PA Blood flow

Figure 5 Differential pulmonary perfusion in an upright individual. Note: Three-zone model designed to account for the uneven topographic distribution of blood flow in the lung. Abbreviations: Pa, pulmonary arterial pressure; PA, pulmonary alveolar pressure; Pv, pulmonary venous pressure. Source: From Ref. 13.

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Figure 6 Gas exchange across the alveolus. Relationship between driving pressures for oxygen and carbon dioxide exchange at alveolocapillary membranes. Abbreviations: CO2, carbon dioxide; O2, oxygen; PaCO2, partial pressure of arterial carbon dioxide; PaO2, partial pressure of arterial oxygen; PCO2, partial pressure of carbon dioxide; PO2, partial pressure of oxygen. Source: From Ref. 2.

Similar to pulmonary perfusion, there are also regional differences in lung ventilation. At FRC, dependent alveoli are less distended due to increased hydrostatic pressure from gravity. Thus, dependent alveoli expand more with inspiration and receive greater ventilation. Accordingly, in an upright healthy individual, during normal respiration the lung bases receive more ventilation than the apices. However, with lower lung volumes approaching RV, intrapleural pressure can exceed intraluminal pressure, resulting in peripheral airway collapse and atelectasis. This volume is called the closing volume (CV). In normal individuals, the CV is about 10% of the VC. As patients age, and especially in bedridden patients, the CV can approach and exceed FRC, resulting in peripheral airway collapse during a significant portion of the respiratory cycle.

hemoglobin for oxygen and facilitating oxygen unloading at the periphery. 2,3-DPG binds to the b chain of deoxyhemoglobin, decreasing the affinity for oxygen and also shifts the curve to the right. Chronic hypoxia stimulates increased synthesis of 2,3-DPG. Blood storage results in a marked decrease in 2,3-DPG.

Diffusion The diffusion of gases across capillary surfaces is affected by the tissue solubility of the gas, dimensions of the alveolar– capillary interface, the driving pressure gradient of the gas, and the rate of equilibration of gas exchange. Changes in the thickness and surface area dimensions of the alveolar–capillary interfaces affect diffusion. Reduction in the exchange surface area as with emphysema, or

Oxygenation The oxygen requirement for a normal healthy adult is about 200 mL/min. The normal oxygen gradient at room air is about 60 mmHg (alveolar PO2 of 100 mmHg, arterial PO2 of 90–95 mmHg; and venous PO2 of 40 mmHg). As oxygen diffuses across the alveolar wall, it dissolves in plasma and then diffuses into red blood cells, where it is bound by hemoglobin. The oxygen-carrying capacity (CO2 ) of blood is far more dependent on the concentration of hemoglobin and percent saturation than the partial pressure of dissolved oxygen. One gram of hemoglobin can bind 1.36 mL of oxygen, and oxygen has a solubility coefficient of 0.0031 mL O2/mmHg/dL blood. Thus, CO2 ¼ 1:36 ðHgbÞ ðSaO2 Þ þ 0:0031 ðPO2 Þ Each molecule of hemoglobin has four binding sites for oxygen. With each binding of an oxygen molecule, there is an increased affinity for the next. This produces a sigmoidal relationship between the oxygen saturation of hemoglobin and the partial pressure of oxygen (Fig. 7). Such an arrangement facilitates hemoglobin loading with oxygen in the lungs with higher oxygen tension and unloading of oxygen in the periphery at lower oxygen tension. The affinity of oxygen for hemoglobin is also affected by other factors, such as temperature, PCO2 , pH, and 2,3-diphosphoglyceric acid (2,3-DPG). Increased exertion and metabolic stress (as reflected by increased temperature, PCO2 , and decreased pH) shift the curve to the right, decreasing the affinity of

Figure 7 Oxygen–hemoglobin dissociation curve. Note: The percent saturation of hemoglobin with oxygen at different oxygen tensions is depicted by the middle sigmoidal curve. The P50 (i.e., oxygen tension at which the hemoglobin molecule is one-half saturated) is about 27 mmHg in normal erythrocytes (dotted lines). Heterotopic modifiers of hemoglobin function can shift the curve leftward by increasing or rightward by decreasing its oxygen affinity. Source: From Ref. 13.

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increase in the thickness as with interstitial lung disease and pulmonary edema, decreases the diffusion of gases and limits gas exchange. The variable affinity of hemoglobin for oxygen as described above, as well as the rate at which hemoglobin is circulated through the capillary bed (i.e., the cardiac output), has an effect on measuring oxygen-diffusing capacity. On average, a red blood cell takes approximately 0.75 second to cross the pulmonary capillary. Oxygen has a higher driving pressure gradient, while CO2 has a higher solubility. Normally, it takes about 0.25 second for the pressure gradient across the alveolar–capillary interface to equilibrate. Thus, gas exchange is normally perfusion limited and the only way to increase gas exchange is to increase perfusion. However, as described above, many diseases can limit gas exchange such that there is no equilibration by the time blood crosses the capillary and gas exchange is diffusion limited. Clinically, the diffusing capacity of carbon monoxide (DLCO, normal about 30–35 mL/min/mmHg) is usually measured as a surrogate with a single breath of a low concentration of carbon monoxide. Carbon monoxide has a molecular weight similar to oxygen but binds with a higher affinity to hemoglobin, creating a low partial pressure and essentially a constant pressure gradient for its diffusion, which simplifies measurement of diffusing capacity.

Ventilation/Perfusion

Pco2 mm Hg

The relationship between ventilation and perfusion is important in the exchange of oxygen and carbon dioxide. Matching alveolar ventilation (V) to pulmonary blood flow (Q) is important for achieving ideal gas exchange and is measured by the V/Q ratio. Normally each liter of blood flow is matched with 0.8 L of ventilation. High V/Q ratios are produced by excessive ventilation or inadequate blood flow. At one extreme is dead space or ventilation that receives no perfusion for gas exchange, with a V/Q ratio of infinity. At the other extreme is shunt, or perfusion without ventilation, with a V/Q ratio of zero. Low V/Q ratios are generally caused by inadequate ventilation or excessive blood flow (Fig. 8). In the research setting, the V/Q ratio can be measured with the multiple inert gas elimination technique, although this is not practical clinically. Assessment of V/Q mismatch becomes clinically important when assessing the etiology of hypoxia.

50

v Decreasing . . VA/Q

A Normal

0

50

100

.

∝

/Q VA

g sin ea

Inc .r

150

Po2 mm Hg Figure 8 V/Q mismatch. Note: Oxygen–carbon dioxide diagram shows how the PO2 and PCO2 of a lung unit alter as the ventilation–perfusion ratio is changed. Abbreviations: I, inspired gas; ¯v, mixed venous blood. Source: From Ref. 15.

Hypoxia In general, hypoxia is caused by V/Q mismatch, shunt, alveolar hypoventilation, and increased diffusion gradient. V/Q mismatch is one of the most common causes of hypoxemia, but can be difficult to assess and is generally a diagnosis of exclusion. Shunt is the fraction of blood that enters arterial blood without gas exchange. Bronchial blood flow causes physiologic shunt. Normal shunt is about 5%. Pathologic intrapulmonary shunt occurs when portions of lung are perfused but not ventilated, as in lung consolidation from pneumonia or atelectasis. Extrapulmonary shunts also occur as in right-to-left cardiac shunts. Shunt can be measured by: QS =QT ¼ ðCiO2  CaO2 Þ=ðCiO2  CvO2 Þ As defined by the following abbreviations: QS/QT: (shunt flow/total flow) CiO2 : ideal O2 content or pulmonary capillary O2 content CaO2 : arterial O2 content CvO2 : mixed venous O2 content Alveolar hypoventilation can be caused by thoracic wall and neuromuscular disorders as well as by central respiratory depression. As described above, an increased diffusion gradient can be caused by changes in the dimensions of the alveolar–capillary interface, as in interstitial lung diseases and with pulmonary edema. Both alveolar hypoventilation and increased diffusion gradient can be treated with oxygen administration. True shunt will not be affected by additional oxygen administration. V/Q mismatch will respond partially to oxygen administration, depending on the amount of tendency toward shunt.

PERIOPERATIVE PULMONARY ASSESSMENT Preoperative Assessment Preoperative assessment of pulmonary risk begins with the history and physical examination. Obviously patients with a history of significant pulmonary disease, especially chronic obstructive pulmonary disease (COPD), are at increased risk, as are patients with significant heart disease and poor nutritional status. Preoperative counseling in patients with a smoking history has been demonstrated to have an impact as well. Physiologically, smoking cessation more than 48 hours has been demonstrated to decrease systemic carbon monoxide levels and improve mucosal ciliary function. Cessation of one to two weeks is associated with decreased sputum production. Cessation more than six weeks is associated with improved spirometry. Patients undergoing coronary artery bypass demonstrate a fourfold decrease in pulmonary complications with smoking cessation of two months. Smokers who stopped smoking for six months had a pulmonary complication rate equivalent to that of nonsmokers (16). Physical examination findings demonstrating use of accessory muscles, prolonged expiration, a barrel chest, cyanosis, heart failure, and pulmonary edema require further investigation. In general, patients without evidence of pulmonary disease on history and physical examination do not require further preoperative testing if they are being prepared for operations not involving the thoracic cavity. Patients with pulmonary disease and/or patients undergoing thoracic surgery should have further testing as indicated. Preoperative

Chapter 31: Pathobiology of Surgically Relevant Pulmonary Disease

arterial PO2 < 60 mmHg, and arterial PCO2 > 45 mmHg is associated with increased perioperative morbidity. In patients with known disease, a preoperative chest X ray can provide a useful baseline for comparison. PFTs can risk stratify high-risk patients and should be performed in all patients undergoing planned pulmonary resections. Pulmonary function testing indicators of high risk in nonthoracic surgery patients include an FVC < 2 L (or < 50% predicted), an FEV1/FVC < 50% predicted, and a diffusing capacity < 50% predicted (17). In patients undergoing pulmonary resection, PFTs are used to define the risk for postoperative respiratory insufficiency. In general, pulmonary resections with a predicted postoperative FEV1 of greater than 800 mL can be tolerated. Patients with an FEV1 > 2 L can tolerate most resections, including pneumonectomy. Patients with an FEV1 < 2 L may still be able to tolerate pulmonary resection, and ventilation perfusion studies can help predict how much the planned area of resection contributes to overall function. As experience with lung volume reduction surgery in patients with emphysema expands, it has been demonstrated that pulmonary resection of severely diseased tissue may even enhance postoperative pulmonary function (18). In patients with borderline PFTs, physiological exercise testing with measurement of VO2 max is predictive of outcomes. Patients who achieved VO2 max of more than 20 mL/ kg/min, even with poor PFTs, will generally tolerate pulmonary resection. Patients with an estimated postoperative VO2 max of less than 10 mL/kg/min have prohibitively high rates of complication and are not surgical candidates (19).

Postoperative Pulmonary Complications Postoperative pulmonary complications involving the lung are a leading cause of morbidity and mortality. In a review of 10,000 major operations, 10% of operative deaths occurred in patients who developed pneumonia (20). Stated another way, there was a 46% mortality in 1.3% of patients who got pneumonia. Postoperative complications involving the lung can be broadly defined and studies differ in their approach to recording and reporting complications. Complications include a spectrum of disorders from dyspnea, atelectasis, and increased sputum production, to pneumonia, respiratory failure, and death. The risk for complications also depends on the anesthetic technique used as well as the surgical procedure. Thoracic incisions, upper abdominal incisions, and procedures lasting more than three hours are at increased risk of resulting in pulmonary complications. Minimally invasive surgery, such as laparoscopic cholecystectomy and video-assisted thoracoscopic surgery have been demonstrated to have fewer pulmonary complications (21). Postoperative pain control techniques, such as patient-controlled analgesia and intercostal nerve blocks, have been demonstrated to decrease complications (22). Chest physiotherapy, incentive spirometry, and/or bronchodilators can prevent or reverse hypoxemia from atelectasis.

COMMON PULMONARY DISORDERS Acute Respiratory Failure In 1967, Ashbaugh et al. described a syndrome of dyspnea, hypoxemia, decreased pulmonary compliance, and diffuse alveolar infiltrates in 12 patients without a prior history of lung disease or congestive heart failure, which was termed adult respiratory distress syndrome or ARDS (23). In 1994,

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the American–European Consensus Committee on ARDS redefined this acronym as Acute Respiratory Distress Syndrome to reflect its occurrence in children as well, and introduced the term Acute Lung Injury (ALI) to identify a similar but lower severity of respiratory failure. Both ALI and ARDS refer to a syndrome defined by inflammation and increased permeability associated with a constellation of clinical, radiologic, and physiologic abnormalities that cannot be explained by left atrial or pulmonary capillary hypertension (i.e., PCWP < 18 mmHg). ALI and ARDS are differentiated by the severity of hypoxemia as defined by the PaO2 /FiO2 (P/F) ratio. ALI is defined by a P/F ratio of 200 to 300, while ARDS is defined by a P/F ratio < 200 (24). The reported incidence of ARDS has varied in part due to previous variations in definitions. A recent 2002 study of every admission to 21 adult Australian intensive care units over a two-month period, using the consensus definition, found an incidence of ALI and ARDS of 34 and 28 per 100,000, respectively. The 30-day mortality was 32% and 34%, respectively, for these conditions (25). Previous studies report a mortality of approximately 50%. Multivariate analysis from multiple studies has demonstrated that the main risk factor for ARDS in patients is some type of systemic infection or sepsis. Blood transfusions, advanced age, and smoking have also been identified as independent risk factors. Recent epidemiologic studies have further found a genetic susceptibility associated with an angiotensin-converting enzyme (ACE) polymorphism. This polymorphism is associated with high circulating levels of ACE, which adversely affect pulmonary vascular tone, vascular permeability, epithelial survival, and fibroblast activation (26). Male sex and black race are also associated with a higher mortality in patients developing ARDS. Clinically, ALI and ARDS present with an acute onset. Fifty percent of patients develop ARDS within 24 hours of the inciting event; 85% develop this condition within 72 hours (27). The earliest signs of ALI include tachypnea and anxiety. This is then followed with a progressively worsening dyspnea, tachycardia, mental status changes, rales, rhonchi, and ultimately consolidation that often requires mechanical ventilation to prevent pulmonary failure. While the degree of hypoxemia distinguishes ALI from ARDS, the initial P/F ratios and ventilatory parameters have not been predictive of outcome. Chest X-rays may reflect the initial inciting event or be normal. As lung injury progresses, X-rays demonstrate edema with bilateral diffuse infiltrates, followed by diffuse alveolar/reticular opacification (i.e., ground-glass opacification). Computed tomography (CT) imaging demonstrates diffuse pulmonary consolidation with air bronchograms and later cystic changes within the pulmonary parenchyma. However, imaging may not parallel the clinical spectrum of disease and often lags well behind the clinical course. Histologically, three phases have been described. Initially there is an exudative phase. Damage to the alveolar epithelium and vascular endothelium allows leakage of fluid, protein, blood, and inflammatory cells into the interstitium and alveolar lumen. This is followed by a proliferative phase. Destruction of type I cells leads to accumulation of protein, fibrin, and other cellular debris forming hyaline membranes. Destruction of type II cells leads to alveolar collapse; type II cells then proliferate (fibroblastic reaction, remodeling, and differentiation to and regeneration of type I epithelium). Finally, there is a fibrotic phase. Fibroblastic remodeling can become irreversible with collagen deposition and development of microcysts (28).

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Treatment of ALI/ARDS has been intensely studied (29). Treatment is focused on aggressive management of the initiating factors, appropriate control of underlying infection, aggressive nutritional support, and gentle mechanical ventilation management. With mechanical ventilation, it is important to avoid both barometric and volumetric trauma. The ARDS network study demonstrated a 22% decrease in mortality with low volume ventilation (TV < 6 mL/kg) and low plateau airway pressure strategy (30). Insisting on a normal pH and PCO2 by increasing minute ventilation may actually worsen lung injury, and strategies of gradual permissive hypercapnia allow lower volume ventilations. Arterial PCO2 of 50 to 77 mmHg with a pH of 7.2 to 7.3 appear to be well tolerated. High concentrations of oxygen (FiO2 > 60%) are also damaging and associated with increased edema, alveolar thickening, and fibrinous exudates. Adding positive end-expiratory pressure can help reduce FiO2 , although this may have the negative effect of impairing venous return and cardiac performance. Reverse inspiratory to expiratory (I:E) ratio ventilation has been proposed to decrease peak inspiratory and plateau pressures, but is associated with higher mean airway pressures that have not been shown to improve outcomes compared to conventional ventilation techniques (31). Prognosis in ARDS is multifactorial. Death in ARDS is usually due to multisystem organ failure (MOF) and not simply respiratory failure itself. Increased age, immunocompromise, and chronic liver disease have also been demonstrated to increased mortality in ARDS (27). In patients who recover, pulmonary dysfunction can persist and present with a mix of obstructive, restrictive, and diffusion pulmonary impairments. Pulmonary function studies demonstrate that most patients will show general improvement at three to six months, with a plateau in improvement at one year (32). Neuropsychiatric testing has also demonstrated significant deficits that may persist beyond two years, associated with prolonged hypoxemia (33). Because MOF is commonly encountered in critically ill surgical patients and is intimately linked with ARDS, further discussion of this linkage can be found in the chapter on MOF (Chapter 11).

Atelectasis Atelectasis is the term used to refer to a loss of lung volume. Depending on the cause, this volume loss may only involve a small portion of the lung that is not readily diagnosed on chest X-ray. In this circumstance, it is commonly called ‘‘micro’’ atelectasis. More substantial involvement can range from subsegmental, segmental, to involvement of an entire lobe. A wide variety of conditions may give rise to this disorder. For example, a space-occupying lesion within the lung parenchyma itself, such as a tumor, may compress adjacent lung tissue so that involved alveoli collapse. Similarly, a space-occupying abnormality in the pleural space, such as pneumothorax or hydrothorax, can also collapse adjacent lung. If a major bronchus or several secondary bronchi are occluded, an absorption-type atelectasis can occur due to resorption of air in the lung tissue distal to the obstruction. Examples of the obstructing agents include a foreign body, tumor, or mucus plug. Abnormalities in surfactant, which is a lipoprotein that is important in keeping alveoli open, may result in atelectasis in various inflammatory conditions such as pneumonia. In this setting, the surfactant may be inadequately synthesized, rapidly degraded, or become functionally suboptimal. The net result of any of these circumstances is alveolar collapse.

Atelectasis is a common postoperative problem that can be related to the effects of anesthesia, the underlying pulmonary status of the patient, and the type of incision used to carry out the operative procedure. Further, obesity, chronic bronchitis, pain, and advanced age are all predisposing factors. The pathophysiology of this condition in the postoperative period is related to various factors, all of which contribute to bronchial obstruction. These include a defective cough response so that retained secretions in the bronchus are not properly expectorated, and a reduction in the caliber of the bronchus, which may occur from direct airway trauma due to intubation, or result in edema and/or inflammation arising from this maneuver. Finally, the thickness of the bronchial secretions and the ability to clear them from the tracheal bronchial tree may prove difficult even when effective coughing seems adequate. Although the true incidence of atelectasis is unknown, most patients undergoing chest or abdominal procedures probably have some degree of microatelectasis. Involvement of segments or subsegments of the lung may occur in as many as 2% to 3% of all operations performed. Atelectasis may be clinically manifested by fever, tachypnea, and tachycardia. The cause of the fever has been debated, but is probably related to secondary bacterial proliferation in the atelectatic areas of the lung (34). By the time these various clinical parameters become apparent, the atelectasis has usually been present for a day or more. Because prevention is always easier than cure, all patients undergoing a general anesthetic, regardless of the operative procedure, should be considered to be at risk for the development of postoperative atelectasis. Accordingly, such patients should be mobilized and encouraged to ambulate as quickly as possible after operation. Further, deep breathing, coughing, and nasotracheal suction should be instituted as appropriate. A bedside spirometer in a patient who has been extubated can be especially helpful in getting patients to maximally aerate their lungs. Pain management through the use of epidural catheters and intercostal nerve blocks can greatly minimize the splinting caused by pain, with resultant lobar collapse that is commonly seen in patients who have undergone upper abdominal and thoracic incisions. Marked global respiratory muscle dysfunction and deterioration are not uncommon following operations in which these incisions have been used. Bronchial breathing or moist rales involving the lung bases are common clinical presentations of atelectasis. Aggressive pulmonary toilet, postural drainage, and nebulizer treatments are effective adjunctive therapies that may shorten the patient’s hospitalization once atelectasis becomes a factor in management. Atelectasis caused by airway obstruction (tumor or foreign body) presents with wheezing and occasionally progresses to pneumonia. In such a patient, clearing secretions distal to the obstruction is often difficult and commonly results in pooling of secretions and bacterial overgrowth. Prompt mobilization with aggressive nasotracheal suctioning is necessary to overcome the tenacious sputum impactions that commonly occur. Flexible bronchoscopy should be utilized liberally to insure a rapid return to normal pulmonary function.

Parenchymal Lung Disease Chronic Obstructive Pulmonary Disease (COPD) COPD is a major source of morbidity and mortality worldwide, and is currently the fourth leading cause of these problems in the United States. Previous definitions of COPD

Chapter 31: Pathobiology of Surgically Relevant Pulmonary Disease

have focused on chronic bronchitits and emphysema, reflecting a heterogeneous mix of airway disease and parenchymal destruction. In an effort to standardize terminology, an international consensus panel (Global Initiative for Chronic Obstructive Lung Disease) has produced a working definition of COPD as a disease state characterized by airflow limitation that is not fully reversible, usually progressive, and associated with an abnormal inflammatory response to noxious stimuli (35). With this broadened definition, emphysema, chronic bronchitis, and asthma are all variants of COPD, and all can evoke varying degrees of bronchospasm and increased airflow resistance. The common result of these abnormalities is an increased work of breathing and impaired gas exchange with enhanced difficulty in clearing the bronchial tree. This circumstance may express itself clinically as atelectasis, pneumonia, or even frank respiratory failure. Because smoking is so commonly linked with COPD, cessation of this habit (as mentioned above) can greatly lessen perioperative complications in patients with obstructive lung disease. Bronchodilation therapy has also proved effective in improving pulmonary mechanics and secretion removal (36). Albuterol (a b2-agonist) has been especially beneficial in this regard when administered as a wet nebulizer. As with other pulmonary conditions, deep breathing and coughing are effective adjunctive measures in the early postoperative period in patients with COPD, along with early ambulation to prevent complications such as atelectasis and pneumonia. Attention to such detail will result in a successful pulmonary outcome for most patients with COPD needing surgical intervention.

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Sarcoidosis Sarcoidosis is a worldwide noncaseating granulomatous disease with multisystem involvement and a variable clinical course (37). This disease is more common in blacks and can affect any organ. While the lungs and mediastinal lymph nodes are most commonly involved, 25% of patients exhibit ocular and skin involvement as well. The diagnosis is established by clinical history and tissue confirmation. The differential diagnosis includes fungal diseases, tuberculosis, and malignancy. The cause of this disease is unknown. While infectious and environmental etiologies are suspected and the disease similarities to tuberculosis are remarkable, to date, no conclusive evidence supports any risk factors. The majority of patients are asymptomatic with hilar adenopathy. Symptomatic patients present with cough and dyspnea. Abnormal findings on chest X-rays are seen in 90% of patients, and the progression of sarcoidosis is easily seen as the hilar involvement advances to incorporate lung involvement. CT reveals the areas of mediastinal lymph node involvement; bronchoscopic biopsy is reliable (90%) in establishing the diagnosis. While 30% to 40% of patients undergo remission, many need corticosteroids to manage progressive involvement. Occasionally, cytotoxic and other alternative therapies are necessary, but responses to such therapy are inconsistent. Although the majority of patients with sarcoidosis who undergo an operation experience no untoward pulmonary problems, those with severe pulmonary fibrosis (approximately 10%) should be carefully screened as postoperative pulmonary sequelae are not infrequent.

Idiopathic Pulmonary Fibrosis

Infectious Lung Disease Pneumonia

Idiopathic pulmonary fibrosis (IPF) is the most commonly diagnosed diffuse lung disease seen in clinical practice (37). It is characterized by acute diffuse interstitial fibrosis of the lungs. Extrapulmonary involvement does not occur. It is heralded by progressive cough, dyspnea, and pulmonary infiltrates on chest X-ray. PFTs reveal a restrictive ventilatory pattern as the lung parenchymal destruction progresses. Peak onset occurs in the sixth decade and is more common in males who smoke. Possible etiologies of this disabling and frustrating disease are numerous and include exposure to various dusts and minerals, as well as being associated with other conditions, including collagen vascular disease, radiation therapy, and exposure to varied pharmacologic and cytotoxic agents. High-resolution CT scan reveals the ground-glass opacities with honeycombing that typifies IPF. From a physiologic standpoint, IPF patients demonstrate a restrictive defect on testing with impaired oxygenation and impaired gas exchange. Exercise is especially known to impair oxygenation and most patients experience hypoxemia at rest. Definitive diagnosis is made through surgical biopsy of the lung. Unfortunately, this disease does not respond to treatment and is rapidly progressive (37). Although high-dose corticosteroids given in combination with immunosuppressive medications are used to modify its progression, there is little improvement in survival or quality of life. Survival is measured in years, with only 15% of patients surviving 10 years from the time of diagnosis. Selected patients with IPF may benefit from lung transplantation (see below). Because of the marked compromise in ventilatory function that exists in IPF, great caution should be exercised in operating on patients with this disease for elective problems that can be adequately managed otherwise.

Pneumonia is a condition in which the respiratory tract is colonized with substantial numbers of microorganisms so that neutrophils migrate to the locus of colonization, and along with alveolar macrophages, induce the development of a cellular alveolar inflammatory exudate (38). As the inflammatory process evolves, it is ultimately seen on the chest X-ray as an infiltrate. The lower respiratory tract is more typically involved with pneumonia than other parts of the lung. The usual signs of pneumonia include a purulent productive cough, fever ( > 38 C), and rales overlying the site of infection on auscultation. In the intubated patient, purulent debris is commonly noted on suctioning. In both situations, leukocytosis is usually present. Pneumonia is a common problem in the postoperative surgical patient. The vast majority of pneumonias that occur in the surgical patient are nosocomial (i.e., hospital acquired). Most are related to endotracheal intubation or tracheostomy and mechanical ventilation. Ventilator-associated pneumonia is a serious issue in critically ill patients with an attributable mortality of 33% to 50% (39). Although the overall risk for nosocomial pneumonia varies between 5 to 10 cases per 1000 hospital admissions, it increases greatly in patients with chronic illness, prolonged malnutrition, advanced age, and conditions of immunodeficiency (e.g., HIV/AIDS). Other risk factors include patients receiving various drugs such as corticosteroids, cytotoxic agents, or inappropriate antibiotic agents, or possessing comorbid conditions such as coma, trauma, burns, and cirrhosis. Prolonged surgery can also be a risk factor. In patients requiring ventilatory support, pneumonia may occur in as many as 30% of those ventilated more than 48 hours (39). Aspiration is a major risk factor for pneumonia in the surgical patient. It can result from inhalation of oropharyngeal secretions, which typically contain high concentrations

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of microorganisms, or inhalation of sterile gastric secretions that reflux up the esophagus from the stomach. Risk factors for aspiration include aberrations in the level of consciousness (e.g., head injury, stroke, or drug overdose), defective cough reflex (e.g., neuromuscular disorders), and problems with swallowing or esophageal function (e.g., tracheostomy, nasogastric intubation, or incompetent lower esophageal sphincter). Aspiration of oropharyngeal contents is particularly common in patients with altered or impaired consciousness, and is often seen in conditions of drug overdose or alcohol abuse. Aspiration of gastric contents is a frequent problem in patients with intestinal obstruction whether functional (e.g., postoperative ileus, dysmotility) or mechanical in nature. It is especially important to keep the head of the bed up and to monitor gastric residuals with some frequency to minimize the potential aspiration volume and protect those who are at highest risk for this complication (i.e., altered mental status). Although intubated patients and those with tracheostomy tubes are often thought to be protected from aspiration, in reality such patients are also at risk. Causative organisms for pneumonias resulting from orophyaryngeal aspiration include anaerobic and gramnegative bacteria. Although gastric fluids are usually sterile, bacterial colonization and secondary infection is not uncommon following aspiration of gastric contents. Diagnosis can be difficult. Critically ill patients have many reasons for fever and elevated white blood cell counts. Pulmonary infiltrates on chest X-ray can represent pneumonia, but can also represent ALI/ARDS, pulmonary edema, and/or pulmonary contusions. Chest X-ray findings often lag behind the clinical presentation. The sensitivity of chest X-ray for pneumonia is only 62% and the specificity is even less at 28% (39). Quantitative bronchoalveolar lavage with a threshold of 10,000 cfu/mL is emerging as the test of choice in diagnosing pneumonia in the intubated patient with a sensitivity and specificity of 91% and 78%, respectively (40). Several studies have looked at ways to reduce nosocomial pneumonia. Elevation of the head of the bed and avoidance of nasogastric tubes helps minimize the risk of aspiration. One randomized trial was stopped early when interim analysis demonstrated that semirecumbent positioning reduced the frequency of pneumonia from 23% to 5% compared to the supine position (41). Maintenance of gastric acidity may also reduce the incidence of pneumonia by preventing colonization of gastric contents, which can occur when acid-suppressing drugs are administered. Prophylactic systemic antibiotics have not been demonstrated to reduce nosocomial pneumonia. Multiple meta-analyses on selective decontamination of the digestive tract by oral antibiotics have shown that this can reduce infection rates and mortality. However, utility of such an approach is limited by development of antimicrobial resistance (42,43). Treatment of pneumonia includes pulmonary toilet (local drainage) and specific tailored antibiotic therapy. Because most pneumonias in the surgical patient are related to intubation, aggressive weaning from the ventilator and extubation are important. Patients not easily weaned should be converted to a tracheostomy. Patients who are suspected of aspiration present with cough, tachypnea, and tachycardia. Many immunocompetent patients mount a febrile response. Chest X-ray reveals atelectasis and infiltrates. Treatment of these patients requires early and repeated suctioning to clear the tracheobronchial tree. Prophylactic antibiotics are not usually indicated initially, but may be required if secondary infection develops. Steroids were previously used to treat aspiration,

but many investigators now believe that they have no place in the management of aspiration because of their deleterious effects on pulmonary host defenses.

Lung Abscess Lung abscesses are usually related to aspiration and typically occur in the superior segments of the right and left lower lobes as well as the posterior segment of the right upper lobe (44). The most common organisms are anaerobic bacteria from the oropharynx and gastrointestinal tract. The organisms stimulate fibroblastic proliferation, which can erode into adjacent bronchoalveolar spaces. Clinical findings include cough (especially hemoptysis, and/or productive of malodorous sputum), fever, and an air–fluid level on chest X-ray. Chest CT is the definitive study for diagnosing a lung abscess. Treatment for lung abscess is generally conservative and basically follows the principles of pneumonia treatment, with focus on pulmonary toilet and tailored antibiotic therapy. Surgical therapy, including drainage and resection, is indicated in patients who fail to respond to conservative measures. Relative indications for surgery include patients with severe hemoptysis, bronchopleural fistula, empyema, and/or an abscess cavity more than 6 cm in diameter.

Tuberculosis Pulmonary tuberculosis is the number one infectious disease resulting in death throughout the world. Despite advances in antibiotic treatment, tuberculosis has seen a recent resurgence due to HIV infections, and other increases in immunocompromised patients (cancer, transplant recipients, etc.). Treatment of pulmonary tuberculosis is primarily pharmacologic. The usual regimen is isoniazid, rifampin, pyrazinamide  2 months þ isoniazid and rifampin  4 months, or isoniazid and rifampin  9 months. Surgery is indicated for patients with positive sputum cultures and cavitary lesions greater than five months despite treatment; severe or recurrent hemoptysis; bronchopleural fistula not resolved by chest tube; mass-associated lesions; and disease due to drug resistant atypicals such as Mycobacterium avium-intracellulare.

Pulmonary Embolism Blood clots from the systemic venous circulation can obstruct the pulmonary artery, causing significant morbidity and mortality. The differential diagnosis of acute pulmonary embolism (PE) is complex because PE can present in a variety of ways depending on the size of the clot, its location, and the underlying comorbidities of the patient. Myocardial infarction, pneumonia, and congestive heart failure may mimic PE. While there are known hypercoagulable states and genetic factor deficiencies, which contribute to PE formation, hospitalized patients have their own acquired risk factors that must be taken into consideration. Surgery and trauma are the key areas for surgical patients that may be impacted for prevention. Low-molecular-weight heparins administered preoperatively in addition to pneumatic compression sleeves for the legs significantly lessen, but do not eliminate, the clot risk. The underlying pathophysiologic abnormality that occurs in PE is occlusion of the pulmonary arteries, so that alveoli subserved by this arterial system are ventilated but no longer perfused. This results in a ventilation–perfusion mismatch, the consequence of which is increased deadspace ventilation (45). Accompanying this event is a reflex airway constriction along with a vasoactive response that

Chapter 31: Pathobiology of Surgically Relevant Pulmonary Disease

initiates a generalized pulmonary vasoconstriction. A variety of mediators have been proposed as possible etiologic agents, but the exact cause of the actions is poorly understood. The net result of these perturbations is an elevation in the pulmonary vascular resistance and a redistribution of pulmonary blood flow that often aggravates the V/Q mismatch triggered by the PE, and local atelectatsis and edema may eventuate in congestive atelectasis or pulmonary edema. It is quite understandable why patients with PE often present with hyperventilation and hypoxia in addition to chest pain in the region of the PE. Clinical suspicion is the key to making the diagnosis of PE. Patients presenting with acute-onset dyspnea, tachypnea, and apprehension should be suspected of harboring a PE. Lab tests, EKG, and physical examination are unreliable and rarely are specific enough to document PE. Ventilation– perfusion scans, which historically were used to make the diagnosis, have generally been supplanted by CT angiography as the imaging modality of choice. Pulmonary angiography is the gold standard in the diagnosis of PE. In the patient suspected of having a PE, immediate anticoagulation with heparin should be administered. Supportive care with supplemental oxygen should also be rendered. These measures are quite efficacious in altering symptomatology and helping to reverse the aberrations induced by the PE.

Pleural Disease Pneumothorax Air in the potential space between the visceral and parietal pleurae is called pneumothorax. The loss of negative intrapleural pressure that occurs from this air collection allows the lung to collapse from elastic recoil. Pneumothorax usually occurs as a result of ruptured alveoli (from a congenital bleb, pneumatocele, or emphysematous bulla) or from small lacerations in the pulmonary parenchyma (rib fractures in blunt trauma, lacerations through the chest wall in penetrating trauma, or iatrogenic injuries such as needle injury during the placement of a central venous line). In most cases of pneumothorax, the damaged lung quickly seals so that the condition is not progressive. Thus, there is no shift in the mediastinal structures and the opposite lung is not adversely affected. A tension pneumothorax, on the other hand, occurs if the pressure of accumulated air in the pleural space exceeds the ambient pressure, resulting in net positive intrathoracic pressure. In this condition, the progressive accumulation of air within the thoracic cavity shifts the cardiomediastinal structures away from the affected lung. If the resultant tension pneumothorax is substantial, compression of the contralateral lung may occur. Tension pneumothorax can be conceived as a one-way valve in which air enters the pleural space during inspiration but cannot escape during expiration. It occurs from a ruptured bleb or lung laceration that has failed to seal. The resultant increase in pleural pressure can have profound effects on the venous return to the heart, usually by direct pressure on the low-pressure vena cava. If not recognized and rapidly treated, hypotension and complete circulatory collapse may promptly occur. Pneumothorax can generally be diagnosed by auscultating the lungs. On the affected side, air movement is compromised to the extent that the pleural space has been replaced by air and the affected lung volume has been compromised. Often percussion of the chest wall will demonstrate hyper-resonance. If a tension pneumothorax has occurred, shifting of the trachea away from the affected side may be seen. There is usually pain in the hemithorax

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involved. Profound dyspnea and panic may accompany tension pneumothorax. Treatment of pneumothorax will depend on its clinical presentation. If diminished breath sounds and mild-tomoderate pain are major presenting clinical findings in the absence of severe dyspnea, pneumothorax probably is not progressive and the offending lung abnormality has sealed off. If marked dyspnea exists and little-to-no breath sounds can be heard on the affected side, irrespective of whether clear evidence of tracheal shift has occurred, a tension pneumothorax is probably responsible for the clinical situation. In this circumstance, immediate decompression of the affected hemithorax is required to obviate the respiratory and/or hemodynamic embarrassment. This is most readily achieved by needle thoracostomy to relieve the positive intrathoracic pressure. Tube thoracostomy after needle decompression constitutes definitive therapy. In the more common circumstance in which tension does not appear to be a component of the pneumothorax, the type of treatment will be dictated by the volume of lung parenchyma compromised. If less than a 30% pneumothorax appears to exist on chest X-ray, watchful waiting may be all that is needed. For a more substantial pneumothorax, tube thoracostomy is usually required. Once the affected lung injury seals (usually 2–3 days), the tube can be removed. In interpreting X-ray findings of pneumothorax, Richardson (2) has emphasized that it must be remembered that the lung is a sphere and that the volume loss is calculated by the equation V ¼ pR3. Thus, if the diameter has been determined to have decreased from 20 to 16 cm on a chest radiograph, which assesses things from a two-dimensional frame of reference, the actual radius changes from 10 to 8 cm. This translates into a 50% net volume loss, rather than the 20% calculated by simple measurement of diameter loss from the radiograph itself (2).

Hemothorax Hemothorax refers to a condition in which blood is present in the pleural space, usually resulting from trauma to the chest wall. Traumatic hemothorax represents a spectrum of clinical challenges. Most patients can be treated by tube thoracostomy and evacuation of the pleural space. However, a small subset of patients require operative intervention for hemorrhage control and adequate evacuation of the pleural space. Posttraumatic hemothorax of sufficient size to be apparent on chest X-ray is most commonly due to laceration of the pulmonary parenchyma or chest wall vessels (intercostals or internal mammary artery). Standard treatment is large caliber–tube thoracostomy, which allows evacuation of the blood, reduces risk of clotted hemothorax, and provides accurate determination of the extent of ongoing bleeding. In the vast majority of cases, bleeding is self-limited, and operative intervention is unnecessary. After tube thoracostomy, current guidelines recommend immediate surgery if 1500 mL of blood is evacuated initially or if drainage of 200 mL/hr for the ensuing two to four hours occurs (46). These guidelines coincide with the amount of blood loss expected to produce hemorrhagic shock in a previously healthy patient. Occasionally, despite early tube thoracostomy, the hemothorax is only partially evacuated. The residual blood then serves as a nidus for the development of empyema or fibrothorax, which ultimately may lead to thoracotomy and decortication to liberate the trapped lung. Advances in video-assisted thoracic surgery (VATS) have allowed the development of minimally

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invasive methods for draining retained hemothorax, and thereby have decreased the likelihood of developing empyema or fibrothorax. Clinical experience suggests that chest X-ray is insufficient to distinguish between retained hemothorax and contusion, and atelectasis or intraparenchymal hemorrhage that are not amenable to VATS treatment. Chest CT is much more useful in this scenario. Progressive clot organization and adherence leaves a window of three to five days postinjury when the semisolid clot and serum can be evacuated via VATS with a high degree of success. It may however, require persistence and multiple procedures to completely clear the pleural space. Repeated episodes of one-lung ventilation may actually increase the alveolar– arterial gradient and exacerbate relative hypoxemia.

Chylothorax Chylothorax is the presence of lymph within the pleural space. It may be caused by congenital or primary lymphatic disease, but is usually due to intrathoracic malignancy with intrinsic or extrinsic obstruction, iatrogenic injury, or trauma. Postoperative chylothorax may complicate surgical procedures anywhere along the path of the thoracic duct between the diaphragm and the neck. Initial symptoms of dyspnea and exercise intolerance are the result of a large volume chylous effusion causing compressive atelectasis of the lung. Prolonged drainage leads to dehydration, malnutrition, and immunologic compromise due to loss of fluid, fat, protein, and lymphocytes, which make up the lymph fluid. Nonoperative management may be appropriate as an initial strategy, particularly in the first few days after surgery or trauma, or in cases of malignancy that may respond to treatment of the primary disease (principally lymphoma). The components of initial management are drainage of the pleural space, reduction of chyle flow, and maintenance of hydration and adequate nutrition. Evacuation of the pleural space is most commonly achieved by tube thoracostomy, which facilitates pulmonary re-expansion and provides continuous drainage and accurate measurements of chyle flow. Chemical sclerotherapy is used to accelerate pleural symphysis and achieve obliteration of the pleural space. Failed nonoperative management warrants surgical thoracic duct ligation. Lymphangiography provides useful information regarding the lymphatic anatomy and fistula site. Because it is quite challenging at times, it is usually only done in refractory chylothoraces that have failed initial surgical closure. Other methods to locate the leak include preoperative injection of Evans blue dye (1% subcutaneous in the thigh) or enteral administration of fat (cream or olive oil). Surgical options include direct ligation of the thoracic duct at the site of the leak, mass ligation of the thoracic duct and surrounding tissues, application of fibrin glue, or creation of a pleuroperitoneal shunt. If the chyle leak can be identified, direct ligation should be performed on either side of the leak. If the leak cannot be identified, mass ligation of all tissue between the aorta, spine, esophagus, and pericardium is best performed above the diaphragm in the right pleural space. This can be achieved either by thoracotomy or video-assisted thoracoscopy.

Traumatic Lung Injury Smoke Inhalation and Pulmonary Dysfunction Following Burns Burn injuries include smoke inhalation, direct thermal airway injuries, and pulmonary dysfunction caused by the

products of combustion. The specific nature of the chemical products determines the lethality of the burn injury. Certain materials and chemicals are direct toxins to the airways and must be addressed aggressively if the burn victim is to survive. Edema formation and bronchoconstriction are early responses to released leukotrienes. Direct alveolar injury leads to increased lung water and difficulty in ventilation. Through the complement cascade, neutrophils migrate to the injured mucosa. All patients with facial burns should be suspect for distal airway injuries. Upper airway edema and obstruction rapidly become life threatening and require bronchoscopy and intubation. This process progresses as high-volume fluid resuscitation and capillary leakage continues. While carbon monoxide levels are routinely obtained, many of the CNS manifestations are masked by intravenous narcotics needed for pain management. Ventilatory support with the judicious use of fluids is critical if the patient is to survive. Pneumonias are expected with the prolonged need for pulmonary toilet and repeated bronchoscopy.

Chest Trauma Chest trauma accounts for 10% to 12% of all trauma admissions to the hospital, but for nearly 25% of all deaths due to trauma (47). Chest wall injury is the most common thoracic injury, and rib fracture is associated with a 12% mortality. Chest trauma from penetrating sources is usually caused by knives or bullets, while blunt trauma injury usually comes from motor vehicle deceleration injuries. Fewer than 30% of all chest trauma patients require thoracotomy. In the immediate period, following a major motor vehicle collision, fatal injuries usually involve the thoracic aorta or heart and these patients typically die at the scene of the accident. Other life-threatening injuries can be managed effectively if they are recognized early. The initial assessment of the trauma patient is the first priority. A patent airway must be confirmed and established rapidly. In certain instances, a surgical airway must be established when passage of an endotracheal tube is not possible or when upper airway obstruction exists. Hemodynamic control is the next priority and a large-bore intravenous access is mandatory for all patients. Most importantly, physical examination will reveal life-threatening injuries, which many times must be treated before obtaining diagnostic X-rays. These include tension pneumothorax, ruptured bronchus and diaphragm, and airway obstruction. While complete management algorithms of each of these entities are beyond the scope of this chapter, a basic understanding of these physiologic derangements is necessary to treat these patients. In many instances, chest tube insertion is the only interventional measure necessary for the management of these patients. Tension pneumothorax must be recognized immediately during physical examination and treatment instituted with equal rapidity. The hallmarks of tension pneumothorax consist of complete lung collapse with concomitant tracheal deviation and mediastinal shift. Tachypnea, distended neck veins, and diaphoresis may be missed in a busy trauma bay. Because there is decreased venous return to the heart, hemodynamic instability in the form of hypotension and tachycardia occurs rapidly. Needle decompression followed by chest tube insertion is life saving and is warranted without X-ray examination. Tracheobronchial injuries may be life threatening as well. Usually occurring within 2 cm of the carina, most

Chapter 31: Pathobiology of Surgically Relevant Pulmonary Disease

injuries can be exposed and repaired through a right thoracotomy. Rarely is cardiopulmonary bypass necessary for the repair. These patients present with subcutaneous emphysema, pneumothorax, and massive air leak. Any patient with a pneumothorax that does not re-expand with chest tube insertion should be suspected of having a tracheobronchial injury. A definitive diagnosis requires careful bronchoscopy. Generally, repair consists of carefully placed interrupted absorbable sutures. Fractures involving the upper six ribs are associated with life-threatening intrathoracic injuries, while fractures involving the lower six ribs are associated with lifethreatening intra-abdominal injuries. Multiple rib fractures resulting in a flail segment have a significantly higher morbidity due to underlying pulmonary contusion. Elderly patients and/or patients with preexisting comorbidities and other underlying physiologic changes tend to have poorer outcomes. Flail chest is the most serious chest wall injury encountered. Mechanically, it is the complete disruption of a portion of the chest wall by segmental fractures of two or more adjacent ribs (Fig. 9). It also may result from disruption of the ribs from the sternum at the costochondral cartilage and a fracture of the rib. Aside from the deleterious effects on chest wall mechanics and respiration, the force required to cause a flail chest places the patient at significant risk for other intrathoracic injuries. Pain management is the most significant component to successful treatment of rib fractures and flail chest. The disruption of chest wall mechanics may decrease TV and impair the ability to generate an effective cough. This situation leads to the development of hypoventilation and subsequent atelectasis and pneumonia (48). Unless the affected segment is large, these alterations generally can be managed with incentive spirometry and aggressive pulmonary toilet, which require active patient participation. Oral narcotics rarely achieve effective pain control. Intravenous narcotics are able to provide adequate pain relief but at a degree of sedation that frequently will impair the patient’s ability to effectively participate in pulmonary toilet. The preferred option for pain management is thoracic epidural

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anesthesia. A combination of narcotic and local anesthetic acts synergistically to provide excellent pain control without sedation. The patient can now breathe deeply and cough, and has increased mobility. This prevents hypoventilation, promotes clearance of secretions, and improves the chances of avoiding endotracheal intubation and mechanical ventilation. Operative stabilization may be necessary for selected patients in whom adequate pain control cannot be achieved or who fail to be weaned from mechanical ventilation. Methods using either permanent or absorbable plates, screws, Kirschner wires, or Judet staples have been described. Stabilizing every other fractured rib is usually adequate to provide normalization of chest wall movement, decrease pain, and improve respiratory mechanics. Pulmonary contusion is a diffuse hemorrhage into the lung parenchyma, resulting from either blunt or ‘‘blast injury’’ penetrating trauma (49). It commonly appears within several hours of the event as a patchy opacity on the chest X-ray, which then progresses over the next several days. Hemoptysis is a frequent manifestation of pulmonary contusion. Small peripheral contusions may produce only blood-tinged sputum, whereas injuries near the hilum may develop massive bleeding into the tracheobronchial tree that rarely may lead to life-threatening airway obstruction. In such circumstances, immediate resection of the damaged lung tissue and clearance of the airway is required. Nonoperative management with attention to pulmonary toilet, incentive spirometry, and pneumonia surveillance is usually sufficient to treat the contusion (50). Strict attention to volume status is critical because overresuscitation can contribute to pulmonary edema and hypoxia and volume depletion may result in hypotension and malperfusion syndromes. Monitoring central venous pressure and urine output is mandatory and some patients may require the use of pulmonary artery catheters. Effective drainage of effusions, hemothorax, or pneumothorax will greatly facilitate pulmonary expansion and maintain adequate oxygenation and ventilation.

NEOPLASTIC CONDITIONS Mediastinum and Mediastinal Masses

Figure 9 Fracture of chest wall in two locations is necessary for development of flair chest. Classic concept of altered mechanics causing ‘‘to-andfro’’ movement of air between major bronchi (double arrow) has largely been dispelled. Source: From Ref. 2.

The anatomy and the borders of the mediastinum predict the lesions that occur in this region. While surgical approaches were previously recommended for diagnosis of mediastinal masses, technological imaging advances have allowed greater noninvasive access to previously remote areas (Table 2). The anterior-superior mediastinum is the largest compartment and contains the greatest variety of pathology (50,51). Specific borders include the posterior sternum extending to the anterior pericardium. Typical components include the thymus gland, fat, and lymph nodes. The wellknown mnemonic, the ‘‘4Ts’’ of the anterior mediastinum, includes thymoma, teratoma, terrible lymphoma, and thyroid. Access to this area can be readily obtained through anterior mediastinotomy and video thoracoscopy. The middle mediastinum, also known as the visceral compartment, contains the heart, superior and inferior vena cava, ascending aorta and arch, main pulmonary arteries, phrenic and vagus nerves, trachea and main stem bronchi, and lymph nodes (50,51). Foregut duplication cysts originating from sequestrations of the ventral foregut are common. Bronchogenic cysts are the most common cysts followed by pericardial cysts. Mediastinoscopy is the most common

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Table 2 Tumors of the Mediastinum Anterior-superior compartment Parathyroid adenomas Thyroid tumors and cysts Thymic tumors and cysts Teratomas Pericardial cysts Germ cell tumors Bronchogenic cysts Lymphomas Middle compartment Lymphatic tumors Lymphomas Foregut cysts Esophageal leiomyomas Pericardial cysts Bronchogenic cysts Posterior compartment Neurogenic tumors Ganglioneuromas Gastroenteric cysts

diagnosis, often utilizing flow cytometry, is all that is necessary. Once obtained, appropriate oncologic regimens are initiated. Substernal goiters cause compressive symptoms, including dyspnea and dysphagia and are more common in females. The majority (95%) can be removed through a cervical collar incision. Larger or deeper lesions may require partial sternal split for access and excision. Recurrent laryngeal nerve injury is rare despite the bulk of these lesions, due to the marked displacement of the normal anatomical structures. Descending necrotizing mediastinitis must be considered when discussing the mediastinum. This rare polymicrobial infection commonly originates from an oropharyngeal source and carries a 50% mortality. The key to understanding this process is the realization that all three deep spaces of the neck (pretracheal, retrovisceral, and prevertebral) communicate with the chest and the mediastinum. Early aggressive drainage and debridement is needed with prolonged critical support if the patient is to survive. Many patients require additional drainage procedures because of developing loculations and empyema collections.

Tumors of the Lung access approach to this area. The posterior mediastinum extends from the posterior pericardium to the posterior chest wall and includes the esophagus, descending aorta, and the thoracic duct (50,51). Neurogenic tumors are the most common lesions in the posterior mediastinum. Typically, these lesions are malignant in children. Clinically, the majority of mediastinal masses are asymptomatic and the physical examination is nondiagnostic. Lesions that are symptomatic have a higher likelihood of malignancy. While CT scan is the diagnostic test of choice, in certain circumstances, magnetic resonance imaging (MRI) is useful for delineating vascular and neuroanatomy relationships. Key tumor markers include LDH for lymphomas and seminoma differentiation. bHCG and alphafetoprotein levels should be obtained in all male patients and are complementary to a testicular examination and ultrasound. Thymoma is the most common tumor of the anterior mediastinum. Thirty to fifty percent of patients have the autoimmune disease myasthenia gravis (MG). While many MG patients have muscle weakness, including diplopia and dysarthria, others present with paraneoplastic syndromes including agammaglobulinemia. CT is the diagnostic test of choice. Staging of thymoma is done at the time of surgery as determined by gross evidence of invasion. Surgical management of thymoma includes transcervical, median sternotomy, or VATS removal. The key surgical principle is complete surgical removal of the gland without leaving rests of residual tissue, precipitating recurrence. Adjuvant radiation therapy is used for frank invasion or residual tumor. The anterior mediastinum is also the most common site of extragonadal germ cell tumors. Because they occur in young males (ages 20–35), all male patients should undergo testicular examination, including ultrasound and measurements of serum tumor markers. In general, cisplatin-based chemotherapy provides 50% five-year survival. Resection is reserved for teratomas and residual postchemotherapeutic tumor burden. Neurogenic tumors are the most common posterior mediastinal tumor, with most being exposed by thoracotomy or VATS. Dumbbell tumors extending into the spinal canal require MRI for delineation and neurosurgical assistance for removal. Lymphomas commonly affect the mediastinum. Resection is rarely indicated or achievable; usually tissue

Lung cancer is the second most common malignancy in the United States. It is second in incidence to only prostate cancer in men and breast cancer in women. It is the leading cause of cancer-related deaths in men and women. The average age at diagnosis is 60 years. Despite some improvements in short-term survival, overall five-year survival remains at only 14%. The major cause of lung cancer has been clearly linked to smoking, with 80% to 90% of lung cancers occurring as a direct result of tobacco use. Although both benign and malignant tumors occur in the lung, the vast majority (95–97%) of them are malignant. Malignant lung tumors are generally divided into non– small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) (52,53). NSCLC makes up about 80%, while SCLC makes up 10% to 15% of malignant lung tumors. Mixed tumor types are possible, and small cell carcinoma can be found with a non–small cell carcinoma in the same tumor, suggesting that both share a common precursor. With respect to benign neoplasia, hamartomas are the most common, followed by a variety of other tumors such as xanthomas, inflammatory pseudotumors, lipomas, myoblastomas, and fibrous mesotheliomas. The vast majority of patients with lung tumors will present with symptomatic disease. Five percent of tumors are found incidentally on chest X-rays. The most common presenting symptoms are cough, weight loss, dyspnea, and chest pain; 30% of patients will present with hemoptysis. Occasionally, an unexplained solitary pulmonary nodule (‘‘coin lesions’’) will be seen on chest X-ray in an asymptomatic patient. Most of these lesions are located in the lung periphery, are well circumscribed, are less than 5 cm in diameter, and occasionally exhibit calcifications. Half or more of these lesions will demonstrate malignancy on biopsy. Advanced tumors invading the mediastinum may present with a wide range of findings depending on the structure involved (52,53). Vocal cord paralysis may result from invasion of the recurrent laryngeal nerve. Superior vena cava (SVC) syndrome results from SVC obstruction and may present with facial, neck, and upper extremity swelling, edema, cyanosis, headache, conjunctival injections, and occasionally orthopnea with a feeling of impending doom. Radiation therapy may alleviate some of these symptoms, but survival is usually measured in weeks to months. Extension of tumors

Chapter 31: Pathobiology of Surgically Relevant Pulmonary Disease

into the thoracic inlet may result in shoulder and arm pain, Horner’s syndrome (ptosis, miosis, exopthalmosis, and decreased sweating on the involved side due to involvement of the sympathetic ganglia), and Pancoast’s syndrome (loss of upper-arm strength and ulnar paresthesisas due to involvement of the brachial plexus). Ten to twenty percent of patients will present with a paraneoplastic syndrome in which various humoral agents are secreted by the tumor. Small-cell carcinoma and squamous cell carcinoma are the histologic subtypes commonly associated with these syndromes. Examples include the secretion of adrenocorticotrophic hormone–like substance that mimics Cushing’s syndrome, a parathormone-like substance simulating hyperparathyroidism, and the manifestation of water retention and symptoms of hyponatremia due to secretion of an antidiuretic hormone–like substance. A particularly interesting extrapulmonary manifestation of lung cancer is hypertrophic pulmonary osteoarthropathy. This condition is characterized by clubbing of the fingers, diffuse bone (not joint) tenderness, and finger X-rays demonstrating linear calcium deposition along the periosteum. The precise mechanism responsible for this abnormality is unknown. Diagnosis and staging of lung cancer is focused on early identification of patients with potentially curable tumors. In addition to the history and physical, imaging can help define tumor extent. In general, patients with X-ray findings of a suspicious pulmonary nodule should have a CT scan of the chest and upper abdomen. Patients with nonspecific neurologic or bony symptoms should have a head CT and/or radionuclide bone scan to assess for metastatic disease. Histologic confirmation of lung cancer is not required prior to resection in an otherwise healthy patient with no evidence of advanced disease. If advanced disease is suspected and nonsurgical treatment is planned, histologic confirmation through bronchoscopy, transthoracic needle aspiration, and thoracoscopic and/or open biopsy should be obtained. Mediastinal lymph nodes larger than 1 cm seen on imaging should be biopsied by cervical mediastinoscopy or video-assisted thoracoscopic techniques.

Non–Small Cell Lung Cancer (NSCLC) NSCLC can be divided into adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Adenocarcinoma is the most common type of lung cancer. Tumors are typically situated in the periphery and arise from subsegmental bronchioles. They can spread by both lymphatic and hematogenous routes. Squamous cell carcinoma is the next most common type of lung cancer. These tumors typically are centrally located. They can grow to a large size before metastasizing and can present with bronchus obstruction and central necrosis. They tend to metastasize to peribronchial or hilar lymph nodes. Large cell carcinoma is an undifferentiated aggressive tumor that can be difficult to distinguish from poorly differentiated adenocarcinoma or small cell carcinoma. Depending on the size of the tumor and its location, lobectomy or pneumonectomy is the usual surgical option. Multiple genetic derangements have been described (54,55). The most common activated proto-oncogene in NSCLC is k-ras. In more than 50% of NSCLC, the tumor suppressor gene p53 is overexpressed or mutated. Other genes implicated include erbB, Rb, and bcl-2. A genetic susceptibility to lung cancer has also been demonstrated, and the most common chromosomal abnormalities involve chromosomes 1, 3, 7, 9, and 17.

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The TNM staging of NSCLC is shown in Figure 10. In general, tumors invading the mediastinum, those associated with a malignant pleural effusion, those with nodal metastasis to the contralateral side (stage IIIB), and those with metastasis to distant organ sites (such as brain, bone, kidneys, adrenals, etc.) represent advanced disease that will not be helped with aggressive surgical therapy. Survival following surgical resection is shown below:

Stage I Stage II Stage IIIa

1-yr survival (%)

5-yr survival (%)

72–94 55–89

38–67 22–55 23–25

Recent studies have shown a survival benefit for patients receiving adjuvant platinum-based chemotherapy after complete surgical resection. In the International Adjuvant Lung Cancer Trial, there was a 4.1% survival advantage in the surgery plus chemotherapy group (over surgery alone) for patients in stage I to stage III (57). In the Cancer and Leukemia Group B Protocol 9633, for patients with stage IB disease, chemotherapy after surgical resection conferred a 12% survival advantage (58). In the NCIC-BR10 study, a similar 15% overall survival advantage was seen for stage IB and stage II patients who received adjuvant chemotherapy (59). Recent trials regarding preoperative induction chemotherapy or chemoradiation therapy suggests there may be a benefit in a patient with stage II to IIIa disease.

Small Cell Lung Cancer (SCLC) Approximately 15% of all lung cancers are SCLC. The vast majority present with advanced disease and surgery is generally not indicated (60). The overall five-year survival is 5% to 10%. One percent of patients with SCLC present with stage I or II disease. Five-year survival rates of approximately 50% have been reported in patients with SCLC with stage I or II disease, who underwent resection followed by chemoradiation.

LUNG TRANSPLANTATION As of 2001, 12,000 lung transplants have been performed worldwide, with one-year survivals being in the 75% range for most patients requiring this form of treatment to manage their underlying pulmonary disease (61). Functional results are durable when the procedure is performed at experienced centers. Clinical indications for single- and doublelung transplantation are very specific and guidelines for both the donor and recipient must be adhered to because of the scarcity of available organs. Improvement in patient selection is the single most important factor responsible for the success of pulmonary transplantation. The majority of adult lung transplants are performed for emphysema due to COPD or alpha-1 antitrypsin deficiency. Other indications include cystic and pulmonary fibrosis. Operative mortality and long-term survival are directly associated with the patient’s underlying diagnosis; patients with pulmonary hypertension and pulmonary fibrosis are typically more difficult to manage. Expected improvements in FEV1 are well documented following successful surgery. Specific lung transplant complications include early allograft dysfunction, which may be caused by poor donor preservation or underlying lung pathology. Airway anastomotic complications have decreased as surgical anastomotic techniques

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Figure 10 Staging of lung cancer. (A) Stage IA disease (T1 N0 M0) identifies a small ( < 3 cm) tumor surrounded by lung parenchyma. (B) Stage IB disease (T2 N0 M0) includes larger tumors that invade the visceral pleura or the main bronchi, or that have evidence of atelectasis/pneumonitis extending to the hilar regions. No metastatic disease is present with stage I tumors. (C) Stage IIA (T1 N1 M0) identifies small tumors with T1 characteristics ( < 3 cm) involving the peribronchial or hilar nodes by extension or metastasis. (D) Stage IIB disease includes larger tumors ( > 3 cm) involving the peribronchial or hilar lymph nodes (T2 N1 M0) or tumors with limited extrapulmonary extension such as involvement of the chest wall or the pericardium (T3 N0 M0) but no evidence of metastasis. (E) Stage IIIA describes tumors with localized extrapulmonary extension and involvement of peribronchial or hilar lymph nodes (T3 N1 M0) as well as any T1, T2, or T3 tumors with metastasis to the ipsilateral mediastinal and subcarinal lymph nodes (T1, T2, or T3 N2 M0). (F) Stage IIIB describes either extensive extrapulmonary tumor invasion (T4 any N M0) or metastasis to the contralateral mediastinal and hilar lymph nodes as well as ipsilateral and contralateral supraclavicular/scalene lymph nodes. Source: From Ref. 56.

and perioperative management have improved. Bronchiolitis obliterans with a decline in FEV1 has continued to plague long-term lung transplantation results and survival. This form of chronic allograft dysfunction is undergoing aggressive research and may be related to the high frequency of gastroesophageal reflux in lung transplant patients.

SUMMARY Oxygen delivery to meet tissue needs is critical to the survival of the human organism. The lungs make this possible

by optimally matching ventilation to pulmonary arterial perfusion, so that inhaled oxygen is effectively diffused across the alveolar-capillary membrane in exchange for carbon dioxide, which is then removed from the body during exhalation. Disturbances in ventilation, perfusion, or alveolar-capillary membrane diffusion can drastically perturb the adequacy of tissue oxygenation and thereby directly influence not only the risk of undergoing an operative procedure, but also the likelihood that postoperative complications will occur. Accordingly, it is essential that the surgeon fully understand the basic mechanisms responsible for normal pulmonary function, and the way to optimize this

Chapter 31: Pathobiology of Surgically Relevant Pulmonary Disease

function in patients with lung disease to insure a smooth perioperative course when surgical intervention is necessary. This chapter has summarized the basic mechanisms of lung function and how they are perturbed by a variety of insults, including intrinsic disease, infection, trauma, and neoplasia.

REFERENCES 1. Jackson CL, Huber JF. Correlated applied anatomy of the bronchial tree and lungs with a system of nomenclature. Dis Chest 1943; 9:319. [Adapted by Putnam JB Jr. Lung (including pulmonary embolism and thoracic outlet syndrome). In: Townsend CM Jr., et al., eds. Sabiston Textbook of Surgery. Philadelphia: Saunders WB and Co. 7th ed. 2001:1207]. 2. Richardson JD. Common pulmonary derangements, respiratory failure, and adult respiratory distress syndrome. In: Miller TA, ed. Modern Surgical Care: Physiologic Foundations & Clinical Applications. 2nd ed. St. Louis: Quality Medical Pub, 1998:738–764. 3. West J. Pulmonary pathophysiology. Baltimore: Williams & Wilkins, 1982. 4. Whitcomb ME. The Lung, Normal and Diseased. St. Louis: Mosby, 1982:viii, 360. 5. Wright JR. Pulmonary surfactant: a front line of lung host defense. J Clin Invest 2003; 111(10):1453. 6. Wu H, Kuzmenko A, Wan S, et al. Surfactant proteins A and D inhibit the growth of Gram-negative bacteria by increasing membrane permeability. J Clin Invest 2003; 111(10):1589. 7. Richardson JD, Woods D, Johanson WG Jr, et al. Lung bacterial clearance following pulmonary contusion. Surgery 1979; 86(5):730. 8. Peters RM, et al. The Scientific Management of Surgical Patients. Little, Brown & Co, Boston: 1983. 9. Joost O, Wilk JB, Cupples LA, et al. Genetic loci influencing lung function: a genome-wide scan in the Framingham Study. Am J Respir Crit Care Med 2002; 165(6):795. 10. McKeever TM, Scrivener S, Broadfield E, et al. Prospective study of diet and decline in lung function in a general population. Am J Respir Crit Care Med 2002; 165(9):1299. 11. Crim C. Physiology of respiration. In: Miller TA, ed. Modern Surgical Care: Physiologic Foundations & Clinical Applications. 2nd ed. St. Louis: Quality Medical Pub, 1998, pp 729–737. 12. Scott–Conner C. Operative Anatomy, Lippincott. 13. West JB, Dollery CT, Naimark A. Distribution of blood flow in isolated lung: relation to vascular and alveolar pressures. J Appl Physiol 1964; 19:713. 14. Benz EJ Jr. Synthesis, structure and function of hemoglobin. In: Kelly WN, Devita VT, eds. Textbook of Internal Medicine. Vol. 1. Philadelphia, JB Lippincott, 1989:236. 15. West JB. Respiratory Physiology–The Essentials. 7th ed: Baltimore: Lippincott Williams & Wilkins, 2005. 16. Warner MA, Offord KP, Warner ME, et al. Role of preoperative cessation of smoking and other factors in postoperative pulmonary complications: a blinded prospective study of coronary artery bypass patients. Mayo Clin Proc 1989; 64(6):609. 17. Dunn WF, Scanlon PD. Preoperative pulmonary function testing for patients with lung cancer. Mayo Clin Proc 1993; 68(4):371. 18. Fessler HE, Scharf SM, Permutt S. Improvement in spirometry following lung volume reduction surgery: application of a physiologic model. Am J Respir Crit Care Med 2002; 165(1):34. 19. Weisman IM. Cardiopulmonary exercise testing in the preoperative assessment for lung resection surgery. Semin Thorac Cardiovasc 2001; 13(2):116. 20. Daly JM, Barie PS, Fahey TJ III. Preparation of the patient. In: Baker RJ, Fischer JF, eds. Mastery of Surgery. 4th ed. Philadelphia: Lippincott William & Wilkins, 2003:23–53. 21. Schauer PR, Luna J, Ghiatas AA, et al. Pulmonary function after laparoscopic cholecystectomy. Surgery 1993; 114:389.

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22. Bonnet F, Marret E. Influence of anaesthetic and analgesic techniques on outcome after surgery. Br J Anaesth 2005; 95(1):52. 23. Ashbaugh DG, Bigelow DB, Petty TL, et al. Acute respiratory distress in adults. Lancet 1967; 2(7511):319. 24. Bernard GR, Artigas A, Brigham KL, et al. The AmericanEuropean Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994; 149(3 Pt 1):818. 25. Bersten AD, Edibam C, Hunt T, et al. Incidence and mortality of acute lung injury and the acute respiratory distress syndrome in three Australian States. Am J Respir Crit Care Med 2002; 165(4):443. 26. Marshall RP, Webb S, Bellingan GJ, et al. Angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome. Am J Respir Crit Care Med 2002; 166(5):646. 27. Luhr OR, Antonsen K, Karlsson M, et al. Incidence and mortality after acute respiratory failure and acute respiratory distress syndrome in Sweden, Denmark, and Iceland. The ARF Study Group. Am J Respir Crit Care Med 1999; 159(6):1849. 28. Tomashefski JF Jr. Pulmonary pathology of the adult respiratory distress syndrome. Clin Chest Med 1990; 11(4):593. 29. Dellinger PR. Adult respiratory distress syndrome: current consideration and future directions. New Horizons 1993; 1. 30. The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000; 342(18):1301. 31. Hirvela ER. Advances in the management of acute respiratory distress syndrome: protective ventilation. Arch Surg 2000; 135(2):126. 32. Aggarwal AN, Gupta D, Behera D, et al. Analysis of static pulmonary mechanics helps to identify functional defects in survivors of acute respiratory distress syndrome. Crit Care Med 2000; 28(10):3480. 33. Hopkins RO, Weaver LK, Collingridge D, et al. Two-year cognitive, emotional, and quality-of-life outcomes in acute respiratory distress syndrome. Am J Respir Crit Care Med 2005; 171(4):340. 34. Shields RT. Pathogenesis of postoperative pulmonary atelectasis. Arch Surg 1949; 58:489. 35. Calverley PM. The GOLD classification has advanced understanding of COPD. Am J Respir Crit Care Med 2004; 170(3):211; discussion 4. 36. Nelson HS. Beta-adrenergic bronchodilators. N Engl J Med 1995; 333:499. 37. Katzenstein AL, Myers JL. Idiopathic pulmonary fibrosis: current relevance of pathologic classification. Am J Respir Crit Care Med 1998; 157:1301. 38. Bowton DL. Nosocomial pneumonia in the ICU—year 2000 and beyond. Chest 1999; 115:28S. 39. Heyland DK, Cook DJ, Griffith L, et al. The attributable morbidity and mortality of ventilator-associated pneumonia in the critically ill patient. The Canadian Critical Trials Group. Am J Respir Crit Care Med 1999; 159(4 Pt 1):1249. 40. Chastre J, Fagon JY, Bornet-Lecso M, et al. Evaluation of bronchoscopic techniques for the diagnosis of nosocomial pneumonia. Am J Respir Crit Care Med 1995; 152(1):231. 41. Drakulovic MB, Torres A, Bauer TT, et al. Supine body position as a risk factor for nosocomial pneumonia in mechanically ventilated patients: a randomised trial. Lancet 1999; 354:1851. 42. Kollef MH. Selective digestive decontamination should not be routinely employed. Chest 2003; 123(suppl 5):464S. 43. Kollef MH. Prevention of hospital-associated pneumonia and ventilator-associated pneumonia. Crit Care Med 2004; 32(6):1396. 44. Pohlson EC, McNamara JJ, et al. Lung abscess: a changing pattern of the disease. Am J Surg 1985; 150:97. 45. Cina G, Marra R, Di Stasi C, Macis G. Epidemiology, pathophysiology and natural history of venous thromboembolism. Rays 1996; 21:315.

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46. Peitzman AB, Puyana JC. Hemothorax. In: Cameron JL, ed. Current Surgical Therapy. 8th ed. Philadelphia: Elsevier Mosby, 679. 47. Mattox KL, Feliciano DV, Moore EE. Trauma. 4th ed. New York: McGraw-Hill, 1999. 48. Ahmed Z, Mohyuddin Z. Management of flail chest injury: internal fixation versus endotracheal intubation and ventilation. J Thoracic Cardiovasc Surg 1995; 110:1676–1680. 49. Trinkle JK, et al. Pulmonary contusion: pathogenesis and effect of various resuscitative measures. Ann Thorac Surg 1973; 16:569. 50. Davis RD, Oldham HN, Sabiston DC. Primary cysts and neoplasms of the mediastinum: recent changes in clinical presentation, methods of diagnosis, management and results. Ann Thorac Surg 1987; 44:229. 51. Cirino LM, Milanez de Campos JR, Fernandez A, et al. Diagnosis and treatment of mediastinal tumors by thoracoscopy. Chest 2000; 117:1787. 52. Depierre A, Milleron B, Moro-Sibilot D, et al. Preoperative chemotherapy followed by surgery compared with primary surgery in resectable stage I (except T1N0), II, and III A nonsmall cell lung cancer. J Clin Oncol 2002; 20:247. 53. Mountain CF, Dresler CM. Regional lymph node classification for lung cancer staging. Chest 1997; 111:1718.

54. Slebos RJC, Kibbelaar RE, Dalesio O, et al. K-ras oncogene activation as a prognostic marker in adenocarcinoma of the lung. N Eng J Med 1990; 323:561. 55. Rusch VW, Dmitrovsky E. Molecular biologic features of non-small cell lung cancer: clinical implications. Chest Surg Clin N Am 1995; 5:39. 56. Mountain CF. International system for staging lung cancer. Semin Surg Oncol 2001; 18:106. 57. Arriagada R, Bergman B, Dunant A, et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 2004; 350(4):351. 58. Kato H, Tsuboi M, Kato Y, et al. Postoperative adjuvant therapy for completely resected early-stage non-small cell lung cancer. Int J Clin Oncol 2005; 10(3):157. 59. Winton T, Livingston R, Johnson D, et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 2005; 352(25):2589. 60. Lassen U, Hansen HH. Surgery in limited stage small cell lung cancer. Cancer Treat Rev 1999; 25:67. 61. Lau CL, Davis RD. Lung transplantation. In: Norton JA, et al., eds. Surgery: Basic Science and Clinical Evidence. New York: Springer-Verlag, 2001:1509.

HEART

32 Normal Cardiac Function Andrew C. Fiore and Andrew S. Wechsler

Troponin T anchors the three troponin subunits to tropomyosin, while troponin C is involved in the initiation of contraction through its calcium-binding site (6–8). In the resting state, tropomyosin blocks the binding sites on actin so that cross-bridge interaction is prevented. The presence of calcium bound to the troponin complex leads to a conformational change in tropomyosin, such that the actin–myosin association is no longer blocked. It is the specific binding of calcium to troponin C that removes the inhibitory effect of troponin I on the myosin-binding site of actin. Such removal allows formation of the actin–myosin cross-bridge (6–8). The head region of myosin is the enzymatically active portion of the molecule (1). Adenosine triphosphate (ATP) binds here and is hydrolyzed to adenosine diphosphate and phosphorus (P). In this form, the affinity of myosin for actin is enhanced, such that if calcium is present, an actin–myosin complex is formed. As the hydrolysis products are released from the complex, the myosin head undergoes a conformational change that displaces the actin filament relative to the myosin. In this manner, force generation and shortening are accomplished. The addition of ATP to the actin–myosin complex results in dissociation of the filaments. The ATP is once again hydrolyzed, and the process repeats (6–10). Force generation during activation depends to a large extent on the number of cross-bridge attachments that are formed (11). This number is a function of the degree of filament overlap and the level of calcium present. The rate of shortening is a measure of the ATPase activity of myosin (12). It has been established that myosin exists in several forms that are distinguished by the composition of their heavy chains (13). These various forms differ in their ATPase kinetics and thus in their rate of fiber shortening (14). The

INTRODUCTION As a component of the cardiovascular system, the heart is responsible for maintaining adequate blood flow to meet the metabolic needs of the body. This is accomplished by the integration of neural, metabolic, anatomic, and physiologic subsystems that combine to form the intact, functioning human heart. An understanding of cardiac function must consider each of these factors, because a knowledge of only one, or even several, without an appreciation of the others gives an incomplete picture of the physiologic mechanisms responsible for this function. In discussing cardiac physiology, it is appropriate to begin with the molecular events underlying contraction and relaxation, to provide the basis for understanding the performance of the intact organ.

MOLECULAR MECHANISMS IN CONTRACTION AND RELAXATION The basis of cardiac function is the relationship between the contractile proteins, actin and myosin. The nature of this relationship determines to a large extent the characteristics of activation and relaxation in individual muscle cells and in the intact heart. As in skeletal muscle, the functional unit of cardiac muscle is the sarcomere. The sarcomere is composed principally of four proteins (1). These are the previously mentioned contractile proteins, actin and myosin and the regulatory complex consisting of tropomyosin and troponin. In electron micrographs, the sarcomere appears as an arrangement of thick and thin filaments. This arrangement is shown schematically in Figure 1. The thick filament exists as an aggregate of myosin molecules. Myosin consists of a pair of heavy, coiled polypeptide chains, each of which is attached to a globular head region. These head regions project from the axial core of the myosin aggregate and form cross-bridges to the thin filament (Fig. 2). The thin filament is made up of actin in association with troponin and tropomyosin. Actin is a globular molecule that polymerizes to form a double-stranded a-helical filament. Actin filaments attach to the Z line of the sarcomere and project inward as the thin filament. Here, they interact to various degrees with the thick filament. This interaction is regulated by troponin and tropomyosin. Tropomyosin spans the length of the thin filament, and the troponin complex is normally located at every seventh actin site (4). Troponin consists of three subgroups that are responsible for binding calcium ions and for regulating the formation of attachments between actin and myosin by way of the cross-bridges (5). Troponin I hugs the myosin-binding site on actin and thereby prevents interaction with myosin, which is necessary to form the actin–myosin cross-bridge.

Figure 1 Schematic diagram showing the pattern of thick and thin filaments of one sarcomere. Degree of filament overlap varies with the phase of contraction. Source: From Ref. 2.

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Figure 2 Detailed representation of filament structure. Helical tails of the myosin molecules form a rigid rod-like structure. Globular heads project from this toward the actin filament. (A–B) Threedimensional relationships. Each myosin is seen to interact with six actin filaments (B). Note steric hindrance provided by troponin (TROP) and tropomyosin (TM). Abbreviations: HMM, heavy meromyosin; LMM, light meromyosin. Source: From Ref. 3.

composition of the myosin subunits is genetically determined; however, it has been shown to change in response to such hormones as thyroxin and to chronic elevations in the mechanical loading of the muscle (15,16).

The Cellular Basis of Cardiac Contraction Cardiomyocytes may be considered to consist of three systems: (i) a sarcolemmal excitation system that participates in the spread of the action potential (AP) and functions as a switch that initiates the intracellular events giving rise to contraction, (ii) an intracellular excitation–contraction coupling (ECC) system that amplifies and converts the electrical excitation signal to a chemical signal that, in turn, activates the contractile system (iii) contractile system, a molecular motor based on formation of chemical crossbridges between the two proteins, actin and myosin.

in invaginations of the sarcolemma called the transversetubule system, in close proximity to the sarcoplasmic reticulum (SR) membrane–associated ryanodine receptor Ca release channels. The AP results in a net movement of Ca ions into and Na ions out of the cytoplasm. Ionic balance is restored mainly by another sarcolemmal ion-transport mechanism, the Na–Ca exchanger. The exchanger is a shuttle that moves one Ca ion out of the cell against its concentration gradient while using energy from the Na gradient to move one Na ion into the cell. The exchanger also can function in the so-called reverse mode, moving a Ca ion into and a Na ion out of the cytoplasm. Normally, the reverse mode does not contribute significantly to inward movement of Ca ions.

Excitation-Contraction Coupling Excitation System The cellular AP consists of a transient, local trans-sarcolemmal depolarizing current that raises the transmembrane potential from its normal resting value of negative 80 to 90 mV to slightly positive values, followed by a depolarizing current that returns the potential to its resting value. The AP is initiated within the specialized conduction tissue and is propagated to individual myocytes. It results from a series of coordinated changes in the conductance of specific ionic species through variably gated sarcolemmal channels. The earliest and largest component of membrane depolarization is caused by a rapid, inward Na current. The resting potential is established and maintained by the trans-sarcolemmal Na-K-ATPase, which uses energy from ATP hydrolysis to pump Na ions out of the cytoplasm. With respect to initiation of contraction, the most important component of AP is a relatively slow, inward Ca current through voltage-sensitive, L-type (for long-lasting) Ca channels. These channels open, and the current begins to flow when transmembrane potential reaches
35 to
20 mV and, because of its slow kinetics, continues well after the Na current has ceased. The Ca current is mainly responsible for the AP plateau phase. It ceases when L-type channels become inactivated and regenerative currents (mainly K efflux) begin the repolarization process. L-type channels, also termed dihydropyridine receptors, are concentrated

Myocardial contraction is initiated following a rise in cytosolic calcium. During the plateau phase of the cardiac AP, a small number of calcium ions enter the muscle cell through slow channels. These ions do not significantly alter myoplasmic calcium (Ca2þ), but they do cause release of calcium stores from SR (17). This release significantly elevates myoplasmic Ca2þ. Calcium is now available to bind to troponin C, and muscle activation occurs. This process, in which calcium entry triggers intracellular calcium release and muscle activation, is called ECC (Fig. 3). It is interesting to note the amplification of the effects of calcium in this process. The small number of ions entering the cell through the slow channel cause the release of intracellular stores that raise the myoplasmic Ca2þ from a resting value of 10
7 to 10
5 M (6). In turn, each calcium ion that binds to troponin C activates seven actin-binding sites. This two-step amplification illustrates the exquisite sensitivity of the muscle cell to calcium (18). Muscle relaxation depends on the presence of adequate levels of ATP, which act to dissociate the actin–myosin complexes and provide energy for the restoration of myoplasmic Ca2þ to resting levels. The latter is accomplished primarily by a calcium-activated ATPase in the membrane of SR. In addition, smaller amounts of calcium are extruded from the cell through an Naþ/Ca2þ exchange mechanism that operates secondary to the Naþ, Kþ-ATPase of the sarcolemma and is not voltage dependent, as are the slow

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Figure 3 Representation of the transmembrane calcium movements during a contraction cycle. At rest, calcium concentration in the sarcoplasm is low when compared with that in the extracellular space and the interior of sarcoplasmic reticulum (SR). Slow channel is closed, and Ca2þ pumps are inactive. During excitation, the slow channel opens, allowing a small number of extracellular Ca2þ ions to enter the cell. This entry triggers a release of Ca2þ from SR, and the contraction proceeds. Relaxation is accomplished by the active restoration of resting gradients. Abbreviations: ADP, adenosine diphosphate; ATP, adenosine triphosphate; Pi, inorganic phosphate. Source: From Ref. 11.

channels (11,19,20). As calcium levels return to normal, troponin I reestablishes its cloaking of the myosin-binding site so that actin–myosin cross-bridging is again prevented.

Energy Metabolism Myocytes are heavily dependent on oxidative metabolism and endowed with large numbers of mitochondria. Under basal conditions, myocytes preferentially take up and oxidize fatty acids to generate ATP. During stress, however, glucose uptake, glycogenolysis, and glycolysis become increasingly important. Certain ion pumps (e.g., SERCA2, see below) may be especially dependent on glycolytic ATP. Nitric oxide generated by vascular endothelium decreases myocardial oxygen consumption (VO2) due to a direct effect on mitochondrial respiration, and may have a significant role in normal control of energy production and utilization. The processes that account for the great majority of myocardial energy consumption are cross-bridge cycling (myosin ATPase), Ca reuptake by SR (SERCA2), and basal metabolism. Each cross-bridge cycle consumes one highenergy phosphate bond, although at very rapid cycling rates, it may be possible for one ATP to fuel more than one cycle. SERCA2 uses one high-energy phosphate bond for every two Ca ions pumped. As indicated earlier, the rate of energy consumption is heavily dependent on loading conditions, and resulting work and power generation. The thermodynamic efficiency of the heart muscle, its total mechanical energy output divided by its total chemical energy input, is uncertain, in large measure because of difficulties in quantifying total energy output. A more conventional approach is estimation of efficiency of external work production. External work efficiency is heavily dependent on loading conditions, ranging from a maximum under unloaded conditions to zero for an isometric contraction.

MECHANICS OF ISOLATED MUSCLE Much of what is known about the nature of cardiac function has been learned from studies of isolated muscle. Under these conditions, it is possible to finely control the loading of the muscle while making accurate measurements of force

development and shortening characteristics. From these studies, three factors have arisen that determine the behavior of isolated muscle. They are muscle preload, afterload, and contractile state (21,22). Preload is defined as the distending force, or load, that is placed on a muscle before contraction. The preload and the distensibility of the muscle are the determinants of the initial length of the muscle before contraction. The load encountered by the muscle after activation is defined as the afterload. The magnitude of the afterload determines the nature of the subsequent contraction. If the muscle is able to generate a force equivalent to the afterload, shortening occurs. Such a contraction is termed isotonic, because the force developed by the muscle is equal to the load and therefore remains constant during shortening. If the muscle is unable to generate force equal to the load, no external shortening occurs and the contraction is said to be isometric. Contractility refers to the intrinsic ability of the muscle to contract independently of loading conditions. This meaning will become clearer as the characteristics of muscle activation are explained. Isotonic contractions are useful for studying the shortening characteristics of isolated muscle. From these studies, several fundamental principles of cardiac-muscle mechanics have been developed. The first of these defines the relationship between afterload and shortening. As the afterload is increased, the extent of muscle shortening and the velocity of shortening decrease (21). This effect is shown in isolated cat papillary muscle in Figure 4. Cardiac muscle exhibits length-dependent properties: the length of the muscle before contraction affects the nature of the contraction. As initial muscle length is increased, there is an increase in both the extent and the velocity of shortening (Fig. 5). A third property of cardiac muscle involves the response of the muscle to inotropic agents. Positive inotropes enhance the contractility of the muscle, as defined by an increase in the rate and extent of shortening generated from a given preload. Figure 6 shows the effects of a positive inotrope on the velocity and extent of shortening. A unique feature of the force–velocity relationship is that it allows an estimation of the contractile state of the muscle. Theoretically, the velocity of muscle shortening at zero load should

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Figure 4 Force–velocity relations of isolated cat papillary muscle. (A) Velocity of the isotonic contraction is seen to be a decreasing function of load. Extrapolation of the velocity at 0 load (dashed line) provides an estimate of maximum velocity (Vmax). (B) Extent of shortening (DL) also decreases with increasing load. (C–D) Concomitant effects of increasing load (P) on power and work (W). PV, load  velocity of muscle shortening. Source: From Ref. 21.

be determined only by the kinetics of the actin–myosin association. Because any muscle contraction is necessarily loaded to some extent by the preload, the velocity of shortening at zero load (Vmax) can be obtained only by extrapolation of

Figure 5 Effects of varied preload on the force–velocity relations of cat papillary muscle. As the preload is increased, the velocity of shortening increases. However, the maximum velocity (Vmax) does not change. Source: From Ref. 21.

Figure 6 (A) Application of norepinephrine causes an increase in the shortening and maximum velocity. (B) Extent of muscle shortening is also increased at any shortening load. (C) and (D) show concomitant effects of load on power and work. Source: From Ref. 21.

the force–velocity curve to zero load. For the relationship shown in Figure 6, the addition of norepinephrine resulted in an increase in the extrapolated value of Vmax. In contrast, Figure 5 demonstrates the required load independence of contractility as suggested by the stable estimates of Vmax (21). Isometric contractions provide a convenient means to study force development in isolated muscle. When a muscle is stimulated to contract isometrically, the amount of force (tension) developed depends only on the length before contraction and the inotropic state of the muscle. Variations in afterload are not a factor, because by definition, the magnitude of the afterload always exceeds the force-generating capability of the muscle. Increasing the initial length of the muscle at a given contractile state results in an increase in the level of resting tension borne by the muscle (Fig. 7). As the length of the muscle increases, the peak force generated from any given length also increases (Fig. 7), as does the rate of force development (dF/dt). The addition of Ca2þ has the effect of a positive inotrope on the isometric preparation. Specifically, resting tension is unaffected, but the peak force, time to peak force, and dF/dt are enhanced. When a muscle fiber is distended, a point is reached at which force development is maximum. The length at this point is termed Lmax. Further increases in muscle length beyond Lmax result in a reduction in the amount of developed tension (6). This and other length-dependent properties of the muscle can be explained in part by relating the various muscle lengths to the degree of overlap in the thick and thin filaments of the sarcomere (Fig. 8). At rest, sarcomere length, defined as

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Figure 8 Representation of the relationship between active tension, resting tension, and filament overlap in the feline right ventricle. These relationships form the basis of the Frank–Starling principle as seen in the intact heart. Note that the degree of active tension that is developed depends on the extent of filament overlap. Maximum active tension (Tmax) is developed at a sarcomere length of 2.2 mm (Lmax), which also corresponds to the optimum length for filament interaction. Abbreviation: NE, norepinephrine. Source: From Ref. 3.

Figure 7 When a muscle contracts isometrically, the amount of tension that is developed depends on the length and inotropic state of the muscle. In this figure, the upward exponential curve (squares) represents the resting tension existing in the muscle as it is stretched to increasing lengths. Developed tension (open triangles) generated during isometric contraction from each length increases as the muscle is stretched. Addition of calcium does not affect the resting length–tension curve but does cause an upward displacement of developed tension. Source: From Ref. 23.

the distance between adjacent Z lines, averages 1.8 mm. As the muscle is lengthened, sarcomere length increases. More importantly, there is an increase in the degree of overlap between the chemically active portions of the thick and thin filaments. Because the potential for the formation of force-generating cross-bridges is increasing, there is a concomitant increase in the amount of force developed. The length of the sarcomere at Lmax averages 2.2 mm. At this distance, the thick and thin filaments are arranged such that all myosin heads lie adjacent to actin filaments. In this state, the probability of interaction between the filaments is greatest; hence, force generation is greatest. With the application of large forces, cardiac muscle can be distended beyond Lmax. Little change occurs in the amount of filament overlap, even though active tension declines sharply. This decline has been attributed to the damage of the myocytes as a result of the large deformations produced by the loading force (24). This relationship explains why overdistention of the heart (excessive filling) results in deterioration of cardiac function. Examination of the resting force–length relationship reveals a nonlinear relationship between applied force and

deformation (25). This behavior is illustrated in the resting length–tension curves of Figures 7 and 8. At the lower ranges of preload, a given increment in applied force results in a relatively large degree of fiber deformation. In the upper range, the same increment in applied force results in a smaller deformation. This behavior is a manifestation of the mechanical properties of the tissue. The significance of this property will become evident when filling of the intact heart is discussed.

FUNCTION OF THE INTACT HEART The heart is composed of a complex array of muscle fibers that are arranged to form the various cardiac chambers. Each of these fibers operates under the same basic principles as those that have been established for isolated muscle, namely a dependence on preload, afterload, and contractility. Heart rate is a fourth determinant of the heart’s performance per unit of time. Each of these factors finds its analog at the organ level, and together they determine the ability of the intact heart to establish and maintain the circulation of blood in the body.

Wall Forces The force relationships that govern the function of muscle fibers in the intact heart are determined by chamber pressures and geometries. At any point in the cardiac cycle, the pressure within a given chamber exerts a load on the wall of the chamber. This load (in dynes) is equivalent to the product of the pressure (dynes/cm2) and the area over which the pressure acts (cm2). In accordance with Newton’s law of motion, this load must be precisely balanced by opposing forces in the wall. These forces, normalized to the areas over which they act, are known as wall stresses (26). Figure 9 shows the chamber pressure acting on a

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Figure 9 Section removed from the wall of the left ventricle is by a force (F) equal to the product of the chamber pressure (P) and the area over which it acts. For this element to be in equilibrium, opposing forces exist in the wall, which precisely balance this load. These forces are called wall stresses. This figure shows the loading pressure and the two principal resultant forces. Source: From Ref. 26.

section of the wall of the left ventricle and the two principal resultant forces. Assuming an ellipsoidal representation for the left ventricle, application of the Laplace relationship results in the following expression for the meridional (s1) and equatorial (s2) components of stress: s1 s2 P þ ¼ R1 R2 h where, R1 and R2 represent the principal radii of curvature for the ellipsoid; P is the ventricular pressure, and h is the wall thickness. A number of expressions are available for independent solutions of s1 and s2 based on ventricular dimensions and pressure. These expressions and their limitations have been reviewed (27). An alternative method of conceptualizing force considers only the net force existing in the wall rather than the normalized force (28). The net wall force at any level may be calculated by imagining that the ventricle has been transected by a plane (Fig. 10). The force necessary to hold the ventricle intact, then, is the net force acting on the wall at that level. This force is equal to the product of the ventricular pressure and the area of the chamber included in the plane. For a sphere, this force is constant at any level. For an ellipsoid, the net force depends on the plane of the section. If the section is made normal to the long axis of the ventricle, the pressure  area product is equivalent to the net force in the meridional direction. The magnitude of this force decreases as the plane of section is moved toward the poles of the ellipse, because chamber area is decreasing (29). Wall thickness also decreases toward the poles (30); therefore, stresses and deformation tend to remain uniform. If the plane of section is considered in the long axis, the pressure  area product approximates the equatorial component of wall force. Figure 11 shows pressure, equatorial wall stress, and net wall force for the left ventricle during one cardiac cycle.

Ventricular Geometry and the Cardiac Cycle Efforts to quantify ventricular function often begin with the adoption of simplified geometric models. The normal left

Figure 10 Net wall force concept considers that the ventricle is divided by an imaginary plane located at the level of interest. Net wall force is simply the force necessary to hold the ventricle together at the given level. It is equal to the ventricular pressure multiplied by the area of the chamber involved in the plane. Source: From Ref. 28.

ventricle has been represented as an ellipsoidal shell, a sphere, or a cylinder, with varying degrees of success. Even during the dynamic events of filling and ejection, accurate determinations of ventricular dimensions can be obtained with the appropriate use of these models. The elliptical model of left ventricular geometry is often used because it accurately represents the configuration of the left ventricle throughout the cardiac cycle (26,30). In this model, the left ventricle is considered as a general ellipse axisymmetric about its major axis, having a finite but varying wall thickness. The base-to-apex (major) axis is consistently greater than the transverse (minor) axis. The thickness of the ventricular wall is maximum in the equatorial minor axis plane and tapers to a minimum value at the poles of the ellipse (30). During the cardiac cycle, muscle shortening produces variations in ventricular dimensions, with the resultant generation of pressures and volume displacements. Figure 12 illustrates left ventricular chamber

Figure 11 Left ventricular pressure and wall forces for one cardiac cycle in the canine heart. Shown here are pressure (open circles), equatorial wall stress (open squares), and net wall force (closed circles). Note the fall in stress and wall force as the ventricle unloads itself during ejection.

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Figure 12 Left ventricular chamber dimensions and pressure in the conscious dog.

dimensions and pressure for several beats. The complex anatomy, configuration, and contraction pattern of the right ventricle have precluded efforts to model this chamber accurately with simple geometric reference figures. Accordingly, the remainder of this section describes the pattern of hemodynamic events in both chambers, with the inclusion of dimensional information for the left ventricle. The cardiac cycle can be thought of as beginning with atrial contraction, as indicated by the P wave of the electrocardiogram (Fig. 13). Atrial contraction provides a final, active increment in ventricular filling before systole (32). With the onset of the QRS complex, the period of isovolumic ventricular contraction begins. This marks the beginning of ventricular systole. As ventricular pressures rise above atrial pressures, the AV valves close. The vibrations generated by the abrupt closure of these valves are responsible for the first heart sound. In the left ventricle, the minor axis dimension shortens, the major axis lengthens, and the thickness of the ventricular wall increases (30), resulting in an ellipsization of the chamber. During this period, there is a rapid rise in the rate of pressure generation (dP/dt). This parameter reaches a maximum value at the onset of the ejection phase. Ejection begins when pressure within each of the ventricles rises above the pressures in their respective outflow tracts. The higher ventricular pressures result in an opening of the semilunar valves, and the phase of rapid ejection ensues. Rapid ejection is followed by reduced ejection as pressures in the ventricles and great arteries fall. In left ventricular ejection, the minor and major axes shorten, and the wall becomes thicker, resulting in a decrease in the internal chamber volume. In the canine heart, the major axis, minor axis, and wall thickness changes account, respectively, for 9%, 47%, and 44% of volume output during systolic ejection (30). In the right ventricle, contraction occurs in a peristaltic wave moving from the sinus region toward the conus (33). As ventricular and

Figure 13 Phases of the cardiac cycle. Shown are left ventricular pressure and volume and the correlation of these measurements to left atrial and aortic pressures, heart sounds, and the electrocardiogram. A, Atrial sound; I, first heart sound; II, second heart sound; III, third heart sound. Source: From Ref. 31.

arterial pressures fall, flows in the great vessels reverse. This point marks the end of systole and the beginning of the first phase of diastole, known as protodiastole. Protodiastole ends with the closure of the semilunar valves, which produces the second heart sound. Such closure is also marked by the incisura of the arterial pressure tracing. Protodiastole is followed by the period of isovolumic relaxation. During this period, the geometric patterns observed during isovolumic contraction generally are reversed, and the peak fall in dP/dt occurs. Ventricular pressures fall until they are less than pressures in the atria. The AV valves open, and diastolic filling begins. Diastolic filling is composed of several phases. The first of these is the rapid filling phase, during which rapid volume expansion occurs. This phase is sometimes associated with an audible third heart sound. As the ventricles become full, the rate of filling slows, and the period of diastasis is approached. During diastole, the left ventricle becomes more spherical as the minor axis dimension increases with respect to the major axis, and the wall becomes thinner (30). The end of diastole is marked by atrial systole and the generation of the fourth heart sound. At slow heart rates, the atrial contribution to ventricular filling is minimal. At more rapid heart rates or with stenosis of the AV valves, the contribution of atrial systole to ventricular filling becomes more important. In the failing heart, the contribution by atrial systole can result in a 20% to 30% increase in cardiac output.

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Diastolic Behavior Relaxation Diastole represents the period of relaxation and filling in the cardiac cycle. During relaxation, the ion fluxes that occurred during the process of ECC are reversed, and the contractile proteins assume their resting configurations. In the filling phases of diastole, the relaxed sarcomeres lengthen as the ventricles distend with blood and the initial muscle length for the next beat is determined. Relaxation is often thought of as a passive event, because pressures and flows are rapidly falling; however, it is a period of considerable metabolic activity, requiring the presence of ATP initially to dissociate the actin–myosin complexes and later to provide the energy for the active transport, which restores the resting ion gradients. For relaxation to occur, sarcoplasmic Ca2þ must be reduced to a level such that Ca2þ dissociates from the troponin complex. This activity is accomplished by pumps in the membrane of SR and to a lesser extent by transport mechanisms in the sarcolemma (11). The common feature of these transport processes is the requirement for ATP. In light of this, abnormalities of relaxation have been explained in part on the basis of reduced ATP availability in the injured or diseased heart (34). An additional role has been suggested for ATP in the relaxation process. Adding ATP to a cell that has normal levels of ATP results in an enhancement of the uptake of Ca2þ by SR. Thus, ATP may act in a regulatory manner in controlling Ca2þ transport. Slight reductions in cellular levels as a result of moderate degrees of energy deprivation could result in impaired relaxation, even though sufficient levels are available to saturate the primary transport mechanisms (11).

Filling The importance of the filling events of diastole as determinants of cardiac function was first noted by Frank in the late 19th century. Frank observed a direct relationship between end-diastolic volume (EDV) and the force of contraction in the isolated frog heart (35). Later, Starling made similar observations in the mammalian heart. This work culminated in the concept of the Frank–Starling relationship, which was simply stated as ‘‘the energy of contraction, however measured, is a function of the length of the muscle fiber’’ (36). In the intact heart, diastolic filling determines the length of the muscle fibers before contraction and therefore influences the force of contraction. The nature and extent of this filling, in turn, are influenced by a number of factors; among these are the level of filling pressure, the material properties of the myocardium, the geometry of the chamber, and such external forces as pericardial and pleural pressures (34). Within any of the cardiac chambers, the filling pressure produces distending forces within the wall of the chamber. These forces are a function of the magnitude of the pressure and the size and shape of the chamber. The resulting distention produced by a given increment of force is governed by the material properties of the myocardium. Because these forces act to determine the length of the muscle fibers before contraction, they may be considered analogs to the preload previously described for isolated muscle. The ‘‘material properties’’ of the myocardium refer specifically to the elastic and viscous characteristics of the muscle. An elastic material deforms when acted on by an external force and recovers from the deformation when

the force is removed. For a substance with linear elastic properties, deformation (e) is related to the force ( f ) as: f ¼ EðeÞ where E, the slope of the relationship, is known as the coefficient of elasticity or Young’s modulus (37). An increase in E reflects an increase in the stiffness of the material. In a viscoelastic material, force is a function of both deformation and the rate of deformation. Heart muscle is known to possess both elastic and viscous properties (38). The analysis of these properties and their influence on diastolic filling is complicated by the fact that the elastic properties, and possibly the viscous properties, are nonlinear entities (38). When a force is applied along the long axis of an isolated papillary muscle, the deformation of the muscle obeys the following relationship, assuming that the rate of deformation is small so that viscous effects are not important (25). 

F
a½ebðx
x Þ
1 where, x is the muscle length, x is the resting muscle length, and a and b are elastic constants analogous to the coefficient of elasticity of Eq. (2). F is the fiber stress. Stress is an expression of normalized force, here equal to the applied force divided by the cross-sectional area of the muscle specimen. This nonlinear elasticity of heart muscle is the principal factor affecting the relationship between diastolic pressure and volume in the intact left ventricle (39). Figure 14 shows the pressure–volume curve obtained by slowly filling a canine heart with saline. Several important points are apparent from this illustration. First, even though the ventricle is composed of muscles that display exponential elastic behavior, the relationship between pressure and volume is not truly exponential. It is approximately linear in the lower pressure ranges and approaches exponentiality in the upper pressure ranges. Second, the elastic nature of the myocardium resists deformation above a filling pressure of about 20 mmHg. The significance of the second factor is that the increasing stiffness of the cardiac muscle prevents overextension of the individual sarcomeres, permitting the heart to function on the ascending limb of the Frank–Starling relationship, where increased volume results in increased output.

Figure 14 Relationship between pressure (dP) and volume (dV) [expressed as time (dt) of infusion of volume at a constant rate] in the isolated, arrested canine heart. The relationship is approximately linear in the lower pressure ranges and becomes exponential in the upper ranges. The increasing instantaneous slope of the pressure–volume curve reflects the increase in chamber stiffness that occurs as the ventricle is filled. Source: From Ref. 40.

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657

Systolic Function Normal pumping of the ventricles requires that they deliver appropriate amounts of blood to the tissues at acceptably low filling pressures (FPs). Thus, the most physiologically relevant means of characterizing the pump is to construct a function curve relating FP to a measure of mechanical output [stroke volume (SV), minute volume, work, and power]. Ventricular function curves display a prominent Frank– Starling effect, manifest as a curvilinear relationship between FP and output (once again, there is no descending limb in the normal ventricle). As discussed earlier, at the myocytes level, the Frank–Starling effect is mainly caused by increased myofilament Ca sensitivity at longer sarcomere lengths. Thus, a function curve relating EDV (ventricular preload) to mechanical output is a more accurate representation of the ventricular Frank–Starling effect. However, in the clinical setting, FP (pulmonary capillary wedge or right atrial pressure) is usually more readily available than volume. Whether FP or volume is employed, changes in intrinsic contractile performance result in upward or downward shifts of the ventricular function curve. However, characterization of ventricular performance in terms of function curves relating FP to output is a ‘‘black box’’ approach; alterations in diastolic compliance (see below) produce effects that are indistinguishable from alterations in contractile performance. The normal heart can pump adequate amounts of blood to meet the needs of the body under the most stressful conditions. Indeed, maximal cardiac output (CO) normally is not limited by pumping capacity but by the ability of the systemic circulation, via venoconstriction and the systemic venous system of valves and muscular pumps, to return blood to the heart. Under pathologic conditions, pumping capacity may limit CO. The peak force that can be generated at a given contractile state and EDV is attained in the isovolumically contracting heart (41). As EDV is raised, the peak developed force increases in a linear fashion (Fig. 15). This behavior demonstrates the operation of the Frank–Starling relationship in the intact ventricle, where force generation is an increasing function of fiber length, expressed here as EDV. The line that results from relating peak force to initial volume defines the limit of force generation for the ventricle. When the ventricle is permitted to eject, this line also defines the limit of systolic shortening (41).

Figure 16 Schematic diagram of the pressure–volume loops for several beats under various loading conditions. Contraction 1 is considered control, contraction 3 shows the effects of increased preload, and contraction 2 shows the effects of increased afterload on SV and pressure generation. Points E and F represent the peak pressures that could be generated if the ventricle were to contract isovolumically from preloads at points 2 and 3, respectively. Note that points E and F define the limit for shortening in the ejecting heart. See text for further details. Abbreviations: SV, stroke volume; LV, left ventricular. Source: From Ref. 23.

Figure 16 depicts the pressure–volume relationships for an ejecting ventricle under changing conditions of preload and afterload. Contraction 1, originating from EDV A, contracts isovolumically to point B. At point B, the ventricular pressure just exceeds aortic pressure, and ejection begins. During ejection (points B to C), the force sustained by the muscle fibers in the wall of the ventricle represents the afterload. Ejection continues until a point is reached at which muscle force is maximum for a given volume (point C). This point contracts the isovolumic pressure–volume line and represents the end of systolic shortening. When preload is altered as in contraction 3, there is a change in SV, but the extent of fiber shortening does not change. Contraction 3 still proceeds to point C. Increasing the afterload by augmenting aortic pressure (contraction 2) results in both decreased SV and a change in the extent of fiber shortening. Thus the degree of fiber shortening in the ejecting heart is determined by the instantaneous load borne by the muscle, not by alterations in loading before contraction (41). The ability of the ventricle to generate force is influenced by the contractile state of the muscle. A change in contractility is represented by a change in the peak force.

Electrical Activity

Figure 15 Development of pressure in the isovolumically contracting canine left ventricle. As resting volume is increased, the peak generated pressure increases. Line connecting the peak pressures defines the limit of force generation for the contracting ventricle. Source: From Ref. 42.

Electrically excitable tissues communicate within themselves and with other structures through the generation of APs. Within the heart, there are certain cells that generate spontaneous APs, which propagate and serve as a stimulus to initiate contraction. This property is referred to as automaticity. A second property, intrinsic to the electrical activity of the heart, is conductivity. Conductivity describes the lowresistance intercellular connections that permit any depolarization to be spread throughout the mass of the heart. Under normal circumstances, contraction of the heart is initiated by APs generated in the sinoatrial (SA) node (43). This structure, located at the junction of the right atrium and the superior vena cava, has the highest rate of intrinsic

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pacemaker activity found in the heart. APs generated here spread slowly over the right and left atria, with resultant atrial contractions. Excitation moves to the cardiac ventricles through the AV node. In contrast to the atria, impulse conduction through this structure is extremely slow. This delay permits the completion of atrial contraction before ventricular activation. Having passed through the AV node, the wave of excitation enters the bundle of His, a structure located in the subendocardium of the right surface of the interventricular septum. The bundle of His then divides into right- and left-sided branches, which ramify in the fibers of the Purkinje system. The Purkinje system extends over the subendocardial surfaces of both ventricles. Its electrical activity is characterized by a high conduction velocity, which permits near-simultaneous activation of the ventricles. Many factors affect the nature of pacemaker activity and excitation in the heart. These include neural, hormonal, physicochemical, and pathologic influences. These influences often exert their effects by alterations of events occurring at the cellular level, specifically by inducing changes in the transmembrane electric potential and ion movement (44). Transmembrane electric potential (Vm) in cardiac cells comes about as a result of an unequal distribution of ions across the cell membrane. In cardiac cells, as in most other cells of the body, the internal potassium concentration is high and the internal sodium concentration is low. The contribution of each of these ions to the net charge on the membrane can be estimated from the Nernst equation (45). For an unspecified ion X, E¼

58 ½Xout  log Z ½Xin 

Ion concentrations across the membrane actually change very little. The arrival of an AP causes a rise in the resting Vm toward threshold value for the particular cell. Once threshold is achieved, a complex pattern of conductance changes ensues. Cardiac muscle cells and cells of the Purkinje system have a high relative gK at rest. Membrane potential is
80 to
90 mV, and threshold is approximately
60 mV. When cardiac muscle cells are stimulated, gNa becomes markedly elevated in what is known as phase 0 of the AP (Figs. 17 and 18). Sodium ions are now better able to cross the membrane. Note that this movement is favored by both chemical and electrical gradients; so it occurs quite rapidly. The net inward movement of positive charge causes depolarization of the cell; Vm moves toward and then past 0 mV. As the cell depolarizes, gNa falls, completing phase 0. Phase 1 is characterized by a rapid fall in Vm, thought to be the result of transient increase in membrane permeability to chloride (Cl
). Phase 2 is the plateau phase of AP. This is brought about by a slow inward Ca2þ and Naþ current balanced by an outward Kþ current. Repolarization occurs in phase 3 and is a result of a further increase in gK combined with an inactivation of the slow inward current of phase 2. There are striking differences between APs seen in the nodal structures and those just described (Fig. 17). Recordings from cells of the SA node reveal a less negative resting potential, a decreased rate of phase 0 depolarization, no plateau, and a reduced rate of phase 3 depolarization. Perhaps most significant is the behavior that nodal tissue displays in phase 4. During this phase, Vm is not constant but moves steadily toward threshold. The basis for this

where, E is the equilibrium potential resulting solely from ion X, and Z is the charge number of the ion. If the membrane is permeable only to X, Vm equals E. When more than one ion is involved, Vm becomes a weighted average of the equilibrium potential of each ion. The weighting factors depend on the relative conductance of each ion. Conductance (g) is the reciprocal of resistance and is an expression of the ease with which an ion can cross the cell membrane. Thus, in general terms, for a cell permeable to ions A, B, and C, Vm could be approximated from the equation: Vm ¼

gA gB EA þ EB gA þ gB þ gC gA þ gB þ gC gC þ EC gA þ gB þ gC

where, in the case of cardiac tissue, the major ions involved in transmembrane flux are Naþ, Kþ, and Ca2þ such that: Vm ¼

gNa gK ENa þ EK gNa þ gK þ gCa gNa þ gK þ gCa gCa þ ECa gNa þ gK þ gCa

In the quiescent cardiac cell, Kþ permeability greatly exceeds Naþ and Ca2þ permeability, or in terms of conductances, gK greatly exceeds gCa and gNa. Given this fact, Eq. (6) then reduces to the Nernst equation for Kþ, and the resting Vm equals or approaches EK. APs in cardiac tissue result from changes in the relative conductances of the principal ions Naþ, Kþ, and Ca2þ.

Figure 17 Action potential seen in various cardiac tissues. (A) Ventricular muscle cell, (B) sinoatrial node, (C) atrial muscle. Time base for (B) is half that of (A) and (C). Source: From Ref. 46.

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Figure 19 Altering the rate of pacemaker activity. (A) Altering the rate of firing by a decrease in the rate of phase 4 depolarization. Threshold potential (TP) is not changed. (B) Changing threshold at a given rate of phase 4 depolarization can alter heart rate by changing the time required to reach TP (tracings a–b and a–c). Hyperpolarization can also influence rate (tracings a–e). Source: From Ref. 46.

Figure 18 Conductance changes seen within a Purkinje fiber. Typical action potential is shown at the top, with the accompanying changes in conductance for potassium (gK), sodium (gNa), chloride (gCl), and calcium (gCa). Source: From Ref. 31.

behavior is believed to be a time-dependent decrease in the outward Kþ movement in the presence of a small, steady, inward movement of Ca2þ. The loss of the Kþ current disrupts the balance of charge and results in membrane depolarization. When the membrane potential reaches threshold, an AP is generated. In this manner, a nodal tissue serves as a pace generator for the heart. The rate of pacemaker activity depends on the minimum phase 4 Vm, the rate of depolarization, and the threshold potential (47). These factors are under neural and hormonal controls that act to vary the heart rate (Fig. 19) (15). For example, increased vagal activity results in the release of acetylcholine at the SA node. This has the effect of increasing gK, which hyperpolarizes the membrane and slows the heart rate. Conversely, catecholamines can increase the inward phase 4 Ca2þ current, which would increase both the rate of depolarization and the heart rate (see section on ‘‘Neural Control’’) (20,44,47,48).

Neural Control The sympathetic and parasympathetic divisions of the autonomic nervous system act in concert to regulate cardiac function. Sympathetic effects are excitatory and are mediated through nerve fibers distributed to the atria, ventricles, and nodal tissue. Parasympathetic influences are generally inhibitory and act predominantly on atrial and nodal tissues.

The terminal regions of the sympathetic fibers synthesize and store norepinephrine, which is released as a result of nerve stimulation. Norepinephrine acts on b1 adrenergic receptors imbedded in the membrane of the cardiac cell. b-receptors in the myocardium are of two types, b1 and b2. b1-receptors are distributed exclusively to the ventricles, and their activation results in an increase in the ventricular contractility (49,50). The mechanism of action is thought to involve increases in the level of cyclic adenosine monophosphate, which in turn promote the phosphorylation and activation of calcium channels in the membrane (51,52). The net effect of b1-stimulation is an increase in calcium influx, which causes an increase in the contractile state of the muscle (14). b2-receptors are found in the atria. The activation of these receptors results in an increased heart rate through their positive chronotropic effects (10). The stimulus for activation of b2-receptors differs from that of b1 types in that b2 receptors are sensitive to epinephrine and norepinephrine. Parasympathetic effects are mediated by fibers of the vagus nerve that are distributed to the atria, and, to a lesser extent, to the ventricles. Activation of these fibers results in a release of acetylcholine, which causes a depression of cardiac function characterized by a reduction in heart rate and atrial contractility. Ventricular contractility is affected to a lesser extent (53). The diminution in ventricular function seen during vagal stimulation can be explained in part by reduced ventricular filling, which occurs secondary to the fall in atrial contractility. Acetylcholine produces its negative chronotropic effects by hyperpolarizing the nodal tissue. Hyperpolarization is a consequence of the increase in potassium permeability caused by the application of acetylcholine. Acetylcholine also binds to muscarinic receptors on the sympathetic nerve fibers. Activation of muscarinic receptors results in reduced catecholamine release during sympathetic stimulation. Thus, the inhibitory influences of parasympathetic activity are more pronounced when sympathetic activity is high. In recent years, an increasing emphasis on neural control of heart function has been evolving. Trauma, anesthesia,

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and anxiety evoke major alternations in cardiovascular function and may be the precipitants of arrhythmias or cardiac dysfunction.

Coronary Flow and Myocardial Oxygen Consumption The energy imparted by the heart to the blood during the process of ejection is linearly related to three factors: heat rate, SV, and developed aortic pressure. A rise in any of these three variables leads to an increase in the myocardial oxygen consumption. Minute work of the heart is defined as the product of these three parameters. Changes in SV are associated with the greatest efficiency and the lowest energy cost to the heart, whereas increases in the heart rate and blood pressure are costly and require the greatest increase in myocardial oxygen delivery. Because heart rate and blood pressure figure so much more prominently in the determination of myocardial oxygen consumption than SV, two clinical indexes based on heart rate and aortic pressure have been developed for estimation of myocardial oxygen consumption. These are the ‘‘double product’’ (the heart rate multiplied by the blood pressure) and the ‘‘tension time’’ index (the average ejection pressure of the left ventricle multiplied by the duration of ejection). Both of these indexes correlate well with cardiac oxygen consumption, but neither takes into account the effect of ventricular dilation or altered contractility. It is obvious from this discussion that myocardial oxygen consumption can be decreased and the efficiency of the heart improved by a reduction in heart rate and a decrease in mean arterial blood pressure (vasodilation). The flow of oxygenated blood into the myocardium is controlled by the coronary circulation. Blood flow is regulated to ensure an environment of aerobic metabolism to support cardiac work. To accomplish this goal, the coronary circulation possesses two unique features: &

&

Under basal conditions, there is a high degree of oxygen extraction (coronary sinus oxygen saturation is 20–30%) so that the heart can adjust to changing oxygen needs by only a small increment in oxygen extraction. Accordingly, increasing oxygen requirements must be met by proportionate increases in coronary flow.

HEART FAILURE Contraction 3 in Figure 20 represents a decreased contractile state, as might be seen in conditions of heart failure (32,54,55). Failure occurs when the heart can no longer pump blood commensurate with the needs of the body. This condition can occur as a result of depression in the intrinsic contractility of the muscle or as a result of the imposition of increased loading conditions on ventricular ejection (23). The heart can compensate in several ways. Contractile state can increase with endogenous catecholamine release. Also, muscle preload can be augmented by the increased filling pressure that often accompanies the reduced pumping ability of the failing ventricle. Hypertrophy and/or chamber dilation also can occur. Associated with these compensatory mechanisms are certain detrimental factors that may contribute to the eventual failure of the heart. Increased preload results in an increased level of wall stress throughout diastole. Wall stress has been shown to be related to myocardial oxygen consumption (56); therefore, incorporation of this mechanism necessarily increases the flow requirements of the myocardium. As chamber

Figure 20 Conceptual pressure–volume loops for hearts at contractile states. Note the effect of the contractile state on the stroke volume (SV) generated from similar preloads at points 1, 2, and 3. During heart failure, SV may be decreased despite a slightly larger end-diastolic volume (EDV) at a comparable level of aortic pressure (see contraction 3). If EDV is further increased, SV may be restored (see contraction 4). Abbreviation: LV, left ventricular. Source: From Ref. 23.

enlargement occurs, several aspects of active force relations are affected. From the net wall force concept developed earlier, it is simple to see how an increase in the chamber size results in a decrease in the efficiency of the ventricular contraction. Recall that wall force (F) is equal to the product of chamber pressure (P) and area (A). Rearranged, this gives P ¼ F/A. The generation of a given pressure within the large ventricle (larger A) then requires the existence of a greater wall force. A second aspect of chamber enlargement concerns the unloading of the ventricle during systole. In a normal heart, the muscle load (stress) peaks soon after the onset of ejection and then declines through the remainder of systole (Fig. 11). This occurs because the decrease in chamber size is more than the increase in pressure , resulting in a partial unloading of the ventricle. To generate a given SV, the enlarged heart undergoes a smaller degree of systolic shortening. It therefore unloads itself less than would a smaller heart ejecting the same volume. Worsened ejection resulting from prolonged high wall tension creates an afterload mismatch in the coupling of the heart to the periphery. Vasodilator therapy normalizes this loading of the heart and thereby facilitates ejection. At the same time, smaller volumes and wall tension decrease myocardial oxygen consumption. A practical clinical index of global cardiac function is the ejection fraction (EF). EF is the percent of EDV that is ejected as the SV and is derived from the following equation: EF ¼

ðEDV
ESVÞ EDV

where ESV is the end-systolic volume. A normal functioning heart has an EF of 55% to 75%. In patients with severe compromise in myocardial reserve due to chronic heart failure and/or scarring from previous myocardial infarction,

Chapter 32:

EF may be as low as 15% to 20%. Although EF is not a perfect measure of cardiac function in that it is sensitive to preload, afterload, heart rate, and ventricular compliance, it is sufficiently reliable overall as to give an accurate index of the contractile capabilities of the heart. It can be measured in a variety of ways including echocardiography, cineangiography, and ventriculography.

SUMMARY For many years, the complexity of the cardiovascular system prevented the systematic study of its properties. Although that complexity remains, several basic principles by which the heart functions have been determined. These principles include the dependence of myocardial performance on preload, afterload, and contractility. Preload is defined as the distending force, or load, that is placed on cardiac muscle before contraction. The preload and the distensibility of the muscle are the determinants of the initial length of the muscle before contraction. The load encountered by the cardiac muscle after activation is defined as the afterload. The magnitude of the afterload determines the nature of the subsequent contraction. Contractility refers to the intrinsic ability of the cardiac muscle to contract, independent of loading conditions. Heart failure occurs when the heart can no longer pump blood commensurate with the needs of the body. This condition can occur as a result of depression in the intrinsic contractility of the cardiac muscle or as a result of the imposition of increased loading conditions on ventricular ejection. Understanding the interplay among these various parameters and how their imbalance can be corrected or lessened, both medically and surgically, underlies the rationale for treatment in patients with cardiac dysfunction.

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45. DeVoe RD, Maloney PC. Principles of cell homeostasis. In: Mount-castle VB, ed. Medical Physiology. 14th ed. St Louis: Mosby, 1980. 46. Berne RM, Levy MN, eds. Physiology. St. Louis: Mosby, 1983. 47. Campbell DL, Rasmusson RL, Strauss HC. Ionic current mechanisms generating vertebrate primary cardiac pacemaker activity at the single cell level: an integrative view. Annu Rev Physiol 1992; 54:279. 48. Zipes DP, Jalife J, eds. Cardiac Electrophysiology: From Cell to Bedside. 3rd ed. Philadelphia: WB Saunders, 2000. 49. Hedberg A, Minneman KP, Molinoff PB. Differential distribution of beta-1 and beta-2 adrenergic receptors in cat and guinea-pig heart. J Pharmacol Exp Ther 1980; 213:503. 50. Homcy CJ, Vatner ST, Vatner DE. Beta-adrenergic receptor regulation in the heart in pathophysiologic states: abnormal adrenergic responsiveness in cardiac disease. Annu Rev Physiol 1991; 53:137.

51. Feldman AM. Classification of positive inotropic agents. J Am Coll Cardiol 1993; 22:1223. 52. Leier CV. Current status of non-digitalis positive inotropic drugs. Am J Cardiol 1992; 69:120G. 53. Levy MN, Martin PJ. Neural control of the heart. In: Berne RM, ed. Handbook of Physiology. Section 2. The Cardiovascular System. Vol. 1. The Heart. Bethesda, Mary Land: American Physiological Society, 1979. 54. Folkow B, Svanborg B. Physiology of cardiovascular aging. Physiol Rev 1993; 73:725. 55. Klug D, Robert V, Swynghedauw B. Role of mechanical and hormonal factors in cardiac remodeling and the biologic limits of myocardial adaptation. Am J Cardiol 1993; 71:46A. 56. Braunwald E. 50th Anniversary Historical Article. Myocardial oxygen consumption: the quest for its determinants and some clinical fall out. J Am Coll Cardiol 2000; 35:45B.

33 Heart Failure and Resuscitation Heinrich Taegtmeyer

myocardial infarction, volume overload, or arrhythmias. Chronic heart failure develops over months or years, and may be due to a slow loss of functional myocardium (e.g., as in hypertensive cardiomyopathy). In addition, a patient with chronic heart failure may achieve a well-compensated state, only to experience a superimposed acute exacerbation of heart failure, for example, caused by arrhythmias, volume overload, systemic infection, or noncompliance with medications. In the hospitalized patient with symptoms and signs of pulmonary edema, it is often difficult to distinguish an acute exacerbation of chronic heart failure (i.e., acute on top of chronic heart failure) from a new presentation of acute heart failure. This is especially difficult in patients in the perioperative period, in patients with renal failure, and in those receiving blood products or intravenous fluids. Thus it is important to understand the etiology and pathophysiology of the various forms of acute and chronic heart failure so that effective diagnostic and therapeutic decisions may be made.

When the patient thinks there is something amiss with his heart, he fears it may fail. It is therefore necessary that the doctor should understand what heart failure is and the signs by which it is made manifest. Sir John Mackenzie, 1916 (1)

INTRODUCTION Heart failure is a systemic disease caused by an impairment of efficient energy transfer in heart muscle. Clinically, heart failure exists when the heart fails in one or both of its primary functions: during diastole to receive blood into the ventricles under low pressure, during systole to propel blood into the systemic circulation under high pressure (Grossman W. Personal communication, 1995). Because the heart is both a consumer and provider of energy, a restriction in energy consumption (e.g., as it occurs in ischemic heart disease) results in impaired energy delivery to the rest of the body (2). Impaired energy delivery, in turn, causes adaptive and ultimately maladaptive responses of the organism as a whole. This chapter focuses on aspects of heart failure most commonly encountered in the practice of surgery. The first part of the chapter reviews the etiology, pathophysiology, clinical manifestations, therapy, and prognosis of acute and chronic heart failure. A discussion of chronic heart failure is important, because it is often a comorbid condition in surgical patients and may significantly alter the care and prognosis of the patient. The second part of the chapter discusses the principles of cardiopulmonary resuscitation (CPR), because cardiopulmonary arrest (also termed ‘‘sudden death’’) is the extreme form of acute heart failure. The discussion includes the pathophysiology and etiology of cardiopulmonary arrest and techniques of resuscitation.

Etiology and Natural History of Heart Failure Heart failure can occur as the result of three general derangements. First, mechanical or anatomic abnormalities may be present within the heart, in the coronary circulation, or in the pulmonary or systemic vascular bed and may result in inefficient pump function. Second, functional myocardial abnormalities may occur as a result of long-standing pressure or volume overload, primary myocardial disease, or myocarditis. Third, rhythm disturbances may bring the rhythmic function of the heart out of order and lead to inefficient pump action. In each situation, the development of heart failure may be acute or chronic. In addition, certain causes of cardiac dysfunction may lead to reversible disease, whereas others, especially those that are chronic and cause intrinsic myocardial changes, may lead to progressive, irreversible derangements. A list of the different causes of heart failure is shown in Table 1.

HEART FAILURE Features of Heart Failure

Mechanical or Anatomic Abnormalities Causing Heart Failure

Irrespective of the causes of heart failure, it is useful to distinguish its clinical features, which can occur either alone or in combination with one another. These features include acute and chronic, high-output and low-output, right ventricular and left ventricular, backward and forward, and systolic and diastolic heart failure (3). The rapidity with which symptoms of heart failure develop depends on the underlying pathophysiology and on the time allowed for compensatory mechanisms to develop. Acute heart failure occurs within minutes or hours and may be caused by loss of cardiac muscle from acute

A hallmark of chronic heart failure is an initial phase of adaptation to environmental changes, which is followed by deadaptation of the heart muscle (4). Adaptation is characterized by hypertrophy, which is brought about either by pressure overload or by volume overload of the heart. When presented with a patient whose main problem is heart failure, an important early step for the physician is to establish the cause of the compensatory hypertrophy. An increased pressure load on one or both of the ventricles may be due to systemic or pulmonary hypertension, aortic or pulmonary valve stenosis, pulmonary embolus, or coarctation of 663

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Table 1 Cardiac and Systemic Abnormalities Resulting in Heart Failure Structural myocardial abnormalities Cardiomyopathies (hypertrophic, dilated, restrictive) Inadequate myocardial mass (myocardial infarction, hypoplasia) Presbycardia (senile cardiomyopathy) Dysdynamic (ventricular aneurysm) Metabolic Endocrine (thyroid dysfunction, acromegaly, pheochromocytoma, hypoparathyroidism, diabetes mellitus) Thiamine deficiency (beriberi) Ischemia Acidosis Infections Viral, bacterial, rickettsial, parasitic, fungal Inflammatory Connective tissue disease Rheumatic fever Toxic Drugs [doxorubicin (Adriamycin), disopyramide, antituberculosis therapy, sulfonamides, heroin, cocaine, amphetamines, alcohol] Cobalt, iron, lead Radiation Infiltrative Amyloidosis Glycogen storage disease Mucopolysaccharidosis Leukemia Wegener’s granulomatosis Uremia Cor pulmonale Acute (pulmonary embolus) Chronic (emphysema) Arrhythmias

the aorta. An increased volume load may be caused by a valvular regurgitant lesion, an increased filling pressure, or a shunt between the systemic and pulmonary circulation such as an arteriovenous fistula, an atrial septal defect, or a patent ductus arteriosus. Obstruction to ventricular filling leads to a volume overload upstream from the stenotic lesion. Examples are mitral or tricuspid valve stenosis or rare congenital abnormalities such as cor triatriatum. Pericardial constriction and tamponade cause an extrinsic mechanical force that may lead to a restrictive pattern of heart failure. Other mechanical causes of heart failure include endocardial or myocardial restrictive disease, ventricular aneurysm, and ventricular asynergy.

Intrinsic Myocardial Abnormalities Causing Heart Failure Intrinsic myocardial abnormalities may cause heart failure either because of primary myocardial diseases, such as hypertrophic cardiomyopathy, or because of secondary influences such as viral infection. Although there are many primary and secondary causes of heart failure, the clinical presentation and treatment are very similar. Identification of the cause is crucial because treatment of the underlying disease may afford partial or complete reversal of the heart failure.

Rhythm and Conduction Disturbances Causing Heart Failure Rhythm and conduction system abnormalities may lead to symptoms and signs of heart failure. Extreme tachycardia such as seen in sinus tachycardia greater than 150 beats/min,

C=11%

D=30%

D=37% A=40%

A=40% C=15%

B=19%

B=7%

Men

Women

Figure 1 The prevalence of coronary artery disease and hypertension among 9405 male and female Framingham study subjects with congestive heart failure. A ¼ Coronary artery disease plus hypertension; B ¼ coronary artery disease alone; C ¼ neither hypertension nor coronary artery disease; D ¼ hypertension alone. Source: From Ref. 5.

ventricular tachycardia, atrial fibrillation or flutter, paroxysmal supraventricular tachycardia (atrioventricular nodal reentrant tachycardia), or multifocal atrial tachycardia may cause symptoms and signs of cardiac failure, often with a normal blood pressure. Electric asynchrony and conduction disturbances, as in atrial dysrhythmias and bundle branch blocks, cause a decrease in cardiac output and can lead to heart failure, especially in patients with underlying impaired ventricular function. The most common underlying abnormalities that result in heart failure include systemic hypertension and coronary artery disease. When the different causes of heart failure were evaluated in a long-term follow-up of 9405 subjects in the Framingham study, it was found that nearly 90% of patients with heart failure have a history of hypertension, coronary artery disease, or both (5). Other causes, including the different forms of cardiomyopathies, make up the remaining 10%. These findings are shown in Figure 1.

Pathophysiology of Heart Failure As stated earlier, heart failure is a systemic disease that begins and ends with the heart. Just as the causes of heart failure may be varied, there are different pathophysiologic mechanisms leading to the clinical entity of heart failure. Cellular biochemical mechanisms may be at work either as the precipitators of acute heart failure or as mediators of chronic heart failure. Pressure overload, volume overload, or both may be initiating factors. Heart failure may be due to loss of contractility from loss of heart muscle, abnormal muscle proteins, or impaired energy metabolism. Lastly, heart failure may also arise from extrinsic influences such as increased pericardial or pleural pressures.

Biochemical Derangements The heart consumes energy locked in the chemical bonds of fuel molecules through their controlled combustion and converts chemical energy into physical energy (predominantly mechanical pump work) (2). When this ability is impaired, it results in functional and metabolic abnormalities in the rest of the body, commonly referred to as ‘‘heart failure.’’ This may occur, for example, because of lack of supply of oxygen, as in coronary artery disease, or in inappropriate use of fuels, as in a cardiomyopathy. Ultimately, the increased energy demands and impaired energy production

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lead to a state of energy starvation, with subsequent further cardiac deterioration (decreased capillary density, decreased number of mitochondria, and increased connective tissue). Other organs deteriorate because the heart no longer effectively provides energy in the form of substrates and oxygen to the rest of the body.

Left ventricular function is dependent on the filling pressure of the ventricle (preload) and contractility (Fig. 2), as well as the resistance of blood flow out of the ventricle (afterload) (Fig. 3). The impedance is the sum of resistance in small arteries and arterioles (resistance vessels) and compliance in larger arteries (conductance vessels). The normal left ventricle is able to adjust to changes in resistance through an increase in contractility. This increase is caused by an increase in ventricular filling pressure (Frank–Starling mechanism). After the ventricle has faced increased loading conditions for some time, the Frank–Starling curve becomes depressed, such that a higher loading condition no longer elicits a comparable increase in contractility. Thus the now dysfunctional ventricle does not respond as well to changes in loading conditions or increases in resistance (6).

Abnormal Cardiac Contractility The mechanism by which cardiac contractility becomes impaired is incompletely understood and may vary significantly depending on the cause. Loss of cardiac muscle may occur because of loss of myofibrillar protein, as seen in acute myocardial infarction. In chronic heart failure, muscular contraction may be compromised because of decreased activity of myofibrillar actinomyosin, or myosin adenosinetriphosphatase (ATPase) proteins (7,8). Additional abnormalities may occur because of decreased release or reuptake of calcium by the sarcoplasmic reticulum (9), decreased sodium/potassium exchange, or decreased cyclic adenosine monophosphate caused by decreased b-receptor activity

Normal

Stroke Volume

Mechanical Derangements

Mild Heart Failure Moderate Heart Failure Severe Heart Failure

Afterload

Figure 3 The relationship between ventricular function and afterload in the normal heart and in heart failure. Small increases in afterload may lead to a significant decline in ventricular function. Conversely, decreasing afterload improves the systolic performance of the failing heart.

(10) or decreased coupling with adenylate cyclase across the sarcolemma (6). We have observed that heart failure can also be caused by impaired substrate flux through metabolic pathways. An example is the acute decrease in contractile function of the working rat heart perfused with ketone bodies as the only substrate, which is completely reversible on addition of glucose. This substrate-induced contractile dysfunction occurs because of inhibition of the Krebs citric acid cycle at the level of the enzyme a-ketoglutarate dehydrogenase and is reversed through replenishment of citric acid cycle intermediates by pyruvate carboxylation (2).

Extrinsic Mechanisms

Stroke Volume

Normal

decreased preload and afterload

decreased afterload increased inotropy

Failing decreased preload

In addition to abnormal loading conditions, other extracardiac factors influence cardiac performance. For example, pericardial disease may produce an extrinsic mechanical stress that may impair myocardial relaxation, leading to a restrictive pattern of heart failure. In a similar way, increased pleural pressures may affect contractility, as seen in tension pneumothorax or mechanically ventilated patients with positive end-expiratory pressure. All these factors may decrease cardiac output, leading to high filling pressures and poor forward flow, thus causing the clinical syndrome of heart failure.

Compensatory Mechanisms

Preload Figure 2 Frank–Starling curves in the normal heart and in heart failure. An improvement in inotropy or reduction in afterload improves the ventricular performance. Reducing the preload alone does not improve performance, because there is no physiologically relevant ‘‘descending limb’’ of the curve. Combining preload reduction with either a reduction in afterload or a direct inotropic stimulus provides better systolic function and a reduction in ventricular filling pressure.

In both the heart and the body, the responses to altered pathophysiology are initially adaptive and later maladaptive. As we discuss the adaptive compensatory mechanisms in both systems, we recognize that the maladaptive responses in the body lead to the clinical presentation of heart failure. Myocardial Compensatory Mechanisms It is well recognized that in heart failure there are alterations of myocardial structure, changes in the contractile function of myocytes, and changes in blood flow to the heart. The myocardial response to volume as well as to pressure overload, results in an increase of contractile units (hypertrophy) and

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thus a change in myocardial composition. This change leads to accelerated cell death with increased loading of the remaining normal cells (11). The mediators of ventricular remodeling and hypertrophy are local (autocrine) and systemic (neuroendocrine). The autocrine mediators are angiotensin, endothelin, endothelinderived relaxing factor, prostaglandin I2, and prostaglandin E2. The systemic mediators include the renin–angiotensin system (8), sympathetic stimulation (12), vasopressin, and atrial natriuretic peptide (ANP). Some of these mediators are vasoconstrictors, others are dilators, and it is the imbalance between these mediators that leads to decompensation and clinical manifestations in heart failure. Overload on the ventricles causes changes in gene expression, altered synthesis of myocardial proteins, and abnormal membrane assembly, resulting in preferential synthesis of fetal isoforms of several proteins, which have a shortened life span. In addition, there is evidence of overexpression of cellular proto-oncogenes c-fos, c-myc, and c-jun in response to myocardial overload, leading to altered protein synthesis and thus an abnormal myocardial structure (11). Pressure or volume overload on the ventricles results in an increase in the length of the sarcomeres and an increase in the total muscle mass. This mechanism allows maintenance of an elevated ventricular systolic pressure (in the case of volume overload) without depressed contractility. As heart failure advances, the alterations in contractility make this compensatory mechanism less and less efficient, ultimately resulting in depressed ventricular function (7). Following the sustained increase in stroke volume, there is cardiac dilation and an increased rate of relaxation. The combination of the above leads to an adequate cardiac performance until a phase of ‘‘exhaustion’’ is reached, which is characterized by lysis of myofibrils, interstitial fibrosis, a decreased capillary density in relation to myocytes, impaired coronary flow reserve, and ultimately deterioration of cardiac performance. Ventricular relaxation during diastole is also altered in the failing, hypertrophied heart (13). In this ‘‘diastolic dysfunction,’’ the delay in relaxation with pressure overload interferes with diastolic filling and leads to elevated left ventricular filling pressures (Fig. 4). Sometimes this mechanism

Normal

Systemic Compensatory Mechanisms Depressed systolic function of the heart leads to an inadequate effective arterial volume, which in turn triggers a series of humoral responses. Adrenergic stimulation, renin release, aldosterone secretion, and excessive release of vasopressin act to ensure adequate perfusion to vital organs. The adrenergic system in heart failure is characterized by increased levels of circulating norepinephrine (12). These levels correlate inversely with the severity of ventricular dysfunction and with prognosis. For example, in acute heart failure following myocardial infarction, the compensatory increase in norepinephrine in the early stages later becomes deleterious because of increased afterload and arrhythmogenicity. In chronic heart failure, the prolonged increase of circulating norepinephrine leads to a downregulation of cardiac b-adrenergic receptors, with a decrease in their density and subsequent reduction in contractility. Reversal of this downregulation may be achieved with b1-antagonists, which have been shown in some studies to be beneficial in low doses in the treatment of heart failure, possibly by restoring the responsiveness to adrenergic inotropic stimulation (14). Aldosterone secretion is stimulated by decreased renal blood flow and increased sympathetic activity (12). The release of renin leads to increased production of angiotensin II, which causes increased afterload and stimulates myocardial hypertrophy. The increased production of aldosterone increases retention of sodium and water with a further increase in preload. This chain of events leads to the so-called ‘‘vicious cycle of heart failure’’ (Fig. 5). Reversal of these effects by angiotensin-converting enzyme (ACE) inhibitors has been shown to decrease mortality in heart failure of different etiologies (15–17). Other systemic changes that occur in heart failure include changes in the levels of vasopressin, ANP, and peripheral oxygen delivery. The circulating levels of vasopressin are elevated in heart failure because of an abnormal response to serum osmolality. This causes systemic vasoconstriction and perhaps contributes to hyponatremia in the later stages of the disease. ANP is a counter-regulatory

Diastolic Dysfunction

Left Ventricular Pressure

Systolic Dysfunction

alone can be severe enough to cause clinically advanced heart failure.

Left Ventricular Volume

Figure 4 Pressure–volume loops comparing normal left ventricular function with impaired systolic and diastolic function. In systolic dysfunction, contractility is depressed and there is diminished capacity to eject blood into a high-pressure aorta. In diastolic dysfunction, there is diminished capacity to fill at low diastolic pressure. The left ventricular ejection fraction is low in systolic dysfunction and normal in diastolic dysfunction.

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Decreased Cardiac Function

Increased Intravascular Volume, Increased Afterload, Stimulation of Hypertrophy

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of the disease, but they do not necessarily signify fundamentally different disease states. Late in the course of the disease, the differences between these forms often become less distinct (4).

Right vs. Left Ventricular Failure Decreased Renal Perfusion

Increased Renin and Aldosterone

Figure 5 This ‘‘vicious cycle of heart failure’’ begins with an impaired cardiac function, leading to a low cardiac output and thus decreased renal perfusion. The subsequent release of renin and aldosterone causes an increased intravascular volume, increased afterload, and stimulation of left ventricular hypertrophy, all of which exacerbate cardiac dysfunction.

hormone opposing vasoconstriction and sodium and water retention, thus protecting the heart from volume overload. In acute heart failure, ANP inhibits the synthesis of renin, opposes the effects of angiotensin II, and stimulates renal excretion of sodium and water, thus, decreasing preload. Finally, there is a change in peripheral oxygen delivery in heart failure caused by the redistribution of cardiac output toward vital organs, an altered oxyhemoglobin dissociation curve, and an increased oxygen extraction by tissues. The compensatory mechanisms in heart failure are a ‘‘double-edged sword,’’ because they support myocardial performance in the early stages of heart failure but later cause undesirable effects leading to accelerated deterioration of the failing heart. Thus the goal in the treatment of heart failure is to modify these compensatory mechanisms using pharmacologic agents to break the cycle of maladaptive changes.

Clinical Manifestations of Heart Failure: A Series of Opposing Adjectives Heart failure is characterized by a number of factors: sodium and water retention, dyspnea or fatigue (limitation of exercise tolerance), neurohormonal activation, decreased peripheral blood flow with subsequent lowering of endorgan metabolism, impaired systolic function, ventricular arrhythmias, and ultimately decreased survival (6). In describing the clinical features of heart failure it is useful to consider a series of opposing adjectives (Table 2). These descriptions are useful particularly early in the course Table 2 Clinical Adjectives Used in Describing Heart Failure Acute vs. chronic Right vs. left sided High vs. low output Forward vs. backward Systolic vs. diastolic Primary vs. secondary Latent vs. overt Reversible vs. irreversible Compensated vs. refractory (intractable) Stable vs. unstable

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The distinction between right and left ventricular failure was first proposed by Harrison et al. (18) in 1932. Pure right ventricular failure is most commonly caused by cor pulmonale from chronic lung disease and increased pulmonary vascular resistance. The symptoms include edema, congestive hepatomegaly, systemic venous distention, weakness, fatigue, and central nervous system symptoms. The signs include an elevated central venous pressure, hepatojugular reflux, ascites, pleural/pericardial effusion, bowel edema (causing anorexia, nausea, vomiting, and malabsorption), and cachexia. Left heart failure is characterized by poor cardiac output, an increased left ventricular filling pressure, and pulmonary congestion. The symptoms include dyspnea, orthopnea, paroxysmal nocturnal dyspnea, cough, nocturia, and hemoptysis. The signs are tachycardia, auscultatory gallop, inspiratory rales, expiratory wheezes, and pulsus alternans. Many patients with advanced left ventricular failure develop right ventricular failure, and a combination of both left and right ventricular failure is a common clinical presentation. This is especially true for patients with mitral stenosis and patients with a dilated cardiomyopathy.

High-Output vs. Low-Output Heart Failure The description, high output/low output, relates the cause to the typical clinical features. High-output heart failure is characterized by decreased peripheral resistance often in the absence of sodium and water retention. Etiologies known to cause high-output heart failure include hyperthyroidism, anemia, arteriovenous fistula, beriberi, Paget’s disease of the bone, Albright’s syndrome, multiple myeloma, hypernephroma with bone metastases, cirrhosis, and acute glomerulonephritis. Low-output heart failure is characterized by retention of sodium and water and often an elevated peripheral vascular resistance and is caused by anything that decreases the cardiac output, including left ventricular dysfunction, and restrictive influences on the heart.

Forward vs. Backward Heart Failure The concepts of forward and backward heart failure date back to 1913 and 1832, respectively (19,20); although they are old concepts, they retain clinical utility today. Forward heart failure involves inadequate discharge of blood into the arterial system, which leads to decreased renal perfusion, activating the renin–aldosterone axis and causing sodium and water retention, mental obtundation, and hypotension. In backward heart failure, the ventricle fails to discharge its contents normally, and the end-diastolic volume and the pressure in the atria and ventricles are elevated, leading to pulmonary and venous congestion and sodium and water retention. The manifestations are hepatomegaly, ascites, and peripheral edema.

Systolic vs. Diastolic Dysfunction Systolic dysfunction leads to increased filling pressures and pulmonary congestion, decreased cardiac output, redistribution of flow toward vital organs, decreased stroke volume, and increased left ventricular end-diastolic volume with dilation of the ventricle (21). There is a growing recognition of diastolic dysfunction (heart failure with normal heart size

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and ejection fraction) as a cause for impaired pump function of the heart (22). As seen in Figure 3, this diastolic dysfunction or ‘‘input failure’’ is characterized by the inability of the ventricle to relax and fill normally, leading to an increased filling pressure, increased ventricular end-diastolic pressure, and a decreased stroke volume because of decreased myofibrillar stretch and impaired diastolic filling. It is important to recognize that traditional therapy aimed at stimulation of systolic ejection may be ineffective or even deleterious in pure diastolic dysfunction (13,22).

Other Adjectives Used to Describe Heart Failure There are other adjectives of value in describing heart failure, which may relate to cause, treatment, and prognosis. In ‘‘reversible heart failure,’’ the manifestations disappear if the underlying cause is removed early in the course of the disease. Examples include ischemia, valvular lesions, constrictive pericarditis, infectious endocarditis, hypertension, and most of the causes of high-output heart failure. ‘‘Irreversible heart failure’’ occurs when the manifestations do not disappear after precipitating factors are eliminated; in fact, they are often progressive. The classic example is myocardial infarction with extensive myocardial necrosis. Other factors leading to irreversibility include isolated myocardial cell loss and interstitial fibrosis with plastic transformation of the adjacent myocardium. The commonly used term ‘‘congestive heart failure’’ refers to abnormal circulatory congestion caused not only by impaired heart function but also by peripheral circulatory and sympathetic renal compensatory mechanisms. A ‘‘congested state’’ is an expanded intravascular volume with preserved ventricular function, for example, caused by vigorous volume infusions, anemia, beriberi, etc. It is often difficult to distinguish congestive heart failure from a congested state, especially in the postoperative patient and in patients with renal failure. It often becomes necessary to use invasive monitoring with determination of cardiac output and pulmonary capillary wedge pressure to make the distinction. If the precipitating factors persist, the congested state may become congestive heart failure (ventricular function becomes impaired). ‘‘Primary heart failure’’ refers to diseases arising from the myocardium, such as congenital heart diseases, neuromuscular diseases, myocarditis, and presbycardia (senile heart). ‘‘Secondary heart failure’’ occurs because of other factors such as ischemic disease, systemic disorders, and metabolic and inflammatory diseases. ‘‘Unstable heart failure’’ means a severe circulatory derangement, which is life threatening if not aggressively treated, and includes acute pulmonary edema and cardiogenic shock. ‘‘Transient heart failure’’ (flash pulmonary edema) is often seen in patients with diastolic dysfunction resulting from hypertension and following cardiopulmonary bypass.

Special Considerations Often a patient with chronic, well-compensated heart failure is hospitalized for a surgical procedure or other reasons and experiences an exacerbation of heart failure, leading to worsening of symptoms or signs of heart failure. There are many factors that may underlie the exacerbation, and most often it can be corrected by simply removing the offending cause (23); however, sometimes the cause leads to a direct worsening of ventricular function, which is irreversible and leads to unstable heart failure or a new level of compensation at a worsened functional class (Table 3).

Table 3 Events Precipitating or Exacerbating Heart Failure in Patients with Compensated Disease Changes in environment or diet Noncompliance with medical therapy Arrhythmias Myocardial ischemia Anemia Drugs: nonsteroidal anti-inflammatory drugs, corticosteroids, calcium channel blockers, b-blockers, etc. Thyroid dysfunction Metabolic deficiencies Infections Worsening renal function Pulmonary embolism Pregnancy Emotional factors Myocarditis Endocarditis Systemic hypertension Myocardial infarction

The New York Heart Association classification of heart failure (Table 4) has gained broad acceptance as the standard clinicians use to communicate with one another regarding the severity of heart failure. It is based on subjective and objective findings, with the objective assessment being based not only on physical examination but also on noninvasive and invasive tests to evaluate cardiac status. It is accepted that the severity of symptoms may not necessarily be matched by equivalent degrees of impaired structure and function of the heart (24).

Therapy Broad Objective: Correct the Deranged Physiology The goal in the treatment of heart failure is to correct the deranged physiology while establishing and treating the underlying cause. Despite this, prevention of heart failure exerts far more salutary effect on public health than treatment. Prevention of the most common causes involves

Table 4 The New York Heart Association Classification of Heart Failure Functional capacity Class I: Patients with cardiac disease, but without resulting limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain Class II: Patients with cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain Class III: Patients with marked limitation of physical activity. They are comfortable at rest. Less-than-ordinary activity causes fatigue, palpitation, dyspnea, or anginal pain Class IV: Patients with cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of heart failure or of the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased Objective assessmenta A. No objective evidence of cardiovascular disease B. Objective evidence of minimal cardiovascular disease C. Objective evidence of moderately severe cardiovascular disease D. Objective evidence of severe cardiovascular disease a

For example, physical examination, electrocardiogram, chest X-ray examination, cardiac catheterization, echocardiography, radiologic imaging, and stress testing.

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early and vigorous treatment of hypertension, hyperlipidemia, diabetes, and the promotion of lifestyle changes to lower the risk of coronary artery disease. In addition, the early use of thrombolytic therapy in acute myocardial infarction decreases the risk of development of heart failure. Finally, the identification and management of the specific causes and precipitating factors in heart failure are important (Tables 1 and 3). Once the diagnosis of heart failure is made, the therapeutic challenge is to alleviate symptoms and prolong life by correcting the abnormal physiology. The abnormal cardiac physiology involves both metabolic and mechanical derangements (25). The correction of mechanical derangements involves the increase in supply of energy substrates and blood flow to meet the increased energy demands. For example, coronary revascularization may improve ventricular performance in patients with coronary artery disease and depressed ventricular function. The treatment of the abnormal mechanical properties of the heart may include the reversal of maladaptive hypertrophy with ACE inhibitors or an increase in contractility with digoxin. The correction of systemic derangements involves lowering preload with salt restriction, diuretics, and venous vasodilators and lowering afterload with arterial vasodilators. The control of heart rate and rhythm is also important, and this can be achieved with b-blockers, antiarrhythmics, and pacemakers if needed. Lastly, in suitable patients with refractory heart failure, the treatment of choice may be cardiac transplantation; however, this option is limited by a supply of donor organs, which is only a fraction of the demand.

Treatment of Acute Heart Failure General Principles The therapy of acute heart failure and cardiogenic shock involves treatment modalities that are both similar and dissimilar to those used in chronic heart failure. The most prominent features include a clinical assessment of the intravascular volume status, invasive hemodynamic monitoring, inotropic pharmacologic therapy, and mechanical assist devices. The goal in treating hemodynamically unstable patients is to optimize oxygen delivery to vital organs by increasing cardiac output and decreasing pulmonary venous congestion. In the critical care setting, this therapy is assisted by a peripheral arterial catheter (for assessment of arterial pressure) and a balloon-tipped, flow-directed pulmonary artery catheter (for assessment of left ventricular filling pressure and cardiac output) (26,27). Before considering invasive or complicated techniques to treat acute heart failure, it is important to remember that there are frequently simple derangements contributing to pump failure that may be easily corrected. For example, acid–base imbalances, electrolyte abnormalities, and hypoxia may directly contribute to myocardial depression and should be aggressively corrected. In addition, arrhythmias, such as sinus bradycardia or atrioventricular block or dissociation, may contribute to a low cardiac output. Finally, mechanical complications of acute myocardial infarction, such as mitral regurgitation caused by papillary muscle infarction, ventricular septal rupture, and ventricular free wall rupture may be the culprit in acute heart failure and require immediate surgical intervention. Specific Measures In the patient with acute heart failure, the inadequate cardiac output may be increased by the following means. First,

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by increasing the end-diastolic volume or preload through volume expansion, one augments cardiac output by utilizing the Frank–Starling mechanism. Inotropic agents such as dopamine, dobutamine, norepinephrine, and digitalis increase cardiac output by directly increasing contractility. Lowering afterload with agents such as nitroprusside and ACE inhibitors improves cardiac output by decreasing resistance to ventricular ejection. Decreasing the degree of ischemia in patients with coronary artery disease may influence cardiac output by improving ventricular wall motion. When the stroke volume is fixed, cardiac output can be augmented by increasing the heart rate with a pacemaker or a positive chronotropic agent. When these measures are undertaken, it is important to weigh the possible negative effects on the myocardium, caused by an increase in oxygen demand with the need to improve the cardiac output (28). An increase in pulmonary venous pressure is corrected by decreasing total circulating blood or fluid volume with diuretics or phlebotomy or by facilitating peripheral venous pooling with vasodilators or rotating tourniquets. In addition to decreasing the intravascular volume, diuretics also facilitate venous pooling (29). Mechanical Assist Devices In the setting of acute myocardial infarction, mechanical circulatory assistance devices such as the ‘‘intra-aortic balloon pump’’ (IABP) increase arterial pressure during diastole (diastolic augmentation) to maintain or enhance coronary arterial perfusion pressure and lower preejection and ejection pressures (systolic unloading) to reduce myocardial work and oxygen demand (28,30). In addition, the IABP improves the hemodynamic status and has been shown to reverse the shock syndrome. Despite these acute hemodynamic effects, the ultimate prognosis in patients using the IABP is not significantly improved. Indications for circulatory assistance using the IABP are cardiogenic shock secondary to myocardial infarction or myocardial depression following cardiac surgery, acute heart failure refractory to medical therapy, and recurrent life-threatening ventricular arrhythmias unresponsive to medication and/or pacing. In addition to these indications, the IABP is commonly used in the stabilization of patients who are hemodynamically compromised immediately after myocardial infarction while waiting for catheterization or cardiac surgery. Placement of an IABP is contraindicated in patients with irreversible brain damage, chronic end-stage heart disease, severe associated disease, or an incompetent aortic valve (26). The ‘‘left ventricular assist device’’ (LVAD) is an extracorporeal or intracorporeal pump that provides the power to shunt oxygenated blood from the left ventricle to the ascending aorta, while reducing the workload of the ventricle. It is used most commonly in patients with end-stage heart failure as a bridge to cardiac transplantation and in patients with stunned myocardium, when cardiac function is slow to recover. Further discussion of the LVAD and IABP can be found in the chapter on Mechanical Support of the Failing Heart. Metabolic Support The concept of providing metabolic support for the ischemic myocardium with glucose, insulin, and potassium has stimulated new interest in the treatment of acute heart failure refractory to conventional therapy (31). The administration of a solution of high doses of glucose, insulin, and potassium (the latter to prevent hypokalemia) has demonstrated utility in improving ventricular function in patients with

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acute heart failure, especially after elective hypothermic ischemic arrest (31,32). Although it has been thought that the accumulation of glycolytic products worsens the functional effects of ischemia, the provision of glucose and insulin improves contractile function in myocardial infarction in the acutely ischemic, reperfused myocardium (33). It is thought that the glucose, insulin, and potassium solution preserves cell integrity (e.g., through preserving glycogen stores, activating ATP-sensitive potassium channels, and maintaining sodium and potassium ATPase activity).

Treatment of Chronic Heart Failure The basic principles in the treatment of chronic heart failure are first to eliminate precipitating factors, second to determine if systolic dysfunction or diastolic dysfunction prevails and treat accordingly, and finally to identify and correct any other underlying cause. Patients may have purely systolic or diastolic dysfunction, but frequently they have some combination of the two (4,34). As stated earlier, the ultimate goal in treatment of chronic heart failure is the reduction of morbidity and mortality. Approach to Asymptomatic Heart Failure Irrespective of its cause, systolic dysfunction has an asymptomatic, a symptomatic, and a refractory stage. In the asymptomatic patient, the treatment consists of modification of risk factors for coronary artery disease, such as smoking, hypertension, hyperlipidemia, and obesity. Whereas strenuous physical activity may overtax the circulation of the patient with compensated heart failure, regular aerobic exercise can enhance the efficiency of the cardiovascular system, with a resultant increase in exercise tolerance (35). ACE inhibitors inhibit the maladaptive myocardial hypertrophy and may prevent progression to the symptomatic stage; thus, they are very important in the treatment of the asymptomatic patient (36). There is mounting evidence that ACE inhibitors influence intracellular signaling cascades, which have effects on growth and thus may inhibit growth of overloaded myocardial cells (36,37). Approach to Symptomatic Heart Failure: Importance of Triple Therapy In the symptomatic patient, the goals of therapy are to relieve symptoms and to prolong life. Specifically, the hallmarks of treatment involve lowering the workload of the heart, increasing contractility, controlling sodium and water retention, and controlling associated arrhythmias. The workload may be lowered by physical and emotional rest, treatment of obesity, and the use of preload- and afterload-reducing agents. ACE inhibitors have been shown to be of the greatest benefit; however, the combination of nitrates and hydralazine has also shown benefit (15,38,39). In addition, ACE inhibitors have been shown to affect favorably long-term outcome in patients who have heart failure as a result of myocardial infarction by decreasing adverse left ventricular remodeling (16). Digoxin continues to be the only positive inotropic agent available for oral administration. Long-term administration of digoxin has been shown to reduce morbidity and mortality when combined with afterload reduction and diuretics (15). Sodium and water retention can be modulated by the use of a low-sodium diet and diuretics. Precautions must be taken when using diuretics to avoid electrolyte imbalances. The combination of afterload reduction, digitalis, and diuretics forms the cornerstone of the management of chronic symptomatic heart failure. Finally, it is important to preserve or restore normal sinus rhythm (40).

Special Considerations There are a number of special considerations in the treatment of heart failure, some of which have already been mentioned but are summarized once more here in context. First, the identification of diastolic dysfunction and pure right ventricular failure is important, because the treatment of these unique physiologic derangements is different from that of systolic left ventricular dysfunction (41). Second, in severe heart failure, the prevention of and treatment of thrombotic complications and arrhythmias is important. Lastly, the pharmacokinetics of many drugs may be altered in heart failure, even in the absence of renal impairment. Diastolic Dysfunction In contrast to the fundamental defect in systolic dysfunction, patients with isolated diastolic dysfunction have normal or often enhanced contractile function of the left ventricle (as measured by the ejection fraction). However, these patients also have dyspnea and fatigue and develop pulmonary edema in the same way as patients with systolic dysfunction. The key problem in this syndrome is that increased ventricular stiffness (or reduced compliance) leads to limitations on the use of preload reserve because of rapid increases in cardiac filling pressures at normal or slightly increased cardiac volume (13). Because the left ventricle contracts normally, there is no need to attempt to conserve or improve left ventricular function with inotropic agents. Similarly, there is no benefit from preload reduction, which may even worsen the situation. Treatment is instead directed at improving relaxation characteristics, mitigating the effects of an abnormal compliance, and prolonging diastole to allow for improved ventricular filling. Calcium channel–blocking agents and b-blocking agents have offered the best utility in this effort. ACE inhibitors cause regression of left ventricular hypertrophy and may have direct myocardial effects that improve diastolic function. Lowering of blood pressure into the normal range is of paramount importance and should be done with one of these three agents. Arrhythmias As ventricular performance deteriorates in chronic heart failure and the cardiac muscle is remodeling in response to overload, electrophysiologic abnormalities develop. The majority of patients with severe chronic heart failure have ventricular arrhythmias often manifested by ventricular tachycardia and ventricular fibrillation. It would be expected that patients with the most frequent or serious arrhythmias would be at the greatest risk for sudden death, but this does not seem to be the case. Complex ventricular arrhythmias are more a reflection of the severity of the patient’s hemodynamic and functional status rather than a specific pathophysiologic event. Nonsustained ventricular tachycardia occurs in 40% to 60% of patients with the New York Heart Association class III and IV heart failure, and sudden death may occur in 40% of patients in class III and IV (Table 4). Antiarrhythmic therapy may suppress ventricular arrhythmias but does not prolong life in these patients (6). Furthermore, antiarrhythmic drugs appear to be most proarrhythmic in these myopathic ventricles. Some of these drugs were actually shown to increase mortality in certain circumstances (such as class IC agents following myocardial infarction) (42,43). Thus the jury is still out on the utility of antiarrhythmic therapy in patients with advanced heart failure. Anticoagulation Dilated atria and/or ventricular chambers can be the site of thrombi; however, because of its inherent morbidity, routine

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anticoagulation for prevention of thromboembolic events is not uniformly recommended. Patients with echocardiographic evidence for mural thrombi, presenting with a history of systemic or pulmonary embolism, or patients with a history of atrial fibrillation should be anticoagulated. Otherwise, the risks of complications from chronic anticoagulation, including intracranial or gastrointestinal hemorrhage, do not warrant the expected benefits (44). Altered Pharmacokinetics In heart failure, decreased gastric emptying delays absorption and decreases the peak plasma concentration of digoxin, furosemide, and bumetanide. Decreased first-pass metabolism in the liver increases the concentration of nitrates, morphine, and hydralazine. Decreased biotransformation to active forms causes diminished activity of ACE inhibitors. Thus the use of various medications necessitates frequent monitoring of blood levels, electrolytes, and clinical effects of the medication. Right Ventricular Infarction Right ventricular infarction, which occurs in less than 7% of patients with acute myocardial infarction, may lead to right ventricular failure. The hemodynamic picture in these patients is characterized by markedly elevated right atrial and right ventricular end-diastolic pressures with a normal or reduced right ventricular systolic pressure, normal or reduced pulmonary artery systolic pressure, and a normal or slightly elevated pulmonary capillary wedge pressure. Because of a markedly reduced right ventricular output, the left ventricle filling pressure becomes inadequate, and left ventricular output therefore decreases. Volume expansion to maintain right ventricular filling pressure and output has been the mainstay of treatment in the acute phase. Vasodilators may improve right ventricular output and, therefore, left ventricular filling pressure and output in the long term (26,27,43).

Therapy of Refractory Heart Failure: Cardiac Transplantation Refractory heart failure does not respond to conventional therapy, and thus more aggressive therapies must be used, usually in an inpatient setting. Inotropic support with parenteral inotropes such as dobutamine, dopamine, and the phosphodiesterase inhibitors amrinone and milrinone has been used widely to alleviate the symptoms and signs of heart failure temporarily. Removal of excess fluid by paracentesis, thoracentesis, or dialysis may be necessary. Mechanically assisted circulation with the IABP or the left or right ventricular assist device may become the last resort, but usually only as a bridge to transplantation. Cardiac transplantation has a greater than 60% five-year survival; however, the greatest hurdle is the timely procurement of donor organs, which limits this option to relatively few patients (45).

Future of Treatment Strategies for Chronic Heart Failure The future of treatment of chronic heart failure will involve the development of new high-technology devices to augment or supplant the pumping function of the heart and also the elucidation of the genetic basis of heart failure and attempts to alter this genetic destiny. In addition, as more knowledge about the complex neurohormonal interactions involved in heart failure becomes available, new therapies such as the use of low-dose b-adrenergic blocking

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agents may come into use (20,46,47). Both modalities merit a brief mention. Total Artificial Heart A new emphasis on the concept of the total artificial heart (TAH) has emerged, and prototypes are being developed at institutions in the United States and Japan. The new generation of TAH will be totally implantable with no transcutaneous implements. Power will be supplied by transmission of energy through intact skin to a subcutaneous receiver from battery packs worn by the patient. The development teams believe that new technology in microminiaturization and computer-aided design will enable the new TAH to overcome the pitfalls of the existing Jarvic TAH, such as thrombosis and infection. It is hoped that this technology will supplant cardiac transplantation and become a therapeutic option for both chronic and acute heart failure (48). Effective devices have already been tested in humans, with limited short-term success (see chapter on Mechanical Support of the Failing Heart). Gene Therapy Gene therapy is aimed at correction of abnormal cardiac gene expression, and it is believed that the gene response to overload may lead to cell death. The target gene(s) has (have) not been identified; however, the genes responsible for some specific cardiac disease states have been found, and research is under way to develop treatments based on them (49,50). For example, it has been shown that a mutation on a specific site on chromosome 14 encoding the myosin heavy chain is associated with familial hypertrophic cardiomyopathy, and thus, theoretically, the reversal of this mutation could prevent the development of this disease (51).

RESUSCITATION Cardiopulmonary arrest is the extreme form of acute heart failure. During cardiopulmonary arrest there is the cessation of systemic blood circulation and effective ventilation. Basic life support, or CPR, provides artificial ventilation and circulation until advanced cardiac life support (ACLS) can be initiated. Modern CPR has revolutionized the treatment of sudden death and began with the observation of Kouwenhoven et al. (52), in 1960, that rhythmic depression of the sternum in animals produced pulsations in arterial pressure and permitted successful closed-chest electric defibrillation after prolonged ventricular fibrillation. Since the introduction of this technique, many modifications have been proposed, but none have consistently been proven superior to the basic idea that to be successful the pump function of the heart must be maintained and/or restored. Because of the poor long-term survival rates of patients receiving CPR, it has been difficult to quantitate the survival benefit of traditional CPR or any newer techniques (53). The clinical scenarios in patients most likely to be successfully resuscitated using traditional CPR are outlined in Table 5.

Pathophysiology of Cardiopulmonary Resuscitation Blood flow during CPR is maintained by a generalized increase in intrathoracic pressure, causing blood to move from the vascular structures of the thorax to the peripheral circulation. When the chest compression is released, blood flows back from the peripheral structures to the thorax. The flow is maintained in the antegrade direction by the valves in the heart and the veins and can reach 1.7 L/min (54). Some investigators have proposed that the increase in

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Table 5 Clinical Scenarios of Patients Most Likely to Be Successfully Resuscitated with Traditional Cardiopulmonary Resuscitation Witnessed sudden arrest caused by ventricular fibrillation outside the hospital, when electric countershock can be performed within 7–8 min Hospitalized patients with primary ventricular fibrillation and ischemic heart disease Cardiac arrest in the absence of life-threatening coexisting conditions Primary respiratory arrest Arrest caused by hypothermia, drug overdose, or airway obstruction

pleural pressures rather than compression of the heart results in blood flow to the periphery (55). It has been shown that mechanical ventilation alone increases intrathoracic pressures. Translocation of blood from the pulmonary bed into the systemic bed with forward flow can be achieved with the left heart chamber as a conduit (56). Forceful, rhythmic cough can also generate systolic pressures equivalent to normal cardiac activity and sustain cardiac output during asystole, maintaining cerebral blood flow and peripheral flow (57). Paradoxically, the compression of the heart and the increase in intrathoracic pressure with CPR can lead to pulmonary edema in one-third to one-half of patients, representing a major cause of hypoxemia during resuscitation. Some investigators have found that pulmonary artery mean pressure and pulmonary capillary wedge pressures increase within 5 to 10 minutes of CPR and return to baseline within five minutes of effective spontaneous circulation (58). The experimental strategies to increase the effectiveness of CPR are aimed at making pleural pressures more positive during cardiac emptying and more negative during filling. The former can be achieved by inflation of the lungs during chest compressions and the use of a pneumatic vest. The latter is accomplished with chest cuirass, stimulation of the inspiratory muscles, negative airway pressure during the filling phase, and increasing the abdominal pressure during filling (59).

Cerebral Blood Flow During Cardiopulmonary Resuscitation Irreversible brain damage occurs within four to six minutes of anoxia. Although isolated neurons show complete recovery after 20 to 60 minutes of anoxia, the postischemic damage is due to hypoperfusion secondary to vasospasm and the release of oxygen-derived free radicals from injured tissues and neuronal calcium overload. Experimental techniques used to preserve cerebral function during CPR include calcium channel blockers, free radical–scavenging agents, transient postresuscitation hypertension, retrograde arterial perfusion with low-viscosity solutions, anticoagulation, hypothermia, barbiturate coma, and hyperosmotic solutions (60). None of these have been shown to be consistently effective in clinical trials. Excessive volume loading is actually detrimental to cerebral perfusion because of cerebral edema or shunting of blood through extracerebral vessels (61).

Coronary Blood Flow During Cardiopulmonary Resuscitation The basal myocardial oxygen consumption is 30% to 40% of normal during ventricular fibrillation; thus if coronary perfusion cannot meet this demand, the likelihood of successful defibrillation is low. Coronary blood flow decreases from

30% to 5% of normal within the first 20 minutes of CPR. This decrease in flow may be due to epinephrine, direct heart compression, abdominal compression, or negative pleural pressure during the filling phase. Other methods employed to increase the effectiveness of CPR include vigorous volume infusion and the use of glucose-containing fluids. These methods are controversial because they may increase cerebral damage during ischemia or after reperfusion or may cause pulmonary edema (56). High doses of epinephrine may increase aortic pressure and coronary flow, and the a-receptor stimulation may restore a spontaneous heartbeat; however, the b-receptor activity increases oxygen consumption and may be detrimental (62,63). Calcium channel blockers theoretically would decrease intracellular damage and postischemic cerebral and coronary vasospasm, but their negative inotropic and chronotropic action precludes their use. Sodium bicarbonate corrects systemic acidosis, which may compromise cardiac function, suppresses spontaneous cardiac activity, decreases the threshold for ventricular fibrillation, and impairs cardiac and peripheral response to catecholamines. Despite these beneficial effects, bicarbonate may also exacerbate central nervous system acidosis, produce a paradoxic intracellular acidosis, change the oxygen dissociation curve so as to decrease oxygen delivery, increase osmolality, and cause hypernatremia. Studies have failed to show an improved outcome with its use in CPR. Ventilation during CPR should be achieved with endotracheal intubation if at all possible. This method is the best at achieving oxygenation during arrest. Other lesseffective methods are mouth-to-mouth ventilation, mouthto-mask ventilation, esophageal obturator, or multiluminal airway device (64–66).

Advanced Cardiac Life Support The initial objective of ACLS has been the treatment of lifethreatening arrhythmias. The prototypical arrhythmias causing cardiopulmonary arrest are ventricular tachycardia and ventricular fibrillation, which are treated with a series of electric countershocks to achieve defibrillation to normal rhythm. This has been shown to be very successful, especially in patients in the intensive care unit setting when defibrillation can be accomplished early. If another rhythm is the cause of the arrest or if ventricular tachycardia or fibrillation persists after countershock, endotracheal intubation, chest compressions, intravenous access, and delivery of medications should take precedence over other measures (64,66). When ventricular fibrillation is successfully electrically cardioverted, 70% to 80% of patients convert to a rhythm that is capable of supporting adequate perfusion if cardioversion is done within three minutes of onset (64). If ventricular fibrillation persists after the initial countershocks, epinephrine should be given prior to further attempts. Although the use of antiarrhythmic agents is encouraged, whether there are true benefits is controversial. Asystole is frequently the initial rhythm identified in patients with cardiac arrest found outside the hospital and in critically ill inpatients. This rhythm carries the worst prognosis, with less than 2% of patients surviving hospitalization. In addition to epinephrine and atropine, the use of transcutaneous and transvenous pacing should be encouraged if they can be instituted in a short period of time. Pulseless electric activity, formerly also termed ‘‘electromechanical dissociation,’’ can be due to metabolic and mechanical derangements. This is a disturbance frequently encountered in the traumatized or burned patient where

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hypovolemia, cardiac tamponade, tension pneumothorax, acidosis, and hypoxia are prevalent. Other causes may include pulmonary embolus and a large myocardial infarction. After ACLS has been initiated, each of the possible causes should be investigated and treated immediately.

Cardiopulmonary Arrest Following Trauma The approach to the patient with cardiopulmonary arrest as a result of trauma is different than that to the patient with arrest as a result of a primary cardiac or pulmonary event. The causes of arrest associated with trauma may include exsanguination with hypovolemia and diminished oxygen delivery, diminished cardiac output resulting from tension pneumothorax or pericardial tamponade from penetrating trauma, or direct trauma to the heart or great vessels. In addition, there may be causes that may not be as readily apparent as the purely mechanical causes, such as cardiovascular collapse or primary respiratory arrest resulting from a neurogenic response to severe central neurologic injury and trauma associated with a primary arrest, such as in the patient who suffers ventricular arrhythmias while driving a car. The management of patients who suffer arrest associated with trauma begins with immediate evaluation of the airway and electrocardiographic rhythm. Ventilation should be accomplished as first priority because the tolerance of pulselessness may be extended in patients who have achieved adequate oxygenation. While establishing an adequate airway, in-line stabilization of the neck should be performed, and lateral neck supports, strapping, and backboards should be used to prevent worsening of a possible neck injury. If after airway control and defibrillation of dysrhythmias there is no pulse or blood pressure, chest compressions may have to be initiated. In penetrating injury to the chest, the thorax should be vented if there is asymmetry of breath sounds or an increase in airway resistance. A thorough survey of the body should be made for penetrating injury that may cause pneumothorax or tension pneumothorax. Once identified, a penetrating injury should be sealed, and immediate monitoring for (and relief of) tension pneumothorax should be performed. Emergency thoracotomy permits direct massage of the heart and allows relief of tamponade, control of thoracic and extrathoracic hemorrhage, and aortic cross-clamping (64). Open cardiac massage increases cardiac output and aortic pressures more than standard CPR; however, it has been shown that there is no benefit of this procedure if initiated after 30 minutes of standard CPR (56,64,66). When a patient becomes pulseless as a result of intravascular volume loss, functional long-term survival is unlikely unless single-organ hemorrhage can be rapidly terminated, along with aggressive volume resuscitation, blood transfusions, and circulatory support. Patients with prehospital arrest caused by multiple-organ hemorrhage, as is commonly seen with blunt trauma, rarely survive neurologically intact, despite rapid prehospital and trauma-center response. Those who survive prehospital arrest associated with trauma are generally young, have penetrating injuries, have received early endotracheal intubation, and undergo rapid transport by highly skilled paramedics to a definitive care facility (64).

Monitoring the Effectiveness of Cardiopulmonary Resuscitation CPR is most effective when the mean and diastolic aortic pressures are maintained continually at an adequate level.

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These are the critical pressures that define perfusion of oxygenated blood to the coronary arteries and systemic circulation. In addition, adequate aortic pressures are needed to promote effective circulation of emergency medications such as catecholamines and antiarrhythmics. However, if the left atrial pressure is as high as the aortic pressures, there may not be forward flow even with adequate aortic pressures, and the result may be reverse flow and pulmonary edema. This situation may be encountered, for example, in patients with mitral or aortic valvular dysfunction. Arterial pH and PO2 do not correlate well with outcome in CPR except in the extreme. With a very high pH, for example, there may be failure of defibrillation. A very low pH portends a poor outcome. Arterial lactate levels are an indicator of perfusion with oxygenated blood and have an inverse correlation with outcome. Mixed venous or coronary venous pH and PCO2 do not correlate with outcome; however, failure to eliminate carbon dioxide as measured by an increased mixed venous carbon dioxide and a low end-tidal carbon dioxide tension is associated with the onset of ventricular fibrillation (64,66,67).

Morbidity, Mortality, and Prognosis With in-hospital cardiopulmonary arrest, there is a 55% rate of successful resuscitation; however, only 15% of the patients survive the hospitalization (64,66,68). The extent of prearrest morbidity plays an important role in the outcome of CPR. Approximately one out of five survivors suffers serious permanent brain damage, and this complication is most correlated to the amount of time in cardiopulmonary arrest prior to beginning CPR and ACLS. The most important prognostic factors are a prolonged delay in the onset of CPR, a prolonged duration of CPR, age less than 40 or greater than 70, the presence of hypotension and lactic acidosis after arrest, severe hypoxia before arrest, azotemia, hyperglycemia, and comorbid conditions such as sepsis, renal failure, and malignancy (64).

SUMMARY As the general population ages, acute and chronic heart failure is an increasingly important cause of morbidity and mortality in the adult surgical patient. While there are a large number of causes and exacerbating factors for heart failure, management issues may be similar. With this in mind, it is important to understand the pathophysiology of heart failure, because the treatment is aimed directly at influencing and hopefully reversing the maladaptive physiologic mechanisms both within the heart and systemically. Although there is great promise in the future for metabolic, molecular biologic, and sophisticated mechanical treatments for acute and chronic heart failure, early diagnosis and aggressive treatment while excluding reversible causes is and will remain the hallmark of treatment of heart failure. After more than 40 years of use, CPR remains a desperate effort to treat cardiopulmonary arrest, and, unfortunately, the benefits are limited to only a small number of patients. It is interesting that despite many efforts at change, the original technique of CPR has changed little throughout the years. Perhaps the greatest impact in the future will be the development of improved measures at prediction and prevention of arrest and improvement in postresuscitation measures.

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64. Kern KB, Halperin HR, Field J. New guidelines for cardiopulmonary resuscitation and emergency cardiac care: changes in the management of cardiac arrest. JAMA 2001; 285:1267. 65. Hallstrom A, Cobb L, Johnson E, et al. Cardiopulmonary resuscitation by chest compression alone or with month-to-month ventilation. N Engl J Med 2000; 342:1546. 66. International guidelines 2000 conference on cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2000; 102(suppl I):II36. 67. Gudipati CV, et al. Expired carbon dioxide: a noninvasive monitor of CPR. Circulation 1988; 77:234. 68. Burns R, et al. Prediction of in-hospital cardiopulmonary arrest outcome. Arch Intern Med 1989; 149:1318.

34 Mechanical Support for the Failing Heart: Current Physiologic Concepts of Management Sina L. Moainie and Bartley P. Griffith

While the activation of the sympathetic nervous system and rennin–angiotensin system are initially compensatory in response to diminished cardiac function, these responses ultimately become maladaptive. The progressive decompensation in ventricular function following an index cardiac event is a consequence of adverse ventricular remodeling. The chronic increase in preload and vascular tone increases myocardial wall stress, which sets in motion a biochemical cascade resulting in regional and global myocardial dysfunction (4). Additionally, angiotensin II and aldosterone stimulate collagen synthesis and inhibit collagen degradation leading to interstitial fibrosis (5–7). Pathologic increases in myocardial interstitial collagen content reduce ventricular filling by increasing diastolic stiffness (8). The physiologic consequences of altered ventricular stiffness are manifest by increased central venous and pulmonary artery pressures as well as decreased cardiac output. Another maladaptive consequence of ventricular remodeling is an increase in ventricular volume and sphericity (9,10). Increased ventricular sphericity, volume, and stiffness have all been demonstrated to result in increased ventricular wall stress with an ensuing increase in myocardial metabolic requirements (8). The mismatch between increasing myocardial metabolic requirements and decreasing cardiac output results in progressive myocardial ischemia. Because intramyocardial pressure has its most profound effects on the subendocardium, it is this region that is most affected by the decrease in blood flow. Several investigators have hypothesized that it is this mismatch between increasing myocardial oxygen demand and decreasing coronary perfusion that leads to the progressive decline in function in advanced heart failure (11,12). Myocyte loss occurs in the failing heart not only due to necrosis from subendocardial ischemia, but also from myocardial apoptosis. Apoptosis, or programmed cell death via an energy-requiring enzymatic destruction of myocyte DNA, has been demonstrated in failing hearts (13,14). The exact mechanism by which myocardial apoptosis is initiated is as yet unclear, but factors that initiate cellular apoptosis such as upregulation of the gene p53, and increase of the cytokine tumor necrosis factor–alpha have been observed in failing hearts. Additionally, oxygen free-radical generation in response to increased ventricular wall stress has also been implicated in the induction of myocyte apoptosis (15). The end result of the combined effects of increased myocardial metabolic need, diminishing cardiac function, and progressive myocyte loss lead to a heart that is unable to meet the metabolic needs of the body. Ongoing tachycardia and increasing sympathetic tone secondary to decreased cardiac output further exacerbate the vicious downward spiral resulting in advancing cardiac dysfunction ultimately

INTRODUCTION The development of the extracorporeal heart–lung machine, or cardiopulmonary bypass (CPB) circuit as it is sometimes called, made possible heart surgery as we know it today. Even with this technology, however, not all patients with cardiac disorders are suitable candidates for coronary bypass operations or valve replacement surgery due to the magnitude of the underlying disease. Fortunately, other technological advances have occurred so that devices are now available to support even the most profound circulatory failure. These include the intra-aortic balloon pump (IABP) for acute management of cardiac failure and the left ventricular assist device (LVAD) for chronic end-stage LV failure. While such devices are generally employed to salvage whatever cardiac function exists in anticipation for future cardiac transplantation, more recent technological approaches have aimed at the management of the failing heart from the standpoint of maintaining additional years of meaningful life even when transplantation is not a suitable alternative. This chapter reviews the technological strategies currently available to support the failing circulation and which patients are likely to benefit most from these approaches.

CARDIAC SUPPORT IN END-STAGE HEART FAILURE Pathophysiology of Heart Failure Heart failure is defined as the pathologic state in which the heart is unable to pump blood at a rate adequate to meet the physiologic requirements of the tissues despite normal cardiac filling pressures (1). This disease affects an estimated five million Americans, with approximately 550,000 new cases diagnosed each year (2). Coronary artery disease is the most common etiology of heart failure with only approximately 30% of cases of heart failure resulting from other causes including congenital malformations, valvular disease, or viral or idiopathic cardiomyopathy (3). Following an initial event resulting in diminished cardiac function, a number of compensatory mechanisms are initiated to maintain normal organ perfusion. In response to the decrease in cardiac function, the sympathetic nervous system and the renin–angiotensin system are activated. Release of the neurotransmitter norepinephrine from cardiac adrenergic nerves results in increased vascular tone, leading to improved preload and increased myocardial contractility. Activation of the renin–angiotensin system not only increases preload via an increased renal fluid retention, but also results in vasoconstriction mediated by angiotensin II. The combined effect of the sympathetic and renin–angiotensin response is an increase in preload and myocardial contractility with an ensuing increase in stroke volume via the Starling mechanism. 677

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leading to a heart that is unable to meet the resting metabolic requirements of the tissues. The disparity between the continually increasing population of patients with advanced heart failure and the fixed supply of donor organs for cardiac transplantation has fueled the interest in mechanical support for the failing heart.

Mechanical Circulatory Support Currently, approximately 6000 patients per year in the United States receive some form of cardiac support following cardiac surgery. The hospital survival for these patients ranges between 20% and 40%. An additional 400 patients per year receive a cardiac support device as a bridge to transplantation, with a survival rate through transplantation ranging between 50% and 70% (16). With the approval of ventricular assist devices for permanent use or ‘‘destination’’ therapy of heart failure, the number of assist devices implanted is expected to increase significantly in the future. Cardiac support devices may be divided into two broad categories; those designed for acute use of days to two weeks and those for longer bridge-to-transplant (BTT) or permanent support.

Acute Support Devices Intra-Aortic Balloon Pump The easiest device to apply and the most commonly used remains intra-aortic balloon counterpulsation, which was introduced clinically in 1967 to support patients with acute cardiac decompensation (17). The IABP (Fig. 1) consists of a catheter-mounted inflation/deflation balloon that is positioned in the descending thoracic aorta just distal to the takeoff of the left subclavian artery. It is usually placed using percutaneous introduction into a femoral artery. Generally, the device is inserted in an intensive care unit, in a cardiac catheterization laboratory, or in a cardiac surgical suite. A patient supported by IABP must remain prone with the hip fully extended. This limits its use to less than a week. The indications for IABP support include (i) cardiogenic shock secondary to an ischemic event, (ii) acute treatment of intractable angina prior to planned coronary intervention, (iii) temporary cardiac support of a patient with perioperative cardiogenic shock, or (iv) periprocedural support during complex angioplasty (18,19). Chief in the decision to proceed with IABP placement is the assumption that the source of the cardiogenic shock and/or ischemia necessitating support is thought to be temporary (planned revascularization of ischemic myocardium or anticipated rapid ventricle recovery from post-CPB myopathy). Contraindications to placement of an IABP include aortic valvular insufficiency, aortic dissection, distal aortic occlusion, large aortic aneurysm, or severe peripheral vascular disease. The IABP augments cardiac function by increasing diastolic blood pressure and reducing afterload. Using ECG, aortic pressure, or set pacing as a trigger, the balloon is set to inflate just after the aortic valve closes and to deflate just after the aortic valve opens. The effectiveness of the device is limited at heart rates above 120 bpm and when ventricular arrhythmia is common. Inflation begins just after the aortic valve closes (the start of diastole), and the increased pressure within the proximal aorta raises the diastolic pressure and thus the coronary perfusion. The augmentation of coronary perfusion pressure reduces myocardial ischemia, which then leads to an improvement in myocardial contractility. Given that the balloon functions in part by augmenting diastolic flow, aortic insufficiency is a

Figure 1 Illustration demonstrating correct positioning of intra-aortic balloon pump with proximal aspect just distal to branching of the left subclavian artery. Source: Courtesy of Arrow International, Reading, Pennsylvania, U.S.A.

contraindication to IABP placement because the increase in diastolic pressure would exacerbate aortic regurgitation and lead to increased LV distention. Deflation of the balloon immediately after the aortic valve opens (the start of systole) causes a decrease in the aortic volume (volume occupied by the inflated balloon). Because pressure is directly proportional to volume, deflation of the balloon leads to a resultant decrease in the systolic aortic pressure (afterload). Decreased afterload and increase in coronary perfusion combine to result in an increase in cardiac output of approximately 10% to 25%. The IABP is most commonly introduced via the femoral artery using a percutaneous Seldinger technique. When extensive occlusive peripheral vascular disease prevents femoral arterial access, the IABP may be introduced directly into the thoracic aorta; this approach is rarely used because this mode of insertion would necessitate a thoracotomy. This approach has been used after cardiac surgery, but most surgeons opt for placement of a temporary ventricular assist device in lieu of an IABP in this circumstance (20). Fluoroscopy is generally not necessary for IABP placement but a chest radiograph should be obtained following placement to confirm correct positioning. The radiopaque tip of the balloon should be positioned just distal to the takeoff of the left subclavian artery, which can be identified radiographically using the second rib as a landmark. The complications of IABP use include visceral or limb ischemia,

Chapter 34: Mechanical Support for the Failing Heart

arterial perforation, retroperitoneal hemorrhage, aortic dissection, and thrombocytopenia resulting from platelet aggregation secondary to a foreign body reaction (21,22). Visceral ischemia may be the result of balloon malposition and may be treated with repositioning of the device. Daily chemistry profiles may alert the clinician to visceral malperfusion as evidenced by rising tests of liver function, serum creatinine or decreasing serum bicarbonate. Limb ischemia is the most common complication of IABP use occurring in 5% to 19% of patients (23). Often limb ischemia resolves with the removal of the IABP, but surgical intervention in the form of angiography, thrombectomy, or angioplasty is required in some cases. Any patient with a femorally placed IABP should have hourly assessment of distal perfusion by physical examination and bedside Doppler. Most physicians opt to anticoagulate patients with heparin to reduce the risk of arterial thrombosis and emboli. Daily complete blood count measurements can alert the clinician to the possibility of hemorrhage or the development of thrombocytopenia. When the patient demonstrates recovery of ventricular function as evidenced by a cardiac index greater than 2.0 L/min/m2, a systolic blood pressure greater that 90, and an absence of metabolic acidosis while on minimal inotropic support, IABP support may be withdrawn. Weaning of the IABP is accomplished by decreasing the frequency of augmentation from 1:1 (in which the IABP augments every heart beat) to 1:2 and then 1:3 (IABP augments every third heart beat) in stepwise increments decreasing support every two to three hours. If the patient has continued stable hemodynamics with no increasing inotrope requirement with the IABP on 1:3 augmentation, the device may be removed (24). Ventricular Assist Devices While the IABP is relatively easy to use and can be applied within minutes, often the degree of cardiac dysfunction is more than can be supported with counterpulsation. Several devices have been approved to address this profound loss of cardiac function. These fully supporting blood pumps are identified commonly as ventricular assist devices. Several have been targeted for very short-term use of approximately one week, while others are designed with more durable components and have supported patients for up to several years (Table 1). Short-Term Ventricular Assist Devices. Both the devices currently in use for short-term ventricular support are extracorporeal pulsatile systems. The Thoratec ventricular assist system (VAS) (Fig. 2) is a pneumatically powered device that may be used for univentricular or biventricular support. This pump is composed of a polyurethane compressible

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Figure 2 Illustration demonstrating biventricular support with Thoratec device. Right ventricular support utilizes right atrial inflow and pulmonary artery outflow. Left ventricular (LV) support is achieved using LV apical inflow and aortic outflow.

sac-like chamber that draws blood from and through inlet and outlet valves. It has been used as short-term postcardiotomy support for 7 to 10 days but also is durable for longer BTT type support, lasting months or even years. The device is approved for out-of-hospital use, and the pneumatic power source has a rechargeable battery and is packaged in a roll-on type suitcase. When used for LV support, the inflow (fill) cannula is placed either into the LV apex or via the right side interatrial groove into the left atrium. The outflow graft is sewn to the ascending aorta. The right atrium provides inflow and the main pulmonary artery is used for outflow in cases of right ventricular support. Bjork-Shiley mechanical tilting-disk valves are incorporated within the device housing to ensure unidirectional flow. The inlet and outlet cannulae are externalized subcostally and connected to the pump that is powered using pressurized air controlled by the external drive console. The Thoratec VAS has a maximum stroke volume of 65 cc and can provide 6.5 L/min of flow (25). When used for biventricular support, the right ventricular assist device (RVAD) is

Table 1 Mechanical Circulatory Assist Available in the United States Device ABIOMED BVS5000 AB50001 Ventricle IAPB Thoratec VAD HeartMate VAD WorldHeart VAD CardioWest TAH MicroMed Axial VAD Jarvik Axial VAD

Power

Type

Target indication

Duration of use

FDA approval

Pneumatic Pneumatic Pneumatic Pneumatic Electric Electric Pneumatic Electric Electric

Pulsatile extracorporeal Pulsatile extracorporeal Pulsatile extracorporeal Pulsatile extracorporeal Pulsatile intracorporeal Pulsatile intracorporeal Pulsatile intracorporeal Continuous flow intracorporeal Continuous flow intracorporeal

Postcardiotomy shock Postcardiotomy shock and BTT Acute cardiac decompensation/ischemia Postcardiotomy shock and BTT BTT permanent use BTT Permanent use BTT BTT BTT

24 hr to 10 days 1–6 mo 1–7 wk 1 wk to 1 yr 1 mo to 1.5 yr 1 mo to 1 yr 1 mo to 1 yr 1 mo to 1 yr 1 mo to 3 yr

þ þ þ þ (BTT) BTT, destination þ (BTT) BTT – –

Abbreviations: BTT, bridge-to-transplant; FDA, Food and Drug Administration; VAD, ventricular assist device; TAH, total artificial heart.

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set at an output that is less than that of the LVAD to prevent pulmonary congestion. The Thoratec VAS may be programmed to operate in a fixed rate, volume, or synchronous mode. In the volume mode, the pump is triggered to contract when the sac is fully filled. The volume mode is most commonly utilized and provides maximum output. The synchronous mode uses the r-wave of the patient’s electrocardiogram for triggering and is most effective for weaning from support. As with the IABP, assist device can be set from a range of 1:1 to 1:3, and weaning is accomplished in a similar manner as with the IABP by gradually reducing the number of assisted heartbeats (26–28). The Thoratec is useful for acute cardiac decompensation usually associated with failed cardiac surgery. It is unique in that it is also durable enough to provide long-term BTT support as well. Because it is positioned paracorporeally, it can be used in patients of small body size (body mass index
1.25 m2) and is the choice of most surgeons when severe biventricular failure indicates the need for combined left and right ventricular support. Because the patient’s blood is in contact with the prosthetic material of the cannula, valves and pump sac that activate clotting, and anticoagulation are required. Generally, the circumstance requiring univentricular support is one in which the left ventricle has suffered an acute (ischemic) or chronic power failure. In this circumstance, the ability of the native right ventricle to deliver blood flow across the left heart is critical in determining the adequacy of univentricular versus biventricular support. As with the Thoratec VAS, the Abiomed BVS5000 (Fig. 3) is a paracorporeal pulsatile ventricular assist device that may be used for left, right, or biventricular support. It is economical and thus is available in most cardiac surgical suites. It is easy to insert and operate, but it lacks durability and has a relatively high incidence of emboli within 10 days of use. Unlike the Thoratec device, the Abiomed BVS5000 requires the patient to remain recumbent. Cannulation for right and left ventricular support is identical to that for the Thoratec device. Like the heart itself, the Abiomed device contains a reservoir that receives blood from the inflow chamber. This chamber in turn loads the pumping chamber. The chambers are connected by a unique trileaflet polyurethane valve that assures unidirectional flow (29). Blood flows into the pump by gravity, and a drive console is used to pneumatically compress the pumping chamber. The device is designed for complete support of the left and/or right heart, and the system microprocessor manages the duration of pump systole and diastole to optimize pump function and maintain a targeted stroke volume of 83 mL after cardiac surgery. The Abiomed BVS5000 also requires the use of systemic anticoagulation as soon as mediastinal hemorrhage abates to prevent formation of device-related thrombus. Recently, the Abiomed company has introduced a pneumatic, sac-like ventricular assist devices (VAD) with polyurethane inlet and outlet valves that connect to the same cannulae for easy exchange. This device, like the Thoratec, is more durable and expensive than the ABVS5000, and permits patients to ambulate in the hospital. Long-Term Ventricular Assist Devices. A number of devices have been developed to target the need for long-term LV support. Most of the systems use a similar cannulation schema with an LV apical conduit used for device inflow and the ascending aorta used for device outflow. Because the aim of all of the long-term assist devices is to provide outpatient support, these devices tend to use small electric

Figure 3 (A) Illustration of Abiomed BVS5000 paracorporeal pulsatile ventricular assist device demonstrating position of chambers in pump diastole and systole. (B) In vivo positioning of Abiomed BVS5000.

AC battery power and controller modules. The newer flexible and small bore percutaneous power cords have been well tolerated and generally have not been a source of inevitable driveline infection that ascends along the subcutaneous track or seeds the intimal components of the device via homologous spread. WorldHeart Novacor LVAS. The WorldHeart Novacor LVAS (Fig. 4) is placed via an extended median sternotomy with

Chapter 34: Mechanical Support for the Failing Heart

681

Figure 5 Illustration demonstrating left ventricular (LV) support with the Thoratec XVE. Inflow is via LV apex and outflow is via proximal aorta. Abbreviations: LVAD, left ventricular assist device. Figure 4 Illustration demonstrating left ventricular (LV) support with the Novacor LVAD. Inflow is via LV apex and outflow is via proximal aorta.

the LV apex inflow and aortic outflow conduits connected to the pump that is positioned in the anterior abdominal wall. The pump utilizes two electrically powered opposing pusher plates to eject blood and bioprosthetic valves within the conduits to ensure unidirectional flow. A percutaneous cable connects the pump to the external controller and battery pack, both of which may be worn on a belt to provide for excellent patient mobility. The cable also contains the vent line for the pump. In addition to the fixed-rate mode, the device may also be operated in a synchronized mode that uses an electrocardiographic signal to time pump diastole to cardiac systole and vice versa. The synchronized mode thus provides the most effective means of cardiac unloading because the heart is ejecting into the low resistance pump hence limiting strain on the heart. Although the Novacor LVAS employs smooth, seamless blood-contacting surfaces and bioprosthetic valves to limit thrombogenicity, systemic anticoagulation is still required during the period of support. Thoratec HeartMate VE LVAS. The Thoratec HeartMate VE LVAS (Fig. 5) is electrically powered. The motor drives a cam mechanism up and down to power the pusher-plate mechanism. An external vent is utilized to equalize air pressure and provide a means for emergency pneumatic device actuation. Should the electrical motor fail, the device may be pneumatically powered by a hand-held portable pump. The electrical motor is normally powered by two rechargeable batteries, delivering four to six hours of power per charge. The batteries may be worn on a vest or belt, thus allowing for high degree of mobility (30,31). A unique feature of the HeartMate device is that the blood-contacting surfaces of the device are designed to promote deposition of circulating cells creating a ‘‘pseudoneointimal’’ layer that discourages platelet adhesion and thrombosis. Additionally,

the device uses a pusher-plate blood pump that creates a central vortex of blood preventing stagnant flow. The combination of these features reduces the likelihood of thrombus formation and so lesser degrees of anticoagulation are required for use of the device, and in fact, the device may be used safely with no anticoagulation when used for longterm support (32). Lionheart LVD2000 LVAS. The Lionheart System (Fig. 6) is similar in design to other long-term displacement pumps in that it includes an LV apex inflow conduit and aortic outflow conduit that are connected to a subdiaphragmatically placed VAD. The device uses an electrically powered roller screw mechanism to power a pusher plate that compresses the blood sac. Tilting-disk valves provide unidirectional flow. Uniquely, the Lionheart system utilizes a transcutaneous energy transmission system that transfers power from the external battery pack across intact skin using electromagnetic induction. By utilizing a transcutaneous power transfer mechanism, the Lionheart device eliminates the need for a transcutaneous driveline or cables, theoretically reducing the risk of infection (33). Because there is no percutaneous driveline to vent the displacement of the sac, the Lionheart includes an intrathoracically placed compliance chamber that allows air to be vented to the chamber during diastole and toward the pump during systole. The compliance chamber is placed in the left thorax. To counteract passive diffusion of gas out of the chamber and into the surrounding tissue, the chamber is recharged with atmospheric air every few weeks through a subcutaneous port. Long-Term Nonpulsatile Ventricular Assist Devices. All of the implantable pulsatile LVADs share several disadvantages that include relatively large size, the need for valves to prevent reversal of flow, and the need for either a large bore percutaneous vent/driveline or a compliance chamber. Several continuous axial flow pumps currently under clinical

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Figure 6 Illustration demonstrating left ventricular (LV) support with the Lionheart Left Ventricular Assist Device (LVAD). Inflow is via LV apex and outflow is via proximal aorta. The compliance is placed within the right chest. Source: Courtesy of Arrow International, Reading, Pennsylvania, U.S.A.

trial potentially overcome these limitations. Given the extremely small ‘‘D-cell battery’’ size of the axial flow pumps, the devices may be thought of essentially as ‘‘powered apicoaortic conduits’’ that can provide up to 5 to 6 L/min of nonpulsatile flow using the LV apex for inflow and the aorta for outflow. The devices currently undergoing investigation in the United States are the HeartMate II, Jarvik 2000 (Fig. 7),

Figure 8 Illustration demonstrating replacement of native heart with the CardioWest Total Artificial Heart.

and DeBakey/NASA LVAD (34–36). These devices provide continuous flow and induce a reduced pulse pressure. Generally, most of these pumps have been used to assist the left ventricle as opposed to completely replacing its function. Most investigators tend to run their pumps at a speed that enables LV ejection and thus pulsatile flow. Total Artificial Heart The CardioWest C-70 Total Artificial Heart (Fig. 8) (formerly called the Symbion or Jarvik Total Artificial Heart) allows for total, biventricular cardiac support using a pulsatile pneumatically powered pump. The device is placed orthotopically and requires native cardiectomy for placement. Mechanical valves housed in the inflow and outflow orifices ensure unidirectional flow. The device is powered and controlled by an external console that is connected to the pump via a percutaneous driveline (37). The device does require anticoagulation to prevent thrombus formation.

Clinical Use of Mechanical Circulatory Support Devices Figure 7 Illustration of the original concept for the Jarvik 2000 fully implanted system with the use of lithium polymer batteries and electronics implanted within the prosthetic ribs. Inflow is via left ventricular apex and outflow is via the descending thoracic aorta. Source: Courtesy of Rob Jarvik, M.D., Jarvik World Heart, New York, New York, U.S.A.

Currently, mechanical cardiac support is used both as a BTT and more recently as destination therapy. A recent study demonstrated significantly improved survival in transplant recipients who were supported with an LVAD versus those in a control group (71% vs. 36%, respectively, 90 days posttransplant) (38). The improved survival is most likely secondary to the superiority of mechanical support over

Chapter 34: Mechanical Support for the Failing Heart

medical therapy in providing tissue perfusion thus enabling improved peritransplant organ function leading to improved survival. The benefits of mechanical circulatory support are balanced to some degree by the complications associated with device use. Bleeding and infection are the most prevalent complications associated with mechanical support devices. Bleeding rates are described as high as 60% and are more likely in patients requiring biventricular support as compared to those requiring univentricular support. The high rate of bleeding is related to coagulopathy due to heart failure–induced hepatic dysfunction, and the combined effects of CPB and device-related rheology resulting in platelet dysfunction (39). Infection rates range from 30% to 40% and this results in significant morbidity. The newer totally implantable devices eliminate percutaneous cables, which should theoretically reduce infection rates by eliminating the significant factor of a percutaneous portal of entry of infectious agents.

11.

12.

13. 14. 15. 16.

17.

SUMMARY This chapter has summarized the enormous advances that have been made in recent years to support the failing circulation due to underlying heart disease. Not only can survival from acute cardiac failure be anticipated in many patients using IABP, but chronic end-stage LV failure can also be now supported for months to years, if necessary, in anticipation of cardiac transplantation. Even when the latter approach is not a suitable option, the LVAD has been shown to afford meaningful life in patients who a decade ago would have been subjected to sudden death. While the total artificial heart is still in its infancy, models currently available have been shown to support the entire circulation satisfactorily for many months. It is only a matter of time until an artificial heart is developed, which can add years to the life of a cardiac cripple who without such technology would die.

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35 Congenital Heart Lesions Ralph S. Mosca and Edward L. Bove

circulations. PVR falls to adult normal levels within two to four weeks in the term infant.

INTRODUCTION The surgical treatment of congenital heart defects has progressed at a rapid rate since its beginning more than half a century ago. Numerous technical achievements have been made possible by advances in many fields. Precise knowledge of anatomy and physiology, detailed noninvasive diagnostic capabilities, better perfusion and myocardial preservation techniques, and improved neonatal intensive care have all played major roles in allowing the management of congenital heart disease to progress to this extent. Nearly all congenital heart defects are now amenable to surgical repair. This chapter discusses the pathophysiology underlying some of the cardiac defects more commonly encountered by the pediatric cardiac surgeon and covers the physiologic rationales behind their treatment.

CONGESTIVE HEART FAILURE Simply defined, congestive heart failure is the failure of myocardial oxygen supply to meet oxygen demand. The classic findings of congestive heart failure in infants include tachypnea, tachycardia, diaphoresis, and hepatomegaly. Peripheral edema and rales are not typically noted in infants. The neonatal myocardium is already functioning at maximal stroke volume and can only increase cardiac output by increasing heart rate. Further, the neonatal myocardium has a reduced density of contractile elements. For these reasons, the already stressed neonate with limited cardiac reserve is easily susceptible to congestive heart failure. Congenital heart disease typically results in congestive heart failure in either of two ways, volume overload or pressure overload. Volume overload occurs with either a large communication between the systemic and pulmonary circulations or valvular regurgitant lesions (Fig. 2). When a left-to-right shunt occurs, the volume of shunted blood depends on

ADJUSTMENTS IN THE CIRCULATION AFTER BIRTH Although it is beyond the scope of this chapter to discuss in detail the physiology of the intrauterine circulation and its adaptation to extrauterine life, a brief description is included to aid in the understanding of the topics to follow. Oxygen-enriched placental blood returns to the fetus through the umbilical vein and then passes through the liver. There it joins the inferior vena caval return and enters the right atrium. Much of this blood passes across the patent foramen ovale (PFO) by preferential streaming into the left atrium, left ventricle, and ascending aorta, from where it is distributed to the brain and coronary circulations (Fig. 1). Superior vena caval return is directed across the right atrium, tricuspid valve, and right ventricle to be ejected into the pulmonary artery. Nearly all this blood passes across the patent ductus arteriosus (PDA) into the descending aorta. Because the ductus is nonrestrictive, both ventricles essentially function as a unit and eject blood against the same overall resistance. However, systemic vascular resistance is low because of the placental circulation, and pulmonary vascular resistance (PVR) is high in the nonaerated fetal lung, resulting in less than 10% of the fetal cardiac output going to the lungs. At birth, the placenta is eliminated from the circulation, resulting in an abrupt rise in the systemic vascular resistance. Expansion of the lungs leads to a fall in PVR. As arterial and alveolar partial pressure of oxygen (PO2) increase, PVR falls further and pulmonary blood flow rises, resulting in an increase in the left arterial pressure and functional closure of the flap valve of the foramen ovale. The increase in arterial PO2 also causes constriction of the smooth muscle in the wall of the ductus arteriosus, closing the duct and completing the separation of the two

Figure 1 Course of the intracardiac circulation before birth. Most inferior vena caval blood passes across the PFO to the left atrium. The superior vena caval return is directed predominantly across the PDA. Abbreviations: PFO, patent foramen ovale; PDA, patent ductus arteriosus.

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and the branch pulmonary arteries (tetralogy of Fallot). Resistance to flow through the obstruction is at least that through the communication, allowing desaturated blood to enter the systemic circulation directly. Cyanosis may also occur as a result of inadequate mixing of the blood between the systemic and pulmonary circulations. This situation is classically seen in transpositiontype physiology. Although total systemic and pulmonary blood flow may be normal or increased, the effective flow is reduced. That is, the amount of desaturated blood actually reaching the lungs and the amount of fully saturated blood reaching the body are decreased. This condition is discussed in detail later in this chapter. Finally, common mixing occurs when desaturated and saturated bloods freely mix, allowing some desaturated blood to reach the body. This can occur at atrial (common atrium), ventricular (common or single ventricle), or great vessel level (truncus arteriosus).

OBSTRUCTIVE LESIONS Coarctation of the Aorta

Figure 2 Chest radiograph of a patient with atrial septal defect. There is cardiomegaly and an increase in pulmonary vascular markings as a result of the large left-to-right shunt.

the relative resistances of the two vascular beds. As the PVR falls during the first few weeks of life, pulmonary blood flow may increase dramatically, producing a large volume overload of the left ventricle. Because this shunt depends on a falling PVR, congestive failure from volume overload is not usually seen until two or three weeks of age. Pressure overload results from an obstruction to ventricular emptying. This obstruction is usually located at the level of the semilunar (pulmonary or aortic) valve, but it may be seen with subvalvular or supravalvular blockage. When the ventricle can no longer eject an adequate blood volume through the obstruction, pulmonary and systemic venous congestions with congestive heart failure result.

Cyanosis Cyanosis is a blue discoloration of the skin and mucous membranes caused by the presence of at least 5 g/dL unsaturated circulating hemoglobin. When it is noted in infancy, the administration of 100% oxygen is a reliable test to establish the presence of intracardiac shunting related to congenital heart disease. If the PO2 in the right radial artery rises above 250 mmHg, cyanotic heart disease is virtually eliminated. Although values less than 250 mmHg are not certain indicators of cardiac disease, a PO2 less than 100 mmHg generally indicates a cardiac problem. Cyanosis resulting from congenital heart disease may be caused by decreased pulmonary blood flow with intracardiac right-to-left shunting or by abnormalities of intracardiac mixing. When cyanosis is caused by decreased pulmonary blood flow, two conditions are necessary— obstruction to flow into the lungs and an intracardiac communication between the two circulations proximal to the obstruction. The obstruction may be located anywhere between the systemic venous atrium (tricuspid atresia)

Coarctation is a narrowing in the thoracic aorta most commonly located just distal to the left subclavian artery, opposite the insertion of the ductus arteriosus or ligamentum arteriosum (Fig. 3A). Obstruction to left ventricular emptying results in a pressure overload of the ventricle, which may lead to congestive heart failure. In infancy, associated defects often dictate the hemodynamic condition. When the ductus arteriosus is patent, blood may flow from the pulmonary artery across the duct into the descending aorta (Fig. 3B). In this situation, differential cyanosis is present, with desaturated blood perfusing the lower extremities and saturated blood perfusing the upper body. Approximately 20% of patients have an associated ventricular septal defect (VSD). The impedance to left ventricular emptying imposed by the coarctation increases the left-to-right shunt and results in severe congestive heart failure from combined pressure and volume overload. Other obstructive lesions in the left side of the heart may also be seen with coarctation; most common is aortic stenosis related to a bicuspid aortic valve. When coarctation results in congestive heart failure in infancy, nonoperative treatment carries a high mortality rate. Most patients with coarctation, however, do not have symptoms, and the defect is not found until after infancy. The discovery of upper-extremity hypertension with diminished or absent femoral pulses typically leads to the diagnosis. Flow murmurs over the back and palpable pulsations in the subscapular area from prominent collaterals may be present. All extremity pulses must be carefully palpated. A decrease in the left-arm pulse may indicate the involvement of the origin of the left subclavian artery in the coarctation. Plain chest radiographs may show dilation of the aorta proximally and distally to the narrowed segment (3 sign) and notching of the ribs related to enlarged intercostal arteries. In the past, aortography was generally recommended to accurately define the anatomy of the coarctation before surgical repair. Today, noninvasive techniques, including Doppler echocardiography and magnetic resonance imaging, are generally adequate to delineate the anatomy. In rare cases, the coarctation may be in an unusual location. The exact cause of hypertension in coarctation remains obscure. The etiology in older patients is apparently more than obstruction alone, because relief of coarctation in adulthood does not result in the restoration of normal blood

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Figure 4 Repair of coarctation with the subclavian angioplasty technique. (A) Left subclavian artery is mobilized and divided distally. (B) Longitudinal incision through the artery and adjacent aorta is made. This incision must extend distally beyond the coarctation until normal aorta is reached. (C) Completed repair.

Figure 3 Hemodynamic abnormalities in coarctation (C) of the aorta. (A) Pathophysiology in the older child or adult. (B) In infancy, PDA allows blood flow to the descending aorta from the right ventricle. Abbreviations: LA, ligamentum arteriosum; LSCA, left subclavian artery; VSD, ventricular septal defect; PDA, patent ductus arteriosus.

pressure in every case. It seems certain that in these cases, a renal mechanism is in part responsible. In a classic experiment performed by Scott et al. (1), coarctation was surgically created in dogs. The resultant hypertension was relieved by removal of one kidney and transplantation of the other above the level of the coarctation. When abnormal plasma renin activity is unmasked by volume depletion, abnormally high renin–angiotensin activity has been found in patients with coarctation (2). Virtually all patients with hemodynamically significant coarctation of the aorta should undergo operative repair. The ideal age for repair in the child without symptoms is not well defined, but it has been moved earlier and earlier in recent years. Repair is probably best accomplished between the ages of one and three years. Earlier operation may increase the risk of recoarctation with growth of the aorta, whereas delaying repair beyond childhood increases the chance of persistent hypertension (3). The presence of congestive heart failure in infancy dictates operative intervention, regardless of age or size. The classic surgical technique remains resection of the narrowed segment with end-to-end anastomosis. The

benefits of this technique include removal of all the ductal tissue, thus decreasing the risk of recoarctation. The potential disadvantages include the need for greater dissection, increased technical difficulty, and the possibility of tension at the repair site. Concerns about growth of the aorta in the face of a circumferential suture line have been minimized by the use of absorbable suture material and further alleviated by good results with other similar neonatal repairs, such as the arterial switch procedure. We prefer the resection and end-to-end anastomosis in virtually all cases. However, the subclavian angioplasty procedure, first reported by Waldhausen in 1966 (Fig. 4) (4), is preferred by some groups. Although this technique does not remove all the ductal tissue and is not suitable for augmentation of more proximal aortic narrowing, it is technically easier and avoids suture line tension. Division of the subclavian artery can, on occasion, lead to disparate upper-extremity growth. Synthetic patch aortoplasty retains abnormal ductal tissue and may lead to aneurysm formation on the aortic wall opposite the patch (also reported with subclavian flap technique). This technique should be used only in cases of discrete recoarctations in which mobilization for end-toend repair is not feasible. Balloon angioplasty is being performed in several centers for both native and recurrent coarctation (5). Controversy continues regarding the safety and efficacy of angioplasty of native coarctation (6); however, new balloon-expandable and covered stents may be useful in older adolescents and adults (7). Results appear quite good for catheter-based treatment of recurrent stenosis (8). Coarctation associated with a large VSD is best treated by a single-stage complete repair through a median sternotomy. During a period of circulatory arrest, the coarctation is resected and repaired with the mobilized distal aortic segment used to augment the transverse aortic arch if necessary. The VSD is then closed from a transatrial approach.

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Aortic Stenosis The most common cause of obstruction to left ventricular ejection is aortic stenosis. The obstruction is typically located at the level of the valve, but it may be subvalvular or supravalvular (Fig. 5). Valvular aortic stenosis is usually caused by a bicuspid aortic valve with varying degrees of fusion of the commissures, although fused tricuspid valves may also be found. A dome-shaped unicusp valve may result in significant obstruction in infancy. Subvalvular aortic stenosis may be discrete or diffuse. In the discrete form, a fibrous membrane is found just below the aortic valve leaflets. The diffuse form is seen in obstructive cardiomyopathies, such as idiopathic hypertrophic subaortic stenosis or muscular tunnel-type subvalvular hypoplasia. In supravalvular stenosis, the obstruction is most commonly caused by an hourglass deformity of the ascending aorta just above the valve. Valvular aortic stenosis may be seen at any age. In infancy, severe stenosis may cause congestive heart failure (9). In most children, however, an asymptomatic heart murmur is detected on physical examination beyond the neonatal period. When symptoms are present in childhood, exertional dyspnea, syncope, and angina pectoris are the usual manifestations. Syncope is caused by the inability of the left ventricle to maintain adequate cerebral blood flow through a narrow, fixed orifice valve during exercise. Angina pectoris, although rare in childhood, may be seen when pressure overload results in significant left ventricular hypertrophy and myocardial blood flow does not adequately perfuse the thickened, hypertensive ventricular muscle.

Figure 5 Anatomic types of left ventricular outflow tract obstruction. (A) Valvular stenosis related to a bicuspid aortic valve. Note the poststenotic dilation of the ascending aorta. (B) Hourglass narrowing of the ascending aorta, resulting in supravalvular stenosis. (C) Subvalvular stenosis resulting from diffuse hypertrophy of the ventricular septum. (D) Subvalvular stenosis resulting from a discrete subaortic membrane.

Indications for operation in patients with valvular aortic stenosis include syncope, congestive heart failure, or angina with a significant left ventricular outflow tract gradient. A significant gradient is usually considered to be at least 50 mmHg, unless cardiac output is greatly diminished. The timing of operative intervention in the child without symptoms who has moderate or severe obstruction is less well defined. Electrocardiographic changes indicating left ventricular strain or ischemia, either at rest or induced during exercise, are considered definite indications. Severe gradients, greater than 70 mmHg, are best treated promptly, even in the absence of symptoms or electrocardiographic changes. Options for relief of critical aortic stenosis in the neonate include open valvotomy, transventricular dilatation, and transcatheter therapy. The standard approach has been open valvotomy with cardiopulmonary bypass. Relief of valvular aortic stenosis is accomplished by direct incision of fused commissures. The incision is stopped 1 to 2 mm from the annulus to avoid detaching all leaflet support and creating significant aortic regurgitation. In a true bicuspid valve, rudimentary commissures must not be incised, or a flail leaflet will result. Although satisfactory reduction of the gradient can usually be accomplished, it may be difficult to provide complete relief of obstruction in all cases (10). Certain bicuspid valves may not lend themselves to valvotomy and may remain obstructive despite lack of commissural fusion. Although a few studies have reported good results with open aortic valvotomy (11,12), the mortality rates have remained high in most series. This may be in part because congenital aortic stenosis is a heterogeneous, complex disorder in which the aortic valvular and annular substrates may not be conducive to direct operative intervention. Transventricular dilatation, first described by Trinkle et al. (13) in 1975, provides a simple and effective technique of closed aortic valvotomy in infants. Through an apical left ventricular approach, progressive dilatation of the valve is accomplished with or without cardiopulmonary bypass. Transventricular dilatation provides effective relief of the obstruction without creating significant aortic insufficiency, and it avoids the myocardial ischemia inherent in open techniques (14). Transcatheter therapy through the femoral, umbilical, or carotid arteries is also quite effective in the neonatal population. The risks of balloon aortic valvotomy continue to include inadvertent aortic cusp perforation, with resultant severe aortic insufficiency as well as arterial injury. Most centers believe that surgical and balloon valvotomy for critical aortic stenosis in the neonate have similar outcomes and therapy is program specific (15–17). The goal of treatment of neonates’ and infants’ critical aortic stenosis is to establish an effective aortic orifice, thereby relieving the left ventricular pressure overload without inducing hemodynamically significant aortic insufficiency. Few of these patients are cured by their initial procedure. Because of the complexity of the disease (valvular stenosis, annular hypoplasia, varying degrees of subaortic stenosis, and the turbulent flow as a result of these), most patients require further operative intervention. Replacement of the aortic valve with a pulmonary autograft (Ross procedure) can be performed at any age, even in the neonate, and is the optimal procedure when more conservative treatment fails. Operation for subvalvular stenosis is recommended for the same indications as in valvular obstruction. The required gradient may be somewhat less for discrete subvalvular stenosis, however, because resection of the

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membrane is more often curative (18). Many patients with untreated discrete subvalvular stenosis later have progressive aortic regurgitation related to turbulence beneath the valve. Early resection of the membrane, often combined with a septal myectomy, may prevent this complication. Diffuse, muscular left ventricular outflow tract obstruction is more difficult to relieve. Transaortic resection of hypertrophied septal muscle, an aortoventriculoplasty, or bypass of the obstruction by insertion of a valved conduit from the left ventricular apex to the aorta is often needed (19,20). Supravalvular aortic stenosis is the least common site of left ventricular outflow tract obstruction. Isolated supravalvular aortic stenosis is rare in infants and may occur as part of the Williams syndrome in older children. This lesion is also highly variable, ranging from a membranous ringlike constriction, the classic hourglass deformity, to a diffuse form involving much of the aorta and brachio-cephalic vessels. The coronary arteries are exposed to high pressure, and degenerative changes may be seen early in life. Indications for operation include a gradient greater than 50 mmHg and evidence of coronary obstruction. Repair involves a longitudinal incision in the ascending aorta, extended proximally into both the noncoronary and right coronary cusps in an inverted Y configuration. The patch is then extended as far distally as necessary to relieve the obstruction.

LEFT-TO-RIGHT SHUNTS Atrial Septal Defect Atrial septal defect (ASD) accounts for approximately 10% of all congenital cardiac lesions. The defect in the septum allows blood to flow from the left to the right atrium, producing a volume overload of the right ventricle and pulmonary circulation. The shunt is directed from left to right because of the greater diastolic compliance and lower diastolic pressure in the right-sided chambers. Moderatesized defects result in pulmonary blood flow from one and one half to three times the systemic flow, whereas in large defects, the pulmonary to systemic flow ratio exceeds three to one. In most cases, pulmonary artery pressure and systemic blood flow remain normal. ASDs often occur as isolated lesions and tend to remain asymptomatic until early adult life (21). When present, symptoms are often nonspecific and consist of fatigue or mild dyspnea on exertion. In the presence of a large left-to-right shunt, overt congestive heart failure can occur at any age. Most commonly, however, nearly normal activity is maintained until the third or fourth decade of life, when symptoms of congestive heart failure become manifest. Any chronic left-to-right shunt may eventually produce changes of pulmonary vascular occlusive disease. Although these changes occur more frequently and earlier in life with defects that cause an increase in both pulmonary blood flow and pressure, uncomplicated ASDs may result in irreversible pulmonary occlusive changes. This problem is discussed in detail in the following section concerning VSDs. Most ASDs occur in the center of the atrial septum and are referred to as ostium secundum ASDs (Fig. 6). In approximately 5% to 10% of patients, the defect is located high in the atrial wall, where the superior vena cava joins the right atrium. These defects, known as sinus venosus ASDs, are almost always associated with drainage of the right upper lobe pulmonary veins into the right atrium or

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Figure 6 Locations of the three common types of atrial septal defect. The sinus venous defect is shown with anomalous drainage of the right upper lobe pulmonary vein (I). The ostium secundum defect is in the mid-portion of the septum (II). The ostium primum defect is located in the base of the septum, with its inferior edge formed by the continuity of the tricuspid and mitral valves (III). Note the cleft-like anomaly in the anterior leaflet of the mitral valve visible through the defect.

superior vena cava. About 5% of patients have another variety of defect, called ostium primum ASDs. These defects, which are located low in the septum, are part of a more complex anomaly referred to as endocardial cushion defect. In its simplest form, the ostium primum ASD is associated with a cleft in the anterior leaflet of the mitral valve. Mitral regurgitation may be present and can be severe. Any ASD in which the ratio of pulmonary to systemic blood flow (Qp/Qs) is at least 1.5:1 should be closed. Operative correction prevents the long-term complications of congestive heart failure and pulmonary vascular occlusive disease. Studies on patients who did not undergo surgery indicated that life expectancy is significantly reduced, to the fourth or fifth decade of life. To prevent these complications, elective repair before school age is advised. The technique of repair involves suture closure during cardiopulmonary bypass in most patients. Through an incision in the right atrium, the anatomy is easily exposed. In large defects, a patch of pericardium or polytetrafluoroethylene (Gore-Tex) may be necessary to avoid tension on the edges of the repair. In sinus venosus defects with partial anomalous pulmonary venous return, closure is achieved by modifying the patch to redirect the pulmonary veins to the left atrium. Ostium primum ASDs must also be repaired with a patch, because no lower rim of atrial septum is present. The lower edge of this defect is the junction of mitral and tricuspid valves on the crest of the ventricular septum. If significant mitral regurgitation is present before the operation, the valve should be studied carefully at operation and a valvuloplasty should be performed (22). Secundum ASDs of the appropriate size and location are now being closed routinely with transcatheter techniques. Results are good and continue to evolve (23).

Ventricular Septal Defect Excluding bicuspid aortic valve, VSD is the most common congenital structural cardiac anomaly. It accounts for 20%

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to 25% of all cardiac lesions and is estimated to occur in 2 of 1000 live-born infants. The hemodynamics, symptoms, and treatment depend on the size of the VSD and on the magnitude of the shunt. With a small VSD, right ventricular pressure remains normal, Qp/Qs is less than 1.5:1, and symptoms are usually absent. Moderate-sized defects have right ventricular pressure as great as half of systemic levels and a Qp/Qs as great as 2.5:1 or 3:1. Some degree of congestive heart failure is often present, but growth is usually normal. A large VSD is present when the Qp/Qs exceeds 3:1. Right ventricular pressure usually exceeds half that of the left ventricle, but it may be normal when PVR is low. Severe congestive heart failure and poor growth are often found. Approximately 50% of VSDs discovered in infancy undergo spontaneous reduction in size or complete closure. Thus, all defects are initially managed medically, with early surgical intervention reserved for those with refractory congestive heart failure. Small VSDs usually do not require treatment, and nearly all eventually close. Spontaneous closure is less likely with larger defects but may still occur. In response to the increasing pulmonary blood flow seen with moderate and large VSDs, pulmonary arteriolar resistance rises, and pulmonary artery pressure may also become elevated. Sustained increases in pulmonary artery flow and pressure can lead to early development of pulmonary vascular occlusive disease. Irreversible changes in resistance may become apparent by two years with an isolated large VSD or by six months in patients with associated trisomy 21. These changes have been classified by Heath and Edwards (24) on a histologic level. The early changes in the small pulmonary arteries and arterioles of medial hypertrophy (grade I) and intimal proliferation (grade II) are considered reversible. More advanced changes, consisting of intimal fibrosis (grade III) and progressive dilation lesions with eventual arterial necrosis (grades IV–VI), are irreversible. Cardiac catheterization documents the magnitude of the shunt, right ventricular and pulmonary artery pressures, and PVR. Left ventricular cineangiography and two-dimensional echocardiography delineate the locations and number of VSDs. Associated defects, including coarctation, aortic stenosis, PDA, and pulmonary stenosis, are common and must be identified. VSDs may be single or multiple. Most VSDs are single and located high in the membranous portion of the ventricular septum, just beneath the aortic valve. These defects are classified by their relationship to structures in the right ventricle (25,26). The typical high VSD, referred to as infundibular VSD, can be found beneath the anteroseptal commissure of the tricuspid valve (Fig. 7). Inlet VSDs are located more inferiorly, beneath the septal leaflet of the tricuspid valve, and subarterial VSDs occur high in the septum immediately below the pulmonary valve. When a VSD extends to the annulus of the tricuspid valve, it is referred to as perimembranous; otherwise, it is a muscular defect. Muscular defects occurring in the heavily trabeculated portion of the septum are more likely to be multiple. The indications for surgery depend on the hemodynamic situation and presence of symptoms. With moderate and large VSDs, persistent, severe congestive heart failure (often with failure to thrive) despite medical management is an operative indication. When heart failure is well controlled medically, the primary factors influencing the decision to operate are the pulmonary arterial pressure and PVR. These should be assessed by 12 months of age. If the pulmonary arterial pressure is greater than half of systemic levels by this age, surgical intervention should be carried

Figure 7 Locations of the common types of ventricular septal defect. Subarterial defects (I) are located in the infundibular portion of the septum, beneath the pulmonary valve. In the most common type, perimembranous infundibular (II), part of the defect edge is formed by the tricuspid valve. Inlet defects (III) are found more inferiorly, beneath the septal leaflet of the tricuspid valve. Muscular defects (IV) are remote from the valve annulus.

out to prevent progressive changes in PVR. Moderate defects with minimal symptoms and normal pulmonary artery pressure and PVR may continue to be observed, because late spontaneous closure could still occur. If VSDs do not close by three to five years of age, operative therapy is indicated. If the PVR is severely elevated, above two-thirds of systemic resistance, VSD closure may be contraindicated. When PVR reaches this level, it will often progress further and eventually exceed that of the systemic circulation. Reversal of flow through the defect then occurs (Eisenmenger’s syndrome), and cyanosis results. Closure of the VSD in this situation would result in right-sided heart failure and shortened life expectancy. The optimal surgical treatment of VSDs consists of patch closure. In infants, deep hypothermia with reduced flow on cardiopulmonary bypass is used to facilitate exposure and reduce operative risk. The operative approach for most defects is through the right atrium and tricuspid valve. A patch of polytetrafluoroethylene (Gore-Tex) is sutured to the right ventricular side of the defect edge; care is taken not to injure the conduction tissue, which must be precisely located for each VSD (27). In complex lesions, the atrioventricular node and bundle of His may be identified with endocardial mapping. Subpulmonary defects are best closed through the right atrium or pulmonary artery. Anterior muscular VSDs can often be quite difficult to close because they are obscured by the heavy trabeculations of the right ventricle. Apical muscular defects may require a small apical left ventriculotomy for proper exposure. In each case, initial exposure and evaluation through the tricuspid valve allow the surgeon to plan the best approach. Complete repair in infancy may not be advisable in all cases. When multiple defects are found, for example, palliation with pulmonary artery banding may be indicated. With constriction of the main pulmonary artery, the resistance to flow into the lungs is markedly increased, reducing the magnitude of the left-to-right shunt and controlling

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congestive heart failure. Further, the pulmonary vascular bed is protected against the development of pulmonary vascular occlusive disease, allowing complete repair to be done at less risk when the patient is older. Because of the good results of complete repair of most congenital heart defects in infants, multiple, complicated VSDs may be one of the few remaining indications for pulmonary artery banding in infants.

Patent Ductus Arteriosus PDA is the most common cause of left-to-right shunting at the great artery level. Because aortic pressure is greater than pulmonary artery pressure throughout all phases of the cardiac cycle, shunting occurs in both systole and diastole. This gives rise to the typical continuous or machinery-like murmur. Additionally, the diastolic runoff into the lowresistance pulmonary circulation results in a wide pulse pressure and bounding arterial pulses. A large PDA may allow substantial left-to-right shunting and significant heart failure. Pulmonary artery pressure and PVR may be elevated as described in the previous section, resulting in eventual pulmonary vascular occlusive disease. The anatomy of the duct is quite constant. Its aortic end originates just distal to the left subclavian artery, and it enters the pulmonary artery bifurcation or proximal left pulmonary artery. Any duct that remains patent beyond infancy should be closed. Elective closure is usually recommended in early childhood. A large PDA in a patient with heart failure and pulmonary hypertension should be closed immediately. Small PDAs may be complicated by bacterial endarteritis, aneurysm formation, or calcification. Closure prevents these complications. The operative approach is through a left thoracotomy. Exposure of the duct is easily accomplished after opening the mediastinal pleura. Care must be taken to avoid injury to the recurrent laryngeal nerve. Closure of the duct may be done by simple ligation, usually over a length of the duct, by division and suture, or by hemoclip occlusion in premature infants. Recently, new forms of therapy have been introduced, including transluminal placement of coils, umbrellas, or clamshell devices (28–30) and clipping of the PDA by means of video-assisted thoracoscopy (31).

Figure 8 (A) Tricuspid atresia with normally related great vessels and without a ventricular septal defect. Pulmonary blood flow is duct dependent. (B) When a septal defect is present, forward flow across the pulmonary valve can occur.

and the pulmonary artery receives the direct output of the left ventricle, resulting in an increase in pulmonary blood flow and pressure. The initial surgical treatment of tricuspid atresia with decreased pulmonary blood flow is aimed at increasing this flow by a systemic artery–to–pulmonary artery shunt (33,34). The modified Blalock–Taussig procedure, in which an interposition graft of polytetrafluoroethylene (Gore-Tex) is placed between the sides of the subclavian and pulmonary arteries, is the most commonly used operation (Fig. 9) (35). This procedure provides a source of pulmonary blood flow with minimum risk of increasing PVR or causing congestive heart failure. A relatively large graft (4 or 5 mm) is used, even in infants, because flow is limited by the smaller-sized native vessels. With growth of the subclavian and pulmonary arteries, flow can potentially increase and maintain effective palliation. Other shunt procedures are used much less commonly today. These include the Waterston (ascending aorta–to–right pulmonary artery), Potts (descending aorta– to–left pulmonary artery), and Glenn (superior vena cava– to–right pulmonary artery) anastomoses.

RIGHT-TO-LEFT SHUNTS Tricuspid Atresia Tricuspid atresia is an uncommon defect in which the tricuspid valve is completely absent. The ASD that is invariably present shunts all vena caval blood directly to the left atrium. The degree of cyanosis depends on the amount of pulmonary blood flow. When no communication between left and right ventricles is present, the ductus arteriosus is the sole source of flow to the lungs (Fig. 8A). These patients are deeply cyanotic in early infancy, and emergency prostaglandin infusion may be necessary (32). Prostaglandins of the E type relax the smooth muscle in the wall of the duct and are used to maintain ductal patency before palliative surgery. In some cases, a VSD allows blood to flow from the left ventricle directly to the hypoplastic right ventricle and then to the pulmonary circuit (Fig. 8B). Depending on the size of this communication, cyanosis may be mild. However, these VSDs often undergo spontaneous reduction in size, thus decreasing pulmonary blood flow as the child grows. Less commonly, the aorta and pulmonary artery are transposed,

Figure 9 (A) Standard Blalock—Taussig anastomosis between the right subclavian and pulmonary arteries. (B) Modification of the procedure with an interposition polytetrafluoroethylene graft.

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The shunt procedure is then followed in many circumstances by a bidirectional Glenn or hemi-Fontan procedure. This second stage removes the volume load imposed by the aortopulmonary shunt, improves the effective pulmonary blood flow, and may allow ventricular remodeling prior to the Fontan procedure. The third stage, and the most satisfactory form of treatment for tricuspid atresia, was first reported in 1971 by Fontan and Baudet (36). Originally done by direct connection of the right atrium to the pulmonary artery or hypoplastic right ventricle, this procedure is now most commonly performed with the lateral tunnel technique (37). A tube of appropriately sized polytetrafluoroethylene (Gore-Tex) is opened longitudinally and sewn within the atrium to incorporate the orifices of the superior and inferior venae cavae without obstructing the pulmonary venous return (Fig. 10). Many centers now routinely incorporate a fenestration of the lateral baffle to allow a small degree of mixing of saturated and desaturated blood. This serves as a ‘‘pop-off’’ mechanism, limiting systemic venous pressures to an extent and preserving cardiac output, albeit with desaturated blood. Later, the fenestration is closed by means of a snare device or by transcutaneous umbrella occlusion, restoring normal systemic oxygenation and eliminating left ventricular volume overload. Although the early results with this procedure have been most gratifying, long-term follow-up is lacking and a late rise in the hazard function for survival has been noted (38–40). Specifically, the late

Figure 10 Fontan procedure (lateral tunnel technique). Following a hemiFontan reconstruction, the inferior vena caval blood is tunneled within the atrium to the confluent pulmonary arteries.

effects of chronic venous hypertension and lack of pulsatile pulmonary blood flow are unknown.

Tetralogy of Fallot The most common congenital heart defect resulting in cyanosis is tetralogy of Fallot. In this abnormality, obstruction to pulmonary blood flow occurs at the level of the right ventricular outflow tract, usually as the result of a combination of infundibular and pulmonary valvular stenoses (Fig. 11). The basic anatomic defect is anterior and superior displacement of the infundibular (outlet) portion of the ventricular septum. This obstructs right ventricular outflow and results in a large malalignment VSD (Fig. 12). Overriding of the aorta above the VSD and right ventricular hypertrophy (related to obstruction) complete the tetrad. The clinical status of patients with tetralogy of Fallot depends on the severity of the right ventricular outflow tract obstruction. In its severest form, pulmonary atresia may be present with duct-dependent pulmonary blood flow. More commonly, infundibular obstruction coexists with varying degrees of pulmonary valve hypoplasia, resulting in moderate cyanosis. Patients with tetralogy of Fallot may have hypercyanotic ‘‘tet’’ spells. These occur when the dynamic portion of the obstruction is transiently worsened as a result of increased contractility of the muscle in the right ventricular outflow tract, often in combination with a decrease in systemic vascular resistance. Pulmonary blood flow is dramatically reduced, with an increase in the right-to-left shunt across the VSD. Complete repair is now possible with good results in the infant and neonate (41). It is believed that by early repair, the consequences of severe right ventricular hypertrophy (ventricular systolic and diastolic dysfunction) can be reduced or eliminated. In addition, early reestablishment of normal pulsatile pulmonary arterial blood flow may

Figure 11 Typical anatomy in tetralogy of Fallot. The large ventricular septal defect (VSD) with overriding of the aorta is shown. The right ventricular outflow tract obstruction results in desaturated blood crossing the VSD directly into the aorta.

Chapter 35: Congenital Heart Lesions

Figure 12 Cineangiogram from a patient with tetralogy of Fallot. Abbreviations: AV, aortic valve; IS, infundibular stenosis; LV, left ventricle; PV, pulmonary valve; RV, right ventricle; VSD, ventricular septal defect.

improve the development of alveoli and intraparenchymal pulmonary arteries (42). Contraindications to repair in infancy may include significant hypoplasia of the pulmonary arteries and the origin of the anterior descending coronary artery from the right coronary artery. Because relief of the obstruction in the latter situation may require the insertion of a valve-bearing conduit or allograft, repair may best be postponed until the patient reaches an age at which a larger conduit may be inserted. Complete repair includes relief of right ventricular outflow tract obstruction and closure of the VSD. Relief of the obstruction is governed by the individual anatomy. Whenever possible, pulmonary valve function should be preserved and resection of right ventricular muscle should be minimized (43). In the past, the standard repair involved a right ventriculotomy to close the VSD and divide or resect the obstructing muscle bundles. Obstruction at the level of the pulmonary valve or annulus was dealt with by a commissurotomy or transannular patch as necessary. In the vast majority of patients, this can be performed through a transatrial approach across the tricuspid valve. In neonates and infants, obstructing muscle bundles need only be divided, not resected. If pulmonary valvular stenosis is present, a commissurotomy is performed. Pulmonary valvular hypoplasia is treated with a limited (< 10 mm) transannular patch. Only in cases of true infundibular hypoplasia are a formal ventriculotomy and large outflow tract patch needed. The operative mortality rate for repair of tetralogy of Fallot is 5% or less. Transatrial repair in the neonatal and infant period may improve the development of the pulmonary vascular bed and help to avoid the late sequelae of a right ventriculotomy (right ventricular dysfunction and ventricular dysrhythmias).

INADEQUATE MIXING Transposition of the Great Arteries In transposition of the great arteries (TGA), two separate and parallel circulations—systemic and pulmonary—are present. In the simplest form of TGA, the aorta arises from

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the right ventricle and receives the desaturated systemic venous return and the pulmonary artery arises from the left ventricle and receives oxygenated pulmonary venous blood (Fig. 13). Some exchange of blood between the two circulations (mixing) must be present to sustain life. This most commonly occurs by means of an interatrial communication allowing saturated blood to pass from the left to the right atrium and then to the right ventricle and aorta. An equal amount of desaturated blood must pass from right to left atrium to reach the pulmonary circulation. The adequacy of this mixing determines the amount of saturated venous blood reaching the aorta (effective systemic blood flow) and desaturated venous blood reaching the pulmonary artery (effective pulmonary blood flow), and thus the clinical status of the infant. Even with adequate intracardiac mixing, the neonate with TGA has noticeable cyanosis. Quite often, the interatrial defect is restrictive, and profound cyanosis is detected within hours of birth. Arterial PO2 may be less than 25 to 30 mmHg, and progressive acidosis during the first days of life can occur. The clinical presentation is also influenced by the presence of associated lesions. In approximately 10% of cases, a large VSD or hemodynamically significant pulmonary stenosis is present. When only a VSD is present, cyanosis is lessened because mixing occurs at both the atrial and ventricular levels. Because total pulmonary blood flow is elevated further, however, severe congestive heart failure usually results. If pulmonary stenosis is also present, volume overload is reduced, tending to lessen the effect of the VSD. When pulmonary stenosis is particularly severe, with or without a VSD, total pulmonary blood flow may be reduced to a level below normal, and cyanosis may be worsened. Finally, communication between the two circulations may also occur from a PDA. Similar to the situation with a large VSD, both effective and total pulmonary blood flows are increased, improving oxygenation but resulting in congestive heart failure.

Figure 13 Anatomy of transposition of the great arteries. The aorta arises from the right ventricle, and the pulmonary artery arises from the left ventricle.

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The initial treatment of an infant with TGA is aimed at improving the intracardiac mixing by enlarging the ASD. This is performed in the cardiac catheterization laboratory after the diagnosis has been established. The procedure, known as balloon atrial septostomy and originated by William Rashkind in 1966, involves passage of a balloon-tipped catheter from the right to the left atrium across the foramen ovale. The procedure can be performed in the catheterization laboratory or in the intensive care unit, with echocardiographic guidance used for accurate catheter placement. Once the catheter tip has been positioned in the left atrium, the balloon is inflated and the catheter is forcibly withdrawn to tear a portion of the atrial septum. This procedure is repeated two or three times to ensure a wide patency in the septum. Improvement in arterial oxygenation is usually noted immediately after the septostomy. A few neonates may continue to have unsatisfactory oxygenation even with a large ASD (44). The poor mixing in these cases may be caused by the failure of the PVR to fall to its normally low level after birth. The diastolic compliances of the two ventricles remain about equal, and no mixing of blood between the two sides occurs. When this is coupled with closure of the ductus arteriosus, effective pulmonary blood flow may be poor. This situation may be treated temporarily by the administration of a prostaglandin infusion, maintaining ductal patency and allowing mixing at the great vessel level (45,46). This restores satisfactory oxygenation for a few days until PVR falls. When TGA is associated with a large VSD, significant congestive heart failure and pulmonary hypertension may be apparent very early in life. Prior to the arterial switch repair, banding of the main pulmonary artery to reduce pulmonary blood flow and pressure was indicated. This procedure, however, invariably results in a drop in arterial PO2 because pulmonary blood flow is reduced by the band. An adequate interatrial communication is mandatory. If severe pulmonary stenosis is present and pulmonary blood flow and pressure are below normal, a systemic artery–to– pulmonary artery (Blalock–Taussig) shunt may be performed. Correction of TGA may be performed at the atrial, ventricular, or great vessel level, depending on the exact anatomy and associated defects. Prior to the 1980s, physiologic correction was achieved at the atrial level by redirecting venous inflow. This technique was first successfully performed by Senning in 1959 and revised by Mustard in 1964. Mustard’s procedure involves the complete removal of the atrial septum, followed by the placement of a ‘‘baffle’’ (usually pericardium) to repartition the atria (Fig. 14). Vena caval blood drains behind the baffle into the mitral valve, left ventricle, and pulmonary artery, and the pulmonary veins drain into the tricuspid valve and then into the systemic circulation through the right ventricle. In the Senning procedure, little prosthetic material is used because redirection of venous inflow is done with the patient’s own atrial tissue. Although more difficult to perform, Senning’s operation may allow better growth and function of the atrial chambers. The operative mortality rates for both procedures are low (< 5%), even in infancy, and long-term results are good. Significant technical complications, such as obstruction to caval (usually superior vena caval) or pulmonary venous flow and troublesome atrial arrhythmias, continue to be a problem. The major long-term difficulty with both the Mustard and the Senning procedures is the possible failure of the right ventricle to perform at systemic workloads for long periods (47). Late congestive heart failure, often with tricuspid insufficiency, has been recognized in a small percentage

Figure 14 Appearance of the atrial baffle in the Mustard procedure. Superior and inferior vena caval blood passes behind the patch to the mitral valve. The pulmonary venous blood passes over the patch to the tricuspid valve.

of children. Careful studies of right ventricular function late after repairs have shown impaired performance even in patients without symptoms. The exact cause remains unclear. Most children, however, have excellent long-term results after Mustard or Senning operations. During the last decade, the arterial switch has emerged as the procedure of choice in patients with TGA (Fig. 15). The arterial repair of TGA has the benefit of restoring the left ventricle as the systemic pump (48). Although early operative mortality rates were quite high, current techniques have reduced the risk to acceptable levels. These technical improvements include the refinement of coronary transfer, repair of the pulmonary artery with a pantaloon pericardial patch, and superior myocardial protection. Successful performance of this procedure seems to require that the left ventricle be prepared to pump against systemic resistance. Patients with TGA and a large VSD retain high pressure in the left ventricle and are ideal candidates for arterial repair. Banding of the pulmonary artery to raise

Figure 15 Steps in the performance of the arterial switch procedure. (A) The pulmonary artery is transected just proximal to its bifurcation. The aorta is transected at the same level. The coronary arteries are removed with wide buttons of adjacent aorta. (B) The distal aorta is brought behind the pulmonary artery confluence and anastomosed to the proximal pulmonary artery. The coronary arteries are then relocated to the new aorta. (C) The right ventricular outflow tract is reconstructed by anastomosing the distal pulmonary artery confluence to the proximal aorta.

Chapter 35: Congenital Heart Lesions

Figure 16 Repair of transposition of the great arteries with ventricular septal defect and pulmonary stenosis. The defect is patched to place both great vessels in continuity with the left ventricle. The pulmonary artery is ligated proximally. The right ventricle is then connected to the distal pulmonary artery with a valved conduit.

left ventricular pressure in some patients with TGA and intact ventricular septum has been advocated to prepare the left ventricle for an arterial switch procedure (49). When arterial repair is done within the first month of life, however, preliminary banding is unnecessary. In patients with TGA, large VSD, and left ventricular outflow tract obstruction (pulmonary stenosis), repair can be carried out at both the ventricular and great vessel levels. The VSD is closed in a way that diverts left ventricular blood through the defect into the aorta (Fig. 16). The main pulmonary artery is ligated, and the right ventricle is connected to the pulmonary artery bifurcation with a valved extracardiac conduit. The left ventricle is restored as the systemic pump, and the coronary arteries do not require relocation (50). Recently, surgeons have been performing a modified Rastelli procedure utilizing a sleeve of autograft aorta to avoid the use of a prosthetic right ventricle to PA conduit. This approach allows for primary correction in the young patient and perhaps reduces the need for further operative intervention (51).

HYPOPLASTIC LEFT HEART SYNDROME Hypoplastic left heart syndrome (HLHS) is a collective term referring to a spectrum of congenital heart defects with varying degrees of hypoplasia of left-sided cardiac structures. The vast majority of patients with HLHS (84%) have aortic and mitral atresia, hypoplasia, or stenosis (classic HLHS), whereas 16% have a malaligned atrioventricular canal defect (52). A coarctation is present in more than 80% of patients. Patients with HLHS have complex cardiopulmonary physiology. The pulmonary arteries, ductus arteriosus, and descending aorta are arranged in parallel circulations. Qp/ Qs depends on the balance between PVR and systemic vascular resistance. Because of its hypoplasia and obstructed outflow, the left ventricle is essentially a nonfunctional structure.

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Pulmonary venous return is directed across an ASD and mixes with the systemic venous return. The right ventricle provides both the pulmonary and systemic output. Coronary and systemic perfusion is maintained through the ductus arteriosus. In most cases, the PVR declines after birth, leading to excessive pulmonary blood flow. Although this produces good arterial oxygen saturations, the systemic perfusion may be poor, resulting in metabolic acidosis. Without intervention, HLHS is almost uniformally fatal in the first weeks of life. Initial therapy is directed at maintaining an adequate PDA with prostaglandin E. This allows the child’s overall condition to stabilize. Surgical options for the treatment of HLHS consist of neonatal cardiac transplantation or staged reconstruction. In the best of situations, neonatal cardiac transplantation is associated with a one-year survival of 80% to 90% (53). However, because of the limited availability of organ donors, approximately 15% to 25% of patients die while awaiting organ transplantation. In addition, the patient faces the need for lifelong immunosuppression, with its attendant risks. For these reasons, many centers have opted to pursue palliative repair in this group of patients. The repair of HLHS involves three separate procedures: the Norwood, bidirectional Glenn, and Fontan procedures. The Norwood operation connects the right ventricle and pulmonary valve to the augmented ascending, transverse, and descending aorta and provides a limited amount of pulmonary blood flow through a modified Blalock–Taussig shunt. In the last two years, a modification of the Norwood procedure utilizing an RV-to-PA conduit for pulmonary blood flow has been revisited (54). The absence of a systemic artery–to– pulmonary artery shunt helps avoid the diastolic runoff inherent in this circulation and may prove beneficial in some patients early after the Norwood procedure (55). Performed at six months, the bidirectional Glenn procedure consists of division of the aortopulmonary shunt and connection of the superior vena cava to the cephalad portion of the right pulmonary artery. This decreases the volume load on the right ventricle and improves the effective pulmonary blood flow. A fenestrated Fontan procedure is then planned at 18 months to channel the desaturated inferior vena caval blood to the undersurface of the right pulmonary artery. Firststage reconstruction is now associated with an 85% to 90% in-hospital survival, and the actuarial survival for the three stages together is approximately 75% at two years (56). Overall, the outlook for patients born with HLHS has improved dramatically during the past few years. Cardiac transplantation offers good intermediate results but is plagued by donor shortages and the need for immunosuppression. Results of palliative procedures have improved greatly, but three operative procedures are required, and the right ventricle is retained as the systemic ventricle. Further study is needed to better categorize which patients benefit most from these treatment modalities.

SUMMARY Successful surgical treatment of most forms of congenital heart disease is now possible. However, the surgeon must be knowledgeable about more than just cardiac anatomy to achieve this success. In particular, a thorough understanding of cardiac physiology in infants and children is essential so that a well-conceived treatment plan can be devised for even the most complex of anomalies. In some cases, one or more palliative procedures may be necessary,

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either because no definitive repair is ultimately possible or because it is best postponed until the patient is older. These procedures must provide satisfactory immediate palliation and, in addition, must ensure that ultimate repair can be performed with the lowest possible risk to the patient. Early corrective surgery, now routinely performed for many defects, is expected to significantly reduce the associated complications of congenital heart disease. The elimination of pulmonary vascular disease, chronic cyanosis, and long-standing congestive heart failure are only a few examples of the advantages of early correction. However, examining the benefits of surgical repair in light of the late results is increasingly important. The development of ventricular dysfunction and electrophysiologic abnormalities are examples of potentially serious consequences that may detract from an apparent early success. In some cases, a number of late studies have led to alterations in surgical technique designed to maintain excellent long-term functional results. These evaluations serve as a stimulus for cardiac surgeons to continue to strive for improvement in the treatment of congenital heart disease.

REFERENCES 1. Scott HW Jr, et al. Study of the renal pressure system in experimental coarctation of the abdominal aorta. Am Surg 1977; 43:771. 2. Parker FB, et al. Preoperative and postoperative renin levels in coarctation of the aorta. Circulation 1982; 66:513. 3. Simsolo R, et al. Long-term systemic hypertension in children after successful repair of coarctation of the aorta. Am Heart J 1988; 115:1268. 4. Waldhausen J. Repair of coarctation of the aorta with a subclavian flap. J Thorac Cardiovasc Surg 1966; 51:532. 5. Tynan M, Finley JP, Fontes V, et al. Balloon angioplasty for the treatment of native coarctation: results of Valvuloplasty and Angioplasty of Congenital Anomalies Registry. Am J Cardiol 1990; 65:790. 6. Hijazi ZM, Geggel RL, Marx GR, Rhodes J, Fulton DR. Balloon angioplasty for native coarctation of the aorta: acute and mid-term results. J Invasive Cardiol 1997; 9(5):344–348. 7. Macdonald S, Thomas SM, Cleveland TJ, Gaines PA. Angioplasty or stenting in adult coarctation of the aorta? A retrospective single center analysis over a decade. Cardiovasc Interventional Radiol 2003; 26(4):357–364. 8. Hijazi ZM, Fahey JT, Kleinman CS, et al. Balloon angioplasty for recurrent coarctation of the aorta. Immediate and long-term results. Circulation 1991; 84:1150. 9. Sandor CGS, et al. Long-term follow-up of patients after valvotomy for congenital valvular aortic stenosis in children. J Thorac Cardiovasc Surg 1980; 80:171. 10. Ankeney JL, Tzeng TS, Liebman J. Surgical therapy for congenital aortic valvular stenosis. J Thorac Cardiovasc Surg 1983; 85:41. 11. Buich M, et al. Open valvotomy for critical aortic stenosis in infancy. Br Heart, J 1990; 63:37. 12. Messina LM, et al. Successful aortic valvotomy for severe congenital valvular aortic stenosis in the newborn infant. J Thorac Cardiovasc Surg 1984; 88:92. 13. Trinkle JK, et al. Closed aortic valvotomy and simultaneous correction of associated anomalies in infants. J Thorac Cardiovasc Surg 1975; 69:758. 14. Mosca RS, Jannettoni MD, Schwartz SM, et al. Critical aortic stenosis in the neonate: a comparison of balloon valvuloplasty and transventricular dilation. J Thorac Cardiovasc Surg 1995; 109(1):147–154. 15. McCrindle BW, Blackstone BH, William WG, et al. Are outcomes of surgical versus transcatheter balloon valvotomy equivalent in neonatal critical aortic stenosis? Circulation 2001; 104(12, suppl 1):1-152–1-158.

16. Marasini M, Zannini L, Ussia GP, et al. Discrete subaortic stenosis: incidence, morphology and surgical impact of associated anomalies. Ann Thorac Surg 2003; 75(6):763–768. 17. McElhinney DB, Retrossian B, Tworetzkyw, et al. Issues and outcomes in the management of supravalvular aortic stenosis. Ann Thorac Surg 2000; 69(2):562–567. 18. Shem-Tov A, et al. Clinical presentation and natural history of mild discrete subaortic stenosis. Circulation 1982; 66:509. 19. Bjornstad PG, et al. Aortoventriculoplarty for tunnel subaortic stenosis and other obstructions of the left ventricular outflow tract. Circulation 1979; 60:59. 20. Sweeney MS, et al. Apioaortic conduits for complex left ventricular outflow obstruction: 10-year experience. Ann Thorac Surg 1986; 42:609. 21. Craig RJ, Selzer A. Natural history and prognosis of atrial septa defect. Circulation 1968; 37:805. 22. Losay J, et al. Repair of atrial septal defect primum. J Thorac Cardiovasc Surg 1978; 75:248. 23. Koenig P, Cao QL, Heitschmidt M, et al. Role of intra cardiac echocardiographic guidance in transcatheter closure of atrial septal defects and patent foramen ovule using the Amplatzer device. J Interventional Cardiol 2003; 16(1):51–62. 24. Heath D, Edwards JE. The pathology of hypertensive pulmonary vascular disease: a description of six grades of structural changes in the pulmonary arteries with special reference to congenital cardiac septal defects. Circulation 1958; 18:533. 25. Becker AE, Anderson RH. Classification of ventricular septal defects—a matter of precision. Heart Vessels 1985; 1:120. 26. Lincoln C, et al. Transatrial repair of ventricular septa defects with reference to their anatomic classification. J Thorac Cardiovasc Surg 1977; 74:183. 27. Milo S, et al. Surgical anatomy and atrioventricular conduction tissues of hearts with isolated ventricular septal defects. J Thorac Cardiovasc Surg 1980; 79:244. 28. Rashkind WJ, Cuaso CC. Transcatheter closure at patent ductus arteriosus. Pediatr Cardiol 1979; 1:3. 29. Sato K, et al. Transfemoral plug closure of patent ductus arteriosus: experience in 61 consecutive cases treated without thoracotomy. Circulation 1975; 51:337. 30. Rothenberg SS. Transcatheter versus surgical closure of patent ductus arteriosus. N Engl J Med 1994; 330:1014. 31. Laborde F, et al. A new video-assisted thoracoscopic surgical technique for interruption of patent ductus arteriosus in infants and children. J Thorac Cardiovasc Surg 1993; 105:278. 32. Freed MD, et al. Prostaglandin E1 in infants with ductus arteriosusdependent congenital heart disease. Circulation 1981; 64:899. 33. de Brux JL, et al. Tricuspid atresia. J Thorac Cardiovasc Surg 1978; 48:378. 34. Dick M, Fyler DC, Nadas AS. Tricuspid atresia: clinical course in 101 patients. Am J Cardiol 1975; 36:327. 35. Blalock A, Taussig HB. The surgical treatment of malformations of the heart. JAMA 1945; 128:189. 36. Fontan F, Baudet S. Surgical repair of tricuspid atresia. Thorax 1971; 26:240. 37. Jonas RA, Castaneda AR. Modified Fontan procedure: atrial baffle and systemic venous to pulmonary artery anatomic techniques. J Cardiac Surg 1988; 3:91. 38. Fontan F, et al. Repair of tricuspid atresia in 100 patients. J Thorac Cardiovasc Surg 1983; 85:647. 39. Fontan F, et al. Outcome after a ‘‘perfect’’ Fontan operation. Circulation 1990; 81:1520. 40. Sanders SP, et al. Clinical and hemodynamic results of the Fontan operation for tricuspid atresia. Am J Cardiol 1982; 49:1733. 41. Touati G, et al. Primary repair of tetralogy of Fallot in infancy. J Thorac Cardiovasc Surg 1990; 99:396. 42. Rabinovitch M, et al. Growth and development of pulmonary vascular bed in patients with tetralogy of Fallot with or without pulmonary atresia. Circulation 1981; 64:1234. 43. Bove EL, et al. The influence of pulmonary insufficiency on ventricular function following repair of tetralogy of Fallot. J Thorac Cardiovasc Surg 1983; 85:691.

Chapter 35: Congenital Heart Lesions 44. Mair DD, Ritter DF. Factors influencing systemic arterial oxygen saturation in complete transposition of the great arteries. Am J Cardiol 1973; 31:742. 45. Benson LN, et al. Role of prostaglandin E1 infusion in the management of transposition of the great arteries. Am J Cardiol 1979; 44:691. 46. Lang P, et al. Use of prostaglandin E1 in infants with D-transposition of the great arteries and intact ventricular septum. Am J Cardiol 1979; 44:76. 47. Benson LN, et al. Assessment of right ventricular function during supine bicycle exercise after Mustard’s operation. Circulation 1981; 65:1052. 48. Jatene AD, et al. Anatomic correction of transposition of the great vessels. J Thorac Cardiovasc Surg 1976; 72:364. 49. Yacoub M, et al. Clinical and hemodynamic results of the twostage anatomic correction of simple transposition of the great arteries. Circulation 1980; 62(suppl 1):1190. 50. Marcelletti C, et al. The Rastelli operation for transposition of the great arteries. J Thorac Cardiovasc Surg 1976; 72:427. 51. Metras D, Kreitmann B. Modified Rastelli using an autograft: a new concept for correction of transposition of the great arteries with ventricular septal defect and left ventricular outflow tract obstruction. Pediatr Cardiac Surg Annu Semin Thorac Cardiovasc Surg 2000; (3):117–124. 52. Bharati S, Lev M. The surgical anatomy of hypoplasia of aortic tract complex. J Thorac Cardiovasc Surg 1984; 88:97.

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53. Bailey L, et al. Pediatric heart transplantation: issues relating to outcome and results. The Loma Linda Pediatric Heart Transplant Group. J Heart Lung Transplant 1992; 11:5267. 54. Sano S, Ishino K, Kawada M, et al. Right ventricle-pulmonary artery shunt in first-stage palliation of hypoplastic left syndrome. J Thorac Cardiovasc Surg 2003; 126(2):504–509. 55. Mair R, Tulzen G, Sames E, et al. Right ventricular to pulmonary artery conduit instead of modified Blalock-Taussig shunt improves postoperative hemodynamics in newborns after the Norwood operation. J Thorac Cardiovasc Surg 2003; 126(5): 1378–1384. 56. Iannettoni MD, Bove EL, Mosca RS. Improving results with first-stage palliation for hypoplastic left heart syndrome. J Thorac Cardiovasc Surg 1994; 107:934.

FURTHER READING Baue AE, et al., eds. Glenn’s Thoracic and Cardiovascular Surgery. 6th ed. Norwalk: Conn. Appleton & Lange, 1996. Castaneda AR, et al. Cardiac Surgery of the Neonate and Infant. Philadelphia: WB Saunders, 1994. Garson A Jr, Bricker JT, McNonara DG, eds. The Science and Practice of Pediatric Cardiology. Philadelphia: Lea & Febiger, 1990.

36 Acquired Cardiac Disorders Dipin Gupta, Andrew C. Fiore, and Glenn J. R. Whitman

The RCA runs in the right atrioventricular groove, where in 80% to 85% of cases it gives off the PDA, continuing with terminal branches to the posterior left ventricular wall. The RCA feeds the anterior surface of the right ventricle with acute marginal branches.

INTRODUCTION In contrast to congenital heart disease, in which surgical intervention is usually required to restore the underlying pathophysiology to normalcy, acquired cardiac disorders are often amenable to medical management. Notwithstanding this circumstance, several diseases are still best treated surgically and will probably remain so for many years to come. Acquired heart disease in which surgical management plays a prominent role forms the basis for this chapter. The first sections focus on ischemic heart disease and abnormalities of the cardiac valvular system, and on the role that surgery plays in correcting disordered physiology in these conditions. Heart failure—and the novel surgical therapies that are currently being developed—forms the basis of the next section. The final sections concentrate on diseases that require surgical attention less commonly, but in which the cardiac surgeon still renders important help in the delivery of optimal care. These disorders include cardiac dysrhythmias, pericardial disease, and cardiac tumors.

Coronary Veins Three venous systems drain the coronary circulation. (i) The coronary sinus located in the posterior atrioventricular groove receives blood from the great, middle, and small cardiac veins. The great cardiac vein ascends along the LAD and then follows the circumflex artery to empty into the coronary sinus. The middle cardiac vein follows the PDA, again emptying into the coronary sinus. The small cardiac vein follows the RCA in the atrioventricular groove before it, too, joins the coronary sinus. (ii) The thebesian veins are tiny venous orifices that drain directly into any of the four chambers of the heart. (iii) The anterior cardiac veins drain the right ventricular coronary system, traversing the right ventricular free wall and crossing the atrioventricular groove to empty directly into the right atrium.

Coronary Blood Flow

ISCHEMIC HEART DISEASE The Coronary Circulation Coronary Arteries

The heart extracts a greater percentage of delivered oxygen than any other organ in the body. In fact, the heart uses 60% to 70% of the oxygen supplied, as opposed to only 25% for the body as a whole. Coronary sinus oxygen content is only 4 to 6 mL oxygen/dL blood, which corresponds to an oxygen tension of approximately 24 mmHg and a hemoglobin oxygen saturation of only 20% to 30%. Therefore, even at rest, the heart is extracting oxygen maximally, and, unlike in other organs, increased oxygen demand can only be met by increased delivery, rather than increased oxygen extraction. The most important factor that regulates coronary blood flow is perfusion pressure. Myocardial blood flow occurs almost entirely during diastole, because during systole, cavitary left ventricular pressure equal to that of aortic pressure prevents coronary flow. Coronary flow also depends on coronary luminal diameter. In general, obstruction is considered clinically significant when luminal diameter decreases to two-thirds of baseline. Myocardial blood flow thus depends on diastolic pressure as well as coronary arterial patency. Tachycardia can therefore lead to ischemia not only by increasing oxygen demand, but also by limiting diastolic perfusion time. A variety of metabolic factors regulate coronary circulation as well. In fact, these autoregulatory capabilities increase blood supply to the heart in response to increased myocardial oxygen requirements. The most important metabolic regulator of this phenomenon is the potent vasodilator adenosine (2). Increased oxygen demand increases

The right coronary artery (RCA) and left coronary artery originate from the aorta just above the aortic valve cusps (Fig. 1). In fact, the positions of these two arteries within the sinuses of Valsalva designate the right and left coronary cusps. The third cusp is referred to as the noncoronary cusp, because it does not have an associated coronary ostium. The left main coronary artery, which travels posterolaterally to the left behind the pulmonary artery, divides into two main branches, the left anterior descending coronary artery (LAD) and the left circumflex coronary artery. The LAD emerges from behind the pulmonary artery to course anteriorly within the interventricular groove. The initial tributary of the LAD is usually the first diagonal, which runs over the anterolateral surface of the left ventricle, followed by the first septal perforator, which emerges at a right angle from the LAD and penetrates into the interventricular septum. The LAD may then give off more diagonal and septal branches. The left circumflex coronary artery descends posteriorly from the left main coronary artery. In 80% to 85% of cases, it terminates with branches to the posterolateral wall of the left ventricle. In the remainder, it extends to the crux of the heart and then gives off the posterior descending coronary artery (PDA), which runs in the posterior interventricular groove. The branches of the circumflex artery are referred to as obtuse marginals and cover the lateral and posterolateral portion of the left ventricle. 699

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Figure 1 (A) Diagram of the right coronary artery circulation in the right anterior oblique and left anterior oblique projections. (B) Diagram of the left coronary arterial circulation in the right anterior oblique and left anterior oblique projections. Abbreviations: SA, sinoatrial; AV, atrioventricular. Source: From Ref. 1.

adenosine triphosphatase (ATP) use, with a resultant increase in adenosine concentration, because it is a direct breakdown product of ATP. This results in coronary vasodilation and increased oxygen delivery. Conversely, thromboxane A2 is thought to play a crucial role in coronary vasoconstriction. Interestingly, it is released by platelets, particularly in the setting of platelet clumping, a situation that occurs almost universally in the setting of angina with myocardial infarction (MI) (3).

Coronary Atherosclerosis The Lesion Atherosclerotic lesions all have in common a mixture of proliferating smooth muscle with a tissue matrix consisting of collagen, elastin, and proteoglycans formed by these cells, as well as the accumulation of intracellular and extracellular lipid (Fig. 2). The lesions characteristically occur within the intima and progress from benign, fatty streaks to complicated, occlusive plaques. It is known that fatty streaks may occur as early as the first decade of life. With time, particularly in populations at risk, the fatty streaks develop into a fibrous plaque, a protruding lesion that may become obstructive. The subintimal smooth muscle cell proliferation that goes along with this fibrous plaque is the factor most responsible for this protrusion. With time, the fibrous plaque may enlarge, become calcified, and degenerate on its intimal surface, resulting in ulcerations that are thrombogenic. Organization of clot with platelet clumping on this surface not only causes increased obstruction to flow, but also, as stated previously, may release thromboxane A2, further exacerbating the compromised delivery of blood and, therefore, oxygen to the myocardium. Risk Factors A number of established risk factors predispose patients toward atherosclerosis (5). These include a genetic predisposition, hypertension, diabetes mellitus, hyperlipidemia, and

cigarette smoking. Genetic factors appear to have a direct effect on endothelial cell biology and predisposition toward the development of atherosclerosis. The risk of coronary artery disease increases with increasing blood pressure; among patients with blood pressure greater than 160/ 95 mmHg, the incidence of coronary disease is five times greater than among those who are normotensive. Of most importance is the fact that control of hypertension decreases this risk. Diabetes mellitus is clearly associated with coronary artery disease. The risk of coronary disease is increased at least twofold in patients with diabetes, with the risk even higher among those with juvenile-onset diabetes. Unfortunately, it is not certain that rigorous control of hyperglycemia decreases coronary mortality rate in this population. The Lipid Research Clinics Trial (6) demonstrated an unequivocal association between cholesterol level and morbidity and mortality from coronary artery disease. As with hypertension, decreasing the level of hyperlipidemia decreases the risk of coronary disease. Interestingly, high-density lipoproteins (HDLs), which contain approximately 20% of total plasma cholesterol, protect one from coronary disease. HDL level is known to be raised by exercise and estrogens and decreased by cigarette smoking. Cigarette smoking is one of the most important risk factors for the development of coronary artery disease, not simply because it is so clearly related to its development but because its cessation so clearly decreases the risk. In patients who smoke only one pack of cigarettes per day, the death rate from coronary artery disease is 70% higher than in nonsmokers. Furthermore, cigarette smoking appears to potentiate other risk factors. Other factors postulated to contribute to the progression of coronary artery atherogenesis include increasing age, male gender, supranormal serum levels of homocysteine and lipoprotein A (7), and low-estrogen states such as menopause (8). Age has a complex association with the development of atherosclerosis, because many other risk factors are associated with aging. It is well documented that

Chapter 36: Acquired Cardiac Disorders

Figure 2 Developmental stages of the lesions of atherosclerosis. (A) The normal muscular artery consists of an internal intima with endothelium and internal elastic lamina. The smooth muscle of the vessel wall is in the media, and the thin adventitial layer contains connective tissue and vasovasorum. With age, the thin, sparsely muscled intima increases in thickness and smooth muscle cell content. (B) In the first phase of an atheroslerotic lesion, there is a focal thickening of the intima with smooth muscle cells and extracellular matrix. There is also initial accumulation of intercellular lipid deposits. (C) Extracellular lipid may also develop. (D) When both intracellular and extracellular lipids are present in the earliest phase, this is referred to as a fatty streak. (E) Fibrous plaque results from continued accumulation of fibroblasts covering proliferating smooth muscle cells laden with lipids and cell debris. The lesion becomes more complex as continuing cell degeneration leads to ingress of blood constituents and calcification. Source: From Ref. 4.

men are three times more likely than women to acquire coronary disease, and, in fact, the development of ischemic syndromes occurs, on the average, 10 years earlier in affected men than in affected women. Because of the recognition that atherosclerosis may begin as early as the first or second decade of life, primary prevention of this disease must begin early. The importance of understanding the risk factors for coronary disease and eliminating or modifying those over which we have control cannot be overemphasized.

Clinical Presentation of Ischemic Heart Disease The clinical presentation of ischemic heart disease can take many forms. As many as 25% of patients with positive stress test results due to coronary occlusive disease may have no symptoms. Similarly, some acute MIs may occur silently. In fact, in some patients sudden cardiac death is the first and only manifestation of this disease process. Another subset of patients without typical symptoms may have

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progressive heart failure. This in general is caused by a slow, diffuse loss of ventricular function associated with increasing coronary obstructions. This entity is often referred to as ischemic cardiomyopathy. Most commonly, however, when significant coronary obstructive disease is present, angina pectoris results. The typical description of angina is as a pressure or heaviness felt in the middle of the chest, radiating to the left shoulder and down the left arm. Abdominal pain, nausea, belching, jaw pain, and hand heaviness or numbness are less typical manifestations of cardiac ischemia. In almost all cases, however, stable angina pectoris is brought on by reproducible increases in myocardial demand for a pathologically limited oxygen supply. Emotional excitement or stress, exposure to cold, eating, and exercise are typical historical events that trigger demand-induced angina. In unstable angina, however, the symptom of chest pain may occur at rest, or even when the patient is sleeping. These patients are exhibiting a phenomenon of myocardial ischemia without demonstrable changes in myocardial oxygen demand. This reflects a situation in which the supply of blood to the myocardium is so marginal that spontaneous coronary vasoreactivity alone may lead to symptoms. Prinzmetal’s or variant angina is a less typical form of angina that also may occur spontaneously without increasing myocardial oxygen demand. It is thought to result from spontaneous coronary arterial spasm, but it is almost always associated with underlying fixed atherosclerotic lesions. Patients may have ST-segment elevation, as opposed to the more typical ST-segment depressions associated with classical angina. Angina may be graded according to the Canadian Heart Classification scheme. Class I patients have no symptoms, class II patients have angina on significant exertion, class III patients have angina on mild exertion, and class IV patients have symptoms at rest. On physical examination, there is usually no detectable sign of coronary artery disease. There may be evidence of associated peripheral vascular disease, however, with loss of pulses or presence of bruits in the carotid arteries, abdominal aorta, or femoral arteries. Xanthomas or hypertensive retinal changes provide evidence of the presence of risk factors for coronary disease. Multiple studies are used to identify factors that may stress the heart. Anemia, of course, can exacerbate underlying coronary insufficiency. Results of electrocardiographic (ECG) examination are frequently normal, but some patients have evidence of old MIs, clearly indicating the presence of coronary disease. Stress testing is an ideal physiologic examination for assessing the functional significance of coronary disease. In this study, the patient undergoes graded exercise on a treadmill with continuous ECG monitoring. If the patient shows signs or symptoms of angina pectoris associated with typical ischemic ECG changes, this is considered a positive test result. Specificity of the test is improved dramatically if it is combined with the administration of thallium. Thallium is a radioactive isotope that is distributed in the intracellular space, like potassium. When thallium is injected during exercise, if a patient has coronary ischemia, the involved area of myocardium fails to pick up thallium and a defect is present on the scan. As the patient recovers from exercise and ischemia resolves, the myocardial defects fills in, suggesting the reversible nature of the problem. A defect on a thallium scan that never fills in is a sign of irreversibly scarred, nonviable myocardium. Despite the specific and sensitive nature of thallium stress testing, coronary arteriography, although invasive, is

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the main modality used to make a definitive anatomic diagnosis of coronary artery disease. It is indicated in patients with atypical presentations in whom it is important to rule out a definitive diagnosis of coronary disease. Otherwise, patients with classic anginal symptoms and ECG changes in whom the diagnosis is not in question should undergo coronary arteriography; if the condition is refractory to medical therapy, they are candidates for revascularization, or both. If patients have suspected severe coronary disease, such as left main or severe proximal three-vessel disease, regardless of symptoms, coronary arteriography should be performed to document this condition in preparation for revascularization. Well-known survival benefits accrue to patients who undergo surgery after such documentation. Diagnostic coronary arteriography should also be performed in patients with other cardiac diseases such as valvular heart disease in whom valve surgery is planned but in whom there is a risk of concomitant coronary disease. Less invasive means of detecting coronary artery disease are being developed, and will likely obviate the need for coronary angiography in some patients in the future. To date, multislice spiral computed tomography has been found to have a sensitivity and specificity of 95% and 86%, respectively, when compared to angiography (9). Similarly, magnetic resonance coronary angiography has been found to have a sensitivity of 76% and specificity of 91% compared to angiography (10). With evolution of this technology, these tests are likely to gain further accuracy. The medical management of coronary disease includes the identification and reduction of controllable risk factors. Once the disease presents itself in the form of clinically significant ischemia, however, the focus for the clinician is on decreasing myocardial oxygen uptake and increasing myocardial oxygen supply. It therefore follows that patients with hyperthyroidism or anemia, one of which affects oxygen demand and the other supply, should have these underlying conditions corrected. In general, though, there are five classes of drugs, in the armamentarium of the physician, which are useful for treating ischemic heart disease. Aspirin plays a critical role in prevention of platelet aggregation. Nitrates are the most commonly used agents. They primarily dilate venous capacitance blood vessels, with resultant decreases in preload, wall tension, and oxygen uptake. Although nitrates do not appear to increase coronary blood flow in the normal heart, improvement in coronary collateral blood flow does occur in patients with ischemic heart disease. b-adrenergic blocking agents reduce myocardial oxygen demand by decreasing both cardiac contractility and heart rate. These agents may also reduce blood pressure and systemic vascular resistance, further reducing the work of the heart. 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors—also known as ‘‘statins’’—have been shown to be effective in primary and secondary prevention of coronary artery disease by lowering serum concentration of low-density lipoprotein (11). Finally, calcium-channel–blocking agents such as nifedipine and diltiazem decrease myocardial oxygen uptake by decreasing ventricular contractility. By causing arterial dilation, they diminish systemic vascular resistance as well, and they are particularly effective in patients with a component of coronary vasospastic disease.

Acute Myocardial Infarction MI is one of the most common diagnoses of hospitalized patients in the United States. Approximately 1.5 million MIs occur each year, with an early mortality rate of approximately

25%. More than half of these deaths occur before the patient ever reaches the hospital. Acute MI is the direct result of interruption of blood supply to the myocardium. It almost always occurs as the result of coronary arterial thrombosis at the site of a significant stenosis over a complicated plaque. Although the acute event associated with acute MI is thrombosis, cardiac catheterization studies show that within days 20% to 30% of culprit coronary arteries are patent. This is more common in nontransmural MI than in transmural MI. A major determinant of prognosis after an acute MI is the amount of ventricular myocardium that undergoes necrosis. In patients who have ejection fractions greater than 50% after MI, three-year survival is close to 90%, but when ejection fraction after MI falls to less than 37%, three-year survival is only 50%. Loss of 25% of ventricular myocardium leads to symptomatic cardiac dysfunction, whereas the loss of more than 40% is frequently associated with cardiogenic shock and death. Therefore, efforts to treat patients who are having an acute MI should be focused on decreasing myocardial loss by improving flow to the area at risk, as soon as possible. Interestingly, although well-developed collaterals may not prevent demand-induced angina, they may significantly diminish the loss of myocardium after an acute MI.

Presentation Pain is the most common presenting complaint in patients with MI. It is by no means universally present, however, with 20% to 25% of patients having no symptoms. Interestingly, acute MIs associated with the LAD distribution frequently result in sympathetic hyperactivity, with tachycardia and hypertension, whereas inferior MIs involving the RCA frequently have parasympathetic activity with bradycardia and hypotension. The classic ECG picture of an acute MI is the development of Q waves and elevated coved ST segments in leads reflecting the affected areas (Fig. 3). In fact, the type of MI can frequently be characterized by the associated ECG changes. Transmural infarctions usually cause Q waves, whereas subendocardial or nontransmural MIs are usually characterized by transient ST-segment changes with inverted T waves, without the development of Q waves.

Figure 3 Acute inferior wall myocardial infarction (MI). The electrocardiogram of 11/29 shows minor nonspecific ST-segment and T-wave changes. On 12/5, an acute MI occurred. There are pathologic Q waves (1), ST-segment elevation (2), and terminal T-wave inversion (3) in leads II, III, and aVF, indicating the location of the infarct on the inferior walls. Reciprocal changes are seen in aVL (small arrow). Increasing R-wave voltage with ST depression and increased voltage of the T wave in V3 is characteristic of true posterior wall extension of the inferior infarction. Source: From Ref. 12.

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The most common modality used for diagnosing MI lies in the evaluation of specific cardiac isoenzymes released by necrotic myocytes in large enough quantities to be detected in the blood. In particular, serum levels of creatine kinase (CK), a cardiac enzyme involved with high-energy phosphate metabolism, are increased after MI, rising within 8 to 24 hours and returning to normal within one to two days. CK is found in brain (CK-BB) and skeletal muscle (CK-MM), and it can rise significantly after a variety of clinical scenarios such as stroke, surgery, cardiac catheterization, or simple intramuscular injection. It is therefore crucial to measure the cardiac-specific isoenzyme, CK-MB, when ruling out an MI. More recently, subunits of the troponin complex that regulates the calcium-mediated contractile process of striated muscle have been used in diagnosis of MI. Troponin T and troponin I have been observed to rise above the reference range within three hours of the onset of chest pain. These markers may persist in the serum for 10 to 14 days.

Medical Treatment During the early phase of MI, principles of management are to maximize oxygen delivery to myocardium and to minimize oxygen consumption. In this regard, oxygen should be administered, heart rhythm and rate should be monitored, and pain should be controlled usually with intravenous morphine. Decreasing pain has a significant therapeutic benefit because it decreases myocardial oxygen demand, helping to limit infarct size. Intravenous nitroglycerin should be initiated, because it may diminish infarct size, decrease the risk of sudden cardiac death, and lower the incidence of congestive heart failure (CHF) (13). b-Blockers have also been shown to limit infarct size and decrease early mortality rates (14). Angiotensinconverting enzyme (ACE) inhibitors have been shown to reduce morbidity and reduce the incidence of chronic CHF following acute MI, and are now regarded as essential therapy (15). In the mid-1970s, it was hypothesized that the administration of thrombolytic agents could lead to the dissolution of coronary thromboses, reversing the process precipitating the MI. A consequent European trial of streptokinase (SK) revealed a significant benefit when the drug was given within 12 hours of acute MI (16). Since then, thrombolytic trials have established without doubt the benefits of this approach, showing that thrombolysis reopens acutely occluded coronary arteries in most cases, restoring flow and reducing mortality rate (17). Four intravenous thrombolytic agents are currently approved by the Food and Drug Administration (FDA) for use in acute MI: SK, Anistreplase (APSAC), Alteplase (rTPA), and Reteplase. The most widely used is SK, which has been effective in several very large trials and is inexpensive. APSAC was developed to enable treating physicians to give one intravenous bolus dose in a few minutes, with maintenance of the effect for several hours because of its long half-life. However, APSAC has not been significantly better than SK, and its prolonged half-life has become a drawback rather than a benefit. rTPA produced by recombinant DNA techniques is more effective than SK. It also yields higher patency rates and generates less of a systemic fibrinolytic effect. However, rTPA is several times more expensive than SK, and it thus may not be cost-effective. What is clear is that the earlier the thrombolytic treatment, the greater the impact on post-MI morbidity and mortality, with the greatest benefit accruing to those patients treated within one to two hours of the onset of symptoms. Heparin and antiplatelet drugs should be added to

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thrombolytic therapy, particularly to rTPA, which has a short half-life and exerts little antithrombin effect, because it does not generate excessive fibrin-degradation products. Hemorrhage is the major problem with all thrombolytic agents, occurring commonly at the site of vascular access. Strokes occur in fewer than 1% of patients but may be catastrophic because of their hemorrhagic nature (18). Platelet membrane glycoprotein IIb/IIIa inhibitors are a new class of potent antiplatelet agents that block the final common pathway in platelet aggregation. FDA approval has been obtained for the following intravenous agents: Abciximab (ReoPro, a monoclonal antibody), Eptifibatide (Integrilin, a synthetic peptide), and Tirofiban (Aggrastat, a nonpeptide mimetic). These agents have been tested with and without percutaneous coronary interventions. In addition, clinical trials are underway involving a new group of oral glycoprotein IIb/IIIa inhibitors. Ticlopidine (Ticlid) and Clopidogrel (Plavix) are a new class of antiplatelet agents, which act by irreversibly inhibiting the adenosine diphosphate receptor involved in platelet aggregation. Both have been shown to improve outcome in patients suffering acute coronary syndromes, though patients who received Clopidogrel plus aspirin suffered more bleeding complications than patients receiving aspirin alone (19).

Mechanical Intervention in Acute Myocardial Infarction After thrombolytic therapy with early recanalization, the issue remains whether anything more needs to be done in the acute setting. Despite early reperfusion, significant residual stenoses remain in the culprit coronary arteries. The Thrombolysis in Myocardial Ischemia (TIMI)-II trial (20) compared immediate cardiac catheterization with percutaneous transluminal coronary angioplasty (PTCA) with elective cardiac catheterization and PTCA, only if ischemia developed during the hospital course. The more invasive approach failed to provide any increased benefit with respect to early or late mortality rates. As a result of this and other studies, cardiac catheterization and mechanical intervention should be withheld in most patients after acute MI unless patients exhibit ischemia during their hospital stay or have poor results of a predischarge low-level exercise stress test.

Indications for Surgery After Acute Myocardial Infarction Postinfarction Angina Recurrent chest pain occurs in 10% to 15% of patients after acute MI, an incidence that increases to 30% to 35% among patients who receive thrombolytic therapy. It is well recognized that after MI, the mortality rate may increase several fold if infarct extension occurs (21). Infarct extension is a powerful predictor of post-MI mortality risk, as seen by an increase in the average one-year mortality rate from approximately 18% to 65%, if infarct extension occurs. Thus, postinfarction angina is an indicator of continued myocardial ischemia and a harbinger of infarct extension. It should be regarded as an indication for cardiac catheterization with mechanical intervention, either PTCA or coronary bypass surgery. Cardiogenic Shock Cardiogenic shock after MI is uncommon, only occurring in approximately 7% of patients with acute MI. Shock after acute

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MI is associated with a 65% mortality rate, compared with a mortality rate of only 4% if shock is not present. The risk factors for development of cardiogenic shock after acute MI are age greater than 65 years, ejection fraction less than 35% on admission, a large MI as evaluated by peak CK-MB serum concentration, a history of diabetes mellitus, and a history of previous MI. Because shock develops after hospitalization in more than 50% of patients, identifying patients with these risk factors is important because it might possibly allow early intervention to prevent development of shock. Animal studies have shown that in cases of prolonged regional MI, intervention with emergency revascularization may decrease the amount of damage sustained by the myocardium. By focusing on ways to decrease myocardial energy expenditure during early reperfusion, as well as decreasing cell swelling and oxidant injury and improving intermediary cellular metabolism, a significant decrease in myocardial injury can be achieved. This has led to a prospective study evaluating the effect of coronary bypass surgery on patients in cardiogenic shock after MI (22). If surgery occurred within 18 hours of the onset of shock, mortality rate was reduced from 65% to 7%, whereas if surgery occurred after 18 hours, mortality rate was 31%, still a definite improvement from medical therapy. At centers capable of performing surgery of this kind, this may be an ideal approach to patients in shock after MI. However, these results have not been duplicated by other institutions. Until they are, they must be viewed as preliminary. Ventricular Septal Defect A ventricular septal defect (VSD) occurs in approximately 2% of patients after MI. This complication, which occurs when the myocardium is at its weakest, approximately three to five days after an MI, has an associated medical mortality rate of more than 90%. It is seen most frequently in elderly hypertensive female patients with anterior transmural infarcts. An increase in the right ventricular oxygen saturation is often observed. The initial medical therapy involves decreasing afterload as much as possible, invariably with the use of the intra-aortic balloon pump as well as vasodilator therapy. Preload is optimized and surgery is performed immediately. Early operation, before the complications of shock occur, appears to carry a much better survival rate (23). Acute Mitral Regurgitation As with VSD, acute papillary muscle rupture with mitral regurgitation occurs in only 2% of patients after acute MI. Posteroinferior MIs lead to this complication more frequently than do anterior MIs, almost certainly because the circumflex artery and PDA distributions are the most crucial blood supplies to the papillary muscles. This complication presents similarly to a VSD. As opposed to the pattern in patients with an acute VSD, however, the pulmonary capillary wedge pressure shows prominent V waves, and there is no right ventricular hemoglobin oxygen saturation step-up. Medical therapy involves maximizing afterload reduction through the use of an intra-aortic balloon pump. Early surgery, although it carries a high risk, decreases mortality rate from 90% to less than 50%. If the mitral valve apparatus can be preserved, mortality risk can be decreased even further. Free Wall Rupture Like the previous two complications, ventricular free wall rupture occurs at a time when the myocardium is at its

weakest, three to five days after acute MI. The medical mortality rate is exceedingly high (>90%), because the patients die acutely in tamponade. Surgical case reports cite dramatic rescues of these patients, but in general, for successful treatment, free wall rupture must be small and contained, allowing time for diagnosis and operative intervention. Most commonly, free wall rupture leads to pericardial tamponade, cardiogenic shock, and death.

Revascularization Angioplasty In the mid-1970s, Gruentzig and Hoff designed a balloon dilatation catheter for use in the coronary arteries and initiated the important treatment option for patients with ischemic heart disease currently known as PTCA. Under fluoroscopic guidance, a catheter is directed into the coronary artery. A guide wire is then placed across the obstructing lesion, and a balloon catheter is then passed over the guide wire and positioned in the mid-portion of the lesion. Under fluoroscopic control, the balloon is inflated to 4 to 10 atm pressure for 20 to 60 seconds in an effort to reduce the degree of coronary obstruction. The indications for PTCA are the same as those for coronary artery bypass surgery, which is the main alternative revascularization technique. Patients with intractable symptoms and those with proximal coronary stenoses that place a large amount of myocardium at risk are potential candidates for angioplasty. The ideal lesion is a symmetric, focal stenosis in a proximal epicardial vessel. PTCA is contraindicated if there is significant disease in the left main coronary artery, if the target coronary artery is less than 2 mm in diameter, if there are multiple significant obstructive lesions in the same artery, or if there are complex obstructive lesions involving arterial bifurcations. The primary risk of angioplasty is the dissection of the coronary artery with acute closure, which occurs in approximately 3% of cases and usually requires emergency coronary bypass surgery. Otherwise, the risks are similar to those of coronary arteriography and include cerebral vascular accidents and local arterial trauma. Under development are atherectomy catheters that incorporate tiny rotating blades for lysis of atheromatous plaque, as well as laser-tipped catheters that vaporize intraluminal obstructions. Coronary stents are small, implantable cylindric devices designed to maintain patency of diseased arteries when more conventional balloon angioplasty is ineffective. Successful dilation of favorable coronary arterial obstructive lesions occurs in more than 90% of PTCA attempts, with an immediate complication rate of only 3%. The most significant long-term problem with PTCA is the high incidence of restenosis, which occurs in between 20% and 40% of patients within the first four to six months after the initial PTCA (24). Although redilatation of recurrent stenotic lesions may be carried out successfully, many of these patients ultimately require coronary bypass surgery. The persistent problem of in-stent restenosis has yielded the development of coronary brachytherapy and drug-eluting stents. Radiation treatment using b-radiation or g-radiation has been observed to effectively reduce the degree of in-stent restenosis and to prevent recurrent restenosis (25). Local delivery of specific agents via the stent is also possible. In this manner, sirolimus (rapamycin, an inhibitor of smooth muscle cell and lymphocyte proliferation) and paclitaxel (an inhibitor of cell division) have been seen to dramatically lower the incidence of adverse cardiac events after stenting. For example, at follow-up of one year,

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major cardiac events were seen in approximately 6% of patients receiving a sirolimus-coated stent versus approximately 30% of patients receiving a standard stent (26). Given these encouraging results, FDA approval was obtained for use of sirolimus-coated coronary stents in 2002. Furthermore, Clopidogrel (Plavix) has been shown to be effective in reducing in-stent stenosis, as an adjunct therapy to aspirin (27), and thus most patients are placed on both drugs after percutaneous interventions.

Coronary Artery Bypass Surgery Coronary bypass surgery is among the most commonly performed operations in the United States today, with more than 250,000 procedures performed yearly. The goal, as with PTCA, is to treat ischemic heart disease by relieving the imbalance between myocardial oxygen supply and demand. Indications In general, data from clinical trials and retrospective studies show that as the number of diseased major coronary arterial segments increases, the greater the survival benefit from coronary bypass surgery. Three major prospective, randomized coronary bypass surgery studies—the Coronary Artery Surgery Study (CASS) (28), the Veterans Affairs Cooperative Study (29), and the European Cooperative Study (30)— are in large part responsible for how we treat patients with ischemic heart disease. Patients with intractable symptoms were not involved in these studies; those patients, in general, should undergo bypass surgery because it is the most successful way to relieve angina. These three studies have provided us with the anatomic indications for bypass surgery, which include left main stenosis and double- and triple-vessel disease involving the proximal LAD (Table 1). As stated previously, the most common indication for bypass surgery continues to be angina refractory to medical therapy. Bypass surgery can be expected to eliminate angina in more than 90% of patients at one year, with benefit continuing for 60% of patients at five years. Patients being medically treated for unstable angina require aggressive therapy, including nitrates, platelet inhibitors, b-blockers, and ACE inhibitors. Often, heparin anticoagulation is necessary. If the patient continues to have angina while receiving maximal medical therapy, urgent revascularization is indicated. Finally, as noted before, emergency coronary bypass surgery is necessary in approximately 3% of patients who have coronary occlusive complications after PTCA. Most of these occlusions result from coronary dissections proximal or distal to the site of dilatation. Most patients in the midst of an evolving MI have some attenuation of the ischemic injury by the placement of Table 1 Indications for Coronary Bypass Surgery Anatomy 1. Left main disease 2. Triple-vessel disease involving the proximal LAD, with normal or diminished ejection fraction 3. Double-vessel disease involving the proximal LAD, with normal or diminished ejection fraction Symptoms 1. Unstable (crescendo) angina 2. Post-MI angina 3. Acute coronary occlusion after PTCA 4. Symptoms unsuccessfully controlled with medical therapy 5. Controlled symptoms, but with unacceptable lifestyle Abbreviations: LAD, left anterior descending coronary artery; MI, myocardial infarction; PTCA, percutaneous transluminal coronary angioplasty.

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an intra-aortic balloon counter-pulsation device before transport to the operating room. If hemodynamic instability continues despite balloon pump support, portable cardiopulmonary bypass perfusion with femoral arterial and femoral venous cannulation may allow sufficient time to stabilize the patient’s condition for an operation. Surgical Technique In coronary artery bypass surgery, the diseased portion of the coronary artery is bypassed by the creation of an alternative conduit for delivery of blood beyond the stenosis. Grafts are constructed by making an end-to-side anastomosis to the coronary artery distal to the obstruction. The proximal end of the vein graft is usually sutured end-to-side to the ascending aorta. Use of arterial grafts has increased in recent years. The most commonly used arterial graft is the left internal thoracic artery (LITA), which is used as a pedicle retaining its origin at the subclavian artery with a distal end-to-side anastomosis to the diseased coronary artery. Most commonly, this is the LAD. The right internal thoracic artery (RITA) may be used as either a pedicle graft or a free graft as well when more than one arterial graft is desired. In a much more limited fashion, the gastroepiploic artery, the radial artery, and the inferior epigastric artery have been used as conduits. The main benefit of these grafts is improved long-term patency; the 10-year patency of the internal thoracic artery is between 90% and 95%, whereas saphenous vein grafts have only a 50% 10-year patency. Use of the LITA has been shown to improve survival and reduce the incidence of late MI, recurrent angina, and the need for further cardiac interventions (31). Simultaneous use of both LITA and RITA is becoming more common, and has been reported to have beneficial effects in large single-center studies (32). Traditionally, to maintain a quiet, bloodless field, cardiopulmonary bypass is employed for coronary bypass surgery (Fig. 4). With the patient on bypass and the heart empty, the distal ascending aorta is cross-clamped and potassium cardioplegic solution injected into the aortic root, causing nearly instantaneous cardiac arrest. The cardioplegic solution is usually between 4 C and 10 C, to induce rapid myocardial cooling. In addition, topical iced saline solution may be employed to provide surface cooling of the heart. The most important protective effects of cardioplegia are hypothermia and potassium, which causes arrest of the heart in diastole. Decreasing myocardial temperature to 10 C to 15 C, decreases the metabolic rate by as much as 80%, with mechanical arrest lowering the metabolic rate to as little as 5% of the normothermic, working heart. A great deal of investigative effort has gone into determining the best type of cardioplegic solution. Again, though, the most important aspects of arresting the ischemic heart are maintaining hypothermia as well as mechanical arrest. Newer techniques employ initial warm induction of arrest followed by cold cardioplegia. Furthermore, on completion of the operation, administration of a warm dose of cardioplegic solution before removal of the cross-clamp has also been advocated. Both the techniques are used in an attempt to allow the metabolic machinery to perform reparative processes before asking the heart to perform any mechanical work. In fact, some surgeons prefer to do the entire operation with the patient and the heart warm, while cardioplegic solution is being administered continuously (34). During the past several years, retrograde cardioplegic administration has come into vogue. Delivery of cardioplegic solution through the coronary sinus and the coronary veins may

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there is no alternative. Because patients with such diffuse disease are already likely to have poor outcomes, it has been difficult to demonstrate a beneficial effect from coronary endarterectomy.

Figure 4 Schematic diagram of a typical cardiopulmonary bypass circuit. Blood is drained by gravity from the venae cavae (1) through venous cannula (2) into a venous reservoir (3). Blood from surgical field suction and from a ventricular vent (if used during operation) is pumped (B, C) into a cardiotomy reservoir (not shown) and then drained into a venous reservoir (3). Venous blood is oxygenated (4), temperature adjusted (5), raised to arterial pressure (6), filtered (7,8), and returned to the patient by way of a cannula in either the aorta (10B) or femoral artery (10A). Arterial line pressure is monitored (9). Source: From Ref. 33.

yield enhanced myocardial protection, because significant coronary stenoses can prevent the homogeneous antegrade delivery of cardioplegic solution. Retrograde cardioplegia is also useful in the presence of significant aortic insufficiency, because effective delivery of cardioplegic solution in an antegrade fashion is severely hindered by an incompetent aortic valve. The distal anastomoses are generally performed with the aid of optical magnification. In addition to individual vein or thoracic artery graft anastomoses, two or more distal anastomoses can be constructed from a single vein or thoracic artery. These sequential grafts are favored when multiple distal sites are planned for anastomoses, or when there is a shortage of suitable conduit material. Sequential grafting is achieved by performing side-to-side anastomoses between the conduit and recipient artery and ending the graft with an end-to-side anastomosis to the most distal coronary artery. After completion of the distal anastomoses and initiation of reperfusion, a partially occluding side-biting clamp is placed on the ascending aorta, and the proximal anastomoses are constructed. Rarely, if the recipient coronary artery is diffusely diseased with no available site for the distal anastomoses, the surgeon may be required to perform an endarterectomy to allow a reliable graft-to-artery anastomosis. Coronary endarterectomy sites are more vulnerable to early thrombosis and reocclusion, and this should be performed only if

New Developments In the last few years, increasing attention has been paid to coronary artery bypass grafting without use of the cardiopulmonary bypass circuit and its inherent need for systemic heparinization, its propensity for inducing a systemic inflammatory reaction, and its known generation of microemboli to the brain. After widespread retrospective reports of improved perioperative morbidity and mortality (35) after ‘‘off-pump’’ coronary artery bypass grafting (OPCABG), a prospective, randomized trial was recently completed. Patients undergoing OPCABG received a similar number of bypass grafts, had equivalent 30-day mortality and stroke rate, required fewer blood transfusions, and had a shorter postoperative hospital length of stay when compared to patients undergoing conventional CABG using cardiopulmonary bypass (36). This technique has been greatly enhanced by the use of cardiac stabilization devices. Current generation devices employ two instruments that contact the epicardium: an apical suction device to retract the heart in various angles, and stabilization plate to isolate a single area of epicardium for suturing (Fig. 5). Minimally invasive direct coronary artery bypass is a new technique that aims to avoid complications associated with a full sternotomy. Using a thoracic approach, all epicardial vessels can potentially be accessed. In addition, femoral artery and vein can be used for cardiopulmonary bypass cannulation sites, and the heart can be arrested and opened through this approach. Upon unclamping of the aortic cross-clamp during the weaning of cardiopulmonary bypass, atheromatous debris is released from the intimal surface, and is often of a significant enough quantity to cause cerebral ischemic or stroke. New intra-aortic filters are being tested, which slide through an additional lumen in the aortic cannula, and open after being placed inside the aortic lumen. These filters have been shown in preliminary trials to reduce the incidence of postCABG neurologic complications. Aortocoronary anastomotic devices are being developed and tested, which will allow complete anastomoses to be constructed without the need for aortic cross-clamping. This device expands once the tip has been introduced into the aortic lumen, and deploys a radially shaped metallic structure, which contains hooks and attaches to the intimal surface of the aorta. Trials are underway to assess orifice patency, operative times, ease of deployment, and potential effect on operative mortality. Postoperative Management After the operation, cardiac surgical patients are monitored in an intensive care unit, with careful hemodynamic evaluation. Arterial blood pressure, central venous pressure, pulmonary artery pressures, cardiac output (CO), mixed venous oxygen saturation, and urinary output all provide valuable information regarding the adequacy of tissue perfusion and organ function. Mediastinal and chest tube drainage should be monitored hourly and, in fact, can be transfused to minimize the use of banked blood products. All patients have a capillary leakage syndrome and fluid accumulation after cardiopulmonary bypass, with a marked increase in total body sodium, such that patients typically gain between 5 and 10 kg. Most patients are able to be extubated within 4 to 12 hours of surgery,

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management and optimization of CO. In the early postoperative period, hypovolemia, increased systemic vascular resistance, hypothermia, and arrhythmias (both bradycardic and tachycardic) may all contribute to low CO. Management of these patients is both challenging and rewarding, because the cause of low CO is almost always reversible. Low CO. When the calculated cardiac index (CI and CO divided by body surface area) is less than 2 L/min/m2, despite optimization of heart rhythm, preload, and afterload, use of an inotropic agent is invariably indicated (Table 2). If a patient remains in cardiogenic shock, despite significant inotropic support, consideration should be given to placement of an intra-aortic balloon pump. The balloon, which may be inserted percutaneously through the femoral artery, is positioned just beyond the subclavian artery takeoff of the aorta. Balloon inflation and deflation are timed so that intra-aortic balloon counter pulsation increases coronary artery perfusion pressure during ventricular diastole and, as a result of active deflation, maximally decreases afterload during ventricular systole. Rarely, if shock persists, a left ventricular-assist device (VAD) should be considered. However, the cause of persistent low CO in the early postoperative period should be pursued aggressively, with any reversible cause identified. Left VAD support is extremely labor intensive and costly, and it should only be considered if myocardial failure is considered to be reversible, or if the patient needs a bridge to transplantation.

Figure 5 (A) Cardiac stabilization device used during off-pump coronary bypass surgery. Newer devices use suction cups on the stabilization platform (1) as well as the apical cup (2) to pull the epicardium into the instrument. Use of suction avoids the need for pressure to accomplish coronary stabilization, thereby minimizing hemodynamic instability during the anastamosis. (B) Diagram of stabilization platform use during bypass of left anterior descending artery. Source: From Ref. 37.

and thereafter can be transferred to a step-down unit, where continuous monitoring for arrhythmias, gentle diuresis to attain preoperative weight, and early ambulation are achieved. Compared with other populations, the patient after cardiac surgery provides an opportunity for sophisticated

Postoperative Complications. The major complications after open-heart surgery include bleeding, tamponade, infection, and stroke. Platelet function and blood clotting factors are severely altered after bypass and may not return to normal for as long as 36 hours. Average postoperative blood loss is between 400 and 800 mL and, as stated previously, may be reinfused to decrease the need for homologous blood transfusions. When bleeding exceeds a rate of 200 mL/hr for four hours or longer, return to the operating room for correction of any surgical cause of the bleeding should be considered. Before then, all medical causes of coagulopathy should be corrected aggressively. It is simple and safe to give additional protamine to reverse the residual heparin used during bypass, but transfusions of platelets, fresh-frozen plasma, or cryoprecipitate should be considered only if indicated by coagulation studies. Cardiac tamponade is a potentially lethal cause of low CO early after operation. Clinically, one sees decreased CO increasing filling pressures and a narrowed pulse pressure. Pulsus paradoxus and a widened mediastinal silhouette on chest radiographs are frequently seen. Transesophageal echocardiography has made this diagnosis more easily established and should be used without hesitation when faced with this possible diagnosis. Table 2 Causes of Low Cardiac Output After Coronary Bypass 1. Inadequate preload 2. Excessive afterload 3. Poor ventricular contractility a. Perioperative ischemia b. Poor myocardial preservation 4. Arrhythmia 5. Severe acidosis 6. Tension pneumothorax 7. Tamponade

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The major wound complication facing surgeons after coronary bypass is sternal infection with mediastinitis, dehiscence, or both. This complication occurs in as many as 2% to 4% of patients, with the incidence increased when bilateral thoracic arteries are used, particularly in elderly patients and those with diabetes. Staphylococci are the most common organisms, and because of the devastating nature of this complication, most patients receive antistaphylococcal prophylaxis in the perioperative period. Mortality after development of this complication is between 20% and 30% (38). Cerebral vascular accidents may be the most tragic of postoperative complications. Stroke is usually caused by atherosclerotic emboli that probably originate from the aorta, loosened by cannulation, cross-clamping, or the construction of the proximal anastomoses. Underlying cerebral vascular disease combined with hypotension during bypass contributes to this problem. Strokes occur in 1% to 2% of patients at low risk, but may occur in as many as 10% of octogenarians. No data suggest that the investigation of asymptomatic carotid bruits, prior to open-heart surgery with subsequent combined coronary bypass and carotid endarterectomy, would reduce the incidence of stroke after surgery. In patients who have both symptomatic carotid and coronary disease with significant stenosis of the carotid, however, a combined procedure is usually carried out. Risk Factors for Operative Death The assessment of the patient’s mortality risk after bypass surgery is an important component of the preoperative evaluation in coronary artery disease. Furthermore, as issues regarding quality assurance and the delivery of efficient, cost-effective health care loom ever larger in our society, scrutiny of the benefits and risks associated with this most expensive of medical procedures has come increasingly in vogue (Table 3). Clearly, patients with concurrent medical problems such as cerebral vascular disease, pulmonary or renal insufficiency, diabetes, and morbid obesity are at higher risk for development of postoperative complications. Poor ventricular function is among the most important factors increasing the mortality rate after bypass surgery (39). Operative risk is also increased when patients require additional operative intervention such as valve repair or replacement. It is well documented that increasing age itself increases mortality rate. In the CASS study (28), the mortality rate among patients older than 70 years was nearly 8%, compared with an overall mortality rate of 3%. It has also been stated that women have a higher mortality rate after bypass surgery than do men. The explanation for this is not exactly clear, but may be related to the fact that women undergoing coronary bypass surgery are on average 10

Table 3 Prediction of the Risk for Operative Death

Age (yr) Sex Diabetes Unstable angina Ejection fraction (%) Three-vessel disease Operative incidence Predicted mortality rate (%)

Low

Medium

High

60 Male No Yes 65 Yes First 0.8

75 Female Yes No 35 Yes First 3.4

75 Female Yes Yes 25 Yes Redo 12

Source: Based on The Society of Thoracic Surgery National Cardiac Database Risk Stratification Algorithm. Summit Medical Systems, Minneapolis, Minnesota, U.S.A.

years older than men and have a higher incidence of unstable angina, preoperative CHF, hypertension, and diabetes. It is more than conceivable that the higher risk for women is related to the higher incidence of these risk factors (40). Long-Term Results Most series show elimination of angina in 90% of patients at one year, with approximately 70% of patients remaining free of any cardiac event at three years. Although relief from symptoms is unquestioned, controversy exists regarding the long-term functional benefit of bypass surgery. However, functional improvement in left ventricular ejection fraction has been documented after bypass surgery and can be attributed to improved contractility in the myocardial regions in which there had been demonstrable ischemia prior to surgery. Clinical improvement obviously depends at least in part on short- and long-term graft patency. The overall occlusion rate for saphenous vein bypass grafts is 5% to 20% during the first operative year and 2% to 4% annually thereafter, for an occlusion rate of approximately 30% at 5 years and 50% at 10 years. Use of the internal thoracic graft has become increasingly favored because of its 95% one-year and 90% 10-year patency rates. Excellent late internal thoracic artery graft patency clearly correlates with increased patient survival, reduced symptoms, and fewer reoperations. In a study at the Cleveland Clinic, where internal thoracic artery grafts have been used extensively, the 10-year survival rate among patients with saphenous vein grafts for triple-vessel disease was 71%, compared with 83% in a comparable group of patients who had an internal thoracic artery graft to the LAD. Approximately 80% of all patients undergoing primary coronary bypass surgery survive for 10 years, and use of the internal thoracic artery graft improves 10-year survival to close to 90%. Furthermore, about one in seven patients who have had only vein grafts require reoperation at 15 years, twice the reoperation rate for those patients who received at least one thoracic artery bypass. Patients who undergo reoperation have approximately twice the primary operative mortality rate, because the operation is technically more difficult and because the patients are older, with more severe atherosclerotic disease (41). In addition, total revascularization is more difficult for technical reasons, and symptomatic relief is therefore usually of shorter duration as well.

Transplantation vs. High-Risk Coronary Surgery In deciding whether to recommend transplantation or bypass surgery to a patient at high risk as a result of severely depressed left ventricular function, it is important to assess whether the myocardium is viable. In patients with ischemic but viable myocardium, ventricular function may improve after bypass surgery once adequate blood flow is restored. The term ‘‘hibernating myocardium’’ has been used to describe ventricular dysfunction caused by inadequate coronary flow (42). This condition should be distinguished from an ischemic cardiomyopathy, which implies irreversible myocardial dysfunction. Anginal symptoms suggestive of reversible ischemia are often a useful measure of myocardial viability. Patients whose only symptom is heart failure should be approached with caution. Currently, myocardial viability may best be assessed by thallium scanning, either with exercise or at rest. Myocardium that takes up thallium either early or late is presumed to be viable. In this way, one may be able to estimate the possibly dramatic potential

Chapter 36: Acquired Cardiac Disorders

for improved ventricular function with revascularization in the patient who has severely depressed ventricular function but viable myocardium. In a patient with these findings, especially if angina is present, surgery rather than transplantation is indicated if there is operable coronary disease. In patients with CHF and no evidence of viable myocardium, however, bypass surgery clearly carries high risk and little benefit, and transplantation should be considered.

Transmyocardial Revascularization For those patients burdened with angina but whose coronaries are not anatomically approachable, transmyocardial revascularization is a new technique with promising initial results. This procedure employs a CO2 laser, a needle, or high frequency ultrasound to create transmural channels in the myocardium and allow oxygenated blood to reach previously ischemic regions of the heart. Nearly four years after this procedure, patients have been found to have fewer anginal symptoms, require fewer hospitalizations, and have equivalent ventricular ejection fraction and mortality compared to patients receiving medical therapy alone (43).

VALVULAR HEART DISEASE Aortic Valve Disease Aortic Valvular Stenosis The normal aortic valve consists of three equal-size leaflets attached to the aortic wall, forming the three aortic sinuses. As mentioned in the section on coronary artery disease, the coronary arteries arise from two of these sinuses, thereby defining the left, right, and noncoronary cusps. Pathologic Anatomy The most common cause of left ventricular outflow tract obstruction is aortic valvular stenosis. Supravalvular and subvalvular obstructions occur much less commonly. Aortic stenosis is the most common isolated valvular abnormality found in humans. Although congenital valvular stenosis may cause symptoms immediately, a congenital bicuspid valve is usually asymptomatic at birth and becomes symptomatic in the sixth to eighth decade of life. The turbulent flow across the bileaflet valve leads to fibrosis and calcification, so that stenosis develops with time. Rheumatic aortic stenosis, initially an inflammatory lesion, leads to fusion of the leaflet commissures, with thickening and calcification of the cusps themselves. Retraction of the leaflet borders, which occurs commonly, leads to regurgitation as well. In rheumatic aortic valvular disease, mitral involvement is invariably also present. In degenerative or senile aortic stenosis, normal leaflet stress leads to calcification and cusp immobility. This calcification can extend either interiorly onto the anterior mitral leaflet or upward along the aorta, occasionally causing coronary osteal stenosis (Fig. 1). Pathophysiology Narrowing of the left ventricular outflow tract becomes important when it obstructs flow, causing a transvalvular pressure gradient. In the presence of a normal CO, a transvalvular gradient of 60 mmHg or a calculated valve area of less than 0.7 cm2 is considered severe aortic stenosis. The normal response to aortic stenosis, a process that in itself can take years, is the development of left ventricular hypertrophy. This hypertrophy initially leads to a decrease in compliance, with an elevation in the left ventricular end-diastolic pressure. With progressive hypertrophy and loss of ventricular compliance, atrial contraction plays an

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increasingly important role in left ventricular filling, so loss of a normal sinus mechanism [such as atrial fibrillation (AF)] can cause acute decompensation in these patients. Furthermore, with severe aortic stenosis, prolongation of the systolic ejection time and a concomitant elevation in left ventricular end-diastolic pressure act to decrease diastolic coronary blood flow, with a resultant oxygen debt. The subendocardium may become chronically ischemic, with cell death and fibrosis. In this situation, the left ventricle begins to fail as stroke volume decreases and CO falls. Paradoxically, follow-up of a patient with aortic stenosis may reveal a low or a decreasing aortic gradient during a period of years, which should not be confused with resolving or stable aortic valvular disease but rather indicates a failing left ventricle with a decreased stroke volume and therefore a decreased transvalvular gradient. The clinical course of aortic stenosis may be divided into two phases. The initial phase involves hypertrophy of the left ventricle because it compensates for increasing afterload. Angina, the hallmark of this stage of aortic stenosis, results from the imbalance of myocardial oxygen demand and myocardial oxygen delivery. The second stage involves the onset of left ventricular dysfunction, which is the result of a progressively stiffening ventricle that requires increasing preload for adequate filling, with resultant pulmonary hypertension, shortness of breath, and dyspnea on exertion. Diagnosis Although auscultation of the patient with aortic stenosis reveals a systolic murmur best heard at the base of the heart at the left sternal border radiating up into the neck, this murmur can also be associated simply with normal systolic ejection. However, a slow, prolonged rise in the arterial pulse, as opposed to a sharp upbeat, is a palpable indicator that significant ventricular outflow tract obstruction is present. Doppler echocardiography has become an invaluable tool in the noninvasive detection of aortic stenosis. The peak aortic valvular gradient can be calculated by the following formula (44): D ¼ 4V 2 where D is the peak gradient and V is the maximal measured blood velocity (in meters per second) across the valve. The most accurate measure of left ventricular outflow tract obstruction is determined invasively by cardiac catheterization, where a simultaneous aortic and ventricular pressure measurement can determine the exact aortic gradient (in the case of AF, this is the only acceptable means of determining this number). The aortic valve area (AVA, in square centimeters) may then be determined by the Gorlin formula (45): AVA ¼ AVF=44:5 ðgradientÞ1=2 where AVF is aortic valve flow, which equals CO in milliliters per minute divided by the systolic ejection period (in seconds per minute), and 44.5 is the empiric orifice constant (obtained by comparing calculated with measured AVA at operation or postmortem). For quick calculations, this simplifies to AVA ¼ CO=ðgradientÞ1=2 Patients frequently have symptoms when the AVA is less than 1 cm2, whereas they invariably have symptoms when the area is less than 0.7 cm2 (46). Angina is usually

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in a retrograde fashion through the aortic orifice and inflated in an effort to crack the calcium that is retarding valvular motion. The immediate results show an increase in the AVA of 50%, with a 3% to 10% mortality rate and a similar stroke rate (55). Long-term results are abysmal, with a oneyear mortality rate of 25% and a 30% to 35% symptomatic recurrence rate during that period. With recurrence of symptoms, death, hemodynamic evidence of restenosis, or a combination of these occuring in more than 50% of patients at six months after percutaneous aortic ballon valvuloplasty, surgical valve replacement will remain the mainstay of therapy. If valvuloplasty has a role at all, it should be limited to the aged and frail patient whose long-term prognosis is also abysmal. Figure 6 Average course of medically treated valvular aortic stenosis in adults (postmortem data). Although one can understand the difficulty in operating on the patient without symptoms, the severe slope of the curve mandates that patients be seriously considered for surgery at the onset of symptoms. Source: From Ref. 47.

the earliest symptom in patients with aortic stenosis. The mean survival after its onset is 4.7 years. However, when a patient has syncope, survival is typically decreased to less than three years, whereas when a patient has dyspnea and CHF, survival is on the order of one to two years (Fig. 6) (48). Treatment The only effective therapy for symptomatic aortic stenosis is operative. Symptoms alone are an indication for aortic valve replacement. Occasionally, a patient with aortic stenosis may have no symptoms. The appropriate timing of surgery in such patients is not clear. Timely surgery provides the opportunity for resolution of left ventricular hypertrophy, whereas allowing the condition to persist may lead to irreversible myocardial fibrosis with dysfunction. In general, patients without symptoms with progressive left ventricular hypertrophy should be offered surgical therapy because survival is superior to that with medical therapy (49). An unwritten dictum is that all patients with aortic stenosis should be given the opportunity for surgical therapy because it is so effective in leading to reversal of symptoms. With progressive fibrosis and irreversible myocardial dysfunction, however, an occasional patient may have a decrease in ejection fraction out of proportion to the increase in wall stress caused by the aortic stenosis. With this ‘‘endstage aortic stenosis’’ (in which contractility has decreased out of proportion to the increase in wall stress), patients derive little benefit from surgical therapy (50,51). In patients with good ventricular function, aortic valve replacement has an associated mortality rate of 2% to 8%. Perioperative risk factors include age, left ventricular function, preoperative New York Heart Association functional classification, and pulmonary function. The projected fiveyear survival for patients after aortic valve replacement is 80% to 85%. Although symptoms are generally relieved in all patients, improvement in ejection fraction with resolution of left ventricular hypertrophy may require months to occur (52,53). In patients with aortic stenosis as well as coronary artery disease, valve replacement and myocardial revascularization should be performed concurrently (54). Percutaneous aortic balloon valvuloplasty is a ‘‘noninvasive’’ alternative to surgical therapy for aortic stenosis. In this procedure, either one or two balloon catheters are placed

Aortic Insufficiency Pathologic Anatomy Incompetence of the aortic valve may be the result of either primary valvular or aortic root disease (56). Rheumatic fever is a major cause of aortic insufficiency. As discussed with aortic stenosis, it causes retraction of the cusps, which prevents adequate apposition and leads to a central leak. Congenital bicuspid valves with time become calcified and generally lead to aortic stenosis. Ocasionally, however, bicuspid valves have a redundant leaflet that leads to regurgitation. Myxoid degeneration of the aortic valve, as seen in Marfan syndrome, Ehlers–Danlos syndrome, and cystic medial necrosis, may lead to redundancy, prolapse, and regurgitation. Infective endocarditis with bacterial destruction of the leaflets may also lead to valvular insufficiency. Ascending aortic dissection as a result of either trauma or hypertensive atherosclerotic disease often leads to loss of commissural suspension, with resultant leaflet prolapse. Furthermore, severe aortic dilation causes annular stretching (as seen in annuloaortic ectasia, syphilis, and ankylosing spondylitis), which leads to annular dilatation and central valvular incompetence. Pathophysiology With aortic regurgitation, there is a significant increase in preload, where end-diastolic volume is the result of both normal left ventricular filling through the mitral valve as well as left ventricular filling through the incompetent aortic valve. At the expense of an increase in left ventricular wall stress, ejection fraction remains normal as stroke volume and end-diastolic volume increase. Left ventricular dilatation increases wall tension, which increases myocardial oxygen demand. To counteract this, left ventricular wall thickness increases to maintain a wall thickness to cavity radius ratio that preserves myocardial efficiency. With time, however, left ventricular volume may become enormous. Increasing wall thickness does not keep pace with this increasing left ventricular dilation. Sharply increased wall tension develops, with resulting systolic dysfunction. At this point, an elevation in left ventricular end-diastolic pressure occurs and patients have symptoms (Fig. 7). Acute aortic regurgitation, on the other hand, such as occurs with dissections or endocarditis, leads to extremely high left ventricular end-diastolic pressures as a result of the acute increase in end-diastolic volume in the unconditioned ventricle. In these patients, symptoms develop immediately. Diagnosis Patients with aortic insufficiency have a characteristic pattern on physical examination that results from the wide pulse

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200 PRESSURE, mmHg

180 160 140 120 100 80 60

A0 LV

40 20 0

Figure 7 Simultaneous left ventricular and aortic pressure–time curves in a patient with severe aortic insufficiency. Note that in this patient with extremely severe aortic insufficiency, the left ventricle has become less and less compliant, and at end-diastole, the aortic pressure and left ventricular enddiastolic pressure have nearly equalized. Abbreviation: LV, left ventricle. Source: From Ref. 57.

pressure associated with this disease. The peripheral pulses rise and fall abruptly (Corrigan’s or water-hammer pulse), the head may bob with each systolic stroke (Musset’s sign), and the capillaries visibly pulsate (Quincke’s sign). Auscultation reveals a soft S2 with a high-frequency, diastolic, regurgitant murmur best heard at the left sternal border. A mid-to-late diastolic rumble can be heard (Austin Flint murmur); this represents rapid diastolic flow across the mitral valve that is becoming narrowed as a result of rapid ventricular filling caused by the aortic insufficiency. Clinical Course In chronic aortic regurgitation, symptoms occur late after left ventricular dilatation and myocardial dysfunction (58). Symptoms occur as a result of elevation in left ventricular end-diastolic pressure, again a situation that occurs later in the course of the disease, because early on, left ventricular volumes increase to maintain compliance. Interestingly, nocturnal angina can occur as the result of a slow heart rate, so that diastolic pressure in the coronary arteries is low, and left ventricular end-diastolic pressure is high, compromising blood flow and oxygen delivery to the endocardium. Acute aortic regurgitation, however, is poorly tolerated, and patients have symptoms almost immediately. This is the result of extremely poor compliance of the ventricle and an excessively high diastolic volume. Management Patients with symptomatic aortic insufficiency require surgical therapy, because survival with medical therapy is only a few years from the onset of symptoms. The patient with no symptoms or mild symptoms but with moderate to severe aortic insufficiency presents a dilemma. Frequently, diuretics and afterload reduction may be able to maintain these patients for a considerable period before they experience symptoms. Without surgery, 75% of patients survive five years from the time of diagnosis, and 50% of patients survive 10 years (Fig. 8) (59). Despite the lack of symptoms, however, irreversible myocardial dysfunction occurs. The goal of the clinician should be to intervene before this happens. When end-systolic volume is less than 30 mL/m2, prognosis after surgical therapy is still excellent. With progressive systolic

Figure 8 Survival of patients with medically treated aortic insufficiency. Unlike with aortic stenosis, cardiac failure from aortic insufficiency occurs much more gradually. Consequently, it is much more difficult to discern where one should intervene, particularly in the patient without symptoms. Source: From Ref. 59.

dysfunction, however, end-systolic volumes may rise above 90 mL/m2, a situation that frequency portends permanent postoperative disability. End-systolic volumes between 30 and 90 mL/m2 have intermediate short- and long-termresults (60). Indications for surgical therapy in the patient without symptoms thus should rest on serial echocardiography or radionuclide ventriculography to discern systolic dysfunction or decreasing ejection fraction. Despite good exercise tolerance, when systolic dysfunction occurs, surgery should be recommended. The mortality rate associated with aortic valve replacement for aortic insufficiency is approximately 4% to 6%, somewhat higher than that seen in aortic stenosis (61–63). As discussed, long-term survival depends on preoperative left ventricular function.

Choice of Prosthetic Aortic Valve Type The Department of Veterans Affairs trial randomized patients between 1982 and 1997 to receive mechanical or bioprosthetic valves. At average follow-up of 15 years, mechanical values were associated with lower mortality and lower reoperation rate. These differences became apparent after 10 years. In addition, the mechanical valves displayed no structural value deterioration, and use of the bioprosthetic valve was associated with fewer bleeding complications. Thus, bioprosthetic valves are at risk for late reoperation, but the avoidance of necessary long-term anticoagulation makes them an attractive option for some subgroups. Generally speaking, patients aged at least 65 to 70 years undergoing only valve replacement should receive a bioprosthetic valve. Patients aged at least 60 years undergoing concomitant procedures such as coronary bypass should also receive a bioprosthetic valve (64).

Mitral Valve Disease Surgical Anatomy The mitral valve appartus is composed of the left ventricular papillary muscles, the mitral valve chordae tendineae, the mitral valve leaflets, and the mitral valve annulus. By means of the chordae tendineae, the mitral leaflets are connected to the apical region of the left ventricle. Normal function of the valve depends on the coordinated interaction of these components. The mitral valve has two leaflets joined at two

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commissures. The anterior leaflet (also called the aortic leaflets) is broad and relatively square in shape. It is attached to the anterior one-third circumference of the mitral valve annulus and is in fibrous continuity with the aortic valve annulus. The posterior leaflet (also called the mural leaflet) is narrower and relatively rectangular. It is attached to the posterior two-thirds circumference of the mitral annulas. Each leaflet is attached by chordae to each of two papillary muscles arising from the luminal surface of the left ventricle, the anterior-lateral and the posterior-medial papillary muscles. The blood supply of the anterior-lateral papillary muscle is from the diagonal branches of LAD or by obtuse marginal branches of the circumflex coronary artery. The posterior-medial papillary muscle is supplied by the PDA coronary artery, which is usually the terminal branch of the RCA. The mitral valve functions to permit antegrade blood flow from the left atrium into left ventricle during diastole and to prevent reflux of blood from left ventricle into the left atrium during systole. Blood flows antegrade through the mitral valve when the left atrial pressure exceeds left ventricular pressure. As the ventricle contracts during systole, closure of the valve is affected by several mechanisms. Once the left ventricular pressure exceeds left atrial pressure, leaflet closure is initiated, and the rate of blood flow from the atrium into the ventricle is decelerated. At the same time, contraction of the left ventricular muscle at the base of the heart serves to narrow the mitral annulus; echocardiographic data suggest that the annular area decreases by approximately one-third from end-diastole to mid-systole (65). This reduction in annular area helps achieve leaflet approximation. During systolic contraction, papillary muscle contraction pulls the chordae taut, preventing prolapse of the leaflets. Any disease process that interferes with the normal function of any portion of the mitral valve apparatus may result in mitral stenosis or regurgitation.

Mitral Stenosis Rheumatic fever is the primary cause of mitral stenosis (66). Other etiologies of mitral stenosis are rare and include congenital mitral stenosis and stenosis resulting from collagen vascular diseases such as systemic lupus erythematosus and rheumatoid arthritis. Two-thirds of patients with rheumatoid mitral stenosis are female. After resolution of acute rheumatic fever, most patients remain free of symptoms for at least two decades before development of symptoms of mitral valve disease. Thereafter, patients have progressively worse symptoms (67). The normal mitral valve orifice measures 4 to 6 cm2 in cross-sectional area. A mitral valve area (MVA) of 2 cm2 is considered moderate mitral stenosis. At this degree of narrowing, flow across the mitral valve may be accomplished only by generation of an abnormally high-pressure gradient across the valve. An MVA of 1 cm2 is considered critical mitral stenosis, because flow across the valve (CO) is relatively fixed; even extremely high-pressure gradients across the valve are unable to increase flow (Fig. 9). As with the aortic valve, the MVA may be calculated according to the Gorlin formula (for the mitral valve, the constant is 38 rather than the 44.5 used for the aortic valve): MVA ¼ ðFlow rate across valveÞ= 38ðmean gradient across valveÞ1=2 For any given MVA, the magnitude of the transvalvular gradient is proportional to the square of the transvalvular

Figure 9 The relationship between mean diastolic gradient across the mitral valve and the rate of flow across the mitral valve per second of diastole. When the valve area is 1.0 cm2, little additional flow can be achieved, despite an increased pressure gradient. Source: From Ref. 68.

flow rate; doubling the CO quadruples the transvalvular pressure gradient. Increased left atrial pressure results in increased pulmonary venous pressure, and in turn increased pulmonary capillary pressure. Should the transvalvular gradient culminate in a left atrial pressure greater than 25 mmHg, pulmonary edema may result. For this reason, exertional dyspnea is commonly the first symptom of mitral stenosis. Patients frequently first have symptoms with the onset of AF. Chronically elevated left atrial pressure produces left atrial distention, ultimately producing AF. With the onset of AF, diastolic time is shortened; the same volume of blood must flow from left atrium to ventricle in less time, which further increases left atrial pressure. The atrial kick contributes approximately 30% to the presystolic transvalvular gradient in patients with mitral stenosis. Its loss with the onset of AF eliminates this mechanical advantage, and left atrial pressure rises and CO declines (69). The contractile function of the left ventricle is typically well preserved in mitral stenosis. The hemodynamic features of mitral stenosis are notable for a reduced CO at rest (because of the mechanical obstruction of the stenotic valve), which rises subnormally with exercise along with pulmonary hypertension. The pulmonary hypertension is derived from retrograde transmission of elevated left atrial pressure, pulmonary arterial vasoconstriction, and obliterative structural changes in the pulmonary circulation produced by chronic left atrial hypertension. Pulmonary hypertension may become severe, resulting in impaired right ventricular function and tricuspid regurgitation. Diagnosis Patients with mitral stenosis typically are seen with easy fatigue, dyspnea on exertion, and orthopnea. As noted previously, symptoms may develop with the onset of AF.

Chapter 36: Acquired Cardiac Disorders

A history of rheumatic fever is noted in approximately one half of cases. If the left atrial enlargement is sufficient to compress surrounding structures, patients may report dysphagia or hoarseness. On cardiac auscultation, an opening snap of the mitral valve is common as a result of sudden tensing of the valve leaflets by the chordae, as the valve leaflets achieve their opening excursion. The opening snap may be heard within the first 100 msec after the second heart sound. Mitral stenosis produces a low-pitched, rumbling diastolic murmur best heard at the apex. The murmur is often difficult to appreciate, but may be provoked by maneuvers that increase CO. Pulmonary hypertension is suggested by a loud pulmonary component of the second heart sound. With pulmonary hypertension, an enlarged right ventricle may shift the left ventricle posteriorly, making the murmur extremely difficult to hear (silent mitral stenosis). The chest roentgenogram is significant for left atrial enlargement. There may be elevation of the left main stem bronchus and posterior displacement of the esophagus on the lateral radiographic view. Pulmonary venous hypertension typically results in cephalization of pulmonary blood flow. Two-dimensional echocardiographic evaluation of mitral stenosis reveals thickened mitral valve leaflets and restricted leaflet motion as the valve opens. The left atrium is typically enlarged, and the left ventricular cavity is usually reduced in size. Mitral annular calcification and left atrial thrombus are identifiable on echocardiography. Doppler echocardiography provides a functional estimate of the severity of mitral stenosis. The peak velocity of blood flow across the valve is increased, allowing an estimate of the transvalvular gradient (see the section on the Aortic Valve). Medical Treatment Medical treatment of mitral stenosis is of limited efficacy. The focus of medical treatment is to minimize pulmonary edema with diuretics and to control the ventricular rate with digoxin. Because left atrial thrombus may form, patients in AF should have anticoagulation with warfarin. Surgical Treatment Because of the efficacy of surgical treatment, the natural history of mitral stenosis is now unclear. However, after acute rheumatic fever, most patients remain free of symptoms for 20 to 25 years. Once these patients experience symptoms, at least five years is required for the progression of symptoms from mild to severe. According to the study of Olesen (70) of patients in the presurgical era, 40% of symptom-free patients with mitral stenosis had a significantly worsened condition or were dead within 10 years. Among patients with mild symptoms, the number was 80%. Munoz et al. (71) reported a 45% five-year survival rate for medically treated patients with mitral stenosis and mitral regurgitation. In a comparable population undergoing mitral commissurotomy, five-year survival rate was 80%. The first report of successful surgical correction of mitral stenosis appeared in 1923; Cutler and Levine (72) reported successful relief of mitral stenosis by incision of the valve with a knife introduced through an apical left ventriculotomy. In 1925, Souttar (73) performed the first successful closed mitral commissurotomy through the left atrial appendage. After the reports of Harken et al. (74) in 1948 and Bailey (75) in 1949, closed mitral commissurotomy became widely used for mitral stenosis. Despite excellent long-term results after closed mitral commissurotomy (76), by the mid-1970s, this technique was supplanted by open

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mitral commissurotomy. Closed mitral commissurotomy is now of historical interest only. Although closed mitral commissurotomy offered good palliation of mitral stenosis, open mitral commissurotomy offers several advantages (77). First, the valvuloplasty may be performed under direct vision. The primary reason for failure of closed mitral commissurotomy was residual stenosis, not restenosis (78,79). In as may as 75% of patients, the subvalvular apparatus of the mitral valve contributes significantly to the stenosis (80). The open technique allows precise and maximal division of fused commissures as well as of fused chordae (81). In addition, calcium may be sharply debrided from the valve, and any residual mitral insufficiency may be corrected at the time of operation. Finally, the closed technique offers the disadvantages of potentially dislodging a left atrial thrombus, resulting in intraoperative embolization and stroke. The results of open mitral commissurotomy are excellent. Operative mortality rate is usually reported as 0.2% to 2%, and in most series, the need for reoperation is reported to be 2% per year (81). Balloon Mitral Valvuloplasty Inoue et al. (82) reported the first successful percutaneous balloon mitral valvuloplasty in 1984. The valvular pathology of mitral stenosis makes the valve unsuitable for balloon dilation. Nonetheless, this procedure is now an alternative to surgical relief of mitral stenosis in a small, select group of patients. After creation of a hole in the interatrial septum, a balloon catheter is introduced through the mitral valve and inflated within its orifice. The procedure is based on the idea that the inflated balloon will split fused commissures. As noted previously, however, the subvalvular apparatus contributes significantly to the stenosis, and this region is not addressed by balloon dilation. Immediate hemodynamic improvement is noted in most patients, with a significant reduction in transvalvular gradient, improved CO, and reduction in pulmonary arterial pressure (39). However, these hemodynamic benefits are not long standing, and the complication rate is significant. Reported mortality rates range from 0% to 4% (83), comparable to that of open mitral commissurotomy. Approximately 30% of patients are left with a significant atrial septal defect (84). Stroke is reported as a complication of the procedure in 3% to 4% (85). Recurrence of mitral stenosis is noted in as many as 30% to 40% of patients within one year (86). The small subset of patients with the best results from balloon mitral valvuloplasty are those with soft, pliable leaflets without calcification and without stenosis of the subvalvular apparatus. Such patents are, of course, rare. Thus, although balloon mitral valvuloplasty attempts to spare the patient a more invasive procedure, the patient is actually exposed to greater risk of complication and death. At the same time, the results are inferior to open mitral commissurotomy, which must be considered the procedure of choice.

Mitral Regurgitation Structural abnormalities of any component of the mitral valve apparatus (mitral leaflets, chordae tendineae, and papillary muscles) may result in mitral regurgitation. Rheumatic fever remains the most common cause of mitral regurgitation; it results in deformity and retraction of the leaflets and shortening of the chordae. Other causes include perforation by trauma and infective endocarditis. Calcification of the mitral annulus may result in annular rigidity, preventing valve closure, and mitral annular dilation resulting from left ventricular dilation may likewise preclude leaflet

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apposition during systole. Chordal rupture may result from trauma, endocarditis, rheumatic fever, or diseases of collagen formation. Chordae to the posterior leaflet rupture more frequently than do those to the anterior. Coronary arterial disease may produce infarction of the papillary muscle, resulting in initial regurgitation. Infarction in distribution of the anterior descending coronary artery may be associated with necrosis of the anterior-lateral papillary muscle, whereas the posterior-medial muscle may infarct if blood flow through the PDA artery is interrupted. Mitral regurgitation caused by MI typically is seen as a new murmur several days after infarction. Pathophysiology The regurgitant mitral valve offers an alternative route by which blood may exit from the left ventricle. During both isovolumetric contraction and systole, blood is preferentially ejected into the low-pressure left atrium. The volume of the regurgitant flow (regurgitant fraction) depends on the size of the regurgitant orifice and the afterload against which the left ventricle must work to pump blood through the aortic valve. The regurgitant fraction is increased with increased left ventricular preload and increased afterload, both of which dilate the left ventricle, thereby enlarging the mitral annulus and regurgitant orifice. Because the valve leaks during systole, the volume of regurgitant flow also increases as heart rate (number of systoles per minute) increases. To maintain an adequate systemic blood flow (CO), the left ventricle becomes volume overloaded; it must pump the combined volume of systemic and regurgitant flows. Because the left ventricle is able to beat against the reduced resistance of the left atrium, parameters of systolic function (ejection fraction) are increased in mitral regurgitation. However, as with aortic insufficiency, the left ventricle ultimately fails, with chronic volume overload. In fact, normal values of systolic function indicate significant contractile dysfunction of the left ventricle. An ejection fraction of 40% to 50% in the setting of mitral regurgitation indicates severe left ventricular contractile dysfunction (66). As in mitral stenosis, left atrial hypertension results from mitral regurgitation. This pressure is transmitted in a retrograde fashion into the pulmonary circulation; if high enough, it produces pulmonary hypertension. The magnitude of the left atrial pressure is a function of the compliance of the left atrium (Fig. 10). A normal or low compliance of the left atrium, such as may occur in acute mitral regurgitation, results in a relatively rapid rise in left atrial pressure. On the other hand, chronic, slowly developing left atrial volume overload may create significant enlargement of a compliant left atrium, with relatively low left atrial pressure. Diagnosis Symptoms result from the degree of mitral regurgitation, the rate of its progression, the degree of pulmonary hypertension, and the magnitude of left ventricular contractile dysfunction. Symptoms in patients with chronic mitral regurgitation typically do not occur until the left ventricle begins to fail. Patients with mild mitral regurgitation may remain free of symptoms for most of their lives (88). The onset of AF does impair the patient’s functional status, but not to the same degree as with mitral stenosis. With moderate to severe chronic mitral regurgitation, patients may be free of symptoms for long periods. However, this lack of symptoms may be deceptive, because the contractile function of

Figure 10 Syndrome of mitral regurgitation. When mitral regurgitation occurs abruptly in patients with previously normal heart, left atrial compliance is normal. This results in a rapid increase in left atrial pressure. On the other hand, the insidious development of mitral regurgitation allows the left atrial compliance to increase along with its size, attenuating the rise in left atrial pressure. Abbreviations: LA, left atrium; LV, left ventricle; PA, pulmonary artery; PT, pulmonary trunk; PV, pulmonary vein; RA, right atrium; RV, right ventricle. Source: From Ref. 87.

the left ventricle may be slowly deteriorating. Once symptoms occur, left ventricular contractile dysfunction may be irreversible. The natural history of mitral regurgitation is obscure, because surgical intervention has effectively altered this history. In the presurgical era, however, approximately 80% of patients with severe mitral regurgitation survived five years and 60% survived 10 years (59). On cardiac auscultation, a holosystolic murmur is best heard at the apex and radiates to the axilla and left scapular region. The ECG is notable for left atrial enlargement and, frequently, AF. The chest roentgenogram is significant for cardiomegaly and left atrial enlargement. Pulmonary venous hypertension may be manifested by cephalization of pulmonary blood flow and pulmonary edema. Echocardiography is extremely valuable in confirming the diagnosis and severity of mitral regurgitation. Transesophageal echocardiography is particularly effective in providing an anatomic explanation for the regurgitation, such as perforated leaflets, poor leaflet coaptation, or ruptured chordae. Doppler echocardiography reveals a high-velocity jet of regurgitant blood flow into the left atrium during systole. The severity of the valve regurgitation is a function of the distance from the mitral annulus that the jet can be visualized (into the pulmonary veins) and the size of the left atrium. Contrast ventriculography performed at cardiac catheterization likewise demonstrates regurgitation during systole.

Chapter 36: Acquired Cardiac Disorders

Management The cornerstone of medical management is diuresis and afterload reduction with ACE inhibitors (66). The importance of afterload reduction cannot be overemphasized. Because blood leaving the left ventricle travels the path of least resistance, lowering systemic vascular resistance increases systemic CO. The indications for surgical intervention are (i) symptoms despite medical management or (ii) evidence of deteriorating left ventricular contractile function, as determined by echocardiography or contract ventriculography. Surgical correction of mitral regurgitation should be undertaken before left ventricular contractile dysfunction becomes irreversible; the operative mortality rate increases substantially as the ventricle fails. The two surgical options are repair and replacement of the valve. The final decision regarding which of these options to employ is made during the operation after inspection of the valve. There are several advantages to mitral valve repair rather than replacement. First, with mitral valve replacement, there is loss of the mitral valve apparatus connecting the mitral annulus to the apex of the left ventricle by means of the chordae and papillary muscles. In the long term, this may lead to left ventricular dysfunction. Mitral valve repair preserves this apparatus. Second, the risks associated with a prosthetic valve, such as prosthetic valve endocarditis and thromboembolic complications, are avoided. Third, the operative mortality rate associated with mitral valve repair is 0% to 4%, which is lower than the 2% to 8% reported for mitral valve replacement (80). Finally, mitral valve repair can now be accomplished using minimally invasive techniques with robotic assistance, so that a median sternotomy incision is no longer required. In contrast, median sternotomy is still needed for mitral valve replacement.

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roughly 18% for ACE inhibitors and 35% for b-blockers compared to control, untreated patients. In patients with extremely poor myocardial function, outpatient inotropes may be used chronically via rate-controlled infusion into a large central vein. In this manner, Milrinone, a cyclic adenosine monophosphate–specific phosphodiesterase inhibitor or Dobutamine (a synthetic catecholamine), may be used to chronically support patients who otherwise would be hospitalized and unable to complete most activities of daily living due to such severe ventricular dysfunction.

Surgical Therapy In patients with a maximal oxygen consumption less than 14 mL/kg/min (normal 30–50), heart transplantation provides the greatest survival advantage (68% 10-year survival) to patients with CHF, but its epidemiologic impact is limited by a severe shortage of donor organs. According to the registry of the International Society for Heart and Lung Transplantation, the number of heart transplants in the United States peaked in 1994 at approximately 4300, and has since fallen to the range of 2000 to 2500 transplants per year. Current efforts to increase the potential number of donor organs for heart transplantation are aimed at increasing public awareness, refinement of end-of-life donation consent policies, improvements in organ preservation techniques, and acceptance of organs previously considered marginal. At least in some part due to the growing shortage of donor organs, a multitude of nontransplantation surgical techniques are being used more frequently to ameliorate CHF. These include cardiac revascularization, mitral valve reconstruction (92), and even left ventricular reconstruction using techniques such as the Batista and Dor procedures. Pathologic geometric remodeling of the left ventricle has been prevented by the CorCap cardiac support device (ACORN Cardiovascular, Inc., St. Paul, Minnesota, U.S.A.) or Myosplint (Myocor, Lie, Maple Grove, Minnesota, U.S.A.). The ACORN device (Fig. 11) is an elastic mesh sleeve that slides

HEART FAILURE Epidemiology CHF is the leading cause of hospitalization and death in the developed world, affecting 0.4% to 2% of the general adult population (89). Approximately 550,000 new cases of heart failure are diagnosed each year, and cause approximately 300,000 deaths per year. In the United States alone, over 34 billion dollars are spent on the medical care of patients with CHF. Among patients in the Framingham Study Group, the mean age at diagnosis was 63 years in the period from 1950 to 1969, and 80 years in the period from 1990 to 1999 (90). The most common cause of heart failure in men is MI, and in women, the most common cause is hypertension (91). Despite recent improvements in medical therapy for this disease, the Framingham Study showed that after the time of diagnosis there was a one-year survival of only approximately 75% and 50% at five years.

Medical Therapy Medical therapy of CHF involves many of the same agents that are used in acute MI. ACE inhibitors are used for chronic unloading of the left ventricle. Chronic use of b-blockers causes myocardial upregulation of b-adrenergic receptors, making the heart more responsive to adrenergic stimulation. The addition of both to the medical regimen of CHF patients is now standard of care with an improvement in survival of

Figure 11 Diagram of ACORN device. During implantation, seam is placed anteriorly and oversewn to allow for the adjustment of circumferential tension, depending on heart size. Holes can be created in the jacket to allow for coronary bypass surgery. One can imagine the potential for postoperative scarring and adhesions making reoperative surgery extremely hazardous. Source: Courtesy of Acorn Cardiovascular, Inc., St. Paul, Minnesota, U.S.A.

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Figure 12 (A) Picture of Thoratec HeartMate# left ventricular assist system. This device is available as either a vented electric (XVE, shown) or an implantable pneumatic LVAD. Both devices are approved for use as bridge to transplantation, and the XVE is also approved for use as destination therapy. During implantation, the in-flow cannula is sewn to the ventricular apex and the out-flow cannula is sewn to the aorta. In-flow and out-flow valves as well as internal surfaces are covered with a material which alleviates the need for systemic anticoagulation. The driveline is the only portion of the device that is external to the body. (B) Schematic demonstrating necessary components of portable ventricular assist devices system. This device is capable of pumping up to 10 L/min, and its pump rate can be adjusted to either a fixed-rate mode or a variablerate mode, depending on the body’s needs. Each battery lasts up to six hours, and patients carry multiple batteries at a time. The device weighs approximately 1200 g (2.6 pounds). Abbreviation: LVAD, left ventricular assist device. Source: Courtesy of Thoratec Corporation, Pleasanton, California, U.S.A.

to cover all surfaces of the heart, and provides passive support to help reduce stress on the ventricular wall with prevention of subsequent ventricular dilatation. Biventricular pacing has been shown to improve quality-of-life measures, New York Heart Association functional class, and maximal exercise performance at follow-up of six months in patients with severe heart failure (93). Novel techniques in gene transfection are being developed to improve myocardial cellular dysfunction. Likewise, muscle cells have been injected into damaged myocardium to improve cardiac function (94). Mechanical VADs have gained widespread popularity, used both as a bridge to transplantation for patients in extremis as well in nontransplant candidates as end therapy (referred to as destination therapy). This type of mechanical support is expected to assume an even larger role in the management of heart failure in the future. Initially developed in the 1960s, VADs have undergone significant evolution to gain their current FDA approval. A multicenter trial in the early 1990s demonstrated a 65% survival to transplantation in CHF patients after implantation of VAD compared to 50% survival to transplantation in medically treated patients (95). On the basis of this and other studies, the FDA approved the use of left VADs as a ‘‘bridge’’ to transplantation in 1994. Encouraging initial results of the Randomized Evaluation of Mechanical Assistance Therapy as an Alternative in Congestive Heart Failure trial—in which VADs were placed into CHF patients as ‘‘destination’’ therapy—led to the 2002 FDA approval for VADs to be used for this indication, no longer just as a bridge to transplantation (Fig. 12). Current areas of improvement in VAD design focus on minimizing risk of thromboembolism, reducing postoperative VADrelated infections, and prevention of mechanical device failure. In the arena of heart replacement therapy, the Abiocor (ABIOMED, Danvers, Massachussets, U.S.A.) totally implantable total artificial heart has achieved good initial results, but more widespread, long-term use is dependent on further reduction in the thromboembolism risk.

CARDIAC DYSRHYTHMIAS Cardiac function can be adversely influenced by changes in both cardiac rhythm and cardiac rate, but in actuality,

perturbations in CO are more commonly rate related. Healthy individuals in sinus rhythm have a frequency of cardiac contraction that can vary considerably. In optimally physically conditioned individuals, resting heart rates may be as low as 40 to 50 beats/min (bpm), although most healthy persons range from 60 to 90 bpm. Cardiac rate can vary across a wide range (40 to 150 bpm) without eliciting symptoms. With the induction of exercise, however, symptoms generally occur at each end of this spectrum, and especially in individuals with underlying cardiovascular pathology. Although dysrhythmias can generally be managed medically, certain situations may necessitate surgical intervention.

Bradycardias In patients with symptomatic bradycardia, implantation of a pacemaker may be indicated to increase the heart rate. The common types of symptomatic bradycardia include (i) congenital heart block, (ii) acquired heart block, (iii) iatrogenic heart block, (iv) sick sinus syndrome, (v) AF, and (vi) bradycardia– tachycardia syndrome. Patients with congenital heart blocks are frequently free of symptoms because the heart is in other respects structurally and functionally normal. As the child enters adolescence and early adulthood, maintenance of adequate exercise tolerance may require pacemaker implantation. In elderly patients, in whom acquired heart block usually occurs, ischemic heart disease is commonly the underlying etiology. Symptoms may be evoked with minimal exercise and occasionally arise even under resting conditions. Acquired heart block is a common cause of syncope (Stokes–Adams attacks). Sudden cardiac death may occur in this situation as the rhythm degenerates into asystole as a result of the development of ventricular escape beats from the block and the resultant ventricular tachycardia and fibrillation. Because the arterial supply to the atrioventricular node is derived from a branch of the RCA, acute MI resulting from occlusion of this artery may give rise to heart block. This occurs because the resultant ischemia from the coronary occlusion alters the normal function of the atrioventricular node. Although the heart block associated with acute MI usually resolves, these patients are candidates for prophylactic, temporary pacemakers. Occasionally, permanent pacing is required.

Chapter 36: Acquired Cardiac Disorders

In patients undergoing repair of damaged valves or septal defects, or complex intra-atrial repairs associated with congenital heart disease, postoperative heart block may occur. Not uncommonly, such blockade does not manifest immediately after operation. Because cardiac surgeons have encountered this situation with sufficient frequency, temporary pacing wires are routinely placed in these patients at the time of surgery, so that external pacing can be administered rapidly should circumstances necessitate this approach. Chronic sinus bradycardia is typically referred to as the sick sinus syndrome. In this condition, heart rates in the range of 30 to 40 bpm are characteristic. Although sudden cardiac death is much less likely than with complete heart block, the symptoms are essentially the same. The bradycardia is usually regular but can on occasion be irregular, and it typically occurs in older patients, many of whom have ischemic heart disease, although this is not a requirement for the syndrome to occur. Permanent pacing is usually required in patients with this condition. Although chronic AF is effectively managed medically in most patients, significant bradycardia can at times occur, necessitating pacemaker placement. It must be confirmed, however, that the bradycardia is not related to digitalis toxicity before a pacemaker is placed. This can be determined by stopping the digoxin therapy to see whether the bradycardia is resolved. In patients with the bradycardia–tachycardia syndrome, profound episodes of supraventricular tachycardia requiring digoxin prophylaxis produce profound symptomatic bradycardia related to the digoxin therapy necessary to manage tachycardia. The explanation for this effect is not clear, but the treatment of this syndrome requires the placement of a pacemaker to enable the administration of sufficient doses of digoxin to manage the tachycardia.

Pacemaker Placement When pacemakers were first introduced approximately 40 years ago to manage cardiac dysrhythmias, they were placed in the left side of the chest through a formal thoracotomy. The pacemakers were large and heavy, and the pacing leads were sutured to the ventricular myocardium. Furthermore, the batteries needed to operate these pacemakers were generally short lived and required replacement at least every two years, often more frequently. In addition, the lead systems were undependable. Much progress has been made in the development of pacemakers during the last several decades, so that current pacemakers approach the size and weight of a silver dollar, use lithium batteries that have life spans of 10 or more years, and possess lead systems that are remarkably dependable. Current pacemaker management makes use of both epicardial and endocardial methodologies. Epicardial insertion employs a subxiphoid approach to the pericardium in which the lead is screwed into the undersurface of the right ventricle, and the battery box itself is implanted subcutaneously, usually in the left upper abdominal quadrant. This technique requires general anesthesia for the lead placement, but the battery box can easily be replaced with local anesthesia. The endocardial approach employs a catheter system that uses the cephalic, subclavian, or jugular vein, through which the catheter tip is advanced and impacted into the apex of the right ventricle. In this circumstance, the battery box is implanted in a subcutaneous pocket inferior to the clavicle. Compared with the epicardial approach, this strategy of pacemaker management is less dependable,

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Figure 13 Schematic representation of the two approaches currently used for pacemaker placement. (A) Epicardial approach employs subxiphoid access in which pacemaker lead is secured to undersurface of right ventricle, and battery box is implanted subcutaneously in left upper abdominal quadrant. (B) Endocardial approach uses subclavian (or cephalic or jugular) vein for access, in which pacemaker tip is impacted into apex of right ventricle, and battery box is implanted subcutaneously inferior to clavicle.

requires more time to position the pacemaker, and is associated with a small but real hazard of perforating the right ventricle. Its major advantage with respect to the epicardial approach is that it can be carried out entirely with local anesthesia. These two approaches are schematically represented in Figure 13. A wide variety of pacemakers are presently available. Despite their current level of sophistication compared with older models, they all fire on ‘‘demand’’ when they do not sense a QRS complex. They all have the capability to be programmed for such modalities as rate, size of electrical impulse, and sensing level after implantation. In recent years, there has been a trend toward dual-chamber pacemakers that pace the atria and ventricles sequentially, as well as pacemakers that sense changes in the native sinus rate (in response to a stimulus such as exercise), and thereby change the rate of ventricular firing. These newer systems, although expensive, have been demonstrated to be extremely beneficial in the vast majority of pacemaker candidates, particularly for patients with exercise intolerance or chronic CHF. Not all patients with dysrhythmias require cardiac pacemaker implantation. Absolute indications for pacemaker implantation include third-degree or advanced seconddegree AV block associated with symptomatic bradycardia, asystolic episodes greater than three seconds or an escape rate less than 40 bpm, or following catheter ablation of AV node (96,97). Relative indications include asymptomatic third-degree bloc and asymptomatic type II second-degree AV block with a narrow QRS complex (96,97). Guidelines for the use of pacemakers are summarized in Table 4.

Tachycardias In addition to problems with bradycardia, tachycardias can also pose difficulties that may require surgical intervention, if medical management is not efficacious.

Supraventricular Tachycardias Supraventricular arrhythmias, the most common rhythm disturbances encountered in surgical practice, usually occur in the postoperative period. Typical arrhythmias of this variety include atrial flutter, paroxysmal atrial tachycardia, and

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Table 4 Guidelines for Cardiac Pacemaker Implantation Accepted In patients with symptoms and chronic conditions Atrioventricular block Complete (third-degree) Incomplete (second-degree) Mobitz type I (rare indication) Mobitz type II Incomplete with 2:1 or 3:1 block Sinus node dysfunction (symptomatic) Sinus bradycardia Sinoatrial block, sinus arrest Bradycardia–tachycardia syndrome Controversial In patients with symptoms Bifascicular/trifascicular intraventricular block Hypersensitive carotid sinus syndrome In patients without symptoms Third-degree block Second-degree atrioventricular block Mobitz type II Transient complete or Mobitz type II atrioventricular block with bundle-branch block in selected situations (e.g., acute myocardial infarction) Congenital atrioventricular block Sinus bradycardia with heart rates < 45 beats/min, with long-term drug therapy necessary Overdrive pacing for ventricular tachycardia Not warranted Syncope of undetermined cause Sinus bradycardia, sinoatrial block, or sinus arrest without symptoms Bundle-branch blocks Mobitz type I block (asymptomatic)

Figure 14 Two tachycardias found in patients with Wolff-Parkinson-White syndrome are shown. (A) Reentry type. The wide QRS of preexcitation changes to a narrow QRS during the reentry tachycardia (box). (B) Fast ventricular response during atrial flutter. The rhythm strip shows the rapid ventricular response progressing to ventricular fibrillation (box). Source: From Ref. 99.

Source: From Ref. 98.

AF. The diagnosis of these dysrhythmias is made with ECG testing. Most of these disturbances can be managed medically with drugs such as digoxin, b-blockers, calcium channel blockers, and amiodarone, or with combinations of these agents. On rare occasions, such medical management does not prove efficacious, and because of the rapid ventricular rate emanating from these dysrhythmias, emergency cardioversion is required. A more worrisome supraventricular tachycardia that does not respond as well to medical management is the Wolff-Parkinson-White (WPW) syndrome. This disorder is caused by reentry of cardiac excitation impulses through an anomalous muscle bundle, known as the bundle of Kent, which connects the atrial and ventricular myocardia, that are normally electrically separate (Fig. 14). This bundle has been demonstrated in a variety of positions in the atrioventricular groove or junction of the atrial and ventricular septa, having been previously mapped experimentally. The seriousness of this condition is that the Kent bundle can conduct as many as 400 bpm with degeneration into ventricular responses characterized by tachycardia or fibrillation, with the potential for cardiac arrest. On ECG, patients with the WPW syndrome demonstrate a short PR interval (< 0.12 seconds) and small delta waves at the beginning of the QRS complex. Although a wide variety of antiarrhythmic drugs have been used to manage this syndrome (including procaine, quinidine, propranolol, verapamil, and amiodarone), such therapy has not proved especially successful. Fortunately, a means of ablating the Kent bundle surgically is now available. First introduced at Duke University in 1968, this modality has proved efficacious, and many patients treated with interruption of the Kent bundle have

had successful outcomes and have gone on to live normal lives (100). Recent experience with catheter-delivered radiofrequency ablation of the Kent bundle has also proved effective and has supplanted the surgical approach (101). The success encountered with treating the WPW syndrome surgically has been extended to other mechanisms of tachycardia, such as concealed accessory connections, nodal and atrial tachycardia, and even refractory AF. Treatment of this last arrhythmia, the Cox-Maze procedure, consists of a series of atrial incisions to prevent atrial reentry and allow sinus node impulses to activate the entire atrial myocardium. In so doing, this procedure restores atrioventricular synchrony. This procedure has been reported to have an operative mortality of 2% and to have cured AF in 99% of cases (102). There is a significant occurrence of temporary postoperative AF (38%) and need for pacemaker implantation (15%). More recently, microwave energy and radiofrequency energy have been used intraoperatively in the treatment of AF to create lines of conduction blockade, which mimic the standard Maze incisions, but without the degree of morbidity seen with that procedure. These newer procedures have been observed to cure AF in 70% to 80% of cases (103). Perioperative AF occurs in over 60% of cases, and 30% to 40% of patients leave the hospital in AF, but this does not appear to be long-lasting and patients subsequently convert to sinus rhythm over the ensuing three to four postoperative months. Instrumentation is currently being tested, which will allow these procedures to be performed with less morbidity in an epicardial, thoracoscopic fashion.

Ventricular Tachycardia Ventricular dysrhythmias are much more serious than supraventricular tachycardias because of the rate-induced

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depression of CO that can degenerate into life-threatening ventricular fibrillation. Most patients with sustained ventricular tachycardias have significant ischemic heart disease and have had one or more MIs, resulting in varying degrees of both reversible and nonreversible ischemic damage. Among patients surviving MI, significant ventricular tachycardias may occur in as many as 5%. Despite the recent development of new antiarrhythmic drugs, approximately one-third of patients with ventricular tachycardia do not have adequate control with them. In this subset of patients, ‘‘mapping’’ the various areas of the epicardium and endocardium, which induce ventricular tachycardias electrically, and then resecting this area has proved efficacious in controlling the ventricular dysrhythmias (104–106). The mapped areas usually comprise subendocardial scar tissue that, from a surgical standpoint, are relatively easy to resect unless vital structures such as the mitral apparatus, membranous septum, and aortic annulus are involved in the scarred area. In such cases, local cryoablation has been substituted and proved useful. Although the risk associated with this type of surgery is substantial, it is directly related to the degree of left ventricular function. The less dysfunction, the better is the outcome. As many as 70% to 80% of patients surviving this type of surgery have relief of their tachycardia without the need for further drug therapy or have substantial reduction in the drug requirements to manage their ventricular dysrhythmias. Implantable Cardioverterdefibrillator Patients who have had a documented cardiac arrest (sudden cardiac death syndrome) in the absence of a documented MI within the preceding 48 hours and who are not candidates for antiarrhythmic drug therapy, as documented by electrophysiologic study, should have an implantable cardioverterdefibrillator (ICD) implanted (106–108). This device, which is similar in size to a pacemaker, is implanted to sustain any cardioversions for several years. Candidates for ICD placement usually have severe coronary artery disease and prior MI. The infarction zone provides the scarring and slow conduction needed for the re-entrant arrhythmias (ventricular tachycardia or ventricular fibrillation). As expected, this patient population is in extremely debilitated condition, with low ejection fractions and chronic CHF. Consequently, these patients are good candidates for ICD insertion, rather than long-term antiarrhythmic drug therapy, which is associated with negative inotropic effects and other morbid drug reactions. This type of therapy is extremely expensive ($12,000 to $20,000 per generator; $2000 to $8000 per lead system). It is, however, worthwhile for selected individuals at high risk, as it has been shown in selected patients to decrease one-year mortality from 90% to 10%.

Evaluation of Pacemakers Before Attempting Surgery In patients about to undergo general anesthesia and surgery, it is mandatory that the surgical and anesthesia teams determine that the pacemaker is sensing and functioning normally. After the pacemaker has been properly identified, the currently active program can be retrieved by interrogation with the manufacturer’s programmer. The first issue is to identify whether the patient is pacemaker dependent. If the pacemaker fails, does it have a dependable and adequate intrinsic rhythm? If the answer to this question is no or cannot be

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determined because the pacemaker is not programmable, a backup method of maintaining a heart rate must be defined. This is particularly important because electrocautery can induce pacemaker failure. Most pacemaker manufacturers recommend against the use of electrocautery in any patient without an adequate intrinsic rhythm. Unipolar cautery is far more hazardous than bipolar cautery. Electrocautery can, by its noise level, be misinterpreted by the pacemaker and cause inhibition of the pacemaker that is reversible when the cautery is turned off. Thus, frequently, electrocautery can cause the pacemaker to revert to a backup mode. This usually is a ventricular demand mode. The most severe problem the electrocautery may cause is complete and permanent loss of pacing. The best way to manage a pacemaker during the use of electrocautery is to program the generator to ventricular demand mode at a rate sufficient to minimize competition with the intrinsic heart rate (109). The simplest way to achieve this is to place a permanent magnet over the pacemaker. This prevents inhibition by electrocautery. If a permanent loss of pacemaker function occurs in the operating room, with no intrinsic heart rate, the quickest and most efficient method of inducing an intrinsic rate is to begin intravenous infusion of a b-stimulant such as isoproterenol. After this maneuver, a temporary transvenous pacemaker should be inserted.

PERICARDIAL DISEASE The pericardium is a fibrous sac that surrounds and envelops the heart. Its purpose is to fix the heart anatomically within the mediastinum, act as a barrier to the spread of infection from surrounding structures such as the lungs, and reduce friction between the enclosed heart and surrounding organs (110). In the nondiseased state, the pericardium has little or no effect on cardiac hemodynamics. Two specific pericardial disorders, however, may necessitate surgical intervention. These include pericardial effusion with tamponade and chronic constrictive pericarditis.

Pericardial Effusion with Tamponade Pericardial effusion by itself is not uncommon. It can occur in response to acute viral pericarditis, MI, CHF, and various immune disorders such as rheumatoid arthritis and lupus erythematosus. In these conditions, the effusion is usually moderate and self-limited, and it abates with treatment of the underlying condition. In patients with chronic uremic pericarditis or malignant involvement of the pericardium, such as may occur from neoplastic spread of bronchogenic carcinoma, excessive amounts of effusion may collect in the pericardial sac so that adverse stresses are placed on the contracting heart, and cardiac dynamics are severely impaired. This state of pericardial tamponade can significantly compress the heart, not only by compressing the great veins and atria with substantial reduction of venous return to the ventricles but also by impeding the optimal filling of the ventricles during diastole, so that CO is severely depressed despite normal systolic function. The fluid accumulating in the pericardial sac that gives rise to tamponade may be serous or sanguineous, depending on the underlying cause. Inflammatory disorders, such as viral infections or immune diseases, usually result in a serous fluid. Liquid or clotted blood within the pericardium is commonly associated with uremic pericarditis as well as with malignant pericardial involvement. Occasionally, the pericardial sac fills with blood after cardiac surgery, but this

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is rare with modern cardiovascular procedures if proper postoperative drainage techniques are employed. Cardiac trauma from penetrating injury, and rarely from blunt trauma, may also produce pericardial tamponade. In these settings, the pericardium is normal and a relatively small volume of blood (as little as 150–200 mL) may produce the tamponade, in contrast to those sustaining tamponade from more chronic pericardial disease, in which the volume may approach 1 L or more of fluid before symptoms develop. Although uncommon, trauma from within the heart as a result of a perforating transvenous pacemaker lead, the placement of a central venous pressure, or Swan–Ganz catheter can produce unsuspected tamponade. Thus, any patient who becomes hypotensive for unknown reasons in the presence of one of these devices may have a cardiac perforation. The clinical presentation of pericardial tamponade is usually characterized by a triad of physical signs, including arterial hypotension, increased jugular venous pressure, and distant (or muffled) heard sounds. Facial cyanosis may also be present, as well as a paradoxic pulse. This latter sign is a drop in arterial blood pressure of 10 mmHg or more with inspiration. It is usually an exaggeration of the normal response to ventilation and is distinctly more prominent in individuals subjected to positive-pressure ventilation. In patients with suspected pericardial tamponade, management depends on ‘‘how tight’’ the effusion is. This tightness is reflected in the degree of hypotension and elevation of venous pressure from the tamponade. In individuals with only moderate tamponade, a Valsalva maneuver is helpful in determining its seriousness. If palpable radial pulses are not lost with a Valsalva maneuver, the situation is not critical. Another useful approach to determine the seriousness of the tamponade is to test a patient’s blood pressure response to a rapid infusion of intravenous fluid. If the tamponade is only moderate, a significant rise in arterial blood pressure should occur from this fluid bolus; in contrast, more serious degrees of tamponade blunt this response. The presence of an unexplained supraventricular dysrhythmia is a sign of significant tamponade and of the potential for incipient circulatory failure, especially if intermittent sinus arrest exists. It is essential in the analysis of suspected pericardial effusion that an echocardiogram be obtained. This modality is extremely useful in patients with pericardial effusions and potential pericardial tamponade. An echocardiogram can determine the location and characteristics of the fluid (loculated or free floating) and also ascertain to a reasonable extent whether the pericardial tamponade is of physiologic significance. In addition, it can be used to guide the insertion of a needle into the pericardial space to aspirate fluid, especially if this is deemed to be the appropriate treatment. Once significant tamponade has been deemed to exist, fluid drainage may be accomplished percutaneously by pericardiocentesis with either a needle or catheter placement (Fig. 15). Alternatively, surgical intervention through a subxiphoid pericardial window can be performed. Situations in which traumatic hemopericardium exists require a sternotomy or thoracotomy for optimal management. It needs to be emphasized that if the tamponade is considered to be of only modest proportions and is not life threatening, great care should be taken to determine the benefit of the pericardiocentesis. This technique, although useful in urgent tamponade, can result in cardiac puncture and actually worsen the situation. An important principle in managing a patient with tamponade is that endotracheal intubation should be

Figure 15 For pericardiocentesis, a 16-gauge plastic-sheathed needle is introduced beneath the costal margin and passed through the properitoncal fat and into the pericardial cavity through the tendinous part of the diaphragm. Source: From Ref. 111.

avoided. The reason for this is that positive-pressure ventilation frequently causes cardiac arrest in individuals with significant tamponade. Consequently, preparation and draping in the operating room should be carried out prior to induction of anesthesia and intubation, so that rapid decompression may be achieved in the event that it becomes necessary. A generous subxiphoid window, instead of formal pericardiectomy, is usually adequate to decompress the pericardial sac in patients with uremic or malignant pericardial tamponade. After removal of the xiphoid cartilage, the pericardium is opened between two silk stitches and the window is created. The fluid is aspirated and sent for appropriate cultures, while the pericardium is formally sampled for biopsy. An angled chest tube is placed within the pericardial cavity along the diaphragmatic surface and exits through a separate stab-wound incision in the skin. This tube is removed when the drainage ceases. Although pericardial effusions can recur after subxiphoid window, this is distinctly uncommon.

Chronic Constrictive Pericarditis Chronic constrictive pericarditis is the other condition of surgical significance involving the pericardium. This form of pericarditis is produced in response to chronic infectious tuberculosis and histoplasmosis, various collagen-vascular diseases, and, less commonly, after what appears to be uncomplicated cardiac surgery or MI, with the development of Dressler’s syndrome (characterized by fever, pericardial friction rub and pain, and often pericardial effusion). The pericardial–epicardial scarring can be severe, with obliteration of the pericardial space, thickening of the pericardium (sometimes as much a 1 in. or more), and severe fibrosis and calcifications in which calcific deposits may actually grow in the myocardium. Pathophysiologically, this massive

Chapter 36: Acquired Cardiac Disorders

pericardial thickening induces several aberrations, including obstruction of venous return with severe diastolic cardiac dysfunction. Physical signs attendant on this condition are similar to those of severe CHF with elevated venous pressure, edema, hepatomegaly, and ascites. If calcification is not apparent on chest radiography, the diagnosis may not be evident. Cardiac catheterization is usually diagnostic. This latter modality usually shows small ventricular cavities, diastolic pressures within 5 mmHg of each other, jugular venous distention with measured mean arterial pressures above 10 mmHg, and the typical ‘‘dip and plateau’’ pattern of diastolic right ventricular pressure (the square-root sign). Because surgical management of chronic constrictive pericarditis can be difficult and dangerous, and it may tax the skill of the most accomplished cardiac surgeon, a median sternotomy incision should be used with cardiopulmonary bypass (112). The absence of an epicardial– pericardial plane can make this procedure bloody. Therefore, a cell saver and aprotinin should be employed. Careful attention must be paid to freeing the atria and vena cavae as well as the ventricles, with recognition of the fact that the visceral pericardial layer may be as important as the parietal layer. This visceral pericardiectomy is complicated by the occasional ‘‘invasion’’ of the ventricular myocardium itself by calcific deposits. The pericardium should be removed from the phrenic nerve anteriorly, but it also should be removed posterior to the phrenic nerve. Complete removal of the constricting pericardium restores the left ventricular pressure–volume loop to normal or nearly normal. Operative mortality rate for this procedure ranges between 10% and 20%, and is adversely influenced by the severity of heart failure, elevation of right atrial pressure, and comorbid disease. Long-term results are poorest in patients with radiation pericarditis, and in all cases results vary primarily in proportion to the preoperative severity of heart failure.

CARDIAC TUMORS The most common tumor of the heart is a metastatic neoplasm. Approximately 10% to 20% of patients who die of disseminated cancer have cardiac metastases (113,114). The most common tumors to metastasize to the heart are from leukemia (50% of the patients have cardiac metastases), breast cancer, lung cancer, lymphoma, and melanoma. Metastatic disease to the heart usually does not warrant surgical intervention, except if it is associated with pericardial effusion and tamponade. Pericardial drainage is best accomplished in these terminally ill patients through subxiphoid pericardiotomy. This operation is performed with local anesthesia and provides reliable relief of symptoms, a recurrence rate of 3%, and minimal morbidity. Primary tumors of the heart are rare. The incidence ranges between 0.002% and 0.19%. Approximately 75% of primary cardiac tumors are benign, and 15% of these are myxomas (113,114). Although myxomas can arise in any cardiac chamber, 90% occur in the atria; 75% are observed in the left atrium, and 15% to 20% are found in the right atrium. Myxomas are distinctly rare in children. The peak incidence is the third to fourth decade of life, they are more common in women than in men, and 94% are solitary. About 5% of myxomas are familial, with an autosomal dominant inheritance. Familial patients tend to be younger, are equally likely to be male or female, and frequently have multicentric

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tumors. Most important, familial myxomas have the highest recurrence rate (20–60%). Atrial myxomas arise from the interatrial septum near the oval fossa. Right atrial myxomas are most common in women and are broad based. Left atrial tumors are round, lobulated, gelatinous, and frequently pedunculated with a stalk. Consequently, they are quite mobile. Their color is usually white or yellow–brown, and they frequently are covered with thrombus. The average size is 5 cm. Myxomas arise from endocardium, not from a thrombotic origin as was formerly speculated. Myxomas have developed after cardiac trauma, especially atrial septal defect closure. Constitutional symptoms include weight loss, fever, and lethargy. This clinical presentation is associated with leukocytosis, elevated sedimentation rate, thrombocytopenia, and elevated C-reactive protein. Immunoglobulin G levels and interleukin-6 are also elevated. Clinical presentation is related most commonly to obstruction to blood flow within the heart. Left atrial myxomas mimic mitral stenosis or, less commonly, mitral regurgitation. Right atrial myxomas produce features of right heart failure, including venous distention, ascites, hepatomegaly, and peripheral edema. Systemic embolization, the second most common mode of presentation, occurs in 30% to 40% of patients. Most commonly the tumor embolus goes into an intracranial vessel, producing a transient ischemic attack or complete stroke. Less commonly, embolization to the lower extremity occurs. Histologic examination of surgically removed peripheral emboli can establish a diagnosis of an otherwise unsuspected tumor. The most useful diagnostic test is echocardiography, which establishes a diagnosis in nearly every case (115). Transesophageal echocardiography is particularly sensitive to detect small tumors, and it can be useful in the operating room to make certain that the entire mass has been removed. Surgical resection employs cardiopulmonary bypass and bicaval cannulation, with care taken to avoid manipulation of the heart because myxomas are friable and can embolize (116,117). After aortic cross-clamping and cardioplegic arrest, the left atrium is opened widely, and the location of the myxoma is determined. In most cases, it is attached with a stalk to the interatrial septum. A second incision in the right atrium allows excision of the stalk with the atrial septum, followed by gentle removal of the mass through the left atrium. The surgically created atrial septal defect is closed with autologous pericardium. The operative mortality rate is 1% to 3%, and the recurrence rate in nonfamilial cases is 1% to 5%.

SUMMARY Aberrations in normal cardiac function can occur when disease adversely affects cardiac rate and rhythm, the efficiency of cardiac pumping, and the optimization of cardiac loading. Acting either alone or in various combinations, derangements in each of these physiologic mechanisms can seriously affect circulatory dynamics, affecting the entire process whereby adequate delivery of oxygen and nutrients maintains cellular health and function. Although some acquired cardiac defects lend themselves to nonsurgical management strategies, in many situations the cardiac surgeon plays a key role in restoring normal cardiac physiology. As reviewed in this chapter, in most instances, ischemic heart disease, valvular heart disease, and heart failure are managed initially through medical

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therapy but with a reliance on surgical approaches when the initial approach fails or when the pathophysiology dictates an initial surgical approach as with left main coronary artery disease in ischemic syndromes or acute valve failure as seen with papillary muscle rupture. In addition, new technologies are emerging, which will prove increasingly useful in the surgical management of virtually all acquired cardiac disorders, from the realm of arrhythmias to ischemic heart disease, to valvular heart disease, and perhaps most dramatically, now in the treatment of end-stage CHF, where immunology and technical advances can add years to the lives of people who previously faced a terminal prognosis. Whether through a medical or surgical approach, the goal of the cardiac specialist is to restore cardiac function to enable adequate delivery of oxygen to the body. Increasingly, the treatment of cardiac disorders is involving a partnership among all disciplines with the traditional lines between surgery and medicine becoming increasingly blurred.

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91. Levy D, Larson MG, Vasan RS, et al. The progression from hypertension to congestive heart failure. JAMA 1996; 275:1557–1562. 92. Bach DS, Boiling SF. Improvement following correction of secondary mitral regurgitation in end-stage cardiomyopathy with mitral annuloplasty. Am J Cardiol 1996; 78:966–969. 93. Ahbraham WT, Fisher WG, Smith Al, et al. Cardiac resynchronization in chronic heart failure. New Engl J Med 2002; 346:1845–1853. 94. Menasche P, Hagege AA, Vilquin JT, et al. Autologous skeletal myoblast transplantation for severe post-infarction left ventricular dysfunction. J Am Coll Cardiol 2003; 41(7):1078–1083. 95. Frazier OH, Rose EA, Macmanus Q, et al. Multicenter clinical evaluation of the Heartmate 1000 IP left ventricular assist device. Ann Thorac Surg 1992; 53:1080–1090. 96. American College of Cardiology/American Heart Association/NASPE Heart Rhythm Society. 2002 Guideline update for implantation of pacemakers and antiarrhythmia devices. J Am Coll Cardiol 2002; 40(9):1703–1719. 97. Belott PH, Reynolds DW. Permanent pacemaker implantation. In: Ellenbogen KA, Kay GN, Wilkoff BL, eds. Clinical Cardiac Pacing. Philadelphia: WB Saunders, 1995:447. 98. AMA Council on Scientific Affairs. The use of cardiac pacemakers in medical practice. JAMA 1985; 254:1952. 99. Sealy WC, Selle JG. Surgical treatment of supraventricular arrhythmias. In: Roberts AJ, Conti CR, eds. Current Surgery of the Heart. Philadelphia: JB Lippincott, 1987. 100. Sealy WC, Anderson RW, Gallagher JJ. Surgical treatment of supraventricular tachyarrhythmias. J Thorac Cardiovasc Surg 1977; 73:511. 101. Ellenbogen KA, Kay GN, Wilkoff BL, eds. Clinical Cardiac Pacing. Philadelphia: WB Saunders, 1995; Furman S, Schwedel JB. An intracardiac pacemaker for Stokes-Adams seizures. N Engl J Med 1959; 261:948. 102. Cox JL, Ad N, Palazzo T, et al. Current status of the Maze procedure for the treatment of atrial fibrillation. Semin Thorac Cardiovasc Surg 2000; 12:15–19.

103. Williams MR, Stewart JR, Boiling SF, et al. Surgical treatment of atrial fibrillation using radiofrequency energy. Ann Thorac Surg 2001; 71:1939–1944. 104. Guiraudon GM, et al. Encircling endocardial ventriculotomy: a new treatment for life-threatening ventricular tachycardia. Ann Thorac Surg 1977; 26:438. 105. Harken AH, Josephson ME, Horowitz LN. Surgical endocardial resection for the treatment of malignant ventricular tachycardia. Ann Surg 1979; 190:456. 106. Bocker D, et al. Do patients with an implantable defibrillator live longer? J Am Coll Cardiol 1993; 21:1638; Lowe JL, Sabiston DC. The surgical management of cardiac arrhythmias. J Cardiovasc Surg 1986; 1:1. 107. Kim SG, et al. Long-term outcomes and modes of death of patients related with nonthoracotomy implantable defibrillators. Am J Cardiol 1995; 75:1229. 108. May CD, et al. The impact of implantable cardioverter defibrillator on quality of life. PACE Pacing Clin Electrophysiol 1995; 18:1411. 109. Levine PA, et al. Electrocautery and pacemakers. Management of the paced patient subject to electrocautery. Ann Thorac Surg 1996; 41:313. 110. Shabetai R. The Pericardium. New York: Grune & Stratton, 1981. 111. Edwards EA, Malone PD, Collins JJ Jr. Operative Management of the Thorax. Philadelphia: Lea & Febiger, 1972. 112. Seifer FC, et al. Surgical treatment of constrictive pericarditis: analysis of outcome and diagnostic error. Circulation 1985; 72(suppl 2):II264. 113. Harvey WP. Clinical aspects of cardiac tumors. Am J Cardiol 1968; 21:328. 114. Heath D. Pathology of cardiac tumors. Am J Cardiol 1968; 21:315. 115. Ensherding R, et al. Diagnosis of heart tumors by transesophageal ochocardiography. Eur Heart J 1993; 14:1223. 116. Miralles A, et al. Cardiac tumors: clinical experience and surgical results in 74 patients. Ann Thorac Surg 1991; 52:886. 117. Murphy MC, et al. Surgical treatment of cardiac tumors: a 25 year experience. Ann Thorac Surg 1990; 49:612.

PART FOUR: The Urinary System

37 Urine Formation: From Normal Physiology to Florid Kidney Failure Akinsan Dosekun, John R. Foringer, and Bruce C. Kone

interlobular arteries, which divide at the level of the corticomedullary junction to form the arcuate arteries (Fig. 1). The arcuate arteries lead to interlobar arteries, which branch into the afferent arterioles. The afferent arterioles give rise to the glomerular capillaries that coalesce to form the efferent arteriole. The efferent arterioles become a second capillary network, the peritubular capillaries, which surround the proximal tubules and successive tubular segments of the nephron (Fig. 2). The vasa recta arise from the juxtamedullary efferent arterioles and give rise to the descending vasa recta, which form a dense network of anastomosing, looping vessels that descend in parallel with Henle’s loops to supply the outer and inner medulla. The venous system runs in parallel to the arterial vessels, with blood from the peritubular capillaries flowing sequentially through the stellate vein, the interlobular vein, arcuate vein, interlobar vein, and renal vein, which tracks beside the ureter. Blood from the ascending vasa recta enters the interlobular and arcuate veins. Despite receiving less than 1% of the renal blood flow (RBF), the vasa recta subserve several critical functions, including the return of reabsorbed solutes and water to the systemic circulation, the delivery of oxygen, nutrients, and substances for secretion to nephron segments, and the concentration and dilution of the urine. The total vascular resistance along the renal vascular tree is estimated to be about 25% before the afferent arteriole, 50% along the length of the afferent arteriole, and 30% along the efferent arteriole (1).

INTRODUCTION The kidney fulfills several major functions. First, the organ regulates the excretion of several important inorganic and organic ions and participates in the regulation of acid–base balance. Second, the kidneys work in an integrated manner with the cardiovascular and central nervous systems to regulate body fluid osmolality and volume. The control of body fluid osmolality is central to the maintenance of normal cell volume in virtually all tissues. Third, the kidney excretes metabolic by-products and exogenous substances, including certain drugs. Finally, the kidney is an important endocrine organ, producing key hormones involved in the regulation of blood pressure and erythropoiesis, as well as calcium, phosphate, and bone metabolism. The kidney has remarkable functional reserve and, through adaptive changes, can maintain fluid, electrolyte, metabolic, and acid–base balance as the number of functioning nephrons is reduced by injury or disease. However, in response to significant injury, the kidney may undergo maladaptive changes that lead to acute irreversible and/or progressive renal disease. The incidence of acute and chronic kidney failure continues to rise, and despite extensive investigation into the pathophysiology of these disorders, major preventive or therapeutic advances have been infrequent. This chapter examines the anatomy and physiology of the normal kidney and then reviews the pathophysiology, diagnosis, and management of acute and chronic kidney failure, with special emphasis on clinical scenarios commonly encountered in modern surgical practice.

Cortex

OVERVIEW OF RENAL PHYSIOLOGY Renal Anatomy and Microanatomy The cut surface of a bisected kidney reveals two major regions: the outer region, termed the cortex, in which the glomeruli reside, and the inner region, termed the medulla. The medulla is divided into 8 to 18 renal pyramids, whose bases begin at the corticomedullary junction and form an apex in a minor calyx of the papilla. The minor calyces drain into major calyces and then into the renal pelvis, an expanded region of the ureter. Smooth muscle contractions by the walls of the calyces, pelvis, and ureters drive the urine to the urinary bladder.

Medulla

Interlobar artery Arcuate artery Interlobular artery Afferent arteriole

Macro- and Microcirculation Although comprising only 0.5% of the total body mass, the kidneys receive roughly 25% of the cardiac output. This disproportionately high rate of blood flow facilitates glomerular filtration. The blood flow is distributed principally to the renal cortex, and diminishes progressively toward the cortex. The renal arteries branch successively into

Figure 1 Organization of the arterial vascular system of the human kidney.

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basement membrane itself, the foot processes of the podocytes, and the fenestrae of the glomerular endothelium (Fig. 4). The normal glomerular filtration barrier will allow the passage of molecules with molecular weight 7) is commonly encountered in metabolic alkalosis or when urea-splitting organisms are infecting the urinary tract. Mildly alkaline urine with concomitant hyperchloremic metabolic acidosis may reflect renal tubular acidosis. Proteinuria Under normal conditions, the urine contains only very small amounts of protein ( < 50 mg/24 hr). However, the amount of protein in the urine may be increased after exercise, in pregnancy, and in some persons when standing (orthostatic

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proteinuria). A large amount of protein, particularly if in the nephrotic range ( > 3.5 g/24 hr), is typically indicative of glomerular disease, for which there are many etiologies. However, chronic tubulointerstitial disease, polycystic kidney disease, renal vein thrombosis, and other disorders may also present with significant proteinuria. In addition, protein overproduction such as in multiple myeloma may overwhelm the capacity of the proximal tubule to reabsorb protein and escape into the urine. Pigmenturia The urinary dipstick test for heme detects both hemoglobin and myoglobin. With hematuria, erythrocytes are observed on microscopic examination of the urine, and the dipstick test for heme gives a positive reaction. With hemoglobinuria from massive hemolysis (e.g., major blood transfusion reaction), however, no erythrocytes are apparent in the urine but the dipstick is still positive for heme. Similarly, with myoglobuniria resulting from muscle breakdown (e.g., rhabdomyolysis), the dipstick heme test is reactive, and no erythrocytes are evident in the urine. These possibilities can be distinguished by the appearance of the plasma or urine supernatant (clear in myoglobinuria and pink or red in hemoglobinuria) or by the measured urinary myoglobin or hemoglobin. Glycosuria The proximal tubule has a fixed capacity to reabsorb filtered glucose. When this capacity is exceeded as a consequence of hyperglycemia, increased GFR, or proximal tubule injury, glycosuria results. In individuals on normal carbohydrate loads, glycosuria typically indicates that the patient has diabetes mellitus. In some healthy persons, however, there may also be an abnormal amount of glucose in the urine because of a low threshold for tubular reabsorption, without any disturbance of glucose metabolism. Ketone bodies (acetone and acetoacetic acid) may be present in traces in normal urine, but may be present in larger quantities in severe untreated diabetes and in carbohydrate starvation. Urine Microscopic Examination Examination of the urinary sediment may provide not only information on the presence of an underlying renal disorder but clues as to its specific etiology. White blood cells, particularly as casts, commonly indicate infectious (e.g., pyelonephritis) or inflammatory acute tubulointerstitial nephritis (ATIN) disease. Urinary eosinophils detected by Hansel’s stain may be found in acute interstitial nephritis, but have also been found in several other disorders. Red blood cells may arise from either upper or lower tract bleeding. However, the presence of dysmorphic red blood cells or red blood cell casts in a freshly voided urine sample is much more suggestive of glomerulonephritis. Cellular casts derived from the renal tubules may indicate injury, and are commonly present in acute tubular necrosis (ATN). Finally a number of crystals may be apparent in the urine. Calcium oxalate dihydrate crystals typically are colorless squares resembling an envelope. In some cases, they result from increased calcium related to disorders of calcium metabolism. These crystals can also be seen in cases of ethylene glycol intoxication. If seen in large numbers in the urine of a patient with AKF, this diagnosis should be entertained. Uric acid crystals may be seen in gout and uric acid stone formation. They appear and often occur in a diamond shape, but may also be prism or hexagon shaped, or simply as amorphous material. Amorphous phosphates and urates cannot

be distinguished by routine microscopy. Struvite crystals (magnesium ammonium phosphate and triple phosphate) usually appear as colorless, three-dimensional, prism-like crystals (‘‘coffin lids’’). Urinary tract infection with ureasepositive bacteria promotes struvite crystalluria by raising urine pH and increasing free ammonia.

Renal Function Tests Serum Creatinine Concentration and GFR Creatinine is a product of creatine metabolism in muscle. A less significant source of creatinine is dietary meat intake. Creatinine generation therefore directly correlates with muscle mass. Individuals with larger muscle mass, such as a young, muscular males have greater creatinine production; at a given level of glomerular filtration, such individuals will have higher levels of serum creatinine. Individuals with smaller muscle mass (e.g., females, the elderly, malnourished patients with muscle wasting, and patients with chronic liver disease) have lower levels of serum creatinine. In particular, patients with CKD with anorexia, weight loss, and muscle wasting, as well as dietary protein restriction will have serum creatinine levels that underestimate the degree of loss of renal function. Factors that interfere with renal tubular secretion of creatinine or with extrarenal excretion of creatinine also change the relationship of serum creatinine and GFR. Extrarenal elimination of creatinine occurs in the gut by colonic secretion into the lumen followed by its degradation by colonic bacteria. Creatinine clearances by this route vary from 1 to 7 mL/min. Although negligible at near-normal levels of renal function, this becomes a significant fraction of creatinine clearance in severe kidney failure. The relationship between serum creatinine concentration and GFR is valid only in the steady state. In the extreme case in which GFR halts, plasma creatinine will still remain normal for several hours until nonexcreted creatinine has accumulated. The relationship between true GFR and serum creatinine is important to consider. During initial reductions in GFR to about 60 mL/min, enhanced tubular secretion of creatinine maintains serum creatinine levels at near normal levels (Fig. 9). With further reductions in GFR corresponding to plasma creatinine concentrations of 1.5

7.5

Plasma (Cr) (mg/dl)

5.0 2.5 1.0 0

50 100 150 GFR (ml/min)

Figure 9 Correlation between plasma creatinine concentration and glomerular filtration rate (GFR). The amount of creatinine that is filtered (GFR  PCr) is equivalent to the amount that is excreted (UCr  V). Because creatinine production by skeletal muscle is also relatively constant, creatinine excretion must be constant to maintain equilibrium. Thus, as GFR falls, PCr must increase proportionately to keep the filtration and excretion of creatinine equal to the creatinine production rate.

Chapter 37: Urine Formation: From Normal Physiology to Florid Kidney Failure

to 2.0 mg/dL, however, the tubular secretion of creatinine is saturated, and creatinine concentrations rise proportionate to the fall in GFR. Thus, significant disease progression can occur, while serum creatinine levels remain in the normal or near-normal range. Careful consideration of these factors is needed when attempting to deduce renal functional status from the creatinine level. Two empiric formulae are frequently used to estimate renal function from the serum creatinine level, which are as follows: The Cockroft–Gault equation (39, 40): creatinine clearance (mL/min) ¼ [140
age (years)]  weight (kg)/72  serum serum Cr (mg/mL) for men, and corrected by a factor of 0.85 for women The MDRD study formula (41): GFR (mL/min per 1.73m2) ¼ 186  (Scr)
1.154  (age)
0.203  (0.724 if female)  (1.210 if African-American), which predicts GFR and not creatinine clearance and takes into consideration race, albumin, and blood urea nitrogen (BUN) levels. Serum creatinine measurements and estimates of creatinine clearance or GFR provide quick and convenient information about renal function. Serial measurements give an idea of the course of disease and the impact of treatment, provided caution is exercised in their interpretation (42). BUN and GFR Like serum creatinine, BUN is excreted by glomerular filtration and tends to vary inversely with GFR. The BUN level is a much less reliable as a marker of GFR than serum creatinine. BUN is greatly influenced by factors other than glomerular filtration. Urea generation is far more variable than creatinine generation: it is elevated with increased protein intake and in states of excessive catabolism—infections, febrile states, and trauma—or decreased during anabolism, as with corticosteroid and tetracycline therapy. Gastrointestinal hemorrhage is of particular clinical importance as a cause of markedly increased urea generation. Conversely, low protein intake, malnutrition, severe liver parenchymal disease, and myxedema are associated with decreased urea generation. Renal handling of urea is more complex than that of creatinine. Urea is freely filtered at the glomerulus, and 35% to 40% of filtered urea is obligatorily reabsorbed in the proximal tubule. Urea is secreted into the tubular lumen in the loop of Henle, and reabsorbed in the medullary collecting duct via urea transporters that are regulated by vasopressin. The state of hydration, RBF rate, and urine flow rates all influence the rate of urea excretion. In states of dehydration or volume depletion, only 35% to 40% of filtered urea appears in the urine, because of increased proximal reabsorption, while in states of volume repletion or diuresis, this proportion may be higher than 80%. Despite these limitations, analysis of BUN can be clinically helpful. A high BUN: serum creatinine ratio ( >20) is suggestive of volume depletion (prerenal azotemia), if renal ischemia, obstruction, or excessive urea generation has been excluded. Clinical Measurement of GFR The GFR is measured by assaying the clearance of creatinine or exogenously administered substances. The most frequently used exogenous substances used in clinical practice are iodinated iothalamate and technetium-labeled diethylenetriaminepentaacetic acid, but several nonradionuclide compounds (e.g., nonradioactive iothalamate) and nonionic iodinated contrast media (e.g., iohexol and iopental) are also used in some instances. The most commonly used method

735

for the routine measurement of GFR is the determination of creatinine clearance. A timed collection of urine is required, which must necessarily be accurate, because an incomplete collection can lead to an underestimation of the GFR. The adequacy of the urine collection can be judged by measuring the total creatinine excretion of the patient, which should approximate 10 to 15 mg/kg/day in women and 15 to 20 mg/kg/day in men. The creatinine clearance is calculated according to the following equations: Assumption: Amount filtered ¼ Amount excreted PCr  GFR ¼ UCr  V UCr V GFR ¼ PCr (PCr and UCr are the serum and urinary concentrations of creatinine, respectively, and V is the urine flow rate.) Creatinine clearances always overestimate GFR, because they do not take into account the contribution of tubular secretion of creatinine to urinary creatinine excretion. The contribution of tubular secretion is negligible at normal levels of renal function and serum creatinine; creatinine clearance overestimation of GFR in this setting is in the range of 5% to 10% approximately. Drugs that block the tubular secretion of creatinine (e.g., cimetidine) can produce an elevated plasma creatinine concentration without affecting GFR. With severe degrees of kidney failure, however, creatinine clearance overestimation of GFR may be in excess of 100%. Because creatinine clearances markedly overestimate GFR in advanced stages of renal failure, while urea clearances underestimate GFR, the mean of creatinine and urea clearances may sometimes be used to estimate more accurately GFR in advanced stages of renal failure. Clinical Estimation of RBF The measurement of RBF is often required in the management of the post–renal transplant patient and occasionally in the evaluation of renovascular disorders. The renal clearance of substances excreted by both glomerular filtration and tubular secretion is used to estimate effective renal plasma flow. Most commonly used are the radionuclides mercaptoacetyltriglycine, chelated to technetium, and iodohippurate. Doppler ultrasonographic methods are also used to estimate RBF.

ACUTE KIDNEY FAILURE AKF is a common clinical problem associated with considerable morbidity and mortality. AKF is primarily a hospital-acquired disease, occurring in approximately 5% of hospitalized patients, 5% to 15% of patients following coronary artery bypass grafting, and up to 25% of patients in an intensive care unit (ICU). Mortality in AKF is greatly influenced by comorbid events. The high mortality associated with AKF is well described and reaches 65% in ICU patients (43–45). Of the patients who experience AKF requiring dialysis, 5% to 30% will require long-term dialysis therapy, without renal recovery (46). Importantly, AKF is an independent risk factor for morbidity and mortality. AKF is associated with a 5.5 odds ratio of dying (47). Thus AKF should not be viewed solely as a treatable complication of a serious illness. AKF can be defined by a decrease in the GFR that occurs over days to weeks. Commonly used definitions

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include an increase of serum creatinine > 0.5 mg/dL over baseline, an increase of serum creatinine over 50% of baseline, or a reduction in creatinine clearance of 50%. However, no standardization of the definition of AKF has been adopted, and the true magnitude of the problem is likely unrecognized. The GFR can decline rapidly with only small changes in the serum creatinine. Understanding the significance of the relationship between early declines in GFR and changes in serum creatinine may help in the early recognition and treatment of AKF.

Classification of AKF It is useful to subcategorize renal disorders based on clinical and pathologic features. AKF has traditionally been divided into prerenal, renal, or postrenal according to the etiology of the insult (Table 2). Distinguishing these three causes of kidney failure is important to the diagnostic and therapeutic strategy. The majority of hospital-acquired AKF is secondary to prerenal azotemia and ischemic or toxic ATN, an intrinsic renal cause of AKF.

Prerenal Azotemia Prerenal azotemia accounts for approximately 70% of AKF cases in hospitalized patients (48,49). Prerenal azotemia is a normal physiologic response to decreased renal perfusion and rapidly resolves with restoration of glomerular ultrafiltration pressure. The decrease in glomerular ultrafiltration pressure may be secondary to a true reduction in circulating blood volume from bleeding or cutaneous, GI, or urinary losses, or from renovascular disease or dysfunction (Fig. 10). Cirrhosis, congestive heart failure, and sepsis produce effective circulating volume depletion with similar hypoperfusion of the glomerulus. Mean arterial pressures (MAP) below 80 to 90 mmHg will induce a fall in RBF. If the fall in the MAP is promptly corrected, renal parenchymal damage does not typically ensue. If the prerenal state is allowed to continue, however, renal pathology may occur, and ATN can develop. Sustained reduction in RBF results in cellular hypoxia leading to pathologic tubular changes and ATN. Prerenal azotemia and ischemic ATN are opposite extremes of a continuum related to renal hypoperfusion: the

Table 2 Common Causes of Acute Kidney Failure: Urinary Findings and Confirmatory Tests Cause of acute kidney failure Prerenal azotemia Volume depletion

Typical urinalysis No cellular elements or proteinuria

Rapid resolution of ARF with correction of renal hypoperfusion Invasive monitoring—CVP or PCWP

Hematuria without dysmorphic red blood cells, casts, or proteinuria

Abdominal X-ray

Decreased EABV NSAIDs ACE-I or ARB Postrenal azotemia Abdominal or flank pain Palpable bladder Enlarged prostate Nephrolithiasis Urinary frequency, oliguria, or anuria Intrinsic renal azotemia Acute tubulointerstitial nephritis

Hemolysis

Hemolytic uremic syndrome and thrombotic thrombocytopenic purpura Glomerulonephritis

Radiocontrast Rhabdomyolysis

Tumor lysis syndrome Ischemia

Confirmation

Renal ultrasound IVP Retrograde pyelography

WBCs Urine eosinophils White cell cast Red blood cells Rarely red blood cell casts Urine supernatant is pink and heme þ Hemoglobinuria No red blood cells Urine red blood cells Heme þ

Proteinuria Red blood cell casts White blood cell casts May have granular, coarse, or tubule epithelial cell casts Urine supernatant Heme þ without red blood cells Myoglobinuria Urate crystals Muddy brown granular, coarse, or tubule epithelial cell casts

Systemic eosinophilia Renal biopsy Biopsy of skin rash Elevated serum Kþ, PO4, uric acid, LDH Hypocalcemia Peripheral smear with fragmented red blood cells Renal biopsy Peripheral smear with schistocytes and fragmented red cells Thrombocytopenia Renal biopsy Serum antibody test Temporal relationship to the contrast infusion Elevated serum myoglobin, creatine phosphokinase, PO4, uric acid, Kþ Hypocalcemia Elevated serum Kþ, PO4, uric acid Decreased serum Ca2þ Clinical assessment and urine findings usually sufficient

Abbreviations: EABV, effective arterial blood volume; NSAIDs, nonsteroidal anti-inflammatory drugs; ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; LDH, lactate dehydrogenase; PCWP, pulmonary capillary wedge pressure; CVP, central venous pressure.

Chapter 37: Urine Formation: From Normal Physiology to Florid Kidney Failure

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and certain surgical patients. Obstruction can occur at any level of the urinary collecting system from intratubular to bladder outlet obstruction. Common causes of intrinsic tubular obstruction include nephrolithiasis, blood clots, myoglobinuria, hyperuricosuria, drug crystallization, tumors, and papillary necrosis (Table 2). External retroperitoneal disease processes can cause ureteral obstruction including retroperitoneal fibrosis or abscess, cancers, and retroperitoneal hemorrhage. Accidental surgical ligation of a ureter is also a possibility. The most common cause of postrenal azotemia arising from the lower urinary tract is bladder outlet obstruction, usually from prostatic disease or neurogenic bladder. With timely resolution of the obstruction, there is often complete resolution of the azotemia.

Intrinsic Renal Azotemia Figure 10 Pathogenesis and etiologies of prerenal azotemia. Abbreviations: ARB, angiotensin II receptor blocker; ACEI, angiotensin converting enzyme inhibitor; NSAIDs, nonsteroidal anti-inflammatory drugs; CO, cardiac output; SVR, systemic vascular resistance; EBV, effective blood volume; ECF, extracellular fluid; CHF, congestive heart failure; MI, myocardial infarction.

severity of the insult will dictate the progression from the normal physiologic response to ischemic tubular damage. Less commonly, prerenal AKF can result from diseases of renal microvasculature, including inflammatory (glomerulonephritis and vasculitis) and noninflammatory insults (malignant hypertension) of the vessel wall, thrombotic microangiopathies, and, rarely, hyperviscosity syndromes (Fig. 10). In many instances, the renal hypoperfusion caused by these disorders progresses from prerenal azotemia to ischemic ATN. Common causes of prerenal azotemia are listed in Table 2 and Fig. 10. The common mechanism leading to a decrease in the GFR is a reduction in the circulating arterial blood volume in the renal vasculature. A reduction in the systemic arterial volume or perfusion pressure causes afferent arteriolar dilation, with concomitant increases in the vasomotor tone of the efferent arteriole. This is accomplished through activation of the renin-angiotensin-aldosterone system. Release of norepinephrine and ADH from the sympathetic nervous system completes the basic neural–hormonal attempt to restore the MAP and circulating blood volume (50,51). The early recognition and correction of prerenal azotemia is paramount in preventing progression to tubular damage from prolonged renal hypoperfusion. In patients with severe hepatic disease, splanchnic vasodilation and reductions in systemic vascular resistance lead to prerenal azotemia. In these patients, however, the decline in GFR is commonly masked by low production rates of urea (from liver disease) and creatinine (from reduced muscle mass). As a result, plasma creatinine concentrations and BUN levels may remain in the ‘‘normal’’ range despite progressive kidney failure. Hepatorenal syndrome is an otherwise unexplained development of AKF in patients with advanced hepatic disease. Mortality is high, unless hepatic function can be improved, as with liver transplantation.

Postrenal Azotemia Postrenal azotemia is defined as AKF secondary to urinary tract obstruction. Postrenal azotemia accounts for less than 5% of all cases of AKF, though the frequency is more common in specific patient populations such as elderly men

The most common cause of renal azotemia is a direct ischemic insult to the kidney usually resulting in ATN. Other common injuries encountered in the surgical patient include pigmented nephropathy from myoglobinuria or hemoglobinuria, direct nephrotoxic insults from medications and intravenous iodinated contrast, and acute interstitial nephritis (Table 2) typically from medications. ATN accounts for approximately 75% of AKF episodes among hospitalized patients. As discussed earlier, ATN differs from prerenal azotemia in that renal hypoperfusion has been severe enough to injure renal parenchymal cells, particularly tubule epithelium, and AKF does not resolve immediately after restoration of RBF as it does in prerenal azotemia. If the ischemic episode is prolonged, cortical necrosis can ensue and lead to irreversible renal failure. Hemoglobinuria and myoglobinuria can lead to direct tubular injury through a pigmented cast nephropathy. Extensive trauma resulting in rhabdomyolysis or mismatched blood transfusions leading to massive hemolysis are two common causes of the pigmented nephropathies. In either circumstance, the myoglobinuria or hemoglobinuria results in accumulation of pigmented cast in the proximal tubular lumen and direct injury to tubular cells. With the proximal tubular obstruction, there is also renal vasoconstriction, and both processes contribute to the decline in GFR (52). Renal atheroembolic disease, often following invasive arterial procedures, can also produce AKF (53). Livido reticularis, peripheral and urinary eosinophilia, hypocomplementemia, and thrombocytopenia are classic clinical manifestations of this disorder. Intravenous iodinated contrast promotes an intense renal vasoconstriction and direct tubular cell injury leading to a prerenal azotemia then progression to an intrinsic renal azotemia and ATN. Patients with preexisting renal disease and/or diabetes mellitus are at greatest risk for developing contrast nephropathy (54,55). The temporal relationship between the decrease in GFR and the exposure to the contrast is the most helpful clinical clue to this diagnosis: decrements in GFR are typically seen within 24 to 48 hours of radiocontrast exposure. Recovery from radiocontrast nephropathy often occurs within two weeks of the insult. Nephrotoxic injury from medications can be caused by a wide array of insults that promote direct tubular damage or injury related to renal vasoconstriction. Common offending agents are the aminoglycoside antibiotics, which can cause a decrease in GFR through multiple mechanisms, including renal vasoconstriction, alterations in glomerular capillary permeability, and direct tubular cell disruption (56). Amphotericin and its lipid-based derivatives cause similar changes in the kidney (57–59). Some medications

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can cause a change in the serum creatinine with or without an acute change in the GFR; two classic examples of this are cimetidine and trimethoprim-sulfamethoxazole. Both drugs can block the secretion of creatinine, resulting in an elevated serum creatinine level despite preserved GFR. However, both can also cause an interstitial nephritis and a true renal azotemia (60–62). ATN can be divided into initiation, maintenance, and recovery phases, the pathophysiology and management of which differs (63). In the initiation phase (hours to days), ischemic injury is evolving. GFR falls because of impaired RBF and glomerular ultrafiltration pressure, disrupted integrity of tubule epithelium with backleak of glomerular filtrate, and obstructed urine flow due to intratubular formation of casts comprising detached epithelial cells and cellular debris. The terminal portion of the proximal tubule and the mTAL are the nephron segments most vulnerable to ischemic injury. Both have high rates of active solute transport and oxygen consumption. Furthermore, both of these segments are located in the outer medulla, an ischemic zone even under basal condition by virtue of the unique countercurrent arrangement of the medullary vasculature. Importantly renal injury can be limited by restoration of RBF during this period. In the maintenance phase (typically 1–2 weeks), during which epithelial cell injury is established, GFR stabilizes at its nadir despite correction of systemic hemodynamics, and uremic complications may arise. In the recovery phase, kidney function is restored to a degree by regeneration and/or repair of kidney parenchymal cells.

Diagnosis In distinguishing prerenal, renal, and postrenal azotemia, the most useful early clinical indices include the timing of the changes in serum creatinine, BUN, and urinary volume following in relation to other clinical events, the urine specific gravity, examination of the urinary sediment, and assessment of the urine electrolytes. In certain circumstances, evaluation of the urine osmolality and special stains for urine eosinophils are valuable. In determining hemodynamic changes from cardiac failure or sepsis, central hemodynamic monitoring is often incorporated into the evaluation of critically ill patients with renal failure. Hourly urine output can be used as a measure of adequate renal perfusion. In a prerenal state with inadequate glomerular perfusion pressure, the urine output will often drop to less than 0.5 mL/kg of body weight. Oliguria, defined by a urine output of less than 400 mL/day, is present in about 50% of AKF cases. In the evaluation of prerenal azotemia, urine indices are predictable based on the effect of norepinephrine, ADH, and Ang II on urine flow rate and sodium and water reabsorption. The BUN-to-creatinine ratio is usually elevated to greater than 20:1 in a prerenal state; it is common to see an elevated BUN in the face of a normal creatinine early in the coarse of glomerular hypoperfusion. In differentiating prerenal azotemia from ATN, the urine sodium and specific gravity are often used, the typical clinical indices are illustrated in Table 3. However, urine sodium, osmolality, and specific gravity, as well as the serum BUN-to-creatinine ratio are relatively insensitive measures for the differential diagnosis of AKF. An alternative method of evaluating the kidneys ability to handle sodium is the fractional excretion of sodium (FENa). The FENa has been adopted to help differentiate, in the oliguric patient, prerenal azotemia from intrinsic renal failure. The FENa utilizes the urine sodium and creatinine

Table 3 Urinary Indices in the Differential Diagnosis of Acute Kidney Failure Index

Normal value

Prerenal azotemia

Acute tubular necrosis

Obstruction

Urinary  0.5 mL/kg/  0.5 mL/kg/ Variable Variable volume hr hr Urine specific 1.003–1.025  1.020 1.010 Variable gravity Urinary Variable < 20 mEq/L > 40 mEq/L < 40 mEq/L sodium early > 40 mEq/ L late < 1% < 1% > 3% < 1% early FENaa > 3% late BUN: 10:1 > 20:1 Variable Variable creatinine a

Fena ð%Þ ¼ U=PNa U=PCr  100

Abbreviation: BUN, blood urea nitrogen.

with simultaneous measurements of serum sodium and creatinine (Table 3). In the normal kidney, the FENa is less than 1%, indicating that less than 1% of the filtered sodium is excreted in the urine. The same is true in prerenal azotemia in which case the tubules are sodium avid in the face of volume depletion and suppressed atrial natriuretic peptide (ANP) release. In contrast, intrinsic kidney failure from ischemic or nephrotoxic injury typically has a FENa greater than 1% (64,65). However, many confounding factors and conditions can alter the FENa much like the other urine indices mentioned above, including saline infusion, diuretics, or bicarbonaturia rendering it of limited value in the differential diagnosis of AKF (66). The urinalysis can often give clues to the underlying etiology of AKF. Hemoglobinuria and myoglobinuria, as well as infectious causes of AKF are easily identifiable by a positive test for large blood on the urine dipstick, despite minimal or no red blood cells in the urine on microscopic exam. A large amount of protein ( > 3 g/day) is suggestive of an intrinsic kidney, and typically glomerular, injury. Pyuria and white blood cell casts can be secondary to infection, glomerulonephritis, or ATIN; with the latter, urine eosinophilia may be present but is not a specific finding restricted to ATIN. Red blood cell casts suggest glomerulonephritis. ATN is associated with tubular epithelial cells, epithelial cell casts, and coarse granular cast, whereas prerenal azotemia is associated with fine granular and hyaline casts (Table 2).

Prevention Given the limited therapeutic options currently available, a clear understanding of which patients are at risk is the best defense against AKF. Patients at the greatest risk for AKF are those with preexisting kidney disease and diabetes mellitus with or without overt signs of nephropathy. It is also paramount to understand the relationship of measured serum creatinine to GFR. A 75-year-old woman who weighs 55 kg with a ‘‘normal’’ serum creatinine of 1.0 mg/dL actually has a calculated GFR of 44 mL/min and moderate kidney failure. Despite her preexisting kidney disease, it is relatively common for a patient like this with a normal serum creatinine value to receive intravenous iodinated contrast or other nephrotoxic agents. A common theme in the prevention of AKF is fluid resuscitation. Often presurgical patients are placed on

Chapter 37: Urine Formation: From Normal Physiology to Florid Kidney Failure

restricted fluid intake prior to procedures. Adequate intravenous hydration is important especially if intravenous contrast will be used during radiographic studies, if bowel preparation is needed, or if insensible losses are high from bowel surgery or in burn patients. Medications that interfere with the autoregulation of renal perfusion, such as amphotericin, nonsteroidal anti-inflammatory medications, or ACE inhibitors put the patient at a greater risk for prerenal azotemia and ATN.

Specific Measures N-Acetylcysteine Newer means of protecting against specific injuries such as contrast-induced nephropathy have become commonplace in the clinical setting. Intravenous contrast can cause AKF by a direct reduction in glomerular perfusion pressure through hemodynamic changes and by exerting a direct toxic effect on the tubular epithelial cells. A proposed mechanism of this action is mediated through the production of oxygen free-radical species. Animal models have shown that free-radical scavengers can reduce the oxidant injury in the kidney and prevent AKF (67). N-acetylcysteine is an antioxidant that promotes renal vasodilation by increasing the bioavailability of NO. Based on these properties and the fact that it is generally well tolerated, N-acetylcysteine has been used for the prevention of AKF from radiocontrast agents in high-risk individuals. Several small clinical trials have shown that its administration prior to radiocontrast significantly reduces the rise in serum creatinine values from baseline as compared to the placebo group (68,69). However, whether N-acetylcysteine prevents severe AKF or the need for dialysis has not been determined. In patients at high risk for radiocontrast nephropathy, it is reasonable to provide N-acetylcysteine given the low potential for harm from the therapy. The most important factors in limiting kidney injury from radiocontrast agents, however, still appear to be providing adequate hydration and minimizing contrast dose (70–73). At the time of this writing, there is no evidence to advocate its routine use in preventing other forms of AKF. There is currently no consensus on its benefit in preventing contrast-induced nephropathy. Low-Dose Dopamine In normal human subjects, low-dose (1–3 mg/kg/min) dopamine increases RBF and GFR and acts on the proximal tubule to promote natriuresis. Numerous studies have used lowdose dopamine either to treat or to prevent AKF resulting from radiocontrast administration, repair of aortic aneurysms, orthotopic liver transplantation, unilateral nephrectomy, renal transplantation, and chemotherapy with interferon (INF) (74,75). However, prevention trials have been small, inadequately randomized, and of limited statistical power. Furthermore, low-dose dopamine has been associated with potentially harmful side effects, including tachyarrhythmias, myocardial ischemia, decreased mesenteric blood flow, and suppressed T-cell function (74–76). In diabetic patients treated with low-dose dopamine to prevent radiocontrast nephropathy, there is an associated increase risk of AKF (77). Therefore, it is generally recommended that the use of low-dose dopamine for the prevention of AKF be abandoned. Low-Dose Fenoldopam Fenoldopam is a pure dopamine type-1 receptor agonist that has similar renal vascular hemodynamic effects as

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dopamine, but without the a- and b-adrenergic stimulation. Animal data have shown that a pure dopamine-1 receptor agonist has the potential to reduce the renal injury induced by hypoperfusion of the kidney. In a hypovolemic dog model, infusion studies with fenoldopam mesylate, a selective dopamine-1 receptor agonist, increases cortical and medullary blood flow and preserves GFR (78). The limited clinical trials available suggest that fenoldopam reduces the occurrence of AKF associated with radiocontrast and aortic aneurysm repairs (79,80). However, there is limited clinical data and, as yet, no large randomized controlled trials to support its indiscriminate use. Diuretics Furosemide is a loop diuretic and vasodilator that may decrease oxygen consumption in the loop of Henle by inhibiting secondary active transport of sodium (69,81). By increasing urine volume, furosemide may reduce intratubular obstruction from cellular debris and reduce backleak of filtrate. This combination of actions in the kidney may lessen the ischemic potential. Clinical studies have shown furosemide to be ineffective in preventing AKF after cardiac surgery (82), but it may actually increase the risk of AKF in patients given radiocontrast (81). Mannitol acts as an osmotic diuretic that can scavenge free radicals. It may have some benefit when added to solutions to preserve organs for transplantation and to protect against AKF associated with rhabdomyolysis (83,84). Like furosemide, mannitol may actually worsen AKF associated with radiocontrast (77). Atrial Natriuretic Peptide ANP increases GFR by causing vasodilatation of the afferent arteriole and constriction of the efferent arteriole, and inhibits tubular sodium reabsorption. Two studies have examined the efficacy of ANP for the prevention of renal dysfunction in renal transplant recipients and found no benefit (85,86). Otherwise, most studies have focused on the treatment of established AKF and found little therapeutic benefit (87). As with low-dose dopamine, furosemide, and mannitol, ANP infusion has been associated with an increased risk of AKF with radiocontrast administration in diabetics (77). Management Management is directed at prevention of ATN in high-risk patients and control or uremic complications with established ATN until spontaneous recovery of renal function (63). In the early management of AKF, quick recognition of the renal insult and resolution of the potential cause are most important. If the patient is volume depleted, volume resuscitation is indicated. It is widely held that the degree of renal injury may be minimized in patients with optimized effective intravascular volume. However, the definition of adequate volume expansion has yet to be determined. Also open to question is the type of fluid that should be utilized. Randomized trials evaluating colloids versus crystalloids have revealed conflicting results (88). Albumin is frequently used for volume expansion, with no clinical evidence of its benefit in critically ill patients. A recent meta-analysis of studies involving albumin use in critically ill patients suggested that albumin infusion actually increases mortality (89). Medications that may inhibit the kidney’s normal ability to autoregulate glomerular filtration pressure, such as ACE inhibitors and Ang II receptor blockers, should be discontinued if possible when AKF is recognized.

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Current evidence suggests that nonoliguric renal failure has a better prognosis than oliguric renal failure. In the nonoliguric patient, volume overload and the potential for prolonged ventilation and poor wound healing are reduced. Volume resuscitation and nutritional support have less potential for complications. Clinical trials have attempted to elucidate if converting oliguric AKF to nonoliguric AKF with pharmacologic measures improves outcome. The use of high doses of loop diuretics early in AKF is common. The potential beneficial effects of loop diuretics include the reduction of intratubular obstruction with cellular debris and limiting oxygen consumption in tubular cells, and thus potentially reducing ischemic tubular damage. The available evidence suggests that using loop diuretics as a continuous infusion will produce a better diuresis than intermittent bolus administration and help manage volume overload (38). While diuretics may simplify patient management, there is no evidence that converting oliguric AKF to nonoliguric AKF with loop diuretics improves renal recovery or patient survival (90,91). Fluid, Acid–Base, and Electrolyte Abnormalities Oliguric AKF is often complicated by derangements in electrolytes and fluid balance. In AKF, water intoxication with resultant hyponatremia is a potential complication if hypotonic solutions are used. If the hyponatremia is significant enough, exacerbation of the effects of uremia on the central nervous system can occur. The critically ill patient is often catabolic; so acute hyperkalemia can arise. Serum potassium levels near 6 mEq/L require therapy, particularly if the patient is symptomatic with muscle cramps or weakness, or has electrocardiographic changes that may be a harbinger of life-threatening cardiac arrhythmias. Immediate temporizing maneuvers should include glucose and insulin infusion (start with 25 g, 50% glucose solution plus 10 U of intravenous regular insulin). If the patient is acidotic, intravenous sodium bicarbonate can be infused. Both the insulin and the bicarbonate are temporary measures to redistribute the potassium into the intracellular space, not to eliminate the potassium from the body. After institution of the acute temporizing measures, attempts should be made to eliminate the total body potassium overload. Ion exchange resins such as sodium polystyrene sulfonate (Kayexalate, 30–60 g given orally or rectally) are effective. Kayexalate acts in the intestinal tract through cationic exchange to increase potassium elimination in the stool. In the postoperative patient, it is advisable to administer sorbitol with Kayexalate to prevent constipation and promote catharsis, especially if the patient is receiving narcotic pain medications. The management of AKF can also be complicated by hypocalcemia, hypermagnesemia, and hyperphosphatemia. Early in AKF, phosphorous levels will rise. The goal of the acute management of hyperphosphatemia is to keep the calcium  phosphate product less than 70. As the calcium  phosphate product rises above 70, the risk of cardiac conduction abnormalities, vascular endothelial damage, and central nervous system injury increases. Phosphorous binders (calcium carbonate, aluminum hydroxide, or cationic polymers such as sevalamer hydrochloride) given with meals can be used to control dietary phosphorous absorption. The phosphate content of enteral feedings or total peripheral nutrition should be reduced. Hypocalcemia is a rare complication of AKF except in the setting of tumor lysis syndrome or rhabdomyolysis, and ionized calcium levels should be monitored in critically ill patients.

AKF is associated with loss of renal acid–base regulation typically resulting in metabolic acidosis. Sodium bicarbonate infusion can help alleviate the metabolic acidosis, but often the associated volume and sodium load is rate limiting. Common solutions for bicarbonate infusion include D5W with 3 amps NaHCO3, 0.25% NaCl with 2 amps NaHCO3, or 0.45% NaCl with 1 amp NaHCO3. It is important to keep the bicarbonate infusion as near to an isotonic solution as possible to limit infusion of excessive Na. In the face of an organic acid such as lactic acid or ketoacids, bicarbonate infusion will produce carbon dioxide, and in a postoperative patient with poor ventilation, this may produce a respiratory acidosis. Frequently the oliguric patient will be unable to tolerate the volume load associated with sodium bicarbonate infusions, so that dialysis is necessary to control the acidosis.

CHRONIC KIDNEY DISEASE CKD results from the loss of normal renal function arising from any of a wide variety of causes. Table 4 lists the major causes of chronic kidney failure. Whatever the original cause of renal disease, whether primarily glomerular or primarily nonglomerular, CKD tends to worsen because of a progressive loss of functioning nephrons. These processes result in the gradual development of a clinical state of uremia. The rate of progression of renal failure may or may not be predictable depending on the nature of the primary renal disease; however several known ‘‘progression’’ factors—hypertension, tubulointerstitial nephritis, proteinuria, hyperlipidemia, tobacco smoking—are known to influence strongly the process. There is a close correlation between clinical symptoms and the GFR; the GFR has therefore become the clinical marker of the stage of CKD. A clear understanding of the relationship of serum creatinine and GFR is needed so as to make right deductions about the degree of CKD.

Uremic Toxins Traditionally, the uremic state has been viewed as a ‘‘toxic’’ state, the result of retained ‘‘uremic toxins’’ that would otherwise be excreted by normally functioning kidneys. This view received strong support from the early successes of dialysis therapy in improving uremic symptoms, presumably by the removal of such toxins (92–94). More recently, the uremic state has also been viewed as a chronic inflammatory condition. There are ongoing efforts to identify the triggers for this inflammation, its mediators and consequences. Uremic ‘‘retention’’ of toxic compounds or solutes are arbitrarily classified according to molecular weight into low Table 4 Causes of Chronic Kidney Failure Glomerular diseases—primary (idiopathic) and secondary Tubulointerstitial diseases Diabetes mellitus Hypertension Obstructive nephropathies Renal cystic diseases Renovascular diseases Renal involvement in multisystem diseases, including diabetes mellitus and hypertension Renal involvement in congenital and heredofamilial diseases Renal injury secondary to medications, chemicals, drug abuse, radiation, heavy metal

Chapter 37: Urine Formation: From Normal Physiology to Florid Kidney Failure

(MW < 300 Da; e.g., urea, uric acid, xanthine, and methylguanidine), middle [e.g., b2-microglobuni, complement factor D, leptin, interleukin-6 (IL-6)], and high-molecular-weight molecules (MW > 500 Da). These are further subdivided into non–protein-bound and protein-bound molecules. Dialysis procedures clear the non–protein-bound, low-molecularweight solutes predominantly by diffusive and convective forces. There is some clearance of larger molecules by hemodialysis filters, by the process of adhesion. Middlemolecular-weight-molecules are hypothesized to contribute to some of the features of uremia, though specific toxins have not yet been identified (95). Laboratory abnormalities associated with retention of middle-molecular-weight-molecules include disturbances of lymphocyte proliferation, cell growth, interleukin production, osteoblast mitogenesis, and apolipoprotein (apo) A-1 secretion, while clinical abnormalities such as anorexia, polyneuropathy, and carpal tunnel syndrome may occur (96). In addition, a number of proteinbound molecules have been suggested to account for some of uremic toxicity.

Pathophysiology of CKD Glomerular and tubulointerstitial scarring characterize the renal histopathology of patients with chronic renal failure. These lesions often are similar in appearance, regardless of the nature of the primary renal disease. Decreased glomerular filtration is the result of atubular glomeruli and of increased backleak of filtrate through denuded tubular basement membranes. In all forms of renal disease, both the degree of interstitial infiltration with inflammatory cells and the interstitial fibrosis predict subsequent renal failure more accurately than does glomerular scarring or sclerosis. Interstitial fibrosis therefore represents the final common pathway of response to injury in the kidney, irrespective of the nature of the initial injury (97). Tubulointerstitial fibrosis is characterized by tubular atrophy, tubular dilatation, increased interstitial matrix deposition, and loss of capillaries. Matrix accumulating in the interstitium contains proteins such as collagens l, lll, and V, fibronectin, and laminin. An important phenomenon is the appearance of myofibroblasts, highly fibrogenic and contractile cells that may originate from tubular cells by ‘‘transdifferentiation.’’ Tubulointerstitial fibrosis is initiated by tubular epithelial cell injury and activation, and by the recruitment of inflammatory cells such as CD4þ lymphocytes and macrophages into the interstitium (98,99). Some of the factors known to activate tubular cells include proteinuria, cytokines, ischemia, and reactive oxygen species. Activated tubular cells release cytokines such as macrophage chemoattractant protein-1 (MCP-1), regulated on activation, normal T expressed and secreted (RANTES), TGF-b1 and PDGF, and cell adhesion molecules such as integrins, vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM), E-selectin, and osteopontin that attract more inflammatory cells into the interstitium. After this initial phase of acute interstitial inflammation, a second phase of inflammatory matrix synthesis ensues with the local release of profibrogenic cytokines and tissue inhibitors of matrix metalloproteinase (TIMPs). Finally, the process of persistent matrix synthesis occurs resulting from sustained action of profibrogenic cytokines and epithelial-mesenchymal transformation (transdifferentiation). The appearance of myofibroblasts in the interstitium is the single worst prognostic predictor of later development of interstitial fibrosis (100,101). The origin of these cells is uncertain. There is evidence to suggest that they are derived from resident interstitial fibroblasts, pericytes, or

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from transdifferentiated tubular epithelial cells. The major issue awaiting clarification is the mechanism whereby the process of scarring, once initiated, continues even after the original or primary insult is in remission. Of the cytokines produced by resident glomerular, tubular, and interstitial cells, as well as by infiltrating lymphocytes, macrophages, fibroblasts, and myofibroblasts, TGF-b1 is the predominant fibrogenic molecule involved in tubulointerstitial scarring (99). TGF-b1 production is stimulated by a variety of vasoactive compounds (e.g., Ang II and endothelin-1), circulating peptides, shear stress, and ischemia. It promotes transcription of genes encoding matrix components, inhibits matrix-degrading enzymes, promotes the evolution of myofibroblasts, and enhances chemotaxis of fibroblasts and monocytes. The fibrinolytic system (and plasmin) plays a major role in degrading fibrin and extracellular matrix, and its inhibition by plasminogen activator inhibitor (PAI) impairs the repair process while promoting interstitial fibrosis. TGF-b1 stimulates and upregulates the gene expression of PAI. Downstream signaling pathways for TGF-b1 have not been fully characterized. TGF-b1 is thought to bind to the type II receptor on the cell membrane, which in turn phosphorylates the type I receptor. This complex activates Smad proteins and the mitogen-activated kinase pathway (99). In addition to glomerular capillary hypertension, significant, positive correlation is observed between the magnitude of proteinuria and the degree of tubulointerstitial fibrosis. Proteinuria itself is toxic to the renal tubules. Candidate plasma proteins that may be toxic to renal epithelial cells are albumin, complement components, transferrin, and lipoproteins.

Clinical Course of CKD Given the large renal functional reserve and slow progression of most renal diseases, most patients remain asymptomatic until 85% to 90% of renal function is lost. Thus, in its early stages, CKD is a subclinical condition, and represents a loss of renal reserve. Excretory and other functions are well maintained, despite a diminution of GFR up to 50%. The usual clinical laboratory parameters—BUN and serum creatinine—may remain in the normal range. Kidney insufficiency ensues at more severe reductions in GFR. Azotemia, impaired concentrating ability resulting in nocturia, anemia, and an easy vulnerability of the kidneys to hemodynamic insults such as volume (salt) depletion, dehydration, hypotension, congestive heart failure, the administration of ACE inhibitors, NSAIDs, and to catabolic drugs and potassium loads, diagnosed as acute-on-chronic renal failure. The stage of clinically overt kidney failure is characterized by severe anemia, fluid overload, hypertension, hyperphosphatemia, hypocalcemia, metabolic acidosis, hyponatremia, isosthenuria, and hyperchloremia. Hyperkalemia still is generally absent unless the patient is receiving large loads of potassium. At end stage, in uremia, there is a constellation of signs and symptoms that involve all the systems—the uremic syndrome (Table 5). Ideally, the full-blown uremic syndrome should not occur, because renal replacement therapy with dialysis or transplantation has already been initiated. The National Kidney Foundation published ‘‘Clinical Practice Guidelines for Evaluation, Classification, and Stratification of Chronic Kidney Disease’’ in 2002 (102). In this scheme, CKD is defined as (i) kidney damage for more than three months, as defined by structural or functional abnormalities of the kidney, with or without decreased GFR, manifested by either (a) pathologic abnormalities or (b) markers of kidney damage, including abnormalities in the

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Table 5 Uremic Manifestations System

Clinical manifestations

Cardiovascular

Hypertension Pericarditis Anorexia Nausea, vomiting Encephalopathy Peripheral neuropathy Anemia Platelet dysfunction Insulin resistance Hyperlipidemia Decreased fertility Renal osteodystrophy Myopathy Uremic arthropathy

Gastrointestinal Neurologic Hematologic Endocrine

Musculoskeletal

composition of the blood or urine, or abnormalities in imaging tests; and (ii) GFR < 60 mL/min per 1.73 m2 for more than three months, with or without kidney damage. These guidelines propose specific functional stages of CKD (Table 6) and clinical action plans to pursue depending on the stage.

Clinical Manifestations of CKD Gastrointestinal System Gastrointestinal symptoms occur frequently and are prominent in CKD (103) (Table 5). Most common among these are anorexia, nausea vomiting, metallic taste, hiccups, and diarrhea. Additional complications include stomatitis, gastritis, duodenitis, esophagitis, parotitis, and gastroparesis.

such that hyperkalemia occurs earlier and with more severity in the course of progressive renal failure. These conditions, in particular diabetic nephropathy, are mostly associated with the syndrome of hyporenninemic hypoaldosteronism. Table 7 lists some of the conditions that are commonly associated with the syndrome of hyporenninemic hypoaldosteronism as well as additional clinical situations that predispose to hyperkalemia in CKD. Patients with CKD are at risk of hyperkalemia when these conditions are present. Hyperkalemia needs close monitoring and anticipation in these patients. With mild-to-moderate degrees of CKD, there is a limitation of sodium excretory capacity despite adaptive compensatory sodium wasting in surviving nephrons. This is manifested mainly as hypertension. Only in severe kidney failure (GFR < 10–15 mL/min) does edema become evident, provided there are no other causes of edema such as nephrotic syndrome or congestive heart failure. Peripheral pitting edema is the most common finding. But with the often coexisting hypertension and left ventricular hypertrophy (LVH) and dysfunction, pulmonary congestion and edema can supervene. Treatment is by dietary sodium restriction (usually 2 g daily), along with the judicious use of diuretics. With moderate CKD, thiazide diuretics are no longer effective. Because of resistance to diuretic therapy, increasing doses of the loop diuretics may be needed before the required dose is determined. Because of their short duration of action (4–6 hours), loop diuretics often need to be dosed frequently. Torsemide, a long-acting (24 hours) loop diuretic, is more convenient and is effective in a once-a-day regimen. The diuretic effect of loop diuretic therapy may be augmented by concomitant administration of hydrochlorothiazide or metalozone. Table 7 Clinical Conditions That Predispose to Hyperkalemia

Acid–Base, Fluid, and Electrolyte Abnormalities Metabolic acidosis occurs uniformly in CKD. At GFRs in the 20 to 50 mL/min range, there is usually already a mild drop in serum bicarbonate concentration. The main cause of the metabolic acidosis is decreased ammonia synthesis by the surviving nephrons, which occurs despite the fact that there is an adaptive increase in ammonia synthesis per nephron. This diminution of total ammoniagenesis limits the capacity to excrete acid loads. Sustained metabolic acidosis has a number of potential adverse effects for which the clinical evidence remains controversial. In CKD, limitation of the capacity to excrete potassium results in hyperkalemia. Hyperkalemia is usually mild (5.0–5.5 mEq/L), even at GFRs as low as 20 mL/min, and requires only dietary potassium restriction and close monitoring as management. With worsening renal failure, however, hyperkalemia becomes more severe and requires definitive treatment. However, there are a number of diseases that are associated with a tendency to hyperkalemia, Table 6 Stages of Chronic Kidney Disease Stage 1 2 3 4 5

Description

GFR (mL/min/1.73 m2)

Kidney damage with normal or increased GFR Kidney damage with mild decrease in GFR Moderate decrease in GFR Severe decrease in GFR Kidney failure

> 90 60–89 30–59 15–29 < 15/dialysis

Abbreviation: GFR, glomerular filtration rate.

Diseases Diabetic nephropathy Obstructive nephropathy Sickle cell nephropathy Tubulointerstitial nephropathies Systemic lupus erythematosis Renal transplantation Elderly patients Amyloidosis Drugs Potassium chloride, including Kþ-containing salt substitutes Angiotensin-converting enzyme inhibitor; angiotensin II receptor blocker Nonsteroidal anti-inflammatory drugs Spironolactone Amiloride and triamterene b-Adrenergic antagonists Digoxin, particularly in digoxin toxicity Heparin Cyclosporine and tacrolimus Trimethoprim and pentamidine Succinylcholine Arginine chloride Mannitol Glycerol Other clinical conditions Acidosis Hyperglycemia Volume depletion Internal bleeding, especially gastrointestinal bleeding Tissue damage, especially rhabdomyolysis

Chapter 37: Urine Formation: From Normal Physiology to Florid Kidney Failure

This potent combination should be used with caution because it can rapidly be complicated by volume depletion and acuteon-chronic renal failure, as well as severe hypokalemia. With progressive CKD, there is the loss of the capacity to dilute or concentrate urine, termed isosthenuria. The individual is prone to excessive and inappropriate water loss and therefore hypernatremia, if water intake is restricted or if the patient is unable to have access to water. Conversely excessive water intake or injudicious administration of hypotonic solutions readily leads to water excess and hyponatremia. Elderly patients are particularly prone to these complications.

Abnormalities of Calcium, Phosphate, and Bone Metabolism Several alterations of calcium, phosphate, and bone metabolism occur in CKD. The major bone pathologic lesions are described as uremic osteodystrophy. Modifications of this primary bone lesion arise from the different therapeutic interventions and nutritional factors, as a result of which there is a spectrum of bone abnormalities in uremia. Bone disease is mainly attributed to severe secondary hyperparathyroidism, which is characterized by elevated serum PTH levels and parathyroid gland hyperplasia and hypertrophy. Several possible ‘‘primary’’ abnormalities have been postulated as responsible for secondary hyperparathyroidism: phosphate retention, hypocalcemia, deficiency of 1,25 dihydroxy vitamin D (calcitriol), parathyroid gland resistance to calcitriol and calcium, and bone resistance to PTH (104). The principal skeletal and extraskeletal consequences of secondary and tertiary hyperparathyroidism in the CKD patient are presented in Table 8. Calcitriol deficiency arises not only as a result of loss of nephrons but also by inhibition of its synthetic enzyme, 1a-hydroxylase, by uremic toxins (105). Calcitriol exerts its biologic action by binding to the vitamin D receptor (VDR), the hormone–receptor complex then binding to vitamin D response elements in the DNA. In uremia, parathyroid resistance to calcitriol results in part from reduced expression of VDR as well as altered binding of the hormone– receptor complex to DNA. Similarly, there is parathyroid resistance to calcium associated with reduced expression of the calcium-sensing receptor. Initial diffuse parathyroid hyperplasia and hypertrophy may transform to nodularity of the gland with monoclonal cellular expansion. Allelic loss at loci on chromosome 11 at the location of the MEN-1 gene, which is associated with primary parathyroid hyperplasia, has been described (106). Other mechanisms

Table 8 Clinical Consequences of Secondary/Tertiary Hyperparathyroidism Skeletal High turn-over bone disease

Osteitis fibrosa Mixed osteodystrophy Bone pain Osteopenia Fractures

Extraskeletal Metastatic calcifications (skin, myocardial, vascular, valvular, pulmonary) Bone marrow fibrosis (resistance to erythropoietin) Myocardial hypertrophy and fibrosis Encephalopathy, electroencephalographic changes Peripheral neuropathy Hypertension, hyperlipidemia, glucose intolerance

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of this transformation include somatic mutation and decreased expression of cell cycle regulatory genes. The principles of treatment and prevention of secondary hyperparathyroidism and renal osteodystrophy derive from the following goals: (i) control of hyperphosphatemia— dietary phosphate restriction: phosphate binders to be taken with meals; (ii) replacement therapy of calcitriol with synthetic 1,25 dihydroxy vitamin D or any of its new analogs; (iii) modulation of dialysate calcium for more effective control of PTH levels; (iv) close monitoring of calcium, phosphate, and PTH levels; and (v) parathyroid surgery or percutaneous ablation for uncontrollable ‘‘tertiary’’ hyperparathyroidism. Ablation can be accomplished by total or subtotal parathyroidectomy, total parathyroidectomy with immediate autotransplantation, total parathyroidectomy with cryopreservation of parathyroid tissue, ultrasoundguided percutaneous ethanol injection directly into the enlarged glands, or ultrasound-guided percutaneous calcitriol injection directly into the enlarged glands. Calcific uremic arteriolopathy (calciphylaxis) is a rare condition involving the calcification of subcutaneous vessels and infarction of the adjacent skin and tissues. Its pathogenesis is not understood, and morbidity and mortality are very high (107,108). Risk factors may include: high calcium  phosphate products, severe hyperparathyroidism, adynamic bone disease, excessive doses of calcitriol, hypercoagulable state, and intravenous iron therapy. Debridement of necrotic tissue, control of infection, skin grafting, and hyperbaric oxygen therapy may aid management.

Uremic Arthropathy Monoarticular and polyarticular arthritides and tendinitis are common in uremic patients (108). The causes of articular disease may be classified into crystal-related, related to secondary hyperparathyroidism, related to dialysis therapy (particularly b2-microglobulin amyloid-associated arthropathy), related to underlying or concomitant systemic diseases, and septic arthritis. Diagnosis usually requires diagnostic joint aspiration. Commonly used arthritic medications such as NSAIDs and colchicine need to be avoided or carefully dosed.

Anemia of CKD Anemia is a leading cause of morbidity and mortality in CKD (109). Erythropoietin deficiency is the most common cause of anemia in these patients. Adequate treatment of anemia is essential in CKD, in particular, because of its role in the development of LVH with all of its attendant complications. Recombinant human erythropoietin (r-HuEPO and epoietin) is the mainstay of anemia management, not only in end-stage kidney disease but also in the predialysis patient. Adequate treatment of anemia has been shown to improve morbidity, quality of life, and mortality. It is therefore essential to screen vigorously for anemia and treat in a cost-efficient manner in view of the high cost of this medication. Iron deficiency is the most common cause of a lack of response (resistance) to erythropoietin action, so that iron status needs to be closely monitored and corrected. Other mechanisms that contribute to anemia include blood loss, shortened RBC survival, inhibition of erythropoiesis by uremic toxins, chronic inflammation, and severe hyperparathyroidism. Subcutaneous administration of r-HuEPO is usually more efficient than intravenous, and target hemoglobin levels are about 12 to 13 g/dL. The uremic patient requires iron administration to maintain adequate erythropoiesis

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and responsiveness to epoietin. Transferrin saturations need to be maintained above 20%. A level of transferrin saturation below 20% is considered to represent iron deficiency in this setting. This level of transferrin saturation is often difficult to achieve with oral iron agents, so that intravenous administration is the preferred route (110). Guidelines for intravenous iron therapy and monitoring of iron stores and availability are provided in the DOQI guidelines of National Kidney Foundation (111).

Cardiovascular Complications There is excessive cardiovascular morbidity and mortality in uremia (112,113). In the most recent report of the United States Renal Data System (USRDS) data, all-cause mortality in patients with end-stage kidney disease is about 20% per year; of these, cardiovascular complications account for approximately 50%. Among cardiovascular complications, atherosclerotic events (acute myocardial infarction, ischemic cardiomyopathy, peripheral vascular disease, cerebral infarctions, and mesenteric infarctions) account for at least 50% of deaths. The proportion of atherosclerotic events is even greater if account is taken of the ischemic component of congestive heart failure and sudden death. Cardiac death rates are 10 to 15 times higher in uremic patients than in agematched controls of both genders. Twenty to thirty percent of cardiac deaths are due to myocardial infarctions. Besides the high prevalence rates of coronary artery disease in uremic patients, there is a high fatality rate in these patients, possibly a reflection of poor coronary perfusion reserve. Mortality rates of first myocardial infarctions are higher and of recurrent myocardial infarctions even more so. There is a higher rate of restenosis after PTCA. These data suggest that uremia further exaggerates the risks of coronary artery disease (112,113). Atherosclerosis in uremic patients is thus particularly severe and aggressive. Although there is controversy whether it progresses at an accelerated pace, the term ‘‘accelerated atherogenesis or atherosclerosis’’ is commonly used to describe this phenomenon. The use of these terms is best reserved, for the present, for the observation that atherogenesis is noted at a very early age in uremic patients. More than 80% of young chronic dialysis patients (age 20–30 years) already have severe and progressive coronary artery calcifications as detected by electron beam computed tomography. In the 20 to 40 years age group, coronary artery disease rates are up to 40 times the background population (112,113). There is evidence that the uremic state per se and not dialysis is the major causative factor in accelerated atherosclerosis. Incidence rates and age at first myocardial infarction are similar in predialysis and end-stage kidney disease (ESKD) patients. Nearly 40% of patients have coronary artery disease and congestive heart disease at the start of dialysis. Some of these observations may be attributed to the high incidence of diabetes, and the older age of patients in the ESKD population. LVH and Uremic Cardiomyopathy LVH and an increased left ventricular mass index are highly prevalent in CKD and ESKD patients (114). In the general population and in uremic patients, LVH is the strongest predictor of adverse cardiovascular events. In the general population, vigorous control of hypertension and the use of ACE inhibitors result in a decline in LVH and cardiovascular morbidity. Unfortunately LVH is frequently underdiagnosed, and hypertension is inadequately treated in CKD and ESKD. Both concentric and eccentric LVH occur in combination in

Figure 11 Risk factors for cardiovascular disease in chronic kidney disease and ESKD patients. Abbreviations: CKD, chronic kidney disease; ESKD, end-stage kidney disease.

CKD. Concentric LVH is mainly secondary to hypertension and aortic stenosis; remodeling of the arterial tree with arterial dilatation, wall thickening, and stiffening also results in pressure overload and concentric hypertrophy. On the other hand, volume overload results in eccentric hypertrophy with enlargement of the left ventricular chamber (Fig. 11). The three main factors contributing to volume overload are sodium and water excess, anemia, and the arterio-venous (A-V) access. Myocardial cells are overloaded and have an increased rate of energy expenditure in the presence of impaired coronary circulation and diminished coronary reserve resulting in myocardial cell death. Abnormal induction of proto-oncogenes, which promote and regulate cell proliferation and differentiation, and activation of growth factors that stimulate the proliferation and activity of cardiac fibroblasts result in cardiomyopathy and myocardial fibrosis: a rapid increase in collagen synthesis and extracellular matrix. Myocardial fibrosis is more marked in pressure overload than in volume overload and is favored by factors such as senescence, ischemia, catecholamines, Ang II, and aldosterone. Other factors such as endothelin, PTH, and sympathetic nerve discharge contribute to myocardial fibrosis. Delayed relaxation resulting from slower uptake of calcium by the sarcoplasmic reticulum contributes to diastolic dysfunction and arrhythmias, which are also favored by conduction abnormalities resulting from myocardial fibrosis and hypertrophy. In ESKD patients without preexisting cardiac disease, systolic function is usually well preserved; diastolic function is usually abnormal as a result of LV stiffness and delayed relaxation. Diastolic dysfunction is characterized by marked sensitivity to changes in left ventricular volume. A small increase in LV volume can cause pulmonary congestion, while a small decrement can lead to systolic hypotension and hemodynamic instability. Coronary Artery Disease The prevalence of ischemic heart disease in ESKD patients on chronic hemodialysis is 10 to 20 times that in the general population (115). According to the USRDS, 42% of chronic

Chapter 37: Urine Formation: From Normal Physiology to Florid Kidney Failure

hemodialysis patients have had an acute myocardial infarction or a coronary revascularization procedure: 20% of cardiovascular deaths in ESKD patients is due to acute myocardial infarction, the excessive risk being highest in the elderly and diabetics. In addition to traditional risk factors, a number of uremia-specific risk factors contribute to coronary atherosclerosis and myocardial ischemia (116) (Fig. 11). In nonuremic patients with suspected myocardial damage, serum levels of myoglobin, creatinine kinase (CK)MB, and troponins are reliable markers for early diagnosis and risk stratification. In chronic hemodialysis patients, there is a high prevalence of silent myocardial ischemia, significant coronary artery disease occurring in 30% to 50% of asymptomatic or mildly symptomatic patients (115). Thus, symptoms of angina pectoris are unreliable. Conversely, because of small-vessel disease and microcirculatory dysfunction, 25% of hemodialysis patients with angina pectoris have no significant stenosis of epicardial coronary arteries. Electrocardiographic findings are often confounded by nonspecific changes due to LVH, electrolyte abnormalities, and uremic pericarditis. Noninvasive ECG stress testing is limited by nonspecific baseline ECG changes, poor exercise tolerance, and excessive hypertension during exercise. Both exercise thallium scintigraphy and pharmacologic stress testing have poor sensitivity and specificity. Dobutamine stress echocardiography is independent of exercise tolerance, and appears to be the most valuable noninvasive test currently available. Coronary angiography is therefore frequently indicated, but with careful consideration of attendant risks. The CKD patient, especially if advanced, is at high risk of contrast nephropathy and acute-on-chronic kidney failure that may require dialysis. Dialysis patients are also at risk of volume overload, pulmonary edema, and bleeding complications. Revascularization Procedures There is a high complication rate associated with coronary bypass surgery. Complications include arrhythmias, myocardial infarction, low-output congestive heart failure, bleeding, and infection. Preoperative risk factors include older age, emergency surgery, LVH and dysfunction, myocardial and coronary calcification, and New York Heart Association class IV. Long-term outcome in dialysis patients undergoing coronary artery bypass surgery is poor. According to the USRDS, in dialysis patients who underwent bypass surgery between 1978 and 1995, five-year survival was 26.5% compared with 90% in nonuremic patients. Balloon angioplasty (PTCA) in dialysis patients is characterized by higher complication rates as well as high rates of recurrent ischemia, myocardial infarction, restenosis, and death (117,118). The lesions are more complex and diffuse; there is extensive vascular calcification and small vessel disease; vessel diameters are smaller; there is more multivessel involvement; there is a higher proportion of diabetes mellitus and hypercoaguability. New techniques may offer particular benefit in these complicated patients, such as coronary artery stenting, newer antiplatelet therapies—the thienopyridines and glycoprotein IIb/IIIa-receptor antagonists—rotational atherectomies, and brachytherapy (117,118). Hypertension It is established that hypertension is a major risk factor for cardiovascular disease in the general population. There is an extremely high incidence of hypertension in CKD (119). Even when hypertension is not currently present, there

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may have been a prior history with the fall in blood pressure coinciding with the development of severe left ventricular systolic dysfunction. After adjusting for age, diabetes mellitus, ischemic heart disease, hemoglobin, and albumin level, each 10 mmHg rise in MAP was independently associated with a progressive increase in concentric LVH, development of de novo congestive heart failure, and new-onset ischemic heart disease (119). Thus hypertension is a major risk factor for the development of cardiac disease in CKD. Impaired coronary perfusion coupled with ventricular hypertrophy leads to a vicious cycle of impaired left ventricular contraction, left ventricular dilatation, progressive alteration of left ventricular geometry, and systolic dysfunction. Vigorous treatment of hypertension is advocated, and the guidelines for target blood pressure as well as for recommended choice of medications are under intense study. No single class of antihypertensive medication is superior to the other in dialysis patients. Pericarditis Before the advent of chronic dialysis therapy, uremic pericarditis was an agonal development in the course of the disease. With chronic dialysis, uremic pericarditis is less common and is treatable. It however remains a significant cause of morbidity and mortality in CKD. In dialysis patients, uremic pericarditis is associated with inadequate dialysis often in relation to a dysfunctioning vascular access or poor compliance with dialysis prescriptions (120). Pericarditis also frequently occurs in hypercatabolic states such as severe infections, postsurgery. Volume overload has been proposed as a risk factor. Clinical presentation is highly variable and most importantly the patient may be asymptomatic. Dialysis patients with pericarditis often present with fluid retention, an increasing difficulty with fluid removal (ultrafiltration) during dialysis treatments and hypotension. Pleural effusions often accompany uremic pericarditis, considered to be part of a diffuse serositis. The pericardial fluid is exudative and frequently hemorrhagic with a lot of organized fibrin; the fluid is often loculated. Uremic pericarditis is usually successfully treated with intensified dialysis. Pericarditis occasionally occurs in patients who are considered to be adequately dialyzed. This appears to be a dialysis-associated pericarditis, for which heparin used in dialysis anticoagulation may be a risk factor. Much less commonly, a constrictive pericarditis occurs. The mainstays of therapy are a high index of suspicion, intensified dialysis for uremic pericarditis, and close monitoring. Patients with dialysis-associated pericarditis do not respond well to intensive dialysis. Heparin should not be administered with dialysis. NSAIDs or steroids are not effective. Pericardiotomy or pericardiectomy is indicated for the persistent or enlarging effusion or at the earliest sign of hemodynamic compromise (120). Other causes of pericarditis should be in the differential diagnosis—viral, bacterial, and mycobacterial infections, autoimmune diseases, malignancies, and drugs. Lower Extremity PAOD Peripheral arterial occlusive disease (PAOD) is a major cause of morbidity and mortality in end-stage renal disease patients on dialysis (121). In ESKD patients, PAOD confers additional risks for hospitalizations, death within six months of the initiation of chronic dialysis, and death following a myocardial infarction, and poor outcomes following renal transplantation—prolonged hospitalizations, poor allograft survival, and increased mortality rates. The incidence of

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nontraumatic lower extremity amputations after renal transplantation is 10 times higher in ESKD patients than in nonESKD patients even after correction for diabetes mellitus. Lower extremity amputation is the most common vascular complication following renal transplantation. Septicemia secondary to PAOD is one of the leading causes of death among ESKD patients. Risk factors for PAOD include advancing age, diabetes mellitus, hypertension, hyperlipidemia, smoking (tobacco), coronary artery disease as well as numerous novel, nontraditional atherosclerosis risk factors. Vascular calcification is very common. With ‘‘noncritical ischemia,’’ patients are either asymptomatic or present with claudication. With more advanced disease, ‘‘critical stenosis,’’ patients present with rest pain, ischemic ulceration, and gangrene. Diagnostic testing needs to be performed early because history and physical examination are not reliable. Because of heavily calcified peripheral arteries, ankle brachial index may be falsely negative. Other noninvasive screening tests such as toe brachial index, transcutaneous partial pressure of oxygen measurements, and toe pulse volume recording are not affected by lower leg arterial calcifications. Digital arterial calcifications occur in ESKD patients, and this may interfere with the toe brachial, and toe pulse volume tests. Duplex scanning, conventional angiographic studies, and, more recently, peripheral magnetic resonance angiography and CO2 angiography are alternative tests in these settings. Because a high proportion of patients progress to critical stenosis and require surgical intervention, preventive and conservative measures should be vigorously pursued (121). Uremia-Associated Immune Deficiency The uremic state is associated with an immunodeficiency state, the mechanisms of which await full elucidation. This immune abnormality is characterized by a chronic state of activation of all the key components of the immune system—T-cell, B-cell, monocyte/macrophage, and polymorphonuclear neutrophil systems—which paradoxically result in immune deficiency (122). The abnormalities occur early in the predialysis stage and are not reversed by dialysis. Therefore, it is postulated that this abnormally activated immune state is triggered by metabolic derangements resulting from uremia or by nondialyzable ‘‘uremic toxins.’’ Additional factors contributing to the immunodeficiency include malnutrition, vitamin deficiencies, anemia, use of drugs such as intravenous iron especially in the presence of iron overload, and vitamin D, known for its immunosuppressive activity, and hemodialysis therapy especially when bioincompatible dialyzer membranes are used. In summary, in uremia, T-lymphocytes exist in a state of activation but exhibit impaired response capacity; B-lymphocytes are in an activation state but are not capable of sustaining an adequate antibody response; monocytes are activated and produce abnormally high levels of interleukin 1 (IL-1), IL-6, and tumor necrosis factor-a (TNF-a), while polymorphonuclear neutrophils are activated, with increased generation of reactive oxygen species and the increased release of their cytoplasmic proteases. CKD patients are susceptible to a high frequency of bacterial, viral (including hepatitis B and C), and mycobacterial infections, and may exhibit cutaneous anergy. Abnormalities of Coagulation A bleeding tendency is the most common abnormality in uremia (123). Numerous laboratory abnormalities of coagulation have been described in uremia, but platelet dysfunction appears to be the most dominant defect. The bleeding

diathesis improves with dialysis, suggesting that retained dialyzable compounds or toxins may play an important role. Minor or major epistaxis, hematuria, menorrhagia, melena, retroperitoneal hemorrhage, and hemorrhagic pleural or pericardial effusions may be encountered. There is a diminution in number and binding affinity of the platelet membrane glycoprotein receptors llb and llla. Possible mediators of the bleeding diathesis include NO, cAMP, urea, phenols, and guanidinosuccinic acid. Altered blood rheology secondary to a low hematocrit may also contribute to bleeding. CKD appears to be a risk factor for postoperative bleeding in patients undergoing coronary artery bypass graft surgery. Even mild levels of renal impairment were associated with increased risk for postoperative bleeding: patients with a GFR of 40 mL/min or less had six times the odds of postoperative bleeding than patients with a GFR greater than 100 mL/min (124). Thrombosis is uncommon in uremia. However, thrombosis occurs frequently in dialysis A-V grafts as well as in the coronary and cerebrovascular circulations (125). Risk factors for thrombosis include smoking, trauma, immobilization, thrombocytosis, antiphospholipid antibodies, resistance to activated protein C (the factor V Leiden mutation), and hyperhomocysteinemia. Abnormalities of Carbohydrate and Lipid Metabolism Hypertriglyceridemia and hypercholesterolemia with decreased HDL levels and elevated Lp(a) levels are common in ESKD patients (126,127). Hyperinsulinemia is secondary to reduced renal catabolism of insulin and insulin resistance (128). As renal failure progresses, insulin requirements fall. Failure to recognize this can result in severe hypoglycemic episodes. Oral hypoglycemics are prone to cause hypoglycemia. Additional abnormalities include altered peripheral glucose utilization. Neurologic Complications Neurologic complications in uremia are a common cause of morbidity and mortality (129–131). The central nervous system as well as peripheral and autonomic nervous systems are affected. Uremic encephalopathy describes central nervous system dysfunction secondary to chronic renal failure. Differential diagnosis includes electrolyte derangements, particularly of sodium and calcium, drug toxicities, hypertensive disorders, ischemic cerebrovascular syndromes, sepsis, and coexisting hepatic neurologic or other multisystemic diseases. Dialysis dementia is a severe, fatal neurologic complication of dialysis first noted in epidemic form and characterized by difficulties of speech with rapid progression and deterioration and death occurring within months of diagnosis (132). There is strong evidence that dialysis dementia is associated with aluminum exposure and toxicity. This devastating complication is now rare and has been largely controlled by the use of reverse osmosis (RO) in deionization of dialysis water. Dialysis disequilibrium syndrome is a complication of hemodialysis comprising headaches, nausea, vomiting, muscle cramps, tremors disorientation, and seizures during hemodialysis, possibly related to rapid fluxes of urea or other solutes and/or disturbances of brain intracellular pH (133). Uremic peripheral neuropathy is usually distal, symmetric, and mixed (sensory and motor) (134). Autonomic neuropathy is characterized by loss of baroreceptor sensitivity resulting in postural hypotension, hypotension during dialysis unresponsive to volume repletion, paroxysmal

Chapter 37: Urine Formation: From Normal Physiology to Florid Kidney Failure

hypertension during dialysis, arrhythmias, gastroparesis and other GI motility problems, and sexual dysfunction (135).

Management of Progressive CKD There is currently no convenient, inexpensive method of measuring progression of renal failure. Serial creatinine measurements are unreliable because creatinine levels do not rise until renal failure is quite advanced. The reciprocal of serum creatinine or logarithm of serum creatinine over time has a more linear relationship with GFR, and these are sometimes used, but intermittent estimations of GFR with creatinine clearance measurements or other methods are often required. The mainstays of management include the assessment of severity and stage of renal failure; renoprotection—monitoring and control of progression factors; control of complications, including appropriate drug dosing; and timely recognition of the need to initiate renal replacement therapy (97) (Tables 9 and 10). All of these goals require effort to inform and educate patient and family of the nature of disease and benefits of adherence to the treatment plan.

Diagnostic Use of Renal Imaging in CKD Diagnostic imaging may be of value in the diagnosis and management of CKD (136–138). Renal ultrasonography is an integral part of the evaluation of chronic renal failure and is now available in many renal clinics. The renal ultrasound is used to assess (i) renal size, position, and number; (ii) parenchymal disease (echogenicity); (iii) obstruction; (iv) tumors, cysts, inflammation, and abscesses; (v) trauma; (vi) renovascular diseases; (vii) abnormalities of the transplanted kidney; (viii) nephrocalcinosis; and (ix) in ultrasoundguided interventional procedures. Computed tomography (CT) scanning is used in evaluation of (i) renal masses, cysts, inflammation, and cysts; (ii) obstruction and site of obstruction; (iii) perinephric hematomas, abscesses, or other collections; and (iv) renal stones and nonopaque filling defects. Magnetic resonance imaging provides additional anatomic information in the evaluation of renal diseases. MR arteriography is now the diagnostic test of choice in the evaluation of renal artery stenosis in many centers. MRvenograms are also useful in detecting renal vein thrombosis.

Perioperative Management of the CKD Patient Because of their limited capacity to maintain fluid, electrolyte, and acid–base homeostasis, CKD and ESKD patients experience increased perioperative morbidity and mortality Table 9 Management of Chronic Kidney Disease Control of hypertension, with attention to evidence-based optimum Blood pressure reduction and choice of antihypertensive agent Dietary restrictions—phosphate, sodium, potassium, protein, lipid, and fluid Glycemic control in diabetics Control of: Anemia Hyperparathyroidism Dyslipidemia Hyperhomocysteinemia Increased oxidant stress Attention to atherosclerosis, coronary artery and peripheral vascular disease, and left ventricular hypertrophy Timely recognition of need to initiate renal replacement therapy Education of patient regarding treatment modalities and early planning of dialysis access

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Table 10 Indications for the Initiation of Chronic Dialysis Absolute indications Progressive advanced chronic kidney failure with: Pericarditis/pericardial effusions Severe encephalopathy—confusion, asterexis, coma, myoclonus Severe, difficult-to-control hypertension Refractory volume overload, anasarca, pulmonary congestion and edema Intractable nausea Bleeding diathesis Malnutrition BUN levels > 100 mg/dL (if primarily reflective of reduced GFR) Serum creatinine levels > 10 mg/dL Relative indications Somnolence (daytime) Inability to concentrate Poor memory Restless leg syndrome Anorexia, nausea, vomiting, weight loss Pruritus Increased vulnerability to infection Depression Abbreviations: BUN, blood urea nitrogen; GFR, glomerular filtration rate.

rates compared to patients with normal renal function (139,140). In CKD and ESKD patients, cardiac arrhythmias and sepsis are the most frequent causes of perioperative mortality. ESKD patient who undergo cardiac surgery tends to require longer postoperative vasopressor support, mechanical ventilation, and ICU and hospitalization stays than patients who do not have kidney disease (141). Meticulous evaluation and management is required in the perioperative period to avoid acute and often catastrophic clinical problems. Previously undetected cardiac or pulmonary disease must be identified and compensated for or corrected in the preoperative period. Preoperative testing may be necessary in patients with cardiac risk factors. The patient must be adequately dialyzed, preferably receiving hemodialysis within 12 to 24 hours of the operative procedure. In the case of CAPD or CCPD, dialysis can generally continue until called to the operating room, at which time the peritoneal cavity is drained. Plasma electrolyte levels, in particular potassium concentrations, must be optimized before surgery, particularly because electrolyte fluxes can be problematic during anesthesia. Preoperative hyperkalemia in ESKD patients is common (142) and can be temporarily improved by the intravenous administration of an insulin–dextrose combination or bicarbonate, and polystyrene-binding resins or dialysis can remove excess stores of potassium. CKD and ESKD patients commonly experience preoperative and intraoperative hypertension. With few exceptions, CKD and ESKD patients with chronic hypertension should continue antihypertensive drug therapy throughout the surgical period. Transdermally administered clonidine two to three days before surgery or intravenously administered agents can potentially substitute for oral agents that cannot be given intravenously. If future vascular access grafting is contemplated, intravenous line placement and blood draws should be avoided in a patient’s nondominant arm. Anesthetics have multiple effects on the renal microcirculation and the release of certain hormones. The volatile anesthetic drugs (e.g., halothane) can reduce cardiac output and blood pressure resulting in glomerular hypoperfusion and prerenal azotemia. The inhaled anesthetics do not appear to directly alter renal autoregulation (143). Renal

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hypoperfusion from volatile anesthetics and increased ADH release associated with surgical procedures may result in intraoperative oliguria. However, in the absence of surgical manipulation, anesthetics are not associated with increased ADH release (144). In addition, halothane and enflurane have been shown to increase renin levels in sodiumdepleted animals (145). Preoperative hydration with normal saline attenuates the prerenal azotemia, and the release of ADH and renin in these clinical settings. Whether inhalation anesthetics cause direct nephrotoxicity is controversial. However, a concentrating defect in the kidney, which can lead to polyuria with dilute urine and associated hypernatremia, has been described with the metabolism of anesthetics such as methoxyflurane, enflurane, and sevoflurane to fluoride (146–149). Patients with CKD have been reported to be at increased risk for worsening renal dysfunction after enflurane inhalation (150). However, there is no evidence that fluoride levels are increased in patients with depressed GFR’s in this circumstance, presumably because of bone uptake of the metabolite. Halothane and isoflurane are not known to be nephrotoxins (151). CKD reduces the clearance of long-acting nondepolarizing muscle relaxants (e.g., pancuronium). The duration of action of vecuronium is unpredictable (152). The clearance of atracurium and mivacurium is not affected by a low GFR, and these agents are safe choices in patients with CKD requiring anesthesia (152). The acetylcholinesterase inhibitors neostigmine, pyridostigmine, and edrophonium are more than 50% excreted in the urine, and CKD may prolong their clearance (153). Careful attention to drug selection and dosing is therefore critical. Because of the increased risk of bleeding related to uremic platelet dysfunction, the ESKD patient should be well dialyzed, and medications with antiplatelet effects should be avoided close to the time of surgery. Bleeding time is the most sensitive indicator of the extent of platelet dysfunction, although test results are variable across laboratories. Bleeding times of greater than 10 to 15 minutes may be associated with a high risk of hemorrhage (154), but a precise correlation between prolonged bleeding times and surgical risk in the ESKD patients has not been clearly established. The synthetic ADH analog, 1-deamino-8-D-arginine vasopressin (DDAVP; 0.3 mcg/kg IV one hour before surgery) (155), cryoprecipitate [10 units over 30 minutes IV; effects generally apparent in one hour (156)], or conjugated estrogens [0.6 mg/kg/day IV or orally for five days; some effect should be apparent in six hours, with peak effect in five to seven days (157,158)] can be administered to improve the bleeding time. Cryoprecipitate can be given repeatedly to effect improvements in bleeding risk, but DDAVP is subject to tachyphylaxis with repeated dosing. Intensive dialysis or transfusion of packed red blood cells to raise the hematocrit to at least 30% may also reduce bleeding risk. Nonetheless, packed blood cell transfusion should generally be reserved for patients with clinically significant anemia, to avoid the potential for antibody formation that may limit the prospects for successful renal transplantation in the future. Many patients with CKD or ESKD receive prophylactic antibiotics for surgical procedures, especially dialysis A-V graft procedures (159), and minor procedures [e.g., dental care (160)]. To avoid bacterial seeding of the grafts before epithelialization occurs, antibiotic prophylaxis using standard endocarditis regimens is recommended for the first several months after synthetic vascular access are placed.

In the postoperative period, strict attention must be paid to volume and hemodynamic status and drug dosing, as well as fluid, electrolyte, and acid–base balance. Surgical trauma, blood product transfusions, and acidosis may promote significant hyperkalemia, which may require emergent treatment. Postoperative hypokalemia is generally not treated unless signs, symptoms, or cardiac dysrhythmias referable to hypokalemia supervene, or the patient requires digitalis therapy. Operative blood losses, third-space volume losses, and fluid losses from drains and fistulae must be carefully evaluated to optimize postoperative care in the renal patient.

Dialysis Different types of dialysis modalities are in clinical use. These can be broadly categorized as intermittent hemodialysis, continuous renal replacement therapy (CRRT), and peritoneal dialysis. The relative advantages and disadvantages of these modalities in various clinical settings are presented in Table 11.

Hemodialysis Hemodialysis became standard treatment for kidney failure in the 1960s. In this process, the blood is circulated through a machine containing a dialyzer (also called an artificial kidney). The dialyzer has two spaces separated by the thin, semipermeable dialysis membrane. Blood passes on one side of the membrane, and dialysis fluid passes on the other. The wastes and excess water pass from the blood through the membrane into the dialysis fluid, which is discarded. The dialyzed blood is returned to the circulation. The process of removing excess fluid is known as ultrafiltration. The blood is circulated and diffused numerous times during a dialysis session. Chronic hemodialysis is commonly performed three or more times a week for four hours or more. Physical Process of Solute and Water Transport Across the Dialyzer Membrane The dialyzer membrane is a semipermeable membrane. Solute molecules and water, the solvent, move across this Table 11 Comparative Advantages (þ) and Disadvantage (
) of Dialysis Modalities Clinical variable Continuous renal replacement Hemodynamic stability Superior attainment of fluid balance Unlimited nutritional support Superior metabolic control Continuous removal of toxins Limited anticoagulation Stable intracranial pressure Rapid removal of poisons, drugs Need for intensive care nursing support Need for hemodialysis nursing support Ease of operation Patient mobility

Intermittent hemodialysis

Peritoneal dialysis

CRRT




þ

þ





þ


þ þ




þ
þ



þ þ þ


þ þ þ
þ





þ

þ

þ

þ





þ

þ


þ/



Abbreviation: CRRT, continuous renal replacement therapy.

Chapter 37: Urine Formation: From Normal Physiology to Florid Kidney Failure

membrane under the influence of three physical processes— diffusion, convection, and ultrafiltration. Diffusion is the process of solute movement down a concentration gradient across the membrane. The flux of solute molecules depends on the size and shape of the solute molecule (characteristics that are described in a term called the diffusion coefficient of the solute); the porosity of the membrane, as well as its thickness, and surface area; and the concentration gradient and temperature of the solution. Whereas these factors enable a close prediction of solute fluxes or clearance in simple solutions, protein binding and electrical charge further influence solute flux in vivo. A second mechanism of the movement of solute molecules is convection. Water (solvent) is moved across the membrane by filtration; the flux of water is determined by the balance of hydrostatic and oncotic pressures across the membrane (the transmembrane pressure), and the permeability of the membrane to water molecules (hydraulic permeability) defined in the term, ‘‘coefficient of hydraulic permeability’’ (Kf). Convective movement of solute is the movement of solute molecules with water, a phenomenon known as solvent drag. The convective flux depends on the ultrafiltration rate and the solute concentration, as well as the sieving coefficient of the membrane for the solute. Sieving coefficients of membranes to solutes are determined by a characteristic of the membrane, the reflection coefficient. Dialysis membranes are classified according to ultrafiltration coefficient and solute sieving profiles into high-flux and low-flux membranes. Low-flux membranes are called dialyzers and clear solute mainly by diffusion, while high-flux membranes are called hemofilters and clear solute mainly by convection. The Dialyzer Membrane and Dialyzer Design Several important characteristics are required of the dialyzer membrane. These include adequate clearance of small molecules such as urea; adequate removal of water; retention of large molecules; biocompatibility (i.e., nonthrombogenic, nontoxic, and noninflammatory); capable of sterilization by steam, gamma irradiation, or ethylene oxide; and possessing microscopic structure that confers strength to the high transmembrane pressures required for ultrafiltration. Dialyzer membranes are classified into categories depending on their method of production. Semisynthetic membranes are cellulose derived or modified/regenerated cellulose (cellulose acetate, cellulose diacetate, and cellulose triacetate). Synthetic membranes include those composed of polysulfone, polyamide, polyacrylonitrile, or polymethylmethacrylate. The dialyzer membranes are assembled or bundled in two main designs—hollow fiber and parallel plate. Modern dialyzers are constructed of hollow fiber filters. Hemodialysis Vascular Access A well-functioning, dependable vascular access is needed for hemodialysis. For chronic hemodialysis, the ideal, permanent access is a ‘‘native’’ A-V fistula: the alternative is a synthetic A-V graft. However, in several clinical situations, temporary vascular access is needed. Percutaneous central venous hemodialysis catheters (CVCs) are available for such situations. Central Venous Catheters. The ability of CVCs to provide high blood flow rates (300–400 mL/min) is compromised by the development of very negative pressures at the catheter tip and pores as a result of high blood velocities in the area—the Bernoulli effect. This effect is worsened by additional obstruction from thrombosis and fibrin sheaths and

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results in the collapse of the venous wall around the catheter. To minimize this problem, catheters are positioned in the right atrium; they are made with a wide internal diameter, multiple pores placed in all directions around the catheter, and the arterial port placed away from the wall of the vein. The ideal CVC should provide adequate blood flows with minimum resistance, pressure drop, and Bernoulli effect; its placement should cause minimal trauma to the vein and its intimal lining; and minimal activation of the coagulation cascade, white cells and platelets, and infection by the migration of bacteria from skin, along the sides of the catheter or through the catheter lumen. The material of the CVC should be able to withstand the negative pressures without collapsing and should not kink, break, or deteriorate with use of antiseptic agents (161,162). The materials of which dialysis CVC catheters are made need to fulfill certain requirements for clinical safety and performance as well as for manufacturing purposes (162). The material should be biocompatible and nonthrombogenic; the body of the catheter must be strong so as not to crack or break easily; it should be able to withstand repeated exposure to alcohol, iodine, and other cleaning and antiseptic chemicals; it should be sufficiently rigid as to enable threading over a guidewire or splitsheath during placement, but not too rigid as to cause injury to the vessel wall; it should resist kinking and collapsing under very negative pressures; it should be flexible so as to negotiate bends, especially in the tunnel; the catheter itself should have as large as possible an internal diameter without being too large so as to minimize trauma to the vessel. For manufacturing purposes, it should be moldable, and bondable for use with other materials used in making of the other parts of components of the catheter. Most catheters in current use are polyurethane. Polyurethane has high material strength—catheters can be made with a very thin wall; it is flexible and can be made very rigid or soft; it is moldable and bonds well with other materials. A main disadvantage is that it is damaged by alcohol and antibiotic ointments such as mupirocin and betadine ointment that contain polyethylene glycol. Common femoral vein cannulation is relatively easy and is preferred in the critically ill patient, where rapid and safe cannulation is required (163). Thus, in the emergency room or ICU, to minimize the risk of pneumothorax in the mechanically ventilated patient, cardiac arrhythmias, hemothorax, and pericardial tamponade, there is a high incidence of catheter-associated bacteremia. Ultrasound guidance or fluoroscopy are usually not required but may be useful in the morbidly obese or where there have been multiple prior cannulations and severe scarring; this may also be useful to determine catheter tip position where there is poor catheter function and high recirculation rates. In this situation, long catheters ( >20 cm) are needed with X-rays to ensure catheter tip placement in the right atrium. Attempts at subclavian vein cannulation are associated with a high rate of severe acute complications—subclavian artery puncture, hemothorax and pneumothorax, and a high rate of subclavian vein stenosis in long-dwelling catheters (164), which will compromise the arm for subsequent placement of A-V accesses. Subclavian vein dialysis catheters are no longer recommended. For internal jugular (IJ) vein cannulation, the right IJ vein is preferred, because it runs straight inferiorly to the superior vena cava. Thus, the risk of malposition and malfunction is minimized, and endothelial injury is minimized so that chronic stenoses and occlusion are less common. There is great anatomic variability in the diameter of the vein and in its relations to the internal carotid artery,

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hence IJ vein placement is preferably done with ultrasound or fluoroscopic guidance or by surgical implantation (where there has been prior extensive neck surgery or multiple cannulations of the IJ with scarring) easily done under local anesthesia to minimize trauma to the vein, and the risk of injury to the IJ artery. The left IJ vein has a tortuous course, and catheters in this vein are complicated more frequently by malfunction, intimal injury, and chronic central venous stenosis, injury to the thoracic duct, pneumothorax, and hemothorax (163). Inadequate Dialysis from Catheter Malfunction and Unreliability. Adequate dialysis delivery requires adequate blood flow (Qb) in the 350 to 400 mL/min range. Access malfunction is therefore not to be tolerated. Blood flow rates as read by the machine tend to overestimate true blood flow rates, more so at more negative pressures. CVCs generate very negative pressures around their ports as a result of direct sucking and of the Bernoulli effect. Thus, machine blood flow readings with CVCs often greatly overestimate the actual blood flow. This, coupled with the fact that CVCs provide blood flows much lower than A-V accesses and have high recirculation rates, explains why CVCs are frequently associated with inadequate dialysis. CVCs are vulnerable to thrombosis, fibrin sheath formation, primary malposition, secondary displacement or dislocation of the catheter tip. Adherence of the catheter tip to the vein wall can be corrected by reversing catheter ports, but this leads to higher recirculation rates. These CVC complications can be successfully managed by interventional radiologic procedures such as changing of the catheter over a guidewire, thrombolysis with tissue plasminogen activator, or fibrin sheath stripping (163). Where chronic hemodialysis has to be done using a CVC, meticulous monitoring of dialysis adequacy with aggressive use of these procedures to optimize catheter function is mandatory (161,165). Hemodialysis Catheter-Related Infections. Catheterrelated bacteremia and septicemia are a major cause of morbidity and mortality in hemodialysis patients (166– 170). The majority of infections are due to Staphylococcus aureus and coagulase-negative staphylococcus. Coagulasenegative S. aureus most commonly colonizes the catheter exit site, but less frequently accounts for sepsis, whereas S. aureus colonization of the exit site is associated with a high incidence of bacteremia. Hemodialysis catheter-related bacteremia is less frequently caused by gram-negative bacteria such as Escherichia coli, Pseudomonas spp., Klebsiella spp., Proteus spp., and Serratia spp. Hemodialysis catheter-related infections due to fungi are not common in chronic dialysis patients; however this complication occurs in long-dwelling dialysis catheters in acute renal failure in hospitalized patients. Adherence of bacteria to the catheter surface is determined by an interplay of host, bacterial, and catheterrelated factors. A layer of thrombin, rich in fibrin and fibronectin, forms around the catheter. S. aureus adheres tightly to fibrin, while coagulase-negative staphylococci adhere tightly to fibronectin and not to fibrin. The bacteria produce a fibrous glycocalyx called extracellular slime; coagulasenegative staphylococci are particularly slime producing. The thrombin and slime are components of a biofilm layer that supports further bacterial adherence and growth and also acts as a barrier protecting the organisms from antibiotics, antibodies, phagocytic neutrophils, and macrophages. The nature of the catheter material also plays a role in biofilm

Table 12 Risk Factors for Catheter-Related Bacteremia Nasal carriage of S. aureus usually associated with skin carriage Catheter hub colonization Duration of catheterization Frequency of catheter manipulation Procedure of dialysis itself, which involves several exposures The conditions of catheter placement and postinsertion catheter care Patient’s personal hygiene Adherence by medial staff to universal precautions, including hand washing, wearing of gloves and masks when catheter is manipulated Catheter clotting Diabetes mellitus Frequent skin needle punctures (e.g., diabetics or drug users)

formation. Following bacterial adherence to the dialysis catheter surface, biofilm organizes into a complex structure regulated by the exchange of chemical signals between bacterial cells, a process known as quorum sensing. This ‘‘multicellular’’ cell–cell communication leads to the emergence of virulence phenotypes. Two quorum-sensing systems are identified in S. aureus, the autoinducer RNAIIIactivating protein (RAP) and its target molecule TRAP; and the peptide pheromone AIP and its receptor AgrC. More understanding of these mechanisms of biofilm formation may lead to novel approaches to the management of CVC. The risk factors for the development of catheter-related bacteremia are presented in Table 12. The Native AVF. The arteriovenous fistula (AVF) is the first choice of hemodialysis vascular access, using the patient’s own artery and vein (171,172). Time, sometimes up to three months, is needed for the vein to arterialize or ‘‘mature.’’ Every effort should be made to create an AVF, in spite of the fact that an increasing proportion of patients needing dialysis are surgically challenging. More dialysis patients are diabetic and elderly, with more severe diffuse atherosclerosis and more venous damage or injury resulting from multiple prior venipuncture for blood draws and intravenous infusions, as well as central vein catheterizations. The radiocephalic AVF, first described by Brescia and Cimino in 1966 (173), is the classical AVF, created at the wrist using the radial artery and the forearm cephalic vein (174) (Fig. 12). In individuals with severe atherosclerosis, the radial artery may not provide adequate blood inflow, and thus it is necessary to use the brachial artery in the antecubital fossa, connected to the lateral upper arm cephalic vein. Careful preoperative evaluation of artery and vein is essential for successful AVF creation. The radial artery usually has a blood flow rate of 20 to 30 mL/min, which increases to 200 to 300 mL/min after AVF creation; by the time of maturation of the AVF, typical blood flows are 600 to 1200 mL/min. This marked increase in blood flow requires a distensible inflow artery, thus the atherosclerotic, thickwalled and calcified artery is a poor candidate for successful AVF creation. The greatest threats to successful maturation of the vein are prior multiple venipunctures, with resulting venous sclerosis, multiple venous tributaries draining blood flow, hypertrophic venous valves, and central venous stenosis or thrombosis, often subclinical or asymptomatic. Preoperative evaluation should include a history taking and physical examination, with careful palpation of arteries and veins, auscultation and blood pressure measurements on both arms, ultrasonographic study of the arteries and veins to evaluate their caliber, wall structure and flow characteristics (this has replaced the Allen test),

Chapter 37: Urine Formation: From Normal Physiology to Florid Kidney Failure

Figure 12 Potential vascular sites for creation of an endogenous arteriovenous fistula for hemodialysis vascular access. The preferred access site is created at the wrist by anastomosing the radial artery and cephalic vein (A). Other potential sites for access creation include the brachial artery with either the medial cubital vein at the elbow (B) or the cephalic vein at the upper arm (C).

and contrast or magnetic resonance venography in selected cases. Recently, the surgical procedure of transposition of the basilic vein in the upper arm has allowed the use of proximal upper arm vessels for AVF creation (175). The NKF-DOQI Clinical Practice Guidelines for Vascular Access has recommended an AVF rate of approximately 50% in new ESRD patients (176). The high prevalence of diabetic, obese, and elderly patients in the ESRD population in the United States demands particular effort to reach this goal. Most AVFs require approximately three months to mature (cf 2–3 weeks for A-V grafts). Fistulas have a high primary failure rate due to a failure to mature or early thrombosis. A common problem in the dialysis center is that of the patient waiting for long durations for their AVF to mature or having successive AVFs thromboses. These patients are forced to continue with CVCs for long periods, which is not ideal. In order to increase the chances of achieving successful AVF placement, maturation, and function, preoperative vein mapping by sonography, contrast, or magnetic resonance venography is needed. Absolute contraindications to A-V access are severe congestive heart failure with low ejection fraction that may be worsened by the A-V shunt, symptomatic steal syndrome, morbid obesity, chronic and intradialytic hypotension, hypercoagulable states, skin disease, and severe venous hypertension leading to severe edema of the arm.

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Arteriovenous Graft. The arteriovenous graft (AVG), introduced in mid-1970, is the second option for vascular access. Graft material may be autogenous, heterogenous, or synthetic. Expanded polytetrafluoroethylene is the most commonly used graft material (177). Grafts may be placed in the upper or lower extremities and may be straight or looped, and the anastomosis may be end-to-end, end-toside, or side-to-side. The end-to-side anastomosis is the most commonly used. Graft thrombosis is the most common complication of AVGs (70%); of these, 90% are associated with venous anastomotic stenosis, the result of neointimal hyperplasia. As a consequence, there is a high incidence of access malfunction and poor outcomes in patients with AVGs. In the United States, AVGs account for approximately 70% of all vascular accesses. Recent studies reveal that chronic AVGs are associated with a chronic inflammatory state with higher levels of inflammatory markers such as C-reactive protein (178). In diabetics, AVGs were associated with an overall mortality risk of 1.41; cause-specific relative risks are significantly higher, and the relative risk of death from infection is more than twice that of diabetics with AVFs (179). AVGs develop an aggressive form of venous anastomotic intimal hyperplasia characterized by smooth muscle cell proliferation, extracellular matrix synthesis and deposition, and neointimal and adventitial angiogenesis. There is no effective pharmacological therapy as yet for this lesion. In view of the high rates of graft dysfunction and thrombosis, and the lack of specific therapy, attempts have been made to develop simple and reliable tests of graft function that will give early warning of dysfunction and impending thrombosis. These methods include dynamic pressure measurements, static intra-access pressure measurements, access blood flow measurements using Doppler ultrasound and ultrasound dilution methods, and recirculation measurements using urea-based methods, ultrasound dilution or thermodilution methods. These programs of graft surveillance have proven useful in prolonging graft survival and have ensured adequate delivery of dialysis. Using well-validated criteria of access function, dysfunctioning vascular accesses are then referred for fistulography or graftography and further interventional procedures (172). Management of AVG Dysfunction. Interventional radiology, interventional nephrology, or vascular surgery departments primarily manage the management of graft thrombosis. Procedures can be performed more promptly, and thus with minimal interruptions of the patients’ dialysis treatment schedules, and they are less invasive and they do not require general anesthesia. These procedures allow access sites to be preserved better for future use and also provide more precise anatomic diagnosis of lesions within the access and on both arterial and venous side, up to the central venous system. This more precise diagnosis makes it possible to develop the appropriate treatment plan, and this should be done in a multidisciplinary approach involving the interventionist, nephrologist, and surgeon. More AV accesses are salvaged in this way, longevity of the access is increased, accesses that are not salvageable are more clearly identified and referral to surgery and outcomes are improved. The usual interventional procedures are thrombolysis, usually mechanical, but occasionally with the aid of thrombolytic agents, and angioplasty of venous anastomotic stenotic lesions as well as venous stenotic lesions that may occur all the way up to the central veins (180). Occasionally lesions are detected on the arterial anastomotic

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region, which may be amenable to angioplasty, and stenting of stenotic venous segments is performed where indicated. Surgery is indicated when the interventional approach has failed or is not feasible and is usually carried out with more detailed anatomic data and with a view to preserve access sites for the future and to address the underlying lesion. Surgical procedures include thrombectomies, placement of patch angioplasties, interpositional or jump grafts, or the creation of new AV accesses. Additionally, surgical intervention is required for the management of bleeding, infections, and pseudoaneurysms. Anticoagulation. Activation of the hemostatic system as a result of contact between blood and the foreign surfaces of extracorporeal circulatory systems is a challenge in hemodialysis dialysis therapies. Clotting occurs within the blood compartment of the dialyzer and/or at different vulnerable points along the dialysis blood lines or circuitry. Filter clotting results in treatment interruptions and inefficiency, nursing difficulties, increased cost of treatment, and, most important, inadequacies of clearances and ultrafiltration capacity. Anticoagulation is therefore usually required for the effective delivery of the dialysis prescription. The anticoagulation regimen must be individualized for the needs of each patient. Hospitalized patients, acutely ill with infection, sepsis, post-trauma, surgery, strokes, or myocardial infarctions and such conditions may be hypercoagulable or coagulopathic. Careful consideration of these factors must go into the determination of the requirements for anticoagulation for dialysis. Anticoagulation is usually systemically administered, but where there are serious bleeding risks, it may be done locally or regionally, across the dialyzer only. Regional anticoagulation is particularly preferred with continuous dialysis therapies in the severely ill intensive care patients and also because of the potential for anticoagulants to accumulate with continuous administration. Treatment characteristics that affect clotting include vascular access— catheter diameter, traumatic catheter placement, catheter malposition, and kinking; blood flow rates; ultrafiltration rates; dialyzer membrane material and geometry; and nursing attention to alarms and other warning signs of impending thrombosis. Anticoagulation may be systemic or regional. Sometimes no anticoagulation is used or required. Patients with liver failure, uremic bleeding diathesis, severe thrombocytopenia, consumptive coagulopathy, or patients receiving medications with anticoagulant effect such as the recently introduced activated protein C may require only intermittent saline flushes to maintain patency of the extracorporeal circuit. Water for Dialysis and Dialysate Composition. Water for dialysis is usually municipal water; occasionally only well water is available. The water undergoes a number of filtration steps to remove particles, dissolved organic compounds, chloramines, and chlorine, after which it is pumped through a water softener, and an ion exchange resin to remove calcium and magnesium ions (181,182). Municipal water is allowed to contain up to 100 colony-forming units of microorganisms per mL. Ion exchange resins promote bacterial growth. Next, the water filtered and softened is pumped through an RO unit, for the elimination of up to 99% of all ions present. The hemodialysis machines are connected to the water purification system by polyvinyl chloride tubing. Water stagnation in the tubing promotes bacterial overgrowth as well as biofilm formation, especially from Pseudomonas species, which are a constant source of endotoxins

and other pyrogenic bacterial products. Failure of the water treatment system results in incorrect electrolyte composition of the final dialysate, patient exposure to unwanted chemical contents such as chloramines, fluorides, nitrates, copper, and aluminum, as well as to microorganisms and their products. Salt concentrates, particularly bicarbonate concentrate, are prone to heavy contamination with microorganisms, especially Pseudomonas species. Solid bicarbonate in powder form is now available. Bacterial products back filtrate from dialysate side to the blood side. There is a current effort to provide pyrogen-free (ultra-pure) dialysate by adding pyrogen-adsorbing membranes, or ultraviolet radiation to the water treatment system. The final dialysate is mixed in a proportioning system from dialysate concentrates and the dialysate water. Dialysate composition is individualized according to clinical requirement. The main variables are dialysate sodium, potassium, calcium, and, more uncommonly, bicarbonate and magnesium. It is easy to imagine that errors of dialysate composition from a faulty proportioning system or human error can have severe deleterious clinical effects. Monitoring of ionic conductivity is used as a safety measure against this possibility. Measurement of Dialysis Adequacy. The effort to quantify dialysis adequacy has engaged the interest of nephrologists for many years. Among the first choices of uremic toxins selected for such analysis was urea, representative of small solutes. Several parameters need consideration—dialyzer membrane transport characteristics, blood and dialysate flow rates, duration of treatment, vascular access performance, in particular blood flow recirculation within the access, ultrafiltration rates, hematocrit, etc. These in turn are factored to a measure of patient size. The most successful parameter to date, dialysis dose, and which has been validated as predictive of patient outcome, is the Kt/V urea index (183). This is the clearance of urea factored to total body water. A Kt/V of one indicates urea clearance equal to the volume of total body water. The NKF/DOQI Clinical Practice Guidelines give evidence-based targets of dialysis dosing to be delivered to patients so as to ensure adequate dialysis (184–186).

Continuous Renal Replacement Therapies CRRT have become the most effective treatment modality in critically ill patients (187,188). Several features of these modalities explain their advantages: 24-hour treatment provides continuous removal of toxic compounds that are presumed to be continuously generated; there is a marked overall increase in dialysis clearances; and small hemofilters and small volume extracorporeal circuits are used to minimize blood volume reduction in the hemodynamically unstable patient. The hemofilters have large pore-size with high hydraulic permeability permitting large volume ultrafiltration [continuous veno-venous hemofiltration (CVVHF) and continuous veno-venous hemodiafiltration (CVVHDF)], as well as the passage of middle and some high–molecularweight toxins (up to 30–50 Da): this enables the clearance of inflammatory cytokines, anaphylatoxins (C3 and C5), platelet-activating factor, and substance such as myocardial depressant factors. The capacity for high volumes of ultrafiltration also enables the safe administration of large volumes of fluid required for administration of medications, nutrition, and blood products. Additionally, these techniques offer gradual and continuous correction of electrolyte, acid–base and osmolality abnormalities, as well as the capacity to cope with the severe azotemia of the severely ill and

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Table 13 Potential Indications for Continuous Renal Replacement Therapy Acute renal failure with: Severe hypercatabolism Cerebral edema Cardiovascular failure Acute or chronic liver failure Adult respiratory distress syndrome Tumor lysis syndrome Lactic acidosis Cardiopulmonary bypass Sepsis syndrome Refractory congestive heart failure Acute necrotizing pancreatitis Rhabdomyolysis Acute intoxications Hyperammonemia associated with inborn errors of metabolism

Dialysis catheter Patient

Air embolus monitor

Venous pressure monitor

Ultrafiltrate tubing pump

hypercatabolic patient. It has recently been demonstrated that adsorption is an important mechanism of solute clearance in CRRT. In many cases the clinical significance of such clearances is yet to be understood. Table 13 lists some of the renal failure and nonrenal conditions that have been reported to benefit from CRRT (189). CRRT may be particularly advantageous when AKF is accompanied by refractory volume overload, hypercatabolism, intracerebral edema, hemodynamic instability, or uncontrollable hyperkalemia or metabolic acidosis. The first continuous therapies were continuous arteriovenous, requiring arterial cannulation, with the force for blood flow provided by the arterial blood pressure. With the introduction of a blood pump into the extracorporeal circuit, and the availability of single dual-lumen catheters, continuous veno-venous therapies became possible and are much preferred. The modalities of continuous therapies can now be classified into three categories: convective therapies, dialysis therapies, and continuous ultrafiltration. Convective Therapies: CVVHF and CVVHDF The convective therapies are hemofiltration (CVVHF) and hemodiafiltration (CVVHDF) (Fig. 13) (187,188). The dialyzing membrane is highly permeable to solutes and water. In CVVHF, there is no dialysis fluid, while in CVVHDF, there is a dialysis fluid flow. In both CVVHF and CVVHDF, very large volumes of ultrafiltration are the goal, far in excess of ultrafiltration required for the purposes of volume balance; therefore, in both procedures there is a need for replacement or substitution fluid. Typical ultrafiltration rates are about 30% of blood flow rates; at blood flow rates of 200 to 300 mL/min, typical ultrafiltration rates are 60 to 90 mL/ min. CVVHF and CVVHDF achieve very high clearances of both small and large-molecular-weight solutes. With CVVHF, clearances of small-molecular–weight-solutes depend mainly on ultrafiltration volume; therefore to achieve high small-solute clearances, high blood-flow rates (approximately 500 mL/min) are required. With the availability of online production of substitution fluid, it is possible to achieve such a high blood flow into the hemofilter (e.g., 250 mL/min actual blood flow and 250 mL/min predilution substitution fluid). With CVVHDF, small solute clearance depends not only on ultrafiltration rates but also on diffusion down a concentration gradient; predilution with substitution while increasing ultrafiltration rates also dilutes concentrations of these solutes, thereby reducing diffusive clearances.

Blood pump

Membrane

Drainage Bag

Figure 13 Continuous venovenous hemofiltration (CVVH) circuit. CVVH offers large-volume ultrafiltration in critically ill patients with specific indications. Blood moves from and to the patient via a dual-lumen central venous catheter, with the filtration pressure being provided by a blood pump.

Predilution therefore reduces clearance of small solutes in CVVHDF. Substitution fluid is administered postfilter. Both CVVHF and CVVHDF can only be accomplished by the availability of large volumes of substitution fluid made possible by its online production. There is currently great interest in the development of the continuous convective therapies, for the treatment of acute renal failure in the setting of sepsis or the multiple organ dysfunction syndrome (MODS). Besides the improved small solute clearances, hemodynamic stability, metabolic control, and nutritional support that can be provided, it is suggested that there is improved clearances of middle and large molecules, especially inflammatory mediators and endotoxins (by convection and adsorption), the removal of which will aid the management of sepsis. This has led to novel therapies aimed at the treatment of sepsis or MODS as opposed to AKF. In principle, two main approaches are being pursued: high volume hemofiltration with filtration rates averaging 35 mL/kg/hr or more and ultrahigh-efficiency clearance using plasma filtration and adsorption. The Dialysis Therapies: CVVHD and SLED CVVHD and sustained low-efficiency dialyis (SLED) are diffusion (dialysis)-based techniques as in regular hemodialysis (187,188,190), but unlike routine hemodialysis, dialysate flow rates are lower, rendering the procedure less efficient. With CVVHD, the dialysate flow rates are in the range of 1 to 2 L/hr (17–35 mL/min); blood flow rates are also slowed, averaging 200 mL/min. The dialysate is completely saturated in its passage through the dialyzer, and dialysate flow rate is the limiting factor to clearance. Small solute clearance is the objective in CVVHD. At this rate of dialysate flow, the dialysate is supplied in bags from the manufacturer or custom-mixed in the hospital pharmacy. Because

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of the undesirability of leaving bicarbonate solution sitting for long periods, the alkalinizing agent in these dialysate solutions has been more commonly citrate than bicarbonate, though both types of solution are in use. With SLED, higher dialysate flows can be achieved using bicarbonate for alkalinization as in regular hemodialysis. Ultrafiltration: SCUF Slow continuous ultrafiltration (SCUF) provides low water and sodium removal continuously and can be useful in the management of refractory congestive heart failure, sometimes as a bridging procedure to cardiac transplantation. Complications of CRRT The major complications of CRRT are related to anticoagulation and metabolic disturbances (191). Continuous therapies often require continuous anticoagulation (192,193). This, in the presence of kidney failure, carries the high risk of excessive anticoagulation and bleeding, more so in critically ill patients with other bleeding risks. The trend therefore is to do regional, rather than systemic, forms of anticoagulation. Citrate anticoagulation is the most commonly used of these methods. Recent increased interest in alternatives to heparin is the result of increasing reports of the devastating complication of heparin-induced thrombocytopenia. Pharmacokinetics and Drug Dosing Adjustments During CRRT Drugs are cleared during CRRT mainly by convection and adsorption (194). Drugs that are normally cleared by the kidneys are usually also removed by CRRT. The critically ill patient already has major abnormalities of drug handling from altered absorption, distribution, metabolism, and excretion. Drug dosing in CRRT is best guided by measuring levels where this is applicable. CRRT drug clearances can be measured or estimated; where this is not feasible, drug dosing can be adjusted (according to reference guidelines) using measured CRRT creatinine clearances. With nontoxic drugs, dosing may be done in excess of estimates (approximately 30%), to ensure adequate levels.

Peritoneal Dialysis In peritoneal dialysis, the intra-abdominal peritoneal microcirculation, with its large surface area, blood flow, and the solute and fluid exchange properties of the capillary network, is exploited. Dialysate is injected into the peritoneal space through a two-way catheter. The peritoneal membrane allows waste and fluid to pass from the blood into the dialysate, which is drained out. The peritoneal dialysate contains electrolytes in physiologic concentrations to facilitate correction of acid–base and electrolyte abnormalities. The dialysate glucose concentration can be increased or decreased depending on the desire to promote or restrict, respectively, osmotic movement of fluid from the peritoneal capillaries into the peritoneal space. Urea clearances of 10 to 15 mL/min can be achieved using this method. The amount of solute removal is a function of the degree of its concentration gradient, the molecular size, membrane permeability and surface area, duration of dialysis, and charge. Peritoneal dialysis must be performed everyday and fluid must be in the abdomen at all times to clean the blood adequately. Advantages of peritoneal dialysis over acute intermittent hemodialysis include the fact that in peritoneal dialysis, fluid removal is more gradual and less hemodynamically stressful, dialysis is slower and more continuous so that

electrolyte shifts may be less dramatic, anticoagulation is not required, and less specialized equipment and personnel are required. In the AKF setting, acute peritoneal dialysis is not as efficient as acute intermittent or continuous hemodialysis in correcting metabolic, fluid, and electrolyte abnormalities. Continuous ambulatory peritoneal dialysis (CAPD) exchanges approximately 2 L of dialysate three to six times a day while the patient is active. The patient connects a bag of dialysate fluid to the peritoneal catheter and allows it to infuse into the abdomen. After the dialysate filters for four to six hours (the ‘‘dwell’’ time), the patient drains the fluid and exchanges it for fresh fluid. In automated peritoneal dialysis, also termed ‘‘continuous cyclic peritoneal dialysis’’ (CCPD), a machine exchanges the fluid while the person sleeps. Over the 8- to 12-hour night, the machine exchanges fluid four to eight times. Upon waking, the patient’s fluid is exchanged and used throughout the day. Some patients require a mid-day exchange. Early peritoneal dialysis fluids composed of solutions varying from normal saline to 5% dextrose. Sodium concentrations were varied as required to correct hypo- or hypernatremia. To correct acidosis, bicarbonate, acetate or lactose was used as base. Dextrose in high concentrations (up to 7%) was used as the osmotic agent to provide ultrafiltration. These high concentrations of glucose posed a problem owing to caramelization during sterilization. With the advent of commercially prepared peritoneal fluid, two problems arose. One was the inability of keeping calcium and bicarbonate in solution in storage for long durations (precipitation of calcium carbonate); the second was that bicarbonate solutions are difficult to keep sterile. Thus modern peritoneal dialysis fluids remain buffered with lactate. The technique, in its early history, was hardly suitable for the chronic treatment necessary for ESKD. The first efforts required repeated catheterization of the peritoneum for each treatment. This ‘‘periodic’’ peritoneal dialysis was extremely painful and uncomfortable for the patient, and had a high rate of infections and peritoneal adhesions. Unsuccessful attempts were made to develop devices such as abdominal buttons or other conduits to facilitate the repeated catheterizations. The earliest peritoneal dialysis catheters were made from tubing easily available on the hospital ward—stainless steel sump drains, trochars, and rubber catheters—all of which were unsuitable for longdwelling use. Polyvinylchloride and polyethylene tubing became available in the early 1950s, but these were limited by their tendency to kink, leak, and get blocked. Catheter placement initially required a trochar, but later designs had pointed stylets for convenience of placement. In 1968, Tenckhoff (195) introduced his catheter, a silicone rubber catheter with two Dacron cuffs, designed to be used as a long-term indwelling dialysis catheter. All other peritoneal dialysis catheters designed since have been modifications of the Tenckhoff catheter. The Tenckhoff catheter is, arguably, the single most important device that has made chronic peritoneal dialysis a reality. Peritoneal dialysis catheters can now be placed laparoscopically at the bedside or in the operating room, or by open surgery. Straight, coiled, singleor double-cuffed, Swan Neck, Ash T-fluted, and presternal catheters are all in use. The coil of the catheter gives it weight in its pelvic location, which minimizes the possibility of migration from the pelvis. The Swan Neck design allows a downward direction of the exit site, which markedly reduces the risk of exit site infection. The Dacron cuffs on the catheter are highly fibrogenic and help to secure the catheter in position and minimize the possibility of pericatheter leak

Chapter 37: Urine Formation: From Normal Physiology to Florid Kidney Failure

and infection. The internal cuff, placed within the rectus abdominus muscle, helps to prevent catheter leak or migration. The coiled intraperitoneal segment helps to prevent catheter migration and minimizes pain from infusion of fluid. Presternal catheters are suitable for the morbidly obese and patients with abdominal ostomies. A variety of peritoneal catheter-related complications may occur (Table 14). At the same time as the indwelling catheter was evolving, efforts in the area of fluid delivery led to the introduction of automatic cycling machines—machines capable of delivering fluid to the patient’s peritoneal cavity in cycles, with varying volume and composition of fluid, duration of inflow, dwell, and outflow. At first, the dialysate was premixed and provided in large containers. Later, the dialysate was available in plastic bags of different dextrose concentrations or strengths, with the possibility of being mixed or matched to provide a final composition appropriate for the patient. Over the years, peritoneal dialysis cyclers have become smaller and more portable. The next major development in peritoneal dialysis was the concept of CAPD proposed by Popovich and Moncrief in 1973 (196). They hypothesized that peritoneal dialysis could be performed on a principle of ‘‘equilibration’’ dialysis: that is, if each exchange of fluid introduced into the peritoneum was allowed to ‘‘dwell’’ there until it equilibrated with the blood and then was drained; they calculated that only a relatively small amount of peritoneal fluid, in a relatively small number of exchanges would be required to provide the necessary amount of solute and fluid clearance. Specifically, they calculated, for example, that exchanges of 2 L, each with an ultrafiltration of 500 mL and thus a drain volume of 2500 mL, four times in the course of a 24-hour period, would result in a 12 L drain volume or effluent. If it is assumed that this volume of dialysis fluid effluent achieved equilibration with blood, then the amounts of urea and creatinine cleared, which can be calculated should be adequate to treat ESKD. The patient in this way achieves steady state chemistries, with minimal fluctuation of serum creatinine or BUN levels. The developments in peritoneal dialysis described thus far formed the basis of modern peritoneal dialysis technique. Further developments have only been the modifications of these principles. Because CAPD requires exchanging peritoneal dialysis fluid four to five times daily, the potential for contamination of fluid and resulting peritonitis is high. Numerous devices and techniques to achieve and maintain sterile connections with minimal risk of contamination have since been developed. Automated cycling machines that can automatically Table 14 Peritoneal Dialysis Catheter-Related Complications Exit-site infections Extrusion of the external cuff Catheter obstruction by: Clot Bowel (constipation) Omentum Adhesions Full bladder Kinks Pericatheter leaks Infusion or drainage pain Peritonitis Migration Cuts, material deterioration and breakdown, organ erosion, and allergic reactions (rare)

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Table 15 Peritoneal Dialysis as Chronic Renal Replacement Therapy Advantages More liberal diet with less fluid intake restrictions Minimal fluctuation of blood chemistries Better anemia control Better hypertension control Improved sense of well-being Suitable for children in school and employed patients Less cost Disadvantages Catheter malfunction Weight gain Patient fatigue with the procedure Development of abdominal hernias Peritonitis

provide the needed dialysis exchanges, usually at night during sleep, have been developed and are in common use. Evidence-based standards for quantification of peritoneal dialysis, guidelines for adequacy of treatment, and protocols for the diagnosis and treatment of peritonitis, exit site infections, and tunnel infections have also been established. Catheter design and placement techniques and peritoneal dialysis fluid composition and biocompatibility have been improved. As a result of these developments, peritoneal dialysis is now widely available for the treatment of ESKD in most parts of the world, and its use is growing much faster than that of hemodialysis. The advantages and disadvantages of peritoneal dialysis, as well as the indications and contraindications for peritoneal dialysis and factors that influence the choice of hemodialysis versus peritoneal dialysis are presented in Table 15.

RENAL TRANSPLANTATION Kidney transplantation is the treatment of choice for ESKD, and the number of kidney transplants (both cadaveric and living donor) performed in the United States has dramatically increased in the past decade. This reflects an increased availability of living kidney donation, the result of increased public education and awareness. Living unrelated kidney donation is the area of greatest increase in the United States. Although cadaveric kidney donation has not substantially increased, there has been a lowering of the threshold of acceptable cadaveric kidney transplantation, which has been largely responsible for the increase in cadaveric kidney transplantation. Donor organ availability continues to fall short of demand, resulting in long transplant waiting lists.

Transplantation Immunobiology The major barrier to successful allotransplantation is immunologic. Renal allograft rejection remains the major cause of graft loss. The delineation of molecular mechanisms of allograft rejection has led to new classes of biologic agents for the abrogation and control of allograft rejection. Additionally, there is the increasing prospect of achieving transplantation tolerance and of successful xenotransplantation. Central to the question of transplantation immunology are the facts of self-identity of the organism and the ability to differentiate self from nonself and mount an immune response to destroy the non–self-‘‘invader.’’ Most of the proteins of the body are oligomorphic or nonpolymorphic, and as such, lack the necessary variation to distinguish individual members of the species, one from the other.

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The vast polymorphism, of almost limitless extent, that is needed to achieve this ‘‘self-identity,’’ is to be found in the major histocompatibility complex (MHC) structure. Unlike any other region of the chromosome, the MHC gene is highly polymorphic, as are its products, the MHC class I and class II cell surface proteins. Individuals with identical MHC proteins [other than identical (monozygotic) twins] are extremely rare. Histocompatibility antigens can be divided into a single MHC or system and numerous minor histocompatibility (miH) systems. Incompatibility for either MHC or miH antigens between donor and recipient leads to an immune response against the graft, although more vigorous reaction occurs with MHC differences. MHC class I glycoproteins are expressed on the surface of most nucleated cells, although at different levels. They are responsible for activating T-cells bearing the CD8 surface protein (CD8þ cells). MHC class II proteins, which are also membrane-anchored glycoproteins, stimulate T-cells bearing CD4 surface protein (CD4þ cells). Under basal conditions, class II proteins are expressed only in B-lymphocytes, dendritic cells, and some endothelial cells. During an immune or inflammatory response, however, many other cell types may be induced to express MHC class II proteins. Both class I and II proteins form a similar threedimensional structure at the cell surface. Within this structure is a groove flanked by two alpha helices; the amino acids in the groove show the highest polymorphism within a species. During the synthesis and transport of MHC class I and II proteins to the cell surface, they become associated with small peptides that fit into the groove. Class I proteins bind peptides derived from the intracellular compartment, while class II proteins bind peptides derived from the extracellular compartment. The combination of MHC protein and peptide is recognized by the antigen receptor on the T-cell, the T-cell receptor (TCR). Thus, antigenic peptides are recognized by T-cells only when they are presented in the groove of (i.e., in the context of) the MHC; antigen recognition is said to be ‘‘MHC restricted.’’ When the renal allograft is placed, host-specialized antigen-presenting cells take up foreign protein from the graft, process them, and load some of the resulting ‘‘foreign’’ peptides onto their MHC grooves. These are then presented at the cell surface to host T-cell. The class III region of the MHC is large and contains many uncharacterized genes. Genes that have been characterized encode proteins with a variety of functions important in immunity, such as TNF-a and TNF-b. miH antigens (e.g., the male antigen or H-Y) may play a prominent role in graft rejection in a recipient who is given an MHC-compatible graft but in whom preexisting sensitization to miH antigens exists. It may, for example, explain graft rejection and loss in renal transplants performed between human leukocyte antigen (HLA)-identical siblings. Multiple miH differences have been shown to represent an immunogenic stimulus that can be equivalent to that of the MHC. The process of graft rejection begins when recipient CD4þ T-cells are activated by graft alloantigen (197). Graft alloantigen is presented to the recipient T-cells by either of the processes of direct antigen presentation or indirect antigen presentation. The transplanted kidney contains bone marrow–derived leukocyte-like cells called passenger leukocytes. These passenger leukocytes rapidly traffic (migrate) out of the graft, via the lymphatic drainage, to the recipient’s lymphoid organs. Here, they rapidly mature into potent antigen-presenting cells (dendritic-like cells). Non–self MHC class II molecules expressed on these specialized, antigenpresenting cells of the graft, directly activate recipient

CD4þ cells. The peptide-binding grooves of these non–selfMHC molecules may contain peptides derived from graft or recipient proteins. Non–self-MHC are extremely potent transplantation antigens, which activate large numbers of T-cell clones in the recipient. Up to 5% of all clones in the body may respond to a non–self-MHC molecule (198). This process of presentation of donor MHC by donor ‘‘dendritic’’ cells is described as direct antigen presentation. In similar fashion, non–self-MHC class I molecules expressed on many cells in the graft may directly activate recipient CD8þ T-cells. Another example of direct antigen presentation is when recipient T-cells react with endothelial cells of the donor (allograft), which in an activated state express MHC molecules. Direct antigen presentation results in powerful stimulation of the immune system and is thought to be mainly responsible for acute allograft rejection. Direct antigen presentation bypasses antigen processing by recipient antigen-presenting cells. The second mechanism of host T-cell activation involves indirect antigen presentation. In this mechanism, antigen-presenting cells of the recipient migrate into the transplanted kidney, take up graft alloantigens, process the molecules, and present the resulting peptides on selfMHC molecules to T-cells, stimulating and activating them. Conversely donor cells could traffic out of the allograft and interact with recipient APCs in the lymphoid organs. Recipient APCs may also react with soluble ‘‘circulating’’ donor proteins that have been released into the bloodstream as a result of processes within the allograft, e.g., ischemia and inflammation that result in cell injury and/or cell death. Following the binding of antigenic protein by the APC, the protein is taken up into intracellular proteolysosomes and digested into peptide fragments. A relatively small number of these peptide fragments, and which are immunogenic, are selected, placed in the groove of the MHC molecule, and transported as the MHC–peptide complex to the cell surface to be presented to T-cells. With indirect antigen presentation, donor antigen-presenting cells such as dendritic cells and macrophages are involved as intermediaries between recipient T-cells and transplanted donor cells. The results of CD4þ and CD8þ activation, whether by direct or indirect mechanism of antigen presentation, are the generation of cytokine synthesis, and the proliferation and differentiation of T-cells into cytotoxic T-cells (CTLs).

Tests for Histocompatibility Antigens Tissue typing consists of the analysis of histocompatibility antigens of donor and recipient so as to determine the degree of foreignness between the two individuals and thus to predict the outcome of the transplantation. There are several ways to determine the degree of parity or disparity between transplantation antigens: (i) serologic detection of cell surface antigens (lymphocytotoxicity test); (ii) measurement of the reaction between leukocytes from the donor and recipient in the mixed lymphocyte reaction; and (iii) genotyping of transplantation epitopes.

T-Cell Antigen Recognition, Processing, and Signaling The TCR expressed on the surface of the T-cell interacts with the antigenic peptide located in the groove of the MHC molecule on the surface of the APC, but does not transduce a signal. The TCR is associated with a transmembrane coreceptor, the CD4 or CD8 molecule; CD4 and CD8 molecules act as

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adhesion molecules tightening the binding of T-cells with APCs, and also transduce signals into the cell. Additional costimulatory molecules expressed on APCs bind with their respective ligands on the T-cell, thereby enhancing and sustaining T-cell activation. Other adhesion molecules, the accessory molecules interact in pairs between APC and T-cells, resulting in the formation of the immunological synapse, which allows full activation of the T-cell. Activation of the CD4þ cell results in proliferation, cytokine synthesis and secretion, migration of T-cells from lymphoid tissue into the allograft and differentiation into memory cells, while activation of CD8þ cells results in their differentiation into cytotoxic T-lymphocytes (T-killer cells). Interaction of the TCR and alloantigen brings results in a complex-signaling cascade that lead to the activation of at least two major signaling pathways: the Ca2þ–calcineurin cascade and the protein kinase C (PKC)–Erk cascade. Calcineurin is a serine/threonine phosphatase that dephosphorylates and functionally inactivates key transcription factors such as nuclear factor of activated T cells (NFAT) involved in IL-2 gene transcription. PKC activation, in a multistep signaling pathway, leads to phosphorylation of Erk, which then phosphorylates and activates transcription factors such as c-fos and Elk-1, leading to the initiation of gene transcription.

Cytokines and Chemokines Graft rejection involves interactions among many cells involved in the immune and inflammatory responses and other cells such as endothelial and parenchymal cells. These cells communicate through direct contact using recognition molecules located on their cell surfaces (e.g., MHC, TCR CD4, CD8, CD40L, and FasL). In addition to the numerous cell–cell-based interactions required for T-cell activation, important signals are also delivered through the binding of soluble proteins, the cytokines, to specific cell surface cytokine receptors. A cascade of cytokines is produced that amplifies immune and inflammatory processes after transplantation (199). Cytokines such as IL-1 and IL-12, derived mainly from antigen-presenting cells, sensitize T-cells, by upregulating their expression of receptors for other cytokines, mainly T-cell derived, such as IL-2 and IL-4, which cause proliferation and differentiation. Many of the phenomena observed in the immune response to a transplant are mediated by several cytokines, acting redundantly and synergistically. On the other hand, calcineurin induces many cytokines, including CD40L, calcineurin, cytokine gc chain, and tyrosine-protein kinase receptor torso precursor (TOR), which all serve nonredundant functions. Activation of the calcineurin pathway results in the activation of transcription factors that regulate the transcription of genes encoding for several key cytokines (e.g., IL-2 and IFN-g) and cytokine receptors. Cytokines regulate MHC expression and the peptide generation and processing pathways. Under basal conditions, parenchymal cells express MHC antigens, adhesion molecules, and costimulatory molecules at levels too low to allow T-cell recognition. Certain cytokines may increase the antigenicity of an allograft by inducing the expression of MHC class I and II, adhesion and signaling molecules, and cytokine receptors. Costimulatory signals are also regulated by cytokines. IFN-g increases the transcription of the large mutifunctional protease genes and the genes for transporters associated with antigen processing, which are encoded in the class II region of the MHC, and could influence the peptides available for binding to the class I grooves. The growth factor cytokines such as IL-2 mediate the triggering, commitment, and clonal expansion of T- and

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B-lymphocytes and the emergence of their effector functions. T-cell receptor triggering is dependent on the presence of costimulatory factors (such as CD28 engaging B7-1/B7-2) and may be promoted by the binding of certain cytokines produced by the APC to their cognate receptors (e.g., IL-2, IL-6, and IL-12) on the T-cell (200). The subsequent lymphocyte differentiation and clonal expansion also require that certain cytokines produced by T-cells (e.g., IL-2, IL-4, IL-7, and IL-13) engage their receptors on T-cells, producing paracrine or autocrine effects. The aggregate strength of those signals may be a rate-limiting step in the immune response. Cytokines also play a crucial role in the organization of inflammation in a rejecting allograft. Cytokines can activate endothelial cells and affect their interactions with leukocytes and platelets, as well as their regulation of vasomotor tone and fluid movement. The primary role of cytokines in an immune response is to initiate proliferation, differentiation, and homing of leukocytes in the generation of immunity. However, certain cytokines also may directly damage tissue acutely or chronically. TNF-a produced by CTLs and macrophages may damage a graft, and blocking the effects of TNF with neutralizing antibodies can prolong organ graft survival. Several chemokines have been identified, which modulate help to determine the extent and kinetics of immune-related transplantation injury and rejection (201). The chemokines are classified into two major groups based on their structure: the cysteine-X-cysteine (CXC) or alpha chemokines (e.g., IL-8 and IFN-g-inducible protein), which primarily attract neutrophils and T-cells, and the CC or beta chemokines (e.g., macrophage inflammatory protein-1a/b (MIP-1a/b, RANTES and MCP-1), which attract T-cells, monocyte/macrophages, dendritic cells, natural killer cells, and some polymorphs. Chemokines orchestrate the trafficking of leukocytes to sites of inflammation. Chemokines and their receptors are important in the development of graft infiltrates as well as in reperfusion injury. They act not only as attractants for various leukocyte populations but also by augmenting the effector functions of leukocytes within the graft.

Migration of Activated Leukocytes into the Graft To enter the site of inflammation or immune response, leukocytes must migrate across the vascular endothelium. This migration process is controlled by the elaboration of chemokines and by cell–cell interactions between leukocytes and the endothelium. The adhesion of leukocytes to the endothelium is a complex multistep process that involves a series of interactions between the surface of the leukocyte and the endothelial cell or its extracellular matrix (202). Activated cells bear adhesion proteins, chemokine receptors, and addressins, which allow homing to and migration into the graft. The expression of many adhesion proteins involved in these interactions is upregulated by proinflammatory cytokines. Ischemic damage alone results in increased expression of several cytokines, and of these, IL-1 upregulates the expression of members of the selectin family. Other adhesion proteins such as ICAM-1, VCAM-1, and E-selectin (endothelial-specific selectin) are known to be upregulated by the type of cytokines also induced after the trauma of transplantation. Antigen-activated lymphocytes may show tissue-specific homing and show preference for sites in which they are most likely to reencounter their specific antigen. This process seems to be facilitated by recognition by the T-cell of MHC class II/peptide complexes on the vascular endothelium. It may be possible to hide the proteins

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involved in leukocyte extravasation, thereby slowing or preventing the rejection process. Blocking the adhesion proteins by using antibodies or inhibiting their expression has been attempted in experimental and clinical transplantation. In general, cocktails of antibodies are more potent than single antibodies.

Destruction of the Graft The immune system generates many different effector mechanisms, most of which are involved in the destruction of the graft. Patients who have been exposed to MHC antigens through transplant, blood transfusions, or pregnancy often develop antibodies reactive to those MHC antigens. These antibodies can cause hyperacute rejection. The conventional cross-match test, however, detects not only harmful MHC-directed cytotoxic antibodies, but also harmless autoantibodies. In most cases, it is now possible to distinguish autoreactive from alloreactive antibodies, and it is now possible to transplant patients across an apparent positive crossmatch, but in whom the reactivity is due to autoantibodies. Many of the changes associated with acute rejection, including arteriolar thrombosis, interstitial hemorrhage, and fibrinoid necrosis of the arteriolar walls, may result from the deposition of antibody and fixation of complement. MHC-mismatched lymphocytes proliferate and produce cytokines that allow the differentiation of precursor CTLs into effector cells that lyse target cells bearing the mismatched MHC antigens. Furthermore, through the elaboration of high levels of IFN-g and other cytokines or chemokines, CTLs are able to recruit and activate cells involved in delayed type hypersensitivity (DTH) lesions, initiating acute or chronic rejection. Macrophages also participate by elaborating proinflammatory and profibrogenic cytokines that may result in the atherosclerotic and fibrotic changes associated with chronic rejection.

Renal Injury During Transplantation Injury to the kidney frequently occurs during transplantation and often manifests clinically as delayed graft function (DGF) (Table 16) (203) or transplant acute tubular necrosis (TxATN). This injury can occur at many stages and also has short- and long-term consequences for the graft. Factors that participate in renal injury include donor hypertension and aging; brain death in the cadaveric donor; injury arising from harvesting, preservation, and implantation; prolonged warm ischemic time; and anastomosis time or rewarm time. The pathology of transplant ATN is not identical to that of native kidney ATN. The extent of tubular necrosis is usually more widespread in transplant ATN, which may be related to the presence of endothelial injury and disseminated intravascular coagulation (DIC) in the brain-dead donor as well as the exposure of the transplant kidney to cold flush and storage. Ischemia/reperfusion injury causes direct injury to the kidney, but also induces an inflammatory response during the phase of healing. Delayed graft function is associated with an increased rate of acute rejection and irreversible graft rejection. Transplant ATN adversely affects survival, while total preservation time and sharing between centers do not predict transplant ATN. Transplant ATN is associated not only with graft loss, but also with patient death and irreversible rejection. These adverse effects of DGF are manifested in the first six months. Pulsatile perfusion is associated with a reduction in DGF. In this era of stronger and improved immunosuppressive therapy, DGF is assuming greater

Table 16 Differential Diagnosis of Delayed Graft Function Prerenal azotemia (e.g., hemorrhage, overdiuresis) Acute tubular necrosis Urologic complications Ureteral anastomotic obstruction Obstruction of the bladder catheter Urine leak, urinoma Vascular complications Hemorrhage Renal artery thrombosis Renal vein thrombosis Renal artery stenosis Calcineurin inhibitor nephrotoxicity (cyclosporine, tacrolimus) Vasoconstriction Thrombotic microangiopathy Other nephrotoxic agents Amphotericin B Aminoglycosides Acyclovir Contrast media Angiotensin-converting enzyme inhibitors Nonsteroidal anti-inflammatory drugs Infection Septicemia Graft pyelonephritis Cytomegalovirus infection Acute rejection Recurrent disease Focal segmental glomerulosclerosis Hemolytic uremic syndrome Other glomerulopathies

importance in graft outcomes. Risk factors for DGF include anastomosis time, total preservation time, black race, donor cerebrovascular accidents, as well as immunological variables such as panel reactive antibodies (PRAs), donorrelated mismatches, and high cytotoxic antibodies. The failure of DGF to recover usually represents severe rejection in an injured transplant. The worst one-year survival rate is recorded in grafts that had both DGF and acute rejection. Evidence suggests that DGF causes an increased frequency of acute rejection, and the real cause of the impaired graft survival is the rejection. Living donor kidneys with extensive HLA mismatching have excellent graft survival, perhaps lacking the injury associated with brain death and prolonged cold storage that accompanies cadaver donation. Several renal syndromes may affect the transplanted kidney (Table 17).

Allograft Rejection Hyperacute rejection is characterized by the sudden, irreversible cessation of graft function minutes to hours after revascularization. Preformed antibodies against donor Table 17 Renal Syndromes Affecting the Transplanted Kidney Hyperacute rejection Accelerated rejection Acute rejection Delayed graft function/transplant acute tubular necrosis Cyclosporine nephrotoxicity Chronic allograft nephropathy Chronic rejection De novo glomerulopathy Recurrent glomerulopathy

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antigens present on the endothelium mediate this form of rejection (204). One setting for hyperacute rejection is ABO incompatibility, wherein circulating antidonor ABO blood group hemagglutinins bind to glycolipid determinants on endothelial cells. A second setting is the attachment of preformed recipient antidonor HLA antibodies to the vascular lining of the graft. Histologically, there is extensive glomerular and vascular thrombosis. However, routine pretransplant cross-match testing minimizes the risk of hyperacute rejection. Accelerated rejection is characterized by anamnestic responses that occur within five days posttransplant. These responses may include the production of generally lowaffinity antidonor antibodies by presensitized B-cells or the generation of CTLs from memory elements. The immune elements bind to the donor endothelium without the involvement of complement (Type II endothelial activation), leading to disruption of the vascular layer and interstitial hemorrhage. Parenchymal rupture may result in acute pain, tenderness, and swelling of the graft and life-threatening hemorrhage. Accelerated rejection is uncommon with current immunosuppressive strategies, and can often be reversed by antilymphocyte globulin (ALG), plasmapheresis, and cyclophosphamide. Acute rejection is the most common type of rejection in clinical practice, affecting up to 40% of patients. It usually occurs between 7 and 90 days posttransplant, but it may occur later. In the early posttransplant period, there is the activation of alloantigen-specific T-cells, which initiate acute rejection or subclinical graft injury (197). It is often responsive to steroid therapy, but sometimes there is an antibody component, in which cases there is resistance to steroids and a partial response to ALG. Histologically, acute rejection is characterized by intimal arteritis and tubulitis (205). Uncontrolled acute rejection can result in graft swelling, vascular occlusion, and necrosis. Acute rejection episodes that are not completely reversed (to serum creatinine < 1.6 mg/dL) increase the probability of graft loss. Chronic rejection occurs in about half of all renal allografts within 10 years. In contrast to acute rejection, chronic rejection does not respond to immunosuppressive therapy (206). Histopathologically, there is arterial narrowing and hyalinization and interstitial fibrosis. Chronic kidney rejection is often associated with the presence of antidonor antibodies, which correlates with the presence of arterial hyalinization. In addition to these antigen-dependent factors, the development of chronic rejection seems to be influenced by nonimmunological factors associated with ischemia/reperfusion injury, including evidence of cardiovascular compromise in the donor, prolonged cold ischemia time prior to transplantation, and impaired RBF in the recipient. The incidence of chronic rejection may be minimized by aggressive treatment of acute rejection episodes with the goal of achieving complete resolution (207); the use of surveillance biopsies to diagnose subclinical rejection, which if treated could result in better long-term outcomes; matching of HLA antigens; effective maintenance immunosuppression; and vigorous control of hypertension, hyperlipidemia, and diabetes mellitus.

Late Graft Dysfunction In addition to chronic rejection, several disorders can potentially cause graft dysfunction remote from the time of initial transplant: recurrent primary disease, infectious, calcineurin inhibitor–related, and mechanical disorders. Some primary

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renal diseases recur at a high and predictable rate and may be a relative contraindication to transplantation (e.g., oxalosis). Others recur at a rate that is acceptable for transplantation but sufficient to be seriously considered as a differential diagnosis of late graft dysfunction (e.g., hemolytic uremic syndrome and diabetes mellitus). Immunoglobulin A nephropathy recurs in up to 50% of cases, but is rarely a cause of graft dysfunction. Membranoproliferative glomerulonephritis (especially Type I) also recurs but also rarely causes graft dysfunction. Recurrent focal segmental glomerulosclerosis can occur within minutes of establishing the transplant arterial anastomosis. Acute urinary tract infections may be complicated by transplant pyelonephritis causing allograft dysfunction. Fever, graft tenderness and swelling, rising serum creatinine, and high-ultrasound resistive indices resemble acute graft rejection. Cytomegalovirus (CMV) infection in its most common form presents with fever, malaise, leukopenia, pancytopenia, myalgia, and occasionally renal dysfunction. More severe forms include pulmonary infiltrates, respiratory failure, hepatitis, and renal failure. CMV may directly involve the graft and cause a CMV glomerulopathy (208). The calcineurin inhibitors, cyclosporine and tacrolimus, are nephrotoxic. Chronic interstitial fibrosis in a striped pattern is the classic histologic finding in chronic calcineurin inhibitor nephropathy. Finally, obstructive uropathy can occur by mechanisms that afflict native kidneys, including renal stone disease, but also those peculiar to the transplanted kidney, including ureteral anastomotic stenosis, lymphoceles, and BK virus infection.

Evaluation and Selection of the Living Donor The living donor evaluation begins with education regarding the process of evaluation and donation, followed by a thorough history, physical examination, and psychosocial evaluation. A comprehensive laboratory screening is performed, including complete blood count, chemistry panel, HIV, HBsAg, antihepatitis C virus, CMV, glucose tolerance test (for diabetic families), urinalysis, urine culture, pregnancy test, and two 24-hour urine determinations for creatinine clearance and protein excretion. Chest X ray, electrocardiogram, and exercise treadmill test are performed for patients aged 50 years and older. Psychosocial evaluation, and intravenous pyelogram, renal angiogram, and/or helical CT urogram are performed. Potential donors are tissue typed and cross-matched. Prospective donors are generally excluded if they are less than 18 or more than 65 years of age, or have hypertension, diabetes, proteinuria, reduced GFR, microscopic hematuria, urologic abnormalities, or significant medical or psychiatric conditions (including active substance abuse).

Evaluation of Prospective Kidney Transplant Recipients An extensive pretransplant evaluation of the prospective recipient is performed to detect and treat reversible medical and surgical conditions that might increase the risk of transplantation if left untreated. Ischemic heart disease substantially increases the risk of transplantation. Cancer screening is directed at common cancers for the age group and gender. Screening for colorectal malignancy is accomplished with a stool occult blood test as well as sigmoidoscopy or colonoscopy in older patients. Chest X rays are used to screen for lung cancer. Digital prostate exam and possibly prostatespecific antigen determinations are performed to detect prostate cancer. Women should undergo pelvic exam and a

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Table 18 Contraindications to Renal Transplantation Disseminated malignancy Refractory cardiac failure Chronic respiratory failure Advanced hepatic disease Extensive vascular disease: coronary, cerebral, or peripheral Severe congenital urinary tract abnormality Chronic infection, refractory to therapy Persistent coagulation disorder Severe mental retardation Psychosocial problems: severe psychosis, alcoholism, or drug addiction

Pap smear. Women over 40 years or younger women with a family history of breast cancer should have a mammogram. In patients with a history of cancer, it is generally recommended that a two-year interval for the most invasive cancers elapse before transplantation. Smoking cessation should be accomplished. Screening for esophagitis and peptic ulcer disease can be reserved for patients with symptoms. Evidence for tuberculosis, CMV, or HIV infection should be established. Pulmonary function studies may be indicated in patients with chronic lung disease. Urologic evaluation can generally be reserved for patients with chronic bladder dysfunction or recurrent infection. Renal ultrasound, computerized tomography, or magnetic resonance imaging study is probably needed to screen for renal malignancies or other structural problems. Psychosocial evaluation is obtained to ensure that the patient is capable of providing informed consent and can comply with the posttransplant immunosuppression regimen. Despite these potential contraindications (Table 18), selection criteria are generally less restrictive than in past, and more patients with significant comorbidity and older patients are receiving renal transplants. The donor and recipient should be ABO blood group compatible and have no preformed antibodies. Antibodies directed against a random panel of lymphocytes from the general population are assayed, and the percentage of these lymphocytes that incite a reaction from the recipient— termed the percent PRA—is measured. Transplant recipients with a high PRA are more likely to have preformed antibody against a donor kidney and thus more susceptible to hyperacute rejection. When a potential donor kidney becomes available, the recipient’s serum is tested for reaction against cells from the potential donor. If the potential recipient’s serum reacts with the donor, transplantation is usually contraindicated. MHC antigens are also measured on cells from both the donor and the recipient. In the United Network for Organ Sharing protocol for organ allocation, highest priority is given to kidneys with no MHC antigen mismatches. Because the average waiting time currently exceeds two years, periodic reevaluation of the recipient may be needed in the interval.

Immunosuppressive Agents The search for the optimal chronic immunosuppression regimen for renal transplant patients continues to evolve as new immunosuppressive agents are introduced and new combinations of therapies tried. All of these agents have therapeutic effects, toxicities related to immunodeficiency (i.e., increased infection and malignancies), and nonimmune toxicities (e.g., nephrotoxicity, hyperlipidemia, and diabetes). The initial period after transplantation requires intense immunosuppression. During the ‘‘induction’’ period, high doses of combinations of calcineurin inhibitors,

mycophenolate mofetil (MMF), rapamycin, or azathioprine, and glucocorticoids are often used. The reversal of acute rejection also requires intense immunosuppression with high doses of glucocorticoids, but also in more severe cases, with anti-CD3 of polyclonal ALG or ATG. Maintenance immunosuppression can generally be achieved after three to six months, and now usually involves cyclosporine or tacrolimus in combination with MMF, rapamycin or azathioprine, and/or steroids. However, drug regimens and treatment guidelines are constantly evolving. Corticosteroids downregulate the expression of several genes that encode for inflammatory cytokines, inhibit leukocyte migration to sites of inflammation, promote apoptosis of lymphocytes and eosinophils, and reduce expression of MHC class II molecules, thereby inhibiting T-cell activation and function. Azathioprine blocks RNA and DNA synthesis by inhibiting inosinic acid, the precursor for the purines adenylic and guanidylic acids. Chlorambucil and cyclophosphamide alkylate DNA and interfere with DNA metabolism. These compounds are cytotoxic to lymphocytes and are thus immunosuppressive. The cytotoxic effects of these compounds are not limited to the immune system; however, they have a wide range of side effects (e.g., anemia, leukopenia, thrombocytopenia, intestinal damage, and hair loss) that may limit the dosage and duration of therapy. Cyclosporine and tacrolimus exert their pharmacologic effects by inhibiting the activity of calcineurin, an intracellular phosphatase essential for transcriptional activation of IL-2 gene, and ultimately T-cell activation. In contrast, sirolimus inhibits a different pathway required for full T-cell activation by blocking the phosphorylation of p70(s6) kinase and the eukaryotic initiation factor-4E-binding protein, PHAS-1 (209). Cyclosporine is effective before transplantation, but is ineffective in suppressing ongoing rejection. Both cyclosporine and tacrolimus are nephrotoxic and associated with a higher risk of cancer in patients who take the drugs long term. Sirolimus is minimally nephrotoxic when given alone; thrombocytopenia and severe dyslipidemia are its major side effects. Leflunomide blocks T-cell activation by inhibiting the activity of tyrosine kinases associated with cytokine receptors. This agent also prevents T-cell proliferation by inhibiting de novo pyrimidine synthesis (210). ALG, prepared in horses immunized with human lymphocytes, has been used to treat acute rejection. It can cause serum sickness. Monoclonal antibodies are less immunogenic than ALG and can be more specifically targeted. OKT3 is a ‘‘humanized’’ mouse antibody directed against CD3 that is in common use. Antibodies to the IL-2 receptor (CD25) on activated T-cells, and to CD4 are also in use. MMF inhibits the de novo synthesis of purines, crucial to cell cycling of T- and B-cells. It thus blocks clonal expansion of T- and B-cells, preventing antibody production and the generation of CTLs, as well as other effector T-cells (211). In contrast to other immunosuppressive drugs, MMF also inhibits antibody production by B-cells. There seems to be a trend toward better graft survival at three years post-transplant (211).

Complications of Renal Transplantation Transplant patients are at risk of numerous medical and surgical complications (Table 19). Infectious complications, arising mainly as a result of immunosuppressive therapy, are among the most common and significant. Infections may be classified according to duration after transplantation, or by organism or system involved. The main risk factors for

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Table 19 Complications of Renal Transplantation

SUMMARY AND CONCLUSIONS

Surgical complications

The kidney is an extremely complex organ with tightly integrated functions that are critically involved in the maintenance and restoration of normal physiology of humans over a wide range of clinical conditions. Perhaps more than any other organ, the physiology and pathophysiology of the kidney is directly tied to numerous, significant clinical disorders. The kidney is vulnerable to both acute and chronic injury, which poses a multitude of potential problems for the management of fluid, mineral, electrolyte, acid–base, and metabolic balance, blood pressure, and anemia, particularly in critically ill surgical patients experiencing acute renal decompensation or in ESKD patients undergoing surgery. The trend toward increasingly aggressive resuscitation and life support measures, growing numbers of trauma victims, and the growth in the rate of surgical procedures performed on patients with significant comorbidities will continue to increase the incidence of AKF in the surgical setting. Given the explosive growth in the incidence rates for CKD and ESKD, surgeons will also encounter an increasing proportion of patients with chronically impaired renal function presenting for surgical interventions of other organ systems. Unfortunately, no therapies to date have been shown to reverse renal injury, so that emphasis must be placed on prevention, early detection, prompt correction of precipitating, contributing, or exacerbating factors, and appropriate timing and choice of renal replacement therapy when indicated. Fortunately, continuous dialysis therapies are evolving, which will continue to facilitate advanced therapeutic options for critically ill surgical patients with AKF, and advances in kidney transplantation have allowed it to become applicable to a much broader population of ESKD patients. The Holy Grail, of course, remains the discovery of methods for therapeutic recovery of renal function.

Medical complications

Urologic Cardiovascular Obstruction Coronary artery disease Stricture Hypertension Edema Metabolic Blood clot Hyperparathyroidism Stone Hyperkalemia Excess ureter redundancy Hypomagnesemia Tumor Hyperuricemia and gout Infection (fungus ball, viral) Posttransplant diabetes mellitus Indwelling ureteric stent Hepatic Fluid collections Viral hepatitis (hepatitis B and C) Lymphocele Drug-induced liver dysfunction (e.g., Hematoma cyclosporine, azathioprine, and, Urinoma rarely, mycophenolate mofetil; Abscess antimicrobials) Urine leaks Hematologic Calyceal Anemia Renal pelvic Polycythemia (usually associated Ureteral with transplant renal artery stenosis) Leukopenia (azathioprine, mycophenolate Ureteroneocystostomy mofetil, ganciclovir, and Vesical cytomegalovirus infection) Vascular Infectious Renal artery thrombosis Intravenous catheter associated Renal artery stenosis Pulmonary Renal vein thrombosis Gastrointestinal infections Complications of Central nervous system infections percutaneous Neurologic allograft biopsy Diffuse encephalopathies Arteriocalyceal fistulas Focal neurological disorders Arteriovenous fistulas Seizure disorders Iliac or mesenteric Peripheral nerve disorders vascular Cancer lacerations Skin cancers Perirenal hematomas Posttransplant lymphoproliferative disease Pseudoaneurysms Sarcomas Gross hematuria Carcinomas of the vulva, anus, cervix, liver Intra-abdominal organ injury

infection are immunosuppressive therapy, the immunocompromised state of uremia, and major surgery involving urologic and vascular procedures. Other risk factors include DGF and acute rejection, hyperglycemia, diabetes, splenectomy, and hepatitis B infection. Infections may be transmitted from the donor. Pretransplant screening for infections is critical as are prophylactic measure post-transplant. The timing of infections posttransplant is of diagnostic importance. Infections within the first month posttransplant are associated with the surgical procedure, usually bacterial infections of the urinary tract, respiratory tract, perinephric space, surgical wound, and vascular access sites (line sepsis). Herpes simplex virus (HSV) infections may occur at this time. From one to six months, the most common infection is due to CMV; other infectious agents during this interval include opportunistic organisms such as pneumocystis carinii, cryptococcus, aspergillus and other fungal infections, nocardia, toxoplasma, listeria, nontyphoid salmonella, tuberculosis, and viral infections, including primary or reactivated CMV, Epstein–Barr virus (EBV) varicella-zoster virus, and adenovirus. After six months, communityacquired infections predominate. Persistent viral infections (e.g., CMV, HSV, EBV, hepatitis B and C, and HIV) can assume great importance in the transplant patients.

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Chapter 37: Urine Formation: From Normal Physiology to Florid Kidney Failure 164. Okadome K, Komori K, Fukumitsu T, Sugimachi K. The potential risk for subclavian vein occlusion in patients on haemodialysis. Eur J Vasc Surg 1992; 6:602–606. 165. Akoh JA. Central venous catheters for haemodialysis: a review. Niger Postgrad Med J 2001; 8:99–103. 166. Saad TF. Central venous dialysis catheters: catheter-associated infection. Semin Dial 2001; 14:446–451. 167. Kovalik EC, Schwab SJ. Treatment approaches for infected hemodialysis vascular catheters. Curr Opin Nephrol Hypertens 2002; 11:593–596. 168. Berns JS. Infection with antimicrobial-resistant microorganisms in dialysis patients. Semin Dial 2003; 16:30–37. 169. Kuti J. Antibiotic treatment of catheter-related bacteremia in the hemodialysis patient. Conn Med 2003; 67:85–88. 170. Sandroni S, McGill R, Brouwer D. Hemodialysis catheterassociated endocarditis: clinical features, risks, and costs. Semin Dial 2003; 16:263–265. 171. Cooper SG, Sofocleous CT. Dialysis access. Semin Roentgenol 2002; 37:327–342. 172. Konner K. Vascular access in the 21st century. J Nephrol 2002; 15(suppl 6):S28–S32. 173. Brescia MJ, Cimino JE, Appel K, Hurwich BJ. Chronic hemodialysis using venipuncture and a surgically created arteriovenous fistula. N Engl J Med 1966; 275:1089–1092. 174. Burkhart HM, Cikrit DF. Arteriovenous fistulae for hemodialysis. Semin Vasc Surg 1997; 10:162–165. 175. Paulson WD, Ram SJ, Zibari GB. Vascular access: anatomy, examination, management. Semin Nephrol 2002; 22:183–194. 176. NKF-DOQI clinical practice guidelines for vascular access. National Kidney Foundation-Dialysis Outcomes Quality Initiative. Am J Kidney Dis 1997; 30:S150–S191. 177. Santoro TD, Cambria RA. PTFE shunts for hemodialysis access: progressive choice of configuration. Semin Vasc Surg 1997; 10:166–174. 178. Nassar GM, Fishbane S, Ayus JC. Occult infection of old nonfunctioning arteriovenous grafts: a novel cause of erythropoietin resistance and chronic inflammation in hemodialysis patients. Kidney Int 2002; 80(suppl):49–54. 179. Konner K. Increasing the proportion of diabetics with AV fistulas. Semin Dial 2001; 14:1–4. 180. Cynamon J, Pierpont CE. Thrombolysis for the treatment of thrombosed hemodialysis access grafts. Rev Cardiovasc Med 2002; 3(suppl 2):S84–S91. 181. Levin R, Hoenich NA. Running water: measuring water quality in a dialysis facility. Part 2. Nephrol News Issues 2003; 17:25–26, 78. 182. Levin R, Miller L. Running water: designing the dialysis clinic water room. Part 1. Nephrol News Issues 2003; 17:65, 68–70. 183. Oreopoulos DG. Beyond Kt/V: redefining adequacy of dialysis in the 21st century. Int Urol Nephrol 2002; 34:393–403. 184. I. NKF-K/DOQI Clinical Practice Guidelines for Hemodialysis Adequacy: update 2000. Am J Kidney Dis 2001; 37:S7–S64. 185. DOQI guidelines/fourth in a series. Adequacy HD dose, reuse, compliance. NKF-Dialysis Outcomes Quality Initiative. Nephrol News Issues 1997; 11:52–53. 186. NKF-DOQI clinical practice guidelines for hemodialysis adequacy. National Kidney Foundation. Am J Kidney Dis 1997; 30:S15–S66. 187. Gibney RT, Kimmel PL, Lazarus M. The Acute Dialysis Quality Initiative—part I: definitions and reporting of CRRT techniques. Adv Ren Replace Ther 2002; 9:252–254. 188. Ronco C, Bellomo R. Continuous renal replacement therapy: evolution in technology and current nomenclature. Kidney Int Suppl 1998; 66:S160–S164.

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38 Urinary Tract Obstruction J. Robert Ramey and Deborah T. Glassman

cells are connected via intermediate junctions (2,3), producing a functional syncytium (4) that allows the conduction of electrical signals down the ureter. Specialized pacemaker cells are found at the pelvicalyceal junction (5). Action potentials generated by these cells are propagated downstream via diffusion. These waves of depolarization produce peristaltic contractions of the renal pelvis and ureter, which serve to propel urine into the bladder (4).

INTRODUCTION Urinary tract obstruction may result from numerous etiologies and at various levels within the urinary system. Sources may be congenital or acquired, benign or malignant. Moreover, patients’ presenting symptoms will vary not only by the location of obstruction, but also with the time course over which the blockage has developed. This chapter systematically addresses the physiologic alterations to renal and bladder function that result from obstruction of normal urinary flow, the pathologic processes that may produce obstruction, and the varied options for restoring proper drainage of the urinary tract.

Unilateral vs. Bilateral Ureteral Obstruction Complete unilateral ureteral obstruction (UUO) has been well studied in a variety of animal models and produces consistent alterations in renal hemodynamics and ureteral function (6–8). There is a triphasic response consisting of an acute increase in both renal blood flow (RBF) and ureteral pressure resulting from preglomerular vasodilation followed by a period of decreasing RBF, during which ureteral pressures remain elevated. Chronically, both ureteral pressure and RBF are maintained at below normal levels secondary to preglomerular vasoconstriction (6,9). These changes are mediated by intrarenally produced prostaglandins, with prostaglandin E (PGE2) producing the initial vasodilation and thromboxane A2 responsible for the subsequent vasoconstriction (10). Bilateral ureteral occlusion (BUO) produces slightly different alterations in RBF as well as ureteral pressure. Initially, rapid increases in both RBF and ureteral pressure occur as with unilateral obstruction; however, unlike UUO, chronic BUO results in decreased RBF with persistently elevated ureteral pressures (10–12). These chronically elevated ureteral pressures are responsible for the reduction in glomerular filtration rate (GFR) during BUO rather than the preglomerular vasoconstriction seen in phase 3 of UUO (12). These divergent responses to BUO and UUO are mediated by elevated levels of atrial natriuretic peptide (ANP) present during BUO, but not UUO (13–15). ANP is secreted in response to atrial stretch that occurs in volume-overloaded states (13). In an unobstructed system, ANP increases GFR by producing afferent arteriolar vasodilation along with efferent arteriolar constriction (16). During BUO, ANP counteracts the thromboxane A2–mediated preglomerular vasoconstriction seen in phase 3 of UUO, while maintaining efferent arteriolar vasoconstriction, thereby producing the elevated ureteral pressures seen with BUO (10,11,13). Chronic obstruction of one or both ureters results in hydroureteronephrosis proximal to the level of obstruction. The degree of dilation that develops varies depending on the duration and degree of obstruction, as well as the anatomy of the collecting system. The ureteral walls become unable to coapt due to the dilation, thus rendering peristaltic contractions ineffective. Subsequently, urine must drain from the obstructed system in a passive fashion via gravity or

THE UPPER URINARY TRACT Normal Physiology of the Renal Pelvis and Ureter The upper urinary tract is a closed drainage system that functions to deliver urine from the kidney to the bladder. It begins at the level of the minor calyces. Each minor calyx receives urine from a single renal papilla and drains via an infundibulum into one of the major calyces (Fig. 1). These major calyces, usually numbering two to three, fuse to form the renal pelvis. The ureter and renal pelvis join at the ureteropelvic junction (UPJ), and the ureter then courses inferiorly through the retroperitoneum to empty into the bladder. These anatomic divisions do not exist on a functional basis; however, they do provide a useful framework for understanding upper tract obstruction (1) and planning correctional interventions. The contractile force that propels each bolus of urine downstream to the bladder is provided by the smooth muscle cells enveloping the mucosa of the upper tract. The smooth muscle of the ureter is arranged into inner longitudinal and outer circumferential layers. Individual

Major calyx

Minor calyces

Renal pelvis Ureteropelvic junction

Ureter

Infundibuli

Figure 1 Anatomy of the renal collecting system.

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pyelovenous backflow (17). Histologically, obstructive nephropathy results in obliterative interstitial fibrosis, with subsequent loss of functional cortex (18).

Presentation and Diagnosis of Upper Tract Obstruction Signs and Symptoms of Ureteral Obstruction The signs and symptoms of upper tract obstruction vary greatly with the time course over which the obstruction occurs. Acute obstruction produces flank pain on the affected side due to distension of the collecting system and renal capsule. The common innervation of the distal urinary tract and genitalia often results in radiation of the pain to the patient’s ipsilateral testicle/labia. Similarly, obstruction in the proximal urinary tract can radiate to the shoulder or across the abdomen due to shared innervation with the gastrointestinal tract. Generally colicky in nature, the pain is often accompanied by nausea and vomiting. Patients are restless and on physical examination have extreme costovertebral angle tenderness on the affected side. If the urine becomes infected, fevers may develop along with bacteremia and even overt sepsis. Gross hematuria may accompany intrinsic obstructing lesions, such as calculi or transitional cell carcinomas. Complete BUO, or UUO of a solitary kidney, will produce anuria. Chronic obstruction often develops asymptomatically. Some patients may have signs of uremia, or vague complaints of lethargy or abdominal discomfort. It may be discovered serendipitously as hydronephrosis seen on abdominal imaging performed for unrelated complaints, or during investigation of previously unrecognized renal failure. Patients may also present with complaints of recurrent urinary tract infections (UTI) or pyelonephritis. Laboratory analysis should include serum chemistries, complete blood count, and urinalysis with culture. Blood urea nitrogen and creatinine allow monitoring of renal function, while leukocytosis may accompany systemic infection. Specific gravity on urinalysis reveals the kidneys’ concentrating ability, while white blood cells and bacteria may indicate a UTI. Crystals may be present on microscopic examination of the urine from patients with renal calculi. Empiric antibiotics may be initiated; however, all infections should be confirmed with a culture.

Diagnostic Studies Renal ultrasonography is often the initial study performed in the evaluation of renal failure. Due to the absence of ionizing radiation, ultrasound is also frequently used during pregnancy and with pediatric patients, as well as for patients with iodinated contrast allergies. It provides anatomic detail of the renal parenchyma and is fairly accurate in detecting the presence of hydronephrosis, especially in the setting of chronic obstruction. However, unless one of the above conditions exists, ultrasound is not the diagnostic study of choice in obstruction because its sensitivity as well as specificity is less than that of intravenous urography (IVU) (19). Duplex Doppler interrogation with calculation of resistive indices improves the ability of ultrasound to diagnose obstruction, yet this technique still falls short of IVU (20). For years, IVU has been the ‘‘gold standard’’ for diagnosing ureteral obstruction, providing both anatomic and functional information. In the setting of acute obstruction, delayed uptake and excretion of contrast by the kidney, along with dilation of the collecting system, are seen. If present, extravasation of contrast indicates the presence of

forniceal rupture. IVU will often reveal cortical thinning, along with a dilated collecting system and tortuous ureter containing a standing column of contrast in chronically obstructed systems (17). Unenhanced computed tomography (CT) scans provide the most sensitive study for the detection of calculi (21,22). Hydroureteronephrosis, perinephric stranding, and periureteral edema indicate the presence of ureteral obstruction (23). CT scans provide excellent anatomic detail of the entire abdomen, and IV contrast may be given following the acquisition of unenhanced images to perform a CT urogram, producing a functional study of the kidneys and making it an ideal study for potentially complex cases. Nuclear medicine renal scans may also be employed in the evaluation of potentially obstructed urinary systems. Using radiolabeled tracers that are given intravenously and excreted by the kidney, the drainage of each system may be assessed by the half-life (t1/2) for tracer transit from renal pelvis to bladder during diuresis. A prolonged t1/2 (more than 20 minutes) is diagnostic of obstruction. Prior to the development and refinement of noninvasive diuretic nuclear renography, the Whitaker test was routinely utilized to demonstrate obstruction. The study is performed by measuring the pressure within the renal pelvis during the infusion of a saline and contrast solution via a percutaneously placed cannula with a Foley catheter in place to drain the bladder. A pressure difference between renal pelvis and bladder greater than 22 cmH2O at a flow rate of 10 cc/min is diagnostic of obstruction. The addition of contrast to the infusate allows fluoroscopic images to be obtained during the study revealing anatomic information regarding the level and degree of obstruction (17). The test remains useful in patients with poor renal function or marked hydronephrosis, because both of these hinder the interpretation of diuretic renograms (24).

Relieving Obstruction Once a renal unit is determined to be obstructed, the physician must decide whether to temporarily drain the system or proceed directly with definitive repair. Indwelling ureteral stents or catheters may be placed endoscopically, while nephrostomy tubes can be inserted percutaneously for temporary relief of ureteral obstruction. Patients with signs of infection should undergo drainage and antibiotic therapy prior to proceeding with definitive repair. Ureteral stents function well in cases of intrinsic obstruction from such etiologies as calculi and strictures; however, in the face of extrinsic compression from retroperitoneal fibrosis (RPF) or malignant lesions, percutaneous nephrostomy tubes usually provide more reliable drainage (25).

Etiologies of Upper Urinary Tract Obstruction Numerous processes may ultimately result in either UUO or BUO. Table 1 lists various sources of urinary tract obstruction, while Figure 2 depicts the locations of common lesions. Determining whether obstruction is due to extrinsic compression or internal blockage is vital in planning definitive correction. The following section addresses some of the more common sources of ureteral occlusion and the surgical options for management.

Extrinsic Compression Retrocaval Ureter During normal embryologic development, the infrarenal inferior vena cava (IVC) arises from the supracardinal vein.

Chapter 38:

Table 1 Common Causes of Urinary Obstruction Intrinsic diseases of the urinary tract

Extrinsic obstruction of the ureter

Congenital disorders Vascular lesions Ureteropelvic junction lesions Accessory vessels Primary megaureter Aortic, Iliac aneurysms Ectopic ureter Ovarian vein syndrome Ectopic ureterocele Circumcaval (retrocaval) ureter Neuropathic bladder disease Pelvic and retroperitoneal masses Urethral valves Pregnancy Detrusor-sphincter dyssynergia Enlarged uterus—benign, malignant Ureteral dysplasia (prune-belly disorders syndrome) Hydrometrocolpos Ovarian lesions Metabolic and inflammatory disorders Embryologic remnants (cysts of Urinary calculi Gartner’s duct) Blood clots Pelvic and retroperitoneal tumors, Fungus balls primary and metastatic Sloughed papillae (papillary Pelvic lipomatosis necrosis) Lymphocele Renal, ureteral, or vesical Uterine prolapse tuberculosis Inflammatory diseases Urethral strictures Retroperitoneal fibrosis Prostatic inflammatory diseases Retroperitoneal abscess Meatal stenosis Retroperitoneal hemorrhage Foreign body Tubo-ovarian abscess; pelvic inflammatory disease Neoplastic disorders Appendiceal or diverticular abscess Benign prostatic hyperplasia Endometriosis Renal pelvic and ureteral tumors Bladder tumors Granulomatous (Crohn’s) disease Prostatic tumors of the bowel Urethral tumors Traumatic disorders Ureteral stricture (postsurgical) Urethral stricture

When this segment forms from the subcardinal vein instead, a portion of the ureter comes to lie in a retrocaval position where the IVC exerts extrinsic compression producing partial obstruction. Contrast-enhanced CT scan is the study of choice for evaluation of this anomaly. Surgical correction involves transection of the ureter with reanastomosis anterior to the IVC, though cases with severe obstructive nephropathy and a nonfunctional kidney may require nephrectomy (26).

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has been established pathologically, definitive therapy may be initiated. Surgical ureterolysis provides the best longterm results for correction of ureteral obstruction (29). Successful medical management utilizing corticosteroids (30) and tamoxifen has been reported in patients who are poor surgical candidates (28,31–33). Long-term indwelling ureteral stents or nephrostomy tubes may be employed for relief of obstruction in patients unfit for surgery. Malignancy Various malignancies may produce ureteral obstruction via extrinsic compression from the primary tumor (carcinoma of the prostate, cervix, ovaries, or bladder) or retroperitoneal lymphadenopathy due to metastatic disease (leukemia, lymphoma, and testicular neoplasm). Regardless of tumor origin, malignant ureteral obstruction portends a poor prognosis because median survival is less than seven months (34). Percutaneous nephrostomy tube placement is often required for palliation of malignant obstruction, because more than half of patients with pelvic malignancies will fail internal drainage with ureteral stents (25).

Intrinsic Obstruction UPJ Obstruction Obstruction at the UPJ may present at any age, though it represents the most common cause of upper urinary tract obstruction in children (35). Patients frequently complain of flank pain that may be intermittent or chronic in nature. Additionally, there may be a history of UTI or stones. The etiology of UPJ obstruction (UPJO) remains an area of some dispute with both congenital and acquired conditions implicated (36). IVU and diuretic renal scan are typically utilized in the diagnosis and treatment planning of UPJO (37). Surgical correction via open pyeloplasty has a 90% success rate, while antegrade endopyelotomy via percutaneous nephrostomy tract produces equivalent results initially (37). Advances in ureteroscopic and laparoscopic instrumentation and techniques have allowed these minimally invasive approaches to yield similar success without the morbidity of open incisions or nephrostomy tubes (36,38).

Arterial Aneurysm Acquired aneurysmal lesions of the abdominal aorta and iliac arteries may also result in ureteral obstruction. Perianeurysmal fibrosis involving the ureter produces occlusion of the lumen (27). CT scan is a valuable tool to evaluate the ureter’s anatomic relationship to vascular structures prior to surgery. If necessary, ureterolysis may be performed prior to aneurysm repair, or concomitantly (17).

Ureteral Stricture Ureteral strictures may develop in response to numerous insults including ischemia, instrumentation, radiation, and calculi. While a diuretic renogram confirms obstruction, it does not provide anatomic detail as to the length or level of the stricture. This information is easily obtained with either an IVU or retrograde pyelogram. Distal and midureteral strictures may be managed endoscopically with balloon dilation or endoluminal incision. Mid-ureteral strictures occasionally require ureteroureterostomy, while distal lesions not amenable to minimally invasive techniques can be corrected via ureteroneocystotomy.

Idiopathic Retroperitoneal Fibrosis RPF is a benign inflammatory process that produces an intense fibrotic infiltrate that may encompass and compress one or both ureters, and the great vessels. Radiographic imaging will reveal a large retroperitoneal mass in addition to hydronephrosis. Excretory urography (IVU or CTurogram) often reveals medial deviation of the involved ureter(s) (28). Biopsy of the mass to rule out malignancy should be performed. This may be accomplished surgically via either an open or laparoscopic approach, or percutaneously under CT or ultrasound guidance (17). Once the diagnosis of RPF

Calculi When a given solute reaches supersaturation in the urine, it precipitates out of the solution, forming a calculus. Calcium stones are most common, but uric acid, struvite, and cystine stones are also seen in humans. A nonenhanced helical CT scan is the study of choice when considering the diagnosis of stone disease (21,22), because it provides details regarding the size, location, and number of stones, all vital information for planning intervention. Extracorporeal shock wave lithotripsy (ESWL) produces excellent results for renal stones less than 2.0 cm, and proximal ureteral stones less than

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Figure 2 (A) Causes of upper urinary tract obstruction. (B) Causes of lower urinary tract obstruction. Source: Courtesy of J. N. Corriere Jr., from Chapter 43 in the Second Edition.

1.0 cm that do not pass spontaneously (39). Distal ureteral calculi, proximal calculi larger than 1.0 cm, and residual fragments from calculi previously treated with ESWL should be treated with ureteroscopic lithotripsy, because patients undergoing ESWL in these cases are more likely to require multiple procedures to be rendered stone free (39,40).

THE LOWER URINARY TRACT Normal Anatomy of the Urinary Bladder and Urethra The detrusor muscle of the bladder overlies a transitional cell mucosa. Its myofibrils are arranged into fasicles oriented in random directions, in contrast to the more organized smooth muscle of the ureter (41). At the lateral aspect of the bladder base, the ureters tunnel through the detrusor obliquely, producing functional antireflux valves. The ureteral orifices then open into the bladder at the posterolateral corners of the trigone. Arising from the bladder neck, the urethra extends to the external meatus. In women, the urethra is relatively short and runs within the distal one-third of the anterior vaginal wall, while the male urethra covers a much longer

course and is comprised of four segments: prostatic, membranous, bulbous, and penile urethra. The smooth muscle of the urethra is arranged into a thick inner layer of longitudinal fibers and a sparse outer layer of circumferential muscle (42). The external sphincter also encircles the urethra; however, it comprises striated muscles and is thus under volitional control.

The Micturition Cycle The intact bladder provides a highly compliant reservoir for urine storage during the filling phase of the micturition cycle. Emptying requires the coordination of detrusor contraction with relaxation of the internal and external sphincters. The pons, located within the brainstem, houses the micturition center responsible for organizing the normal voiding reflex. Spinal sympathetic and somatic reflex arcs are initially inhibited producing relaxation of the internal and external sphincters, respectively. Parasympathetic stimulation subsequently results in the coordinated contraction of the detrusor leading to complete emptying of the intact, unobstructed lower tract (43). Thus, pathologic processes that increase resistance to the outflow of urine or decrease bladder contractility may result in voiding dysfunction. The

Chapter 38:

remainder of this chapter focuses on the diagnosis and treatment of common lesions that produce increased resistance to urine flow, and thus lower urinary tract obstruction.

Bladder Outlet Obstruction Benign Prostatic Hyperplasia As men age, the prostate gland undergoes hyperplasia, with the prevalence of benign prostatic hyperplasia (BPH) increasing from 0% in those below 30 years of age to 88% in men in their 80s (44). Common complaints include urinary frequency and urgency, hesitancy and intermittency of urinary stream, incomplete voiding, and nocturia. This symptom cluster is frequently referred to as the lower urinary tract syndrome, or LUTS. Traditionally, patients with enlarged prostates and significant LUTS have been treated with transurethral resection of the prostate (TURP). However, over the past decade, this ‘‘gold standard’’ has been challenged by the introduction of medical therapies and novel surgical procedures. Medical therapies target alpha1-adrenergic receptors in the smooth muscle of the prostate and bladder neck or the 5-alpha-reductase enzyme. Alpha-blockers relax the smooth muscle within the prostate, prostatic capsule as well as periurethral fibers, thereby decreasing outlet resistance. Meanwhile, 5-alpha-reductase inhibitors prevent the conversion of testosterone to dihydrotestosterone (DHT), the principal active androgen in the prostate. Reduced DHT levels result in decreased prostate volume with long-term therapy (45). Various transurethral techniques have also been introduced to challenge TURP. All aim to produce equivalent reduction in LUTS, with decreases in TURP-associated morbidities (bleeding, infection, and hospitalization). Radio frequency [transurethral needle ablation (TUNA)], microwave energy [transurethral microwave thermal therapy (TUMT)], and various laser media have been utilized to destroy hyperplastic prostate tissue in a minimally invasive fashion (45,46). Smaller glands (prostate volume < 50–60 cc) may be treated effectively with transurethral incision (TUI), rather than formal resection (46). Prostate glands larger than 80 cc may best be treated with open simple prostatectomy.

Bladder Neck Contracture Resection of the prostate via open or endoscopic techniques may result in scarring and contracture of the bladder neck, which subsequently produces bladder outlet obstruction (BOO). Bladder neck contracture (BNC) occurs in 0.48% to 32% of patients undergoing radical prostatectomy (47) versus 0.14% to 20% with TURP (48). Transurethral dilation and endoscopic incision of the contracture are equally effective treatment options (47).

Detrusor–External Sphincter Dyssynergia During normal voiding, the pontine micturition center coordinates relaxation of the striated muscle of the external sphincter with contraction of the detrusor. Lesions between the pons and sacral spinal cord resulting from traumatic spinal cord injury, transverse myelitis, multiple sclerosis, etc. may interfere with this coordination (49). The uncoupling of detrusor contraction and external sphincter relaxation is termed dyssynergia and is commonly referred to as DESD. DESD produces a functional obstruction that often results in elevated voiding pressures and decreased bladder compliance. Chronically, this may lead to vesicoureteral reflux and renal parenchymal deterioration, especially in

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patients with voiding pressures greater than 40 cmH2O (50). Urodynamic evaluation consists of cystometrography and external sphincter electromyography (EMG). Uninhibited detrusor contractions with concomitant increased EMG activity in the external sphincter confirm the diagnosis. Treatment options include anticholinergics and selfcatheterization, transurethral external sphincterotomy, and stenting of the external sphincter (49,51,52).

Urethral Obstruction Posterior Urethral Valves With an estimated incidence between 1:3000 and 1:8000, posterior urethral valves (PUV) are the most common congenital cause of lower urinary tract obstruction. Renal insufficiency and failure due to renal dysplasia are common, while pulmonary hypoplasia with respiratory failure may be seen in neonates with a history of oligohydramnios secondary to obstruction (53). Neonates classically presented with palpable abdominal masses from either a distended bladder or hydronephrotic kidneys, or in pulmonary distress secondary to hypoplasia of the lungs. Later in life, UTI or obstructive voiding symptoms are often the presenting complaint. Presently, most cases are discovered as bilateral hydronephrosis seen on prenatal ultrasonography (54). Voiding cystourethrogram (VCUG) is the diagnostic test of choice for PUV. In addition to upper tract damage, PUV result in a hypertrophied, trabeculated, and noncompliant detrusor that may produce vesicoureteral obstruction as well (53). Thus, initial management should consist of temporary drainage with a Foley catheter, and patients who fail to reach a serum creatinine nadir of less than 2 mg/dL should be considered for upper tract diversion via nephrostomy tube or cutaneous ureterostomy (54). Primary transurethral endoscopic valve ablation is currently the treatment of choice, though patients with significant bilateral reflux may benefit from temporary cutaneous vesicostomy prior to valve ablation (55).

Urethral Stricture Urethral strictures represent scar formation in response to injury of the urethral mucosa and corpus spongiosum (56). Prior to the advent of effective antibiotic therapy, the vast majority of stricture disease was secondary to gonococcal urethritis; however, presently, most strictures result from trauma due to straddle injury, or iatrogenic instrumentation (57–59). Patients present with obstructive voiding complaints such as straining to void, decreased stream, and terminal dribbling. Radiographic evaluation should include dynamic fluoroscopic retrograde urethrogram and VCUG. Some urologists advocate transperineal ultrasonography because they feel it provides further information regarding stricture length, location, and degree of fibrosis within the corpus spongiosum (59). A myriad of treatment options exist for stricture disease including dilatation, endoscopic internal urethrotomy, and open urethroplasty. Ultimately, the procedure of choice is determined by the characteristics of the given stricture (i.e., length, location, and degree of fibrosis). Various models of rigid dilators exist; however, balloon-dilating catheters provide the least traumatic dilatation (57). Unfortunately, with strictures other than the most superficial, membranelike lesions, dilation is rarely curative. In selected patients with short strictures (1.0–1.5 cm) of the bulbous urethra and relatively little spongiofibrosis, internal urethrotomy provides cure rates in excess of 90% (58). Bulbous urethral

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strictures of slightly longer length (< 2.0–3.0 cm) may be successfully managed via excision with a spatulated primary anastomosis (56). Longer strictures and those of the penile urethra require more complex open urethroplasty techniques, which employ various onlay grafts or tissue flaps to reconstruct the urethra (57,58).

Post-Obstructive Diuresis Following the relief of bilateral upper tract obstruction or urinary retention due to lower tract obstruction, patients should be closely monitored for postobstructive diuresis (POD). The tubular dysfunction resulting from obstruction results in an inability to excrete acid and concentrate urine; thus prior to release of obstruction, patients typically present with a hyperchloremic, hyperkalemic metabolic acidosis (9). Signs of volume overload and severe renal impairment with encephalopathy should alert the clinician to the potential for significant POD (60). Retained sodium and urea may both provoke POD. Urea-provoked diuresis is usually selflimited, whereas salt-induced POD may perpetuate into a pathologic state with ensuing dehydration, hypotension, electrolyte disturbances, and death if not recognized and treated appropriately (61). ANP has also been implicated in POD because levels are elevated in patients with obstructive uropathy and return to normal following relief of obstruction with ensuing natriuresis and diuresis (13,62). Recognition and management of POD requires that clinicians maintain a high index of suspicion. Based on clinical examination and serum studies, patients may be categorized as low, medium, or high risk for developing POD (61). The low- and medium-risk patients have minimal to no signs of volume overload, azotemia, or encephalopathy and may be managed with oral rehydration alone unless urine output exceeds 200 cc/hr or signs of hemodynamic instability or mental status changes develop. Patients with significant volume overload, mental confusion, or chronic BOO are at high risk for developing POD. Their urine output should be replaced 1/2 cc:cc with hypotonic saline solution containing 20 mEq KCl/L. If hyponatremia is present on initial serum chemistry, normal saline should be used for replacement of urine output (9,60). Serum electrolytes should be monitored closely and any derangements corrected appropriately. Excessive fluid replacement should be avoided because this may iatrogenically prolong diuresis following recovery of renal function.

SUMMARY Urinary tract obstruction can occur at any age and in either sex, but is most commonly encountered in pediatric patients and those 60 years or older. Symptoms can be acute or chronic and have minimal or significant adverse effects on underlying renal function. The most serious complication of obstruction is renal failure with its attendant life-threatening effects. Fortunately, the refinement in current imaging techniques has enabled early diagnosis of this condition and exact determination of the site of obstruction so that optimal therapy can be rendered in a timely fashion. In the unfortunate subset of patients in whom significant renal dysfunction has occurred, relief of obstruction may still enable recovery of enough function so that dialysis is not needed. Even when intermittent dialysis becomes essential, current approaches to this treatment option will make possible longer life and better quality of living.

REFERENCES 1. Kabalin JN. Surgical anatomy of the retroperitoneum, kidneys, and ureters. In: Walsh PC, Retik AB, Vaughn ED, Wein AJ, eds. Campbell’s Urology. 8th ed. Philadelphia: Saunders, 2002:3–40. 2. Uehara Y, Burnstock G. Demonstration of ‘‘gap junctions’’ between smooth muscle cells. J Cell Biol 1970; 44:215–217. 3. Libertino JA, Weiss RM. Ultrastructure of human ureter. J Urol 1972; 108:71–76. 4. Weiss RM. Physiology and pharmacology of the renal pelvis and ureter. In: Walsh PC, Retik AB, Vaughn ED, Wein AJ, eds. Campbell’s Urology. Philadelphia: Saunders, 2002:377–409. 5. Dixon JS, Gosling JA. The fine structure of pacemaker cells in the pig renal calices. Anat Record 1973; 175:139–153. 6. Vaughn ED, Sorenson EJ, Gillenwater JY. The renal hemodynamic response to chronic unilateral complete ureteral occlusion. Investig Urol 1970; 8:78–90. 7. Moody TE, Vaughn ED, Gillenwater JY. Relationship between renal blood flow and ureteral pressure during 18 hours of total unilateral ureteral occlusion. Investig Urol 1975; 13:246–251. 8. Dal Canton A, Stanziale R, Corradi A, Andreucci VE, Migone L. Effects of acute ureteral obstruction on glomerular hemodynamics in rat kidney. Kidney Int 1977; 12:403–411. 9. Bruce RG, Waid TH, Lucas BA. Understanding postobstructive diuresis. Contemp Urol 1997; 9:53–66. 10. Wilson DR. Pathophysiology of obstructive nephropathy. Kidney Int 1980; 18:281–292. 11. Moody TE, Vaughn ED, Gillenwater JY. Comparison of the renal hemodynamic response to unilateral and bilateral ureteral occlusion. Investig Urol 1977; 14:455–459. 12. Dal Canton A, Corradi A, Stanziale R, Maruccio G, Migone L. Glomerular hemodynamics before and after release of 24-hour bilateral ureteral obstruction. Kidney Int 1980; 17:491–496. 13. Gulmi FA, Matthews GJ, Marion D, Von Lutterotti N, Vaughn ED. Volume expansion enhances the recovery of renal function and prolongs the diuresis and natriuresis after release of bilateral ureteral obstruction: a possible role for atrial natriuretic peptide. J Urol 1995; 153:1276–1283. 14. Purkeson ML, Blaine EH, Stokes TJ, Klahr S. Role of atrial peptide in the natriuresis that follows relief of obstruction in rat. Am J Physiol 1989; 256:F583–F589. 15. Fried TA, Lau AT, Ayon MA, Stein JH. Elevation of atrial natriuretic peptide (ANP) in ureteral obstruction in the rat. Clin Res 1986; 34:596A. 16. Cogan MG. Renal effects of atrial natriuretic factor. Annu Rev Physiol 1990; 52:699–708. 17. Gulmi FA, Felsen D, Vaughn ED. Pathophysiology of urinary tract obstruction. In: Walsh PC, Retik AB, Vaughn ED, Wein AJ, eds. Campbell’s Urology. Philadelphia: Saunders, 2002:411–462. 18. Nagle RB, Bulger RE. Unilateral obstructive nephropathy in the rabbit. II. Late morphologic changes. Lab Investig 1978; 38: 270–278. 19. Laing FC, Jeffrey RB, Wing VW. Ultrasound versus excretory urography in evaluating acute flank pain. Radiology 1985; 154:613–616. 20. Deyoe LA, Cronan JJ, Breslaw BH, Ridlen MS. New techniques of ultrasound and color Doppler in the prospective evaluation of acute renal obstruction. Do they replace the intravenous urogram? Abdominal Imaging 1995; 20:58–63. 21. Smith R, Rosenfield A, Choe K, et al. Acute flank pain: comparison of non-contrast-enhanced CT and intravenous urography. Radiology 1995; 194:789–794. 22. Yilmaz S, Sindel T, Arslan G, et al. Renal colic: comparison of spiral CT, US, and IVU in the detection of ureteral calculi. Eur Radiol 1998; 8:212–217. 23. Youssefzadeh M, Katz DS, Lummerman JH. Unenhanced helical CT in the evaluation of suspected renal colic. Am Urol Assoc Updates 1999; 28:203–207. 24. Whitaker RH, Buxton-Thomas MS. A comparison of pressure flow studies and renography in equivocal upper urinary tract obstruction. J Urol 1984; 131:446–449.

Chapter 38: 25. Feng MI, Bellman GC, Shapiro CE. Management of ureteral obstruction secondary to pelvic malignancies. J Endourol 1999; 13:521–524. 26. Rubinstein I, Cavalcanti AG, Canalini AF, Freitas MA, Accioly PM. Left retrocaval ureter associated with inferior vena caval duplication. J Urol 1999; 162:1373–1374. 27. Lindblad B, Almgren B, Bergqvist D, et al. Abdominal aortic aneurysm with perianeurysmal fibrosis: experience from 11 Swedish vascular centers. J Vasc Surg 1991; 13:231–239. 28. Bourouma R, Chevet D, Michel F, Cercueil JP, Arnould L, Rifle G. Treatment of idiopathic retroperitoneal fibrosis with tamoxifen. Nephrol Dial Transplant 1997; 12:2407–2410. 29. De Luca S, Terrone C, Manassero A, Rocca-Rossetti S. Aetiopathogenesis and treatment of idiopathic retroperitoneal fibrosis. Ann Urol 1998; 32:153–159. 30. Kadar AH, Kattan S, Lindstedt E, Hanash K. Steroid therapy for idiopathic retroperitoneal fibrosis: dose and duration. J Urol 2002; 168:550–555. 31. Frankhart L, Lorge F, Donckier J. Tamoxifen for retroperitoneal fibrosis. Postgrad Med J 1997; 73:653–654. 32. Owens LV, Cance WG, Huth JF. Retroperitoneal fibrosis treated with tamoxifen. Am Surgeon 1995; 61:842–844. 33. Clark CP, Vanderpool D, Preskitt JT. The response of retroperitoneal fibrosis to tamoxifen. Surgery 1991; 109:502–506. 34. Russo P. Urologic emergencies in the cancer patient. Semin Oncol 2000; 27:284–298. 35. Snyder HM, Lebowitz RL, Colodny AH, Bauer SB, Retik AB. Ureteropelvic junction obstruction in children. Urol Clin North Am 1980; 7:273–290. 36. Streem SB, Franke JJ, Smith JA. Management of upper urinary tract obstruction. In: Walsh PC, Retik AB, Vaughn ED, Wein AJ, eds. Campbell’s Urology. 8th ed. Philadelphia: Saunders, 2002: 463–512. 37. Meretyk I, Meretyk S, Clayman RV. Endopyelotomy: comparison of ureteroscopic retrograde and antegrade percutaneous techniques. J Urol 1992; 148:775–783. 38. Soroush M, Bagley DH. Ureteroscopic retrograde endopyelotomy. Tech Urol 1998; 4:77–82. 39. Lam JS, Greene TD, Gupta M. Treatment of proximal ureteral calculi: holmium: YAG laser ureterolithotripsy versus extracorporeal shock wave lithotripsy. J Urol 2002; 167:1972–1976. 40. Pace KT, Weir MJ, Tariq N, Honey RJD. Low success rate of repeat shock wave lithotripsy for ureteral stones after failed initial treatment. J Urol 2000; 164:1905–1907. 41. Donker PJ, Droes JP, Van Alder BM. Anatomy of the musculature and innervation of the bladder and urethra. In: Chisolm GO, Williams DI, eds. Scientific Foundations of Urology. Chicago: Year Book Medical, 1982:404–441. 42. Chancellor MB, Yoshimura N. Physiology and pharmacology of the bladder and urethra. In: Walsh PC, Retik AB, Vaughn ED, Wein AJ, eds. Campbell’s Urology. 8th ed. Philadelphia: Saunders, 2002:831–886. 43. Wein AJ. Pathophysiology and categorization of voiding dysfunction. In: Walsh PC, Retik AB, Vaughn ED, Wein AJ, eds. Campbell’s Urology. 8th ed. Philadelphia: Saunders, 2002: 887–899.

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44. Berry SJ, Coffey DS, Walsh PC, Ewing LL. The development of human benign prostatic hyperplasia with age. J Urol 1984; 132:474–479. 45. Holtgrewe HL. Current trends in management of men with lower urinary tract symptoms and benign prostatic hyperplasia. Urology 1998; 51(suppl 4A):1–7. 46. Jepsen JV, Bruskewitz RC. Recent developments in the surgical management of benign prostatic hyperplasia. Urology 1998; 51(suppl 4A):23–31. 47. Borboroglu PG, Sands JP, Roberts JL, Amling CL. Risk factors for vesicourethral anastomotic stricture after radical prostatectomy. Urology 2000; 56:96–100. 48. Kulb TB, Kamer M, Lingeman JE, Foster RS. Prevention of post-prostatectomy vesical neck contracture by prophylactic vesical neck incision. J Urol 1987; 137:230–231. 49. Kim YH, Kattan MW, Boone TB. Bladder leak point pressure: the measure for sphincterotomy success in spinal cord injured patients with external detrusor-sphincter dyssynergia. J Urol 1998; 159:493–497. 50. McGuire EJ, Woodside JR, Borden TA, Weiss RM. Prognostic value of urodynamic testing in myelodysplastic patients. J Urol 1981; 126:205–209. 51. Rivas DA, Chancellor MB, Bagley D. Prospective comparison of external sphincter prosthesis placement and external sphincterotomy in men with spinal cord injury. J Endourol 1994; 8:89–93. 52. Chancellor MB, Kaplan SA, Blaivas JG. Detrusor-external sphincter dyssynergia. Ciba Foundation Symp 1990; 151:195–206. 53. Yohannes P, Hanna M. Current trends in the management of posterior urethral valves in the pediatric population. Urology 2002; 60:947–953. 54. Gonzales ET Jr. Posterior urethral valves and other urethral anomalies. In: Walsh PC, Retik AB, Vaughn ED, Wein AJ, eds. Campbell’s Urology. 8th ed. Philadelphia: Saunders, 2002:2207–2230. 55. Walker RD, Padron M. The management of posterior urethral valves by initial vesicostomy and delayed valve ablation. J Urol 1990; 144:1212–1214. 56. Jezior JR, Schlossberg SM. Excision and primary anastomosis for anterior urethral stricture. Urol Clin North Am 2002; 29:373–380. 57. Jordan GH, Schlossberg SM. Surgery of the penis and urethra. In: Walsh PC, Retik AB, Vaughn ED, Wein AJ, eds. Campbell’s Urology. 8th ed. Philadelphia: Saunders, 2002:3886–3954. 58. Jezior J, Jordan GH. Management of the bulbous urethral stricture. AUA Update Ser 2002; 22(1):1–7. 59. Gallentine ML, Morey AF. Imaging of the male urethra for stricture disease. Urol Clin North Am 2002; 29:361–372. 60. Vaughan ED, Gillenwater JY. Diagnosis, characterization and management of post-obstructive diuresis. J Urol 1973; 109: 286–292. 61. Baum N, Anhalt M, Carlton CE, Scott R. Post-obstructive diuresis. J Urol 1975; 114:53–56. 62. Gulmi FA, Mooppan UMM, Chou SY, Kim H. Atrial natriuretic peptide in patients with obstructive uropathy. J Urol 1989; 142:268–272.

39 Neurogenic Lower Urinary Tract Dysfunction Hari Siva Gurunadha Rao Tunuguntla and Unyime O. Nseyo

the bladder may be divided into the detrusor and trigone. However, neuropharmacologically the bladder may be conceived as comprising both a body and base, which differ substantially (1). The urinary bladder wall is organized into three layers: inner epithelial layer, or ‘‘mucosa’’ lined by specialized transitional epithelium called the urothelium, which is impervious to fluids and ions; smooth muscle layer (detrusor); and the outer serosal layer comprising of connective tissue. The urothelium characteristically unfolds and expands during bladder filling. The detrusor smooth muscle layer has a heterogeneous composition of smooth muscle cells, fibroblasts, elastin, collagens, and proteoglycans. The actual smooth muscle composition ranges from 50% to 60% and may diminish during bladder outlet obstruction (1). The bundles of the detrusor muscle merge into the trigone and bladder base. These bundles lack uniform orientation during the resting phase. However, reorientation occurs during stretch. Also, at rest and during passive bladder filling, these smooth muscle bundles occlude the bladder outlet. Realignment and coordinated relaxation of these smooth muscle bundles must occur to allow efficient opening of the bladder outlet and the low voiding pressure of less than 40 cm of H2O. The adult female urethra averages 5 cm in length and 6 mm in diameter. Its wall is composed of an outer muscular layer and an inner epithelial layer. The inner epithelial layer forms internal folds, which then form a mucosal seal and contribute to the continence mechanism. The outer longitudinal muscle extends the entire length of the inner epithelial layer. Most investigators have accepted the existence of an inner longitudinal smooth muscle layer. However, the notion by Tanagho of the outer longitudinal layer representing a direct continuation of the detrusor remains controversial (2–4). The middle third of the female urethra contains the intrinsic striated skeletal muscle, which loops around the urethral lumen, probably in an oblique fashion as in the male. Both the intrinsic and extrinsic components of the SS surround the inferior aspect of the female urethra. The distal end of the intrinsic rhabdosphincter aborts in the bulky skeletal muscle of the so-called ‘‘external urinary sphincter.’’ Future research may offer succinct explanation for the presence of a very robust urethral muscle tone that contributes to urinary continence in the female. Anatomically, the male urethra is divided into the anterior component, which contains a penile and bulbar urethra. The posterior urethra contains the membranous and the prostatic urethra, which measures 3 to 4 cm in length. Inner longitudinal and outer circular layers of smooth muscle comprise the wall of the male posterior and membranous urethra. These two layers of smooth muscle extend beyond the apex of the prostate to the bulbar urethra distally. Many investigators believe that the smooth muscles of the trigone extend into the urethra (Fig. 1). Consequently, these proponents

INTRODUCTION The normal function of the urinary bladder is to store and expel urine in a coordinated, controlled fashion. This coordinated activity is regulated by the central and peripheral nervous systems. Neurogenic bladder is a term applied to a malfunctioning urinary bladder due to neurogenic dysfunction or insult emanating from internal or external trauma or disease. Neurogenic lower urinary tract dysfunction (NLUTD) is the new term currently applied to ‘‘neurogenic bladder dysfunction’’. NLUTD is a multi-facetted pathology and an important clinical as well as public health problem that is associated with complex management issues. Therefore, knowledge of the anatomy and pathophysiology of NLUTD remains the prerequisite for the safe and appropriate surgical–medical management of this disorder.

ANATOMY AND PHYSIOLOGY OF CONTINENCE AND MICTURITION Anatomy and Physiology of the Bladder Outlet Functionally, the lower urinary tract (LUT) (bladder and its outlet, the urethra) works in an integrated fashion for a normal voiding cycle to occur. The normal voiding cycle includes bladder filling and storage at a low pressure and without urinary incontinence. The subsequent voluntary and active voiding also occurs at a relatively low pressure. The bladder is one of the most compliant organs in the body, and allows normal filling to occur with only a gradual rise in intravesical pressure independent of large urine volumes. Increased tension in the external urethral sphincter, the so-called rhabdosphincter or striated sphincter (SS), occurs during the bladder filling and ensures continence even with increased intra-abdominal pressure. Urine storage ends when sensory tracts transmit to the central nervous system (CNS) the sensation of bladder fullness. Under appropriate sociocultural environment control, micturition occurs by coordinated neural activities leading to detrusor contraction, funneling of bladder neck, and relaxation of the bladder outlet. Cessation of neural activity leads to relaxation of the external SS during the micturition phase. As voiding ends, neural activities and tension return to the bladder outlet and relaxation of detrusor muscle occurs and a new urine storage cycle begins. Embryologically, the bladder is derived from the urogenital sinus, the anterior portion of the cloacal membrane. The urogenital sinus is further divided into upper and lower segments at the level of the insertion of the fused distal portion of the mullerian ducts. In the male the ventral or pelvic segment forms the bladder and the prostatic urethra above the verumontanum, whereas in the female this portion forms the bladder and the entire urethra. Anatomically, 775

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Figure 2 Detrusor–external sphincter dyssynergia. Note the increased activity of the external urethral sphincter on electromyogram during detrusor contraction; video showing detrusor contracting against contracting external urethral sphincter, the resulting high detrusor pressure leading to bilateral (right > left) vesicoureteral reflux.

Figure 1 Anatomy of the bladder and its outlet as defined by Gosling and Dixon versus El badawi and co-workers. Source: From Ref. 5.

hypothesize that this anatomic arrangement facilitates funneling of the urethrovesical angle for efficient micturition. The contraview is that the trigone is physiologically and neuropharmacologically unique to allow functional funneling of the opening of the bladder neck during micturition. The striated muscle component of the urethra has an intrinsic layer (the so-called ‘‘rhabdosphincter’’) within the urethra, and also tends to wrap around the lumen of the urethra in an obliquely spiral fashion. The rhabdosphincteric fibers interdigitate with fibers of the external component of the extrinsic skeletal muscle intimately to the levator ani muscle group and separate from the urethral wall (3). Anatomically no ‘‘sphincter’’ is observable at the bladder neck, which remains rich with collagen and elastin that co-mingle with smooth muscle bundles. The patency and closing of the bladder neck at rest depends heavily on the passive forces of the components of the extracellular matrix (ECM) and active tone of the smooth muscle. The intrinsic tone in the bladder neck region and the proximal urethra leads to higher urethral pressure than intravesical pressure during bladder filling. The decrease in the internal urethral pressure occurs at the onset of micturition and leads to voiding at a low detrusor pressure. The competence of this ‘‘internal sphincteric mechanism’’ of the smooth muscle is very essential for continence. The external SS works in concert with the so-called internal sphincter of the bladder neck to ensure urinary continence. Unlike in the female urethra, both the intrinsic and extrinsic components of the SS surround the proximal male urethra. The involuntary contraction of the striated external sphincter during bladder contraction leads to striated detrusor– sphincter dyssynergia (DSD) (Fig. 2) common among patients with neurologic disease. This condition manifests also in the presence of a lesion between the brain and sacral cord. The only non-neurologic condition associated with DSD is the so-called Hinman Syndrome, common in children (6).

Innervation of the Urinary Bladder Voiding is an autonomic reflex and involuntary in the infant. However, normal neural maturation leads to somatic control of the LUT in due course. Central and peripheral nervous systems (Figs. 3 and 4) coordinate the complex interactions between the smooth muscle of the detrusor, bladder neck, and urethra during micturition. The contemporary literature supports the ‘‘urogenital short nervous system’’ (USNS), which contains postganglionic neurons that innervate the LUT (1). The USNS arises from the ganglia within or intimately proximal to the bladder wall. Classically, the sympathetic autonomic system leaves the preganglionic neurons of the thoraco-lumbar spinal segment to reach the first synapse in the following ganglia: (i) adjacent to the vertebral bodies (paraganglia), (ii) between the vertebral bodies and the organ (preganglia), and (iii) within the end organ (peripheral ganglia) (1). There is some evidence that urogenital neuronal fibers may connect the muscle with efferent neurons via the peripheral ganglion, which allows function that is

Brain Pontine Micturition Center

Onuf's Nucleus in Spinal Cord

S2, S3, S4

Detrusor Contraction

Figure 3 Micturition pathway.

Chapter 39: Neurogenic Lower Urinary Tract Dysfunction

Figure 4 Innervation of the lower urinary tract.

independent of the spinal cord. Also the sympathetic system may affect the parasympathetic ganglia via alpha-receptors, which modulate motor activity to the bladder. In addition to the traditional autonomic neurotransmitters of acetylcholine and norepinephrine, the noncholinergic and nonadrenergic neurotransmitters include adenosine triphosphate, serotonin, histamine, prostaglandins, peptides, and nitric oxide (1). These transmitters most certainly play a critical role in autonomic neurotransmission most likely through the principle of ‘‘cotransmission,’’ with one molecule/peptide altering the postjunctional cell for the primary neurotransmitter (1). The postsynaptic cell membrane of the smooth muscle contains receptors that recognize the neurotransmitter. The resulting specific binding generates the process of excitation–contraction in the effector cell, accompanied by a rise in the free cytosolic calcium concentration. The cholinergic receptor membrane proteins that bind acetylcholine predominate in neurons of somatic fibers, all preganglionic autonomic fibers, and all postganglionic parasympathetic fibers. The cholinergic receptors are divided into nicotinic (nicotine, a mimicry of acetylcholine) and muscarinic (alkaloid muscarinic inhibitor of acetylcholine). The nicotinic receptors abound in skeletal muscle motor end plates and autonomic ganglia. They may also have control over bladder function. The muscarinic receptors are widely distributed in all autonomic effector cells in sweat glands, large and small bowel, gall bladder, and urinary bladder. Molecular biochemists have defined five subtypes of the muscarinic receptors based on the type of protein, ‘‘M,’’ and mRNA’s (1). Structural differences are difficult to delineate; however, their functions are distinct. The urinary bladder contains only 20% of the muscarinic receptor density. The muscarinic receptor subtype, M2, predominates in the urinary bladder. Nevertheless, activation of M3 subtypes initiate bladder contraction, and activation of M2 subtype inhibits adrenergic pathway, which leads to force generation (1,7). The conditions that affect the density of the muscarinic cholinergic receptors of the bladder include pregnancy (downregulation), estrogen (upregulation), spinal cord injury, acute urinary tract obstruction, and diabetes. The adrenergic receptors bind to the catecholamines (e.g., norepinephrine) and predominate in most postganglionic sympathetic fibers. Classification of the adrenergic receptors is based on physiologic functions referred to as alpha or

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beta. The alpha-receptors mediate nasal congestion and smooth muscle contraction. Stimulation of beta-adrenergic receptors leads to increased myocardial contractility and smooth muscle relaxation. The alpha-receptors have wellcharacterized subtypes, alpha-1 (postsynaptic) and alpha-2 (pre- and postsynaptic). Adrenergic sites in the bladder are predominantly beta-subtypes (1,7,8). They also are localized in the trigone, with sparse distribution in the bladder body. Adrenergic innervation predominates in the smooth muscle of the bladder neck and the proximal urethra. The betaadrenergic receptors exist in several major forms: beta-1, -2, and -3. Affinity of beta-1 receptors remains high for norepinephrine, whereas epinephrine has a greater affinity for beta-2 receptors. Beta-2 receptors predominate in the presynaptic and postsynaptic membranes and in the urinary bladder. Stimulation of beta-2 receptors results in relaxation of the smooth muscle in the urinary bladder. The SS is innervated by the pudendal nerves, which originate from the S2 to S4 spinal cord segments. Somatic control of the SS is responsible for the physiologic increase in activity during bladder filling and abortion of this activity at the initiation of and throughout micturition. Supratrigonal mechanoreceptors control somatic activity of the SS, which explains the failure of the external sphincter in paraplegic patients. The cholinergic receptors for smooth muscle are muscarinic whereas those associated with SS contraction are nicotinic. Anticholinergic agents such as oxybutynin act at muscarinic sites, and therefore, have no effect on SS. The muscarinic receptors of SS can be blocked by endoscopic injection of botulinum toxin to treat refractory voiding dysfunction or as an alternative to sphincterotomy. Less is known about the sensory innervation of the LUT. Afferent nerve fibers have been demonstrated in the pelvic, pudendal, and hypogastric nerves. Sensation of distention originates in the bladder wall and travels in the pelvic nerves. Mechanoreceptors are present in the hypogastric nerves. These nerves carry afferent nociceptive stimuli. The afferent neurons from the sphincter (SS) and urethra carry sensations of pain, temperature, and urinary distention. Denervation leads to increased sensitivity of smooth muscle to neuro-humoral stimuli. This supersensitivity is often associated with injury involving the postganglionic fibers. Injury involving the preganglionic nerve fibers leads to decentralization. Neuronal injuries during radical hysterectomy or abdominal perineal resection constitute examples of decentralization injuries. In summary, the adrenergic efferent neurons modulate the bladder storage function as follows: (i) stimulation of alpha-receptors of the bladder base and urethra increase bladder outlet resistance and facilitate urinary storage, (ii) stimulation of beta receptors in the bladder body engenders increase in bladder compliance and facilitates storage, and (iii) adrenergic fibers and involved alpha-receptors suppress parasympathetic transmission in the pelvic ganglia and inhibit bladder contractions. The classic concept of deGroat maintains that the role of the adrenergic system favors urinary storage at low pressures (9). McGuire (10) and El Badawi (4) endorse the concept, and emphasize that the storage phase of micturition is controlled principally by the sympathetic system and the voiding phase by parasympathetic vesicourethral innervation. The challenge to deGroat’s classic concept centers on the observations that patients on alpha-blockers for hypertension do not loose bladder capacity; and retroperitoneal lymphadenectomy for testicular cancer in normal individuals does not result in urinary incontinence/voiding dysfunction (2).

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CNS Control of Urinary Storage and Micturition Normal voiding essentially is a spinal reflex that is modulated by the CNS (brain and spinal cord) (Fig. 3), which coordinates the functions of the bladder and urethra. The bladder and urethra are innervated by three sets of peripheral nerves arising from the autonomic nervous system (ANS), the somatic nervous system, and the CNS, which comprises the brain, brain stem, and the spinal cord (Figs. 5 and 6).

SUPRAPONTINE CENTERS

Brain

CORTICAL /DIENCEPHALIC

+ –

The brain is the master control of the entire urinary system. The micturition control center is located in the frontal lobe of the brain. The primary activity of this area is to send inhibitory signals tonically to the detrusor muscle to prevent the bladder from emptying (contracting) until a socially acceptable time and place to urinate are available. The signal transmitted by the brain is routed through two intermediate centers (the brainstem and the sacral spinal cord) prior to reaching the bladder. Certain cerebral lesions or diseases, such as stroke, cancer, and dementia, often derange the control of the normal micturition reflex.

Brainstem The brainstem is located at the base of the skull. Within the brainstem is a specialized area known as the pons, a major relay center between the brain and the bladder. The pons is responsible for coordinating the activities of the urinary

PONTINE MICTURITION CENTER

INHIBITS SPHINCTER REFLEXES

+ LUMBAR CORD HYPOGASTRIC NERVE

– BLADDER

PELVIC NERVE + –

+

SACRAL CORD

+

EXTERNAL SPHINCTER

PUDENDAL NERVE

Figure 5 Representation of sphincter reflexes. Distention of bladder during filling produces low-level afferent firing, which triggers (1) hypogastric outflow to the bladder, and (2) pudendal outflow to the external urethral sphincter. Hypogastric pathways may promote urine storage by mediating relaxation (
) of the bladder body via beta-adrenegic receptors and contraction (þ) of the bladder base and urethra via alpha adrenoceptors. Hypogastric input may also inhibit ganglionic transmission in some species. During voiding, inhibition of hypogastric and pudendal pathways promotes complete bladder emptying. Source: From Ref. 11.

PONTINE MICTURITION CENTER

Aδ-MYELINATED BLADDER AFFERENTS

BLADDER +

SPN

SACRAL SPINAL CORD

Figure 6 Schematic of supraspinal micturition reflex pathway. Bladder distention activates unmyelinated Ad fiber afferents. Ascending input is relayed to a region of the pons termed the pontine micturition center. Depending on cortical input, excitatory descending input activates neurons in the sacral parasympathetic nucleus, which cause bladder contraction. Evidence for a spinobulbospinal pathway exists in the cast (de Groat and Ryall, 1969) and rat (Mallory et al, 1989).

sphincters and the bladder so that they work in synergy. The mechanical process of urination is coordinated by the pons in the area known as the pontine micturition center (PMC). The PMC coordinates the urethral sphincter relaxation and detrusor contraction to facilitate urination. The conscious sensations associated with bladder activity are transmitted to the pons from the cerebral cortex. The PMC controls a variety of excitatory and inhibitory neuronal systems and functions as a relay switch in the voiding pathway. Stimulation of the PMC causes the urethral sphincters to open, while facilitating the detrusor to contract and expel the urine. When the bladder becomes full, the stretch receptors of the detrusor muscle send a signal to the pons, which in turn notifies the brain. Patients perceive this signal (bladder fullness) as a sudden desire to go to the bathroom. Under normal situations, the brain sends an inhibitory signal to the pons to inhibit the bladder from contracting until a bathroom is found. Deactivation of the PMC leads to disappearance of the urge to urinate, allowing the patient to delay urination until locating a suitable bathroom. Within the appropriate environment, the brain sends excitatory signals to the pons, allowing the urinary sphincters to open and the detrusor to contract for bladder emptying.

Spinal Cord The spinal cord extends from the brainstem down to the lumbosacral spine. It is located in the spinal canal and is protected by the cerebrospinal fluid, meninges, and the vertebral column. It is approximately 14-inches long in an adult. Along its course, the spinal cord sprouts off many nerve branches to different parts of the body. The spinal cord functions as a long communication pathway between

Chapter 39: Neurogenic Lower Urinary Tract Dysfunction

the brainstem and the sacral spinal cord (Figs. 5 and 6). When the sacral cord receives the sensory information from the bladder, this signal travels up the spinal cord to the pons and then ultimately to the brain. The brain interprets this signal and sends a reply via the pons that travels down the spinal cord via the sacral cord to the bladder. In the normal cycle of bladder filling and emptying, the spinal cord acts as an important intermediary between the pons and the sacral cord. An intact spinal cord is critical for normal micturition. If the spinal cord is severely injured or severed, the affected individual will exhibit constant urinary leakage because of uncontrollable detrusor contracture with bladder spasms, a condition called detrusor hyper-reflexia (Table 1). In a condition of complete spinal cord transection, the patient will demonstrate symptoms of urinary frequency, urgency, and urge incontinence, but will be unable to empty his or her bladder completely. This occurs because the urinary bladder and the external urethral SS are both overactive, a condition termed DSD with detrusor hyper-reflexia (DSD–DH) (Fig. 2; Table 1). The sacral spinal cord is the terminal portion of the spinal cord situated at the lower back in the lumbar area. This is a specialized area of the spinal cord known as the sacral reflex center, which is responsible for bladder contractions. The sacral reflex center (Fig. 3) is the primitive voiding center and the only functional ‘‘micturition center’’ in the infant. In infants, the higher center of voiding control (the brain) is not mature enough to command the bladder, which is why control of urination in infants and young children comes from signals sent from the sacral cord. The full infant bladder triggers an excitatory signal that goes to the sacral cord. The sacral cord responds by signaling the spinal reflex center to automatically trigger detrusor contraction, which results in involuntary coordinated voiding. A continuous cycle of bladder filling and emptying occurs, which is why infants and young children are dependent on diapers until they are toilet trained. As the child’s brain matures and develops, it gradually dominates the control of the bladder and the urinary sphincters to inhibit involuntary voiding until complete control is attained. Voluntary continence usually is attained by age three to four years. By this time, control of the voiding process has been relinquished by the sacral reflex center of the sacral cord to the higher center in the brain. If the sacral cord becomes severely injured (e.g., spinal tumor and herniated disc), the bladder may not function. Affected patients may develop urinary retention, termed ‘‘detrusor areflexia’’ Table 1 Neurogenic Bladder Dysfunction According to the Neurologic Abnormality Level of the lesion Brain Pontine micturition center; S2; lumbar, thoracic, cervical spinal cord lesions Pontine micturition center S3,4 spinal cord lesions S2,3,4 peripheral nerves a

Type of neurogenic bladder dysfunction Detrusor hyper-reflexiaa Detrusor hyper-reflexiaa/detrusor sphincter dyssynergia Detrusor hyper-reflexiaa/detrusor sphincter dyssynergia Detrusor hyporeflexia (hypocontractile detrusor) Detrusor hyporeflexia (hypocontractile detrusor)

Neurogenic detrusor overactivity, according to the current International Continence Society (ICS) nomenclature.

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(Table 1). The detrusor lacks the ability to contract, resulting in inability to urinate and urinary retention.

Peripheral Nerves Peripheral nerves form an intricate network of pathways for sending and receiving information throughout the body. The nerves originate from the main trunk of the spinal cord and branch out in different directions to cover the entire body. Nerves convert the internal and external environmental stimuli to electrical signals so that the human body can understand stimuli as one of the ordinary senses (i.e., hearing, sight, smell, touch, taste, and equilibrium). The bladder and the urethral sphincters are under the influence of their corresponding nerves. The ANS lies outside of the CNS, and regulates the actions of the internal organs (e.g., intestines, heart, and bladder) under involuntary control. The ANS is divided into the sympathetic and the parasympathetic nervous system. Under appropriate conditions, the bladder and the internal urethral sphincter (bladder outlet) primarily are under sympathetic nervous system control (7,8). When the sympathetic nervous system is active, it causes the bladder to increase its capacity without increasing detrusor resting pressure (accommodation) and stimulates the internal urinary sphincter/bladder neck to remain tightly closed. The sympathetic activity also inhibits parasympathetic stimulation, that is, detrusor contraction. The parasympathetic nervous system functions in a manner opposite to that of the sympathetic nervous system. In terms of urinary function, the parasympathetic nerves stimulate the muscarinic (M) receptors that mediate detrusor contraction, leading to bladder emptying (1,7). Immediately preceding parasympathetic stimulation, the sympathetic influence, that is, the activity of the adrenergic receptors on the internal urethral sphincter, becomes suppressed so that the internal sphincter relaxes and opens. In addition, the activity of the pudendal nerve is inhibited to cause the external urethral SS to open, resulting in the facilitation of voluntary urination. Like the ANS, the somatic nervous system is a part of the nervous system that lies outside of the central spinal cord. The somatic nervous system regulates the actions of the muscles under voluntary control. Examples of these muscles are the external urethral SS and the pelvic diaphragm. The pudendal nerve originates from the nucleus of Onuf and regulates the voluntary actions of the external urinary sphincter and the pelvic diaphragm. Activation of the pudendal nerve causes contraction of the external sphincter and the pelvic floor muscles, which occurs with activities such as Kegel exercises. Difficult or prolonged vaginal delivery may cause temporary neuropraxia of the pudendal nerve and stress urinary incontinence. Conversely, suprasacral-infrapontine spinal cord trauma can cause overstimulation of the pudendal nerve that results in urinary retention.

Physiology of LUT Normal bladder function consists of two phases—filling and emptying. The normal micturition cycle requires that the urinary bladder and the urethral sphincter work together as a coordinated unit to store and empty urine. During urinary storage, the bladder acts as a low-pressure receptacle, while the urinary sphincter maintains high resistance to urinary flow to keep the bladder outlet closed. During urine elimination, the bladder contracts to expel urine while the urinary sphincter opens (low resistance) to allow unobstructed urinary flow and bladder emptying.

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Filling Phase During the filling phase, the bladder accumulates increasing volumes of urine while the pressure inside the bladder remains low. As the bladder initially fills, a small rise in intravesical pressure, which is never greater than 10 cm of H2O, occurs (Fig. 7) (12). The filling of the urinary bladder depends on the inherent viscoelastic properties of the bladder and the inhibition of the parasympathetic nerves. Thus, bladder filling primarily is a passive event. However, the sympathetic nerves also facilitate urine storage by (i) inhibiting the parasympathetic nerves from triggering bladder contractions, (ii) directly causing relaxation and expansion of the detrusor muscle, and (iii) causing the closure of the bladder neck by constricting the inner urethral SS. This sympathetic input to the LUT remains very active during bladder filling. As the bladder fills, the pudendal nerve becomes excited. Stimulation of the pudendal nerve results in contraction of the external urethral SS. Contraction of the external sphincter, coupled with that of the internal smooth muscle sphincter, maintains the urethral pressure (resistance) higher than normal bladder pressure. The combination of both urinary sphincters constitutes the purported continence mechanism. The pressure gradients within the bladder and urethra play an important functional role in normal micturition and continence. As long as the urethral pressure is higher than the bladder pressure, urinary continence is ensured. However, abnormally low urethral pressures or abnormally high intravesical pressures result in urinary incontinence. Physical activities, coughing, sneezing, or laughing often result in the sharp rise of pressure within the abdomen, which is transmitted to both the bladder and urethra. As long as the pressure is evenly transmitted to the bladder and urethra, urine will not leak. However, when the pressure transmitted to the bladder is greater than that transmitted to the urethra, stress urinary incontinence results.

Emptying Phase The storage phase of the urinary bladder can be switched to the voiding phase either involuntarily (reflexly) or voluntarily. Involuntary reflex voiding occurs in an infant when the volume of urine exceeds the voiding threshold. When the bladder is filled to capacity, the stretch receptors within the bladder wall signal the sacral cord. The sacral cord, in

turn, sends a message back to the bladder indicating that it is time to empty the bladder. Concurrently, the pudendal nerve causes relaxation of the levator ani so that the pelvic floor muscles relax. The pudendal nerve also signals the external sphincter to open. The sympathetic nerves send a message to the internal sphincter to relax and open, resulting in a lower urethral resistance. As the urethral sphincters relax and open, the parasympathetic nerves trigger contraction of the detrusor. The bladder contracts and the detrusor pressure overcomes the urethral pressure, resulting in urinary flow. These coordinated series of events allow automatic and unimpeded emptying of the bladder. A repetitious cycle of bladder filling and emptying occurs in newborn infants. The bladder empties as soon as it fills because the brain of an infant has not matured enough to regulate the urinary system. Because urination is unregulated by the infant’s brain, predicting when the infant will urinate is difficult. As the infant brain develops, the PMC also matures and gradually assumes voiding control. During childhood (usually at the age of three to four), this primitive voiding reflex becomes suppressed and the brain dominates the control of bladder function, which is why toilet training usually is successful at ages three to four. However, this primitive voiding reflex may reappear in people with spinal cord injuries.

PATHOPHYSIOLOGY OF LUT DYSFUNCTION The bladder appears to be the only human visceral organ that requires an intact central neural system for function and survival of the individual. Any abnormality within the nervous system affects the entire voiding cycle, and any part of the nervous system may be affected, including the brain, pons, spinal cord, sacral cord, and peripheral nerves. Consequently, voiding dysfunction occurs with different symptoms, which range from acute urinary retention to an overactive bladder, or a combination of both. Urinary incontinence results from a dysfunction of the bladder, the sphincter, or both. Bladder hyperactivity (spastic bladder) is associated with the symptoms of urge incontinence, whereas urethral sphincteric hypoactivity (decreased resistance) results in symptomatic stress incontinence. A combination of detrusor hyperactivity and sphincteric deficiency (hypoactivity) may result in mixed symptoms of urge and stress incontinence in the same individual.

Brain Lesions

PRESSURE (cmH2O)

100

50

Voluntary bladder contraction 1st sensation of bladder filling

100

200

400 300 VOLUME (mL)

Figure 7 Normal cystometrogram.

500

Lesions of the brain above the pons may destroy or impair the primary cortical micturition center, resulting in the complete or variable loss of voiding control. However, the voiding reflexes of the LUT—the primitive voiding reflexes—remain intact. Affected individuals show signs of urge incontinence, or spastic bladder (detrusor hyperreflexia) (Table 1). The bladder empties too quickly and too often, with relatively low volumes. Consequently, the storage function of the bladder is deranged, marked clinically by day- and night-time (nocturia) urinary frequency, urgency, and urge incontinence. Typical brain lesions include stroke, brain tumor, Parkinson’s disease, hydrocephalus, cerebral palsy, and Shy–Drager syndrome. The latter disorder is a rare condition associated with open bladder neck, and is discussed later in this chapter.

Lesions of the Spinal Cord Diseases or injuries of the spinal cord between the pons and the sacral spinal cord also result in spastic bladder or

Chapter 39: Neurogenic Lower Urinary Tract Dysfunction

overactive bladder (neurogenic detrusor overactivity) (Table 1). People who are paraplegic or quadriplegic have lower extremity spasticity. Acute spinal cord trauma results in the acute spinal shock syndrome; the patient enters a spinal shock phase which the nervous system shuts down the vesical–neural axis. After 6 to 12 weeks, the nervous system gradually reactivates. This reactivation results in heightened stimulation of the affected organs. For example, the legs become spastic. The bladder suffers a voiding disorder, primarily urinary frequency and urge incontinence, which is similar to that of the brain lesion except that the external SS may have paradoxical contractions as well. If both the bladder and external sphincter become spastic at the same time, the affected individual will sense an overwhelming desire to urinate but only a small amount of urine may dribble out. This is DSD because the bladder and the external SS function in discordance. Spinal cord injury may result from a motor vehicle accident, diving accidents, and gun-shot wounds. Multiple sclerosis (MS) is a common systemic cause of spinal cord disease in young women. Children born with myelomeningocele may have spastic bladders and/or an open urethra. Conversely, some children with myelomeningocele may have hypotonic instead of a spastic bladder.

Sacral Cord Injury Selected injuries of the sacral cord and the corresponding nerve roots arising from the sacral cord may prevent the bladder from emptying. A sensory neurogenic bladder presents with a loss of sense of bladder fullness. In the case of a motor neurogenic bladder, the patient retains the sense of bladder fullness; however, the detrusor may not contract, a condition known as detrusor areflexia (acontractile detrusor). Consequently, there is the failure to empty with associated overflow urinary incontinence and bladder decompensation. Typical causes include sacral cord tumor, herniated disc, crush pelvic injuries, lumbar laminectomy, radical hysterectomy, and abdominoperineal resection. Tethered cord syndrome must be ruled out in a teenager with sudden onset of voiding dysfunction. The spinal cord injury in this syndrome is marked by the tip of the sacral cord being stuck near the sacrum and hence being unable to stretch as the child grows taller. Ischemic changes of the sacral cord associated with the tethering cause the manifestation symptoms of dysfunctional voiding.

Peripheral Nerve Injury Diabetes mellitus and AIDS cause peripheral neuropathy that results in dysfunctional voiding (Table 1). These diseases destroy the nerves to the bladder, resulting in a silent, painless distention of the urinary bladder. Patients with chronic diabetes first lose the sensation of bladder filling and fullness, prior to bladder decompensation. Similar to the case of injury to the sacral cord, affected individuals will have difficulty urinating, with the attendant problems of overflow incontinence and bladder decompensation. Other diseases manifesting this condition are poliomyelitis, Guillain–Barre syndrome, genitoanal herpes, pernicious anemia, and neurosyphilis (tabes dorsalis).

DEFINITION OF COMMON TERMS IN NEUROGENIC VOIDING DYSFUNCTION Neurogenic bladder is a malfunctioning bladder due to any type of neurologic disorder.

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Detrusor overactivity refers to overactive bladder symptoms due to a neurologic (suprapontine upper motor neuron neurologic)/non-neurologic disorder. In neurologic detrusor overactivity, the external sphincter functions normally. There is functional synergy between the bladder and the external urethral SS. However, the patient often presents with frequency, urgency, and urge incontinence. DSD–DH refers to overactive bladder symptoms due to neurologic upper motor neuron disorder of the suprasacral spinal cord. Paradoxically, the patient is in urinary retention. Both the detrusor and the SS are contracting at the same time, that is, synchronous activation of both parasympathetic and pudendal nerves, which act in dyssynergia (lack of coordination). Detrusor overactivity with impaired contractility refers to overactive bladder symptoms, but the detrusor cannot generate enough pressure to allow complete emptying. The external sphincter is in synergy with detrusor contraction. The detrusor is too weak to mount an adequate contraction for proper voiding to occur. The condition is similar to urinary retention, but irritating voiding symptoms are prevalent. Acontractile/hypocontractile detrusor is a complete inability of the detrusor to empty due to a lower motor neuron lesion (e.g., sacral cord and peripheral nerves). Urinary retention is the inability of the urinary bladder to empty, and the problem of failure to empty may have neurologic or non-neurologic etiology.

SPECIFIC NEUROLOGIC LESIONS Supraspinal lesions Supraspinal lesions refer to those lesions of the CNS above the pons, which include cerebrovascular accidents, brain tumors, Parkinson’s disease, and Shy–Drager syndrome (13).

Cerebrovascular Accidents After a stroke, the brain may enter into a temporary acute cerebral shock phase. During this time, the urinary bladder will be in retention due to detrusor areflexia. About 25% of stroke victims develop acute urinary retention. Following the cerebral shock phase, the bladder demonstrates detrusor overactivity with coordinated urethral sphincter activity, because the PMC is released from the cerebral inhibitory center. The symptoms of detrusor overactivity/hyperactivity/ hyper-reflexia often include urinary frequency, urgency, and urge incontinence. The treatment for the cerebral shock phase is indwelling Foley catheter or clean intermittent catheterization (CIC). The resultant hyper-reflexic bladder is often managed with anticholinergic medications to facilitate bladder filling and storage. Detrusor hyper-reflexia (Fig. 8) with coordinated urethral SS is the most commonly observed urodynamic pattern associated with a brain tumor (Fig. 8). Any associated hyper-reflexia is managed similarly with anticholinergic medications.

Parkinson’s Disease This is a degenerative disorder of pigmented neurons of the substantia nigra of the cerebrum, associated with dopamine deficiency and increased cholinergic activity in the corpus striatum. Patients with Parkinson disease manifest symptoms of bradykinesia, skeletal muscle tremor, cogwheel rigidity, and masked facies. Symptoms specific to the urinary bladder include urinary frequency, urgency, nocturia, and urge incontinence. Typical urodynamic findings are

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Figure 8 Detrusor overactivity/hyper-reflexia. Note the phasic detrusor overactivity reflected in the detrusor pressure curve (Pdet); this may or may not be associated with urinary leak (incontinence). Detrusor overactivity is of two types: neurogenic (spinal cord injury) and non-neurogenic. Terminal detrusor overactivity with leak is characterized by end-filling detrusor overactivity.

consistent with detrusor hyper-reflexia (Fig. 8) and urethral SS bradykinesia, that is, the striated urethral sphincter often demonstrates poorly sustained contraction. Similar to other supraspinal lesions, the treatment of voiding dysfunction associated with Parkinson disease is to facilitate bladder filling and promote urinary storage with anticholinergic agents. If Parkinson disease coexists with symptoms of bladder outlet obstruction due to benign prostatic hyperplasia (BPH), the diagnosis of BPH must be confirmed by multichannel urodynamic studies (UDS). The most common cause of postprostatectomy incontinence in the patient with Parkinson disease is detrusor hyper-reflexia. If transurethral resection of the prostate (TURP) is performed without urodynamic confirmation of obstruction, the patient may become totally incontinent after the TURP procedure.

Shy–Drager Syndrome Shy–Drager syndrome is a rare, progressive, and degenerative disease affecting the ANS with multisystem organ atrophy. In addition to Parkinson-like symptoms, cerebellar ataxia and autonomic dysfunction are common. Affected individuals demonstrate orthostatic hypotension, anhidrosis, and urinary incontinence. Degeneration of the nucleus of Onuf results in denervation of the external SS. Sympathetic nerve atrophy causes a nonfunctional bladder and an open bladder neck. Urodynamic evaluation often reveals neurogenic detrusor overactivity (Fig. 8), although a few individuals may have acontractile detrusor (Fig. 9) or poorly sustained bladder contractions. Often, the bladder neck (internal smooth sphincter) will be open at rest, while there is SS denervation. The treatment for Shy–Drager syndrome is to facilitate urinary storage with anticholinergic agents coupled with CIC or indwelling catheter. Patients with Shy–Drager syndrome should avoid undergoing TURP, because the risk of total incontinence is high.

Spinal Cord Lesions Spinal Cord Injury A spinal cord injury from a diving accident or motor vehicle injury results in the initial response of acute spinal shock.

Figure 9 Pressure–flow study in hypocontractile/acontractile bladder (detrusor hyporeflexia). Note the low detrusor-voiding pressure with low urinary flow rate; one of the patterns in spinal cord injury.

During this acute spinal shock phase, the patient experiences flaccid paralysis below the level of injury, and the somatic reflex activity is either depressed or absent. The anal or bulbocavernosus reflex is typically absent. The autonomic activity is depressed, resulting in acute urinary retention and constipation. Urodynamic findings are consistent with acontractile detrusor (Fig. 9). The internal smooth and external urethral striated sphincteric activities, however, are normal. The spinal shock phase typically lasts for 6 to 12 weeks; it may be prolonged in some cases. The urinary bladder is managed either by indwelling urethral catheter or by CIC. The bladder function returns with reflex excitability and detrusor hyper-reflexia following the spinal shock phase (Fig. 8). Depending on the level of the lesion, the individual may develop DSD–DH and urinary leakage between CIC. Periodic UDS is indicated to monitor the effect of this alteration on detrusor behavior. During UDS, intravesical instillation of cold saline may indicate return of reflex activity or help better characterize the lesion. Suprasacral lesions may result initially in acontractile detrusor, which progresses to detrusor overactivity over time. Conversely, sacral cord lesions are associated with acontractile bladders, which may become hypertonic over time.

Spinal Cord Lesions (Above the Sixth Thoracic Vertebrae) A complete cord transection above the sixth thoracic vertebrae (T6) most often will result in urodynamic findings of neurogenic detrusor overactivity and striated and smooth muscle sphincter dyssynergia (Fig. 2). A unique complication of T6 injury is autonomic dysreflexia. Autonomic dysreflexia is an exaggerated sympathetic response to any stimuli below the level of the lesion. This occurs most commonly with lesions of the cervical cord. Often, the inciting event is instrumentation of the urinary bladder or the rectum, causing visceral distention. Symptoms of autonomic dysreflexia include sweating, headache, hypertension, and reflex bradycardia. Acute management of autonomic dysreflexia is to decompress the bladder or rectum. Decompression usually will reverse the effects of unopposed sympathetic outflow. If additional measures are required,

Chapter 39: Neurogenic Lower Urinary Tract Dysfunction

parenteral ganglionic or adrenergic blocking agents, such as chlorpromazine, may be used. Oral blocking agents, including terazosin, may be used for prophylactically treating patients with autonomic dysreflexia. Alternatively, a spinal anesthetic may be used as a prophylactic measure whenever bladder instrumentation is considered.

Spinal Cord Lesions (Below T6) Spinal cord lesions below T6 level reveal urodynamic findings of detrusor hyper-reflexia (Fig. 8), SS dyssynergia (Fig. 2), and smooth sphincter dyssynergia but no autonomic dysreflexia. Neurologic evaluation reveals skeletal muscle spasticity with hyper-reflexic deep tendon reflexes, extensor plantar response, and positive Babinski sign, and above all, incomplete bladder emptying secondary to DSD, or loss of facilitatory input from higher centers. The cornerstone of treatment involves CIC and anticholinergic medications.

Multiple Sclerosis MS is caused by focal demyelination of the CNS. It most commonly involves the posterior and lateral columns of the cervical spinal cord. Usually, poor correlation exists between the clinical symptoms and urodynamic findings. Thus, using UDS to evaluate patients with MS is critical. The most common urodynamic finding is detrusor hyperreflexia (Fig. 8), occurring in as many as 50% to 90% of MS patients. About 50% of these patients will demonstrate DSD–DH. Detrusor areflexia occurs in 20% to 30% of cases. The optimum therapy for a patient with MS and neurogenic voiding dysfunction must be individualized, based on the urodynamic findings.

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ganglia or the sacral nerves. Sacral nerve involvement leads to impairment of detrusor function. The early stages of herpes infection are associated with LUT symptoms of urinary frequency, urgency, and urge incontinence, whereas the late stage is characterized by decreased bladder sensation, increased residual urine, and urinary retention. Urinary retention is self-limited and will resolve spontaneously with resolution of the herpes infection.

Herniated Disc Slow and progressive herniation of the lumbar disc may cause irritation of the sacral nerves resulting in detrusor hyper-reflexia. Conversely, acute compression of the sacral roots associated with deceleration trauma or pathologic fracture impairs nerve conduction, which results in detrusor areflexia. A typical urodynamic finding of sacral nerve injury is acontractile detrusor with intact bladder sensation (Fig. 9). Association with internal sphincter denervation may occur. Damage of the peripheral sympathetic nerves results in an open and nonfunctional internal sphincter. Peripheral sympathetic nerve damage often occurs in association with detrusor denervation. The SS, however, is preserved.

Pelvic Surgery Major pelvic surgery such as radical hysterectomy, abdominoperineal resection, proctocolectomy, or total exenteration will usually result in varying degrees of bladder dysfunction postoperatively. Most commonly, postsurgical symptoms of acontractile detrusor occur. However, spontaneous recovery of function occurs within six months after surgery in about 80% of the patients.

Peripheral Nerve Lesions

CLASSIFICATION OF NLUTD

Peripheral nerve lesions due to diabetes mellitus, tabes dorsalis, herpes zoster, herniated lumbar disk disease, and radical pelvic surgery result in detrusor areflexia.

Numerous schemes have been proposed to classify neurological voiding dysfunction (Table 2) (14–20). Neurourological classifications are predicated based upon descriptive detrusor pathophysiology as well as the site of the neurologic disease. Table 2 summarizes the historic six classification schemes, from the ‘‘neurologic’’ of Bradley to the ‘‘functional’’ of Wein. We have adopted for this chapter the functional classification proposed by Wein (20), which is based on the ability of the patient to either store urine in the bladder or empty the bladder completely. This classification must depend on the technological advances in modern urodynamics including videofluoroscopy and electromyography (EMG), which allow descriptive urodynamic interpretation of McClellan–Lapides nomenclature (1,20). The specific urodynamic interpretation enables appropriate therapeutic intervention for the patient with NLUTD.

Diabetic Cystopathy Usually, neurogenic bladder dysfunction occurs 10 or more years after the onset of diabetes mellitus. Neurogenic bladder occurs because of autonomic and peripheral neuropathy. A metabolic derangement of the Schwann cell results in segmental demyelination and impaired nerve conduction. The first symptoms of diabetic cystopathy are loss of sensation of bladder fullness followed by loss of motor function. Classic urodynamic findings associated with this condition are elevated residual urine, decreased bladder sensation, impaired detrusor contractility, and, eventually, acontractile detrusor (Fig. 9). Paradoxically, DHIC may occur. Treatment of diabetic cystopathy is CIC, long-term indwelling catheterization, or urinary diversion.

Tabes Dorsalis (Neurosyphilis) In tabes dorsalis, central and peripheral nerve conduction is impaired, resulting in decreased bladder sensation and increased voiding intervals. The most common urodynamic finding associated with neurosyphilis is detrusor areflexia with normal striated sphincteric function.

Herpes Zoster Herpes zoster is a neuropathy associated with painful vesicular eruptions in the dermal distribution of the affected nerve. The herpes virus lies dormant in the dorsal root

DIAGNOSIS OF NLUTD History Both in congenital and acquired NLUTD, early diagnosis and treatment are essential because irreversible changes may occur in children with myelomeningocele, but also in patients with traumatic spinal cord injury. Symptoms of neurogenic bladder range from detrusor underactivity to overactivity, depending on the site of neurologic insult. The striated urinary sphincter also may be affected, resulting in sphincter underactivity or overactivity and loss of coordination with bladder detrusor function. The appropriate therapy and a successful outcome are predicated upon accurate diagnosis through thorough history and physical

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Table 2 Major Classification Schemes Bradley (14) Loop 1: Frontal lobe Brainstem

Loop 2: Brainstem–detrusor nucleus (sacral cord) Loop 3: Detrusor–pudendal nucleus (sacral cord)

Loop 4A: Frontal lobe– pudendal nucleus 4B: Pudendal-pudendal

Gibbon (15)

McClellan/Lapides (17,18)

Krane/Siroky (19)

Wein (20)

Suprasacral lesion

Upper motor neuron lesion—complete vs. incomplete; balanced vs. imbalanced

Uninhibited NB Reflex NB

Detrusor hyper-reflexia (or normoreflexia) Coordinated sphincters Striated sphincter dyssynergia Smoother sphincter dyssynergia

Failure to store bladder outlet

Sacral lesion Motor sensory

Lower motor neuron lesion—complete vs. incomplete; balanced vs. imbalanced Mixed lesion

Autonomous NB Motor paralytic bladder Sensory NB

Detrusor areflexia Coordinated sphincters Nonrelaxing striated sphincter

Failure to empty bladder outlet

Mixed lesion

Bors/Comarr (14)

Denervated striated sphincter

Abbreviation: NB, neurogenic bladder.

examination with a variety of clinical evaluations, including urodynamics and selective radiographic imaging studies. The general history should include questions relevant to neurological and congenital abnormalities, information on the previous occurrence and frequency of urinary infections, and on relevant past surgery. Specific urinary history consists of symptoms related to both the storage and emptying functions of the LUT. The onset and the nature of the NLUTD (acute or insidious) should be determined. Specific symptoms and signs must be assessed in NLUTD and, if appropriate, be compared with the patient’s condition before the NLUTD developed. Voiding symptoms of hesitancy, stranguria, decrease in the force and caliber of urinary stream, incomplete bladder emptying, or frank urinary retention suggest differential diagnosis that must include bladder outlet obstruction due to benign prostatic enlargement, prostate cancer, or urethral stricture and neurologic bladder disease. Specific signs such as pain, dysuria, infection, hematuria, or fever may justify further specialized work-up. The history must rule out congenital anomalies or metabolic disorders with possible neurological implications. Also, the history must include present medications, particularly those with known or possible effects on the LUT, and lifestyle factors such as smoking, alcohol, or addictive drug use. The general history should also include the assessment of menstrual, sexual, and bowel function, and obstetric history. Importance of bowel history must be stressed here because patients with NLUTD may suffer from a related neurogenic condition of the lower gastrointestinal tract. The bowel history also must address symptoms related to the storage and the evacuation functions and specific symptoms and signs including anorectal symptoms, previous defecation pattern, fecal incontinence, and rectal sensation. Mode and type of defecation must be compared with the patient’s condition before the neurogenic dysfunction developed. Hereditary or familial risk factors should be recorded. Like the bowel function, the sexual function may also be impaired because of the neurogenic condition. The details of this history of course differ between men and women. However, such a focused evaluation should elicit information on genital or sexual dysfunction symptoms, previous sexual function, sensation in the genital area, and

for sexual functions and erectile, orgasmic, or ejaculatory dysfunction. Specific neurologic history should concentrate on eliciting information regarding acquired or congenital neurologic conditions, neurological symptoms (somatic and sensory), with onset, evolution, and therapy, as well as spasticity or autonomic dysreflexia (lesion level above T6).

Physical Examination A complete and thorough general physical examination must be performed with special emphasis on the urologic and neurologic systems. Performance of a general urological and, when appropriate, gynecological examination is expected in every case. Attention should be paid to the patient’s physical and possible mental handicaps with respect to planned diagnostic investigations. Impaired mobility, particularly in the hips, or extreme spasticity may lead to problems in patient positioning in the urodynamics laboratory. Patients with very high neurological lesions may suffer from a significant drop in blood pressure when moved in a sitting or standing position. Subjective indications of bladder-filling sensations may be impossible in retarded patients. Prostate palpation or observation of pelvic organ descensus is made. The neurourologic examination should investigate the motor and sensory functions of the body and —the limbs, and the hand function. The examination should include the assessment of perineal sensation, the perineal reflexes supplied by the sacral segments S2 to S4, and anal sphincter tone and control.

Laboratory and Radiologic Evaluation In the patient with LUT dysfunctional voiding, laboratory evaluation must include urinalysis and urine culture to rule out urinary tract infection (UTI) that can cause irritative voiding symptoms and urge incontinence. Urine cytology must exclude the diagnosis of carcinoma-in-situ of the urinary bladder, particularly in those patients with hematuria and/or irritative voiding symptoms that are out of proportion to the overall clinical presentation. Cystoscopy is also indicated in the evaluation of this subset of patients. Determination of serum creatinine and blood urea nitrogen

Chapter 39: Neurogenic Lower Urinary Tract Dysfunction

allows important assessment of renal function, which could be impaired in the patient with neurologic bladder dysfunction. Fasting blood glucose may be necessary to rule out diabetes mellitus, and serum serologic test for syphilis may be indicated. Intravenous urogram (IVU) has remained the standard imaging modality to assess the upper urinary system for changes due to neurologic bladder disease. Renal sonogram, which is the screening modality of choice in children, and magnetic resonance imaging (MRI) can be utilized in the patients who may have a contraindication to IVU or impaired renal function. Imaging study is indicated to rule out hydronephrosis, urinary tract stones, and renal scarring from chronic pyelonephritis. Voiding cystourethrogram (VCUG) is indicated to rule out vesicoureteral reflux in children with congenital neurological defect such as myelodysplasia. Additional specialized neurological studies such as head or spine computed tomography scan, MRI, myelogram, or EMG may be indicated to rule out or confirm specific neurological disease. However, long-term follow-up of these patients should include regular periodic imaging of the kidneys and the bladder to rule out stones, hydronephrosis, or masses.

Voiding Studies Uroflometry (UFR) (Fig. 10) with assessment of postvoid residual (PVR) urine remains a useful test to rule out bladder obstruction in the differential diagnosis of LUT dysfunction. This test gives a first impression of the voiding function and is mandatory before any invasive urodynamics is planned. For reliable information, it should be repeated at least two to three times. Possible pathologic findings include low flow rate, low voided volume, intermittent flow, hesitancy, and elevated PVR urine (Fig. 11). Care must be taken in judging the results in patients who are not able to void in a normal position. Both the flow pattern and the flow rate may be modified by inappropriate position and by any construction to divert the flow. More often, UFR and PVR are performed as a part of the complex UDS, which generates other useful clinical parameters such as intravesical pressure, pelvic floor EMG, and VCUG monitored with fluoroscopy.

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Figure 11 Pressure–flow study in bladder outlet obstruction. Note the high detrusor-voiding pressure and low urinary flow rate; the computergenerated graph is compared to the International Continence Society Standards and Schafer’s Nomograms to objectively document the degree of obstruction.

cord injury above T6 may exhibit autonomic dysreflexia, which is characterized by hypertension, bradycardia, sweating, pounding headache, and piloerection among others following certain stimuli such as bladder distension and stimulation of lower portions of the body. Such patients should have blood pressure monitored during the study. The rectal ampulla should be empty of stool before the UDS. Drugs that influence the LUT function should be discontinued, if feasible, at least 48 hours before the investigation or otherwise be taken into account for the interpretation of the data. All urodynamic findings must be reported in detail and performed according to the International Continence Society technical recommendations and standards.

Urodynamic Tests Cystometry Cystometry is the method by which the pressure–volume relationship of the bladder is measured and is used to assess

Urodynamic Studies UDS (Fig. 12) objectively assesses the LUT function. It is important to know that during UDS patients with spinal

25 ml/s Flow Rate

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10

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25 ml/s Flow Rate

0

10

20

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40 Time (s)

Figure 10 Normal free uroflow curve (‘‘bell-shaped’’). The uroflow curve is bell shaped; important parameters to note include maximum flow rate (Qmax), voided volume, and postvoid residual volume.

Figure 12 Normal pressure–flow study. Pdet is normally very low until the end-filling stage of the pressure–flow study, and there is a sustained and effective detrusor contraction with the command to void resulting in urinary flow and relaxation of the external urethral sphincter.

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detrusor activity, sensation, capacity, and compliance (Figs. 7 and 12). Filling Cystometry. An average adult bladder holds approximately 350 to 500 mL of urine. During the test, provocative maneuvers help to unveil bladder instability (Fig. 13A and B). Filling cytometry is important if combined with bladder pressure measurement during micturition (pressure– flow study) and videourodynamics. The latter is necessary to document the status of the LUT function during the filling phase. The bladder should be empty at the start of filling. A relatively physiologic filling rate (< 35 mL/min) should be used with body-warm saline, because fast-filling and room-temperature saline are provocative. Possible pathologic findings during filling cystometry include detrusor overactivity, low detrusor compliance, abnormal bladder sensation, and incontinence and incompetent or relaxing urethra.

Figure 14 Valsalva (abdominal) leak point pressure measurement. The lowest abdominal pressure (Pabd) at which leak is noted with Valsalva maneuver during bladder filling is called valsalva (abdominal) leak point pressure; VLPP of less than 20–30 cmH2O indicates severe intrinsic sphincter deficiency and results in stress urinary incontinence. Abbreviation: VLPP, Valsalva leak point pressure.

LPP Measurements Abdominal or Valsalva Leak Point Pressure. The abdominal pressure (Pabd) at which leak is noted during bladder filling is known as abdominal (or Valsalva) leak point pressure (VLPP) (Fig. 14). This test is useful in patients with urinary incontinence and helps to assess intrinsic sphincter dysfunction. In addition, VLPP of more than 70 to 80 cmH2O carries the risk of upper tract damage. However, there is currently no uniform consensus regarding the methodology of measurement LPP. Detrusor Leak Point Pressure (DLPP). This specific investigation is important to estimate the risk for the upper urinary tract or for secondary bladder damage. The DLPP greater than 40 cmH2O places the upper tract at risk of damage. The DLPP is only a screening test, because it lacks information on the duration of the high pressure that might have more impact on the upper urinary tract. A high DLPP warrants further testing, including videourodynamics to document any associated vesicoureteral reflux.

Figure 13 (A) Normal stable detrusor with normal compliance during filling cystometry. Note the stable detrusor during the filling stage with low detrusor pressure and normal compliance. (B) Poor detrusor compliance. Note the rise in the detrusor pressure (Pdet) during the filling stage; this may be seen in spinal cord injury and interstitial cystitis and may coexist with detrusor overactivity.

Pressure–Flow Study Pressure–flow study reflects the coordination between the detrusor and the urethra or pelvic floor during the voiding phase. This is the only test that can assess bladder contractility and the severity of a bladder outlet obstruction. Pressure–flow study simultaneously records the voiding detrusor pressure and the rate of urinary flow (Fig. 9). Pressure–flow studies can be combined with voiding cystogram and videourodynamics for complicated cases of urinary incontinence. It is even more powerful in combination with filling cystometry and videourodynamics. Possible pathologic findings include detrusor underactivity/ contractility, DSD, nonrelaxing urethra, and residual urine. Most types of bladder obstruction caused by NLUTD are due to DSD or static/nonrelaxing urethra or bladder neck. Pressure–flow analysis mostly assesses the severity of the mechanical obstruction caused by the urethra’s inherent mechanical or anatomic obstruction, and has limited value in patients with NLUTD. Sphincter EMG The cystometrogram may be performed simultaneously with EMG to assess the activity of the external urethral SS, the periurethral striated musculature, the anal sphincter, or

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the striated pelvic floor muscles during micturition (Fig. 2). Normally, the pelvic floor striated muscle electromyographic activity diminishes at the onset of bladder detrusor contraction. Bladder outlet obstruction due to detrusor–external sphincter dyssynergia is diagnosed by persistence of the activity on the EMG during voiding or attempt to void.

also pivotal in the prevention of UTI and perineal area skin infections. Despite the varied neuropathies detected in the patient with NLUTD, a simple practical scheme for their management is based on the premise that NLUTD results primarily in failure to either empty or store urine.

Video Urodynamics This combination of filling cystometry and pressure–flow study with LUT imaging is the gold standard urodynamic investigation in NLUTD. This complex testing combines VCUG and multichannel urodynamics (Fig. 2). The procedure enables documentation of the anatomic and functional integrity of the LUT, as well as the functional pressure–flow relationship between the bladder, the bladder outlet, and urethra. The VCUG can identify a bladder diverticulum, urethral diverticulum, urethral obstruction, and vesicoureteral reflux.

Failure to Empty Assisted Bladder Emptying

Provocative Tests During Urodynamics Coughing, triggered voiding, or anal stretch can provoke LUT dysfunction. Fast-filling cystometry with cooled saline (the ‘‘ice water test’’) is considered a discriminative test between an upper motor neuron lesion (UMNL) and a lower motor neuron lesion (LMNL). Patients with UMNL with intact detrusor muscle will exhibit detrusor contraction, whereas patients with LMNL will not. The test gives false-positive results in young children (21) and may not be fully discriminative in other patients (21). A positive bethanechol supersensitivity test (detrusor contraction more than 15 cmH2O over baseline) was presumed to prove detrusor denervation hypersensitivity, the intactness of the motor innervation of the bladder, and the muscular integrity of an acontractile detrusor. The test often gives equivocal results, and other clinical conditions such as cystitis magnify its false positivity. A recent variation of this method was reported with intravesical electromotive administration of the bethanechol (8). This test turned out to be both selective and predictive for successful oral bethanechol treatment.

Incomplete bladder emptying is a serious risk factor for UTI, for developing high intravesical pressure during the filling phase, and for incontinence. The method of choice to improve the voiding process should be based on practicality, the subject’s compliance, and, most importantly, on longterm clinical impact. Third-Party Bladder Expression (Crede´ Maneuver) Regretfully, this method is still applied, foremost in infants and young children with myelomeningocele and sometimes in tetraplegics. The suprapubic downward compression of the lower abdomen leads to an increase in the intravesical pressure, but also causes a compression of the urethra and thus a functional obstruction that may reinforce an already existing high bladder outlet resistance and lead to inefficient emptying. Because of the high pressures that may be created during this maneuver, it is potentially hazardous for the urinary tract, and thus is contraindicated. Although it is a noninvasive method, its use should be discouraged unless urodynamics shows intravesical pressures to stay within the safe range. Abdominal Straining (Valsalva) In recommending voiding by abdominal straining, the considerations mentioned under Crede´ above also hold for the Valsalva maneuver. Most of these patients are unable to scale the pressure they exert on the bladder during Valsalva; therefore, there is the inherent risk of exceeding the safe range.

MANAGEMENT OF NLUTD The primary aims for treatment of NLUTD include protection of the upper urinary tract, improvement of urinary continence, improvement of the patient’s quality of life, and restoration of the normal LUT function. Preservation of the upper urinary tract function is of paramount importance. Until 25 years ago, renal failure remained the primary long-term cause of mortality in the spinal cord–injured patient surviving the initial trauma. This has led to the golden rule in the treatment of NLUTD: assure that the detrusor pressure remains within safe limits during both the filling phase and the voiding phase. This approach has indeed significantly reduced the mortality and morbidity from urological complications in this patient group. Bladder dysfunction can result in hydronephrosis, vesicoureteral reflux, infections, or stones. In patients with high detrusor pressure during the filling phase (detrusor overactivity, low detrusor compliance, etc.) or during the voiding phase (DSD and other causes of bladder outlet obstruction), therapy is aimed primarily at the conversion of an active, aggressive high-pressure bladder into a passive low-pressure reservoir despite the resulting residual urine, which can be managed by CIC. Therapy of urinary incontinence is important for the social rehabilitation of the patient and thus contributes substantially to the quality of life, but is

Triggered Reflex Voiding Stimulation of the sacral or lumbar dermatomes in patients with UMNL can elicit reflex contraction of the detrusor. Morbidity occurs more often during the first decades of treatment. This method may be used in patients in whom it is urodynamically safe.

Catheter Drainage Indwelling Continuous Catheter Drainage Indwelling continuous catheter drainage (urethral or suprapubic), in general, remains attractive for practicality and effectiveness in the short term. The most common use of a suprapubic catheter is in individuals with spinal cord injuries (paraplegic and quadriplegic) and a malfunctioning bladder. A long-term suprapubic catheter remains an attractive alternative to a long-term indwelling urethral catheter. However, use of smaller (e.g., 14F and 16F) tubes is recommended for either drainage method. In male patients, longterm continuous urethral catheterization is associated with high complication rates of urethral strictures, fistulas, bladder stones, and infection. Although rare, malignancy can also occur with chronic indwelling urethral catheters. This is especially true in paraplegic women (21). In 6 out of 59 patients who had a chronic indwelling urethral catheter

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(22), squamous cell carcinoma developed. In another study, squamous metaplasia and leukoplakia developed in 11 out of 81 spinal cord–injured patients with a chronic indwelling catheter (23). Bacteriuria occurs within 72 hours of placement of a continuous indwelling urethral catheter, and consequently chronic inflammation can result in a contracted fibrotic bladder. Finally, urinary incontinence associated with bladder spasms often is treated by increasing the balloon size with some traction on the catheter, which predisposes to erosion of the bladder neck. Potential complications with chronic suprapubic catheterization are similar to those associated with indwelling urethral catheters, including leakage around the catheter, bladder stone formation, UTI, and catheter obstruction. However, with a suprapubic catheter, the risk of urethral damage is eliminated; because the catheter comes out of the lower abdomen rather than the penis or vaginal area, a suprapubic tube is more patient-friendly. Bladder spasms occur less often because the suprapubic catheter does not irritate the trigone, as does the urethral catheter. In addition, suprapubic tubes are more sanitary for the individual, and bladder infections are minimized because the tube is away from the perineum. Nonetheless, suprapubic tube neither prevents bladder spasms from occurring in unstable bladders nor improves the urethral closure mechanism in an incompetent urethra. If the suprapubic tube falls out inadvertently, the exit hole of the tube will seal up and close quickly within 24 hours if the tube is not replaced with a new one. Regardless of the method employed, the catheter should be changed very regularly, at least once a month. Management with chronic continuous catheter drainage is a risk factor also for renal deterioration. Investigators have reported significant differences in renal scarring and caliectasis in spinal cord–injured patients managed by chronic catheterization versus those using a reflex avoiding method (24,25). Because of the deleterious effects of chronic continuous catheter drainage in this particular patient subgroup, it should be avoided at all costs. Intermittent Catheterization Intermittent catheterization or self-catheterization is a mode of draining the bladder at timed intervals, as opposed to continuous bladder drainage. Intermittent catheterization has become a healthy alternative to indwelling catheters for individuals with chronic urinary retention due to an obstructed bladder, a hypocontractile bladder, or a nonfunctioning bladder. Of the three possible options, i.e., urethral catheter, suprapubic tube, and intermittent catheterization, the latter is the best solution for bladder decompression of a motivated individual who is not physically handicapped or mentally impaired. A prerequisite for self-catheterization is the patient’s ability to use their hands and arms; however, in a situation in which a patient is physically or mentally impaired, a caregiver or health professional can perform intermittent catheterization for the patient. Many studies of young individuals with spinal cord injuries have shown that intermittent catheterization is preferable to indwelling catheters (i.e., urethral catheter and suprapubic tube) for both men and women, including young children with myelomeningocele. Intermittent catheterization may be performed using a soft red-rubber catheter or a short, rigid, plastic catheter. The use of plastic catheters is preferable to red rubber catheters, because they are easier to clean and last longer. The bladder must be drained on a regular basis, either based on a timed interval (e.g., on awakening, every three to six hours during the day, and before bed) or based

on bladder volume, which must be kept at less than 400 to 500 cc during each session. CIC results in lower rates of infection than the rates noted with indwelling catheters. However, all patients should be placed on an antibiotic prophylaxis using an agent such as nitrofurantoin for the initial few weeks, to allow the LUT acclimatization to the bacterial colonization.

Pharmacologic Therapy Aiding Bladder Emptying Acetylcholine mediates the stimulation of the muscarinic, M3-subtype receptors of the detrusor smooth muscles, which results in physiologic bladder contraction and voiding. Activation of the M2-subtype receptor inhibits bladder relaxation through inhibition of the signal transduction pathways, leading to accumulation of cyclic adenosine monophosphate (1,12). Neural injury or denervation leads to upregulation of the M2 receptors. Pharmacologic manipulation involving direct stimulation of the muscarinic receptors would enhance detrusor contraction and bladder emptying. Therefore, useful agents would seem to be those that mimic the action of acetylcholine. Bethanechol chloride is the most commonly recommended acetylcholine-like drug for those patients with failure to empty due to impaired detrusor contractility. Bethanechol exhibits relative selectivity in the bladder, with minimal effect at the level of neural ganglia and cardiovascular targets. Furthermore, bethanechol in doses of 5 to 10 mg has been employed in the treatment of patients with postoperative or postpartum urinary retention. Although, it has remained for many decades the primary therapy in those patients with atonic or hypotonic bladders (26), doubts have continually persisted about its clinical efficacy in aiding bladder emptying. Controversy has also surrounded the use of bethanechol for inducing reflex bladder contraction in patients with supraspinal spinal cord injury, and experience has shown that this agent should not be recommended in those patients with overactive bladder associated with poor compliance, because of the potential deterioration of the upper tract by the rising intravesical pressure. Overall, there is no solid clinical evidence to support the use of bethanechol as a parasympathomimetic agent to aid in the physiologic emptying of the neurogenic bladder. Decreasing Bladder Outlet Resistance In contrast to using a parasympathomimetic agent to stimulate bladder emptying, alpha-blockers have been used with partial success in an attempt to decrease bladder outlet resistance in patients with neurovesical dysfunction. The rationale for these drugs is that increased bladder outlet resistance occurs in response to the stimulation of sympathetic reflexes, and the alpha-adrenergic receptors primarily inhibit the pelvic parasympathetic ganglionic transmission with a resultant increased relaxation of the bladder body and efficient urine storage. Prazosin hydrochloride, terazosin, doxazosin, and alfuzosin are antihypertensive agents with affinity for the postsynaptic a1-adrenergic receptors. These a1-receptor antagonists relax the smooth muscle of the bladder outlet and urethra, and thus lower the outlet resistance. Terazosin and doxazosin are the commonly used alpha-blockers for lowering the outlet resistance and aiding in bladder emptying. Further, these drugs have longer half-lives (12 hours), which improve compliance, and are thus well tolerated. The commonest side effects include asthenia, orthostatic hypotension, and dizziness.

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The doses are usually titrated from 1 to 10 mg with the average dose at 5 mg; the patients are usually instructed to take it at bedtime to minimize the side effects.

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the stimulation parameters, this method can also induce defecation or erection.

Surgical Management Decreasing Outlet Resistance at the SS The centrally acting muscle relaxants such as chlordiazepoxide, methocarbamol, orphenadrine, and diazepam are oral agents that cause relaxation of the striated muscles of the pelvic floor. Dantrolene sodium, which is the most commonly used skeletal muscle relaxant in patients with classic detrusor–SS dyssynergia, has been successful in facilitating voiding in these patients. The recommended adult therapy begins with the dose of 25 mg twice daily, and slowly titrated to the maximum daily divided doses of 400 mg. Sedation is the most common side effect; however, potential adverse events include euphoria, dizziness, diarrhea, and hepatitis. The later is related to high dosage and long-term use. Baclofen, a gamma-amino-amino butyric acid agonist has been used commonly as a centrally acting agent to relax the external urethral sphincter. The purported mode of action is the inhibition of the primary afferent fibers terminal in the spinal cord, thereby abolishing any monosypnatic or polysynaptic spinal reflex activity. Treatment is usually started with a dose of 5 mg, three times a day, and titrated to a total daily dose of 60 mg. The reported benefits of baclofen in the management of neurogenic voiding dysfunction include reduction in SS activity, decrease in residual urine, abolition of hyper-reflexia and nocturia, and increase in bladder compliance. Side effects include lower extremity flaccidity (at the therapeutic doses), respiratory depression, erectile dysfunction, and constipation. Drowsiness, insomnia, rash, pruritus, dizziness, weakness, hallucination, and seizures are other potential complications of baclofen therapy.

Electrical Stimulation Currently, direct electrical stimulation to aid in complete bladder emptying in a patient with neurogenic urinary retention remains an attractive alternative to intermittent catheterization, but clinical application has been limited because of poor results and unwanted side effects. Fifty to sixty percent of patients have been reported to exhibit low residual urine volumes following application of direct electrical stimulation to treat their hypotonic or acontractile bladders. However, the collateral spread of electrical current to other pelvic organs with a low stimulus threshold often results in abdominal, pelvic, and perineal pain, desire to defecate, contraction of pelvic and leg muscles, and erections and ejaculations, making this approach less than ideal. To overcome such undesirable effects, investigators have designed devices to stimulate individual sacral nerve roots (27,28), or employ a tripolar electrode in the differential stimulation of large and small fibers with low current, e.g., anode blockade (29). Development of a patient-friendly device, low morbidity, and nearly complete bladder emptying remain the elusive goals of electrostimulation in the management of incomplete bladder emptying in patients with NLUTD. Sacral anterior root stimulation (SARS) is aimed at producing a detrusor contraction. The urethral sphincter efferents are also stimulated, but as the striated muscle relaxes faster than the smooth muscle of the detrusor, the so-called ‘‘poststimulus voiding’’ will occur. This approach has only been successful in highly selected patients. Unfortunately, by changing

External Sphincterotomy The therapeutic destruction of the external urethral SS is primarily indicated in males with incomplete bladder emptying due to suprasacral lesions, and when other management methods have failed or are impractical. The prerequisites are that there is an adequate involuntary detrusor contraction and an adequate penile shaft to anchor the external collection device, usually a condom catheter. Many patients, particularly paraplegics, with detrusor–SS dyssynergia can be successfully managed with CIC; however, recurrent episodes of UTI and upper urinary tract deterioration warrant recommendation for external sphincterotomy. External sphincterotomy has replaced pudendal neurectomy as the surgical treatment of choice for these patients. A successful acute sphincterotomy will result in a substantial improvement in bladder emptying in 70% to 90% of cases, a stable upper urinary tract, resolution of existing vesicoureteral reflux, and maintenance of sterile urine in patients with low volumes and without indwelling catheters. External sphincterotomy is usually performed endoscopically with a knife or loop electrode, or laser, preferably with laser evaporization. Tissue destruction should occur preferably at the 12 o’clock position deep through the bulk of the SS anterior-laterally from the level of verumontanum to the bulbomembranous junction. To minimize the chance of penile (paired carvenosal nerves) nerve injury with resultant impotence, the incision must avoid the 2 to 3 o’clock position on the right and the 9 to 10 o’clock position on the left urethra. Complications of this procedure include impotence in 5% to 30% of patients and urinary extravasation (30). Hemorrhage is unlikely to occur with high-powered (40–60 W) laser evaporization (Nseyo, unpublished data, 2003). Long-term complications include failure of the procedure in 50% of patients, including renal deterioration, condom catheter problems, and decreased bladder compliance. This long-term failure rate of external sphincterotomy has diminished its appeal and engendered interest in urinary diversion in the management of neurogenic urinary retention in many NLUTD patients. Cutaneous Vesicostomy CIC remains the most widely used and attractive method for the management of failure to empty in young children with neurogenic bladders. However, cutaneous vesicostomy has been an effective alternative to CIC in managing those children with a poorly emptying bladder and persistent UTIs and upper tract deterioration. The decision to perform vesicostomy should be individualized and based on clinical grounds and a satisfactory radiographic response to catheterization. In children, the dome of the bladder is easily mobilized through a small transverse skin incision; a button of the detrusor is excised and the bladder wall is sutured to the skin. This Blocksom technique, popularized by Duckett (31), has replaced the old technique, which involved a skin flap that was internalized and sutured to the bladder. The Blocksom technique has fewer complications including stromal stenosis and vesical herniation. Vesicostomy is managed with drainage of urine into the diaper and prophylactic antibiotics. At an appropriate age, when the patient can perform CIC, the vesicostomy can be closed.

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Failure to Store

Clean Intermittent Catheterization

Patients with NLUTD who fail to store urine and therefore are incontinent tend to exhibit either uninhibited bladder contractions or decreased resistance in the bladder neck and urethra. Generally, this group of patients is more difficult to treat than those whose primary problem is failure to empty.

As discussed above, often the patient with neurogenic urinary incontinence secondary to NLUTD can be treated with anticholinergic agents to induce urinary retention (failure to empty). CIC is then initiated to empty the bladder and prevent the bladder from ever reaching a volume that exerts the high reflex activity leading to urinary incontinence.

Pharmacologic Therapy

Continuous Catheter Drainage

Acetylcholine is the principal neurotransmitter that mediates bladder detrusor contractions; therefore, uninhibited bladder contractions associated with reflex NLUTD can be treated with anticholinergic agents. Clinically, the commonly used anticholinergic agents are nonselective for the muscarinic receptors, M2 and M3 subtypes, which are functionally important in the human bladder (1,12). All available anticholinergic agents with atropine-like actions bind with equal effectiveness to all subtypes of the muscarinic receptors. Treatment leads to an atropine-like response against detrusor hyperactivity with urodynamic evidence of increased volume at first sensation, decreased amplitude and uninhibited contractions, and increased total bladder capacity or compliance with attendant reduction in symptoms of urgency and urgency incontinence. Anticholinergic agents generally do not cure patients of their underlying neurogenic symptoms. In some spinal cord injury patients with decreased detrusor compliance, these agents are often used in combination with intermittent catheterization. Such a strategy may prevent loss of bladder compliance due to change in the ECM secondary to chronic urinary retention. The commonly used anticholinergic agents include oxybutynin, which has both short- and long-acting formulations, tolterodine (standard and extended releases), probantheline, and hyoscyamine. The newer formulations in recent years (darefenacin, solefenacin, trospium) have not eliminated the common side effects of anticholinergic therapy, namely dry mouth (inhibition of secretions of salivary glands), pupillary dilatation (blockade of the ocular iris sphincter muscle), blurred vision (dysfunction of the ciliary muscle of the ocular lens), tachycardia, drowsiness, and decreased gut motility. These agents also exhibit a central effect by inducing confusion in the elderly and restlessness in children. Dental problems, especially in the elderly, are attributable to dry mouth caused by the anticholinergic agents. In an effort to improve effectiveness and minimize side effects, an intravesical formulation of oxybutynin is being investigated. It should be noted that all antimuscarinic agents are contraindicated in patients with narrow-angle glaucoma and symptomatic benign prostatic enlargement. Drugs that increase bladder outlet resistance, such as the alpha-adrenergic receptor agonists, phenyl propanolamine, ephedrine, and pseudoephedrine have been used with variable results to increase adrenergic activities to achieve urine storage. The tricyclic antidepressants, such as imipramine hydrochloride, have been used to facilitate urine storage. This agent has three pharmacologic actions: (i) exhibits central and peripheral anticholinergic effects at some selective sites, (ii) blocks, at the presynaptic nerve terminals, the reuptake of neurotransmitters serotonin and noradrenaline, and (iii) binds to glutamate receptors in the CNS. The net effect of these actions is the enhancement of adrenergic activity peripherally, which leads to increased sympathomimetic action. This results in increased bladder outlet resistance (a-adrenergic receptor stimulation) and relaxation of bladder body (b-adrenergic receptor stimulation).

As discussed previously, chronic long-term continuous catheter drainage should not be the treatment of choice for dysfunctional voiding irrespective of the underlying pathophysiology. When indicated, as in the elderly, the principles and catheter care program outlined previously should be practiced.

Artificial Urinary Sphincter Selection of appropriate patients for implantation of an artificial urinary sphincter (AUS) requires a thorough neurourologic work-up to discern the uniqueness of the patient’s incontinence. The patient should appropriately meet the specific criteria of intrinsic sphincteric deficiency with normal detrusor contractility and compliance. The most commonly used AUS consists of an inflatable cuff placed around the bulbous urethra of the adult male or the bladder neck with the pressure balloon reservoir placed beneath the fascia of the abdominal muscle or in the space of Retzius (Fig. 15). The pump control is placed in the scrotum or labia. Activation occurs by compressing the pump chamber, and deactivation can be achieved by pressing the button on the side of the control assembly. Significant rises in intra-abdominal pressure during vigorous exercises or lifting will trigger urinary leakage. Overall, the success rate is reported at 97% for social dryness, with a reoperation rate of approximately 30%. However, this rate is about 55% in patients with a history of prior radiation (32).

Bladder Augmentation or Substitution (Augmentation or Substitution Cystoplasty) Bladder augmentation, by procedures such as the clam cystoplasty, is a valid option to decrease detrusor pressure and increase bladder capacity whenever more conservative approaches have failed (12,32). The results of the various procedures are very good and comparable. Scaffolds, probably of tissue-engineered material for bladder augmentation or substitution or alternative techniques are promising

Figure 15 Artificial urinary sphincter. Source: Courtesy of George S. Benson, MD, from Chapter 45 of the Second Edition.

Chapter 39: Neurogenic Lower Urinary Tract Dysfunction

future options. Replacing or expanding the bladder by intestine or other passive expandable coverage will increase the detrusor compliance and reduce the pressure effect of the detrusor overactivity. Therefore, patients with NLUTD who develop a noncompliant bladder and are at high risk for vesicoureteral reflux, hydronephrosis, and deterioration of renal function are potential candidates when conservative measures fail. Bladder substitution to create a low-pressure reservoir may be indicated in patients with a severely thick and fibrotic bladder wall. The surgical technique includes resecting most of the anterior hemisphere of the bladder and sparing the trigone, ureteric orifices and the bladder neck. The ‘‘augmentation patch’’ could be an isolated piece of ileum (ileocystoplasty), colon (colocystoplasty), or stomach (gastrocystoplasty, particularly in children) (Table 3), which is then sutured onto the residual bladder (Fig. 16). Another method known as the detrusor myectomy (autoaugmentation) is aimed at improving the shrunken bladder that is enlarged by removal of lateral detrusor tissue to free the entrapped ureter in a nonfunctional fibrotic detrusor. This procedure reduces the detrusor overactivity and increases the compliance. The augmented bladder must be emptied by CIC. Contraindications for augmentation cystoplasty include renal insufficiency, bowel disease, and inability or lack of resources to perform CIC. The inherent complications associated with these procedures include recurrent infection, stone building, perforation, diverticulum formation, possible malignant changes, and intestinal metabolic abnormalities such as mucus production and impaired bowel function.

Neural Manipulation Electrical stimulation, neuromodulation, denervation, and deafferentation constitute various neural manipulations to achieve urinary storage in patients with NLUTD and urinary incontinence. A strong contraction of the urethral sphincter and/or pelvic floor, as well as anal dilatation, manipulation of the genital region, and physical activity reflexly inhibit micturition. Whereas the first mechanism is affected by activation of efferent fibers, the latter ones are produced by activation of afferents. Electrical stimulation of the pudendal nerve afferents produces a strong inhibition of the micturition reflex and the detrusor contraction. This stimulation then might support the restoration of

Table 3 Bowel Segments Used in Various Urinary Diversion Techniques Type of urinary diversion Incontinent diversion Continent diversions Indiana pouch Kock pouch Reddy pouch Mainz pouch UCLA pouch Neobladder

Ureterosigmoidostomy Sigma-rectum pouch

Bowel segment used Ileum (Bricker’s conduit), colon (transverse colon, sigmoid colon) Cecum, ascending colon, and terminal ileum Ileum Colon Cecum, ascending colon, and terminal ileum Right colon, hepatic flexure, and terminal ileum Ileum (Studer pouch, Camey procedure, ‘‘S’’ pouch, and ‘‘M’’ pouch), colon Sigmoid colon Sigmoid colon and rectum

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Figure 16 Augmentation cystoplasty. An isolated segment of bowel is opened along its antimesenteric border and used as a ‘‘patch’’ to reconstruct the bladder. Source: Courtesy of George S. Benson, MD, from Chapter 45 of the Second Edition.

the balance between excitatory and inhibitory inputs at the spinal or supraspinal level, and it might imply that patients with incomplete lesions will benefit, but patients with complete lesions will not. Stimulation of the tibial nerve afferents has not been applied in patients with NLUTD. Sacral rhizotomy, also known as sacral deafferentation, has achieved some success in reducing detrusor overactivity, but it is used nowadays mostly as an adjuvant to SARS (27,28).

Sacral Nerve Neuromodulation (InterstimTM) (33) During sacral nerve stimulation or sacral neuromodulation, the bladder afferents are stimulated, which probably restores the correct balance between excitatory and inhibitory impulses from and to the pelvic organs at a sacral and suprasacral level, thus reducing the detrusor overactivity. It is used either as a temporary procedure using foramen electrodes with an external stimulator, with the expectation of perseverance of the changes after treatment, or as a chronic procedure with an implanted stimulator. In the latter case, a test procedure, the percutaneous nerve evaluation, with an external stimulator is performed before the implant to judge the patient’s response. This procedure also has considerable success in selected patients.

DEVICE THERAPY Inflow Device to Empty the Bladder A rare cause of incontinence is a situation where the bladder never empties completely and overflows. This problem is seen most commonly with nerve problems affecting the bladder, such as MS and spinal cord injury. Thus far, the most effective treatment to empty the bladder is CIC, three to four times per day. The inflow device, an alternative approach, sits in the urethra and allows the bladder to empty with a pump design activated by an external controller without having to catheterize to empty the bladder. The early results with this device are quite encouraging in selected patients.

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URINARY DIVERSION When no other therapy has been successful, urinary diversion must be considered for the protection of the upper tracts and for the patient’s quality of life.

Continent Diversion This should be the first choice for diversion. In patients for whom indwelling catheterization or suprapubic catheterization is the only feasible treatment option, the change to a continent diversion may be a better prospect. Some patients with limited dexterity prefer a cutaneous stoma above using the urethra for catheterization. The continent cutaneous stoma is created following various reservoir techniques (Table 3). They are constructed to create a low-pressure reservoir for urine storage and contain antireflux and continence mechanisms. The patients empty the reservoirs by periodic catheterization of the continent cutaneous stoma. The continent reservoirs are created generally from segments of ileum or colon, or combination of the segments that have been detubularized and folded into a cistern to obtain the low-pressure systems. The detubularization helps to eliminate the unidirectional peristalsis. An example of an ileal-based diversion is the Studer’s diversion (Table 3), which uses 50 to 60 cm of terminal ileum, which results in the creation of a low-pressure reservoir of 300 cc and an antireflux limb. The Indiana pouch consists of the detubularized segment of the proximal colon (cecum, ascending and a portion of the transverse), which is folded into the low-pressure reservoir (Table 3). The ureters are tunneled into the colon with an antireflux technique, whereas the ileocecal valve provides the continent mechanism, and the ileal segment is doubly imbricated or stabled over a 14-French catheter to configure the catheterizable stoma. All of the forms of continent diversion do show frequent complications, including leakage or stenosis of the ureterointestinal anastomosis or the stoma. The short-term continence rates are over 80%, and good protection of the upper urinary tract is achieved. For cosmetic reasons, the umbilicus is often used for the stoma site, but this may have a higher risk of stomal stenosis. An example of continent urinary diversion is shown in Figure 17.

Incontinent Diversion If catheterization is impossible, incontinent diversion with a urine-collection device is indicated. Fortunately, nowadays, this indication is seldom needed because many appropriate

Figure 17. Continent urinary diversion. A low-pressure reservoir is created and is emptied by intermittent catheterization of the efferent limb. Source: Courtesy of George S. Benson, MD, from Chapter 45 of the Second Edition.

alternatives can be offered. Ultimately, it could be considered in patients who are wheelchair bound or bed-ridden with intractable and untreatable incontinence, in devastated LUTs, and when the upper urinary tract is severely compromised, and in patients who refuse other therapy. Various techniques have been described for creating an incontinent urinary diversion; however, several basic principles must be observed in their construction (Table 3). The ureters are first mobilized from the deep pelvis and detached from the bladder, and one ureter is tunneled behind the colonic mesentery to lie next to the contralateral ureter. An adequate ileal or colonic segment is used for the conduit that contains the ureters implanted by the ureteral mucosa–to–bowel mucosa technique into the distal ileal portion, whereas in the colonic conduit, the ureters are tunneled to create antireflux. The proximal end of the conduit is then exteriorized and sutured to the skin to mature the cutaneous intestinal stoma. The continuity of the bowel that was chosen as the conduit is reestablished by bowel–bowel anastomosis. Urine drains continuously into a collection device over the stoma, so the surrounding skin must be protected from urine contact to prevent the aggravation of squamous metaplasia and bleeding. In ureterosigmoidostomy, the ureterointestinal anastomosis is performed similar to the colonic procedure with tunneling of the ureters and the creation of antireflux. Example of these various types of supravesical urinary diversion are shown in Figure 18.

QUALITY OF LIFE The issue of quality of life should remain a paramount consideration in the global scheme of managing patients with NLUTD. Apart from the limitations that relate directly to the neurologic pathology, the NLUTD can be treated adequately in the majority of patients and must not interfere with social independence. The life expectancy of the patient does not need to be impaired by the NLUTD. With appropriate and adequate treatment, and consequent neurourological care over the patient’s lifetime, the quality of life can be assured.

FOLLOW-UP NLUTD is an unstable condition and can vary considerably even within a relatively short period. Meticulous follow-up

Figure 18. Types of supravesical urinary diversion. (A) ileal conduit. (B) colon conduit. (C) ureterosigmoidostomy. Source: Courtesy of George S. Benson, MD, from Chapter 45 of the Second Edition.

Chapter 39: Neurogenic Lower Urinary Tract Dysfunction

and regular evaluation are necessary. Depending on the type of the underlying neurological pathology, the current clinical condition, and the stability of the NLUTD, the interval between the specific follow-up investigations should not exceed one to two years. In patients with MS and acute spinal cord injury, this interval is, of course, much shorter. Urine dipsticks should be available for the patient, and urinalysis should be performed at least every second month to check for signs of infection. The upper urinary tract, the bladder shape, and residual urine should be checked every six months. Physical examination and laboratory assessments of blood and urine should take place every year. Any sign indicating a risk factor warrants specialized investigation and/or referral to a specialist.

SUMMARY Neurogenic bladder dysfunction comprises a spectrum of diseases that can be categorized into two broad subgroups: (i) failure to empty urine properly, and (ii) failure to store urine adequately. With careful history taking and physical examination, and the prudent use of UDS, the specific abnormality in a given patient can usually be identified. Previously, supravesical urinary diversion was the common means of managing most patients with complicated neurogenic bladder disease. Newer therapeutic modalities have obviated the need for this approach except under the most unusual of circumstances. For patients with bladder emptying problems, intermittent self-catheterization and/or pharmacotherapy have offered effective therapy for most conditions. When these approaches have failed, external sphincterotomy has proved useful in selected adults, and cutaneous vesicostomy in children. In patients with bladder storage dysfunction, intermittent self-catheterization has again proved useful in many, either alone or in combination with various forms of pharmacologic manipulation. When these approaches have failed or proved inadequate, artificial urinary sphincter (AUS) implantation or augmentation cystoplasty are often warranted.

REFERENCES 1. Zderic SA, Chacko S, DiSanto ME, Wein AJ. Voiding function: relevant anatomy, physiology and molecular aspects. In: Gillenwater JY, Grayback JT, Howards SS, Mitchell ME, eds. Adult and Pediatric Urology. Philadelphia: Lippincott, Williams and Wilkins, 2002:1061. 2. Tanagho TA. The anatomy, and physiology of micturiction. Clin Obstet Gynecol 1978; 5:3. 3. Gosling JA, Chilton CP. The anatomy of the bladder, urethra and pelvic floor. In: Mundy AR, Stephenson TP, Wein AJ, eds. Urodynamics: Principles, Practice and Application. London: Churchill Livingston, 1984:3. 4. El Badawi A. Autonomic muscular innervation of the vesical outlet and its role in mictirution. In: Himnam F Jr, ed. Benign Prostatic Hypertrophy. Berlin: Springer-Verlag, 1983:330.. 5. Torrens M, Morrison JFB. The physiology of the urinary bladder. Berlin: Springer-Verlag, 1987:1. 6. Hinman F Jr. Syndromes of vesical incoordination. Urol Clin North Am 1980; 7:311. 7. Gosling JA, Dixon JS. The structure and innervation of smooth muscle in the wall of the bladder neck and proximal urethra. Br J Urol 1975; 47(5):549.

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8. Bharia NN, Bradley WE. Neuroanatomy and physiology: innervation of the urinary tract:. In: Raz S, ed. Female Urology. Philadelphia: WB Saunders, 1989:12. 9. deGroat WC. A neurologic basis for the overactive bladder. Urology 1997; 50(6A):36. 10. McGuire EJ, Herlihy E. Bladder and urethral responses to sympathetic stimulation. Invest Urol 1979; 17:9. 11. de Groat WC, Booth AM: In: Dyck PK, et al., eds: Peripheral Neuropathy, 2d ed. Philadelphia: WB Saunders, 1984:289. 12. Benson GS. Neurogenic bladder and urinary diversion. In: Miller TA, 2nd ed. Physiology Basis of Surgical Practice. 13. Steers WD, Barrett O, Wein AJ. Voiding dysfunction: diagnosis, classifications and management. In: Gillenwatter JY, Grayback JT, Howards SS, Mitchell ME, eds. Adult and Pediatric Urology. Philadelphia: Lippincott, Williams and Wilkins, 2002:1061. 14. Bors E, Comarr AE. Neurologic Urology. Baltimore: University Park Press, 1971. 15. Gibbon NOK. Nomenclature of neurogenic bladder. Urology 1976; 8:423. 16. Krane RJ, Siroky MB. Classification of neuro-urologic disorders. In: Clinical Neuro-Urology. Boston: Little, 1979: Brown. 17. Lapides J. Neuromuscular vesical and urethral dysfunction. In: Campbell MF, Harrison JH, eds. Urology. Vol. 2. 3rd ed. Philadelphia: WB Saunders, 1970. 18. McClellan FC. The Neurogenic Bladder. Springfield, IL: Charles C. Thomas, 1979. 19. Krane RJ, Siroky MB. Classification of neuro-urologic disorders. In: Krane RJ, Siroky MB, eds. Clinical Neuro-Urology. Boston: Little, Brown, 1979:143. 20. Wein AJ. Classification of neurogenic voiding dysfunction. J Urol 1981; 125:605. 21. Baldew J, Van Gelderen HH. Urinary retention without a cause in children. Br J Urol 1985; 55:200. 22. Dolin P, Darby S, Beral V. Paraplegia and squamous cell carcinoma of the bladder in the young women: findings from a case control study. Br J Cancer 1984; 70:167. 23. Jacobs SC, Kaufman JM. Complications of permanent catheter drainage in spinal cord injury patients. J Urol 1978; 119:740. 24. Broecker BH, Klein FA, Hackler RH. Cancer of the bladder in spinal cord injury patients. J Urol 1981; 125:196. 25. Chai T, Chung AK, Belville WD, et al. Compliance and complications of clean intermittent catheterization in the spinal cord injured patient. Paraplegia 1995; 33:161. 26. Timoney AG, Shaw PJ. Urological outcome in female patients with spinal cord injury: the effectiveness of intermittent catheterization. Paraplegia 1990; 28:556. 27. The clinical use of urecholine in dysfunctions of the bladder. J Urol 1949; 62:300. 28. Tahagho E, Schmidt R, Orvis B. Neural stimulation for control of voiding dysfunction: a preliminary report on 22 patients with serious neuropathic voiding disorders. J Urol 1989; 142:340. 29. Schmidt RA. Advances in genitourinary neurostimulation. Neurosurgery 1986; 18:1041. 30. Rijkholl NJM, Wijkstra H, van Kerrebroeck PEV, et al. Selective detrusor activation by sacral ventral nerve-root stimulations: results of intraoperative testing in humans during implantation of a Finetech-Brindley system. World J Urol 1998; 16:337. 31. Madersbacher H, Scott FB. Twelve o’clock sphincterotomy; technique, indications, results. Urol Int 1975; 30:75. 32. Duckett JW Jr. Cutaneous vesicostomy in childhood: the Blocksom technique. Urol Clin North Am 1974; 1:485. 33. Bushman W. Spinal cord Injury. In: Gillenwatter JY, Grayback JT, Howards SS, Mitchell ME, eds. Adult and Pediatric Urology. Philadelphia: Lippincott, Williams and Wilkins, 2002:1217. 34. Wyndale JJ, Michelsen D, Van Dromme S. Influence of sacral neuromodulation on electrosensation of the lower urinary tract. J Urol 2000; 163:221–224.

PART FIVE: The Central and Peripheral Nervous Systems

40 Pathophysiology and Management of Head Injury Egon M. R. Doppenberg, M. Ross Bullock, and William C. Broaddus

INTRODUCTION

PATHOPHYSIOLOGY General Considerations

Data on multiple causes of death, as collected and provided by the National Center for Health Statistics, show that of all injury-related deaths, at least 28% involve significant injury to the brain (1). The patients at highest risk for brain injury are between 15 and 24 years of age, with males far more often affected than females. About two million Americans are treated at hospitals in the United States every year because of a head injury, making it the most common cause of death and severe disability in adults under the age of 40 (2,3). Although 80% to 90% of those patients who are admitted to the hospital with a head injury sustain only a mild or moderate injury, the remainder will sustain permanent disability, or die after mild/moderate injury, due to secondary brain damage, caused by ischemia and/or hematoma (4,5). The great majority of death and disability occurs in those with severe head injury, which affects 200,000 people per year in the United States. Even in this severe head injury group, about a third of the patients who die will have spoken at some point during their clinical course after the injury, suggesting that secondary mechanisms are responsible for death (4,6,7). This indicates that there is a window of opportunity for intervention to treat the pathophysiology and try to restore normal physiology before secondary insults could potentially further develop. The quest for understanding the derangements in brain physiology after head injury has resulted in many gradual improvements in the medical and surgical treatment of the head-injured patient. The greatest decrease in mortality due to head trauma has occurred in patients with mild to moderate injuries. In addition to better management strategies, better imaging and diagnostic tools have contributed to the improvement in outcome for these patients (8). However, despite these advances, the outcome for severe head injury patients still remains poor, with death and severe disability affecting close to 50% (6). The limited understanding of the pathophysiological mechanisms following severe head injury is a major reason for this poor outcome after severe head injury. Better strategies to monitor and treat these patients are only possible if the pathophysiology is better understood. In neurotrauma, not only the primary impact injury but also secondary and delayed mechanisms are important to understand and treat, as a means of trying to reduce the damage that results from the injury. The present chapter focuses on these considerations.

Our current understanding of the pathophysiological events in human head injury has been developed mainly from post mortem exams, in vitro and in vivo studies in the laboratory, and studies of head-injured patients during life through imaging and monitoring. Each of these modalities has its limitations in showing the derangements in biological and structural status of the brain after head injury. For example, post mortem studies are limited due to the fact that ischemia is usually far more pronounced due to global, agonal reduction in cerebral blood flow (CBF). Therefore, more subtle and focal ischemic changes, which take place between the time of injury and the actual death, might go undetected. Also, animal models do not exactly mimic the complex mechanisms that occur in human head injury, and most often there is a combination of cascades taking place, which affect one another. Therefore, multiple trauma models are currently in use to address different aspects of trauma (9–11). The events concerned with intracellular energy metabolism, maintenance of neuronal membrane potential, and homeostasis at synapses all have been shown to play a role in various degrees in the derangements seen after human head injury. Different insults to the brain, from intracranial hematomas/contusions, ischemia or shear injury, result in different types of disturbances of the biological homeostasis of the brain. Most often, these insults play a role simultaneously in varying severity, therefore resulting in a pathophysiological state that evolves from different mechanisms.

Intracranial Hematomas and Contusions Intracranial hematomas (epidural and subdural hematomas, and hemorrhagic contusions) occur in about 30% to 45% of severely head-injured patients. They are by far the most important cause for preventable delayed secondary brain damage. Epidural and acute subdural hematomas are usually formed within the first hour after the injury, although they may enlarge over time (5,7). These mass lesions compromise the cerebral microcirculation, resulting in secondary ischemia and brain swelling. Subsequently, shifting of the brain occurs, and further occlusion of cerebrospinal fluid (CSF) pathways leads to increased intracranial pressure (ICP). In this way, a vicious cycle can begin with more ischemia and brain swelling. Epidural hematomas are usually the result of focal impact to the skull with an accompanying fracture of the cranial vault in over 80% of cases (Fig. 1). The middle

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Figure 2 Traumatic subarachnoid hemorrhage over the right convexity, with associated small acute subdural hematoma.

Figure 1 Head computed tomography scan demonstrating bilateral epidural (lentiform-shaped) hematomas with obvious depressed skull fracture over the left convexity.

meningeal artery is classically involved with temporal bone fractures, although venous hemorrhage can also cause or contribute to epidural hematomas. These hematomas can rapidly enlarge due to the frequent ‘‘arterial’’ nature of the bleeding and therefore, emergent evacuation is usually indicated. When evacuated promptly, secondary injury to the underlying brain can often be prevented, and therefore excellent outcome is frequently possible with this type of hematoma. The acute subdural hematoma is usually caused by the tearing of the bridging veins that enter the sagittal sinus or by bleeding from surface vessels as a result of focal contusions and laceration of the pia (Fig. 2) (5,12). The acute subdural hematoma has a poor prognosis with a 60% rate of death or severe disability (13). Interestingly, over 50% of all patients with an acute subdural hematoma have had a period after the injury during which they were conscious, suggesting that secondary insults are taking place, resulting in further deterioration. One explanation is that in the acute subdural hematoma model in the rat, there is a zone of focal cerebral ischemia underneath the hematoma. In this zone, a sevenfold increase in glutamate was found, leading to increased metabolic activity and further ischemic insults to the brain (10,13,14). Severe contusions may undergo delayed hemorrhage over the intermediate period from minutes to hours after impact, especially with coagulopathy (Fig. 3). Zones of ischemically damaged pyknotic shrunken neurons and swollen astrocytes are found to extend many millimeters around the margins of contusions, and this is usually associated with reduced CBF and increased metabolism leading to a flow-metabolism mismatch in the ‘‘penumbra’’ surrounding the contusion. This area may be potentially salvageable in the early stages before cell death and necrosis take place. However, the mechanisms involved in this process are not yet fully understood (5,15,16).

Supratentorial contusions and hematomas may induce brain shift either laterally or in a rostrocaudal direction. Lateral shift causes subfalcine herniation with consequent ischemic damage to the cingulate gyrus of the limbic system (6). Uncal transtentorial herniation is a combination of lateral and rostrocaudal shift, which pushes the medial para-hippocampal gyrus of the temporal lobe through the tentorial hiatus alongside the brain stem. This process causes, ipsilaterally, a fixed dilated pupil, as the

Figure 3 Head computed tomography scan. Right posterior temporal contusions. Note the hypodens surrounding edema.

Chapter 40: Pathophysiology and Management of Head Injury

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Figure 4 (A) Head computed tomography (CT) scan of a two-year old unrestrained female involved in a motor vehicle accident, with massive traumatic subarachnoid hemorrhage. A cerebral angiogram was performed, excluding traumatic aneurysm. (B) Same patient two months later. Head CT scan shows severely enlarged ventricles due to communicating hydrocephalus.

cardinal clinical sign for a mass lesion. If there is not an immediate decompression, irreversible ischemic damage occurs within the brain stem, and may be associated with the classical ‘‘flame-shaped’’ hemorrhage of Duret in the pons. Such brainstem hemorrhages are ominous and these patients usually die or remain in a persistent vegetative state. Herniation seldom occurs when ICP is less than 40 mmHg (normal 4–12 mmHg), but it may develop sooner in the presence of mass lesions within the temporal lobe and when there has been swelling of bilateral, frontal, and temporal lobes to cause anteroposterior shift. Vasospasm has been shown to occur in about 30% of patients with severe head injury (17). It is more frequent in patients who have suffered an extensive subarachnoid hemorrhage (Fig. 4A). The proximal vessels on the pial surface, or around the Circle of Willis are frequently involved. If imaging studies reveal a significant amount of blood in the subarachnoid spaces in a patient, a cerebral angiogram may be warranted to exclude a traumatic arterial aneurysm. Traumatic aneurysms typically arise at the skull base or from distal anterior or middle cerebral arteries or branches consequent to direct mural injury or to acceleration-induced shear. Once diagnosed, these aneurysms should be treated immediately either through surgical or through an endovascular approach. Posttraumatic hydrocephalus (accumulation of CSF and dilatation of the cerebral ventricular system) due to traumatic subarachnoid hemorrhage is a frequent phenomenon that clearly worsens outcome. The blood load can cause arachnoiditis of the villi and result in communicating hydrocephalus, in which ventricular dilatation develops due to poor CSF re-absorption (CSF communication between lateral ventricles and spinal canal is retained, hence the name). This can develop as late as two to three years after the initial injury. Therefore, previously head-injured patients who arrest or regress in their recovery should always be evaluated for increased ICP due to hydrocephalus with a head computed tomography (CT) scan (Fig. 4B). A careful evaluation should be made on imaging studies to not confuse the radiographic findings with ex vacuo hydrocephalus (type of hydrocephalus in which CSF replaces

volume of tissue lost) due to brain atrophy, commonly seen in patients with diffuse axonal injury. The imaging studies should show enlargement of the ventricles, transependymal flow, and effacement of the sulci. A spinal tap may be performed to measure the ICP.

Ischemia Ischemic brain damage is by far the dominant finding in patients who die after head injury, and its distribution is predominantly focal rather than global (6). The interrelationship between metabolic substrate delivery and substrate demand after traumatic brain injury (TBI) has been extensively studied both in animals and in humans. It is known that in the early phase after TBI, CBF is reduced in up to one-third of the patients (18). At the same time, glutamate release is massively increased in subgroups of patients (19). This increase in glutamate then results in increased neuronal activity. This rise in excitatory activity requires an increased metabolic rate and therefore leads to an increased substrate demand. In the absence of a commensurate increase in local CBF (the source of metabolic substrates), a flowmetabolism mismatch occurs. Massive Kþ efflux has been shown to further increase aerobic metabolism, and thereby further deteriorating the already existing discrepancy between supply and demand in brain metabolism (20). Yoshino et al. showed a marked early increase in glucose utilization, followed by a hypometabolic state after animal brain injury (21). Recently, positron emission tomography (PET) studies have shown a hyperglycolytic state of the brain after severe human head injury in as many as 56% of the patients (22). Altogether, these results clearly suggest a coupling between an increased metabolism for glucose and increased extracellular release of glutamate after TBI. Thus, the increase in lactate production seen after TBI is explained by a flow-metabolism mismatch because the increase in substrate demand cannot be met by CBF, resulting in anaerobic glycolysis and lactate generation. However, Andersen and Marmarou have shown that lactate generation is increased, following TBI in the cat, as measured by magnetic resonance (MR) spectroscopy, even when CBF was adequate to ensure substrate delivery (23). This implicates factors other than ischemia as a cause of lactate generation after TBI. This early

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Figure 5 Intraoperative photo of a 56-year-old man who sustained a fall from a ladder. Massive brain swelling is seen, with hemiation of brain tissue through the craniotomy defect.

patients, probably a relatively small number of axons are immediately torn at the moment of impact, but varying numbers are subjected to stretching due to shear forces. The majority of axonal disruption is then a consecutive delayed event that occurs over the first 24 to 48 hours after injury in humans (26). The pathological hallmark of diffuse axonal injuries is a histological picture described as retraction balls and microglial stars, and they are not seen until 12 to 24 hours after injury. Diffuse shearing injury causes widespread changes in neurotransmitter function and ionic homeostasis throughout the neuraxis and this results in instantaneous loss of axonal transport, disruption of energy metabolism, and coma or altered consciousness. Several animal studies using fluid percussion injury models have shown that the impact is immediately followed by massive release of neurotransmitters, including catecholamines, acetylcholine, and glutamate into the extracellular space (11,27). This may cause widespread depolarization with the influx of sodium and calcium ions into cells, and efflux of potassium into the extracellular space (20). This may then cause swelling of neurons and glia, which may proceed to cause brain edema, and high ICP.

Penetrating Head Injury increase in glucose utilization and lactate generation may be a consequence of the massive glutamate release, in accordance with the hypothesis of Pellerin and coworkers. They showed under physiological conditions in an in vitro study that glutamate release due to physiological stimulation results in increased lactate generation (24).

Brain Swelling Brain swelling, as diagnosed by either cistern effacement on CT scan, or by measured raised ICP, occurs in about 70% of patients with severe head injury at some time during the clinical course (Fig. 5). Even though the cause of brain swelling is not fully understood, four pathophysiological mechanisms are thought to play a role. They are vasogenic edema, cytotoxic edema, vascular engorgement, and venous occlusion. Delayed blood–brain barrier disruption is seen more frequently in patients with contusions, and is delayed for days after injury (5). In the early phase after injury, cytotoxic edema seems to be the most important component in the development of brain swelling. Vascular engorgement (hyperemia) is usually a reactive response to a prior focal or global ischemic event. One explanation is that the hyperemic response can only occur in relatively normal tissue, which has not undergone severe ischemic damage, sufficient to cause severe edema, and ‘‘low density’’ on CT (18,25). Vascular engorgement may occur in response to the release of mediators such as lactate, Hþ, adenosine diphosphate, or inflammatory products, such as cytokines, and substance P.

Diffuse Axonal Injury Brain tissue does not have the supporting structures that other organs possess, such as a collagen stroma, and it is therefore much more vulnerable to deformation and injury due to forces during trauma. Previously, diffuse axonal injury was thought to be an acute event in which widespread physical and functional disruption of axons occurred at the moment of impact. However, in severely head-injured

Penetrating head injury has become increasingly common due to increased availability of firearms. The pathophysiology of these injuries is at least in part distinctly different from that of the previously described closed injuries. The injuries can vary from those resulting from low velocity bullets (mostly civilian hand guns) and sharp objects to high velocity bullets and shrapnel in military injuries (Fig. 6A and B). Also, hematomas, cerebral contusions and, sometimes, significant vascular injuries to major blood vessels can occur. Arterial as well as venous injuries may be present, resulting in hematomas and/or subarachnoid hemorrhage. Delayed hemorrhage may also occur, due to development of pseudo aneurysms, arterial dissection, or direct laceration of a vessel or venous sinus. Intracerebral hematomas are the most frequent, followed by subdural hematomas and, to a lesser extent, epidural hematomas (28). High-velocity injuries, especially, may result in extensive fractures of the cranium. Penetrating injuries often cause a variety of injuries, including scalp lacerations and skull base fractures, sometimes complicated by transient or persistent CSF leak. ICP studies have been carried out in animal models demonstrating an immediate peak in pressure after the injury. The ICP then lowers but does not return to baseline (29). At the same time, cardiac output may be impaired despite adequate fluid resuscitation. This is thought to be due, in part, to the effects on the brain stem either through direct impact or through the ‘‘shock wave’’ produced by the traversing projectile. This combination of increased ICP and decreased cardiac output can significantly impair cerebral perfusion, leading to secondary insults with cerebral ischemia with further brain swelling and further impairment of cerebral perfusion.

GENERAL CONSIDERATIONS IN THE CARE OF THE HEAD-INJURED PATIENT The acutely injured brain has been shown to be vulnerable to so-called secondary insults (30). These insults include ischemia, hypoxia, and hypercarbia. The latter can result in increased cerebral blood volume and consequent increased ICP, leading in turn to further ischemia. The

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Figure 6 (A) and (B) Lateral skull X-ray and head computed tomography scan (bone window) showing a 45-year-old man with a penetrating crossbow arrow entering through the right orbit into the skull, ending just anterior of the brain stem. An emergent cerebral angiogram was performed, which was negative for vascular injury. The arrow was removed in the operating theatre through the entry site. This patient made a full recovery.

autoregulation of the brain to maintain its constant supply of oxygen and glucose is impaired in the head-injured patient (31). This leads to hypoperfusion of the already vulnerable brain during episodes of systemic hypotension. Several studies have shown that a large number of head-injured patients who present to a trauma center will have hypotension and/or hypoxia, resulting in a tremendous increase in morbidity and mortality from secondary injury to the brain (32–36). Airway establishment is thus the first priority in the head-injured patient. It should also be kept in mind that approximately 7% of all patients with a Glasgow coma score (GCS) of 8 or less will have a concomitant cervical spine fracture (37). Intubation should be accomplished while the patient is in a rigid collar or preferably with in-line manual cervical immobilization. Recently, several studies have been completed in which inspired oxygen fraction (FiO2) was increased in the head-injured patient. This improves brain biochemistry and outcome in animals. Also, this maneuver appears not to increase free-radical production in the injured brain tissue in animal models, despite concerns to the contrary (38–40). Systemic hypotension should be treated aggressively and rapidly, with intravenous fluid (Ringers or normal saline). Hypovolemia is the most common etiology and only rarely is the hypotension caused by the primary brain injury. The choice of intravenous fluids remains a focus of debate. Hypertonic saline has been shown to redistribute extravascular fluids back into the intravascular compartment, resulting in increased cardiac output and blood pressure (41–43). However, in the injured brain where the blood–brain barrier is disrupted, the extracellular fluid may increase with the use of hypertonic solutions, possibly exacerbating the development of cerebral edema. Contrariwise, some data from animal studies show that there may be a beneficial effect on ICP in severely head-injured patients with the use of these hyperosmotic agents (44). To date, there have been no randomized clinical trials to show a clear-cut benefit (as well as risk) for their use in head-injured patients. The main goal in the multitrauma patient is to maintain normotension and volume expansion to normal status, to ensure adequate cerebral perfusion. It is important to recognize that the fear of inducing increased ICP through aggressive fluid resuscitation to normovolemic status has been proven to be unfounded (45–47).

Furthermore, hyperglycemia may occur in diabetic and nondiabetic patients as a consequence of the physiologic stress response, which is directly related to the severity of the head injury. For this reason, hyperglycemia should be treated appropriately in the acute setting. Increased glucose levels have been linked to a worsened prognosis in animal models of brain injury, independent of the severity of the initial injury (48).

SPECIFIC MANAGEMENT OF THE HEAD-INJURED PATIENT Historically, head-injured patients have been categorized into three main subgroups using the GCS. Mild injury is categorized as 14 or 15, moderate as 9 to 13, and severe as eight or less. The details of this scoring system are summarized in Table 1. The neurological examination of the severely headinjured patient in the acute phase consists at a minimum of establishment of this score. Findings should be interpreted with the knowledge of concomitant injuries. These Table 1 Glasgow Coma Score Response Eye opening Spontaneous To sound To pain None Motor response Obeys commands Localizes pain Normal flexion (withdrawal) Abnormal flexion (decortication) Extension (decerebration) None Verbal response Oriented Confused conversation Inappropriate words Incomprehensive sounds None Source: From Ref. 49.

Points 4 3 2 1 6 5 4 3 2 1 5 4 3 2 1

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Table 2 Admission Criteria for Patient with Mild Head Injury (GCS 14 or 15) History of loss of consciousness Amnesia No reliable supervision at home Skull fracture CSF leak Penetrating head injury Abnormal CT scan No CT scanner available Deteriorating neurological status Moderate/severe headache Inability to reach medical facility quickly while at home Alcohol/drugs intoxication Abbreviations: CSF, cerebrospinal fluid; GCS, Glasgow coma score; CT, computed tomography.

include spinal cord injuries, which can impair motor response, as well as trauma to the orbit/globe, possibly resulting in iridoplegia. Also, intoxication by alcohol or other drugs, and the use of paralytics or other pharmacological agents such as atropine need to be taken into consideration. Unfortunately, the use of paralytic agents is very common, making a reliable neurological exam impossible at times. Eighty percent of the total number of patients with head trauma can be categorized as minor, meaning that they have a GCS of 14 or 15. These patients will need to be admitted for observation if they show any of the findings listed in Table 2. The moderately head-injured patient with a GCS of 9 to 13 will always require close observation, and therefore admission. These are the patients who require skillful clinical judgment and careful, close observation, usually requiring a stay in the intensive care unit (ICU). If necessary, intubation should be performed to protect the airway, with the use of continuous short-acting sedation (e.g., propofol), to ensure the possibility of intermittent neurological exams. The severely head-injured patient, with a GCS of eight or less, is by definition comatose. He is unable to follow simple commands. This patient will always require intubation, because studies have shown that up to 30% of these patients are hypoxemic on arrival in the emergency room (35). Furthermore, these patients require continuous evaluation of their volume status and therefore require continuous blood pressure monitoring as well as central venous pressure or pulmonary artery pressure monitoring. Arterial lines and central venous lines are often placed for these reasons. Mannitol should be given to patients who show localizing signs or who have a fixed pupil when they are hemodynamically stable, even prior to obtaining a CT scan. The osmotic effects of this agent can reduce ICP by decreasing edema in cerebral tissue and therefore decrease ICP and improve cerebral perfusion. Also, the rheological effects play a role in improving cerebral perfusion and therefore potentially might reduce secondary insults to the vulnerable brain (50,51). As soon as the patient is stable enough for transport to the CT scanner, a CT of the head without contrast is to be performed. In general, patients who have a significant mass lesion, with brain compression and shift of normal structures, and who are not fully neurologically intact, require emergent evacuation of these lesions through a craniotomy or craniectomy. This at times can cause ‘‘conflict of interest’’

between the neurosurgeon and trauma surgeon. Patients with a high suspicion of a mass lesion resulting in rapidly deteriorating neurological status and who are suspected to have significant thoracoabdominal injury should undergo a chest X-ray and abdominal CT, and, if necessary, should be taken the operating room to prevent secondary neurological deterioration due to cerebral hypoperfusion. For cranial surgery, the main goal of intervention is to restore the supply of substrate for brain metabolism to the brain. This implies that mass lesions causing increased intracerebral pressure, and therefore decreased cerebral perfusion pressure (CPP), will need to be evacuated as soon as possible. The effects of evacuation of these lesions on brain metabolism have been described in patients recently (52). The exact surgical techniques to perform are beyond the scope of this chapter, but aggressive decompression through a generous bone flap, together with removal of clots and nonviable brain tissue, is mandatory. The neurosurgeon may also elect to leave the bone flap out (craniectomy) for reimplantation later, after subsidence of cerebral edema. In this way, the ICP in the patient will be potentially more manageable in the days after the initial impact when the effects of secondary brain injury may develop. A large bone window can ensure that the swollen brain can expand through the craniectomy site with less chance of dramatic increases in ICP. Overall surgical treatment of gunshot wounds is similar to closed head injury with a few exceptions. First, the rule also applies that when a mass lesion is present, this should be evacuated when it causes significant compression or shift of brain structures and the patient is not fully neurologically intact. Also, bullet and skull fragments should be removed when they are readily accessible and not located in eloquent areas. Studies from Vietnam War patients have shown that less than 5% of patients developed a delayed cerebral abscess, because aggressive entry and debridement was mandatory (53). However, from these studies it became clear that the presence of retained fragments did not result in increased risk of seizures later in life. Also, obvious nonviable brain tissue in penetrating brain injury should be removed because this may help to manage ICP problems in the days after injury. Finally, dura and scalp repair or reconstruction are helpful in the prevention of CSF leak and/or infection. The surgical management of stab wounds is grossly similar to that of gun shot wounds. Debridement and dural closure are the goals during surgery. However, removal of a penetrating object requires careful evaluation of the location of the weapon. Evaluation of vascular structures, especially, is important prior to removal. Cerebral angiography or CT-angiography is mandated, whenever major intracranial vessels maybe injured, and should be performed before removal when feasible. Prophylactic perioperative ‘‘triple’’ antibiotics are frequently used, although no randomized study has shown clinical benefit.

Treatment of Increased Intracranial Pressure There is no absolute critical threshold for ICP. However, prolonged raised ICP over 20 mmHg has been shown to correlate with worsened outcome in head injury patients, and thus should be treated promptly (54). In conjunction with this, maintenance of adequate CPP (defined as mean arterial pressure minus ICP) has been shown to improve outcome (36). Obviously, every severely head-injured patient requires

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close monitoring in an ICU with trained nurses who have the expertise to deal with the challenges that come with these patients. Every patient requires continuous monitoring of all ‘‘basic’’ vital signs, including ventilation parameters [oxygen saturation and end tidal carbon dioxide (CO2)], arterial blood pressure, and central venous pressure. Furthermore, ICP needs to be monitored and any elevation should be aggressively treated. Intracranial hypertension can lead to further damage through direct mechanical impact during herniation of brain tissue as well as through further decrease of blood flow, which in turn leads to ischemia. The goal of treatment is to prevent these events. Currently several devices are available commercially to monitor the ICP reliably. Patients who should be considered for this type of monitoring are the ones with a GCS of 8 or less. Also, patients with a moderate head injury and an abnormal CT, who cannot be neurologically evaluated due to other factors, should undergo ICP monitoring. An intraventricular catheter (ventriculostomy) may be used for this purpose as previous studies and experience have validated (55). Also available are intraparenchymal transducer-tipped monitors that are more easily inserted and may be useful in patients with small ventricles. The ventriculostomy is advantageous in that it can allow treatment of elevated ICP by CSF drainage. However, the procedure to place the catheter is slightly more invasive and difficult. Both monitoring modalities are an acceptable way of following the ICP. The treatment of increased ICP is best done by a stepwise process. First and foremost, one should ensure that any increase in ICP is not due to non-neurological causes such as inadequate ventilation, labile blood pressure, agitation, or pain. Positioning with slight elevation of the head of the bed (approximately 20 degrees) can be helpful, and the use of constricting devices, such as tight cervical collars, or tape to secure the endotracheal tube around the neck, should be avoided. Second, the possibility of an expanding mass lesion needs to be ruled out through a head CT. When a ventriculostomy is in place the next step is to drain CSF to treat raised ICP. Mannitol can be given, with monitoring of electrolytes and renal function after each dose. One should also consider that patients with unexplained raised ICP do not have subclinical seizures, which may occur despite anticonvulsant therapy. Evaluation of intractable ICP elevation may also require evaluation of serum anticonvulsant levels, as well as an electroencephalogram (EEG) to exclude seizures. If the above-mentioned measures do not control the ICP, sedation and paralysis are indicated. The benefit of this is twofold. These measures will decrease cerebral metabolic rate, and ventilation is more easily managed. The arterial oxygen and CO2 partial pressures can now be more effectively controlled. For sedation, several agents can be used. First, morphine will act as both a sedative and pain reliever. However, it should not be used unless the head-injured patient is intubated and ventilated, due to the potential increase in arterial CO2. Sedatives such as propofol or midazolam decrease the cerebral metabolic rate and therefore decrease the amount of metabolic substrate delivery that is required by the brain to maintain homeostasis. This is especially of value because there may already be a flowmetabolism mismatch present in the injured brain. Propofol has the advantage that it is very short acting and therefore can be stopped intermittently to examine the patient. Midazolam is longer acting but is currently less expensive, and

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has the theoretical advantage of reducing seizure activity, which may not be clinically noticeable. Because these sedatives have no analgesic effect, a pain reliever such as morphine should always be used in conjunction with either of these agents. All of these agents may cause hypotension to some extent, and close monitoring of the blood pressure should be maintained. Paralytic agents are also frequently used, in conjunction with sedatives and analgesia for optimal ventilation, CO2 control, and reduction of elevated ICP. Vecuronium is one example of a short-acting nondepolarizing neuromuscular blocker that can be given by continuous intravenous administration. The use of an external nerve stimulator allows for monitoring adequate levels of paralysis. Hyperventilation is a means of decreasing ICP. However, there is now more and more evidence that aggressive and/or prolonged hyperventilation causes cerebral vasoconstriction, decreases CBF, and therefore worsens outcome (56,57). The use of moderate hyperventilation is appropriate and can be extremely helpful to treat elevated ICP. The recommended lower threshold for arterial CO2 is 30 to 32 mmHg (55). Mean arterial pressure needs to be maintained to ensure adequate CPP. This is primarily done by preventing/ treating hypovolemia. If there is doubt about the volume status of the patient, a Swan–Ganz catheter can be used. Usually normovolemia or slight hypervolemia will ensure adequate CPP when ICP is treated. If further increase in mean arterial blood pressure is needed to maintain CPP, pressors may be used. Dopamine and/or phenylephrine are generally effective in doing so. Dobutamine might be used in patients with decreased cardiac output. In general, based on anecdotal evidence, a CPP over 70 mmHg is accepted as adequate for the severely head-injured patient without signs of vasospasm. Moderate hypothermia (32–33
C) has failed to show improved outcome in severely head-injured patients in a recent clinical trial (58). However, it may reduce ICP. This is at least in part due to decreasing cerebral metabolic rate and possibly subsequently reducing the release of excitatory amino acids such as glutamate (59). However, the side effects are significant; they include cardiac arrhythmias and increased risk of systemic infections due to suppression of the immune system, as well as coagulopathies. Nevertheless, the use of hypothermia remains to be more fully evaluated, as a potentially useful tool whenever the abovedescribed measures fail to control the raised ICP.

Other Measures to Reduce ICP Further measures to reduce ICP may be used after the above-described treatments have failed to improve the intracranial hypertension. Their efficacy is less well proven. Decompressive craniectomies are used to give the injured brain ‘‘space to swell’’ as a method to reduce the ICP. A large bone flap is created and the dura is patched with a graft. The brain can now herniate out through the defect. There is some evidence that this measure improves outcome both in terms of morbidity and mortality (60). Induced barbiturate coma is a way to minimize brain activity and therefore the need for substrate delivery, which is compromised in these patients. It requires bedside EEG monitoring to regularly evaluate brain activity. In this way, the cerebral metabolic rate is reduced and the existing flow-metabolism mismatch is positively influenced (61). Unfortunately, this comes with the risk of major complications, such as reduced cardiac output, myocardial infarction,

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and serious systemic infections, and is therefore reserved for situations when all other measures have failed. There is no role for corticosteroid use in the treatment of raised ICP in the severely head-injured patient (62). It is now clear that the edema resulting from trauma to the brain is cytotoxic in nature and therefore not susceptible to the use of steroids that mainly acts on vasogenic edema (63).

Pharmacologic Intervention As previously stated, both shearing injury and ischemic damage have been shown to result in calcium-mediated damage to intracellular structures, massive release of glutamate, and also generation of free radicals (64–66). Selective pharmacological antagonists for both presynaptic release and postsynaptic receptor binding of glutamate have been developed. The most powerful evidence in support of glutamateinduced neurotoxicity in focal ischemia comes from many neuroprotection studies, performed with different N-methyl-D-aspartate (NMDA) and non-NMDA glutamate antagonists (67–69). NMDA antagonists are most effective when administered before the insult (especially competitive antagonists), but others have been effective when given up to two hours after the ischemic event. Newer glutamate antagonists, which block release of glutamate from presynaptic vesicles, may also show protection after global ischemia, which could not be demonstrated with the previous NMDA antagonists. Unfortunately, trials in humans using free-radical scavengers and glutamate antagonists so far have not shown significant benefit. Clearly, it is now becoming accepted that mechanism-driven trials in which individual pathophysiological mechanisms are targeted may be preferable in this heterogeneous patient population. The degree of brain penetration, the safety and tolerability of the compound, and end points used for outcome assessment are major influences upon the success of these new drugs.

MONITORING THE INJURED BRAIN In the last two decades, major advances have been made in understanding the pathophysiological mechanisms following TBI. However, the impact on clinical monitoring and management of cerebral metabolism in severely headinjured patients of this progress has been modest. The only well-established and accepted method currently available is ICP monitoring. Unfortunately, this is a relatively crude technique, and changes in ICP are only seen after major changes and derangements previously have taken place in the physiology and anatomy of the brain. As a consequence, only the final results (brain swelling) of the disturbance of the intracranial milieu are monitored. Clinically, this means that measurements that are being taken to intervene in these harmful events are by definition done relatively late, and may be too late to prevent permanent injury. This lack of sufficient monitoring for brain injury has resulted in a search for more elegant techniques, in the last decade. Another important issue is the time course of events, following trauma. However, in humans, it remains impossible to study the first events taking place immediately after injury. New monitoring devices and imaging techniques have improved the assessment of brain physiology; they include microdialysis to study the extracellular fluid content in the brain parenchyma. In this way, one can assess the levels of metabolites, amino acids, and free-radical

production in the injured brain. Measurements of brain oxygen, CO2, and pH are also being performed more widely and this has the advantage that continuous monitoring of brain is available in the ICU (19,39,40). Also, more advanced imaging studies are now deployed to evaluate these patients. For example, PET scanning is now used to study the brain metabolism in combination with its supply of nutrients, as well as MR diffusion-weighted imaging to evaluate the water/edema seen after head injury in the parenchyma (16,22,63). However, the data and results of these new monitoring devices require careful evaluation and interpretation before their use in actual treatment of these patients will be clinically helpful. Notwithstanding these findings, before any conclusions can be made from data obtained by means of these devices, a thorough and critical analysis is needed to better understand what exactly is measured and whether or not these labor-intensive and expensive techniques are helpful in understanding and treating the derangements in physiology seen after TBI.

SUMMARY Traumatic brain injury is the most common cause of death and severe disability in adults under the age 40. Because a third of patients who die from this injury will have spoken at some point during their clinical course, it seems clear that a window of opportunity exists to treat the underlying pathophysiology before secondary insults develop, which irreversibly prevent restoration of normal physiology. Although much still needs to be learned about the cascade of events that are set in motion following a traumatic brain injury, our current understanding of the pathophysiologic mechanisms that previously led to death or severe disability has been effectively utilized to institute treatment strategies so that many of these patients can become productive individuals leading normal or near normal lives. Thus, adequate fluid resuscitation to ensure euvolemia, antiseizure prophylaxis, and optimization of the blood’s oxygencarrying capacity have all contributed greatly to managing these patients. Other therapeutic measures that have evolved include the prevention of hyperthermia, maintenance of cerebral perfusion pressure above 70 mmHg, and sedation. Early ventricular drainage for elevated ICP and mild hyperventilation (PCO2 of approximately 35 mmHg) have been found to be especially beneficial in patients with a GCS of less than 8. As research continues in this important area of human disease, it is envisioned that other therapeutic alternatives will become available to salvage even more individuals in the early stages of injury when the ‘‘window of opportunity’’ is most advantageous.

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28. Clark WC, Muhlbauer MS, Watridge CB, Ray MW. Analysis of 76 civilian craniocerebral gunshot wounds. J Neurosurg 1986; 65(1):9–14. 29. Crockard HA, Brown FD, Johns LM, Mullan S. An experimental cerebral missile injury model in primates. J Neurosurg 1977; 46(6):776–783. 30. Jenkins LW, Moszynski K, Lyeth BG, et al. Increased vulnerability of the mildly traumatized rat brain to cerebral ischemia: the use of controlled secondary ischemia as a research tool to identify common or different mechanisms contributing to mechanical and ischemic brain injury. Brain Res 1989; 477(1–2): 211–224. 31. Bruce DA, Langfitt TW, Miller JD, et al. Regional cerebral blood flow, intracranial pressure, and brain metabolism in comatose patients. J Neurosurg 1973; 38(2):131–144. 32. Shackford SR, Mackersie RC, Davis JW, Wolf PL, Hoyt DB. Epidemiology and pathology of traumatic deaths occurring at a Level I Trauma Center in a regionalized system: the importance of secondary brain injury. J Trauma 1989; 29(10):1392–1397. 33. Graham DI, Ford I, Adams JH, et al. Ischaemic brain damage is still common in fatal non-missile head injury. J Neurol Neurosurg Psychiatr 1989; 52(3):346–350. 34. Graham DI, Adams JH, Doyle D, et al. Quantification of primary and secondary lesions in severe head injury. Acta Neurochir Suppl (Wien) 1993; 57:41–48. 35. Miller JD, Sweet RC, Narayan R, Becker DP. Early insults to the injured brain. JAMA 1978; 240(5):439–442. 36. Chesnut RM, Marshall LF, Klauber MR, et al. The role of secondary brain injury in determining outcome from severe head injury. J Trauma 1993; 34(2):216–222. 37. Hills MW, Deane SA. Head injury and facial injury: is there an increased risk of cervical spine injury? J Trauma 1993; 34(4):549–553; discussion 553–554. 38. Doppenberg EM, Rice MR, Di X, Young HF, Woodward JJ, Bullock R. Increased free radical production due to subdural hematoma in the rat: effect of increased inspired oxygen fraction. J Neurotrauma 1998; 15(5):337–347. 39. Menzel M, Doppenberg EM, Zauner A, et al. Cerebral oxygenation in patients after severe head injury: monitoring and effects of arterial hyperoxia on cerebral blood flow, metabolism and intracranial pressure. J Neurosurg Anesthesiol 1999; 11(4): 240–251. 40. Menzel M, Doppenberg EM, Zauner A, Soukup J, Reinert MM, Bullock R. Increased inspired oxygen concentration as a factor in improved brain tissue oxygenation and tissue lactate levels after severe human head injury. J Neurosurg 1999; 91(1):1–10. 41. Smith GJ, Kramer GC, Perron P, Nakayama S, Gunther RA, Holcroft JW. A comparison of several hypertonic solutions for resuscitation of bled sheep. J Surg Res 1985; 39(6):517–528. 42. Auler JO Jr, Pereira MH, Gomide-Amaral RV, Stolf NG, Jatene AD, Rocha e Silva M. Hemodynamic effects of hypertonic sodium chloride during surgical treatment of aortic aneurysms. Surgery 1987; 101(5):594–601. 43. Battistella FD, Wisner DH. Combined hemorrhagic shock and head injury: effects of hypertonic saline (7.5%) resuscitation. J Trauma 1991; 31(2):182–188. 44. Gunnar W, Jonasson O, Merlotti G, Stone J, Barrett J. Head injury and hemorrhagic shock: studies of the blood brain barrier and intracranial pressure after resuscitation with normal saline solution, 3% saline solution, and dextran-40. Surgery 1988; 103(4):398–407. 45. Schmoker JD, Shackford SR, Wald SL, Pietropaoli JA. An analysis of the relationship between fluid and sodium administration and intracranial pressure after head injury. J Trauma 1992; 33(3):476–481. 46. James HE, Schneider S. Effects of acute isotonic saline administration on serum osmolality, serum electrolytes, brain water content and intracranial pressure. Acta Neurochir Suppl (Wien) 1993; 57:89–93. 47. Rosner MJ, Daughton S. Cerebral perfusion pressure management in head injury. J Trauma 1990; 30(8):933–40; discussion 940–941.

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48. Lam AM, Winn HR, Cullen BF, Sundling N. Hyperglycemia and neurological outcome in patients with head injury. J Neurosurg 1991; 75(4):545–551. 49. Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practice scale. Lancet 1974; 2:81. 50. Burke AM, Quest DO, Chien S, Cerri C. The effects of mannitol on blood viscosity. J Neurosurg 1981; 55(4):550–553. 51. Muizelaar JP, Wei EP, Kontos HA, Becker DP. Mannitol causes compensatory cerebral vasoconstriction and vasodilation in response to blood viscosity changes. J Neurosurg 1983; 59(5):822–828. 52. Doppenberg EM, Watson JC, Broaddus WC, Holloway KL, Young HF, Bullock R. Intraoperative monitoring of substrate delivery during aneurysm and hematoma surgery: initial experience in 16 patients. J Neurosurg 1997; 87(6):809–816. 53. Rish BL, Dillon JD, Weiss GH. Mortality following penetrating craniocerebral injuries. An analysis of the deaths in the Vietnam Head Injury Registry population. J Neurosurg 1983; 59(5):775–780. 54. Marshall LF, Smith RW, Shapiro HM. The outcome with aggressive treatment in severe head injuries. Part I: the significance of intracranial pressure monitoring. J Neurosurg 1979; 50(1):20–25. 55. Bullock R, Chesnut RM, Clifton G, et al. Guidelines for the management of severe head injury. Brain Trauma Foundation. Eur J Emerg Med 1996; 3(2):109–127. 56. Marion DW, Bouma GJ. The use of stable xenon-enhanced computed tomographic studies of cerebral blood flow to define changes in cerebral carbon dioxide vasoresponsivity caused by a severe head injury. Neurosurgery 1991; 29(6):869–873. 57. Muizelaar JP, Marmarou A, Ward JD, et al. Adverse effects of prolonged hyperventilation in patients with severe head injury: a randomized clinical trial. J Neurosurg 1991; 75(5):731–739. 58. Marion DW. Moderate hypothermia in severe head injuries: the present and the future. Curr Opin Crit Care 2002; 8(2):111–114. 59. Busto R, Dietrich WD, Globus MY, Ginsberg MD. The importance of brain temperature in cerebral ischemic injury. Stroke 1989; 20(8):1113–1114.

60. Gaab MR, Rittierodt M, Lorenz M, Heissler HE. Traumatic brain swelling and operative decompression: a prospective investigation. Acta Neurochir Suppl (Wien) 1990; 51:326–328. 61. Eisenberg HM, Frankowski RF, Contant CF, Marshall LF, Walker MD. High-dose barbiturate control of elevated intracranial pressure in patients with severe head injury. J Neurosurg 1988; 69(1):15–23. 62. Dearden NM, Gibson JS, McDowall DG, Gibson RM, Cameron MM. Effect of high-dose dexamethasone on outcome from severe head injury. J Neurosurg 1986; 64(1):81–88. 63. Marmarou A, Portella G, Barzo P, et al. Distinguishing between cellular and vasogenic edema in head injured patients with focal lesions using magnetic resonance imaging. Acta Neurochir Suppl 2000; 76:349–351. 64. Benveniste H, Drejer J, Schousboe A, Diemer NH. Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. J Neurochem 1984; 43:1369–1374. 65. Butcher SP, Bullock R, Graham DI, Mcculoch J. Correlation between amino acid release and neuropathological outcome in rat striatum and cortex following middle cerebral artery occlusion. Stroke 1990; 1:1727–1733. 66. Shimada N, Graf R, Rosner G, Heiss WD. Ischemia-induced accumulation of extracellular amino acids in cerebral cortex, white matter, and cerebrospinal fluid. J Neurochem 1993; 60:66–71. 67. Meldrum B. Protection against ischemic neuronal damage by drugs acting on excitatory neurotransmission. Cerebrovasc Brain Metab Rev 1990; 2:27–57. 68. Bullock R, Fujisawa H. The role of glutamate antagonists for the treatment of CNS injury. J Neurotrauma 1992(suppl 9): S3443–S3461. 69. Kuroda Y, Fujisawa H, Strebel S, Graham DI, Bullock R. Effect of neuroprotective N-methyl-d-aspartate antagonists on increased intracranial pressure: studies in the rat acute subdural hematoma model. Neurosurgery 1994; 35:106–112.

41 Spinal Cord Injury Kangmin Lee and R. Scott Graham

injury can have prognostic significance, while the severity of secondary injury can limit the potential of rehabilitative processes and contribute to the overall morbidity and mortality.

INTRODUCTION Spinal cord injury (SCI) is an important cause of morbidity and mortality in modern society. Injuries result in significant and permanent neurologic deficits, and the functional consequences can be devastating. Although there are a number of causes, the focus of this chapter is on traumatic cord injury. The following is a summary of the prevailing concepts in pathophysiology and treatment of traumatic SCI.

Primary Mechanisms The primary mechanical injury occurs by way of penetration, laceration, shear, compression, and/or distraction. Depending on the mechanism of injury, duration can be either transient or persistent. Impact with transient compression is often seen with hyperextension injuries in individuals with underlying spondylosis. Burst fractures with canal compromise, fracture dislocations, and disc ruptures are examples of impact with persistent compression. The extent of the primary injury can be used to group patients into severity categories (neurologic grades). Mechanism of injury, spinal level, and neurologic grade on admission to the hospital are important prognostic indicators (8,9). The American Spinal Injury Association (ASIA) SCI grading scale is a common scale used for this purpose (Table 1). The primary mechanical injury has a tendency to damage the central gray matter of the cord. This is probably due to its softer consistency and greater vascular requirements. Within the white matter, axons that pass through the injured segment may be physically disrupted or exhibit a decrease in myelin thickness, resulting in impaired conduction of action potentials. Mechanical disruption of venules and capillaries may result in early hemorrhage within the cord. Larger vessels such as the anterior spinal artery are relatively spared from direct mechanical injury, and the location of vascular damage is primarily in the intramedullary vascular system (8–10).

EPIDEMIOLOGY Approximately 10,000 SCIs occur each year in the United States. Although the true incidence is unknown, the range has been estimated to be between 28 and 55 per million population (1,2). Data from the Olmsted County, Minnesota study from 1935 to 1981 reported an age- and sex-adjusted incidence rate of 54 injuries per million population. This figure was reduced to 34 per million if immediate deaths before reaching the hospital were not included (3). In comparison, the incidence rate in other developed countries ranges from 2 to 53 per million population (1,4). In the United States, injuries are due to motor vehicle accidents (36–48%), violence (5–29%), falls (17–21%) and recreational activities (7–16%) (5–7). Average age at time of injury for each cause of SCI was 30 years for motor vehicle accidents, 27 years for violence, 24 years for recreational activities, and 42 years for falls. Monetary costs are significant, and a recent study estimated total direct costs in the value of the 1995 dollar for all causes of SCI in the United States at $7.7 billion (6). Data from the Major Trauma Outcome Study (5) showed that traumatic SCI occurred in one of every 40 injured persons presenting to trauma centers. Patients with SCI and multitrauma were more common than those with isolated spine injuries. In those with isolated SCI, 65% had cervical cord injury. In those with multiple injuries, cervical cord injury was seen in 52%. Motor vehicle accidents, pedestrian accidents, and falls were associated with the highest percentage of cervical injury, 56% to 65%. Gunshot wounds and motorcycle accidents were associated with the lowest percentage of cervical injury, 30% and 39% respectively (5).

Secondary Mechanisms The initial mechanical insult serves as the impetus for a cascade of deleterious events. Current understanding of these

Table 1 American Spinal Injury Association Impairment Scale
A ¼ Complete: No motor or sensory function is preserved in the sacral

segments S4–S5 B ¼ Incomplete: Sensory but not motor function is preserved below the neurological level and includes the sacral segments S4–S5
C ¼ Incomplete: Motor function is preserved below the neurological level, and more than half of key muscles below the neurological level have a muscle grade less than 3
D ¼ Incomplete: Motor function is preserved below the neurological level, and at least half of key muscles below the neurological level have a muscle grade of 3 or more
E ¼ Normal: Motor and sensory function are normal

PATHOPHYSIOLOGY




Similar to current concepts in traumatic brain injury, the pathophysiology of SCI involves a primary mechanism with initial mechanical damage and local tissue destruction and a complex cascade of secondary mechanisms. The secondary mechanisms are initiated by the primary injury and encompass systemic, cellular, and biochemical processes that lead to cellular damage and cell death. The severity of primary 805

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mechanisms has evolved over the past three decades, and many corollaries to recent advances in cerebral trauma and ischemia have helped to mold understanding. Numerous studies have shown that the central nervous system responds to injury in a prototypical fashion. Vascular changes, ionic derangements, neurotransmitter accumulation, free-radical production, and apoptosis as well as various other cellular and biochemical events have been shown to compromise the spinal cord after injury (Table 2). A thorough discussion of each event is beyond the scope of this chapter, but animal models point to posttraumatic ischemia as a common denominator for secondary processes following SCI. Other mechanisms such as glutamate excitotoxicity and free-radical and apoptotic mechanisms have been shown to be important sequellar posttraumatic ischemia.

Spinal Cord Ischemia Following the initial insult, a number of systemic and local events are initiated; of primary concern is an acute reduction in blood flow to the area of the lesion. Although the precise mechanism behind this hypoperfusion is unclear, it has been shown to persist in rats and monkeys for at least 24 hours. It is speculated that vasospasm or possibly the release of a vasoactive amine is partially responsible. However, it is likely that the mechanism involves a combination

Table 2 Primary and Secondary Mechanisms of Spinal Cord Injury Primary injury mechanisms Compression Impact Missile Stretch Laceration Shear Secondary injury mechanisms Systemic effects Heart rate: brief tachycardia and then prolonged bradycardia Blood pressure: hypertension and then prolonged hypotension Decreased peripheral vascular resistance Decreased cardiac output Increased catecholamine release and then decrease Hypoxia Hyperthermia Local vascular changes Loss of autoregulation Neurogenic shock Hemorrhage (especially in the gray matter) Loss of microcirculation Vasospasm Thrombosis Electrolyte changes Increased intracellular calcium Increased intracellular sodium Increased extracellular potassium Neurotransmitter accumulation Catecholamines Glutamate Arachidonic acid release Free-radical production Eicosanoid production Lipid peroxidation Edema Apoptosis Source: Modified from Ref. 11.

of processes such as hemorrhagic ischemia, thrombosis, endothelial swelling, and edema formation (8,10,12). Normally, gray and white matter blood flow is maintained at a 3:1 ratio, reflecting the greater vascular requirements of the gray matter relative to the adjacent white matter. The metabolic requirement of spinal cord gray and white matter has important implications for understanding the response to secondary injury. Perfusion to the peripheral white matter is typically reduced within the first five minutes postinjury, with a return to normal flow within 15 minutes. In contrast, hemorrhage is often seen in the central gray matter within the first five minutes postinjury, and perfusion virtually halts within the hour. This vascular stasis has been confirmed using microangiography and fluorescent tracer studies (11,13). It is believed that the central gray matter is irreversibly damaged within the first hour after injury, and that white matter damage is irreversible beyond the first 72 hours postinjury (8). Studies by Tator and Koyanagi using silicone rubber microangiography have elucidated some of the vascular changes in SCI. They have shown that the central area of the cord is supplied by the sulcal arteries and encompasses the anterior gray matter, the anterior half of the posterior gray matter, the inner half of the anterior and lateral white columns, and the anterior half of the posterior white columns. The peripheral white matter and the posterior portion of the posterior gray matter are supplied by the posterior spinal and pial arteries. There is also an intermediate watershed zone representing the vascular overlap between the pial and sulcal arterial systems (10). This anatomical arrangement may help to explain the hemorrhagic and ischemic changes seen in the gray matter of traumatized spinal cords. Hemorrhage in the gray matter of traumatized spinal cords has been well documented in clinical and experimental studies. Sekhon and Fehlings have proposed that it may be that obstruction or mechanical disruption of the anterior sulcal arteries leads to the hemorrhagic necrosis and subsequent central myelomalacia seen at the site of injury (11).

Impaired Autoregulation In many cases of SCI, the primary injury is not severe enough to cause the hemorrhagic necrosis discussed above. However, vascular alterations with cord ischemia have been shown to occur in milder forms of injury as well. Loss of autoregulatory homeostasis (i.e., a decreased ability to maintain constant blood flow over a wide range of pressures) and endothelial dysfunction are additional vascular sequelae of SCI. Endothelial dysfunction leads to increased vascular permeability with the leakage of proteinaceous fluid into the interstial space and edema at the injury site. Endothelial damage occurs early after injury, and cellular changes are observed in as early as one to two hours (12). In the setting of a markedly swollen spinal cord, ischemia may be further aggravated by the limited cross-sectional area of the bony spinal canal and rising tissue pressures. Neurologic deterioration due to spinal cord edema is well documented in SCI and may be potentially reversible in the subacute period.

Neurotransmitter Excitotoxicity The notion of glutamate excitotoxicity is a concept that has been implicated in the pathophysiology of head trauma. As the primary excitatory neurotransmitter in the central nervous system, toxic levels are known to initiate a highly disruptive

Chapter 41: Spinal Cord Injury

process known as glutamate excitotoxicity. This process has been implicated in SCI as well. Glutamate has been shown to flood out of injured spinal neurons, axons, and astrocytes, causing an over excitation of neighboring neurons. Glutamate acts on N-methyl-D-aspartate (NMDA) and non-NMDA receptors on neurons or glial cells, causing an influx of Ca2þ. This triggers a series of highly destructive events directly and indirectly through the production of numerous agents such as free-radicals. The ischemia that results from vascular changes may also be instrumental to glutamate accumulation. Hypoxia results in adenosine triphosphate depletion, which then impairs cellular uptake mechanisms. Glutamate receptor activation also appears to result in early accumulation of intracellular Naþ and Ca2þas well (8).

Free-Radical–Mediated Cell Injury Free-radical formation is also known to be an important secondary injury mechanism in SCI. After injury, oxygen freeradicals are formed and have been shown to cause cell membrane peroxidation. Important phospholipid-dependent enzymes can be impaired disrupting ionic gradients and causing membrane lysis (8).

Apoptosis Recent research has implicated the process of programmed cell death in a number of neurological disorders including SCI. Apoptosis can be triggered by a variety of initiating factors including cytokine release, inflammatory insults, free-radical damage, and excitoxicity. Days or weeks after initial trauma, a wave of cell suicide or apoptosis sweeps through neurons, oligodendrocytes, microglia, and, perhaps, astrocytes. This wave can affect cells as many as four segments away from the initial trauma site (8,14,15).

Additional Pathophysiologic Considerations Spinal Shock The term ‘‘neurogenic’’ or ‘‘spinal shock’’ has been used in several ways. For references made in this chapter, spinal shock will refer to a sudden loss of peripheral vascular tone. This results in pooling of blood in the extremities and inadequate central venous return. The unopposed parasympathetic effects of the vagus nerve results in bradycardia, which is in marked contrast to the tachycardia associated with hemorrhagic shock. Although the pathophysiology of spinal shock is not completely understood, it is most probably due to a conduction blockade resulting from cellular Kþ ion leakage. Impulse conduction would then be dependent upon restoration of normal Naþ and Kþ gradient (16).

EVALUATION Neurologic Assessment All individuals with SCI should have a thorough neurologic examination. Traumatic brain injury has been shown to coincide with nearly half of all traumatic SCIs (17). Multilevel injury to the spine is also common, and a thorough examination of the entire spine is warranted, once the diagnosis of SCI is made. The evaluation of a spinal cord–injured patient begins by determining whether the injury is complete or incomplete. This information is important for determining prognosis and often useful clinically in determining the risk and benefit ratio of early surgery

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(18,19). According to the ASIA, an SCI is defined as complete when there is absence of sensory and motor function in the lowest sacral segment. In contrast, an incomplete injury is defined by the presence of sensory and/or motor function at the lowest sacral segment (‘‘sacral sparing’’). Sacral sensation includes pinprick or light touch sensation at the anal mucocutaneous junction, as well as deep anal sensation with digital exam. The test of motor function is marked by the ability to contract the external anal sphincter on digital exam. Among the SCI classification schemes, there is some disagreement regarding definition of the ‘‘level’’ of a SCI. ASIA criteria defines neurologic level as the most caudal segment of the spinal cord with normal sensory and, at least, antigravity strength (greater than or equal to three out of five motor strength) on both sides (20). The severity of SCI is rated by a simple five-level (A–E) ASIA impairment scale (Table 1). The standards for neurological and functional classifications of SCI assess motor function in ten muscle groups (arms: C5-T1, legs L2-S1) and sensation (light touch and pinprick) in 28 dermatomes (C2-S4/5) on both sides of the body (Fig. 1).

CLASSIC INJURY PATTERNS Age, level of injury, and neurologic grade have been demonstrated to be the most important premorbid factors for survival after acute SCI (21). Approximately 45% of SCIs are complete injuries (22). These injuries are more likely to be due to fracture dislocations rather than burst or compression fractures (17). It is generally accepted that thoracic injuries will more frequently produce complete SCIs than cervical or lumbar injuries. When complete injuries do occur, the greatest neurologic recovery occurs in the more rostral injuries. Cervical injuries therefore, have exhibited the greatest degree of recovery following initial complete injury (23).

Complete Spinal Cord Injuries Complete injuries at or above the C3 level result in immediate respiratory arrest, and death will result within minutes if artificial respiration is not instituted (Fig. 2). Additionally, high cervical cord injuries are frequently accompanied by hemodynamic instability, which is the result of sudden loss of sympathetically mediated vasomotor tone, blood loss, and bradycardia from unopposed parasympathetic activity. Patients with complete injuries between the C5 and T1 levels can usually be weaned from mechanical ventilation. Prolonged ventilator support and possible tracheostomy are often necessary during the initial weeks following the injury. The reversible dysfunction of the spinal cord above the level of the injury is presumably due to effects of edema and the secondary pathways discussed earlier in this chapter.

Central Cord Syndrome Central cord syndrome is one of the most well-recognized and common SCI injury patterns. The pattern of injury is classically characterized by disproportionate motor deficit in the upper extremities as compared to deficit in the lower extremities. Bladder dysfunction and varying degrees of sensory loss below the level of the lesion also occur. Injury typically involves hyperextension in the cervical spine,

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Figure 1 Standard neurological classification of spinal cord injury.

usually in association with preexisting cervical spondylosis. These injuries can occur even without apparent damage to the bony spine, but have also been described in association with vertebral body fractures or fracture-dislocation

injuries. The natural history of recovery following central cord syndrome is a gradual return of neurologic function in the early stages followed by a plateau. Some patients experience late deterioration often complicated by spasticity

Figure 2 Radiographic findings in a case of complete spinal cord transection just below the cervicomedullary junction due to a gunshot wound. (A) computed tomography (CT) scout tomogram shows the bullet fragment at the angle of the mandible and a markedly comminuted C2 fracture. (B) Sagittal T2-weighted magnetic resonance imaging demonstrates transection of the spinal cord and thick subarachnoid hemorrhage from injury to the vertebral artery. (C) Axial CT shows the comminuted fractures of C1 and C2. (D) Postoperative lateral radiograph shows the stabilizing titanium loop and tracheostomy in place.

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or pain. Although the prognosis is favorable, recovery is usually incomplete. Impaired intrinsic muscle function of the hand is a common permanent deficit with this injury pattern. Several retrospective studies have shown that increased age and poor initial motor exam are the most important predictive variables (Fig. 3) (24–29).

Conus Medullaris Syndrome Conus medullaris syndrome is another common SCI pattern (Fig. 4). This syndrome most often results from thoracolumbar burst fractures. It involves injury to the distal portion of the spinal cord at the T12 through L2 spinal levels. The clinical presentation of this injury can occasionally be confused with cauda equina syndrome. Patients typically present with severe lower back pain at the level of the fractured vertebra. This may be accompanied by neuropathic pain in the thighs, distal lower extremities, and perineum. Motor and sensory deficits are also seen in a roughly symmetric distribution involving the distal lower extremities. Bladder and sphincter function are usually impaired with severe injuries and are the least likely deficits to regain function. Anatomically, the injured neural elements consist of the terminal portion of the conus (central nervous system) and the cauda equina (peripheral nervous system). The prognosis is relatively good for these injuries, and many patients can regain some useful function in the lower extremities (Fig. 5). The L1 vertebra is involved in the majority of thoracolumbar fractures. At this level, many of the axons for motor neurons to the lower extremities have exited the cord. Permanent impairment is most likely to be seen in the L5 and sacral spinal cord levels, i.e., pelvis instability during gait (glutei), ankle weakness (anterior tibialis, extensor hallius longus, and gastroc), and sphincter dysfunction. Anecdotal data from case series indicate a benefit for early decompression and stabilization of these injuries (30–36).

Figure 3 Sagittal T2-weighted magnetic resonance image of a typical central cord injury in a 67-year-old male. Patient presented with severe symmetric weakness of the deltoids and biceps with preservation of normal intrinsic hand and lower extremity motor function. The patient had brief paraesthsias over the upper portions of the arms, which returned to normal sensory exam shortly after the injury. Note the preexisting spondylosis and high signal within the spinal cord at the C4-5 level.

Cauda Equina Syndrome Although cauda equina syndrome is not a SCI, it is included in this discussion because it is a relatively common

Figure 4 L1 burst fracture with a complete conus medullaris syndrome; 22-year-old male who fell 30 feet from a tree. (A) Plain film of the lumbar spine shows an L1 burst fracture with kyphotic angulation. (B) The sagittal magnetic resonance imaging scan demonstrates compression of the conus and cauda equina with high signal in the distal portion of the spinal cord. (C) Reformated sagittal computed tomography scan shows the decompression of the spinal canal and correction of the kyphotic deformity. (D) The six-month postoperative X-ray shows the final alignment of the repair. The patient underwent early surgery and at six months was ambulatory with bilateral ankle braces.

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Figure 5 (A–C) Neurologic grade at presentation and at the final assessment for three case series of conus medullaris injuries. Data from a case series in the mid-1980s. Delayed surgery was considered the standard approach at this time. (B) Data from the mid-1990s in this series surgery was preformed in the first week following the injury. (C) The senior authors series. Surgery was completed within 24 hour of the injury unless contraindicated. (D) Neurologic grade for the authors’ series over time. (E) Description of the Benzel Larson Grading scale.

compression syndrome. The pattern of neurologic deficits is similar to conus medullaris syndrome. Cauda equina syndrome usually occurs due to acute and severe midline compression of spinal nerve roots, i.e., from a massive disc rupture, most commonly at L4-5 (Fig. 6). This is often superimposed on a preexisting spinal stenosis or spondylosis. In contrast to conus medullaris lesions, pain is often the most prominent symptom and is radicular in nature. Motor and sensory deficits tend to be asymmetric. Urinary retention is the most consistent finding, and ‘‘saddle anesthesia’’

is the most common sensory deficit. Studies have shown that early surgical decompression, i.e., within 24 to 48 hours of onset is particularly important in avoiding permanent neurologic deficits (37–39). This syndrome is considered a neurosurgical emergency, and recognition of patients with a possible diagnosis of cauda equina syndrome requires immediate evaluation with magnetic resonance imaging (MRI) or myelogram/computed tomography (CT) of the lumbar spine and possible urgent surgical decompression.

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Figure 6 Axial T2-weighted magnetic resonance imaging scan in a patient presenting with cauda equina syndrome due to a large L45 herniated disc. Images 31 and 32 show the spinal canal with cerebrospinal fluid and nerve roots in cross section. Images 33 and 34 show the spinal canal completely obstructed with a large free fragment of disc material.

Brown-Sequard Syndrome This syndrome occurs as a result of focal dysfunction in a hemisection of the spinal cord. Classically it was described following penetrating trauma of the cord and is reported to occur in 2% to 4% of traumatic SCIs. Although data for true incidence is lacking, it is more commonly seen in its partial form due to asymmetric distortion of the cord from compression by meningiomas, nerve sheath tumors, and disc herniations. Neurologic symptoms consist of ipsilateral loss of proprioceptive and vibratory sense as well as motor paralysis due to interruption of the posterior column and corticospinal tracts. Contralateral findings are loss of pain and temperature sensation one to two segments below the lesion. Light touch is preserved however, due to redundant ipsilateral and contralateral paths (anterior spinothalamic tracts). The prognosis for this syndrome is the best of any of the incomplete SCIs. The vast majority of patients with this syndrome will regain the ability to ambulate independently, as well as regain anal and urinary sphincter control. Sensory abnormalities are reported to persist in a higher percentage of patients with Brown-Sequard myelopathy, in comparison to other patterns of myelopathy (40–42).

Anterior Cord Syndrome The anterior two-thirds of the spinal cord is affected by this syndrome. The lesion is typically associated with cord infarction in the territory of the anterior spinal artery. This syndrome may occur from occlusion of the anterior spinal

artery or from anterior cord compression, e.g., by a dislocated bone fragment or by traumatic disc herniation. Posterior column function is typically preserved, while spinothalamic and corticospinal tract damage results in loss of pain and temperature sensation as well as paraplegia. Lesions higher than C7 can result in quadriplegia. This syndromes has the worst prognosis of the incomplete injuries. Only 10% to 20% recover functional motor control.

Posterior Cord Syndrome This syndrome is relatively rare and is most frequently associated with isolated damage to the posterior components of the spinal cord. There is usually loss of dorsal column function producing pain and parasthesias in the neck, upper arms, and torso. There also may be mild paresis of the upper extremities.

Posttraumatic Myelopathy Associated with Syringomyelia Posttraumatic syringomyelia is reported to develop in 0.3% to 3.2% of SCIs (43). Typically, the posttraumatic syrinx becomes symptomatic in a delayed and insidious fashion after a few years of stable neurologic functioning. Patients present with signs and symptoms of progressive neurologic dysfunction and pain. The presentation in order of frequency is local pain, loss of motor function, loss of sensory function, increased spasticity, autonomic dysreflexia, hyperhydrosis, increased sphincter dysfunction, increasing

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respiratory insufficiency, and Horner’s syndrome. Diagnosis is confirmed by MRI or in rare cases in which an MRI cannot be obtained by delayed (1–2 hour) postmyelogram CT scanning (the delay allows time for the myelogram dye to enter the syrinx cavity). Controversy exists as to optimal management of the syrinx. Hence, many procedures have been used to treat them, including syringosubarachnoid shunting, syringopleural and syringoperitoneal shunting, fenestration of the syrinx, neurolysis of cord with duraplasty, and correction of spinal deformity. Each of these procedures has purported advantages, and specific associated risks and all of them have relatively high reoccurrence rates.

IMAGING The diagnosis and management of SCI will often require a variety of imaging studies. If cervical injury is suspected, anteroposterior, lateral, and open-mouth radiographs can be used to define integrity and alignment of bony structures. Under these circumstances, it is important to adequately visualize the entire cervical spine from occiput to T1. Gentle traction on the patient’s arms or alternatively a ‘‘swimmers view’’ can usually accomplish this. The negative predictive value of a normal three-view cervical spine series has been reported to range from 93% to 98% in several Class I studies (44–46). Dynamic views with flexion/extension can also be helpful and may aid in the diagnosis of ligamentous laxity. However, these views may be contraindicated, if neurologic dysfunction is noted. For suspected injuries in the thoracic or lumbar spine, anteroposterior and lateral films may be obtained. CT is superior to plain radiography and provides better resolution of bony structures. These films may be obtained when a fracture is suggested by plain film or full visualization of the cervical spine to T1 is not attainable. Sagittal and coronal reconstructions may be done if further anatomic information is required or the patient is a surgical candidate. Ideally, scan thickness in the cervical spine is 1.5 mm and 3 mm in the lumbar and thoracic spine. Highquality images can diagnose cord hemorrhages, mass effects, and disc herniations. Although invasive, the combination of myleography and CT remains the gold standard for visualization of cord or nerve root compression. This combination is especially useful when MRI is contraindicated or spinal instrumentation distorts imaging with artifact. If it is crucial to visualize the spinal cord, MRI remains the best available study. MRI would also be indicted, if evidence of SCI is evident without skeletal abnormality. Each examination should include at least one T1-weighted sagittal sequence, a sagittal sequence with water displayed bright (T2 spin echo, fast spin echo, or gradient refocused images), and a series of axial images. There has been a recent interest in diffusion weighted imaging of the spinal cord, given its significant value in detecting early brain injury.

MANAGEMENT OF ACUTE SCI Initial Management The major causes of immediate death in SCI are aspiration and shock (47). Therefore, the basic tenets of advanced trauma life support procedure are critical in the management of SCI. It is also important to be aware that SCI may mask other injuries, i.e., abdominal injuries below the level of the SCI.

Immobilization prior to and during extrication in the fields is important to prevent passive or active movements of the spine. However, if cardiopulmonary resuscitation is necessary, resuscitation takes precedence. The patient should be placed on a backboard with sandbags placed on both sides of the head. A 3-in. strip of adhesives tape from one side of the backboard to the other across the forehead and allows movement of the jaw and provides access to the airway. The backboard may be maintained to facilitate transfer, i.e., to the CT table. However, once urgent studies are completed, the backboard should be removed as soon as possible. Early removal will improve patient comfort and reduce the risk of decubitus ulcers. It is important to avoid hypotension in SCI patients, and systolic blood pressure should be maintained above 90 mmHg. Therapeutic measures may include the use of pressors, fluids, and military antishock trousers (MAST). MAST immbolizes the spine and can also compensate for decreased or lost muscle tone in the patient and prevent venous pooling. Dopamine may be used if necessary and is the pressor of choice. Vasomotor collapse may also contribute loss of temperature control, and the patient should be provided with cooling or warming blankets. Adequate oxygenation is also vital, and oxygen via nasal cannula or face mask should be delivered if intubation is not indicated. If intubation is required, then chin lift (not jaw thrust), without neck extension should be performed. If at all possible, tracheostomy or cricothyroidotomy should be avoided, because it may compromise later anterior cervical surgical approaches. Nasogastric tube suctioning is also often implemented in order to prevent vomiting and aspiration, as well as provide decompression of the stomach. Placement of a Foley catheter is also advised in order to prevent bladder distension from urinary retention.

Critical Care and Management of Complications Assuming survival after initial injury, it was commonly believed that renal failure and urinary tract infections were the leading causes of death in SCI patients. However, more recent studies show that pulmonary complications such as pneumonia are the leading cause of death (48). Cardiac dysfunction is also known to be common sequelae of SCI. These life-threatening events may occur episodically despite early resuscitation and initial restoration of cardiopulmonary function. Early detection through cardiopulmonary monitoring in the intensive care unit (ICU) setting can result in improved neurologic recovery. This is especially true for the patient with cervical cord injury above C5. The muscles of the diaphragm are innervated by the phrenic nerve (C3–C5). Injury at or above this level can thus result in apnea and require ventilator support for the patient. However, even for injuries below C5, respiratory function is often quite compromised. A flaccid paralysis of the intercostal muscles initially occurs—as the diaphragm contracts and descends, the chest wall contracts rather than expands. Forced vital capacity and maximal inspiratory force are reduced by 70%. Eventually, the intercostal muscles become spastic, and respiratory function improves. Approximately five months after injury, the forced vital capacity and the maximal inspiratory force are about 60% of predicted preinjury levels. Perhaps the most significant respiratory complication associated with SCI is ventilator-associated pneumonia. Common organisms include Streptococcus pneumoniae, Haemophilus influenzae, Pseudomanas aeruginosa, and Staphylococcus aureus. Cardiovascular

Chapter 41: Spinal Cord Injury

irregularities such as hypotension, arrhythmias, and even cardiac arrest can also occur. Therapy involves resuscitation with pressors as well as hemodynamic monitoring with a pulmonary artery catheter. Unfortunately, there is no clear consensus on the appropriate end point for volume resuscitation (49). Patients with SCI have a threefold increase in risk for thromboembolic disease (50). Given this risk, it is important to initiate prophylaxis in the ICU setting. Methods available include pneumatic compression devices, stockings, anticoagulants, and inferior vena cava (IVC) filters. Mechanical devices are clearly advisable but insufficient for prophylaxis. Low-molecular-weight-heparin can be added unless contraindicated, in which case an IVC filter may be a consideration. Studies of patients with spinal injuries have shown that the risk of deep venous thrombosis is quite low in the first 72 hours after SCI (51). Anticoagulation may then be held for this initial period. Thereafter it is advisable that anticoagulation be started. Although the optimum length of stay in the ICU is unknown, the available studies show that cardiac and respiratory events often occur within the first week or two after injury. This time frame may be dependent upon the severity of SCI (52).

Management of Instability Clinical stability can be defined as the ability of the spine to resist displacement, under physiologic loads and prevent irritation or injury to the spinal cord or nerve roots. In general, the spine can be viewed as being composed of three columns. Injury to any two of these columns may be regarded as sufficient to raise suspicion for clinical instability. The anterior column is composed of the anterior longitudinal ligament, the anterior half of the vertebral body, and the anterior half of the annulus fibrosis. The middle column includes the posterior half of the vertebral body, the posterior half of the annulus fibrosis, and the posterior longitudinal ligament. The posterior column consists of the spinous processes, laminae, articular processes, and the ligamentum flavum. After SCI, the objective of management is to mechanically limit displacement and pharmacologically prevent the progression of secondary damage. Mechanical stabilization can be provided by bed rest, external orthoses, or immediately through internal fixation. Cervical traction/reduction restores and maintains normal alignment immobilizing the spine to prevent further injury. Reduction may decompress the spinal cord or roots. The timing of reduction is controversial, and it is contraindicated in atlanto-occipital dislocation as well as type IIA or III Hangman’s fractures. A number of cranial tongs are available, and Gardner-Wells tongs are probably the most common tongs in use. The tongs are placed in the temporal ridge (above the temporalis muscle) 3 to 4 cm above the pinna. Traction weight is 5 lbs for the upper C-spine and 10 lbs for lower levels. Halo rings can be used initially for traction or later as a postoperative measure for immobilization. The indications and timing of surgical decompression for acute SCI have been controversial for many years. Considering the steady improvement in surgical technology and widespread capability to quickly complete the trauma evaluation and obtain necessary studies and radiographic evaluations, early surgery for SCI is becoming increasingly feasible. Therefore, we will briefly consider the knowledge base regarding the timing of decompression of acute SCIs.

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There have been multiple animal studies providing persuasive evidence that SCI has a reversible component. Studies in primates, cats, dogs, and rodents have convincingly shown that early decompressive intervention enhances neurologic recovery in SCI. A study by Dimar et al., using a weight drop model, showed that neurologic recovery in rats was significantly dependent on time to decompression after injury (53). Unfortunately, clinical studies in humans have been less compelling. Basic definitions such as the time frame for ‘‘early surgery’’ have yet to be established. Due to the lack of Class I data, the clinical benefits of surgery for fracture dislocations are difficult to determine. However, there have been several reports of cervical cases receiving significant benefit after decompression with early traction. Overall, the data is lacking and is insufficient to produce practice guidelines or standards.

Posttraumatic Deformity The vast majority of unstable spinal injuries are recognized in the acute setting. However, posttraumatic kyphosis may develop in a delayed fashion. Most cases occur in patients initially managed ‘‘nonoperatively’’ with spinal bracing. Additionally, it is also seen in operatively managed cases that fail to fuse properly or at levels not incorporated into the fusion. The most common presenting symptom is spinal pain, followed by postural changes, increasing neurologic deficits, and, rarely, the development of a syrinx. Treatment is indicated for cases that demonstrate progression over time and for those associated with new or progressive neurologic deficits. A localized kyphotic deformity greater than 30 degrees is associated with an increased risk of chronic pain (54).

Pharmacologic Management There has been a significant evolution of thought in the pathophysiology of SCI within the past two decades. This has led to further progress in the surgical and medical treatment of SCI. The primary strategy has focused on limitation of secondary injury mechanisms. The first positive clinical trial [National Acute Spinal Cord Injury Study (NASCIS II)] for pharmacological treatment for SCI was reported in 1990 (55,56). In a multicenter clinical study, high-dose methylprednisolone was reported to reduce disability when given within eight hours of trauma. Although the mechanism of action has yet to be fully elucidated, it is thought to act in part to reduce swelling, inflammation, glutamate release, and free-radical accumulation. Results of the latest NASCIS III (57,58) showed that high-dose methylprednisolone, started between three and eight hours after injury and continued for 48 hours, was reported to preserve more motor function than treatment for 24 hours. It has become common practice in the United States to administer methylprednisolone (30 mg/ kg) within the first eight hours after injury. Treatment started within the first three hours is continued (5.4 mg/ kg/hr) for 24 hours. Treatment initiated between three and eight hours is continued for 48 hours. However, the use of methylprednisolone remains a topic of heated debate and is a controversial issue in many countries. Treatment with high-dose methylprednisolone is associated with a number of complications, including gastric bleeding and wound infection. The NASCIS studies have opened the door for investigation of other pharmacologic agents such as monosialoganglioside sodium (GM1 ganglioside), naloxone, and tirilazad.

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REHABILITATION Early and aggressive rehabilitation is an important key to prevention of medical complications after SCI and for the psychological adjustment of the patient. Following intensive inpatient rehabilitation, most individuals with SCI continue their rehab work in an outpatient setting with physical, occupational, and vocational therapist. However, yearly follow-ups with functional assessments by physiatrists or other specialists with knowledge of SCI are recommended. Urinary and sexual dysfunction are areas of great concern for the SCI patients. Urinary tract infections are common and more often result in serious complications of sepsis and chronic renal insufficiency. Some patients will require chronic suppressive antibiotics. Many males with SCI struggle with erectile and ejaculatory dysfunction. Semen quality and motility can be reduced secondary to recurrent urinary tract infections, drugs, prostatic fluid stasis, retrograde ejaculation, and changes in seminal fluid. Treatment for these issues can be medical or surgical and are beyond the scope of this chapter. However, pregnancy rates for individuals with SCI have improved over the past decade and are between 10% and 60%.

ADVANCED THERAPIES There have been a number of advancements in the management of the very severe disabilities encountered by individuals with SCI. These therapies attempt to limit the effect of SCI on everyday life and maximize existing functional ability. Common options include tendon transfer, functional electrical stimulation, and the use of adaptive equipment and environmental control devices. Tendon transfer is an underused treatment for restoration of limited but useful motor function. Muscle groups that serve redundant roles (e.g., elbow flexion is done by both biceps brachii and brachioradialis) may be used for transfer. The muscles need to be sufficiently strong (at least four out of five) and should be trained to take over lost movements. The most frequent tendon transfers are used for elbow/wrist extension and thumb flexion. Transcutaneous or direct electrical stimulation of muscle can be achieved, but is only useful when lower motor neurons and peripheral nerves are still intact. Denervated muscle cannot be used because the currents necessary would be injurious to the muscle. Transcutaneous electrical activation of leg muscles has been used for strength training and cardiovascular conditioning. Bowel and bladder control is perhaps the function that is the most distressing to individuals with SCI, and functional electrical stimulation is an available therapy for this issue.

RESTORATION OF FUNCTION Fortunately, the damaged spinal cord does not require complete restoration in order to improve quality of life. Small anatomical gains are known to produce a disproportionate improvement in function. Fewer than 10% of functional long-tract connections are required to allow locomotion. This level of connectivity often remains in the doughnut-like outer rim of white matter following trauma. However, axons in this outer rim may be nonfunctional as a result of demyelination. Therefore, remyelination of intact connections is one reasonable approach to improvement of function.

Spinal Cord Regeneration With the increase in understanding of the pathologic processes involved in SCI and neurobiology of the developing spinal cord obtained over the past two decades, research efforts have begun to focus on strategies to promote regeneration of the injured spinal cord. Clinically useful drugs and techniques are still many years into the future, and a complete discussion of the topic is beyond the scope of this chapter. However, we will highlight some of the hurdles to be overcome. Effective neuroprotection to limit the degree of secondary injury, preserve intact axonal fibers crossing the injured segment, and the neuronal cell bodies at the level of the cord injury is a prerequisite for spinal cord regeneration therapies. The NASCIS II and NASCIS III were positive clinical trials for the use of methylprednisolone and tirilazad as neuroprotectants, following SCI (55–58). However, more effective drugs and timing of decompressive surgery have yet to be established. The regenerative capacity of the central nervous system poses additional substantial hurdles: (i) injured neurons have a limited intrinsic ability to regenerate, and (ii) the area of the injury into which they must send axons is not permissive to regeneration. Intense research efforts are underway focusing on the development of neurotrophic agents and delivery mechanisms to enhance the regenerative capacity of the injured neurons. Stem cell, Schwann cell, and olfactory-ensheathing cell transplantation are under investigation as potential means of bridging the gliotic barrier at the site of the injury (59). Complicating the matter further, animal studies demonstrate that the regenerative responses to both neurotrophic factors and tissue grafting decline precipitously within a few weeks to months following the initial injury (11,59–61).

SUMMARY The pathophysiology of SCI involves a sequence of primary and secondary mechanisms. Although the primary injury is fated by the mechanism of the trauma, the progression of secondary injury may be amenable to therapy. Secondary mechanisms of injury encompass an array of interwoven biochemical and cellular processes. Our continued understanding of these mechanisms will provide a framework for future medical and surgical treatment paradigms.

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42 Injuries to Peripheral Nerves Irvine G. McQuarrie, Thomas C. Chelimsky, and Karen Bitzer

If the ‘‘perineurium’’ enclosing the fascicles has been breached, misdirected axonal sprouts grow for short distances in the ‘‘epineurium’’ (connective tissue that separates fascicles) before rounding up into small neuromas. If the perineurium remains intact, sprouts remain within the fascicle, and there is more than a 90% chance of spontaneous recovery after approximately one year (2). However, there is less than a 60% chance of a good result from excising a neuroma-incontinuity and performing a neurorrhaphy (2) because regenerating axons have a reduced chance of entering the correct fascicle in the distal nerve stump (3–5). When a neuroma-in-continuity contains broken fascicles (perineurial rupture in addition to axonotmesis—an injury termed ‘‘neurotmesis’’), most axon sprouts enter the epineurium and are unable to traverse the lesion. In that event, the only possibility for recovery lies in neurorrhaphy. Because the majority of civilian nerve injuries produce a neuroma-in-continuity that is initially associated with a complete loss of nerve function, the decisions of whether and when to operate assume paramount importance (2).

INTRODUCTION The management of nerve injuries poses special difficulties for the surgeon. Although the majority heal satisfactorily without surgical intervention, a year may pass before it is evident that a particular injured nerve will not heal on its own. By then, it is too late to do a nerve repair (‘‘neurorrhaphy’’) and have this followed by a satisfactory motor recovery. To obtain a good result from neurorrhaphy, it must be performed within six months after injury. On the other hand, the result obtained from carrying out a timely neurorrhaphy is not as good as the result from spontaneous recovery. Neurorrhaphy is to be avoided unless clearly indicated; often this decision must be made before a spontaneous recovery is evident from changes in the neurologic examination. This chapter addresses the pathophysiology of nerve injury and the physiologic basis of nerve repair. It also provides a strategy for the timely identification of nerve lesions that require operative intervention. To accomplish these goals, we only consider mechanical trauma to large mixed (motor and sensory) nerves.

Homeostasis and Microvasculature The special environment of the central nervous system (CNS) tissues is maintained by the blood–brain barrier, which is physically enforced by tight junctions between capillary endothelial cells. Thus, protein is excluded from the extracellular fluid of the CNS. Active transport mechanisms within the endothelial cells permit the transfer of

ANATOMY AND PHYSIOLOGY Fascicular Anatomy Although physicians agree that the safe and effective treatment of injuries is based on a knowledge of the relevant anatomy and physiology, this is especially true for nerve injuries. Here, the most important consideration is the intraneural anatomy. Each mixed nerve contains 4 to 20 bundles (‘‘fascicles’’) of nerve fibers (axons within myelin sheaths) that combine, divide, and rotate within the nerve while moving distally to assemble into motor and cutaneous branches. As shown in Figure 1, an unbranched 3 cm length of a mixed nerve contains 5 to 10 fascicles that interconnect to such an extent that most axons come to lie in a different quadrant and have different neighbors after traveling that distance (1). Because of this anatomic circumstance, it is impossible for the surgeon who performs a neurorrhaphy to perfectly match the fascicles in a proximal nerve stump to those in a distal nerve stump. Even if neurorrhaphy appears necessary, the surgeon may want to carry out an electrophysiologic investigation at the operating table before deciding to resect an incomplete nerve lesion. The incomplete lesion of greatest concern is the ‘‘neuroma-in-continuity,’’ a fusiform enlargement of the nerve, which often occurs within weeks following a nontransecting nerve injury. Although a variable fraction of axons may have been broken (‘‘axonotmesis’’) at the time of injury, the mass effect is less a result of the axonal sprout formation than of a proliferation of Schwann cells, fibroblasts, and collagen, which has been evoked by the force of injury (Fig. 2).

Figure 1 Intraneural fascicular anatomy of a 3-cm segment from the musculocutaneous nerve of a human cadaver. Source: From Ref. 1.

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Figure 2 Schematic representation of a neuroma-in-continuity. (A) Intraneural fascicular anatomy is depicted in contrast with a dark background representing the proliferation of Schwann cells, fibroblasts, and collagen, which occurs at any site of nerve contusion; five of the fascicles have sustained perineurial rupture, producing a neurotmesis-type lesion (1). (B) Intrafascicular axonal anatomy is depicted at a site of perineurial rupture (distal fascicle stump is at the top of the figure); a number of ‘‘minifascicles’’ have formed in response to a complete axotomizing lesion, and one of these has found its way to the distal fascicle stump.

specific substances into the extracellular fluid of the brain. Similar mechanisms remove metabolic waste products and toxic substances from the extracellular fluid, because the CNS has no lymphatic vessels. In the peripheral nervous system, each fiber (axon with its supporting Schwann cells) is bathed in endoneurial fluid, which has a composition similar to that of cerebrospinal fluid. As in the CNS, there are no lymphatic vessels, capillaries are nonfenestrated, and endothelial cells are joined by tight junctions (6). The perineurial cells that enclose the endoneurial space are also joined by tight junctions. A breakdown of this ‘‘blood–nerve barrier’’ causes a loss of function in the nerve fibers of the affected fascicle. This pathophysiologic event may not be associated with any change in the ultrastructure of the fibers, and function is restored on restitution of the perineurium (7). The intraneural blood supply is from longitudinally directed arterioles and venules, located in both the epineurium and endoneurium, which connect with intrafascicular capillaries (Fig. 3). These lie between nerve fibers, and the mean distance between capillaries is only 0.15 mm (1). Although the largest nerves (median and sciatic) have nutrient vessels that are larger than arterioles, more than 90% of the intraneural vessels are less than 10 mm in diameter. Because of the length of the arterioles and venules, and the collateralization of intraneural vessels, blood flow rates are little affected by mobilization of the nerve or nerve transection. Experimental studies in cats show that the flow returns to the normal range of 40 to 50 mL/100 g/min in both stumps by one hour after transection (1,8). The surgeon can safely mobilize 20 to 30 cm lengths of nerve without being concerned about blood supply (1), a maneuver that makes it possible to bridge a 5 cm gap if the extremity is splinted in a position of functional flexion.

Impulse Conduction Nerve impulses (action potentials) are conducted over the axon surface to the axon terminal through a propagated reversal of charge that maintains the impulse at a constant

Figure 3 Microradiograph of the rat sciatic nerve (right) and the caudofemoralis muscle (left) after infra-arterial injection of 25% micropaque. The two arrowheads mark the course of the anastomotic artery as it arises in the muscle, emerges from the anterior muscle border, and joins the arteria comitans along the posterior surface of the nerve (
9). Source: From Ref. 6.

amplitude and velocity. Although the rate of conduction may exceed 100 m/sec (because of myelin insulation, which forces the impulse to jump from one node of Ranvier to the next), it is much slower than electric conduction over a copper wire. Axons are actually poor electric conductors: a 30 V stimulus could not produce a potential of 1 V at the end of an axon 1 m long without the energy-requiring process that mediates the reversal of charge at the axon surface. Following axonotmesis, the nerve action potential (NAP) cannot propagate across the point of injury. However, the axons of the distal nerve stump retain the ability to propagate an impulse for up to four days after injury. Thereafter, the axon surface loses its functional integrity as a result of the segmentation of the axon into myelin-bound ‘‘ovoids’’ or ‘‘digestion chambers,’’ where the axon is phagocytosed— a process termed ‘‘wallerian degeneration’’ (9).

Nerve Cell Body Reaction to Axonotmesis The possibility of axonal regeneration depends on the survival of the neuron. Because 95% to 99% of the cytoplasm in peripherally projecting neurons is located in the axon and a large fraction of the axonal volume is in the terminal arborization (10,11), axonotmesis removes most of the neuronal cytoplasm. This often results in the death of a small percentage of neurons. The main reason neurons survive the loss of such a large amount of cytoplasm is that the protein synthesis machinery of the neuron is spared (12,13). In response to axonotmesis, the nerve cell body undergoes a series of biochemical, physiologic, and anatomic changes that have been termed ‘‘chromatolysis’’ because of the reduction in cytoplasmic basophilia. This tinctorial change is attributable to the diffusion of cytoplasmic RNA (located mainly within polyribosomes), secondary to the disruption of the rough endoplasmic reticulum and an increase in the cell volume (12). Biochemical changes include an early

Chapter 42: Injuries to Peripheral Nerves

and sharp reduction in the synthesis of proteins used for neurotransmitter production. This decrease is roughly balanced by an increase in the synthesis of proteins used for regrowing an axon, which include tubulin, actin, and ‘‘growth-associated proteins’’ (12–15). Physiologic changes include a prompt internalization and degradation of cellsurface receptors, a marked reduction in the amplitude of excitatory postsynaptic potentials (EPSPs), and a reduction in the velocity of impulse conduction in the surviving or ‘‘parent’’ axon (12). Anatomic changes vary with the type of neuron but commonly include a withdrawal of axon terminals from the cell body and dendrites of the injured neuron (accounting for the reduced amplitude of EPSPs), atrophy of dendrites, enlargement of the nucleolus, eccentric positioning of the nucleus, an increase in perikaryal volume, and a thinning of the parent axon (accounting for the reduced rate of impulse propagation) (12). There is abundant evidence that the nerve cell body reaction plays a prominent role in axonal regeneration (12). In addition, the ‘‘environment’’ of the newly formed ‘‘daughter’’ axon is important to the success of regeneration (13,16). Two recent developments support the primacy of neuronal events. First, studies over the past decade have shown that axonal outgrowth can be accelerated by the use of a conditioning lesion. This axonotmesis initiates a ‘‘crop’’ of regenerating axons, which is removed days later by a second (testing) lesion. The second crop forms sooner and advances faster than the first (13,17,18). This acceleration appears to be based on the increased synthesis and axonal transport of tubulin, actin, and certain growthassociated proteins (13). The environment faced by the second crop of axons, an environment of wallerian degeneration, is not the primary cause for accelerated outgrowth (13,17,18). The neuronal control of outgrowth is also evident from its rapid response to changes in the status of the axon tip. The nerve cell body receives information quickly by means of ‘‘retrograde axonal transport’’ and makes appropriate changes in its protein synthesis and axonal transport priorities (14). It is by this process, for example, that the nerve cell body comes to know within a few hours that it has sustained an axotomy (19).

Axonal Transport During Axonal Regeneration The motive force for axonal outgrowth appears to be the axonal transport system, which is responsible for supplying all the protein needs of the axon (11,13,20). Membranous organelles are carried ‘‘by fast transport;’’ structural proteins and the enzymes of intermediary metabolism are carried by the two subcomponents of ‘‘slow transport’’ (10). The proteins that are used for synaptic transmission and renewal of the axolemma are conveyed in tubulovesicular form by fast transport at approximately 400 mm/day. During regeneration, fast transport provides the glycoproteins that form the new axon membrane. In experimental studies, fast transport is labeled with radioactive glycoproteins (which are enriched fivefold in growth cones) to measure axonal outgrowth distances (17). The principal cytoskeletal proteins are tubulin, actin, and the neurofilament triplet. These are conveyed through the axon by slow transport as both monomers and polymers (microtubules, actin microfilaments, and neurofilaments). The 30 to 40 proteins that associate with actin microfilaments move in a group at 2 to 6 mm/day as slow component b (SCb) of slow transport. The protein triplet composing neurofilaments is transported 1 to 2 mm/day as slow component a,

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in association with most of the microtubules. During axonal outgrowth, there are changes in the relative amounts of several proteins moving with both fast and slow transport, but proteins are neither added nor deleted (11). However, both the average rate and the overall amount of protein transport via SCb increases (11,13,20). This correlates with the evidence indicating that the rate of outgrowth cannot exceed the rate of SCb (11,13,20). The governing role of SCb may relate to (i) the dependence of growth cone function on the polymerization of actin into microfilaments and (ii) the dependence of axonal elongation on the assembly of tubulin into microtubules (11,13). Examination of these two hypotheses in laboratory animals favors the former: radiolabeling of axonal proteins following nerve injury shows that polymerization of both actin and tubulin upregulates, and radiolabeling prior to injury shows that only actin upregulates (21).

Stages of Axonal Regeneration Four stages of axonal regeneration precede the onset of voluntary motor activity: (i) the ‘‘initial delay,’’ consisting of sprout formation and the advance of sprouts to the lesion site; (ii) the ‘‘scar delay,’’ during which the sprouts cross the lesion; (iii) the ‘‘outgrowth period,’’ during which the axons elongate within fascicles of the distal nerve; and (iv) the ‘‘maturation delay,’’ during which the axons that contact an appropriate end organ initiate a series of recovery events. These include the reversal of end-organ atrophy, radial growth of the axon, and myelination. In experimental studies on sciatic nerves of the rat, sprouts begin to form within a few hours of injury and many acquire a cytoskeleton by 27 hours (18). The zone of ‘‘traumatic degeneration’’ (same pathology as wallerian degeneration but located at the proximal nerve stump) must be traversed before sprouts can attempt to reach the distal nerve stump (22). The average initial delay in rats is 36 hours, and the scar delay at a neurorrhaphy is approximately 48 hours (23). In monkeys, the combined initial and scar delay is one to three weeks (24,25). This is much shorter than the five to seven weeks required by chimpanzees, suggesting that the evolutionary step from monkeys to anthropoid apes involves a major change in neuronal growth potential (24). The outgrowth period terminates with the arrival of axons at an end organ. If an incompatible end organ is encountered, as in the case of a sensory axon reaching a motor end plate, the maturation phase is not initiated, and the axon remains small in caliber (26). If the contact is appropriate, the axon undergoes radial growth (through the addition of neurofilaments), which triggers the formation of myelin by Schwann cells (27,28). The axon initiates myelin formation through both a chemical signal to the Schwann cell and the physical influence of its radial growth (23,28). After the nerve fiber has matured and end-organ atrophy has been reversed through the resumption of neurotrophic activity, function is recovered. The mismatches between motor axons and muscle fibers (e.g., when a motor axon that had originally projected to a flexor muscle reinnervates an extensor muscle) are partially compensated by changes in the sensory connections within the CNS (5) and the neurotrophic induction of changes in muscle fiber type (29). The pathophysiology that we have gleaned from these animal studies can be related to nerve injuries in humans. If the times of onset for voluntary movements (in a proximalto-distal series of muscles served by an injured nerve) and

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the distances from the lesion to the motor point (where each muscle is innervated) are noted (1), a regression function of distance on time can be plotted. When this is extrapolated to zero distance, the number of days indicated on the x-axis represents the ‘‘latent period’’ (Fig. 4). This is a combination of the initial delay, the scar delay, and the maturation delay. In a classic study that applies this method to a number of patients following neurorrhaphy, the latent period is estimated to be about 13 weeks (30). These patients were compared to others having closed crush injuries (axonotmesis) and therefore a negligible scar delay, where the latent period is about nine weeks. Thus, the average scar delay is four weeks. Because most of the nerve repairs (in this study of World War II injuries) were carried out more than six months after injury, the maturation delay would not have been the optimal four weeks but rather six to eight weeks (25,31). Subtracting that six- to eight-week interval from the nine-week latent period (seen after axonotmesis) leaves an initial delay of one to three weeks. With the four-week scar delay after neurorrhaphy added, there is a five- to

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seven-week delay before axons begin to elongate within the distal nerve stump, as in chimpanzees (24). Experience with testing the NAP across the lesion site during surgery has validated this estimate (2). Accordingly, an operation that is partly done for the purpose of recording NAPs from axons that have crossed a suspected neuroma-in-continuity must be delayed until 8 to 10 weeks after injury (2).

PATHOLOGY With acute nerve compression of mild degree and short duration, the local pathology is limited to ‘‘paranodal demyelination’’ (a retraction and thinning of myelin at the nodes of Ranvier) (32). Greater compression causes a loss of myelin between nodes of Ranvier (‘‘segmental demyelination’’). These forms of demyelination block the transmission of action potentials without interrupting the axon, producing a ‘‘neurapraxia’’ (Fig. 5A) (22). Greater compression breaks the axon without disrupting the basement membrane of the Schwann cell (endoneurial tube) or the perineurium (33). This is termed ‘‘axonotmesis,’’ meaning ‘‘a break in the axon’’ (Fig. 5B). Finally, cutting objects, shearing forces, and percussive forces produce additional connective tissue disruption and break the perineurium and/or the nerve. This is termed ‘‘neurotmesis,’’ meaning ‘‘a break in the nerve.’’ Myelin is readily displaced and thinned by pressure, especially at paranodes. When this occurs, impulse transmission is interrupted even though the axon remains intact. The susceptibility of axons to pressure increases with the degree of myelination. This is best illustrated in a pure neurapraxia, such as ‘‘Saturday night palsy,’’ where an intoxicated person develops paralysis and loss of sensation in the upper extremity because of sleeping for prolonged periods in a position that either stretches or compresses a nerve (usually the radial) or the brachial plexus. Examination often shows total paralysis associated with an absence

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Figure 4 Functional motor recovery in patients sustaining radial nerve injuries, illustrating the progress seen after an axonotmesis-type injury within a neuroma-in-continuity (A) versus a neurotmesis-type injury repaired by nerve suture (B). Distances from the lesion site to the muscle nerve entry point are plotted on the ordinate, and the time from injury (or nerve suture) to the onset of recovery (voluntary contractions) is plotted on the abscissa. Latent period is estimated by extrapolating the regression function of distance on time to zero distance. (A) Radial nerve axonotmesis: high lesion; the regression function indicates that the motor axon outgrowth rate is approximately 3 mm/day. (B) Radial nerve sutures: low versus high lesion; regression functions indicate that the axon outgrowth rate is approximately 1 mm/day. Source: From Ref. 30.

Figure 5 Sequence of changes in a myelinated fiber sustaining a neurapraxia-type injury (A) versus an axonotmesis-type injury (B) as a result of nerve compression. (A) Neurapraxia-type injuries produce segmental demyelination and remyelination. A, Normal fiber; B, retraction of paranodal myelin with widening of nodal gap; C, destruction of myelin sheath and Schwann cell mitoses; D and E, remyelination through the intercalation of short internodes. (B) Axonotmesis-type injuries produce axonal degeneration and regeneration. A, Normal fiber; B, by one week after axotomy, Schwann cells containing axon and myelin debris have divided to form ‘‘bands of Bu¨ngner’’; C, during the second week, axon sprouts extend from the enlarged terminus of the proximal axon stump; D, one of the newly formed sprouts becomes myelinated; E, end-organ reconnection occurs. Source: From Ref. 22.

Chapter 42: Injuries to Peripheral Nerves

of proprioception and touch sensation in the distribution of one or more nerves. However, a pin sensation can be perceived as a dull ache, and a normal density of sweat droplets can be discerned (by examining the skin with an ophthalmoscope set at þ20 D). Thus, the functions served by myelinated axons have been lost, but those served by unmyelinated axons have been retained. These patients begin to recover within two weeks and are fully recovered by three months. When the force of compression is greater, there is a break in the axon (axonotmesis). Axonal transport is blocked at the point of breakage, and the axon distal to that point undergoes wallerian degeneration. This process occurs simultaneously at all levels, and all axons show degeneration by the fifth day after injury (9). The most straightforward classification of acute nerve injuries is open versus closed, depending on whether there has been a break in the skin. If closed, the lesion is either an ‘‘acute compression injury’’ (closed crush) or a ‘‘traction injury.’’ Acute compression injuries are usually secondary to fractures, with the radial nerve being involved most often (34). The pathology is paranodal demyelination secondary to increased endoneurial fluid pressure (35). A traction component occurs if the nerve is stretched over a bone fragment. Pure traction injuries because of motorcycle accidents are commonly seen in emergency rooms. In these accidents, the nerve injury occurs because the rider tries to maintain a grip on the handlebars in an attempt to stay with the motorcycle. The upper brachial plexus is involved if the motorcycle stops suddenly, throwing the rider over the handlebars; the lower plexus is involved if the rider is thrown off and dragged while the motorcycle keeps moving. Of the open injuries, there are two types—those caused by bullet wounds and those caused by cutting objects such as glass. A bullet that misses a nerve may still block function. This is because a ‘‘percussion injury’’ is caused as the bullet passes near the nerve and a pressure wave creates a temporary cavity in the tissues. The pathology is usually a combination of segmental demyelination and wallerian degeneration, producing a combination of neurapraxia and axonotmesis (32,36). The extent of nerve damage depends on the proximity of the bullet to the nerve and the amount of kinetic energy that is transferred to the nerve. With a high-velocity bullet (moving at more than 2500 ft/sec), nerve fascicles can be ruptured even though the bullet misses the nerve. This is because the kinetic energy of the bullet is proportional to its weight and the ‘‘square’’ of its velocity. A small bullet moving at several thousand feet per second is going to cause more damage than a large bullet moving at several hundred feet per second. A military assault rifle (e.g., the M-16 used by the U.S. Forces) produces the former condition, whereas a pistol produces the latter condition. A high-velocity bullet causes a prolonged initial delay because the zone of traumatic degeneration is longer than it would be with a simple laceration (the length of this zone being proportional to the kinetic energy of the bullet) (1). For a low-velocity bullet wound, it is appropriate to wait for 8 to 10 weeks before exploring the nerve to test whether a NAP can be transmitted across the lesion, but a wait of 12 to 16 weeks is necessary for a high-velocity bullet wound (1).

ASSESSMENT OF THE DEFICIT Assessment should (i) name the injured nerve, (ii) locate the injury along its course, (iii) differentiate neurapraxia from a

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complete lesion (axonotmesis or neurotmesis), and (iv) list both negative changes (motor and sensory losses) and positive changes (paresthesias, dysesthesias, pain, and altered autonomic activity). A careful neurologic examination is the most important part of the assessment. In addition, certain neurophysiologic tests are useful. These include nerve conduction studies (NCSs) that are done together with electromyography (EMG). In addition, autonomic testing may be appropriate when pain is present.

Neurologic Examination It is important to assess sensory disturbances, focusing on any loss of sensation that may have occurred in the autonomous cutaneous zone of the injured nerve. Experience has shown that these zones are only innervated by a particular mixed nerve. Neither congenital anomaly nor collateral sprouting from adjacent nerves can provide innervation of these zones; so anesthesia denotes a complete nerve lesion (1). With incomplete nerve lesions, sensation is retained in the autonomous zones, and abnormal spontaneous sensations (paresthesias) or abnormal responses to stimuli (dysesthesias) commonly occur. Dysesthesias can include decreased or increased sensitivity of a normal type (hypoesthesia and hyperesthesia). All sensory changes, including anesthesia, can have a painful component. When a non-noxious stimulus produces pain, the term ‘‘allodynia’’ is used. The pathophysiology of pain after nerve injury has been studied in great detail, and an excellent review has been published by Wall (37). The most important pain syndrome is ‘‘causalgia,’’ which is a severe burning pain that follows nerve injury and may extend beyond the distribution of the injured nerve; both allodynia and abnormalities of autonomic function are typical findings (38,39). It occurs after approximately 2% of incomplete transections (40) but is rarely seen when complete transections are promptly repaired. Causalgia is diagnosed when there is constant burning pain within the distribution of an injured nerve and examination shows allodynia in association with autonomic changes. These changes may include skin that is smooth and glossy, an increase or decrease in the rate of hair growth, tapered digits, thickened nails, periarticular fibrosis, and osteoporosis (41). The pathophysiology of causalgia has been thought to involve an excess of activity in sympathetic motor axons and the transmission of this activity to somatic sensory axons by means of synapse-like connections in the proximal stump neuroma (42,43). Accordingly, there have been many attempts to treat causalgia pharmacologically (by systemic or local administration of agents that block sympathetic activity) and surgically (by sympathectomy) (44). More recently, however, this teaching has come under criticism (39). Following nerve injury, autonomic function is lost in the areas of cutaneous anesthesia. Sweat secretion is undetectable when the skin is examined with the þ20 D lens of an ophthalmoscope. The ninhydrin sweat test can also be used to document both the absence of sweat formation and any recovery caused by collateral sprouting or axonal regeneration. The ‘‘erectores pillae’’ muscles at the base of each hair follicle do not erect the hair in response to cooling, and the skin is warm because of the absence of innervation to arterial smooth muscle. Later, as the b-adrenergic receptors on these muscle cells proliferate in response to the absence of normal innervation, the cells become supersensitive to congeners of the missing neurotransmitter. This may be manifested by the extremity becoming cool in response to

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the epinephrine released from the adrenal medulla during environmental or emotional stress. Assessment of the response of muscles to voluntary effort is achieved through manual testing techniques that are specific to the nerve injury in question. For these to be diagnostic, the examiner must be aware of trick movements or substitution patterns. The distribution and extent of muscle atrophy is recorded as mild to severe and is quantified by measuring the circumference of extremities at fixed distances from the bony landmarks. Deformities of posture must be described and interpreted. For example, a ‘‘claw hand’’ deformity denotes an ulnar nerve lesion. The extent of muscle contractures in the hand is determined by applying standard tests for intrinsic and extrinsic tightness (45). Joint contractures are measured with a goniometer and judged to be either reducible or fixed (46). For motor disturbances, the principal problem is muscle atrophy. Both disuse and the lack of neurotrophic influences contribute to this problem. If the muscle is not reinnervated within two to three years, all the muscle cells are replaced by connective tissue. If the muscle is not maintained in dynamic activity (by passive range-of-motion exercises) while it is denervated, much of the rehabilitative potential is lost because of muscle fiber atrophy occurring in concert with endomysial fibrosis. Immobilization and paralysis also cause venous and lymphatic stasis, which further reduce blood flow and cause edema. Finally, joint contractures often occur because of decreased muscular support, edema, fibrosis, and the unopposed action of normally innervated muscles. Although it is clear that passive range-of-motion exercises are worthwhile, the presence of pain may be a limitation. In that event, the regular use of regional anesthesia may be necessary to allow an exercise program to occur.

Examination of Specific Nerves For the ‘‘median nerve,’’ the autonomous zone of skin innervation includes the digital pads of the thumb and index finger, and the dorsum of the terminal phalanx of the index finger. An absence of pin sensation and sweat formation in these areas indicates a complete nerve lesion. The equivalent loss in terms of motor function is an absence of voluntary contraction of the abductor pollicis brevis muscle; without this muscle, it is impossible to elevate the thumb from the palm and rotate it into a position of grasp. If the median nerve injury is near the elbow, other movements are impossible after a complete lesion. These include pronation of the forearm and flexion of the thumb and index finger joints, which results in the ‘‘benediction sign’’ when the patient is asked to make a fist. For the ‘‘radial nerve,’’ there is no autonomous sensory zone. In most individuals, however, a total nerve lesion causes loss of sensation over the radiodorsal forearm and the dorsum of the thumb. On motor examination, the fingers cannot be extended at the metacarpophalangeal joints, the thumb cannot be extended at any joint, and the hand cannot be extended at the wrist. For the ‘‘ulnar nerve,’’ the autonomous zone is over the terminal phalanx of the fifth finger. None of the fingers can be adducted or abducted, and the metacarpophalangeal joints cannot be flexed without first flexing the interphalangeal joints. A claw hand deformity is common. This involves hyperextension of the metacarpophalangeal joints and flexion of the interphalangeal joints. In the lower extremity, the ‘‘common peroneal nerve’’ does not have an autonomous zone of skin sensation.

However, a complete lesion commonly causes a loss of sensation over part of the mid-dorsum of the foot and the web space between the great and second toes. On motor examination, there is an inability to evert the foot, dorsiflex the ankle, or extend the toes. For the ‘‘tibial nerve,’’ the autonomous zone is the entire sole of the foot. The motor deficit is a loss of plantar flexion at the ankle and metatarsophalangeal joints. Complete lesions of the ‘‘sciatic nerve’’ produce combinations of the patterns of loss for the tibial and common peroneal nerves. Nerve blocks may be needed to be certain of which nerves have been injured and whether those injuries are complete or incomplete in terms of the loss in function. After a thorough neurologic examination, it may appear that an incomplete nerve injury has occurred because there are strong voluntary contractions of one or two muscles served by the injured nerve while all others are unresponsive. In that event, it is important to block conduction in the uninjured nerves that could be providing anomalous innervation to the myotome traditionally served by the injured nerve. For example, function can be retained in median-innervated muscles of the hand (abductor pollicis brevis and opponens pollicis) in 15% of patients following a complete transection of the median nerve at the wrist because of the Martin– Gruber anastomosis between the median and ulnar nerves in the forearm (1). A ‘‘procaine block’’ of the ulnar nerve at the wrist would demonstrate this.

Neurophysiologic Tests Electrophysiologic tests (NCS and EMG) are of great value after nerve injuries. There are two types of NCS, motor and sensory. For motor, the stimulus is a supramaximal electric discharge delivered by a surface (skin) electrode to an underlying nerve (e.g., the median nerve at the wrist). The motor response is the electric potential recorded over a muscle subserved by the nerve (e.g., the abductor pollicis brevis). This consists of the summed motor unit action potentials (MUAPs), each of which represents the response of muscle fibers innervated by a single motor axon. These responses act to amplify the NAP. In contrast, detection of the sensory response requires recording a NAP directly (e.g., from the median nerve at the wrist after stimulating the digital nerves of the index finger). Accordingly, MUAPs have a large amplitude, in the range of 3 to 15 mV, whereas sensory NAPs have a small amplitude, in the range of 5 to 50 mV. NCS yields two values: an amplitude of response (in microvolts or millivolts) and a latency of response (in milliseconds). The conduction velocity, normally 40 to 60 m/sec, is calculated by dividing the latency into the length of the nerve segment over which the study is performed. Nerve conduction is readily examined following nerve injuries, usually by stimulating distally with digital cuff electrodes and recording sensory NAPs proximally with needle or skin electrodes. By five days after axonotmesis, motor axons distal to the lesion are unable to conduct NAPs because of wallerian degeneration (9). Thus, motor NCS can be used to differentiate neurapraxia from axonotmesis within a week after injury. In general, the findings on NCS depend on the type of injury (whether a neurapraxia or complete lesion), the interval since injury, the severity of negative neurologic changes (motor and sensory loss), and the severity of positive neurologic changes (paresthesia, pain, and autonomic changes). The most useful information is obtained if electrophysiologic tests are carried out both immediately and at three weeks after the nerve injury. The first study, if done within

Chapter 42: Injuries to Peripheral Nerves

two to three days, localizes the lesion by NCS because conduction is absent across the site of injury but intact above and below. (A slowing of conduction velocity is characteristic of a demyelinating lesion, but a total loss of myelin results in a ‘‘conduction block,’’ which is indistinguishable from a complete lesion.) The second study determines whether there is a complete lesion, in which case conduction is lost below the lesion and fibrillations are present in denervated muscles. In axonal injury, the degeneration of nerve fibers becomes complete in five days for motor responses and in seven days for sensory responses. (The difference is due to the sensitivity of the neuromuscular junction to blocked axonal transport.) With the demyelinating lesion of neurapraxia, the distal response is never affected. By one week after injury, nerve conduction changes reach their nadir and the character of the lesion can be fully discerned. With a pure neurapraxia, only the myelin must be reconstituted, and this usually occurs in three to six weeks. With a pure axonal lesion, the axon must grow back to an end organ similar to the original. This occurs at approximately 1 mm/day, as previously described, and depends on daughter axons entering a vacated endoneurial tube distal to the lesion, which then directs the outgrowing axon to an appropriate end organ. With neurorrhaphy, the choice of endoneurial tube is essentially random. Recovery usually takes many months. Motor recovery sometimes begins in weeks because of collateral sprouting, which provides motor axons from nearby uninjured nerves to reinnervate muscles denervated by the injury. EMG examines the pattern of individual MUAPs seen after inserting a bipolar (concentric) needle electrode into a muscle. Complete lesions produce two types of abnormalities (Fig. 6). First, spontaneous discharges are the most important, including positive deflections that occur

Figure 6 (A) Fibrillation potentials recorded at slow and fast sweep speeds. (B) EMG responses during weak voluntary contractions: normal EMG contrasted with neuropathic EMG seen following axonal regeneration. Abbreviation: EMG, electromyogram. Source: From Refs 47,48.

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with needle insertion and, later, fibrillation potentials. Both are regular discharges, which represent denervation supersensitivity of the muscle cell. Second, with the onset of motor recovery, there is an alteration in the shape and amplitude of voluntary MUAPs. EMG is of particular value whenever there is a total loss of nerve function as a result of injuries that are unlikely to have divided the nerve. These include nerve compression resulting from a compartment syndrome, nerve traction resulting from a fracture, and nerve percussion resulting from a bullet. The most useful information is obtained when the test is carried out as early as possible after injury and again at three weeks. By this time, wallerian degeneration has eliminated any neurotrophic influence of axonal transport on the denervated muscle, and sufficient time has passed for muscle fibers to become supersensitive to the missing neurotransmitter by producing extrajunctional acetylcholine receptors. Fibrillations depend on these. The EMG method of electrophysiologic testing uses a concentric needle electrode to record from muscles in the distribution of the lesioned nerve. After the needle is placed in a muscle, the patient is asked to attempt a movement using that muscle. If no MUAPs are recorded, the nerve is stimulated by inserting a needle electrode near the nerve between the muscle and the lesion site. When the lesion is a neurapraxia, nerve stimulation elicits MUAPs without difficulty—even though none can be elicited by voluntary effort and the muscle is electrically silent when the nerve is not being stimulated. By one week after axonotmesis or neurotmesis, MUAPs cannot be elicited by stimulation of the distal nerve; by three weeks, the muscle exhibits fibrillations at rest and stimulation does not alter that activity. Fibrillation potentials (Fig. 6A) are never seen in normally innervated muscles and differ from MUAPs by having a regular firing pattern. Fibrillations occur at a frequency of 5 to 15 per second, arise from single muscle fibers, and are thought to be the result of supersensitivity of the muscle fiber membrane to acetylcholine-like molecules that enter extracellular fluid from the blood stream. The EMG is very helpful for detecting axonal reconnection at motor end plates: fibrillations disappear and are replaced by nascent MUAPs that mature into large polyphasic potentials (Fig. 6B). The use of NCS and EMG for differential diagnosis is summarized in Table 1. Imaging techniques have advanced to the point of detecting that a muscle has been denervated. A magnetic resonance imaging technique termed ‘‘short time to inversion recovery’’ reveals a specific increase in signal intensity (49). Further study in a rat model has shown that gadolinium enhancement augments the sensitivity enough to detect denervation 24 to 48 hours after nerve transection (50). Autonomic testing is important when causalgia is suspected. The general principle of testing is to compare the unaffected and affected extremities for measures of autonomic function. Different laboratories may employ different methods. When resting sweat output and axon reflex sweat output are tested, and both results are abnormal, there is a 98% chance of ‘‘reflex sympathetic dystrophy’’ (RSD), a syndrome that differs from causalgia by not requiring a prior nerve injury. RSD and causalgia may or may not be associated with ‘‘sympathetically maintained pain’’ (39). The finding of warmer skin over the affected limb when compared to its normal counterpart suggests a positive response to sympathetic block. If bilateral axon reflex abnormalities are present, the prognosis for response to a sympathetic block is poor. In our laboratory, at this time, we use the combination of six tests of autonomic function: resting and

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Table 1 Uses of NCSs and EMG for Differential Diagnosis Axonal injury (axonotmesis) Time 0 days 5 days 7 days 10 days 21 days 6 wks

3 mos 6 mos

1 yr

NCS Amplitudes drop proximal to point of injury Distal motor amplitude reaches nadir Distal sensory amplitude reaches nadir No change No change Slight motor amplitude improvement by collateral sprouting Sensory amplitude may improve Maximal motor improvement; continued sensory amplitude improvement EMG: collateral sprouts are replaced by regenerating axons (‘‘remodeling’’); MUAP amplitudes may drop, and recruitment may be normalized

Demyelinating injury (neurapraxia) EMG

NCS

EMG

Reduced recruitment; no fibrillations; normal MUAPs No change

Amplitudes drop proximal to point Reduced recruitment; no of injury; slowing may be present fibrillations; normal MUAPs No change No change

No change

No change

No change

Insertional activity appears Insertional activity appears

No change Amplitude and slowing begin to improve Further improvement

No change Recruitment may improve

Maximal recovery

Maximal recovery

No change

No change

No change

No change

Polyphasic MUAPs (nascent units); fibrillations decrease Increased ‘‘duration’’ of MUAPs, less polyphasic Increased ‘‘amplitude’’ of MUAPs No change

Further improvement

Abbreviations: NCS, nerve conduction study; EMG, electromyography; MUAP, motor unit action potentials.

axon reflex sweat output (by direct sudorometry), blood flow in both skin (by laser Doppler) and muscle (by plethysmography), limb volume (by water-volume displacement), and skin temperature (by infrared probe). All but sweat output are done both before and after a quantitated exercise load to the extremity. Thus, autonomic testing after nerve injury can determine whether sympathetically maintained pain is present and whether the pain is likely to respond to sympathetic block.

TREATMENT APPROACH Principles of Nonsurgical Treatment Initially, the potential for rehabilitation is evaluated. This must include a careful assessment of the cause for dysfunction. Otherwise, patients may be treated with a pain management program, for example, when partial paralysis is the main obstacle to progress but goes undetected. Dysfunction may arise from any one or combination of the following, and each should be considered by history, examination, and appropriate neurophysiologic tests: (i) loss of nerve function to produce hypoesthesia and weakness; (ii) excess nerve function to produce pain and hypersensitivity to touch, pressure, temperature change, or movement; (iii) tissue changes, such as edema, loss of hair, loss of skin turgor, or loss of joint mobility; (iv) CNS abnormalities, as may occur with sympathetically maintained pain, which create a ‘‘pain cycle’’ and sometimes adventitial movements (spasms and dystonias); (v) psychologic factors, including adjustment abnormalities, anxiety disorders, and even major depression; and (vi) issues of secondary gain, such as litigation, manipulation of family members, or lack of desire to be in the workforce. A psychologist is needed to help in the assessment of the last two factors. The presence of sympathetically maintained pain requires a multidisciplinary rehabilitation approach. The team includes a neurologist who adjusts oral medications

and coordinates treatment, a surgeon who decides on the appropriateness and timing of operative intervention, an anesthesiologist who carries out nerve blocks, a psychologist who evaluates the patient’s motivation and provides treatment with biofeedback and other modalities, and, most importantly, experienced physical and occupational therapists who provide exercise programs and physical treatments designed to improve function. The patient should be told from the outset that the goal is to increase function rather than reduce pain. Medications are selected according to the requirements for treating the patient’s greatest source of limitation. Tricyclic antidepressants have great utility in addressing several frequent problems: loss of sleep, depressed mood, and deep or burning pain. Anticonvulsants and mexiletene are effective with lancinating pain. Baclofen, metho-carbomol, and clonazepam are useful in reducing spontaneous movements and postures, including spasms and dystonias. Capsaicin ointment is helpful for the treatment of superficial burning pain. Nonsteroidal anti-inflammatory drugs help control deep aching pain. The use of narcotics is controversial. These may be safe and beneficial when used in a patient with whom the physician has a solid and long-term relationship, provided that a clear-cut contract is arrived at, giving both an exact duration of the trial and the end point. The selection of a nerve block method depends primarily on what is effective. Bier blocks provide regional anesthesia to the involved limb and are least invasive. Sympathetic blocks are traditionally used in the diagnosis and treatment of sympathetically maintained pain. Longer lasting analgesia may be obtained from epidural, plexus, and axillary blocks. Psychologic techniques include biofeedback, relaxation training, behavior modification, and psychologic investigation of the basic conflicts that may be exacerbating the pain (e.g., reliving an emotionally traumatic event that caused the injury in the first place). Other techniques that may also be useful, but remain unproved, include

Chapter 42: Injuries to Peripheral Nerves

Principles of Surgical Treatment The main goals are to preserve fascicular anatomy (1) and ensure that the end organs become reinnervated within eight months after injury (1,31). To achieve these goals, axonotmesis must be differentiated from neurotmesis with certainty by three months after injury. This is not difficult if there is a skin laceration directly over the course of a nerve that has lost all function below the level of the laceration. The wound should be explored immediately; if the nerve has been transected, it should be repaired. Any delay results in scar formation that necessitates trimming 1 to 2 cm off each nerve stump when the delayed neurorrhaphy is performed. However, if the soft tissues show evidence of contusion (petechial hemorrhages and discoloration) or if a bacterial infection is likely because the wound was not closed within 12 to 24 hours of injury, delayed neurorrhaphy (two to three weeks) is preferable. When there is a highvelocity bullet wound and the initial debridement does not reveal a nerve lesion, any loss of nerve function must be attributed to the percussive force of the bullet. During the Vietnam War, 69% of the casualties recovered spontaneously after three to nine months (51). Nerve injuries caused by acute compression, traction, or the percussive force of a low-velocity bullet often recover spontaneously (34). An element of neurapraxia is usually present, so that NCS is often effective in identifying the patients with a favorable prognosis. When NCS shows no conduction below the level of injury after two to three months and EMG shows only denervation, the nerve should be explored for intraoperative NAP testing (12,25,52). Most patients who are going to recover spontaneously have EMG evidence of recovery in the most proximal denervated muscles within three months. This includes the disappearance of fibrillation potentials and the appearance of nascent MUAPs. These changes occur one to two months before voluntary contractions can be elicited (2,25). Hoffmann’s sign of sensory axon regeneration may mislead the surgeon into delaying the exploration for NAP testing. This crude test was described by military surgeons during World War I. It is elicited by light percussion of the distal nerve stump, beginning distally and proceeding proximally. When the leading sensory axons are percussed, the patient feels a tingling sensation in the normal cutaneous distribution of the injured nerve. There are two possible causes of false-positive findings. One is that percussion of the nerve within 10 cm of the lesion may produce traction on the lesion. This stimulates regenerating sensory axons that are arrested within a neuroma-in-continuity. The other problem is that the sign is positive even if only a few axons have bridged a neurotmesis to enter the distal nerve stump (53). The sign must be easily elicited at progressively more distal points along the nerve before it can be interpreted as presumptive evidence of sensory axon regeneration, and the rate of progression must be appropriate—at least 1.5 mm/day at points proximal to the wrist or ankle (1,54). Following

50 Sensory axon outgrowth

40 DISTANCE FROM SUTURE (cm)

self-hypnosis and acupuncture. The occupational and physical therapists’ roles are most crucial, and the approach depends on the exact type of limitation. All patients require a combination of limb loading and unloading, usually accomplished by the combination of stress loading and water aerobics. For allodynia, desensitization is used with gradually less abrasive materials. Limitations in range-of-motion can be addressed by a continuous passive range-of-motion machine, used during the night, and set at an ever-increasing range.

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30

20

10 Nerve suture 0

180 240 0 60 120 TIME FROM DATE OF NERVE INJURY (DAYS)

Figure 7 Progress of Hoffmann’s sign of sensory axon outgrowth in a patient sustaining a neurotmesis injury of the ulnar nerve at the elbow. By extrapolating the regression function to zero distance, the latent period can be estimated to be seven to eight weeks after nerve suture. With this test of nerve function, there is no maturation delay; the axon terminal is continuously and exquisitely sensitive to mechanical stimuli (31,55–57). Thus, the latent period simply represents the sum of the initial delay and the scar delay. Source: From Ref. 54.

neurorrhaphy, the sign should be elicited at 10 cm below the repair within 9 to 12 weeks, assuming an initial delay of two weeks and a scar delay of four weeks (Fig. 7) (1).

Treatment of Neuroma-in-Continuity From the point of view of pathology, a neuroma-incontinuity (fusiform enlargement of the nerve) involves a proliferation of connective tissue elements that may, if a fascicle has been ruptured, include thin axons that lack linear organization. Ruptured fascicles must be identified and repaired within three months if the patient is to have a reasonable chance of satisfactory motor recovery (2,31,52). Ruptured fascicles are identified by intraoperative NAP testing (52), done after a period of time that allows the neuroma to be crossed by any axon within the unruptured fascicles. An appropriate interval is two months after injuries caused by acute compression or low-velocity missiles and three months after injuries caused by traction or highvelocity missiles. It is not reasonable to carry out nerve exploration earlier than two months after injury unless there is reason to think that the diagnosis is neurotmesis. Even if all fascicles are intact, one cannot expect to demonstrate NAPs across the lesion site if testing is carried out before seven to eight weeks (2). For high-velocity missile wounds and most traction injuries, there should be a 12-week wait because of the greater extent of traumatic degeneration in the proximal stump. However, delaying definitive diagnosis and treatment any longer only serves to increase the likelihood of a poor result should neurorrhaphy prove necessary.

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This is because axonal regeneration proceeds slowly, at an overall rate of 1 mm/day, and distances of over 250 mm often must be overcome before end-organ atrophy can be reversed by the arrival of regenerating axons. After one year, the effects of atrophy and endomysial fibrosis on striated muscle fibers reach a stage that is not compatible with good motor recovery (1,31). When nerve lesions that are caused by a bullet or fracture are explored, a great amount of scarring is encountered in the region. In these cases, the nerve is initially identified in the normal tissues above or below the site of injury. These operations can be facilitated by consulting a useful guide that has been written by Henry (58).

Treatment of Nerve Gap When a nerve gap is discovered at surgery and the nerve stumps have been trimmed back to the point at which endoneurial tissue bulges beyond the cut edge, and microscopic examination shows no endoneurial fibrosis, the gap between stumps can be measured. When the extremity is flexed to a position of function, and the residual gap is more than 3 to 5 cm, it is unreasonable to expect that a tension-free neurorrhaphy can be achieved with extensive mobilization of the nerve. In this situation, it is preferable to reconnect the fascicles with several free autogenous nerve grafts of small caliber taken from a long cutaneous nerve serving a small skin area (59,60). The sural nerve is most commonly used for this purpose. To restore fascicular anatomy most effectively, it is important to make a map of the location and size of fascicles in the proximal and distal stumps (and the position of blood vessels on the surface of the nerve) as a guide for reconnecting appropriate quadrants of the nerve and matching major fascicles (60).

REHABILITATION AFTER NEURORRHAPHY Principles of Rehabilitation Current rehabilitation programs are effective in addressing most of the sensory, autonomic, and motor disturbances that result from denervation (55). Although we recognize that most nerve lesions consist of a neuroma-in-continuity and that many of these have a neurapraxic element that does not involve denervation, we focus here on the rehabilitation of patients after neurorrhaphy. Three phases of rehabilitation can be recognized: the denervation phase that precedes end-organ reconnection, the recovery phase during which end-organ atrophy is reversed, and the adaptation phase during which the CNS makes adjustments to altered connectivity. In each of these phases, rehabilitation methods are aimed at preventing unnecessary disability. This is accomplished by using the existing motor and sensory capability and by preserving denervated structures in a state that is optimal for reinnervation. Throughout the rehabilitation program, the outlook of the injured person is an important element in recovery. Beginning with that first moment of despair, patients see their skills destroyed, their careers ruined, and their family life jeopardized. Self-esteem and identity invariably suffer. During the slow and tedious recovery process, the personality of the patient is truly tested. Some patients devote considerable time and effort to assist in the recovery process, whereas others remain indifferent and apathetic. To some, the injured part remains useless despite reinnervation; to others, a permanently disabled part is seen as serving in a useful capacity. Still other patients exploit their injury for monetary and secondary gains.

The rehabilitation program must respect the importance of human interactions between the patient and the health professional (especially the occupational therapist). These play a vital role in rebuilding the patient’s feelings of confidence and trust, feelings that are indispensable to the success of the rehabilitation program. However, even the most devoted professional attention can be rendered ineffectual if the patient does not receive the interest and support of friends and family. At every stage, both the patient and these key people must be advised together about the problems and expectations of the rehabilitation effort. In the end, however, the success of the rehabilitation outcome largely depends on the trust, courage, and determination of the patient (45). Retraining in the activities of daily living is promoted throughout the rehabilitation program, regardless of the extent of motor and sensory recovery or the degree to which the patient has made a psychologic adjustment to the injury. Emphasis is placed on the patient’s existing strengths, with the use of adaptive techniques and devices that encourage the patient to achieve the highest level of performance possible. The activities that are important for self-care, homemaking, recreation, school, and work are broken down into their key components, and a graded program is created to facilitate maximal independent function at each stage of recovery.

Denervation Phase The denervation phase begins at the onset of injury and continues until there is evidence of reconnection. Emphasis is placed on keeping denervated tissues in optimal condition pending reinnervation. Absence of sensation, decreased sweating and circulation, and the presence of edema are impairments that must be addressed swiftly and aggressively to minimize their negative effects. The first part of the sensory reeducation process, protective sensory reeducation, starts when wound closure has been achieved and dressings are no longer necessary. Patients must be educated to appreciate the degree and extent of their sensory deficit, learn to compensate for it, and adopt appropriate safety precautions. They must learn to rely more heavily on their vision while performing activities, and avoid applying excessive pressure to denervated skin by looking for signs of trauma—redness, edema, and warmth (45). Skin that is dry and smooth because of the absence of sweat formation should be treated to prevent cracking. Daily warm water soaks followed by the application of oils help to retain moisture and improve circulation. Blood flow through denervated muscles can also be improved by actively contracting nonparalyzed muscles, thereby exerting a pull on paralyzed muscles through the interconnecting fascial sheaths. Retrograde massage, avoidance of extremes of temperature, and passive range-of-motion exercises are also helpful in this regard. Scar massage and gentle soft-tissue mobilization techniques are used to minimize scar hypertrophy and to prevent adherence of the skin to underlying tissues. Ultimately, this serves to minimize loss of motion as a result of restricted soft-tissue mobility and assists in managing hyperesthesias, which may develop as sensation returns. Passive range-ofmotion exercises and active use of uninvolved muscles are essential for improving circulation and maintaining musculotendinous excursion, preventing stiffness and adhesion formation, and decreasing edema (45). This program can minimize the trophic changes that otherwise occur in denervated skin by improving blood flow and reducing the frequency and severity of minor trauma.

Chapter 42: Injuries to Peripheral Nerves

Denervated muscles must be maintained with dynamic activity to slow the process of myofibrillar atrophy and endomysial fibrosis. Immobilization (beyond that which is needed to prevent tension on the neurorrhaphy) must be avoided because it promotes tissue edema, reduces blood flow, and encourages the development of muscle contractures. Nonetheless, splinting may be indicated for several purposes: (i) to prevent the overstretching of paralyzed muscles, (ii) to support joints, (iii) to balance the forces on joints and tendons, and (iv) to facilitate the active contraction of uninvolved muscles in a manner that substitutes for paralyzed muscles. The type and design of these splints must be individualized to the patient’s needs, and relief from the splint must be provided several times daily to combat the adverse effects of immobilization once the repair has undergone adequate healing. The application of heat in the form of warm water or oil increases circulation without harming sensitive, denervated tissues. Joint stiffness and ankylosis can occur as a result of decreased muscular support, edema, contractures, and the unopposed action of normally innervated muscles. Joint mobility and the ranges of tendon excursion can be preserved by daily passive exercises. Edema, which is caused largely by the inactivity of muscle masses, is combated by elevation, active contraction of uninvolved muscles, massage, use of Jobst intermittent pressure pump, and the application of compression wraps. The use of electric stimulation to prevent denervation atrophy of affected muscles remains controversial because there are no controlled studies in human subjects (55). Although muscle stimulation cannot prevent denervation atrophy, there is considerable experimental evidence suggesting that its use reduces the rate and degree of atrophy and that the electric properties of the stimulated muscle more closely resemble those of the normal muscle (56). However, there is no benefit in terms of final twitch tension or tetanic tension after reinnervation. To reduce the degree of atrophy, treatment must begin soon after injury. The stimulus strength must be sufficient to cause long contractions without pain or discomfort; 15 to 20 contractions per session, with low-frequency stimulation in the range of 10 to 12 Hz, are applied three to four times a day. Treatment is abandoned in favor of active contraction after reinnervation has been documented (1).

Recovery Phase The recovery phase begins with axonal reconnection at an appropriate end organ. During this phase, the therapist plays an important role, monitoring the progress of nerve regeneration through the use of manual muscle testing, sensibility testing, and clinical observation. At each visit, the therapist carefully observes the posture of the involved limb, looking for subtle changes that may indicate the early return of motor function (61). In addition, specific tests of innervation density and sensory threshold are performed. These test the responses to pinprick, temperature, vibration, moving touch/pressure, and static touch/pressure. The Semmes– Weinstein Monofilament Test (North Coast Medical), a standardized threshold test, provides the therapist with an accurate measure of sensibility to graded point pressures throughout the reinnervation period: from unresponsiveness to the return of deep pressure sensation, to the return of protective sensation, to the return of light touch sensation, and to the return of normal sensation (62). Test results are recorded in a color-coded diagram of the limb, providing a

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clear, simple visual representation of the reinnervation process, which can be forwarded to the surgeon. Early signs of sensory recovery include feelings that ‘‘something is happening,’’ tenderness to pressure exerted on muscles, and an advancing Hoffmann’s sign (55). The reinnervation of sensory receptors results in altered sensation. Normal tactile stimuli may be perceived as noxious, leading patients to complain of pain, paresthesias, or hyperesthesias. A desensitization program can be quite effective in reducing these symptoms. Patients are taught to expose the sensitive skin to graded textures (e.g., cotton progressing to sandpaper), vibratory stimuli (of increasing frequencies), and solid particles (45). Treatment begins with the exposure to the least aversive stimuli, and the patient is taught to increase the intensity and duration of stimulation each day. This progression continues until normal stimulation is tolerated. The Three-Phase Desensitization Test (originally, the Downey Community Hospital hand sensitivity test) is a readily available (North Coast Medical), standardized test for hypersensitivity that provides a systematic, reliable method for performing and documenting a desensitization protocol with the items described above (62). Other methods of providing sensory input that have been shown to decrease hyperesthesias include massage, application of heat, and percussion or tapping of the sensitive area (62,63). The principles of pain treatment following nerve injury include measures directed at the pain itself and use of the involved part. The latter is of value because pain is largely a result of the combined effects of vasomotor dysfunction, scar tissue near the proximal nerve stump, and traction on this scar from movement of the limb. To address the pain directly, transcutaneous electric nerve stimulation (TENS) provides relief in almost half the patients. TENS uses an electric device to emit a pulsed current to skin electrodes in a biphasic asymmetric wave. TENS is so effective in treating pain from peripheral nerve injuries that mild transcutaneous stimulation using surface electrodes may be sufficient even for the treatment of sympathetically maintained pain (64,57). Different forms of stimulation are achieved by adjusting the amplitude, frequency, and duration of the pulse. Constant stimulation of the large-diameter afferent fibers reduces the perception of pain, which depends on slowly conducting nonmyelinated fibers. TENS is not a cure for pain but rather an adjunct to the specific treatment of the nerve injury. Its purpose is to decrease pain to a degree that allows patients to participate in the rehabilitation program and perform functional activities. The pattern of sensory recovery begins with the return of pain and temperature appreciation. This is followed by awareness of vibration at 30 Hz, moving touch stimuli, and then vibration at 256 Hz. The last modalities to recover are the localization of tactile stimuli and two-point discrimination (65). Modality tests include pinprick, temperature discrimination, vibration, moving touch/pressure, and constant touch/pressure. The return of function is assessed from tests of moving and static two-point discrimination, the response to a ridge-shaped sensitometer, and tactile gnosis (the ability to feel the shape, weight, and texture of objects well enough to identify these) (45). The Moberg pickup test is particularly useful because the ability to pick up a series of 10 to 12 small objects of various sizes and then place them into a small container is readily timed and compared to results for the normal hand (45). Qualitative differences in prehension patterns may also become apparent during testing. An effort must be made to standardize the conditions for these tests at follow-up examination, because

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there are many uncontrollable factors affecting the transmission of sensory impulses from the periphery to the CNS. Muscle atrophy is reversed by reinnervation of the motor end plate, provided that endomysial fibrosis is not advanced. Rehabilitative efforts are aimed at maximizing voluntary motion, motor control, and strength. The therapist must be familiar with the expected order of reinnervation following repair of the particular nerve lesion being treated, information that is readily obtained from standard texts (1). Treatment methods during the recovery phase include muscle reeducation, biofeedback, resistive exercises (initially resisting gravity alone), proprioceptive facilitation techniques (to maximize the stimulation of muscle afferents), and the use of patterns of movement that recruit the maximal number of muscle fibers (46).

Adaptive Phase Once end-organ function has been restored, central changes occur, which reflect adaptation to a new pattern of connectivity. An important part of this phase, which can be influenced by the rehabilitation program, is the reeducation of integrative mechanisms in the CNS. This facilitates new patterns for acquiring sensory information and distributing commands to muscle groups. Sensory recovery may slowly progress for more than three years before it is complete. Improvement occurs both through the maturation of reunited axon-receptor systems and the subliminal reeducation of integrative mechanisms. Because the CNS acquires sensory information differently after neurorrhaphy (because end-organ reinnervation is a random event), the sensations that occur early in the recovery phase may be somewhat foreign to those normally perceived in a particular part of the CNS (5,58). Sensory reeducation involves a graded series of specific sensory exercises that are instituted at appropriate times in the recovery process. An attempt is made to facilitate central reorganization so that patients can interpret the altered profile of neural impulses reaching consciousness. In the early stages of recovery, patients relearn modalityspecific perceptions (e.g., moving vs. constant touch). In the later stages, patients progress to the second phase of sensory reeducation: discriminative sensation. Readiness for progression to this phase is determined by the patient’s results on the Semmes–Weinstein monofilament test. The patient must be able to perceive filament number 4.31 (2.35 g) before discriminative training proves useful (66). At that time, various structured activities are performed with the ultimate goal of the return of tactile gnosis (name recognition of objects in the hand; two-point discrimination). Various stimuli are applied to the patient’s hand with the patient’s vision occluded. The patient attempts to identify the stimulus, and if unsuccessful, the stimulus is applied while the patient watches. The patient continues this training method, alternating eye occlusion and then using direct visualization in an effort to reorganize and integrate the cortical processing of sensory information from the altered periphery. The patient is challenged with the task of first identifying specific characteristics of the object (e.g., metallic vs. wooden and round vs. square). Ultimately, the patient attempts to name the object itself (e.g., key, coin, and paperclip). Graphesthesia activities and puzzles or mazes that are performed with vision occluded are higher-level tasks that also facilitate the return of discriminative sensation (66). This program is continued until the patient assumes responsibility for self-education and returns to work, avocations, and self-care. With sensory reeducation, maximal recovery may

occur within two years (65), shortening the adaptive phase by a year or more. Surgical procedures for the relief of pain caused by peripheral nerve injuries include the excision of any neuromas and sympathectomy. However, the former is rarely effective (67) and the latter has largely been replaced by TENS, ganglion blocks, and phenoxybenzamine (57,68). Muscle mass is regained through repeated exercises and the use of the injured part in activities of daily living.

Permanent Denervation Specific adaptive techniques, support personnel, or appliances may be required when functional impairment is substantial and permanent (63). Sufficient time should be allowed to elapse before evaluating the extent and significance of recovery. Although reconstructive procedures may be effective if performed in a timely manner, the patient will realize that the hoped-for recovery cannot occur. These procedures include arthrodesis, tendon transfers, tendon translocation, tenodesis, nerve transfers (69), microsurgical free muscle transplants, muscle transfers using an intact neurovascular island pedicle, and amputation with prosthetic fitting. These procedures require specific rehabilitation methods and goals.

SUMMARY Peripheral nerve injuries are rarely followed by a full recovery of function and often leave patients with a significant disability. Most nerve injuries involve an upper extremity and therefore threaten hand function. To minimize the extent and incidence of permanent disability, it is important to preserve as much of the microanatomy of the injured nerve as possible. This may mean ‘‘leaving well enough alone.’’ To know when to intervene surgically and, more importantly, when not to intervene requires an in-depth understanding of the anatomy and physiology of normal nerves. Diagnostic tools such as NCS and EMG are critical in sorting out the nature of the injury. To maintain what has been obtained by successful initial management requires the use of active rehabilitation measures that take account of any residual limb pain. Therapy must begin soon after injury, continue during the phases of recovery, and maximize the patient’s independence in the performance of daily activities.

REFERENCES 1. Sunderland S. Nerves and Nerve Injuries. Edinburgh: Churchill Livingstone, 1978. 2. Kline DG, Hackett ER. Reappraisal of timing for exploration of civilian peripheral nerve injuries. Surgery 1975; 78:545. 3. Brushart TM, Mesulam MM. Alteration in connections between muscle and anterior horn motoneurons after peripheral nerve repair. Science 1980; 208:603. 4. Lisney SJW. Changes in the somatotopic organization of the cat lumbar spinal cord following peripheral nerve transection and regeneration. Brain Res 1983; 259:31. 5. Wall JT, Felleman DJ, Kaas JH. Recovery of normal topography in the somatosensory cortex of monkeys after nerve crush and regeneration. Science 1983; 221:771. 6. Bell MA, Weddell AGM. A descriptive study of the blood vessels of the sciatic nerve in the rat, man, and other mammals. Brain 1985; 107:871.

Chapter 42: Injuries to Peripheral Nerves 7. Hudson A, Kline D. Progression of partial experimental injury to peripheral nerve. II. Light and electron microscopic studies. J Neurosurg 1975; 42:15. 8. Smith DR, Kobrine AI, Rizzoli HV. Blood flow in peripheral nerves. Normal and post severance rates. J Neurol Sci 1977; 33:341. 9. Donat JR, Wisniewski HM. The spatio-temporal pattern of wallerian degeneration in mammalian peripheral nerves. Brain Res 1973; 53:41. 10. Grafstein B, McQuarrie IG. Role of the nerve cell body in axonal regeneration. In: Cotman CW, ed. Neuronal Plasticity. New York: Raven Press, 1978. 11. McQuarrie IG. Role of the axonal cytoskeleton in the regenerating nervous system. In: Seil FJ, ed. Nerve, Organ, and Tissue Regeneration: Research Perspectives. New York: Academic Press, 1983. 12. Grafitein B, Forman DS. Intracellular transport in neurons. Physiol Rev 1980; 60:1167. 13. McQuarrie IG. Effect of a conditioning lesion on axonal transport during regeneration: the role of slow transport. In: Elam J, Cancalon P, eds. Advances in Neurochemistry. Vol. 6. New York: Plenum Press, 1984. 14. Benowitz LI, Yoon MG, Lewis ER. Transported proteins in the regenerating optic nerve: regulation by interactions with the optic rectum. Science 1983; 222:185. 15. Skene HHP, Willard M. Axonally transported proteins associated with axon growth in rabbit central and peripheral nervous systems. J Cell Biol 1981; 89:96. 16. Bray GM, Rasminsky M, Aguayo AJ. Interactions between axons and their sheath cells. Annu Rev Neurosci 1981; 4:127. 17. McQuarrie IG. Accelerated axonal sprouting after nerve transection. Brain Res 1979; 167:185. 18. McQuarrie IG. Effect-of a conditioning lesion on axonal sprout formation at nodes of Ranvier. J Comp Neurol 1985; 231:239. 19. Singer PA, Mehler S, Fernandez HL. Blockade of retrograde axonal transport delays the onset of metabolic and morphologic changes induced by axotomy. J Neurosci 1982; 2:1299. 20. Wujek JR, Lasek RJ. Correlation of axonal regeneration and slow component B in two branches of a single axon. J Neurosci 1983; 3:243. 21. Lund LM, Machado VM, McQuarrie IG. Increased Beta-actin and tublin polymerization in regrowing axons: relationship to the conditioning lesion effect. Exper Neurol 2002; 178:306. 22. Weller RO, Cervos-Navarro J. Pathology of Peripheral Nerves. London-Boston: Butterworth Publishers, 1977. 23. Forman DS, Wood DK, DeSilva S. Rate of regeneration of sensory axons in transected rat sciatic nerve repaired with epineurial sutures. J Neurol Sci 1979; 44:55. 24. Kline DG, Hayes GJ, Morse AS. A comparative study of response to species to peripheral nerve injury. J Neurosurg 1964; 21:980. 25. Kline DG, Hackett ER, May PR. Evaluation of nerve injuries by evoked potentials and electromyography. J Neurosurg 1969; 31:128. 26. Sanders FK, Young JZ. The influence of peripheral connexion on the diameter of regenerating nerve fibers. J Exp Biol 1946; 22:203. 27. Friede RL. Control of myelin formation by axon caliber (with a model of the control mechanism). J Comp Neurol 1972; 144:233. 28. Politis MJ et al. Studies on the control of myelinogenesis. IV. Neuronal induction of Schwann cell myelin-specific protein synthesis during nerve fiber regeneration. J Neurosci 1982; 2:1252. 29. Gordon T, Stein RB. Reorganization of motor-unit properties in reinnervated muscles of the cat. J Neurophysiol 1982; 48:1175. 30. Bowden REM, Sholl DA. The advance of functional recovery after radial nerve lesions in man. Brain 1950; 73:17. 31. Richter HP. Impairment of motor recovery after late nerve suture: experimental study in the rabbit. I. Functional and electromyographic findings. Neurosurgery 1982; 10:70. 32. Gilliatt RW. Physical injury to peripheral nerves. Physiologic and electrodiagnostic aspects. Mayo Clin Proc 1981; 56:361.

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33. Dyck PJ et al. Structural alterations of nerve during cuff compression. Proc Nad Acad Sci USA 1990; 87:9828. 34. Pollock FH et al. Treatment of radial neuropathy associated with fractures of the humerus. J Bone Joint Surg 1981; 63A:239. 35. Lundborg G, Myers R, Powell H. Nerve compression injury and increased endoneurial fluid pressure: a ‘‘miniature compartment syndrome.’’ J Neurol Neursurg Psychiatry 1983; 46:1119. 36. Richardson PM, Thomas PK. Percussive injury to peripheral nerve in rats. J Neurosurg 1979; 51:178. 37. Wall PD. The painful consequences of peripheral injury. J Hand Surg 1984; 9B:37. 38. Treede RD et al. Peripheral and central mechanisms of cutaneous hyperalgesia. Prog Neurobio 1992; 38:397. 39. Verdugo RJ, Ochoa JL. Sympathetically maintained pain. Neurology 1994; 44:1003. 40. Rothberg JM, Tahmoush AJ, Oldakowski R. The epidemiology of causalgia among soldiers wounded in Vietnam. Milit Med 1983; 148:347. 41. Merskey H. Classification of chronic pain. Pain 1986(suppl 3):1. 42. Devor M, Janig W. Activation of myelinated afferents ending in a neuroma by stimulation of the sympathetic supply in the rat. Neu Rosci Lett 1981; 24:43. 43. Roberts WJ. A hypothesis on the physiological basis for causalgia and related pains. Pain 1986; 24:297. 44. Shir Y, Seltzer Z. Effects of sympathectomy in a model of causalgiform pain produced by partial sciatic nerve injury in rats. Pain 1991; 45:309. 45. Hunter JM et al. Rehabilitation of the Hand: Surgery and Therapy. 3rd ed. St. Louis: Mosby, 1990. 46. Nickel VL. Orthopedic Rehabilitation. Edinburgh: Churchill Livingstone, 1982. 47. Goodgold J, Eberstein A. Electrodiagnosis of Neuromuscular Diseases. Baltimore: Williams & Wilkins, 1978. 48. Bradley WG. Disorders of Peripheral Nerves. Oxford: Blackwell Scientific Publications, 1974. 49. Mcdonald CM et al. Magnetic resonance imaging of denervated muscle: comparison to electromyography. Muscle Nerve 2000; 23:1431. 50. Bendszus M, Koltzenburg M. Visualization of denervated muscle by gadolinium-enhanced MRI. Neurology 2001; 57:1709. 51. Omer GE. Injuries of nerves of the upper extremity. J Bone Joint Surg 1974; 56A:1615. 52. Terzis JK, Dykes RW, Hakstian RW. Electrophysiological recordings in peripheral nerve surgery: a review. J Hand Surg 1976; 1:52. 53. Napier JR. The significance of Tinel’s sign in peripheral nerve in juries. Brain 1949; 72:63. 54. McQuarrie IG. Nerve regeneration and thyroid hormone treat ment. J Neurol Sci 1975; 26:499. 55. Wynn Parry CB. Rehabilitation of the Hand. 3rd ed. London: Butterworth Publishers, 1978. 56. Nix WA. The effect of low-frequency electrical stimulation on the denervated extensor digitorum longus muscle of the rabbit. Acta Neurol Scand 1982; 66:521. 57. Meyer GA, Fields HL. Causalgia treated by selective large fibre stimulation of peripheral nerve. Brain 1972; 95:163. 58. Henry AK. Extensile Exposure. 2nd ed. Edinburgh: Churchill Livingstone, 1973. 59. Haase J, Bjerre P, Simensen K. Median and ulnar nerve transections treated with microsurgical interfascicular cable grafting with auto genoussural nerve. J Neurosurg 1980; 53:73. 60. Millesi H. Interfascicular grafts for repair of peripheral nerves of the upper extremity. Orthop Clin North Am 1977; 8:387. 61. Hallin RG, Wiesenfeld Z, Lindblom U. Neurophysiological studies on patients with sutured median nerves: faulty sensory localization after nerve regeneration and its physiological correlates. Exp Neurol 1981; 73:90. 62. Waylett-Rendall J. Desensitization of the traumatized hand. In: Hunter JM, Mackin EJ, Callahan AD, eds. Rehabilitation of the Hand: Surgery and Therapy. 4th ed. St. Louis: Mosby, 1995:693. 63. Trombly CA, Scott AD. Occupational Therapy for Physical Dysfunction. Baltimore: Williams & Wilkins, 1977.

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64. Campbell JN, Long DM. Peripheral nerve stimulation in the treatment of intractable pain. J Neurosurg 1976; 45:692. 65. Dellon AL. Evaluation of Sensibility and Reeducation of Sensation in the Hand. Baltimore: Williams & Wilkins, 1981. 66. Callahan AD. Methods of compensation and reeducation for sensory dysfunction. In: Hunter JM, Mackin EJ, Callahan AD, eds. Rehabilitation of the Hand: Surgery and Therapy. 4th ed. St. Louis: Mosby, 1995:701.

67. Noordenbos W, Wall PD. Implications of the failure of nerve re section and graft to cure chronic pain produced by nerve lesions. J Neurol Neurosurg Psychiatr 1981; 44:1068. 68. Ghostine SY et al. Phenoxybenzamine in the treatment of causalgia: report of 40 cases. J Neurosurg 1984; 60:1263. 69. Chacha PB, Krishnamurti A, Soin K. Experimental sensory reinnervation of the median nerve by nerve transfer in monkeys. J Bone Joint Surg 1977; 59A:386.

PART SIX: The Peripheral Vascular System

43 Physiology of Arterial, Venous, and Lymphatic Flow Dennis F. Bandyk and Paul A. Armstrong

pressure energy produced in the heart, by cushioning vessels that convert the pulsatile flow of the blood into smooth flow, and acting as resistance vessels involved in the microcirculation. Arterial wall structure and neural innervations accordingly reflect the specialized function(s) of the various arterial system elements. As blood proceeds through the arterial system, the network of conducting vessels undergoes repeated branching accompanied by a decrease in caliber, resulting in many parallel distributing vessels that terminate in the capillary beds. In the arterial system of the lower extremity, branching produces potential collateral networks that can bypass blood around a hemodynamically significant, i.e., pressurereducing, obstruction in a conduit artery (Fig. 1). The total cross-sectional area progressively increases each time branching occurs, with a concomitant decrease in mean flow

INTRODUCTION Clinical evaluation of patients with vascular disease requires a thorough understanding of the anatomy and hemodynamics of the arterial, venous, and lymphatic circulations. The continued improvement of noninvasive ultrasound techniques that produce high-resolution vascular imaging and depict system hemodynamics has resulted in improved understanding of arterial and venous disease pathophysiology, and has better defined the physiologic significance of anatomic disease. The ability to monitor the hemodynamics of arterial and venous flow and vessel anatomy serially has allowed detection of disease progression, resulting in a more cost-effective and timely intervention. In this chapter, the functional anatomy and hemodynamics of the arterial, venous, and lymphatic components of the circulatory system will be discussed. Special emphasis will be placed on how the biophysical properties of the circulation (e.g., pressure, flow velocity, and turbulence) can be measured in man, and how such measurements are used in the evaluation of patients with vascular disease. The discussion will focus primarily on the principles of arterial, venous, and lymphatic flow in the lower extremity; however, the concepts are equally germane and applicable to the upper extremity and cerebrovascular circulation.

PERIPHERAL ARTERIAL SYSTEM The purpose of the arterial system is to deliver blood and its various components to tissue capillaries in amounts sufficient to maintain normal cellular function. Metabolic demands of body tissues and organs vary widely, in normal (resting), exercising, and diseased states. The ability of the arterial circulation to respond to a variable demand is reflected in the anatomic and physical properties of the cardiovascular system and is mediated through two regulatory mechanisms: local control of blood flow through the tissue according to its metabolic state (autoregulation) and neural control of peripheral vascular resistance. These factors, acting in concert, control tissue blood flow and consequently regulate cardiac output. Control of blood flow is also strongly influenced by factors such as those involved in the regulation of extracellular fluid volume and urinary output. The functional elements of the arterial system include the ‘‘heart,’’ which generates the energy necessary to maintain arterial pressure and blood flow at an appropriate level, ‘‘arteries,’’ which transport blood to the periphery, ‘‘arterioles,’’ which regulate flow of blood into the microcirculation, and ‘‘capillaries,’’ which are the site of nutrient and metabolic exchange to the tissues. Depending on their position in the arterial system, arteries can act as ‘‘storers’’ of

Figure 1 Diagram of the arterial circulation to the lower extremity, indicating the main conduit arteries and corresponding potential collateral arteries.

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Table 1 Physical and Hemodynamic Characteristics of the Human Arterial System Mean flow Crossvelocity Pressure Resistance Total blood sectional (cm/s) (mmHg) (%) volume (%) area (cm2) Aorta Branching arteries Arterioles Capillaries

8 5 2 5

2.5 20 40 2500

14–18 12

100 90

4 21

0.07

55 25

41 27

velocity (Table 1). At the capillary level, the cross-sectional area is approximately 1000 times that of the aorta. Each red blood cell remains in the microcirculation for only one to three seconds, an exceedingly short time during which all nutrient diffusion and fluid exchange occur. Approximately 20% of the entire blood volume of the body is in the arterial system, in contrast to the 64% in the venous system. The heart contains 7% of the blood, and the pulmonary vessels 9%. Surprisingly, only 5% of the total blood volume resides in the capillaries. Although total capillary volume is small, surface and cross-sectional areas are immense to facilitate the transfer of oxygen, carbon dioxide, water, nutrients, and electrolytes through the capillary walls. In the resting state, the lower limbs receive about 300 to 400 mL/min, two to three times of that in the upper limbs, primarily because of differences in muscle mass. The heart, through cyclic muscle wall contraction, generates a complex pressure pulse and provides the energy for blood flow. The ability of the heart to vary its output is based on its three fundamental properties: the capacity to vary the rate of contraction (chronotropism), the rate of isometric tension development, which is a function of cardiac muscle fiber length (Frank–Starling mechanism), and the ability to alter the velocity of muscle fiber shortening (inotropism). From these properties, four factors that are independent determinants of cardiac output can be defined. These are commonly referred to as ventricular preload, ventricular contractility, ventricular afterload, and heart rate. The output of the heart mainly reflects the demands of the peripheral circulation. The frequency of contraction is determined by the interplay of neural and humeral adrenergic and neural cholinergic activity on the sinoatrial node. The velocity and force of ventricular– muscular contraction are influenced by both circulating and neuron-released catecholamines acting on the muscle fibers themselves. The work output of the heart is the amount of energy that the heart transfers to the blood. This energy, which is in the form of potential energy of pressure and the kinetic energy of blood flow, is used to accelerate blood to its ejection velocity through the aortic valve. In the distribution of blood to the various capillary beds, the viscoelastic properties of the artery walls and the tapered, converging vessel caliber are important physical characteristics maintaining blood pressure and minimizing pressure and kinetic fluid energy losses.

Arterial Wall: Structural Features The composition and structure of the arterial wall in the different segments of the arterial system reflect the local wall mechanics and its functional role. With the exception of the capillaries, the artery wall consists of three concentric layers: tunica intima, tunica media, and tunica adventitia.

The tunica intima is the innermost layer and consists of monolayer endothelium lining the lumen, a thin basal lamina, and a subendothelial layer (present in the large elastic arteries of the thorax and abdomen), composed of collagenous bundles, elastic fibrils, and smooth cell muscles. The tunica media is in the middle layer and is made up of predominantly smooth muscle cells in a varied number of elastic sheets (laminae), bundles of collagenous fibrils, and a network of elastic fibrils. The tunica adventitia consists of dense fibroelastic tissue without smooth muscle cells. The adventitia also contains the nutrient vessels of the arterial wall (vaso vasorum) and both vasomotor and sensory nerves of the vascular wall. Arteries can be classified by the respective amounts of elastin, smooth muscle, and collagen in their walls. The distensibility of an artery wall generally correlates with the elastin content. The large arteries of the thorax and abdomen, such as the aorta, innominate, iliac, subclavian, and common iliacs, are referred to as elastic or ‘‘pressure storer’’ arteries because their walls contain a predominance of elastin and few smooth muscle cells. The large elastic arteries instantaneously accommodate each stroke volume of the heart, storing a portion during systole and draining this volume during diastole (windkessel effect). This helps to propel the blood toward the periphery during diastole and promotes continuous flow to the capillaries. The internal systole pressure in the large arteries is normally about 120 to 160 mmHg. Proceeding distally, the muscular or branching arteries such as brachial, radial, femoral, and popliteal have a media with a predominance of smooth muscle and collagen, but little elastic tissue. The varying arterial wall properties distant from the heart are related to the proportions of collagen and elastin in the media, the linkage between these two elements, the insertions of elastin and muscle on collagen fibers, and the contractile state of the vascular smooth muscle. Proceeding from the thoracic aorta distally, there is a gradual decline in the elastin–collagen ratio. Thus, the initial segment of the arterial tree has a lower vascular impedance, and oscillatory component of work required distally to maintain cardiac output is reduced. The increased relative stiffness of the distal muscular arteries is important to ensure that undampened transmission of the pressure pulse to the baroreceptors (e.g., at the carotid bifurcation) occurs. At the level of the arterioles, the arterial wall is composed almost entirely of smooth muscle. These vessels provide the major site of resistance to the arterial system, and provide for the regulation of blood flow to the microcirculation (Table 1). Mean pressure in the arterioles ranges from 40 to 60 mmHg. The smooth muscle of the media is well innervated by sympathetic nerves. At the cutaneous level, these nerve fibers are involved with temperature regulation, vasoconstriction in cool weather to conserve heat and vasodilatation in warm conditions to dissipate heat. Exceptions to this can occur in the septic states, severe emotional distress, or profound shock, where vasodilatation predominates secondary to sympathetic innervation. Additionally, metabolites at a local level also cause vasodilatation, as does exercise. This autoregulation disappears at pressures below 30 mmHg, where flow occurs secondary to perfusion pressure alone. The collagen content of the arterial wall correlates with its tensile strength, with the adventitia collagen responsible for the majority of wall stability. This is evident from the maintenance of vessel integrity by the adventitia following surgical endarterectomy, which removes the intima and

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large portion of the media. In naturally occurring aneurysms, the collagen content of the adventitia is decreased and failure of wall integrity occurs. Degradation of collagen results in arterial wall rupture. The circumferential tension (T) in the arterial wall is calculated as the product of the transmural pressure, Pt (inside pressure minus outside pressure), and the radius (R). This relationship, known as the Law of Laplace, can be expanded to include the factor of wall thickness (mm): T ¼ Pt R=mm ðdynes/cmÞ In arteries with a radius and wall thickness of equal proportions, wall tension varies with transmural pressure. For example, the small radius and low pressure of a capillary requires only a thin wall to support the wall tension, whereas the aorta with its greater pressure and radius requires a thicker wall to prevent rupture. The elastic properties of any blood vessel can be described by Young’s modules (E), which is stress divided by strain. Because arteries are subject to pulsatile pressure, measurements of elasticity are determined from the strain that accompanies a period of time in which stress is varied, producing what is called dynamic modules (Edyn). The most important component of stress in arteries is the first harmonic of the pressure pulse, i.e., heart rate. The dynamic elastic modules of an artery are also a determinant of pulse wave velocity. In vivo arterial wall motion occurs predominantly in the circumferential direction. The variation of vessel diameter with each cardiac cycle closely resembles the pressure waveform. Intrathoracic arteries vary 12% to 18% in diameter with each pressure pulse, whereas peripheral arteries change 8% to 10% in diameter. The distensibility characteristic of arteries also depends on the extent of stretch (transmural pressure). At low pressure and small diameters, arteries are very distensible, whereas they become gradually stiffer with increasing pressure and diameter. The viscoelastic properties of arteries are altered not only in diseased states but also change with age. With age, artery diameter and length increase, and so do the wall thickness and collagen-to-elastin ratios. These changes result in tortuosity, increased arterial stiffness, and an increase in vascular impedance. Although an increase in the thickness of the intima, which initially occurs in atherosclerosis, has little effect on the elastic properties of the artery, the accompanying changes within the media and adventitia, particularly if the wall nutrition through vaso vasorum is involved, may have marked effects of hemodynamic characteristics and further disease progression.

Figure 2 Effect of hematocrit on relative velocity of blood. Note that as the hematocrit increases, the relative viscosity increases disproportionately. Source: From Ref. 1.

tubes (less than 200 mm) such as the arterioles, capillaries, and venules. This phenomenon is known as Fahraeus– Lindqvist effect and is related to red cell orientation and lower hematocrit in small vessels. The rheology of blood in the capillary circulation is poorly understood, although the deformability of the red cell membrane and erythrocyte velocity are important factors. Rheologic agents focus on increasing the membrane flexibility of the red blood cells and therefore decrease the overall viscosity of blood. They also promote decreased platelet aggregation. The viscosity of blood is important not only for its effect on the resistance to blood flow, but also in producing impairment of tissue perfusion. Increased blood viscosity can potentiate the low flow states seen in pathologic conditions such as polycythemia, trauma, and other hyperviscosity syndromes. Increased blood viscosity combined with a low flow promotes erythrocytes to aggregate into stocks or ‘‘rouleaux,’’ with resultant tissue ischemia.

Essentials of Arterial Hemodynamics Hemodynamics is a discipline concerned with the interrelationships of the physical characteristics of blood and pulsatile flow conditions in the visoelastic arterial and venous circulations. As a first step toward understanding the complexity of arterial flow, it is useful to discuss the energy principles involved in arterial circulation and the interrelationships between pressure, flow, and resistance under steady flow conditions.

Viscous Properties of Blood Flow Blood is a viscous fluid composed of cells and plasma. When blood flows, frictional forces develop between the cellular components of blood, causing it to exhibit the property of viscosity. Because the red blood cells comprise the majority of the cellular component, the hematocrit is a major determinant of blood viscosity, as illustrated in Figure 2. If measured with reference to water, the relative viscosity of blood having a hematocrit of 40 is approximately 3.6. This means that three to four times as much pressure is required to force blood than water through the same tube. Blood viscosity is not constant in the arterial system but exhibits a nonNewtonian fluid property: the faster it flows, the lower is its viscosity. The chief determinants of this property are the red cell concentrations and plasma concentration of fibrinogen and globulins. Blood viscosity decreases in small caliber

Fluid Energy In general, blood flows from a point of high pressure to one of lower pressure, but the true driving force is the differential in total fluid energy. ‘‘Total fluid energy’’ associated with blood flow is of three types: intravascular pressure, gravitational, and kinetic. The intravascular pressure (P) has three components: (i) the dynamic pressure produced by the contraction of the heart, (ii) the hydrostatic pressure, and (iii) the static filling pressure. Both the gravitational energy and the hydrostatic pressure are determined by the product of the specific gravity of blood (r), the acceleration of gravity (980 cm/sec)(g), and the distance (h) above the right atrium. Gravitational energy (þrgh) is the ability of the blood to do work on the basis of its height and is of the opposite value of the hydrostatic pressure (-rgh). The static filling pressure is

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the residual pressure that exists in the absence of arterial flow. This pressure is determined by the volume of blood and the compliance of the arterial system, and is in the range of 5 to 10 mmHg. Because the hydrostatic pressure and the gravitational potential energy cancel each other out and the static filling pressure is relatively low, the dynamic pressure produced by the heart is the major source of potential energy used in moving blood. Kinetic energy (Ek) is the ability of blood to do work on the basis of its motion. It is proportional to the specific gravity of blood (p) and the square of the blood velocity (v): Ek ¼1=2 pv2 Omitting the term for gravitational energy (i.e., þpgh), the total fluid energy per volume of blood (E) can be expressed as: Ek ¼ P þ1=2 pv2 where P is intravascular pressure. In an idealized fluid system of steady flow and/or frictional energy losses, total fluid energy along a streamline remains constant with the relationship between the different energy forms described by Bernoulli’s principle of the conservation of energy:

as a result of an atherosclerotic plaque, the Bernouille effect and the production of turbulence with the associated changes in kinetic energy explain the pressure and flow changes that develop under these conditions. It is important to emphasize that the pressure–flow relationship described in Poiseuille’s law is based on assumptions involving idealized fluid mechanics that significantly underestimate the energy losses present in the viscoelastic pulsatile flow conditions of the human circulation. Poiseuille’s law represents the minimum pressure gradient produced by viscous losses that may be expected in arterial flow. In addition to energy loss caused by friction, inertial energy losses related to changes in the velocity and the direction flow occur. In the arterial system, particularly in the presence of disease, energy losses caused by inertial effects usually exceed viscous energy loss. Energy losses related to inertia are proportional to the specific gravity of blood and the square of the blood velocity. Because the density of blood is constant, inertial losses result when blood accelerates, decelerates, or changes direction. In the arterial system, inertial energy losses occur at points of curvature, variations of lumen diameter, and at bifurcations of the vasculature. Blood velocity usually increases from large luminal size to smaller luminal size. The acceleration and deceleration of blood in pulsatile flow add inertial forces to the constant kinetic energy of steady flow.

P þ1=2 pv1 2 ¼ P2 þ1=2 pv2 2 þ heat In the horizontal diverging tube shown in Figure 3, steady flow between two points is accomplished by an increase in cross-sectional area and a decrease in flow velocity. Although fluid energy moves against a pressure gradient (p2
p1) of 2.4 mmHg and gains potential energy, total fluid energy remains constant because of a lower velocity and a proportional loss of kinetic energy. In the normal arterial system in which ideal flow conditions are absent and vessels change diameter only gradually, the pressure gradients caused by viscous losses as predicted by Poiseuille’s law far outweigh the extremely small interconversions to kinetic energy and pressure. In certain disease states, however, such as sudden vessel widening into an aneurysm or narrowing

Figure 3 Vascular resistance in series and parallel. (Top) Total resistance (Rt) of a conducting system with individual resistances in series is the sum of resistances: Rt ¼ (R1 þ R2 þ R3). (Bottom) When resistance vessels are in parallel, the total resistance is the sum of the reciprocals of the individual resistances: Rt¼1-(R1 þ R2 þR3 þ). Note that in a parallel conducting system, the total resistance is less than any individual resistance level. Q indicates blood flow.

Resistance to Flow The relations between flow and pressure in cylindrical tubes were first accurately described by the French physician, Poiseuille, in 1846. Under the conditions of his experiments, the volume flow (Q) through a vessel is determined by: Q¼

Ppr4 ml=min 8lm

where P is perfusion pressure, or the pressure gradient between the ends of the vessel, r is the vessel radius, l is the vessel length, and m is viscosity of the fluid. Poiseuille’s law describes the viscous energy losses that occur in a steady-flow, idealized fluid model. The theoretic derivation rests in the assumptions that each particle of the fluid moves at a constant velocity parallel to the vessel wall, that the force opposing this motion is proportional to fluid viscosity, and that the velocity gradient is perpendicular to the direction of flow. This means that in a cylindrical tube, the fluid moves in a series of concentric lamina and flow is laminar. Steady laminar flow results in a parabolic velocity profile in the tube. As predicted by this law, the resistance to flow is most dependent on vessel radius. Resistance is proportional to vessel length and viscosity, but inversely proportional to the fourth power of the radius. Assuming a constant blood viscosity, a doubling of conduit length will double the resistance, whereas halving the radius increases the resistance 16 times. In the human peripheral arterial system, flow is primarily determined by active changes in the arteriole, arteries less than 200 mm in diameter, and the capillary. Artery caliber varies according to the state of contraction of the vascular smooth muscle, which depends on perfusion pressure, activity of the sympathetic nervous system, and local mechanisms involving metabolic, humeral, and physiologic factors. In a flow model governed by Poiseuille’s law, the physical properties of the system (tube dimensions and fluid viscosity) determine the magnitude of pressure gradient required to produce a given flow. The ratio of mean pressure gradient

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Laminar and Turbulent Flow As previously discussed, the blood flow follows streamlines or is laminar in the steady flow conditions specified by Poiseuille’s law. The velocity profile is parabolic in shape (Fig. 5). In contrast to the concentric laminae of laminar flow, turbulence is a condition in which the flow velocity vectors are moving in a random fashion with respect to space and time. The point at which flow changes from laminar to turbulent, termed the ‘‘critical velocity,’’ depends on the ratio of inertial forces to viscous forces and is best defined in terms of a dimensionless entity known as Reynolds number:

Figure 4 Effect of increasing cross-sectional area on pressure in frictionless fluid system. Although pressure increases, total fluid energy remains constant because of a decrease in velocity. Abbreviations: A, area; V, velocity; P, pressure. Source: From Ref. 2.

to mean flow is thus a measure of the opposition to flow, commonly termed ‘‘vascular resistance.’’ When Poiseuille’s law is simplified to an expression, pressure ¼ flow times resistance, it is exactly analogous to Ohm’s law of electric circuits, V ¼ 1  Re, when Poiseuille’s equation is rearranged to: 8lm P ¼ Q Q 4 mmHg r Q where the term (8lm)/ r4 expresses electrical resistance (Re), P is voltage (V), and Q is flow of current (I). Vascular and electrical resistances both express the dissipation of energy per unit flow within a system. In the arterial system, resistance is expressed as peripheral resistance units (PRU), where 1 PRU equals the resistance to flow encountered when there is a pressure difference between two points of 1 mmHg and flow is 1 m/sec. The resistance of the entire systemic circulation is approximately 1 PRU, calculated using a 100-mmHg pressure gradient between the left ventricle and the right atrium and an average blood flow of 100 mL/sec. The total resistance of a conducting system depends on whether the vessels are in series or in parallel (Fig. 4). When vessels are in series, total resistance is equal to the sum of the individual resistances. On the other hand, if the conducting vessels are in parallel, total resistance is the reciprocal of the total conductance. This means that in a parallel conducting system, total resistance is less than any of the individual resistance vessels. Also resistance usually tends to increase as velocity increases along a fixed diameter artery.

Re ¼ rdv=m where r is the blood density, d is the vessel diameter, v is the mean velocity, and m is the viscosity. Below a Reynolds number of 2000, flow is laminar because viscous forces predominate and damping of random inertial forces on the flow stream occurs. At a Reynolds number above 2000, the inertial forces may disrupt the laminar flow pattern, the result being increased energy dissipation as sound and heat. Energy dissipation in laminar flow is proportional to flow velocity, whereas losses in turbulent flow occur with the velocity squared. Flow conditions that predispose to the development of turbulence include an increased flow velocity (ascending aorta), a decreased vessel diameter (diseased), or a reduced blood viscosity (anemia, over hydration). An important clinical sign of turbulence is the presence of a bruit. Streamline (laminar) flow is silent, but turbulence produces wall vibrations that can often be heard with a stethoscope, termed a ‘‘bruit.’’ Bruits produced by stenoses are loudest over the stenotic segment and are transmitted in a distal direction. Under conditions of turbulent, viscoeleastic flow, the arterial velocity profile changes from the parabolic shape of laminar flow to a blunt or rectangular shape. Although turbulent flow is uncommon in arteries, a condition of disturbed flow commonly occurs. Disturbed flow is a transient perturbation in the laminar streamlines that disappears with time or as the flow proceeds downstream. Sites of focal disturbed flow can be identified in the thoracic aorta during the flow deceleration phase of each heart cycle, in regions of

Arterial Flow Patterns The combination of viscous (frictional) and inertial forces acting on blood determines whether flow is laminar or turbulent (i.e., disturbed flow). The transition to turbulent flow is physiologically important because a greater pressure gradient is needed to maintain flow. Frictional interactions at the inner wall of an artery can also produce flow pattern variations, referred to as boundary layer separation. The clinical importance of local flow patterns in arteries resides in their role in the pathogenesis of atherosclerosis, and the ability of duplex ultrasound systems to detect and grade the severity of disease through the disturbed flow produced.

Figure 5 Relationship between velocity of flow and turbulence. Source: From Ref. 3.

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Figure 6 Center stream flow from a normal artery is laminar and is demonstrated on the spectrum (A) as a narrow band of frequencies during systole, with a clear window beneath the frequency envelope. Disturbed flow caused by mild stenosis appears as spectral broadening on the frequency spectrum (B) without producing changes in the park systolic velocity. Highly disturbed flow (turbulence) is characterized by high peak velocities and spectral broadening throught the cardiac cycle. Also note the increase in end-diastolic velocity associated with severe stenosis (C). Abbreviations: SV, systolic velocity; T, time. Source: From Ref. 4.

arterial branching, and in the carotid bulb. Disturbed flow, however, can represent the initial hemodynamic abnormality produced by atherosclerotic plaque formation seen in occlusive disease. Plaque formation alters wall compliance and reduces cross-sectional lumen area, resulting in disturbed flow and an increase in blood flow velocity. The recognition that the kinetic energy losses associated with disturbed flow conditions helps to explain the gross underestimation of energy loss when Poiseuille’s law is used alone to evaluate flow changes produced by arterial stenosis. The magnitude of disturbed flow can be divided into three categories on the basis of the Doppler velocity spectra pattern: undisturbed (laminar), disturbed, and highly disturbed (turbulent). As shown in Figure 6, the velocity spectra of blood flow through a stenosis demonstrates the focal disruption of laminar flow at and distal to the lesion. Highly disturbed velocity spectra associated with pressure–flow– reducing stenosis exhibit high-frequency Doppler shifts and spectral broadening throughout the pulse cycle. Turbulent flow can initiate platelet aggregation, which may lead to thrombus formation. Disturbed velocity waveforms contain high-frequency components only during peak systole and typically indicate a transitional flow condition detected under normal flow conditions in the ascending aorta and at arterial bifurcations. Undisturbed velocity waveforms exhibit negligible high-frequency content and are representative of laminar flow.

Boundary Layer Separation The outer layer of fluid in a flow stream adjacent to the vessel wall is referred to as the boundary layer. Radial-directed velocity gradients exist as a result of the fractional interactions of fluid with the vessel wall and the more rapidly moving fluid in the center of the vessel. When vessel geometry changes suddenly, such as at points of curvature and

Figure 7 Flow patterns at model carotid bifurcation. Adjacent to the outer wall of the bulb, flow is stagnant (a region of flow separation), may reverse, or may be diverted across the vessel lumen. Rapid flow is associated with high shear stress, whereas the slow flow in the separation zone produces a region of low shear. Source: From Ref. 5.

bifurcations, small pressure gradients are created, causing the boundary layer to stop or reverse direction. This results in a complex, localized flow pattern known as an area of flow separation. Areas of flow separation have been observed in models of arterial anastomoses and the carotid bifurcation depicted in Figure 7; an area of flow separation is seen to have formed along the outer wall as a result of the diverging carotid bulb diameter. The complex flow patterns identified in normal human carotid bifurcation include vortex flow as well as regions of flow separation and reversal along the lateral, posterior wall of the bulb. Shear rate is the variation of velocity of flow changes between concentric laminae of blood. Shear stress at the vessel wall (Dw) can be characterized by the following formula: Dw ¼ 4

V Q ¼4 3 r pr

Gw ¼ 4Z

V Q ¼ 4Z 3 r pr

where Gw is the shear stress at the wall, V, the mean velocity, r, radius, Q, mean flow, and Z, the blood viscosity. Therefore shear rate and stress are directly proportional to mean velocity, turbulence, and viscosity and inversely proportional to the inner radius of the vessel. At bifurcations and vessel curves, shear is highest at the wall where the velocity of flow is also highest. It has been shown that arterial vasoconstriction and vasodilatation occur with shear rate changes, most likely via production of endothelium-derived relaxing factor, now known to be nitric oxide (NO). Production of NO in the wall in response to increased shear causes relaxation of the media smooth muscle, resulting in vasodilatation.

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The disturbed flow and low shear stress in regions of boundary layer separation may contribute to the formation of atherosclerotic plaques. Examination of carotid and iliac bifurcations, both at autopsy and during surgery, indicate that intimal thickening and plaque formation tend to occur in the regions of flow separation. Within these zones, there is an opportunity for a synergistic effect for rheologic and contact activation of blood elements with the intima. The role of localized flow disturbances as an initiator or promoter of atherosclerosis is speculative and awaits further analysis and research.

Principles of Pulsatile Flow In the arterial system, pressure and flow vary continuously with time, and the velocity profile changes throughout the cardiac cycle. The addition of a pulsatile component on steady flow increases fluid energy expenditure. As much as 30% of the energy in cardiac output is dissipated as a result of pulsatile flow. With increasing heart rate, energy losses caused by pulsatile flow decrease exponentially up to a heart rate of approximately 150 beats/min. The remainder of cardiac output energy is used for tissue perfusion, and therefore primarily dissipates in the arteriolar and capillary bed. Although the true nature of pulsatile energy loss remains poorly defined, contributing factors include inertia energy loss with acceleration, geometric vessel tapering, vessel curvature, and bifurcation, production of disturbed flow, and the non-Newtonian character of blood. It is apparent that Poiseuille’s law cannot accurately predict all the hemodynamic characteristics of flow through the artery. Of importance to the surgeon is that, with pulsatile flow, the energy losses produced by arterial reconstructions, which commonly have anatomic and physical characteristics much different from the normal arterial system, are likely to be much greater than predicted by the equations governing steady flow. Although pulsatile flow appears less efficient than steady laminar flow, studies indicate that individual organs require pulsatile flow for optimum function. Perfusion of a kidney with a steady flow instead of pulsatile flow results in a reduction of urine volume and sodium excretion. Pulsatile flow and pressure probably exert their effect at the microvascular level. Although the exact mechanism is unknown, transcapillary exchange, arteriolar and venular tone, and lymphatic flow are all responsive to pulsatile pressure. With each stroke volume of the heart, blood is pumped into the distensible arterial tree, which acts as an elastic reservoir or windkessel absorbing the cardiac energy that is later released during ventricular diastole. The physiologic effect is to damp the flow/no-flow effect of the heart so that the pressure and flow are maintained during diastole. As blood is forced into the aorta, the instantaneous increase in volume is transmitted along the artery as a pressure and flow wave. As shown in Figure 8, the increase in flow starts almost synchronously with the rise in pressure, but the peak flow velocity precedes peak pressure. The instantaneous flow rate is not determined by the magnitude of the pressure pulse but by the pressure gradient developed along the artery. The pressure gradient is determined by recording the pressure at two points, a short distance apart, and subtracting the downstream pressure from the upstream pressure during the cardiac cycle. The effect of the traveling pressure wave is to produce a oscillatory pressure gradient. The magnitude of the pressure gradient determines both instantaneous flow velocity and the

Figure 8 Generation of flow velocity waveform by traveling pressure pulse wave. Simultaneous pressure pulse and flow velocity pulse recordings from an arterial segment. Although similar in configuration, peak flow occurs before the systolic pressure peak, indicating a complex relationship between these hemodynamic parameters. Flow is determined by the pressure gradient that develops along the arterial segment.

direction of flow. Unless there is a marked decrease in the mean pressure along the artery, there will always be a period during the pulse cycle when the pressure gradient is reversed. This reversal of gradient causes a rapid deceleration of flow, and, if it continues after the forward flow has been brought to a halt, flow reversal can occur. Indeed, flow reversal during diastole is a normal pattern of blood flow in peripheral limb arteries. As the pressure-pulse wave travels from the aorta to the periphery, its speed, magnitude, and configuration are altered. The pressure wave is produced by the sudden ejection of blood into the aorta. The pressure wave velocity increases from 4 to 6 cm/sec to approximately 13 cm/sec in the muscular arteries of the lower limb. The velocity of the pressure wave is 20 times greater than the mean velocity imparted to the blood in the aorta (20–40 cm/sec), illustrating that the pressure wave has no direct relationship to flow and can be recorded under ‘‘no flow’’ conditions of acute arterial occlusion. The acceleration of the pressure wave in the peripheral arteries is caused primarily by increasing wall stiffness. Because of this relationship, the transmission velocity of the pressure wave has been used as an index of arterial distensibility. The amplitude of the pressure wave, otherwise known as the pulse pressure, increases, as wave configuration changes with propagation to the periphery (Fig. 9). With increasing distance from the heart, the rate of systolic pressure rise increases, and the sharp inflection of the downslope known as the ‘‘dicrotic notch’’ becomes rounded and disappears in the abdominal aorta, where dicrotic waves appear. In the arteries of the lower limb, systolic pressure is higher, and diastolic pressure is lower than that in the aorta. This is the result of the viscoelastic characteristics of the arterial conduits, the effect of pressure waves being reflected from sites of increased peripheral resistance (i.e., from sites of tapering and branching), and the abrupt increase in resistance at the level of the arterioles.

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Figure 9 Pressure waves at different sites in the arterial tress. With pressure wave transmission into the distal aorta and large arteries, the systolic pressure increases, and the diastolic pressure decreases with a resultant increase in pulse pressure. Note that mean arterial pressure declines steadily.

It is important to note that the mean pressure decreases with the distance from the heart, but the pressure loss in the large arteries of the thorax and abdomen is small because of their large radius. As shown in Table 2, systolic and diastolic pressures recorded from large arteries are influenced by various hemodynamic factors. Careful analysis of the pressure wave configuration and its transmission can provide useful clues to important cardiac and peripheral arterial physiology. The pulsatile characteristics of the pressure wave are dampened considerably at the level of arterioles at which mean pressure reaches values up to 40 to 60 mmHg. In general, perfusion pressure in the capillaries is nonpulsatile, and pressure waves in the venous system are caused primarily by pressure changes in the right heart and not the left. Exercise increases total leg blood flow 5X to 10X in the normal patient. In the diseased extremity seen during treadmill duplex evaluation, ankle pressure drops severely and requires prolonged periods of time to recover.

Measurement of Arterial Pressure A major advance in the understanding of and approach to patients with arterial occlusive disease came with the recognition that the physiologic disturbance responsible for symptoms is predominantly related to development of a pressure gradient in the proximal arterial segment. Pressure measurement is a more sensitive index of an occlusive process than is the measurement of flow, because in the presence of moderate arterial disease blood flow is essentially normal, Table 2 Main Determinants of Aortic Systolic and Diastolic Pressures Systolic pressure Stroke volume Aortic distensibility Ejection velocity

Diastolic pressure Systolic pressure Aortic distensibility Heart rate Peripheral resistance

owing to the reduction of resting arteriolar resistance compensating for the increased resistance of the proximal arterial system. Although flow measurement techniques (i.e., indicator dilution methods and impedance flowmeter) have clinical value in the determination of cardiac output, flow volume measurement in the limbs is of limited value as a clinical or diagnostic tool. For these reasons, a variety of direct and indirect arterial pressure measurement techniques are available using noninvasive instrumentation. Direct pressure measurement involves placing a needle or catheter into the artery and recording the pressure waveform with the aid of manometer or strain-gauge transducers. From a continuous recording of the pressure waveform, systolic pressure is the peak pressure during the pulse cycle, and diastolic pressure is the lowest pressure. The difference between these two pressures is the pulse pressure. Mean pressure, the force responsible for the mean flow of blood to an organ, can be determined electronically by calculating the area of the pulsatile waveform or estimated from systolic and diastolic pressure measurements (mean pressure ¼ diastolic pressure þ 1/3 pulse pressure). Although direct pressure measurements provide the most accurate data, their routine clinical use is not warranted, because the technique is invasive and requires sterile conditions, and pressure data obtained indirectly are sufficiently accurate for diagnostic purposes. Indirect pressure measurements depend on (i) the production of Korotkoff sounds, which are the result of turbulence in the flow stream, (ii) the appearance and disappearance of the pressure pulse, or (iii) the reappearance of flow when a proximally located pneumatic cuff has been inflated and slowly deflated above the regional perfusion pressure. Auscultatory (Riva–Ricci method) and palpatory techniques to measure upper limb arterial pressure are the most common hemodynamic assessments of the arterial circulation. To avoid measurement errors, the occluding cuff should be 20% wider than the limb diameter. If it is too narrow, the pressure will be erroneously high; if it is too wide, the reading may be erroneously low. Several techniques are used clinically to measure systolic pressure in the limbs, including plethysmography (mercury strain gauge, air, and photocell) and the ultrasonic velocity detector (continuous-wave Doppler). These instruments are used as sensors to indicate return of flow with cuff deflation. Plethysmography operates on the principle that changes in the circulation of the blood to a body part (e.g., leg) will result in corresponding changes in the size of that part that are measurable. Such changes in size can be measured by displacement of air or mercury in a strain gauge or emission of light in a photoelectric cell, as is done in photoplethysmography. In general, devices with ultrasound are most commonly used because instruments are inexpensive and simple to use, and the Doppler-derived pressure measurements have been thoroughly evaluated and have been noted to be as accurate as plethysmographic measurements. Even when an ultrasonic signal is difficult to obtain, it is almost always possible to record a pressure with the photoplethysmograph. Digital volume changes are then amplified and can be recorded. This allows pressures to be recorded in digits in the presence of severe obstructive arterial disease, when flow velocities are too low to be picked up by a Doppler transducer. The assessment of arterial flow with ultrasound is made on the basis of the Doppler effect, which refers to the shift in frequency that occurs when sound is reflected from a moving object. Moving red blood cells reflect the

Chapter 43: Physiology of Arterial, Venous, and Lymphatic Flow

ultrasound beam and shift the frequency proportional to the flow velocity. The Doppler signal can be (i) amplified to provide an audible sound, with the pitch directly proportional to blood velocity, (ii) converted into an analog waveform using a zero-crossing frequency meter, or (iii) analyzed for its frequency–amplitude content. Failure to obtain a Doppler signal from an artery usually indicates occlusion; however, an extremely low flow rate (under 2 cm/sec) may not produce detectable Doppler frequency shift. The systolic pressure at any level of an extremity can be measured by applying a pneumatic cuff and positioning the Doppler probe over a patent artery distal to the cuff (Fig. 10). The arterial signal is distinguished from the adjacent venous signal by its characteristic high pitch that corresponds to the cardiac cycle. When the cuff is inflated above systolic pressure, the arterial flow signal disappears. As cuff pressure is gradually lowered, the point at which flow resumes is recorded as the systolic pressure. In the lower limb, the use of multiple cuffs placed at the high-thigh, above and below the knee, ankle, and digital levels permits the measurement of segmental pressures. The level of pressure measurement is determined by cuff placement and not the site of Doppler flow detection. The difference in systolic pressure between any two adjacent cuffs or between corresponding segments in the opposite limb is less than 20 mmHg in normal individuals. Because of cuff artifact, proximal thigh systolic pressure normally exceeds brachial pressure by 30 to 40 mmHg. As the distance increases from the heart, an amplification of the pressure wave produces a higher systolic pressure to be measured at the ankle than in the brachial artery, which, in the absence of disease, is nearly equal to central aortic pressure. To compensate for variation in central perfusion pressure and to permit comparisons of serial measurements, the ankle systolic pressure is expressed as a

Figure 10 Measurement of ankle systolic pressure. Doppler probe is positioned over the posterior tibial artery.

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ratio of brachial pressure, termed the ankle-brachial systolic pressure index (ABI). The normal ABI is equal or greater than 1 (mean value of 1.1 0.1), and reductions correlate with the degree of arterial insufficiency. In limbs with intermittent claudication, the ABI (mean þ S.D.) is 0.58 0.15, in limbs with ischemic rest pain, 0.26 0.13, and in limbs with gangrene, 0.05 0.08. The measure of toe pressures can be used to identify obstructive disease distal to the ankle and to measure pressure in diabetic patients in whom ankle pressure measurement by the cuff method is artifactually high because of the incompressibility of calcified arteries. Normal systolic toe pressure is approximately 80% of the brachial systolic pressure. Photoplethysmographic techniques are better suited than the ultrasonic methods of flow determination at the digital level, because of vessel caliber and a low flow velocity in the digital arteries.

Real-Time Ultrasound Arterial Imaging and Flow Analysis Since the 1970s, ultrasound technology has developed instrumentation to both image vascular anatomy and display blood flow patterns within the lumen in real time. The technique referred to as color duplex ultrasonography, which combines real-time imaging (B-mode) with pulsed Doppler flow detection, is most versatile and permits the arterial and venous circulations to be mapped analogous to arteriography or venography in body regions accessible to interrogation by ultrasonic energy. Duplex scanning can be used to address specific queries concerning location and extent of vascular disease and disease morphology (stenosis, occlusion, or aneurysm), to measure vessel diameter and grade stenosis severity, and to measure occlusion length based on visualization or exit and reentry collateral vessels. In atherosclerotic lesions, B-mode imaging with high (10–15 MHz) frequency transducers can demonstrate features such as ulceration, calcification, acoustic heterogeneity, and intraplaque hemorrhage. Blood flow velocity within visualized vessels is characterized with the use of a Doppler velocity detector. Accurate characterization of blood flow patterns requires the use of a pulsed Doppler whose sample volume (the point in space from which blood flow is detected) is small in relation to the vessel diameter. The Doppler signal is processed by a real-time spectrum analyzer to determine the velocity of blood, the direction of flow, and the velocity distribution of the RBCs in the sample volume. When the pulsed Doppler sample volume is positioned in the midstream of nondisturbed (laminar) arterial flow, the Doppler signal will contain a narrow range of frequencies (spectral width) of similar amplitude corresponding to streamline movement of RBCs during the pulse cycle. Undisturbed flow produces a ‘‘clear window’’ in the spectra beneath the frequency envelope and is characteristic of normal peripheral arterial hemodynamics. Calculation of blood flow velocity requires estimation and assignment of the angle between the incident Doppler beam and the blood velocity vector. An operator-controlled line on the B-mode image indicates the direction of the sound beam from the pulsed Doppler probe. In general, the Doppler beam is adjusted to intersect the flow stream at an angle of approximately 60. A ‘‘cursor’’ on the Doppler beam indicator locates the position of the sample volume and can be placed at any point in the vessel. The Doppler angle is calculated electronically by the operator positioning

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a cursor parallel to the longitudinal axis of the vessel. Blood flow velocity is calculated from the frequency spectra waveform measurements using the Doppler equation: Flow velocity ¼

C Fs cos Yðcm=secÞ 2 Fo

where C is the average speed of sound in tissue [1.54  106 cm/sec], Fs is the shift in frequency between the transmitted and reflected Doppler beam, Fo is the frequency of the transmitted Doppler beam, and Y is the Doppler beam angle. If the mean frequency shift can be electronically extracted from the Doppler spectrum, the spatial average velocity (Vsa) as a function of time can be calculated. Volumetric blood flow (Q) can then be determined from a measurement of lumen diameter (D) by the equation: Q¼

Vsa

Q 4

D2

ðmL=minÞ

Although the determination of volumetric flow is attractive, the accurate calculation of Vsa can be quite difficult, because it requires complete insonation of the flow stream across the vessel lumen, knowledge of the velocity profile configuration, and a correction for both the forward and reverse components of pulsatile flow. Duplex scanning provides both anatomic and physiologic informations regarding arterial flow. Tables 3 and 4 provide normal arterial lower limb mean and peak velocities and velocity waveform configurations seen with duplex scanning. This information has been applied clinically to the evaluation and classification of the atherosclerotic occlusive disease involving the carotid bifurcation, visceral arteries (renal, celiac, and superior mesenteric), the abdominal aorta, and the arteries of the lower limb. Under normal conditions, the flow in peripheral and carotid arteries is undisturbed (Figs. 11 and 12). As discussed previously, turbulence is responsible for most of the fluid energy loss associated with arterial disease. Because turbulence occurs at lesser degrees of stenosis than that causing detectable changes in mean flow and pressure, assessment of arterial flow by duplex scanning permits a more accurate diagnosis of altered hemodynamics than is possible by using techniques that monitor pressure and flow. Distal to a site of stenosis, turbulence is evident in the Doppler signal by an increase in peak systolic velocity, an alteration in the velocity waveform, and the presence of spectral broadening corresponding to the disordered, random movement of red blood cells in the flow stream. Accurate characterization of vessel anatomy and

Table 4 Normal Blood Flow Velocity Waveform Configurations in Peripheral Arteries Arterial location Cerebrovascular Internal, common carotid External carotid Vertebral Visceral Celiac Superior mesenteric Fasting Post-prandial Renal Peripheral (upper/lower limbs) Resting After exercise

Biphasic

Triphasic

X X X X X X X X X

flow in both normal and diseased states is possible by duplex mapping of the peripheral arterial system. Accuracy approximates that of contrast and magnetic resonance imaging and can also estimate whether lesions seen on angiogram are hemodynamically significant. Risks, cost, and discomfort are less than that of contrast and magnetic resonance imaging studies, although it is operator dependent and well-trained experienced technologists are required. Natural history studies of atherosclerosis using duplex scanning have demonstrated anatomic and hemodynamic features associated the initiation and progression of vascular disease. Compared with arteriography, diagnostic accuracy of duplex scanning is in excess of 80% in detection of greater than 50% diameter–reduction arterial stenosis or occlusion. Clinical applications include preintervention testing of peripheral, cerebrovascular, and visceral arterial disease, venous testing for acute/chronic venous thrombosis and venous insufficiency, intraoperative assessment of surgical and endovascular therapies, and postoperative graft surveillance and vascular disease.

Table 3 Duplex-Derived Flow, Diameter, and Mean/Peak Systolic Flow Velocity Measurements from Lower Limb Artery Segments Artery segment Duplex Flow (mL/min) Diameter (mm) Mean velocity (cm/s) Peak velocity (cm/s)

Common femoral

Popliteal

Anterior tibial

Posterior tibial

371 8.6 11

140 6.6 7

11 2.2 4

16 2.3 5

89

66

58

57

Figure 11 Color duplex scan imaging of the internal carotid artery. Sample volume of the pulsed Doppler probe is positioned in the proximal internal carotid artery. Narrow band of frequencies during the pulse cycle and the clear area beneath the waveform are characteristics of laminar flow in a normal carotid artery.

Chapter 43: Physiology of Arterial, Venous, and Lymphatic Flow

Figure 12 Color duplex examination of normal superficial femoral artery flow. Velocity spectra and waveform configuration are typical of normal flow in a limb artery.

THE VENOUS SYSTEM The most important role of the venous system is probably that of a return conduit for blood from the peripheral tissues back to the heart and lungs for oxygenation. Veins also serve as a fluid reservoir for the vascular system, with up to 75% of the circulating blood volume being found in the venous system at any one time. In addition to these functions, the venous system is capable of augmenting ventricular filling pressure, thereby increasing cardiac output and stroke volume by sympathetic stimulated vasoconstriction. The mechanisms responsible are best addressed by considering first the anatomic configuration and unique structure of the venous channels, and then the interaction of the structural characteristics with the forces responsible for normal venous return.

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fascia (Fig. 13). The veins are usually three times the size of their accompanying arteries and are composed of intima, media, and adventitia layers. Generally as one proceeds down the lower extremity, they encounter more valves. These superficial channels are responsible for collection of venous blood from the skin and subcutaneous tissues, and terminate by penetrating the deep fascia at the groin and popliteal fossa, respectively, to enter the deep venous channels. The superficial veins are subject to increased hydrostatic pressure and are therefore relatively thick walled. The superficial veins contain numerous bicuspid valves that facilitate flow from the periphery of the limb to the central portion of the limb and prevent flow in a retrograde direction. Competency of the valves in the lower extremities is more critical as compared to the upper extremity, where a malfunction more often leads to deep vein thrombosis, venous insufficiency, and venous stasis ulcers. The deep system veins accompany the major muscular arteries and are similarly named. In the periphery of the limb, these channels are frequently present in duplicate and, because they are protected from the force of gravity by the muscles in the lower extremity, are relatively thin walled. Bicuspid valves are also present in these veins, with the greatest density occurring peripherally, and relatively few valves being located in the more central larger channels. For example, the superior and inferior vena cava, as well as the common iliac veins are devoid of valves, whereas the external iliac vein infrequently has a single bicuspid valve present. The popliteal vein has one to two valves, while the greater and lesser saphenous systems have about 8 to 10 valves each.

Venous Anatomy The venous system of the lower extremities is divided into superficial and deep systems. There is great variability in the anatomy of the deep and superficial veins, including segmental and complete duplicated systems. In the lower limbs, the common femoral vein is medial to the common femoral artery. The greater saphenous vein joins the common femoral vein at the saphenofemoral junction. The deep and superficial femoral veins generally join 3 to 5 cm cephalad to this point. The greater saphenous venous system begins anterior to the medial malleolus and travels subcutaneously on the anteriomedial aspect of the lower leg, 1 to 2 cm posterior to the tibia. It joins the femoral vein 2 to 4 cm lateral to the pubic tubercle and inferior to the inguinal ligament in the fossa ovalis. The superficial circumflex iliac vein and superficial inferior epigastric vein join the greater saphenous vein also in this area. The venous system is more complex than the arterial system because veins are collapsible, affected by gravity and a low pressure system, contain valves, and are affected by the right side of the heart. The superficial system of the legs consists of the greater and lesser saphenous veins that are located in the subcutaneous tissue superficial to the deep

Figure 13 Diagrammatic representation of the major anatomic features of the greater and lesser saphenous veins and their tributaries.

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Figure 15 Schematic representation of the valvular relationships in the superficial veins, the connecting veins or perforators, and the deep venous system. It can be seen that under normal circumstances flow only occurs from the superficial to deep channels.

Figure 14 Schematic representation of the soleal sinuses and their relationship to the calf muscles and deep venous system. It should be noted that these empty directly into the deep venous system and also on occasion receive communications from the superficial system.

A second major component of the deep venous system is the soleal sinuses, a group of endothelium-lined venous reservoirs or ‘‘lakes’’ located within the substance of the gastrocnemius and soleus muscles (Fig. 14). These venous lakes are compressed by the calf muscles and are emptied during contraction, thereby facilitating venous emptying of the lower limb. These vein segments are also devoid of valves, and are a common site of early thrombus formation. Distally, they coalesce to join the peroneal and posterior tibial vessels. The superficial and deep venous systems of the lower extremity are united by a series of perforating veins that pass from the superficial venous system through the deep fascia to the deep venous channels. These perforators range in number from 100 to 200, and are also most frequently located below the level of the knee. Bicuspid valves are also located in these channels so that, under normal circumstances, the flow occurs only from the superficial to the deep venous system (Fig. 15). Venous flow in the lower extremity, therefore, always travels in centripetal direction from peripheral to central channels. The presence of valves prevents reflux in the superficial, deep, and connecting systems. The necessity for valves is greatest at the most peripheral locations, where the gravitational force is greatest, and is least important in the central venous channels, where the pressure changes generated by respiration are sufficient to overcome the effects of gravity. In addition to blood traveling from the peripheral to central regions, it also moves preferentially from the superficial to the deep system, with only 10% of the venous outflow being conducted by the superficial veins and 90% by the deep veins.

Venous Structural Features Vein wall thickness varies from one-third to one-tenth the thickness of the artery wall. Elastin wall content is

considerably less than in the arterial wall, but like arteries, the amount of smooth muscle in the media is variable. The major factor influencing the smooth muscle content is not the necessity for control of regional blood flow as in arteries, but rather the gravitational force from blood the wall must withstand. The great saphenous vein has the highest percentage of smooth muscle, because it is located in the subcutaneous tissue in the lower limbs where it is exposed to maximum gravitational force with standing. At the foot and ankle, the smooth muscle may account for as much as 80% of the total wall thickness, whereas in the axillary vein, it composes only 5% of the vein wall. The smooth muscle fibers are arranged in helical bundles united by strands of connective tissue, with a tough outer layer of predominately collagen fibers constituting the adventitia. Luminal to the smooth muscle layer is the intima, the most important component of which is the single layer of endothelial cells responsible for the blood and vessel wall interface. Perhaps because of the relatively low velocity in the venous system, these cells contain abundant quantities of fibrinolytic agents, with the veins in the lower extremity having higher concentrations than the intimal cells of the upper extremity. The lowest concentration of fibrinolytic active substances is found in the deep veins of the calf region and may in part explain the predisposition for thrombi to form in this location. Because the deep veins are surrounded by skeletal muscles, which protect them from the adverse effects of gravity, they contain smaller amounts of smooth muscle and larger amounts of collagen. Increased collagen is the major factor responsible for the relative stiffness of these veins. In the large central veins such as the vena cava and iliac veins, this property is of major importance in determining shape changes induced by alterations in pressure–volume characteristics. Reductions in the volume of blood in these vessels result in collapse of the wall and assumption of an elliptical shape (Fig. 16). Restoration of volume to normal is associated with a resumption of the normal resting circular cross section. This shape change can also be demonstrated with more minimal external forces such as that generated by the respiratory cycle. However, the most common factor influencing the central veins is the overall circulatory blood volume. These changes in the venous volume are accomplished with minimal changes in pressure because most

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Pressure–Flow Relationships In contrast to the arterial system, blood flow throughout the venous system is not mediated by a central pumping mechanism. The forces affecting pressure and therefore flow in the venous system are generated by respiration and exercise. The relative importance and interaction of these forces is best understood by considering the independent effects of each one and how they impact on the gravitational forces that must be overcome in the erect position. Figure 16 Capacitance of collapsible tubes. Effect of volume change on the cross-sectional area of veins showing the small cross-sectional ellipsoid state and the significant increase in cross-sectional area associated with filling. This change occurs without a change in circumference; because the wall is not stretched, the change can occur with the application of relatively minor force.

veins are partially collapsed during resting conditions. The importance of this is appreciated when it is realized that 40% of the total blood volume may be found in these large central veins at a pressure of 5 mmHg, whereas a reduction to 5% is accompanied by a fall in pressure of only a few millimeters of mercury. This is an example of how the central veins are able to collapse and auto-transfuse their volume into the arterial system, in order to maintain adequate blood flow. Thus the central venous system may be classified as a high-compliance, high-capacitance system as compared to the low-compliance, low-capacitance arterial system. Then, of practical clinical importance is the fact that the pressure measured in the central veins may be used as an index of the moment-to-moment blood volume, i.e., high pressure represents an expanded blood volume, and low pressure represents a volume deficiency. Unlike arterioles, which are very sensitive to local mediators, veins and venules are controlled exclusively by sympathetic adrenergic activity except for the vein in skeletal muscle, which are without sympathetic influence, and the cutaneous veins, which are primarily thermoregulatory. Venous constriction may occur secondary to Valsalva maneuvers, muscular exercise, pain, hyperventilation, emotional stress, or with vasconstrictive medications. Venous dilation can occur in conditions of shock, general anesthesia, or with vasodilator medications.

Gravitational Effects Gravitational forces have a negative effect on venous flow from the lower extremity, and are best appreciated by considering the pressure relationships first in the supine position when gravity is not a factor. In the supine position, the venular end of the capillaries has a pressure of approximately 15 mmHg, and the pressure in the right atrium is 5 mmHg. There is a point in the venous system located in the inferior vena cave close to the diaphragm, termed the hydrostatic indifference point where the pressure is always zero, regardless of attitude (Fig. 17). These pressure gradients are adequate to sustain normal venous return in the supine position, but are augmented by respiratory-induced pressure changes. Assumption of the erect position results in profound changes in these pressure relationships. The system can then be likened to a vertical column of fluid, approximately 180 cm in height, in a hypothetic six-foot ‘‘dead man,’’ although certain modifications of this model are required to parallel the real circumstances (Fig. 17). As noted earlier, the pressure at the hydrostatic indifference point is unchanged by the erect position, and right atrial pressure is normally 0 mmHg. The veins above this point will either fill or collapse, depending on the degree of filling in the system and the effects of respiration. This is best seen in the external jugular vein clinically, where intermittent filling and decompression are readily apparent. The skull acts as a protective barrier against these collapsing forces and maintains the intracerebral venous channels distended even in the erect position. Below the hydrostatic indifference point, the pressure gradually increases so that at the foot level a hydrostatic pressure of 80 mmHg is produced. This has two profound effects, the first of which is cessation of flow from the lower extremities and progressive pooling

Figure 17 Pressure relationships in the various levels of the arterial and venous system shown in the supine (A) and the erect positions (B). HIP is located just below the diaphragam. Abbreviation: HIP, hydrostatic indifference point.

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in the leg veins. This associated reduction in venous return secondarily produces a major decrease in cardiac output and, if the stimulus is long enough, may activate the syncope reflex. This pressure is also apparent in a change of the fluid dynamics at the tissue level, and, again, if it persists for any prolonged period, massive extravascular fluid extravasation may occur, further depleting venous return. This negative effort on venous circulation by gravity is overcome by the combined effects of respiration and exercise.

Effects of Respiration The effects of respiration on venous flow are, again, most easily understood by first considering the pressure characteristics and changes that occur with the subjects in the supine position. During inspiration, negative pressure is generated in the thoracic cavity, which facilitates flow into the superior mediastinum from the venous channels in the head, neck, and upper extremity. Descent of the diaphragm produces an increase in intra-abdominal pressure that compresses the inferior vena cava and is associated with a marked reduction in flow from the lower extremities. The pressure changes produced by respiration are insufficient to overcome the gradient that exists between the peripheral venules and the right atrium, and therefore, even during inspiration, there is some venous outflow from the lower extremities. However, cessation of flow may be produced by increasing the pressure a few millimeters of mercury, as occurs with a Valsalva maneuver. Conversely, during expiration, venous return from the upper extremities and head and neck is interrupted, and flow from the lower extremities is augmented (Fig. 18). Assumption of the erect position, however, introduces the force of gravity that drastically alters the pressure–flow relationships. Without the pulsatile pump of the arterial system, the venous circulation does not contain an intrinsic mechanism capable of overcoming this effect. Clearly the relatively small changes induced by respiration are inadequate for normal venous return, and additional forces must be activated. Prolonged assumption of the erect position without activation of other mechanisms results in a serious disturbance of the hydrostatic forces at the tissue level, with

the development of both peripheral edema and venous pooling in the lower extremities. A major force responsible for maintenance of normal venous return in the erect position is contraction of the calf muscles of the lower extremities.

Pressure Changes with Exercise The calf muscle pump is to the venous system what the left ventricle is to the arterial system. The changes produced by calf muscle contraction are best considered by reviewing (i) the overall net effect after multiple muscle contractions and (ii) the step-by-step pressure relationships. Calf muscle contractions exert a force in excess of 80 mmHg on the walls of the calf veins, thus exceeding that exerted by gravity and resulting in a net efflux of blood out of the limb. With each contraction, the venous pressure is progressively lowered until the mean pressure at the ankle level falls to approximately 15 mmHg, similar to that in the resting supine state. These pressure changes are responsible for an overall reduction in the resistance of the peripheral vascular system and an associated increase in arterial inflow to the extremity, as required with exercise. Although this is the mean effect of exercise, the moment-to-moment pressure changes are more complex. During the phase of calf muscle relaxation or diastole, the large venous channels are distended, and the pressure in the deep veins falls below that in the superficial veins. During calf muscle contraction, however, the pressure in the deep veins increases dramatically to exceed the pressure in the superficial veins, with a pumping effect being generated and forcing venous blood out of the extremities in an antegrade direction. During calf muscle relaxation, therefore, flow occurs from the superficial venous system to the deep venous system through the perforating veins; this flow is facilitated by the unidirectional valves contained in the perforating veins. During calf muscle contraction, the unidirectional valves in the deep venous system lead to the blood being forced to flow in a centripetal direction, with the valves in the perforating veins preventing reflux of blood into the superficial system. At the completion of calf muscle contraction, the cycle is again repeated (Fig. 19). Therefore, peripheral muscle pump resembles the working heart as it promotes the circulation of blood out of the lower extremities and empties the deep vein system, decreasing edema and venous congestion in the extremities, both of which result in an increased central blood volume. The increase in frequency and depth of respiration associated with exercise acts to facilitate overall venous return as well, although to a somewhat smaller degree.

Venous Endothelium

Figure 18 Relationship between respiration and flow in the femoral and subclavian veins in the supine (A) and in the erect positions (B). Abbreviations: Ins, inspiration; Exp, expiration.

The endothelium is involved in the apperception of changes in blood flow and can influence vessel luminal size by changing the degree of contraction of the smooth muscle present in the vessel wall. Both natural and pharmaceutical grade compounds have been shown to alter vessel size by either vasodilatation or vasoconstriction, depending on the presence of an intact endothelium. Vessels devoid of endothelium, however, most often react with vasoconstriction alone. The endothelial cell–dependant dilation is related to the production of a nonprostanoid endothelial factor that results in a rise in cyclic guanosine monophosphate. NO, which is derived from L-arginine present in high concentrations in small resistant vessels also promotes vasodilatation. Intact endothelium has been shown to reduce platelet-induced spasms of the vessel wall. If the endothelial lining is

Chapter 43: Physiology of Arterial, Venous, and Lymphatic Flow

Figure 19 Pressure relationship between the superficial and deep venous system during walking. It should be noted that during calf muscle contraction or systole, the pressure in the deep system exceeds that in the superficial; whereas during calf muscle relaxation, pressure in the deep system is less than in the superficial. Filling of the calf muscle pump therefore occurs as with the heart during diastole. Posterior tibial veins are deep veins and great saphenous veins are superficial veins.

undiminished, the complete absence of blood flow for a prolonged period of time does not result in clotting. Furthermore, the endothelium produces several antithrombotic substances as well as a number of procoagulants such as heparin sulfate and thrombomodulin prostaglandin I2 (prostacyclin), Factor 8, and von Willebrand Factor (vWF).

Changes Induced by Disease Acute Venous Thrombosis The development of deep venous thrombosis (DVT) in the major axial veins of the venous system will obviously have an effect of preventing normal venous outflow from the extremities (Fig. 20). This effect can be used as a diagnostic test with plethysmographic methods, to identify this condition. In veins with acute thrombosis, the venous pressure initially stays the same, but as obstruction increases, there is steady rise in the venous pressure as well. This results in accompanying increased edema and inflammation seen in this condition. This effect, however, can be quite variable and depends not only on the location and extent of the venous thrombosis, but also on the availability of collateral venous channels to compensate for the obstruction. It is, therefore, not infrequent to observe that venous thrombosis may not be associated with significant edema, especially in the setting of a well-functioning collateral venous network. A secondary effect of an occlusive thrombus and the development of peripheral venous hypertension is that the minor pressure changes produced by respiration are not transmitted beyond the area of obstruction. Duplex venous ultrasound is now the gold standard for the diagnosis of this condition and demonstrates nicely the flow disturbances associated with DVT. With acute DVT, the flow distal to the obstruction loses its normal phasic relationship to respiration and becomes continuous (Fig. 21). Flow now does not augment well with manual compression distal to the obstruction. Visualizing thrombus is possible with duplex, which carries a 96% specificity and a 94% sensitivity with an overall accuracy of 96%. Air plethysmography has been used to quantitate venous reflux and calf muscle pump ejection volume

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Figure 20 Plethysmographic recordings from a 60-year-old man four months after left iliofemoral deep vein thrombasis. Recordings were obtained from the right leg with no deep vein thrombosis and left leg with superficial femoral vein thrombosis. Recordings are obtained by inflating a pressure cuff above venous pressure followed by instantaneous release of the pressure. Rate of emptying is significantly less in right leg compared to left leg, a fact that can be used in a diagnostic investigation. Abbreviations: I, inflate; D, deflate; VC, venous capacitance; VO, venous exit flow.

(Fig. 22). The instrument uses an air-filled chamber wrapped around the lower leg to determine absolute volume changes in the leg as a result of exercise. Baseline limb volume is measured with the patient supine and the leg elevated 45 , to empty the veins. Volume measurements are then made during non–weight-bearing standing, and with single and repetitive calf muscle contractions. Calculations are then made to determine venous filling index, ejection fraction, and residual volume fraction. Plethysmography is usually used to evaluate the venous system in preparation for venous surgery, to correct severe venous valve reflux.

Chronic Post-thrombotic Venous Insufficiency The adverse long-term sequelae of venous thrombosis are produced by the residual venous obstruction and the destruction of valves in both the deep axial veins and the perforating

Figure 21 Venous flow patterns in the normal state (A) and in the presence of venous obstruction (B). It should be noted that in the latter there is a loss of the oscillatory pattern produced by respiration. Abbreviations: Exp, expiration; Ins, inspiration.

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are small aggregates of lymph tissue that filter the lymph circulation as it moves more centrally; and (iii) lymphoid tissues, which are responsible for fat absorption in the form of chylomicrons, when found in the gastrointestinal tract (e.g., lactiles), and are involved in the humeral mechanism of the immune reaction, when found elsewhere (e.g., spleen, tonsils, and thymus). Although the lymphatic system is involved with gastrointestinal and immune function, it is its role in protein and interstitial fluid reabsorption that is of significant importance to circulatory pathophysiology. Disruption of the balance of arteriovenous hydrostatic or oncotic pressures can produce an imbalance in lymphatic transport capacity and lead to the development of lymphedema. Figure 22 Methods of deriving air plethysmography values. Abbreviations: EV, evoked potential; RV, residual volume; RVF, residual volume fraction; VFI, venous filling index; VFT, venous filling time; VV, venous volume. Source: From Ref. 6.

veins. This latter effect, in particular, produces profound changes in the dynamics of the venous circulation during exercise, which at least, in part, is responsible for the clinical changes of edema, hyperpigmentation, and ulceration. The most significant changes are demonstrated during exercise. Valve destruction adversely affects the flow patterns produced by the pressure changes seen with exercise, and, instead of flowing in a centripetal direction and from superficial to deep, blood may be forced under high pressure from the deep system, during calf muscle contraction, through incompetent perforating veins, into the superficial system producing severe superficial hypertension. In the deep system, the normal antegrade flow pattern is completely interrupted and venous return from the leg is significantly reduced. Instead of a gradual reduction in venous pressure in the lower extremity produced by exercise, in severe cases, exercise may actually be associated with an increase in the venous pressure in both the deep and superficial systems, as depicted in Figure 23. The likelihood of developing severe complications such as venous ulceration is closely related to the degree of ambulatory venous hypertension that occurs in such patients as shown in Table 5.

LYMPHATIC SYSTEM The lymphatic system consists of: (i) lymphatic vessels or plexuses, which consist of a network of closed endothelial tubes that function to recover fluid and macromolecules (e.g., albumin and other proteins) that have diffused into the interstitium at the capillary level; (ii) lymph nodes, which Table 5 Relation of Ambulatory Venous Hypertension to Incidence of Ulceration Ambulatory venous pressure (mmHg) 45 45–50 50–59 60–69 70–79 80

Incidence of ulceration (%) 0 5 15 50 75 80

Anatomy Similar to the venous system of the extremities, the lymphatic system is composed of superficial and deep lymphatic systems. The basic unit of the superficial lymphatic vasculature is an initial lymphatic sinus. These terminal sinuses are lined by a single layer of lymphoid endothelial cells. They coalesce to form lymphphatic aerola, which serve as collection stations for lymph drainage from the skin and subcutaneous tissues. Lymphatic aerola are connected by precollector lymph channels and eventually empty into larger collector lymph channels. One way valves are spaced every several millimeters (mm) throughout the precollector and collector lymph channels and provide with one way lymph flow. The superficial lymphatics are estimated to handle 90% to 95% of the lymphatic effluent from the extremities. The deeper system of the lymphatic vasculature serves to drain the subfascial structures of the musculoskeletal system and the deep circulatory vessels. These two systems seem to run parallel in the extremities, joining in the regions of the pelvis or axilla. In the lower extremities, the lymphatic channels approximate 1 to 2 mm in diameter. The major superficial lymph channels begin in the dorsum of the foot and course primarily along the medial aspect of the leg in the distribution of the saphenous vein. In the upper thigh, these channels terminate in the superficial inguinal lymph nodes and in turn empty into the deep nodal basins. Usually five to eight major lymphatic channels are located at this level. The deep lymphatic channels are less numerous and course in close proximity to the deep muscular arteries of the extremities. In the high thigh, they empty into the deep inguinal lymph nodes as well. In the lower extremities, the lymph circulation then flows from the deep nodal basins into the lymph nodes/channels along the pelvic brim. Again these channels course intimately with the major pelvic vessels. At the level of the lumbosacral joints, these channels form the para-aortic lymph channels that course along the aorta and through the central retroperitoneum. At this level, the lymph from the lower extremities now joins chyle from the intestinal lymphatics in the cisterna chyle, which is eventually transported via the thoracic duct through the thorax, terminating in the posterior triangle on the left side at the junction of the internal jugular and subclavian veins. In the upper extremities, the superficial and deep systems coalesce in the axillary regions and the travel in larger lymph channel to the venous circulation. The thoracic duct drains lymph from the entire body except that of the right arm, neck, head, and thorax. The lymphatics on this side of the body use a lymphatic pathway that empties lymph into the right lymphatic duct that in turn empties in the junction of the right subclavian and internal jugular veins.

Chapter 43: Physiology of Arterial, Venous, and Lymphatic Flow

Physiology Bicuspid valves are located every few centimeters along the course of the lymphatic channels and enable lymph flow to occur from peripheral to more central regions. The lymphatic adventitia contains smooth muscle fibers and is capable of exhibiting vasomotion and self-propagation of fluid. Independent contractions, also called propulsor lymphaticum, can produce pressures in the vicinity of 50 mmHg every four to five minutes. These contractions mimic venous and arterial vasomotion and are mediated by sympathomimetic agents (alpha- and beta-adrenergic agents), arachidonic acid metabolism (thromboxanes and prostaglandins), and neurogenic stimuli. Contraction of adjacent muscle groups as well as the respiratory cycle also serves to assist in the return of lymph flow to the venous system. Intrinsic lymphatic contractility increases in response to tissue edema, temperature change, exercise, and hydrostatic pressure. The understanding of the exchange dynamics at the capillary level is paramount in defining the role of the lymphatics in recovering interstitial proteins and fluids. Capillary filtration and diffusion are the two main processes that drive this exchange and recovery process. The movement of fluid across the capillary membrane is known as filtration. This process is governed by the principles of the Starling hypothesis. Basically, intravascular hydrostatic pressure and osmotic pressure oppose interstitial hydrostatic and osmotic pressure at the capillary level (Fig. 23). A relative increase in the intravascular hydrostatic pressure or a decrease in oncotic pressure favors an increased filtration of fluid out of the capillary membrane. Under normal circumstances, there is a slight excess of fluid filtered at the arterial capillary end over that reabsorbed at the venous end. It is this excess fluid, which approximates 0.003 mL/min/g of tissue in the moving lower limb, that is transported in the lymphatics. Diffusion also plays a major role in the exchange of molecules across the capillary membrane. The semipermeable capillary membrane and the size of the pores govern the diffusion process of micro- and macroprotiens. The lymphatic sinuses of the terminal lymphatics are highly permeable to these proteins and act as suction pumps to facilitate the recovery of these lost proteins. Contraction of the lymphatic wall may result in the generation of a positive

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pressure proximal to the area of contraction and a negative pressure at the bulbous terminal portion of the lymphatic that facilitates entry of the protein rich interstitial fluid. As much as 50% (150–200 g) of circulating albumin is lost into the interstitial space every 24 hours. The lymphatic system allows for the return of two to four liters of this protein-rich lymph to the venous circulation.

Lymphatics in Disease Disruption in lymphatic flow from occlusion, trauma, infection, or other illness can interfere with the lymphatic system’s role in fluid dynamics, homeostasis, and immune function, termed as secondary lymphedema. Primary lymphedema reflects heritable defects in lymphatic development and function and is classified by the age of onset. Congenital lymphedema is apparent within the first two years of life, represents 15% of clinical cases, and is caused by aplasia or hypoplasia of lymphatic channels. Lymphedema prascox comprises 75% of clinical cases and is first detected at puberty. Lymphedema tarda, which typically appears after the age of 35, can result from either hypoor hyperplastic lymphatic vasculature. Skin and limb changes with lymphatic obstruction or inefficient lymphatic outflow are different from those seen with arterial or venous obstruction. Obstructed lymphatic vessels have been known to have pressures as high as 50 to 60 mmHg, and unlike the vascular system, a collateral network does not exist. If flow in the vascular system becomes impaired or obstructed, the supply of essential nutrients to tissues is impaired and tissue ischemia results. Because valves are absent in the terminal sinuses of the minute lymphatic capillaries of the dermal plexuses, disruption or obstruction in the larger lymph channels results in a significant increase in extracellular fluid retention and resultant edema. This edema, also called ‘‘lymphedema,’’ appears gradually with lymphatic obstruction. An accumulation of large protein molecules in the tissue results in increased oncotic pressure and a net accumulation of extracellular fluid. The delivery of nutrients is typically only minimally impaired, and tissue viability is generally maintained. Eventually a steady state will be reached at which the hydrostatic pressure exerted by the fluid in the tissues will balance that of the oncotic pressure, and essentially normal fluid exchange will continue. Despite what seems like a restoration of fluid homeostasis, the edema will remain, unless additional therapy is instituted. Treatment programs, also known as lymphedema clinics, institute a multidiscipline team approach toward dealing with this condition. Medical management and dietary counseling is undertaken. Physical therapy and exercise programs are initiated. These programs typically use a combination of compression garments and massage therapies to reduce the peripheral edema. Occasionally, lymphatic pumps can also be employed. The role of surgery for the condition of lymphedema continues to decline due in part to the success of these programs.

SUMMARY

Figure 23 Effect of calf muscle exercise on ankle pressure in patients with the postthrombotic syndrome. There is no significant decrease in venous pressure associated with exercise as is seen in the normal state.

The circulatory system as a whole serves to maintain normal tissue nutrition under conditions of rest and exercise, with both the arterial and venous systems, like many other body systems, having a sizeable functional reserve capacity. The arterial and venous systems are primarily involved in the maintenance of a favorable tissue milieu for normal

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metabolism, with the lymphatics functioning as a scavenger system to remove macromolecules and any excess of fluid that is extravasated from the capillary mechanism. Whereas the arterial system is dynamic with the energy being provided intrinsically by contraction of the left ventricle, both the venous and lymphatic systems are uniquely designed to facilitate movement of fluid under relatively low pressures and rely predominately on extrinsic forces such as respiration and skeletal muscle contraction to offset the ‘‘edema-producing’’ effects of gravity.

Diagnosis of Vascular Disease. Pasadena, Calif: AppeletonDavies, 1984. 5. Summer DS. Pitfalls on noninvasive cerebrovascular testing and angiography. In: Bernhard VM, Towne JB, eds. Complications in Vascular Surgery. 2d ed. New York: Grune & Stratton, 1985. 6. Belcaro G, Laurora G, Christopoulos S, et al. Noninvasive tests in venous insufficiency. J Cardiovasc Surg 34; 3:1993. Reprinted with permission.

FURTHER READINGS REFERENCES 1. Smith JJ, Kampine JP. Circulatory Physiology. 2nd ed. Baltimore: Williams & Wilkins, 1984. 2. Zierler RE, Strandness DE. In: Moore WS, ed. Vascular Surgery–A Comprehensive Review. New York: Grune & Stratton, 1983. 3. Ruch TC, Patton HD. Physiology and Biophysics. Philadelphia: WB Saunders, 1974. 4. Roederer G, Langlois Y, Strandness DE Jr, et al. Comprehensive noninvasive evaluation of extracranial cerebrovascular disease. In: Hershey FB, Barnes RW, Sumner DS, eds. Noninvasive

Burton AC. Physiology and Biophysics of the Circulation. Chicago: Year Book Medical Publishers, 1972. Cockett FB, Dodd H, eds. The Pathology and Surgery of the Veins of the Lower Limb. Edinburgh: Churchill Livingstone, 1976. Folkow B, Neil E. Circulation. Oxford: Oxford University Press, 1971. Guyton AC. Human Physiology and Mechanism of Disease. 2d ed. Phildelphia: WB Saunders, 1982. Milnor WR. Hemodynamics. Baltimore: Williams & Wilkins, 1982. Strandness DE, Sumner DS. Hemodynamics for Surgeons. New York: Grune & Stratton, 1975. Szuba A, Rockson S. Lymphedema anatomy, physiology, and pathogenesis. Vasc Med 1977; 2:321–326.

44 Aorta and Arterial Disease of the Lower Extremity Christopher K. Zarins and Sheila M. Coogan

improved in patients who can successfully abstain from tobacco (7,8). Optimization of serum lipid profiles and control of hypertension have less certain impact on the progression of lower extremity arterial disease, but are known to be beneficial in preventing progression of coronary atherosclerosis (2). Physical exercise may ameliorate the symptoms, of aortic and peripheral occlusive disease, and may play a role in preventing progression of disease. Weight reduction and control of environmental stress also play important roles. Recent data from the Diabetes Control and Complication Trial suggest that close control of serum glucose does not prevent progression or complications of peripheral vascular occlusive disease as measured by limb salvage in the setting of insulin-dependent diabetes mellitus (9).

INTRODUCTION Degenerative changes in the aorta and atherosclerosis of lower extremity arteries account for the majority of vascular complications in elderly patients (1). Aging of the baby boom population will result in rapid growth of the elderly population. By the year 2040, people older than 65 will comprise 22% of the U.S. population, or 67 million people. The most striking aspect of this trend is the increased rate of survival of those older than 75 (2). Obviously, the management of atherosclerotic complications of the aorta and its branches will play an increasingly significant role in the primary health care of a major portion of the adult American population. Atherosclerotic arterial disease is characterized by the formation of intimal plaques. These plaques may obstruct the lumen, ulcerate and embolize, cause thrombosis, or contribute to aneurysmal degeneration of the arterial wall. Each of these processes may result in a spectrum of clinical presentations requiring different diagnostic and therapeutic approaches. In this chapter, we consider some of the general features of the atherosclerosis, along with its pathologic and clinical manifestations in the lower extremity, and discuss diagnostic methods and current treatment alternatives.

Configuration and Composition of Atherosclerotic Plaque Although atherosclerotic plaques contain varying amounts of lipids, it is unclear whether all lesions containing lipids are necessarily precursors of clinically significant atherosclerotic plaques. A prime example of this uncertainty is demonstrated by the questionable significance of the socalled fatty streak lesion. This term describes a flat, yellow, focal luminal patch or streak, representing an accumulation of lipid-laden foam cells in the intima, evident in most people older than three years. They are identified with increasing frequency between the ages of 8 and 18, after which many apparently resolve. Fatty streaks exist at any age, often adjacent to or even superimposed on advanced atherosclerotic plaques. Fatty streaks and atheromata, however, do not have identical patterns of localization, and fatty streaks do not compromise the lumen or ulcerate (10). Although this subject remains controversial, the link and

ATHEROSCLEROSIS Risk Factors The risk factors for atherosclerosis may be divided into two major categories, reversible and irreversible. Major reversible factors include cigarette smoking, diabetes mellitus, hyperglycemia, hypertension, abnormalities of lipid metabolism, obesity, and low levels of physical activity. Nonreversible factors are primarily sex, age, and genetic influences of family history. It has been generally assumed that the factors associated with plaque formation and development in the extracoronary arteries are the same as those in the coronary arteries (2). However, there have been few population-based studies of risk factors associated with atherosclerosis of the aorta or the lower extremity branches. Several early studies considered only the symptomatic form of the disease (3,4). More recently, noninvasive methods have been used to identify and include asymptomatic subjects in these investigations (5,6). These findings are summarized in Table 1. The most significant risk factors apparently have independent effects (i.e., not cumulative) on the vasculature of the abdomen, pelvis, and lower extremity. Control of certain risk factors may have a beneficial effect on the expression, of the disease. Cessation of tobacco use has a beneficial effect on peripheral occlusive disease, and limb loss rates and arterial graft patency rates are

Table 1 Risk Factors Associated with the Development of Lower Extremity Arterial Disease, Disease Progression, and Mortality Risk factor Smoking Diabetes Hyperlipidemia Hypertension Physical activity Hemorheologic factors Obesity

Genetic factors

Development of disease

Progression

Mortality

Yes Yes Yes Yes Yes NAI

Yes NAI NAI NAI NAI NAI

Yes Yes NAI Yes Yes NAI

No; however, may be a weak risk factor in men NAI

NAI

NAI

NAI

Yes

Abbreviation: NAI, not adequately investigated.

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transition between fatty streak and fibrous plaque formation remain to be clarified. The term fibrous plaque identifies the characteristic and unequivocal atherosclerotic lesion. These intimal deposits appear in the second decade of life, becoming predominant or clinically significant only during or after the fourth decade. Fibrous plaques usually are eccentric and are covered by an intact endothelial surface. Although considerable variation exists in plaque composition and configuration, a characteristic architecture prevails. The immediate subendothelial region of the plaque consists of a compact and well-organized stratified layer of smooth muscle cells and connective tissue fibers known as the fibrous cap. This structure may mimic medial architecture, including the formation of a subendothelial elastic lamina, which may function to sequester the underlying necrotic and thrombogenic plaque core from the luminal surface. This surface usually is regular, with a concave contour corresponding to the circular or oval cross-sectional lumen of the uninvolved vessel wall segment. The stable necrotic core occupies the deeper plaque (Fig. 1). The core contains amorphous, crystalline, and droplet forms of lipid. Cells of undetermined origin, with morphologic, functional, and cell surface receptor characteristics of smooth muscles or macrophages are noted beneath the core. These cells also may contain lipid vacuoles. Calcium and myxoid deposits, collagen and elastin matrix fibers, basal lamina, and amorphous ground substance are also evident. Atherosclerotic plaques grow in an episodic fashion, demonstrating dense fibrocellular regions adjacent to organizing thrombus and atheromatous debris. Intermittent ulceration and healing occur, with thrombi being incorporated into the lesion. Vasa vasorum may nourish the plaque, facilitating the organization of thrombotic deposits and the remodeling of

Figure 1 Atherosclerotic plaque demonstrating the fibrous cap over a necrotic center. Note the oval external contour with the round lumen typical of these plaques.

the plaque and artery wall (11). Attenuation of the subadjacent media promotes outward bulging of the plaque toward the adventitia. Although this attenuation sequesters plaque, enlarges the artery, and stabilizes the wall, a predominant lytic reaction may result in excessive arterial dilation or aneurysmal degeneration. Experimental evidence suggesting such a mechanism for aneurysm formation has been obtained in nonhuman primates in our laboratory (12) and by other investigators (13). Tissues between the necrotic core and the media, however, usually are densely fibrotic. Arterial wall support may thus be maintained by the integrity of the fibrous cap or thickened adventitia. Advanced lesions, particularly those associated with aneurysms, may appear to be atrophic and relatively acellular, consisting of dense fibrous tissue and a minimal necrotic center. Calcification is a prominent feature, involving the superficial and deeper layers. Terms such as fibrocalcific, lipid-rich, necrotic, and myxomatous describe various predominant aspects of advanced plaques. Calcific deposits are most prominent in plaques in older people and in the abdominal aorta or coronary arteries, where the earliest plaques form in animal models and in humans (14). The usual eccentric plaque bulges outward from the lumen; the external cross-sectional contour of an atherosclerotic artery becomes oval while retaining a circular lumen (Fig. 1) (15,16).

Localizing Factors in the Development of Atherosclerotic Lesions Adaptive changes in arterial luminal diameter are determined by changes in blood flow. During embryologic growth and development, lumen diameter is determined by the volume of blood flow. After birth, increases in artery diameter continue as a response to increases in blood flow (17). This phenomenon is also demonstrated in mature arteries after cessation of growth, with enlargement of arteries proximal to arteriovenous fistulas and a decrease in the size of arteries proximal to amputated limbs (18). Luminal diameter adaptation is responsive to wall shear stress, as determined by the effective velocity gradient at the endothelial-blood interface (19). In mammals, wall shear stress normally ranges between 10 and 20 dynes/cm2 at all locations throughout the arterial vasculature. In arteriovenous fistulas, the afferent artery enlarges enough to restore shear stress to this physiologic range (20). This response depends on the presence of an intact endothelial surface (21) and may be mediated by the release of endothelium-derived relaxant factors, including nitric oxide or other vasoactive agents (22). Near-wall properties of arterial flow fields and the distribution of mural wall shear stress correspond closely to atherosclerotic plaque localization (23–30). Plaques develop where shear stress is reduced (25,26), not elevated, with an intact endothelial surface, even in the absence of platelet deposition (31). The revised response to injury hypothesis now stresses on metabolic or functional changes sustained by intact endothelial cells that alter binding or metabolism of lipid molecules or modify transendothelial transport, rather than denudation of the endothelium itself (32). Atherosclerosis tends to occur principally in three locations within the arterial vasculature: the carotid-cerebral, coronary, and aortic-peripheral system. Within these predisposed regions, lesions form in predictable geometric configurations, demonstrating the influence of shear stress and flow patterns. Size as well as localization closely correlates with low wall shear stress and departures from unidirectional

Chapter 44: Aorta and Arterial Disease of the Lower Extremity

flow (25,26). Plaque initiation and localization are the result of low rather than high shear stress, low flow velocity, flow separation, and oscillation in wall shear direction (33). Regions of increased mural tensile stress about branches (23), pulsatile wall motion (34), and wall thickness and density (35,36) are also associated with selective plaque localization. Conversely, regions of relatively elevated wall shear stress or reduced tensile stress, at flow dividers and along the outer or convex aspects of curved arterial segments, generally are spared (37). Hemodynamics and tensile influences are also important in plaque progression and evolution (38,39) and influence potential plaque regression (40). As an example of this influence on regression, hypertension was found to sustain experimental plaque progression in a hypercholesterolemic cynomolgus monkey model, despite a reduction in serum cholesterol level (41). Reduced flow and consequent reduction in wall shear stress also tend to induce intimal thickening. An increase in wall volume, including cell enlargement, cell proliferation, and net matrix accumulation, is demonstrated in long-term reactions (42). A sieving effect related to these changes in wall composition (43,44) and porosity (35) has been proposed. Wall thickening, including intimal thickening, may retard transmural mass transport, providing the basis for intimal lipid deposition (45). The accumulation of matrix fibers with affinity for lipid molecules (46–50) and the fusion or accretion of lipid particles on these components may also be responsible.

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vessels are naturally existing branches of large- and mediumsized arteries that enlarge to carry blood flow around an obstruction. They do not represent neovascularization but adaptation of existing vessels to an increased demand of blood flow. The collateral blood flow that develops in the face of a developing, progressive obstruction usually can supply the demands of resting tissue. However, it often is unable to supply the flow necessary for an exercising muscle group. There are a number of well-recognized collateral beds that develop in the presence of atherosclerosis of the aorta and distal tree: 1. 2. 3. 4. 5.

Intercostal and lumbar arteries Superior and inferior mesenteric arteries Hypogastric artery Profunda-genicular arteries Peroneal-tibial arteries

Patients may have a totally occluded abdominal aorta for several years, with relatively mild symptoms of hip and buttock claudication. Under these circumstances, the intercostal arteries, superior epigastric arteries, and visceral arteries become important sources of collateral flow to the lower extremity (Fig. 2). For example, blood supply to the distal aorta may be through the inferior mesenteric artery, which derives collateral supply from the superior mesenteric artery. In addition, the inferior mesenteric artery

PATHOPHYSIOLOGIC PROCESSES AFFECTING THE AORTA AND LOWER EXTREMITY ARTERIES The processes affecting the arteries to the lower extremity include plaque formation with obstruction of the lumen and subsequent limitation of flow, thrombosis resulting in acute ischemia, ulceration of the plaque with distal embolization, and weakening of the arterial wall with aneurysmal formation resulting in rupture or thrombosis.

Stenosis Progressive intimal plaque deposition may result in narrowing of the lumen, or stenosis. Mild degrees of stenosis producing less than 50% reduction in lumen diameter usually do not obstruct blood flow. It is not until lumen diameter falls below a critical point that resistance to blood flow increases. This is referred to as critical arterial stenosis, or the percentage by which the lumen diameter must be reduced to produce a measurable drop in blood flow. Under experimental conditions, there is no significant pressure drop and no reduction in flow until there is more than 80% reduction in lumen cross-sectional area (equivalent to 55% diameter reduction) (51). However, pressure drops across stenoses are critically dependent on flow, and noncritical stenoses at rest may develop significant pressure gradients when flow is increased with exercise. This can account for the clinical observation of disappearing pedal pulses after exercise and symptoms of claudication in patients with palpable pedal pulses. The extent of disability from an obstruction is related to the location of the lesion, the degree of obstruction, the length and number of obstructions, the metabolic needs of the tissues distal to the obstruction, and the ability of collateral vessels to provide the necessary flow. Collateral blood flow may be quite extensive in occlusive disease. Collateral

Figure 2 Angiogram revealing severe aortoiliac disease. Note the large collateral vessels (arrows) that have developed in response to occlusion of the left iliac artery.

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can be an important source of collateral flow to the lower extremity through the superior hemorrhoidal network.

Thrombosis The causes of acute arterial obstruction can be divided into two categories: embolism and thrombosis. Emboli arise from a proximal source, either the heart or proximal great vessels, and obstruct the tapering arterial tree at a branch point or at the point where the embolus is larger than the lumen diameter. Mural thrombus that forms in a fibrillating atrium is the most common source of arterial emboli (52), but emboli can also arise from areas of recent transmural infarction, ventricular aneurysms, and diseased valves. Spontaneous thrombosis usually occurs in arteriosclerotic arteries as a result of slow flow caused by severe stenotic lesions or as a result of sudden dissection or hemorrhage under a previously nonstenotic plaque. Acute thrombosis usually results in very sudden and severe symptoms of arterial ischemia. The severity of clinical symptoms is related to the site of the obstruction, the size and extent of the thrombus, and the adequacy of the collateral vessels. In severe ischemia, one or more of the often-described five Ps may be present: pulselessness, pallor, paresthesia, pain, and paralysis. The loss of motor power and sensation in the toes and foot indicates very severe ischemia and limb loss unless the ischemia is relieved promptly. Acute thrombosis of a previously stenosed artery that has excellent collateral vessels about it may occur with only mild symptoms and little risk of limb loss.

This explains why larger aneurysms have a greater tendency to expand and rupture than do smaller aneurysms. Blood flow in the dilated aneurysmal sac is slower than normal, producing an increased tendency to thrombosis. Most large abdominal aortic aneurysms are lined by laminated mural thrombus. Mural thrombus may be so thick that the lumen caliber on angiography does not appear enlarged. However, mural thrombus provides little, if any, support for the artery wall and no protection from aneurysm rupture.

ARTERIAL OCCLUSIVE DISEASE OF THE AORTA AND PERIPHERAL ARTERIES The manifestations of atherosclerosis in the aorta and peripheral arteries are either occlusive disease or aneurysm formation. The arteries of importance in the circulation to the lower extremities are diagrammed on Figure 3. Obstructive plaques may occur in each of the vessels shown but are most common in the infrarenal abdominal aorta, iliac arteries, and superficial femoral arteries. The profunda femoris artery is relatively spared, and diabetic patients are more prone to develop lesions in the tibial arteries.

Ulceration Ulceration occurs when breakdown of the fibrous cap over a lesion exposes the necrotic core of the plaque to the circulation. This may be the site for platelet deposition (1) and thrombus formation or may result in embolization of the plaque contents itself, producing cholesterol emboli in the distal arterial tree. The most common clinical syndrome in the peripheral circulation associated with distal embolization from a proximal ulcerated plaque is the blue toe syndrome. Patients may have normal pedal pulses but suddenly develop one or more cold, blue, painful toes—a condition that resolves in three to four days. These symptoms may be caused by cholesterol emboli in the digital arteries of the feet. The source of the emboli usually is a proximal ulcerated lesion in the aorta, iliac, or femoral vessels. Unrecognized and untreated repeated embolization to the foot results in obstruction of the small arteries of the foot, gangrene, and limb loss.

Aneurysm Formation An aneurysm is a localized arterial dilation. A true aneurysm is one in which there is thinning or atrophy of all layers of the artery wall, with enlargement of the lumen. This should be distinguished from a false aneurysm, which results from a rupture of the artery wall, usually caused by trauma, with containment of the blood stream by fibrous tissue surrounding the vessel. Thus in a true aneurysm there is an inadequate artery wall, whereas in a false aneurysm there is absence of the artery wall. As the lumen radius of an aneurysm enlarges, there is an increase in tension on the vessel wall (T), according to the law of Laplace (T ¼ Pr), where P is pressure and r is radius. The larger the radius, the greater is the tension and the greater is the tendency for further enlargement of the lumen.

Figure 3 Arterial supply to the viscera and lower extremity. Obstructive or aneurysmal changes can occur in each of these vessels. The clinical signs and symptoms vary depending on the location and blood supply distribution of a given artery. Full angiographic evaluation of the aorta and lower extremity vessels should demonstrate flow through each of these arteries.

Chapter 44: Aorta and Arterial Disease of the Lower Extremity

Clinical Manifestations of Peripheral Occlusive Disease The clinical manifestations and physical findings of peripheral occlusive disease are as follows: Clinical manifestation Claudication Rest pain Ulceration Gangrene Impotence

Physical findings Absent or diminished pulses Bruits Skin pallor Hair loss Dependent rubor Skin and muscle atrophy Trophic changes of the nails Tissue necrosis

Claudication Claudication arises from the term claudicatio, which means to limp. It is a clinical syndrome of pain on exercise, which is relieved by rest and results from a fixed obstruction or stenosis in arteries to the lower extremity. Although circulation may be adequate at rest, with exercise there is an increasing demand for flow. When such flow is obstructed by a stenosis, the muscle served by that vessel becomes ischemic and begins to function with anaerobic metabolism. This results in pain and symptoms of fatigue, causing the patient to stop and rest. Typically, the patient rests for one to two minutes, allowing the circulation to again restore aerobic conditions, after which the patient can again exercise. Patients with aortoiliac occlusive disease have symptoms of claudication in the hips and buttocks, whereas patients with superficial femoral artery obstruction have symptoms of claudication in the calf. The level of claudication is always below the level of the arterial obstruction. Most patients with claudication, although symptomatic, are at low risk for developing gangrene. Only 33% of patients with proven arterial stenosis report symptoms of claudication. It is a stable disease in 70% to 80% of patients, and it is generally clinically accepted that only 25% of claudicants deteriorate (53–57). Thus patients with stable, nonlimiting claudication may be safely followed, and revascularization should be reserved for those with disabling symptoms. Reconstructive surgery to improve blood flow is done in less than 10% of all patients with claudication. Amputation may be required in 1% to 5% (58). The benign nature of this symptom should be carefully considered when planning any type of intervention, either catheter based or via traditional open arterial surgery.

Rest Pain Patients with worsening ischemia develop a clinical syndrome called rest pain. The condition of rest pain indicates a much more severe degree of ischemia than claudication and, unlike claudication, indicates that the patient is at high risk for developing gangrene and limb loss. Typically, the patient experiences pain in the toes and forefoot during the night, which causes him or her to awaken from sleep. The patient usually sits up in bed, dangles the legs over the side of the bed, and frequently relieves the symptoms by getting up and walking. After a short period of time, the patient’s symptoms have disappeared and the patient can return to sleep. The symptoms of rest pain occur because of severe ischemia in the forefoot and toes, brought about by two conditions: (i) the patient is recumbent and thereby eliminates the hydrostatic pressure gradient that assists

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the arteriolar perfusion pressure when erect; and (ii) during sleep there is a diminution of cardiac output that correspondingly diminishes the volume of peripheral blood flow. When the patient dangles the feet, he or she restores the hydrostatic gradient; when the patient gets up to walk, he or she increases cardiac output and thereby improves the perfusion of the lower extremities. Sometimes patients complain of nocturnal cramps in the calf muscles. Such cramps are usually not related to vascular ischemia and should be differentiated from nocturnal rest pain, which typically is in the toes and forefoot rather than in the calf.

Ulceration Cutaneous ulcers may be the first evidence of peripheral vascular disease. These ulcers are caused by severe ischemia from proximal arterial occlusions and often are initiated by minor skin trauma. However, there are many causes of skin ulceration, which must be differentiated from ischemic ulcers: & & & & & & & &

Venous stasis Infection Neoplasm Neurotropism Hematologic abnormalities Allergic reactions Insect bites Injections

Each type of ulcer has certain clinical and physical characteristics. The ischemic ulcer is most commonly found on the toes, heel, dorsum of the foot, or lower third of the leg. The pain is usually severe and persistent, and worsens at night. The ulcer itself is generally irregular, with a pale or necrotic base. At times, patients have ulcerations that are attributed to venous disease that may in fact be the result of a combination of arterial ischemia and venous stasis. Ulcerations not in the classic position for venous disease (at the medial malleolus) should be considered as potentially being of an arterial origin. Even if a component of venous disease is present, the arterial component must be evaluated if effective therapy is to be instituted.

Gangrene Progressive ischemia caused by atherosclerosis can result in gangrenous changes of the tissues. Most commonly the digits are affected initially, but progression to the forefoot is not unusual. Small amounts of infection superimposed on a severe chronic ischemic state can progress very rapidly to gangrene. Clinically, dry and wet gangrene should be differentiated. Dry gangrene represents mummification of tissue, and active purulent tissue and cellulitis are absent. Wet gangrene is characterized by active infection with cellulitis and purulent tissue planes and is an indication for urgent amputation to prevent ascending infection.

Impotence Penile erection requires a threefold increase in blood flow through the penile arteries, which is shunted into the vascular spaces of the corpora cavernosa. Arterial obstruction that prevents this increase in blood flow can result in erectile impotence in much the same way that symptoms of claudication are brought about by exercise when there is an unmet demand for increased blood flow. Rene Leriche in 1923 first noted the association among atherosclerotic occlusion of the

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aorta, hip claudication, buttock atrophy, and erectile impotence. This is now known as the Leriche syndrome. Obstruction can occur at any level from the abdominal aorta, the common iliac arteries, the internal iliac arteries, the internal pudendal arteries, or the penile arteries, resulting in erectile impotence. Although the majority of cases of impotence have psychogenic or urologic causes or are the result of the side effects of medication, the importance of an adequate vascular supply is becoming increasingly recognized and can be objectively assessed, as is discussed below.

EVALUATION OF PERIPHERAL VASCULAR OCCLUSIVE DISEASE Peripheral vascular occlusive disease is evaluated on the basis of a thorough medical history and clinical examination, noninvasive vascular testing, continuous acquisition (‘‘spiral’’) computed tomography (CT) scanning, magnetic resonance (MR) angiography, and intra-arterial contrast angiography.

Clinical Examination Peripheral oscular occlusive disease may be accurately diagnosed with a careful history and thorough physical examination of the patient. In addition to the important determination of symptoms of claudication or rest pain, the patient’s level of activity and walking distance should be noted. Often patients with very severe disease do not walk enough to develop symptoms. A careful evaluation of all pulses should be made, although the presence of a palpable pulse does not rule out the possibility of significant arterial occlusive disease. A bruit may be appreciated during the physical examination. Bruits are produced by the turbulence of blood just distal to a stenosis but may also be produced by angulations and bends in arteries. Bruits may be audible with a stethoscope over and distal to an area of stenosis. A high-pitched bruit may be indicative of a severe stenosis. Finally, the temperature, quality, and color of the skin, hair, and nails should be noted, including the presence of skin ulcerations or gangrenous changes. Noninvasive tests are used after the clinical examination to confirm the presence of occlusive disease, identify the level and severity of the disease, and assess whether angiography is required to further evaluate these patients.

Objective Assessment with Vascular Laboratory Techniques Doppler Ankle Pressure The ready availability of the handheld Doppler ultrasound has made measurement of lower extremity blood pressure simple and convenient and has permitted the development of objective means of assessing lower extremity perfusion. The Doppler ultrasound probe emits high-frequency sound waves in the range of 2 to 10 MHz. The sound is reflected by the movement of red blood cells in the vessel, which produces a frequency shift that is picked up by the receiving crystal of the Doppler probe. This frequency shift is proportional to the blood flow velocity. This Doppler shift can be expressed by the following formula: Df ¼

2fVcosy C

where V is velocity, f is frequency of the incident sound beam, C is velocity of sound in tissue, and y is the angle

of the incident sound beam to the vessel examined. Because V, C, and y can be constant, the shift in frequency is proportional to the velocity of the blood flow. To measure the blood pressure in the legs, a blood pressure cuff is placed at the ankle just above the malleoli and inflated while a handheld Doppler is used to listen to the flow in the dorsalis pedis and posterior tibial artery. Inflation of the cuff above systolic pressure causes obliteration of the Doppler signal, and systolic blood pressure can be recorded as the cuff is deflated and flow resumes in the measured vessel. Because a patient’s blood pressure may fluctuate, more precision can be gained by comparing the ankle pressure to the brachial pressure. Usually, the ankle systolic pressure is divided by the brachial systolic pressure to produce an ankle-brachial index (ABI). Such an index is quite useful in assessing the severity of peripheral occlusive disease. Patients without occlusive disease have an ABI of 1, whereas patients with claudication have an ABI of 0.5 to 0.6. Patients with rest pain, gangrene, and ulceration have an ABI of 0.4 and less (Fig. 4). Despite these ranges, considerable overlap can be present, especially around an ABI of 0.5. This measurement is useful for differentiating patients with lower extremity pain caused by spinal stenosis, arthritis, or other nonvascular conditions. Patients with diabetes frequently have calcified vessels that cannot be compressed by the blood pressure cuff. This may lead to a false elevation of the ABI. In the setting of incompressible ankle vessels, toe pressure or waveforms may be more accurate. It is important to note that the pressure measured is determined by the location of the cuff rather than the location of the listening probe. Thus an ankle pressure can be recorded by placing a cuff at the level of the malleoli, and a below-knee or above-knee pressure can be recorded by appropriate blood pressure cuff placement. Patients with superficial femoral artery occlusion have a normal pressure reading in the upper thigh but an abnormal pressure reading below the knee and at the level of the ankle. The resting ankle index is the most accurate of the noninvasive techniques for objectively assessing the presence or absence of occlusive disease. It is reproducible, and hence the index can be followed to identify the progression of disease. It should also be recognized that listening for and hearing flow in the dorsalis pedis and posterior tibial arteries does not represent a pulse. A pulse is palpated with the fingers. Flow can be heard at very low levels of circulation in the dorsalis pedis and the posterior tibial arteries, and patients may have frank gangrene of their foot even though audible Doppler signals are heard. One should not be lulled into a false sense of security of good perfusion of the foot if Doppler flow signals in the foot are heard but pulses cannot be palpated.

Figure 4 Ankle-brachial index is used to determine severity of lower extremity ischemia. Circles denote range consistent with claudication; Xs denote area of limb-threatening ischemia. Note area of considerable overlap around 0.5.

Chapter 44: Aorta and Arterial Disease of the Lower Extremity

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Stress Testing Because patients with claudication develop their symptoms only with exercise, stress testing is a useful means for documenting the degree of walking impairment. Treadmill exercise can be performed at a standard pace of 1.5 miles/hr at a 7-degree grade. Normally, one has no diminution of the ankle pressure following exercise. On walking to the point of claudication, there is a substantial drop in ABI because blood flow is shunted to the proximal thigh muscle and cannot pass through the obstruction to the distal vascular bed. There is return of ankle pressure to normal with rest. The symptom of reduction in ankle pressure is similar to the finding of disappearing pulses with exercise, seen on clinical examination.

Doppler Waveform Analysis Doppler detectors can provide an analog signal that is proportional to the velocity of the blood in vessels studied. The shape of the waveform reflects the status of the vessel. Normally, a triphasic waveform is seen, indicative of reversal of flow in early diastole. Stenosis proximal to the vessel examined first eliminates this reversed flow. As the stenosis becomes more severe, the peak of the waveform is blunted, and the waveform widens (Fig. 5). Qualitative analysis of these waveforms at different levels of the extremity can identify the level and severity of occlusive lesions. Analysis of the Doppler waveforms in conjunction with systolic pressures at several levels in the leg can allow the clinician to make an accurate diagnosis of the location and extent of peripheral vascular occlusive disease. For example, Figure 6 illustrates the decrease in the waveform and systolic pressures across an obstructed superficial femoral artery. A decrease in systolic blood pressure of 30 mmHg or more between any two levels in the leg usually indicates total occlusion of the intervening artery.

Doppler Ultrasound Imaging and Duplex Scanning B-mode ultrasound imaging of arteries and plaques combined with pulsed Doppler ultrasound flow determination and sound spectral analysis is now a routine method evaluating the common femoral, superficial femoral, and popliteal arteries. This technique provides the ability to noninvasively image arteries and to assess flow. This technology has also been used to image autogenous vein grafts to prevent vein graft thrombosis and failure. Routine postoperative vein graft surveillance using duplex ultrasound imaging every six months can detect elevated flow velocities (peak systolic velocity >200 cm/sec) within the vein graft or at the anastomotic sites (59,60). Early detection

Figure 6 Doppler flow velocity waveforms recorded at four places in an extremity with SFA occlusion demonstrated by angiography. Recordings were made at the CFA, SFA, DP artery, and PT artery. Associated systolic blood pressures were measured to be 140 mmHg in the thigh and 106 mmHg below the knee. This 34 mmHg drop in pressure indicates occlusion of the intervening artery (in this case, the SFA). Distal arteries fill through collateral vessels. Note the change in Doppler velocity waveforms. Abbreviations: CFA, common femoral artery; SFA, superficial femoral artery; DP, dorsalis pedis; PT, posterior tibial.

of vein graft stenoses allows localized treatment with surgical revision or endovascular treatment and thus may prevent graft occlusion and prolong graft patency (61,62). Duplex ultrasound scanning may also be used to identify aneurysms and stenotic and ulcerated lesions in the aortoiliac and femoropopliteal arteries, which may be potential sources for distal emboli.

Penile Brachial Pressure Index

Figure 5 Doppler ultrasound velocity waveforms indicating the normal triphasic waveform, the loss of the reverse flow component seen in moderately stenotic vessels, and the blunted waveform of a severely stenotic vessel.

The simplest and most reliable assessment of the adequacy of penile perfusion is the measurement of arterial pressure in the corpora cavernosa supplied by the penile arteries. A Doppler velocity probe is positioned directly over one of the six penile arteries, and a small pneumatic cuff is placed around the penis proximal to the probe. The cuff is inflated until arterial flow is abolished and is then allowed to slowly deflate until flow returns, which indicates the systolic blood pressure. The penile systolic pressure is divided by the brachial systolic pressure to provide a penile-brachial index (PBI). A PBI greater than 0.9 is normal. A PBI less than 0.7 is consistent with a vascular occlusive cause of impotence.

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Catheter-Based Angiography Catheter-based angiography provides the most definitive anatomic assessment of obstructing vascular lesions and is performed before vascular reconstruction. This includes visualization of the abdominal and infrarenal aorta, the iliac arteries, and the femoral, popliteal, tibial, and pedal vessels throughout their length (Fig. 3). Angiography is usually performed through a transfemoral approach, which has the advantage of allowing selective catheterization and the study of individual arteries as needed. Transbrachial and translumbar aortography can also be used successfully. Newer techniques of digital subtraction and computer enhancement of images permit the use of smaller volumes of iodinated contrast materials. Patients should be well hydrated before and after angiography to minimize the possibility of renal failure caused by the osmotic diuresis produced by the hypertonic contrast medium (63).

CT and MR Angiography Advances in computer technology have resulted in significant advances in CT and MR imaging. Timed bolus injection of a contrast agent allows vascular imaging, which rivals the resolution that can be obtained with contrast arteriography. Continuous acquisition of data using helical or spiral CT techniques allows three-dimensional (3-D) image reconstruction with image rotation, shaded-surface display, and curved planar reformation of images. CT angiographic techniques allow imaging not only of the lumen contour but also of the artery wall and extravascular structures. Thus CT angiographic imaging is the imaging procedure of choice for thoracic and abdominal aortic aneurysms and is used to plan endovascular treatments, as well as to follow patients who have undergone treatment of aneurysms (64,65). CT angiography can also be used to study the carotid artery (66) and peripheral vessels. Multislice spiral CT scans with 16-row detectors can precisely image the aortoiliac and femoral vessels as well as infrageniculate arteries in 13 seconds using as little as 130 mL of iodinated contrast (67). MR angiography using gadolinium contrast agent, which is not nephrotoxic, is currently being used to supplant catheter-based, contrast angiography in some centers (68): In addition to anatomic data, however, MR sequences can encode for flow volume (69) and the oxygen saturation of hemoglobin (70,71). Although still limited in quality and the field of view available compared to a traditional aortogram with bilateral runoff, MR anatomic and flow imaging may ultimately replace catheter-based, invasive arterial diagnostic methods.

TREATMENT OF PERIPHERAL VASCULAR OCCLUSIVE DISEASE The treatment of peripheral vascular occlusive disease is determined by the severity of the patient’s symptoms and the anatomic location and extent of obstructing lesions. Treatment options include nonoperative measures, minimally invasive procedures such as transluminal angioplasty and stenting, and operative revascularization.

Nonoperative Measures Patients with peripheral occlusive disease usually have one or several risk factors for the development of vascular disease, including cigarette smoking, hyperlipidemia, hypertension, and diabetes mellitus. Every effort should be

made to control these factors to prevent progression of obstructive disease. Patients with symptoms of claudication, which are not physically limiting have a low risk for limb loss (72) and usually respond well to a program of cessation of smoking and walking exercise to stimulate enlargement of collateral circulation and to condition the muscles to function at a higher level with the available blood supply. Exercise programs are effective in improving walking distance. In a meta-analysis of randomized trials of supervised exercise trials for intermittent claudication, exercise therapy improved pain-free walking time by 180% and maximal walking time by 150% at six months. However, exercise programs must be maintained in order to remain effective. Cessation of the exercise program usually returns the patient to the same level of claudication as present originally. Patients often adjust their levels of activity and coexist well with occlusive disease for many years. Those who continue to smoke have the poorest outlook.

Risk Factor Modification A comprehensive program of risk factor modification should be undertaken in patients with peripheral artery disease, including smoking cessation, increased physical activity, blood pressure control, reduction of elevated total and low-density lipoprotein (LDL) cholesterol levels, antiplatelet therapy, angiotensin-converting enzyme–inhibitor therapy, weight reduction, and glycemic control in patients with diabetes mellitus. Tobacco use is the single most important modifiable risk factor for peripheral occlusive disease. Smoking increased the risk of intermittent claudication by a factor of 8 to 10 and smoking cessation resulted in a 50% reduction in intermittent claudication over a 20-year period among Icelandic men (73). Rest pain developed in 16% of smokers, with intermittent claudication, but there was no disease progression in nonsmoking patients, with intermittent claudication (74). Long-term graft patency is significantly better in patients who quit smoking than in those who continue to smoke (75). Lowering of cholesterol with statin drugs has been shown to reduce the incidence of new or worsening intermittent claudication by 38% (76). Several studies have confirmed an increase in pain-free and total walking distances, as well as improvement in overall physical function in patients treated with statin drugs. Dietary modifications to reduce cholesterol and statin therapy with a target LDL of less than 100 mg/dL is recommended. Antiplatelet therapy with aspirin has been shown to reduce overall cardiovascular morbidity and mortality in patients with peripheral occlusive disease. Ticlid has benefits similar to aspirin but is associated with a risk of thrombocytopenia and neutropenia and is therefore not routinely recommended. Clopidogrel has been shown to be superior to aspirin but is considerably more expensive than aspirin. There is evidence to suggest that the combined use of clopidogrel and aspirin may provide added benefit. Strict glycemic control with a target hemoglobin A1c of less than 7.0 is recommended for diabetic patients with peripheral occlusive disease (77). Reduction in hemoglobin A1c by 1% has been shown to result in an 18% reduction in myocardial infarction, a 15% reduction in stroke and, a 42% reduction in symptomatic peripheral occlusive disease in the prospective U.K. diabetes study (78).

Medical Therapy A number of vasodilating drugs have been used in an attempt to diminish vasospasm and improve peripheral

Chapter 44: Aorta and Arterial Disease of the Lower Extremity

perfusion in patients with peripheral occlusive disease. These, in general, have been found to be ineffective and most have been removed from the market. Nifedipine has been found to be useful in the treatment of vasospasm as seen in Raynaud’s disease (79), but has no beneficial effect in peripheral occlusive disease. Pentoxifylline was the first medication approved by the Food and Drug Administration (FDA) for the treatment of intermittent claudication. Pentoxyfylline is a xanthine derivative that is believed to exert its effect by decreasing the rigidity of erythrocytes so that they can more readily deform and pass through the small capillary beds, thereby increasing tissue perfusion. A multicenter trial of patients with claudication demonstrated a 30% increase in walking distance in patients treated with pentoxyfylline as compared to placebo (80). However, more recent studies suggest that improvement in walking distance with pentoxyfylline is unpredictable and may offer little benefit over placebo. There is no evidence for a beneficial effect from pentoxyfylline for patients with rest pain, ulceration, or gangrene. Cilostazol is a phosphodiesterase inhibitor with antiplatelet and antiproliferative activity. It is the second FDAapproved drug for the treatment of intermittent claudication and appears to provide significant benefit compared to placebo. In a meta-analysis of eight randomized, placebocontrolled trials of cilostazol in patients with intermittent claudication, after 12 to 24 weeks of therapy, patients on cilostazol had an increase in pain-free walking of 40% to 70% and an increase in maximum walking distance of 65% to 83% compared to placebo controls (81). Cilostazol is contraindicated in patients with congestive heart failure because of a proarrhythmic effect. However, it may be considered as initial medical therapy in addition to smoking cessation and walking exercise in patients with mild-tomoderate claudication. Although metabolism-enhancing drugs such as 6-proprionyl carnitine, agents such as L-arginine, dietary supplements such as gingko biloba, and pneumatic compression stockings may hold promise for patients with intermittent claudication, they have yet to demonstrate clinical efficacy in prospective, controlled clinical trials. Intravenous prostaglandin infusion, which has a significant vasodilator and platelet inhibitory effect, has been proposed for the treatment of ischemic ulcers, but no significant improvement in rest pain of ischemic ulcer healing has been demonstrated in controlled clinical trials.

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Transluminal Angioplasty Transluminal balloon angioplasty is accomplished by first performing a diagnostic arteriogram to localize the occlusive lesion. A catheter with a balloon that has a predetermined maximal diameter at its tip is then passed over a guide wire under X-ray control through the obstructing lesion. Inflation of the balloon disrupts the plaque and stretches the arterial wall, resulting in enlargement of the lumen. This enlargement of the lumen cross-sectional area occurs by separating the plaque from the underlying tunica media and stretching the artery wall (Fig. 7). At times, the media is stretched and thinned to the point of media rupture, in which case vessel integrity is maintained by the adventitia (82). There is no plaque compression or removal of the lesion, and long-term patency depends on the vessel wall remaining in the overstretched state. When the vessel contracts to its predilated state, restenosis occurs. This occurs in a substantial number of patients and is a significant limitation of the procedure. Intra-arterial stents have been introduced as a method, of maintaining lumenal patency after angioplasty. Stents have improved the longterm effectiveness of angioplasty by preventing recoil, intimal flaps, and dissections, such as seen in Figure 8.

Intraluminal Stenting Stenting of recanalized or dilated arterial segments prevents lumen collapse and recoil and maintains lumen caliber. Stents also tack down dissected and separated intimal flaps, preventing lumen obstruction and occlusion (Fig. 8A–C). Stents are either balloon expandable or self-expanding and are widely used for coronary artery stenoses and occlusions. They are FDA approved for use in iliac artery lesions and recently have been approved for high-risk patients with carotid stenosis. Balloon-expandable stents provide maximal radial strength and allow precise positioning. They, however,

Endovascular Treatment Endovascular catheter-based therapy of stenotic lesions and short-segment occlusions has gained acceptance as an effective treatment modality for peripheral occlusive disease. While the overall long-term results are not as durable as surgical reconstruction and bypass procedures, the procedures are minimally invasive and well tolerated by patients. Endovascular treatment is usually percutaneous and is performed in the angiography suite under fluoroscopic image guidance. Proper patient selection is important and clinical criteria for treatment, similar to those used to select patients for surgical treatment, should be used. Treatment consists of transluminal balloon dilation of lesions with or without stenting. Dilation of lesions that appear to be significant on angiographic images but, which produce minimal or no symptoms, should be avoided. The best candidate for transluminal angioplasty is a patient with severe claudication, with an isolated hemodynamically significant common iliac artery stenosis.

Figure 7 Mechanism of balloon dilation of arteries. (A) Human superficial femoral artery that has been fixed with an intraluminal pressure of 100 mmHg and cut in cross section. Note the eccentric plaque and round lumen. (B) Segment of the same artery after balloon dilation. Note the separation of plaque from the media and protrusion of the plaque into the lumen. The media is thinner and has ruptured, and lumen integrity is maintained by the adventitia. Disruption and stretching of the artery wall results in a larger lumen area. There is no plaque compression. Source: From Ref. 82.

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Figure 8 Endovascular treatment of bilateral common iliac stenoses: (A) following balloon angioplasty, dissection flaps and residual stenoses are seen; (B) Balloon expandible stents are deployed in the common iliac arteries; (C) completion angiogram demonstrating no residual stenosis and smooth lumen caliber.

may be compressed by extrinsic force. Self-expending stents are commonly oversized to create a continual outward force resisting recoil. The hoop strength of self-expanding stents is less than for balloon-expandable stents but they are useful in vessels at risk for external compression, such as the carotid artery or the superficial femoral artery. While stenting has largely eliminated intimal flaps and early recoil following balloon angioplasty, restenosis and intimal hyperplasia remain a problem, particularly for smaller-caliber arteries. Promising results in controlling restensosis of the coronary circulation has been achieved with drug-eluting stents. Drug-eluting stents are bare-metal stents that are coated with a drug that acts locally to inhibit or prevent cellular proliferation and restenosis. Restenosis is a significant problem for superficial femoral artery stenting as well as popliteal and tibial artery stenting, and drugeluting stents are not yet available for these vessels.

Adjunctive Endovascular Treatments Laser angioplasty of peripheral artery lesions has fallen into disfavor because of high restenosis and recurrence rates. Transcatheter atherectomy devices that shave or debulk plaque are currently being investigated but there is no evidence that these will be more successful in avoiding restenosis. Secondary treatments of restenotic lesions can be carried out with cutting balloon techniques and cold thermal energy application, but the effectiveness of these therapies are unproved. Medical therapy aimed at inhibiting platelet aggregation with glycoprotein IIb/IIIa complex inhibition has been shown to decrease in-stent restenosis (83) and treatment with the antiplatelet agent cilostazol has been

shown to have a beneficial effect in preventing coronary stent restenosis (84). New and improved methods to control and treat in-stent restenosis can be expected to expand the role of endovascular therapy in the near future.

Results of Endovascular Therapy The results of transluminal balloon angioplasty and stenting are to a large degree determined by the location and character of the lesion being treated. The predictors of success include the location and length of the target lesion, whether the lesion is a stenosis or an occlusion, and the adequacy of the outflow vascular bed. In general, the larger the artery being treated and the shorter the lesion being treated, the better the results. Thus, in the lower extremity vessels, the best results are achieved with short-segment stenoses in the common iliac artery. Long-term patency of angioplasty of selected common iliac lesions is comparable to open surgical bypass. The long-term patency of common iliac balloon angioplasty of common iliac stenoses at one year is 90%, at three years is 80%, and at five years is 70% (85). The results for iliac occlusions with stenting is somewhat less favorable, but considering the minimally invasive nature of the endovascular treatment, iliac angioplasty and stenting should be considered for isolated iliac artery lesions. Results for external iliac stenoses are not as favorable as for common iliac lesions and surgical bypass should probably be considered for patients with diffuse aortoiliac disease, which involves the external iliac artery. Results for angioplasty and stenting below the inguinal ligament are distinctly inferior to those for iliac stenting. Bypass surgery for superficial femoral artery occlusions, particularly

Chapter 44: Aorta and Arterial Disease of the Lower Extremity

with autogenous saphenous vein bypass, is the procedure of choice for such patients. However, even though long-term patency rates may not be high, significant benefit can be achieved in some patients who are facing limb loss and who have no satisfactory options for bypass. An example is shown in Figure 9. This elderly diabetic patient with gangrene of the toes had occlusion of anterior tibial, posterior tibial, and peroneal arteries and no saphenous or upper extremity veins. A balloon angioplasty of the diffusely diseased and occluded anterior tibial artery was successful in restoring flow to the foot and allowed a transmetatarsal amputation to heal. Even though the anterior tibial artery restenosed eight months later, the transmetatarsal amputation remained fully healed and the patient was able to ambulate. The recent codification of reporting standards for endovascular procedures including angioplasty should facilitate future comparisons with existing surgical standards, and help clarify the relative indications for angioplasty (86). Despite technical issues, cost, and ongoing problems with restenosis, interest in non–angioplastyrelated endovascular procedures such as rotational arthrectomy, laser-mediated plaque obligation, and thermal- or laser-assisted angioplasty continues (87).

Surgical Revascularization Endarterectomy Endarterectomy is a surgical procedure in which the obstructing intimal plaque is removed from an artery to restore flow. The cleavage plane for endarterectomy is usually just below the internal elastic lamina, although the media below extensive plaque is often degenerated and is removed along with the intimal plaque. In these circumstances, the cleavage plane is at the external elastic lamina, and thus only the adventitial layer contains the blood stream. The adventitial layer alone provides sufficient structural support, and aneurysmal dilation of endarterectomized arterial segments does not occur. Although endarterectomy is the standard mode of treatment for carotid bifurcation atherosclerosis, it has a more limited usefulness in the treatment of peripheral vascular occlusive disease. This is because carotid plaques are

Figure 9 Angiogram of infrapopliteal arteries in a diabetic patient with gangrene of toe. (A) The posterior tibial and peroneal arteries are occluded in mid calf and the anterior tibial artery is diffusely narrowed with a focal occlusion. The distal anterior tibial artery reconstitutes by a large collateral vessel. (B) Following balloon angioplasty, the anterior tibial artery is patent with restoration of a normal dorsalis pedis pulse. The patient successfully healed a toe amputation.

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localized in the carotid bifurcation, whereas lower extremity atherosclerosis usually is extensive, with no discrete starting or end points. Some patients with localized aortoiliac disease and no distal occlusive disease are candidates for local aortoiliac endarterectomy, but bypass procedures are more commonly performed. If a local endarterectomy is to be considered, these patients must not have aneurysmal disease or fibrotic small-caliber vessels. Results of local aortoiliac endarterectomy compare favorably to aortobifemoral bypass grafts. Most surgeons occasionally use local endarterectomy as an adjunctive procedure to aortobifemoral bypass grafting. Such local endarterectomies are frequently performed in the common and profunda femoris arteries at the time of anastomosis of bypass grafts; but primary endarterectomies have limited usefulness in the peripheral circulation.

Bypass Procedures Procedures to bypass occlusive lesions are the standard surgical methods for treatment of lower extremity peripheral occlusive disease. Procedures are usually considered as inflow or outflow procedures, depending on the level of obstruction. Inflow procedures refer to those used for aortoiliac obstructions, and outflow procedures are those used for superficial femoral and popliteal artery obstructions, with the level of the inguinal ligament usually being the dividing line. Angiographic, vascular, laboratory, and clinical criteria are used to determine the primary level of obstruction. If a patient has both inflow and outflow disease, the proximal, or inflow, obstruction is treated first and usually is sufficient to relieve symptoms.

Aortofemoral Bypass The indications for surgical intervention in patients with aortoiliac occlusive lesions are severe claudication and limb-threatening ischemia as defined by rest pain, ulcerations, and gangrene. The standard surgical treatment for bypass of aortoiliac obstructions is the aortofemoral bypass graft (88). In this procedure, a knitted or woven Dacron bifurcation graft is sutured from the infrarenal aorta, which is usually free of disease, to the common femoral arteries. This graft bypasses the entire aortoiliac segment, which includes the inferior mesenteric artery and internal iliac arteries. The proximal anastomosis is placed just below the level of the renal arteries and may be performed in either an end-to-end or an end-to-side fashion (Fig. 10). When an end-to-end anastomosis is used, the distal aorta is ligated, and the entire aortic outflow passes through the graft. Blood is supplied to the distal aorta and the inferior mesenteric and internal iliac arteries by retrograde flow from the common femoral artery through the external iliac artery. With an end-to-side proximal anastomosis, blood flows in parallel in the bypass graft and in the distal aorta. This anastomosis is preferred when the external iliac arteries are occluded and would prevent retrograde fill of the aorta from the groin. The distal anastomosis is usually placed on the common femoral artery, with outflow through the superficial femoral and profunda femoris vessels. If there is associated superficial femoral artery occlusion, the profunda femoris artery alone can serve as the outflow bed, with relief of symptoms. Concomitant endarterectomy of the orifices of the superficial femoral and profunda femoris arteries can be undertaken to improve the distal anastomosis. Profundaplasty is performed by extending the opening of the common femoral artery onto the profunda femoris artery and suturing the Dacron graft onto the profunda femoris

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Figure 10 Aortofemoral bypass for aortoiliac obstruction. Proximal anastomosis may be performed end-to-end (A) or end-to-side of the aorta (B). With an end-to-end anastomosis, perfusion of the internal iliac arteries and distal aorta is retrograde from the common femoral artery in the groin.

artery. This results in enlargement of the lumen of the proximal profunda femoris artery and is useful when there is a stenosis at that site. Aortofemoral bypass graft is a stable and durable operation that effectively eliminates the inflow obstruction. Surgical mortality rate is less than 2%, and the five-year graft patency rate is greater than 90% (89). Should these operations fail, they generally do so because of progression of disease in the arteries at or distal to the groin anastomosis rather than because of failure of the Dacron graft itself. Early complications of aortobifemoral grafts are caused mainly by technical misadventures. These include postoperative hemorrhage, early graft thrombosis, distal embolization, groin hematomas, and lymph leaks. Longterm complications include graft infection, pseudoaneurysm formation, and aortoduodenal fistula. Details of these problems are expanded on below.

Extra-Anatomic Bypass Patients who require bypass of aortoiliac lesions but are too ill to withstand an intra-abdominal operation for placement of an aortobifemoral graft may be revascularized with an axillofemoral or femorofemoral bypass graft (Fig. 11). These operations are effective in relieving aortoiliac, or inflow, obstruction but do not require that the abdominal cavity be entered. The bypass is tunneled in the subcutaneous space, and incisions to expose the axillary and femoral vessels can be performed while the patient is under local anesthesia. Thus they are safer and more amenable to use in high-risk patients. Axillofemoral bypass grafts are also useful to bypass the aorta in situations of infection within the abdominal cavity. There is no steal of blood from the upper extremity when an axillofemoral bypass is placed because there is an increase in flow in the feeding subclavian artery. This increase is sufficient to supply the arm and both legs. However, the great length of the axillofemoral graft makes it prone to thrombosis. Recent reports suggest that the long-term patency of axillofemoral bypass grafting supports its use in highly selected cases when in-line anatomic reconstruction is less desirable (90). However, proximal anastomotic disruption remains a serious though infrequent complication (91). Afemorofemoml bypass graft can be used to bypass an iliac artery occlusion if the opposite patent iliac artery is

Figure 11 Illustration of extra-anatomic bypasses for aortoiliac obstruction. Axillofemoral bypass graft courses in the subcutaneous space in the midaxillary line and brings blood from the subclavian artery to the femoral artery to bypass an aortic obstruction. Femorofemoral bypass graft brings blood from one femoral artery across to the other. ‘‘Steal’’ phenomenon does not occur if there is no obstruction to the inflow of the donor artery.

disease free. In this situation, one iliac artery is able to deliver enough flow to supply both legs. Five-year patency rates for femorofemoral grafts vary from 44% to 74%. Axillofemoral bypass grafts have a poorer patency rate than aortofemoral grafts, with five-year patency rates reported near 75% (92). These grafts fail more commonly than an aortobifemoral graft because of their longer course and the risk of external compression in the subcutaneous tunnel. Thus extra-anatomic grafts should be considered only when endovascular treatments, aortobifemoral grafts, or local aortoiliac endarterectomies are not feasible.

Femoropopliteal and Femoral Distal Bypass Grafts Claudication or severe ischemia of the legs despite a good aortoiliac segment is usually the result of obstruction of the superficial femoral or popliteal artery and its branches. A preoperative angiogram demonstrates which distal vessels are patent and of adequate caliber to accept a bypass graft. If the popliteal artery is patent with runoff through at least one of the tibial vessels, a femoropopliteal bypass graft is the procedure of choice. If the popliteal artery is occluded, bypass should be performed to the tibial artery that best fills the plantar arch. The saphenous vein is the most suitable conduit for bypasses below the inguinal ligament. It may be used as a reversed or in situ vein bypass (Fig. 12). In a reversed saphenous vein femoropopliteal bypass graft, the saphenous vein is excised, and all branches are ligated and divided. The vein position is reversed so that the distal end of the vein is sewn to the common femoral artery, whereas the proximal portion of the vein is sewn to the popliteal artery. This permits arterial flow to course in the vein in the direction of the valves. An in situ vein bypass graft is left in its normal position (93). The proximal vein is sewn to the common femoral artery, and the distal portion is sewn to the popliteal (or

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sympathectomy was the chief surgical therapeutic approach for peripheral occlusive disease. With progressive improvement in the ability to directly revascularize ischemic tissue, lumbar sympathectomy has fallen into disfavor. It has no beneficial effect in the treatment of claudication but has been reported to improve rest pain in approximately 50% of patients. It has been shown to increase cutaneous, but not muscle, blood flow and thus has been recommended for the treatment of ischemic ulcers. Some surgeons use sympathectomy as an adjunct to arterial reconstruction, believing that sympathectomy adds to the total improvement of blood flow to the extremity by causing vasodilation in the small vessels of the foot. However, there is little evidence that there is improved flow over and above the benefit derived from arterial reconstruction alone. In addition, there are potential complications of lumbar sympathectomy, including postsympathectomy neuralgia and failure of ejaculation. Although sympathectomy has limited usefulness in the treatment of arteriosclerosis obliterans, it is effective in the treatment of causalgia and hyperhidrosis.

Embolectomy/Thrombectomy

Figure 12 Saphenous vein bypass grafts in the lower extremity for treatment of femoropopliteal occlusions. These may be performed as a reversed saphenous vein bypass graft (A) or an in situ saphenous vein bypass graft (B). In the in situ bypass graft, the saphenous vein valves must be cut to render them incompetent. Selection of the site of distal anastomosis depends on angiographic demonstration of the patency of distal arteries.

tibial) artery. To permit blood to flow in the vein against the direction of the valves, the valve leaflets must be cut to render them incompetent. The in situ graft avoids extensive dissection of the vein, provides a better size match between the smaller distal artery and vein, and allows the use of smaller veins that might not be suitable for reversed vein bypass. Autogenous vein is far superior to prosthetic materials in all infrainguinal positions, and every effort should be made to use the vein, even if the arm veins or lesser saphenous veins are employed. Limb salvage rate for patients undergoing femoropopliteal bypass grafting with autogenous tissue is 73% at four years; for femoral distal bypass grafts, limb salvage is 80% at four years (94). The limb salvage rates are usually 15% higher than the actual graft patency rates. The patency of each individual graft depends on the adequacy of inflow, the type of graft material used, the quality of the outflow vessels, and the technical aspects of the procedure (94). The complications of femoropopliteal and femoral distal bypass grafts are similar to those associated with an aortobifemoral procedure. Early thrombosis is the most serious early problem and usually represents technical error or inadequate runoff vessels. Prompt thrombectomy and recognition of the technical problem returns function to the graft but usually results in reduction of long-term patency (95).

Sympathectomy Lumbar sympathectomy produces vasomotor paralysis, which increases blood flow by decreasing peripheral resistance. Before the advent of direct arterial surgery,

Acute arterial occlusion with severe ischemia may be caused by emboli, which usually arise from the heart, or by thrombosis of a diseased artery. In addition to the ischemia caused by the embolus, the limb is threatened by propagation of thrombus in the arteries distal to the embolus where blood flow is slow. Therefore patients with acute arterial occlusion should be immediately anticoagulated with heparin. In addition to preventing clot propagation, anticoagulation helps prevent recurrent embolization from the heart. Removal of the obstructing embolus is readily accomplished using the Fogarty balloon catheter (Fig. 13). An incision is made in the femoral artery, and the catheter with the balloon deflated is passed through the thrombus. The balloon is then inflated, and the clot extracted. This procedure is very effective in removing fresh thrombus and restoring blood flow in patients with embolism. However, bypass may be required to restore flow in patients who have thrombosis induced by severe stenotic plaques.

Figure 13 Fogarty balloon catheter embolectomy. Deflated balloon is passed through the thromboembolus. Balloon is inflated and withdrawn, and the embolus is extracted from the artery.

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Percutaneous catheter-directed thrombolysis may be used as initial therapy for patients with acute arterial ischemia due to embolization or thrombosis and intact neuromuscular function. Thrombolytic agents such as streptokinase, urokinase, and recombinant tissue plasminogen activators (alteplase and recombinant plasminogen activatorreteplase) induce a systemic fibrinolytic state and carry a risk of inducing hemorrhage. However, the risk of hemorrhage may be reduced by direct infusion of the thrombolytic agent into the clot, using an infusion catheter. Such catheterdirected thrombolysis has been shown to be effective in removing thrombus, reducing the need for subsequent surgery and improving limb salvage in three prospective randomized clinical trials (96).

ANEURYSMAL DISEASE OF THE AORTA The abdominal aorta is particularly vulnerable to aneurysm formation and contains 90% of all aneurysms. Aneurysms are usually located in the infrarenal abdominal aortic segment, with sparing of the first 1 to 2 cm below the level of the renal arteries. Aneurysms are usually clinically silent but may enlarge, cause symptoms, and rupture.

Cause of Aortic Aneurysms Special anatomic features of the infrarenal abdominal aorta may make it vulnerable to the development of aneurysms. The aortic media is composed of groups of smooth muscle cells surrounded by layers of elastin in a network of collagen fibers. The elastin layers serve to allow distensibility of the aortic wall in pulse propagation, whereas the collagen fibers provide tensile strength and prevent overdistention and rupture. The number of medial lamellar units increases proportionally with the aortic diameter to support the tensile stress. The aortic media is nourished by diffusion from the lumen to a depth of approximately 29 medial lamellar units (97). However, if the aorta is thicker than 29 layers, adventitial vasa vasorum penetrate the media to supply nutrition. The relationship between the number of medial layers and the depth of penetration of vasa vasorum in the aortic media applies to both the thoracic aorta and abdominal aortic segment in most mammals. However, the human abdominal aorta is a noticeable exception in that it contains fewer lamellar units than would be expected for its diameter and the media is devoid of vasa vasorum (98). Thus each layer is thicker than expected and sustains an increased tension per lamellar unit. This may make the aorta vulnerable to relative ischemic injury of the medial smooth muscle cells, leading to medial atrophy in aneurysm formation (99). Atherosclerotic plaques are also prone to develop in the infrarenal abdominal aorta and may be a factor in aneurysm formation. Intimal plaques may obstruct diffusion of nutrients from the lumen to the media. Usually there is ingrowth of new medial vasa vasorum to supply the media and plaque under these circumstances. When this does not occur, aneurysmal degeneration may take place because of inadequate medial nutrition. Vasa vasorum usually arise from the renal arteries, and the immediate infrarenal aortic segment may have a better vasa vasorum supply than the rest of the aorta. This may explain the relative protection from aneurysm formation in this area. Other etiologic factors in aneurysm formation have been proposed, including increased elastase or collagenase activity, hemodynamic factors in the infrarenal aorta, and genetic predisposition.

Aneurysms are also found in the femoral and popliteal arteries, although much less commonly. Patients with peripheral aneurysms usually have coexistent abdominal aortic aneurysms, suggesting a more general aneurysmal diathesis.

Clinical Manifestations The biologic fate of an aneurysm of the abdominal aorta is to increase in size with eventual rupture. When first detected in a patient, aneurysms may be asymptomatic, symptomatic, or ruptured. In addition, slow flow within the dilated aneurysm may result in thrombus formation along the wall, which occasionally may totally occlude the lumen, causing acute ischemia, or may embolize to the distal arterial vasculature. The prevalence of aneurysms increases with age. Aneurysms are more common in men than in women and approximately 1 in 10 men over the age of 75 will have an aneurysm.

Asymptomatic Aneurysms Aneurysms are remarkable by their clinical silence in the majority of cases. Asymptomatic aneurysms are frequently discovered by palpating a pulsatile mass during physical examination of the abdomen. Because the aortic bifurcation is located at the level of the umbilicus, the pulsatile mass is usually in the epigastrium. However, aneurysms less than 5 cm in diameter are difficult to palpate, especially in corpulent people; most aneurysms are discovered incidentally during ultrasound X ray or CT examination for gastrointestinal, genitourinary, orthopedic, or other lesions. The best screening test for abdominal aortic aneurysms is an abdominal ultrasound examination (100). The single most important prognostic feature of asymptomatic abdominal aortic aneurysms is the size, or transverse diameter. The absolute risk of rupture related to size is unknown. Best estimates suggest that small abdominal aortic aneurysms less than 4 cm in diameter have a low risk of rupture whereas aneurysms greater than 8 cm in diameter have a 75% risk of rupture within five years (Fig. 14).

Figure 14 Relationship between the five-year risk of rupture and the diameter of infrarenal abdominal aortic aneurysms. A 6-cm abdominal aneurysm has a 30% risk of rupturing within five years.

Chapter 44: Aorta and Arterial Disease of the Lower Extremity

Enlarging and Symptomatic Aneurysms Aneurysms tend to progressively enlarge because of the increased tension on and thinning of the artery wall. If this process is slow, symptoms do not appear or are very late in appearing. If, however, enlargement is relatively rapid, symptoms of pain may arise as a result of pressure on the somatic sensory nerve elements of the retroperitoneal soft tissue in the vicinity of the aneurysmal sac. The pain is usually severe, constant, unrelated to posture, and boring in character; it is most commonly located in the lumbar spine region, in the midabdomen, or in the pelvis. Such symptoms indicate the impending rupture of the aneurysm and require immediate clinical attention. Serial follow-up examinations using clinical and radiologic methods identify the patient with an aneurysm that is expanding and yet asymptomatic. The rate of enlargement can be variable and unpredictable. The mean rate of expansion of infrarenal abdominal aortic aneurysms is 0.4 cm/yr (101); however, some do not change at all, whereas others enlarge at twice that rate.

Ruptured Aneurysms Aneurysms may rupture into the retroperitoneal space, with the development of severe back pain and sudden hypotension. If the rupture occurs anteriorly, free intraperitoneal hemorrhage results, with rapid exsanguination and death. Rupture can also occur into the inferior vena cava, resulting in the development of an aortocaval fistula with hypotension and an elevated central venous pressure. Approximately 50% of patients who sustain aneurysm rupture die suddenly, before medical help can arrive. Of those who survive to reach the hospital, mortality rates range from 50% to 80%. For patients who are stable with normal blood pressure, operative mortality may be as low as 10%. However, patients who are in shock and have required cardiopulmonary resuscitation have mortality rates approaching 90%. Thus, overall mortality rates for ruptured aortic aneurysms are in the range of 80% to 90%. On physical examination, ruptured aneurysms, even large ones, may be difficult to palpate because of hypotension and because the aortic aneurysm is often diffuse and ill defined as a result of obliteration of the margins of the aneurysm by retroperitoneal hematoma.

Diagnosis The diagnosis of abdominal aortic aneurysm may be made on physical examination. However, physical examination commonly overestimates the true size of the aneurysm by 1 to 2 cm when compared to ultrasound or CT examination. A cross table lateral X-ray may demonstrate a rim of calcium outlining the anterior wall of the abdominal aorta and indicate the presence of an aneurysm. This X-ray film is taken with the patient lying supine, with the X-ray beam running horizontally, allowing intestinal gas to rise superiorly and the retroperitoneum to be visualized. Physical examination and a lateral X-ray film were in the past the predominant methods of evaluation for an abdominal aortic aneurysm. However, in view of the new development of ultrasound, the lateral abdominal X-ray film is currently used infrequently. B-mode ultrasound is the most commonly used method of diagnosing an abdominal aortic aneurysm. It is simple, safe, noninvasive, and accurate and can be readily repeated for serial evaluation of aneurysms. It provides information on the presence or absence of an aneurysm and on the transverse diameter, length, and presence or absence of mural

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thrombus. It is the procedure of choice for routine evaluation for aneurysm. CT scan provides better resolution and imaging of aneurysms than does ultrasound, especially when intravenous contrast enhancement is used. It provides the most detailed evaluation of the aortic wall and mural thrombus and the most accurate assessment of aneurysm size and characteristics of the infrarenal aortic neck. It also allows the evaluation of retroperitoneal extravasation and rupture. The CT scan offers significant advantages over ultrasound in assessing the thoracoabdominal aorta, because ultrasound does not pass through the air in the lung and cannot visualize the thoracic aorta. Thus it is particularly helpful in assessing thoracoabdominal aneurysms. In addition, CT is very useful in evaluating the pelvis for the presence of internal iliac aneurysms. CT scanning is essential for preoperative planning for endovascular aneurysm repair. Angiography is useful in the evaluation of abdominal aortic aneurysms but provides little information on aneurysm size because only the aortic lumen is visualized. Aneurysms frequently contain mural thrombus, which may result in a normal or relatively normal lumen contour and diameter. This mural thrombus provides no structural strength to the aortic wall, and such aneurysms are just as likely to rupture as those without extensive mural thrombosis. CT scanning has largely replaced angiography in the evaluation of aortic aneurysms and provides, other important information regarding (i) accurate assessment of the proximal extent of the aneurysm in relation to the renal arteries, (ii) the status of the renal arteries and the presence of accessory renal arteries arising from the aneurysm itself, (iii) the inferior mesenteric artery and its collateral blood supply to the left colon, (iv) coexistent occlusive disease of the iliac and femoral vessels, and (v) identification of congenital abnormalities of the kidneys such as horseshoe kidney.

Treatment Indications for Surgery Indications for surgical repair of abdominal aortic aneurysms depend on the presence or absence of symptoms, the size of the aneurysm, and the general medical condition of the patient. If a patient has a ruptured aortic aneurysm, immediate surgical treatment is imperative. No diagnostic tests should be performed, and resuscitation should be carried out in the operating room. Fluid resuscitation may be useful during transport. Patients with symptoms attributable to an aneurysm but without hypotension or signs of rupture should undergo confirmatory CT examination and urgent operative repair of the aneurysm. Similarly, if there is evidence of rapid enlargement of the aneurysm on routine physical examination or imaging follow-up such as B-mode ultrasound, urgent repair of the aneurysm is advised. The absolute size of the aneurysm also determines whether repair should be undertaken. Studies of the natural history of aneurysms reveal that the risk of rupture of untreated aneurysms is directly proportional to their size (102,103). Aneurysms greater than 5 cm in transverse diameter as measured by ultrasound or CT scan or aneurysms that have more than twice the diameter of the adjacent, nonaneurysmal aorta should be surgically repaired if the patient has no medical contraindications to surgery, such as severe cardiac, pulmonary, renal, or neoplastic disease. However, it must be realized that aneurysms smaller than 5 cm can also rupture and must be carefully observed.

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Surgical Repair The surgical treatment of an abdominal aortic aneurysm consists of excluding the aneurysm from the circulation and replacing it with a Dacron prosthetic bypass graft. The aorta is clamped proximal to the aneurysm, below the level of the renal arteries, and distal to the aneurysm. The aneurysm sac is opened, and the graft is sutured to the normal, nonaneurysmal aorta from within the aneurysm. The graft may be a straight ‘‘tube’’ graft confined to the abdominal aorta or a bifurcation graft to the iliac arteries if the aortic bifurcation and iliac arteries are involved (Fig. 15). The aneurysm sac is not excised but closed over the graft after it is in place to isolate the graft from the bowel. This prevents possible erosion of the bowel, aortoduodenal fistula formation, and graft infection. The inferior mesenteric artery, which always arises from the aneurysm, is usually ligated. Collateral circulation from the celiac and superior mesenteric arteries and internal iliac arteries maintains flow to the sigmoid colon. Occasionally, when collateral flow is insufficient, the inferior mesenteric artery must be reimplanted into the bypass graft to avoid colonic ischemia.

Endovascular Aneurysm Repair During the past decade a new less invasive strategy for treating aortic aneurysms has been introduced. This strategy involves the transfemoral placement of self-expanding endoluminal devices to exclude the aneurysm from the circulation. The first FDA-approved devices appeared in 1999 and favorable long-term results extending to six years and longer have been reported (104). All current FDA-approved devices are self-expanding, bifurcated, modular stent grafts that are introduced through the femoral arteries and deployed under fluoroscopic image guidance. Endovascular aneurysm repair requires a suitable infrarenal aortic neck and iliac arteries to allow secure fixation and sealing of the endovascular device (Fig. 16). Precise preoperative imaging with high-quality CT scanning and 3-D image reconstruction is required to select appropriate candidates for endovascular repair. Because endovascular aneurysm repair requires only groin exposure of the femoral arteries, the procedure can be performed in elderly, high-risk patients who are not suitable candidates for open surgical repair. However, not all patients with infrarenal aortic aneurysms are suitable candidates for endovascular repair because of adverse morphologic features such as a short (28 mm) aortic neck, iliac aneurysms, or iliac stenosis. Thus, careful preoperative

Figure 15 Repair of abdominal aortic aneurysm. Aneurysm sac is opened, and a Dacron graft is sutured to the normal, nonaneurysmal artery. Aneurysm is not excised, but it is excluded from the circulation.

Figure 16 (A) Three-dimensional reconstruction of spiral computed tomography (CT) scan demonstrating a 5.8 cm-abdominal aortic aneurysm. (B) CT scan following endovascular aneurysm repair using a stent graft.

patient evaluation and planning are required to obtain satisfactory results.

Results: Open vs. Endovascular Repair Both open and endovascular aneurysm repair are highly effective in achieving the primary objective of aneurysm repair, namely prevention of aneurysm rupture. Operative mortality for elective open surgical repair is approximately 5% to 6% (105,106) although elective operative mortality rates of less than 2% are reported from high-volume specialized centers (107–109). Operative mortality for endovascular aneurysm repair is 1% to 2% even though most series include high-risk patients who would not be candidates for open surgical repair (106). Two recent prospective randomized trials comparing open to endovascular repair in good-risk patients revealed a statistically significant reduction in operative mortality in patients undergoing endovascular repair (1–2%) compared to patients undergoing elective open repair (4–5%) (110,111). In addition to reduced operative mortality, there is a significant reduction in morbidity following endovascular repair, with a reduction in blood loss and transfusion requirements, shorter intensive care unit and hospital stay, and earlier return to function. Thus, endovascular repair has significant shortterm advantages over open surgical repair and is favored for most patients who have suitable anatomy (112). However, the long-term outcome of endovascular repair is uncertain, because long-term outcome data is limited. Adverse outcomes of endovascular aneurysm repair include continued blood flow in the aneurysm sac (endoleak), device migration over time, aneurysm enlargement, and possible late rupture. These adverse events may require secondary procedures, including possible conversion to standard open repair in the future. Although open surgical repair appears to be needed in no more than 5% of patients at five years, more complete long-term outcome analysis will be required to fully define the role of endovascular aneurysm repair.

Chapter 44: Aorta and Arterial Disease of the Lower Extremity

Regardless of the mode of therapy, elective aortic aneurysm repair has far better results than emergent repair of ruptured aortic aneurysms. Operations for ruptured abdominal aortic aneurysms have a mortality rate of 50% to 80% or higher (105,109,113). Thus, every effort should be made to repair abdominal aortic aneurysms before rupture. Improved operative techniques with better preoperative and perioperative care, including central hemodynamic monitoring, earlier diagnosis, improvements in fluid management, and refinements in anesthesia techniques, have allowed elective aneurysm repair to be carried out with a similar low mortality rate even in octogenarians (114). Thus, age alone is not a contraindication to aneurysm repair. The long-term survival of patients who have undergone abdominal aortic aneurysm repair is approximately 60% at five years (106). Associated coronary artery disease is responsible for the majority of deaths in the long-term follow-up of these patients. In a matched group, the expected five-year survival is 80% (108). It is possible that with more aggressive treatment of coexistent coronary disease this mortality rate can be decreased. The overall survival and long-term outlook with elective repair of abdominal aortic aneurysms is significantly better than that for nonsurgical treatment.

PERIPHERAL ARTERY ANEURYSMS Although it is not common, aneurysms can form in arteries other than the aorta. The most commonly involved peripheral arteries are the common femoral and popliteal arteries, which together account for 90% of all peripheral aneurysms. The popliteal artery accounts for 70% of these aneurysms. Popliteal aneurysms are unique in that they are found almost exclusively in males, and the vast majority are atherosclerotic in origin. Approximately two-thirds of the patients have bilateral aneurysms, with one-half of these patients having associated abdominal aortic aneurysms. Popliteal aneurysms are usually symptomatic when discovered, and over 50% have complications at the first medical visit (114). The most common complication is thrombosis of the aneurysm, which is associated with a 33% amputation rate. Embolization of mural thrombus from within the aneurysm to the distal arterial tree also occurs and is associated with a high amputation rate. Rupture of popliteal aneurysms is unusual but can occur. Compression of the popliteal vein with lower extremity edema and neurologic pain syndromes from nerve compression are also possible. Treatment of popliteal aneurysms consists of ligation of the aneurysm to exclude it from the circulation, followed by bypass grafting from the femoral artery to either the popliteal or tibial vessels. Results of surgery are influenced by the status of the leg at the time of presentation and the extent of coexistent occlusive disease in the tibial vessels and vessels of the foot. If these are obstructed because of prior and repeated embolization from the aneurysm, prospects for revascularization are poor. There is minimal risk for limb loss in patients with asymptomatic aneurysms, but 34% of limbs are lost if the patient initially has symptoms (114). Therefore, popliteal aneurysms should be repaired electively when found, before symptoms of embolization or thrombosis occur. Femoral artery aneurysms are similarly found in elderly men and are caused by atherosclerosis. Associated hypertension is extremely common. Associated abdominal aortic aneurysms are present in 51% to 85% of patients (115,116) and associated popliteal aneurysmare present in 17% to 44%

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of patients (116,117), suggesting an aneurysmal diathesis. As in the popliteal artery, symptoms may be caused by local pressure from the expanding aneurysm on the adjacent femoral vein or nerve, distal embolization, acute or chronic thrombosis, or rupture of the aneurysm. Because of the risk for limb loss from acute thrombosis and distal embolization, surgical management of these aneurysms is advised in all patients who are reasonable medical risks. Surgical techniques include replacement of the aneurysm with an interposition graft (118).

COMPLICATIONS OF VASCULAR PROCEDURES Complications following vascular procedures fall into two categories: those involving the generalized disease process of atherosclerosis and those involving local factors related to the vascular procedure or bypass graft. The generalized process of atherosclerosis involves not only the peripheral arteries but also the carotid and coronary arteries. The risk factors of hypertension, hyperlipidemia, diabetes mellitus, and cigarette smoking are important in determining whether there is disease progression, stabilization, or regression, and control of these factors is important. The major cause of morbidity and mortality in the vascular surgical patient is disease progression in the coronary arteries, with myocardial infarctions accounting for the majority of deaths in these patients despite successful peripheral vascular procedures. Stroke from progression of cerebrovascular disease is also a major problem. These same risk factors play a major role in the progression of distal disease following bypass grafts and are a common reason for restenosis and subsequent graft occlusion and its related morbidity. Local factors related to vascular procedures may produce a number of complications following vascular procedures. Graft thrombosis in the early postoperative period may be the result of a technical error in the graft-to-artery anastomosis or caused by an obstructed outflow bed with slow flow in the graft. Late graft occlusion is usually caused by progression of atherosclerotic occlusive disease in the inflow or outflow vessels or by a hypertrophic proliferative response of intima at the anastomosis and can usually be corrected by reoperation. Pseudoaneurysms may form at the sites of vascular anastomoses and must be distinguished from true aneurysms that involve dilation of all layers of the artery wall. In a pseudoaneurysm, there is separation of the vascular graft from the artery wall, and the blood stream is contained by surrounding fibrous tissue. The integrity of an anastomosis of prosthetic graft to artery is forever dependent on the integrity of the suture line. Failure of the suture or excess tension on the suture line can result in the disruption of the anastomosis with pseudoaneurysm formation. In addition, anastomotic breakdown with pseudoaneurysm formation may be a harbinger or sign that infection of the prosthetic bypass graft has occurred. Treatment of a pseudoaneurysm mandates replacement of that segment with a prosthetic graft if it is not infected. However, infected grafts must be totally removed because prosthetic grafts are foreign bodies and infection cannot be eradicated until all foreign material is excised. Revascularization under these circumstances is complex and usually involves the use of an ‘‘extra-anatomic’’ bypass in a clean, noninfected area. An example of such a bypass is an axillofemoral bypass to bypass an infected intra-abdominal aortoiliac bypass graft.

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SUMMARY Atherosclerosis is a degenerative disease process that affects the aorta and peripheral arteries, as well as coronary and carotid arteries. It can result in occlusive disease, obstructing the lumen, or aneurysmal disease, with dilation of the lumen. Occlusive disease can result in stenosis and diminished blood flow or embolization with occlusion of distal arteries. Obstruction of blood flow can result in ischemia of the lower extremities, producing symptoms of claudication, rest pain, ulceration, or gangrene. Obstructions can be detected with the use of clinical, noninvasive, and angiographic diagnostic techniques. Revascularization of the lower extremities with a bypass or with transluminal balloon angioplasty can restore circulation and help avoid limb loss. Aneurysmal disease results in progressive arterial enlargement and weakening of the aortic wall, with eventual rupture unless the patient dies of intercurrent disease. The larger the aneurysm, the higher the risk of rupture. Most aneurysms are asymptomatic and are detectable by noninvasive techniques. Operative replacement of aneurysmal segments of artery with a Dacron graft or endovascular aneurysm repair prevents further degeneration and aneurysm rupture.

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Chapter 44: Aorta and Arterial Disease of the Lower Extremity

40. 41.

42. 43.

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65. Napel S, Rubin GD, Jeffiey RB Jr. STS-MIP: a new reconstruction technique for CT of the chest. J Comput Assist Tomogr 1993; 17:832. 66. Marks MP, et al. Diagnosis of carotid artery diseases: preliminary experience with maximum intensity projection spiral CT angiography. Am J Roentgenol 1993; 160:1267. 67. Boll DT, Lewin JS, Fleiter TR, Duerk JL, Merkle EM. Multidetector CTangiography of arterial inflow and runoff in the lower extremities: a challenge in data acquisition and evaluation. J Endovasc Ther: Official J Int Soc Endovasc Specialists 2004; 11(2):144–151. 68. Carpenter JP, et al. Peripheral vascular surgery with magnetic resonance angiography as the sole preoperative imaging modality. J Vasc Surg 1994; 20:861. 69. Debatin JE, et al. Phase contrast MRI assessment of pedal blood flow. Eur Radiol 1995; 194:321. 70. Li KCP, et al. Oxygen saturation of blood in the superior mesenteric vein: in vivo verification of MR imaging measurements in a canine model. Radiology 1995; 194:321. 71. Li KCP, et al. Simultaneous measurement of flow in the superior mesenteric vein and artery with cine phase-contrast MR imaging: value in diagnosis of chronic mesenteric ischemia. Radiology 1995; 194:327. 72. Peabody CN, Kannel WB, McNamara PM. Intermittent claudication: surgical significance. Arch Surg 1974; 109:693. 73. Ingolfsson IO, Sigurdsson G, Sigvaldason H, Thorgeirsson G, Sigfusson N. A marked decline in the prevalence and incidence of intermittent claudication in Icelandic men 1968–1986: a strong relationship to smoking and serum cholesterol—the Reykjavik Study. J Clin Epidemiol 1994; 47(11):1237–1243. 74. Jonason T, Bergstrom R. Cessation of smoking in patients with intermittent claudication. Effects on the risk of peripheral vascular complications, myocardial infarction and mortality. Acta Med Scand 1987; 221(3):253–260. 75. Ameli FM, Stein M, Provan JL, Prosser R. The effect of postoperative smoking on femoropopliteal bypass grafts. Ann Vasc Surg 1989; 3(1):20–25. 76. Pedersen TR, Kjekshus J, Pyorala K, et al. Effect of simvastatin on ischemic signs and symptoms in the Scandinavian simvastatin survival study (4S). Am J Cardiol 1998; 81(3):333–335. 77. Stoyioglou A, Jaff MR. Medical treatment of peripheral arterial disease: a comprehensive review. J Vasc Interv Radiol 2004; 15(11):1197–1207. 78. Group UPDSU. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group [see comment] [erratum appears in Lancet 1999 Aug 14; 354(9178):602]. Lancet 1998; 352(9131):837–853. 79. Smith CD, McKendry RJ. Controlled trial of nifedipine in the treatment of Raynaud’s phenomenon. Lancet 1982; 2:1299. 80. Porter JM, et al. Pentoxifylline efficacy in the treatment of intermittent claudication. Am Heart J 1982; 104:66. 81. Thompson PD, Zimet R, Forbes WP, Zhang P. Meta-analysis of results from eight randomized, placebo-controlled trials on the effect of cilostazol on patients with intermittent claudication. Am J Cardiol 2002; 90(12):1314–1319. 82. Zarins CK, et al. Arterial disruption and remodeling following dilatation. Surgery 1982; 92:1086. 83. Yalcin R, Erkan A, Ergun MA, Yurtcu E. The effect of clopidogrel on apoptosis an in vivo study. Cell Biol Int 2004; 28(6):477–481. 84. Douglas JS, Weintraub WS, Holmes D. Rationale and design f the randomized, multicenter, cilostazol for RESTenosis (CREST) trial. Clin Cardiol 2003; 26(10):451–454. 85. (TASC) TI-SC. Treatment of intermittent claudication in Management of Peripheral Arterial Disease (PAD). J Vasc Surg 2000; 31(1):S77. 86. Ahn SS, et al. Reporting standards for lower extremity arterial endovascular procedures. J Vasc Surg 1993; 17:1103. 87. Dalman RL, Taylor LM, Porter JM. Current status of extracoronary endovascular procedures. Ann Vasc Surg 1990; 3:1. 88. Rutherford RB. Aortofemoral bypass: the gold standard. Technical considerations. Semin Vasc Surg 1994; 7:11.

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89. Brewster DC, Darling RC. Optimal methods of aortoiliac reconstruction. Surgery 1978; 84:739. 90. Taylor CM, et al. Axillofemoral grafting with externally supported PTFE. Arch Surg 1994; 129:588. 91. Taylor CM, et al. Acute disruption of polytetrafluoroethylene grafts adjacent to axillary anastomosis: A complication of axillofemoral grafting. J Vasc Surg 1994; 20:520. 92. Farm JI, Harris EJ, Dalman RL. Extra-anatomic bypass. Ann Vasc Surg 1993; 7:378. 93. Corson JD, et al. In situ vein bypasses to distal tibial and limited outflow tracts for limb salvage. Surgery 1984; 96:756. 94. Dalman RL, Taylor CM. Basic data regarding intrainguinal revascularization procedures. Ann Vasc Surg 1990; 4:309. 95. Craver JM, et al. Hemorrage and thrombosis as early complications of femoropopliteal bypass grafts: causes, treatment, and prognostic implications. Surgery 1971; 74:839. 96. Giannini D, Balbarini A. Thrombolytic therapy in peripheral arterial disease. Curr Drug Targets Cardiovasc Haematol Disord 2004; 4(3):249–258. 97. Wolinsky H, Glagov S. Nature of species differences in the medial—distribution of aortic vasa vasorum in mammals. Circ Res 1967; 20:409. 98. Wolinsky H, Glagov S. Comparison of abdominal and thoracic aortic medial structure in mammals: deviation of man from the usual pattern. Circ Res 1969; 25:677. 99. Zarins CK, Glagov S. Aneurysms and obstructive plaques: differing local response to atherosclerosis. In: Bergan JJ, Yao JST, eds. Aneurysms: Diagnosis and Treatment. New York: Grune & Stratton, 1982. 100. Lederle FA. Ultrasonographic screening for abdominal aortic aneurysms.[see comment][erratum appears in Ann Intern Med. 2003 Nov 18;139(10):873]. Ann Intern Med 2003; 139(6): 516–522. 101. Bernstein EF, et al Growth rates of small abdominal aortic aneurysms. Surgery 1976; 80:765. 102. Bernstein EF. The natural history of abdominal aortic aneurysms. In: Najarian JS, Delaney JP, eds. Vascular Surgery. Miami, Florida: Symposia Specialists, 1978. 103. Szilagyi DE, Elliott JP, Smith RE. Clinical fate of patients with asymptomatic abdominal aortic aneurysm and unfit for special treatment. Arch Surg 1972; 104:600. 104. Zarins CK. Aneu Rx Clinical I. The US AneuRx Clinical Trial: 6-year clinical update 2002. J Vasc Surg 2003; 37(4):904–908. 105. Zarins CK, Harris EJ Jr. Operative repair for aortic aneurysms: the gold standard. J Endovasc Surg 1997; 4(3):232–241.

106. Zarins CK, Heikkinen MA, Lee ES, Alsac JM, Arko FR. Shortand long-term outcome following endovascular aneurysm repair. How does it compare to open surgery? J Cardiovasc Surg (Torino) 2004; 45(4):321–333. 107. DeBakcy MD, et al. Aneurysms of the abdominal aorta: analysis of results of graft replacement therapy one to eleven years after operation. Ann Surg 1964; 160:622. 108. Thompson JE, et al. Surgical management of abdominal aortic aneurysms: factors influencing mortality and morbidity—a 20 year experience. Ann Surg 1975; 188:654. 109. Brewster DC, Cronenwett JL, Hallett JW Jr, Johnston KW, Krupski WC, Matsumura JS, Joint Council of the American Association for Vascular S, and Society for Vascular S. Guidelines for the treatment of abdominal aortic aneurysms. Report of a subcommittee of the Joint Council of the American Association for Vascular Surgery and Society for Vascular Surgery. J Vasc Surg 2003; 37(5):1106–1117. 110. Prinssen M, Verhoeven EL, Buth J, et al. Dutch Randomized Endovascular Aneurysm Management Trial G. A randomized trial comparing conventional and endovascular repair of abdominal aortic aneurysms. [see comment]. N Eng J Med 2004; 351(16):1607–1618. 111. Greenhalgh RM, Brown LC, Kwong GP, Powell JT, Thompson SG, participants Et. Comparison of endovascular aneurysm repair with open repair in patients with abdominal aortic aneurysm (EVAR trial 1), 30-day operative mortality results: randomised controlled trial. [see comment]. Lancet 2004; 364(9437):843–848. 112. Lee WA, Carter JW, Upchurch G, Seeger JM, Huber TS. Perioperative outcomes after open and endovascular repair of intact abdominal aortic aneurysms in the United States during 2001. J Vasc Surg 2004; 39(3):491–496. 113. Garrett HE, Ilabaca PA. The ruptured abdominal aortic aneurysm. In: Bergan JJ, Yao JST, eds. Aneurysms: Diagnosis and Treatment. New York: Grune & Stratton, 1982. 114. Evans WE, Conley JE, Bernhard V. Popliteal aneurysms. Surgery 1971; 70:762. 115. O’Donnel TF Jr, Darling RC, Linton RR. Is 80 years too old for aneurysmectomy? Arch Surg 1976; 111:1250. 116. Cutler BS, Darling RC. Surgical management of arteriosclerotic femoral aneurysms. Surgery 1973; 74:764. 117. Graham L, et al. Clinical significance of arteriosclerotic femoral artery aneurysms. Arch Surg 1973; 115:502. 118. Baud RJ, et al. Arteriosclerotic femoral artery aneurysms. Can Med Assoc J 1977; 117:1306.

45 Cerebrovascular Disease and Upper-Extremity Vascular Disease Bruce L. Gewertz and James F. McKinsey

INTRODUCTION

CEREBRAL BLOOD FLOW Anatomy

In each calendar year, nearly 500,000 people in the United States suffer cerebral infarctions; in 175,000 patients, the strokes are fatal, and the remaining patients experience variable disability. The emotional and economic consequences of advanced cerebrovascular disease are staggering; the cost of care and loss of earnings secondary to permanent disability or death have been estimated at more than $10 billion annually. In contrast to these depressing statistics, there has been a persistent 10-year decline in the death rate from stroke, which has exceeded the general decline in cardiovascular mortality observed over the same time period (1). It is difficult to explain this phenomenon. Although surgery for extracranial occlusive disease has become much more common in the last 15 years, improved medical and surgical care can account for only a small fraction of the change in death rate. It is most likely that the decline in cardiovascular mortality reflects better control of arterial hypertension, changes in lifestyle, and the general reduction in cigarette smoking (2,3). Although the natural history of stroke in the United States was defined in an earlier era, studies performed from 1950 to 1975 provide useful information regarding the indications and timing of cerebrovascular surgery (4,5). The following are now accepted facts. 1. 2.

3.

The brain is perfused by paired carotid and vertebral arteries that communicate with each other through the circle of Willis at the base of the skull. Although there is substantial variation in the effectiveness of this collateral network (less than 20% of patients have ‘‘complete’’ circles), occlusion of one vessel is frequently compensated for without neurologic deficit. In general terms a carotid artery supplies only the ipsilateral cerebral hemisphere through the middle, anterior, and posterior cerebral vessels. The vertebral arteries join to form a single basilar artery that supplies the brainstem and cerebellum with additional contributions to the posterior aspect of the circle of Willis (Fig. 1). Boundary zones or ‘‘watershed’’ areas between the primary perfusion territories of the middle, anterior, and posterior cerebral arteries can be demonstrated by anatomic studies. These areas are most at risk for ischemia and infarction during hypotension or vascular occlusion. Perhaps because of the lower basal vascular tone of these vessels, boundary zones are frequently the site of intracerebral hemorrhages associated with acute hypertension. The subclavian origin of both vertebral arteries makes possible the unique subclavian steal syndrome that will be discussed in greater detail in the section on ‘‘Vertebrobasilar Disease’’ (Fig. 2). This syndrome occurs when an occlusive lesion proximal to the origin of the vertebral vessels decreases perfusion pressure in the distal subclavian artery. The vertebral artery then functions as a collateral pathway for the arm, and reversal of flow (away from the cranium) can be demonstrated angiographically. This flow pattern ‘‘steals’’ blood from the basilar system and may result in cerebellar ischemia or infarction.

Patients who have survived one cerebral infarction have a high incidence of recurrent strokes (approximately 25%). More than half of these recurrent strokes are fatal. Prodromal symptoms of stroke, such as transient cerebral ischemic attacks, identify the patients at greatest risk of suffering later completed strokes. The cumulative stroke rate approaches 50% at five years and is highest in the first year after the transient ischemic episode (6,7). Patients suffering transient ischemic attacks (TIA) or strokes from atheromatous stenotic lesions of the carotid bifurcation are significantly benefited by carotid endarterectomy if the complications of the procedure are equal to or less than current norms.

Characteristics of Flow The cerebral circulation is supplied with nearly 15% of cardiac output. Resting total blood flows range from 50 to 60 mL/min/ 100 g of tissue, with higher values in the cellular gray matter (100 mL/min/100 g) and lower flows in the cell-poor white matter (20 mL/min/100 g) (8,9). Cerebral blood flow is regulated by both metabolic and myogenic mechanisms that tend to maintain or ‘‘autoregulate’’ perfusion to avoid cerebral infarction during hypotension and cerebral hemorrhage during hypertension (10,11). Cerebral infarcts may result when regional blood flows decline below 15 mL/min/100 g, although the metabolic state of the brain strongly influences the likelihood of cell death (12). Barbiturate coma has been shown to decrease the ischemic limit to as low as 5 mL/min/100 g (13). The cerebral circulation is further distinguished by a blood–brain barrier that effectively isolates brain tissue from

In this chapter, the anatomy and physiology of cerebral blood flow will be reviewed, the variable clinical presentations of cerebral ischemia characterized, and the diagnostic and therapeutic options considered. In addition, clinically relevant upper-extremity vascular disease will also be reviewed. It has become clear that only through better understanding of cerebrovascular physiology and upperextremity vascular pathology can the care of patients with advanced vascular disease be improved.

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Figure 2 Subclavian origin of vertebral arteries allows these vessels to function as collateral pathways for upper extremity. Cerebellar ischemia may result from the ‘‘steal’’ of blood flow.

Figure 1 (A) Carotid artery supplies middle cerebral and anterior cerebral arteries predominantly, with major contributions to posterior cerebral artery. (B) Vertebral arteries form the basilar artery that supplies cerebellar vessels and posterior cerebral arteries.

serum ionic changes and humoral factors (14). The barrier is both a physical and biochemical impediment to the transport of protein and polar substances into cerebral extracellular fluid. Anatomic features include very tight junctions between endothelial cells, with only a few scattered pores and minimal transport by pinocytotic vesicles. A membranebound enzyme system, primarily composed of monoamine oxidase, effectively degrades circulating catecholamines and limits cerebral extraction to less than 5%. It is noteworthy that the areas of the brain responsible for hormone regulation, such as the hypothalamus, pituitary gland, and pineal gland, do not demonstrate the anatomic or functional characteristics of the blood–brain barrier. The blood–brain barrier is disrupted in areas of tissue infarction and during periods of severe hypertension (15). These observations are clinically important because breakdown of the blood–brain barrier (i) facilitates the diagnosis of cerebral infarcts by radionuclide scanning, and (ii) explains the occurrence of late hemorrhage in previously ‘‘bland’’ infarcts when patients become severely hypertensive.

Measurement Techniques Diverse methods have been used to measure cerebral blood flow in experimental settings, including venous outflow

collections, radioactive microspheres, autoradiography, and heat or hydrogen clearance (16). In clinical practice, most measurements of total and regional cerebral blood flow are made on the basis of the clearance of inhaled inert gases including xenon-133. Using the modified Kety–Schmidt technique, xenon-133 washout is monitored by external gamma scintillation counters and subjected to ‘‘curve stripping’’ to remove any component of extracranial blood flow (17). This technique is most accurate in the middle cerebral distribution and least helpful in evaluating the posterior cerebral or cerebellar circulations. The recent introduction of positron emission tomography allows repeated imaging of radionuclide concentration in any transverse section of the brain (18). Depending on the labeled element, regional blood flow H215O or substrate use (C11-glucose) can be measured (19). Although this technology was once only regarded as a research tool, now it provides the most precise metabolic and flow data available in a wide range of clinical settings.

Flow Regulatory Mechanisms Pressure-flow autoregulation is the ability of an organ to maintain normal blood flow despite variations in blood pressure. This protective mechanism is well documented in the cerebral circulation. Most physiologists agree that the process is an intrinsic property of blood vessels, involving a continuous readjustment of the myogenic activity of vascular smooth muscle, which depends on changes in transmural pressure and the local (extracellular) chemical environment. Increased intravascular pressure (hypertension) predictably results in compensatory vasoconstriction, whereas decreased pressure (hypotension) elicits vasodilation (20). Although early experiments suggested that pCO2 was the primary chemical regulator of vascular tone, it has become well accepted that the hydrogen ion concentration in the extracellular space provides the vasodilatory influence (21,22). Decreasing pCO2 results in lower hydrogen ion concentration and vasoconstriction. An elevated pCO2 leads to

Chapter 45: Cerebrovascular Disease and Upper-Extremity Vascular Disease

higher hydrogen ion concentration and vasodilation. This relationship is applied clinically in the management of severe head injuries; hyperventilation with resultant hypocarbia and decreased hydrogen ion concentration decreases cerebral blood flow and attenuates posttraumatic cerebral edema. Responses to changes in pCO2 are less vigorous, although hypoxia does result in moderate cerebral vasodilation. Sympathetic stimulation and other neural stimuli have only a small influence on cerebrovascular resistance and blood flow autoregulation (23). In fact, there is minimal histologic evidence of adrenergic vasoconstrictive fibers on cortical vessels (18). Neurally mediated vasoconstriction is limited to large vessels outside the brain proper and, as such, does not represent a primary regulatory mechanism (24).

CLINICAL PRESENTATION OF CEREBROVASCULAR DISEASE Definitions For purposes of discussion, clinicians have grouped neurologic deficits into four categories. TIA are classically defined as short-lived, often repetitive alterations of mentation, vision, motor, or sensory function that are completely reversed within 24 hours. Although TIA often involve the middle cerebral artery distribution and present with contralateral arm, leg, and facial weakness, perhaps the most well-recognized episodes involve transient monocular blindness (amaurosis fugax or ‘‘fleeting blindness’’). TIA that last only a few minutes may be prognostically different from those deficits that persist for longer than two hours. For this reason, longerlasting episodes (2–72 hours) that still result in no permanent neurologic deficit or radiologic evidence of brain infarction are usually designated reversible ischemic neurologic deficits. A documented cerebral infarction (stroke or cerebrovascular accident) implies a permanent neurologic deficit that is usually associated with computed tomography scan evidence. Neurologic recovery is quite variable and may be complete, but the time course of recovery (weeks or months) clearly distinguishes infarcts from TIA or reversible ischemic neurologic deficits. A ‘‘stuttering stroke’’ in which the neurologic deficit ‘‘waxes and wanes’’ has been termed stroke-in-evolution. This type of presentation is not as common but has received much recent attention because of the potential that therapeutic maneuvers could improve the eventual outcome (25,26). Although the above definitions have aided communication, they can be criticized for arbitrarily grouping diverse mechanisms with quite variable prognoses. For example, TIA can be caused by migraines, seizure disorders, and intracranial aneurysms, as well as carotid artery lesions. This ‘‘lumping’’ phenomenon is most confusing when large multicenter studies attempt to characterize the natural history of a clinical presentation without rigorous preselection on the basis of cause.

Mechanisms Symptoms of cerebrovascular disease reflect both the mechanism of ischemia and the specific areas affected. In general, ischemia and infarction result from either low flow in largeor medium-sized vessels associated with obstructive lesions or hypotension, or emboli in smaller vessels from proximal ulcerative lesions or turbulent flow. Hemodynamic derangements predisposing to the low flow are manifest clinically by neurologic deficits corresponding to the ‘‘watershed areas’’ between the main cerebral artery perfusion territories.

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Symptoms of embolic occlusion depend on the site of distal impaction. Predictably, the size of the embolus determines the vessel it will occlude. Both mechanisms can result in permanent and reversible deficits (27). In particular, repetitive short-lived neurologic deficits (i.e., TIA) are compatible with either (i) recurrent ischemia of watershed areas, or (ii) impaction and lysis of intermittent platelet emboli following a consistent route mandated by hemodynamics and anatomy.

Arterial Pathology The most common disease process involving the cerebral and extracranial vessels is atherosclerosis (28). Although the disease is most prevalent in patients over the age of 50, presentations of younger patients are not rare. In roughly half of the cases, the atheroma is localized to the extracranial bifurcation of the common carotid into the internal and external carotid arteries. Such atherosclerotic plaques may slowly encroach on the arterial lumen or suddenly occlude following intraplaque hemorrhage (29). Other pathologic processes are less common and may more frequently involve younger patients. These include spontaneous subintimal dissections of the internal carotid and fibromuscular dysplasia. Although it is generally accepted that the majority of emboli arise from ulcerated atherosclerotic lesions in the common or internal carotid artery, the intracranial carotid siphon near the origin of the ophthalmic artery can also harbor symptomatic ulcerative lesions. Stenoses and occlusions can involve either the extracranial or the intracranial carotid arteries, both areas simultaneously (tandem lesions), or any portion of a specific cerebral artery (30,31). The mechanisms that underlie plaque instability may involve biologic factors that are intrinsic to plaque structure and biomechanical factors that induce structural breakdown or specific cellular responses. Ongoing histopathologic studies at the University of Chicago have found that large symptomatic and asymptomatic plaques, often highly stenotic, possess remarkably similar histopathologic features with regard to the presence of necrosis, calcification, fibrous-cap ulceration, hemorrhage, and surface thrombosis (32,33). Although intraplaque hemorrhage, hematoma, and surface thrombosis have been regarded by other investigators as cardinal features of symptomatic plaques, such a finding was not substantiated in these studies. It was consistently observed, however, that proximity of the necrotic core to the overlying fibrous cap and lumen was associated with embolic symptoms. In symptomatic plaques, the necrotic core was twice as close to the lumen when compared with asymptomatic plaques, whereas the degree or location of calcification had little effect. Symptomatic plaques also exhibited a greater degree of macrophage infiltration in and about the fibrous cap and were associated with fibrous-cap thinning and erosion. This implicated an ongoing inflammatory or immune-mediated response as a factor in plaque instability. The potential role of biomechanical forces in inducing structural fatigue of plaque constituents and the localization of plaque neoformation and inflammatory cell response is also of interest. Marked elevation of wall shear stress occurs within stenoses that are associated with large plaques. Although high shear may inhibit plaque formation (34), changes in flow dynamics associated with marked stenoses, including wall vibration, flutter, and cyclical collapse (35), could induce disruptions within plaques, lumen ulcer formation, and associated surface irregularities.

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TYPES OF CEREBROVASCULAR DISEASE Extracranial Carotid Artery Disease Clinical Presentation The symptoms of extracranial carotid disease can be described by the timing of impairment (permanent, transient, or relapsing) and the type of neurologic deficit (motor, sensory, cognitive, or communicative). As discussed earlier in this chapter, both decreases in cerebral blood flow and embolic occlusions can produce the entire clinical spectrum. The persistence of any neurologic deficit is synonymous with death of brain tissue. Transient and relapsing episodes unassociated with infarctions are distinguished by the return of the neurologic examination to normal. The exact nature of a deficit can be directly correlated with the area of brain rendered ischemic. The most commonly involved area is the perfusion territory of the middle cerebral artery (the parietal lobe), which is the main outflow vessel of the carotid artery. The patient with middle cerebral ischemia presents with contralateral hemiparesis or hemiplegia, usually more severe in the arm, and paralysis of the contralateral lower part of the face (‘‘central seventh nerve paralysis’’). Associated findings include some degree of hypesthesia (decreased sensation) on the paralyzed side and a contralateral homonymous hemianopsia (visual-field deficit). Aphasia (difficulty with speech) is noted if the dominant hemisphere is involved. The left hemisphere is dominant in nearly all right-handed people and roughly 50% of left-handed people. Such defects can be expressive (Broca’s aphasia), receptive (Wernicke’s aphasia), or complete. If the nondominant hemisphere is affected, a curious ‘‘neglect response’’ is noted in which the paralyzed extremity is essentially ignored by the patient. Ischemia of the anterior cerebral artery most commonly presents with contralateral monoplegia involving only the lower extremity; visual–spatial problems and cortical sensory loss are also common. Posterior cerebral artery ischemia may result from carotid occlusive disease, but is also closely related to vertebral– basilar lesions. Presentations often include visual-field defects and may overlap with symptoms of ischemia of the posterior portion of the middle cerebral distribution, such as language disturbances and contralateral hemiparesis. Other neurologic signs consistent with posterior cerebral artery ischemia include ipsilateral third–cranial nerve palsy and contralateral complete sensory loss (thalamic syndrome).

Diagnosis Symptomatic carotid artery disease is commonly associated with the above neurologic presentations. However, it is essential to exclude other causes for such syndromes, including migraines, brain tumors, intracranial hemorrhage, and vascular malformations. The physical finding most consistent with extracranial carotid disease is a demonstration of a bruit on auscultation of the upper cervical region, reflecting turbulent blood flow at a stenosis. Classic carotid bruits have the following characteristics: they are (i) high pitched and fade into diastole, (ii) localized to the angle of the jaw, and (iii) best heard with the bell rather than the diaphragm of the stethoscope. Unfortunately, even experienced examiners frequently cannot distinguish internal or common carotid bruits from clinically irrelevant turbulence in the distal external carotid artery or other cervical blood vessels. As many as 50% of symptomatic ulcerations may be unassociated with stenoses and hence may not present with bruits. Finally, when a

stenosis exceeds 90% of vascular cross-sectional area, the intensity of the bruit often decreases because of lower volume flow. This lack of specificity of cervical bruits is most disturbing in asymptomatic patients with bruits, because physical examination alone does not allow assessment of the degree, or even the presence, of carotid disease. Many noninvasive tests have been developed to better characterize extracranial carotid disease without the risk of angiographic procedures. They are most widely used in asymptomatic patients with cervical bruits and in the long-term follow-up of patients already treated with carotid endarterectomy.

Imaging Techniques Direct noninvasive tests using ultrasound techniques to visualize the extracranial vessels have largely replaced the indirect methods previously used to detect and quantitate disease (e.g., oculoplethysmography). When combined with sophisticated range-gated pulsed Doppler instruments (duplex scanning), the velocity and volume flow can be determined (1). The resolution of duplex scanning has improved recently such that ulcerative nonstenotic lesions can be detected in most patients. Arteriography for cerebrovascular disease commonly includes imaging of the aortic arch and selective injections of the common carotid arteries, with delineation of the carotid siphon and intracranial vessels (Figs. 3 and 4). The common carotid artery and its bifurcation are readily visualized along with any associated stenoses or ulcerated plaques. Perhaps the most significant advantage of cerebral arteriograms is their ability to demonstrate intracranial lesions and aortic arch disease. Relevant intracranial lesions include tumors, aneurysms, arteriovenous malformations, and arterial occlusive disease, particularly of the carotid siphon. Indeed, ulcerative or occlusive lesions of the aortic arch or intracranial vessels may produce symptoms identical to those associated with carotid artery disease such as TIA or amaurosis fugax. When associated with carotid bifurcation disease, such proximal or distal occlusive lesions are termed ‘‘tandem’’ lesions. Due to its invasive nature, contrast angiography has associated morbidity and mortality (36). These adverse reactions can be grouped into three major categories: local, systemic, and neurologic. Local complication rates (ranging from 5% to 15%) include hemorrhage, hematomas, pseudoaneurysms, and formation of thrombi or emboli at the arterial puncture site. Systemic complications include allergic reactions to the contrast agent, as well as renal and cardiovascular manifestations. While the incidence of serious allergic reactions to radiographic contrast agents is less than 2% in most reported series, in patients with a history of contrast allergy, the incidence of anaphylactic reactions may be as high as 20% (37). Allergic reactions range from minor sequelae such as nausea, vomiting, hives, and chills, to major lifethreatening reactions such as hypotension, bronchospasm, laryngospasm, and pulmonary edema. Radiographic contrast agents can also produce a deterioration in renal function, especially in patients with preexisting kidney disease. One series reported that nonazotemic patients experienced a 2% incidence of acute renal failure following all types of angiography, while patients with chronic azotemia suffered a 33% incidence (38). However, the same study revealed that the occurrence of acute renal failure was less in patients undergoing carotid–vertebral studies than in patients undergoing visceral angiograms with more direct delivery of dye to the kidneys. Cardiac complications of cerebral

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Figure 4 Operative specimen (bivalved) reveals narrow lumen (L) with fresh hemorrhage (H) within atherosclerotic plaque. Extensive ulcerations are noted.

Operative Indications

Figure 3 Preoperative angiogram of patient presenting with repeated episodes of contralateral hemiparesis demonstrates severe stenosis of both internal (arrow) and external carotid arteries.

angiography include hypotension, arrhythmias, myocardial ischemia or infarction, and even cardiac arrest. Neurologic complications are the most important risk of cerebral angiography (39). Events range from TIA (lasting less than 24 hours) to completed strokes. Hankey et al. reviewed eight prospective studies consisting of 2227 patients with mild ischemic cerebrovascular disease (40). A 4% incidence of postangiographic neurologic complications was observed, of which 1% were permanent. As would be expected, the incidence was higher in patients with active symptoms or bilateral severe carotid artery stenoses. Magnetic resonance arteriography (MRA) is another noninvasive method of imaging the extracranial carotid arteries. It has an advantage over conventional angiography in that there is no risk of stroke, arterial injury, or systemic complications such as contrast reactions. Rigorous correlation between magnetic resonance angiography and carotid endarterectomy specimens has yet to be reported. In our early experience with this technique, the degree of stenosis is often factitiously overestimated. Even modest degrees of turbulence at the carotid bifurcation or siphon (such as 50% stenoses) may appear to be critical lesions.

The indications for carotid endarterectomy are constantly being reevaluated and redefined. In a recent multicenter randomized trial, it has been shown that carotid endarterectomy will significantly decrease the risk of stroke in symptomatic patients with carotid stenoses of 70% to 99% of diameter (41). Symptoms referable to carotid stenosis included hemispheric TIA with resultant loss of motor and/or sensory function on one side of the body, monocular ipsilateral blindness (amaurosis fugax), or a nondisabling stroke. In this study, there was a reduction in risk of major or fatal stroke from 13.1% in the medical therapy group to 2.5% in the surgical group over two years. The timing of carotid endarterectomy after a completed stroke due to an ipsilateral carotid lesion is somewhat controversial. Most would agree that endarterectomy should be considered unless the patient has sustained a severely disabling stroke such that there is minimal salvageable function in the affected carotid artery distribution. The procedure should be delayed until the patient’s neurologic status has stabilized, usually three to six weeks after the stroke (42). The risk of recurrent stroke after carotid endarterectomy is approximately 1.6% per year (15% at nine years), as compared to a recurrent stroke rate of 50% at five years in those patients not undergoing carotid endarterectomy (9). Nevertheless, many surgeons will not operate if severe intracranial disease or cardiac risk factors would decrease the effectiveness or increase the morbidity of the procedure. The prognosis of asymptomatic patients with highly stenotic carotid lesions remains difficult to characterize (25,43). Long-term follow-up of patients with persistent disease of the contralateral carotid artery following unilateral carotid endarterectomy documents a 20% incidence of

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cerebrovascular symptoms; the incidence of stroke without antecedent TIA is approximately 3% to 5% (44). The recent Veterans Affairs Cooperative Study found a benefit for endarterectomy if the stenosis was greater than 50%, but the endpoints included all neurologic events, not just stroke (45). Because experienced surgeons document a perioperative stroke rate of less than 2%, operative intervention may be appropriate in asymptomatic patients with limited anesthetic risk factors and those undergoing major surgical procedures that may predispose to hypotension (36).

Nonoperative Treatment The most significant risk factor for stroke is hypertension. Hence, the control of hypertension is most important in the medical management of patients with cerebrovascular disease (46). Evaluation of serum lipoproteins will likely assume a greater role in the prevention and retardation of atherosclerosis as dietary and drug therapies for specific abnormalities become more clear. Direct medical therapy for cerebrovascular disease has focused on anticoagulation (heparin and warfarin) and antiplatelet drugs (aspirin, dipyridamole, and sulfinpyrazone) (47,48). Mechanisms of action differ considerably, but the common rationale includes prevention of sudden thrombosis of stenotic lesions and inhibition of platelet activation on ulcerative lesions. Although many studies have suggested a benefit of long-term anticoagulation, the methodologies of these investigations have been seriously questioned, especially regarding their lack of randomization and precise patient selection. Furthermore, the statistically significant reduction in stroke rate (from 19% to 12% in one series) does not compare to better results achieved by carotid endarterectomy (49,50). Many clinicians believe that antiplatelet agents are most appropriate in patients with minimal ulcerative nonstenotic lesions and only one episode or one closely spaced series of TIA (7). If symptoms recur in such patients, endarterectomy remains an option. Other candidates for anticoagulation include patients with very high operative risk or those with severe associated intracranial disease.

Operative Techniques and Results Carotid endarterectomy is the surgical procedure of choice for disease of the common carotid artery or the extracranial portion of the internal carotid artery (51). The procedure can be performed under general or local anesthesia. Patients at greatest risk for a perioperative ischemic stroke include patients with previous infarcts, those with contralateral carotid occlusions, and those with unstable neurologic deficits (52). Some surgeons routinely use an indwelling vascular shunt to maintain carotid cerebral perfusion during endarterectomy, whereas others use shunts selectively or not at all. Intraoperative monitoring of electroencephalograms or retrograde carotid perfusion pressure (‘‘stump pressure’’) has been used to assess the need for shunt placement. Because it is likely that embolic events account for the majority of perioperative strokes, precise dissection technique is crucial in patients with thrombotic or ulcerative plaques (53). Exposure of the vessels must be carried out in an unhurried and gentle manner, mindful of surrounding cranial nerves, especially the vagus, hypoglossal, superior laryngeal, and glossopharyngeal nerves. We administer heparin and clamp the distal internal carotid prior to any manipulation of the bifurcation. Only then is the lateral

carotid bulb sharply dissected free and rotated anteromedially. The arteriotomy is made in this lateral aspect and usually extended past the distal edge of the plaque. Unhindered visualization of the end point is essential. It is also important that the proximal extent of the endarterectomy achieves a suitable nondiseased segment of the vessel. If there is any question of the distal ‘‘feather’’ of the endarterectomy, fine tacking sutures are placed; such sutures should not be tied too tightly or puckering of the luminal surface may result. It has also been our practice to tack the edges of the proximal end point if a thickened intimal layer has separated from the medial layer. Intraoperatively, Doppler signals are evaluated in both the internal and the external carotid arteries. Completion duplex ultrasonography or arteriography is not used routinely; however, both are employed if deemed necessary. Recently we have applied more liberal indications for placement of prosthetic or vein patch (extensive arteriotomy into the internal carotid artery, vessels smaller than 3 mm, female sex, or active smoking). For example, patching was performed in about 10% of our patients during 1981 through 1987, and nearly half of patients in the more recent period. The type of patch does not seem to strongly influence early or late outcomes, but care must be taken to avoid excessively enlarging the artery and altering flow dynamics. The incidence of perioperative stroke varies with operative indication. Most large series report stroke rates of 1% to 2% in patients with TIA and 3% to 5% in patients with previous strokes or contralateral carotid occlusion (54). Other postoperative complications include cranial nerve injury (especially the hypoglossal and recurrent laryngeal nerves) and myocardial infarction. Because the carotid sinus regulates blood pressure homeostasis, postoperative hypotension or hypertension is noted in many patients during the 24 hours required for baroreceptor reacclimation (55). Death following carotid endarterectomy is infrequent and is more commonly due to myocardial infarction than stroke. In our series of 367 consecutive carotid endarterectomies, two of the three deaths were attributable to acute myocardial infarction, while none of the four patients suffering perioperative neurologic deficits died (56). This experience is not unique. In 1981, Lees and Hertzer (57) reported a total of 10 postoperative deaths in 335 patients, many of whom underwent other major surgical procedures during the same hospitalization. Myocardial infarction was the cause of 6 of the 10 deaths, and only two deaths were due to stroke. In the multicenter Asymptomatic Carotid Atherosclerosis Study (58), only one patient in the 825-patient surgical group died following surgery; the cause of death was myocardial infarction. In the North American Symptomatic Carotid Endarterectomy Trial report (41) in 1991, of the 328 patients undergoing surgical treatment of severe carotid stenoses, two deaths were noted (0.7%), one from stroke and one from myocardial infarction or arrhythmia. In the multicenter Veterans Medical Centers study of asymptomatic stenoses described by Hobson et al. (45), all four surgical deaths (1.9%) resulted from myocardial infarction. The occurrence of myocardial ischemia and infarction has been linked to hypertension. Riles et al. (59) specifically linked the overzealous use of a-adrenergic agents to increase carotid artery ‘‘stump’’ pressure intraoperatively with both myocardial ischemia and infarction. In their view, the incidence of myocardial infarction was 4.9% in 284 patients with hypertension as compared with zero in 207 normotensive patients. The well-described fluctuations in

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systemic blood pressure in the postoperative period (including hypertension and hypotension) also contribute to cardiac morbidity (55,60). The risk for myocardial complications and death appears to increase slightly with age. Meyer et al. (61) reported an overall mortality of 1.3% in 749 carotid endarterectomies performed on patients 70 years of age or older, between 1971 and 1989; 6 of 10 deaths were due to myocardial infarction. A more recent series of 63 endarterectomies in patients 75 years or older, from Perler and Williams (62), included five major cardiac complications but no deaths. It has been well accepted that the indications for surgery and the neurologic status strongly influence outcome. For example, in a large series of more than 1700 carotid endarterectomies, Thompson (63) reported an operative mortality rate of 3.4% for patients with previous stroke, 1.1% for patients with TIA, and 0% for asymptomatic patients. Taken as a whole, it seems clear that mortality reflects cardiac status and management, while neurologic morbidity reflects patient selection and technical aspects of the operation. Recurrent stenoses occur in approximately 8% to 10% of patients, if followed closely, although the incidence of symptomatic recurrence is much lower (3%). Restenosis within 24 months usually represents exuberant intimal regeneration, whereas later presentations reflect recurrent atherosclerosis (64).

ischemic symptoms are generally mild, true posterior fossa infarction can be progressive and lethal, as a result of extensive edema and midbrain compression. Emboli can contribute to posterior cerebral and cerebellar ischemia, but occlusive disease of the vertebral arteries or the basilar artery is the most common mechanism. The thrombotic process may involve the basilar artery proper or the basilar branch vessels that penetrate into the brain stem (49). A classic syndrome of vertebrobasilar insufficiency (subclavian steal syndrome) is associated with subclavian or innominate arterial occlusive disease (71). The subclavian origins of the vertebral arteries allow the vessels to function as collaterals for the upper extremity. During arm exercise, flow is reversed in the vertebral artery, and basilar arterial blood flow and perfusion pressure are decreased. Symptoms of posterior cerebral and cerebellar ischemia can result, especially if any flow-limiting carotid lesions are present. The anatomic relationship favors left-sided involvement, approximately in the ratio of 4:1 (72). The diagnosis of subclavian steal syndrome is supported by complaints of intermittent vertigo, lightheadedness, and nausea and vomiting intensified by arm exercise. Physical findings include supraclavicular bruits and 40- to 60-mmHg blood pressure discrepancies between the arms.

Carotid Angioplasty and Stenting

Diagnosis

The recent and remarkable improvements in interventional devices and skills offer nonsurgical options for treatment of carotid and vertebral lesions. The advantages of angioplasty and stenting include extending the definitive treatment of carotid lesions to higher-risk patients as well as those with special considerations mitigating against operative repair. This population would include patients with previous endarterectomies, in whom cranial nerve injury might be a concern, and patients with cervical radiation (65,66). Initial experience in angioplasty and stenting was limited to patients with severe comorbidities, which precluded safe operative repair (67). Technical success was observed in more than 95% of patients treated in a number of recognized centers, although the incidence of neurologic complications exceeded the best operative endarterectomy series (68). Increasing experience in endovascular techniques and the introduction of various types of ‘‘cerebral protection devices’’ (which filter or trap atheroembolic debris downstream from the dilated lesion) have both contributed to lower complication rates in the current literature (69). More widespread use of this endovascular approach is occurring, although the proper assessments of the safety and durability of these procedures await the completion of a number of ongoing randomized clinical trials.

Measuring blood pressure in both upper extremities is essential in any patient with cerebral symptoms. More sophisticated tests include B-mode imaging of the subclavian and vertebral vessels and the use of directional dopplers to document reversal of vertebral-artery blood flow. The primary diagnostic test remains arteriography (70). It is important to obtain delayed films to adequately demonstrate retrograde flow through the vertebral into the distal subclavian (Figs. 5 and 6). The origin of the contralateral vertebral artery and the status of the basilar artery should also be evaluated with oblique films if necessary. The incidental demonstration of subclavian steal during arteriography for some other reasons is, in itself, not cause for concern or surgical therapy.

Vertebrobasilar Disease Clinical Presentation As noted earlier, the paired vertebral vessels join to form the basilar artery. For this reason, proximal occlusion or ligation of only one vertebral vessel will not cause symptoms unless the contralateral vessel is diseased or hypoplastic. More distal disease of one vertebral vessel with occlusion of the small branches supplying the lateral medulla can result in neurologic deficits. The most frequent symptoms of basilar insufficiency include nausea, vertigo, ipsilateral facial numbness, ipsilateral Horner’s syndrome, and limb ataxia (70). Although

Operative Indications and Techniques Symptomatic patients with multiple vertebral occlusive lesions or subclavian steal syndrome should be considered for elective surgery. Procedures include endarterectomy of the proximal vertebral artery or carotid subclavian bypass to restore antegrade vertebral flow (73). The latter can be accomplished by bypass graft or division of the cervical subclavian artery with reimplantation into the common carotid artery. These procedures can be performed through a cervical incision (Figs. 7 and 8). In patients with associated carotid artery disease, carotid endarterectomy alone may relieve symptoms of vertebrobasilar insufficieny, by increasing collateral flow to the posterior cerebral artery and cerebellum (28). This is most appropriate in symptomatic patients with severe carotid stenoses and those with more distal vertebral or basilar occlusion.

Results and Complications Patency of vertebral endarterectomies and carotid subclavian bypass grafts exceeds 90%. In most cases, symptoms are completely relieved by successful bypass. Failure to

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Figure 5 Preoperative angiogram in patient presenting with stroke in basilar distribution (superior cerebellar) demonstrates complete occlusion of left subclavian artery (arrow).

achieve symptomatic improvement may be caused by continued carotid disease or intracranial lesions (75). Perioperative complications include injuries to the phrenic nerve, cervical sympathetic ganglia (with Horner’s

Figure 7 Postoperative intravenous digital angiogram demonstrates patent carotid–subclavian bypass (arrow) with return of cephalad flow in left vertebral artery.

syndrome), or the thoracic duct. Basilar territory infarction after carotid subclavian bypass is very rare; even early graft failure should not further compromise vertebral flow.

UPPER-EXTREMITY VASCULAR DISEASE Symptomatic arterial insufficiency of the upper extremity is relatively uncommon, accounting for approximately 2% of all peripheral vascular reconstructive procedures. Although atherosclerosis is the predominant cause of arterial ischemia of the upper extremity, there are other etiologies including extrinsic compression, vasospasm, arteritis, connective tissue disorders, trauma, Buerger’s disease, previous radiation therapy, and occupational injury.

Nonatherosclerotic Disease

Figure 6 Delayed films document reversed flow in large left vertebral artery (arrow) with reconstitution of distal subclavian artery (subclavian steal syndrome).

Extrinsic compression of the subclavian artery usually occurs at the thoracic outlet and may result in distal extremity ischemia or emboli. While impingement on the subclavian artery is commonly positional and temporary, long-standing external compression can lead to fibrosis and permanent arterial stenoses. If arteriography with positional maneuvers confirms a persistent and significant stenotic or ulcerative lesion, simple excision of the local soft tissue, primarily the medial scalene muscle and first rib, will not be sufficient treatment. Exclusion and bypass of the involved portion of the subclavian artery should be performed. In some patients, upper-extremity arterioles are exceptionally sensitive to sympathetic stimuli, resulting in vasospasm with intermittent ischemia and even gangrene. Vasospasm of the hands presents with a characteristic progression of color changes in the fingers: digits first become pallorous, secondary to decreases in the flow of oxygenated blood, then cyanotic, and finally ruborous as the vasospasm decreases and reperfusion occurs. This clinical syndrome is

Chapter 45: Cerebrovascular Disease and Upper-Extremity Vascular Disease

Figure 8 Aneurysms of palmar vessels secondary to repetitive hand trauma in a meat packer.

termed ‘‘Raynaud’s phenomenon,’’ after the French physician who first described it. Patients with Raynaud’s phenomenon should be screened for collagen-vascular diseases such as lupus erythematosis, rheumatoid arthritis, and scleroderma. In approximately 50% of patients with manifestations of severe digital ischemia, the phenomenon predates or is associated with these disorders. The most critical therapy of Raynaud’s phenomenon is avoidance of the cold, wind, and moisture, which classically trigger each episode; in some patients, stress also is a major factor. Vasoactive drugs including sympatholytics, which reduce the uptake and subsequent release of local norepinephrine, and calcium-channel blocking agents can be helpful. Finally, cervical dorsal sympathectomy can be employed if tissue loss is threatened or if symptoms are intolerable; unfortunately, the benefits of this procedure are not uniform or particularly durable. Two other causes for digital ischemia are vibratory injury to the palmar and digital vessels and Buerger’s disease. Vibratory injury results from repetitive blunt trauma to the hands, which are associated with certain occupations (construction work, especially with jack-hammers, meat packing, etc.) (76). The cumulative force of the injuries results in medium-vessel occlusions as well as true aneurysms due to medial and adventitial necrosis (Fig. 9). Patients may present with distal ulcers from ischemia and embolization. If aneurysms are demonstrated, direct microvascular

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repair is indicated to prevent enlargement and continued embolization. Buerger’s disease is a progressive medium- and smallvessel obliterative disease associated with nicotine abuse. Patients present with distal ischemia of both upper and lower extremities; recurrent venous thrombophlebitis is a frequent comorbidity. Local treatments of ischemic lesions and sympathectomy may be successful, but only if smoking cessation is complete. Unfortunately, this goal is almost never attained at this level of addiction to smoking. Takayasu’s Disease is an example of an inflammatory large vessel arteritis resulting in fibrosis and scarring of the aorta and its primary branches. Symptoms start as fever, myalgias, and anorexia, but then progress to upperextremity arterial insufficiency (77). The progression of arterial stenosis leads to the loss of the upper-extremity pulses, hence the name ‘‘pulseless disease.’’ Takayasu’s disease primarily affects people of Asian descent, with a strong predominance for females (8:1) less than 40 years of age. The etiology is still uncertain, although infection and autoimmune processes have been implicated; the disease is associated with rheumatoid arthritis, ankylosing spondylitis, and ulcerative colitis. Laboratory evaluation may reflect a generalized inflammatory process with an elevation of the erythrocyte sedimentation rate and a mild hypochromic anemia. Takayasu’s arteritis can be divided into four types based on the distribution of lesions (77,78). Type I is limited to the aortic arch and its primary branches, Type II includes lesions of the descending thoracic and abdominal aorta, Type III extends from the aortic valve to the abdominal aorta, and Type IV includes pulmonary artery involvement and/or associated aneurysms (77,78). The majority of patients present during the ‘‘pulseless’’ stage, and symptoms reflect the organ or extremity that is rendered ischemic. Complaints can include headache, light-headedness, hemiparesis, blurring of vision, diplopia, and blindness. The classic ocular findings include optic atrophy and retinal vein or artery thrombosis (79). Extremity symptoms can be limited to exercise-related complaints or progress to rest pain and tissue loss. Initial therapy, especially in the prepulseless stage, is centered upon the administration of corticosteroids. If a patient with symptomatic lesions has failed corticosteroid therapy, operative therapy is directed toward bypass of the involved or occluded vessels (80). If at all possible, operative intervention should be delayed until the acute phase of the disease has resolved. This may not be possible in patients presenting with active cerebrovascular symptoms. Endarterectomy has not proven effective, due to the transmural inflammatory response and the tendency toward aneurysmal degeneration. Bypass grafts are the preferred treatment and should originate and terminate in arteries known to be free of disease by both angiography and inspection (81); often, grafts must originate from the ascending aorta. Distal anastomotic stenoses occur in 20% to 30% of cases and may require reoperation.

Atherosclerotic Upper-Extremity Arterial Disease Clinical Presentation Atherosclerosis of the subclavian or innominate arteries is the most common cause of upper-extremity ischemia; symptoms may be due to low flow or emboli. Lesions involving the innominate artery can result in thrombotic atherosclerotic emboli to either the right vertebral artery or the right

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Figure 9 (A) Classic lesion at origin of innominate artery presented with right hemispheric transient ischemia attacks. Proximity of left carotid artery origin mandated ascending aorta to innominate bypass graft. (B) Complete occlusion due to radiation injury required bypass to relieve right upper extremity ischemia.

common carotid artery, with resulting TIA or strokes (Fig. 10). Emboli to the left cerebral hemisphere can also originate from the innominate artery lesions, due to the proximity of the origin of the left common carotid artery to the innominate artery. In one large series, 77% of the patients with symptomatic innominate artery lesions presented with neurologic symptoms, not upper-extremity problems (82). Stenosis or occlusion of the subclavian artery occurs three to four times more commonly on the left than the right subclavian artery. As noted earlier, a proximal subclavian artery occlusion or stenosis can result in reversal of flow in the left vertebral artery. The clinical presentation of unilateral upper-extremity weakness or coolness, vertigo with upper-extremity exercise (subclavian ‘‘steal’’ syndrome), or ischemic lesions of the hand should raise a suspicion of subclavian artery stenosis or occlusion. The diagnosis is suspected by comparing upper-extremity arterial pressures, and is confirmed by arteriography. Arteriograms will not only define the extent of disease of the subclavian artery, but will also evaluate the thoracic aorta, carotid arteries, and the vertebral arteries.

Treatment Symptomatic patients should be considered for arterial revascularization (83). Innominate lesions are usually approached directly through a median sternotomy (Fig. 11) (74). Both endarterectomy and bypass from the aortic arch are durable procedures. The selection of the specific procedure is based on the nature of the lesion and the location of origin of the left carotid artery. If it originates close to the innominate, clamping of the latter vessel for endarterectomy is inadvisable and bypass is preferred (82).

Bypass procedures for subclavian disease include transposition of the subclavian artery to the adjacent nondiseased carotid artery or carotid artery to subclavian artery bypass with a prosthetic graft (Fig. 8) (74). Transposition entails the complete mobilization of the subclavian artery proximal to the origin of the vertebral artery. The subclavian artery is divided and the proximal arterial stump oversewn. An anastomosis is created between the side of the proximal carotid artery and the end of the subclavian artery. If the subclavian cannot be mobilized enough for a tension-free apposition to the proximal carotid artery, a carotid– subclavian bypass can be performed. In these instances, the preferred bypass graft conduit is a synthetic graft, due to its decreased tendency to kink. Both subclavian artery transposition and carotid–subclavian artery bypass have similar long-term patencies of greater than 95% (84).

Thoracic Outlet Syndrome Clinical Presentation Thoracic outlet syndrome is best described as an intermittent but reproducible compression irritation of the brachial plexus caused by congenital fibromuscular bands, cervical ribs, or the anterior scalene muscle (Fig. 12) (85,86). Classic symptoms include shoulder pain with radiation to the occiput and down the arm along the C8 to T1 distribution. Numbness and tingling frequently accompany the pain. In advanced cases, weakness of the hands and forearm may be noted. Although the subclavian artery may also be compressed by the same anatomic configuration, most symptoms of thoracic outlet syndrome relate directly to neurologic rather than vascular compromise.

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Figure 12 Brachial plexus compression occurs at triangular outlet between scalene muscles and first rib.

cause-and-effect relationship is nearly impossible. The differential diagnosis includes carpal tunnel syndrome, cervical disk compression, arthritis, tendonitis, and angina pectoris.

Diagnosis

Figure 10 Innominate endarterectomy can be performed if a vascular clamp can be applied proximal to the lesion without also obstructing the left carotid artery origin. Source: From Ref. 74.

A history of neck or shoulder trauma can be elicited in many patients, which some clinicians consider to be suggestive of scalene muscle spasm being an initiating event. Whiplash injuries are frequently implicated, but documentation of a

The chronicity and lack of specificity of the clinical presentation is paralleled by a lack of definitive diagnostic tests other than chest x-ray film demonstration of an abnormal cervical rib. The Adson maneuver is a positional test long associated with thoracic outlet syndrome. The test is considered positive if the radial pulse disappears during abduction and external rotation of the arm. Unfortunately, the Adson maneuver is frequently positive in asymptomatic patients and negative in patients with classic symptoms of thoracic outlet syndrome, again emphasizing the neurologic as opposed to vascular origin of the pain syndrome. Angiographic demonstration of subclavian artery compression in extreme abduction also does not contribute significantly to the diagnosis unless there is evidence of a persistent blood pressure gradient in the involved arm (5). Electromyograms and nerve conduction velocities have been suggested as objective measures of thoracic outlet nerve compression. Unfortunately, enthusiasm for these studies has decreased recently because of the difficulty of electrically stimulating nerves proximal to the presumed site of compression and the intermittent nature of the syndrome. Furthermore, clinical correlations between positive nerve conduction studies and symptomatic relief following surgery have not been very convincing.

Operative Indications and Techniques

Figure 11 Subclavian reconstructions include both carotid–subclavian bypass and transposition of the distal subclavian into the carotid artery (illustrated here). Source: From Ref. 74.

Initial therapy should include shoulder girdle exercises and avoidance of extreme posturing. If pain remains and symptoms are fully consistent and reproducible, surgical therapy is appropriate. Unfortunately, even experienced surgeons report complete relief in only 80% to 85% of patients. The most common operation is transcervical or transaxillary resection of the first rib or a cervical rib, if present. In some patients, merely transecting the insertion of the anterior scalene muscle onto the first rib may suffice (87). Although there has been some enthusiasm for concurrent cervical sympathectomy, this is usually unnecessary unless symptoms of posttraumatic sympathetic dystrophy (causalgia) are evident.

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Complications The failure rate from all procedures remains relatively high in thoracic outlet syndrome (88). Complications of surgery include Horner’s syndrome, direct injury to the brachial plexus, lymphatic leaks, and pneumothorax.

SUMMARY Although cerebrovascular disease remains a major cause of morbidity and mortality in our population, improved understanding of the mechanisms and pathologic processes involved has allowed a wider application of preventive medical and surgical therapies. Appropriate selection of noninvasive tests to evaluate asymptomatic patients with signs of extracranial cerebrovascular disease has further characterized the natural history of these disorders. Although specific recommendations for medical or surgical therapy will continually be modified, it is generally accepted that patients with repetitive neurologic deficits (TIA) associated with extracranial atherosclerotic disease benefit significantly from surgical intervention. In patients with upper-extremity ischemia, extensive medical evaluation and careful assessments of the brachial–cephalic arterial system are mandatory.

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15. Johansson B, Li CL, Olsson Y, Klatzo I. The effect of acute arterial hypertension on the blood-brain barrier to protein tracers. Acta Neuropathol (Berl) 1970; 16(2):117–124. 16. Busija DW, Heistad DD, Marcus ML. Continuous measurement of cerebral blood flow in anesthetized cats and dogs. Am J Physiol 1981; 241(2):H228–H234. 17. Marcus ML, Bischof CJ, Heistad DD. Comparison of microsphere and Xenon-133 clearance method in measuring skeletal muscle and cerebral blood flow. Circ Res 1981; 48(5):748–761. 18. Raichle ME, Hartman BK, Eichling JO, Sharpe LG. Central noradrenergic regulation of cerebral blood flow and vascular permeability. Proc Natl Acad Sci USA 1975; 72(9):3726–3730. 19. Raichle ME, Welch MJ, Grubb RL Jr, Higgins CS, Ter-Pogossian MM, Larson KB. Measurement of regional substrate utilization rates by emission tomography. Science 1978; 199(4332):986–987. 20. Ekstrom-Jodal B. On the relation between blood pressure and blood flow in the canine brain with particular regard to the mechanism responsible for cerebral blood flow autoregulation. Acta Physiol Scand Suppl 1970; 350:1–61. 21. Borgstrom L, Johannsson H, Siesjo BK. The relationship between arterial po2 and cerebral blood flow in hypoxic hypoxia. Acta Physiol Scand 1975; 93(3):423–432. 22. Greenberg JH, Alavi A, Reivich M, Kuhl D, Uzzell B. Local cerebral blood volume response to carbon dioxide in man. Circ Res 1978; 43(2):324–331. 23. D’Alecy LG, Feigl EO. Sympathetic control of cerebral blood flow in dogs. Circ Res 1972; 31(2):267–283. 24. Heistad DD, Marcus ML. Evidence that neural mechanisms do not have important effects on cerebral blood flow. Circ Res 1978; 42(3):295–302. 25. Humphries AW, Young JR, Santilli PH, Beven EG, deWolfe VG. Unoperated, asymptomatic significant internal carotid artery stenosis: a review of 182 instances. Surgery 1976; 80(6):695–698. 26. Mentzer RM Jr, Finkelmeier BA, Crosby IK, Wellons HA Jr. Emergency carotid endarterectomy for fluctuating neurologic deficits. Surgery 1981; 89(1):60–66. 27. Pessin MS, Hinton RC, Davis KR, et al. Mechanisms of acute carotid stroke. Ann Neurol 1979; 6(3):245–252. 28. Solberg LA, Eggen DA. Localization and sequence of development of atherosclerotic lesions in the carotid and vertebral arteries. Circulation 1971; 43(5):711–724. 29. Javid H, Ostermiller WE Jr, Hengesh JW, Dye WS, Najafi H, Julian OC. Natural history of carotid bifurcation atheroma. Surgery 1970; 67(1):80–86. 30. Craig DR, Meguro K, Watridge C, Robertson JT, Barnett HJ, Fox AJ. Intracranial internal carotid artery stenosis. Stroke 1982; 13(6):825–828. 31. Eisenberg RL, Nemzek WR, Moore WS, Mani RL. Relationship of transient ischemic attacks and angiographically demonstrable lesions of carotid artery. Stroke 1977; 8(4):483–486. 32. Bassiouny HS, Davis H, Massawa N, Gewertz BL, Glagov S, Zarins CK. Critical carotid stenoses: morphologic and chemical similarity between symptomatic and asymptomatic plaques. J Vasc Surg 1989; 9(2):202–212. 33. Bassiouny HS, Sakaguchi Y, Mikucki SA, et al. Juxtalumenal location of plaque necrosis and neoformation in symptomatic carotid stenosis. J Vasc Surg 1997; 26(4):585–594. 34. Zarins CK, Bomberger RA, Glagov S. Local effects of stenoses: increased flow velocity inhibits atherogenesis. Circulation 1981; 64(2 Pt 2):221–227. 35. Cancelli C, Pedley TJ. A separated flow model for collapsible rube oscillations. J Fluid Mech 1985; 157:375–404. 36. Makhoul RG, Moore WS, Colburn MD, Quinones-Baldrich WJ, Vescera CL. Benefit of carotid endarterectomy after prior stroke. J Vasc Surg 1993; 18(4):666–670; discussion 670–671. 37. Witten DM, Hirsch FD, Hartman GW. Acute reactions to urographic contrast medium: incidence, clinical characteristics and relationship to history of hypersensitivity states. Am J Roentgenol Radium Ther Nucl Med 1973; 119(4):832–840. 38. D’Elia JA, Gleason RE, Alday M, et al. Nephrotoxicity from angiographic contrast material. A prospective study. Am J Med 1982; 72(5):719–725.

Chapter 45: Cerebrovascular Disease and Upper-Extremity Vascular Disease 39. Faught E, Trader SD, Hanna GR. Cerebral complications of angiography for transient ischemia and stroke: prediction of risk. Neurology 1979; 29(1):4–15. 40. Hankey GJ, Warlow CP, Sellar RJ. Cerebral angiographic risk in mild cerebrovascular disease. Stroke 1990; 21(2):209–222. 41. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med 1991; 325(7):445–453. 42. Whittemore AD, Mannick JA. Surgical treatment of carotid disease in patients with neurologic deficits. J Vasc Surg 1987; 5(6):910–913. 43. Busuttil RW, Baker JD, Davidson RK, Machleder HI. Carotid artery stenosis—hemodynamic significance and clinical course. JAMA 1981; 245(14):1438–1441. 44. Podore PC, DeWeese JA, May AG, Rob CG. Asymptomatic contralateral carotid artery stenosis: a five-year follow-up study following carotid endarterectomy. Surgery 1980; 88(6): 748–752. 45. Hobson RW II, Weiss DG, Fields WS. The Veterans Affairs Cooperative Study Group. Efficacy of carotid endarterectomy for asymptomatic carotid stenosis. N Engl J Med 1993; 328(4):221–227. 46. Kannel WB, Dawber TR, Sorlie P, Wolf PA. Components of blood pressure and risk of atherothrombotic brain infarction: the Framingham study. Stroke 1976; 7(4):327–331. 47. Brust JC. Transient ischemic attacks: natural history and anticoagulation. Neurology 1977; 27(8):701–707. 48. Olsson JE, Brechter C, Backlund H, et al. Anticoagulant versus anti-platelet therapy as prophylactic against cerebral infarction in transient ischemic attacks. Stroke 1980; 11(1):4–9. 49. A randomized trial of aspirin and sulfinpyrazone in threatened stroke. The Canadian Cooperative Study Group. N Engl J Med 1978; 299(2):53–59. 50. Fields WS, Lemak NA, Frankowski RF, Hardy RJ. Controlled trial of aspirin in cerebral ischemia. Stroke 1977; 8(3):301–314. 51. Thompson JE, Talkington CM. Carotid surgery for cerebral ischemia. Surg Clin North Am 1979; 59(4):539–553. 52. Goldstone J, Moore WS. A new look at emergency carotid artery operations for the treatment of cerebrovascular insufficiency. Stroke 1978; 9:599. 53. Steed DL, Peitzman AB, Grundy BL, Webster MW. Causes of stroke in carotid endarterectomy. Surgery 1982; 92(4): 634–641. 54. DeWeese JA, Rob CG, Satran R, et al. Results of carotid endarterectomies for transient ischemic attacks-five years later. Ann Surg 1973; 178(3):258–264. 55. Bove EL, Fry WJ, Gross WS, Stanley JC. Hypotension and hypertension as consequences of baroreceptor dysfunction following carotid endarterectomy. Surgery 1979; 85(6):633–637. 56. McKinsey JF, Desai TR, Bassiouny HS, et al. Mechanisms of neurologic deficits and mortality with carotid endarterectomy. Arch Surg 1996; 131(5):526–531; discussion 531–532. 57. Lees CD, Hertzer NR. Postoperative stroke and late neurologic complications after carotid endarterectomy. Arch Surg 1981; 116(12):1561–1568. 58. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. Endarterectomy for asymptomatic carotid artery stenosis. JAMA 1995; 273(18):1421–1428. 59. Riles TS, Kopelman I, Imparato AM. Myocardial infarction following carotid endarterectomy: a review of 683 operations. Surgery 1979; 85(3):249–252. 60. Towne JB, Bernhard VM. The relationship of postoperative hypertension to complications following carotid endarterectomy. Surgery 1980; 88(4):575–580. 61. Meyer FB, Meissner I, Fode NC, Losasso TJ. Carotid endarterectomy in elderly patients. Mayo Clin Proc 1991; 66(5): 464–469. 62. Perler BA, Williams GM. Carotid endarterectomy in the very elderly: Is it worthwhile? Surgery 1994; 116(3):479–483. 63. Thompson JE. Carotid endarterectomy, 1982—the state of the art. Br J Surg 1983; 70(6):371–376.

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64. Cossman D, Callow AD, Stein A, Matsumoto G. Early restenosis after carotid endarterectomy. Arch Surg 1978; 113(3):275–278. 65. Jordan WD Jr, Voellinger DC, Fisher WS, Redden D, McDowell HA. A comparison of carotid angioplasty with stenting versus endarterectomy with regional anesthesia. J Vasc Surg 1998; 28(3):397–402; discussion 402–403. 66. New G, Roubin GS, Iyer SS, et al. Safety, efficacy, and durability of carotid artery stenting for restenosis following carotid endarterectomy: a multicenter study. J Endovasc Ther 2000; 7(5):345–352. 67. Roubin GS, New G, Iyer SS, et al. Immediate and late clinical outcomes of carotid artery stenting in patients with symptomatic and asymptomatic carotid artery stenosis: a 5-year prospective analysis. Circulation 2001; 103(4):532–537. 68. Hertzer NR, Ouriel K. Results of carotid endarterectomy: the gold standard for carotid repair. Semin Vasc Surg 2000; 13(2): 95–102. 69. Al-Mubarak N, Colombo A, Gaines PA, et al. Multicenter evaluation of carotid artery stenting with a filter protection system. J Am Coll Cardiol 2002; 39(5):841–846. 70. Caplan LR, Rosenbaum AE. Role of cerebral angiography in vertebrobasilar occlusive disease. J Neurol Neurosurg Psychiatry 1975; 38(6):601–612. 71. Fisher CM. A new vascular syndrome: ‘‘the subclavian steal’’. N Engl J Med 1961; 265:912. 72. Fields WS, Lemak NA. Joint Study of extracranial arterial occlusion. VII. Subclavian steal—a review of 168 cases. JAMA 1972; 222(9):1139–1143. 73. Clark K, Perry MO. Carotid vertebral anastomosis: an alternate technic for repair of the subclavian steal syndrome. Ann Surg 1966; 163(3):414–416. 74. Zarins CK, Gewertz BL. Atlas of Vascular Surgery. New York: Churchill Livingstone, Inc., 1989. 75. Allen GS, Cohen RJ, Preziosi TJ. Microsurgical endarterectomy of the intracranial vertebral artery for vertebrobasilar transient ischemic attacks. Neurosurgery 1981; 8(1):56–59. 76. Clark ET, Mass DP, Bassiouny HS, Zarins CK, Gewertz BL. True aneurysmal disease in the hand and upper extremity. Ann Vasc Surg 1991; 5(3):276–281. 77. Ishikawa K. Natural history and classification of occlusive thromboaortopathy (Takayasu’s disease). Circulation 1978; 57(1):27–35. 78. Lupi E, Sanchez G, Horwitz S, Gutierrez E. Pulmonary artery involvement in Takayasu’s arteritis. Chest 1975; 67(1):69–74. 79. Takayasu M. Case with unusual change of the vessels in the retina. Acta Soc Ophthalmol 1908; 12:554. 80. Alpert HJ. The use of immunosuppressive agents in Takayasu’s arteritis. Med Ann Dist Columbia 1974; 43(2):69–71. 81. Weaver FA, Yellin AE, Campen DH, et al. Surgical procedures in the management of Takayasu’s arteritis. J Vasc Surg 1990; 12(4):429–437; discussion 438–439. 82. Cherry KJ Jr, McCullough JL, Hallett JW Jr, Pairolero PC, Gloviczki P. Technical principles of direct innominate artery revascularization: a comparison of endarterectomy and bypass grafts. J Vasc Surg 1989; 9(5):718–723; discussion 723–724. 83. Whitehouse WM Jr, Zelenock GB, Wakefield TW, Graham LM, Lindenauer SM, Stanley JC. Arterial bypass grafts for upper extremity ischemia. J Vasc Surg 1986; 3(3):569–573. 84. Salam TA, Lumsden AB, Smith RB III. Subclavian artery revascularization: a decade of experience with extrathoracic bypass procedures. J Surg Res 1994; 56(5):387–392. 85. Kirgis HD, Reed AF. Significant anatomic relations in the syndrome of the scalene muscles. Ann Surg 1948; 127:1182. 86. Roos DB. Congenital anomalies associated with thoracic outlet syndrome. Anatomy, symptoms, diagnosis, and treatment. Am J Surg 1976; 132(6):771–778. 87. Sanders RJ, Monsour JW, Gerber WF, Adams WR, Thompson N. Scalenectomy versus first rib resection for treatment of the thoracic outlet syndrome. Surgery 1979; 85(1):109–121. 88. Urschel HC Jr, Razzuk MA, Albers JE, Wood RE, Paulson DL. Reoperation for recurrent thoracic outlet syndrome. Ann Thorac Surg 1976; 21(1):19–25.

46 Venous and Lymphatic Abnormalities of the Limbs Jose R. Parra and Julie A. Freischlag

and continues as the external iliac vein. As a rule, deep veins are duplicated below the knee and are the first structures identified when dissecting out the arteries. Perforating veins traverse the deep fascia and connect the superficial and deep venous systems. These veins play a critical role in the pathophysiology of chronic venous insufficiency insofar as they can transmit elevated pressures from the deep venous system into the superficial system. Superficial and deep venous systems are present within the upper extremity (Fig. 3). The major superficial veins are the cephalic vein, which runs from the anatomic snuffbox along the lateral aspect of the arm to empty into the axillary vein at the deltopectoral groove, and the basilic vein, which travels along the medial aspect to empty into the brachial vein in the upper arm. These veins are commonly used as outflow tracts for arteriovenous fistulas created for hemodialysis. The deep veins parallel the radial

INTRODUCTION William Harvey’s monumental work nearly four centuries ago on the circulation of blood first emphasized the important role that the extremity veins play in this process. The impact of derangements in venous and lymphatic function of the limbs is staggering and contributes substantially to human disease. This chapter discusses our current understanding of these disorders and the physiologic rationale underlying their management.

ANATOMY Veins of the lower extremity can be classified as deep, superficial, or perforating venous systems. The superficial veins run in the subcutaneous tissue external to the deep fascia. The two major tributaries in the superficial venous system are the greater and lesser saphenous veins. The greater saphenous vein, formed by the confluence of the medial veins of the dorsum and plantar aspect of the foot, is found anterior to the medial malleolus and travels along the medial aspect of the leg until it crosses laterally at the proximal thigh to join the common femoral vein (Fig. 1). This junction is commonly 2 to 4 cm lateral to the pubic tubercle and inferior to the inguinal ligament. Cutaneous sensation to the medial aspect of the lower leg is provided by the saphenous branch of the femoral nerve, which runs adjacent to or crosses the greater saphenous vein in the lower leg. This is an important anatomic finding in that saphenous nerve injury can result in a troublesome neuropathy. The lesser saphenous vein, arising behind the lateral malleolus, takes its origin from the veins draining the lateral aspect of the foot and travels through the midline of the posterior calf to join the popliteal vein behind the knee (Fig. 1). Both of these major veins are commonly used as bypass conduits and are also the main sites of superficial venous reflux. The deep veins of the calf include the peroneal, posterior tibial, and anterior tibial vein, which ascend along the course of their corresponding artery (Fig. 2). In addition, there is a complex of veins within the soleal and gastrocnemius muscles often referred to as venous lakes, which are important physiologically because of their propensity to generate thrombus. These venous lakes coalesce and join the posterior tibial and peroneal veins. The aforementioned veins then merge with the anterior tibial vein to form the popliteal vein at the knee. This vein continues proximally as the superficial femoral vein and joins the deep femoral vein below the inguinal ligament to become the common femoral vein. The common femoral vein, traveling medial to the femoral artery, passes beneath the inguinal ligament

Figure 1 Diagram depicting the two main superficial tributaries of the venous system: the greater saphenous vein and lesser saphenous vein.

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Figure 2 Diagram depicting the deep venous system of the lower extremity.

and ulnar arteries below the elbow and then coalescence to form the brachial vein. The brachial vein merges with the basilic vein to become the axillary vein followed by the subclavian vein at the lateral border of the first rib. The subclavian vein then drains into the innominate vein ultimately ending up in the superior vena cava.

Figure 3 Diagram depicting the upper-extremity venous anatomy.

pressure. With competent valves and a functioning calf pump during exercise, venous blood in these capacitance vessels is returned to the heart. A clinical application of this action is the use of pneumatic compression devices in patients at bed rest. These devices rhythmically inflate to mimic the function of the calf muscles and reduce stasis and the risk for venous thrombosis.

VENOUS PHYSIOLOGY The venous system is a low-pressure capacitance system with significant redundancy, which depends upon external compression and compartmentalization to return blood to the heart. The veins have an intima, media, and adventitia but lack a significant muscular and elastic layer in all but the most central veins. A feature unique to the venous circulation is the presence of bicuspid valves in all veins distal to the common iliac vein. These one-way valves are oriented so to maintain a unidirectional flow of blood toward the heart. Upon standing, the column of venous blood is arrested as the valves slam shut and reflux is prevented. The valves of the perforating veins are crucial in preventing reflux of blood from the deep to the superficial systems, which prevents superficial venous hypertension. In the supine position at rest, the foot vein has a pressure of approximately 15 mmHg. On standing, the gravitational hydrostatic forces are added increasing the measured foot vein pressure to approximately 115 mmHg. Assuming the standing position also increases venous volume with an increase in the capacitance by about 500 cm3. Ambulation produces contraction of the calf muscles that serve as an external ‘‘pump’’ to squeeze the venous blood in a cephalad direction and lower the venous

VENOUS DISORDERS OF THE LOWER EXTREMITY Deep Venous Thrombosis Deep venous thrombosis (DVT) is the most serious and potentially life-threatening disorder of the venous system. The most lethal complication, pulmonary embolism (PE), is the cause of approximately 200,000 deaths each year in the United States (1). More than half of the patients surviving DVT suffer from the postphlebitic syndrome notable for disabling edema and potential stasis ulcers. Much of the pathophysiology of DVTs was first postulated by Virchow. He described three conditions (Virchow’s triad) that permit the development of a venous thrombus: stasis, hypercoagulability, and vessel wall damage. Stasis is the most important predisposing factor in the surgical patient. With the induction of general anesthesia, there is a considerable reduction in the venous flow because of the loss of the ability to contract the muscles of the lower extremity and a generalized peripheral dilation that is present throughout the procedure. Furthermore, a hospitalized patient frequently remains at bed rest, which also induces stasis and subsequent DVT. It is this consequence that provides the stimulus for early ambulation in most surgical patients. Other risk factors for DVT include age, obesity, malignancy, oral

Chapter 46: Venous and Lymphatic Abnormalities of the Limbs

contraceptive use, hypercoagulability syndromes, and pregnancy (2). Each of these factors alters venous stasis or coagulopathy.

Clinical Presentation Clinical signs of venous thrombosis are found in only 40% of the patients. When symptoms are present, they initially include edema and calf pain. The level at which swelling occurs is determined by the site of venous obstruction. If the swelling is confined to the calf or foot, obstruction is at the femoropopliteal level, whereas swelling at the thigh level implies iliofemoral obstruction. Physical examination reveals calf tenderness on palpation and occasionally a palpable cord representing the thrombosed vein. Homans’ sign, tenderness or tightness in the back of the calf with forcible dorsiflexion of the foot, may be present but is nonspecific and unreliable. There is a higher incidence of DVTs in the left leg compared to the right. Most DVTs involve the popliteal vein and its tributaries. However, if the thrombus extends proximally to involve the iliofemoral system, there may be massive swelling from the toes to the inguinal ligament. The clinical picture of pain, extensive pitting edema, and blanching is referred to as phlegmasia alba dolens or ‘‘milk leg.’’ With the progression of the thrombus, venous return becomes compromised and produces a painful, cyanotic leg known as phlegmasia cerulea dolens (3). If left unchecked, venous congestion and swelling can eventually limit arterial flow leading to gangrene of the extremity (Fig. 4). However, as previously mentioned, most patients are asymptomatic, and these dramatic presentations represent a very small percentage of the patients with venous thrombosis.

Diagnosis Diagnostic tests are critical in establishing the diagnosis because false-positive clinical signs have been found to occur in up to 45% of the patients evaluated (4). Duplex ultrasonography scanning is noninvasive and can be conveniently used at the bedside to detect venous thrombi with an accuracy of approximately 90%. Flow abnormalities such as a loss of phasicity or augmentation with distal compression are suggestive of thrombi. The most sensitive test, however,

Figure 4 Venous gangrene following iliofemoral deep venous thrombosis associated with malignancy.

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is a loss of compressibility of the normally compliant vein (Fig. 5). In the femoral vein, duplex scanning has a specificity of 100% and sensitivity of 95% (5). Diagnostic accuracy is lower in the calf. Nevertheless, it has been suggested that duplex scanning replaces venography as the standard method of diagnosing femoropopliteal DVT. Venography is the most accurate means of establishing the diagnosis of venous thrombosis and its extent of involvement. This test requires injection of a contrast medium into a foot vein while the superficial veins are occluded by a tourniquet to promote filling of the deep venous system. Filling defects and nonvisualization of the deep veins identify the thrombus. This invasive test carries the risk of producing venous thrombosis secondary to the thrombogenicity of the injected contrast medium. Other rare complications include cellulitis or skin necrosis secondary to extravasation of contrast and gangrene (6). This test remains the gold standard. Venography can also be performed with isotope injection and thus eliminate some of these complications. A gamma scintillation counter is then used to record the flow of the isotope. The image with this technique is not as well defined, but this method may be valuable for the sequential study of patients. A similar technique involves radioactivelabeled fibrinogen scanning. This technique involves intravenous injection of 125I-labeled fibrinogen. A developing thrombus incorporates fibrinogen with an increase in radioactivity that represents an organizing thrombus. This test is primarily used in clinical research studies given its oversensitivity to clot formation. Impedance plethysmography is another alternative to venography. This method measures the rate of volume changes in the extremity following rapid deflation of a blood pressure cuff. A prolongation of the outflow following deflation is indicative of occlusive thrombus. This technique has largely been supplanted by duplex ultrasonography.

Prophylaxis Several prophylactic measures can be used in the hospitalized patient. The goals of these measures are to reduce stasis or alter blood coagulability. Early ambulation has become a routine part of a patient’s postoperative course in an attempt to prevent stasis. Other options to reduce stasis include graded compression stockings and intermittent pneumatic compression devices, both of which augment venous flow. These devices are placed on the patient just prior to surgery and remain in place until the patient is actively ambulating. Anticoagulation therapy using heparinoids is commonplace. Heparin and its derivative low-molecular-weight heparin (LMWH) bind to anti–thrombin III, which causes an increased inhibition of factors IIa, Xa, IXa, XIIa, and thrombin. Unfractionated heparin (5000 U subcutaneously) can be given two hours preoperatively and then every 8 to 12 hours postoperatively until the patient is ambulating. Although controversy exists over its efficacy, a large randomized series of surgical patients showed protection against DVT and a markedly decreased incidence of PE (7). LMWH is composed entirely of lower-molecular-weight heparin moieties and has the benefit of lowering the risk of bleeding complications. Other advantages include a lower incidence of the heparin-induced thrombocytopenia (HIT) syndrome and lower risks of osteopenia with long-term use. Several different brands of LMWH are available and the dosing for prophylaxis varies among the brands (8).

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Figure 5 (A) Longitudinal view using the duplex scan to identify normal flow in the superficial femoral artery (SFA) and superficial femoral vein (SFV). (B) Longitudinal view using the duplex scan demonstrating normal SFA and loss of venous flow in the SFV caused by thrombus. (C) Duplex scan of the greater saphenous vein showing nonoccluding thrombus identified by arrows. (D) Transverse view of the SFA and SFV demonstrating no flow in a completely thrombosed SFV.

Colditz et al. (9) evaluated general surgery patients using a variety of different types of prophylaxis. The incidence of DVT using the fibrinogen uptake test or venography was estimated to be 27% without any therapy, while those treated with subcutaneous heparin had an incidence of 9.6%, those with compression stockings 6.3%, and those with pneumatic compression devices 17.6%. A combination of heparin and stockings revealed an incidence of DVT of 6.3%, and stockings with intermittent pneumatic compression revealed an incidence of 4.5% (9). Indications for prophylaxis depend upon the type of surgery as well as associated risk factors. There are three levels of risk ranging from negligible risk not warranting treatment to high risk requiring multi-modality treatment. Patients undergoing outpatient surgery with no risk factors do not require prophylaxis, while patients undergoing major general surgery and/or having multiple risk factors need one of the prophylactic measures described above. Trauma, orthopedic and neurosurgical procedures, and/or

several risk factors require therapy with two of the above measures (e.g., compression devices and LMWH).

Treatment The goal of DVT management is to halt the propagation of thrombus, prevent PE, and promote resolution of existing clot to minimize the risk for postphlebitic syndrome. The mainstay of initial therapy for DVT is anticoagulation with heparin. This can take the form of an adjusted dose heparin drip or LMWH. Traditional dosing of a heparin drip consists of a 80 U/kg intravenous bolus followed by 18 U/kg/hr as a continuous infusion. The adequacy of anticoagulation is monitored by serial partial thromboplastin time levels, which are maintained between 60 and 80 seconds. Adjusted dose heparin therapy requires inpatient treatment. In contradistinction, LMWH is administered as subcutaneous injections and can be given in the outpatient setting. Treatment with LMWH has been shown to have a lower rate of major and minor bleeding as well as lower rates of PE than

Chapter 46: Venous and Lymphatic Abnormalities of the Limbs

adjusted dose heparin (10). A predictable pharmacokinetic profile obviates the need for any type of monitoring except in obese and renal failure patients. However, an anti-Xa assay can be obtained to verify efficacy with a target goal of between 0.6 and 1.0 IU/mL (11). Heparin limits any further propagation of the thrombus and prevents the formation of new thrombi. It does not break up the original thrombus. The affected extremity should be elevated when the patient is not ambulatory to reduce swelling and tenderness. Compression stockings should be used to prevent edema formation. Once the patient is anticoagulated, oral warfarin (Coumadin) therapy is begun. Warfarin acts by inhibiting the synthesis of the vitamin K–dependent clotting factors, II, VII, IX, and X. The prothrombin time (PT) or international normalized ratio (INR) is used to monitor warfarin therapy. The PT is brought to within 1.3 to 1.5 times the control value or an INR of 2 to 3 to maintain sufficient anticoagulation. Warfarin therapy should be continued for at least three months when identifiable risk factors are present, six months for an idiopathic thromboembolism, and 12 months to lifetime in patients with a hypercoagulable condition (12). Recently, a randomized trial demonstrated that lower INRs in the 1.5 to 2.0 range were as efficacious as higher doses with lower bleeding complications (13). Both heparin and warfarin therapy have serious potential side effects. Side effects associated with heparin treatment include bleeding, thrombocytopenia, hypersensitivity reaction, arterial thromboembolism, and osteoporosis in patients receiving long-term therapy (14). HIT syndrome is an antibody-mediated reaction to heparin leading to venous and arterial thromboses (15). A drop in the platelet count by 50% or skin lesions at the site of injection are highly suggestive of HIT syndrome. Laboratory assays that can detect HIT antibodies exist. Treatment of this syndrome involves cessation of heparin use and administration of direct thrombin inhibitors such as lepirudin or argatroban. Coumadin should be avoided in these patients because there are multiple reports of warfarin-induced venous limb gangrene. Arterial thromboembolism caused by HIT is the most severe complication. Complications associated with warfarin therapy include bleeding, skin necrosis, dermatitis, and a painful blue toe syndrome. Skin necrosis occurs in areas with significant adipose tissue such as thighs, breasts, and buttocks. It has been found that thrombosis of venules and capillaries supplying this region occurs as a result of an underlying protein C deficiency. Protein C and protein S are the first factors to decrease following the administration of Coumadin, which results in a transient hypercoagulable state amplified in patients with a preexisting protein C deficiency. A blue toe syndrome can occur secondary to bleeding into an arterial plaque, which results in distal embolization and ischemia. Warfarin is also teratogenic and should not be used during pregnancy. Heparin is the drug of choice during pregnancy and is given subcutaneously for long-term treatment. Fibrinolytic therapy for the management of DVT has been an area of great interest. Bleeding is the major complication associated with this course of treatment and is therefore contraindicated in patients who have had recent surgery, trauma, or hemorrhagic stroke. This technique is most effective when performed within 72 hours of the event and involves placement of a catheter directly into the thrombus and providing a local infusion of the lytic agent. Urokinase has been found to be more effective than streptokinase with fewer hemorrhagic and allergic complications (16).

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Objectives of this form of therapy include reduction of lower-extremity edema and pain and preservation of venous valve function. The presence of an iliofemoral DVT resulting in phlegmasia cerulea dolens or venous gangrene is a situation where thrombolysis or surgical thrombectomy is indicated to prevent limb loss. A more controversial indication for thrombolysis has been to preserve venous valve integrity by rapid resolution of the thrombus so as to protect against the development of valvular incompetence and subsequent postphlebitic syndrome (17). Early recanalization is important in preserving valve integrity; however, it is not clear that postphlebitic syndrome can be prevented by early lytic therapy (18,19). Quality-of-life assessments have shown a benefit to the use of lysis in patients with iliofemoral DVTs (20).

Complications of DVT Pulmonary Embolism The most fatal complication of DVT is a PE. PEs occur most frequently between 7 and 10 days postoperatively; if the symptoms remain unrecognized and untreated, the mortality is approximately 30%. Pathophysiology. A patient with a DVT of the lower extremity has a 50% chance of PE if the thrombus reaches the iliofemoral system. Even though thrombi may develop in the smaller veins of the calf, the risk of PE is less until the thrombus extends to the level of the femoral and iliac veins. Once embolization occurs and pulmonary blood flow is interrupted, a regional ventilation–perfusion mismatch and a bronchoconstrictive response are produced. Occlusion of more than 30% of the pulmonary vascular bed leads to a rise in pulmonary artery pressures, while a 50% occlusion leads to a fall in systemic pressures. The classic presentation is that of sudden pleuritic chest pain, dyspnea, and tachypnea. Other findings can include cough, tachycardia, and hemoptysis; hemoptysis is an uncommon finding indicative of pulmonary infarction. Physical examination reveals tachycardia, a prominent second heart sound, and cyanosis. Diagnosis. The clinical presentation of a PE mimics several other life-threatening conditions. An electrocardiogram is essential to exclude a myocardial infarction. Nonspecific ST and T wave changes are a nonspecific finding with PE. Chest X rays demonstrate enlargement of the central vasculature, a lack of the vascular markings with segmental or lobar ischemia (Westermark’s sign), or pleural effusion. A wedge-shaped infiltrate is occasionally seen. Arterial blood gas analysis shows hypoxemia coupled with alkalosis. Central venous pressure is elevated or normal if hemodynamic compensation has occurred, with a low central venous pressure essentially excluding PE. Definitive diagnosis of PE requires a computed tomography (CT) scan, ventilation–perfusion scan, or pulmonary arteriography. The ventilation–perfusion scan involves intravenous infusion of labeled albumin, to demonstrate perfusion abnormalities, combined with xenon gas inhalation, to demonstrate ventilation abnormalities. The combination of a poorly perfused area that shows excellent ventilation has the highest probability of representing a PE. Lesser concordances are given lower probabilities. With this technique, there is a high false-positive rate, because other diseases such as pneumonia or atelectasis can lead to similar results. Spiral CT scans of the chest with intravenous contrast have sufficient resolution to allow discrimination of thrombosis

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in the segmental pulmonary arteries (21). The sensitivity of this test varies widely (63–94%), but it has a high specificity (22). Pulmonary angiography remains the gold standard for identification of PE, but it is best reserved for situations where there is disagreement or uncertainty with the other imaging techniques. Treatment. Anticoagulation with heparin is the mainstay of treatment, and the technique of administration is the same as that described for DVT. Again, heparin therapy is initiated and is converted to oral anticoagulation for three to six months. Those patients in whom anticoagulation is contraindicated are candidates for inferior vena caval interruption to prevent further DVTs. Surgical thrombectomy is another procedure for treating iliofemoral DVTs. The indications for this treatment include phlegmasia, venous gangrene, and the inability of patients to be treated by anticoagulation or thrombolysis. A longitudinal venotomy is made in the distal common femoral vein and an Esmarch bandage (i.e., a wide, thick rubber band) is used to squeeze thrombus from the distal veins, while balloon catheters are used to extract clot from the proximal veins. A temporary arteriovenous fistula is often created to increase venous patency. This procedure is associated with an early patency rate of 87% and a significant decrease in the incidence of reflux following treatment (23). This procedure is somewhat morbid with potential for significant intraoperative blood loss and high rates of postoperative hematomas and groin infections. Although anticoagulation remains the mainstay of treatment for DVT, this therapy is contraindicated in some patients leaving them at high risk for the development of pulmonary emboli. To treat patients in this situation, several techniques to ‘‘filter’’ the vena cava have been explored. Inferior vena cava filters are made by several manufacturers but basically consist of a metallic screen that filters the vena cava of thrombi. These filters can be placed percutaneously and are usually deployed in the vena cava between the caval bifurcation and the lowest renal vein. Complications of inferior vena cava filters include misplacement, insertion-site DVT, migration of the filter, erosion of the device into the inferior vena cava wall and inferior vena cava obstruction, and PE (24,25). Although this procedure has a relatively low morbidity and mortality, the complications can be severe, and placement should be reserved for those patients who have absolute contraindications to traditional anticoagulation. Temporary filters are currently under investigation. For patients with a massive PE with refractory hypotension, an emergent pulmonary embolectomy may be required. A thoracotomy is performed to surgically remove the thrombus. Given the high mortality rate associated with this procedure, alternative approaches using interventional techniques have been developed although the only Food and Drug Administration–improved device is the Greenfield aspiration (26). Other devices and techniques use mechanical means to break up the thrombus. Thrombolytic therapy has also been used as an alternative treatment for those patients not in shock. Urokinase and tissue plasminogen activator are available lytic agents proven to be effective. The patient’s symptoms often improve quickly with the dissolution of the clot; however, no improvement has been seen in early mortality in patients with pulmonary emboli, who have been treated with thrombolytic therapy (27). In addition, there are significant complications secondary to bleeding, which have limited the use of this therapy.

Postphlebitic Syndrome Chronic venous insufficiency is a disabling venous disorder characterized by chronic lower-extremity edema, skin changes, and a propensity for ischemic ulcer formation. Postphlebitic syndrome is the chronic venous insufficiency that occurs following a DVT; 74% of patients with DVTs involving the femoral or iliac vein develop this condition (28). Clinical Presentation. Hyperpigmentation and edema of the lower extremity are the earliest signs of chronic venous insufficiency (Fig. 6). The swelling has been described as brawny and nonpitting. The hyperpigmentation is associated with a dermatitis (venous eczema) that leads to severe pruritus, frequently the initial complaint. In addition to the skin changes, the patient experiences an aching discomfort or night cramps that are aggravated by dependency and relieved with elevation. Venous claudication or a throbbing pain throughout the leg may occur with ambulation. These changes occur because valves in the deep venous system are compromised by the inflammation associated with a DVT. Blood is diverted into the communicating veins and into the superficial venous system with the development of venous hypertension and varicosities. Chronic venous hypertension leads to increased hydrostatic pressure at the capillary level, causing transudation of fluid and proteins as well as hemosiderin-laden red blood cells. The latter is responsible for the typical brownish skin pigmentation seen in these patients. From a histologic perspective, there is fat necrosis and fibrosis of the skin and subcutaneous tissue, a condition commonly referred to as lipodermatosclerosis. All these factors promote an inflammatory reaction conducive to skin breakdown and ulceration (29). Ultimately, patients can develop ulcerations in the region of the medial or lateral malleolus (Fig. 7). Diagnosis. The diagnosis is generally made on history and physical examination alone. In an attempt to distinguish chronic venous insufficiency from lymphedema, one can focus on the extent of edema. Edema secondary to venous insufficiency begins at the ankle and extends to involve primarily the lower leg, whereas lymphedema begins in the toes and foot and involves the entire extremity. Also, those patients with lymphedema do not have pigmentation of the skin. Diagnostic studies such as duplex scanning or

Figure 6 Chronic venous insufficiency with a small amount of stasis dermatitis around the right toes.

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Varicose Veins

Figure 7 Venous stasis ulcer in a patient with chronic venous insufficiency.

venography are infrequently performed. However, these tests can be used to locate areas of valvular incompetence if surgery is contemplated. Treatment. Ideally, the best treatment is prevention, and this is accomplished by applying the prophylactic measures against DVT previously described. Unfortunately, those who develop postphlebitic syndrome often require a lengthy and frustrating treatment course. It is essential that patients avoid prolonged standing and elevate their legs when sitting and sleeping. Graded compression stockings are also required to increase venous return. The skin is extremely fragile, and all efforts must be taken to avoid trauma. The skin is frequently dry, flaky, and itchy; therefore liberal use of skin emollients to prevent cracking and subsequent ulceration is necessary. When venous ulcers are present, an occlusive protective paste dressing such as Unna’s boot is used. This dressing allows for ambulation while providing compression and protection from trauma. Healing of venous ulcers is slow, and it is not uncommon to require many months of vigilant wound care. Erickson et al. examined 99 limbs with venous stasis ulcers. They found that those patients with low venous refill times (10 seconds), indicative of severe venous insufficiency, took significantly longer to completely heal. Although 91% of the ulcers healed at a median of three months, 56% of the healed ulcers recurred (20). Antibiotics should be reserved for the presence of frank cellulitis. If the ulcer is slow to heal, split thickness skin grafting can be employed if there is a viable granulation bed. A plethora of other wound care treatments have been suggested for use in venous stasis ulcers. Incompetent perforating veins contribute to elevated lower-extremity pressures and are often associated with recalcitrant ulcer healing. Ligation of these veins can be performed via an open approach or an endoscopic approach. Endoscopic perforating vein ligation results in healing of 88% of ulcers at one year, although approximately 28% of the ulcers will reoccur after two years (30). Overall, 50% of patients with postthrombotic deep venous involvement will remain ulcer-free at three years. Transplantation of competent valves from the axillary vein to the popliteal vein has also been employed to assist in the healing of ulcers. This technique results in ulcer healing rates of 79% with 50% to 65% remaining ulcer-free at six years (31). Other procedures that attempt to reduce reflux by surgically reconstructing incompetent valves have been investigated.

Varicose veins are superficial veins that have become dilated and tortuous (Fig. 8). The development of varicose veins is thought to result from venous valve incompetence and defects in the elastic properties of the vein wall. This venous valve incompetence can arise secondary to local trauma, thrombophlebitis, familial weakness in the valve structure, increased blood volume as seen after DVT, and hormonal changes especially during pregnancy (32–34). Incompetence leads to the unimpeded reflux of blood into the lower veins, which results in a significant rise in resting venous pressure. This chronic elevation of pressure contributes to the dilation and elongation of the veins and formation of varicosities. In addition, enzymatic abnormalities in the vein segments distant from the varicosities have been identified suggesting that additional biochemical defects may be present as well (35). Varicosities of the lower extremity can be classified as primary varicose veins or secondary varicose veins depending on the cause. Primary varicose veins have an unclear etiology and occur in individuals with no previous history of DVT. Studies of select populations have found that 20% to 40% of patients with primary varicosities have a family history of this disease (36). Women have a threefold greater risk of developing varicose veins compared to men. Female hormones are thought to contribute to this increased risk. Specifically, progesterone, a hormone whose levels are elevated during the second phase of the menstrual cycle and during pregnancy, causes passive dilation of varicosities (37). This distention renders the valves incompetent and initiates the formation of varicose veins or makes existing varicosities more symptomatic. Advancing age, obesity, and increased intra-abdominal pressure are other factors associated with primary varicose veins. Secondary varicose veins arise subsequent to the consequences of DVTs or as a result of venous obstruction. Venous obstruction may be caused by compression of the proximal venous system or by an intra-abdominal or pelvic tumor. The underlying increased venous pressure and vascular incompetence caused by these conditions result in reflux of blood from the deep to the superficial veins and the development of varicosities.

Clinical Presentation Varicose veins may or may not produce symptoms. In fact, many women have asymptomatic varicosities; however, they seek medical attention because of the unsightly blue, dilated, and tortuous veins. Those with symptoms usually complain of pain, fatigue, and aching, most noticeable in the calves

Figure 8 Varicose veins marked prior to vein stripping.

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and ankles especially at the end of the day. A feeling of heaviness is often described by the patient, particularly if the day has been spent standing or sitting without much walking. These symptoms are relieved by lying down, elevating the leg, or wearing elastic support stockings. The symptoms are exacerbated in women during their menstrual cycle because of venous valve dilation and worsening incompetence. Physical examination must include the abdomen and pelvis to access the possibility of venous obstruction secondary to a tumor. Examination of the legs should be performed in the standing and supine position. Varicose veins should be examined and palpated. Palpation can detect hidden varicosities in obese legs where they may not be visualized. Arterial pulses should be palpated as well.

Preoperative Testing There are several clinical tests that are applied to evaluate deep venous patency and valvular competence. The Perthes test is performed by placing a tourniquet around the proximal thigh snug enough to compress the superficial veins. The patient is then asked to walk, and attention is paid to the superficial ankle veins. If the veins become less prominent, the perforator and deep vein valves are intact; however, if the veins remain the same size, the perforator valves are incompetent. If the veins should become more prominent with exercise and the patient complains of pain, it can be assumed that there is significant deep venous insufficiency along with incompetent perforators. The retrograde filling test or Trendelenburg test aids in distinguishing between superficial valvular incompetence and perforator valvular incompetence. This procedure is done by elevating the leg initially to empty the veins and then placing a tourniquet over the saphenofemoral junction. The patient is then asked to stand, and the pattern of superficial venous refill is noted. If the varicosities do not fill on standing but do so immediately after releasing the tourniquet, the perforating veins are competent and the varicosities are secondary to superficial venous valve incompetence. If the patient stands and there is rapid filling of the varicosities with the tourniquet still in place, the perforator veins are incompetent secondary to deep venous disease. Duplex scanning can be performed to document venous valvular reflux as well. The test is important if there are clinical findings or a history suggestive of DVT. A handheld Doppler probe can also give the information needed to demonstrate deep venous patency and venous reflux especially at the saphenofemoral junction and at the level of the perforators (38). With the patient sitting on the examining table with the legs hanging over the edge of the table, the popliteal and posterior tibial veins can be examined for venous valvular insufficiency using compression above and below the Doppler probe. A delayed response with augmentation can indicate poor outflow secondary to obstruction. This is quite rare unless the patient has a history of DVT. Reflux heard during proximal compression confirms the diagnosis of venous valvular insufficiency. Venous reflux can be determined in a similar manner in the perforator veins. Saphenofemoral junction incompetence can be ascertained with the Doppler probe by placing it over the site and having the patient perform a Valsalva maneuver. This should be repeated with a tourniquet placed around the proximal thigh area. The reflux should disappear when the Valsalva maneuver is performed again with the tourniquet in place.

Treatment Conservative therapy is recommended for those with minimal varicosities or for those who desire to avoid invasive measures to cure the disease. Graded compression stockings can relieve the symptoms. The stockings are put on in the morning and removed at night. Patients are encouraged to avoid long periods of standing and to elevate the legs while sitting. Patients are also encouraged to walk as much as possible, which helps facilitate venous outflow by using the calf muscle pump. For those patients with symptomatic varicosities or for those who do not like the unsightly nature of their varicose veins, there are several treatment options for cure. Sclerotherapy has become a popular treatment option given its success and availability in an outpatient setting. Venous sclerotherapy is an ablative procedure that actually causes thrombosis in the affected vein, preferably without blood in the lumen (27). The procedure is performed by having the patient stand to mark the varicose veins and perforating veins. With the patient remaining standing, 23-gauge butterfly needles are placed approximately 1 cm apart along the course of the varicose veins (Fig. 9). One proceeds from distal to proximal until all veins have been cannulated. The patient is then placed in the supine position, and each site is injected with 0.5% to 1% of the sclerosing agent. The preferred sclerosing agent is sodium tetradecyl sulfate. Up to 60 sites and 30 mL of this solution can be used during venous sclerotherapy of one limb without sequelae. Immediately after the injection, the butterfly needle is removed, and a gauze and foam rubber pad are placed over the injection site. A stockinette and compression stocking are then placed over the gauze and pad. These should remain in place for

Figure 9 Multiple butterfly needles seen placed along the course of symptomatic varicose veins prior to injection of a sclerosing agent.

Chapter 46: Venous and Lymphatic Abnormalities of the Limbs

three weeks without being removed. The patient is encouraged to walk and remain active. When stocking, gauze, and pad are removed after three weeks, inspection and palpation can document the obliteration of the varicose vein. Those patients with saphenofemoral junction incompetence have high recurrence rates with venous sclerotherapy alone; therefore high ligation of the saphenofemoral junction should be performed in these patients either prior to or in conjunction with venous sclerotherapy. The main complication resulting after venous sclerotherapy is localized phlebitis, which occurs approximately 10% of the time (39,40). It is usually self-limiting and requires little intervention. Other uncommon complications include skin necrosis and ulceration secondary to extravasation of the sclerosing agent, intraluminal hematomas, and pigmentation of the surrounding skin. Vein stripping is an alternative method of treating varicose veins. This procedure requires a general or regional anesthetic and potential overnight stay in the hospital, even though most patients do go home the same day of the procedure. After marking all varicosities, the patient is given a general anesthetic, and attention is given to ligation of the saphenous vein and all other tributaries at the saphenofemoral junction. The vein stripper, a flexible rod, is then passed up the length of the vein from a distal venotomy at the level of the medial malleolus. The divided vein at the saphenofemoral junction is tied to the stripper, and the vein is removed with the instrument. Prior to stripping the vein, the other varicosities that are located away from the course of the stripper are treated. This is accomplished by making very small incisions by stabbing the skin over the vein with a No. 11 blade scalpel. The vein is grasped with fine forceps and divided. Each end is then avulsed by direct traction and removed through the incision. Bleeding is controlled with pressure; no ligatures are used. After removal of the stripper and therefore avulsion of the main venous channel from the perforators, the leg is wrapped firmly from the toes to the groin to allow the perforators to thrombose. The patient may resume daily activities but is encouraged to sit with the leg elevated and avoid prolonged standing. Complications after vein stripping are infrequent. They may include bleeding, with ecchymosis being the most common complication appearing three to five days postoperatively. This usually resolves within three to four weeks. Leg edema is common but is relieved by the use of the elastic support stockings. Hypoesthesia of the skin particularly at the level of the ankle may occur because of trauma to the saphenous and sural nerves (39). Other options for the treatment of varicosities include radio frequency and laser ablation of the saphenous vein. These techniques can be performed as outpatient procedures and, when combined with high ligation techniques, have reasonable success rates.

Superficial Thrombophlebitis Thrombophlebitis is a local inflammatory process that is restricted to the superficial veins. This condition most commonly occurs in varicose veins of the lower extremity below the level of the knee. Thrombophlebitis can also occur in association with intravenous cannulation, local trauma, and parenteral drug abuse. The typical clinical finding is an indurated, painful, and erythematous venous cord as a result of the thrombosed superficial vein. When thrombophlebitis involves the distal aspect of the greater saphenous venous system, therapy is managed

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in the outpatient setting. Treatment consists of symptomatic relief with bed rest, leg elevation, and warm compresses to the affected vein. Anticoagulation therapy is not warranted, because embolization virtually never occurs. However, if the thrombophlebitis extends above the knee, the risk of embolization exists. These patients require close observation in the hospital setting; if they remain refractory to symptomatic therapy, anticoagulation is initiated. If the thrombophlebitis worsens despite these interventions, excision of the affected vein may become necessary. Formation of an abscess in the thrombosed segment—septic thrombophlebitis—also mandates surgical excision.

VENOUS DISORDERS OF THE UPPER EXTREMITY Axillary/Subclavian Vein Thrombosis DVT of the upper extremity is now more common than previously reported. Earlier studies have cited a 1% to 2% incidence; however, with the increasing use of subclavian venous access, the incidence has risen (41). In fact, subclavian catheters are the number one cause of axillary and subclavian venous thrombosis (42,43). The presence of an upper-extremity DVT is not an innocuous event. Studies indicate that 12% of patients with an upper-extremity DVT have had a documented pulmonary embolization (43). The most common causes of axillary/subclavian vein thrombosis are (i) central venous lines or pacemakers; (ii) malignancy secondary to tumor compression of the vein or the hypercoagulable state associated with the malignancy; (iii) effort thrombosis or primary thrombosis, frequently referred to as Paget–Schroetter syndrome (42). Several factors are involved in the pathophysiology of effort thrombosis. First, there is compression of the axillary/ subclavian vein resulting in stasis. This may be due to an anomalous subclavius or anterior scalene muscle or the presence of a cervical rib. Second, repetitive movement at the level of the arm and shoulder may cause intimal tears in the vessel. Third, the stress of exercise may temporarily produce a hypercoagulable state. All these factors are conductive to the development of a thrombus. Primary or effort thrombosis develops clinically as an acute swelling of the involved extremity. It is frequently found in young otherwise healthy men with a recent history of trauma or heavy exertion. It is often noted after activities requiring the arm to be hyperabducted and externally rotated such as painting, throwing a baseball or football, or chopping wood. The involved extremity is usually the patient’s dominant arm.

Clinical Presentation The diagnosis of an upper-extremity DVT can be clinically difficult, especially in the case of iatrogenic injury from a central venous catheter. Often, it has a relatively indolent course that is infrequently associated with symptoms. The subtlety of this injury may be a result of the well-developed venous collateral system of the upper extremity and its ability to compensate in the case of obstruction of a major vein (44). With increased activity of the involved arm, arterial flow increases in the face of venous outflow obstruction resulting in venous hypertension. This promotes effusion of edema fluid into the tissues and distention of the superficial veins. This venous congestion may make the arm feel heavy or achy. In addition, a dusky cyanosis may develop especially with exertion and dependency of the arm. Physical examination discloses an obvious size and color discrepancy in the upper extremity. Frequently, the superficial veins of the hand and forearm are distended. This can be

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accentuated with the arm in the dependent position; the veins remain paradoxically distended when the arm is elevated.

Diagnosis Duplex scanning can often diagnose the problem by revealing the presence of the thrombus in the subclavian or axillary vein. Venography is used to locate the thrombus anatomically and provide access for thrombolytic therapy. Venographic demonstration of prominent collateral veins bypassing an obstructed axillary/subclavian vein provides the definitive diagnosis of thrombotic obstruction (Fig. 10).

Treatment The traditional treatment of axillary/subclavian vein thrombosis has been bed rest with limb elevation and anticoagulation. With this conservative approach, resolution without recurrence of symptoms has been reported in only 25% of patients (45). Other studies have shown that 50% to 70% of those with an upper-extremity DVT proceed to develop significant postphlebitic sequelae. The recent development of thrombolytic therapy has improved results dramatically. Most patients with primary or effort thrombosis are young and healthy and excellent candidates for thrombolysis. A successful protocol for effort thrombosis described by Machleder (46) recommends continuing the anticoagulation for three months. This is followed by transaxillary first rib resection and decompression with subsequent balloon angioplasty in cases of residual stenosis. Surgical decompression by first rib resection is advocated to correct the anatomic abnormality that caused the thrombosis and prevent recurrent thrombosis. Subsequent angioplasty or stenting of residual venous stenoses may be required. In cases of secondary thrombosis or catheter-related thrombosis, removal or correction of the offending cause is important. Thrombolytics and anticoagulation are the mainstay of therapy, and surgical intervention is usually not warranted. The most significant complication of upper-extremity DVT is pulmonary embolization. This was formerly thought to be almost nonexistent; however, rising numbers of upperextremity thrombosis studies have found a 12% incidence of pulmonary embolization (43). Other complications include postphlebitic changes and long-term disability, septic

thrombophlebitis, and loss of central venous access. A rare but morbid complication is venous gangrene. Severe edema of the fingers from venous hypertension can occlude arterial inflow and produce ischemia. This rare condition is best treated with thrombectomy or thrombolysis.

Superficial Thrombophlebitis The cause of superficial thrombophlebitis of the upper extremity is usually secondary to prolonged intravenous cannulation or infusion of an acidic fluid. The incidence has risen in the recent years, secondary to intravenous drug abuse. Treatment involves elevation, warm compresses, and pain control with nonsteroidal anti-inflammatory drugs. Surgical excision is reserved for septic thrombophlebitis.

LYMPHEDEMA Clinical Presentation The embryonic development of the lymphatic system begins with paired jugular and iliac sacs, the cisterna chyli, and a second retroperitoneal sac. It is from these sacs that the lymph vessels sprout and course throughout the body following the major venous pathways (Fig. 11). The cisterna chyli within the abdomen communicates with the paired jugular sacs by two lymphatic channels. The more predominant channel connecting the cisterna chyli to the left jugular bud is known as the thoracic duct. The elaborate network of lymphatic channels and regional nodes of the upper and lower extremities drain lymph into the thoracic duct and cisterna chyli, respectively, which then return the lymph to the venous system. The lymphatics are formed by a layer of endothelial cells with a discontinuous basement membrane in contrast to the continuous basement membrane found in blood capillaries (47). The lymphatic capillaries are a valved system that allows for unidirectional flow of lymph back to the venous system. The functions of the lymphatic system include resorption of interstitial fluid, particularly macromolecular proteins such as albumin; lymph node filtering of bacteria and other antigenic particles; and transport of certain substances (vitamin K and long-chain fatty acids) from the gastrointestinal tract to the venous system (48). During a 24-hour period, approximately 4 L of lymph flow containing 100 g of plasma protein is returned to the venous circulation.

Figure 10 (A) Venogram revealing a thrombosed right subclavian vein in a patient with effort thrombosis. (B) Following urokinase infusion, venous outflow is restored. However, an irregular proximal subclavian vein remains.

Chapter 46: Venous and Lymphatic Abnormalities of the Limbs

Figure 11 Normal anatomy of the lymphatic system.

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unilateral extremity swelling is venous disease, one must be able to distinguish between this and lymphedema. Edema secondary to venous disease presents with decreased capillary perfusion, a brawny discoloration of the involved skin, and ulceration. These findings are not indicative of lymphedema. Venous edema also improves after several hours of limb elevation, whereas lymphedema may require several days of extremity elevation to see a decrease in swelling. If there is any question in the differentiation, noninvasive evaluation is required. Duplex examination is the preferred test to rule out DVT. Lymphangiography is rarely used, because it is invasive and hazardous. Complications include dye allergy, oil embolism, and worsening lymphedema. Lymphoscintigraphy is now becoming the diagnostic procedure of choice for lymphedema. This test is noninvasive, without side effects, and has an overall diagnostic accuracy of 93% (50). The procedure involves a subcutaneous injection of a radiolabeled tracer particle specific for the lymphatics. The diagnosis of lymphedema is made when no radioactivity can be detected in the regional lymph nodes one hour after injection. A CT scan of the pelvis should also be considered in those patients with lymphatic obstruction to rule out malignancy.

Treatment

If the lymphatics fail to return this considerable volume of protein-rich fluid, lymphedema results. Lymphedema can be categorized as either primary (congenital) or secondary depending on its cause. Primary lymphedema is subdivided according to the age of onset; however, all forms are a result of the congenial abnormalities in the development of the lymphatic system. Congenital lymphedema is present from birth. Milroy’s disease is a hereditary form of congenital lymphedema with a sex-linked dominant pattern and characteristic hypoplasia of the lymphatic trunks. Lymphedema praecox becomes apparent from the adolescent years to age 35 and accounts for approximately 80% of the patients with congenital lymphedema. Lymphedema tarda occurs after age 35. The anatomic anomalies seen in these three forms of primary lymphedema include hypoplasia (the most common), aplasia, and hyperplasia (varicose pattern) of the lymphatic system. Primary lymphedema is found to affect women three times more frequently than it is found to affect men. The left leg is more often involved than the right, and the upper extremity is rarely involved. There is no single identifiable precipitating factor that can account for these findings. Secondary or acquired lymphedema is the most common form of lymphedema. Worldwide, the most common cause is filariasis, resulting in the obstruction of lymph nodes by the parasite Filaria bancrofti. In the United States, a common cause is surgical excision of lymph nodes and irradiation for malignant disease. For those who undergo mastectomy with axillary node dissection and radiation therapy, the incidence of lymphedema in the ipsilateral arm can be as high as 38% (49). Prostate carcinoma or other pelvic carcinomas can also cause lymphatic obstruction. Other causes of secondary lymphedema include trauma or infection.

Diagnosis The diagnosis of lymphedema can frequently be made on clinical grounds alone. Because the most common cause of

Palliative therapy is the only treatment option for lymphedema, because there is no medical or surgical cure. The goal of therapy is to reduce the limb volume and prevent infectious complications. Medical treatment begins with the treatment of the inciting event if the lymphedema is acquired as in the case of filariasis. Concomitantly, all patients must be fitted with compressive stockings. For those who are refractory to stocking compression, the use of pneumatic compression has been shown to be effective in reducing the swelling. Compression therapy and skin care alone has resulted in an 80% improvement rate in patients with lymphedema of the lower extremity (51). It is imperative that patients understand the chronicity of this disease and the need to maintain the use of compressive stockings. In addition, it must be stressed to these individuals that meticulous foot care is also necessary to avoid fungal infections. Pharmacotherapy has consisted of diuretics and benzopyrones. Diuretics are not recommended for routine use. They do remove excess fluid but do not change the high interstitial protein concentration and therefore do not alter the underlying pathology. Diuretics can provide short-term relief of the painfully swollen limb, when used on an intermittent basis. Benzopyrones have been demonstrated to reduce lymphedema by enhancing proteolysis via increased macrophage phagocytic activity (52). These drugs are used to provide slow relief of chronic lymphedema but have yet to be approved for use in the United States. Only a small percentage of the patients with lymphedema require surgical intervention. Indications for operation include an extremely edematous limb, resulting in loss of function, and recurrent infections that are refractory to medical management. The operations for lymphedema are divided into two categories—excisional and physiologic procedures. Excisional operations remove the lymphedematous subcutaneous tissue and skin. This is preferably accomplished by staged subcutaneous excisions with preservation of a viable skin flap for primary closure. If this is not possible, the wound can be covered with splitthickness skin grafts; however, breakdown and ulceration of the skin graft is common, and therefore primary closure is preferred.

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Part Six: The Peripheral Vascular System

Physiologic procedures are geared toward reconstruction of lymphatic drainage. Microlymphatic venous anastomosis has been used for the treatment of obstructive lymphedema. This procedure is not applicable to those with primary lymphedema caused by hypoplastic lymphatics. The patient must have patent lymphatic vessels distal to the site of obstruction. The microsurgical lymph vessel-tovein anastomosis is constructed to bypass the obstructed lymphatics. Long-term subjective improvement and limb volume reduction have been reported (53).

Complications Episodes of lymphangitis occur several times a year in patients with lymphedema. This accounts for a significant amount of morbidity and accelerates the process of fibrosis. When infection occurs, systemic antibiotics and bed rest with leg elevation are required. Streptococcus is the most common inciting organism. In patients with recurrent infections, prophylactic antibiotic therapy is recommended. A rare but deadly complication of lymphedema is lymphangiosarcoma. This malignant lesion is most frequently associated with postmastectomy lymphedema. It presents as a reddish purple lesion of the skin and subcutaneous tissue, usually appearing approximately 10 years after the onset of lymphedema. Treatment consists of radical amputation; however, prognosis remains dismal with an average survival of less than two years.

SUMMARY Of all the venous disorders, DVT is the most serious and potentially life threatening. More than 50% of those with DVT progress to develop postphlebitic syndrome with its disabling consequences. Prophylactic measures in the hospitalized surgical patient are essential. Heparin therapy remains the mainstay of care for the patient diagnosed with DVT, and the inferior vena cava filter is an effective alternative for those with contraindications to anticoagulation. Of the lymphatic disorders, lymphedema is the most important. This disorder may result from a congenital cause or may be the result of lymphatic obstruction from malignancy and radiation therapy. Therapy is based on external compression and avoidance of infection. A select group of patients with severe disease may benefit from operative intervention. All treatment is palliative, because there is no known cure for lymphedema.

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