Schwartz's Principles of Surgery, Ninth Edition

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Preface When I was asked to serve as editor-in-chief of this historic textbook of surgery, my goal was to preserve its excellent reputation, honoring the commitment of Dr. Seymour Schwartz and previous co-editors and contributors who upheld the highest standard for seven prior editions. I would like to thank all who helped achieve this goal, namely the outstanding contributions by the individual chapter authors and the meticulous dedication of the editorial board, all of whom share a passion for patient care, teaching, and surgery. It is this shared passion that has been channeled now into the creation of this new ninth edition; updating, improving, and finetuning it to secure its place as a leading international textbook of surgery. Each chapter has either been fastidiously updated or created anew by leaders in their respective surgical fields to ensure the highest quality of surgical teaching. Additionally, each chapter has been outfitted with quick-reference key points; highlighted evidencedbased references; and full-color illustrations, images, and information tables. Two new chapters have been added to this edition: Accreditation Council for Graduate Medical Core Competencies and Ethics, Palliative Care, and Care at the End of Life. One new component of this edition is the inclusion of a digital video disc of surgical videos. Many students already augment their more traditional classroom and practical education through the breadth of information available in the electronic realm, such as that available on AccessSurgery.com. This collection of operative and instructional videos, generously provided by chapter authors and editors, provides accurate visual instruction and technique to round out students' surgical training. It is the sincere hope of all who have contributed to this textbook that the knowledge of craft contained within will provide a solid foundation for the acquisition of skill, a haven for the continuation of education, and motivation for the pursuit of excellence. I wish to thank all of those responsible for the publication of this new edition, including the newest member of the editorial board, Dr. Jeffrey Matthews, as well as those who fearlessly signed on as contributors to our newly established international editorial board to provide regional perspective and commentary. I extend many thanks and gratitude to Marsha Loeb, Christie Naglieri, and all at McGraw-Hill for their guidance and knowledge throughout this process. I wish to thank Katie Elsbury for her dedication to the organization and editing of this textbook. I would also like to thank our families, whose love and support continue to make this book possible. F. Charles Brunicardi, MD, FACS

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Copyright Information Schwartz's Principles of Surgery, Ninth Edition Copyright © 2010, 2005, 1999, 1994, 1989, 1984, 1979, 1974, 1969 by The McGraw-Hill Companies, Inc. All rights reserved. Printed in the United States of America. Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a data base or retrieval system, without the prior written permission of the publisher. Book ISBN 978-0-07-1547703 Notice Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required. The editors and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication. However, in view of the possibility of human error or changes in medical sciences, neither the editors nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information contained in this work. Readers are encouraged to confirm the information contained herein with other sources. For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. This recommendation is of particular importance in connection with new or infrequently used drugs.

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Contributors Editor-in-Chief F. Charles Brunicardi, MD, FACS DeBakey/Bard Professor and Chairman, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas

Associate Editors Dana K. Andersen, MD, FACS Professor and Vice-Chair, Department of Surgery, Johns Hopkins University School of Medicine, Surgeon-in-Chief, Johns Hopkins Bayview Medical Center, Baltimore, Maryland Timothy R. Billiar, MD, FACS George Vance Foster Professor and Chairman of Surgery, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania David L. Dunn, MD, PhD, FACS Vice President for Health Sciences, State University of New York, Buffalo, Buffalo, New York John G. Hunter, MD, FACS Mackenzie Professor and Chair, Department of Surgery, Oregon Health and Science University, Portland, Oregon Jeffrey B. Matthews, MD, FACS Dallas B. Phemister Professor and Chairman, Department of Surgery, University of Chicago, Chicago, Illinois Raphael E. Pollock, MD, PhD, FACS Head, Division of Surgery, Professor and Chairman, Department of Surgical Oncology, Senator A.M. Aiken, Jr., Distinguished Chair, University of Texas M.D. Anderson Cancer Center, Houston, Texas

Contributors Louis H. Alarcon, MD Assistant Professor of Surgery, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Chapter 13, Physiologic Monitoring of the Surgical Patient Dana K. Andersen, MD, FACS Professor and Vice-Chair, Department of Surgery, Johns Hopkins University School of Medicine, Surgeon-in-Chief, Johns Hopkins Bayview Medical Center, Baltimore, Maryland Chapter 33, Pancreas Peter Angelos, MD Professor of Surgery and Chief of Endocrine Surgery, University of Chicago Medical Center, Chicago, Illinois Chapter 48, Ethics, Palliative Care, and Care at the End of Life Peter B. Angood, MD

Senior Advisor for Patient Safety, National Quality Forum, Washington, DC Chapter 12, Patient Safety Stanley W. Ashley, MD Frank Sawyer Professor of Surgery, Department of Surgery, Harvard Medical School, Boston, Massachusetts Chapter 28, Small Intestine Samir S. Awad, MD Associate Professor, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 1, Accreditation Council for Graduate Medical Education Core Competencies Adrian Barbul, MD Professor of Surgery, Department of Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland Chapter 9, Wound Healing Joel A. Bauman, MD Resident Physician, Department of Neurosurgery, University of Pennsylvania, Philadelphia, Pennsylvania Chapter 42, Neurosurgery Carlos Bechara, MD Assistant Professor of Surgery, Division of Vascular Surgery and Endovascular Therapy, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 23, Arterial Disease Greg J. Beilman, MD Professor of Surgery and Anesthesia, Chief of Surgical Critical Care/Trauma, University of Minnesota, Minneapolis, Minnesota Chapter 6, Surgical Infections Richard H. Bell Jr., MD Assistant Executive Director, American Board of Surgery, Philadelphia, Pennsylvania Chapter 33, Pancreas Robert L. Bell, MD, MA, FACS Director, Minimally Invasive Surgery, Director, Bariatric Surgery, Associate Professor of Surgery, Department of Surgery, Yale University School of Medicine, New Haven, Connecticut Chapter 35, Abdominal Wall, Omentum, Mesentery, and Retroperitoneum Arie Belldegrun, MD Director, Institute of Urologic Oncology at UCLA, Professor and Chief, Division of Urologic Oncology, Roy and Carol Doumani Chair in Urologic Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California Chapter 40, Urology Peleg Ben-Galim, MD Assistant Professor, Department of Orthopedic Surgery, Baylor College of Medicine, Houston, Texas Chapter 43, Orthopedic Surgery David H. Berger, MD Professor and Vice Chair, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 1, Accreditation Council for Graduate Medical Education Core Competencies Chapter 30, The Appendix

Walter L. Biffl, MD Associate Professor, Department of Surgery, Denver Health Medical Center/University of Colorado-Denver, Denver, Colorado Chapter 7, Trauma Timothy R. Billiar, MD, FACS George Vance Foster Professor and Chairman of Surgery, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Chapter 5, Shock Kirby I. Bland, MD Fay Fletcher Kerner Professor and Chairman, Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama Chapter 17, The Breast Mary L. Brandt, MD Professor and Vice Chair, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 1, Accreditation Council for Graduate Medical Education Core Competencies F. Charles Brunicardi, MD, FACS DeBakey/Bard Professor and Chairman, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 1, Accreditation Council for Graduate Medical Education Core Competencies Chapter 15, Molecular and Genomic Surgery Chapter 33, Pancreas Chapter 37, Inguinal Hernias Jamal Bullocks, MD Assistant Professor, Division of Plastic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 16, The Skin and Subcutaneous Tissue Catherine Cagiannos, MD Assistant Professor of Surgery, Division of Vascular Surgery and Endovascular Therapy, Baylor College of Medicine, Houston, Texas Chapter 23, Arterial Disease Joanna M. Cain, MD Chace/Joukowsky Chair of Obstetrics and Gynecology, Department of Obstetrics and Gynecology, Brown University, Portland, Oregon Chapter 41, Gynecology Rakesh K. Chandra, MD Assistant Professor, Department of Otolaryngology, Head and Neck Surgery, Northwestern University, Chicago, Illinois Chapter 18, Disorders of the Head and Neck Catherine L. Chen, MPH Fellow, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland Chapter 12, Patient Safety Changyi J. Chen, PhD Molecular Surgery Endowed Chair, Professor of Surgery and Molecular and Cellular Biology, Michael E. DeBakey

Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 23, Arterial Disease Orlo H. Clark, MD Professor of Surgery, Department of Surgery, UCSF/Mt. Zion Medical Center, San Francisco, California Chapter 38, Thyroid, Parathyroid, and Adrenal Patrick Cole, MD Resident, Division of Plastic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 16, The Skin and Subcutaneous Tissue Edward M. Copeland III, MD Emeritus Distinguished Professor of Surgery, Department of Surgery, University of Florida, College of Medicine, Gainesville, Florida Chapter 17, The Breast Janice N. Cormier, MD Associate Professor of Surgery, Department of Surgical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas Chapter 36, Soft Tissue Sarcomas Joseph S. Coselli, MD Professor and Cullen Foundation Endowed Chair, Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 22, Thoracic Aneurysms and Aortic Dissection C. Clay Cothren, MD Associate Professor of Surgery, Department of Surgery, University of Colorado, Denver, Denver, Colorado Chapter 7, Trauma Gregory A. Crooke, MD Assistant Professor of Cardiothoracic Surgery, New York University School of Medicine, New York, New York Chapter 21, Acquired Heart Disease Daniel T. Dempsey, MD Professor and Chair, Department of Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania Chapter 26, Stomach Robert S. Dorian, MD Chairman and Program Director, Department of Anesthesia, Saint Barnabas Medical Center, Livingston, New Jersey Chapter 47, Anesthesia of the Surgical Patient David L. Dunn, MD, PhD, FACS Vice President for Health Sciences, State University of New York, Buffalo, Buffalo, New York Chapter 6, Surgical Infections Chapter 11, Transplantation Geoffrey P. Dunn, MD Medical Director, Department of Surgery, Hamot Medical Center, Erie, Pennsylvania Chapter 48, Ethics, Palliative Care, and Care at the End of Life

Kelli M. Bullard Dunn, MD Associate Professor of Surgery, Department of Surgical Oncology, State University of New York, Buffalo, Buffalo, New York Chapter 29, Colon, Rectum, and Anus David T. Efron, MD Associate Professor of Surgery, Chief, Division of Trauma, Critical Care, and Emergency Surgery, Johns Hopkins Hospital, Baltimore, Maryland Chapter 9, Wound Healing Wafic M. ElMasri, MD Cancer Research Training Award Postdoctoral Fellow, Medical Oncology Branch, Molecular Signaling Section, National Institutes of Health, National Cancer Institute, Bethesda, Maryland Chapter 41, Gynecology Fred W. Endorf, MD Clinical Associate Professor, Department of Surgery, University of Minnesota, St. Paul, Minnesota Chapter 8, Burns Xin-Hua Feng, PhD Professor, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 15, Molecular and Genomic Surgery William E. Fisher, MD Professor, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 33, Pancreas Henri R. Ford, MD Vice President and Surgeon-in-Chief, Children's Hospital Los Angeles, Professor of Surgery and Vice Dean for Medical Education, Keck School of Medicine, University of Southern California, Los Angeles, California Chapter 39, Pediatric Surgery Aubrey C. Galloway, MD Seymour Cohn Professor, Chairman Department of Cardiothoracic Surgery, Department of Cardiothoracic Surgery, New York University School of Medicine, New York, New York Chapter 21, Acquired Heart Disease Francis H. Gannon, MD Associate Professor of Pathology and Orthopedic Surgery, Staff Pathologist, DeBakey VA Medical Center, Baylor College of Medicine, Houston, Texas Chapter 43, Orthopedic Surgery David A. Geller, MD Richard L. Simmons Professor of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania Chapter 31, Liver Nicole S. Gibran, MD Professor, Department of Surgery, Harborview Medical Center, Seattle, Washington Chapter 8, Burns Michael Gimbel, MD

Assistant Professor of Surgery, Division of Plastic and Reconstructive Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania Chapter 45, Plastic and Reconstructive Surgery Carlos D. Godinez Jr., MD Fellow and Clinical Instructor, Minimally Invasive Surgery, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland Chapter 34, Spleen Ernest A. Gonzalez, MD Assistant Professor of Surgery, Department of Surgery, University of Texas Health Science Center, Houston, Texas Chapter 4, Hemostasis, Surgical Bleeding, and Transfusion John A. Goss, MD Professor of Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 31, Liver M. Sean Grady, MD Charles Harrison Frazier Professor, Department of Neurosurgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania Chapter 42, Neurosurgery Tom Gregory, MD Associate Professor, Department of Obstetrics and Gynecology, Division of Urogynecology, Oregon Health and Science University, Portland, Oregon Chapter 41, Gynecology Tracy C. Grikscheit, MD Assistant Professor of Surgery, Department of Pediatric Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California Chapter 39, Pediatric Surgery Eugene A. Grossi, MD Professor of Cardiothoracic Surgery, New York University School of Medicine, New York, New York Chapter 21, Acquired Heart Disease David J. Hackam, MD, PhD Roberta Simmons Associate Professor of Pediatric Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Chapter 39, Pediatric Surgery Daniel E. Hall, MD Division of Trauma and General Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania Chapter 48, Ethics, Palliative Care, and Care at the End of Life Rosemarie E. Hardin, MD Resident Cardiothoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania Chapter 46, Surgical Considerations in the Elderly Michael H. Heggeness, MD, PhD Chairman, Division of Orthopedic Surgery, Baylor College of Medicine, Houston, Texas Chapter 43, Orthopedic Surgery

Lior Heller, MD Associate Professor, Division of Plastic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 16, The Skin and Subcutaneous Tissue Daniel B. Hinshaw, MD Veterans Administration Medical Center Chapter 48, Ethics, Palliative Care, and Care at the End of Life John B. Holcomb, MD Professor, Department of Surgery and Director, Center for Translational Injury Research, University of Texas Health Science Center, Houston, Texas Chapter 4, Hemostasis, Surgical Bleeding, and Transfusion Larry H. Hollier, MD Professor, Division of Plastic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 16, The Skin and Subcutaneous Tissue Abhinav Humar, MD Professor of Surgery, Department of Surgery, University of Minnesota, Minneapolis, Minnesota Chapter 11, Transplantation Kelly K. Hunt, MD Professor of Surgery, Department of Surgical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas Chapter 17, The Breast John G. Hunter, MD, FACS Mackenzie Professor and Chair, Department of Surgery, Oregon Health and Science University, Portland, Oregon Chapter 14, Minimally Invasive Surgery, Robotics, and Natural Orifice Transluminal Endoscopic Surgery Chapter 25, Esophagus and Diaphragmatic Hernia Chapter 32, Gallbladder and the Extrahepatic Biliary System Tam T. Huynh, MD Associate Professor of Surgery, Division of Vascular Surgery and Endovascular Therapy, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 23, Arterial Disease Bernard M. Jaffe, MD Professor Emeritus, Department of Surgery, Tulane University School of Medicine, New Orleans, Louisiana Chapter 30, The Appendix Badar V. Jan, MD PGY-4 Surgical Resident, Department of Surgery, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey Chapter 2, Systemic Response to Injury and Metabolic Support Kenneth M. Jastrow, MD Surgery Resident, Department of Surgery, University of Texas Health Science Center, Houston, Texas Chapter 4, Hemostasis, Surgical Bleeding, and Transfusion

Blair A. Jobe, MD Associate Professor of Surgery, The Heart, Lung and Esophageal Surgery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania Chapter 14, Minimally Invasive Surgery, Robotics, and Natural Orifice Transluminal Endoscopic Surgery Chapter 25, Esophagus and Diaphragmatic Hernia Tara B. Karamlou, MD, MSc Cardiothoracic Surgery Fellow, University of Michigan, Ann Arbor, Michigan Chapter 20, Congenital Heart Disease Elise C. Kohn, MD Senior Investigator and Section Head, Department of Molecular Signaling Section, Medical Oncology Branch, National Cancer Institute, Bethesda, Maryland Chapter 41, Gynecology Panagiotis Kougias, MD Assistant Professor, Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 23, Arterial Disease Rosemary A. Kozar, MD Associate Professor of Surgery, Department of Surgery, Memorial Hermann Hospital, Houston, Texas Chapter 4, Hemostasis, Surgical Bleeding, and Transfusion Jeffrey La Rochelle, MD Fellow and Clinical Instructor, David Geffen School of Medicine at UCLA, Los Angeles, California Chapter 40, Urology Geeta Lal, MD Assistant Professor of Surgery, University of Iowa Health Care, Carver College of Medicine, Department of Surgery, Division of Surgical Oncology and Endocrine Surgery, Iowa City, Iowa Chapter 38, Thyroid, Parathyroid, and Adrenal Thu Ha Liz Lee, MD Assistant Professor of Surgery, Department of Surgery, University of Cincinnati, Cincinnati, Ohio Chapter 1, Accreditation Council for Graduate Medical Education Core Competencies Scott A. LeMaire, MD Associate Professor and Director of Research, Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 22, Thoracic Aneurysms and Aortic Dissection Timothy K. Liem, MD Associate Professor of Surgery, Adjunct Associate Professor of Radiology, Division of Vascular Surgery, Oregon Health and Science University, Portland, Oregon Chapter 24, Venous and Lymphatic Disease Scott D. Lifchez, MD Assistant Professor, Department of Surgery, Division of Plastic Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland Chapter 44, Surgery of the Hand and Wrist

Peter H. Lin, MD Associate Professor of Surgery, Division of Vascular Surgery and Endovascular Therapy, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 23, Arterial Disease Xia Lin Associate Professor, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 15, Molecular and Genomic Surgery Joseph E. Losee, MD Associate Professor of Surgery and Pediatrics, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania Chapter 45, Plastic and Reconstructive Surgery Stephen F. Lowry, MD Professor and Chair, Department of Surgery, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey Chapter 2, Systemic Response to Injury and Metabolic Support James D. Luketich, MD Henry T. Bahnson Professor of Cardiothoracic Surgery, Chief, The Heart, Lung and Esophageal Surgery Institute, Department of Surgery, Division of Thoracic and Foregut Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania Chapter 19, Chest Wall, Lung, Mediastinum, and Pleura James R. Macho, MD Emeritus Professor of Surgery, Department of Surgery, University of California, San Francisco, San Francisco, California Chapter 37, Inguinal Hernias Michael A. Maddaus, MD Professor of Surgery, Department of Surgery, Division of General Thoracic and Foregut Surgery, University of Minnesota, Minneapolis, Minnesota Chapter 19, Chest Wall, Lung, Mediastinum, and Pleura Martin A. Makary, MD Mark Ravitch Chair in General Surgery, Associate Professor of Health Policy, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland Chapter 12, Patient Safety Jeffrey B. Matthews, MD, FACS Dallas B. Phemister Professor and Chairman, Department of Surgery, University of Chicago, Chicago, Illinois Funda Meric-Bernstam, MD Associate Professor, Department of Surgical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas Chapter 10, Oncology Gregory L. Moneta, MD Professor of Surgery, Division of Vascular Surgery, Department of Surgery, Oregon Health and Science University, Portland, Oregon Chapter 24, Venous and Lymphatic Disease Ernest E. Moore, MD Vice Chairman and Professor, Department of Surgery, University of Colorado, Denver, Denver, Colorado Chapter 7, Trauma

Katie S. Nason, MD Assistant Professor, Division of Thoracic Surgery, Department of General Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania Chapter 19, Chest Wall, Lung, Mediastinum, and Pleura Kurt D. Newman, MD Professor of Surgery and Pediatrics, Division of Surgery, George Washington University School of Medicine, Washington, DC Chapter 39, Pediatric Surgery Lisa A. Newman, MD Professor, Department of Surgery, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan Chapter 17, The Breast Margrét Oddsdóttir, MD* Professor of Surgery, Chief of General Surgery, Landspitali-University Hospital, Reykjavik, Iceland Chapter 32, Gallbladder and the Extrahepatic Biliary System Adrian E. Park, MD Campbell and Jeanette Plugge Professor and Vice Chair, Division of General Surgery, University of Maryland Medical Center, Baltimore, Maryland Chapter 34, Spleen Timothy M. Pawlik, MD Johns Hopkins University, Baltimore, Maryland Chapter 48, Ethics, Palliative Care, and Care at the End of Life Andrew B. Peitzman, MD Mark M. Ravitch Professor and Vice Chairman, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Chapter 5, Shock Jeffrey H. Peters, MD Chairman, Department of Surgery, University of Rochester Medical Center, Rochester, New York Chapter 25, Esophagus and Diaphragmatic Hernia Thai H. Pham, MD Fellow, Department of General Surgery, Oregon Health and Science University, Portland, Oregon Chapter 32, Gallbladder and the Extrahepatic Biliary System Raphael E. Pollock, MD, PhD, FACS Head, Division of Surgery, Professor and Chairman, Department of Surgical Oncology, Senator A.M. Aiken, Jr., Distinguished Chair, University of Texas M.D. Anderson Cancer Center, Houston, Texas Chapter 10, Oncology Chapter 36, Soft Tissue Sarcomas Charles A. Reitman, MD Associate Professor, Department of Orthopedic Surgery, Baylor College of Medicine, Houston, Texas Chapter 43, Orthopedic Surgery David A. Rothenberger, MD

Professor and Deputy, Department of Surgery, University of Minnesota, Minneapolis, Minnesota Chapter 29, Colon, Rectum, and Anus J. Peter Rubin, MD Director of the Life After Weight Loss Program, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania Chapter 45, Plastic and Reconstructive Surgery Ashok K. Saluja, MD Professor and Vice Chair, Department of Surgery, University of Minnesota, Minneapolis, Minnesota Chapter 33, Pancreas Philip R. Schauer, MD Chief of Minimally Invasive General Surgery, Cleveland Clinic, Cleveland, Ohio Chapter 27, The Surgical Management of Obesity Bruce Schirmer, MD Stephen H. Watts Professor of Surgery, University of Virginia Health System, Charlottesville, Virginia Chapter 27, The Surgical Management of Obesity Charles F. Schwartz, MD Assistant Professor of Cardiothoracic Surgery, New York University School of Medicine, New York, New York Chapter 21, Acquired Heart Disease Subhro K. Sen, MD Clinical Assistant Professor, Division of Plastic & Reconstructive Surgery, Department of Surgery, Stanford University Medical Center, Palo Alto, California Chapter 44, Surgery of the Hand and Wrist Neal E. Seymour, MD Professor, Department of Surgery, Tufts University School of Medicine, Chief of General Surgery, Baystate Medical Center, Springfield, Massachusetts Chapter 35, Abdominal Wall, Omentum, Mesentery, and Retroperitoneum Mark L. Shapiro, MD Associate Professor of Surgery, Associate Director Trauma Services, Department of Surgery, Duke University Medical Center, Durham, North Carolina Chapter 12, Patient Safety Kapil Sharma, MD Assistant Professor, Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 22, Thoracic Aneurysms and Aortic Dissection Vadim Sherman, MD, FRCSC Assistant Professor of Surgery, Director, Comprehensive Bariatric Surgery Center, Program Director, Minimally Invasive Fellowship, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 37, Inguinal Hernias G. Tom Shires III, MD Chair, Surgical Services, Presbyterian Hospital of Dallas, Dallas, Texas Chapter 3, Fluid and Electrolyte Management of the Surgical Patient

Brian Shuch, MD Chief Resident, Department of Urology, David Geffen School of Medicine, Los Angeles, California Chapter 40, Urology Michael L. Smith, MD Assistant Professor, Department of Neurosurgery, Albert Einstein College of Medicine, Bronx, New York Chapter 42, Neurosurgery Samuel Stal, MD Professor, Division of Plastic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Chapter 16, The Skin and Subcutaneous Tissue Ali Tavakkolizadeh, MB BS Assistant Professor of Surgery, Department of Surgery, Harvard Medical School, Boston, Massachusetts Chapter 28, Small Intestine Allan Tsung, MD Assistant Professor, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania Chapter 31, Liver Ross M. Ungerleider, MD Professor of Surgery, Department of Surgery, Oregon Health and Science University, Portland, Oregon Chapter 20, Congenital Heart Disease Christopher G. Wallace, MD Clinical and Research Microsurgery Fellow, Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, Chang Gung University and Medical College, Taipei, Taiwan Chapter 45, Plastic and Reconstructive Surgery Kasper S. Wang, MD Assistant Professor of Surgery, Department of Pediatric Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California Chapter 39, Pediatric Surgery Randal S. Weber, MD Professor and Hubert L. and Olive Stringer Distinguished Professor for Cancer Research and Chairman, Department of Head and Neck Surgery, University of Texas M.D. Anderson Cancer Center, Houston, Texas Chapter 18, Disorders of the Head and Neck Fu-Chan Wei, MD, FACS Professor and Chancellor, Department of Plastic Surgery, College of Medicine, Chang Gung University, Chang Gung Memorial Hospital, Taipei, Taiwan Chapter 45, Plastic and Reconstructive Surgery Richard O. Wein, MD Assistant Professor, Department of Otolaryngology-Head and Neck Surgery, Tufts New England Medical Center, Boston, Massachusetts Chapter 18, Disorders of the Head and Neck Jacob Weinberg, MD Assistant Professor, Department of Orthopedic Surgery, Baylor College of Medicine, Houston, Texas

Chapter 43, Orthopedic Surgery Karl F. Welke, MD Assistant Professor, Division of Cardiothoracic Surgery, Oregon Health and Science University, Portland, Oregon Chapter 20, Congenital Heart Disease Edward E. Whang, MD Associate Professor of Surgery, Department of Surgery, Harvard Medical School, Boston, Massachusetts Chapter 28, Small Intestine Michael E. Zenilman, MD Clarence and Mary Dennis Professor and Chairman, Department of Surgery, SUNY Downstate Medical Center, Brooklyn, New York Chapter 46, Surgical Considerations in the Elderly Michael J. Zinner, MD Moseley Professor of Surgery, Department of Surgery, Harvard Medical School, Boston, Massachusetts Chapter 28, Small Intestine Brian S. Zuckerbraun, MD Assistant Professor of Surgery, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Chapter 5, Shock

Video Contributors Daniel Albo, MD, PhD Chief, General Surgery and Surgical Oncology, Director, Colorectal Cancer Center, Michael E. DeBakey VAMC, Houston, Texas Hand Assisted Laparoscopic LAR Hand Assisted Laparoscopic Right Hemi-Colectomy John Bozinovski, MD, MSc, FRCSC Attending Cardiac Surgeon, Department of Surgery, Royal Jubilee Hospital, Victoria, British Columbia, Canada Open Surgical Treatment of Extent IV Thoracoabdominal Aortic Aneurysms F. Charles Brunicardi, MD, FACS DeBakey/Bard Professor and Chairman, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Knot Tying Suturing Laparoscopic Cholecystectomy on a Patient with Biliary Colic and Gall Stones Laparoscopic Nissen Fundoplication Laparoscopic Distal Pancreatectomy Totally Extra-Peritoneal (TEP) Hernia Repair Laparoscopic Adjustable Gastric Band and Hiatal Hernia Repair Laparoscopic Sleeve Gastrectomy Joseph F. Buell, MD Professor of Surgery, University of Louisville, Louisville, Kentucky Laparoscopic Left Hepatic Lobectomy for Benign Liver Mass

Orlo H. Clark, MD Professor of Surgery, Department of Surgery, UCSF/Mt. Zion Medical Center, San Francisco, California Bilateral Exploration Parathyroidectomy Steven D. Colquhoun, MD Surgical Director, Liver Transplantation, Comprehensive Transplant Center, Cedars-Sinai Medical Center, Associate Professor of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California Right-Lobe Living-Donor Liver Transplantation Joseph S. Coselli, MD Professor and Cullen Foundation Endowed Chair, Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Open Surgical Treatment of Extent IV Thoracoabdominal Aortic Aneurysms David A. Geller, MD Richard L. Simmons Professor of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania Laparoscopic Left Hepatic Lobectomy for Hepatocellular Carcinoma Carlos D. Godinez, MD Fellow and Clinical Instructor, Minimally Invasive Surgery, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland Laparoscopic Splenectomy Marlon Guerrero, MD Assistant Professor and Director of Endocrine Surgery, Department of Surgery, University of Arizona, Tucson, Arizona Bilateral Exploration Parathyroidectomy Shahzeer Karmali, BSc, MD, FRCSC Assistant Professor of Surgery, Minimally Invasive and Bariatric Surgery, University of Alberta, Edmonton, Alberta, Canada Laparoscopic Sleeve Gastrectomy Laparoscopic Adjustable Gastric and Hiatal Hernia Repair Geeta Lal, MD Assistant Professor of Surgery, University of Iowa Health Care, Carver College of Medicine, Department of Surgery, Division of Surgical Oncology and Endocrine Surgery, Iowa City, Iowa Bilateral Exploration Parathyroidectomy Scott A. LeMaire, MD Associate Professor and Director of Research, Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Open Surgical Treatment of Extent IV Thoracoabdominal Aortic Aneurysms Richard E. Link, MD Associate Professor of Urology, Director, Division of Endourology and Minimally Invasive Surgery, The Scott Department of Urology, Baylor College of Medicine, Houston, Texas Robotic-Assisted Laparoscopic Partial Nephractomy Robotic-Assisted Laparoscopic Radial Prostatectomy Paul Martin, MD Professor of Medicine, Chief, Division of Hepatology, Schiff Liver Institute/Center for Liver Dieseases, University of

Miami Miller School of Medicine, Miami, Florida Right-Lobe Living Donor Liver Transplantation Jeffrey B. Matthews, MD, FACS Dallas B. Phemister Professor and Chair, Department of Surgery, University of Chicago, Chicago, Illinois Laparoscopic Cystogastrostomy for Pancreatic Pseudocyst Nicholas N. Nissen, MD Assistant Surgical Director of the Multi-Organ Transplant Program, Center for Liver Diseases and Transplantation, Ceders-Sinai Medical Center, University of California, Los Angeles, Los Angeles, California Right-Lobe Living-Donor Liver Transplantation Adrian E. Park, MD Campbell and Jeanette Plugge Professor and Vice Chair, Division of General Surgery, University of Maryland Medical Center, Baltimore, Maryland Laparoscopic Splenectomy Fred Poordad, MD Chief, Hepatology and Liver Transplantation, Comprehensive Transplant Center, Cedars-Sinai Medical Center, Associate Professor of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California Right-Lobe Living-Donor Liver Transplantation Vivek N. Prachand, MD Assistant Professor of Surgery, Department of Surgery, University of Chicago, Chicago, Illinois Laparoscopic Cystogastrostomy for Pancreatic Pseudocyst Steven Rudich, MD, PhD Associate Professor of Surgery, Department of Surgery, University of Cincinnati, Cincinnati, Ohio Laparoscopic Left Hepatic Lobectomy for Benign Liver Mass Christopher R. Shackleton, MD Principal, QV Research Consultancy, Formerly Professor, Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California Right-Lobe Living-Donor Liver Transplantation Vadim Sherman, MD, FRCSC Assistant Professor of Surgery, Director, Comprehensive Bariatric Surgery Center, Program Director, Minimally Invasive Fellowship, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Laparoscopic Sleeve Gastrectomy Totally Extra-Peritoneal (TEP) Hernia Repair Laparoscopic Adjustable Gastric and Hiatal Hernia Repair Amit D. Tevar, MD Assistant Professor of Surgery, Department of Surgery, University of Cincinnati, Cincinnati, Ohio Laparoscopic Left Hepatic Lobectomy for Benign Liver Mass Mark C. Thomas, MD Assistant Professor, Department of Surgery, University of Cincinnati, Cincinnati, Ohio Laparoscopic Left Hepatic Lobectomy for Benign Liver Mass Tram Tran, MD Assisant Professor of Medicine, Geffen (UCLA) School of Medicine, Comprehensive Transplant Center, Cedars-Sinai

Medical Center, Los Angeles, California Right-Lobe Living-Donor Liver Transplantation John Moore Vierling, MD Professor, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Right-Lobe Living-Donor Liver Transplantation Scott Weldon, MA, CMI Supervisor, Medical Illustrator, Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Open Surgical Treatment of Extent IV Thoracoabdominal Aortic Aneurysms Steve Woodle, MD Professor, Chief, Division of Transplant Surgery, University of Cincinnati, Cincinnati, Ohio Laparoscopic Left Hepatic Lobectomy for Benign Liver Mass

International Advisory Board Gaurav Agarwal, MS (Surgery), FACS Additional Professor, Department of Endocrine and Breast Surgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India Äke Gösta Andrén-Sandberg, MD Chief, Department of Surgery, Karolinska University Hospital at Huddinge, Stockholm, Sweden Claudio Bassi, MD, FRCS Professor, Surgical and Gastroenterological Department, University of Verona, Verona, Italy Jacques Belghiti, MD Professor, Department of Surgery, University of Paris VII, Hospital Beaujon, Clichy, France Kent-Man Chu, MD Professor of Surgery, Chief, Division of Upper Gastrointestinal Surgery, Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China Eugen H. K. J. Faist, MD Department of Surgery, Ludwig-Maximilians University, Campus Grosshadern, Munich, Germany Mordechai Gutman, MD Head, Department of General Surgery, Meir Hospital, Kfar Saba, Israel Serafin C. Hilvano, MD, FPCS, FACS Professor and Chair, Department of Surgery, College of Medicine- Philippine General Hospital, University of the Philippines, Manila, Manila, Philippines Jamal J. Hoballah, MD, MBA Professor and Chairman, Department of Surgery, American University of Beirut Medical Center, Hamra District, Beirut, Lebanon Seon-Hahn Kim, MD Director of Robotic and MIS Center, Head of Colorectal Division, Professor, Department of Surgery, Korea University Anam Hospital, SungBook-gu, Seoul, South Korea

Yuko Kitagawa, MD Professor, Department of Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan J. E. J. Krige, MD, FRCS, FACS, FCS (SA) Professor of Surgery, Surgical Gastroenterology, Department of Surgery, University of Cape Town, Cape Town, South Africa Miguel Angel Mercado Diaz, MD Professor and Chairman, Department of General Surgery, National Institute of Medical Science and Nutrition, Mexico DF, Mexico Gerald C. O'Sullivan, MD, FRCSI, FACS (Hon) Professor of Surgery, University College Cork, Mercy University Hospital, Cork, Ireland Ori D. Rotstein, MD Surgeon-in-Chief, St. Michael's Hospital, Professor, Department of Surgery, University of Toronto, Toronto, Ontario, Canada John F. Thompson, MD Melanoma Institute Australia, Royal Prince Alfred and Mater Hospitals, Sydney, Australia, Discipline of Surgery, The University of Sydney, Sydney, Australia Garth Warnock, MD, MSc, FRCSC Professor and Head, Department of Surgery, Universtiy of British Columbia, Surgeon-in-Chief, Vancouver Teaching Hospitals, Vancouver, British Columbia, Canada Liwei Zhu, MD Department of Surgery, Tianjin Medical University Hospital, Tianjin, China *Deceased

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Note: Large images and tables on this page may necessitate printing in landscape mode. Copyright © The McGraw-Hill Companies. All rights reserved. Schwartz's Principles of Surgery > Chapter 1. Accreditation Council for Graduate Medical Education Core Competencies >

KEY POINTS 1. The Accreditation Council for Graduate Medical Education (ACGME) Outcomes Project changes the focus of graduate medical education from how programs are potentially educating residents to how programs are actually educating residents through assessment of competencies. 2. The six core competencies are patient care, medical knowledge, practice-based learning and improvement, interpersonal and communication skills, professionalism, and systems-based practice. 3. The Residency Review Committee recognizes the importance of simulators for technical training and mandated that all training programs have a skills laboratory by July 2008. A Surgical Skills Curriculum Task Force has developed a National Skills Curriculum to assist programs with training and assessing competency through simulators. 4. The ACGME has developed a professional development tool called the ACGME Learning Portfolio. This interactive web-based portfolio can be used as a tool for residents, faculty, and programs directors to allow for reflection, competency assessment, and identification of weaknesses. 5. There is much to be learned still, and programs should continue to share their experiences to identify benchmark programs.

ACCREDITATION COUNCIL FOR GRADUATE MEDICAL EDUCATION OUTCOMES PROJECT Technologic and molecular advances have fundamentally changed the way medicine is practiced. The Internet has revolutionized the way both physicians and patients learn about diseases. In addition, political and economic pressures have altered the way society views and reimburses medical care. The end result of these changes is that access to medical care, access to information about medical care, and the very nature of the doctor-patient relationship has changed.1 In response to this situation, the Accreditation Council for Graduate Medical Education (ACGME) Outcomes Project was developed. Dr. Leach stated that this initiative was based on three principles: (1) whatever we measure we tend to improve; (2) focusing on outcomes instead of processes allows programs flexibility to adapt based on their needs and resources; and (3) the public deserves to have access to data demonstrating that graduating physicians are competent.2 This initiative changed the focus of graduate medical education from how programs were potentially educating residents by complying with the accreditation requirements to how programs are actually educating residents through assessment of the program's outcomes. In 1999, the Outcomes Project identified six core competencies that would provide a conceptual framework to train residents to competently and compassionately treat patients in today's changing health care system. The six core competencies as

designated by the ACGME are patient care, medical knowledge, practice-based learning and improvement, interpersonal and communication skills, professionalism, and systems-based practice (Table 1-1).3 Starting in July 2001, the ACGME implemented a 10-year timeline to implement these concepts into medical education. The timeline was divided into four phases, allowing flexibility for individual programs to meet these goals (Table 1-2). 4

Table 1-1 Accreditation Council for Graduate Medical Education Core Competencies Core Competency

Description

Patient care

To be able to provide compassionate and effective health care in the modernday health care environment

Medical knowledge

To effectively apply current medical knowledge in patient care and to be able to use medical tools (i.e., PubMed) to stay current in medical education

Practice-based learning and improvement

To critically assimilate and evaluate information in a systematic manner to improve patient care practices

Interpersonal and communication skills

To demonstrate sufficient communication skills that allow for efficient information exchange in physician-patient interactions and as a member of a health care team

Professionalism

To demonstrate the principles of ethical behavior (i.e., informed consent, patient confidentiality) and integrity that promote the highest level of medical care

Systems-based practice

To acknowledge and understand that each individual practice is part of a larger health care delivery system and to be able to use the system to support patient care

Table 1-2 Accreditation Council for Graduate Medical Education Timeline Phase

Dates

Program Focus

Accreditation Focus

1. Forming an initial response to changes in requirements

July 2001–June 2002

Define objectives for residents to demonstrate learning the competencies

Develop operational definitions of compliance

Provide constructive citations and Review current approaches to recommendations with no evaluation of resident learning consequences Begin integrating the teaching and learning of competencies into residents' didactic and clinic experience

2. Sharpening the focus

July 2002–June 2006

Provide learning opportunities in all six competencies Improve evaluation process

Review evidence that programs are teaching and assessing the competencies Provide constructive citations early

Phase

Dates

Program Improve Focus evaluation process to obtain accurate resident performance on the six core competencies Provide aggregated resident performance data for the program's GMEC internal review

3. Full integration

July 2006–June 2011

Use resident performance data as basis for improvement and provide evidence for accreditation review Use external measures to verify resident and program performance levels

4. Expansion

July 2011–beyond

—

Accreditation Focus citations early Provide constructive in the phase and transition to citations with consequences later Review evidence that GMECs' internal reviews of programs include consideration of aggregated performance data

Review evidence that programs are making data-driven improvements Review external program performance measures and input from GMECs as evidence for achieving educational goals

Identify benchmark programs Adapt and adopt generalizable information about models of excellence Invoke community about building knowledge about good graduate medical education

GMEC = graduate medical education committee.

CORE COMPETENCIES The core competencies include six specific areas that have been designated as critical for general surgery resident training. Each surgical training program must provide an environment that is conducive to learning the core competencies, establish a curriculum that addresses each of the competencies, and assess that learning has taken place (see Table 1-1). The six core competencies are as follows5:

1. Patient Care. Residents must be able to provide patient care that is compassionate, appropriate, and effective for the treatment of health problems and the promotion of health. Residents: a. Will demonstrate manual dexterity appropriate for their level;

b. Will develop and execute patient care plans appropriate for the resident's level, including management of pain;

c. Will participate in a program that must document a clinical curriculum that is sequential, comprehensive, and organized from basic to complex. The clinical assignments should be carefully structured to ensure that graded levels of responsibility, continuity in patient care, a balance between education and service, and progressive clinical experience are achieved for each resident. 2. Medical Knowledge. Residents must demonstrate knowledge of established and evolving biomedical, clinical, epidemiological, and social-behavioral sciences, as well as the application of this knowledge to patient care. Residents: a. Will critically evaluate and demonstrate knowledge of pertinent scientific information, and

b. Will participate in an educational program that should include the fundamentals of basic science as applied to clinical surgery, including applied surgical anatomy and surgical pathology; the elements of wound healing; homeostasis, shock and circulatory physiology; hematologic disorders; immunobiology and transplantation; oncology; surgical endocrinology; surgical nutrition, fluid and electrolyte balance; and the metabolic response to injury, including burns. 3. Practice-Based Learning and Improvement. Residents must demonstrate the ability to investigate and evaluate their care of patients, to appraise and assimilate scientific evidence, and to continuously improve patient care based on constant self-evaluation and life-long learning. Residents are expected to develop skills and habits to be able to meet the following goals: a. Identify strengths, deficiencies, and limits in one's knowledge and expertise;

b. Set learning and improvement goals;

c. Identify and perform appropriate learning activities;

d. Systematically analyze practice using quality improvement methods, and implement changes with the goal of practice improvement;

e. Incorporate formative evaluation feedback into daily practice;

f. Locate, appraise, and assimilate evidence from scientific studies related to their patients' health problems;

g. Use information technology to optimize learning;

h. Participate in the education of patients, families, students, residents and other health professions;

i. Participate in mortality and morbidity conferences that evaluate and analyze patient care outcomes; and

j. Utilize an evidence-based approach to patient care.

4. Interpersonal and Communication Skills. Residents must demonstrate interpersonal and communication skills that result in effective exchange of information and collaboration with patients, their families, and health professionals. Residents are expected to:

a. Communicate effectively with patients, families, and the public, as appropriate, across a broad range of socioeconomic and cultural backgrounds;

b. Communicate effectively with physicians, other health professionals, and health related agencies;

c. Work effectively as a member or leader of a health care team or other professional group;

d. Act in a consultative role to other physicians and health professionals;

e. Maintain comprehensive, timely, and legible medical records, if applicable.

f. Counsel and educate patients and families; and

g. Effectively document practice activities.

5. Professionalism. Residents must demonstrate a commitment to carrying out professional responsibilities and an adherence to ethical principles. Residents are expected to demonstrate: a. Compassion, integrity, and respect for others;

b. Responsiveness to patient needs that supersedes self-interest;

c. Respect for patient privacy and autonomy;

d. Accountability to patients, society and the profession;

e. Sensitivity and responsiveness to a diverse patient population, including but not limited to diversity in gender, age, culture, race, religion, disabilities, and sexual orientation;

f. High standards of ethical behavior; and

g. A commitment to continuity of patient care. 6. Systems-Based Practice. Residents must demonstrate an awareness of and responsiveness to the larger context and system of health care, as well as the ability to call effectively on other resources in the system to provide optimal health care. Residents are expected to: a. Work effectively in various health care delivery settings and systems relevant to their clinical specialty;

b. Coordinate patient care within the health care system relevant to their clinical specialty;

c. Incorporate considerations of cost awareness and risk-benefit analysis in patient and/or populationbased care as appropriate;

d. Advocate for quality patient care and optimal patient care systems;

e. Work in inter-professional teams to enhance patient safety and improve patient care quality;

f. Participate in identifying system errors and implementing potential systems solutions;

g. Practice high quality, cost effective patient care;

h. Demonstrate knowledge of risk-benefit analysis; and

i. Demonstrate an understanding of the role of different specialists and other health care professionals in

overall patient management. The goal of any surgical training program is to train physicians to provide the highest quality of patient care. The core competency mandates have set into motion changes in education that result in measurable outcome-based training. The challenge of the surgical educator is to develop innovative and focused learning techniques to accomplish this mandate within an 80-hour work week.

Patient Care Patient care is the foundation for the practice of clinical medicine and must be addressed early and continuously during residency. Historically, patient care has been taught by an apprenticeship model; in other words, by the residents' spending time with attending physicians on the wards or in the operating rooms.6 However, this training method has to be re-evaluated as a result of the ever-increasing constraints and changes in our health care system. Increasing public awareness of medical legal errors has resulted in heightened scrutiny with regard to patient safety issues.1 In addition, there are increasing concerns related to the perceived financial setback and medical-legal impact of resident training in the operating room.7 Even with the inherent flexibility provided by the ACGME, all of these factors, coupled with the work hour restrictions,8 make surgical training in the modern health care system an especially challenging endeavor. Not only must educators impart the medical knowledge of caring for patients and new advances in patient care, but they must also impart the technical skills necessary to perform complex surgical procedures. One of the subcompetencies under patient care is that residents "will demonstrate manual dexterity appropriate for their level." 5 Traditionally, the operating room has been used to train residents in the technical aspects of patient care by "see one, do one, and teach one." A study by Velmahos and colleagues evaluated the knowledge and technical skills of residents who were randomly assigned either to training using the traditional approach or to training in a surgical skills laboratory using the principles of cognitive task analysis. This study revealed that the residents who trained using the laboratory approach had improved medical knowledge and technical skills.9 Multiple studies like the one previously mentioned have revealed improved performance with simulators and advocated their use in technical skills training.10–12 Having recognized the importance of incorporating simulation training into today's residency, the Residency Review Committee (RRC) mandated that all surgery programs be required to have a surgical skills laboratory by July 2008 to maintain their accreditation.1 3 To assist programs, the Surgical Skills Curriculum Task Force, a joint project of the American College of Surgeons (ACS) and the Association of Program Directors in Surgery, developed a standardized skills curriculum. 14,15 This curriculum was developed in three phases (Table 1-3): phase I with modules for junior residents, phase II for senior residents, and phase III for team training. Another resource that programs may use in developing a surgical skills curriculum is the Fundamentals of Laparoscopic Surgery (FLS) program. This program is endorsed by the ACS and the Society of Gastrointestinal and Endoscopic Surgeons. The FLS consists of a comprehensive curriculum with hands-on skills training and an assessment tool designed to teach and assess the fundamentals of laparoscopic surgery.1 6 Future goals for surgical education include a method to ensure that residents are "certified" and deemed competent to perform a procedure in a simulator environment before allowing residents to perform that particular procedure in the operating room.1 7

Table 1-3 National Skills Curriculum Phases and Launch Dates Phase

Dates

I

July 2007

Basic/core skills and tasks

II Advanced procedures

January 2008

III Team-based skills

July 2008

The RRC has mandated that all residency programs develop a surgical skills laboratory, and the majority of program directors feel that this is an important part of residency training. However, a study by Korndorffer and associates just before the mandate was issued revealed that only 55% of the 162 programs that replied to the survey had a surgical skills laboratory facility.1 8 The average cost to develop a laboratory has been reported as $133,000 to $450,000, but the cost can range from $300 to $3 million.18,19 Kapadia and colleagues surveyed 40 programs with surgical skills laboratories in place and found that funding came from industry (68%), surgery departments (64%), hospitals (46%), and other sources (29%). They also found a wide variation in the size of the facility, location, availability of simulators, protected time for skills training, and curriculum. This study also revealed that 65% of the programs believed that it was somewhat difficult to recruit faculty members to staff the laboratory; however, this could be related to the fact that 69% of the laboratories did not offer any faculty incentive to teach.1 9 These studies suggest that although most surgical educators believe that surgical skills laboratories are important for resident education, there is still much room for improvement and standardization. In addition to technical competency, residents are expected to "develop and execute patient care plans appropriate for the resident's level, including management of pain."5 This can be reinforced during attendance at rounds and integrated into many of the conferences that are currently available in many surgery programs, such as grand rounds and the morbidity and mortality conference.20,21 Prince and others demonstrated in an institutional study that use of an interactive format for the morbidity and mortality conference improved the educational value of the conference for residents at all levels.2 2 Rosenfeld restructured the morbidity and mortality conference to make it more competence based. For example, each patient case was further divided into separate categories such as patient communication, ethical dilemmas, system problems, and practice-based improvement to enhance patient care.2 0 Stiles and associates developed a morning report conference after the implementation of the night float system to improve patient sign-out procedures. They found that this forum not only helped to improve communication but also allowed for teaching, discussion of patient care plans, and direct evaluation of resident competence.2 3

Medical Knowledge The ACGME has mandated that "residents must demonstrate knowledge of established and evolving biomedical, clinical, epidemiological, and social-behavioral sciences, as well as the application of this knowledge to patient care."5 Surgery has undergone an exponential growth in new procedures and technology. With this explosion in medical innovation, training programs are posed with the daunting task of not only teaching the technical aspects of surgery, but also imparting the basic science and fundamentals of surgical diseases. Furthermore, development of the field of molecular biology and its application to surgical diseases has mandated that surgeons understand the basic molecular mechanisms of each disease process.24,25 The new era of molecular biology requires understanding the complex science that can lead to

advances such as molecular fingerprinting techniques to tailor treatments that are specific for each individual patient. Other, more cognitive tools such as how to critically review literature and how to logically evaluate the relevance of a study must also be imparted to residents so that they can correctly apply findings of the latest medical studies to each individual patient. The ACGME mandates that residents "will participate in an educational program that should include the fundamentals of basic science as applied to clinical surgery, including applied surgical anatomy and surgical pathology; the elements of wound healing; homeostasis, shock and circulatory physiology; hematologic disorders; immunobiology and transplantation; oncology; surgical endocrinology; surgical nutrition, fluid and electrolyte balance; and the metabolic response to injury, including burns."5 The ability of a surgical program to adequately meet this educational challenge can be improved by using innovative learning techniques. Educational systems such as the SQR3 (Survey, Question, Read, Recite, and Review) system of studying,2 6 the Pimsleur model,2 7 and Rosetta Stone learning techniques2 8 are all tools that can aid in the understanding and application of advances in a rapidly changing surgical field. The authors' surgery residency program combined adult learning principles with some of these learning techniques into a problem-based learning program that met weekly after grand rounds. This mandatory, focused curriculum for the residents incorporated both basic science and its clinical application in an interactive and collaborative format. This educational format led to high resident satisfaction and also a sustainable increase in resident American Board of Surgery In-Training Examination scores.29,30 Residents are also expected to "critically evaluate and demonstrate knowledge of pertinent scientific information."5 Residents can be taught early how to critically review the literature using the format of a journal club. The journal club is a widely used technique through which to disseminate the latest in medical knowledge. Even as early as the late 1980s, a study in the Journal of the American Medical Association found that residents who participated in a journal club had improved reading habits and improved medical knowledge compared with their peers who did not participate in a journal club.3 1 The wide use of journal clubs in surgery education can be seen as a necessary foundation for medical education. In one survey, over 65% of general surgery residency programs have a journal club that meets at least once a month to discuss relevant surgical and medical topics.3 2 MacRae and others took this approach a step further by evaluating the effect of a multifaceted Internet-based journal club and found that this learning format improved the skills of the surgical residents to critically appraise the medical literature.3 3 Many online resources are available for residents that provide an abundant amount of material for study, reference, and interactive learning.34–36 In particular, AccessSurgery provides an extensive online resource with medical data and operative techniques, with a core curriculum organized around the ACGME mandates.3 4 Finally, and perhaps most importantly, it must be conveyed to surgical trainees that surgery is a lifelong learning process, and the ability to continue building on one's medical knowledge is critical for a successful surgical career.

Practice-Based Learning and Improvement The third ACGME mandate states that "residents must demonstrate the ability to investigate and evaluate their care of patients, to appraise and assimilate scientific evidence, and to continuously improve patient care based on constant self-evaluation and life-long learning."5 This mandate comes from the increasing public demand for accountability and increased demand for data regarding outcomes for specific surgeon.2 Practice-based learning and improvement involves a cycle of four steps: identify areas for improvement, engage in learning, apply the new knowledge and skills to a practice, and check for improvement.3 7 This ability to critically and impartially analyze one's practice patterns to continually improve patient care should

start early during training, so that this behavior becomes second nature for residents when they become practicing surgeons. In residency training, the simplest example of practice-based learning is the surgical morbidity and mortality conference. This conference traditionally allows for in-depth discussions of surgical cases and adverse patient outcomes. Complications are categorized (preventable, probably preventable, possibly preventable, and unpreventable) and areas of improvement are identified. Rosenfeld as well as Williams and Dunnington have reformatted this conference to make it more competence based by having residents assess themselves. Residents are required to fill out a practice-based improvement form and identify areas of improvement.20,38 Another innovative modality to teach practice-based learning was described by Canal and colleagues, who developed a 6-week curriculum in continuous quality improvement for surgery residents that included a specific project. In this project, the residents identified a need for quality improvement, implemented a plan for improvement, and developed a method to measure the improvement. These residents scored significantly higher in knowledge of and experience in quality improvement after completing this curriculum and felt that it was an effective and formal way to teach them the science of practice-based improvement.3 9 Clearly, for surgeons to identify areas of improvement, there has to be some method to allow for comparison and reflection. An interesting Internet-based learning portfolio called Computerized Obstetrics and Gynecology Automated Learning Analysis (KOALA) was developed for the obstetrics and gynecology residents in Canada. This portfolio encouraged self-analysis and self-directed learning by allowing residents to log patient encounters, list critical events and questions derived from these events, look up data used to answer these questions, and state how their practice patterns would be altered based on their reflections. Residents who used this method to reflect and critically analyze their performance scored significantly higher on the Self-Directed Learning Readiness Scale, looked forward to learning for life, and had a strong desire to learn new things.4 0 An avenue currently available for practicing surgeons and residents to analyze their outcomes is the ACS Case Log System. This system was developed to support practice-based learning and improvement by allowing surgeons to voluntarily report their own results and compare them to those of other surgeons enrolled in the system. This allows surgeons to critically evaluate their practice outcomes and identify areas that need improvement.4 1 To further improve practice patterns, the ACGME has mandated that trainees must understand the use of information technology systems to manage patient information and support clinical care. Technology is rapidly improving, and hospitals are increasing their efficiency by using electronic medical records. One of the best examples of this is the Computerized Patient Record System (CPRS) used by the Veterans Affairs (VA) hospital system. This fully computerized patient database allows easy access to all patient clinical data, including laboratory tests, radiographic studies, physician notes, and appointment times. Use of this central core information system also has allowed the VA health system to develop the National Surgical Quality Improvement Program (NSQIP).4 2 Using information from the CPRS, nurse reviewers are able to gather and input information into the NSQIP system. NSQIP has been the first prospective risk-adjusted outcomes-based program for comparing and improving surgical outcomes across multiple institutions. This program has revolutionized the reporting and quality control of surgical services within the VA system. Practice-based learning is complex and involves many components, including self-awareness, critical thinking, problem solving, self-directed learning, analysis of outcomes, use of information technology, and focus on evidence-based medicine to improve practice outcomes and patient care.5 This competency is multifaceted, and an extensive literature review by Ogrinc and associates found little instruction on how to

impart these important skills to our residents. Much work appears to be needed before an ideal curriculum can be developed. Future plans should be made for faculty to develop these skills and for programs to continually share their experiences.4 3

Interpersonal and Communication Skills The fourth competency mandated by the ACGME is that "residents must demonstrate interpersonal and communication skills that result in effective exchange of information and collaboration with patients, their families, and health professionals."5 Effective communication between physicians, patients, and other health care professionals is essential to the successful and competent practice of medicine and patient care. Studies reveal that physicians with good communication and interpersonal skills have improved patient outcomes and are subject to less medical litigation. 44–46 In support of this, a root cause analysis by the Joint Commission identified breakdown in communication as the leading cause of wrong-site operations and other sentinel events. 4 7 The ACS has developed a Task Force on Communication and Interpersonal Skills to specifically address this issue and encourage practicing surgeons to develop these important skills.4 8 The goal of this task force is to appropriately address the core competency of interpersonal skills and communication and to use novel educational techniques to improve these skills. Certain areas, such as palliative care and patient mortality, have not been a focus for surgeons or surgical trainees but are critical in the surgeon-patient relationship. Four areas in which surgeons can improve their communication skills have been identified in palliative care: the preoperative visit, and discussion of a poor prognosis, surgical complications, and death. 4 9 These are situations that all surgeons will face at some point in their careers, and the ability to communicate effectively and compassionately with patients during these stressful times is an important skill to develop. Fortunately, multiple techniques for imparting this particular skill have been described in the literature. The group at Southern Illinois University had teams of senior surgical faculty and a faculty member from the Department of Medical Humanities develop a case-based ethics curriculum that covered topics such as resource allocation, research ethics, substituted consent, competition of interests, truth telling, and communication.1 7 Other methods to teach communication skills have relied on the use of standardized patients.38,50,51 Yudkowsky and associates assessed the use of a patient-based communication skills examination. Their conclusion was that the use of a patient-based examination was able to demonstrate consistent results and that verbal feedback was beneficial for resident education on improvement of communication skills.5 0 Other recommended teaching strategies include observation with real-time feedback, role modeling, self-assessment, and videotaping.5 2 Residents also are expected to "work effectively as a member or leader of a health care team or other professional group"5 (Fig. 1-1). This is particularly important for surgeons, because caring for surgical patients requires a team approach to safely get the patient from the preoperative evaluation process, to the operating room, and through the postoperative course. Surgeons are typically the leaders of such teams; hence, it is important for residents to develop the necessary leadership skills during training. With less time spent in the hospital, the ability to learn from real-life situations is limited. Therefore, these principles need to be taught through other creative means such as didactic lectures or problem-based learning. Studies have revealed that formal leadership training not only improves communication skills 53,54 but also helps to develop conflict resolution skills.5 5 Awad and colleagues instituted a formal collaborative leadership training program and found that this format significantly increased the residents' views of leadership in the areas of alignment, communication, and integrity.5 6 Having recognized leadership training as a necessity for surgeons to thrive in today's medical environment, the ACS offers a course called "Surgeons as Leaders: From

Operating Room to Boardroom," whose purpose is to provide surgeons with the skills needed for effective leadership.5 7

Fig. 1-1.

Establishing interpersonal and communication skills equips residents with the necessary tools to communicate effectively with both patients and health professionals.

A subcompetency under communication and interpersonal skills is to "maintain comprehensive, timely, and legible medical records."5 Not only does communication occur in person, but physicians commonly communicate their plans and thoughts in the medical record. One of the predominant issues in health care is medical errors related to poor communication. The consequences of poor communication have been shown to cause delays in patient care, improper use of resources, and serious adverse events that lead to significant morbidity and mortality.5 8 This is especially important now, as many programs have instituted the night float system to maintain compliance with the work hour restrictions. For this system to work effectively, communication is integral for safe patient care during shift changes.59,60 One example of a creative approach to this new challenge of information transfer is a web-based system that allows for secure storage of patient information, maintenance of patient lists, access to laboratory values and vital sign data, and ability to compile this information to a sign-out list that can be passed on to a coverage team. 6 1 The residents that participated in the study of this system reported better sign-out quality, decreased time collecting data on prerounds, increased patient contact time, and improved continuity of care. Other medical centers also have begun to institute the use of computerized web-based systems for resident sign-out, and this format may become more widespread as the efficiency and safety of these systems become more

apparent. Not only should surgeons be technically competent and medically knowledgeable, but interpersonal and communication skills are also vital to patient care. The inherent nature of surgery often requires the bearing of bad news, disclosure of complications, and discussion of end-of-life issues. Learning and harnessing the skill of doing these things well during residency will provide a lifelong tool to effectively and compassionately care for patients.

Professionalism The core competency of professionalism is expressed as follows: "residents must demonstrate a commitment to carrying out professional responsibilities, adherence to ethical principles, and sensitivity to a diverse patient population." 5 The trainee should demonstrate respect, compassion, and integrity while involved in patient care. In addition, residents should understand that their patients' needs supersede their own selfinterest and that they are to be held accountable to their patients, society, and the profession.5 The ACS endorsed the Charter of Medical Professionalism as its Code of Professional Conduct in 2002.62,63 This model of professionalism is based on three principles. First, the physician should be dedicated to the patient's welfare. This should supersede all financial, societal, and administrative forces. Second, the physician should have respect for the patient's autonomy. This entails being honest and providing the patient with all the necessary information to make an informed decision. Third, the medical profession should promote justice in the health care system by removing discrimination due to any societal barriers.6 4 The ACS also has developed a Task Force on Professionalism to address the competency of professionalism for practicing surgeons and surgical residents. In 2004, this task force stated that professionalism is not just a desirable trait for surgeons to acquire peripherally but is the "central core" of the profession of surgery. The task force has stated the principles of professionalism and defined the responsibility of surgeons to commit to excellence.6 5 In addition, it also has created a multimedia program geared toward teaching residents and surgeons about the principles of professionalism through clinical vignettes and discussions.6 6 Kumar and associates evaluated this learning tool and found that residents who watched the ACS DVD had improved conceptual understanding of professionalism and scored higher on tests that evaluated these concepts than their peers who had not watched the video.6 7 Professionalism also has been taught by various other methods reported in the literature. A training program at the University of Washington set out to see if professionalism was teachable, learnable, and measurable. This group defined professionalism, developed a curriculum to teach professionalism, and evaluated these traits by a previously validated tool known as the Global Resident Competency Rating Form. They found that, after implementation of the curriculum, residents evaluated by the faculty were given significantly higher scores for traits that demonstrate professionalism such as (a) demonstrating respect, compassion, integrity, and reliability; (b) showing commitment to ethical principles; and (c) displaying sensitivity to patient culture, age, sex, and disabilities.6 8 Rosenfeld also described a curriculum for professionalism taught by leaders in the community. This 2-year course on professionalism dealt with various topics such as ethics, communication, professional development, respect, sensitivity, and health care delivery. The topics were presented in various formats via lectures, discussion panels, small groups, and videos. The residents were then assessed for competency through quizzes on clinical vignettes and 360-degree evaluations. The preliminary results revealed that residents were treating their patients and other health care workers in a more professional manner.6 9 Heru described the use of role playing and instructional videotapes in teaching

professionalism to residents. The residents who were taught using this format showed an increased awareness of unprofessional behavior and increased sensitivity to others, and were able to better deal with conflict.7 0 Teaching residents how to navigate through difficult situations and manage conflict is also another important aspect of professionalism, which can further promote an environment of integrity and mutual respect. Fisher and Ury have described four principles for successful conflict resolution: (a) maintain objectivity by not focusing on the participants but focusing on the problem, (b) relinquish the position of power and inflexibility to concentrate more on individual interests, (c) create outcomes in which both parties will have gains, and (d) make sure there are objective criteria for the negotiating process. All of these principles are related to maintaining an open mind and dialogue and yielding to principles, not pressure.7 1 These four principles can be integrated into a curriculum through various teaching techniques to help residents deal with conflict in a nonhostile and productive manner. The ACS has set standards on professional behavior in the Code of Professional Conduct. With these standards used as a conceptual framework, the development of professionalism should be a continuous process for any physician. Surgeons should constantly analyze and reflect on their behavior and continue to work toward actions based on integrity, honesty, respect, altruism, compassion, accountability, excellence, and leadership. This is an area in which surgical educators, acting as mentors and role models through daily interactions with their patients, residents, and peers, may be the most powerful teaching tool (Fig. 1-2).72,73

Fig. 1-2.

Dr. Michael E. DeBakey, a surgical pioneer and transformational health care leader, served as a mentor and role model to generations of residents and inspired professionalism and the pursuit of excellence. He is pictured here with a group of chief residents at the Baylor College of Medicine.

Systems-Based Practice The ACGME has mandated that "residents must demonstrate an awareness of and responsiveness to the larger context and system of health care, as well as the ability to call effectively on other resources in the system to provide optimal health care."5 In today's medical world, resources and finances are limited, and each health care provider must understand that the business aspect of medicine is closely interrelated with the effective delivery of care. As health care costs have grown, so have health care management organizations. Learning how to interact with these organizations is crucial for the improvement of health care delivery and allocation of resources. Some reports have demonstrated that surgeons feel deficient in the understanding of public health and the business aspects of surgery.7 4 The ACS has developed a Task Force on Systems-Based Practice to specifically address this particular competency.7 5 Systems-based practice is not inherently integrated into the surgical curriculum; therefore, it may be more challenging to incorporate and teach. Several methods for educating residents about systemsbased practice have been described in the literature. Dunnington and Williams have arranged for residents to participate in hospital committees that focus on quality improvement and patient safety. The residents keep a journal of the issues that are discussed during the meetings and reflect on how these issues will affect the way that they practice medicine in the future. Both committee members and residents have found this to be a constructive learning process.1 7 Davison and colleagues described a longitudinal systems-based practice into their 3-year-long core curriculum which included group discussions (risk management, discharge planning, patient relations), didactic lectures (structure of health care, pathway to surgery, current procedural terminology, governance, contract negotiations), and hospital training sessions. Personnel with expertise in health care delivery systems and health care management were enlisted to teach some of these courses.7 6 Englander and associates applied systems-based practice by involving residents in the process of cost-reduction efforts. The residents identified a project that was cost inefficient then identified key issues, devised improvement plans, and subsequently implemented them. This educational exercise saved the hospital over $500,000 per year. The authors concluded that involving residents in cost-reduction efforts helps to teach and assess the skill of systems-based practice.7 7 Conferences such as grand rounds, morbidity and mortality conferences, and morning reports have also been modified to teach the principles of systemsbased practice.20,21,23 Given today's changing health care economics, surgeons are faced with the need to understand the business aspects of medicine to care optimally for patients. This involves being able to work effectively in different health care settings, incorporating cost awareness and risk-benefit analysis in patient care, improving patient safety and quality of care, and identifying system errors and implementing solutions (Fig. 1-3).5 Unfortunately, this has not been an inherent part of surgical training, and many physicians do not feel that they have an adequate understanding of these concepts.7 4 However, there are strides in the right direction with various novel methods to incorporate systems-based practice into surgical curriculums.

Fig. 1-3.

One of the ACGME core competencies requires that residents demonstrate an awareness of and responsiveness to the larger context and system of health care, as well as the ability to call effectively on other resources in the system to provide optimal health care. The Texas Medical Center in Houston, Texas, encompasses 740 acres and 42 member institutions where residents must learn to navigate, comprehend, and utilize the larger health care system as a whole.

ASSESSMENT AND THE ACCREDITATION COUNCIL FOR GRADUATE MEDICAL EDUCATION LEARNING PORTFOLIO The ACGME not only has mandated the teaching of the six core competencies but also has stated that residents must be evaluated to ensure that they have acquired these necessary skills. There is little doubt that, in the future, these or similar core competencies will be used to assess practicing surgeons as well. Hence, the need to document the acquisition and maintenance of these competencies is important to all surgeons, not just those in training. Competence has been defined as "the ability to do something well measured against a standard, especially ability acquired through training."7 8 Miller has described a model of competency that consists of four levels: "knows," "knows how," "shows how," and "performs." Residents, early in their training, would most likely attain the level of "knows" and "knows how." This would be comparable to a resident's understanding the pathology and clinical diagnosis of appendicitis and the appropriate treatment algorithms. The "shows how" level would be demonstrated by a resident who could demonstrate how to perform an appendectomy while

being supervised by faculty on a simulator or animal model. The "performs" level is the competence level at which the surgeon could perform this operation without any supervision or assistance in a real-life clinical situation. The levels of competency are not based on postgraduate year but are based on the ability to specifically meet a defined objective set forth by a surgical curriculum.7 9 The most pressing question is how to implement a competency-based curriculum and, perhaps even more of a challenge, how to assess the six core competencies. An assessment tool should ideally be reliable, valid, reproducible, and also practical.8 0 The two most common evaluation tools in surgical programs have been the American Board of Surgery In-Training Examination (ABSITE) and the ward evaluation. The ABSITE is administered once a year and attempts to test the general medical knowledge and patient care knowledge of surgical trainees. A direct linear correlation has been described between the ABSITE score and the American Board of Surgery Qualifying Examination score,8 1 which emphasizes the need to perform at an adequate level on the ABSITE. ABSITE scores also have been found to be higher in programs that have instituted mandatory reading programs and focused problem-based learning education programs.29,82 Overall, the ABSITE remains a tried and true method of assessing the basic medical knowledge of surgical trainees. The second method of evaluation has been the ward evaluation. These evaluations are typically performed at the end of the rotation and are subject to biases related to factors such as memory and the general impression of the surgery faculty of the given resident. These evaluations often consist of subjective terms that globally define the residents, for example, excellent, good, and very good. However, these ratings do not provide any objective data on competence.8 3 Even though the ward evaluation provides general information on achievement of educational goals, the new ACGME mandates will require either revising these evaluations to make them more competence based or developing new methods for measuring outcomes. A number of programs have instituted novel evaluation tools to assess for competency in patient care and medical knowledge. The Operative Performance Rating System (OPRS) is an innovative tool used to assess the competence of patient care that was developed by Larson and colleagues. It is an Internet-based system for evaluating sentinel procedures performed by residents that assesses not only technical skills but also the intraoperative decision-making process. They found this to be a feasible and reliable method. The authors concluded that this may be a way to evaluate competence in patient care, track the development of surgical skills, identify problems early on, and certify competence in a particular procedure.8 4 Schell and Flynn described a web-based program for teaching and assessing medical knowledge and patient care. Residents were allowed to follow a self-paced curriculum by viewing a CD-ROM didactic lesson and participating in a minimally invasive skills laboratory to assess competency in the basics of minimally invasive surgery. They found that residents showed significant improvement in their surgical skills, and the trainees described a high satisfaction with this program and felt that it should be an integral component of their education.1 0 The Objective Structured Assessment of Technical Skills (OSATS) test was developed at the University of Toronto to assess technical competency. The test is administered in stations that simulate tasks performed in the operating room, such as a small-bowel anastomosis, placement of a T tube, control of inferior vena cava hemorrhage, and so on. The participants are graded by a surgical evaluator who completes two standardized grading forms for each station. One grading form covers the specific steps and technical points of the station (i.e., correct suture, use of forceps, etc), whereas the second form is a global rating scale that evaluates the flow of operation and more subjective but important aspects of an operation. The authors concluded that this method has high reliability and construct validity for assessing competency in technical skills. 8 5 Furthermore, the OSATS examination has been validated in a number of studies as accurately representing the technical

skills of a surgical trainee when compared with performance in carrying out a procedure on a live patient. 86,87 Virtual simulators have also been used effectively to teach and assess surgical skills, medical knowledge, and practice-based learning and improvement in a controlled environment.12,88 Other competencies, such as communication and professionalism, may require a more interactive and direct means for true assessment. The methods most described in the literature involve standardized patients and the 360-degree evaluations. Yudkowsky and colleagues described a method to assess communication and interpersonal skills, patient care, and professionalism known as the Communication and Interpersonal Skills Objective Structured Clinical Assessment (CIS-OSCE) examination. This examination was administered to residents in multiple specialties at the University of Illinois at Chicago and consisted of resident interaction with standardized patients on various matters such as obtaining informed consent, relaying bad news, and discussing domestic violence. They found this method of evaluation to be valid and feasible.5 0 The Patient Assessment and Management Examination (PAME) to access competencies such as patient care, communication and interpersonal skills, and professionalism has also been described. This examination consists of six stations with standardized patients. It entails an initial assessment, ordering and interpretation of test, discussion of the findings with the patient, and evaluation of a higher level of thinking with implementation of a treatment plan. These interactions are observed by a staff physician, which allows for direct assessment of competencies.38,51 The 360-degree evaluation to assess communication and professionalism has been described for various specialties. This process involves evaluation of the resident by various people who have had interactions with the resident, including patients as well as nurses and other ancillary staff. The resident's ability to communicate effectively and behave in a professional manner is evaluated based on a scale. This method has been found to be a valid and reliable method to assess for the competencies; however, it can be difficult to carry out.89–91 Practice-based learning and systems-based practice have been assessed through existing conferences. Rosenfeld as well as Williams and Dunnington revised their morbidity and mortality conference to allow for assessment of practice-based learning by having residents fill out a practice-based learning log. This allowed staff to determine whether the residents were able to identify key issues and implement improved practice patterns. 20,38 Stiles and associates developed a competency-based morning report format and felt that this was an ideal environment in which to directly assess many of the core competencies, including systemsbased practice and practice-based learning, through direct interactions with the residents.2 3 In 2004, the Association of Program Directors and the ACS worked together to develop a web-based system to evaluate all of the core competencies at the end of residents' rotations. This evaluation system was studied throughout multiple institutions and found to be both a reliable and valid method to assess the core competencies. 9 2 In addition, the ACGME has developed a professional developmental tool called the ACGME Learning Portfolio. This portfolio is an interactive web-based portfolio that allows residents to record, organize, and reflect back on their learning experiences. Residents, faculty, and program directors can use this portfolio as a tool to allow for constructive feedback, to monitor a resident's progress, and to identify areas of weakness. It will also enable program directors to evaluate the quality of their curriculums and isolate deficiencies that require improvement.9 3 Both of these tools use the web for data collection and evaluation, which allows for centralization and ease in interpretation of the data, permits use of real-time data to identify strengths and weaknesses, and may allow programs to provide competency-based performance data for the RRC. The number of assessment tools for the core competencies continues to increase as programs learn from trial and error. Programs should continue to share their work through

publications to identify programs with models of excellence that can be adopted at other institutions (see Table 1-2).

CONCLUSION The goal of the ACGME core competency mandate has been to ensure that patient care continues to improve into the twenty-first century with the development of benchmark programs and best educational practices. The goal of the modern surgical educator is to develop a better means to ensure that the material is properly taught and, even more importantly, truly learned. The defined core competencies provide an excellent framework for surgical education. This supplies an exciting foundation for the introduction of new educational initiatives and the development of novel educational programs through collaboration. These innovations should serve to move surgical education forward and allow for improved training of the surgeons of the future.

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82. de Virgilio C, Stabile BE, Lewis RJ, et al: Significantly improved American Board of Surgery In-Training Examination scores associated with weekly assigned reading and preparatory examinations. Arch Surg 138:1195, 2003. 83. Williams RG, Klamen DA, McGaghie WC: Cognitive, social and environmental resources of bias in clinical competence ratings. Teach Learn Med 15:270, 2003. [PMID: 14612262] 84. Larson JL, Williams RG, Ketchum J, et al: Feasibility, reliability and validity of an operative performance rating system for evaluating surgery residents. Surgery 138:640; discussion 647, 2005. 85. Reznick R, Regehr G, MacRae H, et al: Testing technical skill via an innovative "bench station" examination. Am J Surg 173:226, 1997. [PMID: 9124632] 86. Martin JA, Regehr G, Reznick R, et al: Objective structured assessment of technical skill (OSATS) for surgical residents. Br J Surg 84:273, 1997. [PMID: 9052454] 87. Datta V, Bann S, Beard J, et al: Comparison of bench test evaluations of surgical skill with live operating performance assessments. J Am Coll Surg 199:603, 2004. [PMID: 15454146] 88. Aggarwal R, Ward J, Balasundaram I, et al: Proving the effectiveness of virtual reality simulation for training in laparoscopic surgery. Ann Surg 246:771, 2007. [PMID: 17968168] 89. Wood J, Collins J, Burnside ES, et al: Patient, faculty, and self-assessment of radiology resident performance: A 360-degree method of measuring professionalism and interpersonal/communication skills. Acad Radiol 11:931, 2004. [PMID: 15288041] 90. Joshi R, Ling F, Jaeger J: Assessment of a 360-degree instrument to evaluate residents' competency in interpersonal and communication skills. Acad Med 79:458, 2004. [PMID: 15107286] 91. Larkin G, McKay M, Angelos P: Six core competencies and seven deadly sins: A virtues-based approach to the new guidelines for graduate medical education. Surgery 138:490, 2005. [PMID: 16213903] 92. Tabuenca A, Welling R, Sachdeva AK, et al: Multi-institutional validation of a web-based core competency assessment system. J Surg Educ 64:390, 2007. [PMID: 18063275] 93. http://www.acgme.org/acwebsite/portfolio/cbpac_faq.pdf: ACGME Learning Portfolio: A Professional Development Tool, 2008, Accreditation Council for Graduate Medical Education [accessed June 18, 2008].

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KEY POINTS 1. Systemic inflammation is characterized by exaggerated immune responses to either a sterile or infectious process. The cause of inflammatory activation needs to be addressed to resolve the dysregulated immune state. 2. An understanding of the signaling mechanisms and pathways underlying systemic inflammation can help guide therapeutic interventions in injured and/or septic patients. 3. Management of such patients is optimized with the use of evidence-based and algorithm-driven therapy. 4. Nutritional assessments, whether clinical or laboratory guided, and intervention should be considered at an early juncture in all surgical and critically ill patients. 5. Excessive feeding should be avoided in an effort to limit complications, including ventilator dependency, aspiration events, and infections.

SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORT: INTRODUCTION The immune system has developed to respond to and neutralize pathogenic micro-organisms as well as coordinate tissue repair. The inflammatory response to injury or infection involves cell signaling, cell migration, and mediator release. Minor host insults instigate a local inflammatory response that is transient and in most cases beneficial. Major host insults may propagate reactions that can become amplified, resulting in systemic inflammation and potentially detrimental responses. This topic is highly relevant because systemic inflammation is a central feature 1 of both sepsis and severe trauma. Understanding the complex pathways that regulate local and systemic inflammation is necessary to develop therapies to intervene during overwhelming sepsis or after severe injury. Sepsis, defined by a systemic inflammatory response to infection, is a disease process with an increasing incidence of over 900,000 cases per year. Trauma is the leading cause of mortality and morbidity for individuals under 50 years of age. This chapter reviews the autonomic, cellular, and hormonal responses to injury. These facets of the inflammatory response to injury and infection are discussed in reference to the specific response being considered.

SYSTEMIC INFLAMMATORY RESPONSE SYNDROME The systemic inflammatory response syndrome (SIRS) is characterized by a sequence of host phenotypic and metabolic responses to systemic inflammation that includes changes in heart rate, respiratory rate, blood pressure, temperature regulation, and immune cell activation (Table 2-1). The systemic inflammatory response includes two

general phases: (1) an acute proinflammatory state resulting from innate immune system recognition of ligands, and (2) an anti-inflammatory phase that may serve to modulate the proinflammatory phase. Under normal circumstances, these coordinated responses direct a return to homeostasis 2 (Fig. 2-1).

Table 2-1 Clinical Spectrum of Infection and Systemic Inflammatory Response Syndrome (SIRS) Infection Identifiable source of microbial insult SIRS Two or more of following criteria are met: Temperature Heart rate

38C (100.4F) or 36C (96.8F)

90 beats per minute

Respiratory rate

20 breaths per minute or Pa CO

2

32 mmHg or mechanical ventilation

White blood cell count 12,000/ L or 4000/ L or 10% band forms Sepsis Identifiable source of infection + SIRS Severe sepsis Sepsis + organ dysfunction Septic shock Sepsis + cardiovascular collapse (requiring vasopressor support) Term

PaCO

2

Definition

= partial pressure of arterial carbon dioxide.

Fig. 2-1.

Schematic representation of the systemic inflammatory response syndrome (SIRS) after injury, followed by a period of convalescence mediated by the counterregulatory anti-inflammatory response syndrome (CARS). Severe inflammation may lead to acute multiple organ failure (MOF) and early death after injury (dark blue arrow ). A lesser inflammatory response followed by excessive CARS may induce a prolonged immunosuppressed state that can also be deleterious to the host (light blue arrow ). Normal recovery after injury requires a period of systemic inflammation followed by a return to homeostasis (red arrow ). (Adapted with permission from Guirao X, Lowry SF: Biologic control of injury and inflammation: Much more than too little or too late. World J Surg 20:437, 1996. With kind permission from Springer Science + Business Media.)

CENTRAL NERVOUS SYSTEM REGULATION OF INFLAMMATION Afferent Signals to the Brain The central nervous system (CNS) plays a key role in orchestrating the inflammatory response. The CNS influences multiple organs through both neurohormonal and endocrine signals. Injury or infection signals are recognized by the CNS through afferent signal pathways (Fig. 2-2). The CNS may respond to peripheral inflammatory stimuli through both circulatory and neuronal pathways. Inflammatory mediators activate CNS receptors and establish phenotypic responses such as fever and anorexia. The vagus nerve has been described as highly influential in mediating afferent sensory input to the CNS. 3

Fig. 2-2.

Neural circuit relaying messages of localized injury to the brain (nucleus tractus solitarius). The brain follows with a hormone release (adrenocorticotropic hormone [ACTH], glucocorticoids) into the systemic circulation and by sympathetic response. The vagal response rapidly induces acetylcholine release directed at the site of injury to curtail the inflammatory response elicited by the activated immunocytes. This vagal response occurs in real time and is site specific. EPI = epinephrine; IL-1 = interleukin-1; NOREPI = norepinephrine; TNF = tumor necrosis factor. (Adapted and re-created with permission from Macmillan Publishers Ltd. Tracey KJ: The inflammatory reflex. Nature 420:853, 2002. Copyright 2002.)

Cholinergic Anti-Inflammatory Pathways The vagus nerve exerts several homeostatic influences, including enhancing gut motility, reducing heart rate, and regulating inflammation. Central to this pathway is the understanding of neurally controlled anti-inflammatory pathways of the vagus nerve. Parasympathetic nervous system activity transmits vagus nerve efferent signals primarily through the neurotransmitter acetylcholine. This neurally mediated anti-inflammatory pathway allows for a rapid response to inflammatory stimuli and also for the potential regulation of early proinflammatory mediator release, specifically tumor necrosis factor (TNF).4 Vagus nerve activity in the presence of systemic inflammation may inhibit cytokine activity and reduce injury from disease processes such as pancreatitis, ischemia and

reperfusion, and hemorrhagic shock. This activity is primarily mediated through nicotinic acetylcholine receptors on immune mediator cells such as tissue macrophages. Furthermore, enhanced inflammatory profiles are observed after vagotomy, during stress conditions.4 Experimental trials have studied this pathway to develop therapeutic interventions. Specifically, nicotine, which also activates nicotinic acetylcholine receptors on immune cells, has been shown to reduce cytokine release after endotoxemia in animal models.5

HORMONAL RESPONSE TO INJURY Hormone Signaling Pathways Hormones are chemical signals that are released to modulate the function of target cells. Humans release hormones in several chemical categories, including polypeptides (e.g., cytokines, glucagon, and insulin), amino acids (e.g., epinephrine, serotonin, and histamine), and fatty acids (e.g., glucocorticoids, prostaglandins, and leukotrienes). Hormone receptors are present on or within the target cells and allow signal transduction to progress intracellularly mostly through three major pathways: (1) receptor kinases such as insulin and insulin-like growth factor (IGF) receptors, (2) guanine nucleotide-binding or G-protein receptors such as neurotransmitter and prostaglandin receptors, and (3) ligand-gated ion channels that permit ion transport when activated. On activation, the signal is then amplified through the action of secondary signaling molecules. Intracellular signaling leads to downstream effects such as protein synthesis and further mediator release. Protein synthesis is mediated through intracellular receptor binding either by hormone ligands or through subsequently released secondary signaling molecules. These, together with the targeted DNA sequences, activate transcription. The prototype of the intracellular hormone receptor is the glucocorticoid receptor (Fig. 2-3). This receptor is regulated by the stressinduced protein known as heat shock protein (HSP), which maintains the glucocorticoid receptor in the cytosol; however, on ligand binding, HSP is released, and the receptor-ligand complex is transported to the nucleus for DNA transcription.6

Fig. 2-3.

Simplified schematic of steroid transport into the nucleus. Steroid molecules (S) diffuse readily across cytoplasmic membranes. Intracellularly the receptors (R) are rendered inactive by being coupled to heat shock protein (HSP). When S and R bind, HSP dissociates, and the S-R complex enters the nucleus, where the S-R complex induces DNA transcription, resulting in protein synthesis. mRNA = messenger RNA.

Virtually every hormone of the hypothalamic-pituitary-adrenal axis influences the physiologic response to injury and stress (Table 2-2), but some with direct influence on the inflammatory response or immediate clinical impact are highlighted here.

Table 2-2 Hormones Regulated by the Hypothalamus, Pituitary, and Autonomic System Hypothalamic Regulation Corticotropin-releasing hormone Thyrotropin-releasing hormone Growth hormone–releasing hormone Luteinizing hormone–releasing hormone Anterior Pituitary Regulation Adrenocorticotropic hormone Cortisol Thyroid-stimulating hormone Thyroxine Triiodothyronine Growth hormone

Gonadotrophins Sex hormones Insulin-like growth factor Somatostatin Prolactin Endorphins Posterior Pituitary Regulation Vasopressin Oxytocin Autonomic System Norepinephrine Epinephrine Aldosterone Renin-Angiotensin System Insulin Glucagon Enkephalins

Adrenocorticotropic Hormone Adrenocorticotropic hormone (ACTH) is a polypeptide hormone released by the anterior pituitary gland. ACTH binds with receptors in the zona fasciculata of the adrenal gland, which mediate intracellular signaling and subsequent cortisol release. ACTH release follows circadian rhythms in healthy humans; however, during times of stress this diurnal pattern becomes blunted because ACTH release is elevated in proportion to the severity of injury. Several important stimuli for ACTH release are present in the injured patient, including corticotropin-releasing hormone, pain, anxiety, vasopressin, angiotensin II, cholecystokinin, vasoactive intestinal polypeptide, catecholamines, and proinflammatory cytokines. Within the zona fasciculata of the adrenal gland, ACTH signaling activates intracellular pathways that lead to glucocorticoid production (Fig. 2-4). Conditions of excess ACTH stimulation result in adrenocortical hypertrophy. 7

Fig. 2-4.

Steroid synthesis from cholesterol. Adrenocorticotropic hormone (ACTH) is a principal regulator of steroid synthesis. The end products are mineralocorticoids, glucocorticoids, and sex steroids.

Cortisol and Glucocorticoids Cortisol is a glucocorticoid steroid hormone released by the adrenal cortex in response to ACTH. Cortisol release is increased during times of stress and may be chronically elevated in certain disease processes. For example, burninjured patients may exhibit elevated levels for 4 weeks. Metabolically, cortisol potentiates the actions of glucagon and epinephrine that manifest as hyperglycemia. Cortisol acts on liver enzymes by decreasing glycogenesis, while increasing gluconeogenesis. In skeletal muscle, cortisol facilitates the breakdown of protein and amino acids, and mediates the release of lactate. Subsequently, these substrates are used by the liver for gluconeogenesis. In adipose tissue cortisol stimulates the release of free fatty acids, triglycerides, and glycerol to increase circulating energy stores. Wound healing also is impaired, because cortisol reduces transforming growth factor beta (TGF- ) and insulin-like growth factor I (IGF-I) in the wound. This effect can be partially ameliorated by the administration of vitamin A. Adrenal insufficiency represents a clinical syndrome highlighted largely by inadequate amounts of circulating cortisol and aldosterone. Classically, adrenal insufficiency is described in patients with atrophic adrenal glands caused by exogenous steroid administration who undergo a stressor such as surgery. These patients subsequently manifest signs and symptoms such as tachycardia, hypotension, weakness, nausea, vomiting, and fever. Critical illness may be associated with a relative adrenal insufficiency such that the adrenal gland cannot mount an

effective cortisol response to match the degree of injury. Laboratory findings in adrenal insufficiency include hypoglycemia from decreased gluconeogenesis, hyponatremia from impaired renal tubular sodium resorption, and hyperkalemia from diminished kaliuresis. Diagnostic tests include baseline cortisol levels and ACTH-stimulated cortisol levels, both of which are lower than normal during adrenal insufficiency. Treatment strategies are controversial; however, they include low-dose steroid supplementation.8 Glucocorticoids have immunosuppressive properties that have been used when needed, as in organ transplantation. Immunologic changes associated with glucocorticoid administration include thymic involution, depressed cell-mediated immune responses reflected by decreases in T-killer and natural killer cell function, Tlymphocyte blastogenesis, mixed lymphocyte responsiveness, graft-versus-host reactions, and delayed hypersensitivity responses. In addition glucocorticoids inhibit leukocyte migration to sites of inflammation by inhibiting the expression of adhesion molecules. In monocytes, glucocorticoids inhibit intracellular killing while maintaining chemotactic and phagocytic properties. Glucocorticoids inhibit neutrophil superoxide reactivity, suppress chemotaxis, and normalize apoptosis signaling mechanisms but maintain neutrophil phagocytic function. In clinical settings manifested by hypoperfusion, such as septic shock, trauma, and coronary artery bypass grafting, glucocorticoid administration is associated with attenuation of the inflammatory response.

Macrophage Migration–Inhibiting Factor Macrophage migration–inhibiting factor (MIF) is a neurohormone that is stored and secreted by the anterior pituitary and by intracellular pools within macrophages. MIF is a counterregulatory mediator that potentially reverses the anti-inflammatory effects of cortisol. During times of stress, hypercortisolemia, and host immunosuppression, MIF may modulate the inflammatory response by inhibiting the immunosuppressive effect of cortisol on immunocytes and thereby increasing their activity against foreign pathogens.9

Growth Hormones and Insulin-Like Growth Factors Growth hormone (GH) is a neurohormone expressed primarily by the pituitary gland that has both metabolic and immunomodulatory effects. GH promotes protein synthesis and insulin resistance, and enhances the mobilization of fat stores. GH secretion is upregulated by hypothalamic GH–releasing hormone and downregulated by somatostatin. GH primarily exerts its downstream effects through direct interaction with GH receptors and secondarily through the enhanced hepatic synthesis of IGF-I. IGF circulates primarily bound to various IGF-binding proteins and also has anabolic effects, including increased protein synthesis and lipogenesis. In the liver, IGF stimulates protein synthesis and glycogenesis; in adipose tissue, it increases glucose uptake and lipid utilization; and in skeletal muscles, it mediates glucose uptake and protein synthesis. Critical illness is associated with an acquired GH resistance and contributes to decreased levels of IGF. This effect in part mediates the overall catabolic phenotype manifested during critical illness. In addition, GH enhances phagocytic activity of immunocytes through increased lysosomal superoxide production. GH also increases the proliferation of T-cell populations.1 0 Exogenous GH administration has been studied in critically ill patients and may be associated with worse outcomes, including increased mortality, prolonged ventilator dependence, and increased susceptibility to infection. 1 1 The mechanisms through which GH is associated with these outcomes are unclear, although GH-induced insulin resistance and hyperglycemia may contribute.

Catecholamines Catecholamines are hormones secreted by the chromaffin cells of the adrenal medulla and function as neurotransmitters in the CNS. The most common catecholamines are epinephrine, norepinephrine, and dopamine,

which have metabolic, immunomodulatory, and vasoactive effects. After severe injury, plasma catecholamine levels are increased threefold to fourfold, with elevations lasting 24 to 48 hours before returning toward baseline levels. Catecholamines act on both alpha and beta receptors, which are widely distributed on several cell types, including vascular endothelial cells, immunocytes, myocytes, adipose tissue, and hepatocytes. Epinephrine has been shown to induce a catabolic state and hyperglycemia through hepatic gluconeogenesis and glycogenolysis as well as by peripheral lipolysis and proteolysis. In addition epinephrine promotes insulin resistance in skeletal muscle. Catecholamines also increase the secretion of thyroid hormone, parathyroid hormones, and renin, but inhibit the release of aldosterone. Epinephrine also has immunomodulatory properties mediated primarily through the activation of beta2 receptors on immunocytes. Epinephrine has been shown to inhibit the release of inflammatory cytokines, including TNF, interleukin-1, and interleukin-6, while also enhancing the release of the anti-inflammatory mediator interleukin10. 1 2 Similar to cortisol, epinephrine increases leukocyte demargination with resultant neutrophilia and lymphocytosis. The immunomodulatory sequelae of catecholamines in patients during septic shock have yet to be clearly elucidated. Catecholamines exert several hemodynamic effects, including increased cardiac oxygen demand, vasoconstriction, and increased cardiac output. Catecholamines are used to treat systemic hypotension during septic shock. Because of the increased cardiac stress induced by catecholamines, however, cardioprotective strategies, including beta blockade for patients undergoing surgery, have shown significant benefit in reducing cardiac-related deaths.

Aldosterone Aldosterone is a mineralocorticoid released by the zona glomerulosa of the adrenal cortex. Aldosterone increases intravascular volume by acting on the renal mineralocorticoid receptor of the distal convoluted tubules to retain sodium and eliminate potassium and hydrogen ions. Aldosterone secretion is stimulated by ACTH, angiotensin II, decreased intravascular volume, and hyperkalemia. Aldosterone deficiency is manifested by hypotension and hyperkalemia, whereas aldosterone excess is manifested by edema, hypertension, hypokalemia, and metabolic alkalosis.

Insulin Hyperglycemia and insulin resistance are hallmarks of critical illness due to the catabolic effects of circulating mediators, including catecholamines, cortisol, glucagon, and growth hormone. Insulin is secreted by the islets of Langerhans in the pancreas. Insulin mediates an overall host anabolic state through hepatic glycogenesis and glycolysis, peripheral glucose uptake, lipogenesis, and protein synthesis.1 3 Hyperglycemia during critical illness has immunosuppressive effects, including glycosylation of immunoglobulins and decreased phagocytosis and respiratory burst of monocytes, and thus is associated with an increased risk for infection. Insulin therapy to manage hyperglycemia has grown in favor and has been shown to be associated with both decreased mortality and a reduction in infectious complications in select patient populations; however, caution should be exercised to avoid the deleterious sequelae of hypoglycemia from overaggressive glycemic control.1 4 The ideal blood glucose range within which to maintain critically ill patients and avoid hypoglycemia has yet to be determined.

ACUTE PHASE PROTEINS Acute phase proteins are a class of proteins produced by the liver that manifest either increased or decreased

plasma concentration in response to inflammatory stimuli such as traumatic injury and infection. Specifically, Creactive protein has been studied as a marker of proinflammatory response in many clinical settings, including appendicitis, vasculitis, and ulcerative colitis. Importantly, C-reactive protein levels do not show diurnal variations and are not modulated by feeding. Acute phase protein levels may be unreliable as an index of inflammation in the setting of hepatic insufficiency.

MEDIATORS OF INFLAMMATION Cytokines Cytokines are a class of protein signaling compounds that are essential for both innate and adaptive immune responses. Cytokines mediate a broad sequence of cellular responses, including cell migration, DNA replication, cell turnover, and immunocyte proliferation (Table 2-3). When functioning locally at the site of injury and infection, cytokines mediate the eradication of invading micro-organisms and also promote wound healing. However, an exaggerated proinflammatory cytokine response to inflammatory stimuli may result in hemodynamic instability (i.e., septic shock) and metabolic derangements (i.e., muscle wasting).

Table 2-3 Cytokines and Their Sources TNF Macrophages/monocytes Among earliest responders after injury; half-life Chapter 3. Fluid and Electrolyte Management of the Surgical Patient >

KEY POINTS 1. Proper management of fluid and electrolytes facilitates crucial homeostasis that allows cardiovascular perfusion, organ system function, and cellular mechanisms to respond to surgical illness. 2. Knowledge of the compartmentalization of body fluids forms the basis for understanding pathologic shifts in these fluid spaces in disease states. Although difficult to quantify, a deficiency in the functional extracellular fluid compartment often requires resuscitation with isotonic fluids in surgical and trauma patients. 3. Alterations in the concentration of serum sodium have profound effects on cellular function due to water shifts between the intracellular and extracellular spaces. 4. Different rates of compensation between respiratory and metabolic components of acid-base homeostasis require frequent laboratory reassessment during therapy. 5. Most acute surgical illnesses are accompanied by some degree of volume loss or redistribution. Consequently, isotonic fluid administration is the most common initial IV fluid strategy, while attention is being given to alterations in concentration and composition. 6. Although active investigation continues, alternative resuscitation fluids have limited clinical utility, other than the correction of specific electrolyte abnormalities. 7. Some surgical patients with neurologic illness, malnutrition, acute renal failure, or cancer require special attention to well-defined, disease-specific abnormalities in fluid and electrolyte status.

FLUID AND ELECTROLYTE MANAGEMENT OF THE SURGICAL PATIENT: INTRODUCTION Fluid and electrolyte management is paramount to the care of the surgical patient. Changes in both fluid volume and electrolyte composition occur preoperatively, intraoperatively, and postoperatively, as well as in response to trauma and sepsis. The sections that follow review the normal anatomy of body fluids, electrolyte composition and concentration abnormalities and treatments, common metabolic derangements, and alternative resuscitative fluids. These concepts are then discussed in relationship to management of specific surgical patients and their commonly encountered fluid and electrolyte abnormalities.

BODY FLUIDS Total Body Water Water constitutes approximately 50 to 60% of total body weight. The relationship between total body weight

and total body water (TBW) is relatively constant for an individual and is primarily a reflection of body fat. Lean tissues such as muscle and solid organs have higher water content than fat and bone. As a result, young, lean males have a higher proportion of body weight as water than elderly or obese individuals. Deuterium oxide and tritiated water have been used in clinical research to measure TBW by indicator dilution methods. In an average young adult male 60% of total body weight is TBW, whereas in an average young adult female it is 50%.1 The lower percentage of TBW in females correlates with a higher percentage of adipose tissue and lower percentage of muscle mass in most. Estimates of percentage of TBW should be adjusted downward approximately 10 to 20% for obese individuals and upward by 10% for malnourished individuals. The highest percentage of TBW is found in newborns, with approximately 80% of their total body weight comprised of water. This decreases to approximately 65% by 1 year of age and thereafter remains fairly constant.

Fluid Compartments TBW is divided into three functional fluid compartments: plasma, extravascular interstitial fluid, and intracellular fluid (Fig. 3-1). The extracellular fluids (ECF), plasma and interstitial fluid, together comprise about one third of the TBW and the intracellular compartment the remaining two thirds. The extracellular water comprises 20% of the total body weight and is divided between plasma (5% of body weight) and interstitial fluid (15% of body weight). Intracellular water makes up approximately 40% of an individual's total body weight, with the largest proportion in the skeletal muscle mass. ECF is measured using indicator dilution methods. The distribution volumes of NaBr and radioactive sulfate have been used to measure ECF in clinical research. Measurement of the intracellular compartment is then determined indirectly by subtracting the measured ECF from the simultaneous TBW measurement.

Fig. 3-1.

Functional body fluid compartments. TBW = total body water.

Composition of Fluid Compartments The normal chemical composition of the body fluid compartments is shown in Fig. 3-2. The ECF compartment is balanced between sodium, the principal cation, and chloride and bicarbonate, the principal anions. The intracellular fluid compartment is comprised primarily of the cations potassium and magnesium, and the anions phosphate and proteins. The concentration gradient between compartments is maintained by adenosine triphosphate–driven sodium-potassium pumps located with the cell membranes. The composition of the plasma and interstitial fluid differs only slightly in ionic composition. The slightly higher protein content (organic anions) in plasma results in a higher plasma cation composition relative to the interstitial fluid, as explained by the Gibbs-Donnan equilibrium equation. Proteins add to the osmolality of the plasma and contribute to the balance of forces that determine fluid balance across the capillary endothelium. Although the movement of ions and proteins between the various fluid compartments is restricted, water is freely diffusible. Water is distributed evenly throughout all fluid compartments of the body, so that a given volume of water increases the volume of any one compartment relatively little. Sodium, however, is confined to the ECF compartment, and because of its osmotic and electrical properties, it remains associated with water. Therefore, sodium-containing fluids are distributed throughout the ECF and add to the volume of both the intravascular and interstitial spaces. Although the administration of sodium-containing fluids expands the intravascular volume, it also expands the interstitial space by approximately three times as much as the plasma.

Fig. 3-2.

Chemical composition of body fluid compartments.

Osmotic Pressure The physiologic activity of electrolytes in solution depends on the number of particles per unit volume (millimoles per liter, or mmol/L), the number of electric charges per unit volume (milliequivalents per liter, or mEq/L), and the number of osmotically active ions per unit volume (milliosmoles per liter, or mOsm/L). The concentration of electrolytes usually is expressed in terms of the chemical combining activity, or

equivalents. An equivalent of an ion is its atomic weight expressed in grams divided by the valence:

For univalent ions such as sodium, 1 mEq is the same as 1 mmol. For divalent ions such as magnesium, 1 mmol equals 2 mEq. The number of milliequivalents of cations must be balanced by the same number of milliequivalents of anions. However, the expression of molar equivalents alone does not allow a physiologic comparison of solutes in a solution. The movement of water across a cell membrane depends primarily on osmosis. To achieve osmotic equilibrium, water moves across a semipermeable membrane to equalize the concentration on both sides. This movement is determined by the concentration of the solutes on each side of the membrane. Osmotic pressure is measured in units of osmoles (osm) or milliosmoles (mOsm) that refer to the actual number of osmotically active particles. For example, 1 mmol of sodium chloride contributes to 2 mOsm (one from sodium and one from chloride). The principal determinants of osmolality are the concentrations of sodium, glucose, and urea (blood urea nitrogen, or BUN):

The osmolality of the intracellular and extracellular fluids is maintained between 290 and 310 mOsm in each compartment. Because cell membranes are permeable to water, any change in osmotic pressure in one compartment is accompanied by a redistribution of water until the effective osmotic pressure between compartments is equal. For example, if the ECF concentration of sodium increases, there will be a net movement of water from the intracellular to the extracellular compartment. Conversely, if the ECF concentration of sodium decreases, water will move into the cells. Although the intracellular fluid shares in losses that involve a change in concentration or composition of the ECF, an isotonic change in volume in either one of the compartments is not accompanied by the net movement of water as long as the ionic concentration remains the same. For practical clinical purposes, most significant gains and losses of body fluid are directly from the extracellular compartment.

BODY FLUID CHANGES Normal Exchange of Fluid and Electrolytes The healthy person consumes an average of 2000 mL of water per day, approximately 75% from oral intake and the rest extracted from solid foods. Daily water losses include 800 to 1200 mL in urine, 250 mL in stool, and 600 mL in insensible losses. Insensible losses of water occur through both the skin (75%) and lungs (25%), and can be increased by such factors as fever, hypermetabolism, and hyperventilation. Sensible water losses such as sweating or pathologic loss of GI fluids vary widely, but these include the loss of electrolytes as well as water (Table 3-1). To clear the products of metabolism, the kidneys must excrete a minimum of 500 to 800 mL of urine per day, regardless of the amount of oral intake.

Table 3-1 Water Exchange (60- to 80-kg Man) Routes

Average Daily Volume (mL) Minimal (mL) Maximal (mL)

H2O gain: Sensible: Oral fluids

800–1500

0

1500/h

Solid foods

500–700

0

1500

Water of oxidation 250

125

800

Water of solution

0

0

500

Urine

800–1500

300

1400/h

Intestinal

0–250

0

2500/h

Sweat

0

0

4000/h

600

600

1500

Insensible:

H2O loss: Sensible:

Insensible: Lungs and skin

The typical individual consumes 3 to 5 g of dietary salt per day, with the balance maintained by the kidneys. With hyponatremia or hypovolemia, sodium excretion can be reduced to as little as 1 mEq/d or maximized to as much as 5000 mEq/d to achieve balance except in people with salt-wasting kidneys. Sweat is hypotonic, and sweating usually results in only a small sodium loss. GI losses are isotonic to slightly hypotonic and contribute little to net gain or loss of free water when measured and appropriately replaced by isotonic salt solutions.

Classification of Body Fluid Changes Disorders in fluid balance may be classified into three general categories: disturbances in (a) volume, (b) concentration, and (c) composition. Although each of these may occur simultaneously, each is a separate entity with unique mechanisms demanding individual correction. Isotonic gain or loss of salt solution results in extracellular volume changes, with little impact on intracellular fluid volume. If free water is added or lost from the ECF, water will pass between the ECF and intracellular fluid until solute concentration or osmolarity is equalized between the compartments. Unlike with sodium, the concentration of most other ions in the ECF can be altered without significant change in the total number of osmotically active particles, producing only a compositional change. For instance, doubling the serum potassium concentration will profoundly alter myocardial function without significantly altering volume or concentration of the fluid spaces.

Disturbances in Fluid Balance Extracellular volume deficit is the most common fluid disorder in surgical patients and can be either acute or

chronic. Acute volume deficit is associated with cardiovascular and central nervous system signs, whereas chronic deficits display tissue signs, such as a decrease in skin turgor and sunken eyes, in addition to cardiovascular and central nervous system signs (Table 3-2). Laboratory examination may reveal an elevated blood urea nitrogen level if the deficit is severe enough to reduce glomerular filtration and hemoconcentration. Urine osmolality usually will be higher than serum osmolality, and urine sodium will be low, typically Chapter 4. Hemostasis, Surgical Bleeding, and Transfusion>

KEY POINTS 1. Therapeutic anticoagulation preoperatively and postoperatively is becoming increasingly more common. The patient's risk of intraoperative and postoperative bleeding should guide the need for reversal of anticoagulation therapy preoperatively and the timing of its reinstatement postoperatively. 2. The need for massive transfusion should be anticipated and guidelines should be in place to provide the simultaneous administration of blood, plasma, and platelets. 3. The acute coagulopathy of trauma results from a combination of activation of protein C and fibrinolysis. It is distinct from disseminated intravascular coagulation, is present on arrival to the emergency department, and is associated with an increase in mortality.

BIOLOGY OF HEMOSTASIS Hemostasis is a complex process whose function is to limit blood loss from an injured vessel. Four major physiologic events participate in the hemostatic process: vascular constriction, platelet plug formation, fibrin formation, and fibrinolysis. Although each tends to be activated in order, the four processes are interrelated so that there is a continuum and multiple reinforcements. The process is shown schematically in Fig. 4-1.

Fig. 4-1.

Biology of hemostasis. The four physiologic processes that interrelate to limit blood loss from an injured vessel are illustrated and include vascular constriction, platelet plug formation, fibrin clot formation, and fibrinolysis.

Vascular Constriction Vascular constriction is the initial response to vessel injury. It is more pronounced in vessels with medial smooth muscles and is dependent on local contraction of smooth muscle. Vasoconstriction is subsequently linked to platelet plug formation. Thromboxane A2 (TXA2 ) is produced locally at the site of injury via the release of arachidonic acid from platelet membranes and is a potent constrictor of smooth muscle. Similarly, endothelin synthesized by injured endothelium and serotonin (5-hydroxytryptamine) released during platelet aggregation are potent vasoconstrictors. Lastly, bradykinin and fibrinopeptides, which are involved in the coagulation scheme, also are capable of contracting vascular smooth muscle. The extent of vasoconstriction varies with the degree of vessel injury. A small artery with a lateral incision may remain open due to physical forces, whereas a similarly sized vessel that is completely transected may contract to the extent that bleeding ceases spontaneously.

Platelet Function Platelets are anucleate fragments of megakaryocytes. The normal circulating number of platelets ranges between 150,000 and 400,000/ L. Up to 30% of circulating platelets may be sequestered in the spleen. If not consumed in a clotting reaction, platelets are normally removed by the spleen and have an average life span of 7 to 10 days. Platelets play an integral role in hemostasis by forming a hemostatic plug and by contributing to thrombin formation (Fig. 4-2). Platelets do not normally adhere to each other or to the vessel wall but can form a plug that aids in cessation of bleeding when vascular disruption occurs. Injury to the intimal layer in the vascular wall exposes subendothelial collagen to which platelets adhere. This process requires von Willebrand's factor (vWF), a protein in the subendothelium that is lacking in patients with von Willebrand's disease. The vWF binds to glycoprotein I/IX/V on the platelet membrane. After adhesion, platelets initiate a release reaction that recruits other platelets from the circulating blood to seal the disrupted vessel. Up to this point, this process is known as primary hemostasis. Platelet aggregation is reversible and is not associated with secretion. Additionally, heparin does not interfere with this reaction, and thus hemostasis can occur in the heparinized patient. Adenosine diphosphate (ADP) and serotonin are the principal mediators in platelet aggregation.

Fig. 4-2.

Schematic of platelet activation and thrombus function. ADP = adenosine diphosphate.

Arachidonic acid released from the platelet membranes is converted by COX to prostaglandin G2 (PGG 2 ) and then

to prostaglandin H2 (PGH2 ), which, in turn, is converted to TXA2 . TXA 2 has potent vasoconstriction and platelet aggregation effects. Arachidonic acid may also be shuttled to adjacent endothelial cells and converted to prostacyclin (PGI2 ), which is a vasodilator and acts to inhibit platelet aggregation. Platelet COX is irreversibly inhibited by aspirin and reversibly blocked by NSAIDs but is not affected by COX-2 inhibitors. In the second wave of platelet aggregation, a release reaction occurs in which several substances, including ADP, Ca2+ , serotonin, TXA 2 , and -granule proteins are discharged. Fibrinogen is a required cofactor for this process, acting as a bridge for the glycoprotein IIb/IIIa receptor on the activated platelets. The release reaction results in compaction of the platelets into a plug, a process that is no longer reversible. Thrombospondin, another protein secreted by the

-granule, stabilizes fibrinogen binding to the activated platelet surface and strengthens the

platelet-platelet interactions. Platelet factor 4 (PF4) and

-thromboglobulin also are secreted during the release

reaction. PF4 is a potent heparin antagonist. The second wave of platelet aggregation is inhibited by aspirin and NSAIDs, by cyclic adenosine monophosphate (cAMP), and by nitric oxide. As a consequence of the release reaction, alterations occur in the phospholipids of the platelet membrane that allow calcium and clotting factors to bind to the platelet surface, forming enzymatically active complexes. The altered lipoprotein surface (sometimes referred to as platelet factor 3 ) catalyzes reactions that are involved in the conversion of prothrombin (factor II) to thrombin (factor IIa) (Fig. 4-3) by activated factor X (Xa) in the presence of factor V and calcium, and it is involved in the reaction by which activated factor IX (IXa), factor VIII, and calcium activate factor X. Platelets may also play a role in the initial activation of factors XI and XII.

Fig. 4-3.

Schematic of the coagulation system. HMW = high molecular weight.

Coagulation Under physiologic conditions, hemostasis is accomplished by a complex sequence of interactions between platelets, the endothelium, and multiple circulating or membrane-bound coagulation factors. As shown in Fig. 4-3, the coagulation cascade typically has been depicted as two intersecting pathways. The intrinsic pathway begins with factor XII and through a cascade of enzymatic reactions activates factors XI, IX, and VII in sequence. In the intrinsic pathway all of the components leading ultimately to fibrin clot formation are intrinsic to the circulating plasma and no surface is required to initiate the process. In contrast, the extrinsic pathway requires exposure of tissue factor on the surface of the injured vessel wall to initiate the arm of the cascade beginning with factor VII. The two arms of the coagulation cascade merge to a common pathway at factor X, and activation proceeds in sequence of factors II (prothrombin) and I (fibrinogen). Clot formation occurs after proteolytic conversion of fibrinogen to fibrin. One convenient feature of depicting the coagulation cascade with two merging arms is that commonly used

laboratory tests segregate abnormalities of clotting to one of the two arms (Table 4-1). An elevated activated partial thromboplastin time (aPTT) is associated with abnormal function of the intrinsic arm of the cascade, whereas an elevated prothrombin time (PT) is associated with the extrinsic arm. Vitamin K deficiency and warfarin use affect factors II, VII, IX, and X. Fibrinogen levels usually need to be 20–30 x 109 /L and to minimize side effects of medications. b. Rituximab, an anti-CD20 monoclonal antibody: Acts by eliminating B cells. c. Alternative medications producing mixed results and a limited response: Danazol, cyclosporine A, dapsone, azathioprine, and vinca alkaloids. d. Thrombopoietic agents: A new class of drugs for patients with impaired production of platelets rather than accelerated destruction of platelets. Second-generation drugs still in clinical trials include AMG531 and eltrombopag.

Heparin-induced thrombocytopenia (HIT) is a form of drug-induced immune thrombocytopenia. It is an

immunologic disorder in which antibodies against PF4 formed during exposure to heparin affect platelet activation and endothelial function with resultant thrombocytopenia and intravascular thrombosis.7 The platelet count typically begins to fall 5 to 7 days after heparin has been started, but if it is a re-exposure, the decrease in count may occur within 1 to 2 days. HIT should be suspected if the platelet count falls to 50,000/ L generally requires no specific therapy. Prophylactic platelet administration has now become part of massive transfusion protocols. Platelets also are administered preoperatively to rapidly increase the platelet count in surgical patients with underlying thrombocytopenia. One unit of platelet concentrate contains approximately 5.5

x

101 0 platelets and would be

expected to increase the circulating platelet count by approximately 10,000/ L in the average 70-kg person. Fever, infection, hepatosplenomegaly, and the presence of antiplatelet alloantibodies decrease the effectiveness of platelet transfusions. In patients whose thrombocytopenia is refractory to standard platelet transfusion, the use of human leukocyte antigen (HLA)–compatible platelets coupled with special processors has proved effective.

QUALITATIVE PLATELET DEFECTS Impaired platelet function often accompanies thrombocytopenia. Impaired ADP-stimulated aggregation occurs with massive transfusion (>10 units of packed red blood cells). Uremia may be associated with increased bleeding time and impaired aggregation and can be corrected by hemodialysis or peritoneal dialysis. Defective aggregation and platelet secretion can occur in patients with thrombocythemia, polycythemia vera, or myelofibrosis. Drugs that interfere with platelet function by design include aspirin, clopidogrel, dipyridamole, and the glycoprotein IIb/IIIa inhibitors. Both aspirin and clopidogrel irreversibly inhibit platelet function, clopidogrel through selective irreversible inhibition of ADP-induced platelet aggregation and aspirin through irreversible acetylation of platelet prostaglandin synthase. There are no prospective randomized trials in general surgical patients to guide the timing of surgery in patients taking aspirin and/or clopidogrel. The general recommendation is that, for each, a period of approximately 7 days is required from the time the drug is stopped until an elective procedure can be performed.1 2 Timing of urgent and emergent surgeries is even more unclear. Preoperative platelet transfusions may be beneficial, but again there are no good data to guide their administration. The problem is that accurate tests of platelet function are lacking. Other disorders associated with abnormal platelet function include uremia, myeloproliferative disorders, monoclonal gammopathies, and liver disease. In the surgical patient, platelet dysfunction of uremia often can be corrected by dialysis or the administration of desmopressin acetate. Platelet

transfusion may not be helpful if the patient is uremic when the platelets are given. Platelet dysfunction in myeloproliferative disorders is intrinsic to the platelets and usually improves if the platelet count can be reduced to normal with chemotherapy. If possible, surgery should be delayed until the count has been decreased. These patients are at risk for both bleeding and thrombosis. Platelet dysfunction in patients with monoclonal gammopathies is a result of interaction of the monoclonal protein with platelets. Treatment with chemotherapy, or occasionally plasmapheresis, to lower the amount of monoclonal protein improves hemostasis.

Acquired Hypofibrinogenemia DISSEMINATED INTRAVASCULAR COAGULATION The official definition of disseminated intravascular coagulation (DIC), as put forth by the Scientific Subcommittee on DIC of the Scientific and Standardization Committee of the International Society of Thrombosis and Haemostasis (SSC/ISTH), is that "DIC is an acquired syndrome characterized by the intravascular activation of coagulation with the loss of localization arising from different causes. It can originate from and cause damage to the microvasculature, which if sufficiently severe, can produce organ dysfunction."1 3 Excessive thrombin generation leads to microthrombus formation, followed by consumption and depletion of coagulation factors and platelets, which leads to the classic picture of diffuse bleeding. The presence of an underlying condition that predisposes a patient to DIC is required for the diagnosis. Specific injuries include central nervous system injuries with embolization of brain matter, fractures with embolization of bone marrow, and amniotic fluid embolization. Embolized materials are potent thromboplastins that activate the DIC cascade.1 4 Additional causes include malignancy, organ injury (such as severe pancreatitis), liver failure, certain vascular abnormalities (such as large aneurysms), snakebites, illicit drugs, transfusion reactions, transplant rejection, and sepsis.1 3 DIC frequently accompanies sepsis and may be associated with multiple organ failure. As of yet, scoring systems for organ failure do not routinely incorporate DIC.1 4 The important interplay between sepsis and coagulation abnormalities was demonstrated by Dhainaut and colleagues, who showed that administration of activated protein C was particularly effective in septic patients with DIC.1 5 The diagnosis of DIC is made on the basis of an inciting cause with associated thrombocytopenia, prolongation of the PT, low fibrinogen level, and elevated levels of fibrin markers (fibrin degradation products, D-dimer, soluble fibrin monomers). A scoring system developed by the SSC/ISTH assigns a score between 0 and 1 to the measured value on each of these laboratory tests; a score of 5 or greater is considered to be overt DIC.1 6 The most important facets of treatment are relieving the patient's causative primary medical or surgical problem and maintaining adequate perfusion. If there is active bleeding, hemostatic factors should be replaced using FFP, which generally is sufficient to correct the hypofibrinogenemia, although cryoprecipitate and platelet concentrates also may be needed. Because microthrombi are generated during DIC, heparin therapy has been proposed. Most studies, however, have shown that heparin is not helpful in acute forms of DIC but may be indicated for purpura fulminans or venous thromboembolism.

PRIMARY FIBRINOLYSIS An acquired hypofibrinogenic state in the surgical patient also can be a result of pathologic fibrinolysis. This may occur in patients after prostate resection when urokinase is released during surgical manipulation of the prostate or in patients undergoing extracorporeal bypass. The severity of fibrinolytic bleeding is dependent on the concentration of breakdown products in the circulation. The synthetic amino acid -aminocaproic acid interferes with fibrinolysis by inhibiting plasminogen activation.

Myeloproliferative Diseases

Polycythemia, particularly with marked thrombocytosis, presents a major surgical risk. In such patients, operations should be considered only for the most grave surgical emergencies. If possible, the operation should be deferred until medical management has restored normal blood volume, hematocrit level, and platelet count. Spontaneous thrombosis is a complication of polycythemia vera and can be explained in part by increased blood viscosity, increased platelet count, and an increased tendency toward stasis. Paradoxically, a significant tendency toward spontaneous hemorrhage also is noted in these patients. Myeloid metaplasia frequently represents part of the natural history of polycythemia vera. Approximately 50% of patients with myeloid metaplasia are postpolycythemic. Abnormalities in platelet aggregation and release have been demonstrated in these patients. Thrombocytosis can be reduced by the administration of hydroxyurea or anagrelide. Elective surgical procedures should be delayed until the institution of appropriate treatment. Ideally, the hematocrit level should be kept below 48% and the platelet count under 400,000/ L. When an emergency procedure is required, phlebotomy and blood replacement with lactated Ringer's solution may be beneficial.

Coagulopathy of Liver Disease The liver plays a key role in hemostasis because it is responsible for the synthesis of many of the coagulation factors (Table 4-4). The most common coagulation abnormalities associated with liver dysfunction are thrombocytopenia and impaired humoral coagulation function manifested as prolongation of the PT and increase in the International Normalized Ratio (INR).1 7 Thrombocytopenia in patients with liver disease typically is related to hypersplenism, reduced production of thrombopoietin, and immune-mediated destruction of platelets. As noted earlier, in patients with hypersplenism the total body platelet mass is basically normal, but an abnormally high proportion of the platelets are found in the enlarged spleen. Less bleeding is seen than would be anticipated from the platelet count, because some of the sequestered platelets can be released into the circulation. Thrombopoietin, the primary stimulus for thrombopoiesis, may be responsible for some cases of thrombocytopenia in cirrhotic patients, although its role is not well delineated. Finally, immune-mediated thrombocytopenia may also occur in cirrhotic patients, especially those with hepatitis C and primary biliary cirrhosis.1 8 Before any therapy to ameliorate thrombocytopenia is initiated, the actual need for correction should be strongly considered. In general, correction based solely on a low platelet count should be discouraged. Most often, treatment should be withheld for invasive procedures and surgery. Platelet transfusions are the mainstay of therapy; however, the effect typically lasts only several hours. Risks associated with transfusions in general, and the development of antiplatelet antibodies in a patient population likely to need recurrent correction, should be considered. A potential alternative strategy is administration of interleukin-11, a cytokine that stimulates proliferation of hematopoietic stem cells and megakaryocyte progenitors.1 6 Most studies using interleukin-11 have been in patients with cancer, although some evidence exists that it may be beneficial in cirrhotic patients as well. Significant side effects limit its usefulness.1 9 A less well accepted option is splenectomy or splenic embolization to reduce hypersplenism. Not only are there risks associated with these techniques, but reduced splenic blood flow can reduce portal vein flow with subsequent portal vein thrombosis. Results are mixed after transjugular intrahepatic portosystemic shunt (TIPS). Therefore, treatment of thrombocytopenia should not be the primary indication for a TIPS procedure.

Table 4-4 Coagulation Factors Synthesized by the Liver Vitamin K–dependent factors: II (prothrombin factor), VII, IX, X Fibrinogen Factor V Factor VIII Factors XI, XII, XIII

Antithrombin III Plasminogen Protein C and protein S

Decreased production or increased destruction of coagulation factors as well as a vitamin K deficiency can contribute to a prolonged PT and increased INR in patients with liver disease. As liver dysfunction worsens, so does the liver's synthetic function, which results in decreased production of coagulation factors. Additionally, abnormalities in laboratory results may mimic those of DIC. Elevated D-dimer levels have been reported to increase the risk of variceal bleeding.2 0 The absorption of vitamin K is dependent on bile production. Therefore, patients with liver disease who have impaired bile production, such as those with cholestatic disease, may be at risk for vitamin K deficiency. As with thrombocytopenia, correction of coagulopathy should be reserved for treatment of active bleeding and prophylaxis for invasive procedures and surgery. Coagulopathy caused by liver disease is most often treated with FFP, but because the coagulopathy generally is not a result of decreased levels of factor V, complete correction usually is not possible. If the fibrinogen level is 25 0.804 Schreiber et al7 6 Hgb =11, INR>1.5, penetrating injury 0.80 Wade et al 7 7 SBP, HR, pH, Hct 0.78 Authors

Variables

ROC AUC Value

AUC = area under the curve; BD = base deficit; FAST = focused assessment by sonography in trauma; Hct = hematocrit; Hgb = hemoglobin level; HR = heart rate; INR = International Normalized Ratio; ISS = injury severity

score; ROC = receiver operating characteristic; SBP = systolic blood pressure.

Complications of Transfusion (Table 4-10) Complications of transfusion are primarily related to blood-induced proinflammatory responses. Transfusion-related events are estimated to occur in approximately 10% of all transfusions, but 120 >140 Blood pressure Normal Orthostatic Hypotension Severe hypotension CNS symptoms Normal Anxious Confused Obtunded Class Parameter

I

II

bpm = beats per minute; CNS = central nervous system.

Fig. 5-6.

III

IV

The relationship between systolic blood pressure and mortality in trauma patients with hemorrhage. These data suggest that a systolic blood pressure of less than 110 mmHg is a clinically relevant definition of hypotension and hypoperfusion based upon an increasing rate of mortality below this pressure. Base deficit (BD) is also shown on this graph. ED = emergency department. (From Eastridge et al,53 with permission.)

In addressing the sensitivity of vital signs and identifying major thoracoabdominal hemorrhage, a study retrospectively identified patients with injury to the trunk and an abbreviated injury score of 3 or greater who required immediate surgical intervention and transfusion of at least 5 units of blood within the first 24 hours. Ninety-five percent of patients had a heart rate greater than 80 bpm at some point during their postinjury course. However, only 59% of patients achieved a heart rate greater than 120 bpm. Ninety-nine percent of all patients had a recorded blood pressure of less than 120 mmHg at some point. Ninety-three percent of all patients had a recorded SBP of less than 100 mmHg.5 4 A more recent study corroborated that tachycardia was not a reliable sign of hemorrhage following trauma, and was present in only 65% of hypotensive patients.5 5 Serum lactate and base deficit are measurements that are helpful to both estimate and monitor the extent of bleeding and shock. The amount of lactate that is produced by anaerobic respiration is an indirect marker of tissue hypoperfusion, cellular O2 debt, and the severity of hemorrhagic shock. Several studies have demonstrated that the initial serum lactate and serial lactate levels are reliable predictors of morbidity and mortality with hemorrhage following trauma (Fig. 5-7).5 6 Similarly, base deficit values derived from arterial blood gas analysis provide clinicians with an indirect estimation of tissue acidosis from hypoperfusion. Davis and colleagues stratified the extent of base deficit into mild (–3 to –5 mmol/L), moderate (–6 to –9 mmol/L), and severe (less than –10 mmol/L), and from this established a correlation between base deficit upon admission with transfusion requirements, the development of multiple organ failure, and death (Fig. 5-8).5 7 Both base deficit and lactate correlate with the extent of shock and patient outcome, but interestingly do not firmly correlate with each other.58–60 Evaluation of both values may be useful in trauma patients with hemorrhage.

Fig. 5-7.

Progressive increases in serum lactate, muscle lactate, and liver lactate in a baboon model of hemorrhagic shock. (From Peitzman et al,8 with permission.)

Fig. 5-8.

The relationship between base deficit (negative base excess) and mortality in trauma patients. BEA = base excess arterial; ECF = extracellular fluid. (Reproduced with permission from Siegel JH, Rivkind AI, Dalal S, et al: Early physiologic predictors of injury severity and death in blunt multiple trauma. Arch Surg 125:498, 1990. Copyright 1990 American Medical Association. All rights reserved.)

In management of trauma patients, understanding the patterns of injury of the patient in shock will help direct the evaluation and management. Identifying the sources of blood loss in patients with penetrating wounds is relatively simple because potential bleeding sources will be located along the known or suspected path of the wounding object. Patients with penetrating injuries who are in shock usually require operative intervention. Patients who suffer multisystem injuries from blunt trauma have multiple sources of potential hemorrhage. Blood loss sufficient to cause shock is generally of a large volume, and there are a limited number of sites that can harbor sufficient extravascular blood volume to induce hypotension (e.g., external, intrathoracic, intra-abdominal, retroperitoneal, and long bone fractures). In the nontrauma patient, the GI tract must always be considered as a site for blood loss. Substantial blood loss externally may be suspected from prehospital medical reports documenting a substantial blood loss at the scene of an accident, history of massive blood loss from wounds, visible brisk bleeding, or presence of a large hematoma adjacent to an open wound. Injuries to major arteries or veins with associated open wounds may cause massive blood loss rapidly. Direct pressure must be applied and sustained to minimize ongoing blood loss. Persistent bleeding from uncontrolled smaller vessels can, over time, precipitate shock if inadequately treated. When major blood loss is not immediately visible in the setting of trauma, internal (intracavitary) blood loss should be suspected. Each pleural cavity can hold 2 to 3 L of blood and can therefore be a site of significant blood loss. Diagnostic and therapeutic tube thoracostomy may be indicated in unstable patients based on clinical findings and clinical suspicion. In a more stable patient, a chest radiograph may be obtained to look for evidence of hemothorax. Major retroperitoneal hemorrhage typically occurs in association with pelvic fractures, which is confirmed by pelvic radiography in the resuscitation bay. Intraperitoneal hemorrhage is probably the most common

source of blood loss inducing shock. The physical exam for detection of substantial blood loss or injury is insensitive and unreliable; large volumes of intraperitoneal blood may be present before physical examination findings are apparent. Findings with intra-abdominal hemorrhage include abdominal distension, abdominal tenderness, or visible abdominal wounds. Hemodynamic abnormalities generally stimulate a search for blood loss before the appearance of obvious abdominal findings. Adjunctive tests are essential in the diagnosis of intraperitoneal bleeding; intraperitoneal blood may be rapidly identified by diagnostic ultrasound or diagnostic peritoneal lavage. Furthermore, patients that have sustained high-energy blunt trauma that are hemodynamically stable or that have normalized their vital signs in response to initial volume resuscitation should undergo computed tomography scans to assess for head, chest, and/or abdominal bleeding.

TREATMENT Control of ongoing hemorrhage is an essential component of the resuscitation of the patient in shock. As mentioned in Diagnosis above, treatment of hemorrhagic shock is instituted concurrently with diagnostic evaluation to identify a source. Patients who fail to respond to initial resuscitative efforts should be assumed to have ongoing active hemorrhage from large vessels and require prompt operative intervention. Based on trauma literature, patients with ongoing hemorrhage demonstrate increased survival if the elapsed time between the injury and control of bleeding is decreased. Although there are no randomized controlled trials, retrospective studies provide compelling evidence in this regard. To this end, Clarke and colleagues6 1 demonstrated that trauma patients with major injuries isolated to the abdomen requiring emergency laparotomy had an increased probability of death with increasing length of time in the emergency department for patients who were in the emergency department for 90 minutes or less. This probability increased approximately 1% for each 3 minutes in the emergency department. The appropriate priorities in these patients are (a) secure the airway, (b) control the source of blood loss, and (c) IV volume resuscitation. In trauma, identifying the body cavity harboring active hemorrhage will help focus operative efforts; however, because time is of the essence, rapid treatment is essential and diagnostic laparotomy or thoracotomy may be indicated. The actively bleeding patient cannot be resuscitated until control of ongoing hemorrhage is achieved. Our current understanding has led to the management strategy known as damage control resuscitation . 6 2 This strategy begins in the emergency department, continues into the operating room, and into the intensive care unit (ICU). Initial resuscitation is limited to keep SBP around 90 mmHg. This prevents renewed bleeding from recently clotted vessels. Resuscitation and intravascular volume resuscitation is accomplished with blood products and limited crystalloids, which is addressed further later in this section. Too little volume allowing persistent severe hypotension and hypoperfusion is dangerous, yet too vigorous of a volume resuscitation may be just as deleterious. Control of hemorrhage is achieved in the operating room, and efforts to warm patients and to prevent coagulopathy using multiple blood products and pharmacologic agents are used in both the operating room and ICU. Cannon and colleagues first made the observation that attempts to increase blood pressure in soldiers with uncontrolled sources of hemorrhage is counterproductive, with increased bleeding and higher mortality.3 This work was the foundation for the "hypotensive resuscitation" strategies. Several laboratory studies confirmed the observation that attempts to restore normal blood pressure with fluid infusion or vasopressors was rarely achievable and resulted in more bleeding and higher mortality.6 3 A prospective, randomized clinical study compared delayed fluid resuscitation (upon arrival in the operating room) with standard fluid resuscitation (with arrival by the paramedics) in hypotensive patients with penetrating torso injury.6 4 The authors reported that delayed fluid resuscitation resulted in lower patient mortality. Further laboratory studies demonstrated that fluid restriction in the setting of profound hypotension resulted in early deaths from severe hypoperfusion. These studies

also showed that aggressive crystalloid resuscitation attempting to normalize blood pressure resulted in marked hemodilution, with hematocrits of 5%.6 3 Reasonable conclusions in the setting of uncontrolled hemorrhage include: Any delay in surgery for control of hemorrhage increases mortality; with uncontrolled hemorrhage attempting to achieve normal blood pressure may increase mortality, particularly with penetrating injuries and short transport times; a goal of SBP of 80 to 90 mmHg may be adequate in the patient with penetrating injury; and profound hemodilution should be avoided by early transfusion of red blood cells. For the patient with blunt injury, where the major cause of death is a closed head injury, the increase in mortality with hypotension in the setting of brain injury must be avoided. In this setting, a SBP of 110 mmHg would seem to be more appropriate. Patients who respond to initial resuscitative effort but then deteriorate hemodynamically frequently have injuries that require operative intervention. The magnitude and duration of their response will dictate whether diagnostic maneuvers can be performed to identify the site of bleeding. However, hemodynamic deterioration generally denotes ongoing bleeding for which some form of intervention (i.e., operation or interventional radiology) is required. Patients who have lost significant intravascular volume, but whose hemorrhage is controlled or has abated, often will respond to resuscitative efforts if the depth and duration of shock have been limited. A subset of patients exists who fail to respond to resuscitative efforts despite adequate control of ongoing hemorrhage. These patients have ongoing fluid requirements despite adequate control of hemorrhage, have persistent hypotension despite restoration of intravascular volume necessitating vasopressor support, and may exhibit a futile cycle of uncorrectable hypothermia, hypoperfusion, acidosis, and coagulopathy that cannot be interrupted despite maximum therapy. These patients have deteriorated to decompensated or irreversible shock with peripheral vasodilation and resistance to vasopressor infusion. Mortality is inevitable once the patient manifests shock in its terminal stages. Unfortunately, this is all too often diagnosed in retrospect. Fluid resuscitation is a major adjunct to physically controlling hemorrhage in patients with shock. The ideal type of fluid to be used continues to be debated; however, crystalloids continue to be the mainstay of fluid choice. Several studies have demonstrated increased risk of death in bleeding trauma patients treated with colloid compared to patients treated with crystalloid.6 5 In patients with severe hemorrhage, restoration of intravascular volume should be achieved with blood products. 6 6 Ongoing studies continue to evaluate the use of hypertonic saline as a resuscitative adjunct in bleeding patients.6 7 The benefit of hypertonic saline solutions may be immunomodulatory. Specifically, these effects have been attributed to pharmacologic effects resulting in decreased reperfusion-mediated injury with decreased O2 radical formation, less impairment of immune function compared to standard crystalloid solution, and less brain swelling in the multi-injured patient. The reduction of total volume used for resuscitation makes this approach appealing as a resuscitation agent for combat injuries and may contribute to a decrease in the incidence of ARDS and multiple organ failure. Transfusion of packed red blood cells and other blood products is essential in the treatment of patients in hemorrhagic shock. Current recommendations in stable ICU patients aim for a target hemoglobin of 7 to 9 g/dL; 68,69 however, no prospective randomized trials have compared restrictive and liberal transfusion regimens in trauma patients with hemorrhagic shock. Fresh frozen plasma (FFP) should also be transfused in patients with massive bleeding or bleeding with increases in prothrombin or activated partial thromboplastin times 1.5 times greater than control. Civilian trauma data show that severity of coagulopathy early after ICU admission is predictive of mortality (Fig. 5-9).7 0 Evolving data suggest more liberal transfusion of FFP in bleeding patients, but the clinical efficacy of FFP requires further investigation. Recent data collected from a U.S. Army combat support

hospital in patients that received massive transfusion of packed red blood cells (>10 units in 24 hours) suggests that a high plasma to RBC ratio (1:1.4 units) was independently associated with improved survival (Fig. 5-10).7 1 Platelets should be transfused in the bleeding patient to maintain counts above 50

x

109 /L. There is a potential

role for other blood products, such as fibrinogen concentrate of cryoprecipitate, if bleeding is accompanied by a drop in fibrinogen levels to less than 1 g/L. Pharmacologic agents such as recombinant activated coagulation factor 7, and antifibrinolytic agents such as -aminocaproic acid, tranexamic acid (both are synthetic lysine analogues that are competitive inhibitors of plasmin and plasminogen), and aprotinin (protease inhibitor) may all have potential benefits in severe hemorrhage but require further investigation.

Fig. 5-9.

The relationship between coagulopathy and mortality in trauma patients. Civilian trauma data show that severity of coagulopathy as determined by an increasing International Normalized Ratio (INR) early after intensive care unit (ICU) admission is predictive of mortality. (From Gonzalez et al,70 with permission.)

Fig. 5-10.

Increasing ratio of transfusion of fresh frozen plasma to red blood cells improves outcome of trauma patients receiving massive transfusions. RBC = red blood cell. (From Borgman et al,71 with permission.)

Additional resuscitative adjuncts in patients with hemorrhagic shock include minimization of heat loss and maintaining normothermia. The development of hypothermia in the bleeding patient is associated with acidosis, hypotension, and coagulopathy. Hypothermia in bleeding trauma patients is an independent risk factor for bleeding and death. This likely is secondary to impaired platelet function and impairments in the coagulation cascade. Several studies have investigated the induction of controlled hypothermia in patients with severe shock based on the hypothesis of limiting metabolic activity and energy requirements, creating a state of "suspended animation." These studies are promising and continue to be evaluated in large trials.

Traumatic Shock The systemic response after trauma, combining the effects of soft tissue injury, long bone fractures, and blood loss, is clearly a different physiologic insult than simple hemorrhagic shock. Multiple organ failure, including acute respiratory distress syndrome (ARDS), develops relatively often in the blunt trauma patient, but rarely after pure hemorrhagic shock (such as a GI bleed). The hypoperfusion deficit in traumatic shock is magnified by the proinflammatory activation that occurs following the induction of shock. In addition to ischemia or ischemiareperfusion, accumulating evidence demonstrates that even simple hemorrhage induces proinflammatory activation that results in many of the cellular changes typically ascribed only to septic shock.72,73 At the cellular level, this may be attributable to the release of cellular products termed damage associated molecular patterns (DAMPs , i.e., riboxynucleic acid, uric acid, and high mobility group box 1) that activate the same set of cell surface receptors as bacterial products, initiating similar cell signaling.5,74 These receptors are termed pattern recognition receptors (PRRs) and include the TLR family of proteins. Examples of traumatic shock include small volume hemorrhage accompanied by soft tissue injury (femur fracture, crush injury), or any combination of hypovolemic, neurogenic, cardiogenic, and obstructive shock that precipitate rapidly progressive proinflammatory activation. In laboratory models of traumatic shock, the addition of a soft tissue or long bone injury to hemorrhage produces lethality with significantly less blood loss when the animals are stressed by hemorrhage. Treatment of traumatic shock is focused on correction of the individual elements to diminish the cascade of proinflammatory activation, and includes prompt

control of hemorrhage, adequate volume resuscitation to correct O2 debt, dbridement of nonviable tissue, stabilization of bony injuries, and appropriate treatment of soft tissue injuries.

Septic Shock (Vasodilatory Shock) In the peripheral circulation, profound vasoconstriction is the typical physiologic response to the decreased arterial pressure and tissue perfusion with hemorrhage, hypovolemia, or acute heart failure. This is not the characteristic response in vasodilatory shock. Vasodilatory shock is the result of dysfunction of the endothelium and vasculature secondary to circulating inflammatory mediators and cells or as a response to prolonged and severe hypoperfusion. Thus, in vasodilatory shock, hypotension results from failure of the vascular smooth muscle to constrict appropriately. Vasodilatory shock is characterized by peripheral vasodilation with resultant hypotension and resistance to treatment with vasopressors. Despite the hypotension, plasma catecholamine levels are elevated, and the renin-angiotensin system is activated in vasodilatory shock. The most frequently encountered form of vasodilatory shock is septic shock. Other causes of vasodilatory shock include hypoxic lactic acidosis, carbon monoxide poisoning, decompensated and irreversible hemorrhagic shock, terminal cardiogenic shock, and postcardiotomy shock (Table 5-6). Thus, vasodilatory shock seems to represent the final common pathway for profound and prolonged shock of any etiology.7 5

Table 5-6 Causes of Septic and Vasodilatory Shock Systemic response to infection Noninfectious systemic inflammation Pancreatitis Burns Anaphylaxis Acute adrenal insufficiency Prolonged, severe hypotension Hemorrhagic shock Cardiogenic shock Cardiopulmonary bypass Metabolic Hypoxic lactic acidosis Carbon monoxide poisoning

Despite advances in intensive care, the mortality rate for severe sepsis remains at 30 to 50%. In the United States, 750,000 cases of sepsis occur annually, one third of which are fatal. 7 6 Sepsis accounts for 9.3% of deaths in the United States, as many yearly as MI.7 7 Septic shock is a by-product of the body's response to disruption of the host-microbe equilibrium, resulting in invasive or severe localized infection. In the attempt to eradicate the pathogens, the immune and other cell types (e.g., endothelial cells) elaborate soluble mediators that enhance macrophage and neutrophil killing effector mechanisms, increase procoagulant activity and fibroblast activity to localize the invaders, and increase microvascular blood flow to enhance delivery of killing forces to the area of invasion. When this response is overly exuberant or becomes systemic rather than localized, manifestations of sepsis may be evident. These findings include enhanced cardiac output, peripheral vasodilation, fever, leukocytosis, hyperglycemia, and tachycardia. In septic shock, the vasodilatory effects are due, in part, to the upregulation of the inducible isoform of nitric oxide synthase (iNOS or NOS 2) in the vessel wall. iNOS produces large quantities of nitric oxide for sustained periods of time. This potent vasodilator suppresses

vascular tone and renders the vasculature resistant to the effects of vasoconstricting agents.

DIAGNOSIS Attempts to standardize terminology have led to the establishment of criteria for the diagnosis of sepsis in the hospitalized adult. These criteria include manifestations of the host response to infection in addition to identification of an offending organism. The terms sepsis , severe sepsis , and septic shock are used to quantify the magnitude of the systemic inflammatory reaction. Patients with sepsis have evidence of an infection, as well as systemic signs of inflammation (e.g., fever, leukocytosis, and tachycardia). Hypoperfusion with signs of organ dysfunction is termed severe sepsis. Septic shock requires the presence of the above, associated with more significant evidence of tissue hypoperfusion and systemic hypotension. Beyond the hypotension, maldistribution of blood flow and shunting in the microcirculation further compromise delivery of nutrients to the tissue beds.7 8 Recognizing septic shock begins with defining the patient at risk. The clinical manifestations of septic shock will usually become evident and prompt the initiation of treatment before bacteriologic confirmation of an organism or the source of an organism is identified. In addition to fever, tachycardia, and tachypnea, signs of hypoperfusion such as confusion, malaise, oliguria, or hypotension may be present. These should prompt an aggressive search for infection, including a thorough physical examination, inspection of all wounds, evaluation of intravascular catheters or other foreign bodies, obtaining appropriate cultures, and adjunctive imaging studies, as needed.

TREATMENT Evaluation of the patient in septic shock begins with an assessment of the adequacy of their airway and ventilation. Severely obtunded patients and patients whose work of breathing is excessive require intubation and ventilation to prevent respiratory collapse. Because vasodilation and decrease in total peripheral resistance may produce hypotension, fluid resuscitation and restoration of circulatory volume with balanced salt solutions is essential. Empiric antibiotics must be chosen carefully based on the most likely pathogens (gram-negative rods, grampositive cocci, and anaerobes) because the portal of entry of the offending organism and its identity may not be evident until culture data return or imaging studies are completed. Knowledge of the bacteriologic profile of infections in an individual unit can be obtained from most hospital infection control departments and will suggest potential responsible organisms. Antibiotics should be tailored to cover the responsible organisms once culture data are available, and if appropriate, the spectrum of coverage narrowed. Long-term, empiric, broad-spectrum antibiotic use should be minimized to reduce the development of resistant organisms and to avoid the potential complications of fungal overgrowth and antibiotic-associated colitis from overgrowth of Clostridium difficile . IV antibiotics will be insufficient to adequately treat the infectious episode in the settings of infected fluid collections, infected foreign bodies, and devitalized tissue. This situation is termed source control and involves percutaneous drainage and operative management to target a focus of infection. These situations may require multiple operations to ensure proper wound hygiene and healing. After first-line therapy of the septic patient with antibiotics, IV fluids, and intubation if necessary, vasopressors may be necessary to treat patients with septic shock. Catecholamines are the vasopressors used most often. Occasionally, patients with septic shock will develop arterial resistance to catecholamines. Argininevasopressin, a potent vasoconstrictor, is often efficacious in this setting. The majority of septic patients have hyperdynamic physiology with supranormal cardiac output and low systemic vascular resistance. On occasion, septic patients may have low cardiac output despite volume resuscitation and even vasopressor support. Mortality in this group is high. Despite the increasing incidence of septic shock over the past several decades, the overall mortality rates have changed little. Studies of interventions, including

immunotherapy, resuscitation to pulmonary artery endpoints with hemodynamic optimization (cardiac output and O2 delivery, even to supranormal values), and optimization of mixed venous O2 measurements up to 72 hours after admission to the ICU, have not changed mortality. Over the past decade, multiple advances have been made in the treatment of patients with sepsis and septic shock (Fig. 5-11).78,79 Negative results from previous studies have led to the suggestion that earlier interventions directed at improving global tissue oxygenation may be of benefit. To this end, Rivers and colleagues reported that goal-directed therapy of septic shock and severe sepsis initiated in the emergency department and continued for 6 hours significantly improved outcome.8 0 This approach involved adjustment of cardiac preload, afterload, and contractility to balance O2 delivery with O2 demand. They found that goal-directed therapy during the first 6 hours of hospital stay (initiated in the emergency department) had significant effects, such as higher mean venous O2 saturation, lower lactate levels, lower base deficit, higher pH, and decreased 28-day mortality (49.2 vs. 33.3%) compared to the standard therapy group. The frequency of sudden cardiovascular collapse was also significantly less in the group managed with goal-directed therapy (21.0 vs. 10.3%). Interestingly, the goal-directed therapy group received more IV fluids during the initial 6 hours, but the standard therapy group required more IV fluids by 72 hours. The authors emphasize that continued cellular and tissue decompensation is subclinical and often irreversible when obvious clinically. Goal-directed therapy allowed identification and treatment of these patients with insidious illness (global tissue hypoxia in the setting of normal vital signs).

Fig. 5-11.

An algorithm for the treatment of patients presenting with sepsis syndrome. CVP = central venous pressure; ETI = ejective time index; HCT = hematocrit; MAP = mean arterial pressure; O2 = oxygen; SaO2 = oxygen saturation; SBP = systolic blood pressure. (From Cinel et al,79 with permission.)

Hyperglycemia and insulin resistance are typical in critically ill and septic patients, including patients without underlying diabetes mellitus. A recent study reported significant positive impact of tight glucose management on outcome in critically ill patients.8 1 The two treatment groups in this randomized, prospective study were assigned to receive intensive insulin therapy (maintenance of blood glucose between 80 and 110 mg/dL) or conventional treatment (infusion of insulin only if the blood glucose level exceeded 215 mg/dL, with a goal between 180 and 200 mg/dL). The mean morning glucose level was significantly higher in the conventional treatment as compared to the intensive insulin therapy group (153 vs. 103 mg/dL). Mortality in the intensive insulin treatment group (4.6%) was significantly lower than in the conventional treatment group (8.0%), representing a 42% reduction in mortality. This reduction in mortality was most notable in the patients requiring longer than 5 days in the ICU. Furthermore, intensive insulin therapy reduced episodes of septicemia by 46%, reduced duration of antibiotic therapy, and decreased the need for prolonged ventilatory support and renal replacement therapy. Another treatment protocol that has been demonstrated to increase survival in patients with ARDS investigated the use of lower ventilatory tidal volumes compared to traditional tidal volumes.8 2 The majority of the patients enrolled in this multicenter, randomized trial developed ARDS secondary to pneumonia or sepsis. The trial compared traditional ventilation treatment, which involved an initial tidal volume of 12 mL/kg of predicted body weight and

an airway pressure measured after a 0.5-second pause at the end of inspiration (plateau pressure) of 50 cm of water or less, with ventilation with a lower tidal volume, which involved an initial tidal volume of 6 mL/kg of predicted body weight and a plateau pressure of 30 cm of water or less. The trial was stopped after the enrollment of 861 patients because mortality was lower in the group treated with lower tidal volumes than in the group treated with traditional tidal volumes (31.0 vs. 39.8%, P = .007), and the number of days without ventilator use during the first 28 days after randomization was greater in this group (mean SD, 12 11 vs. 10 11; P = .007). The investigators concluded that in patients with acute lung injury and ARDS, mechanical ventilation with a lower tidal volume than is traditionally used results in decreased mortality and increases the number of days without ventilator use. A recent study reported benefit from IV infusion of recombinant human activated protein C for severe sepsis.8 3 Activated protein C is an endogenous protein that promotes fibrinolysis and inhibits thrombosis and inflammation. The authors conducted a randomized, prospective, multicenter trial assessing the efficacy of activated protein C in patients with systemic inflammation and organ failure due to acute infection. Treatment with activated protein C reduced the 28-day mortality rate from 31 to 25%; the reduction in relative risk of death was 19.4%. However, several follow-up studies have suggested that activated protein C may not improve mortality when patients are followed up to 6 months. The use of corticosteroids in the treatment of sepsis and septic shock has been controversial for decades. The observation that severe sepsis often is associated with adrenal insufficiency or glucocorticoid receptor resistance has generated renewed interest in therapy for septic shock with corticosteroids. A single IV dose of 50 mg of hydrocortisone improved mean arterial blood pressure response relationships to norepinephrine and phenylephrine in patients with septic shock, and was most notable in patients with relative adrenal insufficiency. A more recent study evaluated therapy with hydrocortisone (50 mg IV every 6 hours) and fludrocortisone (50 g orally once daily) vs. placebo for 1 week in patients with septic shock.8 4 As in earlier studies, the authors performed corticotropin tests on these patients to document and stratify patients by relative adrenal insufficiency. In this study, 7-day treatment with low doses of hydrocortisone and fludrocortisone significantly and safely lowered the risk of death in patients with septic shock and relative adrenal insufficiency. In an international, multicenter, randomized trial of corticosteroids in sepsis (CORTICUS study; 499 analyzable patients), steroids showed no benefit in intent to treat mortality or shock reversal.8 5 This study suggested that hydrocortisone therapy cannot be recommended as routine adjuvant therapy for septic shock. However, if SBP remains less than 90 mmHg despite appropriate fluid and vasopressor therapy, hydrocortisone at 200 mg/day for 7 days in four divided doses or by continuous infusion should be considered. Additional adjunctive immune modulation strategies have been developed for the treatment of septic shock. These include the use of antiendotoxin antibodies, anticytokine antibodies, cytokine receptor antagonists, immune enhancers, a non–isoform-specific nitric oxide synthase inhibitor, and O2 radical scavengers. These compounds are each designed to alter some aspect of the host immune response to shock that is hypothesized to play a key role in its pathophysiology. However, most of these strategies have failed to demonstrate efficacy in human patients despite utility in well-controlled animal experiments. It is unclear whether the failure of these compounds is due to poorly designed clinical trials, inadequate understanding of the interactions of the complex host immune response to injury and infection, or animal models of shock that poorly represent the human disease.

Cardiogenic Shock Cardiogenic shock is defined clinically as circulatory pump failure leading to diminished forward flow and

subsequent tissue hypoxia, in the setting of adequate intravascular volume. Hemodynamic criteria include sustained hypotension (i.e., SBP IgG binding to microbes, leading to the release of a number of different complement protein fragments (C3a, C4a, C5a) tha are biologically active, acting to markedly enhance vascular permeability. Bacterial cell wall components and a variety of

enzymes that are expelled from leukocyte phagocytic vacuoles during microbial phagocytosis and killing act in this capacity a well. Simultaneously, the release of substances to which polymorphonuclear leukocytes (PMNs) in the bloodstream are attracted takes place. These consist of C5a, microbial cell wall peptides containing N -formyl-methionine, and macrophage secretion of cytokines such as IL-8. This process of host defense recruitment leads to further influx of inflammatory fluid into the area of

incipient infection, and is accompanied by diapedesis of large numbers of PMNs, a process that begins within several minutes and may peak within hours or days. The magnitude of the response and eventual outcome generally are related to several

factors: (a) the initial number of microbes, (b) the rate of microbial proliferation in relation to containment and killing by host defenses, (c) microbial virulence, and (d) the potency of host defenses. In regard to the latter, drugs or disease states that

diminish any or multiple components of host defenses are associated with higher rates and potentially more grave infections.

Definitions Several possible outcomes can occur subsequent to microbial invasion and the interaction of microbes with resident and

recruited host defenses: (a) eradication, (b) containment, often leading to the presence of purulence—the hallmark of chronic infection (e.g., a furuncle in the skin and soft tissue or abscess within the parenchyma of an organ or potential space), (c) locoregional infection (cellulitis, lymphangitis, and aggressive soft tissue infection) with or without distant spread of infection (metastatic abscess), or (d) systemic infection (bacteremia or fungemia). Obviously, the latter represents the failure of

resident and recruited host defenses at the local level, and is associated with significant morbidity and mortality in the clinica setting. In addition, it is not uncommon that disease progression occurs such that serious locoregional infection is associated with concurrent systemic infection. A chronic abscess also may intermittently drain and/or be associated with bacteremia. Infection is defined by identification of microorganisms in host tissue or the bloodstream, plus an inflammatory response to

their presence. At the site of infection, the classic findings of rubor, calor, and dolor in areas such as the skin or subcutaneous tissue are common. Most infections in normal individuals with intact host defenses are associated with these local manifestations, plus systemic manifestations such as elevated temperature, elevated white blood cell (WBC) count,

tachycardia, or tachypnea. The systemic manifestations noted above comprise the systemic inflammatory response syndrome (SIRS). SIRS can be caused by a variety of disease processes, including pancreatitis, polytrauma, malignancy, and transfusion

reaction, as well as infection (Fig. 6-1). Strict criteria for SIRS (tachycardia, tachypnea, fever, and elevated WBC count) have

been broadened to include additional clinical indicators noted in Table 6-1.1 2 SIRS caused by infection is termed sepsis and is mediated by the production of a cascade of proinflammatory mediators produced in response to exposure to microbial products. These products include lipopolysaccharide (endotoxin) derived from gram-negative organisms; peptidoglycans and teichoic acids from gram-positive organisms; multiple cell wall components such as mannan from yeast and fungi; and many others. Patients have developed sepsis if they have met clinical criteria for SIRS and have evidence of a local or systemic source of infection.

Fig. 6-1.

Relationship between infection and systemic inflammatory response syndrome (SIRS). Sepsis is the presence both of infection and the systemic inflammatory response, shown here as the intersection of these two areas. Other conditions may cause SIRS as well (trauma, aspiration, etc.). Severe sepsis (and septic shock) are both subsets of sepsis.

Table 6-1 Criteria for Systemic Inflammatory Response Syndrome General variables Fever [core temp >38.3C (100.9F)] Hypothermia [core temp 90 bpm Tachypnea Altered mental status Significant edema or positive fluid balance (>20 mL/kg over 24 h) Hyperglycemia in the absence of diabetes Inflammatory variables Leukocytosis (WBC >12,000) Leukopenia (WBC 10% band forms) Plasma C-reactive protein> 2 s.d. above normal value Plasma procalcitonin >2 s.d. above normal value Hemodynamic variables Arterial hypotension (SBP 70% Cardiac index>3.5 L/min per square meter Organ dysfunction variables

Arterial hypoxemia Acute oliguria Creatinine increase Coagulation abnormalities Ileus Thrombocytopenia Hyperbilirubinemia Tissue perfusion variables Hyperlactatemia Decreased capillary filling

bpm = beats per minute; MAP = mean arterial pressure; SBP = systolic blood pressure; s.d. = standard deviations; SVO venous oxygen saturation; WBC = white blood cell count.

2

=

Severe sepsis is characterized as sepsis (defined above) combined with the presence of new-onset organ failure. Severe seps

is the most common cause of death in noncoronary critical care units, with a mortality rate of 51 cases/100,000 population p year in 2003.1 3 A number of organ dysfunction scoring systems have been described.14–16 With respect to clinical criteria, a patient with sepsis and the need for ventilatory support, with oliguria unresponsive to aggressive fluid resuscitation or with hypotension requiring vasopressors, should be considered to have developed severe sepsis. Septic shock is a state of acute circulatory failure identified by the presence of persistent arterial hypotension (systolic blood pressure Chapter 7. Trauma>

KEY POINTS 1. Trauma remains the most common cause of death for all individuals between the ages of 1 and 44 years and is the third most common cause of death regardless of age. 2. The initial management of seriously injured patients consists of performing the primary survey (the "ABCs"—A irway with cervical spine protection, B reathing, and C irculation); the goals of the primary survey are to identify and treat conditions that constitute an immediate threat to life. 3. Patients with ongoing hemodynamic instability, whether "nonresponders" or "transient responders," require prompt intervention; one must consider the four categories of shock that may represent the underlying pathophysiology: hemorrhagic, cardiogenic, neurogenic, and septic. 4. All patients with blunt injury should be assumed to have unstable cervical spine injuries until proven otherwise; one must maintain cervical spine precautions and in-line stabilization. 5. Indications for immediate operative intervention for penetrating cervical injury include hemodynamic instability and significant external arterial hemorrhage; the management algorithm for hemodynamically stable patients is based on the presenting symptoms and anatomic location of injury, with the neck being divided into three distinct zones. 6. Blunt injuries to the carotid and vertebral arteries are usually managed with systemic antithrombotic therapy. 7. The abdomen is a diagnostic black box. However, physical examination and ultrasound can rapidly identify patients requiring emergent laparotomy. Computed tomographic (CT) scanning is the mainstay of evaluation in the remaining patients to more precisely identify the site and magnitude of injury. 8. Manifestation of the "bloody vicious cycle" (the lethal combination of coagulopathy, hypothermia, and metabolic acidosis) is the most common indication for damage control surgery. The primary objectives of damage control laparotomy are to control bleeding and limit GI spillage. 9. The abdominal compartment syndrome may be primary (i.e., due to the injury of abdominal organs, bleeding, and packing) or secondary (i.e., due to reperfusion gut edema and ascites). 10. The gold standard for determining if there is a blunt descending torn aorta injury is CT scanning; indications are primarily based on injury mechanisms.

TRAUMA: INTRODUCTION Trauma, or injury, is defined as cellular disruption caused by an exchange with environmental energy that is

beyond the body's resilience. Trauma remains the most common cause of death for all individuals between the ages of 1 and 44 years and is the third most common cause of death regardless of age.1 It is also the number one cause of years of productive life lost. The U.S. government classifies injury-related death into the following categories: accidents (unintentional injuries), intentional self-harm (suicide), assault (homicide), legal intervention or war, and undetermined causes. Unintentional injuries account for over 110,000 deaths per year, with motor vehicle collisions accounting for over 40%. Homicides, suicides, and other causes are responsible for another 50,000 deaths each year. However, death is a poor indicator of the magnitude of the problem, because most injured patients survive. For example, in 2004 there were approximately 167,000 injury-related deaths, but 29.6 million injured patients treated in emergency departments (EDs).2 Injury-related medical expenditures are estimated to be $117 billion each year in the United States.2 The aggregate lifetime cost for all injured patients is estimated to be in excess of $260 trillion. For these reasons, trauma must be considered a major public health issue. The American College of Surgeons Committee on Trauma addresses this issue by assisting in the development of trauma centers and systems. The organization of trauma systems has had a significant favorable impact on patient outcomes.3–5

INITIAL EVALUATION AND RESUSCITATION OF THE INJURED PATIENT Primary Survey The Advanced Trauma Life Support (ATLS) course of the American College of Surgeons Committee on Trauma was developed in the late 1970s, based on the assumption that appropriate and timely care can significantly improve the outcome for the injured patient. 6 ATLS provides a structured approach to the trauma patient with standard algorithms of care; it emphasizes the "golden hour" concept that timely prioritized interventions are necessary to prevent death. The ATLS format and basic tenets are followed throughout this chapter, with minor modifications. The initial management of seriously injured patients consists of the primary survey, concurrent resuscitation, the secondary survey, diagnostic evaluation, and definitive care. The first step in patient management is performing the primary survey, the goal of which is to identify and treat conditions that constitute an immediate threat to life. The ATLS course refers to the primary survey as assessment of the "ABCs" (A irway with cervical spine protection, B reathing, and C irculation). Although the concepts within the primary survey are presented in a sequential fashion, in reality they often proceed simultaneously. Life-threatening injuries must be identified (Table 7-1) and treated before advancing to the secondary survey.

Table 7-1 Immediately Life-Threatening Injuries to Be Identified during the Primary Survey A irway Airway obstruction Airway injury B reathing Tension pneumothorax Open pneumothorax Flail chest with underlying pulmonary contusion C irculation Hemorrhagic shock Massive hemothorax Massive hemoperitoneum Mechanically unstable pelvis fracture

Extremity losses Cardiogenic shock Cardiac tamponade Neurogenic shock Cervical spine injury Disability Intracranial hemorrhage/mass lesion

AIRWAY MANAGEMENT WITH CERVICAL SPINE PROTECTION Ensuring a patent airway is the first priority in the primary survey. This is essential, because efforts to restore cardiovascular integrity will be futile unless the oxygen content of the blood is adequate. Simultaneously, all patients with blunt trauma require cervical spine immobilization until injury is excluded. This is typically accomplished by applying a hard collar or placing sandbags on both sides of the head with the patient's forehead taped across the bags to the backboard. Soft collars do not effectively immobilize the cervical spine. In general, patients who are conscious, do not show tachypnea, and have a normal voice do not require early attention to the airway. Exceptions are patients with penetrating injuries to the neck and an expanding hematoma; evidence of chemical or thermal injury to the mouth, nares, or hypopharynx; extensive subcutaneous air in the neck; complex maxillofacial trauma; or airway bleeding. Although these patients may initially have a satisfactory airway, it may become obstructed if soft tissue swelling, hematoma formation, or edema progresses. In these cases, elective intubation should be performed before evidence of airway compromise. Patients who have an abnormal voice, abnormal breathing sounds, tachypnea, or altered mental status require further airway evaluation. Blood, vomit, the tongue, foreign objects, and soft tissue swelling can cause airway obstruction; suctioning affords immediate relief in many patients. In the comatose patient, the tongue may fall backward and obstruct the hypopharynx; this may be relieved by either a chin lift or jaw thrust. An oral airway or a nasal trumpet also can be helpful in maintaining airway patency, although the former is not usually tolerated by an awake patient. Establishment of a definitive airway (i.e., endotracheal intubation) is indicated in patients with apnea; inability to protect the airway due to altered mental status; impending airway compromise due to inhalation injury, hematoma, facial bleeding, soft tissue swelling, or aspiration; and inability to maintain oxygenation. Altered mental status is the most common indication for intubation. Agitation or obtundation, often attributed to intoxication or drug use, may actually be due to hypoxia. Options for endotracheal intubation include nasotracheal, orotracheal, or surgical routes. Nasotracheal intubation can be accomplished only in patients who are breathing spontaneously. Although nasotracheal intubation is frequently used by prehospital providers, the primary application for this technique in the ED is in those patients requiring emergent airway support in whom chemical paralysis cannot be used. Orotracheal intubation is the most common technique used to establish a definitive airway. Because all patients are presumed to have cervical spine injuries, manual in-line cervical immobilization is essential. 6 Correct endotracheal placement is verified with direct laryngoscopy, capnography, audibility of bilateral breath sounds, and finally a chest film. The GlideScope, a video laryngoscope that uses fiberoptics to visualize the vocal cords, is being employed more frequently. 7 Advantages of orotracheal intubation include the direct visualization of the vocal cords, ability to use larger-diameter endotracheal tubes, and applicability to apneic patients. The disadvantage of orotracheal intubation is that conscious patients usually require neuromuscular blockade, which may result in inability to intubate, aspiration, or medication

complications. Those who attempt rapid-sequence induction must be thoroughly familiar with the procedure (see Chap. 13). Patients in whom attempts at intubation have failed or who are precluded from intubation due to extensive facial injuries require surgical establishment of an airway. Cricothyroidotomy (Fig. 7-1) is performed through a generous vertical incision, with sharp division of the subcutaneous tissues and strap muscles. Visualization may be improved by having an assistant retract laterally on the neck incision using army-navy retractors. The cricothyroid membrane is verified by digital palpation through the space into the airway. The airway may be stabilized before incision of the membrane using a tracheostomy hook; the hook should be placed under the thyroid cartilage to elevate the airway. A 6.0 tracheostomy tube (maximum diameter in adults) is then advanced through the cricothyroid opening and sutured into place. In patients under the age of 8, cricothyroidotomy is contraindicated due to the risk of subglottic stenosis, and tracheostomy should be performed.

Fig. 7-1.

Cricothyroidotomy is recommended for emergent surgical establishment of a patent airway. A vertical skin incision avoids injury to the anterior jugular veins, which are located just lateral to the midline. Hemorrhage from these vessels obscures vision and prolongs the procedure. When a transverse incision is made in the cricothyroid membrane, the blade of the knife should be angled inferiorly to avoid injury to the vocal cords. A. Use of a tracheostomy hook stabilizes the thyroid cartilage and facilitates tube insertion. B. A 6.0 tracheostomy tube or endotracheal tube is inserted after digital confirmation of airway access.

Emergent tracheostomy is indicated in patients with laryngotracheal separation or laryngeal fractures, in whom cricothyroidotomy may cause further damage or result in complete loss of the airway. This procedure is best performed in the OR where there is optimal lighting and availability of more equipment (e.g., sternal saw). In these cases, often after a "clothesline" injury, direct visualization and instrumentation of the trachea usually is done through the traumatic anterior neck defect or after a collar skin incision (Fig. 7-2). If the trachea is completely transected, a nonpenetrating clamp should be placed on the distal aspect to prevent tracheal retraction into the mediastinum; this is particularly important before placement of the endotracheal tube.

Fig. 7-2.

A "clothesline" injury can partially or completely transect the anterior neck structures, including the trachea. With complete tracheal transection, the endotracheal tube is placed directly into the distal aperture, with care taken not to push the trachea into the mediastinum.

BREATHING AND VENTILATION Once a secure airway is obtained, adequate oxygenation and ventilation must be assured. All injured patients should receive supplemental oxygen and be monitored by pulse oximetry. The following conditions constitute an immediate threat to life due to inadequate ventilation and should be recognized during the primary survey: tension pneumothorax, open pneumothorax, and flail chest with underlying pulmonary contusion. All of these diagnoses should be made during the initial physical examination. The diagnosis of tension pneumothorax is implied by respiratory distress and hypotension in combination with any of the following physical signs in patients with chest trauma: tracheal deviation away from the affected side, lack of or decreased breath sounds on the affected side, and subcutaneous emphysema on the affected side. Patients may have distended neck veins due to impedance of the superior vena cava, but the neck veins may be flat due to systemic hypovolemia. Vital signs differentiate a tension pneumothorax from a simple pneumothorax; each can have similar signs, symptoms, and examination findings, but hypotension qualifies the pneumothorax as a tension pneumothorax. Although immediate needle thoracostomy decompression with a 14-gauge angiocatheter in the second intercostal space in the midclavicular line may be indicated in the field, tube thoracostomy should be performed immediately in the ED before a chest radiograph is obtained (Fig. 7-3). In cases of tension pneumothorax, the parenchymal tear in the lung acts as a one-way valve, with each inhalation allowing additional

air to accumulate in the pleural space. The normally negative intrapleural pressure becomes positive, which depresses the ipsilateral hemidiaphragm and shifts the mediastinal structures into the contralateral chest. Subsequently, the contralateral lung is compressed and the heart rotates about the superior and inferior vena cava; this decreases venous return and ultimately cardiac output, which results in cardiovascular collapse.

Fig. 7-3.

A. Tube thoracostomy is performed in the midaxillary line at the fourth or fifth intercostal space (inframammary crease) to avoid iatrogenic injury to the liver or spleen. B. Heavy scissors are used to cut through the intercostal muscle into the pleural space. This is done on top of the rib to avoid injury to the intercostal bundle located just beneath the rib. C. The incision is digitally explored to confirm intrathoracic location and identify pleural adhesions. D. A 36F chest tube is directed superiorly and posteriorly with the aid of a large clamp.

An open pneumothorax or "sucking chest wound" occurs with full-thickness loss of the chest wall, permitting free communication between the pleural space and the atmosphere (Fig. 7-4). This compromises ventilation due to equilibration of atmospheric and pleural pressures, which prevents lung inflation and alveolar ventilation, and

results in hypoxia and hypercarbia. Complete occlusion of the chest wall defect without a tube thoracostomy may convert an open pneumothorax to a tension pneumothorax. Temporary management of this injury includes covering the wound with an occlusive dressing that is taped on three sides. This acts as a flutter valve, permitting effective ventilation on inspiration while allowing accumulated air to escape from the pleural space on the untaped side, so that a tension pneumothorax is prevented. Definitive treatment requires closure of the chest wall defect and tube thoracostomy remote from the wound.

Fig. 7-4.

A. Full-thickness loss of the chest wall results in an open pneumothorax. B. The defect is temporarily managed with an occlusive dressing that is taped on three sides, which allows accumulated air to escape from the pleural space and thus prevents a tension pneumothorax. Repair of the chest wall defect and tube thoracostomy remote from the wound is definitive treatment.

Flail chest occurs when three or more contiguous ribs are fractured in at least two locations. Paradoxical movement of this free-floating segment of chest wall may be evident in patients with spontaneous ventilation, due to the negative intrapleural pressure of inspiration. Rarely the additional work of breathing and chest wall pain caused by the flail segment is sufficient to compromise ventilation. However, it is the decreased compliance and increased shunt fraction caused by the associated pulmonary contusion that is typically the source of postinjury pulmonary dysfunction. Pulmonary contusion often progresses during the first 12 hours. Resultant hypoventilation and hypoxemia may require presumptive intubation and mechanical ventilation. The patient's initial chest radiograph often underestimates the extent of the pulmonary parenchymal damage (Fig. 7-5); close monitoring and frequent clinical re-evaluation are warranted.

Fig. 7-5.

A. Admission chest film may not show the full extent of the patient's thoracic injury. B. This patient's left pulmonary contusion blossomed 12 hours later, and its associated opacity is noted on repeat chest film.

CIRCULATION WITH HEMORRHAGE CONTROL With a secure airway and adequate ventilation established, circulatory status is the next priority. An initial approximation of the patient's cardiovascular status can be obtained by palpating peripheral pulses. In general, systolic blood pressure (SBP) must be 60 mmHg for the carotid pulse to be palpable, 70 mmHg for the femoral pulse, and 80 mmHg for the radial pulse. At this point in the patient's evaluation, any episode of hypotension (defined as a SBP 35 Urine output (mL/h) >30 20–30 5–15 Negligible CNS/mental status Slightly anxious Mildly anxious Anxious and confused Confused and lethargic Class I

Class II

Class III

Class IV

BV = blood volume; CNS = central nervous system. There are several caveats to be considered and pitfalls to be avoided when evaluating the injured patient for shock. Tachycardia is often the earliest sign of ongoing blood loss. However, individuals in good physical condition with a resting pulse rate in the fifties may manifest a relative tachycardia in the nineties; although clinically significant, this does not meet the standard definition of tachycardia. Conversely, patients receiving cardiac medications such as beta blockers may not be capable of increasing their heart rate despite significant stress. Bradycardia occurs with severe blood loss; this is an ominous sign, often heralding impending cardiovascular collapse. Other physiologic stresses, aside from hypovolemia, may produce tachycardia, such as hypoxia, pain, anxiety, and stimulant drugs (cocaine, amphetamines). As noted previously, hypotension is not a reliable early sign of hypovolemia, because blood volume must decrease by >30% before hypotension occurs. Additionally, younger patients with good sympathetic tone may surprise even the experienced clinician by maintaining SBP despite severe intravascular deficits until they are on the verge of cardiac arrest. Pregnant patients have a progressive increase in circulating blood volume over gestation; therefore, they must lose a relatively larger volume of blood before manifesting signs and symptoms of hypovolemia (see "Special Trauma Populations" below). Based on the initial response to fluid resuscitation, hypovolemic injured patients can be separated into three broad categories: responders, transient responders, and nonresponders. Individuals who are stable or have a good response to the initial fluid therapy as evidenced by normalization of vital signs, mental status, and urine output are unlikely to have significant ongoing hemorrhage, and further diagnostic evaluation for occult injuries can proceed in an orderly fashion (see "Secondary Survey" below). At the other end of the spectrum are patients classified as "nonresponders" who have persistent hypotension despite aggressive resuscitation. These patients require immediate identification of the source of hypotension with appropriate intervention to prevent a fatal outcome. Patients considered as "transient responders" are those who respond initially to volume loading by an increase in blood pressure only to then hemodynamically deteriorate once more. This group of patients can be challenging to triage for definitive management.

PERSISTENT HYPOTENSION Patients with ongoing hemodynamic instability, whether "nonresponders" or "transient responders," require systematic evaluation and prompt intervention. The spectrum of disease in patients with persistent hypotension ranges from nonsurvivable multisystem injury to easily reversible problems such as a tension pneumothorax. One

must first consider the four categories of shock that may be the underlying cause: hemorrhagic, cardiogenic, neurogenic, and septic. Except for patients transferred from outside facilities >12 hours after injury, few patients present in septic shock in the trauma bay. Patients with neurogenic shock as a component of hemodynamic instability often are recognized during the disability section of the primary survey to have paralysis, but those patients chemically paralyzed before physical examination may be misdiagnosed. In most cases, however, the two broad categories of shock causing persistent hypotension are hemorrhagic and cardiogenic. An evaluation of the CVP will usually distinguish between these two categories. A patient with flat neck veins and a CVP of 15 cm H2 O is likely to be in cardiogenic shock. The CVP may be falsely elevated, however, if the patient is agitated and straining, or fluid administration is overzealous; isolated readings must be interpreted with caution. Serial base deficit measurements also are helpful; a persistent base deficit of >8 mmol/L implies ongoing cellular shock. Evolving technology, such as near infrared spectroscopy, will provide noninvasive monitoring of oxygen delivery to tissue. 9 The differential diagnosis of cardiogenic shock in trauma patients is: (a) tension pneumothorax, (b) pericardial tamponade, (c) blunt cardiac injury, (d) myocardial infarction, and (e) bronchovenous air embolism. Tension pneumothorax, the most frequent cause of cardiac failure, and pericardial tamponade have been discussed earlier. Although as many as one third of patients sustaining significant blunt chest trauma experience blunt cardiac injury, few such injuries result in hemodynamic embarrassment. Patients with electrocardiographic (ECG) abnormalities or dysrhythmias require continuous ECG monitoring and antidysrhythmic treatment as needed. Unless myocardial infarction is suspected, there is no role for measurement of cardiac enzyme levels—they lack specificity and do not predict significant dysrhythmias.1 0 The patient with hemodynamic instability requires aggressive resuscitation and may benefit from the placement of a pulmonary artery catheter to optimize preload and guide inotropic support. Echocardiography may be indicated to exclude pericardial tamponade or valvular or septal injuries. It typically demonstrates right ventricular dyskinesia but is less helpful in titrating treatment and monitoring the response to therapy unless done repeatedly. Patients with refractory cardiogenic shock may require placement of an intra-aortic balloon pump to decrease myocardial work and enhance coronary perfusion. Acute myocardial infarction may be the cause of a motor vehicle collision or other trauma in older patients. Although optimal initial management includes treatment for the evolving infarction, such as lytic therapy and emergent angioplasty, these decisions must be individualized in accordance with the patient's other injuries. Air embolism is a frequently overlooked or undiagnosed lethal complication of pulmonary injury. Air emboli can occur after blunt or penetrating trauma, when air from an injured bronchus enters an adjacent injured pulmonary vein (bronchovenous fistula) and returns air to the left heart. Air accumulation in the left ventricle impedes diastolic filling, and during systole air is pumped into the coronary arteries, disrupting coronary perfusion. The typical case is a patient with a penetrating thoracic injury who is hemodynamically stable but experiences arrest after being intubated and placed on positive pressure ventilation. The patient should immediately be placed in Trendelenburg's position to trap the air in the apex of the left ventricle. Emergency thoracotomy is followed by cross-clamping of the pulmonary hilum on the side of the injury to prevent further introduction of air (Fig. 7-14). Air is aspirated from the apex of the left ventricle and the aortic root with an 18-gauge needle and 50-mL syringe. Vigorous massage is used to force the air bubbles through the coronary arteries; if this is unsuccessful, a tuberculin syringe may be used to aspirate air bubbles from the right coronary artery. Once circulation is restored, the patient should be kept in Trendelenburg's position with the pulmonary hilum clamped until the pulmonary venous injury is controlled operatively.

Fig. 7-14.

A. A Satinsky clamp is used to clamp the pulmonary hilum to prevent further bronchovenous air embolism. B. Sequential sites of aspiration include the left ventricle, the aortic root, and the right coronary artery.

Persistent hypotension due to uncontrolled hemorrhage is associated with high mortality. A rapid search for the source or sources of hemorrhage includes visual inspection with knowledge of the injury mechanism, FAST, and chest and pelvic radiographs. During diagnostic evaluation, type O RBCs (O-negative for women of childbearing age) and type-specific RBCs, when available, should be administered. In patients with penetrating trauma and clear indications for operation, essential films should be taken and the patient should be transported to the OR immediately. Such patients include those with massive hemothorax, those with initial chest tube output of >1 L with ongoing output of >200 mL/h, and those with abdominal trauma and ultrasound evidence of hemoperitoneum. In patients with gunshot wounds to the chest or abdomen, a chest and abdominal film, with radiopaque markers at the wound sites, should be obtained to determine the trajectory of the bullet or location of a retained fragment. For example, a patient with a gunshot wound to the upper abdomen should have a chest radiograph to ensure that the bullet did not traverse the diaphragm causing intrathoracic injury. Similarly, physical examination and chest radiograph of a patient with a gunshot wound to the right chest must evaluate the left hemithorax. If a patient has a penetrating weapon remaining in place, the weapon should not be removed in the ED, because it could be

tamponading a lacerated blood vessel (Fig. 7-15). The surgeon should extract the offending instrument in the controlled environment of the OR, ideally once an incision has been made with adequate exposure. In situations in which knives are embedded in the head or neck, preoperative imaging may be useful to exclude arterial injuries. Blunt trauma patients with clear operative indications include hypotensive patients with massive hemothorax and those with a FAST examination documenting extensive free intraperitoneal fluid.

Fig. 7-15.

If a weapon is still in place, it should be removed in the operating room, because it could be tamponading a lacerated blood vessel.

In patients without clear operative indications and persistent hypotension, one should systematically evaluate the five potential sources of blood loss: scalp, chest, abdomen, pelvis, and extremities. Significant bleeding at the scene may be noted by paramedics, but its quantification is unreliable. Examination should detect active bleeding from a scalp laceration that may be readily controlled with clips or staples. Thoracoabdominal trauma should be evaluated with a combination of chest radiograph, FAST, and pelvic radiograph. If the FAST results are negative and no other source of hypotension is obvious, diagnostic peritoneal aspiration should be entertained.1 1 Extremity examination and radiographs should be used to search for associated fractures. Fracture-related blood loss, when additive, may be a potential source of the patient's hemodynamic instability. For each rib fracture there is approximately 100 to 200 mL of blood loss; for tibial fractures, 300 to 500 mL; for femur fractures, 800 to 1000 mL; and for pelvic fractures >1000 mL. Although no single injury may appear to cause a patient's hemodynamic instability, the sum of the injuries may result in life-threatening blood loss. The diagnostic measures advocated earlier are those that can be easily performed in the trauma bay. Transport of a hypotensive patient out of the ED for computed tomographic (CT) scanning may be hazardous; monitoring is compromised, and the environment is suboptimal for dealing with acute problems. The surgeon must accompany the patient and be prepared to abort the CT scan with direct transport to the OR. This dilemma is becoming less common in large trauma centers where CT scanning can be accomplished in the ED. The role of treatment of hypotension in the ED remains controversial, and it is primarily relevant for patients with penetrating vascular injuries. Experimental work suggests that an endogenous sealing clot of an injured artery may be disrupted at an SBP of >90 mmHg 1 2 ; thus, many believe that this should be the preoperative blood pressure target for patients with torso arterial injuries. On the other hand, optimal management of traumatic brain injury (TBI) includes maintaining the SBP at >90 mmHg.1 3

Secondary Survey Once the immediate threats to life have been addressed, a thorough history is obtained and the patient is examined in a systematic fashion. The patient and surrogates should be queried to obtain an AMPLE history (A llergies, M edications, P ast illnesses or Pregnancy, L ast meal, and E vents related to the injury). The physical examination should be head to toe, with special attention to the patient's back, axillae, and perineum, because injuries here are easily overlooked. All potentially seriously injured patients should undergo digital rectal examination to evaluate for sphincter tone, presence of blood, rectal perforation, or a high-riding prostate; this is particularly critical in patients with suspected spinal cord injury, pelvic fracture, or transpelvic gunshot wounds. Vaginal examination with a speculum also should be performed in women with pelvic fractures to exclude an open fracture. Specific injuries, their associated signs and symptoms, diagnostic options, and treatments are discussed in detail later in this chapter. Adjuncts to the physical examination include vital sign and CVP monitoring, ECG monitoring, nasogastric tube placement, Foley catheter placement, repeat FAST, laboratory measurements, and radiographs. A nasogastric tube should be inserted in all intubated patients to decrease the risk of gastric aspiration but may not be indicated in the awake patient. Nasogastric tube placement in patients with complex facial fractures is contraindicated; rather, a tube should be placed orally if required. Nasogastric tube evaluation of stomach contents for blood may suggest occult gastroduodenal injury or the path of the nasogastric tube on a chest film may suggest a diaphragm injury. A Foley catheter should be inserted in patients unable to void to decompress the bladder, obtain a urine specimen, and monitor urine output. Gross hematuria demands evaluation of the genitourinary system for injury. Foley catheter placement should be deferred until urologic evaluation in patients with signs of urethral injury: blood at the meatus, perineal or scrotal hematomas, or a high-riding prostate. Although policies vary at individual institutions, patients in extremis with need for Foley catheter placement should undergo one attempt at catheterization; if the catheter does not pass easily, a percutaneous suprapubic cystostomy should be considered. Repeat FAST is performed if there are any signs of abdominal injury or occult blood loss. Selective radiography and laboratory tests are done early in the evaluation after the primary survey. For patients with severe blunt trauma, lateral cervical spine, chest, and pelvic radiographs should be obtained, often termed the big three. For patients with truncal gunshot wounds, anteroposterior and lateral radiographs of the chest and abdomen are warranted. It is important to mark the entrance and exit sites of penetrating wounds with ECG pads, metallic clips, or staples so that the trajectory of the missile can be estimated. Limited one-shot extremity radiographs also may be taken. In critically injured patients, blood samples for a routine trauma panel (type and cross-match, complete blood count, blood chemistries, coagulation studies, lactate level, and arterial blood gas analysis) should be sent to the laboratory. For less severely injured patients only a complete blood count and urinalysis may be required. Because older patients may present in subclinical shock, even with minor injuries, routine analysis of arterial blood gases in patients over the age of 55 should be considered. Many trauma patients cannot provide specific information about the mechanism of their injury. Emergency medical service personnel and police are trained to evaluate an injury scene and should be questioned. For automobile collisions, the speed of the vehicles involved, angle of impact (if any), use of restraints, airbag deployment, condition of the steering wheel and windshield, amount of intrusion, ejection or nonejection of the patient from the vehicle, and fate of other passengers should all be ascertained. For other injury mechanisms, critical information includes such things as height of a fall, surface impact, helmet use, and weight of an object by which the patient was crushed. In patients sustaining gunshot wounds, velocity, caliber, and presumed path of the bullet are important, if known. For patients with stab wounds, the length and type of object is helpful. Finally, some patients

experience a combination of blunt and penetrating trauma. Do not assume that someone who was stabbed was not also assaulted; the patient may have a multitude of injuries and cannot be presumed to have only injuries associated with the more obvious penetrating mechanism. In sum, these details of information are critical to the clinician to determine overall mechanism of injury and anticipate its associated injury patterns.

Mechanisms and Patterns of Injury In general, more energy is transferred over a wider area during blunt trauma than from a gunshot or stab wound. As a result, blunt trauma is associated with multiple widely distributed injuries, whereas in penetrating wounds the damage is localized to the path of the bullet or knife. In blunt trauma, organs that cannot yield to impact by elastic deformation are most likely to be injured, namely, the solid organs (liver, spleen, and kidneys). For penetrating trauma, organs with the largest surface area when viewed from the front are most prone to injury (small bowel, liver, and colon). Additionally, because bullets and knives usually follow straight lines, adjacent structures are commonly injured (e.g., the pancreas and duodenum). Trauma surgeons often separate patients who have sustained blunt trauma into categories according to their risk for multiple injuries: those sustaining high energy transfer injuries and those sustaining low energy transfer injuries. Injuries involving high energy transfer include auto-pedestrian accidents, motor vehicle collisions in which the car's change of velocity ( V) exceeds 40 km/h or in which the patient has been ejected, motorcycle collisions, and falls from heights >20 ft.1 4 In fact, for motor vehicle accidents the variables strongly associated with lifethreatening injuries, and hence reflective of the magnitude of the mechanism, are death of another occupant in the vehicle, extrication time of >20 minutes, V >40 km/h, lack of restraint use, and lateral impact.1 4 Low-energy trauma, such as being struck with a club or falling from a bicycle, usually does not result in widely distributed injuries. However, potentially lethal lacerations of internal organs still can occur, because the net energy transfer to any given location may be substantial. In blunt trauma, particular constellations of injury or injury patterns are associated with specific injury mechanisms. Frontal impact collisions typically produce multisystem trauma. When an unrestrained driver sustains a frontal impact, the head strikes the windshield, the chest and upper abdomen hit the steering column, and the legs or knees contact the dashboard. The resultant injuries can include facial fractures, cervical spine fractures, laceration of the thoracic aorta, myocardial contusion, injury to the spleen and liver, and fractures of the pelvis and lower extremities. When such patients are evaluated, the discovery of one of these injuries should prompt a search for others. Collisions with side impact also carry the risk of cervical spine and thoracic trauma, diaphragm rupture, and crush injuries of the pelvic ring, but solid organ injury usually is limited to either the liver or spleen based on the direction of impact. Not surprisingly, any time a patient is ejected from the vehicle or thrown a significant distance from a motorcycle, the risk of any injury increases. Penetrating injuries are classified according to the wounding agent (i.e., stab wound, gunshot wound, or shotgun wound). Gunshot wounds are subdivided further into high- and low-velocity injuries, because the speed of the bullet is much more important than its weight in determining kinetic energy. High-velocity gunshot wounds (bullet speed >2000 ft/s) are infrequent in the civilian setting. Shotgun injuries are divided into close-range (250 mL, it does not reliably determine the source of hemorrhage nor grade solid organ injuries.28,29 Patients with fluid on FAST examination, considered a "positive FAST," who do not have immediate indications for laparotomy and are hemodynamically stable undergo CT scanning to quantify their injuries. Injury grading using the American Association for the Surgery of Trauma grading scale (Table 7-7) is a key component of nonoperative management of solid organ injuries. Additional findings that should be noted on CT scan in patients with solid organ injury include contrast extravasation (i.e., a "blush"), the amount of intra-abdominal hemorrhage, and presence of pseudoaneurysms (Fig. 7-29). CT also is indicated for hemodynamically stable patients for whom the physical examination is unreliable. Despite the increasing diagnostic accuracy of multislice CT scanners, CT still has limited sensitivity for identification of intestinal injuries. Bowel injury is suggested by findings of thickened bowel wall, "streaking" in the mesentery, free fluid without associated solid organ injury, or free intraperitoneal air.3 0 Patients with free intra-abdominal fluid without solid organ injury are closely monitored for evolving signs of peritonitis; if patients have a significant closed head injury or cannot be serially examined, DPL should be performed to exclude bowel injury.

Fig. 7-27.

Algorithm for the initial evaluation of a patient with suspected blunt abdominal trauma. CT = computed tomography; DPA = diagnostic peritoneal aspiration; FAST = focused abdominal sonography for trauma; Hct = hematocrit.

Fig. 7-28.

Focused abdominal sonography for trauma imaging detects intra-abdominal hemorrhage. Hemorrhage is presumed when a fluid stripe is visible between the right kidney and liver (A ), between the left kidney and spleen (B ), or in the pelvis (C ).

Table 7-7 American Association for the Surgery of Trauma Grading Scales for Solid Organ Injuries Liver Injury Grade Grade I 10 cm in depth >3 cm Grade IV 25–75% of a hepatic lobe

Grade V >75% of a hepatic lobe Grade VI Hepatic avulsion Splenic Injury Grade Grade I 10 cm in depth >3 cm Grade IV >25% devascularization Hilum Grade V Shattered spleen Complete devascularization Subcapsular Hematoma

Fig. 7-29.

Laceration

Computed tomographic images reveal critical information about solid organ injuries, such as associated contrast extravasation from a grade IV laceration of the spleen (A; arrows ) and the amount of subcapsular hematoma in a grade III liver laceration (B; arrows ).

PELVIS Blunt injury to the pelvis may produce complex fractures with major hemorrhage (Fig. 7-30). Plain radiographs will reveal gross abnormalities, but CT scanning may be necessary to determine the precise geometry. Sharp spicules of bone can lacerate the bladder, rectum, or vagina. Alternatively, bladder rupture may result from the direct blow to the torso if the bladder is full. CT cystography is performed if the urinalysis findings are positive for RBCs. Urethral injuries are suspected if examination reveals blood at the meatus, scrotal or perineal hematomas, or a high-riding prostate on rectal examination. Urethrograms should be obtained for stable patients before placing a Foley catheter to avoid false passage and subsequent stricture. Major vascular injuries causing exsanguination are uncommon in blunt pelvic trauma; however, thrombosis of either the arteries or veins in the iliofemoral system may occur, and CT angiography or formal angiography is diagnostic. Life-threatening hemorrhage can be associated with pelvic fractures and may initially preclude definitive imaging. Treatment algorithms for patients with complex pelvic fractures and hemodynamic instability are presented later in the chapter.

Fig. 7-30.

The three types of mechanically unstable pelvis fractures are lateral compression (A ), anteroposterior compression (B ), and vertical shear (C ).

EXTREMITIES Blunt or penetrating trauma to the extremities requires an evaluation for fractures, ligamentous injury, and neurovascular injury. Plain radiographs are used to evaluate fractures, whereas ligamentous injuries, particularly those of the knee and shoulder, can be imaged with magnetic resonance imaging. Physical examination often identifies arterial injuries, and findings are classified as either hard signs or soft signs of vascular injury (Table 78). In general, hard signs constitute indications for operative exploration, whereas soft signs are indications for further testing or observation. Bony fractures or knee dislocations should be realigned before definitive vascular examination. On-table angiography may be useful to localize the arterial injury and thus limit tissue dissection in patients with hard signs of vascular injury. For example, a patient with an absent popliteal pulse and femoral shaft fracture due to a bullet that entered the lateral hip and exited below the medial knee could have injured either the femoral or popliteal artery anywhere along its course (Fig. 7-31).

Table 7-8 Signs and Symptoms of Peripheral Arterial Injury Pulsatile hemorrhage Proximity to vasculature Absent pulses Significant hematoma Acute ischemia

Associated nerve injury A-A index of 10%, CT angiography or arteriography is indicated. Others argue that there are occult injuries, such as pseudoaneurysms or injuries of the profunda femoris or peroneal arteries, which may not be detected with this technique. If hemorrhage occurs from these injuries, compartment syndrome and limb loss may occur. Although busy trauma centers continue to debate this issue, the surgeon who is obliged to treat the occasional injured patient may be better served by performing CT angiography in selected patients with soft signs.

GENERAL PRINCIPLES OF MANAGEMENT Over the past 20 years there has been a remarkable change in management practices and operative approach for the injured patient. With the advent of CT scanning, nonoperative management of solid organ injuries has replaced routine operative exploration. Those patients who do require operation may be treated with less radical resection techniques such as splenorrhaphy or partial nephrectomy. Colonic injuries, previously mandating colostomy, are now repaired primarily in virtually all cases. Additionally, the type of anastomosis has shifted from a double-layer closure to a continuous running single-layer closure; this method is technically equivalent to and faster than the interrupted multilayer techniques.3 2 Adoption of damage control surgical techniques in physiologically deranged patients has resulted in limited initial operative time, with definitive injury repair delayed until after resuscitation in the surgical intensive care unit (SICU) with physiologic restoration.3 3 Abdominal drains, once considered mandatory for parenchymal injuries and some anastomoses, have disappeared; fluid collections are managed by percutaneous techniques. Newer endovascular techniques such as stenting of arterial injuries and angioembolization are routine adjuncts. Blunt cerebrovascular injuries have been recognized as a significant, preventable source of neurologic morbidity and mortality. The use of preperitoneal pelvic packing for unstable pelvic fractures as well as early fracture immobilization with external fixators are paradigm shifts in management. Finally, the institution of massive transfusion protocols balances the benefit of blood component therapy against immunologic risk. These conceptual changes have significantly improved survival of critically injured patients; they have been promoted and critically reviewed by academic trauma centers via forums such as the American College of Surgeons Committee on Trauma, the American Association for the Surgery of Trauma, the International Association of Trauma Surgery and Intensive Care, the Pan-American Trauma Congress, and other surgical organizations.

Transfusion Practices Injured patients with life-threatening hemorrhage may develop marked coagulopathy requiring clotting factor replacement. Fresh whole blood, arguably the optimal replacement, is no longer available in the United States. Rather, its component parts, packed red blood cells (PRBCs), fresh-frozen plasma, platelets, and cryoprecipitate, are administered. Specific transfusion triggers for individual blood components exist. Although current critical care guidelines indicate that PRBC transfusion should occur once the patient's hemoglobin level is 65 mmHg. This prevents ischemic injury of the spinal cord as well as the splanchnic bed, and reduces left ventricular afterload.1 9 Heparinization is not required, a significant benefit in patients with multiple injuries, particularly in those with intracranial hemorrhage. Unless contraindicated, however, low-dose heparin (100 units/kg) typically is administered to prevent thromboembolic events. Once bypass is initiated, vascular clamps are applied on the aorta between the left common carotid and left subclavian arteries, on the left subclavian, and on the aorta distal to the injury. In most patients a short PTFE graft (usually 18 mm in diameter) is placed using a running 3-0 polypropylene suture. Primary arterial repair should be done when possible. Air and thrombus are flushed from the aortic graft before the final suture is tied, and the occluding vascular clamps are removed. The patient is then weaned from the centrifugal pump, the cannulas are removed, and primary repair of the cannulated vessels is performed.

Fig. 7-56.

When a tear of the descending thoracic aorta is repaired, perfusion of the spinal cord while the aorta is clamped is achieved by using partial left heart bypass. The venous cannula is inserted into the left superior pulmonary vein (solid arrow ) because it is less prone to tearing than the left atrium. The subclavian artery (dashed arrow ) is identified for vascular control. The phrenic nerve (PN) and vagus nerve (VN) should be identified during mediastinal exploration to prevent inadvertent injury.

HEART Blunt and penetrating cardiac injuries have widely differing presentations and therefore disparate treatments. Survivable penetrating cardiac injuries consist of wounds that can be closed; most are stab wounds. Before repair of the injury is attempted, hemorrhage should be controlled; injuries to the atria can be clamped with a Satinsky vascular clamp, whereas digital pressure occludes the majority of ventricular wounds. Foley catheter occlusion of larger stellate lesions may be effective, but even minimal traction may enlarge the original injury. Temporary control of hemorrhage, and at times definitive repair, may be accomplished with skin staples for left ventricular lacerations. Definitive repair of cardiac injuries is performed with either running 3-0 polypropylene suture or interrupted, pledgeted 2-0 polypropylene suture (Fig. 7-57).5 4 Use of pledgets may be particularly effective in the right ventricle to prevent sutures from pulling through the thinner myocardium. Injuries adjacent to coronary arteries should be repaired using horizontal mattress sutures, because use of running sutures results in coronary occlusion and distal infarction. Gunshot wounds may result in stellate lesions or contused, extremely friable myocardium adjacent to the wound. When the edges of such complex wounds cannot be fully approximated and hence the repair is not hemostatic, the authors have used surgical adhesive (BioGlue) to achieve hemostasis. Occasionally, interior structures of the heart may be damaged. Intraoperative auscultation or postoperative hemodynamic assessment usually identifies such injuries.5 5 Echocardiography can diagnose the injury and quantitate its effect on cardiac output. Immediate repair of valvular damage or septal defects rarely is necessary and would require cardiopulmonary bypass, which is associated with a high mortality in this situation.

Fig. 7-57.

A variety of techniques may be necessary to repair cardiac wounds. Generally, pledget support is used for the relatively thinwalled right ventricle.

Patients with blunt cardiac injury typically present with persistent tachycardia or rhythm disturbances, but occasionally present with tamponade due to atrial or right ventricular rupture. There are no pathognomonic ECG findings, and cardiac enzyme levels do not correlate with the risk of cardiac complications.1 0 Therefore, patients for whom there is high clinical suspicion of cardiac contusion and who are hemodynamically stable should be monitored for dysrhythmias for 24 hours by telemetry. Patients with hemodynamic instability should undergo echocardiography to evaluate for wall motion abnormalities, valvular dysfunction, chordae rupture, or diminished ejection fraction. If such findings are noted or if vasoactive agents are required, cardiac function can be continuously monitored using a pulmonary artery catheter. A precisely timed blow to the precordium can provoke sudden cardiac death, termed commotio cordis.

56

This phenomenon, affecting primarily adolescent males, usually

is fatal unless cardiopulmonary resuscitation and defibrillation are instituted immediately.

TRACHEA, BRONCHI, PULMONARY PARENCHYMA, AND ESOPHAGUS Fewer than 1% of all injured patients sustain intrathoracic tracheobronchial injuries, and only a small number require operative intervention. Although penetrating injuries may occur throughout the tracheobronchial system, blunt injuries occur within 2.5 cm of the carina. For patients with a massive air leak requiring emergent exploration, initial control of the injury to provide effective ventilation is obtained by passing an endotracheal tube either beyond the injury or into the contralateral mainstem bronchus. Principles of repair are similar to those for repair of cervical tracheal injuries. Devitalized tissue is dbrided, and primary end-to-end anastomosis with 3-0 PDS suture is performed. Dissection should be careful and limited to the area of injury to prevent disruption of surrounding bronchial vasculature and ensuing ischemia and stricture. Suture lines should be encircled with vascularized tissue, either pericardium, intercostal muscle, or pleura. Expectant management is employed for bronchial injuries that are less than one-third the circumference of the airway and have no evidence of a persistent

major air leak. In patients with peripheral bronchial injuries, indicated by persistent air leaks from the chest tube and documented by endoscopy, bronchoscopically directed fibrin glue sealing is occasionally required. Injuries to the pulmonary parenchyma typically are discovered during exploration for a massive hemothorax after penetrating trauma. Peripheral lacerations with persistent bleeding can be managed with stapled wedge resection. More central injuries traditionally have been managed with pulmonary lobectomy or pneumonectomy. But current treatment relies on pulmonary tractotomy, which permits selective ligation of individual bronchioles and bleeders, prevents the development of an intraparenchymal hematoma or air embolism, and reduces the need for formal lobar resection (see Fig. 7-49).57,58 A stapling device, preferably the longest GIA stapler available, is inserted directly into the injury track and positioned along the thinnest section of overlying parenchyma. The injury track is thus filleted open, which allows direct access to the bleeding vessels and leaking bronchi. The majority of injuries are definitively managed with selective ligation, and the defect is left open. Occasionally, tractotomy reveals a more proximal vascular injury that must be treated with formal lobectomy. Parenchymal injuries severe enough to mandate pneumonectomy usually are fatal because of right heart decompensation, and major pulmonary hilar injuries necessitating pneumonectomy are usually lethal in the field.5 9 One parenchymal injury that may be incidentally discovered during thoracic imaging is a posttraumatic pulmonary pseudocyst, colloquially termed a pneumatocele. Traumatic pneumatoceles typically follow a benign clinical course and are treated with aggressive pain management, pulmonary toilet, and serial chest radiography to monitor for resolution of the lesion. If the patient has persistent fever or leukocytosis, however, chest CT is done to evaluate for an evolving abscess, because up to 30% of pneumatoceles become infected. CT-guided catheter drainage may be required in such cases, because 25% of patients do not respond to antibiotic therapy alone. Surgery, ranging from partial resection to anatomic lobectomy, is indicated for unresolving complex pneumatoceles or infected lesions refractory to antibiotic therapy and drainage. The most common complication after thoracic injury is development of an empyema. Management is based on CT diagnostic criteria. Percutaneous drainage is indicated for single loculations without appreciable rind. Early decortication via video-assisted thoracic surgery is pursued in patients with multiple loculations or a pleural rind of >1 cm.6 0 Antibiotic treatment is based on definitive culture results. Due to the proximity of the structures, esophageal injuries often occur with tracheobronchial injuries, particularly in cases of penetrating trauma. Operative options are based on the extent and location of esophageal injury. With sufficient mobilization, a primary single-layer end-to-end anastomosis may be performed after appropriate dbridement. As with cervical repairs, if there are two suture lines in close approximation (trachea or bronchi and esophagus) interposition of a vascularized pedicle will prevent fistula formation. Perforations close to the gastroesophageal junction may be best treated with segmental resection and gastric pull-up. With large destructive injuries or delayed presentation of injuries, esophageal exclusion with wide drainage, diverting loop esophagostomy, and placement of a gastrostomy tube should be considered.

CHEST WALL AND DIAPHRAGM Virtually all chest wall injuries, consisting of rib fractures and laceration of intercostal vessels, are treated nonoperatively with pain control, pulmonary toilet or ventilatory management, and drainage of the pleural space as indicated. Early institution of effective pain control is essential. The authors advocate rib blocks with 0.25% bupivacaine hydrochloride (Marcaine) in the trauma bay, followed by epidural placement supplemented with patient-controlled anesthesia. Persistent hemorrhage from a chest tube after blunt trauma most often is due to injured intercostal arteries; for unusual persistent bleeding (see Table 7-10), thoracotomy with direct ligation or

angioembolization may be required to arrest hemorrhage. In rare cases of extensive flail chest segments or markedly displaced rib fractures, open reduction and internal fixation of the fracture with plates may be warranted. Chest wall defects, particularly those seen with open pneumothorax, are repaired using local approximation of tissues or tissue transfer for coverage. Scapular and sternal fractures rarely require operative intervention but are markers for significant thoracoabdominal force during injury. Careful examination and imaging should exclude associated injuries, including blunt cardiac injury and aortic tears. On the other hand, clavicle fractures often are isolated injuries and should be managed with pain control and immobilization. The exception is posterior dislocation of the clavicular head, which may injure the subclavian vessels. Blunt diaphragmatic injuries result in a linear tear in the central tendon, whereas penetrating injuries are variable in size and location depending on the agent of injury. Regardless of the etiology, acute injuries are repaired through an abdominal incision or with thoracoscopy/laparoscopy. After delineation of the injury, the chest should be evacuated of all blood and particulate matter, and thoracostomy tube placed if not previously done. Allis clamps are used to approximate the diaphragmatic edges, and the defect is closed with a running No. 1 polypropylene suture. Occasionally, large avulsions or shotgun wounds with extensive tissue loss will require polypropylene mesh or acellular dermal matrix (AlloDerm) to bridge the defect. Alternatively, transposition of the diaphragm cephalad one to two intercostal spaces may allow repair without undue tension. 6 1

Abdominal Injuries LIVER AND GALLBLADDER The liver's large size makes it the organ most susceptible to blunt trauma, and it is frequently involved in upper torso penetrating wounds. Nonoperative management of solid organ injuries is pursued in hemodynamically stable patients who do not have overt peritonitis or other indications for laparotomy. These patients should be admitted to the SICU with frequent hemodynamic monitoring, determination of hematocrit, and abdominal examination. The only absolute contraindication to nonoperative management is hemodynamic instability. Factors such as high injury grade, large hemoperitoneum, contrast extravasation, or pseudoaneurysms may predict complications or failure of nonoperative management. However, angioembolization and endoscopic retrograde cholangiopancreatography (ERCP) are useful adjuncts that can improve the success rate of nonoperative management.62,63 The indication for angiography to control hepatic hemorrhage is transfusion of 4 units of RBCs in 6 hours or 6 units of RBCs in 24 hours without hemodynamic instability. In the >10% of patients for whom emergent laparotomy is mandated, the primary goal is to arrest hemorrhage. Initial control of hemorrhage is best accomplished using perihepatic packing and manual compression. In either case, the edges of the liver laceration should be opposed for local pressure control of bleeding. Hemorrhage from most major hepatic injuries can be controlled with effective perihepatic packing. The right costal margin is elevated, and the pads are strategically placed over and around the bleeding site (see Fig. 7-36). Additional pads should be placed between the liver, diaphragm, and anterior chest wall until the bleeding has been controlled. Ten to 15 pads may be required to control the hemorrhage from an extensive right lobar injury. Packing of injuries of the left lobe is not as effective, because there is insufficient abdominal and thoracic wall anterior to the left lobe to provide adequate compression with the abdomen open. Fortunately, hemorrhage from the left lobe usually can be controlled by mobilizing the lobe and compressing it between the surgeon's hands. If the patient has persistent bleeding despite packing, injuries to the hepatic artery, portal vein, and retrohepatic vena cava should be considered. The Pringle maneuver can help delineate the source of hemorrhage. Hemorrhage from hepatic artery and portal vein injuries will halt with the application of a vascular clamp across the portal triad, whereas bleeding

from the hepatic veins and retrohepatic vena cava will not. Injuries of the portal triad vasculature should be addressed immediately. In general, ligation from the celiac axis to the level of the common hepatic artery at the gastroduodenal arterial branch is tolerated due to the extensive collaterals, but the proper hepatic artery should be repaired. The right or left hepatic artery, or in urgent situations the portal vein, may be selectively ligated; occasionally, lobar necrosis will necessitate delayed anatomic resection. If the right hepatic artery is ligated, cholecystectomy also should be performed. If the vascular injury is a stab wound with clean transection of the vessels, primary end-to-end repair is done. If the injury is destructive, temporary shunting should be performed followed by interposition reversed saphenous vein graft (RSVG). Blunt avulsions of the portal structures are particularly problematic if located at the hepatic plate, flush with the liver; hemorrhage control at the liver can be attempted with directed packing or Fogarty catheters. If the avulsion is more proximal, flush with the border of the pancreatic body or even retropancreatic, the pancreas must be transected to gain access for hemorrhage control and repair. If massive venous hemorrhage is seen from behind the liver despite use of the Pringle maneuver, the patient likely has a hepatic vein or retrohepatic vena cava injury. If bleeding is controlled, the packing should be left undisturbed and the patient observed in the SICU. If bleeding continues despite repeat perihepatic packing, then direct repair, with or without hepatic vascular isolation, should be attempted. Three techniques have been used to accomplish hepatic vascular isolation: (a) isolation with clamps on the diaphragmatic aorta, the suprarenal vena cava, and the suprahepatic vena cava; (b) atriocaval shunt; and (c) Moore-Pilcher balloon shunt. All techniques are performed with an associated Pringle maneuver. Even in experienced centers with readily available equipment, however, such techniques carry a mortality rate of >80%. Instead, recent efforts to control this highly lethal injury have used venovenous bypass (Fig. 7-58).6 4

Fig. 7-58.

Venovenous bypass permits hepatic vascular isolation with continued venous return to the heart. IMV = inferior mesenteric vein; IVC = inferior vena cava; SMV = superior mesenteric vein.

Numerous methods for the definitive control of hepatic parenchymal hemorrhage have been developed. Minor lacerations may be controlled with manual compression applied directly to the injury site. Topical hemostatic techniques include the use of an electrocautery (with the device set at 100 watts), argon beam coagulator, microcrystalline collagen, thrombin-soaked gelatin foam sponge, fibrin glue, and BioGlue. Suturing of the hepatic parenchyma is an effective hemostatic technique. However, the "liver suture," blunt 0 chromic suture, may tear the liver capsule, and its use generally is discouraged due to the associated hepatic necrosis. A running suture is used to approximate the edges of shallow lacerations, whereas deeper lacerations are approximated using interrupted horizontal mattress sutures placed parallel to the edge of the laceration. When the suture is tied, tension is adequate when visible hemorrhage ceases or the liver blanches around the suture. This technique of placing large liver sutures controls bleeding through reapproximation of the liver laceration rather than direct ligation of bleeding vessels. Aggressive finger fracture to identify bleeding vessels followed by individual clip or suture ligation was advocated previously but currently has a limited role in hemostasis. Hepatic lobar arterial ligation may be

appropriate for patients with recalcitrant arterial hemorrhage from deep within the liver and is a reasonable alternative to a deep hepatotomy, particularly in unstable patients. Omentum can be used to fill large defects in the liver. The tongue of omentum not only obliterates potential dead space with viable tissue but also provides an excellent source of macrophages. Additionally, the omentum can provide buttressing support for parenchymal sutures. Translobar penetrating injuries are particularly challenging, because the extent of the injury cannot be fully visualized. As discussed later in "Damage Control Surgery," options include intraparenchymal tamponade with a Foley catheter or balloon occlusion (see Fig. 7-48).6 5 If tamponade is successful with either modality, the balloon is left inflated for 24 to 48 hours followed by judicious deflation in the SICU and removal at a second laparotomy. Hepatotomy, using the finger fracture technique, with ligation of individual bleeders occasionally may be required. However, division of the overlying viable hepatic tissue may cause considerable blood loss in the coagulopathic patient. Finally, angioembolization is an effective adjunct in any of these scenarios and should be considered early in the course of treatment. Several centers have reported patients with devastating hepatic injuries or necrosis of the entire liver who have undergone successful hepatic transplantation. Clearly this is dramatic therapy, and the patient must have all other injuries delineated, particularly those of the central nervous system, and have an excellent chance of survival excluding the hepatic injury. Because donor availability will limit such procedures, hepatic transplantation for trauma will continue to be performed only in extraordinary circumstances. Cholecystectomy is performed for injuries of the gallbladder and after operative ligation of the right hepatic artery. Injuries of the extrahepatic bile ducts are a challenge due to their small size and thin walls. Because of the proximity of other portal structures and the vena cava, associated vascular injuries are common. These factors may preclude primary repair. Small lacerations with no accompanying loss or devitalization of adjacent tissue can be treated by the insertion of a T tube through the wound or by lateral suturing using 6-0 monofilament absorbable suture. Virtually all transections and any injury associated with significant tissue loss will require a Roux-en-Y choledochojejunostomy.6 6 The anastomosis is performed using a single-layer interrupted technique with 4-0 or 5-0 monofilament absorbable suture. To reduce anastomotic tension, the jejunum can be sutured to the areolar tissue of the hepatic pedicle or porta hepatis. Injuries of the hepatic ducts are almost impossible to satisfactorily repair under emergent circumstances. One approach is to intubate the duct for external drainage and attempt a repair when the patient recovers. Alternatively, the duct can be ligated if the opposite lobe is normal and uninjured. Patients undergoing perihepatic packing for extensive liver injuries typically are returned to the OR for pack removal 24 to 48 hours after initial injury. Earlier exploration may be indicated in patients with evidence of ongoing hemorrhage. Signs of rebleeding include a falling hematocrit, accumulation of blood clots under the temporary abdominal closure device, and bloody output from drains; the magnitude of hemorrhage is reflected in hemodynamic instability and the findings of metabolic monitoring. Patients with hepatic ischemia due to prolonged intraoperative use of the Pringle maneuver have an expected elevation but subsequent resolution of transaminases levels, whereas patients requiring hepatic artery ligation may have frank hepatic necrosis. Although patients should be evaluated for infectious complications, patients with complex hepatic injuries typically have intermittent "liver fever" for the first 5 days after injury. The complications after significant hepatic trauma include delayed hemorrhage, bilomas, hepatic necrosis, arterial pseudoaneurysms, and various fistulas (Fig. 7-59). In patients requiring perihepatic packing, postoperative hemorrhage should be re-evaluated in the OR once the patient's coagulopathy is corrected. Alternatively,

angioembolization is appropriate for complex injuries. Bilomas are loculated collections of bile, which may or may not be infected. If infected, they should be treated like an abscess via percutaneous drainage. Although small, sterile bilomas eventually will be reabsorbed, larger fluid collections should also be drained. Biliary ascites, due to the disruption of a major bile duct, often requires reoperation and wide drainage. Primary repair of the injured duct is unlikely to be successful. Resectional dbridement is indicated for the removal of peripheral portions of nonviable hepatic parenchyma.

Fig. 7-59.

Complications after hepatic trauma include bilomas (A; arrow ), hepatic duct injuries (B ), and hepatic necrosis after hepatic artery ligation or embolization (C ).

Pseudoaneurysms and biliary fistulas are rare complications in patients with hepatic injuries. Because hemorrhage from hepatic injuries often is treated without isolating individual bleeding vessels, arterial pseudoaneurysms may develop, with the potential for rupture. Rupture into a bile duct results in hemobilia, which is characterized by intermittent episodes of right upper quadrant pain, upper GI hemorrhage, and jaundice. If the aneurysm ruptures into a portal vein, portal venous hypertension with bleeding esophageal varices may occur. Either scenario is best managed with hepatic arteriography and embolization. Biliovenous fistulas, causing jaundice due to rapid increases in serum bilirubin levels, should be treated with ERCP and sphincterotomy. Rarely, a biliary fistulous communication will form with intrathoracic structures in patients with associated diaphragm injuries, resulting in a bronchobiliary or pleurobiliary fistula. Due to the pressure differential between the biliary tract (positive) and the pleural cavity (negative), the majority require operative closure. Occasionally, endoscopic sphincterotomy with stent placement will effectively address the pressure differential, and the pleurobiliary fistula will close spontaneously.

SPLEEN Until the 1970s, splenectomy was considered mandatory for all splenic injuries. Recognition of the immune function of the spleen refocused efforts on operative splenic salvage in the 1980s.67,68 After success in pediatric patients,

nonoperative management has become the preferred means of splenic salvage. The identification of contrast extravasation as a risk factor for failure of nonoperative management led to liberal use of angioembolization. The true value of angioembolization in splenic salvage has not been rigorously evaluated. It is clear, however, that 20 to 30% of patients with splenic trauma deserve early splenectomy and that failure of nonoperative management often represents poor patient selection. 69,70 Unlike hepatic injuries, which rebleed in 24 to 48 hours, delayed hemorrhage or rupture of the spleen can occur up to weeks after injury. Indications for prompt laparotomy include initiation of blood transfusion within the first 12 hours and hemodynamic instability. Splenic injuries are managed operatively by splenectomy, partial splenectomy, or splenic repair (splenorrhaphy), based on the extent of the injury and the physiologic condition of the patient. Splenectomy is indicated for hilar injuries, pulverized splenic parenchyma, or any injury of grade II or higher in a patient with coagulopathy or multiple injuries. The authors use autotransplantation of splenic implants (Fig. 7-60) to achieve partial immunocompetence in younger patients. 7 1 Drains are not used. Partial splenectomy can be employed in patients in whom only the superior or inferior pole has been injured. Hemorrhage from the raw splenic edge is controlled with horizontal mattress sutures, with gentle compression of the parenchyma (Fig. 7-61). As in repair of hepatic injuries, in splenorrhaphy hemostasis is achieved by topical methods (electrocautery; argon beam coagulation; application of thrombin-soaked gelatin foam sponges, fibrin glue, or BioGlue), envelopment of the injured spleen in absorbable mesh, and pledgeted suture repair.

Fig. 7-60.

Autologous splenic transplantation is performed by placing sections of splenic parenchyma, 40 pouches in the greater omentum.

Fig. 7-61.

x

40

x

3 mm in size, into

Interrupted pledgeted sutures may effectively control hemorrhage from the cut edge of the spleen.

After splenectomy or splenorrhaphy, postoperative hemorrhage may be due to loosening of a tie around the splenic vessels, an improperly ligated or unrecognized short gastric artery, or recurrent bleeding from the spleen if splenic repair was used. An immediate postsplenectomy increase in platelets and WBCs is normal; however, beyond postoperative day 5, a WBC count above 15,000/mm3 and a platelet/WBC ratio of 10 g/dL is generally accepted to optimize oxygen delivery. After the first 24 hours of resuscitation, a more judicious transfusion trigger of a hemoglobin level of 500 mL/min per square meter for the oxygen delivery index and >3.8 L/min per square meter for the cardiac index are the goals. Pulmonary artery catheters also enable the physician to monitor response to vasoactive agents. Although norepinephrine is the agent of choice for patients with low systemic vascular resistance who are unable to maintain a mean arterial pressure of >60 mmHg, patients may have an element of myocardial dysfunction requiring inotropic support. The role of relative adrenal insufficiency is another controversial area. Optimal early resuscitation is mandatory and determines when the patient can undergo definitive diagnosis as well as when the patient can be returned to the OR after initial damage control surgery. Specific goals of resuscitation before repeated "semielective" transport include a core temperature of >35C (95F), base deficit of 1 to 2 mL/kg per hour, thoracotomy should be considered. Aortic injuries are rare in children, and tracheobronchial injuries are more amenable to nonoperative management. Thoracic injuries are second only to brain injuries as the main cause of death according to the National Pediatric Trauma Registry; however, the overall mortality rate of 15% correlates with the levels in many adult studies. The evaluation for abdominal trauma in the pediatric patient is similar to that in the adult. FAST is valid in the pediatric age group to detect intra-abdominal fluid.9 9 The mechanism of injury often correlates with specific injury patterns. A child sustaining a blow to the epigastrium (e.g., hitting the handlebars during a bike accident) should be evaluated for a duodenal hematoma and/or a pancreatic transection. After a motor vehicle collision in which the patient was wearing a passenger restraint, injuries comprising the "lap belt complex" or "seat belt syndrome" (i.e., abdominal wall contusion, small bowel perforation, flexion-distraction injury of the lumbar spine, diaphragm rupture, and occasionally abdominal aortic dissection) may exist. Nonoperative management of solid organ injuries, first used in children, is the current standard of care in the hemodynamically stable patient. If the patient shows clinical deterioration or hemodynamic lability, has a hollow viscus injury, or requires >40 mL/kg of packed RBCs, continued nonoperative management is not an option. Success rates of nonoperative management approach 95%, with an associated 10 to 23% transfusion rate. Blood transfusion rates are significantly lower in patients managed nonoperatively than in patients undergoing operation (13 vs. 44%).100

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19. Fabian TC, Richardson JD, Croce MA, et al: Prospective study of blunt aortic injury: Multicenter trial of the American Association for the Surgery of Trauma. J Trauma 42:374, 1997. [PMID: 9095103] 20. Dyer DS, Moore EE, Ilke DN, et al: Thoracic aortic injury: How predictive is mechanism and is chest computed tomography a reliable screening tool? A prospective study of 1,561 patients. J Trauma 48:673, 2000. [PMID: 10780601] 21. Flowers JL, Graham SM, Ugarte MA, et al: Flexible endoscopy for the diagnosis of esophageal trauma. J Trauma 40:261, 1996. [PMID: 8637076] 22. Cox CS Jr., Allen GS, Fischer RP, et al: Blunt versus penetrating subclavian artery injury: Presentation, injury pattern, and outcome. J Trauma 46:445, 1999. [PMID: 10088848] 23. Renz BM, Feliciano DV: Gunshot wounds to the right thoracoabdomen: A prospective study of nonoperative management. J Trauma 37:737, 1994. [PMID: 7966470] 24. Demetriades D, Hadjizacharia P, Constantinou C, et al: Selective nonoperative management of penetrating abdominal solid organ injuries. Ann Surg 244:620, 2006. [PMID: 16998371] 25. Boyle EM Jr., Maier RV, Salazar JD, et al: Diagnosis of injuries after stab wounds to the back and flank. J Trauma 42:260, 1997. [PMID: 9192846] 26. Biffl WL, Cothren CC, Brasel KJ, et al: A prospective observational multicenter study of the optimal management of patients with anterior abdominal stab wounds. J Trauma 64:250, 2008. 27. Rozycki GS, Ochsner MG, Schmidt JA, et al: A prospective study of surgeon-performed ultrasound as the primary adjuvant modality for injured patient assessment. J Trauma 39:492, 1995. [PMID: 7473914] 28. Branney SW, Wolfe RE, Moore EE, et al: Quantitative sensitivity of ultrasound in detecting free intraperitoneal fluid. J Trauma 39:375, 1995. [PMID: 7674411] 29. Ochsner MG, Knudson MM, Pachter HL, et al: Significance of minimal or no intraperitoneal fluid visible on CT scan associated with blunt liver and splenic injuries: A multicenter analysis. J Trauma 49:505, 2000. [PMID: 11003330] 30. Malhotra AK, Fabian TC, Katsis SB, et al: Blunt bowel and mesenteric injuries: The role of screening computed tomography. J Trauma 48:991, 2000. [PMID: 10866242] 31. Johansen K, Lynch K, Paun M, et al: Noninvasive vascular tests reliably exclude occult arterial trauma in injured extremities. J Trauma 31:515, 1991. [PMID: 2020038] 32. Burch JM, Franciose RJ, Moore EE, et al: Single-layer continuous versus two-layer interrupted intestinal anastomosis—a prospective randomized study. Ann Surg 231:832, 2000. [PMID: 10816626] 33. Moore EE: Staged laparotomy for the hypothermia, acidosis, and coagulopathy syndrome. Am J Surg 172:405, 1996. [PMID: 8942535] 34. Hebert PC, Wells G, Blajchman MA, et al: A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. New Engl J Med 340:409, 1999. [PMID: 9971864] 35. West MA, Shapiro MB, Nathens AB, et al: Inflammation and the host response to injury, a large-scale collaborative project: Patientoriented research core-standard operating procedures for clinical care. IV. Guidelines for transfusion in the trauma patient. J Trauma 61:436, 2006. [PMID: 16917462] 36. Toy P, Popovsky MA, Abraham E, et al: Transfusion-related acute lung injury: Definition and review. Crit Care Med 33:721, 2005. [PMID: 15818095]

37. Moore FA, Moore EE, Sauaia A: Blood transfusion: An independent risk factor for postinjury multiple organ failure. Arch Surg 132:620, 1997. [PMID: 9197854] 38. Kashuk JL, Moore EE, Sauaia A, et al: Postinjury life-threatening coagulopathy: Is 1:1 the answer? J Trauma 65:261, 2008. [PMID: 18695460] 39. Menaker J, Stein DM, Scalea TM: Incidence of early pulmonary embolism after injury. J Trauma 63:620, 2007. [PMID: 18073610] 40. Rinker C, McMurry F, Groeneweg V, et al: Emergency craniotomy in a rural level III trauma center. J Trauma 44:984, 1998. [PMID: 9637153] 41. Cogbill T, Cothren CC, et al: Management of severe hemorrhage associated with maxillofacial injuries: A multicenter perspective. J Trauma 64:250, 2008. 42. Bracken MB, Shepard MJ, Holford TR, et al: Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury. Results of the Third National Acute Spinal Cord Injury Randomized Controlled Trial. National Acute Spinal Cord Injury Study. JAMA 277:1597, 1997. [PMID: 9168289] 43. Fehlings MG, Perrin RG: The timing of surgical intervention in the treatment of spinal cord injury: A systematic review of recent clinical evidence. Spine 31:S28, 2006. 44. Biffl WL, Moore EE, Offner PJ, et al: Blunt carotid arterial injuries: Implications of a new grading scale. J Trauma 47:845, 1999. [PMID: 10568710] 45. Biffl WL, Moore EE, Ryu RK, et al: The unrecognized epidemic of blunt carotid arterial injuries: Early diagnosis improves neurologic outcome. Ann Surg 228:462, 1998. [PMID: 9790336] 46. Cothren CC, Moore EE, Biffl WL, et al: Anticoagulation is the gold standard therapy for blunt carotid injuries to reduce stroke rate. Arch Surg 139:540, 2004. [PMID: 15136355] 47. Edwards NM, Fabian TC, Claridge JA, et al: Antithrombotic therapy and endovascular stents are effective treatment for blunt carotid injuries: Results from long-term followup. J Am Coll Surg 204:1007, 2007. [PMID: 17481530] 48. Bladergroen M, Brockman R, Luna G, et al: A twelve-year study of cervicothoracic vascular injuries. Am J Surg 157:483, 1989. [PMID: 2712204] 49. Johnston RH, Wall MJ, Mattox KL: Innominate artery trauma: A thirty-year experience. J Vasc Surg 17:134, 1993. [PMID: 8421329] 50. Fabian TC, Davis KA, Gavant ML, et al: Prospective study of blunt aortic injury: Helical CT is diagnostic and antihypertensive therapy reduces rupture. Ann Surg 227:666, 1998. [PMID: 9605658] 51. Kim FJ, Moore EE, Moore FA, et al: Trauma surgeons can render definitive surgical care for major thoracic injuries. J Trauma 36:871, 1994. [PMID: 8015011] 52. Karmy-Jones R, Nicholls S, Gleason TG: The endovascular approach to acute aortic trauma. Thorac Surg Clin 17:109, 2007. [PMID: 17650703] 53. Moore EE, Burch JM, Moore JB: Repair of the torn descending thoracic aorta using the centrifugal pump with partial left heart bypass. Ann Surg 240:38, 2004. [PMID: 15213616] 54. Wall MJ, Mattox KL, Chen C, et al: Acute management of complex cardiac injuries. J Trauma 42:905, 1997. [PMID: 9191673] 55. Cothren CC, Moore EE: Traumatic ventricular septal defect. Surgery 142:776, 2007. [PMID: 18041157] 56. Maron BJ, Gohman TE, Kyle SB, et al: Clinical profile and spectrum of commotio cordis. JAMA 287:9, 2002.

57. Wall MJ Jr., Hirshberg A, Mattox KL: Pulmonary tractotomy with selective vascular ligation for penetrating injuries to the lung. Am J Surg 168:665, 1994. [PMID: 7978015] 58. Cothren C, Moore EE, Biffl WL, et al: Lung-sparing techniques are associated with improved outcome compared with anatomic resection for severe lung injuries. J Trauma 53:483, 2002. [PMID: 12352485] 59. Cryer HG, Mavroudis C, Yu J, et al: Shock, transfusion, and pneumonectomy: Death is due to right heart failure and increased pulmonary vascular resistance. Ann Surg 212:197, 1990. [PMID: 2375651] 60. de Souza A, Offner PJ, Moore EE, et al: Optimal management of complicated empyema. Am J Surg 180:507, 2000. 61. Bender JS, Lucas CE: Management of close-range shotgun injuries to the chest by diaphragmatic transposition: Case reports. J Trauma 30:1581, 1990. [PMID: 2258976] 62. Kozar RA, Moore FA, Cothren CC, et al: Risk factors for hepatic morbidity following nonoperative management: Multicenter study. Arch Surg 141:451, 2006. [PMID: 16702516] 63. Malhotra AK, Fabian TC, Croce MA, et al: Blunt hepatic injury: A paradigm shift from operative to nonoperative management in the 1990s. Ann Surg 231:804, 2000. [PMID: 10816623] 64. Biffl WL, Moore EE, Franciose RJ: Venovenous bypass and hepatic vascular isolation as adjuncts in the repair of destructive wounds to the retrohepatic inferior vena cava. J Trauma 45:400, 1998. [PMID: 9715205] 65. Poggetti RS, Moore EE, Moore FA, et al: Balloon tamponade for bilobar transfixing hepatic gunshot wounds. J Trauma 33:694, 1992. [PMID: 1464918] 66. Lillemoe KD, Melton GB, Cameron JL, et al: Postoperative bile duct strictures: Management and outcome in the 1990s. Ann Surg 232:430, 2000. [PMID: 10973393] 67. Pickhardt B, Moore EE, Moore FA, et al: Operative splenic salvage in adults: A decade perspective. J Trauma 29:1386, 1989. [PMID: 2810416] 68. Feliciano DV, Spjut-Patrinely V, Burch JM, et al: Splenorrhaphy: The alternative. Ann Surg 211:569, 1990. [PMID: 2339918] 69. McIntyre LK, Schiff M, Jurkovich GJ: Failure of nonoperative management of splenic injuries: Causes and consequences. Arch Surg 140:563, 2005. [PMID: 15967903] 70. Smith HE, Biffl WL, Majercik SD, et al: Splenic artery embolization: Have we gone too far? J Trauma 61:541, 2006. [PMID: 16966984] 71. Leemans R, Manson W, Snijder JA, et al: Immune response capacity after human splenic autotransplantation: Restoration of response to individual pneumococcal vaccine subtypes. Ann Surg 229:279, 1999. [PMID: 10024111] 72. Toutouzas KG, Velmahos GC, Kaminski A, et al: Leukocytosis after posttraumatic splenectomy: A physiologic event or sign of sepsis? Arch Surg 137:924, 2002. [PMID: 12146991] 73. Burch JM, Franciose RJ, Moore EE, et al: Single-layer continuous versus two-layer interrupted intestinal anastomosis: A prospective randomized trial. Ann Surg 231:832, 2000. [PMID: 10816626] 74. Todd SR, Kozar RA, Moore FA: Nutrition support in adult trauma patients. Nutr Clin Pract 21:421, 2006. [PMID: 16998141] 75. Vaughn GD, Frazier OH, Graham D, et al: The use of pyloric exclusion in the management of severe duodenal injuries. Am J Surg 134:785, 1977.

76. Nelson R, Singer M: Primary repair for penetrating colon injuries. Cochrane Database Syst Rev 3:CD002247, 2003. 77. Accola KD, Feliciano DV, Mattox KL, et al: Management of injuries to the superior mesenteric artery. J Trauma 26:313, 1986. [PMID: 3959136] 78. Asensio JA, Britt LD, Borzotta A, et al: Multi-institutional experience with the management of superior mesenteric artery injuries. J Am Coll Surg 193:354, 2001. [PMID: 11584962] 79. Burch JM, Richardson RJ, Martin RR, et al: Penetrating iliac vascular injuries: Experience with 233 consecutive patients. J Trauma 30:1450, 1990. [PMID: 2258955] 80. Mullins RJ, Lucas CE, Ledgerwood AM: The natural history following venous ligation for civilian injuries. J Trauma 20:737, 1980. [PMID: 7411662] 81. Pachter HL, Drager S, Godfrey N, et al: Traumatic injuries of the portal vein. Ann Surg 189:383, 1979. [PMID: 443892] 82. Roth SM, Wheeler JR, Gregory RT, et al: Blunt injury of the abdominal aorta: A review. J Trauma 42:748, 1997. [PMID: 9137272] 83. Jurkovich GJ, Hoyt DB, Moore FA, et al: Portal triad injuries. J Trauma 39:426, 1995. [PMID: 7473903] 84. Knudson MM, Harrison PB, Hoyt DB, et al: Outcome after major renovascular injuries: A Western trauma association multicenter report. J Trauma 49:1116, 2000. [PMID: 11130498] 85. Cothren CC, Osborn PM, Moore EE, et al: Preperitoneal pelvic packing for hemodynamically unstable pelvic fractures: A paradigm shift. J Trauma 62:834, 2007. [PMID: 17426537] 86. Bosse MJ, MacKenzie EJ, Kellam JF, et al: An analysis of outcomes of reconstruction or amputation of leg-threatening injuries. N Engl J Med 347:1924, 2002. [PMID: 12477942] 87. Moore FA, McKinley BA, Moore EE, et al: Inflammation and the Host Response to Injury, a large-scale collaborative project: Patientoriented research core—standard operating procedures for clinical care. III. Guidelines for shock resuscitation. J Trauma 61:82, 2006. [PMID: 16832253] 88. ACOG Committee on Obstetric Practice: ACOG Committee Opinion. Number 299, September 2004. Guidelines for diagnostic imaging during pregnancy. Obstet Gynecol 104:647, 2004. 89. Morris JA, Rosenbower TJ, Jurkovich GJ, et al: Infant survival after cesarean section for trauma. Ann Surg 223:481, 1996. [PMID: 8651739] 90. Curet MJ, Schermer CR, Demarest GB, et al: Predictors of outcome in trauma during pregnancy: Identification of patients who can be monitored for less than 6 hours. J Trauma 49:18, 2000. [PMID: 10912853] 91. Davis JW, Kaups KL: Base deficit in the elderly: A marker of severe injury and death. J Trauma 45:873, 1998. [PMID: 9820695] 92. Reynolds FD, Dietz PA, Higgins D, et al: Time to deterioration of the elderly, anticoagulated, minor head injury patient who presents without evidence of neurologic abnormality. J Trauma 54:492, 2003. [PMID: 12634528] 93. Bulger EM, Arneson MA, Mock CN, et al: Rib fractures in the elderly. J Trauma 48:1040, 2000. [PMID: 10866248] 94. Bergeron E, Lavoie A, Clas D, et al: Elderly trauma patients with rib fractures are at greater risk of death and pneumonia. J Trauma 54:478, 2003. [PMID: 12634526] 95. Morris JA, MacKenzie EJ, Damiano AM, et al: Mortality in trauma patients: The interaction between host factors and severity. J Trauma 30:1476, 1990. [PMID: 2258958]

96. Milzman DP, Boulanger BR, Rodriguez A, et al: Pre-existing disease in trauma patients: A predictor of fate independent of age and injury severity score. J Trauma 32:236, 1992. [PMID: 1740808] 97. Knudson MM, Lieberman J, Morris JA Jr., et al: Mortality factors in geriatric blunt trauma patients. Arch Surg 129:448, 1994. [PMID: 8154972] 98. Tepas JJ: The national pediatric trauma registry: A legacy of commitment to control childhood injury. Semin Pediatr Surg 13:126, 2004. [PMID: 15362283] 99. Partrick DA, Bensard DD, Moore EE, et al: Ultrasound is an effective triage tool to evaluate blunt abdominal trauma in the pediatric population. J Trauma 45:57, 1998. [PMID: 9680013] 100. Partrick DA, Bensard DD, Moore EE, et al: Nonoperative management of solid organ injuries in children results in decreased blood utilization. J Pediatr Surg 34:1695, 1999. [PMID: 10591573]

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KEY POINTS 1. Follow American Burn Association criteria for transfer of a patient to a regional burn center. 2. IV fluid resuscitation for patients with burns greater than 20% total body surface area (children with >15% total body surface area) should be titrated to mean arterial pressure (MAP) greater than 60 mmHg and urine output greater than 30 mL/h. 3. Never administer prophylactic antibiotics other than tetanus vaccination. 4. Patients with upper airway injury, partial pressure of arterial oxygen:fraction of inspired oxygen ratio less than 200 or carbon monoxide toxicity should be intubated for inhalation injury. 5. Early excision and grafting of full thickness and deep partial thickness burns improves outcomes.

GROWING NEED FOR BURN EXPERTISE Surgical care of the burn patient has evolved into a specialized field incorporating the interdisciplinary skills of burn surgeons, nurses, therapists, and other health care specialists. However, recent mass casualty events have been a reminder that health systems may be rapidly pressed to care for large numbers of burn patients. Naturally, general surgeons will be at the forefront in these events, so it is crucial that they are comfortable with the care of burned patients and well equipped to provide standard of care.

BACKGROUND Burn injury historically carried a poor prognosis. With advances in fluid resuscitation1 and the advent of early excision of the burn wound,2 survival has become an expectation even for patients with severe burns. Continued improvements in critical care and progress in skin bioengineering herald a future in which functional and psychological outcomes are equally important as survival alone. With this shift in priority, the American Burn Association has emphasized referral to specialized burn centers after early stabilization. Specific criteria should guide transfer of patients with more complex injuries or other medical needs to a burn center (Table 8-1). The American Burn Association has published standards of care

3

and created a verification process to ensure that burn

centers meet those standards.4 Because of increased prehospital safety measures, burn patients are being transferred longer distances to receive definitive care at regional burn centers; recent data from one burn center with a particularly wide catchment area confirmed that even transport times averaging 7 hours did not affect the long-term outcomes of burn patients.5

Table 8-1 Guidelines for Referral to a Burn Center

Partial-thickness burns greater than 10% TBSA Burns involving the face, hands, feet, genitalia, perineum, or major joints Third-degree burns in any age group Electrical burns, including lightning injury Chemical burns Inhalation injury Burn injury in patients with complicated pre-existing medical disorders Patients with burns and concomitant trauma in which the burn is the greatest risk. If the trauma is the greater immediate risk, the patient may be stabilized in a trauma center before transfer to a burn center. Burned children in hospitals without qualified personnel for the care of children Burn injury in patients who will require special social, emotional, or rehabilitative intervention

TBSA = total body surface area.

INITIAL EVALUATION Initial evaluation of the burn patient involves four crucial assessments: airway management, evaluation of other injuries, estimation of burn size, and diagnosis of carbon monoxide and cyanide poisoning. With direct thermal injury to the upper airway or smoke inhalation, rapid and severe airway edema is a potentially lethal threat. Anticipating the need for intubation and establishing an early airway is critical. Perioral burns and singed nasal hairs are signs that the oral cavity and pharynx should be further evaluated for mucosal injury, but in themselves these physical findings do not indicate an upper airway injury. Signs of impending respiratory compromise may include a hoarse voice, wheezing, or stridor; subjective dyspnea is a particularly concerning symptom, and should trigger prompt elective endotracheal intubation. In patients with combined multiple trauma, especially oral trauma, nasotracheal intubation may be useful but should be avoided if oral intubation is safe and easy. Burn patients should be first considered trauma patients, especially when details of the injury are unclear. A primary survey should be conducted in accordance with advanced trauma life support guidelines. Concurrently with the primary survey, large-bore peripheral IV catheters should be placed and fluid resuscitation should be initiated; for a burn larger than 40% total body surface area (TBSA), two large-bore IVs are ideal. IV placement through burned skin is safe and effective but requires attention to securing the catheters. Central venous access may be necessary in the severely burned patient, and provides useful information as to volume status in the intensive care unit. Pediatric patients may require intraosseous access in emergent situations. An early and comprehensive secondary survey must be performed on all burn patients, but especially those with a history of associated trauma such as with a motor vehicle collision and a fire. Also, patients from structural fires in which the manner of egress is not known should be carefully evaluated for injuries from a possible jump or fall. Urgent radiology studies, such as a chest x-ray should be performed in the emergency department, but nonurgent skeletal evaluation (i.e., extremity x-rays) can be done in the intensive care unit to avoid hypothermia and delays in burn resuscitation. Hypothermia is one of the common prehospital complications that contributes to resuscitation failure. Patients should be wrapped with clean blankets in transport. Cooling blankets should be avoided in patients with moderate or large burns. Patients with acute burn injuries should never receive prophylactic antibiotics. This intervention has been clearly demonstrated to promote development of fungal infections and resistant organisms and was abandoned in the mid1980s. A tetanus booster should be administered in the emergency room.

Pain management for these patients has been widely recognized over the past 25 years. However, one must also consider treatment of the contribution of long-term anxiety. Therefore, it is important to administer an anxiolytic such as a benzodiazepine with the initial narcotics. Most burn resuscitation formulas (Table 8-2) estimate fluid requirements using the burn size as a percent of TBSA burned. The "rule of nines" is a crude but quick and effective method of estimating burn size (Fig. 8-1). In adults, the anterior and posterior trunk each account for 18%, each lower extremity is 18%, each upper extremity is 9%, and the head is 9%. In children younger than 3 years old, the head accounts for a larger relative surface area and should be taken into account when estimating burn size. Diagrams such as the Lund and Browder chart give a more accurate accounting of the true burn size in children. The importance of an accurate burn size assessment cannot be overemphasized. Superficial or first-degree burns should not be included when calculating the percent of TBSA, and thorough cleaning of soot and debris is mandatory to avoid confusing areas of soiling with burns. Examination of referral data suggests that physicians inexperienced with burns tend to overestimate the size of small burns and underestimate the size of large burns, with potentially detrimental effects on pretransfer resuscitation. 6

Table 8-2 Burn Resuscitation Formulas Isotonic crystalloid formulas Parkland formula Lactated Ringer's 4 mL/kg per % TBSA burn 1

/2 volume during first 8 h postinjury;

1

/2 during next 16 h postinjury

Modified Brooke formula Lactated Ringer's 2.0 mL/kg per % TBSA burn Haifa formula Lactated Ringer's Fresh-frozen plasma 1 mL/kg per % TBSA burn 1.5 mL/kg per % TBSA burn 1

/2 volume during first 8 h postinjury;

1

/2 volume during first 8 h postinjury;

1

/2 during next 16 h postinjury

1

/2 during next 16 h postinjury

Hypertonic formulas

Monafo formula 25 mEq/L NaCl Volume titrated to UOP 30 mL/h Warden formula Lactated Ringer's plus 50 mEq NaHCO3 (180 mEq Na/L) titrated to UOP 30–50 mL/h for 8 h postinjury Lactated Ringer's titrated to UOP 30–50 mL/h beginning 8 h postburn Colloid formulas Evans formula 0.9% saline 1 mL/kg per % TBSA burn Fresh-frozen plasma 2000 mL 1 mL/kg per % TBSA burn Brooke formula Lactated Ringer's Fresh-frozen plasma 2000 mL 1.5 mL/kg per % TBSA burn 0.5 mL/kg per % TBSA burn Slater formula Lactated Ringer's Fresh-frozen plasma 2000 mL/24 h 75 mL/kg per 24 h Demling formula Dextran 40 in 0.9% NaCl Fresh-frozen plasma 2 mL/kg per hour for 8 h postinjury; 0.5 mL/kg per hour starting 8 h postburn continued for 18 h Lactated Ringer's titrated to UOP >30 mL/h for next 18 h postburn Electrolyte Solution

Colloid Solution

D5 W

Note: Individual burn centers may modify these basic formulas for their own needs. D5 W = 5% dextrose in water; NaCl = sodium chloride; NaHCO3 = sodium bicarbonate; TBSA = total body surface area; UOP = urine output.

Fig. 8-1.

The Rule of Nines can be used as a quick reference for estimating a patient's burn size by dividing the body into regions to which total body surface area is allocated in multiples of nine.

Another important contributor to early mortality in burns is carbon monoxide (CO) poisoning resulting from smoke inhalation. The affinity of CO for hemoglobin is approximately 200–250 times more than that of oxygen, which decreases the levels of normal oxygenated hemoglobin and can quickly lead to anoxia and death.7 Unexpected neurologic symptoms should raise the level of suspicion, and an arterial carboxyhemoglobin level must be obtained because pulse oximetry is falsely elevated. Administration of 100% oxygen is the gold standard for treatment of CO poisoning, and reduces the half-life of CO from 250 minutes in room air to 40 to 60 minutes.8 Some authors have proposed hyperbaric oxygen as an adjunctive therapy for CO poisoning.9 However, the data are mixed regarding the success of hyperbaric oxygen, and its associated logistic difficulties and complications have limited its usefulness for patients with moderate or large burns.10,11 Patients who sustain a cardiac arrest as a result of their

CO poisoning have an extremely poor prognosis regardless of the success of initial resuscitation attempts.1 2 Hydrogen cyanide toxicity may also be a component of smoke inhalation injury. Afflicted patients may have a persistent lactic acidosis or S-T elevation on electrocardiogram (ECG). 1 3 Cyanide inhibits cytochrome oxidase, which in turn inhibits cellular oxygenation.1 4 Treatment consists of sodium thiosulfate, hydroxocobalamin, and 100% oxygen. Sodium thiosulfate works by transforming cyanide into a nontoxic thiocyanate derivative; however, it works slowly and is not effective for acute therapy. Hydroxocobalamin quickly complexes with cyanide and is excreted by the kidney, and is recommended for immediate therapy.9 In the majority of patients, the lactic acidosis will resolve with ventilation and sodium thiosulfate treatment becomes unnecessary.1 5

CLASSIFICATION OF BURNS Burns are commonly classified as thermal, electrical, or chemical burns, with thermal burns consisting of flame, contact, or scald burns. Flame burns are not only the most common cause for hospital admission of burns, but also have the highest mortality. This is primarily related to their association with structural fires and the accompanying inhalation injury and/or CO poisoning.1 6 Electrical burns make up only 4% of U.S. hospital admissions but have special concerns, including the potential for cardiac arrhythmias and compartment syndromes with concurrent rhabdomyolysis. A baseline ECG is recommended in all patients with electrical injury, and a normal ECG in a low-voltage injury may preclude hospital admission. Because compartment syndrome and rhabdomyolysis are common in high-voltage electrical injuries, vigilance must be maintained for neurologic or vascular compromise, and fasciotomies should be performed even in cases of moderate clinical suspicion. Long-term neurologic and visual symptoms are not uncommon with high voltage electrical injuries, and ophthalmologic and neurologic consultation should be obtained to better define a patient's baseline function.1 7 Chemical burns are less common, but potentially are severe burns. The most important components of initial therapy are careful removal of the toxic substance from the patient and irrigation of the affected area with water for a minimum of 30 minutes. An exception to this is in cases of concrete powder or powdered forms of lye, which should be swept from the patient to avoid activating the aluminum hydroxide with water. The offending agents in chemical burns can be systemically absorbed and may cause specific metabolic derangements. Formic acid has been known to cause hemolysis and hemoglobinuria, and hydrofluoric acid causes hypocalcemia. Hydrofluoric acid is a particularly common offender due to its widespread industrial uses. Calcium-based therapies are the mainstay of treating hydrofluoric acid burns, with topical calcium gluconate applied to wounds,1 8 and subcutaneous or IV infiltration of calcium gluconate for systemic symptoms. Intra-arterial infusion of calcium gluconate may be effective in the most severe cases.19,20 Patients undergoing intra-arterial therapy need continuous cardiac monitoring. Persistent electrocardiac abnormalities or refractory hypocalcemia may signal the need for emergent excision of the burned areas.

BURN DEPTH Burn wounds are commonly classified as superficial (first degree), partial thickness (second degree), full thickness (third degree), and fourth-degree burns, which affect underlying soft tissue. Partial-thickness burns are then classified as either superficial or deep partial thickness burns by depth of involved dermis. Clinically, first-degree burns are painful but do not blister, second-degree burns have dermal involvement and are extremely painful with weeping and blisters, and third-degree burns are hard, painless, and nonblanching. Jackson described three zones of tissue injury following burn injury.2 1 The zone of coagulation is the most severely burned portion and is typically

in the center of the wound. As the name implies, the affected tissue is coagulated and sometimes frankly necrotic, and will need excision and grafting. Peripheral to that is a zone of stasis, which has a local response of vasoconstriction and resultant ischemia. Appropriate resuscitation and wound care may help prevent conversion to a deeper wound, but infection or suboptimal perfusion may result in an increase in burn depth. This is clinically relevant because many superficial partial-thickness burns will heal with expectant management, while the majority of deep partial-thickness burns require excision and skin grafting. The last area of a burn is called the zone of hyperemia , which will heal with minimal or no scarring. Unfortunately, even experienced burn surgeons have limited ability to accurately predict the healing potential of partial-thickness burns; one reason is that burn wounds evolve over 48–72 hours after a burn injury. Numerous techniques have been developed with the idea that better early prediction of burn depth will expedite appropriate surgical decision making. One of the most effective ways to determine burn depth is full-thickness biopsy, but this has several limitations. Not only is the procedure painful and potentially scarring, but accurate interpretation of the histopathology requires a specialized pathologist and may have slow turnaround times.2 2 Laser Doppler can measure skin perfusion and use those measurements to predict burn depth, with a positive predictive value of up to 80% in some studies.23,24 Noncontact ultrasound has been postulated as a painless modality to predict nonhealing wounds, and has the advantage of easily performed serial measurements.2 5 Unfortunately, none of these newer therapies have proven adequately superior to justify their cost, and so have not yet substituted serial examination by experienced burn surgeons.

PROGNOSIS The Baux score (mortality = age + percent TBSA) was used for many years to predict mortality in burns, and analysis of multiple risk factors for burn mortality validated age and percent TBSA as the strongest predictors of mortality.2 6 Advancements in burn care have lowered overall mortality to the point that the Baux score may no longer be accurate. However, age and burn size, as well as inhalation injury, continue to be the most robust markers for burn mortality. 2 7 Age, even as a single variable, strongly predicts mortality in burns,2 8 and inhospital mortality in elderly burn patients is a function of age regardless of other comorbidities. 2 9 In nonelderly patients, comorbidities such as preinjury HIV, metastatic cancer, and kidney or liver disease may influence mortality and length of stay.3 0 A recent large database study of 68,661 burn patients found that the variables with the highest predictive value for mortality were age, percent TBSA, inhalation injury, coexistent trauma, and pneumonia.3 1

RESUSCITATION A myriad of formulas exist for calculating fluid needs during burn resuscitation, suggesting that no one formula benefits all patients. The most commonly used formula, the Parkland or Baxter formula, consists of 3 to 4 mL/kg per percent burned of lactated Ringer's, of which half is given during the first 8 hours postburn, and the remaining half over the subsequent 16 hours. The concept behind the continuous fluid needs are simple. The burn (and/or inhalation injury) drives an inflammatory response that leads to capillary leak; as the plasma leaks into the extravascular space, crystalloid administration maintains the intravascular volume. Therefore, if a patient receives a large fluid bolus in a prehospital setting or emergency department, that fluid has likely leaked into the interstitium and the patient will still require ongoing burn resuscitation, according to the estimates. Continuation of fluid volumes should depend on the time since injury, urine output, and MAP; as the leak closes, the patient will require less volume to maintain these two resuscitation endpoints. Children under 20 kg have the additional requirement that they do not have sufficient glycogen stores to maintain an adequate glucose level in response to the inflammatory response. Specific pediatric formulas have been described, but the simplest approach is to add

maintenance IV fluid with glucose supplementation in addition to the calculated resuscitation fluid with lactated Ringer's. It is important to remember that any formula for burn resuscitation is merely a guideline, and fluid must be titrated based on appropriate measures of adequate resuscitation. A number of parameters are widely used to gauge burn resuscitation, but the most common remain the simple outcomes of blood pressure and urine output. As in any critically ill patient, the target MAP is 60 mmHg to ensure optimal end-organ perfusion. Goals for urine output should be 30 mL/h in adults and 1 to 1.5 mL/kg per hour in pediatric patients. Because blood pressure and urine output may not correlate perfectly with true tissue perfusion, the search continues for other adjunctive parameters that may more accurately reflect adequate resuscitation. Some centers have found serum lactate to be a better predictor of mortality in severe burns;32,33 others have found that base deficit may be a better predictor of eventual organ dysfunction and mortality.34,35 Burned patients with normal blood pressures and serum lactate levels may still have compromised gastric mucosal blood flow. However, continuous measurement of gastric mucosal pH is logistically difficult and has not been widely implemented.36,37 Invasive monitoring with pulmonary artery catheters typically results in significant excessive fluid administration without resulting in improved cardiac output or preload measurements, and the use of invasive monitoring seems to have variable effects on long-term outcomes. 3 8 Actual administrated fluid volumes typically exceed volumes predicted by standard formulas.3 9 One survey of burn centers showed that 58% of patients receive more fluids than would be predicted by Baxter's formula.4 0 A comparison of modern-day patients with historical controls shows that this over-resuscitation may be a relatively recent trend.4 1 One theory is that increased opioid analgesic use results in peripheral vasodilation and hypotension and thus the need for greater volumes of bloused resuscitative fluids.4 2 A classic study by Navar and associates showed that burned patients with inhalation injury required an average of 5.76 mL/kg per percent burned, versus 3.98 mL/kg per percent burned for patients without inhalation injury. This finding has been corroborated by subsequent studies. 43,44 Prolonged mechanical ventilation may also play a role in increased fluid needs.4 5 A recent multicenter study found that age, weight, percent TBSA, and intubation on admission were significant predictors that the patient would receive more fluid during the resuscitation period. Those patients receiving higher fluid volumes were at increased risk of complications and death.4 6 Common complications include abdominal compartment syndrome, extremity compartment syndrome, intraocular compartment syndrome, and pleural effusions. Monitoring bladder pressures can provide valuable information about the development of intra-abdominal hypertension. The use of colloid as part of the burn resuscitation has generated much interest. In late resuscitation when the capillary leak has closed, colloid administration may decrease overall fluid volumes, and potentially may decrease associated complications such as intra-abdominal hypertension.4 7 However, the use of albumin has never been shown to improve outcomes in burn patients and has controversial effects on mortality in critically ill patients.48,49 Attempts to minimize fluid volumes in burn resuscitation have also led to the study of hypertonic solutions. Hypertonic solutions decrease initial resuscitation volumes as expected, but it appears to be a transient benefit and has the downside of causing hyperchloremic acidosis.5 0 Other adjuncts are being increasingly used during initial burn resuscitation. High-dose ascorbic acid (vitamin C) may decrease fluid volume requirements and ameliorate respiratory embarrassment during resuscitation.5 1 Plasmapheresis may also decrease fluid requirements in patients who require higher volumes than predicted to maintain adequate urine output and MAP. It is postulated that plasmapheresis may filter out inflammatory

mediators, thus decreasing ongoing vasodilation and capillary leak.5 2

TRANSFUSION The role of blood transfusion in burns has undergone a re-evaluation in recent years. A large multicenter study found that increased numbers of transfusions were associated with increased infections and a higher mortality rate in burn patients, even when correcting for burn severity.5 3 A follow-up study implanting a restrictive transfusion policy in burned children showed that a hemoglobin threshold of 7 g/dL had no more adverse outcomes versus a traditional transfusion trigger of 10 g/dL. In addition, costs incurred to the institution were significantly less.5 4 These data, in concert with other reported complications such as transfusion-related lung injury,5 5 have led to recommendations that blood transfusions be used only when there is an apparent physiologic need. Attempts to minimize blood transfusion in nonburned, critically ill patients have led to the use of erythropoietin by some centers. Unfortunately, a randomized study in burn patients showed that recombinant human erythropoietin did not effectively prevent anemia or decrease the number of transfusions given.5 6

INHALATION INJURY AND VENTILATOR MANAGEMENT Inhalation injuries are commonly seen in tandem with burn injuries and are known to drastically increase mortality in burn patients.5 7 Smoke inhalation is present in as many as 35% of hospitalized burn patients, and may triple the hospital stay compared to isolated burn injuries.5 8 The combination of burns, inhalation injury, and pneumonia increases mortality by up to 60% over burns alone.5 9 Subsequent development of the adult respiratory distress syndrome (ARDS) is common in these patients and may be caused in part by recruitment of alveolar leukocytes with an enhanced endotoxin-activated cytokine response.6 0 When ARDS complicates burn and inhalation injury, it may result in mortality of up to 66%, and in one study, patients with 60% TBSA or greater in combination with inhalation injury and ARDS had 100% mortality.6 1 Smoke inhalation causes injury in two ways: by direct heat injury to the upper airways, and by inhalation of combustion products into the lower airways. Direct injury to the upper airway causes airway swelling that typically leads to maximal edema in the first 24 to 48 hours after injury, and will require a short course of endotracheal intubation for airway protection. Lower airway injury is caused by combustion products found in smoke, most commonly from synthetic substances burned in structural fires. These irritants cause direct mucosal injury, which in turn leads to mucosal sloughing, edema, reactive bronchoconstriction, and finally obstruction of the lower airways. Injury to both the epithelium and to pulmonary alveolar macrophages causes release of prostaglandins and chemokines, migration of neutrophils and other inflammatory mediators, a rise in tracheobronchial blood flow, and finally increased capillary permeability, leading to ARDS. The physiologic effects of smoke inhalation are numerous. Inhalation injury decreases lung compliance 6 2 and increases airway resistance work of breathing.6 3 Inhalation injury in the presence of burns will also increase overall metabolic demands.6 4 The most common physiologic derangement seen with inhalation injury is an increase in fluid requirements during resuscitation of patients with burn injuries. Bronchoscopic findings, including carbon deposits, erythema, edema, bronchorrhea, and a hemorrhagic appearance, can be useful for confirmation of inhalation injury. Severe inhalation injury may result in mucosal sloughing with obstruction of smaller airways. Because bronchoscopy is an invasive test, attempts have been made to use other diagnostic modalities, such as thoracic computed tomographic scans6 5 and xenon ventilation-perfusion scanning.6 6 Many of these techniques do not change therapeutic protocols or outcomes,6 7 and for this reason many centers still rely on a clinical diagnosis of inhalation injury. 6 8 A decreased partial pressure of arterial oxygen:fraction of inspired oxygen ratio Chapter 10. Oncology>

KEY POINTS 1. The following alterations are critical for malignant cancer growth: self-sufficiency of growth signals, insensitivity to growth-inhibitory signals, evasion of apoptosis, potential for limitless replication, angiogenesis, and invasion and metastasis. 2. Understanding cancer biology is essential to successfully implement personalized cancer therapy. 3. Modern cancer therapy is multidisciplinary, involving coordinated care by surgeons, medical oncologists, radiation oncologists, reconstructive surgeons, pathologists, radiologists, and primary care physicians.

ONCOLOGY AND SURGICAL PRACTICE As the population ages, oncology is becoming a larger portion of surgical practice. The surgeon often is responsible for the initial diagnosis and management of solid tumors. Knowledge of cancer epidemiology, etiology, staging, and natural history is required for initial patient assessment, as well as to determination of the optimal surgical therapy. Modern cancer therapy is multidisciplinary, involving the coordinated care of patients by surgeons, medical oncologists, radiation oncologists, reconstructive surgeons, pathologists, radiologists, and primary care physicians. Primary (or definitive ) surgical therapy refers to en bloc resection of tumor with adequate margins of normal tissues and regional lymph nodes as necessary. Adjuvant therapy refers to radiation therapy and systemic therapies, including chemotherapy, immunotherapy, hormonal therapy, and, increasingly, biologic therapy. The primary goal of surgical and radiation therapy is local and regional control. On the other hand, the primary goal of systemic therapy is systemic control by treatment of distant foci of subclinical disease to prevent distant recurrence. Surgeons must be familiar with adjuvant therapies to coordinate multidisciplinary care and to determine the best sequence of therapy. Recent advances in molecular biology are revolutionizing medicine. Nowhere has basic biology had a greater and more immediate impact than in oncology. New information is being translated rapidly into clinical use, with the development of new prognostic and predictive markers and new biologic therapies. It is therefore essential that surgeons understand the principles of molecular oncology to appropriately interpret these new contributions and incorporate them into practice.

EPIDEMIOLOGY Basic Principles of Cancer Epidemiology

The term incidence refers to the number of new cases occurring; incidence usually is expressed as the number of new cases per 100,000 persons per year. Mortality refers to the number of deaths occurring and is expressed as the number of deaths per 100,000 persons per year. Incidence and mortality data are usually available through cancer registries. Mortality data are also available as public records in many countries where deaths are registered as vital statistics, often with the cause of death. In areas where cancer registries do not exist, mortality data are used to extrapolate incidence rates. However, these numbers are likely to be less accurate than registry data, because the relationship between incidence and cause-specific death is likely to vary significantly among countries owing to the variation in health care delivery. The incidence of cancer varies by geography. This is due in part to genetic differences and in part to differences in environmental and dietary exposures. Epidemiologic studies that monitor trends in cancer incidence and mortality have tremendously enhanced our understanding of the etiology of cancer. Furthermore, analysis of trends in cancer incidence and mortality allows us to monitor the effects of different preventive and screening measures, as well as the evolution of therapies for specific cancers. The two types of epidemiologic studies that are conducted most often to investigate the etiology of cancer and the effect of prevention modalities are cohort studies and case-control studies. Cohort studies follow a group of people who initially do not have a disease over time and measure the rate of development of a disease. In cohort studies, a group that is exposed to a certain environmental factor or intervention usually is compared to a group that has not been exposed (e.g., smokers vs. nonsmokers). Case-control studies compare a group of patients affected with a disease to a group of individuals without the disease for a given exposure. The results are expressed in terms of an odds ratio, or relative risk. A relative risk 1 indicates an increased risk of developing the disease with exposure.

Cancer Incidence and Mortality in the United States In the year 2008, an estimated 1.44 million new cancer cases were diagnosed in the United States.1 In addition, over a million cases of basal and squamous cell carcinomas of the skin, 54,020 cases of melanoma in situ, and 67,770 cases of carcinoma in situ of the breast were predicted.1 Furthermore, an estimated 565,650 people were expected to die of cancer in the United States in the same year.1 The estimated new cancer cases and deaths by cancer type are shown in Table 10-1. 1 The most common causes of cancer death in men are cancers of the lung and bronchus, prostate, and colon and rectum; in women, the most common cancers are of the lung and bronchus, breast, and colon and rectum (Fig. 10-1).1

Table 10-1 Estimated New Cancer Cases and Deaths, United States, 2007a All cancers 1,444,920 559,650 Oral cavity and pharynx 34,360 7550 Digestive system 271,250 134,710 Esophagus 15,560 13,940

Stomach 21,260 11,210 Small intestine 5640 1090 Colon and rectum 112,340 52,180 Anus, anal canal, and anorectum 4650 690 Liver and intrahepatic bile duct 19,160 16,780 Gallbladder and other biliary 9250 3250 Pancreas 37,170 33,370 Other digestive organs 4800 2200 Respiratory system 229,400 164,840 Larynx 11,300 3660 Lung and bronchus 213,380 160,390 Other respiratory organs 4720 790 Bones and joints 2370 1330 Soft tissue (including heart) 9220 3560 Skin (excluding basal and squamous) 65,050 10,850 Melanoma 59,940 8110

Other nonepithelial 5110 2740 Breast 180,510 40,910 Genital system 306,380 55,740 Uterine cervix 11,150 3670 Uterine corpus 39,080 7400 Ovary 22,430 15,280 Vulva 3490 880 Vagina and other genital, female 2140 790 Prostate 218,890 27,050 Testis 7920 380 Penis and other genital, male 1280 290 Urinary system 120,400 27,340 Urinary bladder 67,160 13,750 Kidney and renal pelvis 51,190 12,890 Ureter and other urinary organs 2050 700 Eye and orbit 2340 220 Brain and other nervous system

20,500 12,740 Endocrine system 35,520 2320 Thyroid 33,550 1530 Other endocrine 1970 790 Lymphoma 71,380 19,730 Multiple myeloma 19,900 10,790 Leukemia 44,240 21,790 Other and unspecified primary sites b 32,100 45,230 Estimated New Cases Both Sexes

a Excludes b

Estimated Deaths Both Sexes

basal and squamous cell skin cancers and in situ carcinomas except those of urinary bladder.

More deaths than cases suggest lack of specificity in recording underlying causes of death on death certificate.

Source: Modified with permission from Jemal et al. 1

Fig. 10-1.

Ten leading cancer types with the estimated new cancer cases and deaths by sex in the United States, 2007. *Excludes basal and squamous cell skin cancers and in situ carcinomas except those of the urinary bladder. Estimates are rounded to the nearest 10. (Modified with permission from Jemal et al.1 )

Trends in Cancer Incidence and Mortality Cancer deaths accounted for 23% of all deaths in the United States in 2005, second only to deaths from heart disease.1 As the life expectancy of the human population increases because of reductions in other causes of death such as infections and cardiovascular disease, cancer is becoming the leading cause of death. Cancer is the leading cause of death among women aged 40 to 79 years and among men aged 60 to 79 years.1 Cancer incidence stabilized in males between 1995 and 2003 but has increased by 0.3% per year in females during the period from 1987 to 2003.1 The annual age-adjusted cancer incidence rates among males and females for selected cancer types are shown in Fig. 10-2.1 Prostate cancer rates rapidly increased and decreased between 1995 and 1998, but stabilized from 1998 to 2004. These trends are thought to be attributable to increased use of prostate-specific antigen (PSA) screening.1 Age-adjusted incidence rate of breast cancer started to decrease from

2001 to 2004.2 This decrease in breast cancer incidence has at least temporally been associated with the first report of the Women's Health Initiative, which documented an increased risk of coronary artery disease and breast cancer with the use of hormone replacement therapy; this was followed by a drop in the use of hormone replacement therapy by postmenopausal women in the United States. 2

Fig. 10-2.

Annual age-adjusted cancer incidence rates among males and females for selected cancer types, United States, 1975 to 2003. Rates are age adjusted to the U.S. standard population. (Modified with permission from Jemal et al.1 )

From 1993 to 2003, for all cancer types combined, cancer death rates decreased by 1.6% per year in males and by 0.8% per year in females. The 5-year survival rates for selected cancers are listed in Table 10-2.1 Mortality for cancer at all four major sites has continued to decrease except for female lung cancer, for which rates increased by 0.3% per year from 1995 to 2003. The decrease in lung cancer death rates in men is thought to be due to a decrease in tobacco use, whereas the decreases in death rates from breast, colorectal cancer, and prostate cancer

reflect advances in early detection and treatment.

Table 10-2 Five-Year Relative Survival Rates Adjusted to Normal Life Expectancy by Year of Diagnosis, United States, 1975–2002 All cancers 50 53 66 Brain 24 29 34 Breast (female) 75 79 89 Uterine cervix 70 68 73 Colon 51 59 65 Uterine corpus 87 83 84 Esophagus 5 10 16 Hodgkin's disease 73 79 86 Kidney 51 56 66 Larynx 66 66 65 Leukemia 35 42 49

Liver 4 6 10 Lung and bronchus 13 13 16 Melanoma of the skin 82 86 92 Multiple myeloma 26 29 33 Non-Hodgkin's lymphoma 48 53 63 Oral cavity 53 55 60 Ovary 37 40 45 Pancreas 2 3 5 Prostate 69 76 100 Rectum 49 57 66 Stomach 16 18 24 Testis 83 93 96 Thyroid

93 94 97 Urinary bladder 73 78 82 Relative 5-Year Survival Rates (%) Cancer Type

1975–1977

1984–1986

1996–2002

Source: Modified with permission from Jemal et al. 1

Global Statistics on Cancer Incidence It has been estimated that there were a total of 10.9 million new cancer cases around the world in 2002.3 Lung cancer is the leading cancer in the world, accounting for 1.35 million new cases and 1.15 million deaths per year. 3 Breast cancer is now the second most common cancer (1.15 million cases per year) and the fifth most common cause of cancer death, after gastric cancer (934,000 cases, 700,000 deaths), colorectal cancer (1.03 million cases, 529,000 deaths), and liver cancer (626,000 cases, 598,000 deaths).3

STOMACH CANCER The incidence of stomach cancer varies significantly among different regions of the world. The age-adjusted incidence is highest in Japan (62.1 per 100,000 men, 26.1 per 100,000 women). In comparison, the rates are much lower in North America (7.4 per 100,000 men, 3.4 per 100,000 women) and in northern and western Africa (4.4 to 3.4 per 100,000 men, 2.5 to 3.6 per 100,000 women).3 The difference in risk by country is presumed to be primarily due to differences in dietary factors. The risk is increased by high consumption of preserved salted foods such as meats and pickles, and decreased by high intake of fruits and vegetables.3 There also is some international variation in the incidence of infection with Helicobacter pylori, which is known to play a major role in gastric cancer development.3 Fortunately, a steady decline is being observed in the incidence and mortality rates of gastric cancer. This may be related to improvements in preservation and storage of foods as well as due to changes in the prevalence of H. pylori.

3

BREAST CANCER The incidence of breast cancer is high in all of the most highly developed regions except Japan, including the United States and Canada, Australia, and Northern and Western Europe, ranging from 82.5 to 99.4 per 100,000 women per year.3 In comparison, the rates are relatively low (100 types of cancer, it has been proposed that there are six essential alterations in cell physiology that dictate malignant growth: self-sufficiency of growth signals, insensitivity to growth-inhibitory signals, evasion of apoptosis (programmed cell death), potential for limitless replication, angiogenesis, and invasion and metastasis (Fig. 10-3).4

Fig. 10-3.

Acquired capabilities of cancer. (Modified with permission from Hanahan et al.4 Copyright Elsevier.)

Cell Proliferation and Transformation In normal cells, cell growth and proliferation are under strict control. In cancer cells, cells become unresponsive to normal growth controls, which leads to uncontrolled growth and proliferation. Human cells require several genetic changes for neoplastic transformation. Cell type–specific differences also exist for tumorigenic transformation. Abnormally proliferating, transformed cells outgrow normal cells in the culture dish (i.e., in vitro) and commonly display several abnormal characteristics.5 These include loss of contact inhibition (i.e., cells continue to proliferate after a confluent monolayer is formed); an altered appearance and poor adherence to other cells or to the substratum; loss of anchorage dependence for growth; immortalization; and gain of tumorigenicity (i.e., the ability

to give rise to tumors when injected into an appropriate host).

Cancer Initiation Tumorigenesis is proposed to have three steps: initiation, promotion, and progression. Initiating events such as gain of function of genes known as oncogenes or loss of function of genes known as tumor-suppressor genes may lead a single cell to acquire a distinct growth advantage. Although tumors usually arise from a single cell or clone, it is thought that sometimes not a single cell but rather a large number of cells in a target organ may have undergone the initiating genetic event; thus many normal-appearing cells may have an elevated malignant potential. This is referred to as a field effect. The initiating events are usually genetic and occur as deletions of tumor-suppressor genes or amplification of oncogenes. Subsequent events can lead to accumulations of additional deleterious mutations in the clone. Cancer is thought to be a disease of clonal progression as tumors arise from a single cell and accumulate mutations that confer on the tumor an increasingly aggressive behavior. Most tumors go through a progression from benign lesions to in situ tumors to invasive cancers (e.g., atypical ductal hyperplasia to ductal carcinoma in situ to invasive ductal carcinoma of the breast). Fearon and Vogelstein proposed the model for colorectal tumorigenesis presented in Fig. 10-4.6 Colorectal tumors arise from the mutational activation of oncogenes coupled with mutational inactivation of tumor-suppressor genes, the latter being the predominant change.6 Mutations in at least four or five genes are required for formation of a malignant tumor, whereas fewer changes suffice for formation of a benign tumor. Although genetic mutations often occur in a preferred sequence, a tumor's biologic properties are determined by the total accumulation of its genetic changes.

Fig. 10-4.

A genetic model for colorectal tumorigenesis. Tumorigenesis proceeds through a series of genetic alterations involving oncogenes and tumor-suppressor genes. In general, the three stages of adenomas represent tumors of increasing size, dysplasia, and villous content. Individuals with familial adenomatous polyposis (FAP) inherit a mutation on chromosome arm 5q. In tumors arising in individuals without polyposis, the same region may be lost or mutated at a relatively early stage of tumorigenesis. A ras gene mutation (usually K-ras ) occurs in one cell of a pre-existing small adenoma which, through clonal expansion, produces a larger and more dysplastic tumor. The chromosome arms most frequently deleted include 5q, 17p, and 18q. Allelic deletions of chromosome arms 17p and 18q usually occur at a later stage of tumorigenesis than do deletions of chromosome arm 5q or ras gene mutations. The order of these changes varies, however, and accumulation of these changes, rather than their order of appearance, seems most important. Tumors continue to progress once carcinomas have formed, and the accumulated chromosomal alterations correlate with the ability of the carcinomas to metastasize and cause death. DCC = deleted in colorectal cancer gene.

(Modified with permission from Fearon et al.6 Copyright Elsevier.)

Gene expression is a multistep process that starts from transcription of a gene into messenger RNA (mRNA) and then translation of this sequence into the functional protein. There are several controls at each level. In addition to alterations at the genome level (e.g., amplifications of a gene), alterations at the transcription level (e.g., methylation of the DNA leading to transcriptional silencing) or at the level of mRNA processing, mRNA stability, mRNA translation, or protein stability all can alter the levels of critical proteins and thus contribute to tumorigenesis. Alternatively, changes in the genomic sequence can lead to a mutated product with altered function.

Cell-Cycle Dysregulation in Cancer The proliferative advantage of tumor cells is a result of their ability to bypass quiescence. Cancer cells often show alterations in signal transduction pathways that lead to proliferation in response to external signals. Mutations or alterations in the expression of cell-cycle proteins, growth factors, growth factor receptors, intracellular signal transduction proteins, and nuclear transcription factors all can lead to disturbance of the basic regulatory mechanisms that control the cell cycle, allowing unregulated cell growth and proliferation. The cell cycle is divided into four phases (Fig. 10-5).7 During the synthetic or S phase, the cell generates a single copy of its genetic material, whereas in the mitotic or M phase, the cellular components are partitioned between two daughter cells. The G1 and G2 phases represent gap phases during which the cells prepare themselves for completion of the S and M phases, respectively. When cells cease proliferation, they exit the cell cycle and enter the quiescent state referred to as G0 . In human tumor cell-cycle regulators like INK4A, INK4B, and KIP1 are frequently mutated or altered in expression. These alterations underscore the importance of cell-cycle regulation in the prevention of human cancers.

Fig. 10-5.

Schematic representation of the phases of the cell cycle. Mitogenic growth factors can drive a quiescent cell from G0 into the cell cycle. Once the cell cycle passes beyond the restriction point, mitogens are no longer required for progression into and through S phase. The DNA is replicated in S phase, and the chromosomes are condensed and segregated in mitosis. In early G 1 phase, certain signals can drive a cell to exit the cell cycle and enter a quiescent phase. Cell-cycle checkpoints have been identified in G1 , S, G2 , and M phases. CDK = cyclin-dependent kinase. (Adapted from Kastan et al.7 )

Oncogenes Normal cellular genes that contribute to cancer when abnormal are called oncogenes. The normal counterpart of such a gene is referred to as a proto-oncogene. Oncogenes are usually designated by three-letter abbreviations, such as myc or ras. Oncogenes are further designated by the prefix "v-" for virus or "c-" for cell or chromosome, corresponding to the origin of the oncogene when it was first detected. Proto-oncogenes can be activated (show increased activity) or overexpressed (expressed at increased protein levels) by translocation (e.g., abl ), promoter insertion (e.g., c-myc ), mutation (e.g., ras ), or amplification (e.g., HER-2 /neu ). More than 100 oncogenes have been identified. Oncogenes may be growth factors (e.g., platelet-derived growth factor), growth factor receptors (e.g., HER2),

intracellular signal transduction molecules (e.g., ras ), nuclear transcription factors (e.g., c-myc ), or other molecules involved in the regulation of cell growth and proliferation. Growth factors are ubiquitous proteins that are produced and secreted by cells locally and that stimulate cell proliferation by binding specific cell-surface receptors on the same cells (autocrine stimulation) or on neighboring cells (paracrine stimulation). Persistent overexpression of growth factors can lead to uncontrolled autostimulation and neoplastic transformation. Alternatively, growth factor receptors can be aberrantly activated (turned on) through mutations or overexpressed (continually presenting cells with growth-stimulatory signals, even in the absence of growth factors), which leads cells to respond as if growth factor levels are altered. The growth-stimulating effect of growth factors and other mitogens is mediated through postreceptor signal transduction molecules. These molecules mediate the passage of growth signals from the outside to the inside of the cell and then to the cell nucleus, initiating the cell cycle and DNA transcription. Aberrant activation or expression of cell-signaling molecules, cell-cycle molecules, or transcription factors may play an important role in neoplastic transformation. Two of the best-studied oncogenes, HER2 and ras, are discussed here.

HER2 Protein tyrosine kinases account for a large portion of known oncogenes. HER2, also known as neu or c-erb B-2, is a member of the epidermal growth factor receptor (EGFR) family and is one of the best-characterized tyrosine kinases. Unlike other receptor tyrosine kinases, HER-2/neu does not have a direct soluble ligand. It plays a key role in signaling, however, because it is the preferred partner in heterodimer formation with all the other EGFR family members (EGFR/c-erb B-1, HER2/c-erb B-3, and HER3/c-erb B-4), which bind at least 30 ligands, including epidermal growth factor (EGF), transforming growth factor

(TGF ), heparin-binding EGF-like growth factor,

amphiregulin, and heregulin. 8 Heterodimerization with HER2 potentiates recycling of receptors rather than degradation, enhances signal potency and duration, increases affinity for ligands, and increases catalytic activity.8 HER2 can interact with different members of the HER family and activate mitogenic and antiapoptotic pathways (Fig. 10-6).9 The specificity and potency of the intracellular signals are affected by the identity of the ligand, the composition of the receptors, and the phosphotyrosine-binding proteins associated with the erbB molecules. The Ras- and Shc-activated mitogen-activated protein kinase (MAPK) pathway is a target of all erbB ligands, which increase the transcriptional activity of early-response genes such as c-myc, c-fos, and c-jun.

10

MAPK-independent

pathways such as the phosphoinositide-3 kinase (PI3K) pathway also are activated by most erbB dimers, although the potency and kinetics of activation may differ. Stimulation of the PI3K pathway through HER2 signaling also can lead to activation of survival molecule Akt, which suppresses apoptosis through multiple mechanisms.

Fig. 10-6.

Selected HER2 signaling pathways. HER2 can interact with different members of the HER family and activate mitogenic and antiapoptotic pathways. 4E-BP1= eIF4E binding protein 1; CREB = cyclic adenosine monophosphate element binding; eIF4E = eukaryotic initiation factor 4E; EZH = enhancer of zeste homolog; FAK = focal adhesion kinase; Fas-L = Fas ligand; GSK3 = glycogen synthase kinase-3; HER = human epidermal growth receptor; IKK = I B kinase; ILK= integrin-linked kinase; IP3 = inositol triphosphate; I B = inhibitor of NF- B; MAPK = mitogen-activated protein kinase; MDM2 = mouse double minute 2 homologue; MEK = mitogen-activated protein/extracellular signal regulated kinase kinase; MEKK = MEK kinase; mTOR = mammalian target of rapamycin; NF- B = nuclear factor B; PI3K = phosphoinositide-3 kinase; PLC- = phospholipase C ; SAPK = stress-activated protein kinase; SEK = SAPK/extracellular signal regulated kinase kinase; TSC = tuberous sclerosis complex. (Modified with permission from Meric-Bernstam et al.9 )

The mutant rat neu gene was first recognized as an oncogene in neuroblastomas from carcinogen-treated rats. 1 1 The HER2 gene is frequently amplified and the protein overexpressed in many cancers, including breast, ovarian, lung, gastric, and oral cancers. Overexpression of HER2 results in ligand-independent activation of HER2 kinase, which leads to mitogenic signaling. HER2 overexpression is associated with increased cell proliferation and anchorage-independent growth as well as resistance to proapoptotic stimuli. Further, overexpression of HER2

increases cell migration and upregulates the activities of matrix metalloproteinases (MMPs) and in vitro invasiveness. In animal models, HER2 increases tumorigenicity, angiogenesis, and metastasis. These results all suggest that HER2 plays a key role in cancer biology.

RAS The ras family of genes encodes small guanosine triphosphate (GTP)–binding proteins that regulate several cellular processes. The H- and K-ras genes were first identified as the cellular counterparts of the oncogenes of the Harvey and Kirsten rat sarcoma viruses, whereas N-ras was isolated from a neuroblastoma.1 2 The N-, H-, and K-ras genes are located on chromosomes 1, 11, and 12, respectively, and encode for 21-kDa proteins that are nearly identical in amino acid sequence but appear not to be redundant in function.1 2 ras cycles between active GTP-bound and inactive guanosine diphosphate–bound states. Various extracellular stimuli can promote ras activation, including various receptor and nonreceptor tyrosine kinases, G protein–coupled receptors, and integrins. 1 3 Guanine nucleotide exchange factors stimulate formation of ras-GTP. ras has an intrinsic ability to hydrolyze GTP, but this hydrolysis is slow. Guanosine triphosphatase–activating proteins (GAPs) stimulate hydrolysis of the bound GTP to return ras to its inactive form. Mutations of ras at amino acid positions 12, 13, or 61 may render ras insensitive to GAPs, which results in mutant proteins that are persistently activated. Approximately 20% of all tumors have activating mutations in one of the ras genes. 1 4 The frequency of ras mutations varies widely by cancer type (e.g., 90% of pancreatic cancers, but 30 genes for autosomal dominant hereditary cancers have been identified (Table 103).3 0 A few of these hereditary cancer genes are oncogenes, but most are tumor-suppressor genes. Although hereditary cancer syndromes are rare, somatic mutations that occur in sporadic cancer have been found to disrupt the cellular pathways altered in hereditary cancer syndromes, which suggests that these pathways are critical to normal cell growth, cell cycle, and proliferation.

Table 10-3 Genes Associated with Hereditary Cancer APC 17q21 Familial adenomatous polyposis (FAP) Colorectal adenomas and carcinomas, duodenal and gastric tumors, desmoids, medulloblastomas, osteomas BMPRIA 10q21-q22 Juvenile polyposis coli Juvenile polyps of the GI tract, GI and colorectal malignancy BRCA1 17q21

Breast-ovarian syndrome Breast cancer, ovarian cancer, colon cancer, prostate cancer BRCA2 13q12.3 Breast-ovarian syndrome Breast cancer, ovarian cancer, colon cancer, prostate cancer, cancer of the gallbladder and bile duct, pancreatic cancer, gastric cancer, melanoma p16; CDK4 9p21; 12q14 Familial melanoma Melanoma, pancreatic cancer, dysplastic nevi, atypical moles CDH1 16q22 Hereditary diffuse gastric cancer Gastric cancer hCHK2 22q12.1 Li-Fraumeni syndrome and hereditary breast cancer Breast cancer, soft tissue sarcoma, brain tumors hMLH1; hMSH2; hMSH6; PMS1; hPMS2 3p21; 2p22-21; 2p16; 2q31-33; 7p22 Hereditary nonpolyposis colorectal cancer Colorectal cancer, endometrial cancer, transitional cell carcinoma of the ureter and renal pelvis, and carcinomas of the stomach, small bowel, ovary, and pancreas MEN1 11q13 Multiple endocrine neoplasia type 1 Pancreatic islet cell cancer, parathyroid hyperplasia, pituitary adenomas MET 7q31 Hereditary papillary renal cell carcinoma Renal cancer NF1 17q11 Neurofibromatosis type 1 Neurofibroma, neurofibrosarcoma, acute myelogenous leukemia, brain tumors NF2 22q12 Neurofibromatosis type 2 Acoustic neuromas, meningiomas, gliomas, ependymomas PTC 9q22.3 Nevoid basal cell carcinoma Basal cell carcinoma PTEN 10q23.3 Cowden disease Breast cancer, thyroid cancer, endometrial cancer rb

13q14 Retinoblastoma Retinoblastoma, sarcomas, melanoma, and malignant neoplasms of brain and meninges RET 10q11.2 Multiple endocrine neoplasia type 2 Medullary thyroid cancer, pheochromocytoma, parathyroid hyperplasia SDHB; SDHC; SDHD 1p363.1-p35; 11q23; 1q21 Hereditary paraganglioma and pheochromocytoma Paraganglioma, pheochromocytoma SMAD4/DPC4 18q21.1 Juvenile polyposis coli Juvenile polyps of the GI tract, GI and colorectal malignancy STK11 19p13.3 Peutz-Jeghers syndrome GI tract carcinoma, breast carcinoma, testicular cancer, pancreatic cancer, benign pigmentation of the skin and mucosa p53 17p13 Li-Fraumeni syndrome Breast cancer, soft tissue sarcoma, osteosarcoma, brain tumors, adrenocortical carcinoma, Wilms' tumor, phyllodes tumor of the breast, pancreatic cancer, leukemia, neuroblastoma TSC1; TSC2 9q34; 16p13 Tuberous sclerosis Multiple hamartomas, renal cell carcinoma, astrocytoma VHL 3p25 von Hippel-Lindau disease Renal cell carcinoma, hemangioblastomas of retina and central nervous system, pheochromocytoma WT 11p13 Wilms' tumor Wilms' tumor, aniridia, genitourinary abnormalities, mental retardation Gene Location Syndrome Cancer Sites and Associated Traits

Source: Modified with permission from Marsh DJ, Zori RT: Genetic insights into familial cancers – update and recent discoveries. Cancer Lett 181:125, 2002. Copyright Elsevier. The following factors may suggest the presence of a hereditary cancer3 1 :

1. Tumor development at a much younger age than usual 2. Presence of bilateral disease

3. Presence of multiple primary malignancies 4. Presentation of a cancer in the less affected sex (e.g., male breast cancer) 5. Clustering of the same cancer type in relatives 6. Occurrence of cancer in association with other conditions such as mental retardation or pathognomonic skin lesions It is crucial that all surgeons caring for cancer patients be aware of hereditary cancer syndromes, because a patient's genetic background has significant implications for patient counseling, planning of surgical therapy, and cancer screening and prevention. Some of the more commonly encountered hereditary cancer syndromes are discussed here.

RB1 GENE AND HEREDITARY RETINOBLASTOMA The retinoblastoma generb1 was the first tumor suppressor to be cloned. The rb1 gene product, the Rb protein, is a regulator of transcription that controls the cell cycle, differentiation, and apoptosis in normal development.3 2 Retinoblastoma has long been known to occur in hereditary and nonhereditary forms. Interestingly, although most children with an affected parent develop bilateral retinoblastoma, some develop unilateral retinoblastoma. Furthermore, some children with an affected parent are not affected themselves but then have an affected child, which indicates that they are rb1 mutation carriers. These findings led to the theory that a single mutation is not sufficient for tumorigenesis. Dr. Alfred Knudson hypothesized that hereditary retinoblastoma involves two mutations, of which one is germline and one somatic, whereas nonhereditary retinoblastoma is due to two somatic mutations (Fig. 10-8).3 3 Thus both hereditary and nonhereditary forms of retinoblastoma involve the same number of mutations, a hypothesis known as Knudson's "two-hit" hypothesis. A "hit" may be a point mutation, a chromosomal deletion referred to as allelic loss, or a loss of heterozygosity, or silencing of an existing gene.

Fig. 10-8.

"Two-hit" tumor formation in both hereditary and nonhereditary cancers. A "one-hit" clone is a precursor to the tumor in nonhereditary cancers, whereas all cells are one-hit clones in hereditary cancer. (Modified with permission from Macmillan Publishers Ltd. Knudson AG: Two genetic hits (more or less) to cancer. Nat Rev Cancer 1:157-162. Copyright 2001.)

Retinoblastoma is a pediatric retinal tumor. Most of these tumors are detected within the first 7 years of life. Bilateral disease usually is diagnosed earlier, at an average age of 12 months. There is a higher incidence of second extraocular primary tumors, especially sarcomas, malignant melanomas, and malignant neoplasms of the brain and meninges in patients with germline mutations. In addition to hereditary retinoblastoma, Rb protein is commonly inactivated directly by mutation in many sporadic tumors.3 4 Moreover, other molecules in the Rb pathway, such as p16 and cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), have been identified in a number of sporadic tumors, which suggests that the Rb pathway is critical in malignant transformation.

P53 AND LI-FRAUMENI SYNDROME Li-Fraumeni syndrome (LFS) was first defined on the basis of observed clustering of malignancies, including earlyonset breast cancer, soft tissue sarcomas, brain tumors, adrenocortical tumors, and leukemia.3 5 Criteria for classic LFS in an individual (the proband) include (a) a bone or soft tissue sarcoma when younger than 45 years, (b) a first-degree relative with cancer before age 45 years, and (c) another first- or second-degree relative with either a sarcoma diagnosed at any age or any cancer diagnosed before age 45 years.3 6 Approximately 70% of LFS families have been shown to have germline mutations in the tumor-suppressor gene p53.3 7 Breast carcinoma, soft tissue

sarcoma, osteosarcoma, brain tumors, adrenocortical carcinoma, Wilms' tumor, and phyllodes tumor of the breast are strongly associated; pancreatic cancer is moderately associated; and leukemia and neuroblastoma are weakly associated with germline p53 mutations.3 8 Mutations of p53 have not been detected in approximately 30% of LFS families, and it is hypothesized that genetic alterations in other proteins interacting with p53 function may play a role in these families. Of the known genes in human cancer, p53 is the most commonly mutated. The p53 protein regulates cell-cycle progression as well as apoptotic cell death as part of stress response pathways after exposure to ionizing or ultraviolet (UV) irradiation, chemotherapy, acidosis, growth factor deprivation, or hypoxia. When cells are exposed to stressors, p53 acts as a transcription factor for genes that induce cell-cycle arrest or apoptosis. A majority of p53 mutations are found within a central DNA recognition motif and disrupt DNA binding by p53. Families with germline missense mutations in the DNA-binding domain show a more highly penetrant phenotype than families with other p53 mutations.3 9 Furthermore, proband cancers are linked with significantly younger age at diagnosis in patients with missense mutations in the DNA-binding domain.3 9

HCHK2, LI-FRAUMENI SYNDROME, AND HEREDITARY BREAST CANCER Germline mutations in the hCHK2 gene have recently been identified as another susceptibility gene for LFS. The hCHK2 gene encodes for the human homologue of the yeast Cds1 and the RAD53 G2 checkpoint, whose activation by DNA damage prevents entry into mitosis. CHK2 directly phosphorylates p53, which suggests that CHK2 may be involved in p53 regulation after DNA damage. CHK2 also regulates BRCA1 function after DNA damage. The protein truncation mutation 1100delC in exon 10 identified in LFS and breast cancer abolishes the kinase function of CHK2. Another reported mutation in hCHK2 is a missense mutation (R145W) that destabilizes the protein, shortening its half-life.4 0 Although some investigators found hCHK2 mutations in classic LFS families, others have reported that the phenotypes of CHK2 families are not typical for LFS and involve no sarcomas or childhood cancers. The CHK2 mutation originally reported in LFS (1100delC) is found in 1.4% of population controls but is found at an increased frequency (3.1%) among breast cancer patients with a family history of the cancer.4 1 Patients with bilateral breast cancers are six times more likely to have the mutation than patients with unilateral breast cancer. Thus hCHK2 mutations may play a role in families with hereditary breast cancer as well as in families with LFS, but the extent of this is unclear. Mutations of hCHK2 are rare in sporadic breast tumors.

BRCA1, BRCA2, AND HEREDITARY BREAST-OVARIAN CANCER SYNDROME It is estimated that 5 to 10% of breast cancers are hereditary. Of women with early-onset breast cancer (aged 40 years or younger), nearly 10% have a germline mutation in one of the breast cancer genesBRCA1 or BRCA2.

42

Mutation carriers are more prevalent among women who have a first- or second-degree relative with premenopausal breast cancer or ovarian cancer at any age. The likelihood of a BRCA mutation is higher in patients who belong to a population in which founder mutations may be prevalent, such as in the Ashkenazi Jewish population. For a female BRCA1 mutation carrier, the cumulative risks of developing breast cancer and ovarian cancer by age 70 have been estimated to be 87 and 44%, respectively.4 3 The cumulative risks of breast cancer and ovarian cancer by age 70 in families with BRCA2 mutation have been estimated to be 84 and 27%, respectively. 4 4 Although male breast cancer can occur with either BRCA1 or BRCA2 mutation, the majority of families (76%) with both male and female breast cancer have mutations in BRCA2.

44

Besides breast and ovarian cancer, BRCA1 and

BRCA2 mutations may be associated with increased risks for several other cancers. BRCA1 mutations confer a fourfold increased risk for colon cancer and threefold increased risk for prostate cancer. 4 3 BRCA2 mutations confer

a fivefold increased risk for prostate cancer, sevenfold in men younger than 65 years.4 5 Furthermore, BRCA2 mutations confer a fivefold increased risk for gallbladder and bile duct cancers, fourfold increased risk for pancreatic cancer, and threefold increased risk for gastric cancer and malignant melanoma.4 5 BRCA1 was the first breast cancer susceptibility gene identified and has been mapped to 17q21. BRCA2, mapped to 13q12.3, was reported shortly afterward. BRCA1 and BRCA2 encode for large nuclear proteins, 208 kDa and 384 kDa, respectively, that have been implicated in processes fundamental to all cells, including DNA repair and recombination, checkpoint control of the cell cycle, and transcription.4 6 Although early studies suggested that the two proteins function together as a complex, subsequent data demonstrated that they have distinct functions.47,48 In fact, breast cancers arising from BRCA1 or BRCA2 mutations are different at the molecular level and have been found to have distinct gene expression profiles.4 9 BRCA1 -associated tumors are more likely to be estrogen receptor negative, whereas BRCA2 -associated tumors are more likely to be estrogen receptor positive. Currently, studies are ongoing to determine whether BRCA1 and BRCA2 status can be used to guide systemic therapy choices for breast cancer.

APC GENE AND FAMILIAL ADENOMATOUS POLYPOSIS Patients affected with familial adenomatous polyposis (FAP) characteristically develop hundreds to thousands of polyps in the colon and rectum. The polyps usually appear in adolescence and, if left untreated, progress to colorectal cancer. FAP is associated with benign extracolonic manifestations that may be useful in identifying new cases, including congenital hypertrophy of the retinal pigment epithelium, epidermoid cysts, and osteomas. In addition to colorectal cancer, patients with FAP are at risk for upper intestinal neoplasms (gastric and duodenal polyps, duodenal and periampullary cancer), hepatobiliary tumors (hepatoblastoma, pancreatic cancer, and cholangiocarcinoma), thyroid carcinomas, desmoid tumors, and medulloblastomas. The product of the adenomatous polyposis coli tumor-suppressor gene (APC ) is widely expressed in many tissues and plays an important role in cell-cell interactions, cell adhesion, regulation of

-catenin, and maintenance of

cytoskeletal microtubules. Alterations in APC lead to dysregulation of several physiologic processes that govern colonic epithelial cell homeostasis, including cell-cycle progression, migration, differentiation, and apoptosis. Mutations in the APC gene have been identified in FAP and in 80% of sporadic colorectal cancers.5 0 Furthermore, APC mutations are the earliest known genetic alterations in colorectal cancer progression, which emphasizes its importance in cancer initiation. The germline mutations in APC may arise from point mutations, insertions, or deletions that lead to a premature stop codon and a truncated, functionally inactive protein. The risk of developing specific manifestations of FAP is correlated with the position of the FAP mutations, a phenomenon referred to as genotype-phenotype correlation. For example, desmoids usually are associated with mutations between codons 1403 and 1578.51,52 Mutations in the extreme 5' or 3' ends of APC, or in the alternatively spliced region of exon 9, are associated with an attenuated version of FAP. Better understanding of the genotype-phenotype correlations may assist in patient counseling and therapeutic planning.

MISMATCH REPAIR GENES AND HEREDITARY NONPOLYPOSIS COLORECTAL CANCER Hereditary nonpolyposis colorectal cancer (HNPCC), also referred to as Lynch syndrome, is an autosomal dominant hereditary cancer syndrome that predisposes to a wide spectrum of cancers, including colorectal cancer without polyposis. Some have proposed that HNPCC consists of at least two syndromes: Lynch syndrome 1, which entails hereditary predisposition for colorectal cancer with early age of onset (approximately age 44 years) and an excess of synchronous and metachronous colonic cancers; and Lynch syndrome 2, featuring a similar colonic phenotype

accompanied by a high risk for carcinoma of the endometrium, transitional cell carcinoma of the ureter and renal pelvis, and carcinomas of the stomach, small bowel, ovary, and pancreas.5 3 The diagnostic criteria for HNPCC are referred to as the Amsterdam criteria, or the 3-2-1-0 rule. The classic Amsterdam criteria were revised to include other HNPCC-related cancers (Table 10-4).5 4 These criteria are met when three or more family members have histologically verified, HNPCC-associated cancers (one of whom is a first-degree relative of the other two), two or more generations are involved, at least one individual was diagnosed before age 50 years, and no individuals have FAP.5 4

Table 10-4 Revised Criteria for Hereditary Nonpolyposis Colon Cancer (HNPCC) (Amsterdam Criteria II) Three or more relatives with an HNPCC-associated cancer (colorectal cancer, endometrial cancer, cancer of the small bowel, ureter, or renal pelvis), one of whom is a first-degree relative of the other two At least two successive generations affected At least one case diagnosed before age 50 y Familial adenomatous polyposis excluded Tumors verified by pathologic examination Source: Modified with permission from Vasen et al.5 4 Copyright Elsevier. During DNA replication, DNA polymerases may introduce single nucleotide mismatches or small insertion or deletion loops. These errors are corrected through a process referred to as mismatch repair. When mismatch repair genes are inactivated, DNA mutations in other genes that are critical to cell growth and proliferation accumulate rapidly. In HNPCC, germline mutations have been identified in several genes that play a key role in DNA nucleotide mismatch repair: hMLH1 (human mutL homologue 1), hMSH2 (human mutS homologue 2), hMSH6, and hPMS1 and hPMS2 (human postmeiotic segregation 1 and 2), of which hMLH1 and hMSH2 are the most common.55–60 The hallmark of HNPCC is microsatellite instability, which occurs on the basis of unrepaired mismatches and small insertion or deletion loops. Microsatellite instability can be tested by comparing the DNA of a patient's tumor with DNA from adjacent normal epithelium, amplifying the DNA with polymerase chain reaction (PCR) using a standard set of markers, comparing the amplified genomic DNA sequences, and classifying the degree of microsatellite instability as high, low, or stable. Such microsatellite instability testing may help select patients who are more likely to have germline mutations.

PTEN AND COWDEN DISEASE Somatic deletions or mutations in the tumor-suppressor genePTEN (phosphatase and tensin homologue deleted on chromosome 10) have been observed in a number of glioma and breast, prostate, and renal carcinoma cell lines and several primary tumor specimens.6 1 PTEN also is referred to as the gene mutated in multiple advanced cancers 1 (MMAC1). PTEN was identified as the susceptibility gene for the autosomal dominant syndrome Cowden disease (CD) or multiple hamartoma syndrome.6 2 Trichilemmomas, benign tumors of the hair follicle infundibulum, and mucocutaneous papillomatosis are pathognomonic of CD. Other common features include thyroid adenomas and multinodular goiters, breast fibroadenomas, and hamartomatous GI polyps. The diagnosis of CD is made when an individual or family has a combination of pathognomonic major and/or minor criteria proposed by the International Cowden Consortium (Table 10-5).6 3 CD is associated with an increased risk of breast and thyroid cancers. Breast cancer develops in 25 to 50% of affected women.6 3

Table 10-5 Cowden Disease Diagnostic Criteria

Pathognomonic criteria Mucocutaneous lesions Facial trichilemmomas Acral keratoses Papillomatous lesions Mucosal lesions Major criteria Breast cancer Thyroid cancer, especially follicular thyroid carcinoma type Macrocephaly (=97th percentile) Lhermitte-Duclos disease Endometrial carcinoma Minor criteria Other thyroid lesions (e.g., goiter) Mental retardation (intelligence quotient =75) GI hamartomas Fibrocystic disease of the breast Lipomas Fibromas Genitourinary tumors (e.g., uterine fibroids) or malformation Operational diagnosis in an individual Mucocutaneous lesions alone if there are: Six or more facial papules, of which three or more must be trichilemmoma, or Cutaneous facial papules and oral mucosal papillomatosis, or Oral mucosal papillomatosis and acral keratoses, or Palmoplantar keratoses, six or more Two major criteria, but one must be macrocephaly or Lhermitte-Duclos disease One major and three minor criteria Four minor criteria

Source: Modified with permission from Eng C: Will the real Cowden syndrome please stand up: revised diagnostic criteria. J Med Genet 37:828, 2000. With permission from the BMJ Publishing Group. PTEN encodes a 403-amino-acid protein, tyrosine phosphatase. PTEN negatively controls the PI3K signaling pathway for the regulation of cell growth and survival by dephosphorylating phosphoinositol 3,4,5-triphosphate; thus mutation of PTEN leads to constitutive activation of the PI3K/Akt signaling pathway. The "hot spot" for PTEN mutations has been identified in exon 5. Forty-three percent of CD mutations have been identified in this exon, which contains the tyrosine phosphatase core domain. This suggests that the PTEN catalytic activity is vital for its biologic function.

P16 AND HEREDITARY MALIGNANT MELANOMA The geneP 16, also known as INK4A, CDKN1, CDKN2A, and MTS1, is a tumor suppressor that acts by binding CDK4 and CDK6 and inhibiting the catalytic activity of the CDK4-CDK6/cyclin D complex that is required for phosphorylation of Rb and subsequent cell-cycle progression. Studies suggest that germline mutations in p16 can be found in 20% of melanoma-prone families.6 4 Mutations in p16 that alter its ability to inhibit the catalytic activity of the CDK4-CDK6/cyclin D complex not only increase the risk of melanoma by 75-fold but also increase the risk of

pancreatic cancer by 22-fold.6 5 Interestingly, p16 mutations that do not appear to alter its function increase the risk of melanoma by 38-fold and do not increase the risk of pancreatic cancer. 6 5 Genetic evaluation of primary tumors has revealed that p16 is inactivated through point mutation, promoter methylation, or deletion in a significant portion of sporadic tumors, including cancers of the pancreas, esophagus, head and neck, stomach, breast, and colon, as well as melanomas.

E-CADHERIN AND HEREDITARY DIFFUSE GASTRIC CANCER E-cadherin is a cell adhesion molecule that plays an important role in normal architecture and function of epithelial cells. The adhesive function of E-cadherin is dependent on interaction of its cytoplasmic domain with

- and -

catenins and may be regulated by phosphorylation of -catenin. Hereditary diffuse gastric carcinoma is an autosomal dominant cancer syndrome that results from germline mutations in the E-cadherin gene, CDH1. Carriers of CDH1 mutations have a 70 to 80% chance of developing gastric cancer. 6 6 Furthermore, mutations of CDH1 have been described in sporadic cancers of the ovary, endometrium, breast, and thyroid. However, frequent mutations have been identified in only two particular tumors: diffuse gastric carcinomas and lobular breast carcinomas. Invasive lobular breast carcinomas often show inactivating mutations in combination with a loss of heterozygosity of the wild-type CDH1 allele.6 7 Interestingly, in gastric carcinomas the predominant mutations are exon skipping causing in-frame deletions, whereas most mutations identified in lobular breast cancers are premature stop codons; this suggests a genotype-phenotype correlation.

RET PROTO-ONCOGENE AND MULTIPLE ENDOCRINE NEOPLASIA TYPE 2 The RET (rearranged during transfection) gene encodes for a transmembrane receptor tyrosine kinase that plays a role in proliferation, migration, and differentiation of cells derived from the neural crest. Gain-of-function mutations in the RET gene are associated with medullary thyroid carcinoma in isolation or multiple endocrine neoplasia type 2 (MEN2) syndromes. MEN2A is associated with medullary thyroid carcinoma and pheochromocytoma (in 50%) or parathyroid adenoma (in 20%), whereas MEN2B is associated with medullary thyroid carcinoma, marfanoid habitus, mucosal neuromas, and ganglioneuromatosis.6 8 RET mutations lead to uncontrolled growth of the thyroid C cells, and in familial medullary cancer, C-cell hyperplasia progresses to bilateral, multicentric medullary thyroid cancer. Mutations in the RET gene have also been identified in half of sporadic medullary thyroid cancers. The activating RET mutations in medullary thyroid cancer are being pursued as a therapeutic target.

TISSUE SPECIFICITY OF HEREDITARY CANCER In spite of our increasing understanding of hereditary cancer genes, the tissue specificity of the hereditary cancers remains poorly understood. For example, although mutations in genes such as rb and p53 are encountered frequently in sporadic cancers arising in a variety of tissues, it is unclear why germline mutations in these genes would lead to tumors predominantly in selected tissues. However, mutations in tumor-suppressor genes alone are insufficient to produce tumors, and usually the development of cancer involves accumulation of multiple genetic alterations. The rate at which these changes occur in different tissues after inactivation of different tumorsuppressor genes may account for some of the tissue distribution seen with hereditary cancer syndromes.

GENETIC MODIFIERS OF RISK Individuals carrying identical germline mutations vary in regard to cancer penetrance (whether cancer will develop or not) and cancer phenotype (the tissues involved). It is thought that this variability may be due to environmental influences or, if genetic, to genetic modifiers of risk. Similarly, genetic modifiers of risk also can play a role in

determining whether an individual will develop cancer after exposure to carcinogens.

Chemical Carcinogens The first report indicating that cancer could be caused by environmental factors was by John Hill, who in 1761 noted the association between nasal cancer and excessive use of tobacco snuff.6 9 Currently, approximately 60 to 90% of cancers are thought to be due to environmental factors. Any agent that can contribute to tumor formation is referred to as a carcinogen and can be a chemical, physical, or viral agent. Chemicals are classified into three groups based on how they contribute to tumor formation. The first group of chemical agents, the genotoxins, can initiate carcinogenesis by causing a mutation. The second group, the cocarcinogens, by themselves cannot cause cancer but potentiate carcinogenesis by enhancing the potency of genotoxins. The third group, tumor promoters, enhances tumor formation when given after exposure to genotoxins. The International Agency for Research on Cancer (IARC) maintains a registry of human carcinogens that is available through the World Wide Web (http://www.iarc.fr). The compounds are categorized into five groups based on an analysis of epidemiologic studies, animal models, and short-term mutagenesis tests. Group 1 contains what are considered to be proven human carcinogens, based on formal epidemiologic studies among workers who were exposed for long periods (several years) to the chemicals. Group 2A contains what are considered to be probable human carcinogens. Suggestive epidemiologic evidence exists for compounds in this group, but the data are insufficient to establish causality. There is evidence of carcinogenicity, however, from animal studies carried out under conditions relevant to human exposure. Group 2B contains what are considered to be possible carcinogens, because these substances are associated with a clear statistically and biologically significant increase in the incidence of malignant tumors in more than one animal species or strain. Group 3 agents are not classifiable as to carcinogenicity in humans. Group 4 agents are probably not carcinogenic to humans. Selected substances that have been classified as proven carcinogens (group 1) by the IARC are listed in Table 10-6.7 0

Table 10-6 Selected IARC Group 1 Chemical Carcinogensa Aflatoxins Liver cancer Arsenic Skin cancer Benzene Leukemia Benzidine Bladder cancer Beryllium Lung cancer Cadmium Lung cancer Chinese-style salted fish Nasopharyngeal carcinoma Chlorambucil Leukemia Chromium [VI] compounds Lung cancer Coal tar Skin cancer, scrotal cancer Cyclophosphamide

Bladder cancer, leukemia Diethylstilbestrol (DES) Vaginal and cervical clear cell adenocarcinomas Ethylene oxide Leukemia, lymphoma Estrogen replacement therapy Endometrial cancer, breast cancer Nickel Lung cancer, nasal cancer Tamoxifenc Endometrial cancer Vinyl chloride Angiosarcoma of the liver, hepatocellular carcinoma, brain tumors, lung cancer, malignancies of lymphatic and hematopoietic system TCDD (2,3,7,8-tetrachlorodibenzo-para-dioxin) Soft tissue sarcoma Tobacco products, smokeless Oral cancer Tobacco smoke Lung cancer, oral cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer (squamous cell), pancreatic cancer, bladder cancer, liver cancer, renal cell carcinoma, cervical cancer, leukemia Chemical

a Based

Predominant Tumor Typeb

on information in the IARC monographs. 7 0

b

Only tumor types for which causal relationships are established are listed. Other cancer types may be linked to the agents with a lower frequency or with insufficient data to prove causality. c

Tamoxifen has been shown to prevent contralateral breast cancer.

IARC = International Agency for Research on Cancer.

Physical Carcinogens Physical carcinogenesis can occur through induction of inflammation and cell proliferation over a period of time or through exposure to physical agents that induce DNA damage. Foreign bodies can cause chronic irritation that can expose cells to carcinogenesis due to other environmental agents. In animal models, for example, subcutaneous implantation of a foreign body can lead to the development of tumors that have been attributed to chronic irritation from the foreign objects. In humans, clinical scenarios associated with chronic irritation and inflammation such as chronic nonhealing wounds, burns, and inflammatory bowel syndrome have all been associated with an increased risk of cancer. H. pylori infection is associated with gastritis and gastric cancer, and thus its carcinogenicity may be considered physical carcinogenesis. Infection with the liver fluke Opisthorchis viverrini similarly leads to local inflammation and cholangiocarcinoma. The induction of lung and mesothelial cancers by asbestos fibers and nonfibrous particles such as silica are other examples of foreign body–induced physical carcinogenesis.7 1 Animal experiments have demonstrated that the dimensions and durability of the asbestos and other fibrous minerals are the key determinants of their

carcinogenicity.7 2 Short fibers can be inactivated by phagocytosis, whereas long fibers (>10 m) are cleared less effectively and are encompassed by proliferating epithelial cells. The long fibers support cell proliferation and have been shown to preferentially induce tumors. Asbestos-associated biologic effects also may be mediated through reactive oxygen and nitrogen species. Furthermore, an interaction occurs between asbestos and silica and components of cigarette smoke. Polycyclic aromatic hydrocarbons (PAHs) in cigarette smoke are metabolized by epithelial cells and form DNA adducts. If PAH is coated on asbestos, PAH uptake is increased.7 1 Both PAH and asbestos impair lung clearance, potentially increasing uptake further. Therefore, physical carcinogens may be synergistic with chemical carcinogens. Radiation is the best-known agent of physical carcinogenesis and is classified as ionizing radiation (x-rays, gamma rays, and alpha and beta particles) or nonionizing radiation (UV). The carcinogenic potential of ionizing radiation was recognized soon after Wilhelm Conrad Roentgen's discovery of x-rays in 1895. Within the next 20 years, a large number of radiation-related skin cancers were reported. Long-term follow-up of survivors of the atomic bombing of Hiroshima and Nagasaki revealed that virtually all tissues exposed to radiation are at risk for cancer. Radiation can induce a spectrum of DNA lesions that includes damage to the nucleotide bases and cross-linking, and DNA single- and double-strand breaks (DSBs). Misrepaired DSBs are the principal lesions of importance in the induction of chromosomal abnormalities and gene mutations. DSBs in irradiated cells are repaired primarily by a nonhomologous end-joining process, which is error prone; thus DSBs facilitate the production of chromosomal rearrangements and other large-scale changes such as chromosomal deletions. It is thought that radiation may initiate cancer by inactivating tumor-suppressor genes. Activation of oncogenes appears to play a lesser role in radiation carcinogenesis. Although it has been assumed that the initial genetic events induced by radiation constitute direct mutagenesis from radiation, other indirect effects may contribute to carcinogenesis. For example, radiation induces genomic instability in cells that persists for at least 30 generations after irradiation. Therefore, even if cells do not acquire mutations at initial irradiation, they remain at risk for developing new mutations for several generations. Moreover, even cells that have not been directly irradiated appear to be at risk, a phenomenon referred to as the bystander effect. Nonionizing UV radiation is a potent DNA-damaging agent and is known to induce skin cancer in experimental animals. Most nonmelanoma human skin cancers are thought to be induced by repeated exposure to sunlight, which leads to a series of mutations that allow the cells to escape normal growth control. Patients with inherited xeroderma pigmentosum lack one or more DNA repair pathways, which confers susceptibility to UV-induced cancers, especially on sun-exposed body parts. Patients with ataxia telangiectasia mutated syndrome also have a radiation-sensitive phenotype.

Viral Carcinogens One of the first observations that cancer may be caused by transmissible agents was by Peyton Rous in 1910 when he demonstrated that cell-free extracts from sarcomas in chickens could transmit sarcomas to other animals injected with these extracts.7 3 This was subsequently discovered to represent viral transmission of cancer by the Rous sarcoma virus. At present, several human viruses are known to have oncogenic properties, and several have been causally linked to human cancers (Table 10-7).7 4 It is estimated that 15% of all human tumors worldwide are caused by viruses.7 5

Table 10-7 Selected Viral Carcinogens a

Epstein-Barr virus Burkitt's lymphoma Hodgkin's disease Immunosuppression-related lymphoma Sinonasal angiocentric T-cell lymphoma Nasopharyngeal carcinoma Hepatitis B virus Hepatocellular carcinoma Hepatitis C virus Hepatocellular carcinoma HIV type 1 Kaposi's sarcoma Non-Hodgkin's lymphoma Human papillomavirus 16 and 18 Cervical cancer Anal cancer Human T-cell lymphotropic viruses Adult T-cell leukemia/lymphoma Virus

a

Predominant Tumor Typeb

Based on information in the International Agency for Research on Cancer monographs. 7 4

b

Only tumor types for which causal relationships are established are listed. Other cancer types may be linked to the agents with a lower frequency or with insufficient data to prove causality. Viruses may cause or increase the risk of malignancy through several mechanisms, including direct transformation, expression of oncogenes that interfere with cell-cycle checkpoints or DNA repair, expression of cytokines or other growth factors, and alteration of the immune system. Oncogenic viruses may be RNA or DNA viruses. Oncogenic RNA viruses are retroviruses and contain a reverse transcriptase. After the viral infection, the single-stranded RNA viral genome is transcribed into a double-stranded DNA copy, which is then integrated into the chromosomal DNA of the cell. Retroviral infection of the cell is permanent; thus integrated DNA sequences remain in the host chromosome. Oncogenic transforming retroviruses carry oncogenes derived from cellular genes. These cellular genes, referred to as proto-oncogenes, usually are involved in mitogenic signaling and growth control, and include protein kinases, G proteins, growth factors, and transcription factors (Table 10-8). 7 5

Table 10-8 Cellular Oncogenes in Retroviruses abl Abelson murine leukemia virus Mouse Tyrosine kinase fes

ST feline sarcoma virus Cat Tyrosine kinase fps Fujinami sarcoma virus Chicken Tyrosine kinase src Rous sarcoma virus Chicken Tyrosine kinase erbB Avian erythroblastosis virus Chicken Epidermal growth factor receptor fms McDonough feline sarcoma virus Cat Colony-stimulating factor receptor kit Hardy-Zuckerman 4 feline sarcoma virus Cat Stem cell factor receptor mil Avian myelocytoma virus Chicken Serine/threonine kinase mos Moloney murine sarcoma virus Mouse Serine/threonine kinase raf Murine sarcoma virus 3611 Mouse Serine/threonine kinase sis Simian sarcoma virus Monkey Platelet-derived growth factor H-ras Harvey murine sarcoma virus Rat GDP/GTP binding K-ras Kirsten murine sarcoma virus Rat GDP/GTP binding erbA Avian erythroblastosis virus

Chicken Transcription factor (thyroid hormone receptor) ets Avian myeloblastosis virus E26 Chicken Transcription factor fos FBJ osteosarcoma virus Mouse Transcription factor (AP1 component) jun Avian sarcoma virus 17 Chicken Transcription factor (AP1 component) myb Avian myeloblastosis virus Chicken Transcription factor myc MC29 myelocytoma virus Chicken Transcription factor (NF- B family) Oncogene

Virus Name

Origin

Protein Product

AP1 = activator protein 1; FBJ = Finkel-Biskis-Jinkins; GDP = guanosine diphosphate; GTP = guanosine triphosphate; NF- B = nuclear factor B. Source: Modified with permission from Butel JS: Viral carcinogenesis: revelation of molecular mechanisms and etiology of human disease. Carcinogenesis 21:405, 2000. By permission of Oxford University Press. Integration of the provirus upstream of a proto-oncogene may produce chimeric virus-cell transcripts and recombination during the next round of replication that could lead to incorporation of the cellular gene into the viral genome.7 5 On the other hand, many retroviruses do not possess oncogenes but can cause tumors in animals regardless. This occurs by integration of the provirus near a normal cellular proto-oncogene and activation of the expression of these genes by the strong promoter and enhancer sequences in the integrated viral sequence. Unlike the oncogenes of the RNA viruses, those of the DNA tumor viruses are viral, not cellular, in origin. These genes are required for viral replication using the host cell machinery. In permissive hosts, infection with an oncogenic DNA virus may result in a productive lytic infection, which leads to cell death and the release of newly formed viruses. In nonpermissive cells, the viral DNA can be integrated into the cellular chromosomal DNA, and some of the early viral genes can be synthesized persistently, which leads to transformation of cells to a neoplastic state. The binding of viral oncoproteins to cellular tumor-suppressor proteins p53 and Rb is fundamental to the carcinogenesis induced by most DNA viruses, although some target different cellular proteins. Like other types of carcinogenesis, viral carcinogenesis is a multistep process. Some retroviruses contain two cellular oncogenes, rather than one, in their genome and are more rapidly tumorigenic than single-gene transforming retroviruses, which emphasizes the cooperation between transforming genes. Furthermore, some

viruses encode genes that suppress or delay apoptosis. Although immunocompromised individuals are at elevated risk, most patients infected with oncogenic viruses do not develop cancer. When cancer does develop, it usually occurs several years after the viral infection. It is estimated, for example, that the risk of hepatocellular carcinoma (HCC) among individuals infected with hepatitis C virus is 1 to 3% after 30 years. 7 6 There may be synergy between various environmental factors and viruses in carcinogenesis. Recognition of a viral origin for some tumors has lead to the pursuit of vaccination as a preventive strategy. The use of childhood hepatitis B vaccination has already translated into a decrease in liver cancer incidence in the Far East.3 Recently, vaccines against human papillomavirus have shown very promising results in preventing the development of cervical intraepithelial neoplasia and are now being pursued for primary prevention of cervical carcinoma.7 7

CANCER RISK ASSESSMENT Cancer risk assessment is an important part of the initial evaluation of any patient. A patient's cancer risk not only is an important determinant of cancer screening recommendations but also may alter how aggressively an indeterminant finding will be pursued for diagnosis. A "probably benign" mammographic lesion, for example, defined as one with 14 1.00 12–13 1.10 Chapter 11. Transplantation>

KEY POINTS 1. The field of transplantation has made tremendous advances in the last 30 years, due mainly to refinements of surgical technique and development of effective immunosuppression medications. 2. Although immunosuppression drugs are essential for transplant, they are associated with significant short- and long-term morbidity. 3. Kidney transplantation now represents the treatment of choice for almost all patients with end-stage renal disease. 4. Liver transplantation is the viable option at present for patients with end-stage organ failure. 5. Pancreas transplantation and in the future islet cell transplantation represent the most reliable way to achieve euglycemia in the poorly controlled diabetic patient. 6. Opportunistic infections can be significantly lowered by the use of appropriate prophylaxis agents.

BACKGROUND Although references to transplantation have existed in the scientific literature for centuries, the field of modern transplantation did not come into being until the latter half of the twentieth century. Thus, given its short history, it is truly remarkable how far this area of medicine has advanced. From an experimental procedure just 50 years ago, transplantation has evolved to become the treatment of choice for end-stage organ failure resulting from almost any of a wide variety of causes. Transplantation of the kidney, liver, pancreas, intestine, heart, and lung has now become commonplace in all parts of the world. In fact, transplantation is now so widely accepted and successful that the main problem facing the field today is not surgical technique, rejection, or management of complications, but rather supply of organs. An increasing number of diseases and patients are now potentially treatable with transplants; however, this increase, coupled with the decrease in contraindications to transplants, has meant an increasing number of patients are now awaiting organ replacement therapy. The number of transplants performed yearly has increased over the last decade, but has not kept pace with the steadily growing waiting list. As a result, the gap is ever widening between the number of transplants performed and the number of waiting patients (Fig. 11-1).

Fig. 11-1.

Patients on waiting list and number of organ transplants for 2005. (U.S. data from Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipients Annual Report, http://www.ustransplant.org). KP = kidney and pancreas.

Transplantation statistics in the United States are tracked by the United Network for Organ Sharing (UNOS). By the end of 2007, roughly 98,000 patients were awaiting a transplant, while the number of transplants performed in that year was approximately 28,000.

DEFINITIONS Transplantation is the act of transferring an organ, tissue, or cell from one place to another. Broadly speaking, transplants are divided into three categories based on the similarity between the donor and the recipient: autotransplants, allotransplants, and xenotransplants. Autotransplants involve the transfer of tissue or organs from one part of an individual to another part of the same individual. They are the most common type of transplants and include skin grafts, vein grafts for bypasses, bone and cartilage transplants, and nerve transplants. Because the donor and the recipient are the same person and no immunologic disparity exists, no immunosuppression is required. Allotransplants involve transfer from one individual to a different individual of the same species—the most common scenario for most solid organ transplants performed today. Immunosuppression is required for

allograft recipients to prevent rejection. Finally, xenotransplants involve transfer across species barriers. Currently, xenotransplants are largely relegated to the laboratory, given the complex, potent immunologic barriers to success. This chapter deals mainly with allotransplantation. The first part discusses immunobiology, mechanisms of the rejection process, and medications currently used to achieve immunosuppression. The second part focuses on the various transplants, including kidney, pancreas, islet cell, liver, intestine, heart, and lungs. Clinical indications, surgical care, and posttransplant follow-up of these abdominal and thoracic organ recipients are described.

HISTORY Attempts at transplantation have been documented since ancient times, but they are largely of only historic interest. They had no lasting impact on the field of modern transplantation, which did not originate until the latter half of the twentieth century. Important events in the first half of the twentieth century included the development of the surgical techniques for vascular anastomosis by Alexis Carrel; the first human-to-human kidney transplants by Yu Yu Voronoy in the 1930s (which were unsuccessful because of failure to address the immunologic barriers); and the studies of skin transplantation in animal models by Sir Peter Medawar in the 1940s.1–3 Medawar's work was especially crucial: It provided scientific evidence for the role of the immune system in the failure of allografts to function long term, through a process later termed rejection . His work and observations formed the basis for modern transplant immunobiology. The first human kidney transplant with long-term success was performed in Boston by Joseph Murray in 1954.4 Because it was a living-donor transplant between identical twin brothers, the recipient required no immunosuppression and lived for more than 20 years, eventually dying of coronary artery disease. Soon, other centers performed similar transplants, which then led to attempts at kidney transplants between nonidentical individuals, using total body radiation and agents such as 6-mercaptopurine for immunosuppression. By the late 1950s to early 1960s, the combination of azathioprine (AZA) with corticosteroids allowed kidney allotransplantation to advance out of the realm of experimental therapy.5,6 Along with AZA and corticosteroids, the development of antilymphocyte serum (antibodies against human lymphoid tissue) gave clinicians reliable, adequate immunosuppression, allowing the birth of extrarenal transplants.7 In 1963, the first liver transplant was performed by Thomas Starzl in Denver. The first pancreas transplant was performed in 1966 in Minneapolis by William Kelly and Richard Lillehei. Christiaan Barnard performed the first heart transplant in 1967 in Cape Town, South Africa. The 1970s saw other firsts with intestine, lung, and islet transplants. Kidney transplants flourished during the 1970s, but extrarenal transplants remained largely experimental. One major reason was that rejection remained a major obstacle to the success of these transplanted organs. A dramatic change occurred, however, with the introduction in the early 1980s of cyclosporine. At that time, it was the most specific immunosuppressive agent available. It improved graft survival after kidney transplants by 30% and allowed extrarenal transplants to develop as viable therapies. Since that time, and especially in the 1990s, many new agents have been developed and approved for use in clinical transplantation; scores of others are currently being tested in clinical trials. These agents have allowed for progressively more specific targeting of the immune system pathways involved in the rejection process. As a result, rejection rates have substantially declined for all types of transplants, and graft survival rates have increased. A large part of the recent success of transplants is due to the developments in clinical immunosuppression. But

other discoveries also have played a role. More powerful immunosuppression has often meant more risk of infection with opportunistic viral, fungal, and bacterial pathogens. The development of powerful and effective antimicrobial, antifungal, and antiviral therapy (in parallel with immunosuppressive agents) has been crucial to successful solid organ transplantation. Surgical innovations, beyond the first successful attempts at the various transplants, have continued. In the late 1980s and early 1990s, the development of deceased-donor split-liver transplant techniques and of living-donor liver transplants expanded the donor pool and helped alleviate the significant shortage of donors. The development of laparoscopic donor nephrectomy enabled faster recovery of living kidney donors, thereby increasing their numbers. The 1990s ushered in innovations with thoracic, pancreatic, and cellular transplants.

TRANSPLANT IMMUNOBIOLOGY The technical advances and techniques that made transplants possible were described almost a hundred years ago. Yet it was only after a basic understanding of transplant immunobiology was obtained that the obstacle of rejection could be overcome, thus making clinical transplants possible. The success of transplants today is due in large part to control of the rejection process, thanks to an ever-deepening understanding of the immune process triggered by a transplant.8 The immune system is important not only in graft rejection, but also in the body's defense system against viral, bacterial, fungal, and other pathogens. It also helps prevent tumor growth and helps the body respond to shock and trauma. As with the body's reaction to an infection, graft rejection is triggered when specific cells of the transplant recipient, namely T and B lymphocytes, recognize foreign antigens.

TRANSPLANT ANTIGENS The main antigens involved in triggering rejection are coded for by a group of genes known as the major histocompatibility complex (MHC). These antigens, and hence genes, define the "foreign" nature of one individual to another within the same species. In humans, the MHC complex is known as the human leukocyte antigen (HLA) system. It comprises a series of genes located on chromosome 6. The HLA antigens are grouped into two classes, which differ in their structure and cellular distribution. Class I molecules (named HLA-A, -B, and -C) are found on the membrane of all nucleated cells. Class II molecules (named HLA-DR, -DP, and -DQ) generally are expressed by antigen-presenting cells (APCs) such as B lymphocytes, monocytes, and dendritic cells. In a nontransplant setting, the function of the HLA gene product is to present antigens as fragments of foreign proteins that can be recognized by T lymphocytes. In the transplant setting, HLA molecules can initiate rejection and graft damage via either humoral or cellular mechanisms. Humoral rejection occurs if the recipient has circulating antibodies specific to the donor's HLA. These antibodies may be from prior exposure (i.e., blood transfusion, previous transplant, or pregnancy), or posttransplant, the recipient may develop antibodies specific to the donor's HLA. The antibodies then bind to the donor's recognized foreign antigens, activating the complement cascade and leading to cell lysis. The blood group antigens of the ABO system, although not part of the HLA system, may also trigger this form of humoral rejection. Cellular rejection is the more common type of rejection after organ transplants. Mediated by T lymphocytes, it results from their activation and proliferation after exposure to donor MHC molecules.

ALLORECOGNITION AND DESTRUCTION

The recognition of foreign HLA antigens by the recipient T cells is referred to as allorecognition . 9 This process may occur by either a direct or an indirect pathway. In the direct pathway, the recipient's T cells directly interact with donor HLA molecules, leading to the generation of activated cytotoxic T cells. In the indirect pathway, the recipient's own APCs first process the donor's antigens (which may be shed from the parenchymal cells of the graft into the recipient's circulation, or alternatively may be encountered by the recipient's APCs in the graft itself); then the recipient's APCs present the donor's antigens to the recipient T cells, leading to the activation of those T cells. Regardless of the method of presentation of foreign MHC, the subsequent steps are similar. Binding of the T cell to the foreign molecule occurs at the T-cell receptor (TCR)-CD3 complex on the surface of the lymphocyte. This binding leads to transduction of a signal to the cell, named signal 1 . This signal by itself, however, is not sufficient to result in T-cell activation. Full activation requires transduction of a second signal that is not antigen dependent. Signal 2 is provided by the binding of accessory molecules on the T cell to corresponding molecules (ligands) on the APC. An example is CD25 on the T lymphocytes binding with its ligand B7 on the surface of the APC. Transmission of signal 1 and 2 to the cell nucleus leads to interleukin-2 (IL-2) gene expression and to production of this important cytokine. IL-2 then permits the entire cascade of T-cell activation to proceed, leading to proliferation and differentiation of these cells into cells capable of causing damage to the graft. T-cell activation is key in initiating the rejection process, but B-cell activation and antibody production also play a role. Foreign antigens are acquired by immunoglobulin (Ig) receptors on the surface of B cells. These antigens are then processed similarly to the way that APCs process the donor's antigens. The antigen-presenting B cells can then interact with activated helper T cells. This interaction leads to B-cell proliferation, differentiation into plasma cells, and to antibody production.

CLINICAL REJECTION Graft rejection is a complex process involving several components, including T lymphocytes, B lymphocytes, macrophages, and cytokines, with resultant local inflammatory injury and graft damage.10–12 Rejection can be classified into four types, based on timing and pathogenesis: hyperacute , accelerated acute , acute , and chronic .

Hyperacute This type of rejection, which usually occurs within minutes after the transplanted organ is reperfused, is due to the presence of preformed antibodies in the recipient, antibodies that are specific to the donor. These antibodies may be directed against the donor's HLA antigens or they may be anti-ABO blood group antibodies. Either way, they bind to the vascular endothelium in the graft and activate the complement cascade, leading to platelet activation and to diffuse intravascular coagulation. The result is a swollen, darkened graft, which undergoes ischemic necrosis. This type of rejection generally is not reversible, so prevention is key. Prevention is best done by making sure the graft is ABO-compatible and by performing a pretransplant crossmatch. The cross-match is an in vitro test that involves mixing the donor's cells with the recipient's serum to look for evidence of donor cell destruction by recipient antibodies. A positive cross-match indicates the presence of preformed antibodies in the recipient that are specific to the donor, thus a high risk of hyperacute rejection if the transplant is performed.

Accelerated Acute This type of rejection, seen within the first few days posttransplant, involves both cellular and antibody-mediated injury. It is more common when a recipient has been sensitized by previous exposure to antigens present in the

donor, resulting in an immunologic memory response.

Acute This used to be the most common type of rejection, but with modern immunosuppression, it is becoming less and less common. Acute rejection usually is seen within days to a few months posttransplant. It is predominantly a cellmediated process, with lymphocytes being the main cells involved. Biopsy of the affected organ demonstrates a cellular infiltrate, with membrane damage and apoptosis of graft cells. The process may be associated with systemic symptoms such as fever, chills, malaise, and arthralgias. However, with current immunosuppressive drugs, most acute rejection episodes are generally asymptomatic. They usually manifest with abnormal laboratory values (e.g., elevated creatinine in kidney transplant recipients, and elevated transaminase levels in liver transplant recipients). Acute rejection episodes may also be mediated by a humoral, rather than cellular, immune response. B cells may generate antidonor antibodies, which can damage the graft. Establishing the diagnosis may be difficult, as biopsy may not demonstrate a significant cellular infiltrate; special immunologic stains may be necessary.

Chronic This form of rejection occurs months to years posttransplant. Now that short-term graft survival rates have improved so markedly, chronic rejection is an increasingly common problem. Histologically, the process is characterized by atrophy, fibrosis, and arteriosclerosis. Both immune and nonimmune mechanisms are likely involved. Clinically, graft function slowly deteriorates over months to years posttransplant.

CLINICAL IMMUNOSUPPRESSION The success of modern transplantation is in large part due to the successful development of effective immunosuppressive agents. Without these agents, only transplants between genetically identical individuals would be possible. In the 1960s, just two immunosuppressive agents were available, but more than 15 agents are now approved in the United States by the Food and Drug Administration (FDA) for clinical immunosuppression, with scores of others in various stages of clinical trials (Table 11-1). Thus the therapeutic armamentarium for transplant patients has broadened significantly, with a variety of drug combinations and protocols. Characteristics of some common immunosuppressive agents are shown in Table 11-2.

Table 11-1 Immunosuppressive Drugs by Grouping Immunophilin binders Calcineurin inhibitors Cyclosporine Tacrolimus Noninhibitors of calcineurin Sirolimus Antimetabolites Inhibitors of de novo purine synthesis Azathioprine Mycophenolate mofetil Inhibitors of de novo pyrimidine synthesis Leflunomide Biologic immunosuppression Polyclonal antibodies

ATGAM Antithymocyte immunoglobulin Monoclonal antibodies Muromonab-CD3 IL-2R (humanized) Belatacept Alemtuzumab Rituximab Others Corticosteroids JAK-3 inhibitor Protein kinase C inhibitor (e.g., AEB)

ATGAM = antithymocyte globulin; IL-2R = interleukin-2R; JAK-3 = Janus kinase-3.

Table 11-2 Summary of the Main Immunosuppressive Drugs Cyclosporine (CSA) Binds to cyclophilin Nephrotoxicity Improved bioavailability of microemulsion form Oral dose is 8–10 mg/kg per day (given in two divided doses) Inhibits calcineurin and IL-2 synthesis Tremor Hypertension Used as mainstay of maintenance protocols Hirsutism Tacrolimus (FK506) Binds to FKBP Nephrotoxicity Improved patient and graft survival in (liver) primary and rescue therapy IV 0.05–0.1 mg/kg per day Inhibits calcineurin and IL-2 synthesis Hypertension PO 0.15–0.3 mg/kg per day (given q12h) Neurotoxicity GI toxicity (nausea, diarrhea) Used as mainstay of maintenance, like CSA Mycophenolate mofetil Antimetabolite Leukopenia Effective for primary and rescue therapy (kidney transplants) 1 g bid PO (may need 1.5 g in black recipients) Inhibits enzyme necessary for de novo purine synthesis GI toxicity

May replace azathioprine Sirolimus Inhibits lymphocyte effects driven by IL-2 receptor Thrombocytopenia May allow early withdrawal of steroids and decreased calcineurin doses 2–4 mg/d, adjusted to trough drug levels Increased serum cholesterol/LDL Vasculitis (animal studies) Corticosteroids Multiple actions Cushingoid state Used in induction, maintenance, and treatment of acute rejection Varies from mg to several grams/d Anti-inflammatory Glucose intolerance Maintenance doses, 5–10 mg/d Inhibits lymphokine production Osteoporosis Azathioprine Antimetabolite Thrombocytopenia Used in maintenance protocols 1–3 mg/kg per day for maintenance Interferes with DNA and RNA synthesis Neutropenia Liver dysfunction Drug Mechanism of Action

Adverse Effects

Clinical Uses

Dosage

FKBP = FK506-binding protein; IL = interleukin; LDL = low-density lipoprotein. Immunosuppressive drugs generally are used in combination with others rather than alone. Induction immunosuppression refers to the drugs administered immediately posttransplant to induce immunosuppression. Maintenance immunosuppression refers to the drugs administered to maintain immunosuppression once recipients have recovered from the operative procedure. Individual drugs can be categorized as either biologic or nonbiologic agents. Biologic agents consist of antibody preparations directed at various cells or receptors involved in the rejection process; they generally are used in induction (rather than maintenance) protocols. Nonbiologic agents form the mainstay of maintenance protocols.

Nonbiologic Agents

CORTICOSTEROIDS Historically, corticosteroids represent the first family of drugs used for clinical immunosuppression. Today steroids remain an integral component of most immunosuppressive protocols, and often are the first-line agents in the treatment of acute rejection. Despite their proven benefit, steroids have significant side effects, especially with long-term use. Hence, there has been considerable interest recently in withdrawing steroids from long-term maintenance protocols. The newer immunosuppressive agents may make doing so possible. Steroids have both anti-inflammatory and immunosuppressive properties as the two are closely related. Their effects on the immune system are complex. Although they have been used clinically for years, their exact mechanism of action is not fully understood. Primarily, they inhibit the production of T-cell lymphokines, which are needed to amplify macrophage and lymphocyte responses. Steroids also have a number of other immunosuppressive effects that are not as specific. For example, they cause lymphopenia secondary to the redistribution of lymphocytes from the vascular compartment back to lymphoid tissue, inhibit migration of monocytes, and function as anti-inflammatory agents by blocking various permeability-increasing agents and vasodilators. Steroids in high doses are the first-line choice of many clinicians for the initial treatment of acute cellular rejection. Steroids also are an integral part of most maintenance immunosuppressive regimens. High-dose IV steroids usually are administered immediately posttransplant as induction therapy, followed by relatively high-dose oral steroids (e.g., prednisone at 30 mg/d in adults), tapering to the maintenance dose of 5 to 15 mg/d over 3 to 6 months. Adverse effects of steroid therapy are numerous and contribute significantly to morbidity in transplant recipients.1 3 Individual response varies markedly, but many of the side effects are dose dependent. Common side effects include mild cushingoid facies and habitus, acne, increased appetite, mood changes, hypertension, proximal muscle weakness, glucose intolerance, and impaired wound healing. Less common are posterior subcapsular cataracts, glaucoma, and aseptic necrosis of the femoral heads. High-dose steroid use, such as bolus therapy for treatment of acute rejection, increases the risk of opportunistic infections, osteoporosis, and in children, growth retardation. These serious side effects have fueled the current interest in withdrawing patients from steroids within a few months posttransplant, or avoiding steroids altogether. Promising results with steroid withdrawal and avoidance protocols have been reported with the different organ types.14,15 Most recent studies have concentrated on complete steroid avoidance or rapid steroid discontinuation (usually within 1 week posttransplant) rather than steroid withdrawal after 3 to 6 months posttransplant. Success rates as measured by acute rejection rates generally have been better with the former approaches. Additionally, many of the steroid-related side effects occur early, and so much of the benefit of steroid-free regimens may be lost with a withdrawal regimen. Rapid discontinuation or complete avoidance of steroids has been associated with equivalent or superior results with regard to acute rejection rates compared to steroid maintenance groups, but with significantly less steroid-related and infectious complications.

AZATHIOPRINE An antimetabolite, AZA is a derivative of 6-mercaptopurine, the active agent. It was first introduced for clinical immunosuppression in 1962; in combination with corticosteroids, it became the standard agent worldwide for the next two decades. Until the introduction of cyclosporine, it was the most widely used immunosuppressive drug, but now has become an adjunctive component of immunosuppressive drug regimens. With the introduction of newer agents such as mycophenolate mofetil (MMF), the use of AZA has decreased significantly, and may be discontinued

altogether in the near future. AZA acts late in the immune process, affecting the cell cycle by interfering with DNA synthesis, thus suppressing proliferation of activated B and T lymphocytes. AZA is valuable in preventing the onset of acute rejection, but is not effective in the treatment of rejection episodes themselves. The most significant side effect of AZA is bone marrow suppression. All three hematopoietic cell lines can be affected, leading to leukopenia, thrombocytopenia, and anemia. Suppression often is dose related; it usually is reversible with dose reduction or temporary cessation of the drug. Other significant side effects include hepatotoxicity, GI disturbances (nausea and vomiting), pancreatitis, and alopecia.

CYCLOSPORINE The introduction of cyclosporine in the early 1980s dramatically altered the field of transplantation.16–18 It significantly improved results after kidney transplants, but its greatest impact was on extrarenal transplants. When it was introduced, cyclosporine was the most specific immunosuppressive agent available. Compared with steroids or AZA, it much more selectively inhibits the immune response. Currently, cyclosporine plays a central role in maintenance immunosuppression in many types of organ transplants. Cyclosporine binds with its cytoplasmic receptor protein, cyclophilin, which subsequently inhibits the activity of calcineurin. Doing so impairs expression of several critical T-cell activation genes, the most important being for IL2. As a result, T-cell activation is suppressed. The metabolism of cyclosporine is via the cytochrome P-450 system, therefore several drug interactions are possible. Inducers of P-450 such as phenytoin decrease blood levels; drugs such as erythromycin, cimetidine, ketoconazole, and fluconazole increase them. Adverse effects of cyclosporine can be classified as renal or nonrenal. Nephrotoxicity is the most important and troubling adverse effect of cyclosporine. Cyclosporine has a vasoconstrictor effect on the renal vasculature. This vasoconstriction (likely a transient, reversible, and dose-dependent phenomenon) may cause early posttransplant graft dysfunction or may exaggerate existing poor graft function. Also, long-term cyclosporine use may result in interstitial fibrosis of the renal parenchyma, coupled with arteriolar lesions. The exact mechanism is unknown, but renal failure may eventually result. A number of nonrenal side effects may also be seen with the use of cyclosporine. Cosmetic complications, most commonly hirsutism and gingival hyperplasia, may result in considerable distress, possibly leading to noncompliant behavior. Several neurologic complications, including headaches, tremor, and seizures, also have been reported. Other nonrenal side effects include hyperlipidemia, hepatotoxicity, and hyperuricemia.

TACROLIMUS Tacrolimus (FK506) is a metabolite of the soil fungus Streptomyces tsukubaensis , found in Japan. Released in the United States in April 1994 for use in liver transplantation, it is currently used in a fashion similar to cyclosporine. Tacrolimus, like cyclosporine, is a calcineurin inhibitor and has a very similar mechanism of action. Cyclosporine acts by binding cyclophilins, while tacrolimus acts by binding FK506-binding proteins (FKBPs). The tacrolimus-FKBP complex inhibits the enzyme calcineurin, which is essential for activating transcription factors in response to the rise in intracellular calcium seen with stimulation of the TCR. The net effect of tacrolimus is to inhibit T-cell function by preventing synthesis of IL-2 and other important cytokines. The main difference between tacrolimus and cyclosporine, other than the actual immunophilin each binds to, is in relative potency: Tacrolimus is 100 times more potent than cyclosporine on a molar basis. Similarly to cyclosporine, tacrolimus primarily is metabolized by the P-450 enzyme system of the liver; therefore similar drug interactions occur.

Adverse effects of tacrolimus and cyclosporine are similar. The most common problems include nephrotoxicity, neurotoxicity, impaired glucose metabolism, hypertension, infection, and GI disturbances. Nephrotoxicity is dose related and reversible with dose reduction. Neurotoxicity seen with tacrolimus ranges from mild symptoms (tremors, insomnia, and headaches) to more severe events (seizures and coma); it usually is related to high levels and resolves with dose reduction. These side effects are most common early posttransplant and subsequently tend to decrease in incidence. The hyperglycemic effect of tacrolimus does not appear to be dose related. Its cause is unknown. However, in most studies, its incidence is significantly higher with tacrolimus than with cyclosporine. Other common side effects involve the GI tract, ranging from mild cramps to severe diarrhea. Hypertension, hypercholesterolemia, and hypomagnesemia occur with equal frequency with tacrolimus. As with other immunosuppressive drugs, infection and malignancy remain the most serious, long-term adverse events.

SIROLIMUS A macrolide antibiotic derived from a soil actinomycete originally found on Easter Island (Rapa Nui), sirolimus (previously known as rapamycin ) is structurally similar to tacrolimus and binds to the same immunophilin (FKBP). Unlike tacrolimus, it does not affect calcineurin activity, and therefore does not block the calcium-dependent activation of cytokine genes. Rather, the active complex binds so-called target of rapamycin proteins (Fig. 11-2), resulting in inhibition of P7056 kinase (an enzyme linked to cell division). The net result is to prevent progression from the G 1 to the S phase of the cell cycle, halting cell division.

Fig. 11-2.

Sites of action of immunosuppressive drugs. APC = antigen-presenting cell; CTLA4-Ig = cytotoxic T-lymphocyte-associated protein 4 immunoglobulin; IL = interleukin; MMF = mycophenolate mofetil; MAb = monoclonal antibody; mTOR = mammalian target of rapamycin; T-H Cell = helper T cell.

To date, sirolimus has been used in a variety of combinations and situations. It may be used in conjunction with

one of the calcineurin inhibitors. In such combinations, sirolimus usually is used to help withdraw or avoid the use of steroids completely in maintenance immunosuppressive regimens. It also has been used as an alternative to tacrolimus or cyclosporine, as part of a calcineurin-sparing protocol.1 9 The advantage of this type of protocol is that it may not be associated with long-term nephrotoxicity (as may be seen with the calcineurin agents). Hence, sirolimus may prove to be better for long-term preservation of renal function in transplant recipients. The major side effects of sirolimus include neutropenia, thrombocytopenia, and a significant elevation of the serum triglyceride and cholesterol levels. It also has been associated with impaired wound healing, leading to a higher incidence of wound-related complications.

MYCOPHENOLATE MOFETIL MMF was approved in May 1995 by the FDA for use in the prevention of acute rejection after kidney transplants. It since has been rapidly incorporated into routine clinical practice at many centers as part of maintenance regimens.2 0 A semisynthetic derivative of mycophenolate acid, it is isolated from the moldPenicillium glaucum . It works by inhibiting inosine monophosphate dehydrogenase, which is a crucial, rate-limiting enzyme in de novo synthesis of purines. Specifically, this enzyme catalyzes the formation of guanosine nucleotides from inosine. Many cells have a salvage pathway and therefore can bypass this need for guanosine nucleotide synthesis by the de novo pathway. Activated lymphocytes, however, do not possess this salvage pathway and require de novo synthesis for clonal expansion. The net result is a selective, reversible antiproliferative effect on T and B lymphocytes. MMF differs from cyclosporine, tacrolimus, and sirolimus in that it does not affect cytokine production or the events immediately after antigen recognition. Rather, MMF works further distally in the chain of activation events to prevent proliferation of the stimulated T cell (see Fig. 11-2). Like AZA, it is an antimetabolite; unlike AZA, its impact is selective: It only affects lymphocytes, not neutrophils or platelets. In several clinical trials, it has proven to be more effective than AZA, and has largely replaced it. The incidence and types of adverse events with MMF are similar to those seen with AZA. Notable exceptions are GI side effects (diarrhea, gastritis, and vomiting), which are more common with MMF. Clinically, significant leukopenia also is more common, affecting about one third of recipients. Dose reduction or temporary drug cessation usually is adequate to treat leukopenia (Table 11-3).

Table 11-3 Side Effects and Drug Interactions of the Main Immunosuppressive Drugs Cyclosporine (CSA) Hypertension, nephrotoxicity, hirsutism, neurotoxicity, gingival hyperplasia Verapamil, clarithromycin, doxycycline, azithromycin, erythromycin, fluconazole, itraconazole, ketoconazole Isoniazid, carbamazepine, phenobarbital, phenytoin, rifampin Nephrotoxicity: Acyclovir, ganciclovir, aminoglycosides, NSAIDs Tacrolimus (FK506) Hypertension, nephrotoxicity, hyperglycemia, neurotoxicity Verapamil, clarithromycin, doxycycline, azithromycin, erythromycin, fluconazole, itraconazole, ketoconazole Isoniazid, carbamazepine, phenobarbital, phenytoin, rifampin Nephrotoxicity: Acyclovir, ganciclovir, aminoglycosides, NSAIDs Sirolimus Thrombocytopenia and nutropenia, elevated cholesterol, extremity edema, impaired wound healing — — —

Mycophenolate mofetil Leukopenia, thrombocytopenia, GI upset — Cholestyramine, antacids — Corticosteroids Hyperglycemia, osteoporosis, cataracts, myopathy, weight gain — — — Azathioprine Leukopenia, anemia, thrombocytopenia, GI upset — — Bone marrow suppression: Allopurinol, sulfonamides Common Side Effects

Other Medications That Increase Blood Levels

Other Medications That Decrease Blood Levels

Other Medications That Potentiate Toxicity

Biologic Immunosuppression Polyclonal antibodies directed against lymphocytes have been used in clinical transplantation since the 1960s. Monoclonal antibody (mAb) techniques were later developed and, in turn, allowed for the development of biologic agents such as muromonab-CD3 (OKT3), which were targeted to specific subsets of cells. A number of different mAbs are currently under development or have entered the phase of clinical testing for use in transplantation. Many are directed against functional secreted molecules of the immune system or their receptors, rather than against actual groups of cells.

POLYCLONAL ANTIBODIES Polyclonal antibodies are produced by immunizing animals such as horses or rabbits with human lymphoid tissue, allowing for an immune response, removing the resultant immune sera, and purifying the sera in an effort to remove unwanted antibodies. These lymphocyte-depleting antibodies are potent suppressors of the T-cell mediated immune response and selectively prevent the activation of B-cells by a range of stimuli. Polyclonal antibodies have been successfully used as induction agents to prevent rejection and to treat acute rejection episodes.

Antithymocyte Globulin Antithymocyte globulin (ATGAM) is a purified gamma globulin solution obtained by immunization of horses with human thymocytes. It contains antibodies to a wide variety of human T-cell surface antigens, including the MHC antigens. ATGAM generally must be infused via a central vein because infusion into a peripheral vein often is associated with thrombophlebitis. To avoid allergic reactions, patients should be premedicated with methylprednisolone and diphenhydramine hydrochloride. Even so, side effects may be significant because of the large amount of foreign protein. Symptoms of cytokine release syndrome include fever, chills, arthralgia, thrombocytopenia, leukopenia, and a serum sickness-like illness.

Thymoglobulin Antithymocyte immunoglobulin (Thymoglobulin) is a polyclonal antibody obtained by immunizing rabbits with human thymocytes. It has been approved by the FDA to prevent and treat rejection in solid organ transplant

recipients. Multicenter randomized studies comparing antithymocyte immunoglobulin (Thymoglobulin) vs. ATGAM as induction therapy have shown that at 1-year posttransplant, there was less incidence and severity of rejection in antithymocyte immunoglobulin treated patients.2 1 Five-year follow-up studies have shown that this is sustained long term. Safety profile comparison shows a higher incidence of leukopenia with antithymocyte immunoglobulin, although the rate of cytomegalovirus (CMV) infection seems to be lower. Some data suggest that antithymocyte immunoglobulin may be associated with an increased risk of posttransplant lymphoproliferative disorder (PTLD) compared with no induction, but more studies are needed for confirmation.2 2 Comparison studies with muromonab-CD3 showed that muromonab-CD3 reversed a slightly higher number of rejection episodes than antithymocyte immunoglobulin in renal transplant recipients, but that both were efficient treatments; first-time use of antithymocyte immunoglobulin was associated with fewer side effects than muromonab-CD3.

MONOCLONAL ANTIBODIES mAbs have emerged as a new class of immunosuppressive agents, which appear to be effective in both the treatment and prevention of acute rejection and are well tolerated in renal transplant recipients. 2 3 mAbs are produced by the hybridization of murine antibody-secreting B-lymphocytes with a nonsecreting myeloma cell line. The highly specific nature of these drugs makes them less toxic than the oral, long-term maintenance agents such as corticosteroids and calcineurin inhibitors. Muromonab-CD3 remains a commonly used mAb but some of the new mAbs already have confirmed their efficacy in clinical phase III trials and are part of well-established immunosuppressive regimens. These include anti-CD25 mAbs (basiliximab and daclizumab). Other recently developed mAbs, like humanized anti-CD52 mAb alemtuzumab (Campath-1H), anti-CD20 (rituximab), anti–lymphocyte function-associated antigen-1 (anti–LFA-1), anti–intercellular adhesion molecule-1 (anti–ICAM-1) and anti–tumor necrosis factor alpha (TNF- ) (infliximab) currently are being tested and show encouraging immunosuppressive potential.

Muromonab-CD3 This MoAb is directed against the CD3 antigen complex found on all mature human T cells. The CD3 complex is an integral part of the TCR. Inactivation of CD3 by muromonab-CD3 causes the TCR to be lost from the cell surface. The T cells are then ineffective, and are rapidly cleared from the circulation and deposited into the reticuloendothelial system. The standard dose is 5 mg/d, given IV. Smaller doses may be just as effective. Efficacy can be measured by monitoring CD3+ cells in the circulation. If the drug is effective, the percentage of CD3+ cells should fall to and stay below 5%. Failure to reach this level indicates an inadequate dose or the presence of antibodies directed against muromonab-CD3. Muromonab-CD3 is highly effective and versatile. Most commonly, it is used to treat severe acute rejection episodes (i.e., those resistant to steroids). Muromonab-CD3 also has been used as prophylaxis against rejection, as induction therapy, and as primary rejection treatment. Significant, even life-threatening adverse effects may be seen with muromonab-CD3, most commonly with the first few doses. Because muromonab-CD3 is a T-cell mitogen, most of these symptoms are thought to be mediated by T-cell release of cytokines via CD3 binding. The most common symptoms are fever, chills, and headaches. Muromonab-CD3's most serious side effect is a rapidly developing, noncardiogenic pulmonary edema. The risk of this side effect significantly increases if the patient is fluid-overloaded before beginning muromonab-CD3 treatment. Other serious side effects include encephalopathy, aseptic meningitis, and nephrotoxicity. Use of muromonab-CD3, especially multiple courses, significantly increases the risk of infection (e.g., CMV) and of

neoplasms (e.g., PTLD). To reduce the side effects and the antigenicity of murine muromonab-CD3, a nonmitogenic "humanized" variant has been developed. Both in vitro and in vivo studies have found that the humanized variant of muromonab-CD3 does not activate human T cells, but retains significant immunosuppressive properties. The drug was well tolerated with minimal first-dose reactions (including lack of IL-2 release); induction of antibodies against muromonab-CD3 was not observed. Because it is less immunogenic, its half-life is much longer than that of conventional muromonab-CD3.

Anti-CD25 Monoclonal Antibodies (Basiliximab and Daclizumab) The alpha subunit of the IL-2 receptor, also known as Tac or CD25 is found exclusively on activated T cells. Blockade of this component by mAbs selectively prevents IL-2–induced T-cell activation. This selectivity makes the anti-CD25 mAbs powerful antirejection agents with no significant added risks of infection, malignancy, or other major side effects. There are two types of anti-CD25 mAbs: chimeric (approximately 75% human and 25% murine protein) and humanized (approximately 90% human and 10% murine). Basiliximab (Simulect) and daclizumab (Zenapax) are currently the two anti-CD25 mAbs approved for clinical use. They are used as part of induction immunosuppression in renal transplantation, in association with calcineurin inhibitors, corticosteroids, and MMF. A randomized, double-blind, placebo-controlled phase III trial was done comparing daclizumab vs. no induction in renal patients receiving their first cadaveric kidney transplant who received triple immunosuppression of cyclosporine, AZA, and prednisolone.2 4 In the daclizumab group, fewer patients developed rejection during the first 6 months after transplantation, time to develop rejection was longer, and the numbers of rejection episodes were lower. Moreover, infusion of the antibody was not associated with any adverse reactions. There also was no difference in infection or cancer rates between the two groups. A comparable study also has been published using basiliximab in renal transplantation.2 5

Anti-CD52 Monoclonal Antibody Alemtuzumab (Campath-1h) Alemtuzumab (Campath-1H) is a humanized rat mAb (rat Ig G2b) directed against the CD-52 antigen. It is a powerful cytolytic agent and has been used therapeutically in bone marrow transplantation, several autoimmune diseases, and organ transplantation.2 6 The CD52 antigen is expressed on T and B lymphocytes, monocytes, macrophages, and eosinophils, as well as on the lining of the male reproductive tract. It is one of the most abundant antigens on the surface of lymphocytes, accounting for approximately 5% of the surface antigens. This probably explains, in part, the profound and long-lasting lymphopenia produced after the administration of one or two doses of the antibody; these depressed lymphocyte levels may take months to years to return to normal levels. For example, two doses of alemtuzumab, 40 mg in total, given over 2 days in patients receiving a kidney transplant produce profound lymphopenia. Although B-lymphocyte counts return to normal levels within 3 to 12 months, CD4+ and CD8+ lymphocyte counts remain significantly depressed for as long as 3 years. After binding to its target, alemtuzumab causes cell death through several mechanisms, including complement-mediated cytolysis, antibody-mediated cytotoxicity, and apoptosis. The most extensive experience with the use of alemtuzumab in solid organ transplantation has been in renal transplantation. It has been used in induction and maintenance therapy and treatment of acute rejection. Randomized trials comparing alemtuzumab with antithymocyte immunoglobulin found that there was no difference in patient or graft survival, acute rejection rates, or renal function; nor were there any differences in infections or incidence of diabetes or hyperlipidemia. As with all antibody treatments, there is an initial reaction with alemtuzumab administration. However, it is relatively modest and suppressed with an IV bolus injection of 1 g of methylprednisolone before administration of the antibody. Because of the long-lasting T-cell depletion, there is still concern regarding the risk of infection. An interesting observation is the occurrence of autoimmune disorders in the

form of autoimmune hypothyroidism and autoimmune hemolytic anemia in rare patients treated with alemtuzumab. There is a need for large, prospective randomized control trials and long-term follow-up to establish the true role of alemtuzumab especially with respect to safety.

Anti-CD20 (Rituximab) CD20 (human B-lymphocyte-restricted differentiation antigen, Bp35), is a protein which is located on pre-B and mature B lymphocytes. The antigen is expressed on most B-cell non-Hodgkin's lymphomas but is not found on stem cells, pro-B cells, normal plasma cells, or other normal tissues. It regulates an early step in the activation process for cell cycle initiation and differentiation, and possibly functions as a calcium ion channel. Rituximab, a chimeric murine/human mAb, approved in the United States only for the treatment of refractory or relapsed B-cell lymphomas, reacts with the CD20 antigen.2 7 In transplant recipients, it is used for treatment of posttransplant lymphoproliferative disease, to anecdotally reduce preformed anti-HLA and anti-ABO antibodies, and for the prevention and treatment of acute humoral rejection. A need for controlled clinical trials clearly is needed to determine the best clinical situation in which to use this agent.

Monoclonal Antibodies to Adhesion Molecules Adhesion molecules play a dual role in graft injury posttransplant. Initial ischemic reperfusion injury is characterized by a cellular infiltrate in the graft. This migration of cells into the graft is regulated by the endothelium, which recruits the infiltrating cells by expressing adhesion molecules on its surface. Adhesion molecules, such as the LFA-1: ICAM-1 receptor ligand pair also participate in subsequent antigen-dependent T-cell activation. When the TCR comes into contact with its target antigen, LFA-1 binds to ICAM-1 on the antigenpresenting cell (APC) surface. This binding then potentiates T-cell activation by stabilizing TCR binding to its target and transmitting amplifying signals to the cytoplasm. Therefore, mAb directed against adhesion molecules could simultaneously interrupt both the effect of ischemic injury and the alloresponse. This potential dual effect currently is being evaluated in laboratory and clinical studies. Comparisons of the mAb directed against the alpha chain of LFA-1 (odulimomab) with antithymocyte immunoglobulin as induction therapy found, at 3 and 12 months after transplantation, similar rate and severity of rejection episodes as well as incidence of infection. An anti–LFA-1 mAb (efalizumab) was found capable of inhibiting lymphocyte adhesion, circulation, and activation. Another potential benefit of anti-LFA mAbs observed in both animal models and human beings is that they can diminish the ischemia-reperfusion injury associated with delayed graft function. The anti-CD4 mAb (priliximab) already has shown immunosuppressive potential in some therapeutic pilot studies. However, in another clinical trial, this mAb, although well tolerated, was associated with a high acute rejection rate (50% of patients developed an acute rejection episode within the first 3 months), probably because of poor drug bioavailability or possibly because of anti-murine antibody development. Due to these conflicting results, anti-CD4 mAbs are not recommended for clinical use at this time. Costimulatory blockade with anti-CD154 mAb prolongs allograft survival in nonhuman primates; but in clinical transplantation, the rejection rate has been unacceptably high and can have serious side effects, particularly thromboembolism, mediated probably by platelet activation leading to enhanced aggregation. Belatacept: The best-characterized pathway of T-cell costimulation includes CD28, its homologue cytotoxic Tlymphocyte-associated protein 4 (CTLA4), and their ligands CD80 and CD86. CTLA4-Ig (abatacept) is a fusion protein consisting of the extra cellular domain of CTLA4 and the Fc domain of IgG. Two amino acid substitutions to this protein resulted in the development of LEA29Y or belatacept, a high-avidity molecule with slower dissociation rates.28,29 A phase II, randomized multicenter study was done based on costimulation blockade with belatacept in

renal transplantation. Renal transplant recipients were randomly assigned to receive an intensive or a less intensive regimen of belatacept or cyclosporine. All patients received induction therapy with basiliximab, MMF, and corticosteroids. The study showed that the rate of acute rejection was similar among the groups: 6% for intensive belatacept, 6% for less intensive belatacept, and 8% for cyclosporine. Subclinical rejection at routine biopsy in 6 months was more common with less intensive belatacept (20%) than with intensive belatacept (9%) or cyclosporine (11%). At 12 months, glomerular filtration rate was significantly higher with both intensive and less intensive belatacept than those treated with cyclosporine (66.3, 62.1, and 53.5 mL/min per 1.73 m2 , respectively), and chronic allograft nephropathy was less common with both regimens of belatacept than with cyclosporine (29%, 20%, and 44%, respectively). Lipid levels and blood pressure values were similar or slightly lower in the belatacept groups. The frequency of infection was similar in all three groups, around 75%. Cancers occurred in two patients treated with intensive belatacept (one breast cancer and one PTLD) and in two patients treated with cyclosporine (one skin cancer and one thyroid cancer). However, PTLD developed in two additional patients treated with the intensive regimen 2 and 13 months after replacement of belatacept with conventional immunosuppressive agents. As belatacept interacts with the CD28 pathway, there were no reports of thrombotic complications seen with intervention in the CD40: CD154 pathway. Belatacept did not appear to affect the number or activity of T regulatory cells and clinical monitoring of lymphocytes did not reveal any depleting effects. These findings suggest that belatacept acts by depleting initial T-cell activation rather than selective depletion or complement-mediated lysis. Although these results are exciting, they are preliminary, and the long-term implications can only be known with larger studies and longer-term observation.

New Agents 1. AEB: This is a new oral compound that effectively blocks early T-cell activation by selective inhibition of protein kinase C. Therefore, it has a different mechanism of action from that of calcineurin inhibitors, and early studies suggest it is not associated with the nephrotoxicity seen with calcineurin inhibitors. This agent is currently in phase II testing. 2. ISA247: This is a novel semisynthetic analogue of cyclosporine that is structurally similar to it except for a modification of a functional group. This agent has not been associated with the nephrotoxicity seen with cyclosporine and currently is in phase II testing. 3. Janus kinase-3 (JAK-3) inhibitors: JAKs are cytoplasmic tyrosine kinases that participate in the signaling of a broad range of cell surface receptors, particularly members of the cytokine receptor superfamily. JAK-3 is found primarily on hematopoietic cells and blocking this may provide a significant degree of selectivity in immunosuppression. It is currently in phase II trials.

ORGAN PROCUREMENT AND PRESERVATION The biggest problem facing transplant centers today is the shortage of organ donors. Mechanisms that might increase the number of available organs include: (a) Optimizing the current donor pool (e.g., the use of multiple organ donors or marginal donors); (b) increasing the number of living-donor transplants (e.g., the use of living unrelated donors); (c) using unconventional and controversial donor sources (e.g., using deceased donors without cardiac activity or anencephalic donors); and (d) performing xenotransplants. The largest potential increase in the number of available organs would result from improving donation rates from suitable deceased donors. By recent estimates, over 10,000 brain-dead donors are potentially available in the United States annually. Currently, however, only about one half of them are actually used. The single most important reason for the lack of deceased-

donor organ retrieval is the inability to obtain consent from the surviving next-of-kin. The need for public education is crucial, including more effective educational campaigns to increase awareness of the importance of organ transplants.

Deceased Donors Most extrarenal transplants performed today, and roughly one half of all renal transplants, are from deceased donors. These donors are deceased individuals who meet the criteria for brain death, but whose organs are being perfused by life-support measures, allowing adequate time for referral to an organ procurement organization. A member of that organization can then ascertain whether donation is possible, and if so, approach the potential donor's family and possibly obtain consent to procure suitable organs. Crucial to the concept of deceased-donor organ donation is the concept of brain death. Brain death means that all brain and brain stem function has irreversibly ceased, while circulatory and ventilatory functions are maintained temporarily. The clinical diagnosis of brain death rests on three criteria: (a) irreversibility of the neurologic insult; (b) absence of clinical evidence of cerebral function; and most important, (c) absence of clinical evidence of brain stem function. When testing for brain death, hypothermia, medication side effects, drug overdose, and intoxication must be excluded. Brain death can be diagnosed by routine neurologic examinations (including cold caloric and apnea testing on two separate occasions at least 6 hours apart), coupled with prior establishment of the underlying diagnosis. Confirmatory tests must verify the absence of intracranial blood flow on brain flow studies or the presence of an isoelectric electroencephalogram reading. Once the diagnosis of brain death has been established, the process of organ donation can be initiated.30,31 The focus then switches from the treatment of elevated intracranial pressure (ICP) to preserving organ function and optimizing peripheral oxygen delivery.3 2 It is important to keep in mind that management of the deceased organ donor is an active process, requiring aggressive monitoring and intervention to ensure that perfusion to the organs of interest is not compromised. For all organ donors, core temperature, systemic arterial blood pressure, arterial oxygen saturation, and urine output must be determined routinely and frequently. Arterial blood gases, serum electrolytes, blood urea nitrogen, serum creatinine, liver enzymes, hemoglobin, and coagulation tests also need to be monitored regularly. Hemodynamic instability can be marked after brain death, with wide swings between the extremes of hypotension and hypertension. Hypotension is usually secondary to hypovolemia, due to a combination of vasomotor collapse after brain death and the effects of treatment protocols to decrease ICP. Hypertension may also be seen, often secondary to raised ICP. It can be treated with short-acting vasodilatory agents or with rapidly reversible beta blockers. Other key factors in donor management include respiratory maintenance, good renal perfusion with brisk urine output, and avoidance of hypothermia. Surgical technique: The technique of multiple organ procurement (kidney, liver, pancreas, small bowel) was first described by Starzl and his colleagues in 1984.3 3 Most centers have now added their own modifications to these pioneering techniques and differ primarily on their degree of in vivo dissection. Some centers perform extensive dissection of the organs to be recovered before flushing the organs with preservative solution. Other centers prefer to flush the organs early, remove the abdominal contents "en-bloc," and perform the separation and dissection of the individual organs on the back table.3 4 Each technique has its potential advantages and disadvantages. Regardless of personal technique and preference, it is paramount that the transplant surgeon develops a systematic approach to safely procure the liver, pancreas, and kidneys even in the unstable donor. The basic steps involve a long incision to provide wide exposure of all thoracic and abdominal organs (Fig. 11-3).

Complete mobilization of the distal small bowel, right colon, and duodenum is performed to allow for identification of the distal aorta, iliac bifurcation, and the distal inferior vena cava (IVC). The infrarenal aorta will serve as the site for insertion of the cannula that will allow for flushing of the organs with cold preservative solution (Fig. 11-4). The supraceliac aorta is encircled followed by limited dissection of the hepatic hilum and the pancreas. The portal system can be cannulated via the inferior mesenteric vein and the organs can then be flushed with preservative solution and topically cooled with slush. The thoracic organs, liver, pancreas, and kidneys are then removed individually.

Fig. 11-3.

Incision for multiorgan abdominal procurement with wide exposure of all abdominal organs.

Fig. 11-4.

A and B. With the small bowel and right colon completely mobilized, the infrarenal aorta can be isolated for insertion of the cannula that will allow the organs to be flushed with cold preservative solution. Black arrow = aorta; blue arrow = inferior vena cava (IVC); yellow arrow = cannula insertion site.

Donation after cardiac death: The non–heart-beating donor (NHBD), also referred to as the donation after cardiac death donor, is one type of expanded criteria donor that is increasingly being used by transplant centers to successfully boost the number of deceased donors and decrease the dire shortage of transplantable organs.3 5 NHBD death is characterized by irreversible absence of circulation, in contrast to heart-beating donor death, defined by irreversible cessation of all brain functions. Organ ischemia is minimized in the brain-dead donor because circulatory arrest typically occurs concurrently with perfusion of preservation solution and rapid core cooling. NHBDs are less than ideal because the organs suffer ischemia during the prolonged periods between circulatory dysfunction, circulatory arrest, and subsequent perfusion and cooling. Furthermore, the surgical procedure for NHBD organ recovery is demanding and rushed. It is important to differentiate controlled from uncontrolled NHBDs. Uncontrolled NHBDs sustain circulatory arrest and either fail to respond to cardiopulmonary resuscitation and/or are declared dead on arrival to the hospital. Uncontrolled NHBD death is unplanned, so the organs suffer protracted ischemia before recovery. Although kidneys tolerate a short period of the resultant warm ischemia, transplantation of extrarenal organs from uncontrolled

NHBDs carries a much greater risk. In contrast, controlled NHBDs undergo circulatory arrest following planned withdrawal of life support, most often in the operating room, with a donor surgical team readily available. Controlled NHBDs suffer terminal illness, usually a severe neurologic injury without the possibility of meaningful recovery or survival. Controlled NHBDs provide organs that are exposed to significantly less ischemic damage than those of uncontrolled NHBDs and, in general, offer superior posttransplant function when compared with uncontrolled NHBDs.

Living Donors Living-donor transplantation is unique in that surgeons are operating on a healthy individual (i.e., a living donor) who has no medical disorders and does not require an operation. The use of living donors is an integral and important part of the field of transplantation today. The first transplants ever performed used living donors. Today, living donors are commonly used for every type of transplant except heart transplants. The number of such transplants continues to increase on a yearly basis. But living-donor transplants pose a unique set of medical, ethical, financial, and psychosocial problems that must be dealt with by the transplant team. The use of living donors offers numerous advantages. Primary is the availability of a life-saving organ. A certain percentage of transplant candidates die while waiting for a deceased-donor organ as a direct result of a complication, or of progression of their underlying disease. For such ill candidates, the advantage of a living donor is obvious. In certain parts of the world, such as the Far East, where deceased-donor transplants are not accepted by the public, the advantage and need of the living donor is obvious. Even in countries where deceased-donor transplants are accepted, a living-donor transplant may significantly shorten the waiting time for potential recipients. A shorter waiting time generally implies a healthier candidate—one whose body has not been ravaged by prolonged end-stage organ failure. Moreover, living-donor transplants are planned (rather than emergency) procedures, allowing for better preoperative preparation of the potential recipient. Receiving an organ from a closely matched relative may also have immunologic benefits. Lastly, long-term results may be superior with livingdonor transplants, which is certainly the case with kidney transplants. The disadvantages of a living-donor transplant for the potential recipient are minimal. With some organ transplants (e.g., living-donor liver or lung), the procedure may be more technically complex, resulting in an increased incidence of surgical complications. However, this disadvantage is offset by the numerous advantages. The major disadvantage of living-donor transplants is to the donor. Medically, there is no possibility of benefit for the donor, only potential for harm. The risk of death associated with donation depends on the organ being removed. For nephrectomy, the mortality risk is estimated to be less than 0.05%. However, for partial hepatectomy, it is about 0.5%. Risks for surgical and medical complications also depend on the procedure being performed. In addition, long-term complications or problems may be associated with partial loss of organ function through donation. The guiding principle of all living-donor transplants should be the minimization of risk to the donor. What risk there is must be carefully explained to the potential donor, and written informed consent should be obtained. The kidney, the first organ to be used for living-donor transplants, is the most common type of organ donated by living donors today. Living-donor liver transplants are not as common, but have been performed for almost 15 years now. Initially, they involved adult donors and pediatric recipients, but now an adult donor for an adult recipient is more common. Living-donor transplants with organs besides the kidney and liver are fairly uncommon, but are performed at various centers. Living-donor pancreas transplants involve a distal pancreatectomy, with the graft consisting of the body and tail of the pancreas; vascular inflow and outflow are provided by the splenic artery

and splenic vein. Living-donor intestinal transplants usually involve removal of about 200 cm of the donor's ileum, with inflow and outflow provided by the ileocolic vessels. Living-donor lung transplants involve removal of one lobe of one lung from each of two donors; both grafts are then transplanted into the recipient.

Preservation Organ preservation methods have played an important role in the success of cadaver-donor transplants. They have resulted in improved graft function immediately posttransplant and have diminished the incidence of primary nonfunction of organs. By prolonging the allowable cold ischemia times, they have also allowed for better organ allocation and for safer transplants.36,37 The most common methods involve the use of hypothermia and pharmacologic inhibition to slow down metabolic processes in the organ once it has been removed from the deceased donor. Hypothermia very effectively slows down enzymatic reactions and metabolic activity, allowing the cell to make its limited energy reserves last much longer. A temperature decrease from 37 to 4C (98.6 to 39.2F) (the temperature of most preservation solutions) slows metabolism about 12-fold. However, in the absence of any energy inflow into the cell, degradative reactions begin to provide the cell with an energy source. The result can be destruction of important structural elements and, eventually, structural damage to the cells and the organ. So, although hypothermia greatly slows enzymatic reactions, they continue nonetheless, leading to accumulation of potentially detrimental end products within the cell. Hypothermia also contributes to the development of cellular swelling because the membrane ion pumps are slow to function. Cold storage solutions have been developed to improve organ preservation by ameliorating some of the detrimental effects of hypothermia alone. Essentially, these solutions suppress hypothermia-induced cellular swelling and minimize the loss of potassium from the cell. Agents that do not readily permeate the cell membrane and that have an electrolyte composition resembling the intracellular environment (low sodium, high potassium) are used, thus preventing the loss of cellular potassium. The most commonly used fluid worldwide is the University of Wisconsin solution.3 8 It contains lactobionate, raffinose, and hydroxyethyl starch. Lactobionate is impermeable and prevents intracellular swelling; it also lowers the concentration of intracellular calcineurin and free iron, which may be beneficial in reducing reperfusion injury. Hydroxyethyl starch, a synthetic colloid, may help decrease hypothermia-induced cell swelling of endothelial cells and reduce interstitial edema. Another solution that is now being used commonly is histidine-tryptophanketoglutarate solution.3 9 Although cold preservation has improved cadaver-donor transplant results, the amount of time that an organ can be safely preserved is limited. After that, the incidence of organ nonfunction starts to increase. With kidneys, exceeding the preservation time limit results in delayed graft function, requiring dialysis support for the recipient until function improves. With livers, the result is primary nonfunction, requiring an urgent retransplant. How long an organ can be safely preserved depends on the type of organ and on the condition of the donor. With kidneys, cold ischemic times should be kept below 36 to 40 hours; after that, delayed graft function significantly increases. With pancreata, more than 24 hours of ischemia increases problems due to pancreatitis and duodenal leaks. With livers, more than 16 hours of ischemia increases the risk for primary nonfunction and biliary complications. Hearts and lungs tolerate preservation poorly; ideally, ischemia times should be below 6 hours. With marginal donors, all of these times should be adjusted further downward.

KIDNEY TRANSPLANTATION

A kidney transplant now represents the treatment of choice for patients with end-stage renal disease (ESRD). It offers the greatest potential for restoring a healthy, productive life in most such patients. Compared with dialysis, it is associated with better patient survival and superior quality of life, and is more cost effective.40,41 Currently, there are nearly 70,000 patients in the United States awaiting a kidney transplant. Because of the success of the procedure, the waiting list has grown dramatically since the 1990s. Unfortunately, the number of available organs has not kept pace, resulting in longer waiting times for recipients.

History The history of kidney transplantation is in many ways the history of transplantation itself. The kidney was the first organ to be transplanted regularly, and it remains the most common organ transplanted today. The first clinical deceased-donor kidney transplant was performed in 1933 by Voronoy, a Ukrainian surgeon, with unsuccessful results secondary to rejection. In the 1950s, this immunologic barrier was circumvented by performing the kidney transplants between identical twins. The era of modern kidney transplantation began with the introduction of AZA to suppress the immune system. With the demonstration of the synergistic effect with glucocorticoids, renal transplantation was established as a viable option for the treatment of ESRD. Polyclonal antilymphocyte agents, such as antilymphocyte globulin, were soon developed, significantly contributing to the treatment of acute rejection. The introduction of cyclosporine in the 1980s significantly improved graft and patient survival rates, allowing for a dramatic increase in the number of kidney transplants.

Preoperative Evaluation Very few absolute contraindications to kidney transplants exist. Therefore, most patients with ESRD should be considered as potential transplant candidates. However, the surgery and general anesthesia impose a significant cardiovascular stress. Subsequent lifelong immunosuppression also is associated with some risk. Pretransplant evaluation should identify any factors that would contraindicate a transplant or any risk factors that could be minimized pretransplant.4 2 The preoperative evaluation can be divided into four parts: medical, surgical, immunologic, and psychosocial. The purpose of the medical evaluation is to identify risk factors for the surgical procedure. Mortality posttransplant usually is due to underlying cardiovascular disease, so a detailed cardiac evaluation is necessary. Any history of congestive heart failure, angina, myocardial infarction, or stroke should be elicited. Patients with symptoms suggestive of cardiovascular disease or with significant risk factors (e.g., diabetes, age over 50, previous myocardial infarction) should undergo further cardiac evaluation with stress testing or angiography. Any problems identified should be treated appropriately (medically or surgically) before proceeding with the transplant. Untreated malignancy and active infection are absolute contraindications to a transplant, because of the requisite lifelong immunosuppression. After curative treatment of malignancy, an interval of 2 to 5 years is recommended pretransplant. This recommendation is influenced by the type of malignancy, with longer observation periods for neoplasms such as melanoma or breast cancer and shorter periods for carcinoma in situ or low-grade malignancies such as basal cell carcinoma of the skin. Chronic infections such as osteomyelitis or endocarditis must be fully treated and a suitable waiting period must occur to ensure lack of recrudescence. The medical evaluation also should concentrate on GI problems such as peptic ulcer disease, symptomatic cholelithiasis, and hepatitis. Patients who demonstrate serologic evidence of hepatitis C or B, but without evidence of active hepatic inflammation or cirrhosis, are acceptable transplant candidates. A biopsy may be helpful to determine the extent of the underlying liver disease. These patients are at increased risk for progression of their underlying liver disease after receiving immunosuppression, but exhibit excellent long-term survival rates and

improved quality of life posttransplant, as compared with patients undergoing chronic dialysis. The surgical evaluation should identify vascular or urologic abnormalities that may contraindicate or complicate a transplant. Evidence of vascular disease that is revealed by the history (claudication or rest pain) or the physical examination (diminished or absent pulse or bruit) should be evaluated further by Doppler studies or angiography. Severe aortoiliac disease may make a transplant technically impossible; an option in such patients is a revascularization procedure such as aortobifemoral graft placement pretransplant. Areas of significant arterial stenosis proximal to the planned site of implantation may need preoperative balloon angioplasty. Urologic evaluation should exclude chronic infection in the native kidney, which may require nephrectomy pretransplant. Other indications for nephrectomy include huge polycystic kidneys, significant vesicoureteral reflux, or uncontrollable renovascular hypertension. Children especially require a complete urologic examination to evaluate reflux and bladder outlet obstruction. The immunologic evaluation involves determining blood type, tissue type (HLA-A, -B, or -DR antigens), and presence of any cytotoxic antibodies against HLA antigens (because of prior transplants, blood transfusions, or pregnancies). If a living-donor transplant is planned, a cross-match should be performed early on during the initial evaluation. The psychosocial evaluation is necessary to ensure that transplant candidates understand the nature of the transplant procedure and its attendant risk. They must be capable of rigorously adhering to the medical regimen posttransplant. Patients who have not been compliant with their medical regimen in the past must demonstrate a willingness and capability to do so before they undergo the transplant. Living-donor kidney transplant: One important aspect of the preoperative evaluation is the search for and evaluation of potential living donors. Living-donor kidney recipients enjoy improved long-term success, avoid a prolonged wait, and are able to plan the timing of their transplant in advance. Moreover, they have a significantly decreased incidence of acute tubular necrosis (ATN) and increased potential for HLA matching. As a result, livingdonor transplants generally have better short- and long-term results, as compared with deceased-donor transplants. Of course, the risks to the living donor must be acceptably low. The donor must be fully aware of potential risks and must freely give informed consent. The search for a living donor should not be restricted to immediate family members. Results with living, unrelated donors are comparable to those with living, related (non–HLA-identical) donors.4 3 Potential living donors are first evaluated to ensure that they have normal renal function with two equally functioning kidneys and that they do not have any significant risk factors for developing renal disease (e.g., hypertension or diabetes). The anatomy of their kidneys and the vasculature can be determined by using various radiologic imaging techniques, including an IV pyelogram, arteriogram, or computed tomographic (CT) angiogram. Which kidney is removed depends on the anatomy. If there is any minor abnormality in one kidney, that kidney should be removed. If both kidneys are the same, the left kidney is preferred because of the longer left renal vein. Nephrectomy can be performed through a flank incision, by an anterior retroperitoneal approach, or by a laparoscopic technique. With the laparoscopic technique, an intraperitoneal approach is used. This involves mobilization of the colon, isolation of the ureter and renal vessels, mobilization of the kidney, division of the renal vessels, and removal of the kidney (Fig. 11-5).

Fig. 11-5.

A through F. Hand-assisted laparoscopic donor nephrectomy for living-donor kidney transplant.

Recipient Surgical Procedure The surgical technique for kidney transplantation has changed very little from the original pelvic operation described in the 1950s. The transplanted kidney is usually placed in a heterotopic position, with no need for native nephrectomy except in select circumstances. Retroperitoneal placement is preferred, to allow for easy access for percutaneous renal biopsy. Usually, the right iliac fossa is chosen because of the more superficial location of the iliac vein on this side (Figs. 11-6 and 11-7). However, the left iliac fossa should be used if the recipient may be a candidate for a future pancreas transplant, if it is a second transplant, or if there is significant arterial disease on the right side.

Fig. 11-6.

Placement of incision for heterotopic kidney transplant in the right iliac fossa. The incision starts just above the pubic bone in the midline, curves up laterally, and then passes superiorly along the edge of the rectus muscle.

Fig. 11-7.

The incision is deepened along the lateral edge of the rectus muscle, identifying and dividing the epigastric vessels.

With the standard approach, the dissection is extraperitoneal. The iliac vessels are identified and assessed for suitability for anastomosis. The internal iliac artery can be used as the inflow vessel, with an end-to-end anastomosis, or the external iliac artery can be used with an end-to-side anastomosis. To minimize the risk of lymphocele formation after surgery, only a modest length of artery is dissected free and the lymphatics overlying the artery are ligated (Figs. 11-8 and 11-9). The donor renal vein is anastomosed end to side to the external iliac vein and the artery in a similar fashion to the iliac artery (Fig. 11-10).

Fig. 11-8.

The peritoneum is reflected medially to expose the retroperitoneal space.

Fig. 11-9.

The external iliac vessels are isolated in preparation for anastomosis to the renal vessels. Yellow arrow = external iliac artery; blue arrow = external iliac vein; dotted lines = planned site of arteriotomy and venotomy.

Fig. 11-10.

An end-to-side anastomosis of the renal artery to the external iliac artery is performed. Yellow arrow = external iliac artery.

After the vascular anastomosis is completed and the kidney perfused (Fig. 11-11), urinary continuity can be restored by a number of well-described techniques. The important principles are to attach the ureter to the bladder mucosa in a tension-free manner and to cover the distal 1 cm of the ureter with a submucosal tunnel, thus protecting against reflux during voiding (Figs. 11-11 and 11-12).

Fig. 11-11.

The clamps are removed, allowing the kidney to reperfuse.

Fig. 11-12.

A. Preparation of the bladder for the ureter anastomosis by division of the detrusor muscle (arrow ). B. Completion of the ureter (dashed lines ) to bladder anastomosis with closure of the detrusor muscle over the distal ureter to create an antireflux tunnel.

In approximately 10 to 15% of cases, there are multiple arteries to the kidney. Several options are possible for reconstruction in these cases, including implantation of the multiple vessels individually in the recipient (Fig. 1113A) or back table reconstruction onto the main donor renal artery to allow for one arterial anastomosis in the recipient (Fig. 11-13B).

Fig. 11-13.

Options for multiple renal arteries, including (A ) implantation of both arteries separately onto recipient iliac vessel (blue and yellow arrows ) or (B ) bench preparation of multiple vessels with end-to-side anastomosis to main donor renal artery.

Intraoperative care of kidney transplant recipients is not unlike that of other patients undergoing major surgical procedures. To decrease the incidence of ATN posttransplant, a liberal hydration policy is used intraoperatively. Adequate perfusion of the transplanted kidney is important to ensure postoperative diuresis. Central venous pressure (CVP) should be maintained around 10 mmHg, and systolic blood pressure should be greater than 120 mmHg. Maintaining adequate CVP is especially important in smaller, pediatric recipients because reperfusion of an adult-sized kidney graft may divert a significant amount of their own blood volume. Administering mannitol and furosemide just before reperfusion usually is helpful in maximizing perfusion to the kidney graft.

Early Postoperative Care The immediate postoperative care of all recipients involves (a) stabilizing the major organ systems (e.g., cardiovascular, pulmonary, and renal); (b) evaluating graft function; (c) achieving adequate immunosuppression; and (d) monitoring and treating complications directly and indirectly related to the transplant. Initially, hemodynamic stability is assessed, as with all postsurgical patients. Blood pressure, heart rate, and urine output are measured. CVP monitoring may be useful in guiding fluid replacement therapy. Achieving hemodynamic stability is important for the recipient's overall status, but it also is necessary to optimize graft function; hemodynamically unstable recipients experience poor perfusion of their kidney graft. Careful attention to fluid and electrolyte management is crucial. In general, recipients should be kept euvolemic or slightly hypervolemic. If initial graft function is good, fluid replacement can be regulated by hourly replacement of urine. Half-normal saline is a good solution to use for urine replacement. Aggressive replacement of electrolytes, including calcium, magnesium, and potassium, may be necessary, especially for recipients undergoing brisk diuresis. Those with ATN and fluid overload or hyperkalemia may need fluid restriction and even hemodialysis. Magnesium levels should be kept above 2 mEq/L to prevent seizures, and phosphate levels kept between 2 and 5 mEq/L for proper support of the respiratory and alimentary tracts. Marked hyperglycemia, which may be secondary to steroids, should be treated with insulin. Hypotension is unusual early after a kidney transplant. When it occurs, it is usually related to hypovolemia. The treatment is to optimize preload and afterload and, only if necessary, to use inotropic agents such as dopamine. Systemic hypertension is more common early posttransplant. If hypertension is catecholamine-mediated or an effect of immunosuppressive agents, it usually responds well to treatment with calcium channel blockers. However, if it is secondary to fluid overload, and if the recipient has poor kidney function, dialysis may be necessary. A critical aspect of postoperative care is the repeated evaluation of graft function, which in fact begins intraoperatively, soon after the kidney is reperfused. Signs of good kidney function include appropriate color and texture along with evidence of urine production. Postoperatively, urine output is the most readily available and easily measured indicator of graft function. Urine volume may range from none (anuria) to large quantities (polyuria). When using posttransplant urine volume to monitor graft function, the clinician should have knowledge of the recipient's pretransplant urine volume. If an individual was relatively anuric pretransplant, but then has normal urine output posttransplant, graft function is evident. However, if urine volume was significantly high pretransplant, normal urine output posttransplant does not necessarily mean good graft function; the urine may be from the native kidneys rather than from the graft. Laboratory values of obvious use in assessing graft function include serum blood urea nitrogen and creatinine levels. Recipients can be divided into three groups (by initial graft function as indicated by their urine output and serum creatinine) as those with (a) immediate graft function, characterized by a brisk diuresis posttransplant and rapidly

falling serum creatinine level; (b) slow graft function, characterized by a moderate degree of kidney dysfunction posttransplant, with modest amounts of urine and a slowly falling creatinine level, but no need for dialysis at any time posttransplant; and (c) delayed graft function, which represents the far end of the spectrum of posttransplant graft dysfunction and is defined by the need for dialysis posttransplant.4 4 Decreased or minimal urine output is a frequent concern posttransplant. Most commonly, it is due to an alteration in volume status. Other causes include a blocked urinary catheter, vascular thrombosis, a urinary leak or obstruction, early acute rejection, drug toxicity, or delayed graft function (Table 11-4). Early diagnosis is important, and begins with an assessment of the recipient's volume status. The urinary catheter is checked to exclude the presence of occlusion with clots or debris. Other diagnostic tests that may be warranted, depending on the suspected cause, include a Doppler ultrasound, nuclear medicine scan, or a biopsy.

Table 11-4 Causes of Increased Serum Creatinine Early after Kidney Transplant Hypovolemia Decreased CVP Check Hgb and CVP Rehydrate with appropriate fluids Decreasing urine output Low blood pressure Low Hgb if due to bleeding Vascular thrombosis Sudden drop in urine output Ultrasound with Doppler Re-explore for thrombectomy or nephrectomy Dark hematuria Tender, swollen graft Bladder outlet obstruction Clots in urinary catheter Distended bladder on examination or by ultrasound Irrigate or change bladder catheter Sudden drop in urine output Ureter obstruction — Euvolemic Do percutaneous nephrostogram Ultrasound showing hydroureter Drainage of lymphocele (if it is the cause of ureter obstruction) Possible lymphocele on ultrasound Drug toxicity High CSA or FK506 level

Check drug levels Decrease dosage of drugs Acute rejection May have risk factors such as low drug levels, high PRA Kidney biopsy Administer bolus steroid or antilymphocyte treatment Begin plasmapheresis (and IVIG if humoral rejection) Cause

Characteristics

Diagnosis

Treatment

CSA = cyclosporin A; CVP = central venous pressure; Hgb = hemoglobin; IVIG = intravenous immunoglobulin; PRA = panel reactive antibody.

Complications Monitoring for potential surgical and medical complications is important. Early diagnosis and appropriate intervention can minimize the detrimental impact on the graft and recipient. Potential complications that may occur early after surgery include hemorrhage, vascular complications, urologic complications, lymphocele, and several others.

HEMORRHAGE Bleeding is uncommon after a kidney transplant; usually it occurs from unligated vessels in the graft hilum or from the retroperitoneum of the recipient. A falling hematocrit level, hypotension, or tachycardia should raise the possibility of bleeding. Surgical exploration seldom is required because bleeding often tamponades. However, ongoing transfusion requirements, hemodynamic instability, and compression of the kidney by hematoma are all indications for surgical re-exploration.

VASCULAR COMPLICATIONS Vascular complications can involve the donor vessels (renal artery thrombosis or stenosis, renal vein thrombosis), the recipient vessels [iliac artery thrombosis, pseudoaneurysms, and deep venous thrombosis (DVT)], or both. Renal artery thrombosis usually occurs early posttransplant; it is uncommon, with an incidence of less than 1%. However, it is a devastating complication, usually resulting in graft loss. Typically, it occurs secondary to a technical problem such as intimal dissection or torsion of the vessels. Risk factors for thrombosis include hypotension, multiple renal arteries, unidentified injury to the intima of the artery, hyperacute rejection, unrelenting acute rejection, and a hypercoagulable state. Under these circumstances there is a sudden cessation of urine output. Diagnosis is made easily with color flow Doppler studies. Urgent thrombectomy is indicated, but most such grafts cannot be salvaged and require removal. Stenosis of the renal artery is a late complication and presents with evidence of graft dysfunction or hypertension. First-line treatment is with interventional radiologic techniques; surgery is reserved for stenosis that does not respond to this therapy. Renal vein thrombosis is not as common as its arterial counterpart, but again, graft loss is the usual end result. Causes include angulation or torsion of the vein, compression by hematomas or lymphoceles, anastomotic stenosis, and extension of an underlying DVT. Again, Doppler studies are the best diagnostic test. Urgent thrombectomy rarely is successful, and nephrectomy is usually required. Venous thromboembolic complications that affect the recipient vessels [DVT and pulmonary embolism (PE)] are not uncommon. The incidence of DVT is close to 5%; the

incidence of PE 1%. Identified risk factors include recipient age over 40, hypercoagulable states, diabetes, and a history of DVT. For recipients with these risk factors, prophylaxis with low-dose heparin is recommended.

UROLOGIC COMPLICATIONS Urinary tract complications, manifesting as leakage or obstruction, generally occur in 2 to 10% of kidney recipients. The underlying cause often is related to poor blood supply and ischemia of the transplant ureter. Leakage most commonly occurs from the anastomotic site. Causes other than ischemia include undue tension created by a short ureter, and direct surgical injury. Presentation is usually early (before the fifth posttransplant week); symptoms include fever, pain, swelling at the graft site, increased creatinine level, decreased urine output, and cutaneous urinary drainage. Diagnosis can be confirmed initially with a hippurate renal scan, although a percutaneous nephrostogram is required for precise definition. Early surgical exploration with ureteral reimplantation usually is indicated, although small leaks may be managed by percutaneous nephrostomy and stent placement with good results. Ureteral obstruction may develop early or late. Early obstruction may be due to edema, blood clots, hematomas, or torsion of the ureter. Late obstruction generally is due to scarring and fibrosis from chronic ischemia. Patients develop an elevated serum creatinine level. An ultrasound to look for hydronephrosis is a good initial test. Percutaneous transluminal dilatation, followed by placement of an internal or external stent, is a good initial treatment. If repeated dilatations and stenting are required, surgical intervention (e.g., ureteral reimplantation or ureteropyelostomy using the native ureter) should be undertaken.

LYMPHOCELE The reported incidence of lymphoceles (fluid collections of lymph that generally result from cut lymphatic vessels in the recipient) is 0.6 to 18%. Lymphoceles usually do not occur until at least 2 weeks posttransplant. Symptoms are generally related to the mass effect and compression of nearby structures (e.g., ureter, iliac vein, allograft renal artery), and patients develop hypertension, unilateral leg swelling on the side of the transplant, and elevated serum creatinine. Ultrasound is used to confirm a fluid collection, although percutaneous aspiration may be necessary to exclude presence of other collections such as urinomas, hematomas, or abscesses. The standard surgical treatment is creation of a peritoneal window to allow for drainage of the lymphatic fluid into the peritoneal cavity, where it can be absorbed. Either a laparoscopic or an open approach may be used. Another option is percutaneous insertion of a drainage catheter, with or without sclerotherapy; however, it is associated with some risk of recurrence or infection.

OTHER COMPLICATIONS A wide variety of medical complications can be seen after a kidney transplant. Infections are probably the most common, but the incidence has declined significantly in recent years due to improvements in prophylaxis regimens. Common sites for infection include the urinary tract, the pulmonary system, and the wound. Noninfectious medical complications affecting the cardiac, GI, and neurologic systems also have been well described posttransplant.4 5 Such complications are often related to the administration of immunosuppressive drugs.

Late Posttransplant Care The goal of late posttransplant care of the kidney transplant recipient is to optimize immunosuppression, carefully monitor graft function, and screen and monitor for complications that are directly or indirectly related to immunosuppressive medications. Optimizing immunosuppression entails fitting it to the individual recipient's needs. Recipients at low risk for rejection should have their immunosuppression lowered to minimize side effects

and complications. Careful attention should be paid to compliance; it often is easy for recipients to become less attentive to their medications as they progress through the posttransplant period. Monitoring kidney function may help detect noncompliance, but also is important to detect late rejection episodes, recurrence of disease, or late technical problems (such as renal artery stenosis or ureteric stricture). Other potential problems in these recipients include hypercholesterolemia, hypertriglyceridemia, and increased blood pressure, which may or may not be related to the immunosuppressive drugs. Screening for malignancy (especially skin, colorectal, breast, cervical, and prostate) is important, although the incidence of many of these malignancies is equivalent to those seen in the general population. Patients should be immunized, ideally pretransplant, for Haemophilus influenzae , Streptococcus pneumoniae , and Neisseria meningitidis , as this is important to minimize infectious complications due to these pathogens.

Results Posttransplant outcomes have steadily improved over the past 3 decades due to improvements in immunosuppression, organ retrieval techniques, perioperative care, and treatment of infectious posttransplant complications.46–48 Since the late 1980s, the use of modern immunosuppressive drugs has been a primary factor, especially in those previously considered to be at high risk, such as diabetic, pediatric, and older recipients. Most centers now report patient survival rates exceeding 95% during the first posttransplant year for all kidney recipients (Table 11-5). Living-donor transplants still have an advantage over deceased-donor transplants, but even this difference is diminishing with modern immunosuppression. The survival advantage after a transplant, as compared with dialysis, is probably greatest for diabetic patients. Without a transplant, their overall survival is 26% at 5 years; with a transplant, it jumps to about 80%. The major cause of death in all kidney recipients is cardiovascular (myocardial infarction or stroke); sepsis accounts for less than 3%, while malignancy accounts for 2%.

Table 11-5 Patient Survival Rates (%) after the Various Transplants Kidney Deceased donor 97.9 94.7 88.1 80.7 60.7 Living donor 99.2 98.0 94.5 90.4 76.4 SPK 97.7 95.1 90.8 85.8 69.2 PAK 98.3

95.5 89.9 83.6 60.7 PTA 97.9 94.9 91.6 90.2 66.9 Liver Deceased donor 93.2 86.9 79.0 73.4 59.4 Living donor 95.8 91.2 82.9 76.8 76.2 Intestine 93.2 87.5 62.2 50.2 40.6 Heart 92.5 88.1 80.2 73.7 53.4 Lung 93.2 84.9 66.4 51.6 25.6 Heart-lung 77.8 66.7 53.8 43.6 27.3 Time Posttransplant

3 Mo

1Y

3Y

5Y

10 Y

PAK = pancreas after kidney; PTA = pancreas transplant alone; SPK = simultaneous pancreas-kidney. Source: Reproduced with permission from 2006 OPTN/SRTR Annual Report, http://www.ustransplant.org. The incidence of acute rejection has declined steadily since the early 1990s. Most centers now report acute rejection rates of 10 to 20% at 1 year posttransplant. This decline has been a major factor in the improvement in graft survival rates, which are now about 75 to 80% at 5 years and 60 to 65% at 10 years posttransplant for all kidney recipients4 9 (Table 11-6). Currently, the most common cause of graft loss is recipient death (usually from cardiovascular causes) with a functioning graft. The second most common cause is chronic allograftnephropathy. Characterized by a slow, unrelenting deterioration of graft function, it likely has multiple causes (both immunologic and nonimmunologic).50,51 The graft failure rate due to surgical technique has remained at about 2%.

Table 11-6 Graft Survival Rates (%) after the Various Transplants Kidney Deceased donor 94.3 89.5 78.6 67.1 40.8 Living donor 97.2 95.1 88.4 80.3 56.5 SPK (pancreas) 89.2 85.2 79.3 71.1 54.5 PAK 86.7 78.7 67.3 56.4 27.6 PTA 87.5 72.8 58.4 53.4 25.9 Liver Deceased donor 89.6

82.4 73.6 67.4 53.0 Living donor 90.0 84.0 76.0 68.8 66.5 Intestine 88.3 78.5 50.6 40.1 27.9 Heart 92.0 87.5 79.4 72.6 51.5 Lung 92.5 83.3 64.4 48.9 23.4 Heart-lung 75.2 64.1 53.1 41.5 26.5 Time Posttransplant

3 Mo

1Y

3Y

5Y

10 Y

PAK = pancreas after kidney; PTA = pancreas transplant alone; SPK = simultaneous pancreas-kidney. Source: Reproduced with permission from 2006 OPTN/SRTR Annual Report, http://www.ustransplant.org.

PANCREAS TRANSPLANTATION Diabetes mellitus is a very common medical condition with immense medical, social, and financial costs. In North America, it is the leading cause of kidney failure, blindness, nontraumatic amputations, and impotence. The discovery of insulin in 1922 by Banting and Best changed diabetes from a lethal disease to a chronic illness. However, even though exogenous insulin can prevent the acute metabolic complications and decrease the incidence of secondary complications associated with diabetes, it cannot provide a homeostatic environment

comparable to that afforded by a functioning pancreas. Only a functioning pancreas can provide immediate insulin responses to the moment-to-moment changes in glucose levels. A successful pancreas transplant can establish normoglycemia and insulin independence in diabetic recipients, with glucose control similar to that seen with a functioning native pancreas. A pancreas transplant also has the potential to halt progression of some secondary complications of diabetes. No current method of exogenous insulin administration can produce a euglycemic, insulin-independent state akin to that achievable with a technically successful pancreas graft. In addition to improved metabolic control and beneficial effects on secondary complications, a pancreas transplant can substantially enhance quality of life, more than that achieved by exogenous insulin administration. Indeed, the modern management of diabetes by exogenous insulin may be as burdensome as dialysis is for kidney failure, as it consists of four blood glucose determinations daily, coupled with four insulin injections or a constantly present needle. A successful pancreas transplant obviates the need for such constant invasive monitoring. Currently, the main drawback of a pancreas transplant is the need for immunosuppression. Pancreas transplants are now preferentially performed in diabetic patients with kidney failure who also are candidates for a kidney transplant, as they already require immunosuppression to prevent kidney rejection. However, a pancreas transplant alone (PTA) is appropriate for nonuremic diabetics if their day-to-day quality of life is so poor (e.g., labile serum glucose with ketoacidosis and/or hypoglycemic episodes, or progression of severe diabetic retinopathy, nephropathy, neuropathy, and/or enteropathy) that chronic immunosuppression is justified to achieve insulin independence.5 2 As immunosuppressive agents become safer, it is likely that PTA will become increasingly common.

History The first human pancreas transplant was performed in 1966; however, the procedure was not performed with any frequency until many years later. During the 1970s, a small number of institutions performed a few pancreas transplants, and their success rates were low, mainly because of problems with rejection. A dramatic improvement in outcome occurred in the 1980s, after advances in surgical techniques and the introduction of cyclosporine for immunosuppression. In the United States, the inception of UNOS in 1987 facilitated nationwide organ procurement and allocation. A steady growth in the application of pancreas transplants soon followed. By the mid-1990s, more than 1000 pancreas transplants were being performed annually in the United States, with improved results paralleling the introduction of even newer immunosuppressive drugs such as tacrolimus and MMF. Results also improved because of refinements in surgical technique. By the mid-1970s, the following three techniques were in use: enteric drainage (ED), urinary drainage (first into the ureter, and later modified by direct implantation into the bladder), and duct injection. During the 1980s, bladder drainage (BD) was shown to be safe, and it became the predominant technique in all pancreas recipient categories, as it facilitated allograft monitoring via measurement of urine amylase levels. The 1990s saw a shift back to ED, especially in patients who underwent a simultaneous kidney transplant. In such recipients, the serum creatinine level could be used as a surrogate marker for pancreas rejection when both organs came from the same donor.

Preoperative Evaluation The preoperative evaluation for pancreas transplant recipients does not differ substantially from that for diabetic kidney transplant recipients. Examination of the cardiovascular system is most important because significant coronary artery disease may be present without angina.5 3 Noninvasive testing may not identify coronary artery disease, so coronary angiography is routinely performed. Detailed neurologic, ophthalmologic, metabolic, and

kidney function testing may be needed to assess the degree of progression of secondary complications. Any contraindications to a transplant, such as active malignancy or infection, must be ruled out. A thorough evaluation of the peripheral vascular system is essential, given the high incidence of peripheral vascular disease in diabetics. The patency of the iliac system needs to be determined, because the iliac vessels will serve as the inflow source for the pancreas. Once a patient is determined to be a good candidate for a pancreas transplant, with no obvious contraindications, it is important to decide which type of pancreas transplant is best for that individual. First, the degree of kidney dysfunction and the need for a kidney transplant must be determined. Patients with stable kidney function (creatinine less than 2 mg/dL and minimal protein in the urine) are candidates for a PTA. However, patients with moderate kidney insufficiency will likely require a kidney transplant as well; further deterioration of kidney function often occurs once calcineurin inhibitors are started for immunosuppression. For patients requiring both a kidney and a pancreas transplant, various options are available. The two transplants can be performed either simultaneously or sequentially. A living donor or a deceased donor can be used, or both. Which option is best for the individual patient depends on the degree of kidney dysfunction, the availability of donors, and personal preference. The following options are currently possible: Deceased-donor, simultaneous pancreas-kidney transplant (SPK): The most common option worldwide, deceased-donor SPK transplants have well-documented, long-term survival results for both the kidney and the pancreas grafts. The recipient has the advantage of undergoing both transplants at the same time, and therefore may potentially become dialysis free and insulin independent at the same time. There is also an immunologic advantage, as acute rejection rates are significantly lower for SPK (vs. PTA) recipients. Living-donor kidney transplant, followed weeks to months later by a deceased-donor pancreas transplant [pancreas after kidney (PAK) transplant]: If a living donor is available for the kidney transplant, then this is a good option for uremic diabetic patients. It offers the possibility of performing the kidney transplant as soon as the living-donor evaluation is complete, rendering the recipient dialysis free within a short period. A living-donor (vs. deceased-donor) kidney transplant has superior long-term results. By performing the two operations sequentially instead of simultaneously, the overall surgical complication rate may be decreased, perhaps because by the time of the pancreas transplant, the effects of uremia have resolved and patients are in better metabolic and nutritional condition.5 4 The disadvantage is that the long-term pancreas graft survival rates for PAK recipients are still somewhat inferior to those of individuals receiving SPK transplants. Simultaneous deceased-donor pancreas and living-donor kidney transplant: Candidates with a suitable living donor for the kidney transplant who have not yet progressed to dialysis can be placed on the deceased-donor pancreas transplant waiting list. When a deceased-donor pancreas becomes available, the living donor for the kidney is called in at the same time, and both procedures are performed simultaneously. Advantages include use of a living donor for the kidney, shorter waiting times, and a single operation.5 5 Technically, this option may be more difficult to organize, as it requires using two full surgical teams and two full operating rooms, and at times the donor and the recipient will need to be called in from different locations. It also may create difficult timing issues for the living donor, who must come in quickly for an emergent operation. Living-donor, SPK transplant: If a single individual is suitable to donate both a kidney and a hemipancreas, then this may be a potential option. It is especially useful for candidates with a high level of preformed antibodies, or those who have difficulty acquiring a deceased-donor organ. The main

disadvantage of this approach is to the living donor, who has to undergo a surgical procedure of substantial magnitude with its attendant risks and morbidity.

Surgical Procedure The initial preparation of the donor pancreas is a crucial component of a successful transplant. Direct physical examination of the pancreas often is the best or only way to confirm its suitability (Fig. 11-14). If it is sclerotic, calcific, or markedly discolored, it should not be used. Before implantation, a surgical procedure is undertaken to remove the spleen and any excess duodenum, and to ligate blood vessels at the root of the mesentery (Fig. 1115A-C). The inflow vessels to the graft are the splenic and superior mesenteric arteries; outflow is via the portal vein. Arterial reconstruction is performed before implanting the graft in the recipient. The donor superior mesenteric and splenic arteries are connected, most commonly using a reversed segment of donor iliac artery as a Y-graft (Figs. 11-15D and 11-16); doing so allows for a single arterial anastomosis in the recipient.

Fig. 11-14.

Pancreas graft before bench preparation with spleen attached.

Fig. 11-15.

Bench preparation of pancreas graft. Steps include (A ) removal of the spleen; (B ) removal of tissue along the superior and inferior aspect of the tail of the pancreas; (C ) trimming of excess duodenum; and (D ) ligation of vessels at the root of the mesentery and placement of arterial Y-graft.

Fig. 11-16.

Final appearance of benched pancreas before implantation in the recipient.

The pancreas graft is then implanted via an anastomosis of the aforementioned arterial graft to the recipient common iliac artery or distal aorta, and, via a venous anastomosis of the donor portal vein to the recipient iliac vein (for systemic drainage, Fig. 11-17), or to the superior mesenteric vein (for portal drainage).5 6 If both a kidney and a pancreas are transplanted, they are placed in an intraperitoneal position, with the kidney usually in the left iliac fossa and the pancreas in the right iliac fossa (Fig. 11-18). If the pancreas is drained via the portal route, then it usually sits higher in the mid-abdomen (Fig. 11-19).

Fig. 11-17.

Preparation of iliac vessels for implantation of the pancreas with ligation and division of all hypogastric veins.

Fig. 11-18.

Reperfused pancreas allograft after completion of the vascular anastomosis.

Fig. 11-19.

Combined kidney and pancreas transplant with portal enteric drainage of pancreas graft. The pancreas transplant is situated higher in the abdomen and is oriented pointing toward the head of the recipient.

Once the pancreas is revascularized, a drainage procedure must be performed to handle the pancreatic exocrine secretions. Options include anastomosing the donor duodenum to the recipient bladder (Fig. 11-20) or to the small bowel, with the small bowel either in continuity or connected to a Roux-en-Y limb. Some centers always use ED, others always use BD, and others tailor the approach according to the recipient category. Both ED and BD now have a relatively low surgical risk. The main advantage of BD is the ability to directly measure enzyme activity in the pancreatic graft exocrine secretions by measuring the amount of amylase in the urine. A decrease in urine amylase is a sensitive marker for rejection, even though it is not entirely specific. Urine amylase always decreases before hyperglycemia ensues. A rise in serum amylase may precede a decrease in urine amylase, but serum amylase by itself is less sensitive (it does not always rise, but urine amylase always decreases), and is no more specific for the diagnosis of rejection. The leak rate is the same whether the pancreas is drained to the bladder or to the bowel, but the consequences of a bladder leak are much less severe than those associated with a bowel leak. The disadvantages of BD include complications such as dehydration and acidosis (from loss of alkalotic pancreatic secretions in the urine), and local problems with the bladder such as infection, hematuria, stones, and urethritis. Because of these chronic complications, between 10 and 20% of bladder-drained graft recipients are

ultimately converted to ED.

Fig. 11-20.

A and B. Drainage of the exocrine secretions by anastomosis of the recipient bladder to the donor duodenum in a two-layer fashion.

ED is more physiologic and has fewer long-term complications. However, the ability to monitor for rejection is decreased, given the absence of urinary amylase. Rejection in SPK transplant recipients almost always affects both the kidney and the pancreas; therefore, the serum creatinine level can be used as a marker for rejection of the pancreas. Hence, most centers now use ED for SPK transplants. If the kidney and the pancreas are from different donors, or if a PTA is performed, then BD is preferred, so rejection of the pancreas can be detected earlier.

Postoperative Care In general, pancreas recipients do not require intensive care monitoring in the postoperative period. Laboratory values—serum glucose, hemoglobin, electrolytes, and amylase—are monitored daily. The serum glucose level is monitored even more frequently if normoglycemia is not immediately achieved. Nasogastric suction and IV fluids are continued for the first several days until bowel function returns. In the early postoperative period, regular insulin is infused to maintain plasma glucose levels less than 150 mg/dL, because chronic hyperglycemia may be detrimental to

-cells. In recipients who undergo BD, a Foley catheter is left in place for 10 to 14 days. At most

centers, some form of prophylaxis is instituted against bacterial, fungal, and viral infections. In addition, many centers routinely institute some form of prophylaxis against thrombosis of the allograft; options include low-dose heparin, low molecular weight heparin, or oral antiplatelet agents for the first week posttransplant.

Complications One crucial aspect of posttransplant care is monitoring for rejection and complications (both surgical and medical). Rejection episodes may be identified by an increase in serum creatinine (in SPK recipients), a decrease in urinary amylase (in recipients with BD), an increase in serum amylase, or by an increase in serum glucose levels. Complications are, unfortunately, common after pancreas transplants. The pancreas graft is susceptible to a unique set of complications because of its exocrine secretions and low blood flow. However, the incidence of graft-related complications has decreased significantly since the early 1990s due to better preservation techniques, better surgical methods, improved prophylaxis regimens, and improved immunosuppression. 5 7 Potential complications are described below.

THROMBOSIS The incidence of thrombosis is approximately 6% for pancreas transplants reported to the UNOS registry. Low-dose heparin, dextran, or antiplatelet agents are administered routinely in the early postoperative period at many centers, although these agents slightly increase the risk of postoperative bleeding. Arterial or venous thrombosis is most common within the first several days posttransplant, heralded by an increase in blood glucose levels, an increase in insulin requirements, or a decrease in urine amylase levels. Venous thrombosis also is characteristically accompanied by hematuria, tenderness and swelling of the graft, and ipsilateral lower extremity edema. Treatment consists of graft removal.

HEMORRHAGE Postoperative bleeding may be minimized by meticulous intraoperative control of bleeding sites. Hemorrhage may be exacerbated by anticoagulants and antiplatelet drugs, but their benefits seem to outweigh the risks. Bleeding is a much less significant cause (95%). Pancreas graft survival rates at 1 year remain higher in the SPK (~90%) than in the PAK (~85%) and PTA (~80%) categories, according to IPTR data. The differences are due in part to the decreased ability to monitor for rejection episodes in enteric-drained, solitary pancreas transplant recipients. With improving immunosuppressive protocols and the decreasing incidence of acute rejection, the difference between the three categories has been steadily decreasing since the late 1990s.59,60

ISLET CELL TRANSPLANTATION The pancreas consists of two separate functional systems (endocrine and exocrine), but it is only the endocrine component that is of use in the transplant process. However, many of the complications seen with whole-organ pancreas transplants are due to the exocrine component. Therefore, the concept of transplanting simply the cells responsible for the production of insulin is very logical and attractive. Islet cell transplantation involves extracting islets of Langerhans from a donor's pancreas and then injecting them into a diabetic recipient. These islet cells then engraft into the recipient and secrete insulin, providing excellent moment-to-moment control of blood glucose, as is seen with a whole-organ pancreas transplant. Compared with exogenous insulin injections, an islet cell transplant offers advantages similar to those of a whole-organ pancreas transplant. A successful islet transplant provides perfect glucose homeostasis, freeing the diabetic patient from the burden of frequent glucose monitoring and insulin injections. It potentially prevents secondary complications of diabetes and significantly improves quality of life. Unlike a whole-organ pancreas transplant, an islet cell transplant is not a major surgical procedure. It generally can be performed as an outpatient procedure, with minimal recovery time for the recipient. It avoids a major surgical procedure, with its associated mortality and morbidity. Given this significantly lower surgical risk, islet cell transplants could theoretically have much wider application than whole-organ transplants. Typically, a pancreas is procured from a suitable deceased donor. Isolating the islets is a complex process, which

generally involves digesting the pancreas with a collagenase solution to separate the islet cells. The islets may then be purified (i.e., separated from the acinar cells). The purified islets can then be injected into the recipient, most commonly into the portal vein. The islet cells then engraft in the hepatic parenchyma and secrete insulin, which drains into the circulation. Potential complications associated with the injection include portal hypertension, hepatic abscesses, and bacteremia. One major disadvantage of an islet cell transplant (similar to that of a whole-organ transplant) is the need for longterm immunosuppression. This disadvantage has limited the use of islet cell transplants to patients with kidney failure who require immunosuppression because of a kidney transplant. This immunologic problem is compounded by the fact that islet cell rejection can be difficult to monitor and diagnose. One possible method of avoiding the need for immunosuppression is to surround the islets with a semipermeable membrane, a process called microencapsulation . This process would allow small molecules such as oxygen and glucose to reach the islet cells and would allow insulin to reach the systemic circulation. But microencapsulation would prevent immune cells and large molecules such as antibodies from reaching the islet cells. The islet cells would then survive and function well inside the membranes, while being protected from immunologic damage. Islet cell transplants have been a possibility for many years, but the results have generally been poor. In 1995, a report of the International Islet Transplant Registry indicated that of 270 recipients, only 5% were insulin independent at 1 year posttransplant. Recently, however, significantly improved results have been reported by using steroid-free immunosuppression and islet injections from multiple donors. These recent successes have stimulated a flurry of islet transplant activity at centers across the world. As results are likely to continue to improve, it is possible that islet cell transplants may come to replace whole-organ pancreas transplants.

LIVER TRANSPLANTATION The field of liver transplantation has undergone remarkable advances in the last 2 decades. An essentially experimental procedure in the early 1980s, a liver transplant is now the treatment of choice for patients with acute and chronic liver failure. Patient survival at 1 year posttransplant has increased from 30% in the early 1980s to more than 85% at present. The major reasons for this dramatic increase include refined surgical and preservation techniques, better immunosuppressive protocols, more effective treatment of infections, and improved care during the critical perioperative period. However, a liver transplant remains a major undertaking, with the potential for complications affecting every major organ system.

History The history of liver transplantation began with experimental transplants performed in dogs in the late 1950s. The first liver transplant attempted in humans was in 1963 by Thomas Starzl. The recipient was a 3-year-old boy with biliary atresia who unfortunately died of hemorrhage. The first successful liver transplant was in 1967, again by Starzl. Yet, for the next 10 years, liver transplants remained essentially experimental, with survival rates well below 50%. Still, advances in the surgical procedure and in anesthetic management continued to be made during that time. The major breakthrough for the field came in the early 1980s, with the introduction and clinical use of the immunosuppressive agent cyclosporine. Patient survival dramatically improved, and liver transplantation was soon being recognized as a viable therapeutic option. Results continued to improve through the 1980s, due to ongoing improvements in immunosuppression, critical care management, surgical technique, and preservation solutions.

The late 1980s and 1990s saw a dramatic increase in the number of liver transplants, and an even greater increase in the number of patients waiting for a transplant. This, in turn, increased waiting times as well as mortality rates for those waiting. The longer waiting time and higher mortality rates for patients on the deceased-donor liver transplant waiting list led to the development of innovative surgical techniques such as split-liver transplants and living-donor liver transplants. Initially, these new techniques were mainly applied to pediatric patients because of the difficulty associated with finding appropriate size-matched organs for them. However, as the number of adults on the waiting list grew, these techniques began to be applied for adult recipients as well. The use of living-donor liver transplants progressed at an even more rapid pace in countries such as Japan, where the concept of deceaseddonor organ donation was not widely accepted.

Preoperative Evaluation A liver transplant is indicated for liver failure, whether acute or chronic. Liver failure is signaled by a number of clinical symptoms [e.g., ascites, variceal bleeding, hepatic encephalopathy (HE), and malnutrition], and by biochemical liver test results that suggest impaired hepatic synthetic function (e.g., hypoalbuminemia, hyperbilirubinemia, and coagulopathy). The cause of liver failure often influences its presentation. For example, patients with acute liver failure generally have HE and coagulopathy, whereas patients with chronic liver disease most commonly have ascites, GI bleeding, and malnutrition.

Diseases Treatable by Transplant A host of diseases are potentially treatable by a liver transplant (Table 11-7). Broadly, they can be categorized as acute or chronic, and then subdivided by the cause of the liver disease. Chronic liver diseases account for the majority of liver transplants today. The most common cause in North America is chronic hepatitis, usually due to hepatitis C and less commonly to hepatitis B. Chronic alcohol abuse accelerates the process, especially with hepatitis C. Progression from chronic infection to cirrhosis is generally slow, usually occurring over a period of 10 to 20 years. Chronic hepatitis may also result from autoimmune causes, primarily in women. It can present either acutely over months or insidiously over years. Alcohol often plays a role in end-stage liver disease secondary to hepatitis C, but it may also lead to liver failure in the absence of viral infection. In fact, alcohol is the most common cause of end-stage liver disease in the United States. Such patients generally are suitable candidates for a transplant as long as an adequate period of sobriety can be documented.

Table 11-7 Diseases Amenable to Treatment by a Liver Transplant Cholestatic liver diseases Primary biliary cirrhosis Primary sclerosing cholangitis Biliary atresia Alagille syndrome Chronic hepatitis Hepatitis B Hepatitis C Autoimmune hepatitis Alcohol liver disease Metabolic diseases Hemochromatosis Wilson's disease

Alpha1-antitrypsin deficiency Tyrosinemia Cystic fibrosis Hepatic malignancy Hepatocellular carcinoma Neuroendocrine tumor metastatic to liver Fulminant hepatic failure Others Cryptogenic cirrhosis Polycystic liver disease Budd-Chiari syndrome Amyloidosis

Cholestatic disorders also account for a significant percentage of transplant candidates with chronic liver disease. In adults, the most common causes are primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). PBC, a destructive disorder of interlobular bile ducts, can progress to cirrhosis and liver failure over several decades. It most commonly affects middle-aged women. PSC, a disease characterized by inflammatory injury of the bile duct, occurs mostly in young men, 70% of whom have inflammatory bowel disease. In children, biliary atresia is the most common cholestatic disorder. It is a destructive, inflammatory condition of the bile ducts, and if left untreated, it usually results in death within the first 1 to 2 years of life. A variety of metabolic diseases can result in progressive, chronic liver injury and cirrhosis, including hereditary hemochromatosis (an autosomal recessive disorder characterized by chronic iron accumulation, which may result in cirrhosis, cardiomyopathy, and endocrine disorders including diabetes), alpha1-antitrypsin deficiency (which may result in cirrhosis at any age, most commonly in the first or second decade of life), and Wilson's disease [an autosomal recessive disorder of copper excretion, which may present as either fulminant hepatic failure (FHF) or chronic hepatitis and cirrhosis]. Hepatocellular carcinoma (HCC) may be a complication of cirrhosis from any cause, most commonly with hepatitis B, hepatitis C, hemochromatosis, and tyrosinemia. HCC patients may have stable liver disease, but are often not candidates for hepatic resection because of the underlying cirrhosis. The desire to remove the malignancy and replace the remaining liver parenchyma (both to improve liver function and remove the diseased parenchyma at risk for further carcinogenesis) led clinicians to consider the use of orthotopic liver transplantation (OLT). Longterm patient survival in early series of OLT for HCC, however, only reached 30 to 40%. It was not until patient selection strategies evolved that OLT became a more effective treatment. In a landmark 1996 study by Mazzaferro and colleagues at the University of Milan,6 1 characteristics of patients with HCC that were good candidates for OLT were described. These characteristics, now commonly referred to as the Milan criteria , included (a) a single lesion 300 mol/L (>3.4 mg/dL) No acetaminophen toxicity Prothrombin time >100 s (INR >6.5) age 40 y Non-A, non-B hepatitis Duration of jaundice before onset of encephalopathy>7 d Serum creatinine >300 mol/L (>3.4 mg/dL)

INR = International Normalized Ratio.

Indications for Transplant The presence of chronic liver disease alone with established cirrhosis is not an indication for a transplant. Some patients have well-compensated cirrhosis with a low expectant mortality. Patients with decompensated cirrhosis, however, have a poor prognosis without transplant. The signs and symptoms of decompensated cirrhosis include: HE: In its early stages, HE may begin with subtle sleep disturbances, depression, and emotional lability. Increasing severity of HE is indicated by increasing somnolence, altered speech, and in extreme cases, coma. Physical examination shows the typical flapping tremor of asterixis. Blood tests often reveal an elevated serum ammonia level. HE may occur spontaneously, but more commonly is triggered by a precipitating factor such as spontaneous bacterial peritonitis (SBP), GI bleeding, use of sedatives, constipation, or excessive dietary protein intake. Ascites: Ascites generally is associated with portal hypertension. The initial approach to the management of ascites is sodium restriction and diuretics. If this approach is not successful, patients may require repeated large-volume (4 to 6 L) paracentesis. A better option to diuretic-resistant ascites requiring frequent paracentesis is transjugular intrahepatic portosystemic shunting (TIPS). A potential complication of TIPS is progression of liver failure or disabling encephalopathy. Patients with signs of far-advanced

liver disease, such as hyperbilirubinemia, HE, and renal dysfunction, generally are not good candidates for TIPS. SBP: This complication of chronic liver failure generally signals advanced disease. It often tends to be recurrent. Anaerobic gram-negative bacteria account for 60% of the cultured organisms; gram-positive cocci account for the remainder. Diagnosis is confirmed if percutaneous sampling of the abdominal fluid shows a neutrophil count of greater than 250 cells/mL. Treatment with a third-generation cephalosporin is generally effective. Portal hypertensive bleeding: The likelihood of patients with cirrhosis developing varices ranges from 35 to 80%. About one third of those with varices will experience bleeding. The risk of recurrent bleeding approaches 70% by 2 years after the index bleeding episode. Each episode of bleeding is associated with a 30% mortality rate. Thus, urgent treatment of the acute episode and steps to prevent rebleeding are essential. Endoscopy is indicated to diagnose and treat the acute bleed with either band ligation or sclerotherapy. Other therapies include vasoactive drugs such as octreotide or vasopressin, balloon tamponade, TIPS, and emergency surgical procedures (such as a portosystemic shunt or transection of the esophagus). Generally, patients whose endoscopic procedure fails should undergo emergency TIPS, if feasible, to control bleeding. Beta blockers have been shown to be of value in preventing the first bleeding episode in patients with varices and in preventing rebleeding. Hepatorenal syndrome (HRS): In patients with advanced liver disease and ascites, HRS is characterized by oliguria (100/20

From The Leapfrog Group, 3 2 with permission. In a recent study, Brooke and associates analyzed whether achieving Leapfrog's established evidence-based standards for abdominal aortic aneurysm (AAA) repair, including meeting targets for case volume and perioperative beta blocker usage, correlated with improved patient outcomes over time.3 1 After controlling for differences in hospital and patient characteristics, hospitals that implemented a policy for perioperative beta blocker usage had an estimated 51% reduction in mortality following open AAA repair cases, as compared to control hospitals. Among 111 California hospitals in which endovascular AAA repair was performed, inhospital mortality was reduced by an estimated 61% over time among hospitals meeting Leapfrog case volume standards when compared to control hospitals, although this result was not statistically significant. These results suggest that hospital compliance with Leapfrog standards for elective AAA repair are an effective means to help improve inhospital mortality outcomes over time, and support further efforts aimed at standardizing patient referral to hospitals that comply with other evidence-based medicine standards for other surgical procedures.

World Health Organization "Safe Surgery Saves Lives" Initiative In October 2004, the WHO launched a global initiative to strengthen health care safety and monitoring systems by creating the World Alliance for Patient Safety. As part of the group's efforts to improve patient safety, the alliance implemented a series of safety campaigns that brought together experts in specific problem areas through individual Global Patient Safety Challenges. The second Global Patient Safety Challenge focuses on improving the safety of surgical care. The main goal of the campaign, called Safe Surgery Saves Lives, is to reduce surgical deaths and complications through the universal adaptation of a comprehensive perioperative surgical safety checklist in ORs worldwide. In addition, the WHO has defined a set of uniform measures for national and international surveillance of surgical care to better assess the quantity and quality of surgical care being delivered worldwide (Table 12-7).2 2 At the population level, metrics include the number of surgeon, anesthesia, and nurse providers per capita, the number of ORs per capita, and overall surgical case volumes and mortality rates. At the hospital level, metrics include safety improvement structures and a surgical "Apgar score," a validated method of prognosticating patient outcomes based on intraoperative events (i.e., hypotension, tachycardia, blood loss).3 3

Table 12-7 World Health Organization Basic Surgical Vital Statistics Number of operating theatres per capita Number of trained surgeons and trained anesthesia professionals per capita Number of operations performed in operating theatres within per capita Number of deaths on the day of surgery Number of inhospital deaths following surgery From World Health Organization, 2 2 with permission.

National Quality Forum The National Quality Forum (NQF) is a coalition of health care organizations that has worked to develop and implement a national strategy for health care quality measurement and reporting. The mission of the NQF is to improve the quality of American health care by setting national priorities and goals for performance improvement, endorsing national consensus standards for measuring and publicly reporting on performance, and promoting the attainment of national goals through education and outreach programs. One of the major contributions of the NQF is the development of a list of Serious Reportable Events, which is frequently referred to as "never events."3 4 According to the NQF, "never events" are errors in medical care that are clearly identifiable, preventable, and serious in their consequences for patients, and that indicate a real problem in the safety and credibility of a health care facility. Examples of "never events" include surgery performed on the wrong body part; a foreign body left in a patient after surgery; a mismatched blood transfusion; a major medication error; a severe "pressure ulcer" acquired in the hospital; and preventable postoperative deaths (Table 12-8). Criteria for inclusion as a "never event" are listed below. The event must be: Unambiguous (i.e., the event must be clearly identifiable and measurable, and thus feasible to include in a reporting system); Usually preventable, with the recognition that some events are not always avoidable, given the complexity of health care; Serious, resulting in death or loss of a body part, disability, or more than transient loss of a body function; and Any one of the following: Adverse and/or, Indicative of a problem in a health care facility's safety systems and/or, Important for public credibility or public accountability.

Table 12-8 Surgical "Never Events" Surgery performed on the wrong body part Surgery performed on the wrong patient Wrong surgical procedure performed on a patient Unintended retention of a foreign object in a patient after surgery or other procedure Intraoperative or immediately postoperative death in an ASA Class I patient ASA = American Society of Anesthesiologists. From National Quality Forum,3 4 with permission. These events are not a reasonable medical risk of undergoing surgery that the patient must accept, but medical errors that should never happen (Case 12-4). The occurrence of any of these events signals that an organization's patient safety culture or processes have defects that need to be evaluated and corrected to prevent the event from happening again (Table 12-9).

Case 12-4 Surgical "Never-Event" In 2002, Mike Hurewitz, a reporter for The Times Union of Albany, suddenly began vomiting blood 3 days after donating part of his liver to his brother while recovering on a hospital floor in which 34 patients were being cared for by one first-year resident. He aspirated and died immediately with no other physician available to assist the overworked first-year resident. Recognized for its advances in the field of liver transplantation, at the time, Mount Sinai Hospital was performing more adult-to-adult live-donor operations than any other hospital in the country. But the program was shut down by this event. Mount Sinai was held accountable for inadequate care and was banned from performing any live-donor adult liver transplants for more than 1 year. Of the 92 complaints investigated by the state, 75 were filed against the liver transplant unit, with 62 involving patient deaths. The state concluded that most of the 33 serious violations exhibited by the hospital occurred within the liver transplant unit. As a result of the investigation, Mount Sinai revamped many of the procedures within its transplant unit. Among the changes, first-year residents no longer staffed the transplant service, two health care practitioners physically present in the hospital oversaw the transplant unit at all times, and any page coming from the transplant unit had to be answered within 5 minutes of the initial call. In addition, nurses monitored patients' vital signs more closely after surgery, transplant surgeons were required to make postoperative visits to both organ donor and recipient, and each registered nurse was assigned to four patients, rather than six or seven. The death also led New York to become the first state to develop guidelines for treating live organ donors. Finally, Mike Hurewitz's widow became a patient safety advocate, urging stricter controls on live donor programs.

Table 12-9 Four Patient Events That Advanced the Modern Field of Patient Safety Patient

Institution

Libby Zion Betsy Lehman

Root Cause

Outcome

New York Hospital, 1984 Missed allergy to New York, NY Demerol

Physician fatigue

Bell Commission shortened resident work hours

Dana-Farber Cancer Institute, Boston, MA

1994 Chemotherapy overdose

Lack of medication checks and triggers

Fired doctor, three pharmacists, 15 nurses; overhauled safety program

2001 Severe dehydration

Poor communication Increased safety research funding

Josie King Johns Hopkins Hospital, Baltimore, MD Mike Hurewitz

Year Event

Mt. Sinai Hospital, 2002 Inadequate New York, NY postoperative care

Inadequate supervision

Transplant program shut down until better patient safety safeguards implemented

"NEVER EVENTS" IN SURGERY Retained Surgical Items35 A retained surgical item refers to any surgical item that is found to be inside a patient after he or she has left the OR, thus requiring a second operation to remove the item. Estimates of retained foreign bodies in surgical procedures range from one case per 8000 to 18,000 operations, corresponding to one case or more each year for a typical large hospital or approximately 1500 cases per year in the United States. 3 6 This estimate is based on an analysis of malpractice claims and is likely to underestimate the true incidence. The risk of having a retained surgical item increases during emergency surgery, when there are unplanned changes in procedure (due to new diagnoses encountered in the OR), and in patients with higher body-mass index (Table 12-10).3 6

Table 12-10 Risk Factors for Retained Surgical Sponges Emergency surgery Unplanned changes in procedure Patient with higher body-mass index Multiple surgeons involved in same operation Multiple procedures performed on same patient Involvement of multiple operating room nurses/staff members Case duration covers multiple nursing "shifts" The most common retained surgical item is a surgical sponge, but other items, such as surgical instruments and needles, can also be inadvertently left inside a patient after an operation. Retained surgical sponges are commonly discovered as an incidental finding on a routine postoperative radiograph, but also have been

discovered in patients presenting with a mass or abdominal pain. Patients with sponges that were originally left in an intracavitary position (such as inside the chest or abdomen) also can present with complications such as erosion through the skin, fistula formation, bowel obstruction, hematuria, or the development of a new, tumor-like lesion. Retained surgical needles usually are discovered incidentally, and reports of retained needles are uncommon. Retained surgical needles have not been reported to cause injury in the same way that nonsurgical needles (e.g., sewing needles, hypodermic needles) have been reported to perforate bowel or lodge in vessels and migrate. However, there have been reports of chronic pelvic pain and ocular irritation caused by retained surgical needles. A study of plain abdominal radiographs in pigs has demonstrated that medium to large size needles can easily be detected. The decision to remove these retained needles depends on whether they are symptomatic and the preference of the patient. Needles smaller than 13 mm have been found to be undetectable on plain radiograph in several studies, have not been shown to cause injury to vessels or visceral organs, and can probably be left alone. Although the actual incidence of retained surgical instruments is unknown, they are known to be retained with far less frequency than surgical sponges. However, most of the cases that do occur are sensationalized by the lay media and draw significant attention from the general public. The initial presentation of a retained surgical instrument is pain in the surgical site or the sensation of a mass of fullness after a surgical procedure that led to the discovery of a metallic object on a radiographic study. Commonly retained instruments include the malleable and "FISH" instrument that are used when closing abdominal surgery. A retained surgical foreign body should be included in the differential diagnosis of any postoperative patient who presents with pain, infection, a palpable mass, or a radiopaque structure on imaging. The diagnosis can usually be made using a computed tomographic (CT) scan, and this is often the only test that will be needed. If a retained surgical item is identified in the setting of an acute clinical presentation, the treatment usually is removal of the item. However, if the attempt to remove the retained surgical item can potentially cause more harm than the item itself, as in the case of a needle or a small part of a surgical item, then removal is occasionally not recommended. Retained surgical sponges should always be removed. The American College of Surgeons and the Association of Perioperative Registered Nurses, in addition to the Joint Commission, have issued guidelines to try to prevent the occurrence of retained surgical items. Current recommendations include the use of standard counting procedures, performing a thorough wound exploration before closing a surgical site, and using only x-ray detectable items in the surgical wound. These organizations also strongly endorse the completion of a postoperative debriefing after every operation. An xray at the completion of an operation is encouraged if there is any concern for a foreign body based on any confusion regarding the counts by even a single member of the OR team, or in the presence of a risk factor.

Surgical Counts The benefit of performing surgical counts to prevent the occurrence of retained surgical items is controversial. The increased risk of a retained surgical item during emergency surgery in the study by Gawande and colleagues appeared to be related to bypassing the surgical count in many of these cases, suggesting that the performance of a surgical count can be useful in reducing the incidence of this sentinel event.3 6 However, the "falsely correct count," in which a count is performed and declared correct when it is actually incorrect, occurred in 21 to 100% of cases in which a retained surgical item was found.3 5 This type of count was the most common circumstance encountered in all retained surgical item cases, which suggests

that performing a surgical count in and of itself does not prevent this error from taking place. The counting protocol also imposes significant demands on the nursing staff and distracts them from focusing on other primarily patient-centered tasks.1 7 A retained surgical item can occur even in the presence of a known incorrect count. This event is usually a result of poor communication in which a surgeon will dismiss the incorrect count and/or fail to obtain a radiograph before the patient leaves the OR. Having stronger institutional policies in place in case of an incorrect count (such as requiring a mandatory radiograph while the patient is still in the OR) can avoid conflict among caregivers and mitigate the likelihood of a retained surgical item occurring as a result of a known incorrect count. Although there is no single tool to prevent all errors, the development of multiple lines of defense to prevent retained surgical items and universally standardizing and adhering to OR safety protocols by all members of the surgical team will help reduce the incidence of this never event.3 7 Surgeons should take the lead in the prevention of retained surgical items by avoiding the use of small or nonradiologically detectable sponges in large cavities, performing a thorough wound inspection before closing any surgical incision, and by having a vested interest in the counting procedure performed by nursing staff to keep track of sponges, needles, instruments, and any other potential retained surgical item. The value of routine radiography in the setting of emergency cases or when multiple major procedures involving multiple surgical teams are being performed to prevent a retained surgical item is becoming more apparent. The widely accepted legal doctrine when a foreign body is erroneously left in a patient is that the mere presence of the item in the plaintiff's body indicates that the patient did not receive proper surgical care. Proof of negligence is not required in these cases because the doctrine of Res ipsa loquitur, or "the thing speaks for itself," applies. The characteristics of the surgeon, their style, bedside manner, honesty, and confidence demonstrated in the management of the case can go a long way in averting a lawsuit or mitigating damages.

Wrong-Site Surgery Wrong-site surgery is any surgical procedure performed on the wrong patient, wrong body part, wrong side of the body, or wrong level of a correctly identified anatomic site. It is difficult to determine the true incidence of wrong-site surgery for several reasons. First, there is no standard definition for what constitutes wrong-site surgery among various health care organizations. Another factor is that wrong-site surgery is underreported by health care providers. Finally, the total number of potential opportunities for each type of wrong-site error is unknown. However, various studies show incidences ranging from one in 112,994 cases to one in 15,500 cases. 3 8 The Washington University School of Medicine suggests a rate of one in 17,000 operations, which adds up to approximately 4000 wrong-site surgeries in the United States each year. If these numbers are correct, wrong-site surgery is the third most frequent life-threatening medical error in the United States.3 9 Despite the difficulty in determining the overall incidence of wrong-site surgery, several states now require mandatory reporting of all wrong-site surgery events, including near misses. These data provide some insight into the number of actual errors compared to the number of potential opportunities to perform wrong-site surgery. Of the 427 reports of wrong-site surgery submitted from June 2004 through December 2006 to the Pennsylvania Patient Safety Reporting System, more than 40% of the errors actually reached the patient, and nearly 20% involved completion of a wrong-site procedure.3 8

The risk of performing wrong-site surgery increases when there are multiple surgeons involved in the same operation or multiple procedures are performed on the same patient, especially if the procedures are scheduled or performed on different areas of the body. 3 9 Time pressure, emergency surgery, abnormal patient anatomy, and morbid obesity are also thought to be risk factors.3 9 Communication errors are the root cause in more than 70% of the wrong-site surgeries reported to the Joint Commission.3 8 Other risk factors include receiving an incomplete preoperative assessment because documents are either unavailable or not reviewed for other reasons; having inadequate procedures in place to verify the correct surgical site; or having an organizational culture that lacks teamwork or reveres the surgeon as someone whose judgment should never be questioned.3 8 There is a one in four chance that surgeons who work on symmetric anatomic structures will be involved in a wrong-site error sometime during their careers.3 9 No surgical specialty is immune. The specialties most commonly involved in reporting wrong-site surgeries according to the Joint Commission are orthopedic/podiatric surgery (41%), general surgery (20%), neurosurgery (14%), urology (11%), and maxillofacial, cardiovascular, otolaryngology, and ophthalmology (14%).3 8 Most errors involved symmetric anatomic structures: lower extremities (30%), head/neck (24%), and genital/urinary/pelvic/groin (21%).3 8 Although orthopedic surgery is the most frequently involved, this may be due to the higher volume of cases performed as well as the increased opportunity for lateralization errors inherent in the specialty. In addition, because the American Academy of Orthopaedic Surgeons has historically tried as a professional organization to reduce wrong-site operations, orthopedic surgeons may be more likely to report these events when they do occur.3 9

The Joint Commission Universal Protocol to Ensure Correct Surgery The movement to eliminate wrong-site surgery began among professional orthopedic societies in the mid1990s, when both the Canadian Orthopaedic Association and the American Academy of Orthopaedic Surgeons issued position statements and embarked on educational campaigns to prevent the occurrence of wrong-site surgery within their specialty.3 9 Other organizations that issued position statements advocating for the elimination of wrong-site surgery include the North American Spine Society, the American Academy of Ophthalmology, the Association of Perioperative Registered Nurses, and the American College of Surgeons. After issuing a review of wrong-site surgery in their Sentinel Event Alert in 1998, the Joint Commission made the elimination of wrong-site surgery one of their first National Patient Safety Goals in 2003 and adopted a universal protocol for preventing wrong-site, wrong-procedure, and wrong-person surgery in 2004. The protocol has been endorsed by more than 50 professional associations and organizations. A preoperative "time-out" or "pause for the cause" to confirm the patient, procedure, and site to be operated on before incision was recommended by the Joint Commission and is now mandatory for all ORs in the United States. Elements of the protocol include the following: Verifying the patient's identity Marking the surgical site Using a preoperative site verification process such as a checklist Confirming the availability of appropriate documents and studies before the start of a procedure Taking a brief time-out immediately before skin incision, in which all members of the surgical team actively communicate and provide oral verification of the patient's identity, surgical site, surgical

procedure, administration of preoperative medications, and presence of appropriate medical records, imaging studies, and equipment Monitoring compliance with protocol recommendations Focusing on individual process components of the universal protocol, such as surgical site marking or the time-out, is not enough to prevent wrong-site surgery. Over a 30-month period in Pennsylvania, 21 wrongside errors occurred despite the proper use of time-out procedures, with 12 of these errors resulting in complete wrong-side procedures. During the same period, correct site markings failed to prevent another 16 wrong-site surgeries, of which six were not recognized until after the procedure had been completed.3 9 Site verification begins with the initial patient encounter by the surgeon, continues throughout the preoperative verification process and during multiple critical points in the OR, and requires the active participation of the entire operating team, especially the surgeon and anesthesia provider. Based on a recent review of malpractice claims, two thirds of wrong-site operations could have been prevented by a siteverification protocol.4 0 Despite the proliferation of wrong-site protocols in the last decade, the effectiveness of surgical site verification is difficult to measure. As discussed earlier in this section, the incidence of wrong-site surgery is too rare to measure as a rate. Interestingly, the number of sentinel events reported to the Joint Commission has not changed significantly since the widespread implementation of the Universal Protocol in 2004. 3 9 This could be due to an increase in reporting rather than an actual increase in the incidence of wrong-site surgery. The number of sentinel events reported does not actually indicate whether or not surgical site verification protocols are effective in reducing the likelihood that a patient will be harmed when undergoing surgery. The legal treatment of wrong-site surgery is similar to that of surgical items erroneously left in a patient: The mere fact that wrong-site surgery occurred indicates that the patient did not receive proper surgical care. Proof of negligence is not required in these cases because the doctrine of Res ipsa loquitur, or "the thing speaks for itself," applies. A malpractice claim may lead to a settlement or award on verdict in the 6- or 7figure range in 2005 U.S. dollars.3 9 Ultimately, the occurrence of retained surgical items or wrong-site surgery is a reflection of the quality of professional communication between caregivers and the degree of teamwork among the members of the operating team. In addition to standardizing procedures like the surgical count, instituting mandatory postoperative radiographs in the presence of a known miscount, and reforming the processes of patient identification and site verification, to successfully minimize the risk of wrong-site surgery, organizations should also strive to create a culture of safety, create independent and redundant checks for key processes, and create a system in which caregivers can learn from their mistakes (Table 12-11).4 1

Table 12-11 Best Practices for Operating Room Safety Conduct the Joint Commission Universal Protocol ("time-out") to prevent wrong-site surgery. Perform an operating room briefing (checklist) to identify and mitigate hazards early. Promote a culture of speaking up about safety concerns. Use a screening x-ray to detect foreign bodies in high-risk cases. Begin patient sign-outs with the most likely immediate safety hazard. From Michaels et al, 4 1 with permission.

RISK MANAGEMENT Between one half and two thirds of hospitalwide adverse events are attributable to surgical care. Most surgical errors occur in the OR and are technical in nature, including direct manual errors (such as transection of the ureter during hysterectomy) as well as judgment and knowledge errors leading to performance of an inappropriate, inadequate, or untimely procedure (i.e., performing a simple cholecystectomy for invasive adenocarcinoma of the gallbladder, or failing to intervene promptly in a patient with a leaking aortic aneurysm). Surgical complications and adverse outcomes have previously been linked to lack of surgeon specialization, low hospital volume, communication breakdowns, fatigue, surgical residents and trainees, and numerous other factors.4 2 However, poor surgical outcomes are not necessarily correlated with a surgeon's level of experience in performing a certain procedure. In one study, three fourths of the technical errors that occurred in a review of malpractice claims data involved fully trained and experienced surgeons operating within their area of expertise, and 84% occurred in routine operations that do not require advanced training beyond a standard surgical training program. Rather than surgeon expertise, these errors likely occurred due to situations complicated by patient comorbidity, complex anatomy, repeat surgery, or equipment problems (Table 1212). Because these errors occurred during routine operations, previous suggestions to limit the performance of high-complexity operations using selective referral, regionalization, or limitation of privileging may not actually be effective in reducing the incidence of technical error among surgical patients.4 2

Table 12-12 Common Causes of Lawsuits in Surgery Positional nerve injury Common bile duct injury Failure to diagnose or delayed diagnosis Failure to treat, delayed treatment, or wrong treatment Inadequate documentation Inappropriate surgical indication Failure to call a specialist Cases resulting in amputation/limb loss

In any event, although there has been much emphasis on reducing the prevalence of surgical technical errors as a way of improving surgical care, the occurrence of a technical error in the OR may not be the most important indicator of whether or not a surgeon will be sued by a patient. Recent studies point to the importance of a surgeon's communication skills in averting malpractice litigation. In the American College of Surgeons' Closed Claims Study, although intraoperative organ injuries occurred in 40% of patients, reviewers felt that a surgical technical misadventure was the most deficient component of care in only 12% of patients. In fact, communication and practice pattern violations were the most common deficiency in care identified for one third of the patients in the Closed Claims Study who received the expected standard of surgical care.4 3

The Importance of Communication in Managing Risk The manner and tone in which a physician communicates is potentially more important to avoiding a malpractice claim than the actual content of the dialogue. For example, a physician relating to a patient in a "negative" manner (e.g., using a harsh or impatient tone of voice) may trigger litigious feelings when there is a bad result, whereas a physician relating in a "positive" manner may not. Expressions of dominance, in which the voice tone is generally deep, loud, moderately fast, unaccented, and clearly articulated, may communicate a lack of empathy and understanding for the patient, whereas concern or anxiety in the surgeon's voice is often positively related to expressing concern and empathy. General and orthopedic surgeons whose tone of voice was judged to be more dominant were more likely to have been sued than those who sounded less dominant. 4 4 When significant medical errors do occur, physicians have an ethical and professional responsibility to immediately disclose them to patients. Failure to disclose errors to patients undermines the public confidence in medicine and can create legal liability related to fraud. Physicians' fear of litigation represents a major barrier to error disclosure. However, when handled appropriately, immediate disclosure of errors frequently leads to improved patient rapport, satisfaction, and fewer malpractice claims.4 5 In fact, rapport is the most important factor in determining whether a lawsuit is filed against a physician. In 1987, the Department of Veterans Affairs Hospital in Lexington, Kentucky, implemented the nation's first formal apology and medical error full disclosure program, which called for the hospital and its doctors to work with patients and their families to settle a case. As a result, the hospital improved from having one of the highest malpractice claims totals in the VA system to being ranked among the lowest quartile of a comparative group of similar hospitals for settlement and litigation costs over a 7-year period. Its average payout in 2005 was $16,000 per settlement, vs. the national VA average of $98,000 per settlement, and only two lawsuits went to trial during a 10-year period. As a result of the success of this program, the Department of Veteran Affairs expanded the program to all VA hospitals nationwide in October 2005. This model also was replicated at the University of Michigan Health System with similar results. Its full-disclosure program cut the number of pending lawsuits by one half and reduced litigation costs per case from $65,000 to $35,000, thus saving the hospital approximately $2 million in defense litigation bills each year. In addition, University of Michigan doctors, patients, and lawyers are happier with this system. The cultural shift toward honesty and openness also has led to the improvement of systems and processes to reduce medical errors, especially repeat medical errors.4 6 With regard to risk management, the importance of good communication by surgeons and other care providers cannot be overemphasized. Whether alerting other members of the care team about a patient's

needs, openly discussing any concerns the patient and/or family might have, or disclosing the cause of a medical error, open communication with all parties involved can reduce anger and mistrust of the medical system, the frequency, morbidity, and mortality of preventable adverse events, and the likelihood of litigation.

COMPLICATIONS Despite the increased focus on improving patient safety and minimizing medical errors, it is impossible to eliminate human error entirely. Individual errors can cause minor or major complications during or after a surgical procedure. Although these types of errors may not be publicized as much as wrong-site surgery or a retained surgical item, they can still lead to surgical complications that prolong the course of illness, lengthen hospital stay, and increase morbidity and mortality rates.

Complications in Minor Procedures CENTRAL VENOUS ACCESS CATHETERS Complications of central venous access catheters are common. Steps to decrease complications include the following: Ensure that central venous access is indicated. Experienced (credentialed) personnel should insert the catheter, or should supervise the insertion. Use proper positioning and sterile technique. Controversy exists as to whether or not placing the patient in the Trendelenburg position facilitates access. Central venous catheters should be exchanged only for specific indications (not as a matter of routine) and should be removed as soon as possible. Common complications of central venous access include:

Pneumothorax Occurrence rates from both subclavian and internal jugular vein approaches are 1 to 6%. Pneumothorax rates appear to be higher among the inexperienced but occur with experienced operators as well. If the patient is stable, and the pneumothorax is small (38°C or 100.4°F or 90 beats/min Respiratory rate >20 breaths/min or PaCO2 10% immature forms

PaCO 2 = partial pressure of arterial carbon dioxide. Sepsis is categorized as sepsis, severe sepsis, and septic shock. An oversimplification of sepsis would be to define it as SIRS plus infection. Severe sepsis is defined as sepsis plus signs of cellular hypoperfusion or endorgan dysfunction. Septic shock would then be sepsis associated with hypotension after adequate fluid resuscitation. MODS is the culmination of septic shock and multiple end-organ failure. 107 Usually there is an inciting event (e.g., perforated sigmoid diverticulitis), and as the patient undergoes resuscitation, he or she develops cardiac hypokinesis and oliguric or anuric renal failure, followed by the development of ARDS and eventually septic shock with death. Management of SIRS/MODS includes aggressive global resuscitation and support of end-organ perfusion, correction of the inciting etiology, control of infectious complications, and management of iatrogenic complications.108–110 Drotrecogin

, or recombinant activated protein C, appears to specifically counteract

the cytokine cascade of SIRS/MODS, but its use is still limited.111,112 Other adjuncts for supportive therapy include tight glucose control, low tidal volumes in ARDS, vasopressin in septic shock, and steroid replacement therapy.

Nutritional and Metabolic Support Complications NUTRITION-RELATED COMPLICATIONS A basic principle is to use enteral feeding whenever possible, but complications can intervene such as aspiration, ileus, and to a lesser extent, sinusitis. There is no difference in aspiration rates when a smallcaliber feeding tube is placed transpylorically into the duodenum or if it remains in the stomach. Patients who are fed via nasogastric tubes are at risk for aspiration pneumonia, because these relatively large-bore tubes stent open the esophagus, creating the possibility of gastric reflux. The use of enteric and gastric feeding tubes obviates complications of TPN, such as pneumothorax, line sepsis, upper extremity DVT, and the related expense. There is growing evidence to support the initiation of enteral feeding in the early postoperative period, before the return of bowel function, where it is usually well tolerated. In patients who have had any type of nasal intubation that are having high, unexplained fevers, sinusitis must be entertained as a diagnosis. CT scan of the sinuses is warranted, followed by aspiration of sinus contents so the organism(s) are appropriately treated. Patients who have not been enterally fed for prolonged periods secondary to multiple operations, those who have had enteral feeds interrupted for any other reason, or those with poor enteral access are at risk for the refeeding syndrome, which is characterized by severe hypophosphatemia and respiratory failure. Slow progression of the enteral feeding administration rate can avoid this complication. Common TPN problems are mostly related to electrolyte abnormalities that may develop. These electrolyte errors include deficits or excesses in sodium, potassium, calcium, magnesium, and phosphate. Acid-base abnormalities can also occur with the improper administration of acetate or bicarbonate solutions. The most common cause for hypernatremia in hospitalized patients is underresuscitation, and conversely, hyponatremia is most often caused by fluid overload. Treatment for hyponatremia is fluid restriction in mild or moderate cases and the administration of hypertonic saline for severe cases. An overly rapid correction of the sodium abnormality may result in central pontine myelinolysis, which results in a severe neurologic deficit. Treatment for hyponatremic patients includes fluid restriction to correct the free water deficit by 50% in the first 24 hours. An overcorrection of hyponatremia can result in severe cerebral edema, a neurologic deficit, or seizures.

GLYCEMIC CONTROL In 2001, Van den Berghe and colleagues demonstrated that tight glycemic control by insulin infusion is associated with a 50% reduction in mortality in the critical care setting.113 This prospective, randomized, controlled trial of 1500 patients had two study arms: the intensive-control arm, where the serum glucose was maintained between 80 and 110 mg/dL with insulin infusion; and the control arm, where patients received an insulin infusion only if blood glucose was greater than 215 mg/dL, but serum glucose was then maintained at 180 to 200 mg/dL. The tight glycemic control group had an average serum glucose level of 103 mg/dL, and the average glucose level in the control group was 153 mg/dL. Hypoglycemic episodes (glucose 40°C, (104°F)], anxiety, copious diaphoresis, congestive heart failure (present in about one fourth of episodes), tachycardia (most commonly atrial fibrillation), and hypokalemia (up to 50% of patients) are hallmarks of the disease. The treatment of thyrotoxicosis includes glucocorticoids, propylthiouracil, beta blockade, and iodide (Lugol's solution) delivered in an emergent fashion. As the name suggests, these patients are usually toxic and require supportive measures as well. Acetaminophen, cooling modalities noted in the paragraph above, and vasoactive agents often are indicated.

ISSUES IN CARING FOR OBESE PATIENTS AND PATIENTS AT THE EXTREMES OF AGE Surgery in the obese patient has multiple risks, and it is important to optimize these patients before surgery to minimize these risks. Optimization begins preoperatively with teaching about dietary modifications, exercise, and pulmonary toilet issues. Obese patients often have eccentric left ventricular hypertrophy, right ventricular hypertrophy, and congestive heart failure. Sleep studies and patient history may also reveal significant sleep apnea and gastroesophageal reflux disease. Glycemic control is often poor and contributes significantly to infection and diabetes. The obese patient has a decrease in antithrombin III levels, and a higher risk of DVT and PE. Measures to optimize physiologic function in obese patients include keeping the head of the bed elevated at all times. This can improve the FRC of the lungs by almost a liter, thereby decreasing complications associated with atelectasis and pneumonia. Proper glycemic control via a tight insulin sliding scale is also recommended. Finally, the risk of DVT may be attenuated by immediate use of prophylactic doses of low molecular weight heparin and early ambulation. Issues for surgery in the very young and the very old have many similarities when it comes to potential errors and complications. Perhaps the most notable similarity is the lack of physiologic reserve. The elderly may have end-organ insufficiency, while the young can have underdeveloped or anomalous organ function that may not yet have become manifest. Similarly, the immune responses at the extremes of age are often compromised. This makes diagnosing an infection difficult; elderly adults may not be capable of mounting a febrile response, and young children can often resolve fevers overnight, and the cause may remain undiagnosed. Other alterations in these groups include the amount and distribution of total body water and total body fat. This is important to consider because some medications are predominantly distributed to fat stores, and this deposition may lead to altered drug clearance. Similarly, total body water is decreased and serum concentrations of medications may be higher than anticipated. In both groups there is a lower lean body mass, which may potentiate the adverse effects of some anesthetic agents. Metabolism of various analgesic and anesthetic agents can be protracted, leading to postoperative problems such as prolonged intubation and the need for the administration of reversal agents. Other issues that can lead to complex decision making include those related to communication. Whether due to neurologic impairments, agitation, confusion, or an inability to comprehend a language, these factors associated with the extremes of age increase the potential for medical errors. Open and direct communication with the supporting family members is critical for optimal outcomes in these patient groups.

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68. Franklin RH: Ivor Lewis Lecture, 1975. The advancing frontiers of oesophageal surgery. Ann R Coll Surg Engl 59:284, 1977. [PMID: 327899] 69. Stewart BT, Woods RJ, Collopy BT, et al: Early feeding after elective open colorectal resections: A prospective randomized trial. Aust N Z J Surg 68:125, 1998. [PMID: 9494004] 70. Asao T, Kuwano H, Nakamura J, et al: Gum chewing enhances early recovery from postoperative ileus after laparoscopic colectomy. J Am Coll Surg 195:30, 2002. [PMID: 12113542] 71. Tang CL, Seow-Choen F, Fook-Chong S, et al: Bioresorbable adhesion barrier facilitates early closure of the defunctioning ileostomy after rectal excision: A prospective, randomized trial. Dis Colon Rectum 46:1200, 2003. [PMID: 12972964] 72. Beck DE, Cohen Z, Fleshman JW, et al: A prospective, randomized, multicenter, controlled study of the safety of Seprafilm adhesion barrier in abdominopelvic surgery of the intestine. Dis Colon Rectum 46:1310, 2003. [PMID: 14530667] 73. Smoot RL, Gostout CJ, Rajan E, et al: Is early colonoscopy after admission for acute diverticular bleeding needed? Am J Gastroenterol 98:1996, 2003. [PMID: 14499777] 74. Sorbi D, Gostout CJ, Peura D, et al: An assessment of the management of acute bleeding varices: A multicenter prospective member-based study. Am J Gastroenterol 98:2424, 2003. [PMID: 14638344] 75. Domschke W, Lederer P, Lux G: The value of emergency endoscopy in upper gastrointestinal bleeding: Review and analysis of 2014 cases. Endoscopy 15:126, 1983. [PMID: 6603354] 76. Cash BD: Evidence-based medicine as it applies to acid suppression in the hospitalized patient. Crit Care Med 30:S373, 2002. 77. Lidwig K, Bernhardt J, Steffen H, et al: Contribution of intraoperative cholangiography to incidence and outcome of common bile duct injuries during laparoscopic cholecystectomy. Surg Endosc 16:1098, 2002. Epub 2002 Apr 9. 78. Flum DR, Dellinger EP, Cheadle A, et al: Intraoperative cholangiography and risk of common bile duct injury during cholecystectomy. JAMA 289:1639, 2003. [PMID: 12672731] 79. Yoon, YH, Yi Hsiao-ye, Grant BF, et al: Liver cirrhosis mortality in the United States, 1970-98. National Institute on Alcohol Abuse and Alcoholism. Surveillance Report No. 57, December 2001. 80. Solomon R, Werner C, Mann D, et al: Effects of saline, mannitol, and furosemide to prevent acute decreases in renal function induced by radiocontrast agents. N Engl J Med 331:1416, 1994. [PMID: 7969280]

81. Stevens MA, McCullough PA, Tobin KJ, et al: A prospective randomized trial of prevention measures in patients at high risk for contrast nephropathy: Results of the P.R.I.N.C.E. study. Prevention of radiocontrast induced nephropathy clinical evaluation. J Am Coll Cardiol 33:403, 1999. [PMID: 9973020] 82. Birck R, Krzossok S, Markowetz F, et al: Acetylcysteine for prevention of contrast nephropathy: Metaanalysis. Lancet 362:598, 2003. [PMID: 12944058] 83. Baker CS, Wragg A, Kumar S, et al: A rapid protocol for the prevention of contrast-induced renal dysfunction: The RAPPID study. J Am Coll Cardiol 41:2114, 2003. [PMID: 12821233] 84. Laffan M, O'Connell NM, Perry DJ, et al: Analysis and results of the recombinant factor VIIa extended-use registry. Blood Coagul Fibrinolysis 14:S35, 2003. 85. Hedner U: Dosing with recombinant factor viia based on current evidence. Semin Hematol 41:35, 2004. [PMID: 14872419] 86. Midathada MV, Mehta P, Waner M, et al: Recombinant factor VIIa in the treatment of bleeding. Am J Clin Pathol 121:124, 2004. [PMID: 14750250] 87. Bloomfield GL, Dalton JM, Sugerman HJ, et al: Treatment of increasing intracranial pressure secondary to the acute abdominal compartment syndrome in a patient with combined abdominal and head trauma. J Trauma 39:1168, 1995. [PMID: 7500414] 88. Kron I, Harman PK, Nolan SP: The measurement of intra-abdominal pressure as a criterion for abdominal re-exploration. Ann Surg 199:28, 1984. [PMID: 6691728] 89. Ivatury RR, Porter JM, Simon RJ, et al: Intra-abdominal hypertension after life-threatening penetrating abdominal trauma: Prophylaxis, incidence, and clinical relevance to gastric mucosal pH and abdominal compartment syndrome. J Trauma 44:1016, 1998. [PMID: 9637157] 90. Ivatury RR, Sugerman HJ, Peitzman AB: Abdominal compartment syndrome: Recognition and management. Adv Surg 35:251, 2001. [PMID: 11579814] 91. Saggi BH, Sugerman HJ, Ivatury RR, et al: Abdominal compartment syndrome. J Trauma 45:597, 1998. [PMID: 9751558] 92. Anglen J, Apostoles PS, Christensen G, et al: Removal of surface bacteria by irrigation. J Orthop Res 14:251, 1966. 93. Lewis DA, Leaper DJ, Speller DC: Prevention of bacterial colonization of wounds at operation: Comparison of iodine-impregnated ("Ioban") drapes with conventional methods. J Hosp Infect 5:431, 1984. [PMID: 6085099]

94. O'Rourke E, Runyan D, O'Leary J, et al: Contaminated iodophor in the operating room. Am J Infect Control 31:255, 2003. [PMID: 12806364] 95. Ostrander RV, Brage ME, Botte MJ: Bacterial skin contamination after surgical preparation in foot and ankle surgery. Clin Orthop 406:246, 2003. [PMID: 12579025] 96. Ghogawala Z, Furtado D: In vitro and in vivo bactericidal activities of 10%, 2.5%, and 1% povidoneiodine solution. Am J Hosp Pharm 47:1562, 1990 [PMID: 2368748] 97. Anderson RL, Vess RW, Carr JH: Investigations of intrinsic Pseudomonas cepacia contamination in commercially manufactured povidone-iodine. Infect Control HospEpidemiol 12:297, 1991. [PMID: 1865100] 98. Birnbach DJ, Meadows W, Stein DJ, et al: Comparison of povidone iodine and DuraPrep, an iodophor-inisopropyl alcohol solution, for skin disinfection prior to epidural catheter insertion in parturients. Anesthesiology 98:164, 2003. [PMID: 12502993] 99. Moen MD, Noone MG, Kirson I: Povidone-iodine spray technique versus traditional scrub-paint technique for preoperative abdominal wall preparation. Am J Obstet Gynecol 187:1434, 2002; discussion 1436. 100. Strand CL, Wajsbort RR, Sturmann K: Effect of iodophor vs iodine tincture skin preparation on blood culture contamination rate. JAMA 269:1004, 1993. [PMID: 8429580] 101. Paterson DL, Ko WC, Von Gottberg A, et al: International prospective study of Klebsiella pneumoniae bacteremia: Implications of extended-spectrum beta-lactamase production in nosocomial infections. Ann Intern Med 140:26, 2004. [PMID: 14706969] 102. Wittmann DH, Schein M: Let us shorten antibiotic prophylaxis and therapy in surgery. Am J Surg 172:26S, 1966. 103. Dellinger EP: Duration of antibiotic treatment in surgical infections of the abdomen. Undesired effects of antibiotics and future studies. Eur J Surg Suppl 576:29, 1996; discussion 31. 104. Fry DE: Basic aspects of and general problems in surgical infections. Surg Infect (Larchmt) 2(Suppl 1):S3, 2001. 105. Barie PS: Modern surgical antibiotic prophylaxis and therapy—less is more. Surg Infect (Larchmt) 1:23, 2000. [PMID: 12594906] 106. Grobmyer SR, Graham D, Brennan MF, et al: High-pressure gradients generated by closed-suction surgical drainage systems. Surg Infect (Larchmt) 3:245, 2002. [PMID: 12542925]

107. Power DA, Duggan J, Brady HR: Renal-dose (low-dose) dopamine for the treatment of sepsis-related and other forms of acute renal failure: Ineffective and probably dangerous. Clin Exp Pharmacol Physiol Suppl 26:S23, 1999. 108. Vincent JL, Abraham, E, Annane D, et al: Reducing mortality in sepsis: New directions. Crit Care 6(Suppl 3):S1, 2002. 109. Malay MB, Ashton RC Jr., Landry DW, et al: Low-dose vasopressin in the treatment of vasodilatory septic shock. J Trauma 47:699, 1999; discussion 703. 110. Annane D, Sebille V, Charpentier C, et al: Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 288:862, 2002. [PMID: 12186604] 111. Dhainaut JF, Laterre PF, LaRosa SP, et al: The clinical evaluation committee in a large multicenter phase 3 trial of drotrecogin alfa (activated) in patients with severe sepsis (PROWESS): Role, methodology, and results. Crit Care Med 31:2291, 2003; comment, 2405. 112. Betancourt M, McKinnon PS, Massanari RM, et al: An evaluation of the cost effectiveness of drotrecogin alfa (activated) relative to the number of organ system failures. Pharmacoeconomics 21:1331, 2003. [PMID: 14750900] 113. Van den Berghe G, Wouters P, Weekers F, et al: Intensive insulin therapy in the critically ill patients. N Engl J Med 345:1359, 2001. 114. Finney SJ, Zekveld C, Elia A, et al: Glucose control and mortality in critically ill patients. JAMA 290:2041, 2003. [PMID: 14559958] 115. Furnary AP, Gao G, Grunkemeier GL, et al: Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg 125:1007, 2003. [PMID: 12771873] 116. La Rochelle GE Jr., La Rochelle AG, Ratner RE, et al: Recovery of the hypothalamic-pituitary-adrenal axis in patients with rheumatic diseases receiving low-dose prednisone. Am J Med 95:258, 1993. 117. Bromberg JS, Alfrey EJ, Barker CF, et al: Adrenal suppression and steroid supplementation in renal transplant recipients. Transplantation 51:385, 1991. [PMID: 1847249] 118. Freidman RJ, Schiff CF, Bromberg JS: Use of supplemental steroids in patients having orthopaedic operations. J Bone Joint Surgery 77:1801, 1995. 119. Kempainen RR, Brunette DD: The evaluation and management of accidental hypothermia. Respir Care 49:192, 2004. [PMID: 14744270]

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Note: Large images and tables on this page may necessitate printing in landscape mode. Copyright © The McGraw-Hill Companies. All rights reserved. Schwartz's Principles of Surgery > Chapter 13. Physiologic Monitoring of the Surgical Patient >

KEY POINTS 1. The delivery of modern critical care is predicated on the ability to monitor a large number of physiologic variables and formulate evidenced-based therapeutic strategies to manage these variables. 2. Technologic advances in monitoring have at least a theoretical risk of exceeding our ability to understand the clinical implications of the derived information. This could result in the use of monitoring data to make inappropriate clinical decisions. Therefore, the implementation of any new monitoring technology must take into account the relevance and accuracy of the data obtained, the risks to the patient, as well as the evidence supporting any intervention directed at correcting the detected abnormality. 3. The routine use of invasive monitoring devices, specifically the pulmonary artery catheter, must be questioned in light of the available evidence that does not demonstrate a clear benefit to its widespread use in various populations of critically ill patients. 4. The future of physiologic monitoring will be dominated by the application of noninvasive and highly accurate devices that guide evidenced-based therapy.

BACKGROUND The Latin verb monere, which means "to warn, or advise" is the origin for the English word monitor. In contemporary medical practice, patients undergo monitoring to detect pathologic variations in physiologic parameters, providing advanced warning of impending deterioration in the status of one or more organ systems. The intended goal of this endeavor is that by using this knowledge, the clinician takes appropriate actions in a timely fashion to prevent or ameliorate the physiologic derangement. Furthermore, physiologic monitoring is used not only to warn, but also to titrate therapeutic interventions, such as fluid resuscitation or the infusion of vasoactive or inotropic drugs. Monitoring tools also can be valuable for diagnostic evaluation and assessment of prognosis. The intensive care unit (ICU) and operating room are the two locations where the most advanced monitoring capabilities are routinely used in the care of critically ill patients. In the broadest sense, physiologic monitoring encompasses a spectrum of endeavors, ranging in complexity from the routine and intermittent measurement of the classic vital signs (i.e., temperature, pulse, arterial blood pressure, and respiratory rate) to the continuous recording of the oxidation state of cytochrome oxidase, the terminal element in the mitochondrial electron transport chain. The ability to assess clinically relevant parameters of tissue and organ status and use this knowledge to improve patient outcomes represents the "holy grail" of critical care medicine. Unfortunately, consensus is often lacking regarding the most appropriate parameters to monitor to achieve this goal. Furthermore, making an inappropriate therapeutic decision due to inaccurate physiologic data or misinterpretation of good data can lead to a worse

outcome than having no data at all. Of the highest importance is the integration of physiologic data obtained from monitoring into a coherent and evidenced-based treatment plan. Current technologies available to assist the clinician in this endeavor are summarized in this chapter, as well as a brief look at emerging techniques that may soon enter into clinical practice. In essence, the goal of hemodynamic monitoring is to ensure that the flow of oxygenated blood through the microcirculation is sufficient to support aerobic metabolism at the cellular level. Mammalian cells cannot store oxygen (O 2) for subsequent use in oxidative metabolism, although a relatively tiny amount is stored in muscle tissue as oxidized myoglobin. Thus aerobic synthesis of adenosine triphosphate, the energy "currency" of cells, requires the continuous delivery of O2 by diffusion from hemoglobin (Hgb) in red blood cells to the oxidative machinery within mitochondria. Delivery of O2 to mitochondria may be insufficient for several reasons. For example, cardiac output, Hgb, or the O 2 content of arterial blood can each be inadequate for independent reasons. Alternatively, despite adequate cardiac output, perfusion of capillary networks can be impaired as a consequence of dysregulation of arteriolar tone, microvascular thrombosis, or obstruction of nutritive vessels by sequestered leukocytes or platelets. Hemodynamic monitoring that does not take into account all of these factors will portray an incomplete and perhaps misleading picture of cellular physiology. Under normal conditions when the supply of O2 is plentiful, aerobic metabolism is determined by factors other than the availability of O2. These factors include the hormonal milieu and mechanical workload of contractile tissue. However, in pathologic circumstances when O2 availability is inadequate, O 2 utilization ( O2 )

becomes dependent upon O2 delivery (

O2 ).

The relationship of

O2

to

O2

over a broad range of

values is commonly represented as two intersecting straight lines. In the region of higher slope of the line is approximately equal to zero, indicating that in the region of low

O2

O2

O2

is largely independent of

values, the slope of the line is nonzero and positive, indicating that

O2 . O2

dependent. The region where the two lines intersect is called the point of critical O2 delivery (

O2

values, the In contrast,

is supply

O2crit),

and

represents the transition from supply-independent to supply-dependent O2 uptake. Below this critical threshold of O2 delivery (approximately 4.5 mL/kg per minute), increased O 2 extraction cannot compensate for the delivery deficit; hence, O2 consumption begins to decrease.1 The slope of the supply-dependent region of the plot reflects the maximal O2 extraction capability of the vascular bed being evaluated. The dual-line representation for depicting

O2 - O2

Nevertheless, other approaches for depicting

relationships has proven useful and informative.

O2 - O2

relationships may be equally or even more relevant. For

example, some investigators believe that experimentally derived

O2 - O2

data are optimally characterized by

using the classic Michaelis-Menten relationship for describing the kinetics of an enzymatic reaction, a view that is prompted by the recognition that the oxygen-consuming reaction in mitochondria is catalyzed by an enzyme, cytochrome oxidase.2

ARTERIAL BLOOD PRESSURE The pressure exerted by blood in the systemic arterial system, commonly referred to as blood pressure, is a cardinal parameter measured as part of the hemodynamic monitoring of patients. Extremes in blood pressure are either intrinsically deleterious or are indicative of a serious perturbation in normal physiology. In the past, blood pressure served as a proxy for cardiac output; the term shock was used more or less as a synonym for arterial hypotension. Although it is now known that arterial blood pressure is a complex function of both cardiac output and vascular input impedance, clinicians, especially inexperienced ones, tend to

assume that the presence of a normal blood pressure is evidence that cardiac output and tissue perfusion are adequate. This assumption is frequently incorrect and is the reason why some critically ill patients may benefit from forms of hemodynamic monitoring in addition to measurement of arterial pressure. Blood pressure can be determined directly by measuring the pressure within the arterial lumen or indirectly using a cuff around an extremity. When the equipment is properly set up and calibrated, direct intra-arterial monitoring of blood pressure provides accurate and continuous data. Additionally, intra-arterial catheters provide a convenient way to obtain samples of blood for measurements of arterial blood gases and other laboratory studies. Despite these advantages, intra-arterial catheters are invasive devices and occasionally are associated with serious complications. Noninvasive monitoring of blood pressure is desirable in many circumstances.

Noninvasive Measurement of Arterial Blood Pressure Both manual and automated means for the noninvasive determination of blood pressure use an inflatable cuff to increase pressure around an extremity. If the cuff is too narrow (relative to the extremity), the measured pressure will be artifactually elevated. Therefore, the width of the cuff should be approximately 40% of its circumference. In addition to using a cuff to cause vascular compression and thereby cessation of blood flow, noninvasive means for measuring blood pressure also require some means for detecting the presence or absence of arterial pulsations. Several methods exist for this purpose. The time-honored approach is the auscultation of the Korotkoff sounds, which are heard over an artery distal to the cuff as the cuff is deflated from a pressure higher than systolic pressure to one less than diastolic pressure. Systolic pressure is defined as the pressure in the cuff when tapping sounds are first audible. Diastolic pressure is the pressure in the cuff when audible pulsations first disappear. Another means for pulse detection when measuring blood pressure noninvasively depends upon the detection of oscillations in the pressure within the bladder of the cuff. This approach is simple, and unlike auscultation, can be performed even in a noisy environment (e.g., a busy emergency room). Unfortunately, this approach is neither accurate nor reliable. Other methods, however, can be used to reliably detect the reappearance of a pulse distal to the cuff and thereby estimate systolic blood pressure. Two excellent and widely available approaches for pulse detection are use of a Doppler stethoscope (reappearance of the pulse produces an audible amplified signal) or a pulse oximeter (reappearance of the pulse is indicated by flashing of a light-emitting diode). A number of automated devices are capable of repetitively measuring blood pressure noninvasively. Some of these devices measure pressure oscillations in the inflatable bladder encircling the extremity to detect arterial pulsations as pressure in the cuff is gradually lowered from greater than systolic to less than diastolic pressure.3 Another automated noninvasive device uses a piezoelectric crystal positioned over the brachial artery as a pulse detector.3 According to one clinical study of these approaches, the most accurate is oscillometry combined with stepped deflation of the sphygmomanometric cuff. Using this approach and comparing the results of oscillometry to those obtained by invasive intra-arterial monitoring, errors in the measurement of mean blood pressure greater than 10 or 20 mmHg occur in 0% and 8.5% of readings, respectively.3 Another noninvasive approach for measuring blood pressure relies on a technique called photoplethysmography. This method is capable of providing continuous information because systolic and

diastolic blood pressures are recorded on a beat-to-beat basis. Photoplethysmography uses the transmission of infrared light to estimate the amount of Hgb (directly related to the volume of blood) in a finger placed under a servo-controlled inflatable cuff. A feedback loop controlled by a microprocessor continually adjusts the pressure in the cuff to maintain the blood volume of the finger constant. Under these conditions, the pressure in the cuff reflects the pressure in the digital artery. Although results obtained using photoplethysmography generally agree closely with those obtained by invasive monitoring of blood pressure, the difference between the two methods occasionally can be large (20 to 40 mmHg) in some patients.4 This problem limits the usefulness of photoplethysmography as a stand-alone method for monitoring arterial blood pressure, particularly in high-risk situations. However, if initial photoplethysmographic readings are corrected by comparison with measurements obtained noninvasively by an oscillometric device, then photoplethysmography is sufficiently accurate to be used for continuous monitoring in most situations. 4

Invasive Monitoring of Arterial Blood Pressure Direct monitoring of arterial pressure in critically ill patients may be performed by using fluid-filled tubing to connect an intra-arterial catheter to an external strain-gauge transducer. The signal generated by the transducer is electronically amplified and displayed as a continuous waveform by an oscilloscope. Digital values for systolic and diastolic pressure also are displayed. Mean pressure, calculated by electronically averaging the amplitude of the pressure waveform, also can be displayed. The fidelity of the catheter-tubing-transducer system is determined by numerous factors, including the compliance of the tubing, the surface area of the transducer diaphragm, and the compliance of the diaphragm. If the system is underdamped, then the inertia of the system, which is a function of the mass of the fluid in the tubing and the mass of the diaphragm, causes overshoot of the points of maximum positive and negative displacement of the diaphragm during systole and diastole, respectively. Thus in an underdamped system, systolic pressure will be overestimated and diastolic pressure will be underestimated. In an overdamped system, displacement of the diaphragm fails to track the rapidly changing pressure waveform, and systolic pressure will be underestimated and diastolic pressure will be overestimated. It is important to note that even in an underdamped or overdamped system, mean pressure will be accurately recorded, provided the system has been properly calibrated. For these reasons, when using direct measurement of intra-arterial pressure to monitor patients, clinicians should make clinical decisions based on the measured mean arterial blood pressure. The degree of ringing (i.e., overshoot and undershoot) in a minimally damped system is determined by its resonant frequency. Ideally, the resonant frequency of the system should be at least five times greater than the highest frequency component of the pressure waveform. The resonant frequency can be too low for optimal performance if the connector tubing is too compliant or there are air bubbles in the fluid column between the arterial pressure source and the diaphragm of the transducer. For arterial pressure monitoring, the optimal resonance frequency is higher than is practically obtainable. Therefore, to prevent excessive ringing, some degree of damping is essential. To determine if the combination of resonance frequency and damping is adequate, one can pressurize the system to approximately 300 mmHg by pulling the tab that controls the valve between the monitoring system and the high-pressure bag of flush solution. When the valve is abruptly closed by allowing the tab to snap back into its normal position, a sharp pressure transient will be introduced into the system. The resulting pressure tracing can be observed on a strip chart recording. Damping is optimal if at least two oscillations are observed, and there is at least a threefold decrease in the amplitude of successive oscillations.

The radial artery at the wrist is the site most commonly used for intra-arterial pressure monitoring. It is important to recognize, however, that measured arterial pressure is determined in part by the site where the pressure is monitored. Central (i.e., aortic) and peripheral (e.g., radial artery) pressures typically are different as a result of the impedance and inductance of the arterial tree. Systolic pressures typically are higher and diastolic pressures are lower in the periphery, whereas mean pressure is approximately the same in the aorta and more distal sites. Distal ischemia is an uncommon complication of intra-arterial catheterization. The incidence of thrombosis is increased when larger-caliber catheters are used and when catheters are left in place for an extended period of time. The incidence of thrombosis can be minimized by using a 20-gauge (or smaller) catheter in the radial artery and removing the catheter as soon as feasible. The risk of distal ischemic injury can be reduced by ensuring that adequate collateral flow is present before catheter insertion. At the wrist, adequate collateral flow can be documented by performing a modified version of the Allen test, wherein the artery to be cannulated is digitally compressed while using a Doppler stethoscope to listen for perfusion in the palmar arch vessels. Another potential complication of intra-arterial monitoring is retrograde embolization of air bubbles or thrombi into the intracranial circulation. In order to minimize the risk of this rare but potentially devastating complication, great care should be taken to avoid flushing arterial lines when air is present in the system, and only small volumes of fluid (less than 5 mL) should be used for this purpose. Catheter-related infections can occur with any intravascular monitoring device. However, catheter-related bloodstream infection is a relatively uncommon complication of intra-arterial lines used for monitoring, occurring in 0.4 to 0.7% of catheterizations.5 The incidence increases with longer duration of arterial catheterization.

ELECTROCARDIOGRAPHIC MONITORING The electrocardiogram (ECG) records the electrical activity associated with cardiac contraction by detecting voltages on the body surface. A standard 3-lead ECG is obtained by placing electrodes that correspond to the left arm (LA), right arm (RA), and left leg (LL). The limb leads are defined as lead I (LA-RA), lead II (LL-RA), and lead III (LL-LA). The ECG waveforms can be continuously displayed on a monitor, and the devices can be set to sound an alarm if an abnormality of rate or rhythm is detected. Continuous ECG monitoring is widely available and applied to critically ill and perioperative patients. Monitoring of the ECG waveform is essential in patients with acute coronary syndromes or blunt myocardial injury, because dysrhythmias are the most common lethal complication. In patients with shock or sepsis, dysrhythmias can occur as a consequence of inadequate myocardial O2 delivery or as a complication of vasoactive or inotropic drugs used to support blood pressure and cardiac output. Dysrhythmias can be detected by continuously monitoring the ECG tracing, and timely intervention may prevent serious complications. With appropriate computing hardware and software, continuous ST-segment analysis also can be performed to detect ischemia or infarction. This approach has proven useful to detect silent myocardial ischemia in patients undergoing weaning from mechanical ventilation.6,7 Additional information can be obtained from a 12-lead ECG, which is essential for patients with potential myocardial ischemia or to rule out cardiac complications in other acutely ill patients. Continuous monitoring of the 12-lead ECG now is available and is proving to be beneficial in certain patient populations. In a study of 185 vascular surgical patients, continuous 12-lead ECG monitoring was able to detect transient myocardial ischemic episodes in 20.5% of the patients.7 This study demonstrated that the precordial lead V4, which is

not routinely monitored on a standard 3-lead ECG, is the most sensitive for detecting perioperative ischemia and infarction. To detect 95% of the ischemic episodes, two or more precordial leads were necessary. Thus, continuous 12-lead ECG monitoring may provide greater sensitivity than 3-lead ECG for the detection of perioperative myocardial ischemia, and is likely to become standard for monitoring high-risk surgical patients.

CARDIAC OUTPUT AND RELATED PARAMETERS Bedside catheterization of the pulmonary artery was introduced into clinical practice in the 1970s. Although the pulmonary artery catheter (PAC) initially was used primarily to manage patients with cardiogenic shock and other acute cardiac diseases, indications for this form of invasive hemodynamic monitoring gradually expanded to encompass a wide variety of clinical conditions. Clearly, many clinicians believe that information valuable for the management of critically ill patients is afforded by having a PAC in place. However, unambiguous data in support of this view are scarce, and several studies suggest that bedside pulmonary artery catheterization may not benefit most critically ill patients, and in fact lead to some serous complications, as is discussed in Effect of Pulmonary Artery Catheterization on Outcome below.

Determinants of Cardiac Performance PRELOAD Starling's law of the heart states that the force of muscle contraction depends on the initial length of the cardiac fibers. Using terminology that derives from early experiments using isolated cardiac muscle preparations, preload is the stretch of ventricular myocardial tissue just before the next contraction. Preload is determined by end-diastolic volume (EDV). For the right ventricle, central venous pressure (CVP) approximates right ventricular (RV) end-diastolic pressure (EDP). For the left ventricle, pulmonary artery occlusion pressure (PAOP), which is measured by transiently inflating a balloon at the end of a pressure monitoring catheter positioned in a small branch of the pulmonary artery, approximates left ventricular EDP. The presence of atrioventricular valvular stenosis will alter this relationship. Clinicians frequently use EDP as a surrogate for EDV, but EDP is determined not only by volume but also by the diastolic compliance of the ventricular chamber. Ventricular compliance is altered by various pathologic conditions and pharmacologic agents. Furthermore, the relationship between EDP and true preload is not linear, but rather is exponential.

AFTERLOAD Afterload is another term derived from in vitro experiments using isolated strips of cardiac muscle, and is defined as the force resisting fiber shortening once systole begins. Several factors comprise the in vivo correlate of ventricular afterload, including ventricular intracavitary pressure, wall thickness, chamber radius, and chamber geometry. Because these factors are difficult to assess clinically, afterload is commonly approximated by calculating systemic vascular resistance, defined as mean arterial pressure (MAP) divided by cardiac output.

CONTRACTILITY Contractility is defined as the inotropic state of the myocardium. Contractility is said to increase when the force of ventricular contraction increases at constant preload and afterload. Clinically, contractility is difficult to quantify, because virtually all of the available measures are dependent to a certain degree on preload and

afterload. If pressure-volume loops are constructed for each cardiac cycle, small changes in preload and/or afterload will result in shifts of the point defining the end of diastole. These end-diastolic points on the pressure-versus-volume diagram describe a straight line, known as the isovolumic pressure line. A steeper slope of this line indicates greater contractility.

Placement of the Pulmonary Artery Catheter In its simplest form, the PAC has four channels. One channel terminates in a balloon at the tip of the catheter. The proximal end of this channel is connected to a syringe to permit inflation of the balloon with air. Before insertion of the PAC, the integrity of the balloon should be verified by inflating it. To minimize the risk of vascular or ventricular perforation by the relatively inflexible catheter, it is important to verify that the inflated balloon extends just beyond the tip of the device. A second channel in the catheter contains wires that are connected to a thermistor located near the tip of the catheter. At the proximal end of the PAC, the wires terminate in a fitting that permits connection to appropriate hardware for the calculation of cardiac output using the thermodilution technique (see Measurement of Cardiac Output by Thermodilution below). The final two channels are used for pressure monitoring and the injection of the thermal indicator for determinations of cardiac output. One of these channels terminates at the tip of the catheter; the other terminates 20 cm proximal to the tip. Placement of a PAC requires access to the central venous circulation. Such access can be obtained at a variety of sites, including the antecubital, femoral, jugular, and subclavian veins. Percutaneous placement through either the jugular or subclavian vein generally is preferred. Right internal jugular vein cannulation carries the lowest risk of complications, and the path of the catheter from this site into the right atrium is straight. In the event of inadvertent arterial puncture, local pressure is significantly more effective in controlling bleeding from the carotid artery as compared to the subclavian artery. Nevertheless, it is more difficult to keep occlusive dressings in place on the neck than in the subclavian fossa. Furthermore, the anatomic landmarks in the subclavian position are quite constant, even in patients with anasarca or massive obesity; the subclavian vein is always attached to the deep (concave) surface of the clavicle. In contrast, the appropriate landmarks to guide jugular venous cannulation are sometimes difficult to discern in obese or very edematous patients. However, ultrasonic guidance has been shown to facilitate bedside jugular venipuncture.8 Cannulation of the vein normally is performed percutaneously, using the Seldinger technique. A small-bore needle is inserted through the skin and subcutaneous tissue into the vein. After documenting return of venous blood, a guidewire with a flexible tip is inserted through the needle into the vein and the needle is withdrawn. A dilator/introducer sheath is passed over the wire, and the wire and the dilator are removed. The introducer sheath is equipped with a side port, which can be used for administering fluid. The introducer sheath also is equipped with a diaphragm that permits insertion of the PAC while preventing the backflow of venous blood. The proximal terminus of the distal port of the PAC is connected through low-compliance tubing to a strain-gauge transducer, and the tubing-catheter system is flushed with fluid. While constantly observing the pressure tracing on an oscilloscope, the PAC is advanced with the balloon deflated until respiratory excursions are observed. The balloon is then inflated, and the catheter advanced further, while monitoring pressures sequentially in the right atrium and right ventricle en route to the pulmonary artery. The pressure waveforms for the right atrium, right ventricle, and pulmonary artery are each characteristic and easy to recognize. The catheter is advanced out the pulmonary artery until a damped tracing indicative of the "wedged" position is obtained. The balloon is then deflated, taking care to ensure that a normal

pulmonary arterial tracing is again observed on the monitor; leaving the balloon inflated can increase the risk of pulmonary infarction or perforation of the pulmonary artery. Unnecessary measurements of the PAOP are discouraged as rupture of the pulmonary artery may occur.

Hemodynamic Measurements Even in its simplest embodiment, the PAC is capable of providing clinicians with a remarkable amount of information about the hemodynamic status of patients. Additional information may be obtained if various modifications of the standard PAC are used. By combining data obtained through use of the PAC with results obtained by other means (i.e., blood Hgb concentration and oxyhemoglobin saturation), derived estimates of systemic O2 transport and utilization can be calculated. Direct and derived parameters obtainable by bedside pulmonary arterial catheterization are summarized in Table 13-1. The equations used to calculate the derived parameters are summarized in Table 13-2. The approximate normal ranges for a number of these hemodynamic parameters (in adults) are shown in Table 13-3.

Table 13-1 Directly Measured and Derived Hemodynamic Data Obtainable by Bedside Pulmonary Artery Catheterization Standard PAC

PAC with Additional Feature(s)

Derived Parameters

CVP

S

SV (or SVI)

PAP

QT or QT * (continuous)

SVR (or SVRI)

PAOP

RVEF

PVR (or PVRI)

S

O2

(intermittent)

QT or QT * (intermittent)

O2

(continuous)

RVEDV o2

O2

ER QS/QT

CVP = mean central venous pressure; O2 = systemic oxygen delivery; ER = systemic oxygen extraction ratio; PAC = pulmonary artery catheter; PAOP = pulmonary artery occlusion (wedge) pressure; PAP = pulmonary artery pressure; PVR = pulmonary vascular resistance; PVRI = pulmonary vascular resistance index; QS/QT = fractional pulmonary venous admixture (shunt fraction); QT = cardiac output; QT * = cardiac output indexed to body surface area (cardiac index); RVEDV = right ventricular end-diastolic volume; RVEF = right ventricular ejection fraction; SV = stroke volume; SVI = stroke volume index; S O2 = fractional mixed venous (pulmonary artery) hemoglobin saturation; SVR = systemic vascular resistance; SVRI = systemic vascular resistance index; O2 = systemic oxygen utilization.

Table 13-2 Formulas for Calculation of Hemodynamic Parameters that Can Be Derived by Using Data Obtained by Pulmonary Artery Catheterization QT * (L·min– 1·m– 2) = QT /BSA, where BSA is body surface area (m2) SV (mL) = Q T /HR, where HR is heart rate (min– 1) SVR (dyne·sec·cm– 5) = [(MAP – CVP)

x

80]/QT, where MAP is mean arterial pressure (mmHg)

SVRI (dyne·sec·cm– 5·m– 2) = [(MAP – CVP) PVR (dyne·sec·cm– 5) = [(PAP – PAOP)

x

x

80]/QT*

80]/QT, where PPA is mean pulmonary artery pressure

PVRI (dyne·sec·cm– 5·m– 2) = [(PAP – PAOP)

x

80]/QT *

RVEDV (mL) = SV/RVEF O2

(mL·min– 1·m– 2) = QT *

x

CaO2

O2

(mL·min– 1·m– 2) = QT *

x

(CaO2 – C

x

10, where CaO 2 is arterial oxygen content (mL/dL) O2 ) x

10, where C

O2

is mixed venous oxygen content (mL/dL)

Ca O2 = (1.36 x Hgb x SaO2) + (0.003 + PaO2), where Hgb is hemoglobin concentration (g/dL), SaO2 is fractional arterial hemoglobin saturation, and PaO2 is the partial pressure of oxygen in arterial blood C O2 = (1.36 x Hgb x S O2) + (0.003 + P arterial (mixed venous) blood QS/QT = (CcO2 – CaO2)/(CcO2 – C capillary blood Cc O2 = (1.36

x

O2 ),

O2 ),

where P

O2

is the partial pressure of oxygen in pulmonary

where CcO2 (mL/dL) is the content of oxygen in pulmonary end

Hgb) + (0.003 + PAO 2), where PAO2 is the alveolar partial pressure of oxygen

PAO2 = [FiO2 x (PB – PH2O )] – PaCO 2/RQ, where FiO2 is the fractional concentration of inspired oxygen, PB is the barometric pressure (mmHg), PH2O is the water vapor pressure (usually 47 mmHg), Pa CO2 is the partial pressure of carbon dioxide in arterial blood (mmHg), and RQ is respiratory quotient (usually assumed to be 0.8)

C O2 = central venous oxygen pressure; CVP = mean central venous pressure; O2 = systemic oxygen delivery; PAOP = pulmonary artery occlusion (wedge) pressure; PVR = pulmonary vascular resistance; PVRI = pulmonary vascular resistance index; QS/QT = fractional pulmonary venous admixture (shunt fraction); QT = cardiac output; Q T * = cardiac output indexed to body surface area (cardiac index); RVEDV = right ventricular end-diastolic volume; RVEF = right ventricular ejection fraction; SV = stroke volume; SVI =

stroke volume index; S O2 = fractional mixed venous (pulmonary artery) hemoglobin saturation; SVR = systemic vascular resistance; SVRI = systemic vascular resistance index; O2 = systemic oxygen utilization.

Table 13-3 Approximate Normal Ranges for Selected Hemodynamic Parameters in Adults Parameter

Normal Range

CVP

0–6 mmHg

Right ventricular systolic pressure

20–30 mmHg

Right ventricular diastolic pressure

0–6 mmHg

PAOP

6–12 mmHg

Systolic arterial pressure

100–130 mmHg

Diastolic arterial pressure

60–90 mmHg

MAP

75–100 mmHg

QT

4–6 L/min

QT *

2.5–3.5 L·min– 1·m– 2

SV

40–80 mL

SVR

800–1400 dyne·sec·cm– 5

SVRI

1500–2400 dyne·sec·cm – 5·m– 2

PVR

100–150 dyne·sec·cm– 5

PVRI

200–400 dyne·sec·cm– 5·m– 2

Cao2

16–22 mL/dL

C

~15 mL/dL

O2

O2

400–660 mL·min– 1·m– 2

O2

115–165 mL·min– 1·m– 2

Ca O2 = arterial oxygen content; C O2 = central venous oxygen pressure; CVP = mean central venous pressure; O2 = systemic oxygen delivery; MAP = mean arterial pressure; PAOP = pulmonary artery occlusion (wedge) pressure; PVR = pulmonary vascular resistance; PVRI = pulmonary vascular resistance index; QT = cardiac output; QT * = cardiac output indexed to body surface area (cardiac index); SV = stroke volume; SVI = stroke volume index; SVR = systemic vascular resistance; SVRI = systemic vascular

resistance index;

O2

= systemic oxygen utilization.

Measurement of Cardiac Output by Thermodilution Before the development of the PAC, determining cardiac output (Q T ) at the bedside required careful measurements of O2 consumption (Fick method) or spectrophotometric determination of indocyanine green dye dilution curves. Measurements of QT using the thermodilution technique are simple and reasonably accurate. The measurements can be performed repetitively, and the principle is straightforward. If a bolus of an indicator is rapidly and thoroughly mixed with a moving fluid upstream from a detector, then the concentration of the indicator at the detector will increase sharply and then exponentially diminish back to zero. The area under the resulting time-concentration curve is a function of the volume of indicator injected and the flow rate of the moving stream of fluid. Larger volumes of indicator result in greater areas under the curve, and faster flow rates of the mixing fluid result in smaller areas under the curve. When QT is measured by thermodilution, the indicator is heat and the detector is a temperature-sensing thermistor at the distal end of the PAC. The relationship used for calculating Q T is called the Stewart-Hamilton equation:

where V is the volume of the indicator injected, TB is the temperature of blood (i.e., core body temperature), TI is the temperature of the indicator, K 1 is a constant that is the function of the specific heats of blood and the indicator, K2 is an empirically derived constant that accounts for several factors (the dead space volume of the catheter, heat lost from the indicator as it traverses the catheter, and the injection rate of the indicator), and TB(t)dt is the area under the time-temperature curve. In clinical practice, the StewartHamilton equation is solved by a microprocessor. Determination of cardiac output by the thermodilution method is generally quite accurate, although it tends to systematically overestimate Q T at low values. Changes in blood temperature and Q T during the respiratory cycle can influence the measurement. Therefore, results generally should be recorded as the mean of two or three determinations obtained at random points in the respiratory cycle. Using cold injectate widens the difference between T B and TI and thereby increases signal-to-noise ratio. Nevertheless, most authorities recommend using room temperature injectate (normal saline or 5% dextrose in water) to minimize errors resulting from warming of the fluid as it transferred from its reservoir to a syringe for injection. Technologic innovations have been introduced that permit continuous measurement of QT by thermodilution. In this approach, thermal transients are not generated by injecting a bolus of a cold indicator, but rather by heating the blood with a tiny filament located on the PAC upstream from the thermistor. By correlating the amount of current supplied to the heating element with the downstream temperature of the blood, it is possible to estimate the average blood flow across the filament and thereby calculate QT . Based upon the results of several studies, continuous determinations of QT using this approach agree well with data generated by conventional measurements using bolus injections of a cold indicator.9 Information is lacking regarding the clinical value of being able to monitor QT continuously.

Mixed Venous Oximetry The Fick equation can be written as Q T = and C

O2

= Ca O2 –

O2 /(CaO2

–C

O2 ),

where CaO2 is the content of O2 in arterial blood

is the content of O2 in mixed venous blood. The Fick equation can be rearranged as follows: C O2 /QT .

If the small contribution of dissolved O2 to C

equation can be rewritten as S

O2

= SaO2 –

O2 /(QT x

Hgb

x

O2

O2

and CaO2 is ignored, the rearranged

1.36), where S

O2

is the fractional saturation of

Hgb in mixed venous blood, SaO2 is the fractional saturation of Hgb in arterial blood, and Hgb is the concentration of Hgb in blood. Thus, it can be seen that S SaO2, and Hgb. Accordingly, subnormal values of S

O2

O2

is a function of

(i.e., metabolic rate), QT ,

O2

can be caused by a decrease in QT (due, for example,

to heart failure or hypovolemia), a decrease in SaO2 (due, for example, to intrinsic pulmonary disease), a decrease in Hgb (i.e., anemia), or an increase in metabolic rate (due, for example, to seizures or fever). With a conventional PAC, measurements of S

O2

require aspirating a sample of blood from the distal (i.e.,

pulmonary arterial) port of the catheter and injecting the sample into a blood gas analyzer. Therefore for practical purposes, measurements of S

O2

can be performed only intermittently.

By adding a fifth channel to the PAC, it has become possible to monitor S

O2

continuously. The fifth channel

contains two fiber-optic bundles, which are used to transmit and receive light of the appropriate wavelengths to permit measurements of Hgb saturation by reflectance spectrophotometry. A clinical study of the Abbott Oximetrix PAC has documented that the device provides measurements of S

O2

that agree quite closely with

those obtained by conventional analyses of blood aspirated from the pulmonary artery.1 0 Despite the theoretical value of being able to monitor S

O2

continuously, data are lacking to show that this capability

favorably improves outcome. Indeed, in several studies, the ability to monitor S

O2

was not shown to affect

the management of critically ill patients.11,12 Moreover, in another large study, titrating the resuscitation of critically ill patients to maintain S

O2

greater than 69% (i.e., in the normal range) failed to improve

mortality or change length of ICU stay.1 3 In a recent prospective, observational study of 3265 patients undergoing cardiac surgery with either a standard PAC or a PAC with continuous S

O2

monitoring, the

oximetric catheter was associated with fewer arterial blood gases and thermodilution cardiac output determinations, but no difference in patient outcome.1 4 Because PACs that permit continuous monitoring of S O2

are much more expensive than conventional PACs, the routine use of these devices cannot be

recommended. The saturation of O2 in the right atrium or superior vena cava (ScvO2) correlates closely with S wide range of

conditions,1 5

although the correlation between ScvO2 and S

O2

O2

over a

has recently been

questioned.1 6 Since measurement of ScvO2 requires placement of a central venous catheter (CVC) rather than a PAC, it is somewhat less invasive and easier to carry out. By using a CVC equipped to permit fiberoptic monitoring of ScvO2, it may be possible to titrate the resuscitation of patients with shock using a less invasive device than the PAC.15,17

Right Ventricular Ejection Fraction Ejection fraction (EF) is calculated as (EDV – ESV)/EDV, where ESV is end-systolic volume. EF is an ejectionphase measure of myocardial contractility. By equipping a PAC with a thermistor with a short time constant, the thermodilution method can be used to estimate RVEF. Measurements of RVEF by thermodilution agree reasonably well with those obtained by other means, although values obtained by thermodilution typically are lower than those obtained by radionuclide cardiography.1 8 Stroke volume (SV) is calculated as EDV – ESV. Left ventricular stroke volume (LVSV) also equals QT /HR, where HR is heart rate. Because LVSV is equal to RVSV, it is possible to estimate right ventricular end-diastolic volume by measuring RVEF, QT , and HR. Several studies have attempted to assess the clinical value of RVEF measurements using these catheters. In one study, use of an RVEF catheter did not alter therapy in 93% of patients with sepsis, hemorrhagic shock, or acute respiratory distress syndrome (ARDS), but was useful in cases of abdominal compartment syndrome (ACS) with high PAOP despite low preload.1 9 In a series of 46 trauma patients who required more than 10 L

of fluid in the first 24 hours of resuscitation, there was a better correlation between RV volume and Q T than there was with PAOP. 2 0 However, data are lacking to show that outcomes are improved by making measurements of RVEF in addition to QT and other parameters measured by the conventional PAC.

Effect of Pulmonary Artery Catheterization on Outcome In 1996, Connors and colleagues reported surprising results in a major observational study evaluating the value of pulmonary artery catheterization in critically ill patients.2 1 They took advantage of an enormous data set, which had been previously (and prospectively) collected for another purpose at five major teaching hospitals in the United States. These researchers compared two groups of patients: those who did and those who did not undergo placement of a PAC during their first 24 hours of ICU care. The investigators recognized that the value of their intended analysis was completely dependent on the robustness of their methodology for case-matching, because sicker patients (i.e., those at greater risk of mortality based upon the severity of their illness) were presumably more likely to undergo pulmonary artery catheterization. Accordingly, the authors used sophisticated statistical methods for generating a cohort of study (i.e., PAC) patients, each one having a paired control matched carefully for severity of illness. A critical assessment of their published findings supports the view that the cases and their controls were indeed remarkably well matched with respect to a large number of pertinent clinical parameters. Connors and associates concluded that placement of a PAC during the first 24 hours of stay in an ICU is associated with a significant increase in the risk of mortality, even when statistical methods are used to account for severity of illness. Although the report by Connors and coworkers generated an enormous amount of controversy in the medical community, the results reported actually confirmed the results of two prior similar observational studies. The first of these studies used as a database 3263 patients with acute myocardial infarction treated in central Massachusetts in 1975, 1978, 1981, and 1984 as part of the Worcester Heart Attack Study.2 2 For all patients, hospital mortality was significantly greater for patients treated using a PAC, even when multivariate statistical methods were used to control for key potential confounding factors such as age, peak circulating creatine kinase concentration, and presence or absence of new Q waves on the ECG. The second large observational study of patients with acute myocardial infarction also found that hospital mortality was significantly greater for patients managed with the assistance of a PAC, even when the presence or absence of "pump failure" was considered in the statistical analysis.2 3 In neither of these reports did the authors conclude that placement of a PAC was truly the cause of worsened survival after myocardial infarction. The available prospective, randomized controlled trials of PACization are summarized in Table 13-4. The study by Pearson and associates was underpowered with only 226 patients enrolled.2 4 In addition, the attending anesthesiologists were permitted to exclude patients from the CVP group at their discretion; thus randomization was compromised. The study by Tuman and coworkers was large (1094 patients were enrolled), but different anesthesiologists were assigned to the different groups.2 5 Furthermore, 39 patients in the CVP group underwent placement of a PAC because of hemodynamic complications. All of the individual single-institution studies of vascular surgery patients were relatively underpowered, and all excluded at least certain categories of patients (e.g., those with a history of recent myocardial infarction).26,27

Table 13-4 Summary of Randomized, Prospective Clinical Trials Comparing Pulmonary Artery Catheter with Central Venous Pressure Monitoring Author

Study Population

Groups

Outcomes

Pearson, et "Low-risk" patients al2 4 undergoing cardiac or vascular surgery

CVP catheter (group 1); PAC (group 2); PAC with continuous Sv-O2, readout (group 3)

No differences among groups for mortality or length of ICU stay; significant differences in costs (group 1 < group 2 < group 3)

Tuman, et al2 5

Cardiac surgical patients

PAC; CVP

No differences between groups for mortality, length of ICU stay, or significant noncardiac complications

Bender, et al2 6

Vascular surgery patients

PAC; CVP

No differences between groups for mortality, length of ICU stay, or length of hospital stay

Valentine, et al 2 7

Aortic surgery patients

PAC + hemodynamic optimization in ICU night before surgery; CVP

No difference between groups for mortality or length of ICU stay; significantly higher incidence of postoperative complications in PAC group

Sandham, et al 2 8

"High-risk" major surgery

PAC; CVP

No differences between groups for mortality, length of ICU stay; increased incidence of pulmonary embolism in PAC group

Harvey, et al2 9

Medical and surgical ICU patients

PAC vs. no PAC, with option No difference in hospital mortality for alternative CO measuring between the two groups, increased device in non-PAC group incidence of complications in the PAC group

Binanay, et Patients with CHF al3 1

PAC vs. no PAC

No difference in hospital mortality between the two groups, increased incidence of adverse events in the PAC group

Wheeler, et Patients with ALI al3 2

PAC vs. CVC with a fluid and No difference in ICU or hospital mortality, inotropic management or incidence of organ failure between the protocol two groups; increased incidence of adverse events in the PAC group

ALI = acute lung injury; CHF = congestive heart failure; CO = cardiac output; CVC = central venous catheter; CVP = central venous pressure; ICU = intensive care unit; PAC = pulmonary artery catheter; Sv-O2 = fractional mixed venous (pulmonary artery) hemoglobin saturation. In the largest randomized controlled trial of the PAC, Sandham and associates randomized 1994 American Society of Anesthesiologists class III and IV patients undergoing major thoracic, abdominal, or orthopedic surgery to placement of a PAC or CVP catheter.2 8 In the patients assigned to receive a PAC, physiologic, goal-directed therapy was implemented by protocol. There were no differences in mortality at 30 days, 6

months, or 12 months between the two groups, and ICU length of stay was similar. There was a significantly higher rate of pulmonary emboli in the PAC group (0.9 vs. 0%). This study has been criticized because most of the patients enrolled were not in the highest risk category. In the "PAC-Man" trial, a multicenter, randomized trial in 65 United Kingdom hospitals, more than 1000 ICU patients were managed with or without a PAC.2 9 The specifics of the clinical management were then left up to the treating clinicians. There was no difference in hospital mortality between the two groups (with PAC 68% vs. without PAC 66%, P = .39). However, a 9.5% complication rate was associated with the insertion or use of the PAC, although none of these complications was fatal. Clearly, these were critically ill patients, as noted by the high hospital mortality rates. Supporters of the PAC may cite methodology problems with this study, such as loose inclusion criteria and the lack of a defined treatment protocol. A recent meta-analysis of 13 randomized studies of the PAC that included more than 5000 patients was recently published. 3 0 A broad spectrum of critically ill patients was included in these heterogeneous trials, and the hemodynamic goals and treatment strategies varied. Although the use of the PAC was associated with an increased use of inotropes and vasodilators, there were no differences in mortality or hospital length of stay between the patients managed with a PAC and those managed without a PAC. Next, the ESCAPE trial (which was one of the studies included in the previous meta-analysis)3 1 evaluated 433 patients with severe or recurrent congestive heart failure admitted to the ICU. Patients were randomized to management by clinical assessment and a PAC or clinical assessment without a PAC. The goal in both groups was resolution of congestive heart failure, with additional PAC targets of a pulmonary capillary occlusion pressure of 15 mmHg and a right atrial pressure of 8 mmHg. There was no formal treatment protocol, but inotropic support was discouraged. Substantial reduction in symptoms, jugular venous pressure, and edema was noted in both groups. There was no significant difference in the primary endpoint of days alive and out of the hospital during the first 6 months, or hospital mortality (PAC 10%; vs. without PAC 9%). Adverse events were more common among patients in the PAC group (21.9% vs. 11.5%; P = .04). Finally, the Fluids and Catheters Treatment Trial (FACTT) conducted by the Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network was recently published.3 2 The risks and benefits of PAC compared with CVCs were evaluated in 1000 patients with acute lung injury. Patients were randomly assigned to receive either a PAC or a CVC to guide management for 7 days via an explicit protocol. Patients also were randomly assigned to a conservative or liberal fluid strategy in a 2

x

2 factorial design (outcomes based on

the fluid management strategy were published separately). Mortality during the first 60 days was similar in the PAC and CVC groups (27% and 26%; P = .69). The duration of mechanical ventilation and ICU length of stay also were not influenced by the type of catheter used. The type of catheter used did not affect the incidence of shock, respiratory or renal failure, ventilator settings, or requirement for hemodialysis or vasopressors. There was a 1% rate of crossover from CVC-guided therapy to PAC-guided therapy. The catheter used did not affect the administration of fluids or diuretics, and the fluid balance was similar in the two groups. The PAC group had approximately twice as many catheter-related adverse events (mainly arrhythmias). Few subjects in critical care medicine generate more emotional responses among experts in the field than the use of the PAC. Some experts may be able to use the PAC to titrate vasoactive drugs and IV fluids for specific patients in ways that improve their outcomes. But, as these studies indicate, it is impossible to verify that use of the PAC saves lives when it is evaluated over a large population of patients. Certainly, given the

current state of knowledge, routine use of the PAC cannot be justified. Whether very selective use of the device in a few relatively uncommon clinical situations is warranted or valuable remains a controversial issue. Consequently, a marked decline in the use of the PAC from 5.66 per 1000 medical admissions in 1993 to 1.99 per 1000 medical admissions in 2004 has been seen.3 3 These significant reductions in the use of the PAC were noted for a variety of patients, including those admitted with myocardial infarction, surgical patients, and for patients with septicemia. Based upon the results and exclusion criteria in these prospective randomized trials, reasonable criteria for perioperative monitoring without use of a PAC are presented in Table 13-5.

Table 13-5 Suggested Criteria for Perioperative Monitoring Without Use of a Pulmonary Artery Catheter in Patients Undergoing Cardiac or Major Vascular Surgical Procedures No anticipated need for suprarenal or supraceliac aortic cross-clamping No history of myocardial infarction during 3 mo before operation No history of poorly compensated congestive heart failure No history of coronary artery bypass graft surgery during 6 wk before operation No history of ongoing symptomatic mitral or aortic valvular heart disease No history of ongoing unstable angina pectoris One of the reasons for using a PAC to monitor critically ill patients is to optimize cardiac output and systemic O2 delivery. Defining what constitutes the optimum cardiac output, however, has proven to be difficult. Based upon an extensive observational database and comparisons of the hemodynamic and O2 transport values recorded in survivors and nonsurvivors, Bland and colleagues proposed that "goal-directed" hemodynamic resuscitation should aim to achieve a QT greater than 4.5 L/min per square meter and greater than 600 mL/min per square

meter.3 4

O2

Prompted by these observational findings, a number of

investigators have conducted randomized trials designed to evaluate the effect on outcome of goal-directed as compared to conventional hemodynamic resuscitation. Some studies provide support for the notion that interventions designed to achieve supraphysiologic goals for

O2 ,

O2 ,

and Q T improve outcome.35–37

However, other published studies do not support this view, and a meta-analysis concluded that interventions designed to achieve supraphysiologic goals for O2 transport do not significantly reduce mortality rates in critically ill patients.19,38,39 At this time, supraphysiologic resuscitation of patients in shock cannot be endorsed. There is no simple explanation for the apparent lack of effectiveness of pulmonary artery catheterization. Connors has offered several suggestions.4 0 First, even though bedside pulmonary artery catheterization is quite safe, the procedure is associated with a finite incidence of serious complications, including ventricular arrhythmias, catheter-related sepsis, central venous thrombosis, pulmonary arterial perforation, and as noted above, pulmonary embolism.28,40 The adverse effects of these complications on outcome may equal or even outweigh any benefits associated with using a PAC to guide therapy. Second, the data generated by the PAC may be inaccurate, leading to inappropriate therapeutic interventions. Third, the measurements, even if accurate, are often misinterpreted in practice. A study by Iberti and associates showed that 47% of 496 clinicians were unable to accurately interpret a straightforward recording of a tracing obtained with a PAC,

and 44% could not correctly identify the determinants of systemic

O2 .4 1

A more recent study has confirmed

that even well-trained intensivists are capable of misinterpreting results provided by pulmonary artery catheterization.4 2 Furthermore, the current state of understanding is primitive when it comes to deciding what is the best management for certain hemodynamic disturbances, particularly those associated with sepsis or septic shock. Taking all of this into consideration, it may be that interventions prompted by measurements obtained with a PAC are actually harmful to patients. As a result, the marginal benefit now available by placing a PAC may be quite small. Less invasive modalities are available that can provide clinically useful hemodynamic information. It may be true that aggressive hemodynamic resuscitation of patients, guided by various forms of monitoring, is valuable only during certain critical periods, such as the first few hours after presentation with septic shock or during surgery. For example, Rivers and colleagues reported that survival of patients with septic shock is significantly improved when resuscitation in the emergency department is guided by a protocol that seeks to keep ScvO2 greater than 70%.1 7 Similarly, a study using an ultrasound-based device (see Doppler Ultrasonography below) to assess cardiac filling and SV showed that maximizing SV intraoperatively results in fewer postoperative complications and shorter hospital length of stay.4 3

Minimally Invasive Alternatives to the Pulmonary Artery Catheter Because of the cost, risks, and questionable benefit associated with bedside pulmonary artery catheterization, there has been interest for many years in the development of practical means for less invasive monitoring of hemodynamic parameters. Several approaches have been developed, which have achieved variable degrees of success. None of these methods render the standard thermodilution technique of the PAC obsolete. However, these strategies may contribute to improvements in the hemodynamic monitoring of critically ill patients.

DOPPLER ULTRASONOGRAPHY When ultrasonic sound waves are reflected by moving erythrocytes in the bloodstream, the frequency of the reflected signal is increased or decreased, depending on whether the cells are moving toward or away from the ultrasonic source. This change in frequency is called the Doppler shift, and its magnitude is determined by the velocity of the moving red blood cells. Therefore, measurements of the Doppler shift can be used to calculate red blood cell velocity. With knowledge of both the cross-sectional area of a vessel and the mean red blood cell velocity of the blood flowing through it, one can calculate blood flow rate. If the vessel in question is the aorta, then QT can be calculated as:

where A is the cross-sectional area of the aorta and V(t)dt is the red blood cell velocity integrated over the cardiac cycle. Two approaches have been developed for using Doppler ultrasonography to estimate QT . The first approach uses an ultrasonic transducer, which is manually positioned in the suprasternal notch and focused on the root of the aorta. Aortic cross-sectional area can be estimated using a nomogram, which factors in age, height, and weight, back calculated if an independent measure of QT is available, or by using two-dimensional transthoracic or transesophageal ultrasonography. Although this approach is completely noninvasive, it requires a highly skilled operator to obtain meaningful results, and is labor intensive. Moreover, unless QT measured using thermodilution is used to back-calculate aortic diameter, accuracy using the suprasternal

notch approach is not acceptable.4 4 Accordingly, the method is useful only for obtaining very intermittent estimates of QT , and has not been widely adopted by clinicians. A more promising, albeit more invasive, approach has been introduced. In this method blood flow velocity is continuously monitored in the descending thoracic aorta using a continuous-wave Doppler transducer introduced into the esophagus in sedated or anesthetized patients. The probe is advanced into the esophagus to about 35 cm from the incisors (in adults) and connected to a monitor, which continuously displays the blood flow velocity profile in the descending aorta as well as the calculated QT . To maximize the accuracy of the device, the probe position must be adjusted to obtain the peak velocity in the aorta. To transform blood flow in the descending aorta into QT , a correction factor is applied that is based on the assumption that only 70% of the flow at the root of the aorta is still present in the descending thoracic aorta. Aortic cross-sectional area is estimated using a nomogram based on the patient's age, weight, and height. Results using these methods appear to be reasonably accurate across a broad spectrum of patients. In a multicenter study, good correlation was found between esophageal Doppler and thermodilution (r = 0.95), with a small systematic underestimation (bias 0.24 L/min) using esophageal Doppler.4 5 The ultrasonic device also calculates a derived parameter termed flow time corrected (FTc), which is the systolic flow time in the descending aorta corrected for HR. FTc is a function of preload, contractility, and vascular input impedance. Although it is not a pure measure of preload, Doppler-based estimates of SV and FTc have been used successfully to guide volume resuscitation in high-risk surgical patients undergoing major operations.4 3

IMPEDANCE CARDIOGRAPHY The impedance to flow of alternating electrical current in regions of the body is commonly called bioimpedance. In the thorax, changes in the volume and velocity of blood in the thoracic aorta lead to detectable changes in bioimpedance. The first derivative of the oscillating component of thoracic bioimpedance (dZ/dt) is linearly related to aortic blood flow. On the basis of this relationship, empirically derived formulas have been developed to estimate SV, and subsequently QT , noninvasively. This methodology is called impedance cardiography. The approach is attractive because it is noninvasive, provides a continuous readout of QT , and does not require extensive training for use. Despite these advantages, studies suggest that measurements of QT obtained by impedance cardiography are not sufficiently reliable to be used for clinical decision making and have poor correlation with standard methods such as thermodilution and ventricular angiography.46,47 Impedance cardiography also has been proposed as a way to estimate LVEF, but the results obtained show poor agreement with those obtained by radionuclide ventriculography.48,49 Based upon these data, impedance cardiography cannot be recommended at the present time for hemodynamic monitoring of critically ill patients.

PULSE CONTOUR ANALYSIS Another method for determining cardiac output is an approach called pulse contour analysis for estimating SV on a beat-to-beat basis. The mechanical properties of the arterial tree and SV determine the shape of the arterial pulse waveform. The pulse contour method of estimating QT uses the arterial pressure waveform as an input for a model of the systemic circulation to determine beat-to-beat flow through the circulatory system. The parameters of resistance, compliance, and impedance are initially estimated based on the patient's age and sex, and can be subsequently refined by using a reference standard measurement of QT . The reference standard estimation of QT is obtained periodically using the indicator dilution approach by injecting the indicator into a CVC and detecting the transient increase in indicator concentration in the blood using an arterial catheter.

Measurements of QT based on pulse contour monitoring are comparable in accuracy to standard PACthermodilution methods, but it uses an approach that is less invasive since arterial and central venous, but not transcardiac, catheterization is needed.5 0 Using on-line pressure waveform analysis, the computerized algorithms can calculate SV, QT , systemic vascular resistance, and an estimate of myocardial contractility, the rate of rise of the arterial systolic pressure (dP/dT). The use of pulse contour analysis has been applied using noninvasive photoplethysmographic measurements of arterial pressure. However, the accuracy of this technique has been questioned and its clinical use remains to be determined.5 1

PARTIAL CARBON DIOXIDE REBREATHING Partial carbon dioxide (CO2) rebreathing uses the Fick principle to estimate QT noninvasively. By intermittently altering the dead space within the ventilator circuit via a rebreathing valve, changes in CO 2 production (VCO2) and end-tidal CO2 (ETCO 2) are used to determine cardiac output using a modified Fick equation (QT =

VCO2/

ETCO 2 ).

Commercially available devices use this Fick principle to calculate QT using

intermittent partial CO2 rebreathing through a disposable rebreathing loop. These devices consist of a CO2 sensor based on infrared light absorption, an airflow sensor, and a pulse oximeter. Changes in intrapulmonary shunt and hemodynamic instability impair the accuracy of QT estimated by partial CO2 rebreathing. Continuous in-line pulse oximetry and inspired fraction of inspired O2 (FiO2) are used to estimate shunt fraction to correct QT . Some studies of the partial CO2 rebreathing approach suggest that this technique is not as accurate as thermodilution, the gold standard for measuring QT.50,52 However, other studies suggest that the partial CO2 rebreathing method for determination of QT compares favorably to measurements made using a PAC in critically ill patients.5 3

TRANSESOPHAGEAL ECHOCARDIOGRAPHY Transesophageal echocardiography (TEE) has made the transition from operating room to ICU. TEE requires that the patient be sedated and usually intubated for airway protection. Using this powerful technology, global assessments of LV and RV function can be made, including determinations of ventricular volume, EF, and QT . Segmental wall motion abnormalities, pericardial effusions, and tamponade can be readily identified with TEE. Doppler techniques allow estimation of atrial filling pressures. The technique is somewhat cumbersome and requires considerable training and skill to obtain reliable results.

Assessing Preload Responsiveness Although pulse contour analysis or partial CO 2 rebreathing may be able to provide estimates of SV and QT , these approaches alone can offer little or no information about the adequacy of preload. Thus, if QT is low, some other means must be used to estimate preload. Most clinicians assess the adequacy of cardiac preload by determining CVP or PAOP. However, neither CVP nor PAOP correlate well with the true parameter of interest, left ventricular end-diastolic volume (LVEDV).5 4 Extremely high or low CVP or PAOP results are informative, but readings in a large middle zone (i.e., 5 to 20 mmHg) are not very useful. Furthermore, changes in CVP or PAOP fail to correlate well with changes in SV.5 5 Echocardiography can be used to estimate LVEDV, but this approach is dependent on the skill and training of the individual using it, and isolated measurements of LVEDV fail to predict the hemodynamic response to alterations in preload.5 6 When intrathoracic pressure increases during the application of positive airway pressure in mechanically ventilated patients, venous return decreases, and as a consequence, LVSV also decreases. Therefore, pulse

pressure variation (PPV) during a positive pressure episode can be used to predict the responsiveness of cardiac output to changes in preload.5 7 PPV is defined as the difference between the maximal pulse pressure and the minimum pulse pressure divided by the average of these two pressures. This approach has been validated by comparing PPV, CVP, PAOP, and systolic pressure variation as predictors of preload responsiveness in a cohort of critically ill patients. Patients were classified as being "preload responsive" if their cardiac index increased by at least 15% after rapid infusion of a standard volume of IV fluid.5 8 Receiver-operating characteristic curves demonstrated that PPV was the best predictor of preload responsiveness. Although atrial arrhythmias can interfere with the usefulness of this technique, PPV remains a useful approach for assessing preload responsiveness in most patients because of its simplicity and reliability. 5 6

Tissue Capnometry Global indices of QT ,

O2 ,

or

O2

provide little useful information regarding the adequacy of cellular

oxygenation and mitochondrial function. On theoretical grounds, measuring tissue pH to assess the adequacy of perfusion is an attractive concept. As a consequence of the stoichiometry of the reactions responsible for the substrate level phosphorylation of adenosine diphosphate to form adenosine triphosphate, anaerobiosis is associated with the net accumulation of protons. Accordingly, knowing that tissue pH is not in the acid range should be enough information to conclude that global perfusion as well as arterial O2 content are sufficient to meet the metabolic demands of the cells, even without knowledge of the actual values for tissue blood flow or O2 delivery. The detection of tissue acidosis should alert the clinician to the possibility that perfusion is inadequate. Thus, tonometric measurements of tissue PCO 2 in the stomach or sigmoid colon could be used to estimate mucosal pH (pHi) and thereby monitor visceral perfusion in critically ill patients. Unfortunately, the notion of using tonometric estimates of GI mucosal pHi for monitoring perfusion is predicated on a number of assumptions, some of which may be partially or completely invalid. Furthermore, currently available methods for performing measurements of gastric mucosal P CO2 in the clinical setting remain rather cumbersome and expensive. It is perhaps for these reasons that gastric tonometry for monitoring critically ill patients has primarily been used as a research tool. Tonometric determination of mucosal CO2 tension, PCO2muc, can be used to calculate pHi by using the Henderson-Hasselbalch equation as follows:

where [HCO3–]muc is the concentration of bicarbonate anion in the mucosa. Whereas PCO2muc can be measured with reasonable accuracy and precision using tonometric methods, [HCO3–]muc cannot be measured directly, but must be estimated by assuming that the concentration of bicarbonate anion in arterial blood, [HCO3–]art, is approximately equal to [HCO3–]muc. Under normal conditions, the assumption that [HCO3–]art

[HCO 3–]muc is probably valid. Under pathologic conditions, however, the assumption that

[HCO3–]art

[HCO 3–]muc is almost certainly invalid. For example, when blood flow to the ileal mucosa is very

low, HCO3– in the tissue is titrated by hydrogen ions produced as a result of anaerobic metabolism, and replenishment of tissue HCO3– stores from arterial blood is impeded by stagnant perfusion. Thus under such conditions, [HCO3–]muc is less than [HCO3–]art, and tonometric estimates of pHi based on the HendersonHasselbalch equation underestimate the degree of tissue acidosis present.5 9 There is another inherent problem in using pH i as an index of perfusion. As noted above, pH i calculated using

the Henderson-Hasselbalch equation is a function of both PCO2muc and [HCO3–]art. Under steady-state conditions, the first of these parameters, PCO2muc, reflects the balance between inflow of CO2 into the interstitial space and outflow of CO2 from the interstitial space. CO2 can enter the interstitial compartment via three mechanisms: diffusion of CO2 from arterial blood, production as a result of aerobic metabolism of carbon-containing fuels, and production as a result of titration of HCO3– by protons liberated during anaerobic metabolism. CO2 leaves the interstitial compartment by diffusing into venous blood. If blood flow to the mucosa decreases, then P CO 2muc increases as a result of decreased extraction of CO2 into venous blood. If mucosal perfusion decreases sufficiently, (i.e., to less than the anaerobic threshold for the tissue), then P CO 2muc also increases as a result of increased production due to titration of HCO3–.5 2 Clearly, therefore, an increase in P CO 2muc can reflect a decrease in mucosal perfusion. However, as documented experimentally by Salzman and colleagues, an increase in PCO2muc also can be caused by arterial hypercarbia, leading to increased diffusion of CO2 from arterial blood into the interstitium.6 0 Similarly, changes in [HCO3–]art can occur as a result of factors unrelated to either tissue perfusion or the adequacy of aerobic metabolism (e.g., diabetic ketoacidosis, iatrogenic alkalinization due to administration of sodium bicarbonate solution). For these reasons, tonometrically derived estimates of pHi are not a reliable way to assess mucosal perfusion. Although PCO2 and pH are affected by changes in perfusion in all tissues, efforts to monitor these parameters in patients using tonometric methods have focused on the mucosa of the GI tract, particularly the stomach, for both practical and theoretical reasons. From a practical standpoint, the stomach is already commonly intubated in clinical practice for purposes of decompression and drainage or feeding. However, there are theoretical reasons why monitoring GI mucosal perfusion might be more desirable than monitoring perfusion in other sites. First, when global perfusion is compromised, blood flow to the splanchnic viscera decreases to a greater extent than does perfusion to the body as a whole.6 1 Thus, the finding of compromised splanchnic perfusion may be an indicator of impending adverse changes in blood flow to other organs. Second, the gut has been hypothesized to be the "motor" of the multiple organ dysfunction syndrome (MODS), and in experimental models, intestinal mucosal acidosis, whether due to inadequate perfusion or other causes, has been associated with hyperpermeability to hydrophilic solutes.6 2 Therefore, ensuring adequate splanchnic perfusion might be expected to minimize derangements in gut barrier function and, on this basis, improve outcome for patients. The stomach, however, may not be an ideal location for monitoring tissue PCO2. First, CO2 can be formed in the lumen of the stomach when hydrogen ions secreted by parietal cells in the mucosa titrate luminal bicarbonate anions, which are present either as a result of backwash of duodenal secretions or secretion by gastric mucosal cells. Measurements of gastric PCO2 and pHi can be confounded by gastric acid secretion. 6 3 Consequently, accurate measurements of gastric PCO2 and pHi depend on pharmacologic blockade of luminal proton secretion using histamine receptor antagonists or proton pump inhibitors. The need for using pharmacologic therapy adds to the cost and complexity of the monitoring strategy. Second, enteral feeding can interfere with measurements of gastric mucosal PCO2, necessitating temporary cessation of the administration of nutritional support or the placement of a postpyloric tube.6 4 Despite the problems noted above, measurements of gastric pHi and/or mucosal-arterial PCO2 gap have been proven to be a remarkably reliable predictor of outcome in a wide variety of critically ill individuals, including general medical ICU patients, victims of multiple trauma, patients with sepsis, and patients undergoing major surgical procedures. 65–67 In studies using endoscopic measurements of gastric mucosal blood flow by laser Doppler flowmetry, the development of gastric mucosal acidosis has been shown to correlate with

mucosal hypoperfusion.6 8 Moreover, in a landmark prospective, randomized, multicentric clinical trial of monitoring in medical ICU patients, titrating resuscitation to a gastric pHi endpoint rather than conventional hemodynamic indices resulted in a higher 30-day survival rate. 6 9 In another study, trauma patients were randomized to resuscitation titrated to a gastric pHi greater than 7.30, or to resuscitation titrated to achieve systemic

O2

or

O2

goals.7 0 Although survival was not significantly different in the two arms of the study,

failure to normalize gastric pH i within 24 hours was associated with a high mortality rate (54%), whereas normalization of pHi was associated with a significantly lower mortality rate (7%). There is also interest in measuring tissue capnometry in less invasive sites. Results from some preliminary clinical studies support the view that the monitoring of tissue PCO2 in the sublingual mucosa may provide valuable clinical information. Increased sublingual PCO2 (PslCO 2) was associated with decreases in arterial blood pressure and QT in patients with shock due to hemorrhage or sepsis.7 1 In a study of critically ill patients with septic or cardiogenic shock, the PslCO2-PaCO2 gradient was found to be a good prognostic indicator, being 9.2 ± 5.0 mmHg in the survivors and 17.8 ± 11.5 mmHg in nonsurvivors.7 2 This study also demonstrated that sublingual capnography was superior to gastric tonometry in predicting patient survival. The PslCO2-PaCO2 gradient also correlated with the mixed venous-arterial PCO 2 gradient, but failed to correlate with blood lactate level, mixed venous O 2 saturation (Sv–O2), or systemic

O2 .

These latter findings suggest

that the PslCO2-PaCO2 gradient may be a better marker of tissue hypoxia than are these other parameters.

Near Infrared Spectroscopic Measurement of Tissue Hemoglobin Oxygen Saturation Near infrared spectroscopy (NIRS) allows continuous, noninvasive measurement of tissue Hgb O2 saturation (StO2) using near infrared wavelengths of light (700–1000 nm). This technology is based on Beer's law, which states that the transmission of light through a solution with a dissolved solute decreases exponentially as the concentration of the solute increases. In mammalian tissue, three compounds change their absorption pattern when oxygenated: cytochrome a,a3, myoglobin, and Hgb. Because of the distinct absorption spectra of oxyhemoglobin and deoxyhemoglobin, Beer's law can be used to detect their relative concentrations within tissue. Thus, the relative concentrations of the types of Hgb can be determined by measuring the change in light intensity as it passes through the tissue. Because about 20% of blood volume is intra-arterial and the StO2 measurements are taken without regard to systole or diastole, spectroscopic measurements are primarily indicative of the venous oxyhemoglobin concentration. NIRS has been evaluated to assess the severity of traumatic shock in animal models and in trauma patients. Studies have shown that peripheral muscle StO2, as determined by NIRS, is as accurate as other endpoints of resuscitation [i.e., base deficit (BD), mixed venous O2 saturation] in a porcine model of hemorrhagic shock.7 3 Continuously-measured StO2 has been evaluated in blunt trauma patients as a predictor of the development of multiple organ dysfunction syndrome (MODS) and mortality. 7 4 At seven level 1 trauma centers, 383 patients were prospectively studied. StO2 was monitored for 24 hours after admission along with vital signs and other endpoints of resuscitation such as BD. Minimum StO 2 (using a minimum StO2 =75% as a cutoff) had a similar sensitivity and specificity in predicting the development of MODS as BD =6 mEq/L. StO2 and BD were also comparable in predicting mortality. Thus, NIRS-derived muscle StO2 measurements perform similarly to BD in identifying poor perfusion and predicting the development of MODS or death after severe torso trauma, yet have the additional advantages of being continuous and noninvasive. Ongoing prospective studies will help determine the clinical use of continuous monitoring of StO2 in clinical scenarios such as trauma, hemorrhagic shock, sepsis, etc.

RESPIRATORY MONITORING The ability to monitor various parameters of respiratory function is of utmost importance in critically ill patients. Many of these patients require mechanical ventilation. Monitoring of their respiratory physiology is necessary to assess the adequacy of oxygenation and ventilation, guide weaning and liberation from mechanical ventilation, and detect adverse events associated with respiratory failure and mechanical ventilation. These parameters include gas exchange, neuromuscular activity, respiratory mechanics, and patient effort.

Arterial Blood Gases The standard for respiratory monitoring has been to carry out intermittent measurements of arterial blood gases. Blood gas analysis provides useful information when caring for patients with respiratory failure. However, even in the absence of respiratory failure or the need for mechanical ventilation, blood gas determinations also can be valuable to detect alterations in acid-base balance due to low QT , sepsis, renal failure, severe trauma, medication or drug overdose, or altered mental status. Arterial blood can be analyzed for pH, PO2, PCO2, HCO3– concentration, and calculated BD. When indicated, carboxyhemoglobin and methemoglobin levels also can be measured. In recent years, efforts have been made to decrease the unnecessary use of arterial blood gas analysis. Serial arterial blood gas determinations are not necessary for routine weaning from mechanical ventilation in the majority of postoperative patients. Most bedside blood gas analyses still involve removal of an aliquot of blood from the patient, although continuous bedside arterial blood gas determinations are now possible without sampling via an indwelling arterial catheter that contains a biosensor. In studies comparing the accuracy of continuous arterial blood gas and pH monitoring with a conventional laboratory blood gas analyzer, excellent agreement between the two methods has been demonstrated. 7 5 Continuous monitoring can reduce the volume of blood loss due to phlebotomy and dramatically decrease the time necessary to obtain blood gas results. Continuous monitoring, however, is expensive and is not widely used.

Determinants of Oxygen Delivery The primary goal of the cardiovascular and respiratory systems is to deliver oxygenated blood to the tissues. O2

is dependent to a greater degree on the O2 saturation of Hgb in arterial blood (SaO2) than on the partial

pressure of O 2 in arterial blood (Pa O2).

O2

also is dependent on QT and Hgb. Dissolved O2 in blood, which is

proportional to the PaO2, makes only a negligible contribution to

O2 ,

as is apparent from the equation:

SaO2 in mechanically ventilated patients depends on the mean airway pressure, the fraction of inspired O2 (Fi O2), and Sv–O2. Thus, when SaO2 is low, the clinician has only a limited number of ways to improve this parameter. The clinician can increase mean airway pressure by increasing positive end-expiratory pressure (PEEP) or inspiratory time. FiO2 can be increased to a maximum of 1.0 by decreasing the amount of room air mixed with the O2 supplied to the ventilator. Sv–O2 can be increased by increasing Hgb or Q T or decreasing O2 use (e.g., by administering a muscle relaxant and sedation).

Peak and Plateau Airway Pressure Airway pressures are routinely monitored in mechanically ventilated patients. The peak airway pressure

measured at the end of inspiration (Ppeak) is a function of the tidal volume, the resistance of the airways, lung/chest wall compliance, and peak inspiratory flow. The airway pressure measured at the end of inspiration when the inhaled volume is held in the lungs by briefly closing the expiratory valve is termed the plateau airway pressure (Pplateau). As a static parameter, plateau airway pressure is independent of the airway resistance and peak airway flow, and is related to the lung/chest wall compliance and delivered tidal volume. Mechanical ventilators monitor Ppeak with each breath and can be set to trigger an alarm if the Ppeak exceeds a predetermined threshold. Pplateau is not measured routinely with each delivered tidal volume, but rather is measured intermittently by setting the ventilator to close the exhalation circuit briefly at the end of inspiration and record the airway pressure when airflow is zero. If both Ppeak and Pplateau are increased (and tidal volume is not excessive), then the problem is a decrease in the compliance in the lung/chest wall unit. Common causes of this problem include pneumothorax, hemothorax, lobar atelectasis, pulmonary edema, pneumonia, acute respiratory distress syndrome (ARDS), active contraction of the chest wall or diaphragmatic muscles, abdominal distention, and intrinsic PEEP, such as occurs in patients with bronchospasm and insufficient expiratory times. When Ppeak is increased but Pplateau is relatively normal, the primary problem is an increase in airway resistance, such as occurs with bronchospasm, use of a small-caliber endotracheal tube, or kinking or obstruction of the endotracheal tube. A low Ppeak also should trigger an alarm, as it suggests a discontinuity in the airway circuit involving the patient and the ventilator. Ventilator-induced lung injury is now an established clinical entity of great relevance to the care of critically ill patients. Excessive airway pressure and tidal volume adversely affect pulmonary and possibly systemic responses to critical illness. Subjecting the lung parenchyma to excessive pressure, known as barotrauma, can result in parenchymal lung injury, diffuse alveolar damage similar to ARDS, and pneumothorax, and can impair venous return and therefore limit cardiac output. Lung-protective ventilation strategies have been developed to prevent the development of ventilator-induced lung injury and improve patient outcomes. In a large, multicenter randomized trial of patients with ARDS from a variety of etiologies, limiting plateau airway pressure to less than 30 cm H2O and tidal volume to less than 6 mL/kg of ideal body weight reduced 28-day mortality by 22% relative to a ventilator strategy that used a tidal volume of 12 mL/kg.7 6 For this reason, monitoring of plateau pressure and using a low tidal volume strategy in patients with ARDS is now the standard of care.

Pulse Oximetry The pulse oximeter is a microprocessor-based device that integrates oximetry and plethysmography to provide continuous noninvasive monitoring of the O2 saturation of arterial blood (SaO2). It is considered one of the most important and useful technologic advances in patient monitoring. Continuous, noninvasive monitoring of arterial O2 saturation is possible using light-emitting diodes and sensors placed on the skin. Pulse oximetry uses two wavelengths of light (i.e., 660 nm and 940 nm) to analyze the pulsatile component of blood flow between the light source and sensor. Because oxyhemoglobin and deoxyhemoglobin have different absorption spectra, differential absorption of light at these two wavelengths can be used to calculate the fraction of O2 saturation of Hgb. Under normal circumstances, the contributions of carboxyhemoglobin and methemoglobin are minimal. However, if carboxyhemoglobin levels are elevated, the pulse oximeter will incorrectly interpret carboxyhemoglobin as oxyhemoglobin and the arterial saturation displayed will be falsely elevated. When the concentration of methemoglobin is markedly increased, the SaO2 will be displayed as 85%, regardless of the true arterial saturation.7 7 The accuracy of pulse oximetry begins

to decline at SaO2 values less than 92%, and tends to be unreliable for values less than 85%. 7 8 Several studies have assessed the frequency of arterial O2 desaturation in hospitalized patients and its effect on outcome. For example, in a study of general medical patients, Bowton and associates found that patients who had an episode of hypoxemia (SaO2 25 mmHg. The groups had similar mean daily ICP and CPP levels. The mortality rate in the historical controls treated with standard ICP and CPP management was 44%. Mortality was significantly lower in the patients who had therapy guided by PbtO2 monitoring in addition to ICP and CPP (25%; P or = 50 years of age: A prospective, randomized trial. Crit Care Med 26:1011, 1998. [PMID: 9635648] 38. Heyland DK, Cook DJ, King D, et al: Maximizing oxygen delivery in critically ill patients: A methodologic appraisal of the evidence. Crit Care Med 24:517, 1996. [PMID: 8625644] 39. Alia I, Esteban A, Gordo F, et al: A randomized and controlled trial of the effect of treatment aimed at maximizing oxygen delivery in patients with severe sepsis or septic shock. Chest 115:453, 1999. [PMID: 10027447] 40. Connors AF Jr.: Right heart catheterization: Is it effective? New Horiz 5:195, 1997. [PMID: 9259330] 41. Iberti TJ, Fischer EP, Leibowitz AB, et al: A multicenter study of physicians' knowledge of the pulmonary artery catheter. Pulmonary Artery Catheter Study Group. JAMA 264:2928, 1990. [PMID: 2232089] 42. Gnaegi A, Feihl F, Perret C: Intensive care physicians' insufficient knowledge of right-heart catheterization at the bedside: Time to act? Crit Care Med 25:213, 1997. [PMID: 9034253] 43. Gan TJ, Soppitt A, Maroof M, et al: Goal-directed intraoperative fluid administration reduces length of hospital stay after major surgery. Anesthesiology 97:820, 2002. [PMID: 12357146] 44. Cerny JC, Ketslakh M, Poulos CL, et al: Evaluation of the Velcom-100 pulse Doppler cardiac output computer. Chest 100:143, 1991. [PMID: 2060334] 45. Valtier B, Cholley BP, Belot JP, et al: Noninvasive monitoring of cardiac output in critically ill patients using transesophageal Doppler. Am J Respir Crit Care Med 158:77, 1998. [PMID: 9655710] 46. Genoni M, Pelosi P, Romand JA, et al: Determination of cardiac output during mechanical ventilation by electrical bioimpedance or thermodilution in patients with acute lung injury: Effects of positive end-expiratory pressure. Crit Care Med 26:1441, 1998. [PMID: 9710107]

47. Imhoff M, Lehner JH, Lohlein D: Noninvasive whole-body electrical bioimpedance cardiac output and invasive thermodilution cardiac output in high-risk surgical patients. Crit Care Med 28:2812, 2000. [PMID: 10966255] 48. Marik PE, Pendelton JE, Smith R: A comparison of hemodynamic parameters derived from transthoracic electrical bioimpedance with those parameters obtained by thermodilution and ventricular angiography. Crit Care Med 25:1545, 1997. [PMID: 9295830] 49. Miles DS, Gotshall RW, Quinones JD, et al: Impedance cardiography fails to measure accurately left ventricular ejection fraction. Crit Care Med 18:221, 1990. [PMID: 2298016] 50. Mielck F, Buhre W, Hanekop G, et al: Comparison of continuous cardiac output measurements in patients after cardiac surgery. J Cardiothorac Vasc Anesth 17:211, 2003. [PMID: 12698404] 51. Remmen JJ, Aengevaeren WR, Verheugt FW, et al: Finapres arterial pulse wave analysis with Modelflow is not a reliable non-invasive method for assessment of cardiac output. Clin Sci(Lond) 103:143, 2002. [PMID: 12149105] 52. van Heerden PV, Baker S, Lim SI, et al: Clinical evaluation of the non-invasive cardiac output (NICO) monitor in the intensive care unit. Anaesth Intensive Care 28:427, 2000. 53. Odenstedt H, Stenqvist O, Lundin S: Clinical evaluation of a partial CO2 rebreathing technique for cardiac output monitoring in critically ill patients. Acta AnaesthesiolScand 46:152, 2002. [PMID: 11942862] 54. Godje O, Peyerl M, Seebauer T, et al: Central venous pressure, pulmonary capillary wedge pressure and intrathoracic blood volumes as preload indicators in cardiac surgery patients. Eur J Cardiothorac Surg 13:533, 1998. [PMID: 9663534] 55. Lichtwarck-Aschoff M, Zeravik J, Pfeiffer UJ: Intrathoracic blood volume accurately reflects circulatory volume status in critically ill patients with mechanical ventilation. Intensive Care Med 18:142, 1992. [PMID: 1644961] 56. Gunn SR, Pinsky MR. Implications of arterial pressure variation in patients in the intensive care unit. Curr Opin Crit Care 7:212, 2001. [PMID: 11436530] 57. Michard F, Chemla D, Richard C, et al: Clinical use of respiratory changes in arterial pulse pressure to monitor the hemodynamic effects of PEEP. Am J Respir Crit Care Med 159:935, 1999. [PMID: 10051276] 58. Michard F, Boussat S, Chemla D, et al: Relation between respiratory changes in arterial pulse pressure and fluid responsiveness in septic patients with acute circulatory failure. Am J Respir Crit Care Med 162:134, 2000. [PMID: 10903232]

59. Antonsson JB, Boyle CC III, Kruithoff KL, et al: Validation of tonometric measurement of gut intramural pH during endotoxemia and mesenteric occlusion in pigs. Am J Physiol 259:G519, 1990. 60. Salzman AL, Strong KE, Wang H, et al: Intraluminal "balloonless" air tonometry: A new method for determination of gastrointestinal mucosal carbon dioxide tension. Crit Care Med 22:126, 1994. [PMID: 8124955] 61. Reilly PM, Wilkins KB, Fuh KC, et al: The mesenteric hemodynamic response to circulatory shock: An overview. Shock 15:329, 2001. [PMID: 11336191] 62. Fink MP: Intestinal epithelial hyperpermeability: Update on the pathogenesis of gut mucosal barrier dysfunction in critical illness. Curr Opin Crit Care 9:143, 2003. [PMID: 12657978] 63. Kolkman JJ, Groeneveld AB, Meuwissen SG: Gastric PCO2 tonometry is independent of carbonic anhydrase inhibition. Dig Dis Sci 42:99, 1997. [PMID: 9009122] 64. Levy B, Perrigault PF, Gawalkiewicz P, et al: Gastric versus duodenal feeding and gastric tonometric measurements. Crit Care Med 26:1991, 1998. [PMID: 9875909] 65. Bjorck M, Hedberg B: Early detection of major complications after abdominal aortic surgery: Predictive value of sigmoid colon and gastric intramucosal pH monitoring. Br J Surg 81:25, 1994. [PMID: 8313112] 66. Roumen RM, Vreugde JP, Goris RJ: Gastric tonometry in multiple trauma patients. J Trauma 36:313, 1994. [PMID: 8145309] 67. Miller PR, Kincaid EH, Meredith JW, et al: Threshold values of intramucosal pH and mucosal-arterial CO2 gap during shock resuscitation. J Trauma 45:868, 1998. [PMID: 9820694] 68. Elizalde JI, Hernandez C, Llach J, et al: Gastric intramucosal acidosis in mechanically ventilated patients: Role of mucosal blood flow. Crit Care Med 26:827, 1998. [PMID: 9590311] 69. Gutierrez G, Palizas F, Doglio G, et al: Gastric intramucosal pH as a therapeutic index of tissue oxygenation in critically ill patients. Lancet 339:195, 1992. [PMID: 1346170] 70. Ivatury RR, Simon RJ, Islam S, et al: A prospective randomized study of end points of resuscitation after major trauma: Global oxygen transport indices versus organ-specific gastric mucosal pH. J Am Coll Surg 183:145, 1996. [PMID: 8696546] 71. Weil MH, Nakagawa Y, Tang W, et al: Sublingual capnometry: A new noninvasive measurement for diagnosis and quantitation of severity of circulatory shock. Crit Care Med 27:1225, 1999. [PMID: 10446813] 72. Marik PE: Sublingual capnography: A clinical validation study. Chest 120:923, 2001. [PMID: 11555530]

73. Crookes BA, Cohn SM, Burton EA, et al: Noninvasive muscle oxygenation to guide fluid resuscitation after traumatic shock. Surgery 135:662, 2004. [PMID: 15179373] 74. Cohn SM, Nathens AB, Moore FA, et al: Tissue oxygen saturation predicts the development of organ dysfunction during traumatic shock resuscitation. J Trauma 62:44, 2007. [PMID: 17215732] 75. Haller M, Kilger E, Briegel J, et al: Continuous intra-arterial blood gas and pH monitoring in critically ill patients with severe respiratory failure: A prospective, criterion standard study. Crit Care Med 22:580, 1994. [PMID: 8143467] 76. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 342:1301, 2000. 77. Tremper KK: Pulse oximetry. Chest 95:713, 1989. [PMID: 2647421] 78. Shoemaker WC, Belzberg H, Wo CC, et al: Multicenter study of noninvasive monitoring systems as alternatives to invasive monitoring of acutely ill emergency patients. Chest 114:1643, 1998. [PMID: 9872201] 79. Bowton DL, Scuderi PE, Haponik EF: The incidence and effect on outcome of hypoxemia in hospitalized medical patients. Am J Med 97:38, 1994. [PMID: 8030655] 80. Jubran A, Tobin MJ: Monitoring during mechanical ventilation. Clin Chest Med 17:453, 1996. [PMID: 8875007] 81. Ivatury RR, Porter JM, Simon RJ, et al: Intra-abdominal hypertension after life-threatening penetrating abdominal trauma: Prophylaxis, incidence, and clinical relevance to gastric mucosal pH and abdominal compartment syndrome. J Trauma 44:1016, 1998. [PMID: 9637157] 82. The Brain Trauma Foundation. The American Association of Neurological Surgeons. The Joint Section on Neurotrauma and Critical Care: Indications for intracranial pressure monitoring. J Neurotrauma 17:479, 2000. 83. The Brain Trauma Foundation. The American Association of Neurological Surgeons. The Joint Section on Neurotrauma and Critical Care: Recommendations for intracranial pressure monitoring technology. J Neurotrauma 17:497, 2000. 84. Juul N, Morris GF, Marshall SB, et al: Intracranial hypertension and cerebral perfusion pressure: Influence on neurological deterioration and outcome in severe head injury. The Executive Committee of the International Selfotel Trial. J Neurosurg 92:1, 2000. [PMID: 10616075]

85. Eisenberg HM, Frankowski RF, Contant CF, et al: High-dose barbiturate control of elevated intracranial pressure in patients with severe head injury. J Neurosurg 69:15, 1988. [PMID: 3288723] 86. The Brain Trauma Foundation. The American Association of Neurological Surgeons. The Joint Section on Neurotrauma and Critical Care: Guidelines for cerebral perfusion pressure. J Neurotrauma 17:507, 2000. 87. Cremer OL, van Dijk GW, van Wensen E, et al: Effect of intracranial pressure monitoring and targeted intensive care on functional outcome after severe head injury. Crit Care Med 33:2207, 2005. [PMID: 16215372] 88. Sigl JC, Chamoun NG: An introduction to bispectral analysis for the electroencephalogram. J Clin Monit 10:392, 1994. [PMID: 7836975] 89. Gan TJ, Glass PS, Windsor A, et al: Bispectral index monitoring allows faster emergence and improved recovery from propofol, alfentanil, and nitrous oxide anesthesia. BIS Utility Study Group. Anesthesiology 87:808, 1997. [PMID: 9357882] 90. Simmons LE, Riker RR, Prato BS, et al: Assessing sedation during intensive care unit mechanical ventilation with the Bispectral Index and the Sedation-Agitation Scale. Crit Care Med 27:1499, 1999. [PMID: 10470756] 91. Qureshi AI, Sung GY, Razumovsky AY, et al: Early identification of patients at risk for symptomatic vasospasm after aneurysmal subarachnoid hemorrhage. Crit Care Med 28:984, 2000. [PMID: 10809270] 92. Czosnyka M, Matta BF, Smielewski P, et al: Cerebral perfusion pressure in head-injured patients: A noninvasive assessment using transcranial Doppler ultrasonography. J Neurosurg 88:802, 1998. [PMID: 9576246] 93. Feldman Z, Robertson CS: Monitoring of cerebral hemodynamics with jugular bulb catheters. Crit Care Clin 13:51, 1997. [PMID: 9012576] 94. Vigue B, Ract C, Benayed M, et al: Early SjVo2 monitoring in patients with severe brain trauma. Intensive Care Med 25:445, 1999. [PMID: 10401936] 95. McCormick PW, Stewart M, Goetting MG, et al: Noninvasive cerebral optical spectroscopy for monitoring cerebral oxygen delivery and hemodynamics. Crit Care Med 19:89, 1991. [PMID: 1986896] 96. Stiefel MF, Spiotta A, Gracias VH, et al: Reduced mortality rate in patients with severe traumatic brain injury treated with brain tissue oxygen monitoring. J Neurosurg 103:805, 2005. [PMID: 16304983]

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Print CloseWindow Note: Large images and tables on this page may necessitate printing in landscape mode. Copyright The McGraw-Hill Companies.All rights reserved. Schwartz's Principles of Surgery >Chapter 14. Minimally Invasive Surgery, Robotics, and Natural Orifice Transluminal Endoscopic Surgery>

KEY POINTS 1. Minimally invasive surgery describes a philosophical approach to surgery in which access trauma is minimized without compromising the quality of the surgical procedure. 2. Minimally invasive surgery is dependent upon videoscopic, ultrasonographic, radiologic, and magnetic resonance imaging. 3. The carbon dioxide pneumoperitoneum used for laparoscopy induces some unique pathophysiologic consequences. 4. Training for laparoscopy requires practice outside of the operating room in a simulation laboratory and/or in animal models. 5. Laparoscopy during pregnancy is best performed in the second trimester and is safe if appropriate monitoring is performed. 6. Laparoscopic surgery for cancer is also appropriate if good tissue handling techniques are maintained. 7. Robotic surgery has been most valuable in the pelvis for performance of minimally invasive prostatectomy and gynecologic and fertility procedures. 8. Natural orifice transluminal endoscopic surgery represents a new opportunity to develop truly scar-free surgery.

MINIMALLY INVASIVE SURGERY, ROBOTICS, AND NATURAL ORIFICE TRANSLUMINAL ENDOSCOPIC SURGERY: INTRODUCTION Minimally invasive surgery describes an area of surgery that crosses all traditional disciplines, from general surgery to neurosurgery. It is not a discipline unto itself, but more a philosophy of surgery, a way of thinking. Minimally invasive surgery is a means of performing major operations through small incisions, often using miniaturized, hightech imaging systems, to minimize the trauma of surgical exposure. Some believe that the term minimal access surgery more accurately describes the small incisions generally necessary to gain access to surgical sites in hightech surgery, but John Wickham's term minimally invasive surgery (MIS) is widely used because it describes the paradox of postmodern high-tech surgery—small holes, big operations—and the "minimalness" of the access and invasiveness of the procedures, captured in three words. Robotic surgery today is practiced using a single platform (Intuitive, Inc., Sunnyvale, CA) and should better be termed computer enhanced surgery as the term robotics assumes autonomous action that is not a feature of the da

Vinci robotic system. Instead, the da Vinci robot couples an ergonomic workstation that features stereoptic video imaging and intuitive micromanipulators (surgeon side) with a set of arms delivering specialized laparoscopic instruments enhanced with more degrees of freedom than is allowed by laparoscopic surgery alone (patient side). A computer between the surgeon side and patient side removes surgical tremor and scales motion to allow precise microsurgery, helpful for microdissection and difficult anastomoses. Natural orifice transluminal endoscopic surgery (NOTES) is a recent extension of interventional endoscopy. Using the mouth, the anus, the vagina, and the urethra (natural orifices), flexible endoscopes are passed through the wall of the esophagus, stomach, colon, bladder, or vagina entering the mediastinum, the pleural space, or the peritoneal cavity. The advantage of this method of minimal access is principally the elimination of the scar associated with laparoscopy or thoracoscopy. Other advantages are yet to be elucidated, including pain reduction, need for hospitalization, and cost savings.

HISTORICAL BACKGROUND Although the term minimally invasive surgery is relatively recent, the history of its component parts is nearly 100 years old. What is considered the newest and most popular variety of MIS, laparoscopy, is, in fact, the oldest. Primitive laparoscopy, placing a cystoscope within an inflated abdomen, was first performed by Kelling in 1901.1 Illumination of the abdomen required hot elements at the tip of the scope and was dangerous. In the late 1950s, Hopkins described the rod lens, a method of transmitting light through a solid quartz rod with no heat and little light loss.1 Around the same time, thin quartz fibers were discovered to be capable of trapping light internally and conducting it around corners, opening the field of fiber-optics and allowing the rapid development of flexible endoscopes. 2,3 In the 1970s, the application of flexible endoscopy grew faster than that of rigid endoscopy except in a few fields such as gynecology and orthopedics.4 By the mid-1970s, rigid and flexible endoscopes made a rapid transition from diagnostic instruments to therapeutic ones. The explosion of video-assisted surgery in the past 20 years was a result of the development of compact, high-resolution, charge-coupled devices (CCDs) that could be mounted on the internal end of flexible endoscopes or on the external end of a Hopkins telescope. Coupled with bright light sources, fiber-optic cables, and high-resolution video monitors, the videoendoscope has changed our understanding of surgical anatomy and reshaped surgical practice. Flexible endoscopic imaging started in the 1960s with the first bundling of many quartz fibers into bundles, one for illumination and one for imaging. The earliest upper endoscopes revolutionized the diagnosis and treatment of gastroesophageal reflux, peptic ulcer disease, and made possible early detection of upper and lower GI cancer at a stage that could be cured. The first endoscopic surgical procedure was the colonoscopic polypectomy, developed by Shinya and Wolfe, two surgeons from New York City. The percutaneous endoscopic gastrostomy (PEG) invented by Gauderer and Ponsky may have been the first NOTES procedure, reported in 1981.5 Endoscopic pancreatic pseudocyst drainage is thought to be the next NOTES procedure developed; however, there was little energy and money put into the development of NOTES until a number of gastroenterologists claimed the ability to remove the gallbladder with a flexible endoscope, using a transgastric technique. With this pronouncement, the surgical community "woke up" and seized the momentum for NOTES research and development. Although optical imaging produced the majority of MIS procedures, other (traditionally radiologic) imaging technologies allowed the development of innovative procedures in the 1970s. Fluoroscopic imaging allowed the adoption of percutaneous vascular procedures, the most revolutionary of which was balloon angioplasty. Balloonbased procedures spread into all fields of medicine used to open up clogged lumens with minimal access. Stents were then developed that were used in many disciplines to keep the newly ballooned segment open. The

culmination of fluoroscopic balloon and stent proficiency is exemplified by the transvenous intrahepatic portosystemic shunt and by the aortic stent graft, which has nearly replaced open elective abdominal aortic aneurysm repair. MIS procedures using ultrasound imaging have been limited to fairly crude exercises, such as fragmenting kidney stones and freezing liver tumors, because of the relatively low resolution of ultrasound devices. Newer, highresolution ultrasound methods with high-frequency crystals may act as a guide while performing minimally invasive resections of individual layers of the intestinal wall. Axial imaging, such as computed tomography (CT), has allowed the development of an area of MIS that often is not recognized because it requires only a CT scanner and a long needle. CT-guided drainage of abdominal fluid collections and percutaneous biopsy of abnormal tissues are minimally invasive means of performing procedures that previously required a celiotomy. CT-guided percutaneous radiofrequency (RF) ablation has emerged as a useful treatment for primary and metastatic liver tumors. This procedure also is performed laparoscopically under ultrasound guidance.6 A powerful, noninvasive method of imaging that will allow the development of the least invasive—and potentially noninvasive—surgery is magnetic resonance imaging (MRI). MRI is an extremely valuable diagnostic tool, but it is only slowly coming to be of therapeutic value. One obstacle to the use of MRI for MIS is that image production and refreshment of the image as a procedure progresses are slow. Another is that all instrumentation must be nonmetallic when working with the powerful magnets of an MRI scanner. Moreover, MRI magnets are bulky and limit the surgeon's access to the patient. Open magnets have been developed that allow the surgeon to stand between two large MRI coils, obtaining access to the portion of the patient being scanned. The advantage of MRI, in addition to the superb images produced, is that there is no radiation exposure to patient or surgeon. Some neurosurgeons are accumulating experience using MRI to perform frameless stereotactic surgery. Robotic surgery has been dreamed about for some time, and many "Rube Goldberg" devices have been developed over the years to provide mechanical assistance for the surgeon. The first computer-assisted robot, the "RoboDoc" was designed to accurately drill femoral shaft bone for wobble-free placement of hip prostheses. Although the name was appealing, the robot proved no better than a skilled orthopedic surgeon and was a good deal slower. Following this, the first and only two commercially successful robots for laparoscopic surgery were in development in California. Computer Motion, founded by Yulun Wang in Santa Barbara, used National Science Foundation funds to create a mechanical arm, the Aesop robot, which held and moved the laparoscope with voice, foot, or hand control. In Northern California, a master-slave system first developed for surgery on the multinational space station by Philip Green was purchased by Fred Moll and Lonnie Smith, then re-engineered with the surgeon in mind to create a remarkably intuitive computer-enhanced surgical platform. The company, Intuitive Surgical, was aptly named, and their primary product, the da Vinci robot, is the only major "robotic" surgical device currently on the market. Although eschewed by many experienced laparoscopists, the da Vinci achieved a toehold among many skilled surgeons who found that the robot could facilitate MIS procedures that were difficult with standard laparoscopic procedures.

PHYSIOLOGY AND PATHOPHYSIOLOGY OF MINIMALLY INVASIVE SURGERY Even with the least invasive of the MIS procedures, physiologic changes occur. Many minimally invasive procedures

require minimal or no sedation, and there are few adverse consequences to the cardiovascular, endocrinologic, or immunologic systems. The least invasive of such procedures include stereotactic biopsy of breast lesions and flexible GI endoscopy. Minimally invasive procedures that require general anesthesia have a greater physiologic impact because of the anesthetic agent, the incision (even if small), and the induced pneumoperitoneum.

Laparoscopy The unique feature of laparoscopic surgery is the need to lift the abdominal wall from the abdominal organs. Two methods have been devised for achieving this.7 The first, used by most surgeons, is a pneumoperitoneum. Throughout the early twentieth century, intraperitoneal visualization was achieved by inflating the abdominal cavity with air, using a sphygmomanometer bulb. 8 The problem with using air insufflation is that nitrogen is poorly soluble in blood and is slowly absorbed across the peritoneal surfaces. Air pneumoperitoneum was believed to be more painful than nitrous oxide (N2 O) pneumoperitoneum, but less painful than carbon dioxide (CO2 ) pneumoperitoneum. Subsequently, carbon dioxide and N 2 O were used for inflating the abdomen. N2 O had the advantage of being physiologically inert and rapidly absorbed. It also provided better analgesia for laparoscopy performed under local anesthesia when compared with CO2 or air.9 Despite initial concerns that N2 O would not suppress combustion, controlled clinical trials have established its safety within the peritoneal cavity.1 0 In addition, N2 O has been shown to reduce the intraoperative end-tidal CO2 and minute ventilation required to maintain homeostasis when compared to CO 2 pneumoperitoneum.1 0 The effect of N2 O on tumor biology and the development of port site metastasis are unknown. As such, caution should be exercised when performing laparoscopic cancer surgery with this agent. Finally, the safety of N 2 O pneumoperitoneum in pregnancy has yet to be elucidated. The physiologic effects of CO2 pneumoperitoneum can be divided into two areas: (a) gas-specific effects and (b) pressure-specific effects (Fig. 14-1). CO2 is rapidly absorbed across the peritoneal membrane into the circulation. In the circulation, CO2 creates a respiratory acidosis by the generation of carbonic acid.1 1 Body buffers, the largest reserve of which lies in bone, absorb CO2 (up to 120 L) and minimize the development of hypercarbia or respiratory acidosis during brief endoscopic procedures.1 1 Once the body buffers are saturated, respiratory acidosis develops rapidly, and the respiratory system assumes the burden of keeping up with the absorption of CO2 and its release from these buffers.

Fig. 14-1.

Carbon dioxide gas insufflated into the peritoneal cavity has both local and systemic effects that cause a complex set of hemodynamic and metabolic alterations. [Reproduced with permission from Hunter JG (ed): Baillieres Clinical Gastroenterology Laparoscopic Surgery . London/Philadelphia: Bailliere Tindall, 1993, p 758.]

In patients with normal respiratory function, this is not difficult; the anesthesiologist increases the ventilatory rate or vital capacity on the ventilator. If the respiratory rate required exceeds 20 breaths per minute, there may be less efficient gas exchange and increasing hypercarbia. 1 2 Conversely, if vital capacity is increased substantially, there is a greater opportunity for barotrauma and greater respiratory motion-induced disruption of the upper abdominal operative field. In some situations, it is advisable to evacuate the pneumoperitoneum or reduce the intra-abdominal pressure to allow time for the anesthesiologist to adjust for hypercarbia. 1 3 Although mild respiratory acidosis probably is an insignificant problem, more severe respiratory acidosis leading to cardiac arrhythmias has been reported.1 4 Hypercarbia also causes tachycardia and increased systemic vascular resistance, which elevates blood pressure and increases myocardial oxygen demand.11,14 The pressure effects of the pneumoperitoneum on cardiovascular physiology also have been studied. In the hypovolemic individual, excessive pressure on the inferior vena cava and a reverse Trendelenburg position with loss of lower extremity muscle tone may cause decreased venous return and decreased cardiac output. 11,15 This is not seen in the normovolemic patient. The most common arrhythmia created by laparoscopy is bradycardia. A rapid stretch of the peritoneal membrane often causes a vagovagal response with bradycardia and, occasionally, hypotension.1 6 The appropriate management of this event is desufflation of the abdomen, administration of vagolytic agents (e.g., atropine), and adequate volume replacement.1 7 With the increased intra-abdominal pressure compressing the inferior vena cava, there is diminished venous return from the lower extremities. This has been well documented in the patient placed in the reverse Trendelenburg position for upper abdominal operations. Venous engorgement and decreased venous return promote venous thrombosis.18,19 Many series of advanced laparoscopic procedures in which deep venous thrombosis (DVT) prophylaxis was not used demonstrate the frequency of pulmonary embolus. This usually is an avoidable complication with the use of sequential compression stockings, subcutaneous heparin, or low molecular weight

heparin.2 0 In short-duration laparoscopic procedures, such as appendectomy, hernia repair, or cholecystectomy, the risk of DVT may not be sufficient to warrant extensive DVT prophylaxis. The increased pressure of the pneumoperitoneum is transmitted directly across the paralyzed diaphragm to the thoracic cavity, creating increased central venous pressure and increased filling pressures of the right and left sides of the heart. If the intra-abdominal pressures are kept under 20 mmHg, the cardiac output usually is well maintained. 19–21 The direct effect of the pneumoperitoneum on increasing intrathoracic pressure increases peak inspiratory pressure, pressure across the chest wall, and also, the likelihood of barotrauma. Despite these concerns, disruption of blebs and consequent pneumothoraces are rare after uncomplicated laparoscopic surgery.2 1 Pneumothoraces occurring with laparoscopic esophageal surgery may be very significant. The pathophysiology and management are discussed at the end of this section. Increased intra-abdominal pressure decreases renal blood flow, glomerular filtration rate, and urine output. These effects may be mediated by direct pressure on the kidney and the renal vein.22,23 The secondary effect of decreased renal blood flow is to increase plasma renin release, thereby increasing sodium retention. Increased circulating antidiuretic hormone levels also are found during the pneumoperitoneum, increasing free water reabsorption in the distal tubules.2 4 Although the effects of the pneumoperitoneum on renal blood flow are immediately reversible, the hormonally mediated changes such as elevated antidiuretic hormone levels decrease urine output for up to 1 hour after the procedure has ended. Intraoperative oliguria is common during laparoscopy, but the urine output is not a reflection of intravascular volume status; IV fluid administration during an uncomplicated laparoscopic procedure should not be linked to urine output. Because insensible fluid losses through the open abdomen are eliminated with laparoscopy, the need for supplemental fluid during a laparoscopic surgical procedure should only keep up with venous pooling in the lower limbs, third-space losses into the bowel, and blood loss, which is generally less than occurs with an equivalent open operation. The hemodynamic and metabolic consequences of pneumoperitoneum are well tolerated by healthy individuals for a prolonged period and by most individuals for at least a short period. Difficulties can occur when a patient with compromised cardiovascular function is subjected to a long laparoscopic procedure. It is during these procedures that alternative approaches should be considered or insufflation pressure reduced. Alternative gases that have been suggested for laparoscopy include the inert gases helium, neon, and argon. These gases are appealing because they cause no metabolic effects, but are poorly soluble in blood (unlike CO2 and N2 O) and are prone to create gas emboli if the gas has direct access to the venous system.1 9 Gas emboli are rare but serious complications of laparoscopic surgery.20,25 They should be suspected if hypotension develops during insufflation. Diagnosis may be made by listening (with an esophageal stethoscope) for the characteristic "mill wheel" murmur. The treatment of gas embolism is to place the patient in a left lateral decubitus position with the head down to trap the gas in the apex of the right ventricle.2 0 A rapidly placed central venous catheter then can be used to aspirate the gas out of the right ventricle. In some situations, minimally invasive abdominal surgery should be performed without insufflation. This has led to the development of an abdominal lift device that can be placed through a 10- to 12-mm trocar at the umbilicus.2 6 These devices have the advantage of creating little physiologic derangement, but they are bulky and intrusive. The exposure and working room offered by lift devices also are inferior to those accomplished by pneumoperitoneum. Lifting the anterior abdominal wall causes a "pinching in" of the lateral flank walls, displacing the bowel medially and anteriorly into the operative field. A pneumoperitoneum, with its well-distributed intra-abdominal pressure, provides better exposure. Abdominal lift devices also cause more postoperative pain, but they do allow the performance of MIS with standard (nonlaparoscopic) surgical instruments.

Endocrine responses to laparoscopic surgery are not always intuitive. Serum cortisol levels after laparoscopic operations are often higher than after the equivalent operation performed through an open incision.2 7 The greatest difference between the endocrine response of open and laparoscopic surgery is the more rapid equilibration of most stress-mediated hormone levels after laparoscopic surgery. Immune suppression also is less after laparoscopy than after open surgery. There is a trend toward more rapid normalization of cytokine levels after a laparoscopic procedure than after the equivalent procedure performed by celiotomy.2 8 Transhiatal mobilization of the distal esophagus is commonly performed as a component of many laparoscopic upper abdominal procedures. If there is compromise of the mediastinal pleura with resultant CO2 pneumothorax, the defect should be enlarged so as to prevent a tension pneumothorax. Even with such a strategy, tension pneumothorax may develop, as mediastinal structures may seal the hole during inspiration, allowing the chest to fill during expiration. In addition to enlargement of the hole, a thoracostomy tube (chest tube) should be placed across the breach into the abdomen with intra-abdominal pressures reduced below 8 mmHg, or a standard chest tube may be placed. When a pneumothorax occurs with laparoscopic Nissen fundoplication or Heller myotomy, it is preferable to place an 18 F red rubber catheter with multiple side holes cut out of the distal end across the defect. At the end of the procedure, the distal end of the tube is pulled out a 10-mm port site (as the port is removed), and the pneumothorax is evacuated to a primitive water seal using a bowl of sterile water or saline. During laparoscopic esophagectomy, it is preferable to leave a standard chest tube, as residual intra-abdominal fluid will tend to be siphoned through the defect postoperatively, if the tube is removed at the end of the case.

Thoracoscopy The physiology of thoracic MIS (thoracoscopy) is different from that of laparoscopy. Because of the bony confines of the thorax, it is unnecessary to use positive pressure when working in the thorax.2 9 The disadvantages of positive pressure in the chest include decreased venous return, mediastinal shift, and the need to keep a firm seal at all trocar sites. Without positive pressure, it is necessary to place a double-lumen endotracheal tube so that the ipsilateral lung can be deflated when the operation starts. By collapsing the ipsilateral lung, working space within the thorax is obtained. Because insufflation is unnecessary in thoracoscopic surgery, it can be beneficial to use standard instruments via extended port sites in conjunction with thoracoscopic instruments. This approach is particularly useful when performing advanced procedures such as thoracoscopic anatomic pulmonary resection.

Extracavitary Minimally Invasive Surgery Many MIS procedures create working spaces in extrathoracic and extraperitoneal locations. Laparoscopic inguinal hernia repair usually is performed in the anterior extraperitoneal Retzius space.30,31 Laparoscopic nephrectomy often is performed with retroperitoneal laparoscopy. Endoscopic retroperitoneal approaches to pancreatic necrosectomy have seen some limited use.3 2 Lower extremity vascular procedures and plastic surgical endoscopic procedures require the development of working space in unconventional planes, often at the level of the fascia, sometimes below the fascia, and occasionally in nonanatomic regions.3 3 Some of these techniques use insufflation of gas, but many use balloon inflation to develop the space, followed by low-pressure gas insufflation or lift devices to maintain the space (Fig. 14-2). These techniques produce fewer and less severe adverse physiologic consequences than does the pneumoperitoneum, but the insufflation of carbon dioxide into extraperitoneal locations can spread widely, causing subcutaneous emphysema and metabolic acidosis.

Fig. 14-2.

Balloons are used to create extra-anatomic working spaces. In this example (A through C ), a balloon is introduced into the space between the posterior rectus sheath and the rectus abdominal muscle. The balloon is inflated in the preperitoneal space to create working room for extraperitoneal endoscopic hernia repair.

Anesthesia

Proper anesthesia management during laparoscopic surgery requires a thorough knowledge of the pathophysiology of the CO2 pneumoperitoneum.1 7 The laparoscopic surgeon can influence cardiovascular performance by reducing or removing the CO2 pneumoperitoneum. Insensible fluid losses are negligible, and therefore, IV fluid administration should not exceed that necessary to maintain circulating volume. MIS procedures are often outpatient procedures, so short-acting anesthetic agents are preferable. Because the factors that require hospitalization after laparoscopic procedures include the management of nausea, pain, and urinary retention, the anesthesiologist should minimize the use of agents that provoke these conditions and maximize the use of medications that prevent such problems. Critical to the anesthesia management of these patients is the use of nonnarcotic analgesics (e.g., ketorolac) when hemostasis allows it, and the liberal use of antiemetic agents, including ondansetron and steroids.

The Minimally Invasive Team From the beginning, the tremendous success of MIS was founded on the understanding that a team approach was necessary. The many laparoscopicprocedures performed daily range from basic to advanced complexity, and require that the surgical team have an intimate understanding of the operative conduct (Table 14-1). Minimally invasive procedures require complicated and fragile equipment that demands constant maintenance. In addition, multiple intraoperative adjustments to the equipment, camera, insufflator, monitors, and patient/surgeon position are made during these procedures. As such, a coordinated team approach is mandated to ensure patient safety and excellent outcomes. More and more, flexible endoscopes are used to guide or provide quality control for laparoscopic procedures. As NOTES evolves, hybrid procedures (laparoscopy and endoscopy) and sophisticated NOTES technology will require a nursing staff capable of maintaining flexible endoscopes and understanding the operation of sophisticated endoscopic technology.

Table 14-1 Laparoscopic Surgical Procedures Appendectomy Nissen fundoplication Cholecystectomy Heller myotomy Hernia repair Gastrectomy Esophagectomy Enteral access Bile duct exploration Colectomy Splenectomy Adrenalectomy Nephrectomy Lymph node dissection

Robotics Stereo imaging Telemedicine Laparoscopy-assisted procedures Hepatectomy Pancreatectomy Prostatectomy Hysterectomy Basic

Advanced

A typical MIS team may consist of a laparoscopic surgeon and an operating room (OR) nurse with an interest in laparoscopic and endoscopic surgery. Adding dedicated assistants and circulating staff with an intimate knowledge of the equipment will add to and enhance the team nucleus. Studies have demonstrated that having a designated laparoscopic team increases the efficiency and safety of laparoscopic surgery, which is translated into a benefit for patient and hospital.3 4

Room Setup and the Minimally Invasive Suite Nearly all MIS, whether using fluoroscopic, ultrasound, or optical imaging, incorporates a video monitor as a guide. Occasionally, two images are necessary to adequately guide the operation, as in procedures such as endoscopic retrograde cholangiopancreatography, laparoscopic common bile duct exploration, and laparoscopic ultrasonography. When two images are necessary, the images should be displayed on two adjacent video monitors or projected on a single screen with a picture-in-picture effect. The video monitor(s) should be set across the operating table from the surgeon. The patient should be interposed between the surgeon and the video monitor; ideally, the operative field also lies between the surgeon and the monitor. In pelviscopic surgery it is best to place the video monitor at the patient's feet, and in laparoscopic cholecystectomy, the monitor is placed at the 10 o'clock position (relative to the patient) while the surgeon stands on the patient's left at the 4 o'clock position. The insufflating and patient-monitoring equipment ideally also is placed across the table from the surgeon, so that the insufflating pressure and the patient's vital signs and end-tidal CO 2 tension can be monitored. The development of the minimally invasive surgical suite has been a tremendous contribution to the field of laparoscopy in that it has facilitated the performance of advanced procedures and techniques (Fig. 14-3). By having the core equipment (monitors, insufflators, and imaging equipment) located within mobile, ceiling-mounted consoles, the surgery team is able to accommodate and make small adjustments rapidly and continuously throughout the procedure. The specifically designed minimally invasive surgical suite serves to decrease equipment and cable disorganization, ease the movements of operative personnel around the room, improve ergonomics, and facilitate the use of advanced imaging equipment such as laparoscopic ultrasound.3 5 Although having a minimally

invasive surgical suite available is very useful, it is not essential to successfully carry out advanced laparoscopic procedures.

Fig. 14-3.

An example of a typical minimally invasive surgery suite. All core equipment is located on easily movable consoles.

Patient Positioning Patients usually are placed in the supine position for laparoscopic surgery. When the operative field is the gastroesophageal junction or the left lobe of the liver, it is easiest to operate from between the legs. The legs may be elevated in Allen stirrups or abducted on leg boards to achieve this position. When pelvic procedures are performed, it usually is necessary to place the legs in Allen stirrups to gain access to the perineum. A lateral decubitus position with the table flexed provides the best access to the retroperitoneum when performing nephrectomy or adrenalectomy. For laparoscopic splenectomy, a 45-tilt of the patient provides excellent access to the lesser sac and the lateral peritoneal attachments to the spleen. For thoracoscopic surgery, the patient is placed in the lateral position with table flexion to open the intercostal spaces and the distance between the iliac crest and costal margin (Fig. 14-4).

Fig. 14-4.

Proper padding and protection of pressure points is an essential consideration in laparoscopic and thoracoscopic approaches. In preparation for thoracoscopy, this patient is placed in left lateral decubitus position with the table flexed, which serves to open the intercostal spaces and increase the distance between the iliac crest and the inferior costal margin.

When the patient's knees are to be bent for extended periods or the patient is going to be placed in a reverse Trendelenburg position for more than a few minutes, DVT prophylaxis should be used. Sequential compression of the lower extremities during prolonged (>90 minutes) laparoscopic procedures increases venous return and provides inhibition of thromboplastin activation.

General Principles of Access The most natural ports of access for MIS and NOTES are the anatomic portals of entry and exit. The nares, mouth, urethra, and anus are used to access the respiratory, GI, and urinary systems. The advantage of using these points of access is that no incision is required. The disadvantages lie in the long distances between the orifice and the region of interest. For NOTES procedures, the vagina may serve as another point of access, entering the abdomen via the posterior cul–de-sac of the pelvis. Similarly, the peritoneal cavity may be reached through the side wall of the stomach or colon. Access to the vascular system may be accomplished under local anesthesia by cutting down and exposing the desired vessel, usually in the groin. Increasingly, vascular access is obtained with percutaneous techniques using a small incision, a needle, and a guidewire, over which are passed a variety of different sized access devices. This approach, known as the Seldinger technique , is most frequently used by general surgeons for placement of Hickman catheters, but also is used to gain access to the arterial and venous system for performance of minimally invasive procedures. Guidewire-assisted, Seldinger-type techniques also are helpful for gaining access to the gut for procedures such as PEG, for gaining access to the biliary system through the liver, and for gaining access to the

upper urinary tract. In thoracoscopic surgery, the access technique is similar to that used for placement of a chest tube. In these procedures general anesthesia and single lung ventilation are essential. A small incision is made over the top of a rib and, under direct vision, carried down through the pleura. The lung is collapsed, and a trocar is inserted across the chest wall to allow access with a telescope. Once the lung is completely collapsed, subsequent access may be obtained with direct puncture, viewing all entry sites through the videoendoscope. Because insufflation of the chest is unnecessary, simple ports that keep the small incisions open are all that is required to allow repeated access to the thorax.

Laparoscopic Access The requirements for laparoscopy are more involved, because the creation of a pneumoperitoneum requires that instruments of access (trocars) contain valves to maintain abdominal inflation. Two methods are used for establishing abdominal access during laparoscopicprocedures.36,37 The first, direct puncture laparoscopy, begins with the elevation of the relaxed abdominal wall with two towel clips or a well-placed hand. A small incision is made in the umbilicus, and a specialized spring-loaded (Veress) needle is placed in the abdominal cavity (Fig. 14-5). With the Veress needle, two distinct pops are felt as the surgeon passes the needle through the abdominal wall fascia and the peritoneum. The umbilicus usually is selected as the preferred point of access because, in this location, the abdominal wall is quite thin, even in obese patients. The abdomen is inflated with a pressure-limited insufflator. CO2 gas usually is used, with maximal pressures in the range of 14 to 15 mmHg. During the process of insufflation, it is essential that the surgeon observe the pressure and flow readings on the monitor to confirm an intraperitoneal location of the Veress needle tip (Fig. 14-6). Laparoscopic surgery can be performed under local anesthesia, but general anesthesia is preferable. Under local anesthesia, N2 O is used as the insufflating agent, and insufflation is stopped after 2 L of gas is insufflated or when a pressure of 10 mmHg is reached.

Fig. 14-5.

A. Insufflation of the abdomen is accomplished with a Veress needle held at its serrated collar with a thumb and forefinger. B. Because linea alba is fused to the umbilicus, the abdominal wall is grasped with fingers or penetrating towel clip to elevate the abdominal wall away from the underlying structures.

Fig. 14-6.

It is essential to be able to interpret the insufflator pressure readings and flow rates. These readings indicate proper intraperitoneal placement of the Veress needle.

After peritoneal insufflation, direct access to the abdomen is obtained with a 5- or 10-mm trocar. The critical issues for safe direct-puncture laparoscopy include the use of a vented stylet for the trocar, or a trocar with a safety shield or dilating tip. The trocar must be pointed away from the sacral promontory and the great vessels.3 8 Patient position should be surveyed before trocar placement to ensure a proper trajectory. For performance of laparoscopic cholecystectomy, the trocar is angled toward the right upper quadrant. Occasionally, the direct peritoneal access (Hasson) technique is advisable. 3 9 With this technique, the surgeon makes a small incision just below the umbilicus and under direct vision locates the abdominal fascia. Two Kocher clamps are placed on the fascia, and with curved Mayo scissors, a small incision is made through the fascia and underlying peritoneum. A finger is placed into the abdomen to make sure that there is no adherent bowel. A sturdy suture is placed on each side of the fascia and secured to the wings of a specialized trocar, which is then passed directly into the abdominal cavity (Fig. 14-7). Rapid insufflation can make up for some of the time lost with the initial dissection. This technique is preferable for the abdomen of patients who have undergone previous operations in which small bowel may be adherent to the undersurface of the abdominal wound. The close adherence of bowel to the peritoneum in the previously operated abdomen does not eliminate the possibility of intestinal injury but should make great vessel injury extremely unlikely. Because of the difficulties in visualizing the abdominal region immediately adjacent to the primary trocar, it is recommended that the telescope be passed through a secondary trocar to inspect the site of initial abdominal access. 3 7 Secondary punctures are made with 5- and 10-mm trocars. For safe access to the abdominal cavity, it is critical to visualize all sites of trocar entry.38,39 At the completion of the operation, all trocars are removed under direct vision, and the insertion sites are inspected for bleeding. If

bleeding occurs, direct pressure with an instrument from another trocar site or balloon tamponade with a Foley catheter placed through the trocar site generally stops the bleeding within 3 to 5 minutes. When this is not successful, a full-thickness abdominal wall suture has been used successfully to tamponade trocar site bleeding.

Fig. 14-7.

The open laparoscopy technique involves identification and incision of the peritoneum, followed by the placement of a specialized trocar with a conical sleeve to maintain a gas seal. Specialized wings on the trocar are attached to sutures placed through the fascia to prevent loss of the gas seal.

It is generally agreed that 5-mm trocars need no site suturing. Ten-millimeter trocars placed off the midline and above the transverse mesocolon do not require repair. Conversely, if the fascia has been dilated to allow the passage of the gallbladder or other organ, it should be repaired at the fascial level with interrupted sutures. The port site may be closed with suture delivery systems similar to crochet needles enabling mass closure of the abdominal wall. This is especially helpful in obese patients where direct fascial closure may be challenging, through a small skin incision. Failure to close lower abdominal trocar sites that are 10 mm in diameter or larger can lead to an incarcerated hernia.

Access for Subcutaneous and Extraperitoneal Surgery There are two methods for gaining access to nonanatomic spaces. For retroperitoneal locations, balloon dissection is effective. This access technique is appropriate for the extraperitoneal repair of inguinal hernias and for retroperitoneal surgery for adrenalectomy, nephrectomy, lumbar discectomy, pancreatic necrosectomy, or paraaortic lymph node dissection.40,41 The initial access to the extraperitoneal space is performed in a way similar to

direct puncture laparoscopy, except that the last layer (the peritoneum) is not traversed. Once the transversalis fascia has been punctured, a specialized trocar with a balloon on the end is introduced. The balloon is inflated in the extraperitoneal space to create a working chamber. The balloon then is deflated and a Hasson trocar is placed. An insufflation pressure of 10 mmHg usually is adequate to keep the extraperitoneal space open for dissection and will limit subcutaneous emphysema. Higher gas pressures force CO2 into the soft tissues and may contribute to hypercarbia. Extraperitoneal endosurgery provides less working space than laparoscopy but eliminates the possibility of intestinal injury, intestinal adhesion, herniation at the trocar sites, and ileus. These issues are important for laparoscopic hernia repair because extraperitoneal approaches prevent the small bowel from sticking to the prosthetic mesh.3 1 Subcutaneous surgery has been most widely used in cardiac, vascular, and plastic surgery.3 3 In cardiac surgery, subcutaneous access has been used for saphenous vein harvesting, and in vascular surgery for ligation of subfascial perforating veins (Linton procedure). With minimally invasive techniques, the entire saphenous vein above the knee may be harvested through a single incision42,43 (Fig. 14-8). Once the saphenous vein is located, a long retractor that holds a 5-mm laparoscope allows the coaxial dissection of the vein and coagulation or clipping of each side branch. A small incision above the knee also can be used to ligate perforating veins in the lower leg.

Fig. 14-8.

A. With two small incisions, virtually the entire saphenous vein can be harvested for bypass grafting. B. The lighted retractor in the subcutaneous space during saphenous vein harvest is seen illuminating the skin. [Reproduced with permission from Jones GE, Eaves FE III, Howell RL et al: Harvest of muscle, nerve, fascia, and vein, in Bostwick J III, Eaves FE III, Nahai F (eds): Endoscopic Plastic Surgery. St Louis: Quality Medical Publishing, Inc., 1995, p 542.]

Subcutaneous access also is used for plastic surgery procedures.4 3 Minimally invasive approaches are especially well suited to cosmetic surgery, in which attempts are made to hide the incision. It is easier to hide several 5-mm incisions than one long incision. The technique of blunt dissection along fascial planes combined with lighted retractors and endoscope-holding retractors is most successful for extensive subcutaneous surgery. Some prefer gas insufflation of these soft tissue planes. The primary disadvantage of soft tissue insufflation is that subcutaneous emphysema can be created.

Hand-Assisted Laparoscopic Access Hand-assisted laparoscopic surgery is thought to combine the tactile advantages of open surgery with the minimal access of laparoscopy and thoracoscopy. This approach commonly is used to assist with difficult cases before conversion to celiotomy is necessary. Additionally, hand-assisted laparoscopic surgery is used to help surgeons negotiate the steep learning curve associated with advanced laparoscopic procedures.4 4 This technology uses a "port" for the hand that preserves the pneumoperitoneum and enables endoscopic visualization in combination with the use of minimally invasive instruments (Fig. 14-9). Formal investigation of this modality has been limited

primarily to case reports and small series, and has focused primarily on solid organ and colon surgery.

Fig. 14-9.

This is an example of hand-assisted laparoscopic surgery during left colectomy. The surgeon uses a hand to provide retraction and counter tension during mobilization of the colon from its retroperitoneal attachments, as well as during division of the mesocolon. This technique is particularly useful in the region of the transverse colon.

Intraperitoneal, intrathoracic, and retroperitoneal access for robotic surgery adheres to the principles of laparoscopic and thoracoscopic access; however, the port size for the primary puncture is 12 mm to allow placement of the stereo laparoscope.

Port Placement Trocars for the surgeon's left and right hand should be placed at least 10 cm apart. For most operations, it is possible to orient the telescope between these two trocars and slightly back from them. The ideal trocar orientation creates an equilateral triangle between the surgeon's right hand, left hand, and the telescope, with 10 to 15 cm on each leg. If one imagines the target of the operation (e.g., the gallbladder or gastroesophageal junction) oriented at the apex of a second equilateral triangle built on the first, these four points of reference create a diamond (Fig. 14-10). The surgeon stands behind the telescope, which provides optimal ergonomic orientation but frequently requires that a camera operator (or mechanical camera holder) reach between the surgeon's hands to guide the telescope.

Fig. 14-10.

The diamond configuration created by placing the telescope between the left and the right hand, recessed from the target by about 15 cm. The distance between the left and the right hand is also ideally 10 to 15 cm. In this "baseball diamond" configuration, the surgical target occupies the second base position.

The position of the operating table should permit the surgeon to work with both elbows in at the sides, with arms bent 90 at the elbow.4 5 It usually is necessary to alter the operating table position with left or right tilt with the patient in the Trendelenburg or reverse Trendelenburg position, depending on the operative field.46,47

Imaging Systems

Two methods of videoendoscopic imaging are widely used. Both methods use a camera with a CCD, which is an array of photosensitive sensor elements (pixels) that convert the incoming light intensity to an electric charge. The electric charge is subsequently converted into a black-and-white image.4 8 With videoendoscopy, the CCD chip is placed on the internal end of a long, flexible endoscope. With older flexible endoscopes, thin quartz fibers are packed together in a bundle, and the CCD camera is mounted on the external end of the endoscope. Most standard GI endoscopes have the CCD chip at the distal end, but small, delicate choledochoscopes and nephroscopes are equipped with fiber-optic bundles.4 9 Distally mounted CCD chips were developed for laparoscopy as well but have not become popular. Video cameras come in two basic designs. Nearly all laparoscopic cameras contain a red, green, and blue input, and are identical to the color cameras used for television production. 4 8 An additional feature of many video cameras is digital enhancement. Digital enhancement detects edges, areas where there are drastic color or light changes between two adjacent pixels.5 0 By enhancing this difference, the image appears sharper and surgical resolution is improved. New laparoscopic cameras contain a high-definition (HD) chip which increases the lines of resolution from 480 to 1080 lines. To enjoy the benefit of the clarity of HD video imaging, HD monitors also are necessary. Although this technology will inevitably replace more standard video imaging, it is not clear that the safety or efficiency of laparoscopic surgery is benefited by HD video imaging. Priorities in a video imaging system for MIS are illumination first, resolution second, and color third. Without the first two attributes, video surgery is unsafe. Illumination and resolution are as dependent on the telescope, light source, and light cable as on the video camera used. Imaging for laparoscopy, thoracoscopy, and subcutaneous surgery uses a rigid metal telescope, usually 30 cm in length. Longer telescopes are available for obese patients and for reaching the mediastinum and deep in the pelvis from a periumbilical entry site. The standard telescope contains a series of quartz optical rods and focusing lenses. 5 1 Telescopes vary in size from 2 to 12 mm in diameter. Because light transmission is dependent on the cross-sectional area of the quartz rod, when the diameter of a rod/lens system is doubled, the illumination is quadrupled. Little illumination is needed in highly reflective, small spaces such as the knee, and a very small telescope will suffice. When working in the abdominal cavity, especially if blood is present, the full illumination of a 10-mm telescope usually is necessary. Rigid telescopes may have a flat or angled end. The flat end provides a straight view (0), and the angled end provides an oblique view (30 or 45).4 8 Angled telescopes allow greater flexibility in viewing a wider operative field through a single trocar site (Fig. 14-11); rotating an angled telescope changes the field of view. The use of an angled telescope has distinct advantages for most videoendoscopic procedures, particularly in visualizing the common bile duct during laparoscopic cholecystectomy or visualizing the posterior esophagus or the tip of the spleen during laparoscopic fundoplication.

Fig. 14-11.

The laparoscope tips come in a variety of angled configurations. All laparoscopes have a 70 field of view. A 30-angled scope enables the surgeon to view this field at a 30 angle to the long axis of the scope.

Light is delivered to the endoscope through a fiber-optic light cable. These light cables are highly inefficient, losing >90% of the light delivered from the light source. Extremely bright light sources (300 watts) are necessary to provide adequate illumination for laparoscopic surgery. The quality of the videoendoscopic image is only as good as the weakest component in the imaging chain (Fig. 1412). Therefore, it is important to use a video monitor that has a resolution equal to or greater than the camera being used.5 1 Resolution is the ability of the optical system to distinguish between line pairs. The larger the number of line pairs per millimeter, the sharper and more detailed the image. Most high-resolution monitors have up to 700 horizontal lines. High-definition television can deliver up to eight times more resolution than standard monitors; when combined with digital enhancement, a very sharp and well-defined image can be achieved. 48,51 A heads-up display is a high-resolution liquid crystal monitor that is built into eyewear worn by the surgeon. 5 2 This technology allows the surgeon to view the endoscopic image and operative field simultaneously. The proposed advantages of heads-up display include a high-resolution monocular image, which affords the surgeon mobility and reduces vertigo and eyestrain. However, this technology has not yet been widely adopted.

Fig. 14-12.

The Hopkins rod lens telescope includes a series of optical rods that effectively transmit light to the eyepiece. The video camera is placed on the eyepiece to provide the working image. The image is only as clear as the weakest link in the image chain. CCD = charge-coupled device. (Reproduced with permission from Prescher et al.48 )

Interest in three-dimensional (3-D) laparoscopy has waxed and waned. 3-D laparoscopy provides the additional depth of field that is lost with two-dimensional endosurgery and improves performance of novice laparoscopists performing complex tasks of dexterity, including suturing and knot tying.5 3 The advantages of 3-D systems are less obvious to experienced laparoscopists. Additionally, because 3-D systems require the flickering of two similar images, which are resolved with special glasses, the images' edges become fuzzy and resolution is lost. The optical accommodation necessary to rectify these slightly differing images is tiring and may induce headaches when one uses these systems for a long period of time. The da Vinci robot uses a specialized laparoscope with two optical bundles on opposite sides of the telescope. A specialized binocular eyepiece receives input from two CCD chips, each capturing the image from one of the two quartz rod lens systems, thereby creating true 3-D imaging without using the "tricks" that have made 3-D laparoscopy so disappointing.

Energy Sources for Endoscopic and Endoluminal Surgery Many MIS procedures use conventional energy sources, but the benefits of bloodless surgery to maintain optimal visualization has spawned new ways of applying energy. The most common energy source is RF electrosurgery using an alternating current with a frequency of 500,000 cycles/s (Hz). Tissue heating progresses through the wellknown phases of coagulation [60C (140F)], vaporization and desiccation [100C (212F)], and carbonization [>200C (392F)].5 4

The two most common methods of delivering RF electrosurgery are with monopolar and bipolar electrodes. With monopolar electrosurgery, a remote ground plate on the patient's leg or back receives the flow of electrons that originate at a point source, the surgical electrode. A fine-tipped electrode causes a high current density at the site of application and rapid tissue heating. Monopolar electrosurgery is inexpensive and easy to modulate to achieve different tissue effects.5 5 A short-duration, high-voltage discharge of current (coagulation current) provides extremely rapid tissue heating. Lower-voltage, higher-wattage current (cutting current) is better for tissue desiccation and vaporization. When the surgeon desires tissue division with the least amount of thermal injury and least coagulation necrosis, a cutting current is used. With bipolar electrosurgery, the electrons flow between two adjacent electrodes. The tissue between the two electrodes is heated and desiccated. There is little opportunity for tissue cutting when bipolar current is used, but the ability to coapt the electrodes across a vessel provides the best method of small-vessel coagulation without thermal injury to adjacent tissues5 6 (Fig. 14-13).

Fig. 14-13.

An example of bipolar coagulation devices. The flow of electrons passes from one electrode to the other, and the intervening tissue is heated and desiccated.

To avoid thermal injury to adjacent structures, the laparoscopic field of view must include all uninsulated portions of the electrosurgical electrode. In addition, the integrity of the insulation must be maintained and assured. Capacitive coupling occurs when a plastic trocar insulates the abdominal wall from the current; in turn, the current is bled off of a metal sleeve or laparoscope into the viscera5 4 (Fig. 14–14A). This may result in thermal necrosis and a delayed fecal fistula. Another potential mechanism for unrecognized visceral injury may occur with the direct

coupling of current to the laparoscope and adjacent bowel5 4 (Fig. 14-14B).

Fig. 14-14.

A. Capacitive coupling occurs as a result of high current density bleeding from a port sleeve or laparoscope into adjacent bowel. B. Direct coupling occurs when current is transmitted directly from the electrode to a metal instrument or laparoscope, and then into adjacent tissue. (Reproduced with permission from Odell.54 )

Another method of delivering RF electrosurgery is argon beam coagulation. This is a type of monopolar electrosurgery in which a uniform field of electrons is distributed across a tissue surface by the use of a jet of argon gas. The argon gas jet distributes electrons more evenly across the surface than does spray electrofulguration. This technology has its greatest application for coagulation of diffusely bleeding surfaces such as the cut edge of liver or spleen. It is of less value in laparoscopic procedures because the increased intra-abdominal pressures created by the argon gas jet can increase the chances of a gas embolus. It is paramount to vent the ports and closely monitor insufflation pressure when using this source of energy within the context of laparoscopy. With endoscopic endoluminal surgery, RF alternating current in the form of a monopolar circuit represents the mainstay for procedures such as snare polypectomy, sphincterotomy, lower esophageal sphincter ablation, and "hot" biopsy.57,58 A grounding ("return") electrode is necessary for this form of energy. Bipolar electrocoagulation is used primarily for thermal hemostasis. The electrosurgical generator is activated by a foot pedal so the endoscopist may keep both hands free during the endoscopic procedure. Gas, liquid, and solid-state lasers have been available for medical application since the mid-1960s.5 9 The CO2 laser (wavelength 10.6 m) is most appropriately used for cutting and superficial ablation of tissues. It is most helpful in

locations unreachable with a scalpel such as excision of vocal cord granulomas. The CO 2 laser beam must be delivered with a series of mirrors and is therefore somewhat cumbersome to use. The next most popular laser is the neodymium yttrium-aluminum garnet (Nd:YAG) laser. Nd:YAG laser light is 1.064 m (1064 nm) in wavelength. It is in the near-infrared portion of the spectrum, and, like CO 2 laser light, is invisible to the naked eye. A unique feature of the Nd:YAG laser is that 1064-nm light is poorly absorbed by most tissue pigments and therefore travels deep into tissue.6 0 Deep tissue penetration provides deep tissue heating (Fig. 14-15). For this reason, the Nd:YAG laser is capable of the greatest amount of tissue destruction with a single application.5 9 Such capabilities make it the ideal laser for destruction of large fungating tumors of the rectosigmoid, tracheobronchial tree, or esophagus. A disadvantage is that the deep tissue heating may cause perforation of a hollow viscus.

Fig. 14-15.

This graph shows the absorption of light by various tissue compounds (water, melanin, and oxyhemoglobin) as a function of the wavelength of the light. The nadir of the oxyhemoglobin and melanin curves is close to 1064 nm, the wavelength of the neodymium yttrium-aluminum garnet laser. [Reproduced with permission from Hunter JG, Sackier JM (eds): Minimally Invasive Surgery. New York: McGraw-Hill, 1993, p 28.]

When it is desirable to coagulate flat lesions in the cecum, a different laser should be chosen. The frequencydoubled Nd:YAG laser, also known as the KTP laser (potassium thionyl phosphate crystal is used to double the Nd:YAG frequency), provides 532-nm light. This is in the green portion of the spectrum, and at this wavelength, selective absorption by red pigments in tissue (such as hemangiomas and arteriovenous malformations) is optimal. The depth of tissue heating is intermediate, between those of the CO2 and the Nd:YAG lasers. Coagulation (without

vaporization) of superficial vascular lesions can be obtained without intestinal perforation.6 0 In flexible GI endoscopy, the CO 2 and Nd:YAG lasers have largely been replaced by heater probes and endoluminal stents. The heater probe is a metal ball that is heated to a temperature [60 to 100C (140 to 212F)] that allows coagulation of bleeding lesions without perforation. Photodynamic therapy is a palliative treatment for obstructing cancers of the GI tract.6 1 Patients are given an IV dose of porfimer sodium, which is a photosensitizing agent that is taken up by malignant cells. Two days after administration, the drug is endoscopically activated using a laser. The activated porfimer sodium generates oxygen free radicals, which kill the tumor cells. The tumor is later endoscopically dbrided. The use of this modality for definitive treatment of early cancers is in experimental phases and has yet to become established. A unique application of laser technology provides extremely rapid discharge (103 volts). These high-energy lasers, of which the pulsed dye laser has seen the most clinical use, allow the conversion of light energy to mechanical disruptive energy in the form of a shock wave. Such energy can be delivered through a quartz fiber, and with rapid repetitive discharges, can provide sufficient shock-wave energy to fragment kidney stones and gallstones.6 2 Shock waves also may be created with miniature electric spark-plug discharge systems known as electrohydraulic lithotriptors . These devices also are inserted through thin probes for endoscopic application. Lasers have the advantage of pigment selectivity, but electrohydraulic lithotriptors are more popular because they are substantially less expensive and are more compact. Methods of producing shock waves or heat with ultrasonic energy are also of interest. Extracorporeal shockwave lithotripsy creates focused shock waves that intensify as the focal point of the discharge is approached. When the focal point is within the body, large amounts of energy are capable of fragmenting stones. Slightly different configurations of this energy can be used to provide focused internal heating of tissues. Potential applications of this technology include the ability to noninvasively produce sufficient internal heating to destroy tissue without an incision. A third means of using ultrasonic energy is to create rapidly oscillating instruments that are capable of heating tissue with friction; this technology represents a major step forward in energy technology.6 3 An example of its application is the laparoscopic coagulation shears device (Harmonic Scalpel), which is capable of coagulating and dividing blood vessels by first occluding them and then providing sufficient heat to weld the blood vessel walls together and to divide the vessel. This nonelectric method of coagulating and dividing tissue with a minimal amount of collateral damage has facilitated the performance of numerous endosurgical procedures.6 4 It is especially useful in the control of bleeding from medium-sized vessels that are too big to manage with monopolar electrocautery and require bipolar desiccation followed by cutting.

Instrumentation Hand instruments for MIS usually are duplications of conventional surgical instruments made longer, thinner, and smaller at the tip. It is important to remember that when grasping tissue with laparoscopic instruments, a greater force is applied over a smaller surface area, which increases the risk for perforation or injury.6 5 Certain conventional instruments such as scissors are easy to reproduce with a diameter of 3 to 5 mm and a length of 20 to 45 cm, but other instruments such as forceps and clamps cannot provide remote access. Different configurations of graspers were developed to replace the various configurations of surgical forceps and clamps. Standard hand instruments are 5 mm in diameter and 30 cm in length, but smaller and shorter hand instruments are now available for pediatric surgery, for microlaparoscopic surgery, and for arthroscopic procedures.6 5 A unique

laparoscopic hand instrument is the monopolar electrical hook. This device usually is configured with a suction and irrigation apparatus to eliminate smoke and blood from the operative field. The monopolar hook allows tenting of tissue over a bare metal wire with subsequent coagulation and division of the tissue. Instrumentation for NOTES is still evolving, but many long micrograspers, microscissors, suturing devices, clip appliers, and visceral closure devices are evolving in design and application.

Robotic Surgery The term robot defines a device that has been programmed to perform specific tasks in place of those usually performed by people. The devices that have earned the title "surgical robots" would be more aptly termed computer-enhanced surgical devices , as they are controlled entirely by the surgeon for the purpose of improving performance. The first computer-assisted surgical device was the laparoscopic camera holder (Aesop, Computer Motion, Goleta, Calif), which enabled the surgeon to maneuver the laparoscope either with a hand control, foot control, or voice activation (Fig. 14-16). Randomized studies with such camera holders demonstrated a reduction in operative time, steadier image, and a reduction in the number of required laparoscope cleanings. 6 6 This device had the advantage of eliminating the need for a human camera holder, which served to free valuable OR personnel for other duties. This technology has now been eclipsed by simpler systems using passive positioning of the camera with a mechanical arm, but the benefit of a steadier image and fewer members of the OR team remain.

Fig. 14-16.

Robotic instruments and hand controls. The surgeon is in a sitting position and the arms and wrists are in an ergonomic and relaxed position.

The "Big Bang" in robotic surgery was the development of a master-slave surgical platform that returned the wrist to laparoscopic surgery and improved manual dexterity by developing an ergonomically comfortable work station,

with 3-D imaging, tremor elimination, and scaling of movement (e.g., large, gross hand movements can be scaled down to allow suturing with microsurgical precision) (see Fig. 14-16). The surgeon is physically separated from the operating table, and the working arms of the device are placed over the patient (Fig. 14-17). An assistant remains at the bedside and changes the instruments as needed, providing retraction as needed to facilitate the procedure. This "robotic" platform (da Vinci, Intuitive Surgical, Sunnyvale, Calif) was initially greeted with some skepticism by expert laparoscopists, as it was difficult to prove additional value for operations performed with the da Vinci robot. Not only were the operations longer, and the equipment more expensive, but additional quality could not be demonstrated. Two randomized controlled trials compared robotic and conventional laparoscopic approaches to Nissen fundoplication.67,68 In both these trials, the operative time was longer for robotic surgery, and there was no difference in ultimate outcome. Similar results were achieved for laparoscopic cholecystectomy.6 9 Nevertheless, the increased dexterity provided by the da Vinci robot convinced many surgeons and health administrators that robotic platforms were worthy of investment, for marketing purposes if for no other reason.

Fig. 14-17.

Room setup and position of surgeon and assistant for robotic surgery.

The success story for computer-enhanced surgery with the da Vinci started with cardiac surgery and migrated to the pelvis. Mitral valve surgery, performed with right thoracoscopic access became one of the more popular

procedures performed with "the robot."7 0 The tidal wave of enthusiasm for robotic surgery came when most minimally invasive urologists declared robotic prostatectomy to be preferable to laparoscopic and open prostatectomy.7 1 The great advantage—it would appear—of robotic prostatectomy is the ability to visualize and spare the pelvic nerves responsible for erectile function. In addition, the creation of the neocystourethrotomy, following prostatectomy, was greatly facilitated by needle holders and graspers with a wrist in them. Female pelvic surgery with the "robot" also is picking up steam. The magnified imaging provided makes this approach ideal for microsurgical tasks such as reanastomosis of the Fallopian tubes. The final frontier for computer-enhanced surgery is the promise of telesurgery, in which the surgeon is a great distance from the patient (e.g., combat or space). This application has rarely been used, as the safety provided by having the surgeon at bedside cannot be sacrificed to prove the concept. However, remote laparoscopic cholecystectomy has been performed when a team of surgeons located in New York performed a cholecystectomy on a patient located in France.7 2

Endoluminal and Endovascular Surgery The fields of vascular surgery, interventional radiology, neuroradiology, gastroenterology, general surgery, pulmonology, and urology all encounter clinical scenarios that require the urgent restoration of luminal patency of a "biologic cylinder." Based on this need, fundamental techniques have been pioneered that are applicable to all specialties and virtually every organ system. As a result, all minimally invasive surgical procedures, from coronary artery angioplasty to palliation of pancreatic malignancy, involve the use of access devices, catheters, guidewires, balloon dilators, stents, and other devices (e.g., lasers, atherectomy catheters) that are capable of opening up the occluded biologic cylinder7 3 (Table 14-2). Endoluminal balloon dilators may be inserted through an endoscope, or they may be fluoroscopically guided. Balloon dilators all have low compliance—that is, the balloons do not stretch as the pressure within the balloon is increased. The high pressures achievable in the balloon create radial expansion of the narrowed vessel or orifice, usually disrupting the atherosclerotic plaque, the fibrotic stricture, or the muscular band (e.g., esophageal achalasia).7 4

Table 14-2 Modalities and Techniques of Restoring Luminal Patency Core out Photodynamic therapy Laser Coagulation Endoscopic biopsy forceps Chemical Ultrasound Fracture Ultrasound Endoscopic biopsy

Balloon Dilate Balloon Bougie Angioplasty Endoscope Bypass Transvenous intrahepatic portosystemic shunt Surgical (synthetic or autologous conduit) Stent Self-expanding metal stent Plastic stent Modality

Technique

Once the dilation has been attained, it is frequently beneficial to hold the lumen open with a stent.7 5 Stenting is particularly valuable in treating malignant lesions and atherosclerotic occlusions or aneurysmal disease (Fig. 1418). Stenting is also of value to seal leaky cylinders, including aortic dissections, traumatic vascular injuries, leaking GI anastomoses, and fistulas. Stenting usually is not applicable for long-term management of benign GI strictures except in patients with limited life expectancy

Fig. 14-18.

75–77

(Fig. 14-19).

The deployment of a metal stent across an isolated vessel stenosis is illustrated. [Reproduced with permission from Hunter JG, Sackier JM (eds): Minimally Invasive Surgery. New York: McGraw-Hill, 1993, p

235.]

Fig. 14-19.

This is an esophagram in a patient with severe dysphagia secondary to advanced esophageal cancer (A ) before and (B ) after placement of a covered self-expanding metal stent.

A variety of stents are available that are divided into six basic categories: plastic stents, metal stents, drug-eluting stents (to decrease fibrovascular hyperplasia), covered metal stents, anchored stent grafts, and removable covered plastic stents7 6 (Fig. 14-20). Plastic stents came first and are used widely as endoprostheses for temporary bypass of obstructions in the biliary or urinary systems. Metal stents generally are delivered over a balloon and expanded with the balloon to the desired size. These metal stents usually are made of titanium or nitinol, and are still used in coronary stenting. A chemotherapeutic agent was added to coronary stents several years ago to decrease endothelial proliferation. These drug-eluting stents provide greater long-term patency but require long-term anticoagulation with antiplatelet agents to prevent thrombosis.7 8 Coated metal stents are use to prevent tissue ingrowth. Ingrowth may be an advantage in preventing stent migration, but such tissue ingrowth may occlude the lumen and cause obstruction anew. This is a particular problem when stents are used for palliation of GI malignant growth, and may be a problem for the long-term use of stents in vascular disease. Filling the interstices with Silastic or other materials may prevent tumor ingrowth but also makes stent migration more likely. In an effort to minimize stent migration, stents have been incorporated with hooks and barbs at the proximal end of the stent to

anchor it to the wall of the vessel. Endovascular stenting of aortic aneurysms has nearly replaced open surgery for this condition. Lastly, self-expanding plastic stents have been developed as temporary devices to be used in the GI tract to close internal fistulas and bridge leaking anastomoses.

Fig. 14-20.

Covered self-expanding metal stents. These devices can be placed fluoroscopically or endoscopically.

Natural Orifice Transluminal Endoscopic Surgery The "latest rage" in MIS is NOTES, the use of the flexible endoscope to enter the GI, urinary, or reproductive tracts, then traverse the wall of the structure to enter the peritoneal cavity, the mediastinum, or the chest. In truth, transluminal surgery has been performed in the stomach for a long time, either from the inside out (e.g. percutaneous, PEG, and transgastric pseudocyst drainage) or from the outside in (e.g., laparoscopic assisted intragastric tumor resection). The catalyzing event for NOTES was the demonstration that a porcine gallbladder could be removed with a flexible endoscope passed through the wall of the stomach, then removed through the mouth, and the demonstration in a series of 10 human cases from India of the ability to perform transgastric appendectomy. Since that time, a great deal of money has been invested by endoscopic and MIS companies to

help surgeons and gastroenterologists explore this new territory. To date, the most headline-grabbing procedures have been the transvaginal and transgastric removal of the gallbladder79–81 (Fig. 14-21). To ensure safety, all cases thus far have involved laparoscopic assistance to aid in retraction, and ensure adequate closure of the stomach. As such, the benefits of NOTES cholecystectomy have not been demonstrated convincingly, but when all laparoscopic assistance has been eliminated, this approach will surely appeal to many. Additional procedures performed with NOTES might include staging of intra-abdominal malignancy, segmental colectomy, gastrojejunostomy, and a host of other procedures capable of exciting the curious mind. In addition, the rapid growth of endoscopic technology catalyzed by NOTES has already spun off new technologies capable of performing a wide variety of endoscopic surgical procedures from endoscopic mucosal resection to ablation of Barrett's esophagus, to creation of competent antireflux valves in patients with gastroesophageal reflux disease. Although some of these applications are still considered experimental, there is little doubt that when equivalent operations can be performed with less pain, fewer scars, and less disability, patients will flock to it. Surgeons should engage only when they can perform these procedures with the safety and efficacy demanded by our profession.

Fig. 14-21.

Transgastric cholecystectomy using natural orifice transluminal endoscopic surgery technology and one to three laparoscopic ports has been performed occasionally in several locations around the world. (Reproduced with permission from The Johns Hopkins University School of Medicine, Baltimore, Maryland.)

SPECIAL CONSIDERATIONS Pediatric Laparoscopy The advantages of MIS in children may be more significant than in the adult population. MIS in the adolescent is

little different from that in the adult, and standard instrumentation and trocar positions usually can be used. However, laparoscopy in the infant and young child requires specialized instrumentation. The instruments are shorter (15 to 20 cm), and many are 3 mm in diameter rather than 5 mm. Because the abdomen of the child is much smaller than that of the adult, a 5-mm telescope provides sufficient illumination for most operations. The development of 5-mm clippers and bipolar devices has obviated the need for 10-mm trocars in pediatric laparoscopy.8 2 Because the abdominal wall is much thinner in infants, a pneumoperitoneum pressure of 8 mmHg can provide adequate exposure. DVT is rare in children, so prophylaxis against thrombosis probably is unnecessary. A wide variety of pediatric surgical procedures are frequently performed with MIS access, from pull-through procedures for colonic aganglionosis (Hirschsprung's disease) to repair of congenital diaphragmatic hernias.8 3

Laparoscopy during Pregnancy Concerns about the safety of laparoscopic cholecystectomy or appendectomy in the pregnant patient have been thoroughly investigated and are readily managed. Access to the abdomen in the pregnant patient should take into consideration the height of the uterine fundus, which reaches the umbilicus at 20 weeks. In order not to damage the uterus or its blood supply, most surgeons feel that the open (Hasson) approach should be used in favor of direct puncture laparoscopy. The patient should be positioned slightly on the left side to avoid compression of the vena cava by the uterus. Because pregnancy poses a risk for thromboembolism, sequential compression devices are essential for all procedures. Fetal acidosis induced by maternal hypercarbia also has been raised as a concern. The arterial pH of the fetus follows the pH of the mother linearly; and therefore, fetal acidosis may be prevented by avoiding a respiratory acidosis in the mother.8 4 The pneumoperitoneum pressure induced by laparoscopy is not a safety issue either as it has been proved that midpregnancy uterine contractions provide a much greater pressure in utero than a pneumoperitoneum of 15 mmHg. Experience in >100 cases of laparoscopic cholecystectomy in pregnancy have been reported with uniformly good results.8 5 The operation should be performed during the second trimester of pregnancy if possible. Protection of the fetus against intraoperative x-rays is imperative. Some believe it advisable to track fetal pulse rates with a transvaginal ultrasound probe; however, the significance of fetal tachycardia or bradycardia is a bit unclear in the second trimester of pregnancy. To be prudent, however, heart rate decelerations reversibly associated with pneumoperitoneum creation might signal the need to convert to open cholecystectomy or appendectomy.

Minimally Invasive Surgery and Cancer Treatment MIS techniques have been used for many decades to provide palliation for the patient with an obstructive cancer. Laser treatment, intracavitary radiation, stenting, and dilation are outpatient techniques that can be used to reestablish the continuity of an obstructed esophagus, bile duct, ureter, or airway. MIS techniques also have been used in the staging of cancer. Mediastinoscopy is still used occasionally before thoracotomy to assess the status of the mediastinal lymph nodes. Laparoscopy also is used to assess the liver in patients being evaluated for pancreatic, gastric, or hepatic resection. New technology and greater surgical skills allow for accurate minimally invasive staging of cancer.8 6 Occasionally, it is appropriate to perform palliative measures (e.g., laparoscopic gastrojejunostomy to bypass a pancreatic cancer) at the time of diagnostic laparoscopy if diagnostic findings preclude attempts at curative resection. Initially controversial, the role of MIS to provide a safe curative treatment of cancer has proven to be no different from the principles of open surgery. All gross and microscopic tumor should be removed (an R0 resection), and an adequate lymphadenectomy should be performed to allow accurate staging. Generally, this number has been 10 to 15 lymph nodes, although there is still debate as to the value of more extensive lymphadenectomy. All of the

major abdominal cancer operations have been performed with laparoscopy. Of the three major cancer resections of GI cancer (liver lobe, pancreatic head, and esophagus), only esophagectomy is routinely performed by a fair number of centers.87,88 Laparoscopic hepatectomy has attracted a loyal following, and distal pancreatectomy frequently is performed with laparoscopic access. In Japan, laparoscopic-assisted gastrectomy has become quite popular for early gastric cancer, an epidemic in Japan far exceeding that of colon cancer in North America and Northern Europe. The most common cancer operation performed laparoscopically is segmental colectomy, which has proven itself safe and efficacious in a multicenter controlled randomized trial.8 9

Considerations in the Elderly and Infirm Laparoscopic cholecystectomy has made possible the removal of a symptomatic gallbladder in many patients previously thought to be too elderly or too ill to undergo a laparotomy. Older patients are more likely to require conversion to celiotomy because of disease chronicity. 8 9 Operations on these patients require close monitoring of anesthesia. The intraoperative management of these patients may be more difficult with laparoscopic access than with open access. The advantage of MIS lies in what happens after the operation. Much of the morbidity of surgery in the elderly is a result of impaired mobility. In addition, pulmonary complications, urinary tract sepsis, DVT, pulmonary embolism, congestive heart failure, and myocardial infarction often are the result of improper fluid management and decreased mobility. By allowing rapid and early mobilization, laparoscopic surgery has made possible the safe performance of procedures in the elderly and infirm.

Cirrhosis and Portal Hypertension Patients with hepatic insufficiency pose a significant challenge for any type of surgical intervention.9 0 The ultimate surgical outcome in this population relates directly to the degree of underlying hepatic dysfunction.9 1 Often, this group of patients has minimal reserve, and the stress of an operation will trigger complete hepatic failure or hepatorenal syndrome. These patients are at risk for major hemorrhage at all levels, including trocar insertion, operative dissection in a field of dilated veins, and secondary to an underlying coagulopathy. Additionally, ascitic leak from a port site may occur, leading to bacterial peritonitis. Therefore, a watertight port site closure should be carried out in all patients. It is essential that the surgeon be aware of the severity of hepatic cirrhosis as judged by a MELD score (Model of Endstage Liver Disease) or Child's classification. Additionally, the presence of portal hypertension is a relative contraindication to laparoscopic surgery until the portal pressures are reduced with portal decompression. For example, if a patient has an incarcerated umbilical hernia and ascites, a preoperative paracentesis or transjugular intrahepatic portosystemic shunt procedure in conjunction with aggressive diuresis may be considered. Because these patients commonly are intravascularly depleted, insufflation pressures should be reduced to prevent a decrease in cardiac output and minimal amounts of Na+ sparing IV fluids should be given.

Economics of Minimally Invasive Surgery Minimally invasive surgical procedures reduce the costs of surgery most when length of hospital stay can be shortened and return to work is quickened. For example, shorter hospital stays can be demonstrated in laparoscopic cholecystectomy, Nissen fundoplication, splenectomy, and adrenalectomy. Procedures such as inguinal herniorrhaphy that are already performed as outpatient procedures are less likely to provide cost savings. Procedures that still require a 4- to 7-day hospitalization, such as laparoscopy-assisted colectomy, are less likely to deliver a lower bottom line than their open surgery counterparts. Nonetheless, with responsible use of disposable

instrumentation and a commitment to the most effective use of the inpatient setting, most laparoscopic procedures can be made less expensive than their conventional equivalents.

Education and Skill Acquisition Historically, surgeons in training (residents, registrars, and fellows) acquired their skills in minimally invasive techniques through a series of operative experiences of graded complexity. This training occurred on patients. Although such a paradigm did not compromise patient safety, learning in the OR is costly. In addition, the recent worldwide constraint placed on resident work hours makes it attractive to teach laparoscopic skills outside of the OR. Skills labs started at nearly every surgical training center in the 1990s with a "box trainer," a rudimentary or sophisticated simulated abdominal cavity with a video camera, a monitor, trocars, laparoscopic instruments, and target models as simple as a pegboard and rubber rings, or a latex drain to practice suturing and knot tying. Virtual reality training devices present a unique opportunity to improve and enhance experiential learning in endoscopy and laparoscopy for all surgeons. This technology has the advantage of enabling objective measurement of psychomotor skills, which can be used to determine progress in skill acquisition, and ultimately, technical competency.9 2 Several of these devices have been validated as a means of measuring proficiency in skill performance. More importantly, training on virtual reality platforms has proven to translate to improved operative performance in randomized trials.93,94 In the near future, and today in some institutions, simulator training to the expert level will become a prerequisite for performance of laparoscopic procedures in the OR. The American College of Surgeons has taken a leadership position in accrediting these skills labs at American College of Surgeons–accredited educational institutes.

Telementoring In response to the Institute of Medicine's call for the development of unique technologic solutions to deliver health care to rural and underserved areas, surgeons are beginning to explore the feasibility of telementoring. Teleconsultation or telementoring is two-way audio and visual communication between two geographically separated providers. This communication can take place in the office setting or directly in the OR when complex scenarios are encountered. Although local communication channels may limit its performance in rural areas, the technology is available and currently is being used, especially in states and provinces with large geographically remote populations9 4 (Fig. 14-22).

Fig. 14-22.

Teleconsultation and telementoring are carried out between two providers who are geographically separated. The console has a video camera, microphone, and flat screen display that can be positioned at the operating room table or in the clinic.

Innovation and Introduction of New Procedures The revolution in minimally invasive general surgery, which occurred in 1990, created ethical challenges for the profession. The problem was this: If competence is gained from experience, how was the surgeon to climb the competence curve (otherwise known as the learning curve ) without injuring patients? If it was indeed impossible to achieve competence without making mistakes along the way, how should one effectively communicate this to patients such that they understand the weight of their decisions? Even more fundamentally important is determining the path that should be followed before one recruits the first patient for a new procedure. Although procedure development is fundamentally different than drug development (i.e., there is great individual variation in the performance of procedures, but no difference between one tablet and the next), adherence to a process similar to that used to develop a new drug is a reasonable path for a surgical innovator. At the outset, the surgeon must identify the problem that is not solved with current surgical procedures. For example, although the removal of a gallbladder through a Kocher incision is certainly effective, it creates a great deal of disability, pain, and scarification. As a result of those issues, many patients with very symptomatic biliary colic delayed operation

until life-threatening complications occurred. Clearly, there was a need for developing a less invasive approach (Fig. 14-23).

Fig. 14-23.

The progress of general surgery can be reflected by a series of performance curves. General anesthesia and sterile technique allowed the development of maximally invasive open surgery over the last 125 years. Video optics allowed the development of minimally invasive surgery over the last 25 years. Noninvasive (seamless) surgery will result when a yet undiscovered transformational event allows surgery to occur without an incision, and perhaps without anesthesia.

Once the opportunity has been established, the next step involves a search through other disciplines for technologies and techniques that might be applied. Again, this is analogous to the drug industry, where secondary drug indications have often turned out to be more therapeutically important than the primary indication for drug development. The third step is in vivo studies in the most appropriate animal model. These types of studies are controversial because of the resistance to animal experimentation, and yet without such studies, many humans would be injured or killed during the developmental phase of medical drugs, devices, and techniques. These steps often are called the preclinical phase of procedure development . The decision as to when such procedures are ready to come out of the lab is a difficult one. Put simply, the procedure should be reproducible, provide the desired effect, and not have serious side effects. Once these three criteria are reached, the time for human application has arrived. Before the surgeon discusses the new procedure with patients, it is important to achieve full institutional support. Involvement of the medical board, the chief of the medical staff, and the institutional review board is essential before commencing on a new procedure. These bodies are responsible for the use of safe, high-quality medical practices within their institution, and they will demand that great caution and all possible safeguards are in place before proceeding.

The dialogue with the patient who is to be first must be thorough, brutally honest, and well documented. The psychology that allows a patient to decide to be first is quite interesting, and may, under certain circumstances, require psychiatric evaluation. Certainly if a dying cancer patient has a chance with a new drug, this makes sense. Similarly, if the standard surgical procedure has a high attendant morbidity and the new procedure offers a substantially better outcome, the decision to be first is understandable. On the other hand, when the benefits of the new approach are small and the risks are largely unknown, a more complete psychological profile may be necessary before proceeding. For new surgical procedures, it generally is wise to assemble the best possible operative team, including a surgeon experienced with the old technique, and assistants who have participated in the earlier animal work. This initial team of experienced physicians and nurses should remain together until full competence with the procedure is attained. This may take 10 procedures, or it may take 50 procedures. The team will know that it has achieved competence when the majority of procedures take the same length of time, and the team is relaxed and sure of the flow of the operation. This will complete phase I of the procedure development. In phase II, the efficacy of the procedure is tested in a nonrandomized fashion. Ideally, the outcome of new techniques must be as good or better than the procedure that is being replaced. This phase should occur at several medical centers to prove that good outcomes are achievable outside of the pioneering institution. These same requirements may be applied to the introduction of new technology into the OR. The value equation requires that the additional measurable procedure quality exceeds the additional measurable cost to the patient or health care system. In phase III, a randomized trial pits the new procedure against the old. Once the competence curve has been climbed, it is appropriate for the team to engage in the education of others. During the ascension of the competence curve, other learners in the institution (i.e., surgical residents) may not have the opportunity to participate in the first case series. Although this may be difficult for them, the best interest of the patient must be put before the education of the resident. The second stage of learning occurs when the new procedure has proven its value and a handful of experts exist, but the majority of surgeons have not been trained to perform the new procedure. In this setting, it is relatively unethical for surgeons to forge ahead with a new procedure in humans as if they had spent the same amount of time in intensive study that the first team did. The fact that one or several surgical teams were able to perform an operation does not ensure that all others with the same medical degrees can perform the operation with equal skill. It behooves the learners to contact the experts and request their assistance to ensure an optimal outcome at the new center. Although it is important that the learners contact the experts, it is equally important that the experts be willing to share their experience with their fellow professionals. As well, the experts should provide feedback to the learners as to whether they feel the learners are equipped to forge ahead on their own. If not, further observation and assistance from the experts are required. Although this approach may sound obvious, it is fraught with difficulties. In many situations ego, competitiveness, and monetary concerns have short-circuited this process and led to poor patient outcomes. To a large extent, MIS has recovered from the black eye it received early in development, when inadequately trained surgeons caused an excessive number of significant complications. If innovative procedures and technologies are to be developed and applied without the mistakes of the past, surgeons must be honest when they answer these questions: Is this procedure safe? Would I consider undergoing this procedure if I developed a surgical indication? Is the procedure as good or better than the procedure it is replacing? Do I have the skills to apply this procedure safely and with equivalent results to the more experienced surgeon? If the answer to any of these questions is "no," or "I don't know," there is a professional obligation to

seek another procedure or outside assistance before subjecting a patient to the new procedure.

REFERENCES Entries Highlighted in Bright Blue Are Key References. 1. Hopkins HH: Optical principles of the endoscope, in Berci G (ed): Endoscopy . New York: Appleton-Century-Crofts. 1976, p 3. 2. Katzir A: Optical fibers in medicine. Sci Am 260:120, 1989. [PMID: 2717913] 3. Hirschowitz BI: A personal history of the fiberscope. Gastroenterology 76:864, 1979. [PMID: 369936] 4. Veritas TF: Coelioscopy: A synthesis of Georg Kelling's work with insufflation, endoscopy, and luft tamponade, in Litynski GS (ed): Highlights in the History of Laparoscopy . Frankfurt/Main: Barbara Bernert Verlag, 1996, p 3. 5. Ponsky JL, Gauderer MW: Percutaneous endoscopic gastrostomy: A nonoperative technique for feeding gastrostomy. Gastrointest Endosc 27:9, 1981. [PMID: 6783471] 6. Wood BJ, Ramkaransingh JR, Fogo T, et al: Percutaneous tumor ablation with radiofrequency. Cancer 94:443, 2002. [PMID: 11900230] 7. Smith RS, Fry WR, Tsoi EK, et al: Gasless laparoscopy and conventional instruments: The next phase of minimally invasive surgery. Arch Surg 128:1102, 1993. [PMID: 8215870] 8. Litynski GS: Highlights in the History of Laparoscopy . Frankfurt/Main: Barbara Bernert Verlag, 1996, p 78. 9. Hunter JG, Staheli J, et al.: Nitrous oxide pneumoperitoneum revisited: Is there a risk of combustion? Surg Endosc 9:501, 1995. [PMID: 7676370] 10. Tsereteli Z, Terry ML, et al: Prospective randomized clinical trial comparing nitrous oxide and carbon dioxide pneumoperitoneum for laparoscopic surgery. J Am Coll Surg 195:173, 2002. [PMID: 12168963] 11. Callery MP, Soper NJ: Physiology of the pneumoperitoneum, in Hunter (ed): Baillire's Clinical Gastroenterology: Laparoscopic Surgery . London/Philadelphia: Baillire Tindall, 1993, p 757. 12. Ho HS, Gunther RA, et al: Intraperitoneal carbon dioxide insufflation and cardiopulmonary functions. Arch Surg 127:928, 1992. [PMID: 1386506] 13. Wittgen CM, Andrus CH, et al: Analysis of the hemodynamic and ventilatory effects of laparoscopic cholecystectomy. Arch Surg 126:997, 1991. [PMID: 1830738] 14. Cullen DJ, Eger EI: Cardiovascular effects of carbon dioxide in man. Anesthesiol 41:345, 1974. [PMID: 4412334] 15. Cunningham AJ, Turner J, et al: Transoesophageal echocardiographic assessment of haemodynamic function during laparoscopic cholecystectomy. Br J Anaesth 70:621, 1993. [PMID: 8329253] 16. Harris MNE, Plantevin OM, Crowther A, et al: Cardiac arrhythmias during anaesthesia for laparoscopy. Br J Anaesth 56:1213, 1984. [PMID: 6237663] 17. Borten M, Friedman EA: Choice of anaesthesia, in: Laparoscopic Complications : Prevention and Management . Toronto: BC Decker, 1986, p 173. 18. Jorgenson JO, Hanel K, Lalak NJ, et al: Thromboembolic complications of laparoscopic cholecystectomy (Letter). Br Med J 306:518, 1993. 19. Ho HS, Wolfe BM: The physiology and immunology of endosurgery, in Toouli JG, Gossot D, Hunter JG (eds): Endosurgery . New

York/London: Churchill-Livingstone, 1996, p 163. 20. Sackier JM, Nibhanupudy B: The pneumoperitoneum-physiology and complications, in Toouli JG, Gossot D, Hunter JG (eds): Endosurgery . New York/London: Churchill-Livingstone, 1996, p 155. 21. Kashtan J, Green JF, Parsons EQ, et al: Hemodynamic effects of increased abdominal pressure. J Surg Res 30:249, 1981. [PMID: 7230773] 22. McDougall EM, Monk TG, Wolf JS Jr, et al: The effect of prolonged pneumoperitoneum on renal function in an animal model. J Am Coll Surg 182:317, 1996. [PMID: 8605555] 23. Lindberg F, Bergqvist D, Bjorck M, et al: Renal hemodynamics during carbon dioxide pneumoperitoneum: An experimental study in pigs. Surg Endosc 17:480, 2003. [PMID: 12415336] 24. Hazebroek EJ, de Vos tot Nederveen Cappel R, Gommers D, et al: Antidiuretic hormone release during laparoscopic donor nephrectomy. Arch Surg 137:600; discussion 605, 2002. 25. Ostman PL, Pantle-Fisher FH, Fanre EA, et al: Circulatory collapse during laparoscopy. J Clin Anesth 2:129, 1990. [PMID: 2140690] 26. Alijani A, Cuschieri A: Abdominal wall lift systems in laparoscopic surgery: Gasless and low-pressure systems. Semin Laparosc Surg 8:53, 2001. [PMID: 11337737] 27. Ozawa A, Konishi F, Nagai H, et al: Cytokine and hormonal responses in laparoscopic-assisted colectomy and conventional open colectomy. Surg Today 30:107, 2000. [PMID: 10664330] 28. Burpee SE, Kurian M, Murakame Y, et al: The metabolic and immune response to laparoscopic versus open liver resection. Surg Endosc 16:899, 2002. [PMID: 12163951] 29. Gossot D: Access modalities for thoracoscopic surgery, in Toouli JG, Gossot D, Hunter JG (eds): Endosurgery . New York/London: Churchill-Livingstone, 1996, p 743. 30. Memon MA, Cooper NJ, Memon B, et al: Meta-analysis of randomized clinical trials comparing open and laparoscopic inguinal hernia repair. Br J Surg 90:1479, 2003. [PMID: 14648725] 31. Himpens J: Laparoscopic preperitoneal approach to the inguinal hernia, in Toouli JG, Gossot D, Hunter JG (eds): Endosurgery . New York/London: Churchill-Livingstone, 1996, p 949. 32. Horvath KD, Kao LS, Wherry KL, et al: A technique for laparoscopic-assisted percutaneous drainage of infected pancreatic necrosis and pancreatic abscess. Surg Endosc 15:1221, 2001. [PMID: 11727105] 33. Eaves FF: Basics of endoscopic plastic surgery, in Bostwick J, Eaves FF, Nahai F (eds): Endoscopic Plastic Surgery . St Louis: Quality Medical Publishing, 1995, p 59. 34. Kenyon TA, Lenker MP, Bax TW, et al: Cost and benefit of the trained laparoscopic team. A comparative study of a designated nursing team vs a nontrained team. Surg Endosc 11:812, 1997. [PMID: 9266641] 35. Herron DM, Gagner M, Kenyon TL, et al: The minimally invasive surgical suite enters the 21st century. A discussion of critical design elements. Surg Endosc 15:415, 2001. [PMID: 11409412] 36. Byron JW, Markenson G, et al: A randomised comparison of Veress needle and direct insertion for laparoscopy. Surg Gynecol Obstet 177:259, 1993. [PMID: 8356499] 37. Fletcher DR: Laparoscopic access, in Toouli JG, Gossot D, Hunter JG (eds): Endosurgery . New York/London: Churchill-Livingstone, 1996, p 189.

38. Hanney RM, Alle KM, Cregan PC: Major vascular injury and laparoscopy. Aust N Z J Surg 65:533, 1995. [PMID: 7611976] 39. Catarci M, Carlini M, Gentileschi P, et al: Major and minor injuries during the creation of pneumoperitoneum. A multicenter study on 12,919 cases. Surg Endosc 15:566, 2001. [PMID: 11591941] 40. Siperstein AE, Berber E, Engle KL, et al: Laparoscopic posterior adrenalectomy: Technical considerations. Arch Surg 135:967, 2000. [PMID: 10922260] 41. Vasilev SA, McGonigle KF: Extraperitoneal laparoscopic para-aortic lymph node dissection. Gynecol Oncol 61:315, 1996. [PMID: 8641608] 42. Schurr UP, Lachat ML, Reuthebuch O, et al: Endoscopic saphenous vein harvesting for CABG—a randomized prospective trial. Thorac Cardiovasc Surg 50:160, 2002. [PMID: 12077689] 43. Lumsden AB, Eaves FF: Vein harvest, in Bostwick J, Eaves FF, Nahai F (eds): Endoscopic Plastic Surgery . St. Louis: Quality Medical Publishing, 1995, p 535. 44. Targarona EM, Gracia E, Rodriguez M, et al: Hand-assisted laparoscopic surgery. Arch Surg 138:138, 2003. 45. Berquer R, Smith WD, Davis S: An ergonomic study of the optimum operating table height for laparoscopic surgery. Surg Endosc 16:416, 2002. [PMID: 11928019] 46. Berguer R, Smith WD, Chung YH: Performing laparoscopic surgery is significantly more stressful for the surgeon than open surgery. Surg Endosc 15:1204, 2001. [PMID: 11727101] 47. Emam TA, Hanna G, Cuschieri A: Ergonomic principles of task alignment, visual display, and direction of execution of laparoscopic bowel suturing. Surg Endosc 16:267, 2002. [PMID: 11967676] 48. Prescher T: Video imaging, in Toouli JG, Gossot D, Hunter JG (eds): Endosurgery . New York/London: Churchill-Livingstone, 1996, p 41. 49. Margulies DR, Shabot MM: Fiberoptic imaging and measurement, in Hunter JG, Sackier JM (eds): Minimally Invasive Surgery . New York: McGraw-Hill, 1993, p 7. 50. Wenzl R, Lehner R, Holzer A, et al: Improved laparoscopic operating techniques using a digital enhancement video system. J Am Assoc Gynecol Laparosc 5:175, 1998. [PMID: 9564067] 51. Berci G, Paz-Partlow M: Videoendoscopic technology, in Toouli JG, Gossot D, Hunter JG (eds): Endosurgery . New York/London: Churchill-Livingstone, 1996, p 33. 52. Levy ML, Day JD, Albuquerque F, et al: Heads-up intraoperative endoscopic imaging: A prospective evaluation of techniques and limitations. Neurosurgery 40:526, 1997. [PMID: 9055292] 53. Taffinder N, Smith SG, Huber J, et al: The effect of a second-generation 3D endoscope on the laparoscopic precision of novices and experienced surgeons. Surg Endosc 13:1087, 1999. [PMID: 10556444] 54. Odell RC: Laparoscopic electrosurgery, in Hunter JG, Sackier JM (eds): Minimally Invasive Surgery . New York: McGraw-Hill, 1993, p 33. 55. Voyels CR, et al: Education and engineering solutions for potential problems with laparoscopic monopolar electrosurgery. Am J Surg 164:57, 1992. 56. Blanc B, d'Ercole C, Gaiato ML, et al: Cause and prevention of electrosurgical injuries in laparoscopy. J Am Coll Surg 179:161, 1994. 57. Tucker RD: Principles of electrosurgery, in Sivak MV (ed): Gastroenterologic Endoscopy , 2nd ed. Philadelphia: WB Saunders, 2000, p

125. 58. Barlow DE: Endoscopic application of electrosurgery: A review of basic principles. Gastrointest Endosc 28:73, 1982. [PMID: 7084646] 59. Trus TL, Hunter JG: Principles of laser physics and tissue interaction, in Toouli JG, Gossot D, Hunter JG (eds): Endosurgery . New York/London: Churchill-Livingstone, 1996, p 103. 60. Bass LS, Oz MC, Trokel SL, et al: Alternative lasers for endoscopic surgery: Comparison of pulsed thulium-holmium-chromium:YAG with continuous-wave neodymium:YAG laser for ablation of colonic mucosa. Lasers Surg Med 11:545, 1991. [PMID: 1753849] 61. Greenwald BD: Photodynamic therapy for esophageal cancer. Chest Surg Clin North Am 10:625, 2000. [PMID: 10967762] 62. Hunter JG, Bruhn E, Godman G, et al: Reflectance spectroscopy predicts safer wavelengths for pulsed laser lithotripsy of gallstones (abstract). Gastrointest Endosc 37:273, 1991. 63. Amaral JF, Chrostek C: Comparison of the ultrasonically activated scalpel to electrosurgery and laser for laparoscopic surgery. Surg Endosc 7:141, 1993. 64. Huscher CG, Liriei MM, Di Paola M, et al: Laparoscopic cholecystectomy by ultrasonic dissection without cystic duct and artery ligature. Surg Endosc 17:442, 2003. [PMID: 12399846] 65. Jobe BA, Kenyon T, Hansen PD, et al: Mini-laparoscopy: Current status, technology and future applications. Minim Invasive Ther Allied Technol 7:201, 1998. 66. Aiono S, Gilbert JM, Soin B, et al: Controlled trial of the introduction of a robotic camera assistant (EndoAssist) for laparoscopic cholecystectomy. Surg Endosc 16:1267, 2002. [PMID: 12235507] 67. Melvin WS, Needleman BJ, Krause KR, et al: Computer-enhanced vs. standard laparoscopic anti-reflux surgery. J Gastrointest Surg 6:11, 2002. [PMID: 11986012] 68. Costi R, Himpens J, Bruyns J, et al: Robotic fundoplication: From theoretic advantages to real problems. J Am Coll Surg 197:500, 2003. [PMID: 12946806] 69. Ruurda JP, Broeders IA, Simmermacher RP, et al: Feasibility of robot-assisted laparoscopic surgery: An evaluation of 35 robotassisted laparoscopic cholecystectomies. Surg Laparosc Endosc Percutan Tech 12:41, 2002. [PMID: 12008761] 70. Rodriguez E, Nifong LW, Chu MW, et al: Robotic mitral valve repair for anterior leaflet and bileaflet prolapsed. Ann Thorac Surg 85:438; discussion 444, 2008. 71. Menon M, Tewari A, Baize B, et al: Prospective comparison of radical retropubic prostatectomy and robot-assisted anatomic prostatectomy: The Vattikuti Urology Institute experience. Urology 60:864, 2002. [PMID: 12429317] 72. Marescaux J, Leroy J, Gagner M, et al: Transatlantic robot-assisted telesurgery. Nature 413:379, 2001. [PMID: 11574874] 73. Fleischer DE: Stents, cloggology, and esophageal cancer. Gastrointest Endosc 43:258, 1996. [PMID: 8857148] 74. Foutch P, Sivak M: Therapeutic endoscopic balloon dilatation of the extrahepatic biliary ducts. Am J Gastroenterol 80:575, 1985. [PMID: 4014111] 75. Hoepffner N, Foerster EC, et al: Long-term experience in wall stent therapy for malignant choledochostenosis. Endoscopy 26:597, 1994. [PMID: 8001486] 76. Kozarek RA, Ball TJ, et al: Metallic self-expanding stent application in the upper gastrointestinal tract: Caveats and concerns. Gastrointest Endosc 38:1, 1992. [PMID: 1612364]

77. Anderson JR, Sorenson SM, Kruse A, et al: Randomized trial of endoscopic endoprosthesis versus operative bypass in malignant obstructive jaundice. Gut 30:1132, 1989. 78. Ruygrok PN, Sim KH, Chan C, et al: Coronary intervention with a heparin-coated stent and aspirin only. J Invasive Cardiol 15:439, 2003. [PMID: 12890872] 79. Bessler M, Stevens PD, Milone L, et al: Transvaginal laparoscopic cholecystectomy: Laparoscopically assisted. Surg Endosc 22:1715, 2008. [PMID: 18322746] 80. Marescaux J, Dallemagne B, Perretta S, et al: Surgery without scars: Report of transluminal cholecystectomy in a human being. Arch Surg 142:823; discussion 826, 2007. 81. Bessler M, Stevens PD, Milone L, et al: Transvaginal laparoscopic cholecystectomy: Laparoscopically assisted. Surg Endosc 22:1715, 2008. [PMID: 18322746] 82. Georgeson KE: Pediatric laparoscopy, in Toouli JG, Gossot D, Hunter JG (eds): Endosurgery . New York/London: ChurchillLivingstone, 1996, p 929. 83. Holcomb GW: Diagnostic laparoscopy: Equipment, technique, and special concerns in children, in Holcomb GW (ed): Pediatric Endoscopic Surgery . Norwalk, CT: Appleton & Lange, 1993, p 9. 84. Hunter JG, Swanstrom LL, et al: Carbon dioxide pneumoperitoneum induces fetal acidosis in a pregnant ewe model. Surg Endosc 9:272, 1995. [PMID: 7597597] 85. Morrell DG, Mullins JR, et al: Laparoscopic cholecystectomy during pregnancy in symptomatic patients. Surgery 112:856, 1992. [PMID: 1440236] 86. Callery MP, Strasberg SM, Doherty GM, et al: Staging laparoscopy with laparoscopic ultrasonography: Optimizing resectability in hepatobiliary and pancreatic malignancy. J Am Coll Surg 185:33, 1997. [PMID: 9208958] 87. Luketich JD, Alvelo-Rivera M, Buenaventura PO, et al: Minimally invasive esophagectomy: Outcomes in 222 patients. Ann Surg 238:486; discussion 494, 2003. 88. Fleshman J, Sargent DJ, Green E, for The Clinical Outcomes of Surgical Therapy Study Group: Laparoscopic colectomy for cancer is not inferior to open surgery based on 5-year data from the COST Study Group trial. Ann Surg 246:655; discussion 662, 2007. 89. Fried GM, Clas D, Meakins JL: Minimally invasive surgery in the elderly patient. Surg Clin North Am 74:375, 1994. [PMID: 8165473] 90. Borman PC, Terblanche J: Subtotal cholecystectomy: For the difficult gallbladder in portal hypertension and cholecystitis. Surgery 98:1, 1985. 91. Litwin DWM, Pham Q: Laparoscopic surgery in the complicated patient, in Eubanks WS, Swanstrom LJ, Soper NJ (eds): Mastery of Endoscopic and Laparoscopic Surgery . Philadelphia: Lippincott, Williams & Wilkins, 2000, p 57. 92. Gallagher AG, Smith CD, Bowers SP, et al: Psychomotor skills assessment in practicing surgeons experienced in performing advanced laparoscopic procedures. J Am Coll Surg 197:479, 2003. [PMID: 12946803] 93. Seymour NE, Gallagher AG, Roman SA, et al: Virtual reality training improves operating room performance: Results of a randomized, double-blinded study. Ann Surg 236:458; discussion 463, 2002. 94. Anvari M: Telesurgery: Remote knowledge translation in clinical surgery. World J Surg 31:1545, 2007. [PMID: 17534550]

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KEY POINTS 1. The advent of recombinant DNA technology, polymerase chain reaction techniques, and completion of the human genome have revolutionized the understanding of disease development and also radically transformed the practice of medicine and surgery. 2. Genes govern cell activity in different cell types, which ultimately leads to the health of the human organism. The cellular diversity is controlled by the genome and accomplished by tight regulation of gene expression in a given cell at a given time. 3. Human diseases arise from improper changes in the genome. The continuous understanding of how the genome functions will make it possible to tailor medicine on an individual basis. The goal of personalized genomic medicine is to attack the disease by choosing personalized treatments that work with the individual's genomic profile. Personalized genomic medicine will undoubtedly revolutionize the practice of modern medicine. 4. Improving the outlook for human diseases can only come from a better understanding of the molecular signaling mechanisms that cause these diseases and subsequent successful therapeutic regimens.

OVERVIEW OF MOLECULAR CELL BIOLOGY One of the goals of modern biology is to analyze the molecular structure and gain a fuller understanding of how cells, tissues, organs, and entire organisms function, both in a normal state and under pathologic conditions. Significant progress has been made in molecular studies of metabolism pathways, gene expression, cellular signaling, and organ development in human beings. The advent of recombinant DNA technology, polymerase chain reaction (PCR) techniques, and completion of the Human Genome Project are positively affecting human society by not only broadening our knowledge and understanding of disease development but also by bringing about necessary changes in disease treatment. Today's practicing surgeons are becoming increasingly aware that many modern surgical procedures rely on the information gained through molecular research. Genomic information, such as BRCA and RET proto-oncogene, is being used to help direct prophylactic procedures to remove potentially harmful tissues before they do damage to patients. Molecular engineering has led to cancer-specific gene therapy that could serve in the near future as a more effective adjunct to surgical debulking of tumors than radiation or chemotherapy, so surgeons will benefit from a clear introduction to how basic biochemical and biologic principles relate to the developing area of molecular biology. This chapter reviews the current information on modern molecular biology for the surgical community. It is written

with the intent of serving two functions. The first is to introduce or update the readers about the general concepts of molecular cell biology, which are essential for comprehending the real power and potential of modern molecular technology. The second aim is to inform the reader about the modern molecular techniques that are commonly used for surgical research and to provide a fundamental introduction on the background of how these techniques are developed and applied to benefit patients.

Basic Concepts of Molecular Research The modern era of molecular biology, which has been mainly concerned with how genes govern cell activity, began in 1953 when James D. Watson and Francis H. C. Crick made one of the greatest scientific discoveries by deducing the double-helical structure of deoxyribonucleic acid, or DNA.1,2 The year 2003 marked the fiftieth anniversary of this great discovery. Before 1953, one of the most mysterious aspects of biology was how genetic material was precisely duplicated from one generation to the next. Although DNA had been implicated as genetic material, it was the base-paired structure of DNA that provided a logical interpretation of how a double helix could "unzip" to make copies of itself. This DNA synthesis, termed replication , immediately gave rise to the notion that a template was involved in the transfer of information between generations, and thus confirmed the suspicion that DNA carried an organism's hereditary information. Within cells, DNA is packed into chromosomes. One important feature of DNA as genetic material is its ability to encode important information for all of a cell's functions (Fig. 15-1). Based on the principles of base complementarity, scientists also discovered how information in DNA is accurately transferred into the protein structure. DNA serves as a template for RNA synthesis, termed transcription , including messenger RNA (mRNA, or the protein-encoding RNA), ribosomal RNA (rRNA), and transfer RNA (tRNA). mRNA carries the information from DNA to make proteins, termed translation , with the assistance of rRNA and tRNA. Each of these steps is precisely controlled in such a way that genes are properly expressed in each cell at a specific time and location. In recent years, new classes of noncoding RNAs, for example, microRNA (or miRNA) and Piwi-interacting RNA (or piRNA), have been identified that regulate gene expression through mRNA degradation. Consequently, the differential gene activity in a cell determines its actions, properties, and functions.

Fig. 15-1.

The flow of genetic information from DNA to protein to cell functions. The process of transmission of genetic information from DNA to RNA is called transcription , and the process of transmission from RNA to protein is called translation . Proteins are the essential controlling components for cell structure, cell signaling, and metabolism. Genomics and proteomics are the study of the genetic composition of a living organism at the DNA and protein level, respectively. The study of the relationship between genes and their cellular functions is called functional genomics .

Molecular Approaches to Surgical Research Rapid advances in molecular and cellular biology over the past half century have revolutionized the understanding of disease and will radically transform the practice of surgery. In the future, molecular techniques will be increasingly applied to surgical disease and will lead to new strategies for the selection and implementation of operative therapy. Surgeons should be familiar with the fundamental principles of molecular and cellular biology so that emerging scientific breakthroughs can be translated into improved care of the surgical patient. The greatest advances in the field of molecular biology have been in the areas of analysis and manipulation of DNA.1 Since Watson and Crick's discovery of DNA structure, an intensive effort has been made to unlock the deepest biologic secrets of DNA. Among the avalanche of technical advances, one discovery in particular has drastically changed the world of molecular biology: the uncovering of the enzymatic and microbiologic techniques that produce recombinant DNA. Recombinant DNA technology involves the enzymatic manipulation of DNA and, subsequently, the cloning of DNA. DNA molecules are cloned for a variety of purposes including safeguarding DNA samples, facilitating sequencing, generating probes, and expressing recombinant proteins in one or more host organisms. DNA can be produced by a number of means, including restricted digestion of an existing vector, PCR, and cDNA synthesis. As DNA cloning techniques have developed over the last quarter century, researchers have moved from studying DNA to studying the functions of proteins, and from cell and animal models to molecular therapies in humans. Expression of recombinant proteins provides a method for analyzing gene regulation, structure, and function. In recent years the uses for recombinant proteins have expanded to include a variety of new applications, including gene therapy and biopharmaceuticals. The basic molecular approaches for modern surgical research include DNA cloning, cell manipulation, disease modeling in animals, and clinical trials in human

patients.

FUNDAMENTALS OF MOLECULAR AND CELL BIOLOGY DNA and Heredity DNA forms a right-handed, double-helical structure that is composed of two antiparallel strands of unbranched polymeric deoxyribonucleotides linked by phosphodiester bonds between the 5' carbon of one deoxyribose moiety to the 3' carbon of the next (Fig. 15-2). DNA is composed of four types of deoxyribonucleotides: adenine (A), cytosine (C), guanine (G), and thymine (T). The nucleotides are joined together by phosphodiester bonds. In the double-helical structure deduced by Watson and Crick, the two strands of DNA are complementary to each other. Because of size, shape, and chemical composition, A always pairs with T, and C with G, through the formation of hydrogen bonds between complementary bases that stabilize the double helix.

Fig. 15-2.

Schematic representation of a DNA molecule forming a double helix. DNA is made of four types of nucleotides, which are linked covalently into a DNA strand. A DNA molecule is composed of two DNA strands held together by hydrogen bonds between the pair bases. The arrowheads at the ends of the DNA strands indicate the polarities of the two strands, which run antiparallel to each other in the DNA molecule. The diagram at the bottom left of the figure shows the DNA molecule straightened out. In reality, the DNA molecule is twisted into a double helix, of which each turn of DNA is made up of 10.4 nucleotide pairs, as shown on the right.

(From Alberts et al,1 with permission.)

Recognition of the hereditary transmission of genetic information is attributed to the Austrian monk, Gregor Mendel. His seminal work, ignored upon publication until its rediscovery in 1900, established the laws of segregation and of independent assortment. These two principles established the existence of paired elementary units of heredity and defined the statistical laws that govern them.3 DNA was isolated in 1869, and a number of important observations of the inherited basis of certain diseases were made in the early part of the twentieth century. Although today it appears easy to understand how DNA replicates, before the 1950s, the idea of DNA as the primary genetic material was not appreciated. The modern era of molecular biology began in 1944 with the demonstration that DNA was the substance that carried genetic information. The first experimental evidence that DNA was genetic material came from simple transformation experiments conducted in the 1940s using Streptococcus pneumoniae . One strain of the bacteria could be converted into another by incubating it with DNA from the other, just as the treatment of the DNA with deoxyribonuclease would inactivate the transforming activity of the DNA. Similarly, in the early 1950s, before the discovery of the double-helical structure of DNA, the entry of viral DNA and not the protein into the host bacterium was believed to be necessary to initiate infection by the bacterial virus or bacteriophage. Key historical events concerning genetics are outlined in Table 15-1.

Table 15-1 Historical Events in Genetics and Molecular Biology 1865 Mendel Laws of genetics established 1869 Miescher DNA isolated 1905 Garrod Human inborn errors of metabolism 1913 Sturtevant Linear map of genes 1927 Muller X-rays cause inheritable genetic damage 1928 Griffith Transformation discovered 1941 Beadle and Tatum "One gene, one enzyme" concept 1944 Avery, MacLeod, McCarty DNA as material of heredity 1950 McKlintock Existence of transposons confirmed 1953

Watson and Crick Double-helical structure of DNA 1957 Benzer and Kornberg Recombination and DNA polymerase 1966 Nirenberg, Khorana, Holley Genetic code determined 1970 Temin and Baltimore Reverse transcriptase 1972 Cohen, Boyer, Berg Recombinant DNA technology 1975 Southern Transfer of DNA fragments from sizing gel to nitrocellulose (Southern blot) 1977 Sanger, Maxim, Gilbert DNA sequencing methods 1982 — GenBank database established 1985 Mullis Polymerase chain reaction 1986 — Automated DNA sequencing 1989 Collins Cystic fibrosis gene identified by positional cloning and linkage analysis 1990 — Human Genome Project initiated 1997 Roslin Institute Mammalian cloning (Dolly) 2001 IHGSC and Celera Genomics Draft versions of human genome sequence published 2003 — Human Genome Project completed Year

Investigator

IHGSC = International Human Genome Sequencing Consortium.

Event

For cells to pass on the genetic material (DNA) to each progeny, the amount of DNA must be doubled. Watson and Crick recognized that the complementary base-pair structure of DNA implied the existence of a template-like mechanism for the copying of genetic material.2 The transfer of DNA material from the mother cell to daughter cells takes place during somatic cell division (also called mitosis ). Before a cell divides, DNA must be precisely duplicated. During replication, the two strands of DNA separate and each strand creates a new complementary strand by precise base-pair matching (Fig. 15-3). The two, new, double-stranded DNAs carry the same genetic information, which can then be passed on to two daughter cells. Proofreading mechanisms ensure that the replication process occurs in a highly accurate manner. The fidelity of DNA replication is absolutely crucial to maintaining the integrity of the genome from generation to generation. However, mistakes can still occur during this process, resulting in mutations , which may lead to a change of the DNA's encoded protein and, consequently, a change of the cell's behavior. The reliable dependence of many features of modern organisms on subtle changes in genome is linked to Mendelian inheritance and also contributes to the processes of Darwinian evolution. In addition, massive changes, so-called genetic instability , can occur in the genome of somatic cells such as cancer cells.

Fig. 15-3.

DNA replication. As the nucleotide A only pairs with T, and G with C, each strand of DNA can determine the nucleotide sequence in its complementary strand. In this way, double-helical DNA can be copied precisely. (From Alberts et al,1 with permission.)

Gene Regulation Living cells have the necessary machinery to enzymatically transcribe DNA into RNA and translate the mRNA into protein. This machinery accomplishes the two major steps required for gene expression in all organisms: transcription and translation (Fig. 15-4). However, gene regulation is far more complex, particularly in eukaryotic organisms. For example, many gene transcripts must be spliced to remove the intervening sequences. The

sequences that are spliced off are called introns , which appear to be useless, but in fact may carry some regulatory information. The sequences that are joined together, and are eventually translated into protein, are called exons . Additional regulation of gene expression includes modification of mRNA, control of mRNA stability, and its nuclear export into cytoplasm (where it is assembled into ribosomes for translation). After mRNA is translated into protein, the levels and functions of the proteins can be further regulated posttranslationally. However, the following sections will mainly focus on gene regulation at transcriptional and translational levels.

Fig. 15-4.

Four major steps in the control of eukaryotic gene expression. Transcriptional and posttranscriptional control determine the level of messenger RNA (mRNA) that is available to make a protein, while translational and posttranslational control determine the final outcome of functional proteins. Note that posttranscriptional and posttranslational controls consist of several steps.

TRANSCRIPTION Transcription is the enzymatic process of RNA synthesis from DNA.4 In bacteria, a single RNA polymerase carries out all RNA synthesis, including that of mRNA, rRNA, and tRNA. Transcription often is coupled with translation in such a way that an mRNA molecule is completely accessible to ribosomes, and bacterial protein synthesis begins on an mRNA molecule even while it is still being synthesized. Therefore, a discussion of gene regulation with a look at the simpler prokaryotic system precedes that of the more complex transcription and posttranscriptional regulation of eukaryotic genes.

Transcription in Bacteria Initiation of transcription in prokaryotes begins with the recognition of DNA sequences by RNA polymerase. First, the bacterial RNA polymerase catalyzes RNA synthesis through loose binding to any region in the double-stranded DNA and then through specific binding to the promoter region with the assistance of accessory proteins called factors (sigma factors). A promoter region is the DNA region upstream of the transcription initiation site. RNA polymerase binds tightly at the promoter sites and causes the double-stranded DNA structure to unwind. Consequently, few nucleotides can be base-paired with the DNA template to begin transcription. Once transcription begins, the

factor is released. The growing RNA chain may begin to peel off as the chain elongates. This occurs in

such a way that there are always about 10 to 12 nucleotides of the growing RNA chains that are base-paired with

the DNA template. The bacterial promoter contains a region of about 40 bases that include two conserved elements called –35 region and –10 region . The numbering system begins at the initiation site, which is designated +1 position, and counts backward (in negative numbers) on the promoter and forward on the transcribed region. Although both regions on different promoters are not the same sequences, they are fairly conserved and very similar. This conservation provides the accurate and rapid initiation of transcription for most bacterial genes. It is also common in bacteria that one promoter serves to transcribe a series of clustered genes, called an operon . A single transcribed mRNA contains a series of coding regions, each of which is later independently translated. In this way, the protein products are synthesized in a coordinated manner. Most of the time these proteins are involved in the same metabolic pathway, thus demonstrating that the control by one operon is an efficient system. After initiation of transcription, the polymerase moves along the DNA to elongate the chain of RNA, although at a certain point, it will stop. Each step of RNA synthesis, including initiation, elongation, and termination, will require the integral functions of RNA polymerase as well as the interactions of the polymerase with regulatory proteins.

Transcription in Eukaryotes Transcription mechanisms in eukaryotes differ from those in prokaryotes. The unique features of eukaryotic transcription are as follows: (a) Three separate RNA polymerases are involved in eukaryotes: RNA polymerase I transcribes the precursor of 5.8S, 18S, and 28S rRNAs; RNA polymerase II synthesizes the precursors of mRNA as well as microRNA; RNA polymerase III makes tRNAs and 5S rRNAs. (b) In eukaryotes, the initial transcript is often the precursor to final mRNAs, tRNAs, and rRNAs. The precursor is then modified and/or processed into its final functional form. RNA splicing is one type of processing to remove the noncoding introns (the region between coding exons) on an mRNA. (c) In contrast to bacterial DNA, eukaryotic DNA often is packaged with histone and nonhistone proteins into chromatins. Transcription will only occur when the chromatin structure changes in such a way that DNA is accessible to the polymerase. (d) RNA is made in the nucleus and transported into cytoplasm, where translation occurs. Therefore, unlike bacteria, eukaryotes undergo uncoupled transcription and translation. Eukaryotic gene transcription also involves the recognition and binding of RNA polymerase to the promoter DNA. However, the interaction between the polymerase and DNA is far more complex in eukaryotes than in prokaryotes. Because the majority of studies have been focused on the regulation and functions of proteins, this chapter primarily focuses on how protein-encoding mRNA is made by RNA polymerase II.

TRANSLATION DNA directs the synthesis of RNA; RNA in turn directs the synthesis of proteins. Proteins are variable-length polypeptide polymers composed of various combinations of 20 different amino acids and are the working molecules of the cell. The process of decoding information on mRNA to synthesize proteins is called translation (see Fig. 151). Translation takes place in ribosomes composed of rRNA and ribosomal proteins. The numerous discoveries made during the 1950s made it easy to understand how DNA replication and transcription involves base-pairing between DNA and DNA, or DNA and RNA. However, at that time it was still impossible to comprehend how mRNA transfers the information to the protein-synthesizing machinery. The genetic information on mRNA is composed of arranged sequences of four bases that are transferred to the linear arrangement of 20 amino acids on a protein. Amino acids are characterized by a central carbon unit linked to four side chains: an amino group (–NH2 ), a carboxy group (–COOH), a hydrogen, and a variable (–R) group. The amino acid chain is assembled via peptide bonds between the amino group of one amino acid and the carboxy group of the next. Because of this decoding, the information carried on mRNA relies on tRNA. Translation involves all three RNAs. The precise transfer of

information from mRNA to protein is governed by genetic code , the set of rules by which codons are translated into an amino acid (Table 15-2). A codon , a triplet of three bases, codes for one amino acid. In this case, random combinations of the four bases form 4

x

4

x

4, or 64 codes. Because 64 codes are more than enough for 20 amino

acids, most amino acids are coded by more than one codon. The start codon is AUG, which also corresponds to methionine; therefore, almost all proteins begin with this amino acid. The sequence of nucleotide triplets that follows the start codon signal is termed the reading frame . The codons on mRNA are sequentially recognized by tRNA adaptor proteins. Specific enzymes termed aminoacyl-tRNA synthetases link a specific amino acid to a specific tRNA. The translation of mRNA to protein requires the ribosomal complex to move stepwise along the mRNA until the initiator methionine sequence is identified. In concert with various protein initiator factors, the methionyl-tRNA is positioned on the mRNA and protein synthesis begins. Each new amino acid is added sequentially by the appropriate tRNA in conjunction with proteins called elongation factors . Protein synthesis proceeds in the aminoto-carboxy-terminus direction.

Table 15-2 The Genetic Code First Base in Codon UUU Phe [F] UCU Ser [S] UAU Tyr [Y] UGU Cys [C] U Third Base in Codon U UUC Phe [F] UCC Ser [S] UAC Tyr [Y] UGC Cys [C] C UUA Leu [L]

UCA Ser [S] UAA STOP — UGA STOP — A UUG Leu [L] UCG Ser [S] UAG STOP — UGG Trp [W] G CUU Leu [L] CCU Pro [P] CAU His [H] CGU Arg [R] U CUC Leu [L] CCC Pro [P] CAC His [H] CGC

Arg [R] C C CUA Leu [L] CCA Pro [P] CAA Gln [Q] CGA Arg [R] A CUG Leu [L] CCG Pro [P] CAG Gln [Q] CGG Arg [R] G AUU Ile [I] ACU Thr [T] AAU Asn [N] AGU Ser [S] U AUC Ile [I]

ACC Thr [T] AAC Asn [N] AGC Ser [S] C A AUA Ile [I] ACA Thr [T] AAA Lys [K] AGA Arg [R] A AUG Met [M] ACG Thr [T] AAG Lys [K] AGG Arg [R] G GUU Val [V] GCU Ala [A] GAU Asp [D] GGU

Gly [G] U GUC Val [V] GCC Ala [A] GAC Asp [D] GGC Gly [G] C G GUA Val [V] GCA Ala [A] GAA Glu [E] GGA Gly [G] A GUG Val [V] GCG Ala [A] GAG Glu [E] GGG Gly [G] G Second Base in Codon U

C

A

G

A = adenine; C = cytosine; G = guanine; U = uracil; Ala = alanine; Arg = arginine; Asn = asparagine; Asp = aspartic acid; Cys = cysteine; Glu = glutamic acid; Gln = glutamine; Gly = glycine; His = histidine; Ile = isoleucine; Leu = leucine; Lys = lysine; Met = methionine; Phe = phenylalanine; Pro = proline; Ser = serine; Thr = threonine; Trp = tryptophan; Tyr = tyrosine; Val = valine. Letter in [ ] indicates single lettercode for amino acid. The biologic versatility of proteins is astounding. Among many other functions, proteins serve as enzymes that catalyze critical biochemical reactions, carry signals to and from the extracellular environment, and mediate diverse signaling and regulatory functions in the intracellular environment. They also transport ions and various small molecules across plasma membranes. Proteins make up the key structural components of cells and the extracellular matrix and are responsible for cell motility. The unique functional properties of proteins are largely determined by their structure (Fig. 15-5).

Fig. 15-5.

Maturation of a functional protein. Although the linear amino acid sequence of a protein often is shown, the function of a protein also is controlled by its correctly folded three-dimensional structure. In addition, many proteins also have covalent posttranslational modifications such as phosphorylation or noncovalent binding to a small molecule or a protein.

REGULATION OF GENE EXPRESSION The human organism is made up of a myriad of different cell types that, despite their vastly different characteristics, contain the same genetic material. This cellular diversity is controlled by the genome and accomplished by tight regulation of gene expression. This leads to the synthesis and accumulation of different complements of RNA and, ultimately, to the proteins found in different cell types. For example, muscle and bone express different genes or the same genes at different times. Moreover, the choice of which genes are expressed in a given cell at a given time depends on signals received from its environment. There are multiple levels at which gene expression can be controlled along the pathway from DNA to RNA to protein (see Fig. 15-4). Transcriptional control refers to the mechanism for regulating when and how often a gene is transcribed. Splicing of the primary RNA transcript (RNA processing control ) and selection of completed mRNAs for nuclear export (RNA transport control ) represent additional potential regulatory steps. The mRNAs in the cytoplasm can be selectively translated by ribosomes (translational control ), or selectively stabilized or degraded (mRNA degradation control ). Finally, the resulting proteins can undergo selective activation, inactivation, or compartmentalization (protein activity control ). Because a large number of genes are regulated at the transcriptional level, regulation of gene transcripts (i.e., mRNA) often is referred to as gene regulation in a narrow definition. Each of the steps during transcription is properly regulated in eukaryotic cells. Because genes are differentially regulated from one another, one gene can be differentially regulated in different cell types or at different developmental stages. Therefore, gene regulation at the level of transcription is largely context dependent. However, there is a common scheme that applies to transcription at the molecular level (Fig. 15-6). Each gene promoter possesses unique sequences called TATA boxes that can be recognized and bound by a large complex containing RNA polymerase II, forming the basal transcription machinery. Usually located upstream of the TATA box (but sometimes longer distances) are a number of regulatory sequences referred to as enhancers that are recognized by regulatory proteins called transcription factors . These transcription factors specifically bind to the enhancers, often in response to environmental or developmental cues, and cooperate with each other and with basal transcription factors to initiate transcription. Regulatory sequences that negatively regulate the initiation of transcription also are present on the promoter DNA. The transcription factors that bind to these sites are called repressors , in contrast to the activators that activate transcription. The molecular interactions between transcription factors and promoter DNA, as well as between the cooperative transcription factors, are highly regulated and context-dependent. Specifically, the recruitment of transcription factors to the promoter DNA occurs in response to physiologic signals. A number of structural motifs in these DNA-binding transcription factors facilitate this recognition and interaction. These include the helix-turnhelix, the homeodomain motif, the zinc finger, the leucine zipper, and the helix-loop-helix motifs.

Fig. 15-6.

Transcriptional control by RNA polymerase. DNA is packaged into a chromatin structure. TATA = the common sequence on the promoter recognized by TBP and polymerase II holoenzyme; TBP = TATA-binding protein and associated factors; TF = hypothetical transcription factor; TFBS = transcription factor binding site; ball-shaped structures = nucleosomes. Coactivator or corepressor are factors linking the TF with the Pol II complex.

Human Genome Genome is a collective term for all genes present in one organism. The human genome contains DNA sequences of 3 billion base-pairs, carried by 23 pairs of chromosomes. The human genome has an estimated 25,000 to 30,000 genes, and overall it is 99.9% identical in all people. 5,6 Approximately 3 million locations where single-base DNA differences exist have been identified and termed single nucleotide polymorphisms . Single nucleotide polymorphisms may be critical determinants of human variation in disease susceptibility and responses to environmental factors. The completion of the human genome sequence in 2003 represented another great milestone in modern science. The human genome project created the field of genomics , which is the study of genetic material in detail (see Fig. 15-1). The medical field is building upon the knowledge, resources, and technologies emanating from the human genome to further the understanding of the relationship of the genes and their mutations to human health and disease. This expansion of genomics into human health applications resulted in the field of genomic medicine. The emergence of genomics as a science will transform the practice of medicine and surgery in this century. This breakthrough has allowed scientists the opportunity to gain remarkable insights into the lives of humans. Ultimately, the goal is to use this information to develop new ways to treat, cure, or even prevent the thousands of diseases that afflict humankind. In the twenty-first century, work will begin to incorporate the information embedded in the human genome sequence into surgical practices. By doing so, the genomic information can be used for diagnosing and predicting disease and disease susceptibility. Diagnostic tests can be designed to detect errant genes in patients suspected of having particular diseases or of being at risk for developing them. Furthermore, exploration into the function of each human gene is now possible, which will shed light on how faulty genes play a role in disease causation. This knowledge also makes possible the development of a new generation of therapeutics based on genes. Drug design is being revolutionized as researchers create new classes of medicines based on a reasoned approach to the use of information on gene sequence and protein structure function rather than the traditional trial-and-error method. Drugs targeted to specific sites in the body promise to have fewer side effects than many of today's medicines. Finally, other applications of genomics will involve the transfer of genes to

replace defective versions or the use of gene therapy to enhance normal functions such as immunity. Proteomics refers to the study of the structure and expression of proteins as well as the interactions among proteins encoded by a human genome (see Fig. 15-1).7 A number of Internet-based repositories for protein sequences exist, including Swiss-Prot (http://www.expasy.ch). These databases allow comparisons of newly identified proteins with previously characterized sequences to allow prediction of similarities, identification of splice variants, and prediction of membrane topology and posttranslational modifications. Tools for proteomic profiling include two-dimensional gel electrophoresis, time-of-flight mass spectrometry, matrix-assisted laser desorption/ionization, and protein microarrays. Structural proteomics aims to describe the three-dimensional structure of proteins that is critical to understanding function. Functional genomics seeks to assign a biochemical, physiologic, cell biologic, and/or developmental function to each predicted gene. An ever-increasing arsenal of approaches, including transgenic animals, RNA interference (RNAi), and various systematic mutational strategies, will allow dissection of functions associated with newly discovered genes. Although the potential of this field of study is vast, it is in its early stages. It is anticipated that a genomic and proteomic approach to human disease will lead to a new understanding of pathogenesis that will aid in the development of effective strategies for early diagnosis and treatment.8 For example, identification of altered protein expression in organs, cells, subcellular structures, or protein complexes may lead to development of new biomarkers for disease detection. Moreover, improved understanding of how protein structure determines function will allow rational identification of therapeutic targets, and thereby not only accelerate drug development, but also lead to new strategies to evaluate therapeutic efficacy and potential toxicity.7

Cell Cycle and Apoptosis Every organism has many different cell types. Many cells grow, while some cells such as nerve cells and striated muscle cells do not. All growing cells have the ability to duplicate their genomic DNA and pass along identical copies of this genetic information to every daughter cell. Thus, the cell cycle is the fundamental mechanism to maintain tissue homeostasis. A cell cycle comprises four periods: G1 (first gap phase before DNA synthesis), S (synthesis phase when DNA replication occurs), G2 (the gap phase before mitosis), and M (mitosis, the phase when two daughter cells with identical DNA are generated) (Fig. 15-7). After a full cycle, the daughter cells enter G1 again, and when they receive appropriate signals, undergo another cycle, and so on. The machinery that drives cell cycle progression is made up of a group of enzymes called cyclin-dependent kinases (CDK). Cyclin expression fluctuates during the cell cycle, and cyclins are essential for CDK activities and form complexes with CDK. The cyclin A/CDK1 and cyclin B/CDK1 drive the progression for the M phase, while cyclin A/CDK2 is the primary S phase complex. Early G1 cyclin D/CDK4/6 or late G1 cyclin E/CDK2 controls the G1 -S transition. There also are negative regulators for CDK termed CDK inhibitors , which inhibit the assembly or activity of the cyclin-CDK complex. Expression of cyclins and CDK inhibitors often are regulated by developmental and environmental factors.

Fig. 15-7.

The cell cycle and its control system. M is the mitosis phase, when the nucleus and the cytoplasm divide; S is the phase when DNA is duplicated; G1 is the gap between M and S; G2 is the gap between S and M. A complex of cyclin and cyclin-dependent kinase (CDK) controls specific events of each phase. Without cyclin, CDK is inactive. Different cyclin/CDK complexes are shown around the cell cycle. A, B, D, and E stand for cyclin A, cyclin B, cyclin D, and cyclin E, respectively.

The cell cycle is connected with signal transduction pathways as well as gene expression. While the S and M phases rarely are subjected to changes imposed by extracellular signals, the G1 and G2 phases are the primary periods when cells decide whether to move on to the next phase or not. During the G1 phase, cells receive green- or redlight signals, S phase entry or G1 arrest, respectively. Growing cells proliferate only when supplied with appropriate mitogenic growth factors. Cells become committed to entry of the cell cycle only toward the end of G1 . Mitogenic signals stimulate the activity of early G1 CDKs (e.g., cyclin D/CDK4) that inhibit the activity of pRb protein and activate the transcription factor called E2F to induce the expression of batteries of genes essential for G 1 -S progression. Meanwhile, cells also receive antiproliferative signals such as those from tumor suppressors. These antiproliferative signals also act in the G1 phase to stop cells' progress into the S phase by inducing CKI production. For example, when DNA is damaged, cells will repair the damage before entering the S phase. Therefore, G1 contains one of the most important checkpoints for cell cycle progression. If the analogy is made that CDK is to a cell as an engine is to a car, then cyclins and CKI are the gas pedal and brake, respectively. Accelerated proliferation or improper cell cycle progression with damaged DNA would be disastrous. Genetic gain-of-function mutations in oncogenes (that often promote expression or activity of the cyclin/CDK complex) or loss-of-function mutations in tumor suppressor (that stimulate production of CKI) are causal factors for malignant transformation.

In addition to cell cycle control, cells use genetically programmed mechanisms to kill cells. This cellular process, called apoptosis or programmed cell death , is essential for the maintenance of tissue homeostasis (Fig. 15-8).

Fig. 15-8.

A simplified view of the apoptosis pathways. Extracellular death receptor pathways include the activation of Fas and tumor necrosis factor (TNF) receptors, and consequent activation of the caspase pathway. Intracellular death pathway indicates the release of cytochrome c from mitochondria, which also triggers the activation of the caspase cascade. During apoptosis, cells undergo DNA fragmentation, nuclear and cell membrane breakdown, and are eventually digested by other cells.

Normal tissues undergo proper apoptosis to remove unwanted cells, those that have completed their jobs or have been damaged or improperly proliferated. Apoptosis can be activated by many physiologic stimuli such as death receptor signals (e.g., Fas or cytokine tumor necrosis factor), growth factor deprivation, DNA damage, and stress signals. Two major pathways control the biochemical mechanisms governing apoptosis: the death receptor and mitochondrial. However, recent advances in apoptosis research suggest an interconnection of the two pathways. What is central to the apoptotic machinery is the activation of a cascade of proteinases called caspases. Similarly to CDK in the cell cycle, activities and expression of caspases are well controlled by positive and negative regulators.

The complex machinery of apoptosis must be tightly controlled. Perturbations of this process can cause neoplastic transformation or other diseases.

Signal Transduction Pathways Gene expression in a genome is controlled in a temporal and spatial manner, at least in part by signaling pathways.9 A signaling pathway generally begins at the cell surface and, after a signaling relay by a cascade of intracellular effectors, ends up in the nucleus (Fig. 15-9). All cells have the ability to sense changes in their external environment. The bioactive substances to which cells can respond are many and include proteins, short peptides, amino acids, nucleotides/nucleosides, steroids, retinoids, fatty acids, and dissolved gases. Some of these substances are lipophilic and thereby can cross the plasma membrane by diffusion to bind to a specific target protein within the cytoplasm (intracellular receptor). Other substances bind directly with a transmembrane protein (cell-surface receptor). Binding of ligand to receptor initiates a series of biochemical reactions (signal transduction ) typically involving protein-protein interactions and the transfer of high-energy phosphate groups, leading to various cellular end responses.

Fig. 15-9.

Cell-surface and intracellular receptor pathways. Extracellular signaling pathway: Most growth factors and other hydrophilic signaling molecules are unable to move across the plasma membrane and directly activate cell-surface receptors such as Gprotein coupled receptors and enzyme-linked receptors. The receptor serves as the receiver, and in turn activates the downstream signals in the cell. Intracellular signaling pathway: Hormones or other diffusible molecules enter the cell and bind to the intracellular receptor in the cytoplasm or in the nucleus. Either extracellular or intracellular signals often reach the nucleus to control gene expression.

Control and specificity through simple protein-protein interactions—referred to as adhesive interactions —is a common feature of signal transduction pathways in cells.1 0 Signaling also involves catalytic activities of signaling molecules, such as protein kinases/phosphatases, that modify the structures of key signaling proteins. Upon binding and/or modification by upstream signaling molecules, downstream effectors undergo a conformational (allosteric) change and, consequently, a change in function. The signal that originates at the cell surface and is relayed by the cytoplasmic proteins often ultimately reaches the transcriptional apparatus in the nucleus. It alters

the DNA binding and activities of transcription factors that directly turn genes on or off in response to the stimuli. Abnormal alterations in signaling activities and capacities in otherwise normal cells can lead to diseases such as cancer. Advances in biology in the last two decades have dramatically expanded the view on how cells are wired with signaling pathways. In a given cell, many signaling pathways operate simultaneously and crosstalk with one another. A cell generally may react to a hormonal signal in a variety of ways: (a) by changing its metabolite or protein, (b) by generating an electric current, or (c) by contracting. Cells continually are subject to multiple input signals that simultaneously and sequentially activate multiple receptor and non–receptor-mediated signal transduction pathways, which form a signaling network. Although the regulators responsible for cell behavior are rapidly identified as a result of genomic and proteomic techniques, the specific functions of the individual proteins, how they assemble, and the networks that control cellular behavior remain to be defined. An increased understanding of cell regulatory pathways—and how they are disrupted in disease—will likely reveal common themes based on protein interaction domains that direct associations of proteins with other polypeptides, phospholipids, nucleic acids, and other regulatory molecules. Advances in the understanding of signaling networks will require methods of investigation that move beyond traditional "linear" approaches into medical informatics and computational biology. The bewildering biocomplexity of such networks mandates multidisciplinary and transdisciplinary research collaboration. The vast amount of information that is rapidly emerging from genomic and proteomic data mining will require the development of new modeling methodologies within the emerging disciplines of medical mathematics and physics. Signaling pathways often are grouped according to the properties of signaling receptors. Many hydrophobic signaling molecules are able to diffuse across plasma membranes and directly reach specific cytoplasmic targets. Steroid hormones, thyroid hormones, retinoids, and vitamin D are examples that exert their activity upon binding to structurally related receptor proteins that are members of the nuclear hormone receptor superfamily . Ligand binding induces a conformational change that enhances transcriptional activity of these receptors. Most extracellular signaling molecules interact with transmembrane protein receptors that couple ligand binding to intracellular signals, leading to biologic actions. There are three major classes of cell-surface receptors: transmitter-gated ion channels , seven-transmembrane Gprotein coupled receptors (GPCRs) , and enzyme-linked receptors . The superfamily of GPCRs is one of the largest families of proteins, representing over 800 genes of the human genome. Members of this superfamily share a characteristic seven-transmembrane configuration. The ligands for these receptors are diverse and include hormones, chemokines, neurotransmitters, proteinases, inflammatory mediators, and even sensory signals such as odorants and photons. Most GPCRs signal through heterotrimeric G proteins , which are guanine-nucleotide regulatory complexes. Thus the receptor serves as the receiver, the G protein serves as the transducer, and the enzyme serves as the effector arm. Enzyme-linked receptors possess an extracellular ligand-recognition domain and a cytosolic domain that either has intrinsic enzymatic activity or directly links with an enzyme. Structurally, these receptors usually have only one transmembrane-spanning domain. Of at least five forms of enzyme-linked receptors classified by the nature of the enzyme activity to which they are coupled, the growth factor receptors such as tyrosine kinase receptor or serine/threonine kinase receptors mediate diverse cellular events including cell growth, differentiation, metabolism, and survival/apoptosis. Dysregulation (particularly mutations) of these receptors is thought to underlie conditions of abnormal cellular proliferation in the context of cancer. The following sections will further review two examples of growth factor signaling pathways and their connection with human diseases.

INSULIN PATHWAY AND DIABETES11 The discovery of insulin in the early 1920s is one of the most dramatic events in the treatment of human disease. Insulin is a peptide hormone that is secreted by the -cell of the pancreas. Insulin is required for the growth and metabolism of most mammalian cells, which contain cell-surface insulin receptors (InsR). Insulin binding to InsR activates the kinase activity of InsR. InsR then adds phosphoryl groups, a process referred to as phosphorylation , and subsequently activates its immediate intracellular effector, called insulin receptor substrate (IRS). IRS plays a central role in coordinating the signaling of insulin by activating distinct signaling pathways, the PI3K-Akt pathway and MAPK pathway, both of which possess multiple protein kinases that can control transcription, protein synthesis, and glycolysis (Fig. 15-10).

Fig. 15-10.

Insulin-signaling pathway. Insulin is a peptide growth factor that binds to and activates the heterotetrameric receptor complex (InsR). InsR possesses protein tyrosine kinase activity and is able to phosphorylate the downstream insulin receptor substrate (IRS). Phosphorylated IRS serves as a scaffold and controls the activation of multiple downstream pathways for gene expression, cell survival, and glucose metabolism. Inactivation of the insulin pathway can lead to type 2 diabetes.

The primary physiologic role of insulin is in glucose homeostasis, which is accomplished through the stimulation of

glucose uptake into insulin-sensitive tissues such as fat and skeletal muscle. Defects in insulin synthesis/secretion and/or responsiveness are major causal factors in diabetes, one of the leading causes of death and disability in the United States, affecting an estimated 16 million Americans. Type 2 diabetes accounts for about 90% of all cases of diabetes. Clustering of type 2 diabetes in certain families and ethnic populations points to a strong genetic background for the disease. More than 90% of affected individuals have insulin resistance, which develops when the body is no longer able to respond correctly to insulin circulating in the blood. Although relatively little is known about the biochemical basis of this metabolic disorder, it is clear that the insulin-signaling pathways malfunction in this disease. It is also known that genetic mutations in the InsR or IRS cause type 2 diabetes, although which one is not certain. The majority of type 2 diabetes cases may result from defects in downstream-signaling components in the insulin-signaling pathway. Type 2 diabetes also is associated with declining -cell function, resulting in reduced insulin secretion; these pathways are under intense study. A full understanding of the basis of insulin resistance is crucial for the development of new therapies for type 2 diabetes. Furthermore, apart from type 2 diabetes, insulin resistance is a central feature of several other common human disorders, including atherosclerosis and coronary artery disease, hypertension, and obesity.

TRANSFORMING GROWTH FACTOR

(TGF ) PATHWAY AND CANCERS12

Growth factor signaling controls cell growth, differentiation, and apoptosis. Although insulin and many mitogenic growth factors promote cell proliferation, some growth factors and hormones inhibit cell proliferation. Transforming growth factor

(TGF ) is one of them. The balance between mitogens and TGF

plays an important role in

controlling the proper pace of cell cycle progression. The growth inhibition function of TGF

signaling in epithelial

cells plays a major role in maintaining tissue homeostasis. The TGF

superfamily comprises a large number of structurally related growth and differentiation factors that act

through a receptor complex at the cell surface (Fig. 15-11). The complex consists of transmembrane serine/threonine kinases. The receptor signals through activation of heterotrimeric complexes of intracellular effectors called SMADs (which are contracted from homologous Caenorhabditis elegans Sma and Drosophila Mad, two evolutionarily conserved genes for TGF

signaling). Upon phosphorylation by the receptors, SMAD complexes

translocate into the nucleus, where they bind to gene promoters and cooperate with specific transcription factors to regulate the expression of genes that control cell proliferation and differentiation. For example, TGF induces the transcription of a gene called

p15INK4B

strongly

(a type of CKI) and, at the same time, reduces the expression of

many oncogenes such as c-Myc . The outcome of the altered gene expression leads to the inhibition of cell cycle progression. Meanwhile, the strength and duration of TGF

signaling is fine-tuned by a variety of positive or

negative modulators, including protein phosphatases. Therefore, controlled activation of TGF intrinsic mechanism for cells to ensure controlled proliferation.

Fig. 15-11.

signaling is an

TGF signaling pathway. The TGF family has at least 29 members encoded in the human genome. They are also peptide growth factors. Each member binds to a heterotetrameric complex consisting of a distinct set of type I and type II receptors. TGF receptors are protein serine/threonine kinases and can phosphorylate the downstream substrates called SMAD proteins . Phosphorylated SMADs are directly transported into the nucleus, where they bind to the DNA and regulate gene expression that is responsible for inhibition of cell proliferation. Inactivation of the TGF pathway through genetic mutations in the TGF receptors or SMADs is frequent in human cancer, leading to the uncontrolled proliferation of cancer cells.

Resistance to TGF 's anticancer action is one hallmark of human cancer cells. TGF identified as tumor suppressors. The TGF types of human tumors. Some lose TGF

receptors and SMADs are

signaling circuit can be disrupted in a variety of ways and in different responsiveness through downregulation or mutations of their TGF

receptors. The cytoplasmic SMAD4 protein, which transduces signals from ligand-activated TGF

receptors to

downstream targets, may be eliminated through mutation of its encoding gene. The locus encoding cell cycle inhibitor p15 INK4B may be deleted. Alternatively, the immediate downstream target of its actions, cyclin-dependent kinase 4 (CDK4), may become unresponsive to the inhibitory actions of p15INK4B because of mutations that block p15INK4B binding. The resulting cyclin D/CDK4 complexes constitutively inactivate tumor suppressor pRb by hyperphosphorylation. Finally, functional pRb, the end target of this pathway, may be lost through mutation of its gene. For example, in pancreatic and colorectal cancers, 100% of cells derived from these cancers carry genetic defects in the TGF

signaling pathway. Therefore, the antiproliferative pathway converging onto pRb and the cell

division cycle is, in one way or another, disrupted in a majority of human cancer cells. Besides cancer, dysregulation of TGF

signaling also has been associated with other human diseases such as Marfan syndrome and

thoracic aortic aneurysm.

Gene Therapy and Molecular Drugs in Cancer Modern advances in the use of molecular biology to manipulate genomes have greatly contributed to the understanding of the molecular basis for how cells live, die, or differentiate. Given the fact that human diseases arise from improper changes in the genome, the continuous understanding of how the genome functions will make it possible to tailor medicine on an individual basis. Although significant hurdles remain, the course toward therapeutic application of molecular biology already has been mapped out by many proof-of-principle studies in the literature. In this section, cancer is used as an example to elaborate some therapeutic applications of molecular biology. Modern molecular medicine includes gene therapy and molecular drugs that target genes or gene products that wire human cells. Cancer is a complex disease, involving uncontrolled growth and spread of tumor cells (Fig. 15-12). Cancer development depends on the acquisition and selection of specific characteristics that set the tumor cell apart from normal somatic cells. Cancer cells have defects in regulatory circuits that govern normal cell proliferation and homeostasis. Many lines of evidence indicate that tumorigenesis in humans is a multistep process and that these steps reflect genetic alterations that drive the progressive transformation of normal human cells into highly malignant derivatives. The genomes of tumor cells are invariably altered at multiple sites, having suffered disruption through lesions as subtle as point mutations and as obvious as changes in chromosome complement. A succession of genetic changes, each conferring one or another type of growth advantage, leads to the progressive conversion of normal human cells into cancer cells.

Fig. 15-12.

Tumor clonal evolution and metastasis. A tumor develops from mutant cells with multiple genetic mutations. Through repeated alterations in the genome, mutant epithelial cells are able to develop into a cluster of cells (called a tumor clone ) that proliferates in an uncontrollable fashion. Further changes in the tumor cells can transform the tumor cells into a population of cells that can enter the blood vessels and repopulate in a new location.

Cancer research in the past 20 years has generated a rich and complex body of knowledge, revealing cancer to be a disease involving dynamic changes in the genome. The causes of cancer include genetic predisposition, environmental influences, infectious agents, and aging. These transform normal cells into cancerous ones by derailing a wide spectrum of regulatory pathways including signal transduction pathways, cell cycle machinery, or

apoptotic pathways.1 3 The early notion that cancer was caused by mutations in genes critical for the control of cell growth implied that genome stability is important for preventing oncogenesis. There are two classes of cancer genes in which alteration has been identified in human and animal cancer cells: oncogenes, with dominant gain-offunction mutations, and tumor suppressor genes, with recessive loss-of-function mutations. In normal cells, oncogenes promote cell growth by activating cell cycle progression, while tumor suppressors counteract oncogenes' functions. Therefore, the balance between oncogenes and tumor suppressors maintains a well-controlled state of cell growth. During the development of most types of human cancer, cancer cells can break away from primary tumor masses, invade adjacent tissues, and hence travel to distant sites where they form new colonies. This spreading process of tumor cells, called metastasis , is the cause of 90% of human cancer deaths. Metastatic cancer cells that enter the bloodstream can reach virtually all tissues of the body. Bones are one of the most common places for these cells to settle and start growing again. Bone metastasis is one of the most frequent causes of pain in people with cancer. It also can cause bones to break and create other symptoms and problems for patients. The progression in the knowledge of cancer biology has been accelerating in recent years. All of the scientific knowledge acquired through hard work and discovery has made it possible for cancer treatment and prevention. As a result of explosive new discoveries, some modern treatments were developed. The success of these therapies, together with traditional treatments such as surgical procedures, is further underscored by the fact that in 2002 the cancer rate was reduced in the United States. Current approaches to the treatment of cancer involve killing cancer cells with toxic chemicals, radiation, or surgery. Alternatively, several new biologic- and gene-based therapies are aimed at enhancing the body's natural defenses against invading cancers. Understanding the biology of cancer cells has led to the development of designer therapies for cancer prevention and treatment. Gene therapy, immune system modulation, genetically engineered antibodies, and molecularly designed chemical drugs are all promising fronts in the war against cancer.

IMMUNOTHERAPY The growth of the body is controlled by many natural signals through complex signaling pathways. Some of these natural agents have been used in cancer treatment and have been proven effective for fighting several cancers through the clinical trial process. These naturally occurring biologic agents, such as interferons, interleukins, and other cytokines, can now be produced in the laboratory. These agents, as well as the synthetic agents that mimic the natural signals, are given to patients to influence the natural immune response agents either by directly altering the cancer cell growth, or by acting indirectly to help healthy cells control the cancer. One of the most exciting applications of immunotherapy has come from the identification of certain tumor targets called antigens and the aiming of an antibody at these targets. This was first used as a means of localizing tumors in the body for diagnosis, and was more recently used to attack cancer cells. Trastuzumab (Herceptin) is an example of such a drug.1 4 Trastuzumab is a monoclonal antibody that neutralizes the mitogenic activity of cell-surface growth factor receptor HER-2. Approximately 25% of breast cancers overexpress HER-2. These tumors tend to grow faster and generally are more likely to recur than tumors that do not overproduce HER-2. Trastuzumab is designed to attack cancer cells that overexpress HER-2. Trastuzumab slows or stops the growth of these cells and increases the survival of HER-2–positive breast cancer patients. Another significant example is the administration of interleukin-2 (IL-2) to patients with metastatic melanoma or kidney cancer, which has been shown to mediate the durable regression of metastatic cancer. IL-2, a cytokine produced by human helper T lymphocytes, has a wide range of immune regulatory effects, including the expansion of lymphocytes following activation by a specific antigen. IL-2 has no direct impact on cancer cells. The impact of IL-2 on cancers in vivo derives from its ability to expand

lymphocytes with antitumor activity. The expanded lymphocytes somehow recognize the antigen on cancer cells. Thus, the molecular identification of cancer antigens has opened new possibilities for the development of effective immunotherapies for patients with cancer. Clinical studies using immunization with peptides derived from cancer antigens have shown that high levels of lymphocytes with antitumor activity can be produced in cancer-bearing patients. Highly avid antitumor lymphocytes can be isolated from immunized patients and grown in vitro for use in cell-transfer therapies.

CHEMOTHERAPY The primary function of anticancer chemicals is to block different steps involved in cell growth and replication. These chemicals often block a critical chemical reaction in a signal transduction pathway or during DNA replication or gene expression. For example, STI571, also known as Gleevec , is one of the first molecularly targeted drugs based on the changes that cancer causes in cells.1 5 STI571 offers promise for the treatment of chronic myeloid leukemia (CML) and may soon surpass interferon- as the standard treatment for the disease. In CML, STI571 is targeted at the Bcr-Abl kinase, an activated oncogene product in CML (Fig. 15-13). Bcr-Abl is an overly activated protein kinase resulting from a specific genetic abnormality generated by chromosomal translocation that is found in the cells of patients with CML. STI571-mediated inhibition of Bcr-Abl-kinase activity not only prevents cell growth of Bcr-Abl–transformed leukemic cells, but also induces apoptosis. Clinically, the drug quickly corrects the blood cell abnormalities caused by the leukemia in a majority of patients, achieving a complete disappearance of the leukemic blood cells and the return of normal blood cells. Additionally, the drug appears to have some effect on other cancers including certain brain tumors and GI stromal tumors, a very rare type of stomach cancer.

Fig. 15-13.

Mechanism of STI571 as a molecular drug. Bcr-Abl is an overly activated oncogene product resulting from a specific genetic abnormality generated by chromosomal translocation that is found in cells of patients with chronic myeloid leukemia. Bcr-Abl is an activated protein kinase and thus requires adenosine triphosphate (ATP) to phosphorylate substrates, which in turn promote cell proliferation. STI571 is a small molecule that competes with the ATP-binding site and thus blocks the transfer of

phosphoryl group to substrate. PO 4 = phosphate; Tyr = tyrosine.

GENE THERAPY Gene therapy is an experimental treatment that involves genetically altering a patient's own tumor cells or lymphocytes (cells of the immune system, some of which can attack cancer cells). For years, the concept of gene therapy has held promise as a new, potentially potent weapon to attack cancer. Although a rapid progression in the understanding of the molecular and clinical aspects of gene therapy has been witnessed in the past decade, gene therapy treatment has not yet been shown to be superior to standard treatments in humans. Several problems must be resolved to transform it into a clinically relevant form of therapy. The major issues that limit its translation to the clinic are improving the selectivity of tumor targeting, improving the delivery to the tumor, and the enhancement of the transduction rate of the cells of interest. In most gene therapy trials for malignant diseases, tumors can be accessed and directly injected (in situ gene therapy). The in situ gene therapy also offers a better distribution of the vector virus throughout the tumor. Finally, a combination of gene therapy strategies will be more effective than the use of a single gene therapy system. An important aspect of effective gene therapy involves the choice of appropriate genes for manipulation. Genes that promote the production of messenger chemicals or other immune-active substances can be transferred into the patient's cells. These include genes that inhibit cell cycle progression, induce apoptosis, enhance host immunity against cancer cells, block the ability of cancer cells to metastasize, and cause tumor cells to undergo suicide. Recent development of RNAi technology, which uses a loss-of-function approach to block gene functions, ensures a new wave of hopes for gene therapy. Nonetheless, gene therapy is still experimental and is being studied in clinical trials for many different types of cancer. The mapping of genes responsible for human cancer is likely to provide new targets for gene therapy in the future. The preliminary results of gene therapy for cancer are encouraging, and as advancements are made in the understanding of the molecular biology of human cancer, the future of this rapidly developing field holds great potential for treating cancer. It is noteworthy that the use of multiple therapeutic methods has proven more powerful than a single method. The use of chemotherapy after surgery to destroy the few remaining cancerous cells in the body is called adjuvant therapy. Adjuvant therapy was first tested and found to be effective in breast cancer. It was later adopted for use in other cancers. A major discovery in chemotherapy is the advantage of multiple chemotherapeutic agents (known as combination or cocktail chemotherapy ) over single agents. Some types of fast-growing leukemias and lymphomas (tumors involving the cells of the bone marrow and lymph nodes) responded extremely well to combination chemotherapy, and clinical trials led to gradual improvement of the drug combinations used. Many of these tumors can be cured today by combination chemotherapy. As cancer cells carry multiple genetic defects, the use of combination chemotherapy, immunotherapy, and gene therapies may be more effective in treating cancers.

Stem Cell Research Stem cell biology represents a cutting-edge scientific research field with potential clinical applications.1 6 It may have an enormous impact on human health by offering hope for curing human diseases such as diabetes mellitus, Parkinson's disease, neurologic degeneration, and congenital heart disease. Stem cells are endowed with two remarkable properties (Fig. 15-14). First, stem cells can proliferate in an undifferentiated but pluripotent state, and as a result can self-renew. Second, they have the ability to differentiate into many specialized cell types. There are two groups of stem cells: embryonic stem (ES) cells and adult stem cells. Human ES cells are derived from early preimplantation embryos called blastocysts (5 days postfertilization), and are capable of generating all

differentiated cell types in the body. Adult stem cells are present in and can be isolated from adult tissues. They often are tissue specific and only can generate the cell types comprising a particular tissue in the body; however, in some cases they can transdifferentiate into cell types found in other tissues. Hematopoietic stem cells are adult stem cells. They reside in bone marrow and are capable of generating all cell types of the blood and immune system.

Fig. 15-14.

Stem cells. A stem cell is capable of self-renewal (unlimited cell cycle) and differentiation (becoming nondividing cells with specialized functions). Differentiating stem cells often undergo additional cell divisions before they become fully mature cells that carry out specific tissue functions.

Stem cells can be grown in culture and be induced to differentiate into a particular cell type, either in vitro or in vivo. With the recent and continually increasing improvement in culturing stem cells, scientists are beginning to understand the molecular mechanisms of stem cell self-renewal and differentiation in response to environmental cues. It is believed that discovery of the signals that control self-renewal vs. differentiation will be extremely important for the therapeutic use of stem cells in treating disease. It is possible that success in the study of the changes in signal transduction pathways in stem cells will lead to the development of therapies to specifically differentiate stem cells into a particular cell type to replace diseased or damaged cells in the body. Recently, stem cell research has been transformed by the discovery from the Shinya Yamanaka group and the James Thomsen group, who have found that a simple genetic manipulation can reprogram adult differentiated cells into pluripotent cells. 1 7 This exciting discovery not only bypasses the ethical issues of using early embryos to generate ES cells, but also ensures a potentially limitless source of patient-specific stem cells for tissue engineering and transplantation medicine.

Personalized Genomic Medicine Genes determine our susceptibility to diseases and direct our body's response to medicine. Because an individual's genes differ from those of another, the determination of each individual's genome has the potential to improve the predication, prevention, and treatment of disease. Sequencing of individual genomes holds the key to realize this revolution called personalized genomic medicine . Next generation sequencing such as 454 Life Sciences technology is promising to reduce the time and cost so that genome sequencing can be affordable in the health

care system. The goal of personalized genomic medicine is to spot the gene variations in each individual and to attack the disease by choosing personalized treatments that work with the individual's genomic profile. Personalized genomic medicine will undoubtedly revolutionize the practice of modern medicine.

TECHNOLOGIES OF MOLECULAR AND CELL BIOLOGY DNA Cloning Since the advent of recombinant DNA technology three decades ago, hundreds of thousands of genes have been identified. Recombinant DNA technology is the technology that uses advanced enzymatic and microbiologic techniques to manipulate DNA.1 8 Pure pieces of any DNA can be inserted into bacteriophage DNA or other carrier DNA such as plasmids to produce recombinant DNA in bacteria. In this way, DNA can be reconstructed, amplified, and used to manipulate the functions of individual cells or even organisms. This technology, often referred to as DNA cloning , is the basis of all other DNA analysis methods. It is only with the awesome power of recombinant DNA technology that the completion of the Human Genome Project was possible. It also has led to the identification of the entire gene complements of organisms such as viruses, bacteria, worms, flies, and plants. Molecular cloning refers to the process of cloning a DNA fragment of interest into a DNA vector that ultimately is delivered into bacterial or mammalian cells or tissues19,20 (Fig. 15-15). This represents a very basic technique that is widely used in almost all areas of biomedical research. DNA vectors often are called plasmids , which are extrachromosomal molecules of DNA that vary in size and can replicate and be transmitted from bacterial cell to cell. Plasmids can be propagated either in the cytoplasm, or after insertion, as part of the bacterial chromosome in Escherichia coli . The process of molecular cloning involves several steps of manipulation of DNA. First, the vector plasmid DNA is cleaved with a restriction enzyme to create compatible ends with the foreign DNA fragment to be cloned. The vector and the DNA fragment are then joined in vitro by a DNA ligase. Alternatively, DNA cloning can be simply done through the so-called Gateway Technology that allows for the rapid and efficient transfer of DNA fragments between different cloning vectors while maintaining reading frame and orientation, without the use of restriction endonucleases and DNA ligase. The technology, which is based on the site-specific recombination system of bacteriophage l, is simple, fast, robust and automatable, thus compatible for high-throughput DNA cloning.

Fig. 15-15.

Generation of recombinant DNA. The vector is a circular DNA molecule that is capable of replicating in Escherichia coli cells. Insert DNA (often your favorite gene) is ligated to the vector after ends of both DNA are properly treated with restriction enzymes. Ligated DNA (i.e., the recombinant plasmid DNA) is then transformed into E. coli cells, where it replicates to produce recombinant progenies. E. coli cells carrying the recombinant plasmid can be propagated to yield large quantities of

plasmid DNA.

Finally, the ligation product or the Gateway reaction product is introduced into competent host bacteria; this procedure is called transformation , which can be done by either calcium/heat shock or electroporation. Precautions must be taken in every step of cloning to generate the desired DNA construct. The vector must be correctly prepared to maximize the creation of recombinants; for example, it must be enzymatically treated to prevent selfligation. Host bacteria must be made sufficiently competent to permit the entry of recombinant plasmids into cells. The selection of desired recombinant plasmid-bearing E. coli normally is achieved by the property of drug resistance conferred by the plasmid vectors. The plasmids encoding markers provide specific resistance to (i.e., the ability to grow in the presence of) antibiotics such as ampicillin, kanamycin, and tetracycline. The foreign component in the plasmid vector can be a mammalian expression cassette, which can direct expression of foreign genes in mammalian cells. The resulting plasmid vector can be amplified in E. coli to prepare large quantities of DNA for its subsequent applications such as transfection, gene therapy, transgenics, and knockout mice.

Detection of Nucleic Acids and Proteins SOUTHERN BLOT HYBRIDIZATION Southern blotting refers to the technique of transferring DNA fragments from an electrophoresis gel to a membrane support, and the subsequent analysis of the fragments by hybridization with a radioactively labeled probe (Fig. 1516).2 1 Southern blotting is named after E. M. Southern, who in 1975 first described the technique of DNA analysis. It enables reliable and efficient analysis of size-fractionated DNA fragments in an immobilized membrane support. Southern blotting is composed of several steps. It normally begins with the digestion of the DNA samples with appropriate restriction enzymes and the separation of DNA samples in an agarose gel with appropriate DNA size markers. The DNA gel is stained with ethidium bromide and photographed with a ruler laid alongside the gel so that band positions can later be identified on the membrane. The DNA gel then is treated so the DNA fragments are denatured (i.e., strand separation). The DNA then is transferred onto a nitrocellulose membrane by capillary diffusion or under electricity. After immobilization, the DNA can be subjected to hybridization analysis, enabling bands with sequence similarity to a radioactively labeled probe to be identified.

Fig. 15-16.

Southern blotting. Restriction enzymatic fragments of DNA are separated by agarose gel electrophoresis, transferred to a membrane filter, and then hybridized to a radioactive probe.

The development of Southern transfer and the associated hybridization techniques made it possible for the first time to obtain information about the physical organization of single and multicopy sequences in complex genomes. The later application of Southern blotting hybridization to the study of restriction fragment length polymorphisms opened up new possibilities such as genetic fingerprinting and prenatal diagnosis of genetic diseases.

NORTHERN BLOT HYBRIDIZATION

Northern blotting refers to the technique of size fractionation of RNA in a gel and the transferring of an RNA sample to a solid support (membrane) in such a manner that the relative positions of the RNA molecules are maintained. The resulting membrane then is hybridized with a labeled probe complementary to the mRNA of interest. Signals generated from detection of the membrane can be used to determine the size and abundance of the target RNA. In principle, Northern blot hybridization is similar to Southern blot hybridization (and hence its name), with the exception that RNA, not DNA, is on the membrane. Although reverse-transcriptase polymerase chain reaction has been used in many applications (described in Polymerase Chain Reaction below), Northern analysis is the only method that provides information regarding mRNA size and has remained a standard method for detection and quantitation of mRNA. The process of Northern hybridization involves several steps, as does Southern hybridization, including electrophoresis of RNA samples in an agarose-formaldehyde gel, transfer to a membrane support, and hybridization to a radioactively labeled DNA probe. Data from hybridization allow quantification of steady-state mRNA levels, and at the same time, provide information related to the presence, size, and integrity of discrete mRNA species. Thus, Northern blot analysis, also termed RNA gel blot analysis , commonly is used in molecular biology studies relating to gene expression.

POLYMERASE CHAIN REACTION PCR is an in vitro method for the polymerase-directed amplification of specific DNA sequences using two oligonucleotide primers that hybridize to opposite strands and flank the region of interest in the target DNA (Fig. 15-17).2 2 One cycle of PCR reaction involves template denaturation, primer annealing, and the extension of the annealed primers by DNA polymerase. Because the primer extension products synthesized in one cycle can serve as a template in the next, the number of target DNA copies nearly doubles at each cycle. Thus, a repeated series of cycles result in the exponential accumulation of a specific fragment in which the termini are sharply defined by the 5' ends of the primers. The introduction of the thermostable DNA polymerase (e.g., Taq polymerase) transforms the PCR into a simple and robust reaction. The reaction components (e.g., template, primers, Taq polymerase, 2'deoxynucleoside 5'-triphosphates, and buffer) could all be assembled and the amplification reaction carried out by simply cycling the temperatures within the reaction tube. The specificity and yield in amplifying a particular DNA fragment by PCR reaction is affected by the proper setting of the reaction parameters (e.g., enzyme, primer, and Mg 2+ concentration, as well as the temperature cycling profile). Modifying various PCR parameters to optimize the specificity of amplification yields more homogenous products, even in rare template reactions.

Fig. 15-17.

Amplification of DNA using the polymerase chain reaction technique. Knowledge of the DNA sequence to be amplified is used to design two synthetic DNA oligonucleotides, each complementary to the sequence on one strand of the DNA double helix at opposite ends of the region to be amplified. These oligonucleotides serve as primers for in vitro DNA synthesis, which is performed by a DNA polymerase, and they determine the segment of the DNA that is amplified. A. PCR starts with a doublestranded DNA, and each cycle of the reaction begins with a brief heat treatment to separate the two strands (Step 1 ). After strand separation, cooling of the DNA in the presence of a large excess of the two primer DNA oligonucleotides allows these primers to hybridize to complementary sequences in the two DNA strands (Step 2 ). This mixture is then incubated with DNA polymerase and the four deoxyribonucleoside triphosphates so that DNA is synthesized, starting from the two primers (Step 3 ). The entire cycle is then begun again by a heat treatment to separate the newly synthesized DNA strands. B. As the procedure is performed over and over again, the newly synthesized fragments serve as templates in their turn, and, within a few cycles, the predominant DNA is identical to the sequence bracketed by and including the two primers in the original template. Of the DNA put into the original reaction, only the sequence bracketed by the two primers is amplified because there are no primers attached anywhere else. In the example illustrated in B , three cycles of reaction produce 16 DNA chains, eight of which (boxed in brown ) are the same length as and correspond exactly to one or the other strand of the original bracketed sequence shown at the far left; the other strands contain extra DNA downstream of the original sequence, which is replicated in the first few cycles. After three more cycles, 240 of the 256 DNA chains correspond exactly to the original bracketed sequence, and after several more cycles, essentially all of the DNA strands have this unique length. (From Alberts et al,1 with permission.)

The emergence of the PCR technique has dramatically altered the approach to both fundamental and applied biologic problems. The capability of amplifying a specific DNA fragment from a gene or the whole genome greatly advances the study of the gene and its function. It is simple, yet robust, speedy, and most of all, flexible. As a recombinant DNA tool, it underlies almost all of molecular biology. This revolutionary technique enabled the modern methods for the isolation of genes, construction of a DNA vector, introduction of alterations into DNA, and quantitation of gene expression, making it a fundamental cornerstone of genetic and molecular analysis.

IMMUNOBLOTTING AND IMMUNOPRECIPITATION Analyses of proteins are primarily carried out by antibody-directed immunologic techniques. For example, Western blotting, also called immunoblotting , is performed to detect protein levels in a population of cells or tissues, whereas immunoprecipitation is used to concentrate proteins from a larger pool. Using specific antibodies, microscopic analysis called immunofluorescence and immunohistochemistry is possible for the subcellular localization and expression of proteins in cells or tissues, respectively. Immunoblotting refers to the process of identifying a protein from a mixture of proteins (Fig. 15-18). It consists of five steps: (a) sample preparation; (b) electrophoresis (separation of a protein mixture by sodium dodecyl sulfatepolyacrylamide gel electrophoresis); (c) transfer (the electrophoretic transfer of proteins from gel onto membrane support, (e.g., nitrocellulose, nylon, or polyvinylidene difluoride); (d) staining (the subsequent immunodetection of target proteins with specific antibody); and (e) development (colorimetric or chemiluminescent visualization of the antibody-recognized protein). Thus, immunoblotting combines the resolution of gel electrophoresis with the specificity of immunochemical detection. Immunoblotting is a powerful tool used to determine a number of important characteristics of proteins. For example, immunoblotting analysis will determine the presence and the quantity of a protein in a given cellular condition and its relative molecular weight. Immunoblotting also can be used to determine whether posttranslational modification such as phosphorylation has occurred on a protein. Importantly, through immunoblotting analysis, a comparison of the protein levels and modification states in normal vs. diseased tissues is possible.

Fig. 15-18.

Immunoblotting. Proteins are prepared from cells or tissues, separated according to size by sodium dodecyl sulfatepolyacrylamide gel electrophoresis, and transferred to a membrane filter. Detection of a protein of interest can be done by sequential incubation with a primary antibody directed against the protein, and then with an enzyme-conjugated secondary antibody that recognizes the primary antibody. Visualization of the protein is carried out by using colorimetric or luminescent substrates for the conjugated enzyme.

Immunoprecipitation, another widely used immunochemical technique, is a method that uses antibody to enrich a protein of interest and any other proteins that are associated with it (Fig. 15-19). The principle of the technique lies in the property of a strong and specific affinity between antibodies and their antigens to locate and pull down target proteins in solution. Once the antibody-antigen (target protein) complexes are formed in the solution, they are collected and purified using small agarose beads with covalently attached protein A or protein G. Both protein A and protein G specifically interact with the antibodies, thus forming a large immobilized complex of antibodyantigen bound to beads. The purified protein can then be analyzed by a number of biochemical methods. When

immunoprecipitation is combined with immunoblotting, it can be used for the sensitive detection of proteins in low concentrations, which would otherwise be difficult to detect. Moreover, combined immunoprecipitation and immunoblotting analysis is very efficient in analyzing the protein-protein interactions or determining the posttranslational modifications of proteins. In addition, immunoprecipitated proteins can be used as preparative steps for assays such as intrinsic or associated enzymatic activities. The success of immunoprecipitation is influenced by two major factors: (a) the abundance of the protein in the original preparation and (b) the specificity and affinity of the antibody for this protein.

Fig. 15-19.

Immunoprecipitation. Proteins prepared from cells or tissues can be enriched using an antibody directed against them. The antibody is first conjugated to agarose beads and then incubated with protein mixture. Owing to the specific high-affinity interaction between antibody and its antigen (the protein), the antigen-antibody complex can be collected on beads by centrifugation. The immunoprecipitated protein can then be analyzed by immunoblotting. Alternatively, if proteins are radiolabeled in cells or tissues, detection of immunoprecipitated proteins can be achieved by simple sodium dodecyl sulfatepolyacrylamide gel electrophoresis followed by autoradiography.

DNA MICROARRAY Now that the human genome sequence is completed, the primary focus of biologists is rapidly shifting toward gaining an understanding of how genes function. One of the interesting findings about the human genome is that

there are only approximately 25,000 to 30,000 protein-encoding genes. However, it is known that genes and their products function in a complicated and yet orchestrated fashion and that the surprisingly small number of genes from the genome sequence is sufficient to make a human being. Nonetheless, with the tens of thousands of genes present in the genome, traditional methods in molecular biology, which generally work on a one-gene-in-oneexperiment basis, cannot generate the whole picture of genome function. In the past several years, a new technology called DNA microarray has attracted tremendous interest among biologists as well as clinicians. This technology promises to monitor the whole genome on a single chip so researchers can have a better picture of the interactions among thousands of genes simultaneously. DNA microarray, also called gene chip , DNA chip , and gene array , refers to large sets of probes of known sequences orderly arranged on a small chip, enabling many hybridization reactions to be carried out in parallel in a small device (Fig. 15-20).2 3 Like Southern and Northern hybridization, the underlying principle of this technology is the remarkable ability of nucleic acids to form a duplex between two strands with complementary base sequences. DNA microarray provides a medium for matching known and unknown DNA samples based on base-pairing rules, and automating the process of identifying the unknowns. Microarrays require specialized robotics and imaging equipment that spot the samples on a glass or nylon substrate, carry out the hybridization, and analyze the data generated. DNA microarrays containing different sets of genes from a variety of organisms are now commercially available, allowing biologists to simply purchase the chips and perform hybridization and data collection. The massive scale of microarray experiments requires the aid of computers. They are used during the capturing of the image of the hybridized target, the conversion of the image into usable measures of the extent of hybridization, and the interpretation of the extent of hybridization into a meaningful measure of the amount of the complementary sequence in the target. Some data-analysis packages are available commercially or can be found in the core facility of certain institutions.

Fig. 15-20.

DNA microarrays. DNA microarrays, also referred to as gene chips , have arrayed oligonucleotides or complementary DNAs (cDNAs) corresponding to tens or hundreds of distinct genes. DNA microarray is used to comparatively analyze gene expression in different cells or tissues. Messenger RNAs (mRNAs) extracted from different sources are converted into cDNAs, which are then labeled with different fluorescent dyes. The two fluorescent cDNA probes are mixed and hybridized to the same DNA microarrays. The ratio of dark brown to light brown fluorescence at each spot on the chip represents the relative expression of levels of that gene between two different cells. In the example shown in the figure, cDNA from cell #1 is labeled with dark brown fluorescence and the cell #2 light brown fluorescence. On the microarray, dark brown spots demonstrate that the gene in cell sample #1 is expressed at a higher level than the corresponding gene in cell sample #2. The light brown spots indicate that the gene in cell sample #1 also is expressed at a higher level than the corresponding gene in cell sample #2. Beige spots represent equal expression of the gene in both cell samples.

DNA microarray technology has produced many significant results in quite different areas of application. There are two major application forms for the technology: identification of sequence (gene/gene mutation) and determination of expression level (abundance) of genes. For example, analysis of genomic DNA detects amplifications and deletions found in human tumors. Differential gene expression analysis also has uncovered networks of genes differentially present in cancers that cannot be distinguished by conventional means. Significantly, recent advancements in next generation sequencing (e.g., Solexa and 454 technology) have demonstrated the precision and speed to analyze gene expression in any genome.

Cell Manipulations CELL CULTURE

Cell culture has become one of the most powerful techniques, as cultured cells are being used in a diversity of biologic fields ranging from biochemistry to molecular and cellular biology.2 4 Through their ability to be maintained in vitro, cells can be manipulated by the introduction of genes of interest (cell transfection) and be transferred into in vivo biologic receivers (cell transplantation) to study the biologic effect of the interested genes (Fig. 15-21). In general, cell culture procedures are simple and straightforward. In the laboratory, cells are cultured either as a monolayer (in which cells grow as one layer on culture dishes) or in suspension.

Fig. 15-21.

Cell culture and transfection. A. Primary cells can be isolated from tissues and cultured in medium for a limited period of time. After genetic manipulations to overcome the cell aging process, primary cells can be immortalized into cell lines for long-term culture. B. DNA can be introduced into cells to produce recombinant gene products or to analyze the biologic functions of the gene.

It is important to know the wealth of information concerning cell culturing before attempting the procedure. For example, conditions of culture will depend on the cell types to be cultured (e.g., origins of the cells such as epithelial or fibroblasts, or primary vs. immortalized/transformed cells). It also is necessary to use special culture medium that has been used to establish the cell line (if it is a cell line), including the type and concentration of

serum used to maintain the growth of cells in vitro. If primary cells are derived from human patients or animals, some commercial resources have a variety of culture media available for testing. Generally, cells are manipulated in a sterile hood and the working surfaces are wiped with 80% ethyl alcohol solution. Cultured cells are maintained in a humidified carbon dioxide incubator at 37C (98.6F), and need to be examined daily under an inverted microscope to check for possible contamination and confluency (the area cells occupy on the dish). As a general rule, cells should be fed with fresh medium every 2 to 3 days and split when they reach confluency. Depending upon the growth rate of cells, the actual time and number of plates required to split cells in two varies from cell line to cell line. Splitting a monolayer requires the detachment of cells from plates by using a trypsin treatment, of which concentration and time period vary depending on cell lines. If cultured cells grow continuously in suspension, they are split or subcultured by dilution. Because cell lines may change their properties when cultured, it is not possible to maintain cell lines in culture indefinitely. Therefore, it is essential to store cells at various time passages for future use. The common procedure is to use cryopreservation. The solution for cryopreservation is fetal calf serum containing 10% dimethyl sulfoxide or glycerol, stored in liquid nitrogen [–196C (–320.8F)]. Cells can be stored for many years using this method.

CELL TRANSFECTION Cells are cultured for two reasons: to maintain and to manipulate them (see Fig. 15-21). The transfer of foreign macromolecules, such as nucleic acid, into living cells provides an efficient method for studying a variety of cellular processes and functions at the molecular level. DNA transfection has become an important tool for studying the regulation and function of genes. The cDNA to be expressed should be in a plasmid vector, behind an appropriate promoter working in mammalian cells (e.g., the constitutively active cytomegalovirus promoter or inducible promoter). Depending on the cell type, many ways of introducing DNA into mammalian cells have been developed. Commonly used approaches include calcium phosphate, electroporation, liposome-mediated transfection, the nonliposomal formulation, and the use of viral vectors. These methods have shown variable success when attempting to transfect a wide variety of cells. Transfection can be performed in the presence or absence of serum. It is suggested to test the transfection efficiency of cell lines of interest by comparing transfection with several different approaches. For a detailed transfection protocol, it is best to follow the manufacturer's instructions for the particular reagent. General considerations for a successful transfection depend on several parameters, such as the quality and quantity of DNA and cell culture (type of cell and growth phase). To minimize variations in both of these in transfection experiments, it is best to use cells that are healthy, proliferate well, and are plated at a constant density. After DNA is introduced into the cells, it is normally maintained epitopically in cells and will be diluted while host cells undergo cell division. Therefore, functional assays should be performed 24 to 72 hours after transfection, also termed transient transfection . In many applications, it is important to study the long-term effects of DNA in cells by stable transfection. Stable cell clones can be selected for DNA integration into the host cell genome, when plasmids carry an antibiotic-resistant marker. In the presence of antibiotics, only those cells that continuously carry the antibiotic-resistant marker (after generations of cell division) can survive. One application of stable transfection is the generation of transgenic or knockout mouse models, in which the transgene has to be integrated in the mouse genome. Stable cells also can be transplanted into host organs.

Genetic Manipulations Understanding how genes control the growth and differentiation of the mammalian organism has been the most challenging topic of modern research. It is essential for us to understand how genetic mutations and chemicals lead to the pathologic condition of human bodies. The knowledge and ability to change the genetic program will

inevitably make a great impact on society and have far-reaching effects on how we think of ourselves. The mouse has become firmly established as the primary experimental model for studying how genes control mammalian development. Genetically altered mice are powerful model systems in which to study the function and regulation of genes.2 5 The gene function can be studied by creating mutant mice through homologous recombination (gene knockout). A gene of interest also can be introduced into the mouse (transgenic mouse) to study its effect on development or diseases. As mouse models do not precisely represent human biology, genetic manipulations of human somatic or ES cells provide a great means for the understanding of the molecular networks in human cells. In all cases, the gene to be manipulated must first be cloned. Gene cloning has been made easy by recombinant DNA technology and the availability of human and mouse genomes (see the Human Genome section). The following section briefly describes the technologies and the principles behind them.

TRANSGENIC MICE During the past 20 years, DNA cloning and other techniques have allowed the introduction of new genetic material into the mouse germline. As early as 1980, the first genetic material was successfully introduced into the mouse germline by using pronuclear microinjection of DNA (Fig. 15-22). These animals, called transgenic , contain foreign DNA within their genomes. In simple terms, a transgenic mouse is created by the microinjection of DNA into the one-celled mouse embryo, allowing the efficient introduction of cloned genes into the developing mouse somatic tissues, as well as into the germline.

Fig. 15-22.

Transgenic mouse technology. DNA is microinjected into a pronucleus of a fertilized egg, which is then transplanted into a foster mother. The microinjected egg develops offspring mice. Incorporation of the injected DNA into offspring is indicated by the different coat color of offspring mice.

Designs of a Transgene The transgenic technique has proven to be extremely important for basic investigations of gene regulation, creation

of animal models of human disease, and genetic engineering of livestock. The design of a transgene construct is a simple task. Like constructs used in cell transfection, a simple transgene construct consists of a protein-encoding gene and a promoter that precedes it. The most common applications for the use of transgenic mice are similar to those in the cell culture system: (a) to study the functions of proteins encoded by the transgene and (b) to analyze the tissue-specific and developmental-stage–specific activity of a gene promoter. Examples of the first application include overexpression of oncogenes, growth factors, hormones, and other key regulatory genes, as well as genes of viral origins. Overexpression of the transgene normally represents gain-of-function mutations. The tissue distribution or expression of a transgene is determined primarily by cis -acting promoter enhancer elements within or in the immediate vicinity of the genes themselves. Thus, controlled expression of the transgene can be made possible by using an inducible or tissue-specific promoter. Furthermore, transgenic mice carrying dominant negative mutations of a regulatory gene also have been generated. For example, a truncated growth factor receptor that can bind to the ligand, but loses its catalytic activity when expressed in mice, can block the growth factor binding to the endogenous protein. In this way, the transgenic mice exhibit a loss of function of phenotype, possibly resembling the knockout of the endogenous gene. The second application of the transgenic expression is to analyze the gene promoter of interest. The gene promoter of interest normally is fused to a reporter gene that encodes -galactosidase (also called LacZ ), luciferase, or green fluorescence protein. Chemical staining of LacZ activity or detection of chemiluminescence/fluorescence can easily visualize the expression of the reporter gene. The amount of the reporter gene activity represents the activity of the promoter, and thus, reporter activities are tightly correlated to expression of the gene in which the promoter is used to drive the reporter gene expression.

Production of Transgenic Mice The success of generating transgenic mice is largely dependent upon the proper quality and concentration of the DNA supplied for microinjection. For DNA to be microinjected into mouse embryos, it should be linearized by restriction digestion to increase the chance of proper transgene integration. Concentration of DNA should be accurately determined. Mice that develop from injected eggs often are termed founder mice.

Genotyping of Transgenic Mice The screening of founder mice and the transgenic lines derived from the founders is accomplished by determining the integration of the injected gene into the genome. This normally is achieved by performing PCR or Southern blot analysis with a small amount of DNA extracted from the mouse tail. Once a given founder mouse is identified to be transgenic, it will be mated to begin establishing a transgenic line.

Analysis of Phenotype of Transgenic Mice Phenotypes of transgenic mice are dictated by both the expression pattern and biologic functions of the transgene. Depending on the promoter and the transgene, phenotypes can be predictable or unpredictable. Elucidation of the functions of the transgene-encoded protein in vitro often offers some clue to what the protein might do in vivo. When a constitutively active promoter is used to drive the expression of transgenes, mice should express the gene in every tissue; however, this mouse model may not allow the identification and study of the earliest events in disease pathogenesis. Ideally, the use of tissue-specific or inducible promoter allows one to determine if the pathogenic protein leads to a reversible or irreversible disease process. For example, rat insulin promoter can target transgene expression exclusively in the

-cells of pancreatic islets. The phenotype of insulin promoter-

mediated transgenic mice is projected to affect the function of human

GENE KNOCKOUT IN MICE

-cells.

The isolation and genetic manipulation of ES cells represents one of the most important milestones for modern genetic technologies. Several unique properties of these ES cells, such as the pluripotency to differentiate into different tissues in an embryo, make them an efficient vehicle for introducing genetic alterations into this species. Thus, this technology provides an important breakthrough, making it possible to genetically manipulate ES cells in a controlled way in the culture dish and then introduce the mutation into the germline (Fig. 15-23). This not only makes mouse genetics a powerful approach for addressing important gene functions but also identifies the mouse as a great system to model human disease.

Fig. 15-23.

Knockout mouse technology. Summary of the procedures used for making gene replacements in mice. In the first step (A ), an altered version of the gene is introduced into cultured embryonic stem (ES) cells. Only a few rare ES cells will have their corresponding normal genes replaced by the altered gene through a homologous recombination event. Although the procedure is often laborious, these rare cells can be identified and cultured to produce many descendants, each of which carries an altered gene in place of one of its two normal corresponding genes. In the next step of the procedure (B ), these altered ES cells are injected into a very early mouse embryo; the cells are incorporated into the growing embryo, and a mouse produced by such an embryo will contain some somatic cells that carry the altered gene. Some of these mice also will contain germline cells that contain the altered gene. When bred with a normal mouse, some of the progeny of these mice will contain the altered gene in all of their cells. If two such mice are in turn bred (not shown), some of the progeny will contain two altered genes (one on each chromosome) in all of their cells. If the original gene alteration completely inactivates the function of the gene, these mice are known as knockout mice . When such mice are missing genes that function during development, they often die with specific defects long before they reach adulthood. These defects are carefully analyzed to help decipher the normal function of the missing gene. (From Alberts et al,1 with permission.)

Targeting Vector The basic concept in building a target vector to knock out a gene is to use two segments of homologous sequence to a gene of interest that flank a part of the gene essential for functions (e.g., the coding region). In the target vector, a positive selectable marker (e.g., the neo gene) is placed between the homology arms. Upon the homologous recombination between the arms of the vector and the corresponding genomic regions of the gene of interest in ES cells, the positive selectable marker will replace the essential segment of the target gene, thus creating a null allele. In addition, a negative selectable marker also can be used alone or in combination with the positive selectable marker, but must be placed outside of the homologous arms to enrich for homologous recombination. To create a conditional knockout (i.e., gene knockout in a spatiotemporal fashion), site-specific recombinases such as the popular cre-loxP system are used. If the consensus loxP sequences that are recognized by cre recombinases are properly designed into targeting loci, controlled expression of the recombinase as a transgene can result in the site-specific recombination at the right time and in the right place (i.e., cell type or tissue). This method is markedly useful to prevent developmental compensations and to introduce null mutations in the adult mouse that would otherwise be lethal. Overall, this cre-loxP system allows for spatial and temporal control over transgene expression and takes advantage of inducers with minimal pleiotropic effects.

Introduction of the Targeting Vector into ES Cells ES cell lines can be obtained from other investigators, commercial sources, or established from blastocyst-stage embryos. To maintain ES cells at their full developmental potential, optimal growth conditions should be provided in culture. If culture conditions are inappropriate or inadequate, ES cells may acquire genetic lesions or alter their gene expression patterns, and consequently decrease their pluripotency. Excellent protocols are available in public domains or in mouse facilities in most institutions. To alter the genome of ES cells, the targeting vector DNA then is transfected into ES cells. Electroporation is the most widely used and the most efficient transfection method for ES cells. Similar procedures for stable cell transfection are used for selecting ES cells that carry the targeting vector. High-quality, targeting-vector DNA free of contaminating chemicals is first linearized and then electroporated into ES cells. Stable ES cells are selected in the presence of a positive selectable antibiotic drug. After a certain period of time and depending on the type of antibiotics, all sensitive cells die and the resistant cells grow into individual colonies of the appropriate size for subcloning by picking. It is extremely important to minimize the time during which ES cells are in culture between selection and injection into blastocysts. Before injecting the ES cells, DNA is prepared from ES colonies to screen

for positive ES cells that exhibit the correct integration or homologous recombination of the targeting vector. Positive ES colonies are then expanded and used for creation of chimeras.

Creation of the Chimera A chimeric organism is one in which cells originate from more than one embryo. Here, chimeric mice are denoted as those that contain some tissues from the ES cells with an altered genome. When these ES cells give rise to the lineage of the germ layer, the germ cells carrying the altered genome can be passed on to the offspring, thus creating the germline transmission from ES cells. There are two methods for introducing ES cells into preimplantation-stage embryos: injection and aggregation. The injection of embryonic cells directly into the cavity of blastocysts is one of the fundamental methods for generating chimeras, but aggregation chimeras also have become an important alternative for transmitting the ES cell genome into mice. The mixture of recognizable markers (e.g., coat color) that are specific for the donor mouse and ES cells can be used to identify chimeric mice. However, most experimenters probably use existing mouse core facilities already established in some institutions, or contract a commercial vendor for the creation of a chimera.

Genotyping and Phenotyping of Knockout Animals The next step is to analyze whether germline transmission of targeted mutation occurs in mice. DNA from a small amount of tissue from offspring of the chimera is extracted and subjected to genomic PCR or Southern blot DNA hybridization. Positive mice (i.e., those with properly integrated targeting vector into the genome) will be used for the propagation of more knockout mice for phenotype analysis. When the knockout genes are crucial for early embryogenesis, mice often die in utero, an occurrence called embryonic lethality . When this happens, only the phenotype of the homozygous (both alleles ablated) knockout mouse embryos and the phenotype of the heterozygous (only one allele ablated) adult mice can be studied. Because most are interested in the phenotype of adult mice, in particular when using mice as disease models, it is recommended to create the conditional knockout using the cre-loxP system so that the gene of interest can be knocked out at will. To date, more than 5000 genes have been disrupted by homologous recombination and transmitted through the germline. The phenotypic studies of these mice provide ample information on the functions of these genes in growth and differentiation of organisms, and during development of human diseases.

RNA INTERFERENCE Although gene ablation in animal models provides an important means to understand the in vivo functions of genes of interest, animal models may not adequately represent human biology. Alternatively, gene targeting can be used to knock out genes in human cells, including human ES cells. A number of recent advances have made gene targeting in somatic cells as easy as in murine ES cells.2 5 However, gene targeting (knocking out both alleles) in somatic cells is a time-consuming process. Development of RNAi technology in the past few years has provided a more promising approach to understanding the biologic functions of human genes in human cells.2 6 RNAi is an ancient natural mechanism by which small, double-stranded RNA (dsRNA) acts as a guide for an enzyme complex that destroys complementary RNA and downregulates gene expression in a sequence-specific manner. Although the mechanism by which dsRNA suppresses gene expression is not entirely understood, experimental data provide important insights. In nonmammalian systems such as Drosophila , it appears that longer dsRNA is processed into 21–23 nt dsRNA (called small interfering RNA or siRNA ) by an enzyme called Dicer containing RNase III motifs. The siRNA apparently then acts as a guide sequence within a multicomponent nuclease complex to target complementary

mRNA for degradation. Because long dsRNA induces a potent antiviral response pathway in mammalian cells, short siRNAs are used to perform gene silencing experiments in mammalian cells (Fig. 15-24).

Fig. 15-24.

RNA inference in mammalian cells. Small interfering RNA (siRNA) can be produced from a polymerase III–driven expression vector. Such a vector first synthesizes a 19–29 nt double-stranded (ds)RNA stem and a loop (labeled as shRNA in the figure), and then the RNase complex called Dicer processes the hairpin RNA into a small dsRNA (labeled as siRNA in the figure). siRNA can be chemically synthesized and directly introduced into the target cell. In the cell, through RNA-induced silencing complex (RISC), siRNA recognizes and degrades target messenger RNAs (mRNAs).

For siRNA studies in mammalian cells, researchers have used two 21-mer RNAs with 19 complementary nucleotides and 3' terminal noncomplementary dimers of thymidine or uridine. The antisense siRNA strand is fully complementary to the mRNA target sequence. Target sequences for an siRNA are identified visually or by software. The target 19 nucleotides should be compared to an appropriate genome database to eliminate any sequences with significant homology to other genes. Those sequences that appear to be specific to the gene of interest are the potential siRNA target sites. A few of these target sites are selected for siRNA design. The antisense siRNA strand is the reverse complement of the target sequence. The sense strand of the siRNA is the same sequence as the target mRNA sequence. A deoxythymidine dimer is routinely incorporated at the 3' end of the sense strand siRNA, although it is unknown whether this noncomplementary dinucleotide is important for the activity of siRNAs. There are two ways to introduce siRNA to knock down gene expression in human cells:

1. RNA transfection: siRNA can be made chemically or using an in vitro transcription method. Like DNA oligos, chemically synthesized siRNA oligos can be commercially ordered. However, synthetic siRNA is expensive and several siRNAs may have to be tried before a particular gene is successfully silenced. In vitro transcription provides a more economic approach. Both short and long RNA can be synthesized using bacteriophage RNA polymerase T7, T3, or SP6. In the case of long dsRNAs, RNase such as recombinant Dicers will be used to process the long dsRNA into a mixture of 21–23 nt siRNA. siRNA oligos or mixtures can

be transfected into a few characterized cell lines such as HeLa (human cervical carcinoma) and 293T cells (human kidney carcinoma). Transfection of siRNA directly into primary cells may be difficult. 2. DNA transfection: Expression vectors for expressing siRNA have been made using RNA polymerase III promoters such as U6 and H1. These promoters precisely transcribe a hairpin structure of dsRNA, which will be processed into siRNA in the cell (see Fig. 15-24). Therefore, properly-designed DNA oligos corresponding to the desired siRNA will be inserted downstream of the U6 or H1 promoter. There are two advantages of the siRNA expression vectors over siRNA oligos. First, it is easier to transfect DNA into cells. Second, stable populations of cells can be generated that maintain the long-term silencing of target genes. Furthermore, the siRNA expression cassette can be incorporated into a retroviral or adenoviral vector to provide a wide spectrum of applications in gene therapy. There has been a fast and fruitful development of RNAi tools for in vitro and in vivo use in mammals. These novel approaches, together with future developments, will be crucial to put RNAi technology to use for effective disease therapy or to exert the awesome power of mammalian genetics. Therefore, the applications of RNAi to human health are enormous. siRNA can be applied as a new tool for sequence-specific regulation of gene expression in functional genomics and biomedical studies. With the availability of the human genome sequences, RNAi approaches hold tremendous promise for unleashing the dormant potential of sequenced genomes. Practical applications of RNAi will possibly result in new therapeutic interventions. In 2002, the concept of using siRNA in battling infectious diseases and carcinogenesis was proven effective. These include notable successes in blocking replication of viruses, such as HIV, hepatitis B virus, and hepatitis C virus, in cultured cells using siRNA targeted at the viral genome or the human gene encoding viral receptors. RNAi has been shown to antagonize the effects of hepatitis C virus in mouse models. In cancers, silencing of oncogenes such as c-Myc or Ras can slow down the proliferation rate of cancer cells. Finally, siRNA also has potential applications for some dominant genetic disorders. The twenty-first century, already heralded as the "century of the gene," carries great promise for alleviating suffering from disease and improving human health. On the whole, completion of the human genome blueprint, the promise of gene therapy, and the existence of stem cells has captured the imagination of the public and the biomedical community for good reason. Aside from their potential in curing human diseases, these emerging technologies also have provoked many political, economic, religious, and ethical discussions. As more is discerned about the technologic advances, more attention must also be paid to concerns for their inherent risks and social implications. Surgeons must take the opportunity to collaborate with basic scientists to develop the field of personalized genomic surgery this century.

REFERENCES Entries Highlighted in Bright Blue Are Key References. 1. Alberts B, Johnson A, Lewis J, et al: Molecular Biology of the Cell , 4th ed. New York: Garland Science, 2002. 2. Watson JD, Crick FH: Molecular structure of nucleic acids; a structure for deoxyribose nucleic acid. Nature 171:737, 1953. [PMID: 13054692] 3. Mendel G: Versuche ber Planzen-Hybriden. Verhandlungen des naturforschenden Vereines, Abhandlungen . Brnn: 4, 3, 1866. 4. Carey M, Smale ST: Transcriptional Regulation in Eukaryotes . New York: Cold Spring Harbor Laboratory Press, 2000. 5. Wolfsberg TG, Wetterstrand KA, Guyer MS, et al: A user's guide to the human genome. Nature Genetics Supplement, 2002. (Also see

the Nature website: http://www.nature.com/nature/supplements/collections/humangenome/) 6. U.S. Department of Energy: Genomics and its impact on science and society: The human genome project and beyond. Published online by Human Genome Management Information System (HGMIS): http://www.ornl.gov/hgmis/publicat/primer, March 2003. 7. Simpson RJ: Protein and Proteomics . New York: Cold Spring Harbor Laboratory Press, 2003. 8. Hanash S: Disease proteomics. Nature 422:226, 2003. [PMID: 12634796] 9. Ptashne M, Gann A: Genes & Signals . New York: Cold Spring Harbor Laboratory Press, 2002. 10. Pawson T, Nash P: Assembly of cell regulatory systems through protein interaction domains. Science 300:445, 2003. [PMID: 12702867] 11. Lizcano JM, Alessi DR: The insulin signalling pathway. Curr Biol 12:R236, 2002. 12. Feng XH, Derynck R: Specificity and versatility in TGF-beta signaling through Smads. Annu Rev Cell Dev Biol 21:659, 2005. [PMID: 16212511] 13. Hanahan D, Weinberg RA: The hallmarks of cancer. Cell 100:57, 2000. [PMID: 10647931] 14. McNeil C: Heceptin raises its sights beyond advanced breast cancer. J Natl Cancer Inst 90:882, 1998. [PMID: 9637135] 15. 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 2:561, 1996. [PMID: 8616716] 16. Kiessling AA, Anderson SC: Human Embryonic Stem Cells: An Introduction to the Science and Therapeutic Potential . Boston: Jones & Bartlett Pub, 2003. 17. Vogel G: Breakthrough of the year: Reprogramming cells. Science 322:1766, 2008. 18. Cohen SN, Chang AC, Boyer HW, et al: Construction of biologically functional bacterial plasmids in vitro. Proc Natl Acad Sci U S A 70:3240, 1973. 19. Sambrook J: Molecular Cloning, A Laboratory Manual , 3rd ed. New York: Cold Spring Harbor Laboratory Press, 2001. 20. Ausubel FM, Brent R, Kingston RE, et al: Current Protocols in Molecular Biology . New York: John Wiley & Sons, 2003. 21. Southern EM: Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol 98:503, 1975. [PMID: 1195397] 22. Mullis K, Faloona F, Scharf S, et al: Specific enzymatic amplification of DNA in vitro: The polymerase chain reaction. Cold Spring Harb Symp Quant Biol 51:263, 1986. [PMID: 3472723] 23. Bowtell D, Sambrook J: DNA Microarrays, A Molecular Cloning Manual . New York: Cold Spring Harbor Laboratory Press, 2003. 24. Bonifacino JS, Dasso M, Harford JB, et al: Current Protocols in Cell Biology . New York: John Wiley & Sons, 2003. 25. Nagy A, Gertsenstein M, Vintersten K, et al: Manipulating The Mouse Embryo, A Laboratory Manual , 3rd ed. New York: Cold Spring Harbor Laboratory Press, 2003. 26. Hannon GJ: RNAi, A Guide To Gene Silencing . New York: Cold Spring Harbor Laboratory Press, 2003.

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KEY POINTS 1. The epidermis consists of five layers. The two most superficial layers (the stratum corneum and lucidum) contain nonviable keratinocytes. 2. Collagen III provides tensile strength to the dermis and epidermis. 3. Adult dermis contains a 4:1 ratio of type I:type III collagen. 4. Of the congenital skin disorders, only pseudoxanthoma elasticum and cutis laxia are responsive to surgical rejuvenation. 5. Hemangioma is the most common cutaneous lesion of infancy and a large majority spontaneously involute (resolve) past the first year of patient age. 6. Basal cell carcinoma (BCC) is the most common form of skin cancer and nodular BCC is the most frequent form of this tumor. 7. Breslow thickness is the most important prognostic variable predicting survival in those with cutaneous melanoma.

BACKGROUND As the largest human organ, the skin is one of the most complex and physiologically underappreciated elements of our bodies. Beneath its uniform appearance, the skin demonstrates profound regional variation due to the highly structured organization of many different cell types and dermal elements. Although primarily valued as a protective barrier allowing interface with our surroundings, the structure and physiology of the skin is complex and fascinating. As an environmental buffer, the skin protects against a vast array of destructive forces: The structural integrity of the epidermis creates a semipermeable barrier to chemical absorption, prevents fluid loss, protects against penetration of solar radiation, rebuffs infectious agents, and dermal durability resists physical forces. In addition, the skin's ability to regulate body heat makes it the body's primary thermoregulatory organ. The relative ease of analyzing skin specimens has made the skin one of the best-studied tissues of the human body. Not only does this fascinating organ form the primary focus of the subspecialties of plastic surgery and dermatology, but it also has driven research in a broad number of fields, including immunology, transplantation, and would healing.

ANATOMY AND PHYSIOLOGY OF THE SKIN Anatomically, the skin may be divided into three layers: the epidermis, basement membrane, and dermis.1–3 With very little extracellular matrix (ECM), the epidermis is composed primarily of specialized cells that

perform vital functions. Sandwiched between epidermal and dermal structures, the basement membrane anchors these layers together. 1–3 This membrane fulfills many biologic functions, including tissue organization, growth factor reservoir, support of cell monolayers during tissue development, and semipermeable selective barrier. In addition to its role in providing soft-tissue durability, the dermis is primarily composed of a dense ECM that provides support for a complex network of nerves, vasculature, and adnexal structures.3,4 The ECM is a collection of fibrous proteins and associated glycoproteins embedded in a hydrated ground substance of glycosaminoglycans and proteoglycans. These distinct molecules are organized into a highly ordered network that is closely associated with the cells that produce them. In addition to providing the architectural framework that imparts mechanical support and viscoelasticity, the ECM can regulate the neighboring cells, including their ability to migrate, proliferate, and survive injury. 2,4,5

The Epidermis Composed primarily of keratinocytes, the epidermis is a dynamic, multilayered composite of maturing cells. From internal to external-most layer, the epidermis is composed of the (a) stratum germinatum, (b) stratum spinosum, (c) stratum granulosum, (d) stratum lucidum, and finally, (e) the stratum corneum. Basal cells are a mitotically active, single-cell layer of the least-differentiated keratinocytes at the base of epidermal structure.2,6 As basal cells multiply, they leave the basal lamina to begin their differentiation and upward migration. In the spinous layer, keratinocytes are linked together by tonofibrils and produce keratin. As these cells drift upward, they lose their mitotic ability. With entry into the granular layer, cells accumulate keratohyalin granules.1,4,6 In the horny layer, keratinocytes age, lose their intercellular connections, and shed. From basal layer exit to shedding, keratinocyte transit time approximates 40 to 56 days.2,3 Melanocytes and other cellular components within the skin deter absorption of harmful radiation. Initially derived from precursor cells of the neural crest, melanocytes extend dendritic processes upward into epidermal tissues from their position beneath the basal cell layer.5,7 They number approximately one for every 35 keratinocytes, and produce melanin from tyrosine and cysteine. Once the pigment is packaged into melanosomes within the melanocyte cell body, these pigment molecules are transported into the epidermis via dendritic processes.6,7 As dendritic processes (apocopation) are sheared off, melanin is transferred to keratinocytes via phagocytosis. Despite differences in skin tone, the density of melanocytes is constant among individuals. It is the rate of melanin production, transfer to keratinocytes, and melanosome degradation that determine the degree of skin pigmentation.5,6 Whereas people of North European ancestry have melanocytes that release relatively low amounts of melanin, those of African descent demonstrate the same overall quantity of melanocytes, but with much higher melanin production. Genetically activated factors as well as ultraviolet (UV) radiation, hormones such as estrogen, adrenocorticotropic hormone, and melanocyte-stimulating hormone, increase melanin production.6,7 Cutaneous melanocytes play a critical role in neutralizing the sun's harmful rays. UV-induced damage affects the function of tumor suppressor genes, directly causes cell death, and facilitates neoplastic transformation.2–5 Although a majority of solar radiation that reaches the Earth is UVA (315 to 400 nm), the majority of skin damage is caused by UVB (240 to 315 nm). UVB is the major factor in sunburn injury, and is a known risk factor in the development of melanoma. Although UVB causes considerable DNA damage in the skin, UVA has only recently has been shown to damage DNA, proteins, and lipids.8–11 In addition, UV-related damage can either be potentiated by or contribute to effects of other harmful agents such as ionizing radiation, viruses, or chemical carcinogens. 3–6

As a durable barrier against external forces, the skin relies on a complex network of filaments to maintain cellular integrity. Intermediate filaments, called keratins, are found within the spindle layer and provide flexible scaffolding that enables the keratinocyte to resist external stress.4,6 Various keratins are expressed according to keratinocyte maturation phase, and mitotically active keratinocytes mainly express keratins 5 and 14.6,7 Point mutations affecting these genes may result in blistering diseases, such as epidermolysis bullosa, associated with spontaneous release of dermal-epidermal attachments.4,7 In addition to its role in resisting radiation, toxin absorption, and deforming forces, the skin is a critically immunoreactive barrier.4,6 Following migration into epidermal structure from the bone marrow, Langerhans' cells act as the skin's macrophages. This specialized cell type expresses class II major histocompatibility antigens, and has antigen-presenting capabilities. 4,7 In addition to initiating rejection of foreign bodies, Langerhans' cells play a crucial role in immunosurveillance against viral infections and neoplasms of the skin. 2,7

The Dermis The dermis is mostly comprised of structural proteins, and to a smaller degree, cellular components.2,4–6 Collagen, the main functional protein within the dermis, constitutes 70% of dermal dry weight and is responsible for its remarkable tensile strength.4,5 Tropocollagen, a collagen precursor, consists of three polypeptide chains (hydroxyproline, hydroxylysine, and glycine) wrapped in a helix.2,6 These long molecules are then cross-linked to one another to form collagen fibers. Of the seven structurally distinct collagens, the skin primarily contains type I. Fetal dermis contains mostly type III (reticulin fibers) collagen, but this only remains in the basement membrane zone and perivascular regions during postnatal development.6,7 Elastic fibers are highly branched proteins capable of stretching to twice their resting length. In addition to resisting stretch forces, these fibers allow a return to baseline form after the skin responds to deforming stress.4,6 Ground substance, consisting of various polysaccharide–polypeptide (glycosaminoglycans) complexes, is an amorphous material that occupies the remaining spaces. These glycosaminoglycans, secreted by fibroblasts, can hold up to 1000 times their own volume in water and constitute most of dermal volume.6,7 The blood supply to the dermis is based on an intricate network of blood vessels which provide vascular inflow to superficial structures, as well as regulate body temperature.3–7 This is achieved with the help of vertical vascular channels that interconnect two horizontal plexuses, one within the papillary dermis, and the other at the dermal–subcutaneous junction. 4,6 Glomus bodies are tortuous arteriovenous shunts that allow a substantial increase in superficial blood flow when stimulated to open. 3,5 Cutaneous sensation is achieved via activation of a complicated plexus of dermal autonomic fibers synapsed to sweat glands, erector pili, and vasculature control points. 6,7 These fibers also connect to corpuscular receptors that relay information from the skin back to the central nervous system. Meissner's, Ruffini's, and Pacini's corpuscles transmit information on local pressure, vibration, and touch.4,6 In addition, "unspecialized" free nerve endings report temperature, touch, pain, and itch sensations.4,6

Cutaneous Adnexal Structures The skin has three main adnexal structures: eccrine glands, pilosebaceous units, and apocrine glands.4–7 The sweat-producing eccrine glands are located over the entire body but are concentrated on the palms, soles, axillae, and forehead.3,4 Although pheromone-producing apocrine glands play a distinct role in lower mammalian life, these structures have not been shown to demonstrate significant activity in human

populations.5,7 However, large populations of apocrine glands are primarily found in the human axillae and anogenital region. It is these structures that predispose both regions to suppurative hydroadenitis.4,6 Hair follicles are mitotically active germinal centers that produce hair, a cylinder of tightly packed cornified epithelial cells. Together with oil-secreting sebaceous glands, these two structures form a pilosebaceous unit.3,4,7 In addition to the production of hair, hair follicles perform several vital functions. The hair follicle contains a reservoir of pluripotential stem cells critical in epidermal reproductivity. 2,7 These cells are capable of near limitless expansion to replace lost or injured cells, as well as restore epidermal continuity after wounding. For example, in skin graft harvest, residual hair follicles supply new keratinocytes to regenerate the epidermis and restore skin integrity.3,5

INJURIES TO THE SKIN AND SUBCUTANEOUS TISSUE Each day, the skin and subcutaneous tissue face an endless supply of stimuli that threaten to break tissue integrity. Such lapses in continuity provide entry of microorganisms, allow injury to deeper tissue layers, and prompt local tissue inflammation. In addition to penetrating trauma, the environment offers a host of potentially injurious elements, such as caustic substances, extreme temperatures, prolonged or excessive pressure, and radiation.

Traumatic Injuries Traumatic wounds may be caused by penetrating, blunt, and shear force, bite, and degloving injuries. Although clean lacerations may be closed primarily after irrigation, débridement, and careful evaluation, contaminated or infected wounds should be allowed to heal by secondary intention or delayed primary closure.8–10 Débridement of nonviable tissue and aggressive irrigation of the wound are principles guiding the management of more complex wounds. Tangential abrasions should be approached similarly to seconddegree burns, and degloving injuries considered third-degree or full-thickness burns.8–10 Degloved skin may be partially salvaged by placing it back on the wound like a skin graft. In addition, replacement of clean, avulsed tissue can effectively provide wound coverage as a biologic dressing.8–10 As the injured tissues declare their viability throughout the post-injury period, necrotic debris is removed. Areas of uncovered wound bed undergo delayed primary closure, are allowed to granulate in, or undergo definitive reconstruction. 8–10 Bite wounds account for 4.5 million injuries each year, and prompt 2% of all emergency rooms visits.8–10 These small puncture wounds may initially seem innocuous, but the impregnation of oral bacteria into deep, contained tissue layers can lead to significant morbidity if unrecognized (Fig. 16-1). The most common infectious organisms found with human bites are Viridans streptococci, Staphylococcus aureus, Eikenella corrodens, Haemophilus influenzae, and beta-lactamase-producing bacteria. 8–10 Dog bites account for the most frequent animal-related wound. Because the canine jaw can exert over 450 pounds of pressure per square inch,9,10 dog bites often add a crushing element in addition to penetrating injury as well as an avulsion element. Although the dog bite injury may contaminate tissues with both aerobic and anaerobic organisms, the most commonly cultured bacteria include Pasteurella multocida, Staphylococcus species, alpha-hemolytic streptococci, E. corrodens, Actinomyces, and Fusobacterium.8–10 The bite wound, whether from human or animal, is a contaminated wound and should not be closed primarily. Selected facial wounds may be closed primarily after very thorough cleansing and initiation of antibiotic therapy. Although there remains a potential risk of serious infection, this risk may be low enough on the face to weigh in favor of the improved long-term wound appearance after primary closure. The great majority of bite wounds should be

approached via drainage, copious irrigation, débridement of necrotic material, antibiotic therapy, extremity immobilization, and elevation.8–10

Fig. 16-1.

Digital infection following puncture or bite wounds often contain a variety of bacteria, and rapid spread of infection is possible in the absence of antibiotic therapy.

Exposure to Caustic Substances Injuries secondary to caustic substance exposure may be categorized as resulting from either acidic or alkali solutions. The effect of acid exposure on the skin is determined by the concentration, duration of contact, amount, and penetrability.11–13 Deep tissue coagulative injury may result, damaging nerves, blood vessels, tendons, and bone.12–15 The initial treatment should include copious skin irrigation for at least 30 minutes with either saline or water.11–15 This dilutes active acid solution and helps return the skin to normal pH. Injuries associated with hydrofluoric acid present an additional treatment challenge. Fluoride ions continue to injure underlying tissue until they are neutralized with calcium, and absorb the body's calcium supply, which

may prompt cardiac arrythmia.12,14,15 Topical quaternary ammonium compounds are widely used, and topical calcium carbonate gel also effectively detoxifies fluoride ions.14,15 Alkaline agents often used as household cleaning agents are responsible for more than 15,000 skin burns in the United States annually.12,13 After penetrating the skin, alkaline substances cause fat saponification that facilitates tissue penetration and increases tissue damage. In addition, the liquefactive injury produced by alkali burns provides a longer, more sustained period of injury.12,13 Immediate irrigation of the affected area with continuous water flow should be maintained for at least 2 hours, or until symptomatic relief is achieved. Intravenous fluid (IVF) extravasation—leakage of injectable fluids into interstitial space—is considered a chemical burn (Fig. 16-2). In contrast to many cutaneous injuries, this type of insult occurs from underneath the skin surface and is actually a deep injury. Extravasation produces injury via chemical toxicity, osmotic toxicity, or from pressure effects in a closed environment.12,13 This displacement may be the result of IV catheter movement or increased vascular permeability. The most common substances associated with these injuries are cationic solutions (e.g., potassium ion, calcium ion, bicarbonate), osmotically active chemicals (e.g., total parenteral nutrition or hypertonic dextrose solutions), and antibiotics or cytotoxic drugs.12,13 The dorsum of the hand is the most common site of extravasation in the adult, which may result in extensor tendon exposure.

Fig. 16-2.

Infiltration of IV fluid may produce significant soft-tissue injury. However, a great majority of these wounds respond well to conservative management, including frequent dressing change and continued wound care.

Patients undergoing chemotherapy have a 4.7% risk for developing extravasation, and children present an incidence as high as 58%.16,17 Newborn babies are at particular risk due to the fragility and small caliber of their veins, their poor ability to verbalize pain, and the frequent use of pressurized IVF pumps used in their care. The most common IVF extravasations causing necrosis in the infant are high-concentration dextrose solutions, calcium, bicarbonate, and parenteral nutrition.16,17 In the adult population, commonly extravasated drugs are chemotherapeutic agents, such as doxorubicin (Adriamycin) and paclitaxel.1 8 The direct toxic effects of doxorubicin causes cellular death that is perpetuated by release of doxorubicin-DNA complexes from dead cells. This cellular death prevents release of cytokines and growth factors, which may ultimately result in wound healing failure.1 8 Following extravasation, edema, erythema, and induration usually are present. Injury to underlying nerves, muscles, tendons, and blood vessels must be taken into account. Although a majority of such injuries are successfully managed through a conservative approach, many treatment options are available. 16–18 In the severe infusion injury, vigorous liposuction with a small cannula may be used to introduce saline flush into the injured area. The flush is then allowed to egress via the small liposuction wounds. 16–18 Although patients more than 24 hours after extravasation injury have

shown no benefit from flush-out, this technique has proved useful in the acute setting. Surgery should be limited to patients with necrotic tissue, pain, or damage of underlying structures.16–18

Hyper- and Hypothermic Injury Skin exposed to temperature extremes is at significant risk of hypo- or hyperthermic injury. Depending upon the temperature, period, and method of exposure, hyperthermic burns may cause varying degrees of tissue injury affecting the skin at different levels of depth.1 9 The central area of injury, the zone of coagulation, is exposed to the most direct heat transfer and typically becomes necrotic.20,21 Surrounding the zone of coagulation is the zone of stasis, which has marginal tissue perfusion and questionable viability. The outermost area, the zone of hyperemia, is most similar to uninjured tissue and demonstrates increased blood flow due to the body's response to injury.20,21 A more detailed discussion of burn wounds may be found in Chap. 8. Hypothermic injury (frostbite) results in the acute freezing of tissues and is the product of two factors: (a) duration of exposure, and (b) the temperature gradient at the skin surface.22,23 Severe hypothermia primarily exerts its damaging effect by causing direct cellular injury to blood vessel walls and microvascular thrombosis. In addition, the skin's tensile strength decreases by 20% in a cold environment [12°C, (53.6°F)]. 22,23 The treatment protocol for frostbite includes rapid rewarming, close observation, elevation and splinting, daily hydrotherapy, and serial débridements.22,23

Pressure Injury Prolonged, excessive pressure often results in pressure ulcer formation. As pressure is applied to overlying tissues, cutaneous vascular flow is decreased, rendering local tissues functionally ischemic.23–25 As little as 1 hour of 60 mmHg pressure produces histologically identifiable venous thrombosis, muscle degeneration, and tissue necrosis.23–25 Although normal arteriole, capillary, and venule pressures are 32, 20, and 12 mmHg, respectively, sitting can produce pressures as high 300 mmHg at the ischial tuberosities.23–25 Healthy individuals regularly shift their body weight, even while asleep. However, sacral pressure can build to 150 mmHg when lying on a standard hospital mattress.24,25 Patients unable to sense pain or shift their body weight, such as paraplegics or bedridden individuals, may develop prolonged elevated tissue pressures and local necrosis. Because muscle tissue is more sensitive to ischemia than skin, necrosis usually extends to a deeper area than that apparent on superficial inspection.24,25 The elements of pressure sore treatment include relief of pressure, wound care, and systemic enhancement, such as optimization of nutrition. Air flotation mattresses and gel seat cushions redistribute pressure, decrease the incidence of pressure ulcers, and are cost-effective in the care of patients at high risk.24,25 In addition, many institutions provide nutritional support services to facilitate proper dietary intake. Surgical management should include débridement of all necrotic tissue followed by thorough irrigation. Shallow ulcers may be allowed to close by secondary intention, but deeper wounds with involvement of the underlying bone require surgical débridement and coverage.24,25

Radiation Exposure Radiation injuries are frequently produced by a wide range of environmental elements, such as solar (UV) exposure, iatrogenic management, and industrial/occupational applications.26,27 Solar or UV radiation is the most common form of radiation exposure. The UV spectrum is divided into UVA (400 to 315 nm), UVB (315 to 290 nm), and UVC (290 to 200 nm).27–29 With regard to skin damage and development of skin cancers, significant wavelengths are in the UV spectrum. The ozone layer absorbs UVC wavelengths below 290 nm, allowing only UVA and UVB to reach the earth.50,52 UVB is responsible for the acute sunburns and for the

chronic skin damage leading to malignant degeneration, although it makes up less than 5% of the solar UV radiation that hits the earth.27–29 Ionizing radiation effectively blocks mitosis in rapidly dividing cell types,26,28,29 and has become a mainstay in the treatment of various malignancies. The extent of cellular damage is dependent on radiation dose, exposure period, and the cell type being treated.27–29 Acute radiation changes include erythema and basal epithelial cellular death in the area of direct application. With cellular repair, permanent hyperpigmentation is observed in healing areas. Four to 6 months following radiation application, chronic radiation changes are characterized by a loss of capillaries via thrombosis and fibrinoid necrosis of vessel walls.27,29 Progressive fibrosis and hypovascularity may eventually lead to ulceration when poor vascular inflow results in poor tissue perfusion that progresses as the skin ages.27–29

INFECTIONS OF THE SKIN AND SUBCUTANEOUS TISSUE Heralded by erythema, warmth, tenderness, and edema, cellulitis is a superficial, spreading infection of the skin and subcutaneous tissue. The most common organisms associated with cellulitis are group A streptococci and S. aureus. 3 0 Unless associated with significant patient morbidities, uncomplicated cellulitis usually can be managed with oral antibiotics on an outpatient basis.

Folliculitis, Furuncles, and Carbuncles Folliculitis is an infection of the hair follicle. The causative organism is usually Staphylococcus, but gramnegative organisms may cause follicular inflammation as well. A furuncle (boil) begins as folliculitis, but may eventually progress to form a fluctuant nodule.30,31 Whereas folliculitis usually resolves with adequate hygiene, soaking the furuncle in warm water hastens liquefaction and hastens spontaneous rupture. More involved, deep-seated infections that result in multiple draining cutaneous sinuses are called carbuncles. Along with furuncles, these lesions often require incision and drainage before healing can be initiated.30,31

Necrotizing Soft-Tissue Infections Although many soft-tissue infections remain localized, some result in rapid, necrotizing spread and septic shock. The most common sites are the external genitalia, perineum, or abdominal wall (Fournier gangrene).30–32 Currently, classification of these infections is based on (a) the tissue plane affected and extent of invasion, (b) the anatomic site, and (c) the causative pathogen(s).30–32 Deep soft-tissue infections are classified as either necrotizing fasciitis or necrotizing myositis. Necrotizing fasciitis represents a rapid, extensive infection of the fascia deep to the adipose tissue. Necrotizing myositis primarily involves the muscles but typically spreads to adjacent soft tissues.30–32 The most common organisms isolated from patients presenting with necrotizing soft-tissue infections include the gram-positive organisms: group A streptococci, enterococci, coagulase-negative staphylococci, S. aureus, S. epidermidis, and Clostridium species.30–32 Gram-negative species frequently associated with necrotizing infections include Escherichia coli, Enterobacter, Pseudomonas species, Proteus species, Serratia species, and bacteroides.30–32 Polymicrobial infections tend to be more common than single organism disease in these cases.31,32 Clinical risk factors for necrotizing soft-tissue infection include diabetes mellitus, malnutrition, obesity, chronic alcoholism, peripheral vascular disease, chronic lymphocytic leukemia, steroid use, renal failure, cirrhosis, and autoimmune deficiency syndrome. 30–32 Appropriate management starts with prompt recognition, broad-spectrum IV antibiotics, aggressive surgical débridement, and intensive care unit support.30–32 Débridement must be extensive, including all skin, subcutaneous tissue, and muscle, until there

is no further evidence of infected tissue. Initial resection is followed by frequent returns to the operating room for additional débridement as required.31,32 In addition, aggressive fluid replacement is typically needed to offset acute renal failure from ongoing sepsis.31,32

Hidradenitis Suppurativa Hidradenitis suppurativa is a defect of the terminal follicular epithelium.33,34 Because the follicular defect results in apocrine gland blockage, obstructed infection leads to abscess formation throughout affected axillary, inguinal, and perianal regions. Following spontaneous rupture of these localized collections, foulsmelling sinuses form and repeated infections create a wide area of inflamed, painful tissue.33,34 Treatment of acute infections includes application of warm compresses, antibiotics, and open drainage. In cases of chronic hidradenitis, wide excision is required and closure may be achieved via skin graft or local flap placement.33,34

Actinomycosis Actinomycosis is a granulomatous suppurative bacterial disease caused by Actinomyces. In addition to Nocardia, Actinomadura, and Streptomyces, Actinomyces infections may produce deep cutaneous infections that present as nodules and spread to form draining tracts within surrounding soft tissue.35,36 Forty to 60% of the actinomycotic infections occur within the face or head.35,36 Actinomycotic infection usually results following tooth extraction, odontogenic infection, or facial trauma. 35,36 Accurate diagnosis depends on careful histologic analysis, and the presence of sulfur granules within purulent specimen is pathognomonic. 3 5 Penicillin and sulfonamides are typically effective against these infections. However, areas of deep-seated infection, abscess, or chronic scarring may require surgical therapy.35,36

VIRAL INFECTIONS OF THE SKIN AND SUBCUTANEOUS TISSUE Human Papillomavirus Warts are epidermal growths resulting from human papillomavirus (HPV) infection. Different morphologic types have a tendency to occur at different areas of the body. The common wart (verruca vulgaris) is found on the fingers and toes and is rough and bulbous (Fig. 16-3). Plantar warts (verruca plantaris) occur on the soles and palms, and may resemble a common callus. Flat warts (verruca plana) are slightly raised and flat. This particular subtype tends to appear on the face, legs, and hands.37–39 Venereal warts (condylomata acuminata) grow in the moist areas around the vulva, anus, and scrotum. Histologic examination demonstrates hyperkeratosis (hypertrophy of the horny layer), acanthosis (hypertrophy of the spinous layer), and papillomatosis.37–39 A multitude of various therapies have been created to eradicate the papillomatous growth. Warts may be removed via application of chemicals, such as formalin, podophyllum, and phenol-nitric acid.37–39 Curettage with electrodesiccation also can be used for scattered lesions. Treatment of extensive areas of skin requires surgical excision under general anesthesia. 37–39 Because of the infectious etiology, recurrences are common, and repeated excisions are often necessary. Some warts (especially HPV types 5, 8, and 10) are associated with squamous cell cancers, therefore lesions that grow rapidly, atypically, or ulcerate should be biopsied.38,39

Fig. 16-3.

The common wart, caused by cutaneous infection with human papillomavirus, may affect all areas covered by epidermal tissues.

Condylomata acuminata is one of the most common sexually transmitted diseases, and largely results from HPV types 6 and 11 (Fig. 16-4).37–39 Extensive growths, facilitated by concomitant HIV infection, are often multiple and can grow large in size (Buschke-Löwenstein tumor). In addition to local destruction or excision, adjuvant therapy with interferon, isotretinoin, or autologous tumor vaccine decreases recurrence rates.38,39 Immune response modifiers, such as imiquimod, may also optimize long-term eradication of HPV-induced anogenital lesions. 37–39 Because larger lesions have a significant risk of malignant transformation, close observation of lesion return or atypical presentation should be advised.

Fig. 16-4.

Human papillomavirus affecting digital and genitourinary sites often proves most problematic for the patient.

Human Immunodeficiency Virus Patients with HIV commonly display a variety of skin manifestations. As a result of intrinsic wound-healing deficiencies and much lower resilience, these patients frequently develop chronic wounds.40–42 In addition, the risk of postoperative soft-tissue complications directly increases with disease progression. The cause for delayed wound healing is unknown but is thought to be secondary to: (a) decreasing T-cell CD4+ count, (b) opportunistic infection, (c) low serum albumin, and (d) poor nutrition.40–42 Overall, these effects are thought to result in poor collagen cross-linking and deposition producing a profound compromise in wound healing.40–42

INFLAMMATORY DISEASES OF THE SKIN AND SUBCUTANEOUS SOFT TISSUE Pyoderma Gangrenosum Pyoderma gangrenosum is a relatively uncommon destructive cutaneous lesion. Clinically, a rapidly enlarging, necrotic lesion with undermined border and surrounding erythema characterize this disease. 43–45 Linked to underlying systemic disease in 50% of cases, these lesions are commonly associated with inflammatory bowel disease, rheumatoid arthritis, hematologic malignancy, and monoclonal immunoglobulin

A gammapathy.43–45 Recognition of the underlying disease is of paramount importance. Management of pyoderma gangrenosum ulcerations without correction of underlying systemic disorders is fraught with complication. A majority of patients receive systemic steroids or cyclosporine.43–45 Although medical management alone may slowly result in wound healing, many physicians advocate chemotherapy with aggressive wound care and skin graft coverage.43–45

Staphylococcal Scalded Skin Syndrome and Toxic Epidermal Necrolysis Staphylococcal scalded skin syndrome (SSSS) and toxic epidermal necrolysis (TEN) create a similar clinical picture including skin erythema, bullae formation, and wide areas of tissue loss (Fig. 16-5).46,47 SSSS is caused by an exotoxin produced during staphylococcal infection of the nasopharynx or middle ear.46,47 TEN is an immune response to certain drugs such as sulfonamides, phenytoin, barbiturates, and tetracycline.46,47 Diagnosis is made via skin biopsy. Histologic analysis of SSSS reveals a cleavage plane in the granular layer of the epidermis.46,47 In contrast, TEN results in structural defects at the dermoepidermal junction and is similar to a second-degree burn.46,47 Treatment involves fluid and electrolyte replacement, as well as wound care similar to burn therapy. Whereas those with more than 30% of total body surface area involvement are classified as TEN, patients with less than 10% of epidermal detachment are categorized as Stevens-Johnson syndrome.46,47 In Stevens-Johnson syndrome, respiratory and alimentary tract epithelial sloughing may result in intestinal malabsorption and pulmonary failure. Patients with significant soft-tissue loss should be treated in burn units with specially trained staff and critical equipment.46,47 Although corticosteroid therapy has not been efficacious, temporary coverage via cadaveric, porcine skin, or semisynthetic biologic dressings (Biobrane) allows the underlying epidermis to regenerate spontaneously.46,47

Fig. 16-5.

Staphylococcal scalded skin syndrome is associated with retained foreign objects colonized with toxin-secreting staphylococcus strains.

BENIGN TUMORS OF THE SKIN AND SUBCUTANEOUS TISSUE Cysts (Epidermal, Dermoid, Trichilemmal) Cutaneous cysts are categorized as either epidermal, dermoid, or trichilemmal.48,49 Although surgeons often refer to cutaneous cysts as sebaceous cysts because they appear to contain sebum, this is a misnomer and the substance is actually keratin.48,49 Epidermal cysts are the most common type of cutaneous cyst, and may present as a single, firm nodule anywhere on the body. Dermoid cysts are congenital lesions that result when epithelium is trapped during fetal midline closure.48,49 Although the eyebrow is the most frequent site of presentation, dermoid cysts are common anywhere from the nasal tip to the forehead. 48,49 Trichilemmal (pilar) cysts, the second most common cutaneous cyst, occur more often on the scalp of females. 48,49 When ruptured, these cysts have an intense, characteristic odor. On clinical examination, it is difficult to distinguish one type of cyst from another: Each cyst presents as a subcutaneous, thin-walled nodule containing a white, creamy material.48,49 Histologic examination reveals several key features. Cyst walls consist of an epidermal layer oriented with the basal layer superficial, and the more mature layers deep (i.e., with the epidermis growing into the center of the cyst).48,49 The desquamated cells (keratin) collect in the center to form the cyst. Epidermal cysts have a mature epidermis complete with granular layer.48,49 Dermoid cysts demonstrate squamous epithelium, eccrine glands, and pilosebaceous units. In addition, these particular cysts may develop bone, tooth, or nerve tissue on occasion.48,49 Trichilemmal cyst walls do not contain a granular layer; however, these cysts contain a

distinctive outer layer resembling the root sheath of a hair follicle (trichilemmoma).48–50 Each of these cysts typically remain unnoticed and asymptomatic until they rupture, cause local inflammation, or become infected. Once infected, these cysts behave similar to abscesses, and incision and drainage is recommended. After resolution of inflammation, the cyst wall must be removed in its entirety or the cyst will recur. 48–50

Keratoses (Seborrheic, Solar) Seborrheic keratoses arise in sun-exposed areas of the body such as the face, forearms, and back of the hands.51–53 Most notable in the older age groups, lesions appear light brown or yellow and have a velvety, greasy texture. Seborrheic keratoses are considered premalignant lesions, and squamous cell carcinoma (SCC) may develop over time.52,53 Interestingly, sudden eruptions of multiple lesions may be associated with internal malignancies.50,52 However, seborrheic keratoses are rarely mistaken for other lesions, so biopsy and treatment are seldom required.50,52 Histologically, these lesions contain atypical-appearing keratinocytes and evidence of dermal solar damage.50,52 Although malignancies that do develop rarely metastasize, lesion destruction is the treatment of choice. Treatments often include application of topical 5-fluorouracil, surgical excision, electrodesiccation, and dermabrasion.50,52

Nevi (Acquired and Congenital) Depending on the location of nevus cells, acquired melanocytic nevi are classified as junctional, compound, or dermal.54–57 This classification does not represent different types of nevi, but rather different stages in nevus maturation. Initially, nevus cells accumulate in the epidermis (junctional).55–57 As they mature, nevus cells migrate partially into the dermis (compound) and finally rest completely within dermal tissues (dermal). Eventually most lesions undergo involution. Congenital nevi are relatively rare, and may be found in less than 1% of neonates.54,56,57 These lesions are larger and often contain hair. Histologically, congenital and acquired nevi appear similar. Giant congenital lesions (giant hairy nevi) most often occur in a swim trunk distribution, chest, or back (Fig. 16-6).54–57 Not only are these lesions cosmetically unpleasant, but congenital nevi may develop into malignant melanoma in 1 to 5% of cases.54–57 Total excision of the nevus is the treatment of choice; however, the lesion is often so large that inadequate tissue for wound closure precludes complete resection. Instead, serial excisions with local tissue expansion/advancement are frequently required over several years.54–57

Fig. 16-6.

Although the giant nevus may be aesthetically concerning, these lesions present a roughly 5% risk of malignant transformation over one's lifetime.

Vascular Tumors of the Skin and Subcutaneous Tissue Hemangiomas are benign vascular neoplasms that present soon after birth (Fig. 16-7). They initially undergo rapid cellular proliferation over the first year of life, then undergo slow involution throughout childhood. 58–60 Histologically, hemangiomas are composed of mitotically active endothelial cells surroundings several, confluent blood-filled spaces. Although these lesions may enlarge significantly in the first year of life, approximately 90% involute over time.58–60 Acute treatment is limited to hemangiomata that interfere with function, such as airway, vision, and feeding. In addition, lesions resulting in systemic problems, such as thrombocytopenia or high-output cardiac failure, should prompt resection. The growth of rapidly enlarging lesions also can be halted with systemic prednisone or interferon alpha-2a treatment use.58–60 In the absence of acute surgical indications or significant patient/parent concern, many lesions are allowed to spontaneously involute. However, hemangiomata that remain into adolescence or involute to leave an unsightly telangiectasia typically require surgical excision for optimal resolution.58–60

Fig. 16-7.

Hemangiomas most often present at approximately 2 to 4 weeks after birth, rapidly proliferate during infancy, reach a plateau phase, then involute over several years. Unless the hemangiomatous mass obstructs the airway, visual axis, or imposes psychological harm to a preschool age child, these tumors typically are allowed to spontaneously involute.

In contrast to neoplasms, vascular malformations are a result of structural abnormalities formed during fetal development.61,62 Unlike hemangiomas, vascular malformations grow in proportion to the body and never involute. Histologically, they contain enlarged vascular spaces lined by nonproliferating endothelium.61,62 Arteriovenous malformations are high-flow lesions that often present as subcutaneous masses associated with locally elevated temperature, dermal stain, thrill, and bruit. In addition, overlying ischemic ulcers, adjacent bone destruction, or local hypertrophy may occur.61,62 Very large malformations may cause cardiac enlargement and congestive heart failure. Complications of arteriovenous malformations, such as pain, hemorrhage, ulceration, cardiac effects, or local tissue destruction, should prompt attempts at lesion destruction.61,62 Therapy consists of surgical resection. Even when complete lesion resection is not possible,

significant debulking may greatly diminish symptomatology. In addition, angiography with selective embolization just before surgery greatly facilitates operative removal. 61,62 The capillary malformation, or port-wine stain, is a flat, dull-red lesion often located on the trigeminal (cranial nerve V) distribution on the face, trunk, or extremities (Fig. 16-8). 61,62 Presentation within the V1 or V2 facial regions should prompt concern of a possible link to more systemic syndromes such as SturgeWeber syndrome (leptomeningeal angiomatosis, epilepsy, and glaucoma).61,62 Histologically, these nevi are composed of ectatic capillaries lined by mature endothelium. Unsightly lesions may be treated with pulsed dye laser, covered with cosmetics, or surgically excised. 61,62

Fig. 16-8.

A capillary hemangioma (also known as a port-wine stain) present upon the midface may signify Churg-Strauss syndrome, and computed tomography of the brain is appropriate to rule out intracranial berry aneurysms.

Glomus tumor is an uncommon, benign neoplasm of the extremity. Representing less than 1.5% of all benign, soft-tissue extremity tumors, these lesions arise from dermal neuromyoarterial apparatus (glomus

bodies).63,64 Glomus tumor more commonly affects the hand, and presentation within the subungual region of the toe is rare. Diagnosis of these lesions is traditionally delayed, and atypical presentation on the foot or toes often leads to even greater diagnostic challenges. In addition to the severe pain, point tenderness and cold sensitivity are associated with these lesions and subungual glomus tumors typically appear as blue, subungual discolorations of 1 to 2 mm. Tumor excision is the treatment of choice.63,64

Soft-Tissue Tumors (Acrochordons, Dermatofibromas, Lipomas) Lipomas are the most common subcutaneous neoplasm.6 4 Although they are found most frequently on the trunk, these lesions may appear anywhere. Typically soft and fleshy on palpation, lipomas may grow to a large size and become substantially deforming. Histologic examination reveals a lobulated tumor composed of normal fat cells.6 4 Although fears of malignant degeneration have prompted resection in the past, no report of such malignancy has been substantiated. To date, the lipoma is widely viewed as benign with essentially no risk of malignant devolvement.6 4 Although observation is an option, surgical excision is required for tumor removal. Acrochordons (skin tags) are fleshy, pedunculated masses located on the preauricular areas, axillae, trunk, and eyelids.65–67 They are composed of hyperplastic epidermis over a fibrous connective tissue stalk. These lesions are usually small, and are frequently treated via "tying off" or with resection in the clinic.65–67 Dermatofibromas are solitary, soft-tissue nodules usually approximating 1 to 2 cm in diameter, and are found primarily on the legs and flanks. Histologically, these lesions are composed of unencapsulated connective tissue whorls containing fibroblasts.65–67 Although a majority of dermatofibromas can be diagnosed clinically, atypical presentation or course should prompt excisional biopsy to assess for malignancy. Although these tumors may be managed conservatively, operative removal is the treatment of choice.66–68

Neural Tumors (Neurofibromas, Neurilemomas, Granular Cell Tumors) Benign, cutaneous neural tumors such as neurofibromas, neurilemomas, and granular cell tumors primarily arise from the nerve sheath.65,68 Neurofibromas can be sporadic and solitary. However, a majority are associated with café au lait spots, Lisch nodules, and an autosomal dominant inheritance (von Recklinghausen's disease).65,66 These lesions are firm, discrete nodules attached to a nerve. Histologically, proliferation of perineurial and endoneurial fibroblasts with Schwann cells embedded in collagen are noted. In contrast to direct nerve attachment as seen with neurofibromas, neurilemomas are solitary tumors arising from cells of the peripheral nerve sheath.65,66 These lesions are discrete nodules that may induce local or radiating pain along the distribution of the nerve. Microscopically, the tumor contains Schwann cells with nuclei packed in palisading rows. Surgical resection is the management option of choice. Granular cell tumors are usually solitary lesions of the skin or, more commonly, the tongue.65,66 They consist of granular cells derived from Schwann cells that often infiltrate the surrounding striated muscle. Based on the severity of symptomatology, operative resection is the primary therapy of choice.65–68

MALIGNANT TUMORS OF THE SKIN Although malignancies arising from cells of the dermis or adnexal structures are relatively uncommon, the skin is frequently subject to epidermal tumors, such as basal cell carcinoma (BCC), SCC, and melanoma.69–72 Each of these tumors has received exhaustive study, and several key factors associated with their development have been identified. Perhaps of greatest significance is that increased exposure to UV radiation

is associated with an increased development of all skin cancer.69–72 Clinical studies reveal that persons with outdoor occupations are at greater risk, as are those with fair complexions and people living in regions receiving higher per capita sunlight. In addition, albino individuals of dark-skinned races are prone to develop cutaneous neoplasms that are typically rare in nonalbino members of the same group. This observation suggests that melanin, and its ability to limit UV radiation tissue penetration, plays a large role in carcinogenesis protection.69–72 Skin cancer development also has been strongly linked to chemical carcinogens such as tar, arsenic, and nitrogen mustard. Radiation therapy directed at skin lesions increases the risk for local BCC and SCC.69–72 As an ongoing area of intense research interest, certain subtypes of HPV have been linked to SCC.69–72 Additionally, chronically irritated or nonhealing areas such as burn scars, sites of repeated bullous skin sloughing, and decubitus ulcers present an elevated risk of developing SCC.69–72 Systemic immunologic dysfunction is also related to an increase in cutaneous malignancies. Immunosuppressed patients receiving chemotherapy, those with advanced HIV/AIDS, and immunosuppressed transplant recipients have an increased incidence of BCC, SCC, and melanoma.69–72

Basal Cell Carcinoma Arising from the basal layer of the epidermis, BCC is the most common type of skin cancer. Based on gross and histologic morphology, BCC has been divided into several subtypes: nodular, superficial spreading, micronodular, infiltrative, pigmented, and morpheaform.69–72 Nodulocystic or noduloulcerative type accounts for 70% of BCC tumors. Waxy and frequently cream colored, these lesions present with rolled, pearly borders surrounding a central ulcer. Although superficial basal cell tumors commonly occur on the trunk and form a red, scaling lesion, pigmented BCC lesions are tan to black in color. Morpheaform BCC often appears as a flat, plaque-like lesion.69–72 This particular variant is considered relatively aggressive and should prompt early excision. A rare form of BCC is the basosquamous type, which contains elements of both basal cell and squamous cell cancer. These lesions may metastasize similar to SCC, and should be treated aggressively.69–72 BCCs are slow growing, and metastasis is extremely rare. 69–72 Due to this slow developmental progression, patients often neglect these lesions for years and presentation with extensive local tissue destruction is common. The majority of small (less than 2 mm), nodular lesions may be treated via curettage, electrodesiccation, or laser vaporization.69–72 Although effective, these techniques destroy any potential tissue sample for confirmatory pathology diagnosis and tumor margin analysis. Surgical excision may be used to both effect complete tumor removal as well as allow proper laboratory evaluation. Basal cell tumors located at areas of great aesthetic value, such as the cheek, nose, or lip, may be best approached with Mohs' surgery.69–72 Typically completed by specialized dermatology surgeons, Mohs' surgery uses minimal tissue resection and immediate microscopic analysis to confirm appropriate resection. Large tumors, those that invade surrounding structures, and aggressive histologic types (morpheaform, infiltrative, and basosquamous) are best treated by surgical excision with 0.5-cm to 1-cm margins.69–72

Squamous Cell Carcinoma SCCs arise from epidermal keratinocytes (Fig. 16-9). While less common than BCC, SCC is more devastating due to an increased invasiveness and tendency to metastasize.69–72 Before local invasion, in situ SCC lesions

are termed Bowen's disease. In situ SCC tumors specific to the penis are referred to as erythroplasia of Queyrat. 67,68 Following tissue invasion, tumor thickness correlates well with malignant behavior. Tumor recurrence is more prevalent once SCC tumors grow more than 4 mm in thickness, and lesions that metastasize are typically at least 10 mm in diameter.69–72 Tumor location is also of great prognostic importance. Although SCC tumors in areas with cumulative solar damage are less aggressive, and respond well to local excision, lesions arising in burn scars (Marjolin's ulcer), areas of chronic osteomyelitis, and areas of previous injury metastasize early.69–72

Fig. 16-9.

Although basal cell carcinoma is the most common tumor involving the head and neck, squamous cell carcinoma (pictured here) occurs with high frequency on the nose, ears, and lower lip.

Although small lesions can be treated with curettage and electrodesiccation, most surgeons recommend surgical excision. Lesions should be excised with a 1-cm margin, and histologic confirmation of tumor-free borders is mandatory.69–72 Tumors within areas of great aesthetic value, such as the cheek, nose, or lip, may be best approached with Mohs' surgery. This precise, specialized surgical technique uses minimal tissue

resection and immediate microscopic analysis to confirm appropriate resection yet limit removal of valuable anatomy. The need for lymph node (LN) dissection in the setting of SCC remains a topic of debate. Regional LN excision is indicated for clinically palpable nodes.69–72 However, SCC lesions arising in chronic wounds are more aggressive and regional lymph node metastases are observed more frequently. In this instance, lymphadenectomy before development of palpable nodes (prophylactic LN dissection) is indicated. Metastatic disease is a poor prognostic sign, and only 13% of patients typically survive 10 years.69–72

Mohs' Surgery for Squamous and Basal Cell Carcinomas Basal and squamous cell lesions often present on sun-exposed portions of the body such as the head and face. Unfortunately, these areas are of great aesthetic value and significant tissue loss may significantly alter facial symmetry, contour, and continuity. Developed in 1936, Mohs' technique uses serial excision in small increments coupled with immediate microscopic analysis to ensure tumor removal, yet limit resection of aesthetically valuable tissue.70–72 One distinct advantage of Mohs' technique is that all specimen margins are evaluated. In contrast, traditional histologic examination surveys selected portions on surgical margin. The major benefit of Mohs' technique is the ability to remove a tumor with minimal sacrifice of uninvolved tissue. 70–72 Although this procedure is of particular value when managing tumors of the eyelid, nose, or cheek, one major drawback is procedure length. Total lesion excision may require multiple attempts at resection, and many procedures may be carried out over several days. Recurrence and metastases rates are comparable to those of wide local excision.70–72

Malignant Melanoma The increasing rate of melanoma diagnoses is the highest of any cancer in the United States. The ageadjusted incidence of invasive melanoma in the United States increased from approximately 4 to 18 per 100,000 white males between 1973 and 1998.7 3 With this increasing prevalence, it is critical that physicians recognize and appropriately manage these lesions early. The pathogenesis of melanoma is complex and remains poorly understood to date. Melanoma may arise from transformed melanocytes anywhere that these cells have migrated during normal embryogenesis (Fig. 1610).73–76 Although nevi (freckles) are benign melanocytic neoplasms found on the skin of many people, dysplastic nevi contain a histologically identifiable focus of atypical melanocytes. These lesions are thought to represent an intermediate stage between benign nevus and true malignant melanoma.73–76 Studies demonstrate increased relative risk of melanoma development based on increasing numbers of dysplastic nevi found on the patient. In addition, a strong genetic component has been described.73–76 Up to 14% of malignant melanomas occur in a familial pattern, and family members of those with either dysplastic nevi or melanoma are at increased risk for tumor development.73–76

Fig. 16-10.

Following malignant transformation, invasive melanoma cells replicate, penetrate surrounding epidermal layers, and migrate to more distant tissues.

Once the melanocyte has transformed into the malignant phenotype, tumor growth occurs radially in the epidermal plane.73–76 Even though microinvasion of the dermis may have occurred, metastases do not occur until these melanocytes form dermal nests. During the subsequent vertical growth phase, cells develop different cell-surface antigens and their malignant behavior becomes much more aggressive.73–76 Study of these cell populations in culture medium demonstrates substantially lengthened cellular life span and increased malignant growth despite significantly poor nutrient medium.73–76 Although the eye and anus are notable sites, over 90% of melanomas are found on the skin (Fig. 1611).73–76 In addition, 4% of tumors are discovered as metastases without any identifiable primary site. Suspicious features suggestive of melanoma include any pigmented lesion with an irregular border, darkening coloration, ulceration, and raised surface.73–76 Although many benign lesions may fit these

descriptors, it is perhaps most critical to note recent changes in nevus appearance that may denote malignant transformation. In addition, approximately 5 to 10% of melanomas are nonpigmented.73–76

Fig. 16-11.

Lateral view of a subungual melanoma demonstrating apparent proximal digital extension.

In order of decreasing frequency, the four types of melanoma are superficial spreading, nodular, lentigo maligna, and acral lentiginous.73–76 The most common type, superficial spreading, accounts for up to 70% of melanomas. These lesions occur anywhere on the skin except the hands and feet. They are typically flat and measure 1 to 2 cm in diameter at diagnosis.73–76 Before vertical extension, a prolonged radial growth phase is characteristic of these lesions. Typically of darker coloration and often raised, the nodular type accounts for 15 to 30% of melanomas.73–76 These lesions are noted for their lack of radial growth; hence, all nodular melanomas are in the vertical growth phase at diagnosis. Although considered a more aggressive lesion, the prognosis for patients with nodular-type melanomas is similar to that for a patient with a superficial spreading lesion of the same depth. Lentigo maligna accounts for 4 to 15% of melanomas, and occurs most frequently on the neck, face, and hands of the elderly.73–76 Although they tend to be quite large at diagnosis, these lesions have the best prognosis because invasive growth occurs late. Less than 5% of lentigo maligna are estimated to evolve into melanoma.74,75 Acral lentiginous melanoma is the least common subtype, and constitutes only 2 to 8% of melanomas in white populations. Although acral lentiginous melanoma among dark-skinned people is relatively rare, this type accounts for 29 to 72% of all melanomas in dark-skinned people (African Americans, Asians, and Hispanics).74,75 Acral lentiginous melanoma most frequently is encountered on the palms, soles, and subungual regions. Most common on the great toe or thumb, subungual lesions appear as blue-black discolorations of the posterior nail fold. The additional presence of

pigmentation in the proximal or lateral nail folds (Hutchinson's sign) is diagnostic of subungual melanoma.73–76 Several clinical features of melanoma have been identified as significant prognostic indicators. Independent of histologic type and depth of invasion, those with lesions of the extremities have a better prognosis than patients with melanomas of the head, neck, or trunk (10-year survival rate of 82% for localized disease of the extremity compared to a 68% survival rate with a lesion of the face).73–76 Lesion ulceration carries a worse prognosis. The 10-year survival rate for patients with local disease (stage I) and an ulcerated melanoma was 50% compared to 78% for the same stage lesion without ulceration.73–76 Early studies identified that the incidence of ulceration increases with increasing thickness, from 12.5% in melanomas less than 0.75 mm to 72.5% in melanomas greater than 4.0 mm.74,76 Recent evidence suggests that tumors ulcerate as the result of increased angiogenesis.73–76 Gender is also a substantial prognostic indicator. Numerous studies demonstrate that females have an improved survival compared to males.74,75 Women tend to acquire melanomas in more favorable anatomic sites, and these lesions are less likely to contain ulceration. After correcting for thickness, age, and location, females continue to have a higher survival rate than men (10-year survival rate of 80% for women vs. 61% for men with stage I disease).74–76 In general, there is no significant difference between different histologic tumor types in terms of prognosis, when matched for tumor thickness, gender, age, or other. Nodular melanomas have the same prognosis as superficial spreading types when lesions are matched for depth of invasion. Lentigo maligna types, however, have a better prognosis even after correcting for thickness, and acral lentiginous lesions have a worse prognosis. Even though the various types of melanoma have similar prognoses when controlled for the other prognostic factors, acral lentiginous melanoma has a shorter interval to recurrence.74–76 The most current staging system, from the American Joint Committee on Cancer (AJCC), contains the best method of interpreting clinical information in regard to prognosis of this disease (Fig. 16-12).74–76 Historically, the vertical thickness of the primary tumor (Breslow thickness) and the anatomic depth of invasion (Clark level) have represented the dominant factors in the T classification. The T classification of lesions comes from the original observation by Clark that prognosis is directly related to the level of invasion of the skin by the melanoma. Whereas Clark used the histologic level [I, superficial to basement membrane (in situ); II, papillary dermis; III, papillary/reticular dermal junction; IV, reticular dermis; and V, subcutaneous fat], Breslow modified the approach to obtain a more reproducible measure of invasion by the use of an ocular micrometer. The lesions were measured from the granular layer of the epidermis or the base of the ulcer to the greatest depth of the tumor (I, 0.75 mm or less; II, 0.76 to 1.5 mm; III, 1.51 to 4.0 mm; IV, 4.0 mm or more).74–76 These levels of invasion have been subsequently modified and incorporated in the AJCC staging system. The new staging system has largely replaced the Clark level with another histologic feature, ulceration, based on analysis of large databases available to the AJCC Melanoma Committee.75,76

Fig. 16-12.

Although Breslow's thickness has traditionally been used to anticipate clinical outcomes based on the depth of melanoma invasion, more recent staging criteria advanced by the American Joint Committee on Cancer (AJCC) are today's standard of care.

Evidence of tumor in regional LNs is a poor prognostic sign associated with a precipitous drop in survival at 15-year follow-up. 77–81 Based on the tumor, node, and metastasis tumor staging system, this finding advances any classification from stage I or II to stage III. Identification of distant metastasis is the worst prognostic sign and is classified as stage IV disease. Although occasional survival for several years has been noted, median survival ranges from 2 to 7 months depending on the number and site of metastases.77–81 Diagnosis of melanoma typically requires excisional biopsy (Fig. 16-13). A 1-mm margin of normal skin is taken if the wound can be closed primarily.73–76 If removal of the entire lesion creates too large a defect, then an incisional biopsy of a representative part is recommended. Biopsy incisions should be made with the expectation that a subsequent wide excision of the biopsy site may be done.

Fig. 16-13.

The diagnosis of melanoma should be made via excisional biopsy. Based on tumor depth, appropriate margins may be planned. Indications for lymph node evaluation continue to advance as our understanding of tumor behavior improves and outcome data become available. LAD = lymphadenopathy.

With diagnosis made, treatment of melanoma may range from simple excision to more complex lymphadenectomy or immunotherapy (see Fig. 16-13). Regardless of tumor depth or extension, surgical excision is the management of choice. Lesions 1 mm or less in thickness can be treated with a 1-cm margin.73–76 For lesions 1 mm to 4 mm thick, a 2-cm margin is recommended. Lesions of greater than 4 mm may be treated with 3-cm margins.73–76 The surrounding tissue should be removed down to the fascia to remove all lymphatic channels. If the deep fascia is not involved by the tumor, removing it does not affect recurrence or survival rates, so the fascia is left intact.73–76 Treatment of regional LNs that do not obviously contain tumor in patients without evidence of metastasis is an area of continued debate. In patients with thin lesions (less than 1 mm), the tumor cells are still localized in the surrounding tissue, and the cure rate is excellent with wide excision of the primary lesion; therefore treatment of regional LNs is not beneficial (Fig. 16-14).73–76 With lesions deeper than 4 mm, it is highly likely that the tumor cells already have spread to the regional LNs and distant sites. Removal of the melanomatous LNs has no effect on survival.73–76 Most of these patients die of metastatic disease before developing problems in regional nodes.

Fig. 16-14.

Melanoma treatment algorithm. The algorithmic approach to melanoma has taken many forms throughout the last several decades. However, as our diagnostic technology, therapeutic approaches, and ability to assess outcome improves, the current algorithm incorporates these advances. ELND = elective lymph node dissection; IFN-a2b = interferon alfa-2b; LAD = lymphadenopathy; LN = lymph node; SLND = sentinel lymph node dissection.

In patients with intermediate-thickness tumors (T2 and T3, 1 to 4.0 mm) and no clinical evidence of nodal or metastatic disease, the use of prophylactic dissection (elective LN dissection on clinically negative nodes) is controversial. To date, no prospective, randomized studies have demonstrated that elective LN dissection improves survival in patients with intermediate-thickness melanomas. However, 25 to 50% of LN specimens contain micrometastases in these cases and recurrence may be decreased with LN dissection.77–81 Sentinel lymphadenectomy for malignant melanoma is gaining acceptance (Fig. 16-15). The sentinel node

may be preoperatively located with the use of a gamma camera, which identifies the radioisotope injected into the primary lesion.77–81 Whereas preoperative identification may provide the surgeon greater reliability in localizing the LN, intraoperative mapping with 1% isosulfan blue dye injection may be equally effective.77–81 Both techniques identify the lymphatic drainage from the primary lesion, and determine the first (sentinel) LN draining the tumor area. 77–81 If micrometastasis is identified in the removed node by frozen-section examination, a complete LN dissection is performed.77–81 This method may be used to identify patients who would benefit from LN dissection, while sparing others an unnecessary operation.

Fig. 16-15.

Intraoperative view of sentinel lymph node identification during distal melanoma excision.

All microscopically or clinically positive LNs should be removed by regional nodal dissection.77–81 When groin LNs are removed, the deep (iliac) nodes must be removed along with the superficial (inguinal) nodes, or disease will recur in that region. For axillary dissections, the nodes medial to the pectoralis minor muscle also must be resected.77–81 For lesions on the face, anterior scalp, and ear, a superficial parotidectomy to remove parotid nodes and a modified neck dissection is recommended.77–81 Once melanoma has spread to a distant site, median survival is 7 to 8 months and the 5-year survival rate is less than 5%.77–81 Solitary lesions in the brain, GI tract, or skin that are symptomatic should be excised when possible. Although cure is extremely rare, the degree of palliation can be high and asymptomatic survival prolonged.77–81 A decision to operate on metastatic lesions must be made after careful deliberation with the patient and the treating oncologist. Locally recurrent, lymphatic-invading, or tumors unamenable to surgical excision present a significant

management challenge. In-transit disease (local disease in lymphatics) develops in 5 to 8% of melanoma patients with a high-risk primary melanoma (>1.5 mm).77–81 Hyperthermic regional perfusion with a chemotherapeutic agent (e.g., melphalan) is presently the treatment of choice. The goal of regional perfusion therapy is to increase the dosage of the chemotherapeutic agent to maximize tumor response while limiting systemic toxic effects.77–81 Melphalan generally is heated to an elevated temperature [up to 41.5°C, (106.7°F)] and perfused for 60 to 90 minutes. Although difficult to perform and associated with complications (neutropenia, amputation, death), it does produce a high response rate (greater than 50%).74,77–79 The introduction of tumor necrosis factor alpha or interferon- with melphalan results in the regression of more than 90% of cutaneous in-transit metastases.75–77 Although initially thought to be ineffective in the treatment of melanoma, the use of radiation therapy, regional and systemic chemotherapy, and immunotherapy are all under investigation. High-dose-per-fraction radiation produces a better response rate than low-dose large-fraction therapy.79–81 As the treatment of choice for patients with symptomatic multiple brain metastases, radiation therapy produced measurable improvement in tumor size, symptomatology, or performance status in 70% of treated patients.79–81 Another promising area of nonsurgical melanoma treatment is the use of immunologic manipulation. Interferon alfa-2b is the only Food and Drug Administration–approved adjuvant treatment for AJCC stages IIB/III melanoma. 80,81 In these patients, both the relapse-free interval and overall survival were improved with use of INF- .80,81 Side effects were common and frequently severe; the majority of the patients required modification of the initial dosage and 24% discontinued treatment.80,81 Immunotherapy also continues to be a field of great promise. Vaccines have been developed with the hope of stimulating the body's own immune system against the tumor. Melanoma cells contain a number of distinctly different cellsurface antigens, and monoclonal antibodies have been raised against these antigens.80,81 These antibodies have been used alone or linked to a radioisotope or cytotoxic agent in an effort to selectively kill tumor cells. All treatments are currently investigational. One defined-antigen vaccine has entered clinical testing; the ganglioside GM2. Gangliosides are carbohydrate antigens found on the surface of melanomas as well as many other tumors.80,81

ADDITIONAL MALIGNANCIES OF THE SKIN Merkel Cell Carcinoma (Primary Neuroendocrine Carcinoma of the Skin) Once thought to be a variant of SCC, Merkel cell carcinomas are actually of neuroepithelial differentiation.82,83 These tumors are associated with a synchronous or metasynchronous SCC 25% of the time. Due to their aggressive nature, wide local resection with 3-cm margins is recommended.82,83 Local recurrence rates are high, and distant metastases occur in one third of patients. Prophylactic regional LN dissection and adjuvant radiation therapy are recommended. Overall, the prognosis is worse than for malignant melanoma.82,83

Kaposi's Sarcoma Kaposi's sarcoma (KS) appears as rubbery bluish nodules that occur primarily on the extremities but may appear anywhere on the skin and viscera. These lesions are usually multifocal rather than metastatic.84–88 Histologically, the lesions are composed of capillaries lined by atypical endothelial cells. Early lesions may resemble hemangiomas, while older lesions contain more spindle cells and resemble sarcomas.84–86

Classically, KS is seen in people of Eastern Europe or sub-Saharan Africa. The lesions are locally aggressive but undergo periods of remission. A different variety of KS has been described for people with AIDS or with immunosuppression from chemotherapy.84–86 For reasons not yet understood, AIDS-related KS occurs primarily in male homosexuals and not in IV drug abusers or hemophiliacs. In this form of the disease, the lesions spread rapidly to the nodes, and the GI and respiratory tract often are involved.84–86 Development of AIDS-related KS is associated with concurrent infection with a herpes-like virus.84–86 Treatment for all types of KS consists of radiation to the lesions. Combination chemotherapy is effective in controlling the disease, although most patients develop an opportunistic infection during or shortly after treatment. Surgical treatment is reserved for lesions that interfere with vital functions, such as bowel obstruction or airway compromise.84–86

Extramammary Paget's Disease This tumor is histologically similar to the mammary type. It is a cutaneous lesion that appears as a pruritic red patch that does not resolve.8 5 Biopsy demonstrates classic Paget's cells. Paget's disease is thought to be a cutaneous extension of an underlying adenocarcinoma, although an associated tumor cannot always be demonstrated.8 5

Angiosarcoma Angiosarcomas may arise spontaneously, mostly on the scalp, face, and neck. They usually appear as a bruise that spontaneously bleeds or enlarges without trauma.87,88 Tumors also may arise in areas of prior radiation therapy or in the setting of chronic lymphedema of the arm, such as after mastectomy (StewartTreves syndrome).87,88 The angiosarcomas that arise in these areas of chronic change occur decades later. The tumors consist of anaplastic endothelial cells surrounding vascular channels. Although total excision of early lesions can provide occasional cure, the prognosis usually is poor, with 5-year survival rates of less than 20%. Chemotherapy and radiation therapy are used for palliation.87,88

Dermatofibrosarcoma Protuberans Dermatofibrosarcoma protuberans (DFSP) accounts for 1 to 2% of all soft-tissue sarcomas, occurs most frequently in persons aged 20 to 50 years, and is more common in males.88,89 The most common presenting location is on the trunk (50 to 60%), although the proximal extremities (20 to 30% of cases), as well as head and neck also are frequently affected (10 to 15%).88,89 DFSP often appears as a pink, nodular lesion that may ulcerate and become infected. Histologically, the lesions contain atypical spindle cells, probably of fibroblast origin, located around a core of collagen tissue. Despite what appears to be complete lesion excision, local recurrence remains frequent and mortality associated with metastasis relatively high.88,89 To date, the minimum resection margin needed to achieve local control remains undefined. Local recurrence rates of up to 50% have been reported after simple excision, and wide local excision with 3-cm margins is linked to a 20% recurrence rate. Most authorities seem to advocate a three-dimensional margin of 2 to 3 cm with resection of skin, subcutaneous tissue, and the underlying investing fascia.88,89 The periosteum and a portion of the bone may also need to be resected to achieve negative deep surgical margins. In addition to achieving wide macroscopic resection, conformation of negative microscopic margins is especially critical. DFSP is considered to be a radiosensitive tumor, and radiotherapy following wide local excision has reached local control rates approximating 95% at 10 years.88,89 Continued study of chemotherapy efficacy on DFSP also has produced optimistic results. Imatinib, a selective inhibitor of platelet-derived growth factor (PDGF) -chain alpha and PDGF receptor beta protein-tyrosine kinase activity, alters the biologic effects of

deregulated PDGF receptor signaling. Clinical trials have shown activity against localized and metastatic DFSP containing the t(17:22) translocation, suggesting that targeting the PDGF receptors may become a new therapeutic option for DFSP. Phase II clinical trials are underway.88,89

Fibrosarcoma Fibrosarcomas are hard, irregular masses found in the subcutaneous fat.88,89 The fibroblasts appear markedly anaplastic with disorganized growth. If they are not excised completely, metastases usually develop. The 5-year survival rate after excision is approximately 60%.88,89

Liposarcoma Liposarcomas arise in the deep muscle planes, and, rarely, from the subcutaneous tissue.88,89 They occur most commonly on the thigh. An enlarging lipoma should be excised and inspected to distinguish it from a liposarcoma. Wide excision is the treatment of choice, with radiation therapy reserved for metastatic disease.88,89

SYNDROMIC SKIN MALIGNANCIES Several genetic syndromes are associated with an increased incidence of skin malignancy. Although many are related to development of a specific lesion, others appear to produce a more generic prevalence for neoplastic formation. Based on their respective genetic defects, syndromes associated with BCC, SCC, and melanoma have all been identified and well described. Diseases linked with BCC include the basal cell nevus (Gorlin's) syndrome and nevus sebaceus of Jadassohn.90–92 Basal cell nevus syndrome is an autosomal dominant disorder characterized by the growth of hundreds of BCCs during young adulthood. Palmar and plantar pits are a common physical finding and represent foci of neoplasms.90–92 Treatment is limited to excision of only aggressive and symptomatic lesions. Nevus sebaceus of Jadassohn is a lesion containing several cutaneous tissue elements that develops during childhood.90–92 This lesion is associated with a variety of neoplasms of the epidermis, but most commonly BCC. Diseases associated with SCC may have a causative role in the development of carcinoma. Skin diseases that cause chronic wounds, such as epidermolysis bullosus and lupus erythematosus, are associated with a high incidence of SCC.90–92 Epidermodysplasia verruciformis is a rare autosomal recessive disease associated with infection with HPV. Large verrucous lesions develop early in life and often progress to invasive SCC in middle age.90–92 Xeroderma pigmentosum is an autosomal recessive disease associated with a defect in cellular repair of DNA damage. The inability of the skin to correct DNA damage from UV radiation leaves these patients prone to cutaneous malignancies. 90–92 SCCs are most frequent, but BCCs, melanomas, and even acute leukemias are seen. Dysplastic nevi are considered precursors to melanoma. Familial dysplastic nevus syndrome is an autosomal dominant disorder.90–92 Patients develop multiple dysplastic nevi, and longitudinal studies have demonstrated an almost 100% incidence of melanoma. Gene mapping of the defects found in familial dysplastic nevus syndrome has identified several candidate "melanoma" genes.90–94 It remains to be determined whether these germline mutations also are found in sporadic cases of melanoma. Much like other familial malignancy syndromes, genetic analysis of the hereditary defect may shed much needed light on the molecular mechanisms that lead to malignant transformation. Much like familial polyposis coli and the association with colon cancer, familial dysplastic nevus syndrome is treated by close surveillance and frequent biopsy of all suspicious lesions. Similarly, the development of colon cancer can be arrested with total proctocolectomy; unfortunately, a similar solution is not possible in patients with familial dysplastic

nevi. 90–94

FUTURE DEVELOPMENTS IN SKIN SURGERY The last decade has seen unprecedented advances in our understanding of the skin and its pathology as well as our ability to protect and replace it. Autologous skin grafts remain the best method to cover skin defects, but donor-site problems and limited availability of autologous skin remain problematic.95–98 Tissue expansion with subcutaneous balloon implants produces new epidermis, and mobilization achieved via expansion remains a highly effective approach to wound coverage.95–98 Still, optimal wound coverage lies in the development of engineered skin replacements. Current research is directed at identifying different materials and cells that can be used to replace both epidermis and dermis. Several dermal replacements based on synthetic materials or cadaveric sources are in clinical use (Fig. 1616). A bovine-collagen and shark-proteoglycan–based dermis (Integra) has been used primarily in burn patients for more than a decade.95–98 This prosthetic dermis, available in ready-to-use form, can cover large surface areas. Vascularization of this dermis takes 2 to 3 weeks, and final epidermal coverage of the wound requires a thin skin graft.95–98 The final result is functionally and aesthetically good, but the high cost has been problematic. Cadaveric dermis, with all of the cellular elements removed, is not antigenic and is not rejected by the recipient patient.95–98 This human dermal matrix is commercially-available (AlloDerm) and functions much like Integra, with similar limitations of engraftment and high cost. Both forms of dermal replacements are more frequently used in delayed reconstruction of burn patients than in the acute setting. 95–98

Fig. 16-16.

Another issue confounding surgeons is the lack of means to quickly provide numerous autologous skin cells for permanent skin replacement. The expansion of epidermis by the growth and maturation of keratinocytes in culture is readily performed.95–98 A small skin biopsy specimen can produce enough autologous epithelium to cover the entire body surface. However, on the body, the cultured epidermis often blisters and sloughs as a consequence of slow restoration of the basement membrane. Improving the durability of these cells may one day negate autologous skin grafting technique or the requirement for cadaveric soft tissues. In addition,

The most recent generation of dermal matrix replacement tissues includes both cadaveric and xenographic materials. AlloDerm (pictured here) may be placed over various deeper tissues to provide a dermal scaffold onto which autologous skin may be grafted.

Another issue confounding surgeons is the lack of means to quickly provide numerous autologous skin cells for permanent skin replacement. The expansion of epidermis by the growth and maturation of keratinocytes in culture is readily performed.95–98 A small skin biopsy specimen can produce enough autologous epithelium to cover the entire body surface. However, on the body, the cultured epidermis often blisters and sloughs as a consequence of slow restoration of the basement membrane. Improving the durability of these cells may one day negate autologous skin grafting technique or the requirement for cadaveric soft tissues. In addition, as more is learned about the protein factors that control wound healing and tissue growth, the replacement for damaged skin will eventually come from complete organogenesis of tissue.95–98 Characterization of these growth factors on a structural and functional level is progressing rapidly. Factors have been isolated that cause specific mesenchymal cells to proliferate, migrate, and organize into structures such as capillaries or even rudimentary organoid tissue.95–98

CONCLUSION Anatomically, the epidermal, basement membrane, and dermal layers of the skin each play a vital role in maintaining dermal/epidermal integrity. Multiple, complex mechanisms within these soft tissues protect us from injury as well as relay external information along a vast neural network. In addition to penetrating trauma, the environment offers a host of potentially injurious elements such as caustic substances, extreme temperatures, prolonged or excessive pressure, and radiation. Infections ranging from simple bacterial to necrotizing, life-threatening disease may also affect the skin and subcutaneous tissues. Perhaps of greatest public concern, a multitude of benign and malignant tumors threaten to disrupt, disfigure, and invade normal skin structure. Although the risks associated with many of these lesions are great, a broad variety of medical and surgical management options currently exist. Although contemporary medicine may not have an optimal answer for each threat the skin may face, continued research, advances in our understanding, and technical improvements in the field promise to enhance our ability to replace and protect the skin well into the future.

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35. Miller M, Haddad AJ: Cervicofacial actinomycosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 83:496, 1998. 36. Nielsen PM, Novak A: Acute cervicofacial actinomycosis. Int J Oral Maxillofac Surg 16:440, 1987. [PMID: 3117916] 37. Brentjens MH, Yeung-Yue KA, Lee PC, et al: Human papillomavirus: A review. Dermatol Clin 20:315, 2002. [PMID: 12120445] 38. Welch JL, Edison KE: Treatment options for the common wart. Mo Med 104:502, 2007. [PMID: 18210913] 39. Davis PA, Corless DJ, Gazzard BG, et al: Increased risk of wound complications and poor wound healing following laparotomy in HIV-seropositive and AIDS patients. Dis Surg 16:60, 1999. [PMID: 9949269] 40. Eriguchi M, Takeda Y, Yoshizaki I, et al: Surgery in patients with HIV infection: Indications and outcome. Biomed Pharmacother 51:474, 1997. [PMID: 9863509] 41. Luck JV Jr.: Orthopaedic surgery on the HIV-positive patient: Complications and outcome. Instr Course Lect 43:543, 1994. [PMID: 9097185] 42. Davis PA, Wastell C: A comparison of biomechanical properties of excised mature scars from HIV patients and non-HIV controls. Am J Surg 180:217, 2000. [PMID: 11084133] 43. Brunsting LA, Goeckerman WH, O'Leary PA: Pyoderma (ecthyma) gangrenosum—clinical and experimental observations in five cases occurring in adults. Arch Dermatol 22:655, 1930. 44. Von Den Driesch P: Pyoderma gangrenosum: A report of 44 cases with follow-up. Br J Dermatol 137:1000, 1997. 45. Wollina U: Clinical management of pyoderma gangrenosum. Am J Clin Dermatol 3:149, 2002. [PMID: 11978136] 46. Patel GK, Finlay AY: Staphylococcal scalded skin syndrome: Diagnosis and management. Am J Clin Dermatol 4:165, 2003. [PMID: 12627992] 47. Atiyeh BS, Dham R, Yassin MF, et al: Treatment of toxic epidermal necrolysis with moisture-retentive ointment: A case report and review of the literature. Dermatol Surg 29:185, 2003. [PMID: 12562352] 48. Mackie RM: Epidermoid cyst, in Champion RH, Burton JL, Burns DA, et al (eds): Rook/Wilkinson/Ebling Textbook of Dermatology, vol. 2, 6th ed. Oxford: Blackwell Science, 1998, p 1666.

49. Szeremeta W, Parikh TD, Widelitz JS: Congenital nasal malformations. Otolaryngol Clin North Am. 40:97, 2007. [PMID: 17346563] 50. Satyaprakash AK, Sheehan DJ, Sangüeza OP: Proliferating trichilemmal tumors: A review of the literature. Dermatol Surg 33:1102, 2007. [PMID: 17760602] 51. Braun RP, Rabinovitz H, Oliviero M, et al: Dermoscopic diagnosis of seborrheic keratosis. Clin Dermatol 20:270, 2002. [PMID: 12074865] 52. Fu W, Cockerell CJ: The actinic (solar) keratosis. Arch Dermatol 139:66, 2003. [PMID: 12533168] 53. Robins P, Gupta AK: The use of topical fluorouracil to treat actinic keratosis. Cutis 70:4, 2002. [PMID: 12353679] 54. Castilla EE, DaGraca-Dutra M, Orioli-Parreiras IM: Epidemiology of congenital pigmented nevi: I. Incidence rates and relative frequencies. Br J Dermatol 104:307, 1981. [PMID: 7213564] 55. Rhodes AR, Melsk JW: Small congenital nevocellular nevi and the risk of cutaneous melanoma. J Pediatr 100:216, 1982. 56. Schaffer JV. Pigmented lesions in children: When to worry. Curr Opin Pediatr 16:430, 2007. 57. Krengel S, Hauschild A, Schäfer T: Melanoma risk in congenital melanocytic naevi: A systematic review. Br J Dermatol 155:1, 2006. [PMID: 16792745] 58. Fishman SJ, Mulliken JB: Hemangiomas and vascular malformations of infancy and childhood. Pediatr Clin North Am 40:1177, 1993. [PMID: 8255621] 59. Sadan N, Wolach B: Treatment of hemangiomas of infants with high doses of prednisone. J Pediatr 128:141, 1996. [PMID: 8551406] 60. Marler JJ, Mulliken JB: Vascular anomalies: Classification, diagnosis, and natural history. Facial Plast Surg Clin North Am 9:495, 2001. [PMID: 17590938] 61. Garzon MC, Huang JT, Enjolras O, et al: Vascular malformations: Part I. J Am Acad Dermatol 56:353, 2007. [PMID: 17317485] 62. Legiehn GM, Heran MK: Classification, diagnosis, and interventional radiologic management of vascular malformations. Orthop Clin North Am 37:435, 2006. [PMID: 16846771] 63. McDermott EM, Weiss AP: Glomus tumors. J Hand Surg [Am] 31:1397, 2006. [PMID: 17027805] 64. Mentzel T: Cutaneous lipomatous neoplasms. Semin Diagn Pathol 18:250, 2001. [PMID: 11757864]

65. Marks R, Kopf AW: Cancer of the skin in the next century. Int J Dermatol 34:445, 1995. [PMID: 7591403] 66. Luce EA: Oncologic considerations in nonmelanotic skin cancer. Clin Plast Surg 22:39, 1995. [PMID: 7743708] 67. Epstein JH: Photocarcinogenesis, skin cancer, and aging. J Am Acad Dermatol 9:487, 1983. [PMID: 6355213] 68. Sober AJ, Burstein JM: Precursors to skin cancer. Cancer 75:645, 1995. [PMID: 7804989] 69. Gallagher RP, Hill GB, Bajdik CD, et al: Sunlight exposure, pigmentation factors, and risk of nonmelanocytic skin cancer: II. Squamous cell carcinoma. Arch Dermatol 131:164, 1995. [PMID: 7857112] 70. Fleming ID, Amonette R, Monaghan T, et al: Principles of management of basal and squamous cell carcinoma of the skin. Cancer 75(Suppl 2):699, 1995. 71. Friedman HI, Cooper PH, Wanebo HJ: Prognostic and therapeutic use of microstaging of cutaneous squamous cell carcinomas of the trunk and extremities. Cancer 56:109, 1985. 72. Mohs FE: Chemosurgery, Microscopically Controlled Surgery for Skin Cancer. Springfield: Charles C Thomas, 1978. 73. Desmond RA, Soong S-J: Epidemiology of malignant melanoma. Surg Clin North Am 83:1, 2003. [PMID: 12691448] 74. Balch CM, Buzaid AC, Soong SJ, et al: Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 16:3635, 2001. 75. Balch CM, Soong SJ, Gershenwald JE, et al: Prognostic factors analysis of 17,600 melanoma patients: Validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 16:3622, 2001. 76. Essner R: Surgical treatment of malignant melanoma. Surg Clin North Am 83:109, 2003. [PMID: 12691453] 77. Leong SPL: Selective lymphadenectomy for malignant melanoma. Surg Clin North Am 83:157, 2003. [PMID: 12691454] 78. Lee ML, Tomsu K, Von Eschen KB: Duration of survival for disseminated malignant melanoma: Results of a meta-analysis. Melanoma Res 10:81, 2000. [PMID: 10711644]

79. Karakousis CP, Velez A, Driscoll DL, et al: Metastasectomy in malignant melanoma. Surgery 115:295, 1994. [PMID: 8128354] 80. Kirkwood JM, Strawderman MH, Ernstoff MS, et al: Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: The Eastern Cooperative Oncology Group trial EST 1684. J Clin Oncol 14:7, 1996. [PMID: 8558223] 81. Kadison AS, Morton DL: Immunotherapy of malignant melanoma. Surg Clin North Am 83:343, 2003. [PMID: 12744613] 82. O'Connor WJ, Brodland DG: Merkel cell carcinoma. Dermatol Surg 22:262, 1996. [PMID: 8599738] 83. Chanda JJ: Extramammary Paget's disease: Prognosis and relationship to internal malignancy. J Am Acad Dermatol 13:1009, 1985. [PMID: 3001158] 84. Noel JC, Hermans P: Herpes virus-like DNA sequence and Kaposi's sarcoma: Relationship with epidemiology, clinical spectrum, and histologic features. Cancer 77:2132, 1996. [PMID: 8640682] 85. Szajerka T, Jablecki JL: Kaposi's sarcoma revisited. AIDS Rev 9:230, 2007. [PMID: 18219366] 86. Angeletti PC, Zhang L, Wood C: The viral etiology of AIDS-associated malignancies. Adv Pharmacol 56:509, 2008. [PMID: 18086422] 87. Skubitz KM, D'Adamo DR: Sarcoma. Mayo Clin Proc 82:1409, 2007. [PMID: 17976362] 88. McArthur G: Dermatofibrosarcoma protuberans: Recent clinical progress. Ann Surg Oncol 14:2876, 2007. [PMID: 17647063] 89. Korkolis DP, Liapakis IE, Vassilopoulos PP: Dermatofibrosarcoma protuberans: Clinicopathological aspects of an unusual cutaneous tumor. Anticancer Res 27:1631, 2007. [PMID: 17595787] 90. Miettinen M: From morphological to molecular diagnosis of soft tissue tumors. Adv Exp Med Biol 587:99, 2006. [PMID: 17163160] 91. Wolf K, Friedl P: Molecular mechanisms of cancer cell invasion and plasticity. Br J Dermatol 154(Suppl 1):11, 2006. 92. Barbagallo JS, Kolodzieh MS, Silverberg NB, et al: Neurocutaneous disorders. Dermatol Clin 20:547, 2002. [PMID: 12170887] 93. Goyal JL, Rao VA, Srinivasan R, et al: Oculocutaneous manifestations in xeroderma pigmentosa. Br J Ophthalmol 78:295, 1994. [PMID: 8199117]

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KEY POINTS 1. The breast receives its principal blood supply from perforating branches of the internal mammary artery, lateral branches of the posterior intercostal arteries, and branches from the axillary artery, including the highest thoracic, lateral thoracic, and pectoral branches of the thoracoacromial artery. 2. The axillary lymph nodes usually receive >75% of the lymph drainage from the breast, and the rest flows through the lymph vessels that accompany the perforating branches of the internal mammary artery and enters the parasternal (internal mammary) group of lymph nodes. 3. Breast development and function are initiated by a variety of hormonal stimuli, with the major trophic effects being modulated by estrogen, progesterone, and prolactin. 4. Benign breast disorders and diseases are related to the normal processes of reproductive life and to involution, and there is a spectrum of breast conditions that ranges from normal to disorder to disease (aberrations of normal development and involution classification). 5. To calculate breast cancer risk using the Gail model, a woman's risk factors are translated into an overall risk score by multiplying her relative risks from several categories. This risk score is then compared with an adjusted population risk of breast cancer to determine the woman's individual risk. This model is not appropriate for use in women with a known BRCA1 or BRCA2 mutation or women with lobular or ductal carcinoma in situ. 6. Routine use of screening mammography in women

50 years of age reduces mortality from breast cancer by

33%. 7. Core-needle biopsy is the preferred method for diagnosis of palpable or nonpalpable breast abnormalities. 8. When a diagnosis of breast cancer is made, the surgeon should determine the clinical stage, histologic characteristics, and appropriate biomarker levels before initiating local therapy. 9. Sentinel node dissection is the preferred method for staging of the regional lymph nodes in women with clinically node-negative invasive breast cancer. 10. Local-regional and systemic therapy decisions for an individual patient with breast cancer are best made using a multidisciplinary treatment approach.

A BRIEF HISTORY OF BREAST CANCER THERAPY Breast cancer, with its uncertain cause, has captured the attention of surgeons throughout the ages. Despite centuries of theoretical meandering and scientific inquiry, breast cancer remains one of the most dreaded of human

diseases.1–12 The story of efforts to cope with breast cancer is complex, and there is no successful conclusion as in diseases for which cause and cure are known. However, progress has been made in lessening the horrors that formerly devastated the body and psyche. Currently, 50% of American women will consult a surgeon regarding breast disease, 25% will undergo breast biopsy, and 12% will develop some variant of breast cancer. The Smith Surgical Papyrus (3000–2500

B .C

.) is the earliest known document to refer to breast cancer. The cancer

was in a man, but the description encompassed most of the common clinical features. In reference to this cancer, the author concluded, "There is no treatment."1 There were few other historical references to breast cancer until the first century. In De Medicina, Celsus commented on the value of operations for early breast cancer: "None of these may be removed but the cacoethes (early cancer), the rest are irritated by every method of cure. The more violent the operations are, the more angry they grow."2 In the second century, Galen inscribed his classical clinical observation: "We have often seen in the breast a tumor exactly resembling the animal the crab. Just as the crab has legs on both sides of his body, so in this disease the veins extending out from the unnatural growth take the shape of a crab's legs. We have often cured this disease in its early stages, but after it has reached a large size, no one has cured it. In all operations we attempt to excise the tumor in a circle where it borders on the healthy tissue."3 The galenic system of medicine ascribed cancers to an excess of black bile and concluded that excision of a local bodily outbreak could not cure the systemic imbalance. Theories espoused by Galen dominated medicine until the Renaissance. The majority of respected surgeons considered operative intervention to be a futile and ill-advised endeavor. However, beginning with Morgagni, surgical resections were more frequently undertaken, including some early attempts at mastectomy and axillary dissection. Le Dran repudiated Galen's humoral theory in the eighteenth century and stated that breast cancer was a local disease that spread by way of lymph vessels to axillary lymph nodes. When operating on a woman with breast cancer, he routinely removed any enlarged axillary lymph nodes.5 In the nineteenth century, Moore, of the Middlesex Hospital, London, emphasized complete resection of the breast for cancer and stated that palpable axillary lymph nodes also should be removed. 1 1 In a presentation before the British Medical Association in 1877, Banks supported Moore's concepts and advocated the resection of axillary lymph nodes even when palpable lymphadenopathy was not evident, recognizing that occult involvement of axillary lymph nodes was frequently present. In 1894, Halsted and Meyer reported their operations for treatment of breast cancer.4 By demonstrating superior local-regional control rates after radical resection, these surgeons established radical mastectomy as state-of-the-art treatment for that era. Both Halsted and Meyer advocated complete dissection of axillary lymph node levels I to III. Both routinely resected the long thoracic nerve and the thoracodorsal neurovascular bundle with the axillary contents. In 1943, Haagensen and Stout described the grave signs of breast cancer, which included (a) edema of the skin of the breast, (b) skin ulceration, (c) chest wall fixation, (d) an axillary lymph node >2.5 cm in diameter, and (e) fixed axillary lymph nodes. Women with two or more signs had a 42% local recurrence rate and only a 2% 5-year disease-free survival rate.6 Based on these findings, they declared that women with grave signs were beyond cure by radical surgery. Approximately 25% of women were excluded from surgery based on these criteria of inoperability. Today, with comprehensive mammography screening, only 10% of women are found to have such advanced breast cancers. In 1948, Patey and Dyson of the Middlesex Hospital, London, advocated a modified radical mastectomy for the management of advanced operable breast cancer, explaining, "Until an effective general agent for treatment of carcinoma of the breast is developed, a high proportion of these cases are doomed to die."1 2 Their technique included removal of the breast and axillary lymph nodes with preservation of the pectoralis major muscle. They showed that removal of the pectoralis minor muscle allowed access to and clearance of axillary

lymph node levels I to III. Subsequently, Madden advocated a modified radical mastectomy that preserved both the pectoralis major and pectoralis minor muscles, even though this approach prevented complete dissection of the apical (level III) axillary lymph nodes.7 In the 1970s, there was a transition from the Halsted radical mastectomy to the modified radical mastectomy as the surgical procedure most frequently used by American surgeons to treat breast cancer. This transition acknowledged that (a) extirpation of the pectoralis major muscle was not essential for local-regional control in stage I and stage II breast cancer, and (b) neither the modified radical mastectomy nor the Halsted radical mastectomy consistently achieved local-regional control of stage III breast cancer. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-04 trial conducted by Fisher and colleagues compared local and regional treatments of breast cancer. Life table estimates were obtained for 1665 women enrolled and followed for a mean of 120 months (Fig. 17-1). This study randomly divided clinically node-negative women into three treatment groups: (a) Halsted radical mastectomy; (b) total mastectomy plus radiation therapy; and (c) total mastectomy alone. Clinically node-positive women were treated with Halsted radical mastectomy or total mastectomy plus radiation therapy. This trial accrued patients between 1971 and 1974, an era that predated widespread availability of effective systemic therapy for breast cancer. Outcomes from this trial therefore reflect survival associated with local-regional therapy only. There were no differences in survival between the three groups of node-negative women or between the two groups of node-positive women (see Fig. 17-1A). Correspondingly, there were no differences in survival during the first and second 5-year follow-up periods (see Fig. 17-1B and 17-1C). These overall survival equivalence patterns have persisted at 25 years of follow-up.1 3

Fig. 17-1.

Results of the National Surgical Adjuvant Breast and Bowel Project B-04 trial. Disease-free survival for women treated by radical mastectomy (orange circles ), total mastectomy plus radiation (x 's), or total mastectomy alone (blue circles ). (Reproduced with permission from Fisher B, et al: Ten-year results of a randomized clinical trial comparing radical mastectomy and total mastectomy with or without radiation. N Engl J Med 312:674, 1985. Copyright Massachusetts Medical Society. All rights reserved.)

Other prospective clinical trials that compared the Halsted radical mastectomy to the modified radical mastectomy were the Manchester trial, reported by Turner and colleagues, and the University of Alabama trial, reported by Maddox and colleagues.8,9 In both studies, the type of surgical procedure did not influence recurrence rates for patients with stage I and stage II breast cancer. The criterion for accrual to the Alabama Breast Cancer Project (1975 to 1978) was a T1 to T3 breast cancer with no apparent distant metastases. Patients received a radical or a modified radical mastectomy. Node-positive patients received adjuvant cyclophosphamide (Cytoxan), methotrexate, and 5-fluorouracil chemotherapy or adjuvant melphalan. After a median follow-up period of 15 years, neither type of surgery nor type of chemotherapy was shown to affect local-regional, disease-free, or overall survival.8 Since the 1970s, considerable progress has been made in the integration of surgery, radiation therapy, and chemotherapy to control local-regional disease, enhance survival, and increase the possibility of breast conservation. Local-regional control is achieved for nearly 80% of women with advanced breast cancers.

EMBRYOLOGY AND FUNCTIONAL ANATOMY OF THE BREAST Embryology At the fifth or sixth week of fetal development, two ventral bands of thickened ectoderm (mammary ridges, milk lines) are evident in the embryo.1 4 In most mammals, paired breasts develop along these ridges, which extend from the base of the forelimb (future axilla) to the region of the hind limb (inguinal area). These ridges are not prominent in the human embryo and disappear after a short time, except for small portions that may persist in the pectoral region. Accessory breasts (polymastia ) or accessory nipples (polythelia ) may occur along the milk line (Fig. 17-2) when normal regression fails. Each breast develops when an ingrowth of ectoderm forms a primary tissue bud in the mesenchyme. The primary bud, in turn, initiates the development of 15 to 20 secondary buds. Epithelial cords develop from the secondary buds and extend into the surrounding mesenchyme. Major (lactiferous) ducts develop, which open into a shallow mammary pit. During infancy, a proliferation of mesenchyme transforms the mammary pit into a nipple. If there is failure of a pit to elevate above skin level, an inverted nipple results. This congenital malformation occurs in 4% of infants. At birth, the breasts are identical in males and females, demonstrating only the presence of major ducts. Enlargement of the breast may be evident and a secretion, referred to as witch's milk, may be produced. These transitory events occur in response to maternal hormones that cross the placenta.

Fig. 17-2.

The mammary milk line. (Reproduced with permission from Bland et al,14 p 214. Copyright Elsevier.)

The breast remains undeveloped in the female until puberty, when it enlarges in response to ovarian estrogen and progesterone, which initiate proliferation of the epithelial and connective tissue elements. However, the breasts remain incompletely developed until pregnancy occurs. Absence of the breast (amastia ) is rare and results from an arrest in mammary ridge development that occurs during the sixth fetal week. Poland's syndrome consists of hypoplasia or complete absence of the breast, costal cartilage and rib defects, hypoplasia of the subcutaneous tissues of the chest wall, and brachysyndactyly. Breast hypoplasia also may be iatrogenically induced before puberty by trauma, infection, or radiation therapy. Symmastia is a rare anomaly recognized as webbing between the breasts across the midline. Accessory nipples (polythelia) occur in 3 cm) are disease. Similarly, multiple fibroadenomas (more than five lesions in one breast) are very uncommon and are considered disease. The precise etiology of adolescent breast hypertrophy is unknown. A spectrum of changes from limited to massive stromal hyperplasia (gigantomastia) is seen. Nipple inversion is a disorder of development of the major ducts, which prevents normal protrusion of the nipple. Mammary duct fistulas arise when nipple inversion predisposes to major duct obstruction, leading to recurrent subareolar abscess and mammary duct fistula.

Fig. 17-12.

Fibroadenoma (x 10). (Courtesy of Dr. R. L. Hackett.)

LATER REPRODUCTIVE YEARS

Cyclical mastalgia and nodularity usually are associated with premenstrual enlargement of the breast and are regarded as normal. Cyclical pronounced mastalgia and severe painful nodularity are viewed differently than are physiologic discomfort and lumpiness. Painful nodularity that persists for >1 week of the menstrual cycle is considered a disorder. In epithelial hyperplasia of pregnancy, papillary projections sometimes give rise to bilateral bloody nipple discharge.

INVOLUTION Involution of lobular epithelium is dependent on the specialized stroma around it. However, an integrated involution of breast stroma and epithelium is not always seen, and disorders of the process are common. When the stroma involutes too quickly, alveoli remain and form microcysts, which are precursors of macrocysts. Macrocysts are common, are often subclinical, and do not require specific treatment. Sclerosing adenosis is considered a disorder of both the proliferative and the involutional phases of the breast cycle. Duct ectasia (dilated ducts) and periductal mastitis are other important components of the ANDI classification. Periductal fibrosis is a sequela of periductal mastitis and may result in nipple retraction. Sixty percent of women

70 years of age exhibit some

degree of epithelial hyperplasia (Fig. 17-13). Atypical proliferative diseases include ductal and lobular hyperplasia, both of which display some features of carcinoma in situ. Women with atypical ductal or lobular hyperplasia have a fourfold increase in breast cancer risk (Table 17-4).

Fig. 17-13.

A. Ductal epithelial hyperplasia. The irregular intracellular spaces and variable cell nuclei distinguish this process from carcinoma in situ. B. Lobular hyperplasia. The presence of alveolar lumina and incomplete distention distinguish this process from carcinoma in situ. (Courtesy of Dr. R. L. Hackett.)

Table 17-4 Cancer Risk Associated with Benign Breast Disorders and In Situ Carcinoma of the Breast Nonproliferative lesions of the breast No increased risk Sclerosing adenosis No increased risk Intraductal papilloma No increased risk Florid hyperplasia 1.5 to 2-fold Atypical lobular hyperplasia 4-fold Atypical ductal hyperplasia 4-fold Ductal involvement by cells of atypical ductal hyperplasia 7-fold Lobular carcinoma in situ 10-fold Ductal carcinoma in situ

10-fold Abnormality

Relative Risk

Source: Modified from Dupont WD, et al: Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med 312:146, 1985.

Pathology of Nonproliferative Disorders Of paramount importance for the optimal management of benign breast disorders and diseases is the histologic differentiation of benign, atypical, and malignant changes.27,28 Determining the clinical significance of these changes is a problem that is compounded by inconsistent nomenclature. The classification system originally developed by Page separates the various types of benign breast disorders and diseases into three clinically relevant groups: nonproliferative disorders, proliferative disorders without atypia, and proliferative disorders with atypia (Table 17-5). Nonproliferative disorders of the breast account for 70% of benign breast conditions and carry no increased risk for the development of breast cancer. This category includes cysts, duct ectasia, periductal mastitis, calcifications, fibroadenomas, and related disorders.

Table 17-5 Classification of Benign Breast Disorders Nonproliferative disorders of the breast Cysts and apocrine metaplasia Duct ectasia Mild ductal epithelial hyperplasia Calcifications Fibroadenoma and related lesions Proliferative breast disorders without atypia Sclerosing adenosis Radial and complex sclerosing lesions Ductal epithelial hyperplasia Intraductal papillomas Atypical proliferative lesions Atypical lobular hyperplasia Atypical ductal hyperplasia

Source: Modified from Consensus Meeting2 9 with permission. Copyright American Medical Association. Breast macrocysts are an involutional disorder, have a high frequency of occurrence, and are often multiple. Duct ectasia is a clinical syndrome characterized by dilated subareolar ducts that are palpable and often associated with thick nipple discharge. Haagensen regarded duct ectasia as a primary event that led to stagnation of secretions, epithelial ulceration, and leakage of duct secretions (containing chemically irritating fatty acids) into periductal tissue. 3 0 This sequence was thought to produce a local inflammatory process with periductal fibrosis and subsequent nipple retraction. An alternative theory considers periductal mastitis to be the primary process, which leads to weakening of the ducts and secondary dilatation. It is possible that both processes occur and together explain the wide spectrum of problems seen, which include nipple discharge, nipple retraction, inflammatory masses, and abscesses. Calcium deposits are frequently encountered in the breast. Most are benign and are caused by cellular secretions

and debris or by trauma and inflammation. Calcifications that are associated with cancer include microcalcifications, which vary in shape and density and are 50% of the areolar circumference Recurrence involving the same segment Recurrence involving a different segment Mild or no nipple inversion Marked nipple inversion Patient unconcerned about nipple inversion Patient requests correction of nipple inversion Younger patient Older patient No discharge from other ducts Purulent discharge from other ducts No prior fistulectomy Recurrence after fistulectomy Suitable for Fistulectomy

Suitable for Total Duct Excision

Source: Modified with permission from Hughes LE: The duct ectasia/periductal mastitis complex, in Hughes LE, et al (eds): Benign Disorders and Diseases of the Breast: Concepts and Clinical Management. London: WB Saunders,

2000, p 162. Copyright Elsevier.

NIPPLE INVERSION More women request correction of congenital nipple inversion than request correction for the nipple inversion that occurs secondary to duct ectasia. Although the results are usually satisfactory, women seeking correction for cosmetic reasons should always be made aware of the surgical complications of altered nipple sensation, nipple necrosis, and postoperative fibrosis with nipple retraction. Because nipple inversion is a result of shortening of the subareolar ducts, a complete division of these ducts is necessary for permanent correction of the disorder.

RISK FACTORS FOR BREAST CANCER Hormonal and Nonhormonal Risk Factors Increased exposure to estrogen is associated with an increased risk for developing breast cancer, whereas reducing exposure is thought to be protective.35–41 Correspondingly, factors that increase the number of menstrual cycles, such as early menarche, nulliparity, and late menopause, are associated with increased risk. Moderate levels of exercise and a longer lactation period, factors that decrease the total number of menstrual cycles, are protective. The terminal differentiation of breast epithelium associated with a full-term pregnancy is also protective, so older age at first live birth is associated with an increased risk of breast cancer. Finally, there is an association between obesity and increased breast cancer risk. Because the major source of estrogen in postmenopausal women is the conversion of androstenedione to estrone by adipose tissue, obesity is associated with a long-term increase in estrogen exposure. Nonhormonal risk factors include radiation exposure. Young women who receive mantle radiation therapy for Hodgkin's lymphoma have a breast cancer risk that is 75 times greater than that of age-matched control subjects. Survivors of the atomic bomb blasts in Japan during World War II have a very high incidence of breast cancer, likely because of somatic mutations induced by the radiation exposure. In both circumstances, radiation exposure during adolescence, a period of active breast development, magnifies the deleterious effect. Studies also suggest that the risk of breast cancer increases as the amount of alcohol a woman consumes increases. Alcohol consumption is known to increase serum levels of estradiol. Finally, evidence suggests that long-term consumption of foods with a high fat content contributes to an increased risk of breast cancer by increasing serum estrogen levels.

Risk Assessment Models The average lifetime risk of breast cancer for newborn U.S. females is 12%.42,43 The longer a woman lives without cancer, the lower her risk of developing breast cancer. Thus, a woman aged 50 years has an 11% lifetime risk of developing breast cancer, and a woman aged 70 years has a 7% lifetime risk of developing breast cancer. Because risk factors for breast cancer interact, evaluating the risk conferred by combinations of risk factors is difficult. Two risk assessment models are currently used to predict the risk of breast cancer. From the Breast Cancer Detection Demonstration Project, a mammography screening program conducted in the 1970s, Gail and colleagues developed the most frequently used model, which incorporates age at menarche, the number of breast biopsies, age at first live birth, and the number of first-degree relatives with breast cancer. It predicts the cumulative risk of breast cancer according to decade of life. To calculate breast cancer risk using the Gail model, a woman's risk factors are translated into an overall risk score by multiplying her relative risks from several categories (Table 17-7). This risk score is then compared to an adjusted population risk of breast cancer to determine a woman's individual risk. A

software program incorporating the Gail model is available from the National Cancer Institute at http://bcra.nci.nih.gov/brc. This model was recently modified to more accurately assess risk in African American women.45,46

Table 17-7 Relative Risk Estimates for the Gail Model Age at menarche (years) 14 1.00 12–13 1.10 95% of the women who die of breast cancer have distant metastases, the most important prognostic correlate of disease-free and overall survival is axillary lymph node status (see Fig. 17-18A). Women with node-negative disease have less than a 30% risk of recurrence, compared with as much as a 75% risk for women with node-positive disease.

DISTANT METASTASES At approximately the twentieth cell doubling, breast cancers acquire their own blood supply (neovascularization). Thereafter, cancer cells may be shed directly into the systemic venous blood to seed the pulmonary circulation via the axillary and intercostal veins or the vertebral column via Batson's plexus of veins, which courses the length of the vertebral column. These cells are scavenged by natural killer lymphocytes and macrophages. Successful implantation of metastatic foci from breast cancer predictably occurs after the primary cancer exceeds 0.5 cm in diameter, which corresponds to the twenty-seventh cell doubling. For 10 years after initial treatment, distant metastases are the most common cause of death in breast cancer patients. For this reason, conclusive results cannot be derived from breast cancer trials until at least 5 to 10 years have elapsed. Although 60% of the women who develop distant metastases will do so within 24 months of treatment, metastases may become evident as late as 20 to 30 years after treatment of the primary cancer. Common sites of involvement, in order of frequency, are bone, lung, pleura, soft tissues, and liver.

HISTOPATHOLOGY OF BREAST CANCER Carcinoma in Situ Cancer cells are in situ or invasive depending on whether or not they invade through the basement membrane.80,81

Broders's original description of in situ breast cancer stressed the absence of invasion of cells into the surrounding stroma and their confinement within natural ductal and alveolar boundaries.8 0 Because areas of invasion may be minute, the accurate diagnosis of in situ cancer necessitates the analysis of multiple microscopic sections to exclude invasion. In 1941, Foote and Stewart published a landmark description of LCIS, which distinguished it from DCIS.8 1 In the late 1960s, Gallagher and Martin published their study of whole-breast sections and described a stepwise progression from benign breast tissue to in situ cancer and subsequently to invasive cancer. They coined the term minimal breast cancer (LCIS, DCIS, and invasive cancers smaller than 0.5 cm in size) and stressed the importance of early detection.8 5 It is now recognized that each type of minimal breast cancer has a distinct clinical and biologic behavior. Before the widespread use of mammography, diagnosis of breast cancer was by physical examination. At that time, in situ cancers constituted 2:1. However, when screening mammography became popular, a 14-fold increase in the incidence of in situ cancer (45%) was demonstrated, and DCIS was more frequently diagnosed than LCIS by a ratio of >2:1. Table 17-9 lists the clinical and pathologic characteristics of DCIS and LCIS. Multicentricity refers to the occurrence of a second breast cancer outside the breast quadrant of the primary cancer (or at least 4 cm away), whereas multifocality refers to the occurrence of a second cancer within the same breast quadrant as the primary cancer (or within 4 cm of it). Multicentricity occurs in 60 to 90% of women with LCIS, whereas the rate of multicentricity for DCIS is 40 to 80%. LCIS occurs bilaterally in 50 to 70% of cases, whereas DCIS occurs bilaterally in 10 to 20% of cases.

Table 17-9 Salient Characteristics of In Situ Ductal (DCIS) and Lobular (LCIS) Carcinoma of the Breast Age (years) 44–47 54–58 Incidencea 2–5% 5–10% Clinical signs None Mass, pain, nipple discharge Mammographic signs None Microcalcifications Premenopausal 2/3 1/3 Incidence of synchronous invasive carcinoma 5% 2–46% Multicentricity 60–90% 40–80% Bilaterality 50–70% 10–20%

Axillary metastasis 1% 1–2% Subsequent carcinomas: Incidence 25–35% 25–70% Laterality Bilateral Ipsilateral Interval to diagnosis 15–20 y 5–10 y Histologic type Ductal Ductal LCIS

a

DCIS

In biopsy specimens of mammographically detected breast lesions.

Source: Reproduced with permission from Frykberg ER, et al: Current concepts on the biology and management of in situ (Tis, stage 0) breast carcinoma, in Bland KI, et al (eds): The Breast: Comprehensive Management of Benign and Malignant Diseases. Philadelphia: WB Saunders, 1998, p 1020. Copyright Elsevier.

LOBULAR CARCINOMA IN SITU LCIS originates from the terminal duct lobular units and develops only in the female breast. It is characterized by distention and distortion of the terminal duct lobular units by cancer cells, which are large but maintain a normal nuclear:cytoplasmic ratio. Cytoplasmic mucoid globules are a distinctive cellular feature. LCIS may be observed in breast tissues that contain microcalcifications, but the calcifications associated with LCIS typically occur in adjacent tissues. This neighborhood calcification is a feature that is unique to LCIS and contributes to its diagnosis. The frequency of LCIS in the general population cannot be reliably determined because it usually presents as an incidental finding. The average age at diagnosis is 44 to 47 years, which is approximately 15 to 25 years younger than the age at diagnosis for invasive breast cancer. LCIS has a distinct racial predilection, occurring 12 times more frequently in white women than in African American women. Invasive breast cancer develops in 25 to 35% of women with LCIS. Invasive cancer may develop in either breast, regardless of which breast harbored the initial focus of LCIS, and is detected synchronously with LCIS in 5% of cases. In women with a history of LCIS, up to 65% of subsequent invasive cancers are ductal, not lobular, in origin. For these reasons, LCIS is regarded as a marker of increased risk for invasive breast cancer rather than as an anatomic precursor.

DUCTAL CARCINOMA IN SITU Although DCIS is predominantly seen in the female breast, it accounts for 5% of male breast cancers. Published series suggest a detection frequency of 7% in all biopsy tissue specimens. The term intraductal carcinoma is frequently applied to DCIS, which carries a high risk for progression to an invasive cancer. Histologically, DCIS is characterized by a proliferation of the epithelium that lines the minor ducts, resulting in papillary growths within the duct lumina. Early in their development, the cancer cells do not show pleomorphism, mitoses, or atypia, which

leads to difficulty in distinguishing early DCIS from benign hyperplasia. The papillary growths (papillary growth pattern) eventually coalesce and fill the duct lumina so that only scattered, rounded spaces remain between the clumps of atypical cancer cells, which show hyperchromasia and loss of polarity (cribriform growth pattern). Eventually pleomorphic cancer cells with frequent mitotic figures obliterate the lumina and distend the ducts (solid growth pattern). With continued growth, these cells outstrip their blood supply and become necrotic (comedo growth pattern). Calcium deposition occurs in the areas of necrosis and is a common feature seen on mammography. DCIS is now frequently classified based on nuclear grade and the presence of necrosis (Table 1710). Based on multiple consensus meetings, grading of DCIS has been recommended. Although there is no universal agreement on classification, most systems endorse the use of cytologic grade and presence or absence of necrosis. 8 2

Table 17-10 Classification of Breast Ductal Carcinoma In Situ (DCIS) Comedo High Extensive High Intermediatea Intermediate Focal or absent Intermediate Noncomedob Low Absent Low Histologic Subtype

Determining Characteristics Nuclear Grade

a Often b

Necrosis

DCIS Grade

a mixture of noncomedo patterns.

Solid, cribriform, papillary, or focal micropapillary.

Source: Adapted with permission from Connolly JL, et al: Ductal carcinoma in situ of the breast: Histologic subtyping and clinical significance. PPO Updates 10:1, 1996. The risk for invasive breast cancer is increased nearly fivefold in women with DCIS. 8 3 The invasive cancers are observed in the ipsilateral breast, usually in the same quadrant as the DCIS that was originally detected, which suggests that DCIS is an anatomic precursor of invasive ductal carcinoma (Fig. 17-19).

Fig. 17-19.

Ductal carcinoma in situ (DCIS). Craniocaudal (A ) and mediolateral oblique (B ) mammographic views show a poorly defined 1.2-cm mass (arrow ) containing microcalcifications. Histopathologic preparation of the surgical specimen (C ) confirms DCIS with areas of invasion (hematoxylin and eosin stain, x 32).

Invasive Breast Carcinoma Invasive breast cancers have been described as lobular or ductal in origin.84–87 Early classifications used the term lobular to describe invasive cancers that were associated with LCIS, whereas all other invasive cancers were referred to as ductal. Current histologic classifications recognize special types of breast cancers (10% of total cases), which are defined by specific histologic features. To qualify as a special-type cancer, at least 90% of the cancer must contain the defining histologic features. Eighty percent of invasive breast cancers are described as invasive ductal carcinoma of no special type (NST). These cancers generally have a worse prognosis than specialtype cancers. Foote and Stewart originally proposed the following classification for invasive breast cancer8 1 :

1. Paget's disease of the nipple 2. Invasive ductal carcinoma

3. Adenocarcinoma with productive fibrosis (scirrhous, simplex, NST), 80% 4. Medullary carcinoma, 4% 5. Mucinous (colloid) carcinoma, 2% 6. Papillary carcinoma, 2% 7. Tubular carcinoma, 2% 8. Invasive lobular carcinoma, 10% 9. Rare cancers (adenoid cystic, squamous cell, apocrine) Paget's disease of the nipple was described in 1874. It frequently presents as a chronic, eczematous eruption of the nipple, which may be subtle but may progress to an ulcerated, weeping lesion. Paget's disease usually is associated with extensive DCIS and may be associated with an invasive cancer. A palpable mass may or may not be present. A nipple biopsy specimen will show a population of cells that are identical to the underlying DCIS cells (pagetoid features or pagetoid change). Pathognomonic of this cancer is the presence of large, pale, vacuolated cells (Paget cells) in the rete pegs of the epithelium. Paget's disease may be confused with superficial spreading melanoma. Differentiation from pagetoid intraepithelial melanoma is based on the presence of S-100 antigen immunostaining in melanoma and carcinoembryonic antigen immunostaining in Paget's disease. Surgical therapy for Paget's disease may involve lumpectomy, mastectomy, or modified radical mastectomy, depending on the extent of involvement and the presence of invasive cancer. Invasive ductal carcinoma of the breast with productive fibrosis (scirrhous, simplex, NST) accounts for 80% of breast cancers and presents with macroscopic or microscopic axillary lymph node metastases in up to 60% of cases. This cancer usually occurs in perimenopausal or postmenopausal women in the fifth to sixth decades of life as a solitary, firm mass. It has poorly defined margins and its cut surfaces show a central stellate configuration with chalky white or yellow streaks extending into surrounding breast tissues. The cancer cells often are arranged in small clusters, and there is a broad spectrum of histologic types with variable cellular and nuclear grades (Fig. 17-20).

Fig. 17-20.

Invasive ductal carcinoma with productive fibrosis (scirrhous, simplex, no special type) (x 62.5). (Courtesy of Dr. R. L. Hackett.)

Medullary carcinoma is a special-type breast cancer; it accounts for 4% of all invasive breast cancers and is a frequent phenotype of BRCA1 hereditary breast cancer. Grossly, the cancer is soft and hemorrhagic. A rapid increase in size may occur secondary to necrosis and hemorrhage. On physical examination, it is bulky and often positioned deep within the breast. Bilaterality is reported in 20% of cases. Medullary carcinoma is characterized microscopically by (a) a dense lymphoreticular infiltrate composed predominantly of lymphocytes and plasma cells; (b) large pleomorphic nuclei that are poorly differentiated and show active mitosis; and (c) a sheet-like growth pattern with minimal or absent ductal or alveolar differentiation (Fig. 17-21). Approximately 50% of these cancers are associated with DCIS, which characteristically is present at the periphery of the cancer, and 0.1 cm but not >0.5 cm in greatest dimension T1b Tumor >0.5 cm but not >1 cm in greatest dimension T1c Tumor >1 cm but not >2 cm in greatest dimension T2 Tumor >2 cm but not >5 cm in greatest dimension T3 Tumor >5 cm in greatest dimension T4 Tumor of any size with direct extension to (a) chest wall or (b) skin, only as described below T4a Extension to chest wall, not including pectoralis muscle T4b Edema (including peau d'orange), or ulceration of the skin of the breast, or satellite skin nodules confined to the same breast T4c Both T4a and T4b T4d

Inflammatory carcinoma Regional lymph nodes—Clinical (N) NX Regional lymph nodes cannot be assessed (e.g., previously removed) N0 No regional lymph node metastasis N1 Metastasis to movable ipsilateral axillary lymph node(s) N2 Metastases in ipsilateral axillary lymph nodes fixed or matted, or in clinically apparent a ipsilateral internal mammary nodes in the absence of clinically evident axillary lymph node metastasis N2a Metastasis in ipsilateral axillary lymph nodes fixed to one another (matted) or to other structures N3 Metastasis only in clinically apparenta ipsilateral internal mammary nodes and in the absence of clinically evident axillary lymph node metastasis; metastasis in ipsilateral infraclavicular lymph node(s) with or without axillary lymph node involvement, or in clinically apparenta ipsilateral internal mammary lymph node(s) and in the presence of clinically evident axillary lymph node metastasis; or metastasis in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph node involvement N3a Metastasis in ipsilateral infraclavicular lymph node(s) N3b Metastasis in ipsilateral internal mammary lymph nodes(s) and axillary lymph node(s) N3c Metastasis in ipsilateral supraclavicular lymph node(s) Regional lymph nodes—Pathologic (pN) pNX Regional lymph nodes cannot be assessed (e.g., previously removed, or not removed for pathologic study) pN0b No regional lymph node metastasis histologically, no additional examination for isolated tumor cells [NOTE: Isolated tumor cells (ITC) are defined as single tumor cells or small cell clusters not >0.2 mm, which are usually detected only by immunohistochemical (IHC) or molecular methods but which may be verified on hematoxylin and eosin stains; ITCs do not usually show evidence of malignant activity (e.g., proliferation or stromal reaction)] pN0(i–) No regional lymph node metastasis histologically, negative IHC results pN0(i+) No regional lymph node metastasis histologically, positive IHC results, no IHC cluster >0.2 mm pN0(mol–) No regional lymph node metastasis histologically, negative molecular findings [reverse-transcriptase polymerase chain reaction (RT-PCR)] pN0(mol+) No regional lymph node metastasis histologically, positive molecular findings (RT-PCR) pN1 Metastasis in 1 to 3 axillary lymph nodes, and/or in internal mammary nodes with microscopic disease detected by sentinel lymph nodes dissection, not clinically apparentc

pN1mi Micrometastasis (>0.2 mm, none >2.0 mm) pN1a Metastasis in 1 to 3 axillary lymph nodes pN1b Metastasis in internal mammary nodes with microscopic disease detected by sentinel lymph node dissection, not clinically apparentc pN1c Metastasis in 1 to 3 axillary lymph nodes and in internal mammary lymph nodes with microscopic disease detected by sentinel lymph node dissection but not clinically apparentc (if associated with >3 positive axillary lymph nodes, the internal mammary nodes are classified as pN3b to reflect increased tumor burden) pN2 Metastasis in 4 to 9 axillary lymph nodes, or in clinically apparenta internal mammary lymph nodes in the absence of axillary lymph node metastasis pN2a Metastasis in 4 to 9 axillary lymph nodes (at least one tumor deposit >2.0 mm) pN2b Metastasis in clinically apparent a internal mammary lymph nodes in the absence of axillary lymph node metastasis pN3 Metastasis in 10 axillary lymph nodes, or in infraclavicular lymph nodes, or in clinically apparent a ipsilateral internal mammary lymph nodes in the presence of 1 or more positive axillary lymph nodes; or in >3 axillary lymph nodes with clinically negative microscopic metastasis in internal mammary lymph nodes; or in ipsilateral supraclavicular lymph nodes pN3a Metastasis in 10 axillary lymph nodes (at lease one tumor deposit >2.0 mm), or metastasis to the infraclavicular lymph nodes pN3b Metastasis in clinically apparent a ipsilateral internal mammary lymph nodes in the presence of 1 positive axillary lymph nodes; or in >3 axillary lymph nodes and in internal mammary lymph nodes with microscopic disease detected by sentinel lymph node dissection, not clinically apparent c pN3c Metastasis in ipsilateral supraclavicular lymph nodes Distant metastasis (M) MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis

a Clinically

apparent is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination or grossly visible pathologically. b

Classification is based on axillary lymph node dissection with or without sentinel lymph node dissection. Classification based solely on sentinel lymph node dissection without subsequent axillary lymph node dissection is designated (sn) for "sentinel node" e.g., pN–(l+) (sn). c

Not clinically apparent is defined as not detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination. Source: Reprinted with permission from American Joint Committee on Cancer: AJCC Cancer Staging Manual , 6th ed. New York: Springer, 2002, p 227–228. Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source of the material is the AJCC Cancer Staging Manual, Sixth Edition (2002) published by Springer Science and Business Media LLC, www.springerlink.com.

Table 17-12 TNM Stage Groupings Stage 0 Tis N0 M0 Stage I T1a N0 M0 Stage IIA T0 N1 M0 T1 a N1 M0 T2 N0 M0 Stage IIB T2 N1 M0 T3 N0 M0 Stage IIIA T0 N2 M0

T1a N2 M0 T2 N2 M0 T3 N1 M0 T3 N2 M0 Stage IIIB T4 N0 M0 T4 N1 M0 T4 N2 M0 Stage IIIC Any T N3 M0 Stage IV Any T Any N M1

a T1

includes T1mic.

Source: Reprinted with permission from American Joint Committee on Cancer: AJCC Cancer Staging Manual , 6th ed. New York: Springer, 2002, pp 228. Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source of the material is the AJCC Cancer Staging Manual, Sixth Edition (2002) published by Springer Science and Business Media LLC, www.springerlink.com.

Biomarkers Breast cancer biomarkers are of several types. Risk factor biomarkers are those associated with increased cancer risk.101–105 These include familial clustering and inherited germline abnormalities, proliferative breast disease with

atypia, and mammographic densities. Exposure biomarkers are a subset of risk factors that include measures of carcinogen exposure such as DNA adducts. Surrogate endpoint biomarkers are biologic alterations in tissue that occur between cancer initiation and development. These biomarkers are used as endpoints in short-term chemoprevention trials and include histologic changes, indices of proliferation, and genetic alterations leading to cancer. Prognostic biomarkers provide information regarding cancer outcome irrespective of therapy, whereas predictive biomarkers provide information regarding response to therapy. Candidate prognostic and predictive biomarkers and biologic targets for breast cancer include (a) indices of proliferation such as proliferating cell nuclear antigen (PCNA) and Ki-67; (b) indices of apoptosis and apoptosis modulators such as bcl-2 and the bax:bcl-2 ratio; (c) indices of angiogenesis such as vascular endothelial growth factor (VEGF) and the angiogenesis index; (d) growth factors and growth factor receptors such as human epidermal growth factor receptor 2 (HER2)/neu , epidermal growth factor receptor (EGFr), transforming growth factor, platelet-derived growth factor, and the insulin-like growth factor family; (e) the steroid hormone receptor pathway; (f) the cell cycle, cyclins, and cyclin-dependent kinases; (g) the proteasome; (h) the COX-2 enzyme; (i) the peroxisome proliferator-activated receptors (PPARs); (j) tumor-suppressor genes such as p53; and (k) the mammalian target of rapamycin (mTOR) signaling pathway.

INDICES OF PROLIFERATION PCNA is a nuclear protein associated with a DNA polymerase whose expression increases in phase G 1 of the cell cycle, reaches its maximum at the G1 /S interface, and then decreases through G2 . 106–109 Immunohistochemical staining for PCNA outlines the proliferating compartments in breast tissue. Good correlation is noted between PCNA expression and (a) cell-cycle distributions seen on flow cytometry based on DNA content, and (b) uptake of bromodeoxyuridine and the proliferation-associated Ki-67 antigen. Individual proliferation markers are associated with slightly different phases of the cell cycle and are not equivalent. PCNA and Ki-67 expression are positively correlated with p53 overexpression, high S-phase fraction, aneuploidy, high mitotic index, and high histologic grade in human breast cancer specimens, and are negatively correlated with estrogen receptor content.

INDICES OF APOPTOSIS Alterations in programmed cell death (apoptosis), which may be triggered by p53-dependent or p53-independent factors, may be important prognostic and predictive biomarkers in breast cancer.110–112 Bcl-2 family proteins appear to regulate a step in the evolutionarily conserved pathway for apoptosis, with some members functioning as inhibitors of apoptosis and others as promoters of apoptosis. BCL2 is the only oncogene that acts by inhibiting apoptosis rather than by directly increasing cellular proliferation. The death-signal protein bax is induced by genotoxic stress and growth factor deprivation in the presence of wild-type (normal) p53 and/or AP-1/fos. The bax:bcl-2 ratio and the resulting formation of either bax-bax homodimers, which stimulate apoptosis, or bax–bcl-2 heterodimers, which inhibit apoptosis, represent an intracellular regulatory mechanism with prognostic and predictive implications. In breast cancer, overexpression of bcl-2 and a decrease in the bax:bcl-2 ratio correlate with high histologic grade, the presence of axillary lymph node metastases, and reduced disease-free and overall survival rates. Similarly, decreased bax expression correlates with axillary lymph node metastases, a poor response to chemotherapy, and decreased overall survival.

INDICES OF ANGIOGENESIS Angiogenesis is necessary for the growth and invasiveness of breast cancer and promotes cancer progression through several different mechanisms, including delivery of oxygen and nutrients and the secretion of growthpromoting cytokines by endothelial cells.113,114 VEGF induces its effect by binding to transmembrane tyrosine

kinase receptors. Overexpression of VEGF in invasive breast cancer is correlated with increased microvessel density and recurrence in node-negative breast cancer. An angiogenesis index has been developed in which microvessel density (CD31 expression) is combined with expression of thrombospondin (a negative modulator of angiogenesis) and p53 expression. Both VEGF expression and the angiogenesis index may have prognostic and predictive significance in breast cancer. Antiangiogenesis breast cancer therapy is now being studied in human trials. The use of bevacizumab (a monoclonal antibody to VEGF) was recently approved by the U.S. Food and Drug Administration (FDA) for use in metastatic breast cancer in combination with paclitaxel chemotherapy. This approval was based on results from a phase III trial by the Eastern Cooperative Oncology Group. The group's E2100 trial showed that when bevacizumab was added to paclitaxel chemotherapy, median progression-free survival increased to 11.3 months from the 5.8 months seen in patients who received paclitaxel alone.115

GROWTH FACTOR RECEPTORS AND GROWTH FACTORS Overexpression of EGFr in breast cancer correlates with estrogen receptor–negative status and with p53 overexpression.116–118 Similarly, increased immunohistochemical membrane staining for the HER-2/neu growth factor receptor in breast cancer is associated with mutated p53 Ki-67 overexpression and estrogen receptor–negative status. HER-2/neu is a member of the EGFr family of growth factor receptors in which ligand binding results in receptor homodimerization and tyrosine phosphorylation by tyrosine kinase domains within the receptor. Tyrosine phosphorylation is followed by signal transduction, which results in changes in cell behavior. An important property of this family of receptors is that ligand binding to one receptor type also may result in heterodimerization between two different receptor types that are coexpressed; this leads to transphosphorylation and transactivation of both receptors in the complex (transmodulation). In this context, the lack of a specific ligand for the HER-2/neu receptor suggests that HER-2/neu may function solely as a coreceptor, modulating signaling by other EGFr family members. HER-2/neu is both an important prognostic factor and a predictive factor in breast cancer.119 When overexpressed in breast cancer, HER-2/neu promotes enhanced growth and proliferation, and increases invasive and metastatic capabilities. Clinical studies have shown that patients with HER-2/neu –overexpressing breast cancer have poorly differentiated tumors with high proliferation rates, positive lymph nodes, decreased hormone receptor expression, and an increased risk of recurrence and death due to breast cancer.119–123 Routine testing of the primary tumor specimen for HER-2/neu expression should be performed on all invasive breast cancers. This can be done with immunohistochemical analysis to evaluate for overexpression of the cell-surface receptor at the protein level or by using fluorescent in situ hybridization to evaluate for gene amplification. Patients whose tumors overexpress HER-2/neu are candidates for anti–HER-2/neu therapy. Trastuzumab (Herceptin) is a recombinant humanized monoclonal antibody directed against HER-2/neu . Randomized clinical trials have demonstrated that single-agent trastuzumab therapy is an active and well-tolerated option for first-line treatment of women with HER-2/neu –overexpressing metastatic breast cancer. More recently, adjuvant trials demonstrated that trastuzumab also was highly effective in the treatment of women with earlystage breast cancer when used in combination with chemotherapy. Patients who received trastuzumab in combination with chemotherapy had a 52% reduction in the risk of breast cancer recurrence compared with those who received chemotherapy alone.124

STEROID HORMONE RECEPTOR PATHWAY Hormones play an important role in the development and progression of breast cancer. Estrogens, estrogen metabolites, and other steroid hormones such as progesterone all have been shown to have an effect. Breast cancer risk is related to estrogen exposure over time. In postmenopausal women, hormone replacement therapy consisting of estrogen plus progesterone increases the risk of breast cancer by 26% compared to placebo. 125

Patients with hormone receptor–positive tumors survive two to three times longer after a diagnosis of metastatic disease than do patients with hormone receptor–negative tumors. Patients with tumors negative for both estrogen receptors and progesterone receptors are not considered candidates for hormonal therapy. Tumors positive for estrogen or progesterone receptors have a higher response rate to endocrine therapy than tumors that do not express estrogen or progesterone receptors. Tumors positive for both receptors have a response rate of >50%, tumors negative for both receptors have a response rate of 33% of the skin over the breast. Erythema is usually confined to the lesion, and edema is less extensive. Lymph node involvement is present in >75% of cases. Lymph nodes are involved in approximately 50% of the cases. Distant metastases are present in 25% of cases. Distant metastases are less common at presentation. Distant metastases are more common at initial presentation. Inflammatory

Noninflammatory

Source: Modified with permission from Chittoor SR, et al: Locally advanced breast cancer: Role of medical oncology, in Bland KI, et al (eds): The Breast: Comprehensive Management of Benign and Malignant Diseases. Philadelphia: WB Saunders, 1998, p 1281. Copyright Elsevier. Surgery alone and surgery with adjuvant radiation therapy have produced disappointing results in women with inflammatory breast cancer. However, neoadjuvant chemotherapy with a doxorubicin-containing regimen may effect dramatic regressions in up to 75% of cases. In this setting, modified radical mastectomy is performed to remove residual cancer from the chest wall and axilla. Adjuvant chemotherapy may be indicated depending on final pathologic assessment of the breast and regional nodes. Finally, the chest wall and the supraclavicular, internal mammary, and axillary lymph node basins receive adjuvant radiation therapy. This multimodal approach results in 5-year survival rates that approach 30%.

Rare Breast Cancers SQUAMOUS CELL (EPIDERMOID) CARCINOMA Squamous cell (epidermoid) carcinoma is a rare cancer that arises from metaplasia within the duct system and generally is devoid of distinctive clinical or radiographic characteristics.213 Regional metastases occur in 25% of patients, whereas distant metastases are rare.

ADENOID CYSTIC CARCINOMA Adenoid cystic carcinoma is very rare, accounting for Chapter 18. Disorders of the Head and Neck>

KEY POINTS 1. Disorders of the head and neck can cause significant cosmetic and functional impairment. The practitioner must be empathetic to the effect of these morbidities on quality of life. 2. Infectious conditions of the head and neck may present with life-threatening sequelae such as loss of airway or intracranial extension. 3. Patients with obstructive sleep apnea require evaluation to determine the specific anatomic site(s) of involvement. Long-term cardiovascular problems are a significant concern in these patients. 4. Repair of traumatic soft-tissue injuries requires precise realignment of anatomic landmarks such as the gray line and vermilion border. 5. The key principle in the surgical repair of facial fractures is immobilization, which may require plates, screws, wires, and/or intermaxillary fixation. 6. Concurrent abuse of tobacco and alcohol are synergistic in increasing the risk of developing head and neck cancer. 7. Hoarseness, a nonhealing oral ulcer, or cervical lymphadenopathy of greater than 2 weeks duration requires evaluation. 8. Monomodality therapy (surgery or radiation) is used for early stage (I/II) head and neck cancer, whereas combination surgery and chemoradiation is used with advanced stage (III/IV) malignancies. 9. The most significant recent advance in the treatment of head and neck cancer is the use of epidermal growth factor receptor inhibitor-based chemotherapy.

A COMPLEX REGION The head and neck constitute a complex anatomic region where different pathologies may affect an individual's ability to see, smell, hear, speak, obtain nutrition and hydration, or breathe. The use of a multidisciplinary approach to many of the disorders in this region is essential in an attempt to achieve the best functional results with care. This chapter reviews many of the common diagnoses encountered in the field of otolaryngology-head and neck surgery and aims to provide an overview that clinicians can use as a foundation for understanding of this region. As is the case with every field of surgery, care for patients with disorders of the head and neck is constantly changing as issues of quality of life and the economics of medicine continue to evolve.

BENIGN CONDITIONS OF THE HEAD AND NECK Ear Infections Infections may involve the external, middle, and/or internal ear. In each of these scenarios, the infection may follow an acute or chronic course and may be associated with both otologic and intracranial complications. Otitis externa typically refers to infection of the skin of the external auditory canal (EAC). 1 Acute otitis externa is commonly known as swimmer's ear , because moisture that persists within the canal after swimming often initiates the process and leads to skin maceration and itching. Typically, the patient subsequently traumatizes the canal skin by scratching (i.e., with a cotton swab or fingernail), thus eroding the normally protective skin/cerumen barrier. Because the environment within the external ear canal is already dark, warm, and humid, it then becomes susceptible to rapid microbial proliferation and tissue cellulitis. The most common organism responsible is Pseudomonas aeruginosa , although other bacteria and fungi may also be implicated. Table 18-1 summarizes the microbiology of common otolaryngologic conditions. Symptoms and signs of otitis externa include itching during the initial phases and pain with swelling of the canal soft tissues as the infection progresses. Infected, desquamated debris accumulates within the canal. In the chronic inflammatory stage of the infection, the pain subsides, but profound itching occurs for prolonged periods with gradual thickening of the external canal skin. Standard treatment requires removal of debris under otomicroscopy and application of appropriate topical antimicrobials such as neomycin/polymyxin or quinolone-containing eardrops, which often include topical steroid such as hydrocortisone or dexamethasone to nonspecifically decrease pain and swelling. Recent studies have demonstrated superiority of quinolone-containing preparations in achieving faster clinical resolution.1 Nonantibiotic antimicrobial preparations, such as 2% acetic acid, may also have a role, particularly for mixed bacterial/fungal infections. The patient should also be instructed to keep the ear dry. Systemic antibiotics are reserved for those with severe infections, diabetics, and immunosuppressed patients.

Table 18-1 Microbiology of Common Otolaryngologic Infections Otitis externa and malignant otitis externa Pseudomonas aeruginosa , fungi (Aspergillus most common) Acute otitis media Streptococcus pneumoniae , Haemophilus influenzae , Moraxella catarrhalis Chronic otitis media Above bacteria, staphylococci, other streptococci; may be polymicrobial; exact role of bacteria unclear Acute sinusitis Viral upper respiratory infection, S. pneumoniae , H. influenzae , M. catarrhalis Chronic sinusitis Above bacteria, staphylococci, other streptococci; may be polymicrobial; exact role of bacteria unclear; may represent immune response to fungi Pharyngitis Viral, streptococci (usually pyogenes) Condition

Microbiology

Diabetic, elderly, and immunodeficient patients are susceptible to a condition called malignant otitis externa , a fulminant necrotizing infection of the otologic soft tissues combined with osteomyelitis of the temporal bone. In addition to the above findings, cranial neuropathies may be observed. The classic physical finding is granulation tissue along the floor of the EAC. Symptoms include persistent otalgia for longer than 1 month and purulent

otorrhea for several weeks. These patients require aggressive medical therapy, including IV antibiotics covering Pseudomonas . 2 Other gram-negative bacteria and fungi are occasionally implicated, necessitating culture-directed therapy in those cases. Patients who do not respond to medical management require surgical dbridement. This condition may progress to involvement of the adjacent skull base and soft tissues, meningitis, brain abscess, and death. In its acute phase, otitis media typically implies a bacterial infection of the middle ear. This diagnosis accounts for 25% of pediatric antibiotic prescriptions and is the most common bacterial infection of childhood. Most cases occur before 2 years of age and are secondary to immaturity of the eustachian tube. Contributing factors include upper respiratory viral infection and day-care attendance, as well as craniofacial conditions affecting eustachian tube function, such as cleft palate. It is also possible that social factors such as day-care attendance and the overprescription of antibiotics has led to antibiotic resistance. Classification of the infection as acute is based upon the duration of the process being less than 3 weeks. In this phase, otalgia and fever are the most common symptoms and physical exam reveals a bulging, opaque tympanic membrane (Fig. 18-1). The most common organisms responsible are Streptococcus pneumoniae , Haemophilus influenzae , and Moraxella catarrhalis . If the process lasts 3 to 8 weeks, it is deemed subacute. Chronic otitis media, lasting more than 8 weeks, usually results from an unresolved acute otitis media. Twenty percent of patients demonstrate a persistent middle ear effusion 8 weeks after resolution of the acute phase. Rather than a purely infectious process, however, it represents chronic inflammation and hypersecretion by the middle ear mucosa associated with eustachian tube dysfunction, viruses, allergy, ciliary dysfunction, and other factors. The bacteriology is variable, but often includes those found in acute otitis media and may be polymicrobial. The exact role of bacteria in the pathophysiology is controversial. The patient experiences otalgia, ear fullness, and conductive hearing loss. Physical examination reveals a retracted tympanic membrane that may exhibit an opaque character or an air-fluid level. Bubbles may be seen behind the retracted membrane.

Fig. 18-1.

Acute otitis media.

Treatment for uncomplicated otitis media is oral antibiotic therapy. However, penicillin resistance of the commonly implicated organisms is rising such that almost 100% of Moraxella , 50 to 70% of Haemophilus , and up to 40% of pneumococcal strains are resistant. 3 Beta-lactamase-resistant combinations, cephalosporins, and macrolides are often required, although amoxicillin and sulfas are still considered first-line drugs. Chronic otitis media is frequently treated with myringotomy and tube placement (Fig. 18-2). This is indicated for frequent acute episodes, chronic effusions persisting beyond 3 months, and those associated with significant conductive hearing loss. The purpose of this procedure is to remove the effusion and provide a route for middle ear ventilation. Tympanic membrane perforation during acute otitis media frequently results in resolution of severe pain and provides for drainage of purulent fluid and middle ear ventilation. These perforations will heal spontaneously after the infection has resolved in the majority of cases. Chronic otitis media, however, may be associated with nonhealing tympanic membrane perforations. Patients may have persistent otorrhea, which is treated with topical drops. Preparations containing aminoglycoside are avoided, because this class of drugs is toxic to the inner ear. Solutions containing alcohol or acetic acid may be irritative or caustic to the middle ear, and are also avoided in the setting of a perforation.

Fig. 18-2.

Myringotomy and tube.

Nonhealing perforation requires surgical closure (tympanoplasty) after medical treatment of any residual acute infection. Chronic inflammation may also be associated with erosion of the ossicular chain, which can be reconstructed with various prostheses or autologous ossicular replacement techniques. Cholesteatoma is an epidermoid cyst of the middle ear and/or mastoid, which causes bone destruction secondary to its expansile nature and through enzymatic destruction. Cholesteatoma develops as a consequence of eustachian tube dysfunction and chronic otitis media secondary to retraction of squamous elements of the tympanic membrane into the middle ear space. Squamous epithelium may also migrate into the middle ear via a perforation. Chronic mastoiditis that fails medical management or is associated with cholesteatoma is treated by mastoidectomy. Complications of otitis media may be grouped into two categories: intratemporal (otologic) and intracranial.4 Fortunately, complications are rare in the antibiotic era, but mounting antibiotic resistance necessitates an increased awareness of these conditions. Intratemporal complications include acute coalescent mastoiditis, petrositis, facial nerve paralysis, and labyrinthitis. In acute coalescing mastoiditis, destruction of the bony lamellae by an acute purulent process results in severe pain, fever, and swelling behind the ear. The mastoid air cells coalesce into one common space filled with pus. Mastoid infection may also spread to the petrous apex, causing retro-orbital pain and sixth-nerve palsy. These diagnoses are confirmed by computed tomographic (CT) scan. Facial nerve paralysis may also occur secondary to an acute inflammatory process in the middle ear or mastoid.5 Intratemporal complications are managed by myringotomy tube placement in addition to appropriate IV antibiotics. In acute coalescent mastoiditis, and petrositis, mastoidectomy is also performed as necessary to drain purulent foci. Labyrinthitis refers to inflammation of the inner ear. Most cases are idiopathic or are secondary to viral infections of the endolymphatic space. The patient experiences vertigo with sensorineural hearing loss, and

symptoms may smolder over several weeks. Labyrinthitis associated with middle ear infection may be serous or suppurative. In the former case, bacterial products and/or inflammatory mediators transudate into the inner ear via the round window membrane, establishing an inflammatory process therein. Total recovery is eventually possible after the middle ear is adequately treated. Suppurative labyrinthitis, however, is a much more toxic condition in which the acute purulent bacterial infection extends into the inner ear and causes marked destruction of the sensory hair cells and neurons of the eighth-nerve ganglion. This condition may hallmark impending meningitis and must be treated rapidly. The goal of management of inner ear infection, which occurs secondary to middle ear infection, is to "sterilize" the middle ear space with antibiotics and the placement of a myringotomy tube. Meningitis is the most common intracranial complication. Otologic meningitis in children is most commonly associated with a H. influenzae type B infection. Other intracranial complications include epidural abscess, subdural abscess, brain abscess, otitic hydrocephalus (pseudotumor), and sigmoid sinus thrombophlebitis. In these cases, the otogenic source must be urgently treated with antibiotics and myringotomy tube placement. Mastoidectomy and neurosurgical consultation may be necessary. Bell's palsy, or idiopathic facial paralysis, may be considered within the spectrum of otologic disease given the facial nerve's course through the temporal bone. This entity is the most common etiology of facial nerve paralysis and is clinically distinct from that occurring as a complication of otitis media in that the otologic exam is normal. Historically, Bell's palsy was synonymous with "idiopathic" facial paralysis. It is now accepted, however, that the majority of these cases represent a viral neuropathy caused by herpes simplex. Treatment includes oral steroids plus antiviral therapy (i.e., acyclovir). Complete recovery is the norm, but does not occur universally, and selected cases may benefit from surgical decompression of the nerve within its bony canal. Electrophysiologic testing has been used to identify those patients in whom surgery might be indicated.6 The procedure involves decompression of the nerve via exposure in the middle cranial fossa. Varicella zoster virus may also cause facial nerve paralysis when the virus reactivates from dormancy in the nerve. This condition, known as Ramsay Hunt syndrome , is characterized by severe otalgia followed by the eruption of vesicles of the external ear. Treatment is similar to Bell's palsy, but full recovery is only seen in approximately two thirds of cases. Traumatic facial nerve injuries may occur secondary to accidental trauma or surgical injury. The former is detailed in Sinus Inflammatory Disease below. Iatrogenic facial nerve trauma most often occurs during mastoidectomy.7 When the facial nerve is injured intraoperatively, it is explored. Injury to greater than 50% of the neural diameter of the facial nerve is addressed either with primary reanastomosis or reconstructed with the use a nerve graft. Complete recovery of nerve function is uncommon in these cases.

Sinus Inflammatory Disease Sinusitis is a clinical diagnosis based on patient signs and symptoms.8 The Task Force on Rhinosinusitis (sponsored by the American Academy of Otolaryngology–Head and Neck Surgery) has established criteria to define "a history consistent with sinusitis" (Table 18-2). To qualify for the diagnosis, the patient must exhibit at least two major factors or one major and two minor factors. The classification of sinusitis as acute vs. subacute or chronic is primarily based on the time course over which those criteria have been met. If signs and symptoms are present for at least 7 to 10 days, but for less than 4 weeks, the process is designated acute sinusitis. Subacute sinusitis is present for 4 to 12 weeks and chronic sinusitis is diagnosed when the patient has had signs and symptoms for at least 12 weeks. In addition, the diagnosis of chronic sinusitis requires some objective demonstration of mucosal inflammatory disease. This may be accomplished by endoscopic examination or radiologically (i.e., CT scan).

Table 18-2 Factors Associated with a History of Rhinosinusitisa Facial congestion/fullness Headache Facial pain/pressure Maxillary dental pain Nasal drainage/discharge Cough Postnasal drip Halitosis (bad breath) Nasal obstruction/blockage Fatigue Hyposmia/anosmia (decreased or absent sense of smell) Ear pain, pressure, or fullness Fever Fever (acute sinusitis only) Purulence on nasal endoscopy (diagnostic by itself) Major Factors

Minor Factors

a

Either two major factors or one major and two minor factors are required. Purulence on nasal endoscopy is diagnostic. Fever is a major factor only in the acute stage. Acute sinusitis typically follows a viral upper respiratory infection whereby sinonasal mucosal inflammation results in closure of the sinus ostium. This results in stasis of secretions, tissue hypoxia, and ciliary dysfunction. These conditions promote bacterial proliferation and acute inflammation. The mainstay of treatment is the use of antibiotics that are empirically directed toward the three most common organisms S. pneumoniae , H. influenzae , and M. catarrhalis . As with otitis media, antibiotic resistance is a mounting concern. Nosocomial acute sinusitis frequently involves Pseudomonas or S. aureus , both of which may also exhibit significant antibiotic resistance. Other treatments include topical and systemic decongestants, nasal saline spray, topical nasal steroids, and oral steroids in selected cases. In the acute setting, surgery is reserved for complications or pending complications, which may include extension to the eye (orbital cellulitis or abscess) or the intracranial space (meningitis, intracranial abscess). It should also be noted that, strictly speaking, a viral upper respiratory infection (common cold) is a form of acute sinusitis. The working definition outlined above, however, attempts to exclude these cases by requiring that symptoms be present for at least 7 to 10 days, by which time the common cold should be in a resolution phase. Use of this working definition strives to avoid unnecessary antibiotic prescriptions and further promotion of resistance. Chronic sinusitis represents a heterogeneous group of patients with multifactorial etiologies contributing to ostial obstruction, ciliary dysfunction, and inflammation. Components of genetic predisposition, allergy, anatomic obstruction, bacteria, fungi, and environmental factors play varying roles, depending on the individual patient. As of yet, no immunologic "final common pathway" has been defined, but the clinical picture is well described. Diagnosis is suspected according to the criteria in Table 18-2, with clinical signs and symptoms persisting for at least 12 weeks. Chronic sinusitis may also be associated with the presence of nasal polyps. Chronic sinusitis with and without polyposis is thought to reflect an immunologically distinct disease process.8 Mucosal inflammation in nonpolypoid chronic sinusitis is predominantly mediated by neutrophils, consistent with immune response to bacterial infection. In contrast, inflammatory infiltrates observed in polypoid chronic sinusitis are typically

eosinophilic. Multiple theories have been proposed for the latter condition, and recent investigation has suggested that patients with polyposis may mount abnormal immunologic reactions toward fungi that colonize the sinonasal tract or to staphylococcal enterotoxin.8 Regardless of pathophysiology, polyps themselves may further block sinus outflow, resulting in further stasis of secretions and bacterial proliferation. Nasal endoscopy is a critical element of the diagnosis of chronic sinusitis. Anatomic abnormalities, such as septal deviation, nasal polyps, and purulence may be observed (Figs. 18-3 and 18-4). The finding of purulence or polypoid change by nasal endoscopy is supportive of the diagnosis of chronic sinusitis, if symptoms persist for at least 12 weeks. In this setting, purulence may represent an acute exacerbation of chronic sinusitis. Pus found on endoscopic exam may be cultured, and subsequent antibiotic therapy can be directed accordingly. The spectrum of bacteria found in chronic sinusitis is highly variable and includes higher prevalences of polymicrobial infections and antibiotic-resistant organisms. Overall, S. aureus , coagulase-negative staphylococci, gram-negative bacilli, and streptococci are isolated, in addition to the typical pathogens of acute sinusitis. The increased prevalence of community acquired methicillin resistant S. aureus is a mounting concern. 9

Fig. 18-3.

Endoscopic view of nasal polyp obstructing the posterior nasal airway. A small residual air passage (A ) is seen between the polyp and the nasal septum.

Fig. 18-4.

Endoscopic view of pus in the middle meatus admixed with polypoid change. This can be swabbed for culture, as shown, in the outpatient setting under endoscopic guidance.

The diagnosis of chronic sinusitis can be confirmed by CT scan, which demonstrates mucosal thickening and/or sinus opacification. It should be underscored, however, that CT scan is probably not the diagnostic gold standard because many asymptomatic patients will demonstrate findings on sinus CT scan. Also, patients with positive findings on nasal endoscopy may have normal CT scans. Overall, the decision to treat medically should be based upon patient history and nasal endoscopy, rather than results of the CT scan. Furthermore, over 75% of patients with normal findings on nasal endoscopy will have normal CT scans, underscoring the importance of endoscopy in the decision-to-treat process. Although acute sinusitis often is treated empirically by the primary care practitioner, when clinical criteria for chronic sinusitis are met, this typically prompts otolaryngology referral for nasal endoscopy, aggressive medical therapy, and possibly surgery. When surgery is used, the CT scan, if acquired with the appropriate protocol, can also be used for stereotactic intraoperative navigation to confirm relationships between the disease process, medial orbital wall, and skull base during surgery (Fig. 18-5).

Fig. 18-5.

Triplanar computed tomographic reconstructions as used for intraoperative stereotactic navigation. The coronal (upper left ), axial (lower left ), and sagittal (upper right ) planes are seen, with the cross hairs localizing the anatomic position indicated in the endoscopic view (lower left ). This particular patient has classic allergic fungal sinusitis, which has the radiologic hallmark of whitish hyperdense foci with areas of gray sinus opacification, as is seen in the maxillary sinus on the coronal image and in the sphenoid on the sagittal view.

Medical management of chronic sinusitis includes a prolonged course of oral antibiotics for 3 to 6 weeks, nasal and/or oral steroids, and nasal irrigations with saline or antibiotic solutions.8 Underlying allergic disease may be

managed with antihistamines and possible allergy immunotherapy. Although the role of these treatments in resolving chronic sinusitis remains questionable, they may be considered in patients with comorbid allergic rhinitis or as part of empiric management before consideration of surgery. The use of oral steroids may also be selected empirically, particularly in patients with comorbid chronic airway inflammatory diseases such as nasal polyps, allergic rhinitis, or asthma.1 0 The decision to use oral steroids must be individualized with consideration of the risks and side effects of these medications. As yet, there is no consensus regarding what constitutes a "maximum" course of medical therapy that should be attempted before consideration of surgery for chronic sinusitis. A proposed therapeutic algorithm is outlined (Fig. 18-6). It should be noted that unless there is suspicion of neoplasm or pending complication of sinusitis, the decision to proceed with surgery is highly individualized. This is because surgery for uncomplicated chronic sinusitis is elective, and patients who "fail" medical management will exhibit significant variability in symptoms, physical signs, and CT findings. More aggressive medical and surgical management may be necessary in patients with comorbid chronic inflammatory disease of the airways such as allergic rhinitis, nasal polyposis, and asthma. Surgery is typically preformed endoscopically where the goals are to remove polyps, enlarge the natural sinus ostia (see Fig. 18-5, Fig. 18-7), and to remove chronically infected bone to promote both ventilation and drainage of the sinus cavities. Inspissated mucin or pus is drained and cultured. Eventual resolution of the chronic inflammatory process can be attained with a combination of meticulous surgery and directed medical therapy, although the patient must understand that surgery may not alter the underlying immunologic pathophysiology.

Fig. 18-6.

Algorithm of chronic sinusitis signs and symptoms for 12 weeks. CT = computed tomography; ENT = ear, nose, and throat; PCP = primary care physician.

Fig. 18-7.

Endoscopic surgical enlargement of the left maxillary sinus and view of pus within the sinus lumen.

The role of fungi in sinusitis is an area of active investigation. Fungal sinusitis may take on both noninvasive and invasive forms. The noninvasive form includes the presence of a fungal ball and allergic fungal sinusitis, both of which occur in immunocompetent patients. A fungal ball is typically seen in individuals with chronic (or recurrent acute) symptoms that are often subtle and limited to a single sinus. Patients may complain about the perception of a foul odor and occasionally report expelling fungal debris upon nose blowing. A fungal ball (Fig. 18-8) consisting of Aspergillus fumigatus usually is found in the maxillary sinus, with scant inflammatory cell infiltration. Surgery to remove the fungal ball and reestablish sinus ventilation is almost always curative. This can be accomplished endoscopically.

Fig. 18-8.

Sinus fungal ball.

Classic allergic fungal sinusitis is thought to involve direct stimulation of eosinophils by a subset of helper T cells (TH 2) primed by fungal antigens. This results in vigorous inflammation and polyp growth, and some have proposed that other forms of chronic sinusitis may represent more subtle manifestations of this pathophysiology.1 1 Patients often present with chronic sinusitis that has been especially refractory to medical management. CT scan has characteristic features, and endoscopic evaluation reveals florid polyposis and inspissated mucin containing fungal debris and products of eosinophil breakdown. The implicated organisms are usually those of the Dematiaceae family, but Aspergillus species are also seen. Treatment includes systemic steroids, surgery, and nasal irrigations. Oral antifungal therapy is sometimes indicated as well. Immunocompetent patients may occasionally develop an indolent form of invasive fungal sinusitis, but more commonly, invasive fungal sinusitis affects immunocompromised patients, diabetics, or the elderly.1 1 Fungal invasion of the microvasculature causes ischemic necrosis and black eschar of the sinonasal mucosa. Aspergillus and fungi of the Mucoraceae family are often implicated with the latter more common in diabetic patients. Treatment requires aggressive surgical dbridement and IV antifungals, but the prognosis is dismal.

Pharyngeal and Adenotonsillar Disease The pharyngeal mucosa contains significant concentrations of lymphoid tissue, predisposing this area to reactive

inflammatory changes. Lymphoid tissue of various pharyngeal subsites forms the so-called Waldeyer's tonsillar ring , consisting of the palatine tonsils ("the tonsils"), lingual tonsil (lymphoid tissue accumulation within the tongue base), and adenoid. The mucosa of the posterior and lateral pharyngeal walls is also rich with lymphoid cells. Infection, immune-mediated inflammatory disease, or local stressors, such as radiation or acid reflux, may initiate lymphoid reactivity and associated symptoms. Chronic or recurrent adenotonsillitis and adenotonsillar hypertrophy are the most common disorders affecting these structures. In the vast majority of cases, infectious pharyngitis is viral rather than bacterial in origin. Most cases resolve without complication from supportive care and possibly antibiotics. Patients with tonsillitis typically present with sore throat, dysphagia, and fever. The mucosa is inflamed. Tonsillar exudates and cervical adenitis may be seen when the etiology is bacterial. If adenoiditis is present, the symptoms may be similar to those of sinusitis, but visual evaluation of the adenoid, at least in children, requires endoscopy and/or radiographic imaging (lateral neck soft-tissue x-ray). Tonsillitis and adenoiditis may follow acute, recurrent acute, and chronic temporal patterns. It should be noted, however, that clinical diagnosis often is inaccurate for determining whether the process is bacterially induced. When the patient also has hoarseness, rhinorrhea, cough, and no evidence of exudates or adenitis, an upper respiratory viral infection can be presumed. When a bacterial cause is suspected,1 2 antibiotics should be initiated to cover the usual organisms: group A beta-hemolytic streptococci (Streptococcus pyogenes ), S. pneumoniae , and group C and G streptococci. H. influenzae and anaerobes also have been implicated. It is particularly important to identify group A beta-hemolytic streptococci in pediatric patients to initiate timely antibiotic therapy, given the risk of rheumatic fever, which may occur in up to 3% of cases if antibiotics are not used. Historically, if bacterial pharyngitis was suspected in a child, oropharyngeal swab with culture was performed to identify group A beta-hemolytic streptococci. Currently, rapid antigen assays are available with sensitivity and specificity of approximately 85% and 90%, respectively. Some authors advocate culture only when these are negative. Unnecessary antibiotic therapy for patients who are unlikely to have a bacterial etiology should be avoided, given the already mounting antibiotic resistance problem. When suspicion for a bacterial process is high, or with positive culture/antigen assay results, treatment may include penicillins, cephalosporins, or macrolides in penicillin-allergic patients. Complications of S. pyogenes pharyngitis may be systemic, including rheumatic fever, poststreptococcal glomerulonephritis, and scarlet fever. The incidence of glomerulonephritis is not influenced by antibiotic therapy. Scarlet fever results from production of erythrogenic toxins by streptococci. This causes a punctate rash, first appearing on the trunk and then spreading distally, sparing the palms and soles. The so-called strawberry tongue also is seen. Locoregional complications include peritonsillar abscess and, rarely, deep-neck space abscess. Peritonsillar abscess is typically drained transorally under local anesthesia, as is the authors' practice, but some suggest that needle aspiration without incision is sufficient.1 3 Deep neck space abscess, which more commonly is odontogenic in origin, usually requires operative incision and drainage via a transcervical approach. Atypical cases of pharyngitis may be caused by Corynebacterium diphtheriae , Bordetella pertussis (whooping cough), syphilis, Neisseria gonorrhoeae , and fungi. Diphtheria is a potentially fatal condition associated with toxinmediated tissue necrosis and a gray membrane on the mucosal surface. Cardiorespiratory collapse may ensue from systemic circulation of the toxin. Treatment includes the use of antitoxin. Fortunately, diphtheria is rare in developed countries as a consequence of childhood vaccinations. Childhood vaccination also has almost eliminated whooping cough in developed nations. This entity follows a protracted, but usually self-limiting course. During the secondary phase of syphilis, ulcerations with raised red margins (resembling the chancre lesion) may be observed on the pharyngotonsillar mucosa. Identification of these less typical organisms requires a high index of suspicion

and application of appropriate culture techniques and/or serologic tests. Candida albicans is the most common fungal organism to cause pharyngitis. This organism is a normal component of the oral flora, but under conditions of immunosuppression, broad-spectrum antibacterial therapy, poor oral hygiene, or vitamin deficiency, it may become pathogenic. Whitish-cheesy or creamy mucosal patches are observed with underlying erythema, and diagnosis is easily established by Gram's stain of this material, revealing budding yeast and pseudohyphae. Oral and topical antifungals are usually effective, and immunosuppressed patients may require prophylactic therapy. In addition to viral upper respiratory viruses, herpes simplex virus, Epstein-Barr virus (EBV), cytomegalovirus, and HIV are associated with pharyngitis. Systemic EBV infection represents clinical mononucleosis, although syphilis, cytomegalovirus, and HIV are known to cause mononucleosis-like syndromes. These conditions, particularly EBV, may exhibit an exudative pharyngotonsillitis that may be confused with a bacterial etiology. Progression of the clinical picture reveals lymphadenopathy, splenomegaly, and hepatitis. Diagnosis is established based on the detection of heterophile antibodies or atypical lymphocytes in the peripheral blood. Occasionally, pharyngeal biopsy or cervical lymph node biopsy is required to establish the diagnosis. Noninfectious causes of pharyngitis must also be considered. These include mucositis from chemoradiation therapy, which may be associated with fungal superinfection. Pharyngitis may also be seen in immune-mediated conditions such as erythema multiforme, bullous pemphigoid, and pemphigus vulgaris. In addition, reflux is being increasingly identified as a cause of both laryngitis and pharyngitis, particularly when the symptoms are chronic. A 24-hour pH probe is the gold standard diagnostic test, and treatment is usually successful with lifestyle modification, although proton pump inhibitors are often prescribed.1 4 Obstructive adenotonsillar hyperplasia may present with nasal obstruction, rhinorrhea, voice changes, dysphagia, and sleep-disordered breathing or OSA, depending on the particular foci of lymphoid tissue involved. Tonsillectomy and adenoidectomy are indicated for chronic or recurrent acute infection and for obstructive hypertrophy.1 5 The American Academy of Otolaryngology–Head and Neck Surgery Clinical Indicators Compendium suggests tonsillectomy after three or more infections per year despite adequate medical therapy. Some feel that tonsillectomy is indicated in children who miss 2 or more weeks of school annually secondary to tonsil infections. Multiple techniques have been described, including electrocautery, sharp dissection, laser, and radiofrequency ablation. There is no consensus as to the best method. In cases of chronic or recurrent infection, surgery is considered only after failure of medical therapy. Patients with recurrent peritonsillar abscess should undergo tonsillectomy when the acute inflammatory changes have resolved. Selected cases, however, require tonsillectomy in the acute setting for the management of severe inflammation, systemic toxicity, or impending airway compromise. Adenoidectomy, in conjunction with myringotomy and tube placement, may be beneficial for children with chronic or recurrent otitis media.1 6 This is because the adenoid appears to function as a bacterial reservoir that seeds the middle ear via the eustachian tube. Adenoidectomy is also the first line of surgical management for children with chronic sinusitis. In addition to acting as a bacterial reservoir, an obstructive adenoid impairs mucociliary clearance from the sinonasal tract into the pharynx. The primary complications of tonsillectomy1 7 include bleeding, airway obstruction, death, and readmission for dehydration secondary to postoperative dysphagia. Complications of adenoidectomy also include hemorrhage, as well as nasopharyngeal stenosis and velopharyngeal insufficiency. In the latter condition, nasal regurgitation of liquids and hypernasal speech are experienced. Patients with significant airway obstruction secondary to adenotonsillar hypertrophy are also at risk for postobstructive pulmonary edema syndrome, once the obstruction is relieved by adenotonsillectomy. Overall, bleeding is the most significant risk and may require a return trip to the

operating room for control. With the exception of bleeding, which is observed in 3 to 5% of patients, most of these complications are rare or self limiting. It deserves special notation that adenotonsillectomy in a child with Down syndrome requires attention to the cervical spine. Patients with this syndrome may exhibit atlantoaxial instability, resulting in cervical spine injury if the neck is extended for the procedure. Baseline radiographs, with appropriate orthopedic or neurosurgical consultation, are indicated preoperatively. Surgery for adenotonsillar hypertrophy may be indicated when the patient exhibits sleep-disordered breathing. Sleep disorders represent a continuum from simple snoring to upper airway resistance syndrome to obstructive sleep apnea (OSA). 1 8 Upper airway resistance syndrome and OSA are associated with snoring, excessive daytime somnolence, fatigue, and frequent sleep arousals. In OSA, polysomnogram demonstrates at least 10 episodes of apnea or hypopnea per hour of sleep. The average number of apneas and hypopneas per hour can be used to calculate a respiratory disturbance index, which, along with oxygen saturation, can be used to grade the severity of OSA. These episodes occur as a result of collapse of the pharyngeal soft tissues during sleep. In adults, it should be noted that in addition to tonsil size, factors such as tongue size and body mass index (especially >35 kg/m2 ) are significant predictors of OSA. Other anatomic findings associated with OSA include obese neck, retrognathia, low hyoid bone, and enlarged soft palate. Surgery should be considered after failure of more conservative measures, such as weight loss, elimination of alcohol use, use of oral appliances to open the airway during sleep, and continuous positive airway pressure. Selection of surgical procedure should be tailored to the particular patient's pattern of obstruction. In children, surgical management typically involves tonsillectomy and/or adenoidectomy, because the disorder is usually caused, at least in part, by hypertrophy or collapse of these structures. In any individual patient, the anatomy must be carefully evaluated to determine whether the site of airway collapse is in the retropalatal region, retrolingual area, or both. A therapeutic algorithm for adults is proposed (Fig. 18-9), based on site of obstruction and severity of disease. In adults, uvulopalatoplasty is frequently performed to alleviate softpalate collapse and is the most common operation performed for sleep-disordered breathing. The goal of this procedure is to remove redundant tissue from the uvula and soft palate, along with obstructive tonsillar tissue. This can be accomplished with cold steel, laser, and/or cautery. Adults with significant nasal obstruction may benefit from septoplasty, reduction in size of the inferior turbinates, and possibly external nasal surgery. Patients with a significant component of retrolingual obstruction may be candidates for tongue base reduction, tongue base advancement, or hyoid suspension. Additionally, a variety of maxillomandibular advancement procedures also have been described to enlarge the anterior-posterior dimension of the retrolingual airway. Patients with moderate to severe sleep apnea frequently manifest involvement of the tongue base. However, management of this subgroup may be difficult, as procedures addressing the retrolingual airway can involve difficult recovery, significant morbidity, and limited success. These patients often continue to require continuous positive airway pressure despite performance of multilevel surgical procedures. Patients with severe OSA (respiratory disturbance index>40, lowest nocturnal oxygen saturation 72 hours). The chosen antibiotic should cover S. aureus . In many such wounds, healing by secondary intention may be preferable. Wound closure must be understood in the context of the cosmetic and functional anatomic landmarks of the head and neck. Management of injuries to the eyelid requires identification of the orbicularis oculi, which is closed in a separate layer. The gray line (conjunctival margin; Fig. 18-14) must be carefully approximated to avoid lid notching or height mismatch. Management of lip injuries follows the same principle. The orbicularis oris must be closed, and the vermilion border carefully approximated (Fig. 18-15). Injuries involving one fourth the width of the eyelid or one third the width of the lip may be closed primarily; otherwise, flap or grafting procedures may be required. With laceration of the auricle, key structures such as the helical rim and antihelix must be carefully aligned. These injuries must be repaired so that the cartilage is covered. The principles of auricular repair are predicated on the fact that the cartilage has no intrinsic blood supply and is thus susceptible to ischemic necrosis following trauma. The suture should be passed through the perichondrium, while placement through the cartilage itself should be avoided.

Fig. 18-14.

Alignment of the gray line is the key step in the repair of eyelid lacerations.

Fig. 18-15.

Approximation of the vermilion border is the key step in the repair of lip lacerations.

Auricular hematomas should be drained promptly, with placement of a bolster as a pressure dressing. A pressure dressing is frequently advocated after closure of an ear laceration. It also deserves note that the surgeon must avoid the temptation to perform aggressive dbridement after injuries to the eyelid or auricle. Given the rich vascular supply to the face and neck, many soft-tissue components that appear devitalized will indeed survive. Most traumatic facial nerve injuries are secondary to temporal bone trauma, which is discussed below in this section. Soft-tissue injuries occurring in the misfile may involve distal facial nerve branches. Those injured anterior to a vertical line dropped from the lateral cantus do not require repair secondary to collateral innervation in the anterior midface. Posterior to this line, the nerve should be repaired, primarily if possible, using 8-0 to 10-0 monofilament suture to approximate the epineurium under microscopic visualization. If neural segments are missing, cable grafting is performed using either the greater auricular (provides 7 to 8 cm) or sural nerve (up to 30

cm) as a donor. Injuries to the buccal branch should alert the examiner to a possible parotid duct injury. This structure lies along an imaginary line drawn from the tragus to the midline upper lip, running along with the buccal branch of the facial nerve. The duct should be repaired over a 22-gauge stent or marsupialized into the oral cavity. Facial bone fractures most commonly involve the mandible. Fractures most often involve the angle, body, or condyle, and in most cases, two or more sites are almost always involved (Fig. 18-16). Fractures are described as either favorable or unfavorable, depending on whether or not the masticatory musculature tends to pull the fracture into reduction or distraction. Vertically favorable fractures are brought into reduction by the masseter, while horizontally favorable fractures are brought into reduction by the pterygoid musculature. The fracture is usually evaluated radiographically using a Panorex, but specialized plain film views, and occasionally CT scan, are necessary in selected cases. Classical management of mandible fractures dictated closed reduction and a 6-week period of intermaxillary fixation (IMF) with arch bars applied via circumdental wiring. Comminuted, displaced, or unfavorable fractures underwent open reduction and wire fixation in addition to IMF. Currently, arch bars and IMF are performed to establish occlusion. The fracture is then exposed and reduced, using transoral approaches where possible.

Fig. 18-16.

Sites of common mandible fractures.

Transcervical approaches are required to address fractures of the ramus or posterior body, with careful attention given to preserving the marginal mandibular branch of the facial nerve. Rigid fixation is then accomplished by the application of plates and screws. Selected fractures, such as those of the body, benefit from dynamic compression plating, which applies pressure toward the fracture line. With rigid fixation, IMF is required to establish occlusion intraoperatively, and is not necessarily continued for a full 6 weeks postoperatively. This is preferable because IMF is associated with gingival and dental disease, as well as with significant weight loss and malnutrition, during the

fixation period. New techniques have included the 4-point fixation technique, where the maxilla and mandible are held in occlusion by wires attached to intraoral cortical bone screws, with two screws above and below the occlusal line anteriorly. In edentulous patients, determining the baseline occlusion is of less significance because dentures may be refashioned once healing is complete. If IMF is required to aid in immobilization of the fracture in an edentulous patient, interosseous wiring and/or the fabrication of custom-made splints is required. Midface fractures are classically described in three patterns: Le Fort I, II, and III. A full understanding of midface structure is first necessary (Fig. 18-17). Three vertical buttresses support the midface: the nasofrontal-maxillary, the frontozygomaticomaxillary, and pterygomaxillary.3 1 The five weaker, horizontal buttresses include the frontal bone, nasal bones, upper alveolus, zygomatic arches, and the infraorbital region. Classical signs of midface fractures in general include subconjunctival hemorrhage; malocclusion; midface numbness or hypesthesia (maxillary division of the trigeminal nerve); facial ecchymoses/hematoma; ocular signs/symptoms; and mobility of the maxillary complex.

Fig. 18-17.

Major buttresses of the midface.

Le Fort I fractures occur transversely across the alveolus, above the level of the teeth apices. In a pure Le Fort I

fracture, the palatal vault is mobile while the nasal pyramid and orbital rims are stable. The Le Fort II fracture extends through the nasofrontal buttress, medial wall of the orbit, across the infraorbital rim, and through the zygomaticomaxillary articulation. The nasal dorsum, palate, and medial part of the infraorbital rim are mobile. The Le Fort III fracture is also known as craniofacial disjunction . The frontozygomaticomaxillary, frontomaxillary, and frontonasal suture lines are disrupted. The entire face is mobile from the cranium. It is convenient to conceptualize complex midface fractures according to these patterns (Fig. 18-18); however, in reality, fractures reflect a combination of these three types. Also, the fracture pattern may vary between the left and right sides of the midface. Lateral blows to the cheek may be associated with isolated zygoma fractures. The zygoma is typically displaced inferiorly and medially with disruption of the suture lines between the temporal, frontal, and maxillary bones and the zygoma. Disruption of the latter articulation may be associated with depression into the maxillary sinus and blood in the sinus cavity. Fractures of the midface and/or zygoma may be associated with an orbital blowout, whereas the orbital floor is disrupted and orbital soft tissues subsequently herniate into the maxillary sinus (Fig. 18-19). The mechanism of orbital blowout may involve propagation of adjacent fracture lines or may be the result of a sudden increase in intraorbital pressure during the injury. This may be associated with enophthalmos or entrapment of the inferior oblique muscle. The latter results in diplopia upon upward gaze. Entrapment is confirmed by forced duction testing, where, under topical or general anesthesia, the muscular attachment of the inferior oblique is grasped with forceps and manipulated to determine passive ocular mobility. Fractures of the midface, zygoma, and orbital floor are best evaluated using CT scan, and repair requires a combination of transoral and external approaches to achieve at least two points of fixation for each fractured segment.3 2 Significant areas of bone loss can be reconstructed with commercially available hydroxyapatite bone cements, an osteoconductive calcium-phosphate matrix. Blowout fractures demonstrating significant entrapment or enophthalmos are treated by orbital exploration and reinforcement of the floor with mesh or bone grafting.

Fig. 18-18.

Classic Le Fort fracture patterns.

Fig. 18-19.

Coronal computed tomography demonstrating an orbital blowout fracture with herniation of orbital contents into the maxillary sinus.

Temporal bone fractures occur in approximately one fifth of skull fractures. As with fractures of the mandible and midface, blunt trauma (from motor vehicle accident or assault) usually is implicated. Unfortunately, the incidence of temporal bone fracture from gunshot wounds to the head is rising. Fractures are divided into two patterns (Fig. 18-20), longitudinal and transverse, based on the clinical picture and CT imaging. In practice, most fractures are oblique. By classical descriptions, longitudinal fractures constitute 80% and are associated with lateral skull trauma. Signs and symptoms include conductive hearing loss, ossicular injury, bloody otorrhea, and labyrinthine concussion. The facial nerve is injured in approximately 20% of cases. In contrast, the transverse pattern constitute only 20% of temporal bone fractures and occurs secondary to fronto-occipital trauma. The facial nerve is injured in 50% of cases. These injuries frequently involve the otic capsule to cause sensorineural hearing loss and loss of vestibular function. Hemotympanum may be observed. A cerebrospinal fluid (CSF) leak must be suspected in temporal bone trauma. This resolves with conservative measures in most cases. The most significant consideration in the management of temporal bone injuries is the status of the facial nerve. Delayed or partial paralysis will almost always resolve with conservative management. However, immediate paralysis that does not recover within 1 week should be considered for nerve decompression. Electroneurography and EMG have been used to help determine which patients with delayed-onset complete paralysis will benefit from surgical decompression. The finding of greater than 90% degeneration more than 72 hours after the onset of complete paralysis is considered an indication for surgery. 3 3 Multiple approaches have been described for facial nerve decompression, some of which sacrifice hearing. These patients may have severe intracranial or vascular injuries such that the decision to operate must also be made in the context of the patient's overall medical stability. It is of paramount

importance to protect the eye in patients with facial nerve paralysis of any etiology, because absence of an intact blink reflex will predispose to corneal drying and abrasion. This requires the placement of artificial tears throughout the day with lubricant ointment, eye taping, and/or a humidity chamber at night.34,35

Fig. 18-20.

View of cranial surface of skull base. Longitudinal (left ) and transverse (right ) temporal bone fractures.

TUMORS OF THE HEAD AND NECK When a discussion of neoplasms of the head and neck is initiated, the conversation frequently focuses on squamous cell carcinoma. This is because the majority of malignancies of this region are represented by this pathology. The

diagnosis and treatment of lesions spanning from the lips and oral cavity to the larynx and hypopharynx requires a similar methodic approach. The selection of treatment protocols varies for each site within the upper aerodigestive tract. The importance of multidisciplinary management cannot be underestimated. Presentation of cases before a tumor board allowing review of a patient's history, physical examination findings, imaging, and prior pathology specimens allows for confirmation of the patient's status. Additionally, it should encourage discussion from multiple points of view concerning the most appropriate treatment options available. Participation in the discussion with representatives of radiation oncology, medical oncology, surgical oncology, oral maxillofacial surgery/dental medicine, along with radiologists and pathologists specializing in upper aerodigestive tract disorders benefits not only the patient but also represents an excellent teaching opportunity for all disciplines. The development of organ preservation protocol and the evolution of free tissue reconstructive techniques are some of the most significant advances made within the field during the last two decades. The future of the treatment of head and neck cancer lies within the field of molecular biology. As more is understood about the genetics of cancer, tailoring treatment options to a particular tumor mutation has the capacity to maximize survival while achieving the highest quality of life.

Etiology and Epidemiology It should come as no surprise that abuse of tobacco and alcohol are the most common preventable risk factors associated with the development of head and neck cancers. This relationship is synergistic rather than additive. Smoking confers a 1.9-fold increased risk to males and a threefold increased risk to females for developing a head and neck carcinoma, when compared to nonsmokers. The risk increases as the number of years smoking and number of cigarettes smoked per day increases. Alcohol alone confers a 1.7-fold increased risk to males drinking one to two drinks per day, when compared to nondrinkers. This increased risk rises to greater than threefold for heavy drinkers. Individuals who both smoke (two packs per day) and drink (four units of alcohol per day) had an odds ratio of 35 for the development of a carcinoma when compared to controls. 3 6 Users of smokeless tobacco have a four times increased risk of oral cavity carcinoma when compared to nonusers. Tobacco is the leading preventable cause of death in the United States and is responsible for one of every five deaths.3 7 Approximately one fourth of U.S. adults habitually use tobacco products, with recent trends demonstrating an increase in the use of tobacco products by women. The evidence supporting the need for head and neck cancer patients to pursue smoking cessation after treatment is compelling. In a study by Moore,3 8 40% of patients who continued to smoke after definitive treatment for an oral cavity malignancy went on to recur or develop a second head and neck malignancy. For patients who stopped smoking after treatment, only 6% went on to develop a recurrence. Induction of specific p53 mutations within upper aerodigestive tract tumors has been noted in patients with histories of tobacco and alcohol use.39,40 When smokers who develop head and neck squamous cell carcinomas are compared to nonsmokers, differences between the two populations emerge. Koch and associates4 1 noted that nonsmokers were represented by a disproportionate number of women and were more frequently at the extremes of age (85 years of age). Tumors from nonsmokers presented more frequently in the oral cavity, specifically within the oral tongue, buccal mucosa, and alveolar ridge. Smokers presented more frequently with tumors of the larynx, hypopharynx, and floor of mouth. Former smokers, defined as those individuals who had quit greater than 10 years prior, demonstrated a profile more consistent with nonsmokers. In India and Southeast Asia, the product of the areca catechu tree, known as a betel nut, is chewed in a habitual

manner and acts as a mild stimulant similar to that of coffee. The nut is chewed in combination with lime and cured tobacco as a mixture known as a quid. The long-term use of the betel nut quid can be destructive to oral mucosa and dentition and is highly carcinogenic.4 2 Another habit associated with oral malignancy is that of reverse smoking, where the lighted portion of the tobacco product is within the mouth during inhalation. The risk of hard palate carcinoma is 47 times greater in reverse smokers when compared to nonsmokers. HPV is an epitheliotropic virus that has been detected to varying degrees within samples of oral cavity squamous cell carcinoma. Infection alone is not considered sufficient for malignant conversion; however, results of multiple studies suggest a role of HPV in a subset of head and neck squamous cell carcinoma. Approximately 40% of tonsillar carcinomas demonstrate evidence of HPV types 16 and 18. Environmental ultraviolet light exposure has been associated with the development of lip cancer. The projection of the lower lip, as it relates to this solar exposure, has been used to explain why the majority of squamous cell carcinomas arise along the vermilion border of the lower lip. In addition, pipe smoking also has been associated with the development of lip carcinoma. Factors such as mechanical irritation, thermal injury, and chemical exposure have been described as an explanation for this finding. Other entities associated with oral malignancy include Plummer-Vinson syndrome (achlorhydria, iron-deficiency anemia, mucosal atrophy of mouth, pharynx, and esophagus), chronic infection with syphilis, and immunocompromised status (30-fold increase with renal transplant). Although evidence linking HIV infection to squamous cell carcinoma of the head and neck is lacking, several AIDSdefining malignancies, including Kaposi's sarcoma, and non-Hodgkin's lymphoma may require the care of an otolaryngologist.

Anatomy and Histopathology The upper aerodigestive tract is divided into several distinct sites that include the oral cavity, pharynx, larynx, and nasal cavity/paranasal sinuses. Within these sites are individual subsites with specific anatomic relationships that affect diagnosis, tumor spread, and selection of treatment options. The spread of a tumor from one site to another is determined by the course of the nerves, blood vessels, lymphatic pathways, and fascial planes. The fascial planes serve as barriers to the direct invasion of tumor and facilitate the pattern of spread to regional lymph nodes. The oral cavity extends from the vermilion border of the lip to the hard-palate/soft-palate junction superiorly, to circumvallate papillae inferiorly, and to the anterior tonsillar pillars laterally (Fig. 18-21). It is divided into seven subsites: lips, alveolar ridges, oral tongue, retromolar trigone, floor of mouth, buccal mucosa, and hard palate. Advanced oral cavity lesions may present with mandibular and/or maxillary involvement requiring special consideration at the time of resection and reconstruction. Regional metastatic spread of lesions of the oral cavity is to the lymphatics of the submandibular and the upper jugular region (levels I, II, and III).

Fig. 18-21.

Oral cavity landmarks.

The pharynx is divided into three regions: nasopharynx, oropharynx, and hypopharynx. The nasopharynx extends from the posterior nasal septum and choana to the skull base and includes the fossa of Rosenmller and torus tubarius of the eustachian tubes laterally. The inferior margin of the nasopharynx is the superior surface of the soft palate. The adenoids, typically involuted in adults, are located with the posterior aspect of this site. Given the midline location of the nasopharynx, bilateral regional metastatic spread is common in these lesions. Lymphadenopathy of the posterior triangle (level V) of the neck should provoke consideration for a nasopharyngeal primary. The major sites within the oropharynx are the tonsillar region, base of tongue, soft palate, and posterolateral pharyngeal walls. Regional lymphatic drainage for oropharyngeal lesions frequently occurs to the upper and lower cervical lymphatics (levels II, III, IV). Retropharyngeal metastatic lymphatic spread may occur with oropharyngeal lesions. The hypopharynx extends from the vallecula to the lower border of the cricoid posterior and lateral to the larynx. The subsites of this region include the pyriform fossa, the postcricoid space, and posterior pharyngeal wall. Regional lymphatic spread is frequently bilateral and to the mid- and lower cervical lymph nodes (levels III, IV). The larynx is divided into three regions: the supraglottis, glottis, and subglottis. The supraglottic larynx includes

the epiglottis, false vocal cords, medial surface of the aryepiglottic folds, and the roof of the laryngeal ventricles. The glottis includes the true vocal cords, anterior and posterior commissure, and the floor of the laryngeal ventricle. The subglottis extends from below the true vocal cords to the cephalic border of the cricoid within the airway. The supraglottis has a rich lymphatic network, which accounts for the high rate of bilateral spread of metastatic disease that is not typically seen with the glottis. Glottic and subglottic lesions, in addition to potential spread to the cervical chain lymph nodes, may also spread to the paralaryngeal and paratracheal lymphatics and require attention to prevent lower central neck recurrence.

Carcinogenesis Development of a tumor represents the loss of cellular signaling mechanisms involved in the regulation of growth. Following malignant transformation, the processes of replication (mitosis), programmed cell death (apoptosis), and the interaction of a cell with its surrounding environment are altered. Advances in molecular biology have allowed for the identification of many of the mutations associated with this transformation. Overexpression of mutant p53 is associated with carcinogenesis at multiple sites within the body. Point mutations in p53 have been reported in up to 45% of head and neck carcinomas. Koch and associates4 1 noted that p53 mutation is a key event in the malignant transformation of greater than 50% of head and neck squamous cell carcinomas in smokers. Carcinogenesis has long been explained as a two-hit process, involving DNA damage and the progression of mutated cells through the cell cycle. These two events also are known as initiation and promotion . It has been proposed that up to six to 10 independent genetic mutations are required for the development of a malignancy. Overexpression of mitogenic receptors, loss of tumor-suppressor proteins, expression of oncogene-derived proteins that inhibit apoptosis, and overexpression of proteins that drive the cell cycle can allow for unregulated cell growth. Genetic mutations may occur as a result of environmental exposure (e.g., radiation or carcinogen exposure), viral infection, or spontaneous mutation (deletions, translocations, frame shifts). Common genetic alterations, such as loss of heterozygosity at 3p, 4q, and 11q13, and the overall number of chromosomal microsatellite losses are found more frequently in the tumors of smokers than in the tumors of nonsmokers.4 1

Second Primary Tumors in the Head and Neck Patients diagnosed with a head and neck cancer are predisposed to the development of a second tumor within the aerodigestive tract. The overall rate of second primary tumors is approximately 14%. A second primary tumor detected within 6 months of the diagnosis of the initial primary lesion is defined as a synchronous neoplasm. The prevalence of synchronous tumors is approximately 3 to 4%. The detection of a second primary lesion more than 6 months after the initial diagnosis is referred to as metachronous tumor. Eighty percent of second primaries are metachronous and at least half of these lesions develop within 2 years of the diagnosis of the original primary. The incidence and site of the second primary tumor vary and depend on the site and the inciting factors associated with the initial primary tumor. The importance of advocating smoking cessation and addressing alcoholism in these patients cannot be overemphasized. Patients with a primary malignancy of the oral cavity or pharynx are most likely to develop a second lesion within the cervical esophagus, whereas patients with a carcinoma of the larynx are at risk for developing a neoplasm in the lung. As such, the presentation of a new-onset dysphagia, unexplained weight loss, or chronic cough/hemoptysis must be assessed thoroughly in patients with a history of prior treatment for a head and neck cancer.

A staging examination is recommended at the initial evaluation of all patients with primary cancers of the upper aerodigestive tract. This may involve a direct laryngoscopy, rigid/flexible esophagoscopy, and rigid/flexible bronchoscopy also known as "panendoscopy." Some surgeons argue against the use of bronchoscopy because of the low yield of the examination in asymptomatic patients with a normal chest x-ray. Additionally, some surgeons prefer to use a barium swallow instead of esophagoscopy as a preoperative evaluation. Despite the different practices concerning pretreatment evaluation of asymptomatic patients, it should be noted that patients with symptoms potentially representing those of metastatic spread of disease require a work-up greater than a screening evaluation.

Staging Staging for upper aerodigestive tract malignancies is defined by the American Joint Committee on Cancer4 3 and follows the TNM (primary tumor, regional nodal metastases, distant metastasis) staging format. The T staging criteria for each site varies depending upon the relevant anatomy (e.g., vocal cord immobility is typical of T3 lesions). Table 18-3 demonstrates TNM staging for oral cavity lesions. The N classification system is uniform for all head and neck sites except for the nasopharynx.

Table 18-3 TNM Staging for Oral Cavity Carcinoma Primary tumor TX Unable to assess primary tumor T0 No evidence of primary tumor Tis Carcinoma in situ T1 Tumor is 2 cm and 4 cm in greatest dimension T4 (lip) Primary tumor invading cortical bone, inferior alveolar nerve, floor of mouth, or skin of face (e.g., nose or chin) T4a (oral) Tumor invades adjacent structures (e.g., cortical bone, into deep tongue musculature, maxillary sinus) or skin of face T4b (oral) Tumor invades masticator space, pterygoid plates, or skull base and/or encases the internal carotid artery Regional lymphadenopathy NX Unable to assess regional lymph nodes N0 No evidence of regional metastasis N1 Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension N2a Metastasis in single ipsilateral lymph node, >3 cm and Chapter 19. Chest Wall, Lung, Mediastinum, and Pleura>

KEY POINTS 1. Lung cancer continues to be a highly lethal and extremely common cancer, with 5-year survival of 15%. Lung cancer incidence is second only to the incidence of prostate cancer in men and breast cancer in women. Squamous cell carcinoma and adenocarcinoma of the lung are the most common subtypes and are rarely found in the absence of a smoking history. Nonsmokers who live with smokers have a 24% increased risk of lung cancer compared to nonsmokers who do not live with smokers. 2. Endoscopic bronchial ultrasound is a valuable new tool that can enhance the accuracy and safety of transbronchial biopsies of both the primary tumor (when it abuts the central airways) and the mediastinal lymph nodes and should become part of the surgeon's armamentarium for the diagnosis and treatment of lung cancer. 3. The assessment of patient risk before thoracic resection is based on clinical judgment and data. 4. Impaired exchange of carbon monoxide is associated with a significant increase in the risk of postoperative pulmonary complications, independent of the patient's smoking history. In patients undergoing pulmonary resection, the risk of any pulmonary complication increases by 42% for every 10% decline in the percent carbon monoxide diffusion capacity (%DLCO), and this measure may be a useful parameter in risk stratification of patients for surgery. 5. Maximum oxygen consumption (

O 2

max) values provide important additional information in those patients with

severely impaired DLCO and forced expiratory volume in 1 second. Values of 15 mL/kg per minute generally indicate

the patient's ability to tolerate pneumonectomy. 6. Major changes in the tumor, node, and metastasis (TNM) staging system for lung cancer have been proposed. Tumor stage will be further subdivided into T1a and T1b, T2a and T2b, T3, and T4. Satellite nodules in the same lobe will be considered T3 and malignant pleural and pericardial effusions will be considered metastatic disease rather than T4 disease. 7. Increasing evidence suggests a significant role for gastroesophageal reflux disease in the pathogenesis of chronic lung diseases such as bronchiectasis and idiopathic pulmonary fibrosis, and it may also contribute to bronchiolitis obliterans syndrome in lung transplant patients. 8. Multidrug-resistant tuberculosis (MDRTB) organisms are present in approximately 10% of new tuberculosis cases and 40% of recurrent cases. Another rare disease variant termed extensively drug-resistant tuberculosis has also been identified. The causative organisms are resistant not only to isoniazid and rifampin, as are the MDRTB

organisms, but also to at least one of the injectable second-line drugs such as capreomycin, amikacin, and kanamycin. 9. Treatment of pulmonary aspergilloma is individualized. Asymptomatic patients can be observed without any additional therapy. Similarly, mild hemoptysis, which is not life-threatening, can be managed with medical therapy, including antifungals and cough suppressant. Amphotericin B is the drug of choice, although voriconazole has recently been used for treatment of aspergillosis, with fewer side effects and equivalent efficacy. Massive hemoptysis had traditionally been an indication for urgent or emergent operative intervention. However, with the advancement of endovascular techniques, bronchial artery embolization in select centers with experience in these techniques has been effective. 10. Treatment for candidal infection, like that for other fungal infections, has changed dramatically in the past decade. The availability of multiple effective therapies allows for specific tailoring of treatment, including combination regimens, based on the patient's ability to tolerate associated toxicities, the microbiologic information for the specific candidal species, and the route of administration. Although their demonstrated efficacy is similar to that of other classes of antifungal drugs, the triazoles and echinocandins appear to have fewer side effects and are better tolerated than these other drug classes. 11. In patients with malignant pleural effusion, poor expansion of the lung (because of entrapment by tumor or adhesions) generally predicts a poor result with pleurodesis and is the primary indication for placement of indwelling pleural catheters. These catheters have dramatically changed the management of end-stage cancer treatment, because they substantially shorten the amount of time patients spend in the hospital during their final weeks of life.

TRACHEA Anatomy An understanding of the relevant anatomy of the trachea is essential for surgeons of all specialties (Fig. 19-1).1 The trachea is composed of cartilaginous and membranous portions, beginning with the cricoid cartilage, the first complete cartilaginous ring of the airway. The cricoid cartilage consists of an anterior arch and a posterior broadbased plate. Articulating with the posterior cricoid plate are the arytenoid cartilages. The vocal cords originate from the arytenoid cartilages and then attach to the thyroid cartilage. The subglottic space, the narrowest part of the trachea with an internal diameter of approximately 2 cm, begins at the inferior surface of the vocal cords and extends to the first tracheal ring. The remainder of the distal trachea is 10.0 to 13.0 cm long, consists of 18 to 22 rings, and has an internal diameter of 2.3 cm.

Fig. 19-1.

Anatomy of the larynx and upper trachea. m. = muscle; n. = nerve.

The tracheal blood supply enters the airway near the junction of the membranous and cartilaginous portions of the airway (Fig. 19-2). It is segmental, which means that each entering small branch supplies a segment of 1.0 to 2.0 cm, which limits circumferential mobilization to that same distance. The arteries supplying the trachea include the inferior thyroid, subclavian, supreme intercostal, internal thoracic, innominate, and superior and middle bronchial arteries. The vessels are interconnected along the lateral surface of the trachea by an important longitudinal vascular anastomosis that feeds transverse segmental vessels to the soft tissues between the cartilages.

Fig. 19-2.

Arterial blood supply to the larynx and upper trachea. a. = artery.

Tracheal Injury Injury secondary to endotracheal intubation is most commonly the result of overinflation of the cuff. Although highvolume/low-pressure cuffs are now ubiquitous, they can easily be overinflated, and pressures can be generated that are high enough to cause ischemia of the contiguous airway wall. In some patients, periods of ischemia as short as 4 hours may be all that is required to induce an ischemic event significant enough to lead to scarring and stricture. With prolonged overinflation and consequent full-thickness destruction of the airway, fistula development between the innominate artery and esophagus may ensue. For these reasons, it is good practice in all intubations, no matter how brief, to inflate the cuff only to the level necessary to prevent air leakage around the cuff. In circumstances of prolonged ventilatory support and high airway pressures, cuff pressure monitoring (to maintain pressures below 20 mmHg) is advisable. Tracheal stenosis is nearly always iatrogenic. It is secondary to either endotracheal intubation or tracheostomy. Collectively, such tracheal injuries are referred to as postintubation injuries. Clinically significant tracheal stenosis is common after tracheostomy due to scarring and local injury, and occurs in 3 to 12% of cases.2 Factors associated with an increased risk of tracheal stenosis include incorrect placement of the tracheostomy through the first tracheal ring or the cricothyroid membrane where the airway is narrowest, use of a large tracheostomy tube, and transverse incision on the trachea. However, even a properly placed tracheostomy can lead to tracheal stenosis secondary to scarring and local injury, and mild ulceration and stenosis frequently are seen after tracheostomy removal. The rate of stomal stenosis can be minimized by using the smallest tracheostomy tube possible and

downsizing as soon as the patient will tolerate it, and by using a vertical tracheal incision without removing cartilage. Clinically, stridor and dyspnea on exertion are the primary symptoms of tracheal stenosis. The length of time to onset of symptoms after extubation or after tracheostomy decannulation varies, usually ranging from 2 to 12 weeks; however, symptoms can appear immediately or as long as 1 to 2 years later. Frequently, patients are misdiagnosed as having asthma or bronchitis, and treatment for such illnesses can persist for some time before the correct diagnosis is discovered. Generally, the intensity of symptoms experienced is related to the degree of stenosis and to the patient's underlying pulmonary disease.

ACUTE MANAGEMENT The treatment of tracheal stenosis is resection and primary anastomosis. In nearly all postintubation injuries the injury is transmural, and significant portions of the cartilaginous structural support are destroyed (Fig. 19-3). Measures such as laser ablation are temporizing. In the early phase of evaluating patients, dilation using a rigid bronchoscope is useful to gain immediate relief of dyspnea and to allow full assessment of the lesion. It is important to carefully document the length and position of the stenosis as well as the location in relation to the vocal cords. Rarely, if ever, is a tracheostomy necessary. For patients who are not operative candidates due to associated comorbidities, internal stents, typically silicone T tubes, are useful. Wire mesh stents should not be used, given their known propensity to erode through the wall of the airway. The use of balloon dilation and tracheoplasty also has been described, although their efficacy is marginal. Efforts focused on tissue engineering may provide suitable material for tracheal replacement in long-segment tracheal stenosis in the future.

Fig. 19-3.

Diagram of the principal postintubation lesions. A. A circumferential lesion at the cuff site after the use of an endotracheal

tube. B. Potential lesions after the use of tracheostomy tubes. Anterolateral stenosis can be seen at the stomal level. Circumferential stenosis can be seen at the cuff level (lower than with an endotracheal tube). The segment in between is often inflamed and malacotic. C. Damage to the subglottic larynx. D. Tracheoesophageal fistula occurring at the level of the tracheostomy cuff. Circumferential damage is usual at this level. E. Tracheoinnominate artery fistula. (Adapted with permission from Grillo.2 )

Most intubation injuries are located in the upper third of the trachea, so tracheal resection usually is done through a collar incision. Resection typically involves 2 to 4 cm of trachea for benign stenosis. However, a primary anastomosis can still be performed without undue tension, even if up to one half of the trachea needs to be resected.2 When resection for a postintubation injury is performed, it is critical to fully resect all inflamed and scarred tissue. Tracheostomies and stents are not required postoperatively, and the patient often is extubated in the operating room or shortly thereafter.

Tracheal Fistulas TRACHEOINNOMINATE ARTERY FISTULA Tracheoinnominate artery fistula has two causes: too low a placement of the tracheostomy and hyperinflation of the tracheal cuff. When performing a tracheostomy, the surgeon must be diligent about proper identification of the tracheal rings. Tracheostomies should be placed through the second to fourth tracheal rings without reference to the location of the sternal notch. When they are placed below the fourth tracheal ring, the inner curve of the tracheostomy cannula will be positioned to exert pressure on the upper surface of the innominate artery, which will lead to arterial erosion. Similarly, the tracheal cuff, when hyperinflated, will cause ischemic injury to the airway and subsequent erosion into the artery and fistula development. Most cuff-induced fistulas develop within 2 weeks after placement of the tracheostomy. Clinically, tracheoinnominate artery fistulas present with bleeding. A premonitory hemorrhage often occurs, and although it usually is not massive, it must not be ignored or simply attributed to general airway irritation or wound bleeding. With significant bleeding, the tracheostomy cuff can be hyperinflated to temporarily occlude the arterial injury. If such an effort is unsuccessful, the tracheostomy incision should immediately be opened widely and a finger inserted to compress the artery against the manubrium (Fig. 19-4). The patient can then be orally intubated, and the airway suctioned free of blood. Emergent surgical resection of the involved segment of artery is performed, usually without reconstruction.

Fig. 19-4.

Steps in the emergency management of a tracheoinnominate artery fistula.

TRACHEOESOPHAGEAL FISTULA Tracheoesophageal fistulas (TEFs) occur primarily in patients with an indwelling nasogastric tube who are also receiving prolonged mechanical ventilatory support.3 Cuff compression of the membranous trachea against the nasogastric tube leads to airway and esophageal injury and fistula development. Clinically, saliva, gastric contents,

or tube feeding contents are noted in the material suctioned from the airway. Distention of the stomach secondary to positive pressure ventilation can occur. Diagnosis of a suspected TEF is by bronchoscopy. Withdrawal of the endotracheal tube with the bronchoscope inserted allows the fistula at the cuff site to be seen. Alternatively, esophagoscopy will enable visualization of the cuff of the endotracheal tube in the esophagus. First and foremost, treatment of a TEF requires weaning the patient from the ventilator and then extubating as soon as possible. During the weaning period, the nasogastric tube should be removed, with attention given to ensuring that the cuff of the endotracheal tube is placed below the fistula and that it is not overinflated. Then a gastrostomy tube should be placed for aspiration (to prevent reflux) and a jejunostomy tube for feeding. If aspiration is relentless and is not managed by the aforementioned steps, esophageal diversion with esophagostomy can be performed. Once the patient is weaned from the ventilator, a single-stage operation should be done, consisting of tracheal resection and primary anastomosis, repair of the esophageal defect, and interposition of a muscle flap between the trachea and esophagus (Fig. 19-5).4

Fig. 19-5.

Single-stage operation for closure of a tracheoesophageal fistula and tracheal resection. A. The fistula is divided and the trachea is transected below the level of damage. B. The fistula is closed on the tracheal side in a single layer and on the esophageal side in a double layer. C. The damaged trachea segment is resected. D. View of completed tracheal anastomosis. m. = muscle.

Tracheal Neoplasms Primary tracheal neoplasms are exceedingly rare, and the diagnosis frequently is delayed. The most common primary tracheal neoplasms are squamous cell carcinomas (related to smoking) and adenoid cystic carcinomas. Clinically, tracheal tumors present with cough, dyspnea, hemoptysis, stridor, or symptoms of invasion of contiguous structures (such as the recurrent laryngeal nerve or the esophagus). The most common radiologic finding of tracheal malignancy is tracheal stenosis, but it is seen in only 50% of cases. With tumors other than squamous cell carcinomas, symptoms may persist for months because of slow tumor growth rates. Stage of presentation is advanced, with approximately 50% of patients presenting with stage IV disease. Overall 5-year survival for patients with tracheal neoplasms is 40%, but survival falls to 15% for those with stage IV disease.5 Squamous cell carcinomas often present with regional lymph node metastases and are frequently not resectable at the time of presentation. Their biologic behavior is similar to that of squamous cell carcinomas of the lung. Adenoid cystic carcinomas, which are a type of salivary gland tumor, are generally slow growing, spread submucosally, and tend to infiltrate along nerve sheaths and within the tracheal wall. Spread to regional lymph nodes can occur. Although indolent in nature, adenoid cystic carcinomas are malignant and can spread to the lungs and bones. Squamous cell carcinomas and adenoid cystic carcinomas represent approximately 65% of all tracheal neoplasms. The remaining 35% is composed of small cell carcinomas, mucoepidermoid carcinomas, adenocarcinomas, lymphomas, and others.6

THERAPY A treatment algorithm for tracheal neoplasms is presented in Fig. 19-6. Evaluation and treatment of patients with

tracheal tumors should include neck and chest computed tomography (CT) and rigid bronchoscopy. Rigid bronchoscopy permits general assessment of the airway and tumor; it also allows dbridement or laser ablation of the tumor to provide relief of dyspnea. If the tumor is judged to be completely resectable, primary resection and anastomosis is the treatment of choice.7

Fig. 19-6.

Algorithm for evaluation and treatment of tracheal neoplasm. PET = positron emission tomography.

The length limit of tracheal resection is roughly 50% of the trachea. To prevent tension on the anastomosis postoperatively, specialized maneuvers are necessary, such as anterolateral tracheal mobilization, suturing of the chin to the sternum with the head flexed forward for 7 days, laryngeal release, and right hilar release. For most tracheal resections (which involve much less than 50% of the airway), anterolateral tracheal mobilization and suturing of the chin to the sternum for 7 days are done routinely. Use of laryngeal and hilar release is determined at the time of surgery, based on the surgeon's judgment of the degree of tension present. Radiotherapy is frequently given postoperatively after resection of both adenoid cystic carcinomas and squamous cell carcinomas, due to their radiosensitivity.8 A dose of 50 Gy or higher is usual. For patients with unresectable tumors, radiation may be given as the primary therapy with the expectation of temporary local control, but it is rarely curative. For recurrent airway compromise, stenting or laser therapies should be considered part of the treatment algorithm.

LUNG Anatomy SEGMENTAL ANATOMY The segmental anatomy of the lungs and bronchial tree is illustrated in Fig. 19-7.9 Note the continuity of the pulmonary parenchyma between adjacent segments of each lobe. In contrast, separation of the bronchial and vascular stalks allows subsegmental and segmental resections, if the clinical situation requires it or if lung tissue can be preserved.

Fig. 19-7.

Segmental anatomy of the lungs and bronchi.

LYMPHATIC DRAINAGE Many lymphatic vessels are located beneath the visceral pleura of each lung, in the interlobular septa, in the submucosa of the bronchi, and in the perivascular and peribronchial connective tissue. Lymph nodes that drain the lungs are divided into two groups according to the tumor, node, and metastasis (TNM) staging system for lung cancer: the pulmonary lymph nodes, N1; and the mediastinal nodes, N2 (Fig. 19-8).

Fig. 19-8.

The location of regional lymph node stations for lung cancer staging. Station, Description: 1, highest mediastinal lymph nodes; 2, upper paratracheal nodes; 3, prevascular, precarinal and retrotracheal nodes; 4, lower paratracheal nodes; 5, aorto-pulmonary nodes; 6, pre-aortic nodes; 7, subcarnal nodes; 8, paraesophageal nodes; 9, pulmonary ligament nodes; 10, tracheobronchial nodes; 11, interlobular nodes; 12, lobar bronchial nodes; 13, segmental nodes; 14, subsegmental nodes. Note: Stations 12, 13, and 14 are not shown in their entirety. (Reproduced with permission from Ferguson, MK: Thoracic Surgery Atlas. W.B. Saunders, Inc., Philadelphia, PA, 2007. Copyright Elsevier.)

The N1 lymph nodes consist of the following: (a) intrapulmonary or segmental nodes that lie at points of division of segmental bronchi or in the bifurcations of the pulmonary artery; (b) lobar nodes that lie along the upper, middle,

and lower lobe bronchi; (c) interlobar nodes that are located in the angles formed by the bifurcation of the main bronchi into the lobar bronchi; and (d) hilar nodes that are located along the main bronchi. The interlobar lymph nodes lie in the depths of the interlobar fissure on each side and constitute a lymphatic sump for each lung, referred to as the lymphatic sump of Borrie ; all of the pulmonary lobes of the corresponding lung drain into this group of nodes (Fig. 19-9). On the right side, the nodes of the lymphatic sump lie around the bronchus intermedius (bounded above by the right upper lobe bronchus and below by the middle lobe and superior segmental bronchi). On the left side, the lymphatic sump is confined to the interlobar fissure, with the lymph nodes in the angle between the lingular and lower lobe bronchi and in apposition to the pulmonary artery branches.

Fig. 19-9.

The lymphatic sump of Borrie includes the groups of lymph nodes that receive lymphatic drainage from all pulmonary lobes of the corresponding lung.

The N2 lymph nodes consist of four main groups: (a) anterior mediastinal, (b) posterior mediastinal, (c) tracheobronchial, and (d) paratracheal. The anterior mediastinal nodes are located in association with the upper surface of the pericardium, the phrenic nerves, the ligamentum arteriosum, and the left innominate vein. Within the inferior pulmonary ligament on each side are the paraesophageal lymph nodes, which are part of the posterior mediastinal group. Additional paraesophageal nodes can be located more superiorly, between the esophagus and trachea near the arch of the azygos vein. The tracheobronchial lymph nodes are made up of three subgroups that are located near the bifurcation of the trachea: the subcarinal nodes, the lymph nodes that lie in the obtuse angle between the trachea and each main stem bronchus, and nodes that lie anterior to the lower end of the trachea. The paratracheal lymph nodes are located in proximity to the trachea in the superior mediastinum. Those on the right side form a chain with the tracheobronchial nodes inferiorly and with some of the deep cervical nodes above (scalene lymph nodes). Lymphatic drainage of the right lung is ipsilateral, except for occasional bilateral drainage to the superior mediastinum. Ipsilateral and contralateral drainage from the left lung, particularly the left lower

lobe, to the superior mediastinum occur with the same frequency.

COMPUTED TOMOGRAPHY Spiral (helical) CT allows continuous scanning as the patient is moved through a scanning gantry so that an x-ray beam can trace a helical curve in relation to the patient's position. The entire thorax can be imaged during a solitary breath hold, so motion artifacts are eliminated, which results in superior image quality (compared with conventional CT scanning), particularly in the detection of pulmonary nodules and central airway abnormalities.1 0 The shorter acquisition time of spiral CT allows for consistent contrast filling of the great vessels, which results in markedly improved visualization of pathologic states and anatomic variation contiguous to vascular structures. In addition, three-dimensional spiral CT images can be reconstructed for enhanced visualization of spatial anatomic relationships.1 1 In general, slice thickness is proportional to image resolution; as slice thickness increases, volume averaging increases, which results in a decline in image resolution. Slice thickness is determined by the structure being imaged as well as by the indication for the study. Thin sections (1- to 2-mm collimation) at 1-cm intervals should be used to evaluate pulmonary parenchyma and peripheral bronchi. If the goal is to find any pulmonary metastases, thin sections at intervals of 5- to 7-mm collimation are recommended. For assessing the trachea and central bronchi, collimation of 3 to 5 mm is recommended. Virtually all institutions have protocols for spiral CT scanning. Providing accurate clinical history and data is of paramount importance to obtaining appropriate imaging. In addition, the astute clinician must be well versed in normal thoracic anatomy to appreciate pathologic changes and management strategies (Fig. 19-10).

Fig. 19-10.

Spiral computed tomographic scan showing normal transverse chest anatomy at four levels. A. At the level of the tracheal bifurcation, the aorticopulmonary window (APW) can be seen. B. The origin of the left pulmonary artery (LPA) can be seen at a level 1 cm inferior to A. C. The origin and course of the right pulmonary artery (RPA) can be seen at this next most cephalad level. The left upper lobe bronchus can be seen at its origin from the left main bronchus (LMB). D. Cardiac chambers and pulmonary veins are seen in the lower thorax. AA = ascending aorta; DA = descending aorta; LA = left atrium; LV = left ventricle; MPA = main pulmonary artery; RA = right atrium; RV = right ventricle; SVC = superior vena cava; T = trachea.

Thoracic Surgical Approaches Thoracic surgical approaches have changed over recent years with advancements in minimally invasive approaches. A surgeon trained in advanced minimally invasive techniques can now perform sympathectomy, segmental lung resections, lobectomies, and mediastinal resections through multiple thoracoscopic ports and small access incisions without the need for a substantial, rib-spreading incision. Although there has not been a documented change in mortality using these approaches, subjective measures of quality of life after video-assisted thoracic surgery (VATS), such as pain level (Fig. 19-11) and perceived functional recovery, consistently and reproducibly favor VATS over thoracotomy. Objective measures such as functional status as measured by 6-minute walk, return to work, and ability to tolerate chemotherapy also favor VATS over thoracotomy. Finally, recovery of respiratory function occurs earlier in patients undergoing VATS. These findings are pronounced in patients with chronic obstructive pulmonary disease (COPD) and in the elderly, populations whose quality of life can be dramatically impacted by changes in their respiratory symptoms and function, thoracic pain, and physical performance.1 2 Table 19-1 provides a summary of populations that may benefit from VATS approaches.

Fig. 19-11.

Pie chart comparison of pain control at 3 weeks after lobectomy by standard thoracotomy or video-assisted thoracic surgery (VATS). The pie charts show that patients undergoing VATS have significantly less pain (P 70 y Vascular problems Aneurysm, severe peripheral vascular disease Recent or impending major operation Urgent abdominal operation, joint replacement requiring use of crutches, need for contralateral thoracotomy Psychologic/neurologic conditions Substance abuse, poor command following, pain syndromes

Immunosuppression/impaired wound healing Recent transplantation, diabetes Condition

Examples

DLCO = carbon monoxide diffusion capacity; FEV 1 = forced expiratory volume in 1 s. Source: Reproduced with permission from Demmy TL, et al: Is video-assisted thoracic surgery lobectomy better? Quality of life considerations. Ann Thorac Surg 85:S719, 2008. Copyright Elsevier. Mediastinoscopy is generally used for diagnostic assessment of mediastinal lymphadenopathy and staging of lung cancer. Mediastinoscopy is performed via a transverse 2- to 3-cm incision approximately 1 cm above the suprasternal notch. The incision is carried through the platysma. The midline of the strap muscles is identified and dissected laterally. Care is taken to avoid any venous structures that may overlie these muscles, which are highly variable in size and position. The pretracheal fascia is incised. Blunt dissection along the anterior trachea is performed to the level of the carina with careful note of the position of the innominate artery. The innominate artery can be located close to the suprasternal notch, particularly in women; therefore, blind use of electrocautery is to be avoided. The mediastinoscope is inserted, and anatomic definition of the trachea, carina, and lateral aspect of both proximal bronchi is achieved with blunt dissection using a long suction catheter. Long biopsy forceps can be inserted through the scope for sampling. The standard staging procedure for lung cancer includes biopsies of the paratracheal (stations 4R and 4L) and subcarinal lymph nodes (station 7). Before the widespread use of VATS and CT-guided biopsy, a modified Chamberlain procedure was used for evaluation of aortopulmonary window lymph nodes. In this procedure a 4- to 5-cm incision is made over the left second costal cartilage, which, on occasion, is excised. The internal mammary vessels may be ligated or preserved. The dissection proceeds into the mediastinum along the aortic arch. Biopsy of the aortopulmonary window lymph nodes and anterior mediastinal lymphomas just beneath the second and third costal cartilage can then be performed. Improved techniques in CT-guided biopsy, positron emission tomography (PET), and VATS have significantly reduced the need for this operative approach. The most frequently used incision for an open procedure in thoracic surgery is the posterolateral thoracotomy. The posterolateral thoracotomy incision can be used for most pulmonary resections, for esophageal operations, and for the approach to the posterior mediastinum and vertebral column (Fig. 19-12). The patient is placed in the lateral decubitus position. A pitfall of thoracic incisions in a lateral decubitus position is the potential for injury to the brachial plexus and axillary vascular structures secondary to displacement of the shoulder. Therefore careful attention must be paid to positioning the patient on the operating table after anesthesia has been induced. The skin incision typically starts at the anterior axillary line just below the nipple level and extends posteriorly below the tip of the scapula. The incision then proceeds in a cranial direction halfway between the vertebral border of the scapula and the spinous processes of the vertebrae. The latissimus dorsi is divided and the serratus anterior is retracted. Before entering the pleural space, the surgeon confirms that the anesthesiologist has excluded ventilation to the operative lung by clamping the proper lumen of a double-lumen endotracheal tube. The pleural space is then entered at the fifth interspace by dividing the intercostal muscles with electrocautery above the sixth rib. A rib spreader is placed into the thoracic cavity and minimally opened. The division of the intercostal muscles anteriorly (to the level of the internal mammary artery) and posteriorly (to the level of the paraspinous tendons) is continued using electrocautery from the inside of the thoracic cavity as an internal thoracotomy. The internal thoracotomy will prevent rib fracture during subsequent spreading of the retractor. If necessary, a portion of rib can be removed posteriorly to improve visibility and prevent injury to a rib, which can lead to increased

postoperative pain and prolong restricted motion of the rib cage. Should a rib fracture occur, resection of any broken edges is recommended to help reduce postoperative pain.

Fig. 19-12.

The posterolateral thoracotomy incision. A. Skin incision from the anterior axillary line to the lower extent of the scapula tip. B and C. Division of the latissimus dorsi and shoulder girdle musculature. D. The pleural cavity is entered after dividing the intercostal muscles along the lower margin of the interspace, with care taken not to injure the neurovascular bundle lying below each rib.

The anterolateral thoracotomy has traditionally been used in trauma victims. This approach allows quick entry into the chest with the patient supine. When hemodynamic instability is present, the lateral decubitus position significantly compromises control over the patient's cardiopulmonary system and resuscitation efforts, whereas the supine position allows the anesthesiologist full access to the patient. The incision is submammary, beginning at the sternal border overlying the fourth intercostal space and extending to the midaxillary line. The pectoralis major muscle and some of the pectoralis minor are divided, and the incision is carried through the serratus anterior muscle. The intercostal muscles are divided with cautery over the top of the subjacent rib. Should more exposure be necessary, the sternum can be transected and the incision carried to the contralateral thoracic cavity ("clamshell" thoracotomy). A bilateral anterior thoracotomy incision with a transverse sternotomy (clamshell thoracotomy) is a standard operative approach to the heart and mediastinum in certain elective circumstances. It is the preferred incision for double-lung transplantation. A partial median sternotomy also can be added to an anterior thoracotomy ("trap door" or "hemiclam" thoracotomy) for access to mediastinal structures. A hypesthetic nipple is a frequent complication of this approach. The median sternotomy incision allows exposure of anterior mediastinal structures and is principally used for cardiac operations. The surgeon has access to both pleural cavities and can avoid incision into the pleural cavity if it is unnecessary. The skin incision extends from the suprasternal notch to the xiphoid process (Fig. 19-13). A sternal saw is used to split the sternum. Advantages of this approach include decreased postoperative pain and less compromise of pulmonary function than with a lateral thoracotomy. Disadvantages of the incision include an increased risk of infection if a tracheostomy is needed concomitantly or before the sternotomy is completely healed.

Fig. 19-13.

The median sternotomy incision. A. Skin incision from the suprasternal notch to the xiphoid process. B. Exposure of the pleural space. a. = artery; v. = vein.

Video-Assisted Thoracoscopic Surgery VATS has become an accepted approach for diagnosis and treatment of pleural effusions and recurrent pneumothorax, and for lung biopsy, lobectomy or segmental resection, resection of bronchogenic and mediastinal cysts, esophageal myotomy, and intrathoracic esophageal mobilization for esophagectomy.1 3 VATS is performed via two to four incisions measuring 0.5 to 1.2 cm in length to allow insertion of the thoracoscope and instruments.

The incision location varies according to the procedure. For VATS lobectomy, port placement varies according to the lobe being resected and is highly variable among surgeons.1 4 The basic principle is to position the ports high enough on the thoracic cage to have access to the hilar structures (Fig. 19-14). Endoscopic staplers are used to divide the major vascular structures and bronchus.

Fig. 19-14.

Selected video-assisted thoracic surgery lobectomy maneuvers. All the maneuvers are shown with the patient positioned in the left lateral decubitus position. The same maneuvers can be performed in mirror image for left-sided work. A. Medial

viewing and inferior holding of lung to allow dissection through the access incision. Example shows dissection of the apical hilum. B. Medial viewing and access holding of lung to allow stapling of hilar structures from below. Example shows division of the apical pulmonary artery trunk to the right upper lobe (upper lobe branch of vein divided and reflected away). C. Standard viewing and use of working port to dissect and divide structures while lung is retracted through access incision. Example shows use of stapler to divide pulmonary artery to right lower lobe. D. Standard viewing and use of working port to retract lung and access incision to dissect structures. This method is commonly used to dissect the pulmonary artery in the major fissure. Example shows inferior pulmonary vein after the pulmonary ligament was divided using this maneuver. E. Standard viewing and use of access incision to deliver stapler to divide fissures. Example shows division of the posterior fissure between the right lower lobe and the upper lobe. (Reproduced with permission from Demmy et al.14 Copyright Elsevier.)

At the conclusion of a thoracic operation, the pleural cavity typically is drained with one or more chest tubes. Each chest tube is brought out through a separate stab incision in the chest wall below the level of the thoracotomy or through a VATS port site. If the visceral pleura has not been violated and there is no concern of pneumothorax or hemothorax (i.e., after VATS sympathectomies), a chest tube is unnecessary. The lung is then ventilated and placed under positive pressure ventilation to assist with re-expansion of atelectatic segments. Thoracic incisions should be closed in layers: the intercostal space with three to four interrupted sutures, two running sutures for musculofascial layers, and a running subcuticular suture or staples for the skin closure.

Postoperative Care CHEST TUBE MANAGEMENT Chest tubes are routinely placed into the pleural space at the conclusion of all operations involving resection or manipulation of lung tissue. The reason for pleural tube placement is twofold: first, the tube allows evacuation of air if an air leak is present. Second, blood and pleural fluid can be drained, which prevents accumulations within the pleural space that would compromise the patient's respiratory status. The tube is removed when the air leak is resolved and when the volume of drainage decreases below an acceptable level over 24 hours. The ideal volume of drainage over a 24-hour period that predicts safe chest tube removal is unknown. The ability of the pleural lymphatics to absorb fluid is substantial. It can be as high as 0.40 mL/kg per hour in a healthy individual, possibly resulting in the absorption of up to 500 mL of fluid over a 24-hour period. The capacity of the pleural space to manage and absorb fluid is high if the pleural lining and lymphatics are healthy. In the past, many surgeons required a drainage volume of 5% of body weight) suggest either a large tumor burden or the presence of metastases. Physical examination should focus on the patient's overall appearance, and any evidence of weight loss such as redundant skin or muscle wasting should be noted. A complete examination of the head and neck, including evaluation of cervical and supraclavicular lymph nodes and the oropharynx, should be performed because of the strong association of oropharyngeal primary tumors and lung cancer. This is particularly true for patients with a significant history of tobacco use. The skin should be thoroughly examined. Routine laboratory studies include serum levels of hepatic enzymes (e.g., serum glutamic oxaloacetic transaminase and alkaline phosphatase), as well as serum calcium level (to detect bone metastases or the ectopic parathyroid syndrome). Elevation of either hepatic enzyme levels or serum calcium levels typically occurs with extensive metastases.

Mediastinal Lymph Nodes Chest CT scanning permits assessment of possible metastatic spread to the mediastinal lymph nodes. It continues to be the most effective noninvasive method available to assess the mediastinal and hilar nodes for enlargement. However, a positive CT finding (i.e., nodal diameter >1.0 cm) predicts actual metastatic involvement in only approximately 70% of lung cancer patients. Thus even when enlarged mediastinal lymph nodes are noted on CT scan, up to 30% of such nodes are enlarged due to noncancerous reactive causes such as inflammation related to atelectasis or pneumonia secondary to the tumor. Therefore, no patient should be denied an attempt at curative resection just because of a positive CT finding of mediastinal lymph node enlargement. Any CT finding of metastatic nodal involvement must be confirmed histologically. The negative predictive value of normal-appearing lymph nodes by CT (lymph nodes 36 months, and a single metastasis.7 6

Table 19-17 Actuarial Survival Data from the International Registry of Lung Metastases 5y 36 13 10 y 26 7 15 y 22 — Survival Complete Resection (%)

Incomplete Resection (%)

Pulmonary Infections LUNG ABSCESS A lung abscess is a localized area of pulmonary parenchymal necrosis caused by an infectious organism. Tissue destruction results in a solitary or dominant cavity measuring at least 2 cm in diameter. Less often, there may be multiple, smaller cavities (6 weeks is considered chronic. Based on the etiology (Table 19-18), lung abscesses are further classified as primary or secondary. A primary lung abscess occurs, for example, in immunocompromised patients (as a result of malignancy, chemotherapy, organ transplantation, etc), in patients in whom highly virulent organisms incite a necrotizing pulmonary infection, and in patients who have a predisposition to aspirate oropharyngeal or GI secretions. A secondary lung abscess occurs in patients with an underlying condition such as a partial bronchial obstruction, a lung infarct, or adjacent suppurative infections (subphrenic or hepatic abscesses).7 7

Table 19-18 Causes of Lung Abscess I. Primary A. Necrotizing pneumonia 1. Staphylococcus aureus, Klebsiella, Pseudomonas, Mycobacterium 2. Bacteroides, Fusobacterium, Actinomyces

3. Entamoeba, Echinococcus B. Aspiration pneumonia 1. Anesthesia 2. Stroke 3. Drugs or alcohol C. Esophageal disease 1. Achalasia, Zenker's diverticulum, gastroesophageal reflux D. Immunodeficiency 1. Cancer (and chemotherapy) 2. Diabetes 3. Organ transplantation 4. Steroid therapy 5. Malnutrition II. Secondary A. Bronchial obstruction 1. Neoplasm 2. Foreign body B. Systemic sepsis 1. Septic pulmonary emboli 2. Seeding of pulmonary infarct C. Complication of pulmonary trauma 1. Infection of hematoma or contusion 2. Contaminated foreign body or penetrating injury D. Direct extension from extraparenchymal infection 1. Pleural empyema 2. Mediastinal, hepatic, subphrenic abscess

Source: Adapted with permission from Rusch VW, et al: Chest wall, pleura, and mediastinum, in Schwartz SI, et al (eds): Principles of Surgery, 7th ed. New York: McGraw-Hill, 1999, p 735. The incidence of bacterial lung abscess in the United States has declined significantly over the past 50 years, with a concomitant decrease in the mortality rate from between 30 and 40% to between 5 and 10%. This decrease has been attributed to the development of bactericidal antibiotics. Factors associated with a worse outcome include advanced patient age, prolonged symptoms, comorbid disease, nosocomial infection, and perhaps larger cavity size. More recently, a greater proportion of lung abscesses have been associated with pulmonary malignancies or immunosuppression, which has resulted in an increase in lung abscesses caused by unusual or opportunistic organisms.

Pathogenesis Lung abscess is the result of a lower respiratory tract infection only by organisms that cause necrosis. Microorganisms gain access to the respiratory tract via inhalation of aerosolized particles, aspiration of oropharyngeal secretions, or hematogenous spread from distant sites. Direct extension from a contiguous site is less frequent. Most primary lung abscesses are suppurative bacterial infections secondary to aspiration. Risk factors for increased aspiration include impaired consciousness, suppressed cough reflex, dysfunctional esophageal motility, laryngopharyngeal reflux disease, and centrally acting neurologic diseases (e.g., stroke). At the time of

aspiration, the composition of the oropharyngeal flora determines the etiologic organisms; those organisms that are most numerous or virulent proliferate and emerge as single or predominant pathogens. With increasing use of proton pump inhibitors to suppress acid secretion in the stomach, the oropharyngeal flora has shifted, and risk of aspiration-associated bacterial infections has increased.7 8 Secondary lung abscesses occur most often distal to an obstructing bronchial carcinoma. Infected cysts or bullae are not considered true abscesses. The characteristic pathologic features of aspiration pneumonia include alveolar edema and infiltration with inflammatory cells. Because of the effect of gravity, foci of infection tend to develop in the subpleural regions of the superior segments of the lower lobes and in the posterior segments of the upper lobes. The right lung is involved more frequently, presumably because of the less acute angle of the right main bronchus. Thus, the right upper and lower lobes are most commonly affected, followed by the left lower lobe and right middle lobe.

Microbiology In community-acquired pneumonia, the causative bacteria are predominantly gram positive; in hospital-acquired pneumonia, 60 to 70% of the organisms are gram negative. Gram-negative bacteria associated with nosocomial pneumonia include Klebsiella pneumoniae, Haemophilus influenzae, Proteus species, Pseudomonas aeruginosa, Escherichia coli, Enterobacter cloacae, and Eikenella corrodens. Immunosuppressed patients may develop abscesses caused by the usual pathogens as well as less virulent and opportunistic organisms such as Salmonella species, Legionella species, Pneumocystis jiroveci, atypical mycobacteria, and fungi. Normal oropharyngeal secretions contain many more Streptococcus species and more anaerobes (approximately 1 x

108 organisms/mL) than aerobes (approximately 1

x

107 organisms/mL). Pneumonia that follows from aspiration,

with or without abscess development, is typically polymicrobial. An average of two to four isolates present in large numbers have been cultured from lung abscesses sampled percutaneously. Overall, at least 50% of these infections are caused by purely anaerobic bacteria, 25% are caused by mixed aerobes and anaerobes, and 25% or fewer are caused by aerobes only.

Clinical Features and Diagnosis The typical presentation may include productive cough, fever [>38.9C (102F)], chills, leukocytosis (>15,000 cells/mm3 ), weight loss, fatigue, malaise, pleuritic chest pain, and dyspnea. Lung abscesses also may present in a more indolent fashion, with weeks to months of cough, malaise, weight loss, low-grade fever, night sweats, leukocytosis, and anemia. After aspiration pneumonia, 1 to 2 weeks typically elapse before cavitation occurs; 40 to 75% of such patients produce a putrid, foul-smelling sputum. Severe complications such as massive hemoptysis, endobronchial spread to other portions of the lungs, rupture into the pleural space and development of pyopneumothorax, or septic shock and respiratory failure are rare in the modern antibiotic era. The mortality rate is approximately 5 to 10% except in immunosuppressed patients, in whom rates range from 9 to 28%. The chest radiograph is the primary tool for diagnosing a lung abscess (Fig. 19-28). Its distinguishing characteristic is a density or mass with a relatively thin-walled cavity. Frequently, an air-fluid level is observed within the abscess, indicating a communication with the tracheobronchial tree. CT scan of the chest is useful to clarify the diagnosis when the chest radiograph is equivocal, assess for endobronchial obstruction and/or an associated mass, and evaluate other pathologic anomalies. A cavitating lung carcinoma frequently is mistaken for a lung abscess. Other possible differential diagnoses include loculated or interlobar empyema, infected lung cysts or bullae, tuberculosis, bronchiectasis, fungal infections, and noninfectious inflammatory conditions (e.g., Wegener's granulomatosis).

Fig. 19-28.

Lung abscess resulting from emesis and aspiration after an alcoholic binge. A. Chest radiograph showing an abscess cavity in the left upper lobe (arrow ). B. Coronal tomogram highlighting the thin wall of the abscess (arrow ). C. Healing of the abscess cavity after 4 weeks of antibiotic therapy and postural drainage.

Identification of the specific etiologic organism should ideally occur before antibiotic administration. Attempts should be made to obtain an adequate specimen for culture analysis to appropriately direct antibiotic therapy and minimize the risk of promoting drug-resistant bacterial speciation. Unfortunately, routine sputum cultures are often of limited usefulness because of contamination with upper respiratory tract flora. Bronchoscopy, which is essential to rule out endobronchial obstruction due to tumor or foreign body, is ideal for obtaining uncontaminated cultures using bronchoalveolar lavage. Culture samples also can be obtained by percutaneous transthoracic FNA under ultrasound or CT guidance.

Management Systemic antibiotics directed against the causative organism represent the mainstay of therapy. For communityacquired infections secondary to aspiration, likely pathogens are oropharyngeal streptococci and anaerobes. Penicillin G, ampicillin, and amoxicillin are the main therapeutic agents, but a beta-lactamase inhibitor or metronidazole should be added because of the increasing prevalence of gram-negative anaerobes that produce

beta-lactamase. Clindamycin is also a primary therapeutic agent. For hospital-acquired infections, frequently encountered causative agents include Staphylococcus aureus and aerobic gram-negative bacilli, common organisms of the oropharyngeal flora. Piperacillin or ticarcillin with a beta-lactamase inhibitor (or equivalent alternatives) provides better coverage of likely pathogens. The duration of antimicrobial therapy is variable: 1 to 2 weeks for simple aspiration pneumonia and 3 to 12 weeks for necrotizing pneumonia and lung abscess. It is probably best to treat until the cavity is resolved or until serial radiographs show significant improvement. Parenteral therapy generally is used until the patient is afebrile and able to demonstrate consistent enteral intake. Oral therapy can then be used to complete the course of therapy. Surgical drainage of lung abscesses is uncommon, because drainage usually occurs spontaneously via the tracheobronchial tree. Indications for intervention are listed in Table 19-19.

Table 19-19 Indications for Surgical Drainage Procedures for Lung Abscesses 1. 2. 3. 4. 5. 6. 7.

Failure of medical therapy Abscess under tension Abscess increasing in size during appropriate treatment Contralateral lung contamination Abscess >4–6 cm in diameter Necrotizing infection with multiple abscesses, hemoptysis, abscess rupture, or pyopneumothorax Inability to exclude a cavitating carcinoma

External drainage may be accomplished with tube thoracostomy, percutaneous drainage, or surgical cavernostomy. The choice between thoracostomy placement and radiologic placement of a drainage catheter depends on the treating physician's preference and the availability of interventional radiology. Surgical resection is required in 40%. Treatment options for this disease vary depending on the severity of the disease as well as the stage. Amphotericin B deoxycholate or the triazoles continue to be the primary antifungal medications. Treatment of primary pulmonary coccidioidomycosis remains controversial, because in most patients the infection will resolve without further intervention. Itraconazole and fluconazole are effective treatments for patients with mild to moderate disease with evidence of pulmonary cavitation or progressive chronic pulmonary lesions. Amphotericin B is warranted for patients with severe pulmonary or disseminated disease and for immunocompromised patients. Blastomyces dermatitidis is a round, single-budding yeast with a characteristic thick, refractile cell wall. It resides in the soil as a nonmotile spore called a conidia. Exposure occurs when contaminated soil is disturbed and the conidia are aerosolized. The spore is inhaled and transforms into a yeast phase at body temperature.105 The majority of exposed persons develop a self-limited infection. A small minority of patients develop chronic pulmonary infection or disseminated disease, including cutaneous, osteoarticular, or genitourinary involvement. B. dermatitidis has a worldwide distribution. In the United States it is endemic in the central states.106 In the chronic infection, the organism induces a granulomatous and pyogenic reaction with microabscesses and giant cells; caseation, cavitation, and fibrosis may also occur. Symptoms are nonspecific and consistent with chronic pneumonia in 60 to 90% of patients. They include cough, mucoid sputum production, chest pain, fever, malaise,

weight loss, and, uncommonly, hemoptysis. In acute disease, radiographs are either completely negative or have nonspecific findings; in chronic disease, fibronodular lesions (with or without cavitation) similar to those of tuberculosis are noted. Pulmonary parenchymal abnormalities in the upper lobe(s) may be noted. Mass lesions similar to carcinoma are common, and lung biopsy is frequently performed. Over 50% of patients with chronic blastomycosis also have extrapulmonary manifestations, but 600 mL of blood within a 24-hour period. It is a medical emergency associated with a mortality rate of 30 to 50%. Most clinicians would agree that losing over a liter of blood via the airway within 1 day is significant, yet use of an absolute volume criterion presents difficulties.

First, it is difficult for the patient or caregivers to quantify the volume of blood being lost. Second, and most relevant, the rate of bleeding necessary to produce respiratory compromise is highly dependent on the individual's prior respiratory status. For example, the loss of 100 mL of blood over 24 hours in a 40-year-old male with normal pulmonary function would be of little immediate consequence, because his normal cough would ensure his ability to clear the blood and secretions. In contrast, the same amount of bleeding in a 69-year-old male with severe COPD, chronic bronchitis, and an FEV1 of 1.1 L may be life-threatening.

ANATOMY The lungs have two sources of blood supply: the pulmonary and bronchial arterial systems. The pulmonary system is a high-compliance, low-pressure system, and the walls of the pulmonary arteries are very thin and delicate. The bronchial arteries, part of the systemic circulation, have systemic pressures and thick walls; most branches originate from the proximal thoracic aorta. Most cases of massive hemoptysis involve bleeding from the bronchial artery circulation or from the pulmonary circulation pathologically exposed to the high pressures of the bronchial circulation. In many cases of hemoptysis, particularly those due to inflammatory disorders, the bronchial arterial tree becomes hyperplastic and tortuous. The systemic pressures within these arteries, combined with a disease process within the airway and erosion, lead to bleeding.

CAUSES Significant hemoptysis has many causes, which can broadly be categorized into pulmonary, extrapulmonary, and iatrogenic causes. Table 19-21 summarizes the most common causes of hemoptysis.109 Most are secondary to inflammatory processes. An acute necrotizing pneumonic infection can lead to destruction and erosion of vascular structures and bleeding. Chronic inflammatory disorders (e.g., bronchiectasis, cystic fibrosis, tuberculosis) lead to localized bronchial arterial proliferation, and with erosion, bleeding of these hypervascular areas occurs.

Table 19-21 Pulmonary and Extrapulmonary Causes of Massive Hemoptysis Pulmonary parenchymal disease Congestive heart failure Intrapulmonary catheter Bronchitis Coagulopathy Bronchiectasis Mitral stenosis Tuberculosis Medications Lung abscess Pneumonia Cavitary fungal infection (e.g., aspergilloma) Lung parasitic infection (ascariasis, schistosomiasis, paragonimiasis) Pulmonary neoplasm Pulmonary infarction or embolism Trauma Arteriovenous malformation Pulmonary vasculitis Pulmonary endometriosis Wegener's granulomatosis Cystic fibrosis

Pulmonary hemosiderosis Pulmonary

Extrapulmonary

Iatrogenic

Tuberculosis also can cause hemoptysis by erosion of a broncholith (a calcified tuberculous lymph node) into a vessel or, when a tuberculous cavity is present, by erosion of a blood vessel within the cavity. Within such cavities, aneurysms of the pulmonary artery (referred to as Rasmussen aneurysms ) can develop that are accompanied by subsequent erosion and massive bleeding. Hemoptysis due to lung cancer is usually mild, resulting in blood-streaked sputum. Massive hemoptysis in patients with lung cancer typically is caused by malignant invasion of pulmonary artery vessels by large central tumors. Although rare, it is often a terminal event.

MANAGEMENT The treatment of patients with life-threatening hemoptysis is best carried out by a multidisciplinary team of intensive care physicians, interventional radiologists, and thoracic surgeons. Table 19-22 provides an algorithm for management of patients with massive hemoptysis.

Table 19-22 Treatment Priorities in the Management of Massive Hemoptysis 1. 2. 3. 4. 5.

Achieve respiratory stabilization and prevent asphyxiation. Localize the bleeding site. Control the hemorrhage. Determine the cause. Definitively prevent recurrence.

The pragmatic clinical definition of massive hemoptysis is a degree of bleeding that threatens respiratory stability. Therefore clinical judgment of the risk of respiratory compromise is the first step in evaluating a patient.110,111 Two scenarios are possible: (a) bleeding is significant and persistent, but its rate allows a rapid but sequential diagnostic and therapeutic approach, and (b) bleeding is so rapid that emergency airway control and therapy are necessary.

Scenario 1: Significant, Persistent, But Nonmassive Bleeding Although bleeding is brisk in scenario 1, the patient may be able to maintain clearance of the blood and secretions with his or her own respiratory reflexes. Immediate measures are admission to an intensive care unit, strict bedrest, Trendelenburg positioning with the affected side down (if known), administration of humidified oxygen, monitoring of oxygen saturation and arterial blood gas levels, and insertion of large-bore IV catheters. Strict bedrest with sedation may lead to slowing or cessation of bleeding, and the judicious use of IV narcotics or other relaxants to mildly sedate the patient and diminish some of the reflexive airway activity is often necessary. Also recommended are administration of aerosolized adrenaline, IV antibiotic therapy if needed, and correction of abnormal blood coagulation. Finally, unless contraindicated, IV vasopressin (20 units over 15 minutes, followed by an infusion of 0.2 unit/min) can be given. A chest radiograph is the first test and often proves to be the most revealing. Localized lesions may be seen, but the effects of blood soiling of other areas of the lungs may predominate, obscuring the area of pathology. Chest CT scanning provides more detail and is nearly always performed if the patient is stable. Pathologic areas may be

obscured by blood soiling. Flexible bronchoscopy is the next step in evaluating the patient's condition. Some clinicians argue that rigid bronchoscopy should always be performed. However, if the patient is clinically stable and the ongoing bleeding is not imminently threatening, flexible bronchoscopy is appropriate. It allows diagnosis of airway abnormalities and will usually permit localization of the bleeding site to a lobe or even a segment. The person performing the bronchoscopy must be prepared with excellent suction and must be able to perform saline lavage with a dilute solution of epinephrine. Most cases of massive hemoptysis arise from the bronchial arterial tree; therefore, the next therapeutic option frequently is selective bronchial arteriography and embolization. Prearteriogram bronchoscopy is extremely useful to direct the angiographer. However, if bronchoscopy fails to localize the bleeding site, then bilateral bronchial arteriography can be performed. Typically, the abnormal vascularity is visualized, rather than extravasation of the contrast dye. Embolization will acutely arrest the bleeding in 80 to 90% of patients. However, 30 to 60% of patients will have recurrences. Therefore, embolization should be viewed as an immediate but probably temporizing measure to acutely control bleeding. Subsequently, definitive treatment of the underlying pathologic process is appropriate. If bleeding persists after embolization, a pulmonary artery source should be suspected and pulmonary angiography performed. If respiratory compromise is impending, orotracheal intubation should be performed. After intubation, flexible bronchoscopy should be performed to clear blood and secretions and to attempt localization of the bleeding site. Depending on the possible causes of the bleeding, bronchial artery embolization or (if appropriate) surgery can be considered.

Scenario 2: Significant, Persistent, and Massive Bleeding Life-threatening bleeding requires emergency airway control and preparation for potential surgery. Such patients are best cared for in an operating room equipped with rigid bronchoscopy equipment. Immediate orotracheal intubation may be necessary to gain control of ventilation and suctioning. However, rapid transport to the operating room and rigid bronchoscopy should be facilitated. Rigid bronchoscopy allows adequate suctioning of bleeding with visualization of the bleeding site; the nonbleeding side can be cannulated with the rigid scope and the patient ventilated. After stabilization, ice-saline lavage of the bleeding site can then be performed (up to 1 L in 50-mL aliquots); bleeding stops in up to 90% of patients.112 Alternatively, blockade of the main stem bronchus of the affected side can be accomplished with a double-lumen endotracheal tube, with a bronchial blocker, or by intubation of the nonaffected side using an uncut standard endotracheal tube. Placement of a double-lumen endotracheal tube is challenging in these circumstances, given the bleeding and secretions. Proper placement and suctioning may be difficult, and attempts could compromise the patient's ventilation. The best option is to place a bronchial blocker in the affected bronchus with inflation. The blocker is left in place for 24 hours and the area is then re-examined bronchoscopically. After this 24-hour period, bronchial artery embolization can be performed.

Surgical Intervention In most patients, bleeding can be stopped, recovery can occur, and plans can be made to definitively treat the underlying cause. In scenario 1 (significant, persistent, but nonmassive bleeding), the patient may undergo further evaluation as an inpatient or outpatient. Chest CT scanning and pulmonary function studies should be performed preoperatively. In scenario 2 (significant, persistent, and massive bleeding), surgery, if appropriate, usually will be

performed during the same hospitalization in which the rigid bronchoscopy or main stem bronchus blockade is carried out. In 0.5 and the LDH ratio is >0.6 or the absolute pleural LDH level is more than two thirds of the normal upper limit for serum. If these criteria suggest a transudate, the patient should be carefully evaluated for congestive heart failure, cirrhosis, and other conditions associated with transudative effusion.

Table 19-35 Differential Diagnosis of Pleural Effusions I. Transudative pleural effusions A. Congestive heart failure B. Cirrhosis C. Nephrotic syndrome D. Superior vena caval obstruction

E. Fontan procedure F. Urinothorax G. Peritoneal dialysis H. Glomerulonephritis I. Myxedema J. Cerebrospinal fluid leaks to pleura K. Hypoalbuminemia L. Pulmonary emboli M. Sarcoidosis II. Exudative pleural effusions A. Neoplastic diseases 1. Metastatic disease 2. Mesothelioma 3. Body cavity lymphoma 4. Pyothorax-associated lymphoma B. Infectious diseases 1. Tuberculosis 2. Other bacterial infections 3. Fungal infections 4. Parasitic infections 5. Viral infections C. Pulmonary embolization D. Gastrointestinal disease 1. Pancreatic disease 2. Subphrenic abscess 3. Intrahepatic abscess 4. Intrasplenic abscess 5. Esophageal perforation 6. After abdominal surgery 7. Diaphragmatic hernia 8. Endoscopic variceal sclerosis 9. After liver transplantation E. Heart diseases 1. After coronary artery bypass graft surgery 2. Post–cardiac injury (Dressler's) syndrome 3. Pericardial disease F. Obstetric and gynecologic diseases 1. Ovarian hyperstimulation syndrome 2. Fetal pleural effusion 3. Postpartum pleural effusion 4. Megis' syndrome 5. Endometriosis G. Collagen vascular diseases 1. Rheumatoid pleuritis 2. Systemic lupus erythematosus 3. Drug-induced lupus 4. Immunoblastic lymphadenopathy 5. Sjgren's syndrome 6. Familial Mediterranean fever

7. Churg-Strauss syndrome 8. Wegeners granulomatosis H. Drug-induced pleural disease 1. Nitrofurantoin 2. Dantrolene 3. Methysergide 4. Ergot alkaloids 5. Amiodarone 6. Interleukin-2 7. Procarbazine 8. Methotrexate 9. Clozapine I. Miscellaneous diseases and conditions 1. Asbestos exposure 2. After lung transplantation 3. After bone marrow transplantation 4. Yellow nail syndrome 5. Sarcoidosis 6. Uremia 7. Trapped lung 8. Therapeutic radiation exposure 9. Drowning 10. Amyloidosis 11. Milk of calcium pleural effusion 12. Electrical burns 13. Extramedullary hematopoiesis 14. Rupture of mediastinal cyst 15. Acute respiratory distress syndrome 16. Whipple's disease 17. Iatrogenic pleural effusions J. Hemothorax K. Chylothorax

Source: Reproduced with permission from Light RW: Approach to the patient, in Light RW (ed): Pleural Diseases. Philadelphia: Lippincott Williams & Wilkins, 2001, p 88. If an exudative effusion is suggested, further diagnostic studies may be helpful. If total and differential cell counts reveal a predominance of neutrophils (>50% of cells), the effusion is likely to be associated with an acute inflammatory process (such as a parapneumonic effusion or empyema, pulmonary embolus, or pancreatitis). A predominance of mononuclear cells suggests a more chronic inflammatory process (such as cancer or tuberculosis). Gram's staining and culture should be performed, if possible with inoculation of fluid specimens into culture bottles at the bedside. Pleural fluid glucose levels are frequently decreased (70% of malignant effusions associated with adenocarcinomas but is less sensitive for those associated with mesotheliomas (40 units/L) in the pleural fluid.176,177 Pulmonary embolism should be suspected in a patient with a pleural effusion occurring in association with pleuritic chest pain, hemoptysis, or dyspnea out of proportion to the size of the effusion. These effusions may be transudative, but if an associated infarct occurs near the pleural surface, an exudate may be seen. If a pulmonary embolism is suspected in a postoperative patient, most clinicians would obtain a spiral CT scan. Alternatively, duplex ultrasonography of the lower extremities may yield a diagnosis of deep vein thrombosis, which calls for anticoagulant therapy and precludes the need for a specific diagnosis of pulmonary embolism. In some patients, a blood test for levels of Ddimer may be helpful; if results of a sensitive D-dimer blood test are negative, pulmonary embolism may be ruled out.

MALIGNANT PLEURAL EFFUSION Malignant pleural effusions may occur in association with a number of different malignancies, most commonly lung cancer, breast cancer, and lymphomas, depending on the patient's age and gender (Tables 19-36 and 19-37). 178 Malignant effusions are exudative and often tinged with blood. An effusion in the setting of a malignancy means a more advanced stage of disease and generally indicates an unresectable tumor. Mean survival in such cases is 3 to 11 months. Occasionally, benign pleural effusions may be associated with a bronchogenic NSCLC, and surgical resection may still be indicated if the results of cytologic testing of the effusion is negative for malignancy. An important issue is the size of the effusion and the degree of dyspnea that results. Symptomatic, moderate to large effusions should be drained by chest tube, pigtail catheter, or VATS, followed by instillation of a sclerosing agent. Before the pleural cavity is sclerosed, whether by chest tube or VATS, the lung should be nearly fully expanded. Poor expansion of the lung (because of entrapment by tumor or adhesions) generally predicts a poor result with pleurodesis and is the primary indication for placement of indwelling pleural catheters. These catheters have dramatically changed the management of end-stage cancer treatment because they substantially shorten the amount of time patients spend in the hospital during their final weeks of life. 179 The choices for sclerosing agent include talc, bleomycin, and doxycycline. Success rates for controlling the effusion range from 60 to 90%, depending on the exact scope of the clinical study, the degree of lung expansion after the pleural fluid is drained, and the care with which the outcomes were reported. Figure 19-48 presents a decision algorithm for the management of malignant pleural effusion.

Table 19-36 Primary Organ Site or Neoplasm Type in Male Patients with Malignant Pleural Effusions Lung 140 49.1 Lymphoma/leukemia 60 21.1 Gastrointestinal tract 20 7.0 Genitourinary tract

17 6.0 Melanoma 4 1.4 Miscellaneous less common tumors 10 3.5 Primary site unknown 31 10.9 Total 285 100 Primary Site or Tumor Type

No. of Male Patients

Percentage of Male Patients

Source: Reproduced with permission from Johnston WW: The malignant pleural effusion: A review of cytopathologic diagnoses of 584 specimens from 472 consecutive patients. Cancer 56:905, 1985.

Table 19-37 Primary Organ Site or Neoplasm Type in Female Patients with Malignant Pleural Effusions Breast 70 37.4 Female genital tract 38 20.3 Lung 28 15.0 Lymphoma 14 8.0 Gastrointestinal tract 8 4.3 Melanoma 6 3.2 Urinary tract 2 1.1 Miscellaneous less common tumors 3 1.6 Primary site unknown 17

9.1 Total 187 100.0 Primary Site or Tumor Type

No. of Female Patients

Percentage of Female Patients

Source: Reproduced with permission from Johnston WW: The malignant pleural effusion: A review of cytopathologic diagnoses of 584 specimens from 472 consecutive patients. Cancer 56:905, 1985.

Fig. 19-48.

Treatment decision algorithm for the management of malignant pleural effusion (MPE). CT = computed tomography; VATS = video-assisted thoracic surgery.

Empyema Thoracic empyema is defined by a purulent pleural effusion. The most common causes are parapneumonic, but postsurgical or posttraumatic empyema also is common (Table 19-38). The finding of grossly purulent, foulsmelling pleural fluid makes the diagnosis of empyema obvious on visual examination at the bedside. In the early stage, small to moderate turbid pleural effusions in the setting of a pneumonic process may require further pleural fluid analysis. Close clinical follow-up also is imperative to determine if progression to empyema is occurring. A deteriorating clinical course or a pleural pH of 60 mg/dL, and a low LDH level ( Chapter 21. Acquired Heart Disease >

KEY POINTS 1. The long-term outcomes of coronary artery bypass graft surgery remain superior to coronary stenting for patients with left main disease and multivessel coronary artery disease in diabetic patients. 2. Congestive heart failure is reaching epidemic proportions. Effective surgical strategies exist for these patients, ranging from valve repair to ventricular assist devices. 3. Mitral valve repair rather than replacement affords superior long-term benefits to patients with degenerative mitral valve disease. 4. Aortic valve replacement is routinely and safely performed in patients over 80 years old.

CARDIAC ASSESSMENT Clinical Evaluation The importance of the history and physical examination when evaluating a patient with acquired heart disease for potential surgery cannot be overemphasized. It is imperative that the surgeon be well aware of the functional status of the patient and the clinical relevance of each symptom, because surgical decisions depend upon the accurate assessment of the significance of a particular pathologic finding. Likewise, as the number of diagnostic tests continues to increase, appropriate sequencing of the diagnostic work-up requires a clinical perspective that is obtained through the history and physical examination. Associated risk factors and coexisting conditions must be identified, as they significantly influence a patient's operative risk for cardiac or noncardiac surgery. Furthermore, the operative strategy is affected by specific physical findings and important history, such as previous cardiac or thoracic surgery, peripheral vascular occlusive disease, or prior saphenous vein stripping. The safe surgeon is one who can integrate clinical evidence and diagnostic information to establish a scientifically based operative plan.

SYMPTOMS The classic symptoms of heart disease are fatigue, angina, dyspnea, edema, hemoptysis, palpitations, and syncope, as outlined by Braunwald.1 When a patient describes or complains of any of these symptoms, the clinical scenario leading to it must be explored in detail, including symptom intensity, duration, provocation, and conditions that lead to relief. The initial goal is to determine whether a symptom is cardiac or noncardiac in origin, as well as to determine the clinical significance of the complaint. An important feature of cardiac disease is that myocardial function or coronary blood supply that may be adequate at rest may become completely inadequate with exercise or exertion. Thus, chest pain or dyspnea that occurs primarily during exertion is frequently cardiac in origin, while symptoms that occur at rest often are not.

In addition to evaluating the patient's primary symptoms, the history should include a family history, past medical history [prior surgery or myocardial infarction (MI), concomitant hypertension, diabetes, and other associated diseases], personal habits (smoking, alcohol or drug use), functional capacity, and a detailed review of systems. After a careful assessment of a patient's symptoms, appropriate diagnostic studies are ordered and interpreted. The classic symptoms are reviewed in detail below. Easy fatigability is a frequent but nonspecific symptom of cardiac disease that can arise from many causes. In some patients, this symptom reflects a generalized decrease in cardiac output or low-grade heart failure. The significance of subjective easy fatigability is vague and nonspecific. Angina pectoris is the hallmark of myocardial ischemia secondary to coronary artery disease (CAD), although a variety of other conditions can produce chest pain, and the clinician must determine if chest pain is of cardiac or noncardiac origin. Classic angina is precordial pain described as squeezing, heavy, or burning in nature, lasting from 2 to 10 minutes. The pain is usually substernal, radiating into the left shoulder and arm, but occasionally occurs in the midepigastrium, jaw, right arm, or midscapular region. Angina usually is provoked by exercise, emotion, sexual activity, or eating, and is relieved by rest or nitroglycerin. Angina is present in its classic form in 75% of patients with coronary disease, while atypical symptoms occur in 25% of patients and more frequently in women. A small but significant number of patients have "silent" ischemia, typically occurring in diabetics. Angina also is a classic symptom of aortic stenosis, occurring secondary to a combination of left ventricular (LV) hypertrophy, increased intracardiac pressure, increased ventricular wall tension (leading to higher oxygen requirements), and decreased cardiac output. This combination results in a myocardial oxygen supply-demand mismatch with resultant ischemia and angina. Noncardiac causes of chest pain that may be confused with angina include gastroesophageal reflux disease, esophageal spasm, musculoskeletal pain, peptic ulcer disease, pulmonary embolus, costochondritis (Tietze's syndrome), biliary tract disease, pleuritis, pulmonary hypertension, pericarditis, and aortic dissection. The physiologic change in most patients with heart failure is a rise in LV end-diastolic pressure, followed by cardiac enlargement. While Starling's law describes the compensatory mechanism of the heart of increased work in response to increased diastolic fiber length, symptoms develop as this compensatory mechanism fails, resulting in a progressive rise in LV end-diastolic pressure. Because this development is eventually damaging to the myocardial muscle and may ultimately result in a dilated cardiomyopathy, data suggest that surgery should be considered for many patients before the development of dyspnea or congestive heart failure (CHF). Nevertheless, exertional dyspnea is often the first sign of LV dysfunction, and should prompt an evaluation for an underlying cardiac cause. Dyspnea may appear as an early sign in patients with mitral stenosis due to restriction of flow from the left atrium into the left ventricle. However, with other forms of heart disease, dyspnea is a late sign, as it develops only after the left ventricle has failed and the end-diastolic pressure rises significantly. Dyspnea associated with mitral insufficiency, aortic valve disease, or coronary disease represents relatively advanced pathophysiology. A number of other respiratory symptoms represent different degrees of pulmonary congestion. These include orthopnea, paroxysmal nocturnal dyspnea, cough, hemoptysis, and pulmonary edema. Occasionally, dyspnea represents an "angina equivalent," occurring secondary to ischemia-related LV dysfunction. This finding is more common in women and in diabetic patients. Left-sided heart failure may result in fluid retention and pulmonary congestion, subsequently leading to

pulmonary hypertension and progressive right-sided heart failure. A history of exertional dyspnea with associated edema is frequently due to heart failure. In contrast, primary right heart failure may result from right ventricular injury and dysfunction or from primary tricuspid valve (TV) disease. Right atrial pressure, normally 7 to 10 lb of fluid results in visible lower extremity edema, usually equal bilaterally. Additionally, jugular venous distention and hepatomegaly develop with severe right heart failure. In chronic, severe heart failure, generalized fluid retention may be quite severe, accompanied by ascites and massive hepatomegaly. Palpitations are secondary to rapid, forceful, ectopic, or irregular heartbeats. Palpitations frequently are innocuous, but occasionally represent significant or potentially life-threatening arrhythmias. The underlying cardiac arrhythmia may range from premature atrial or ventricular contractions to atrial fibrillation, atrial flutter, paroxysmal atrial or junctional tachycardia, or sustained ventricular tachycardia. Atrial fibrillation is one of the most common causes of palpitations. It is a common arrhythmia in patients with mitral stenosis, and results from left atrial enlargement that evolves from sustained elevation in left atrial pressure. With other forms of heart disease, arrhythmias are less common and occur sporadically. In general, arrhythmias are more frequent in older patients, resulting from intrinsic disease in sinus node (sick sinus syndrome) or disease of the atrioventricular (AV) conduction mechanism resulting in complete or intermittent heart block. Severe, life-threatening forms of ventricular tachycardia or ventricular fibrillation may occur in any patient with ischemic disease, either from ongoing ischemia or from prior infarction and myocardial scarring. Syncope, or sudden loss of consciousness, is usually a result of sudden decreased perfusion of the brain. The differential diagnosis includes: (a) third-degree heart block with bradycardia or asystole, (b) malignant ventricular tachyarrhythmias or ventricular fibrillation, (c) aortic stenosis, (d) hypertrophic cardiomyopathy, (e) carotid artery disease, (f) seizure disorders, and (g) vasovagal reaction. Any episode of syncope must be evaluated thoroughly, as many of these conditions can result in sudden death.

FUNCTIONAL DISABILITY AND ANGINA An important part of the history is the assessment of the patient's overall cardiac functional disability, which is a good approximation of the severity of the patient's underlying disease. The New York Heart Association (NYHA) has developed a classification of patients with heart disease based on symptoms and functional disability (Table 21-1). The NYHA classification has been extremely useful in evaluating a patient's severity of disability, in comparing treatment regimens, and in predicting operative risk.

Table 21-1 New York Heart Association Functional Classification Class I: Patients with cardiac disease but without resulting limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or angina 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 angina pain. Class III: Patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation, dyspnea, or anginal pain. Class IV: Patients with cardiac disease resulting in an inability to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased. The NYHA functional classification system is widely used and adequate for the majority of patients. However, when a more precise functional analysis is necessary, the specific activity scale proposed by Goldman and based upon the estimated metabolic cost of various activities is used. A different grading system for patients with ischemic disease, developed by the Canadian Cardiovascular Society (CCS), is used to assess the severity of angina (Table 21-2).

Table 21-2 Canadian Cardiovascular Society Angina Classification Class I: Ordinary physical activity, such as walking or climbing stairs, does not cause angina. Angina may occur with strenuous or rapid or prolonged exertion at work or recreation. Class II: There is slight limitation of ordinary activity. Angina may occur with walking or climbing stairs rapidly, walking uphill, walking or stair climbing after meals or in the cold, in the wind, or under emotional stress, or walking more than two blocks on the level, or climbing more than one flight of stairs under normal conditions at a normal pace. Class III: There is marked limitation of ordinary physical activity. Angina may occur after walking one or more blocks on the level or climbing one flight of stairs under normal conditions at a normal pace. Class IV: There is inability to carry on any physical activity without discomfort; angina may be present at rest.

Cardiac Risk Assessment in General Surgery Patients Cardiac risk stratification for patients undergoing noncardiac surgery is a critical part of the preoperative evaluation of the general surgery patient. The joint American College of Cardiology/American Heart Association task force, chaired by Eagle, recently reported guidelines and recommendations, which are summarized in this section. In general, the preoperative cardiovascular evaluation involves an assessment of clinical markers, the patient's underlying functional capacity, and various surgery-specific risk factors. The clinical markers that predict an increased risk of a cardiac event during noncardiac surgery are divided into three grades. Major predictors include unstable coronary syndromes, including acute or recent MI and unstable angina (CCS class III or IV), decompensated heart failure (NYHA class IV), and significant arrhythmias and severe valvular disease. Intermediate predictors are mild angina (CCS class I or II), old MI,

compensated heart failure (NYHA class II and III), diabetes, and renal insufficiency. Mild predictors are advanced age, uncontrolled systemic hypertension, irregular rhythm, prior stroke, abnormal electrocardiogram (ECG), and mild functional disability. Specific surgical risk factors or procedures expose the patient to greater or lesser risk of a cardiovascular event. High-risk procedures include emergent, major procedures in the elderly; major vascular procedures (e.g., thoracic, abdominal aortic, or peripheral vascular); and long general surgical procedures with anticipated large fluid shifts and/or blood loss (e.g., pancreatectomy, hepatic resection, or abdominoperineal resection). Intermediate-risk procedures include any intraperitoneal or intrathoracic operation, carotid endarterectomy, and orthopedic, prostate, and head and neck procedures. Low-risk procedures include endoscopic, breast, cataract, and superficial operations. Based upon the clinical markers, the functional class of the patient, and the proposed surgical procedure, the patient is assigned a high, intermediate, or low cardiac risk, and then managed appropriately. In some patients, further risk stratification is required, such as patients with intermediate cardiac risk factors who are undergoing a high-risk surgical procedure. These patients should undergo exercise stress testing or provocative testing (dipyridamole thallium or dobutamine stress echocardiography) before an operation. In patients who are considered high cardiac risk due to clinical markers or by virtue of noninvasive testing, coronary angiography may be recommended before surgery. CAD is then managed according to the classic indications. In patients who are thought to be low or moderate cardiac risk, medical management alone is sufficient. Due to the common atherosclerotic etiology and the close association between clinically relevant CAD and peripheral vascular disease (PVD), patients undergoing major vascular surgery should be screened closely, either by history or provocative stress testing. Those patients with symptoms suggestive of ischemia, with a decreased ejection fraction due to prior MI, or with provocative stress testing suggestive of ischemia should undergo coronary angiography or a newer cardiac computed tomography (CT) modality before vascular surgery. Any significant underlying coronary disease should be aggressively treated, either with intensive perioperative management or with coronary revascularization before surgery, using standard indications. This aggressive screening approach, followed by appropriate intervention in patients with significant CAD, has greatly lowered the operative risk of patients undergoing major vascular surgery.

Diagnostic Studies ELECTROCARDIOGRAM AND CHEST X-RAY ECG and the chest x-ray are two classic diagnostic studies. The ECG is used to detect rhythm disturbances, heart block, atrial or ventricular hypertrophy, ventricular strain, myocardial ischemia, and MI. Standard posterior-anterior and lateral chest x-rays are excellent for determining cardiac enlargement and pulmonary congestion, as well as for assessing associated pulmonary pathology.

ECHOCARDIOGRAPHY Echocardiography has become the most widely used cardiac diagnostic study. This test incorporates the use of ultrasound and reflected acoustic waves for cardiac imaging. Blood flow velocities are assigned colors to help visually evaluate them. This information is superimposed onto the two-dimensional image, giving a graphic illustration of the directional intracardiac flow pattern and an assessment of valvular insufficiency. Standard transthoracic echocardiography has become an excellent noninvasive screening test to evaluate

cardiac size, wall motion, and valvular pathology. Corrective operation for valvular disease is now frequently performed on younger patients based on this study alone. Transesophageal echocardiography (TEE), performed by the placement of a two-dimensional transducer in a flexible endoscope, improves the image quality by minimizing scatter from the chest wall. This test, although invasive, is particularly useful in the evaluation of valvular disease, and may elucidate exact leaflet pathology. Additionally, atherosclerotic disease of the aortic arch and descending aorta can be accurately assessed with this study. Moreover, TEE studies are used when more precise imaging is required or when the diagnosis is uncertain after a transthoracic study. Dobutamine stress echocardiography has evolved as an important noninvasive provocative study. This study is used to assess cardiac wall motion in response to inotropic stimulation, as wall motion abnormalities reflect underlying ischemia. Several reports have documented the accuracy of dobutamine stress echocardiography in identifying patients with significant CAD. The predictive value of a positive test for MI or death after noncardiac surgery is approximately 10%, while 20 to 40% will have some cardiac event. A negative test is 93 to 100% predictive that no cardiac event will occur.

RADIONUCLIDE STUDIES Currently the most widely used myocardial perfusion screening study is the thallium scan, which uses the nuclide thallium-201. Initial uptake of thallium-201 into myocardial cells is dependent upon myocardial perfusion, while delayed uptake depends on myocardial viability. Thus, reversible defects occur in underperfused, ischemic, but viable zones, while fixed defects occur in areas of infarction. Fixed defects on the thallium scan suggest nonviable myocardium and may be of prognostic value. The exercise thallium test is widely used to identify inducible areas of ischemia and is 95% sensitive in detecting multivessel coronary disease. This is the best overall test to detect myocardial ischemia, but requires the patient to exercise on the treadmill. The study also gives excellent, specific information about the patient's cardiac functional status. The dipyridamole thallium study is a provocative study using IV dipyridamole, which induces vasodilation and consequently unmasks myocardial ischemia in response to stress. This is the most widely used provocative study for risk stratification for patients who cannot exercise. In patients undergoing noncardiac surgery, the predictive value of a positive dipyridamole thallium study is 5 to 20% for MI or death, while a negative study is 99 to 100% predictive that a cardiac event will not occur. It is, therefore, a very effective screening study for moderate- to high-risk patients who require a general surgery procedure. Global myocardial function is frequently evaluated by a gated blood pool scan (equilibrium radionuclide angiocardiography) using technetium-99m. This study can detect areas of hypokinesis and measure left ventricular ejection fraction (LVEF), end-systolic volume, and end-diastolic volume. An exercise-gated blood pool scan is an excellent method to assess a patient's global cardiac response to stress. Normally, the ejection fraction will increase with exercise, but with significant CAD or valvular disease, the ejection fraction may remain unchanged or even decrease. The resting-gated blood pool scan determines the degree of prior cardiac injury and assesses baseline cardiac function, whereas the exercise-gated blood pool scan assesses the functional response to stress.

POSITRON EMISSION TOMOGRAPHY SCAN The positron emission tomography (PET) scan is a radionuclide imaging technique used to assess myocardial

viability in underperfused areas of the heart. The technique may be more sensitive than the thallium scan for this purpose.2 The PET scan is based on the myocardial metabolism of glucose or other compounds tagged with positron-emitting isotopes. PET allows the noninvasive functional assessment of perfusion, substrate metabolism, and cardiac innervation in vivo. The PET scan may be most useful in determining whether an area of apparently infarcted myocardium may, in fact, be hibernating and capable of responding to revascularization. These data can be used to determine whether patients with CHF might improve with operative revascularization.

MAGNETIC RESONANCE IMAGING VIABILITY STUDIES Magnetic resonance imaging (MRI) may be used to delineate the transmural extent of MI and to distinguish between reversible and irreversible myocardial ischemic injury.3 This test has proven to be useful in the assessment of patients with myocardial scarring and ventricular aneurysms, when ventricular remodeling surgery is an option.

CARDIAC CATHETERIZATION The cardiac catheterization study remains an important part of cardiac diagnosis. Complete cardiac catheterization includes the measurement of intracardiac pressures and cardiac output, localization and quantification of intracardiac shunts, determination of internal cardiac anatomy and ventricular wall motion by cineradiography, and determination of coronary anatomy by coronary angiography. However, most cardiac catheterizations today are focused studies (e.g., coronary angiography alone), because echocardiography and other noninvasive studies can accurately evaluate valvular pathology and cardiac function. During cardiac catheterization the cardiac output can be calculated using the Fick oxygen method, where cardiac index (1/min per square meter) = oxygen consumption (mL/min per square meter) arteriovenous oxygen content difference (mL/min). For determining the arteriovenous oxygen difference, the oxygen content is calculated separately in the arterial and venous circulations by the formula:

Calculation of systemic vascular resistance (SVR) is by the formula:

The pulmonary vascular resistance (PVR) is calculated by the formula:

The area of a cardiac valve can be determined from measured cardiac output and intracardiac pressures using Gorlin's formula. This formula relates valve area to the flow across the valve divided by the square root of the transvalvular pressure gradient. The Gorlin formula indicates that a relatively small transvalvular

pressure gradient may actually represent severe valvular stenosis when the patient's cardiac output is low, demonstrating the danger of basing a surgical decision on the transvalvular gradient alone. The significance of valvular stenosis should be based on the calculated valve area [the normal mitral valve (MV) area is 4 to 6 cm2 and the normal aortic valve area is 2.5 to 3.5 cm 2 in adults]. Coronary angiography remains the primary diagnostic procedure for determining the degree of CAD (Fig. 211). The left coronary system supplies the major portion of the LV myocardium through the left main, left anterior descending, and circumflex coronary arteries. The right coronary artery supplies the right ventricle, and the posterior descending artery supplies the inferior wall of the left ventricle. The AV nodal artery arises from the right coronary artery in 80 to 85% of patients, termed right dominant circulation. In 15 to 20% of cases, the circumflex branch of the left coronary system supplies the posterior descending branch and the AV nodal artery, termed left dominant, while 5% are codominant.

Fig. 21-1.

Cardiac catheterization. A. Coronary angiogram demonstrating a severely stenotic atherosclerotic lesion in the right coronary artery. B. A systolic left ventriculogram of a patient with a normal ejection fraction (arrows indicate normal systolic contraction of LV walls).

COMPUTED TOMOGRAPHY CORONARY ANGIOGRAPHY Technologic advances in CT now allow less invasive imaging of the coronary anatomy. Newer rapid CT coronary angiography has been shown to be extremely sensitive in detecting coronary stenoses. These tests initially assess luminal calcium and a "calcium score" is derived. CT angiography has provided comparable results to traditional angiography in some recent studies.4

Extracorporeal Perfusion HISTORY With initial intracardiac surgical procedures being performed by brief asystole and systemic hypothermia or cross-perfusion from a parent, reliable cardiopulmonary support of the patient became a necessary development. The pioneering efforts of Gibbon were largely responsible for such a development of the extracorporeal

circulation circuit (cardiopulmonary bypass or CPB). Starting in 1932, Gibbon's laboratory investigations continued until, in 1953, he performed the first successful open heart operation in a human supported by a CPB machine.5 Intrinsic to this device was the capacity for gas exchange with oxygenation and carbon dioxide (CO 2) removal. Subsequently, refinements in the circuit led to the development of bubble oxygenators and the now widely used membrane oxygenators which use a hollow fiber membrane for the blood-gas interface. In recent years, the focus of perfusion technology has been on the development of perfusion systems that inflict less trauma on the patient's blood. One such advance was the introduction of biocompatible circuits to perfusion technology. This concept involves coating the plastic circuits with biocompatible materials that result in less activation of complement and other inflammatory cytokines during extracorporeal perfusion.

TECHNIQUE Heparin is the most important medication used during CPB; it allows the blood to transverse the CPB circuit without clotting. Typically, 3 to 4 mg/kg of heparin is given to elevate activated clotting time (ACT) above 500 seconds. In a typical modern circuit, vacuum-assisted venous drainage removes blood from a patient and a pump then pushes it thru a membrane oxygenator and filter before returning it to the patient. Traditionally, venous blood was drained from the right atrium by gravity through large bore cannulas, but more recently, vacuum-assisted venous drainage has been increasingly used, which allows use of smallerdiameter venous drainage cannulas. Systemic flow rates during extracorporeal perfusion depend on the body oxygen consumption requirements of the patient, which are dependent upon the patient's body temperature. Normothermic perfusion is done at a flow rate of about 2.5 to 3.5 L/min per square meter, which is the normal cardiac index. Because hypothermia decreases the metabolic rate [approximately 50% for each 7°C (12.6°F)], the necessary flow rates can be diminished as the patient is cooled. Safe bypass flow rates for 30°C (86°F) are 1.8 to 2.3 L/min per square meter, for 25°C (77°F) 1.5 to 1.8 L/min per square meter, and for 20°C (68°F) 1.2 to 1.5 L/min per square meter. Gas flow through the oxygenator is adjusted to produce an arterial oxygen tension above 150 mmHg and the CO2 tension 35 to 45 mmHg. Systemic temperature is controlled with a heat exchanger in the circuit; the temperature is usually lowered to 25 to 32°C (77° to 89.6°F), although colder temperatures are occasionally necessary for some complicated procedures. Free intrapericardial or intracardiac blood is aspirated with a suction apparatus, filtered, and returned to the pump circuit's reservoir. A cell-saving device is likewise used to reprocess spilled blood before and after the heparinization of CPB. This technique washes the blood and extracts the red blood cells for transfusion back to the patient. Venous blood returning to the heart-lung machine will usually have an oxygen saturation >60%. With adequate flow rates and oxygen saturations, metabolic acidosis of a significant degree does not occur. Patients are constantly monitored for signs of underoxygenation. Heparin is gradually metabolized by the body, and so additional heparin is given to keep the ACT above 500 to 600 seconds. Once the operation is completed and the patient is systemically rewarmed to normothermic levels, the perfusion is slowed and then stopped as the patient's blood is returned from the pump reservoir to the patient. Before discontinuing bypass, the surgeon checks several important variables: ECG (for rate, rhythm, and ST-segment changes), potassium level, hematocrit, myocardial contractility, and hemostasis of the suture lines. Both visual inspection and TEE are used to assess contractility. Postbypass, the patient's blood pressure and cardiac function are monitored closely. A Swan-Ganz catheter can measure the cardiac output

and the pulmonary capillary wedge pressure to provide a guide to left atrial preload. If the cardiac output and blood pressure are inadequate despite an adequate preload, inotropic support is initiated. Hypotension from a low peripheral vascular resistance and normal myocardial contractility is treated with vasoconstrictors. Once hemodynamic stability is achieved, heparin is neutralized with protamine. If a coagulopathy is present, the ACT may not return to prebypass levels, indicating the need for coagulation products, such as freshfrozen plasma, platelets, or clotting factor concentrates. Although this is infrequent, it does occur in complex operations and longer pump runs.

SYSTEMIC RESPONSE Systemic responses to extracorporeal perfusion mainly involve platelet dysfunction and a generalized systemic inflammatory response syndrome. This is apparently due to the activation of complement and other acute-phase inflammatory components by blood contact with the extracorporeal circuit. The severity of the inflammatory response and the level of subsequent end-organ dysfunction are related to the length of the pump time, with complement and cytokine activation leading to an upregulation of white blood cell adhesion molecules and the ability of white blood cells to release superoxide. White blood cell upregulation or "priming" produced by extracorporeal circulation results in increased capillary permeability throughout the body, with the "primed" white blood cells placing the patient in a potentially vulnerable state for 24 to 48 hours, during which any secondary insult may result in various levels of multiorgan dysfunction. Other effects may include mental confusion, renal insufficiency, decreased oxygen exchange (pulmonary dysfunction), transient hepatic dysfunction, and hyperamylasemia. Low levels of a consumptive coagulopathy and hyperfibrinolysis from plasmin activation may also be present. Current research is focused on minimizing the body's systemic inflammatory response during extracorporeal circulation by coating circuits with biocompatible materials or by blockading specific cytokines. Aprotinin and steroids may attenuate the inflammatory response to bypass, while aprotinin and -aminocaproic acid diminish coagulopathy. There remains controversy as to the risk-benefit ratio of aprotinin, with concerns about renal and neurologic adverse events. Zero-balance ultrafiltration (Z-BUF) is a method of ultrafiltration during CPB. This technique removes significant amounts of inflammatory mediators associated with CPB and potentially attenuates the adverse effects of bypass while maintaining the patient's volume status. Recent studies have shown that ZBUF reduces pulmonary edema and protects against lung injury.6 Additionally, the use of Z-BUF has been shown to decrease the concentrations of interleukin-6 and interleukin-8 that are markers of systemic inflammation associated with CPB.

MYOCARDIAL PROTECTION Cardioplegia was developed as a protective solution to induce both cardiac asystole and protect the myocardium from ischemic injury. When infused through the coronary circulation, cold high-potassium cardioplegic solution produces diastolic arrest and slows the metabolic activity, protecting the heart from ischemia. The arrested heart allows the surgeon to work precisely on the heart in a motionless, bloodless field. With current cardioplegic techniques the heart can be stopped and protected for 2 to 3 hours quite safely, allowing time for complicated procedures to be performed with good recovery of cardiac function. Both crystalloid and blood cardioplegic solutions are widely used, with the exact composition of the cardioplegic mixture varying among different institutions. With periods of cardiac arrest up to 90 minutes, there is little measurable difference in the two techniques, although blood cardioplegia may allow the heart

to be safely arrested for longer periods.

CORONARY ARTERY DISEASE History In the 1930s, investigators attempted to increase the blood supply to the ischemic heart by developing collateral circulation with vascular adhesions. Beck, the leading investigator, tried different methods for many years, but ultimately failed. An ingenious concept arose in 1946, when Vineberg developed the technique of implantation of the internal mammary artery (IMA) into a tunnel in the myocardium. This was applied clinically by Vineberg and Miller in 1951 and continued for many years. Interestingly, the artery remained patent in >90% of patients, but the amount of flow through the artery was small, and the procedure was subsequently abandoned. Coronary artery endarterectomy for coronary revascularization was attempted by Longmire in 1956 with short-term success. Late results were poor, however, due to progressive restenosis and occlusion. Shortly thereafter, CPB was used to facilitate coronary revascularization, and Senning reported vein patch graft arterioplasty in 1961. The development of the coronary artery bypass operation in the 1960s was a dramatic medical milestone. In the United States, the principal credit belongs to Favalaro and Effler from the Cleveland Clinic. In 1967, they began the first series of coronary bypass grafts with saphenous vein grafts using CPB. This launched the modern era of coronary bypass surgery. An additional breakthrough came in 1968 when Green and colleagues performed the first left IMA to left anterior descending artery (LAD) bypass, using CPB and an operative microscope. Kolessov had independently performed IMA to left coronary artery bypass grafting (CABG) on the beating heart in Russia in 1964, although his work was largely unknown for many years. Subsequently, coronary artery bypass surgery became one of the most widely applied surgical procedures in the United States and throughout the world.

Etiology and Pathogenesis The etiology of CAD is primarily atherosclerosis. The disease is multifactorial, with the primary risk factors being hyperlipidemia, smoking, diabetes, hypertension, obesity, sedentary lifestyle, and male gender. Newly identified risk factors include elevated levels of C-reactive protein, lipoprotein (a), and homocysteine. The atherosclerotic process results in the formation of obstructive lesions in the aorta, the peripheral vessels, and the coronary arteries. Atherosclerosis is the leading cause of death in the Western world, and acute MI alone accounts for 25% of the deaths in the United States each year. The most important factor in the long-term treatment of coronary disease is modification of risk factors, including the immediate cessation of smoking, control of hypertension, weight loss, exercise, and reduction of serum cholesterol. If dietary control of cholesterol cannot be achieved in patients with coronary disease, evidence suggests that the early use of medications (such as statins) to lower cholesterol can significantly reduce cardiovascular risk. The basic lesion is a segmental plaque within the coronary artery. Involvement of small distal vessels is usually less extensive, while arterioles and intramyocardial vessels are usually free of disease. This segmental localization makes CABG possible. Among the three major coronary arteries, the proximal LAD is frequently stenosed or occluded, with the distal half of the artery remaining patent. The right coronary artery is often stenotic or occluded throughout its course, but the posterior descending and left AV groove branches are almost always patent. The circumflex artery is often diseased proximally, but one or more distal marginal branches are usually patent. With progressive disease, platelet aggregation in the narrowed lumen or plaque

hemorrhage or rupture may lead to unstable symptoms or to acute thrombosis and MI.

Clinical Manifestations Myocardial ischemia from CAD may result in angina pectoris, MI, CHF, cardiac arrhythmias, and sudden death. Angina is the most frequent symptom, but MI may appear without prior warning. CHF usually results as a sequela of MI, with significant muscular injury resulting in an ischemic myopathy. Myocardial injury and scarring can then lead to serious ventricular arrhythmias that may result in sudden death. Angina pectoris, the most common manifestation, manifests by periodic chest discomfort, usually substernal, and typically appears with exertion. These symptoms usually subside within 3 to 5 minutes and are relieved by sublingual nitroglycerin. In 20 to 25% of patients, the pain may be atypical and radiate to the jaw, shoulder, or epigastrium. Some patients, especially women or diabetics, have no symptoms of angina and experience primarily exertional dyspnea. Establishing a diagnosis of myocardial ischemia in these patients is difficult and perhaps impossible without provocative diagnostic studies. The differential diagnosis in patients with atypical symptoms includes aortic stenosis, hypertrophic cardiomyopathy, musculoskeletal disorders, pulmonary disease, gastritis or peptic ulcer disease, gastroesophageal reflux, diffuse esophageal spasm, and anxiety. MI is the most common serious complication of CAD, with 1.1 million infarcts occurring in the United States annually. Modern therapy, which involves early reperfusion with either thrombolytic therapy or emergent angioplasty, has lowered the mortality to 50%, corresponding to a reduction in cross-sectional area >75%. Furthermore, the number, location, and severity of the coronary stenoses are used to determine the appropriate method of revascularization. Ventricular function is expressed as the LVEF, with 0.55 to 0.70 considered as normal, 0.40 to 0.55 as mildly depressed, 90% in patients with degenerative mitral insufficiency. Valve repair offers significant advantages over valve replacement, primarily lower risks of thromboembolic- and anticoagulant-related complications. Survival may also be improved in certain groups of patients after valve repair.

Mitral Valve Disease In the 1920s the first attempts to surgically correct mitral stenosis via a closed atrial approach demonstrated the feasibility of mitral valve surgery. Now, with good preoperative pathophysiologic evaluation and precise surgical technique, mitral valve surgery has become one of the most successful procedures performed by cardiac surgeons.

MITRAL STENOSIS Etiology MV stenosis or mixed mitral stenosis and insufficiency almost always are caused by rheumatic heart disease, although a definite clinical history can be obtained in only 50% of patients. Congenital mitral stenosis is rarely seen in adults. Occasionally, intracardiac tumors such as a left atrial myxoma may obstruct the mitral orifice and cause symptoms that mimic mitral stenosis.

Pathology Although the rheumatic inflammatory process is associated with some degree of pancarditis involving the endocardium, myocardium, and pericardium, permanent injury results predominantly from the endocarditis, with progressive fibrosis of the valves. Rheumatic valvulitis produces three distinct degrees of pathologic change: fusion of the commissures alone, commissural fusion plus subvalvular shortening of the chordae tendineae, and extensive fixation of the valve and subvalvular apparatus with calcification and scarring of both leaflets and chordae (Fig. 21-10). The degree of pathology present should be determined preoperatively, as this predicts the suitability of balloon valvuloplasty, surgical commissurotomy, or valve replacement.

Fig. 21-10.

Mitral replacement. A. Operative photograph of rheumatic mitral valve with calcific mitral stenosis, viewed through a left atriotomy incision. Arrow points to "bar" of heavily calcified posterior annulus. B. Excised calcified mitral valve with fibrotic, shortened chordae tendineae. C. St. Jude mechanical mitral valve visualized through the open left atrium. Pledget reinforced sutures were used to secure the valve into the native annulus.

Pathophysiology Mitral stenosis usually has a prolonged course after the initial rheumatic infection, and symptoms may not appear for 10 to 20 years. The progression to valvular fibrosis and calcification may be related to repeated episodes of rheumatic fever, or may result from scarring produced by inflammation and turbulent blood flow. Mitral stenosis leads to a progressive decrease in the MV area, which results in a transvalvular gradient across the stenotic valve during diastole. The normal cross-sectional area of the MV is 4 to 6 cm2. Symptoms may progressively develop with moderate stenosis, defined as a cross-sectional area of 1.0 to 1.5 cm2. Severe symptomatic stenosis occurs when the MV area is 55 years of age. Right heart catheterization may be valuable in patients with pulmonary hypertension, although a reliable estimate of the PA pressures can usually be determined from Doppler echocardiography.

Indications for Valvuloplasty or Commissurotomy Although percutaneous balloon valvuloplasty has become an acceptable alternative for many patients with uncomplicated mitral stenosis, open mitral commissurotomy remains an extremely reproducible and durable option. Commissurotomy has the advantage of allowing the surgeon to address nonpliable or calcified MVs, mobilize fused papillary muscles to correct subvalvular restrictive disease, effectively repair patients with mixed stenosis and insufficiency, and remove left atrial clot. Either balloon valvuloplasty or open surgical

commissurotomy is indicated for symptomatic patients with moderate (MV area 4.5 to 5 cm. The LV diastolic dimensions become enlarged relatively early because of volume overload, but LV systolic function is usually well maintained early in the course of the disease. Once the echocardiogram demonstrates a decrease in LV systolic function, manifested as a rise in the end-systolic dimension of the heart and a drop in the ejection fraction, this is an indication that the left ventricle is beginning to decompensate. If there is uncertainty about the physiologic significance of mitral insufficiency, exercise stress-echocardiography may be used. Normally the ejection fraction rises with exercise, but a fall in ejection fraction with exercise is an early sign of LV systolic dysfunction.

Indications for Operation Delaying an operation until the patient is severely symptomatic and the heart is markedly dilated often results in a certain degree of irreversible ventricular injury. According to the American College of Cardiology/American Heart Association guidelines, MV repair or replacement is recommended in any symptomatic patient with mitral insufficiency, even with normal LV function (defined as ejection fraction >60% and end-systolic dimension 1000 patients. A report by Grossi and colleagues demonstrated that patients treated with the minimally invasive approach had less need for blood transfusions, fewer infections, and a shorter hospital stay than matched patients receiving traditional surgery.5 4 Sharony and coworkers reported results in elderly patients, demonstrating shorter hospital stay and rehabilitation time.6 7 Thus, minimally invasive approaches for aortic valve replacement appear promising and deserve further investigation.

Idiopathic Hypertrophic Subaortic Stenosis Patients with hypertrophic cardiomyopathy or IHSS have varying degrees of subaortic LV outflow tract obstruction, usually associated with systolic anterior motion of the MV. Systolic anterior motion of the valve has been explained by the presence of Venturi forces created by the high-velocity flow in the narrowed outflow tract, which pulls the adjacent anterior leaflet of the MV into the outflow tract, worsening outflow obstruction. The subaortic obstruction may have a dynamic component and can usually be provoked with volume depletion, vasodilators, or inotropes. The intracavitary pressure of the left ventricle is usually markedly elevated, and the ventricle is hypercontractile with impaired diastolic relaxation. The degree of LV outflow tract obstruction at rest is a strong predictor of progression to severe symptoms of heart failure and death. However, most patients with hypertrophic cardiomyopathy and subaortic obstruction will respond to medical therapy, and only a minority will require surgical intervention.

OPERATIVE TECHNIQUES Surgical septal myotomy and myectomy, developed by Morrow, has shown consistent results and remains the primary technique for treatment of IHSS.7 0 This approach requires resection of a trough of muscle from the subaortic outflow tract. Typically, the resection is 1 cm wide and 1 cm deep, and extends the length of the septum to below the lower edge of the anterior leaflet of the MV. The resected trough should remain leftward of the right coronary ostium to avoid heart block but should routinely produce a left bundle-branch block. A modification of the Morrow myectomy, termed extended myectomy, involves mobilization and partial excision of the papillary muscles. The extended approach has been suggested to resect the deeper portion of the septal bulge and redirect the flow medially and anteriorly away from the MV, abolishing systolic anterior motion. However, there are few data to suggest that the extended myectomy procedure improves late outcomes.

Tricuspid Stenosis and Insufficiency Acquired TV disease can be classified as organic or functional. Organic disease is almost always a result of either rheumatic fever or endocarditis. In patients with rheumatic disease, tricuspid stenosis or insufficiency virtually never occurs as an isolated lesion, but only in association with extensive disease of the MV. With mitral disease, the frequency of associated tricuspid disease is 10 to 15%, although an incidence as high as 30% has been reported. Rarely, blunt trauma produces rupture of a papillary muscle or chordae tendineae with resultant tricuspid insufficiency. Functional tricuspid regurgitation is much more common than insufficiency from organic disease. Functional tricuspid regurgitation develops from dilatation of the tricuspid annulus and right ventricle as a result of pulmonary hypertension and right ventricular failure. These abnormalities usually result from MV disease or from other conditions that result in LV failure and pulmonary hypertension. With tricuspid stenosis, the pathologic changes are similar to those found with the more familiar mitral stenosis, with fusion of the commissures. Because right atrial pressure is normally only 4 to 5 mmHg, significant tricuspid stenosis may be present with a valve orifice considerably larger than that seen with mitral stenosis. With rheumatic disease, mixed tricuspid stenosis and insufficiency or pure insufficiency may result from fibrosis and contraction of the valve leaflets, often in association with shortening and fusion of chordae tendineae. Calcification is rare. Functional dilatation of the tricuspid annulus results in tricuspid insufficiency. The valve leaflets appear stretched, but otherwise are pliable and seemingly normal, even though serious regurgitation is present. The dilatation and deformity of the annulus are irreversible. Valves with severe functional insufficiency and a markedly dilated annulus usually do not regain competency, even after the MV disease is corrected and PA systolic pressure returns to normal.

PATHOPHYSIOLOGY With tricuspid stenosis or severe insufficiency, the mean right atrial pressure becomes elevated to 10 to 20 mmHg or higher. The higher pressures are found with a TV orifice 15 mmHg, hepatomegaly, ascites, and leg edema usually appear.

CLINICAL MANIFESTATIONS The symptoms and signs of TV disease are similar to those of right heart failure resulting from MV disease. They result from chronic elevation of right atrial pressure above the range of 15 to 20 mmHg. Clinical manifestations include jugulovenous distention, hepatomegaly, pedal edema, and ascites. With long-standing severe tricuspid insufficiency, hepatic dysfunction and clotting abnormalities may develop. The characteristic murmur of tricuspid stenosis is best heard as a diastolic murmur at the lower end of the sternum. It is a low-pitched murmur of medium intensity and can easily be overlooked because it is well localized at the lower end of the sternum. During inspiration, the intensity of the murmur increases as the volume of blood returning to the heart is temporarily raised by an increase in intrathoracic negative pressure. Tricuspid insufficiency produces a prominent systolic murmur heard best at the left lower sternal border. The murmur often is found in association with an enlarged, pulsating liver and prominent and engorged jugular veins. A prominent jugular venous pulsation, especially when the cardiac rhythm is sinus,

may be the best clue to unsuspected tricuspid disease. A hepatojugular reflex also may be noted.

DIAGNOSTIC STUDIES The x-ray shows enlargement of the right atrium and right ventricle. Echocardiography confirms the diagnosis and differentiates stenosis from insufficiency. Cardiac catheterization is no longer necessary in most cases.

INDICATIONS FOR SURGERY Indications for surgery are based primarily on clinical findings, which are correlated with echocardiographic findings and hemodynamics. Severe insufficiency is indicated by echocardiography when the area of the regurgitant jet occupies a large part of the atrium, the effective regurgitant orifice is >40 mm2, or the width of the vena contracta (narrowest flow) is >6.5 mm.7 1 Severe tricuspid regurgitation should clearly be repaired because it has been widely demonstrated that annuloplasty provides excellent late results with little added morbidity. Mild degrees of tricuspid insufficiency are usually left alone, especially in the absence of pulmonary hypertension, while repair of moderate insufficiency requires further consideration of the clinical findings and symptoms present. However, effective TV repair minimizes the risk of late right-sided heart failure and reoperation.

OPERATIVE TECHNIQUES In the small minority of patients whose tricuspid stenosis is secondary to pure commissural fusion, a commissurotomy may be performed, usually combined with an annuloplasty. More commonly, valve replacement is necessary when significant tricuspid stenosis is present because the entire valve and subvalvular apparatus are damaged. When a prosthetic valve is inserted, care is required in suture placement along the septal leaflet where the conduction bundle is located, and sutures should be placed more superficially in this area. In patients with functional tricuspid insufficiency, the annulus is markedly dilated while the leaflets appear entirely normal. Virtually all such patients can be treated by annuloplasty. The suture annuloplasty techniques proposed by Kay and Boyd and the De Vega annuloplasty technique have been highly reliable. Alternatively, a flexible or rigid annuloplasty device may be used.

RESULTS Data on more than 300 patients from the authors' institution show that the suture annuloplasty repair for functional tricuspid insufficiency is reproducible in the absence of significant intrinsic leaflet disease. Valve repair using a posterior suture annuloplasty technique was 98% durable at 7 years. Similar results have been reported with the De Vega annuloplasty.7 2 Other centers prefer the use of rigid or flexible annuloplasty devices for correction of tricuspid insufficiency, especially if the right heart pressures are expected to remain chronically elevated. When TV replacement is required, the options include use of either a tissue valve or a mechanical valve. Carrier and associates reported follow-up on 97 patients who underwent TV replacement with either tissue valves (n = 82) or mechanical valves (n = 15).7 3 The 5-year freedom from reoperation was 92% in patients with mechanical valves and 97% in patients with tissue valves (P = .2). Data suggest that the risk of valve thrombosis is increased in mechanical valves placed in the tricuspid position, as emphasized in a report by Kawano and colleagues that demonstrated a 30% risk of mechanical valve thrombosis in the tricuspid position over 15 years, with a linearized rate of 2.9% per patient-year.7 4 Bioprostheses are therefore

preferred for most patients requiring TV replacement.

Multivalve Disease Disease involving multiple valves is relatively common, particularly in patients with rheumatic disease. Prominent signs in one valve can readily mask disease in others. With aortic valve disease, functional mitral insufficiency can result from a progressive rise in the LV end-diastolic pressure and volume. Similarly, MV disease may result in pulmonary hypertension, right heart failure, and functional tricuspid insufficiency. Often these secondary functional changes resolve without treatment if the primary pathology is corrected in a timely fashion. Certainly, multiple-valve surgery has a higher operative risk than single-valve procedures, in part because the condition often represents more advanced disease and is associated with significant cardiac dysfunction. In a 1992 report by Galloway and colleagues, 513 patients with multiple-valve disease treated surgically between 1976 and 1985 were studied to assess factors influencing operative risk and long-term survival.7 5 Three groups accounted for the majority of the cases: 58% had aortic valve and MV disease, 29% had MV and TV disease, and 12% had triple-valve disease (aortic, MV, and TV). Preoperative CHF was present in 91%, 41% were NYHA class III, and 54% were NYHA class IV. The average PA systolic pressure was 60 mmHg. Despite chronic symptoms and severe disease, the overall operative mortality rate was 12.5% and the 5-year survival rate was 67%. The variables predicting decreased survival time were systolic PA pressure, age, triple-valve procedures, concomitant coronary bypass grafting, previous heart surgery, and diabetes. After operation, 80% of the patients improved to NYHA class I or II, demonstrating that most patients will have significant clinical improvement despite advanced symptoms preoperatively. The 5-year freedom from late cardiac-related death or complications was 82%.

AORTIC AND MITRAL VALVE DISEASE Nine combinations of valvular pathology can produce aortic and MV disease because each valve can be stenotic, insufficient, or both. Stenosis in both valves may lead to underestimation of the degree of aortic stenosis, because return of blood to the left ventricle is limited as a result of mitral stenosis. Aortic insufficiency, which produces the Austin Flint murmur, might overshadow and mask true mitral stenosis. With functional mitral insufficiency resulting from severe aortic disease, aortic valve replacement can lead to resolution of insufficiency in some patients, but patients with more severe mitral insufficiency may require mitral repair or replacement. Patients presenting with aortic valve and MV disease should be examined closely for these and other considerations.

MITRAL AND TRICUSPID VALVE DISEASE Multiple combinations of valvular pathology are possible with mitral and tricuspid disease, but mitral disease with functional tricuspid insufficiency is the most common scenario, resulting from chronic pulmonary hypertension and right heart failure. The presence of associated tricuspid insufficiency increases the operative risk for patients undergoing MV surgery. The risk for isolated MV and TV disease is approximately 6%.

TRIPLE-VALVE DISEASE Triple-valve surgery can be challenging because the clinical condition usually is a result of chronic aortic and mitral disease with severe pulmonary hypertension, biventricular failure, and functional tricuspid insufficiency. Occasionally, rheumatic disease affects all three valves. The degree of pulmonary hypertension

is the most significant predictor of survival in patients with triple-valve disease. The operative morality for 61 triple-valve procedures in an NYU report was only 5.6% when the PA systolic pressure was 25% when the PA pressures were above 60 mmHg and the patients were >70 years of age.7 5 This emphasizes the value of an early operation, before the development of irreversible ventricular dysfunction and chronic pulmonary hypertension.

SURGICAL THERAPY FOR THE FAILING HEART Epidemiology of Congestive Heart Failure CHF affects 5.2 million people in the United States with >500,000 new cases per year. Patients with NYHA IV CHF from CAD have an extremely poor outlook, with 43% and 18% survival at 1 and 3 years, respectively, and the risk of sudden cardiac death is higher, being 6 to 9 times greater than the general population. In the United States, there were >1 million hospital discharges for CHF in 2005 and >3.4 million outpatient visits. The estimated cost of care in 2008 was $3.48 billion.

Etiology and Pathophysiology The causes of heart failure differ widely. It can be broken down to idiopathic or secondary causes. Causes include hypertension, CAD, structural valve disease, and other miscellaneous causes such as postviral, postpartum, and hypertrophic. Often, the inciting event is an injury. This can be regional or global. In the case of MI, after a heart attack, the affected region becomes akinetic with the ingrowth of scar tissue. This area no longer contracts. If the area is large enough, the remaining walls have to compensate. This sometimes requires enlargement of the ventricle to maintain adequate cardiac output. An additional effect is the change in the normal elliptical shape of the ventricle. Additional adverse side effects include elevated left atrial pressures, ventricular and atrial dysrhythmias, LV dyssynchrony, and geometric distortion of the MV apparatus. This process is referred to as remodeling.

Surgery for Cardiomyopathy and Congestive Heart Failure Heart transplant remains the gold standard for the surgical treatment of end-stage heart disease. Late- and end-stage heart disease, also known as cardiomyopathy, often is accompanied by symptoms of CHF. The increasing incidence of heart failure combined with new surgical modalities, improved safety of conventional surgery, and better understanding of the natural history of heart failure, has pushed surgery for CHF into the mainstream of cardiac surgery. There is an increased demand for patients with late-stage or end-stage heart disease to be considered for surgical therapies.7 6 The goals of surgical therapy include improving survival, improving symptoms or the quality of life, or preventing further ongoing insults. Although ideal, a survival benefit in the short or intermediate term is not always possible, and certainly, by the time CHF has presented, surgical therapy is palliative in most cases. Dobutamine echocardiography is a valuable diagnostic test in patients with cardiomyopathy. This test provides the usual two-dimensional pictures of regional cardiac function. Improved segmental contractility at low doses (5 mcg/kg per minute) and worsening function higher doses indicate both viability and predict functional recovery after revascularization. Cardiac MRI has become a preferred diagnostic test, providing the surgeon with the three-dimensional shape and function of the heart. Wall thinness and lack of myocardial thickening are good indicators of chronic scaring. Gadolinium hyperenhancement quantifies the amount of

scar tissues in the segments of heart and its absence is highly predictive of recovery of function after revascularization. Finally, cardiopulmonary exercise testing is used to measure the degree of cardiac dysfunction as it pertains to a heart's ability to support metabolism. In patients with severe heart failure, it allows interpretation of symptoms and determination of prognosis. It also can be used to determine whether a patient is potentially best suited for cardiac transplantation.

Ischemic Cardiomyopathy Surgical coronary revascularization is one of the most commonly performed procedures for CHF. Coronary bypass grafting is the primary strategy of treatment for ischemic cardiomyopathy. Good target vessels are essential to successful revascularization in ischemic cardiomyopathy. Old age and poor quality of distal coronary vessels were the significant risk factors for successful outcome after surgical revascularization, with completely poor distal vessels having a 100% predictive value of hospital death and, thus, should be considered a strong contraindication.7 7 Myocardial viability is the pivotal variable in the assessment of these patients. Ongoing angina is often a sufficient indicator to proceed to surgery. In the patient with ischemic cardiomyopathy and CHF symptoms alone that are not related to acute ischemia, viability testing is used to determine whether surgery will improve outcomes. Patients with viability have significantly improved hospital survival and 2-year outcomes compared to those without, whereas patients with no viability show no benefit from surgical revascularization. In fact, patients with viable myocardium who did not undergo revascularization had double the mortality rate of all patients without viability and five times the mortality rate of those who underwent revascularization.7 8 This underscores both the importance of viable myocardium as well as the adverse consequences of not offering a patient with viability surgical intervention. Other risk factors for short and intermediate term outcomes include LV size and LV dyssynchrony. A LV endsystolic dimension >100 mL/m2 carries an adverse prognosis. Short-term and long-term survival after CABG were significantly reduced in those patients whose preoperative LV dimensions exceeded this threshold, 85 vs. 53% at 5 years (P Chapter 22. Thoracic Aneurysms and Aortic Dissection>

KEY POINTS 1. Assessing urgency of repair for an aortic aneurysm is essential to developing an appropriate management plan. Although emergent repair carries greater operative risk than does elective repair, any inappropriate delay of repair risks death. 2. Surgical repair of an aortic aneurysm requires the development of a patient-tailored plan based on careful preoperative medical evaluation. When possible, optimization of a patient's health status to mitigate existing comorbidities is essential before surgical intervention. 3. Ascending aortic aneurysms that are symptomatic or >5.5 cm should be repaired. 4. Ascending aortic dissection is a life-threatening condition, and immediate operative repair is indicated. 5. The natural progression of an aortic aneurysm is continued expansion and eventual rupture. Hence, regular noninvasive imaging studies, as part of a lifelong surveillance plan, are necessary to ensure long-term patient health. Even small asymptomatic aneurysms are routinely imaged to assess overall growth and yearly rate of expansion. 6. Although endovascular devices are approved for use in repairing simple descending thoracic aortic aneurysms, the long-term durability of this type of aortic repair has yet to be clearly established. 7. The development and use of surgical adjuncts like antegrade selective cerebral perfusion and cerebrospinal fluid drainage have significantly reduced morbidity rates associated with complex aortic repair.

ANATOMY OF THE AORTA The aorta consists of two major segments—the proximal aorta and the distal aorta—whose anatomic characteristics affect both the clinical manifestations of disease in these segments and the selection of treatment strategies for such disease (Fig. 22-1). The proximal aortic segment includes the ascending aorta and the transverse aortic arch. The ascending aorta begins at the aortic valve and ends at the origin of the innominate artery. The first portion of the ascending aorta is the aortic root, which includes the aortic valve annulus and the three sinuses of Valsalva; the coronary arteries originate from two of these sinuses. The aortic root joins the tubular portion of the ascending aorta at the sinotubular ridge. The transverse aortic arch is the area from which the brachiocephalic branches arise. The distal aortic segment includes the descending thoracic aorta and the abdominal aorta. The descending thoracic aorta begins distal to the origin of the left subclavian artery and extends to the diaphragmatic hiatus, where it joins the abdominal aorta. The descending thoracic aorta gives rise to multiple bronchial and esophageal branches, as well as to the segmental intercostal arteries, which provide circulation to the spinal cord.

Fig. 22-1.

Illustration of normal thoracic aortic anatomy. The brachiocephalic vessels arise from the transverse aortic arch and are used as anatomic landmarks to define the aortic regions. The ascending aorta is proximal to the innominate artery, whereas the descending aorta is distal to the left subclavian artery.

The volume of blood that flows through the thoracic aorta at high pressure is far greater than that found in any other vascular structure. For this reason, any condition that disrupts the integrity of the thoracic aorta, such as aortic dissection, aneurysm rupture, or traumatic injury, can have catastrophic consequences. Historically, open surgical repair of such conditions has been an intimidating undertaking associated with significant morbidity and mortality. Strategies for protecting the brain and spinal cord during such repairs have become

critical in preventing devastating complications. In recent years, endovascular therapy for thoracic aortic disease in selected patients has become accepted practice, producing fewer adverse outcomes than traditional approaches do.

THORACIC AORTIC ANEURYSMS Aortic aneurysm is defined as a permanent, localized dilatation of the aorta to a diameter that is at least 50% greater than is normal at that anatomic level.1 The annual incidence of thoracic aortic aneurysms is estimated to be 5.9 per 100,000 persons.2 The clinical manifestations, methods of treatment, and treatment results in patients with aortic aneurysms vary according to the cause and the aortic segment involved. Causes of thoracic aortic aneurysms include degenerative disease of the aortic wall, aortic dissection, aortitis, infection, and trauma. Aneurysms can be localized to a single aortic segment, or they can involve multiple segments. Thoracoabdominal aortic aneurysms, for example, involve both the descending thoracic aorta and the abdominal aorta. In the most extreme cases, the entire aorta is aneurysmal; this condition is often called mega-aorta. Aortic aneurysms can be either "true" or "false." True aneurysms can take two forms: fusiform and saccular. Fusiform aneurysms are more common and can be described as symmetrical dilatations of the aorta. Saccular aneurysms are localized outpouchings of the aorta. False aneurysms, also called pseudoaneurysms, are leaks in the aortic wall that cause blood to collect in pouches of scar tissue on the exterior of the aorta. Aneurysms of the thoracic aorta consistently increase in size and eventually progress to cause serious complications. These include rupture, which is usually a fatal event. Therefore, aggressive treatment is indicated in all but the poorest surgical candidates. Small, asymptomatic thoracic aortic aneurysms can be followed, especially in high-surgical-risk patients, and can be treated surgically later if symptoms or complications develop, or if progressive enlargement occurs. Meticulous control of hypertension is the primary medical treatment for patients with small, asymptomatic aneurysms. Elective resection with graft replacement is indicated in asymptomatic patients with an aortic diameter of at least twice normal in the involved segment (5 to 6 cm in most thoracic segments). Elective repair is contraindicated by extreme operative risk due to severe coexisting cardiac or pulmonary disease and by other conditions that limit life expectancy, such as malignancy. An emergency operation is performed for any patient in whom a ruptured aneurysm is suspected. Patients with thoracic aortic aneurysm often have coexisting aneurysms of other aortic segments. A common cause of death after repair of a thoracic aortic aneurysm is rupture of a different aortic aneurysm. Therefore, staged repair of multiple aortic segments often is necessary. As with any major operation, careful preoperative evaluation for coexisting disease and subsequent medical optimization are essential for successful surgical treatment. An alternative to traditional open repair of a descending thoracic aortic aneurysm is endovascular stent grafting. Certain anatomic criteria must be satisfied for this treatment option to be considered, including the presence of at least a 2-cm landing zone of healthy aortic tissue proximally and distally to the aneurysm to be excluded. Although data on long-term outcomes are still lacking, endovascular repair of descending thoracic aortic aneurysm has become an accepted practice that produces excellent midterm results.

Etiology and Pathogenesis GENERAL CONSIDERATIONS The normal aorta derives its elasticity and tensile strength from the medial layer, which contains approximately 45

to 55 lamellae of elastin, collagen, smooth muscle cells, and ground substance. Elastin content is highest within the ascending aorta, as would be expected because of its compliant nature, and decreases distally into the descending and abdominal aorta. Maintenance of the aortic matrix involves complex interactions among smooth muscle cells, macrophages, proteases, and protease inhibitors. Any alteration in this delicate balance can lead to aortic disease. Thoracic aortic aneurysms have a variety of causes (Table 22-1). Although these disparate pathologic processes differ in biochemical and histologic terms, they share the final common pathway of progressive aortic expansion and eventual rupture.

Table 22-1 Causes of Thoracic Aortic Aneurysms Nonspecific medial degeneration Aortic dissection Genetic disorders Marfan syndrome Loeys-Dietz syndrome Ehlers-Danlos syndrome Familial aortic aneurysms Congenital bicuspid aortic valve Poststenotic dilatation Infection Aortitis Takayasu's arteritis Giant cell arteritis Rheumatoid aortitis Trauma

Hemodynamic factors clearly contribute to the process of aortic dilatation. The vicious cycle of increasing diameter and increasing wall tension, as characterized by Laplace's law (tension = pressure

x

radius), is well established.

Turbulent blood flow is also recognized as a factor. Poststenotic aortic dilatation, for example, occurs in some patients with aortic valve stenosis or coarctation of the descending thoracic aorta. Hemodynamic derangements, however, are only one piece of a complex puzzle. Atherosclerosis is commonly cited as a cause of thoracic aortic aneurysms. However, although atherosclerotic disease often is found in conjunction with aortic aneurysms, the notion that atherosclerosis is a distinct cause of aneurysm formation has been challenged. In thoracic aortic aneurysms, atherosclerosis appears to be a coexisting process, rather than the underlying cause. Research into the pathogenesis of abdominal aortic aneurysms has focused on the molecular mechanisms of aortic wall degeneration and dilatation. For example, imbalances between proteolytic enzymes (e.g., matrix metalloproteinases) and their inhibitors contribute to abdominal aortic aneurysm formation. Building on these advances, current investigations are attempting to determine whether similar inflammatory and proteolytic mechanisms are involved in thoracic aortic disease, in hope of identifying potential molecular targets for pharmacologic therapy.

NONSPECIFIC MEDIAL DEGENERATION Nonspecific medial degeneration is the most common cause of thoracic aortic disease. Histologic findings of mild

medial degeneration, including fragmentation of elastic fibers and loss of smooth muscle cells, are expected in the aging aorta. However, an advanced, accelerated form of medial degeneration leads to progressive weakening of the aortic wall, aneurysm formation, and eventual dissection, rupture, or both. The underlying causes of medial degenerative disease remain unknown.

AORTIC DISSECTION An aortic dissection usually begins as a tear in the inner aortic wall, which initiates a progressive separation of the medial layers and creates two channels within the aorta. This event profoundly weakens the outer wall. As the most common catastrophe involving the aorta, dissection represents a major, distinct cause of thoracic aortic aneurysms and is discussed in detail in the second half of this chapter.

GENETIC DISORDERS Marfan Syndrome Marfan syndrome is an autosomal dominant genetic disorder characterized by a specific connective tissue defect that leads to aneurysm formation. The phenotype of patients with Marfan syndrome typically includes a tall stature, high palate, joint hypermobility, eye lens disorders, mitral valve prolapse, and aortic aneurysms. The aortic wall is weakened by fragmentation of elastic fibers and deposition of extensive amounts of mucopolysaccharides (a process previously called cystic medial degeneration ). Patients with Marfan syndrome have a mutation in the fibrillin gene located on the long arm of chromosome 15. The traditionally held view is that abnormal fibrillin in the extracellular matrix decreases connective tissue strength in the aortic wall and produces abnormal elasticity, which predisposes the aorta to dilatation from wall tension caused by left ventricular ejection impulses.3 More recent evidence, however, shows that the abnormal fibrillin causes degeneration of the aortic wall matrix by increasing the activity of transforming growth factor beta (TGF- ).4 Between 75 and 85% of patients with Marfan syndrome have dilatation of the ascending aorta and annuloaortic ectasia (dilatation of the aortic sinuses and annulus).5 Such aortic abnormalities are the most common cause of death among patients with Marfan syndrome.6 Marfan syndrome also is frequently associated with aortic dissection.

Ehlers-Danlos Syndrome Ehlers-Danlos syndrome includes a spectrum of inherited connective tissue disorders of collagen synthesis. The subtypes represent differing defective steps of collagen production. Vascular type Ehlers-Danlos syndrome is characterized by an autosomal dominant defect in type III collagen synthesis, which can have life-threatening cardiovascular manifestations. Spontaneous arterial rupture, usually involving the mesenteric vessels, is the most common cause of death in these patients. Thoracic aortic aneurysms and dissections are less commonly associated with Ehlers-Danlos syndrome, but when they do occur, they pose a particularly challenging surgical problem because of the reduced integrity of the aortic tissue in patients with Ehlers-Danlos syndrome.

Loeys-Dietz Syndrome Recently described, Loeys-Dietz syndrome is phenotypically distinct from Marfan syndrome. It is characterized as an aneurysmal syndrome with widespread systemic involvement. Loeys-Dietz syndrome is an aggressive, autosomal dominant condition that is distinguished by the triad of arterial tortuosity and aneurysms, hypertelorism (widely spaced eyes), and bifid uvula or cleft palate. It is caused by heterozygous mutations in the genes encoding TGF-

receptors, rather than fibrillin 1.7,8

Familial Aortic Aneurysms

Families without the heritable connective tissue disorders described earlier also can be affected by genetic conditions that cause thoracic aortic aneurysms. In fact, it is estimated that at least 20% of patients with thoracic aortic aneurysms and dissections have a genetic predisposition to them. The involved mutations are characterized by autosomal dominant inheritance with decreased penetrance and variable expression. Thus far, mutations involving the genes for TGF- receptor 2 (TGF R2 ), -myosin heavy chain (MYH11 ), and

-smooth muscle cell

actin (ACTA2 ) have been identified as causes of familial thoracic aortic aneurysms and dissection. Two other loci—on chromosomes 5 and 11—also have been associated with this condition, but the responsible genes have not yet been clearly identified.9

Congenital Bicuspid Aortic Valve Bicuspid aortic valve is the most common congenital malformation of the heart or great vessels, affecting up to 2% of Americans.1 0 Compared to patients with normal, trileaflet aortic valves, patients with bicuspid aortic valves have an increased incidence of ascending aortic aneurysm formation and, often, a more rapid rate of aortic enlargement. 1 1 Fifty percent to 70% of adults with bicuspid aortic valve, but without significant valve dysfunction, have echocardiographically detectable aortic dilatation.12,13 This dilatation usually is limited to the ascending aorta and root.1 4 Dilation occasionally is found in the arch and only rarely in the descending or abdominal aorta. In addition, aortic dissection occurs 10 times more often in patients with bicuspid valves than in the general population. 1 5 Recent findings suggest that aneurysms associated with bicuspid aortic valves have a fundamentally different pathobiologic cause than aneurysms that occur in patients with trileaflet valves.1 6 The exact mechanism responsible for aneurysm formation in patients with bicuspid aortic valves remains controversial. The two most popular theories posit that the dilatation is caused by (a) a congenital defect involving the aortic wall matrix that results in progressive degeneration, or (b) ongoing hemodynamic stress caused by turbulent flow through the diseased valve. It is likely that both proposed mechanisms are involved: patients with bicuspid aortic valves may have a congenital connective tissue abnormality that predisposes the aorta to aneurysm formation, especially in the presence of chronic turbulent flow through a deformed valve. In support of the theory that aneurysms result from vascular matrix remodeling that causes structural weakness of the aortic wall, evidence suggests that fibrillin 1 content is significantly lower and matrix metalloproteinase activity is significantly higher in the aortic media in patients with bicuspid aortic valves than in persons with normal tricuspid aortic valves.16–18 In recent years, clinical studies have increasingly supported the theory that aortic wall fragility, not turbulent flow, is the main mechanism of dilatation in these patients. For example, one study showed that the aorta progressively dilates when the bicuspid valve is replaced with a prosthesis, despite the elimination of the hemodynamic lesion.1 9 In addition, several studies have found evidence of a genetic predisposition to this condition.20–22

INFECTION Primary infection of the aortic wall resulting in aneurysm formation is rare. Although these lesions are termed mycotic aneurysms, the responsible pathogens usually are bacteria rather than fungi. Bacterial invasion of the aortic wall may result from bacterial endocarditis, endothelial trauma caused by an aortic jet lesion, or extension from an infected laminar clot within a pre-existing aneurysm. The most common causative organisms are Staphylococcus aureus, Staphylococcus epidermidis, Salmonella, and Streptococcus.

23,24

Unlike most other causes

of thoracic aortic aneurysms, which generally produce fusiform aneurysms, infection often produces saccular aneurysms located in areas of aortic tissue destroyed by the infectious process. Although syphilis was once the most common cause of ascending aortic aneurysms, the advent of effective

antibiotic therapy has made syphilitic aneurysms a rarity in developed nations. In other parts of the world, however, syphilitic aneurysms remain a major cause of morbidity and mortality. The spirocheteTreponema pallidum causes an obliterative endarteritis of the vasa vasorum that results in medial ischemia and loss of the elastic and muscular elements of the aortic wall. The ascending aorta and arch are the most commonly involved areas. The emergence of HIV infection in the 1980s was associated with a substantial increase in the incidence of syphilis in both HIV-positive and HIV-negative patients. Because syphilitic aortitis often presents 10 to 30 years after the primary infection, the incidence of associated aneurysms may increase in the near future.

AORTITIS In patients with pre-existing degenerative thoracic aortic aneurysms, localized transmural inflammation and subsequent fibrosis can develop. The dense aortic infiltrate responsible for the fibrosis consists of lymphocytes, plasma cells, and giant cells. The cause of the intense inflammatory reaction is unknown. Although the severe inflammation is a superimposed problem rather than a primary cause, its onset within an aneurysm can further weaken the aortic wall and precipitate expansion. Systemic autoimmune disorders also cause thoracic aortitis. Aortic Takayasu's arteritis generally produces obstructive lesions related to severe intimal thickening, but associated medial necrosis can lead to aneurysm formation. In patients with giant cell arteritis (temporal arteritis), granulomatous inflammation may develop that involves the entire thickness of the aortic wall, causing intimal thickening and medial destruction. Rheumatoid aortitis is an uncommon systemic disease that is associated with rheumatoid arthritis and ankylosing spondylitis. The resulting medial inflammation and fibrosis can affect the aortic root, causing annular dilatation, aortic valve regurgitation, and ascending aortic aneurysm formation.

PSEUDOANEURYSMS Pseudoaneurysms of the thoracic aorta usually represent chronic leaks that are contained by surrounding tissue and fibrosis. By definition, the wall of a pseudoaneurysm is not formed by intact aortic tissue; rather, the wall develops from organized thrombus and associated fibrosis. Pseudoaneurysms can arise from primary defects in the aortic wall (e.g., after trauma or contained aneurysm rupture) or from anastomotic leaks that occur after cardiovascular surgery. Anastomotic pseudoaneurysms can be caused by technical problems or by deterioration of the native aortic tissue, graft material, or suture. Tissue deterioration usually is related to either progressive degenerative disease or infection. Improvements in sutures, graft materials, and surgical techniques have decreased the incidence of thoracic aortic pseudoaneurysms.

Natural History Treatment decisions in cases of thoracic aortic aneurysm are guided by our current understanding of the natural history of these aneurysms, which classically is characterized as progressive aortic dilatation and eventual dissection, rupture, or both. An analysis by Elefteriades of data from 1600 patients with thoracic aortic disease has helped quantify these well-recognized risks. 2 5 Average expansion rates were 0.07 cm/y in ascending aortic aneurysms and 0.19 cm/y in descending thoracic aortic aneurysms. As expected, aortic diameter was a strong predictor of rupture, dissection, and mortality. For thoracic aortic aneurysms >6 cm in diameter, annual rates of catastrophic complications were 3.6% for rupture, 3.7% for dissection, and 10.8% for death. Critical diameters, at which the incidence of expected complications significantly increased, were 6.0 cm for aneurysms of the ascending aorta and 7.0 cm for aneurysms of the descending thoracic aorta; the corresponding risks of rupture after reaching these diameters were 31 and 43%, respectively.2 6

Certain types of aneurysms have an increased propensity for expansion and rupture. For example, aneurysms in patients with Marfan syndrome dilate at an accelerated rate and rupture or dissect at smaller diameters than non–Marfan-related aneurysms. Before the era of surgical treatment for aortic aneurysms, this aggressive form of aortic disease resulted in an average life expectancy of 32 years for Marfan patients; aortic root complications caused the majority of deaths.2 7 Saccular aneurysms, which commonly are associated with aortic infection and typically affect only a discrete small section of the aorta, tend to grow more rapidly than fusiform aneurysms, which are associated with more widespread degenerative changes and generally affect a larger section of the aorta. One common clinical scenario deserves special attention. A moderately dilated ascending aorta (i.e., 4 to 5 cm) often is encountered during aortic valve replacement or coronary artery bypass operations. The natural history of these ectatic ascending aortas has been defined by several studies. Michel and colleagues2 8 studied patients whose ascending aortic diameters were >4 cm at the time of aortic valve replacement; 25% of these patients required reoperation for ascending aortic replacement. Prenger and colleagues2 9 reported that aortic dissection occurred in 27% of patients who had aortic diameters of >5 cm at the time of aortic valve replacement.

Clinical Manifestations In many patients with thoracic aortic aneurysms, the aneurysm is discovered incidentally when imaging studies are performed for unrelated reasons. Therefore, patients often are asymptomatic at the time of diagnosis. However, thoracic aortic aneurysms that initially go undetected eventually create symptoms and signs that correspond with the segment of aorta that is involved. These aneurysms have a wide variety of manifestations, including compression or erosion of adjacent structures, aortic valve regurgitation, distal embolism, and rupture.

LOCAL COMPRESSION AND EROSION Initially, aneurysmal expansion and impingement on adjacent structures causes mild, chronic pain. The most common symptom in patients with ascending aortic aneurysms is anterior chest discomfort; the pain is frequently precordial in location but may radiate to the neck and jaw, mimicking angina. Aneurysms of the ascending aorta and transverse aortic arch can cause symptoms related to compression of the superior vena cava, the pulmonary artery, the airway, or the sternum. Rarely, these aneurysms erode into the superior vena cava or right atrium, causing acute high-output failure. Expansion of the distal aortic arch can stretch the recurrent laryngeal nerve, which results in left vocal cord paralysis and hoarseness. Descending thoracic and thoracoabdominal aneurysms frequently cause back pain localized between the scapulae. When the aneurysm is largest in the region of the aortic hiatus, it may cause middle back and epigastric pain. Thoracic or lumbar vertebral body erosion typically causes severe, chronic back pain; extreme cases can present with spinal instability and neurologic deficits from spinal cord compression. Although mycotic aneurysms have a peculiar propensity to destroy vertebral bodies, spinal erosion also occurs with degenerative aneurysms. Descending thoracic aortic aneurysms may cause varying degrees of airway obstruction, manifesting as cough, wheezing, stridor, or pneumonitis. Pulmonary or airway erosion presents as hemoptysis. Compression and erosion of the esophagus cause dysphagia and hematemesis, respectively. Thoracoabdominal aortic aneurysms can cause duodenal obstruction or, if they erode through the bowel wall, GI bleeding. Jaundice due to compression of the liver or porta hepatis is uncommon. Erosion into the inferior vena cava or iliac vein presents with an abdominal bruit, widened pulse pressure, edema, and heart failure.

AORTIC VALVE REGURGITATION Ascending aortic aneurysms can cause displacement of the aortic valve commissures and annular dilatation. The resulting deformation of the aortic valve leads to progressively worsening aortic valve regurgitation. In response to the volume overload, the heart remodels and becomes increasingly dilated. Patients with this condition may

present with progressive heart failure, a widened pulse pressure, and a diastolic murmur.

DISTAL EMBOLIZATION Thoracic aortic aneurysms—particularly those involving the descending and thoracoabdominal aorta—are commonly lined with friable, atheromatous plaque and mural thrombus. This debris may embolize distally, causing occlusion and thrombosis of the visceral, renal, or lower-extremity branches.

RUPTURE Patients with ruptured thoracic aortic aneurysms often experience sudden, severe pain in the anterior chest (ascending aorta), upper back or left chest (descending thoracic aorta), or left flank or abdomen (thoracoabdominal aorta). When ascending aortic aneurysms rupture, they usually bleed into the pericardial space, producing acute cardiac tamponade and death. Descending thoracic aortic aneurysms rupture into the pleural cavity, producing a combination of severe hemorrhagic shock and respiratory compromise. External rupture is extremely rare; saccular syphilitic aneurysms have been observed to rupture externally after eroding through the sternum.

Diagnostic Evaluation Although certain constellations of symptoms and signs are highly suggestive of thoracic aortic aneurysm, diagnosing and characterizing these aneurysms requires imaging studies. In addition to establishing the diagnosis, imaging studies provide critical information that guides the selection of treatment options. Optimal imaging techniques for the thoracic and thoracoabdominal aorta are somewhat institution-specific, varying with the availability of imaging equipment and expertise.

PLAIN RADIOGRAPHY Plain radiographs of the chest, abdomen, or spine often provide enough information to support the initial diagnosis of thoracic aortic aneurysm. Ascending aortic aneurysms produce a convex shadow to the right of the cardiac silhouette. The anterior projection of an ascending aneurysm results in the loss of the retrosternal space in the lateral view. An aneurysm may be indistinguishable from elongation and tortuosity.3 0 It is important to recognize that chest radiographs (CXRs) often appear normal in patients with thoracic aortic disease and thus cannot exclude the diagnosis of aortic aneurysm. Aortic root aneurysms, for example, often are hidden within the cardiac silhouette. Plain CXRs may reveal convexity in the right superior mediastinum, loss of the retrosternal space, or widening of the descending thoracic aortic shadow, which may be highlighted by a rim of calcification outlining the dilated aneurysmal aortic wall. Aortic calcification also may be seen in the upper abdomen on a standard radiograph made in the anteroposterior or lateral projection (Fig. 22-2). Once a thoracic aortic aneurysm is detected on plain radiographs, additional studies are required to define the extent of aortic involvement.

Fig. 22-2.

Chest radiographs showing a calcified rim (arrows ) in the aortic wall of a thoracoabdominal aortic aneurysm. A. Anteroposterior view. B. Lateral view.

ULTRASONOGRAPHY Although useful in evaluating infrarenal abdominal aortic aneurysms, standard transabdominal ultrasonography does not allow visualization of the thoracic aorta. During ultrasound evaluation of a suspected infrarenal abdominal aortic aneurysm, if a definitive neck cannot be identified at the level of the renal arteries, the possibility of thoracoabdominal aortic involvement should be suspected and investigated by using other imaging modalities.

ECHOCARDIOGRAPHY Ascending aortic aneurysms are commonly discovered during echocardiography in patients presenting with symptoms or signs of aortic valve regurgitation. Both transthoracic and transesophageal echocardiography provide excellent visualization of the ascending aorta, including the aortic root.3 1 Transesophageal echocardiography (TEE) also allows visualization of the descending thoracic aorta but is not ideal for evaluating the transverse aortic arch (which is obscured by air in the tracheobronchial tree) or the upper abdominal aorta. Effective echocardiography requires considerable technical skill, both in obtaining adequate images and in interpreting them. This imaging modality has the added benefit of assessing cardiac function and revealing any other abnormalities that may be

present.

COMPUTED TOMOGRAPHY Computed tomographic (CT) scanning is widely available and provides visualization of the entire thoracic and abdominal aorta. Consequently, CT is the most common—and arguably the most useful—imaging modality for evaluating thoracic aortic aneurysms.3 2 Systems capable of constructing multiplanar images and performing threedimensional aortic reconstructions are widely available. In addition to establishing the diagnosis, CT provides information about an aneurysm's location, extent, anatomic anomalies, and relationship to major branch vessels. CT is particularly useful in determining the absolute diameter of the aorta, especially in the presence of laminated clot. Contrast-enhanced CT provides information about the aortic lumen and can detect mural thrombus, aortic dissection, inflammatory periaortic fibrosis, and mediastinal or retroperitoneal hematoma due to contained aortic rupture. The major disadvantage of contrast-enhanced CT scanning is the possibility of contrast-induced acute renal failure in patients who are at risk (e.g., patients with pre-existing renal disease or diabetes).3 3 If possible, surgery is performed =1 day after contrast administration to allow time to observe renal function and to permit diuresis of the contrast agent. If renal insufficiency occurs or is worsened, elective surgery is postponed until renal function returns to normal or stabilizes.

MAGNETIC RESONANCE ANGIOGRAPHY Magnetic resonance angiography (MRA) is becoming widely available and has the ability to facilitate visualization of the entire aorta. This modality produces aortic images comparable to those produced by contrast-enhanced CT but does not necessitate exposure to ionizing radiation. In addition, MRA offers excellent visualization of branch vessel details, and it is useful in detecting branch vessel stenosis.3 4 Current limitations of MRA include high expense and a susceptibility to artifacts created by ferromagnetic materials. Also, a few recent studies have suggested that gadolinium—the contrast agent for MRA—may be linked to nephrogenic systemic fibrosis and acute renal failure in patients with advanced renal insufficiency.3 5 Furthermore, the MRA environment is not appropriate for many critically ill patients.

AORTOGRAPHY AND CARDIAC CATHETERIZATION Although diagnostic aortography was, until recently, considered the gold standard for evaluating thoracic aortic disease, CT and MRA have largely replaced this modality. Technologic improvements have enabled CT and MRA to provide excellent aortic imaging while causing less morbidity than catheter-based studies do, so CT and MRA should now be considered the gold standard. Therefore, the role of diagnostic angiography in patients with thoracic aortic disease is currently limited. However, the advent of endovascular therapies has given catheter-based angiography a new role, because intraprocedural angiography is an essential component of endovascular procedures. In selected cases, aortography is used to gain important information when other types of studies are contraindicated or have not provided satisfactory results. For example, information about obstructive lesions of the brachiocephalic, visceral, renal, or iliac arteries is useful when surgical treatment is being planned; if other imaging studies have not provided adequate detail, aortograms can be obtained in patients with suspected branch vessel occlusive disease. Unlike standard aortography, cardiac catheterization continues to play a major role in diagnosis and preoperative planning, especially in patients with ascending aortic involvement. Proximal aortography can reveal not only the status of the coronary arteries and left ventricular function but also the degree of aortic valve regurgitation, the

extent of aortic root involvement, coronary ostial displacement, and the relationship of the aneurysm to the arch vessels. The value of the information one can obtain from catheter-based diagnostic studies should be weighed against the established limitations and potential complications of such studies. A key limitation of aortography is that it images only the lumen and may therefore underrepresent the size of large aneurysms that contain laminated thrombus. Manipulation of intraluminal catheters can result in embolization of laminated thrombus or atheromatous debris. Proximal aortography carries a 0.6 to 1.2% risk of stroke. Other risks include allergic reaction to contrast agent, iatrogenic aortic dissection, and bleeding at the arterial access site. In addition, the volumes of contrast agent required to adequately fill large aneurysms can cause significant renal toxicity. To minimize the risk of contrast nephropathy, patients receive periprocedural IV fluids for hydration, mannitol for diuresis, and acetylcysteine.36,37 As with contrast-enhanced CT, surgery is performed =1 day after angiography whenever possible to ensure that renal function has stabilized or returned to baseline.

Treatment DETERMINATION OF THE APPROPRIATE TREATMENT Once a thoracic aortic aneurysm is detected, management begins with patient education, particularly if the patient is asymptomatic. A detailed medical history is collected, a physical examination is performed, and a systematic review of medical records is carried out to clearly assess the presence or absence of pertinent symptoms and signs, despite any initial denial of symptoms by the patient. Signs of genetic diseases such as Marfan syndrome are thoroughly reviewed. If clinical criteria are met for such a genetic condition, confirmatory laboratory tests are conducted. Patients with such genetic diseases are best treated in a dedicated aortic clinic where they can be appropriately followed. Surveillance CT scans and aggressive blood pressure control are the mainstays of initial management for asymptomatic patients. When patients become symptomatic or their aneurysms grow to meet certain size criteria, the patients become surgical candidates. Since the last edition of this textbook was published, endovascular therapy has become an accepted treatment for thoracic aortic aneurysms. Although its role in treating proximal aortic disease and thoracoabdominal aortic aneurysms remains experimental, endoluminal stenting is approved by the Food and Drug Administration for the treatment of isolated descending thoracic aortic aneurysms. For aneurysms with proximal aortic involvement and for thoracoabdominal aortic aneurysms, open procedures remain the gold standard and preferred approach.

DETERMINATION OF THE EXTENT AND SEVERITY OF DISEASE Serial CT scans are critical when one is evaluating a thoracic aneurysm, determining treatment strategy, and planning necessary procedures. Note that, commonly, patients with a thoracic aortic aneurysm also have a remote aneurysm.2 In such cases, the more threatening lesion usually is addressed first. In many patients, staged operative procedures are necessary for complete repair of extensive aneurysms involving the ascending aorta, transverse arch, and descending thoracic or thoracoabdominal aorta.3 8 When the descending segment is not disproportionately large (compared with the proximal aorta) and is not causing symptoms, the proximal aortic repair is carried out first. An important benefit of this approach is that it allows treatment of valvular and coronary artery occlusive disease at the first operation. Proximal aneurysms (proximal to the left subclavian artery) usually are addressed via a sternotomy approach. Left thoracotomy incisions are used for open repairs of aneurysms involving the descending thoracic aorta, unless the aneurysm fulfills certain endovascular criteria. A CT scan can reveal detailed information about aortic calcification

and luminal thrombus. These details are important in preventing embolization during surgical manipulation.

Indications for Operation Thoracic aortic aneurysms are repaired to prevent fatal rupture. Therefore, on the basis of the natural history studies discussed earlier, elective operation is recommended when the diameter of an ascending aortic aneurysm is >5.5 cm, when the diameter of a descending thoracic aortic aneurysm is >6.5 cm, or when the rate of dilatation is >1 cm/y. 25,39 In patients with connective tissue disorders, such as Marfan and Loeys-Dietz syndromes, the threshold for operation is lower with regard to both absolute size (5.0 cm for the ascending aorta and 6.0 cm for the descending thoracic aorta) and rate of growth. Smaller ascending aortic aneurysms (4.0 to 5.5 cm) also are considered for repair when they are associated with significant aortic valve regurgitation. The acuity of presentation is a major factor in decisions about the timing of surgical intervention. Many patients are asymptomatic at the time of presentation, so there is time for thorough preoperative evaluation and improvement of their current health status, such as through smoking cessation and other optimization programs. In contrast, patients who present with symptoms may need urgent operation. Symptomatic patients are at increased risk of rupture and warrant expeditious evaluation. The onset of new pain in patients with known aneurysms is especially concerning, because it may herald significant expansion, leakage, or impending rupture. Because emergent interventions produce worse outcomes than elective procedures do, emergent intervention is reserved for patients who present with rupture or superimposed acute dissection.4 0

Open Repair vs. Endovascular Repair As noted earlier, endovascular repair of thoracic aortic aneurysms has become an accepted treatment option in selected patients, particularly patients with isolated degenerative descending thoracic aortic aneurysms. For endovascular repairs to produce optimal outcomes, several anatomic criteria must be met. For one, the proximal and distal neck diameters should fall within a range that will allow proper sealing. Also, the proximal and distal necks should be at least 20 mm long so that an appropriate landing-zone seal can be made. Note that the limiting structures proximally and distally are the brachiocephalic vessels and celiac axis, respectively. Another anatomic limitation for this therapy relates to vascular access: The femoral and iliac arteries have to be wide enough to accommodate the large sheaths necessary to deploy the stent grafts. Occasionally, a "side graft" must be anastomosed to the iliac artery through a retroperitoneal incision because of poor distal access. When any of these anatomic criteria is not met, an open approach is preferable to an endovascular approach. Of note, attempts have been made to extend the use of endovascular therapy to aortic arch aneurysms and thoracoabdominal aortic aneurysms. Reports of these types of purely endovascular repair are limited. Still experimental, hybrid approaches involve debranching the aortic arch or the visceral vessels of the abdominal aorta followed by endovascular exclusion of the aneurysm. Figure 22-3 provides an algorithm for the management of descending thoracic aortic aneurysm.

Fig. 22-3.

Algorithm for the management of descending thoracic aortic aneurysm as used to facilitate decisions regarding treatment.

The patients who benefit more from an endovascular approach than from traditional open techniques are those who are of advanced age or have significant comorbidities. The open repair of a descending thoracic aortic aneurysm can result in significant pulmonary morbidity. Therefore, patients with borderline pulmonary reserve may be best suited for an endovascular or hybrid procedure. In contrast, patients with significant intraluminal atheroma are best served by an open approach because of the risk of embolization and stroke posed by catheter manipulations. Similarly, patients with connective tissue disease should undergo an open procedure and generally are not considered candidates for endovascular repair. Endovascular repair in the setting of connective tissue disorders has been met with poor results, which are mainly due to progressive dilatation, stent graft migration, and endoleak.

PREOPERATIVE ASSESSMENT AND PREPARATION Given the impact of comorbid conditions on perioperative complications, a careful preoperative assessment of physiologic reserve is critical in assessing operative risk. Therefore, most patients undergo a thorough evaluation—with emphasis on cardiac, pulmonary, and renal function—before undergoing elective surgery.41,42

Cardiac Evaluation Coronary artery disease is common in patients with thoracic aortic aneurysms and is responsible for a substantial proportion of early and late postoperative deaths in such patients. Similarly, valvular disease and myocardial dysfunction have important implications when one is planning anesthetic management and surgical approaches for aortic repair. Transthoracic echocardiography is a satisfactory noninvasive method for evaluating both valvular and biventricular function. Dipyridamole-thallium myocardial scanning identifies regions of myocardium that have reversible ischemia, and this test is more practical than exercise testing in older patients with concomitant lowerextremity peripheral vascular disease. Cardiac catheterization and coronary arteriography are performed in patients who have evidence of coronary disease—as indicated by either the patient's history or the results of noninvasive studies—or who have a left ventricular ejection fraction of 30%. If significant valvular or coronary artery disease is identified before a proximal aortic operation, the disease can be addressed directly during the procedure. Patients who have asymptomatic distal aortic aneurysms and severe coronary occlusive disease undergo percutaneous transluminal angioplasty or surgical revascularization before the aneurysmal aortic segment is replaced.

Pulmonary Evaluation Pulmonary function screening with arterial blood gas measurement and spirometry is routinely performed before thoracic aortic operations. Patients with a forced expiratory volume in 1 second of >1.0 L and a partial pressure of carbon dioxide of 1 cm during a 1-year period. A lower threshold often is used for patients with Marfan syndrome.

Endovascular Treatment Malperfusion Syndrome Endovascular therapy is routinely used in patients with descending aortic dissection complicated by visceral

malperfusion.132 Abdominal malperfusion syndrome often is fatal; prompt identification of visceral ischemia and expedited treatment to restore hepatic, GI, and renal perfusion are imperative for a positive outcome. As described in a later section, several open surgical techniques can be used to re-establish blood flow to compromised organs. However, in the acute setting, open surgery is associated with poor outcomes. Therefore, endovascular intervention is the preferred initial approach in this setting. In one endovascular technique known as endovascular fenestration, a balloon is used to create a tear in the dissection flap, which allows blood to flow in both the true and false lumens. This technique can be used when a visceral branch is being supplied by an underperfused true or false lumen. Placement of a stent graft in the true lumen of the aorta can resolve a "dynamic" malperfusion. Occasionally, a small stent must be placed directly in the lumen of a visceral or renal artery because the dissection has propagated into the branch, creating "static" malperfusion at the origin. Iliofemoral malperfusion causing limb-threatening leg ischemia also can be treated via an endovascular approach. However, direct surgical revascularization—usually by placing a femoral-to-femoral arterial bypass graft—is a better option whenever the endovascular procedure cannot be performed expeditiously.

Acute Dissection There is considerable interest in using endovascular stent grafts to treat uncomplicated acute descending dissection. The goal of this treatment strategy is to use the stent graft to cover the intimal tear, seal the entry site of the dissection, and eventually cause thrombosis of the false lumen. However, whether this approach is more effective than conventional nonoperative management has not been established; therefore, at this time, the use of endografts in patients with classic dissection remains investigational.133 Such procedures take place in a hybrid operating room, where access to the true lumen is gained from the femoral arteries. An aortogram is taken, and the intimal tear is identified. Note that the diameter of the true lumen is measured on both the aortogram and a preoperative contrast-enhanced CT scan. A stent graft approximately 10% wider in diameter than the true lumen is selected for these cases. Unlike stents deployed in treating most descending thoracic aortic aneurysms, stents deployed in treating descending aortic dissections must not be ballooned, because ballooning can cause a new intimal tear, retrograde dissection into the ascending aorta, or even aortic rupture.

Chronic Dissection Endovascular treatment of chronic descending aortic dissection also is currently under investigation.134 These dissections are particularly challenging, because the relative rigidity of the dissecting membrane and the presence of multiple re-entry sites make it difficult to exclude the false lumen. Furthermore, interfering with false lumen perfusion may cause ischemic complications, such as bowel infarction or renal failure. Until the safety and effectiveness of endovascular repair for this condition have been demonstrated, patients with chronic descending aortic dissection should be treated with conventional nonoperative management until indications for open surgical repair develop.

Penetrating Aortic Ulcer Unlike patients with classic descending aortic dissection, those with PAUs appear to be very well suited for endovascular intervention. Covering the focal ulceration with a stent graft has been shown to be an effective treatment.135

Open Repair Acute Dissection In patients with acute aortic dissection, surgical repair of the descending thoracic or thoracoabdominal aorta is

associated with high morbidity and mortality.114 Therefore, the primary goals of surgery are to prevent fatal rupture and to restore branch vessel perfusion.131 A limited graft repair of the life-threatening aortic lesion achieves these goals while minimizing risks. Because the most common site of rupture in descending aortic dissection is in the proximal third of the descending thoracic aorta, the upper half of the descending thoracic aorta is usually repaired. The distal half also may be replaced if it exceeds 4 cm in diameter. Graft replacement of the entire thoracoabdominal aorta is not attempted in this setting unless a large coexisting aneurysm mandates this radical approach. Similarly, the repair is not extended into the aortic arch unless the arch is aneurysmal, even if the primary tear is located there. Patients with chronic dissection who require emergency repair because of acute pain or rupture also undergo limited graft replacement of the symptomatic segment. Because repairing acute dissections entails an increased risk of paraplegia, adjuncts that provide spinal cord protection, such as cerebrospinal fluid drainage and left heart bypass, are used liberally during such repairs,136 even if the repair is confined to the upper descending thoracic aorta. Proximal control usually is obtained between the left common carotid and left subclavian arteries; any mediastinal hematoma near the proximal descending thoracic aorta is avoided until proximal control is established. After the aorta is opened, the dissecting membrane is excised from the section undergoing graft replacement. The proximal and distal anastomoses use all layers of the aortic wall, thereby excluding the false lumen in the suture lines and directing all blood flow into the true lumen. Although the relative lack of mural thrombus assures the presence of multiple patent intercostal arteries, extreme tissue fragility may preclude their reattachment.

Malperfusion Syndrome Lower-extremity ischemia is commonly addressed with surgical extra-anatomic revascularization techniques, such as femoral-to-femoral bypass grafting. In patients with abdominal organ ischemia, flow to the compromised bed must be re-established swiftly. When an endovascular approach is unavailable or unsuccessful, open surgery is necessary. Although they are considered second-line therapies, multiple techniques are available, including graft replacement of the aorta (with flow redirected into the true lumen), open aortic fenestration, and visceral or renal artery bypass.

Chronic Dissection A more aggressive replacement usually is performed during elective aortic repairs in patients with chronic dissection. In many regards, the operative approach used in these patients is identical to that used for descending thoracic and thoracoabdominal aortic aneurysms, as described in the first half of this chapter (Fig. 22-20). One key difference is the need to excise as much dissecting membrane as possible to clearly identify the true and false lumens and to locate all important branch vessels. When the dissection extends into the visceral or renal arteries, the membrane can be fenestrated, or the false lumen can be obliterated with sutures or intraluminal stents. Asymmetric expansion of the false lumen can create wide separation of the renal arteries. This problem is addressed by reattaching the mobilized left renal artery to a separate opening in the graft or by performing a left renal artery bypass with a side graft. Wedges of dissecting membrane also are excised from the aorta adjacent to the proximal and distal anastomoses, which allows blood to flow through both true and false lumens. When placing the proximal clamp is not technically feasible, hypothermic circulatory arrest can be used to facilitate the proximal portion of the repair.

Fig. 22-20.

Illustration of distal aortic repair of a chronic dissection. A. Thoracoabdominal incision. B. Extent II thoracoabdominal aortic aneurysm resulting from chronic aortic dissection. The patient has previously undergone composite valve graft replacement of the aortic root and ascending aorta. After left heart bypass is initiated, the proximal portion of the aneurysm is isolated by placing clamps on the left subclavian artery, between the left common carotid and left subclavian arteries, and across the

middle descending thoracic aorta. C. The isolated segment of aorta is opened by using electrocautery. D. The dissecting membrane is excised, and bleeding intercostal arteries are oversewn. The aorta is prepared for proximal anastomosis by transecting it distal to the proximal clamp and separating this portion from the esophagus (not shown). E. The proximal anastomosis between the aorta and an appropriately sized Dacron graft is completed with continuous polypropylene suture. F. After left heart bypass has been stopped and the distal aortic cannula has been removed, the proximal clamp is repositioned onto the graft, the other two clamps are removed, and the remainder of the aneurysm is opened. G. The rest of the dissecting membrane is excised, and the openings to the celiac, superior mesenteric, and renal arteries are identified. H. Selective visceral perfusion with oxygenated blood from the bypass circuit is delivered through balloon perfusion catheters placed in the celiac and superior mesenteric arterial ostia. Cold crystalloid is delivered to the renal arteries. The critical intercostal arteries are reattached to an opening cut in the graft. I. To minimize spinal cord ischemia, the proximal clamp is repositioned distal to the intercostal reattachment site. A second oval opening is fashioned in the graft adjacent to the visceral vessels. Selective perfusion of the visceral arteries continues during their reattachment to the graft. A separate anastomosis is often required to reattach the left renal artery. J. After the balloon perfusion catheters are removed and the visceral anastomosis is completed, the clamp is again moved distally, restoring blood flow to the celiac, renal, and superior mesenteric arteries. The final anastomosis is created between the graft and the distal aorta. [Reproduced with permission from Creager MA, Dzau VS, Loscalzo J (eds): Vascular Medicine. Philadelphia: WB Saunders, 2006. Copyright Saunders/Elsevier, 2006, Fig. 35-8A–J.]

OUTCOMES Improvements in anesthesia, surgical techniques, and perioperative care have led to substantial improvements in outcome after thoracic aortic aneurysm repair. When performed in specialized centers, these operations are associated with excellent survival rates and acceptable morbidity rates. The interpretation of outcomes data is complicated by site-specific variables, such as the number of years reported and whether data are taken from single-practice centers or from pooled, multi-center, or national registries, and by patient-specific variables, such as type of enrollment, urgency and extent of repair, concomitant procedures performed, and the presence of preexisting risk factors such as advanced age, previous cardiovascular repair, disease of any system or organ, or connective tissue disorder.

Repair of Proximal Aortic Aneurysms Risks associated with the open repair of the proximal aorta vary by extent of repair and are greatest for repairs involving total arch replacement. All varieties of aortic root replacement have shown acceptable early mortality rates and few complications. Two groups with 20 and 27 years' experience with composite valve graft replacement reported early mortality rates of 5.6% and 1.9%, respectively, with the more recent repairs having better outcomes. 137,138 Early mortality rates for stentless porcine tissue root replacements are also low, ranging from 3.6 to 6.0%

139–143

Repairs incorporating the ascending aorta and aortic arch have acceptable outcomes, with risk increasing as larger sections of the aortic arch are incorporated into the repair.144,145 Reported early mortality rates after stage 1 elephant trunk repairs range from 2.3 to 13.9%.56,71,146–148 The risk of operative death and stroke in these repairs is additionally increased by severe atherosclerosis of the ascending aorta, and a revised surgical strategy is often needed to avoid clamping this section of the aorta. In a review of literature accompanying Zingone and colleagues' own data for 36 such patients, pooled early death rates averaged 9.0% (ranged from 3.7 to 25.0%) and pooled stroke rates averaged 5.3% (ranged from 0 to 17.6%). 149 Their revised patient strategy included the use of hypothermic circulatory arrest in most patients (94%) and resulted in two early deaths (6%), one stroke (3%), and five patients with neurocognitive disturbances (14%).

Other studies indicate that the enhanced risk of neurocognitive disturbances in ascending repairs using circulatory arrest are not offset by lower rates of early mortality.150,151 In a report by Kazui and Bashar152 covering 20 years of experience and 472 consecutive patients who underwent aortic arch repair with selective antegrade cerebral perfusion, early mortality was 9.3% for all repairs and 4.1% for more recent repairs. The stroke rate was 3.2% for permanent deficits and 4.7% for temporary deficits. Recent innovations in aortic arch replacement, such as the use of extra-anatomic grafts and moderate hypothermia, have also produced good results, including early mortality rates ranging from 0 to 4.7%, permanent stroke rates ranging from 0 to 4.0%, and rates of transient neurologic dysfunction ranging from 0 to 4.9%.153–155

Treatment of Acute Ascending Aortic Dissection The International Registry of Acute Aortic Dissection (IRAD) provides the most comprehensive data on contemporary outcomes in patients with acute aortic dissection. This registry was established in 1996 and has accumulated data from >1600 patients treated for acute aortic dissection at 22 centers in 11 countries. A recent IRAD analysis of data for 682 patients who underwent surgical repair of acute ascending aortic dissection revealed an inhospital mortality rate of 23.9%. The investigators identified several preoperative predictors of early mortality, including age >70 years, previous cardiac surgery, hypotension or shock at presentation, migrating pain, cardiac tamponade, pulse deficit, and evidence of myocardial ischemia or infarction on ECG.156

Repair of Distal Aortic Aneurysms ENDOVASCULAR REPAIR OF DESCENDING THORACIC AORTIC ANEURYSMS In the earliest series of endovascular repairs of descending thoracic aortic aneurysms, mortality and morbidity were difficult to assess. Most of the reported series were small and contained a large proportion of high-risk patients with substantial comorbidity. For example, in the Stanford experience with "first-generation" stent grafts in 103 patients with descending thoracic aortic aneurysms, the operative mortality rate was 9%, the stroke rate was 7%, the paraplegia/paraparesis rate was 3%, and actuarial survival was only 73 5% at 2 years. However, 62 patients (60%) were not considered candidates for thoracotomy and open surgical repair; as expected, this group experienced the majority of the morbidity and mortality.9 7 In a follow-up series, the Stanford group reported survival rates of 74% at 1 year and 31% at 5 years after stent grafting in patients who were deemed not to be surgical candidates; in contrast, survival rates were 93% at 1 year and 78% at 5 years (P 0.24. In the case of unilateral renal artery stenosis with normal contralateral kidney, the increase in ipsilateral renin release is normally balanced by suppression of the contralateral kidney renin production, which results in a drop in its RSRI to 0.48. The prognostic value of RSRI remains limited in that approximately 10% of patients with favorable clinical response following renovascular revascularization do not exhibit contralateral renin suppression. As a result, the use of RSRI must be applied with caution in the management of patients with renovascular hypertension. MRA with IV gadolinium contrast enhancement has been increasingly used for renal artery imaging because of its ability to provide high-resolution images (Figs. 23-46 and 23-47) while using a minimally nephrotoxic agent. Flow void may be inaccurately interpreted as occlusion or stenosis in MRA. Therefore, unless the quality of the image analysis software is superior, MRA should be interpreted with caution and used in conjunction with other modalities before making plans for operative or endovascular treatment.

Fig. 23-46.

Magnetic resonance angiography of the abdominal aorta revealed bilateral normal renal arteries.

Fig. 23-47.

Magnetic resonance angiography of the abdominal aorta revealed bilateral ostial renal artery stenosis (arrows ).

DSA remains the gold standard to assess renal artery occlusive disease. A flush aortogram is performed first so that any accessory renal arteries can be detected and the origins of all the renal arteries are adequately displayed. The presence of collateral vessels circumventing a renal artery stenosis strongly supports the hemodynamic importance of the stenosis. A pressure gradient of 10 mmHg or greater is necessary for collateral vessel development, which also is associated with activation of the renin-angiotensin cascade.

Treatment Indications The therapeutic goals in patients with renovascular disease include: (a) improved BP control to prevent end-organ damage on systems such as the cerebral, coronary, pulmonary, and peripheral circulations; and (b) preservation and possibly improvement of the renal function (Table 23-12).

Table 23-12 Indications for Renal Artery Revascularization Fibromuscular dysplasia lesion Pressure gradient >20 mmHg Affected/unaffected kidney renin ratio >1.5:1 Clinical criteria

Refractory or rapidly progressive hypertension Hypertension associated with flash pulmonary edema without coronary artery disease Rapidly progressive deterioration in renal function Intolerance to antihypertensive medications Chronic renal insufficiency related to bilateral renal artery occlusive disease or stenosis to a solitary functioning kidney Dialysis-dependent renal failure in a patient with renal artery stenosis but without another definite cause of endstage renal disease Recurrent congestive heart failure or flash pulmonary edema not attributable to active coronary ischemia Angiography criteria

The indications for endovascular treatment for renal artery occlusive disease include 70% or greater stenosis of one or both renal arteries and at least one of the following clinical criteria: Inability to adequately control hypertension despite appropriate antihypertensive regimen. Chronic renal insufficiency related to bilateral renal artery occlusive disease or stenosis to a solitary functioning kidney. Dialysis-dependent renal failure in a patient with renal artery stenosis but without another definite cause of end-stage renal disease. Recurrent congestive heart failure or flash pulmonary edema not attributable to active coronary ischemia. Before 1990, the most common treatment modality in patients with renal artery occlusive disease was surgical revascularization, with either renal artery bypass grafting or renal artery endarterectomy. The advancement of endovascular therapy in the past decade has led to various minimally invasive treatment strategies such as renal artery balloon angioplasty or stenting to control hypertension or to preserve renal function.

Surgical Reconstruction The typical approach for surgical renal artery revascularization involves a midline xiphoid-to-pubis incision. The posterior peritoneum is incised, and the duodenum is mobilized to the right, starting at the ligament of Treitz. The left renal hilum can be exposed by extending the retroperitoneal dissection to the left along the avascular plane along the inferior border of the pancreas. Mobilization of the left renal vein is essential in these cases and can be achieved by dividing the gonadal, iliolumbar, and adrenal veins. The proximal portion of the right renal artery can be exposed through the base of the mesentery by retraction of the left renal vein cephalad and the vena cava to the right. Accessing the most distal portion of the right renal artery requires a Kocher maneuver and duodenal mobilization. Another approach useful for treating bilateral renal artery lesions involves mobilization of the entire small bowel and the right colon, with a dissection that starts at the ligament of Treitz, and proceeds toward the cecum and then along the line of Todd in the right paracolic gutter. Simultaneous dissection along the inferior border of the pancreas provides additional visualization of the left renal artery. Finally, division of the diaphragmatic crura that encircle the suprarenal aorta may sometimes be necessary to achieve suprarenal clamping.

TYPES OF SURGICAL RECONSTRUCTION Aortorenal bypass is the most frequently performed reconstruction of ostial occlusive renal artery disease. After

proximal and distal control is obtained, an elliptical segment of the aorta is excised, and the proximal anastomosis is performed in end-to-side fashion. Autologous vein is the preferred conduit. If the vein is not suitable, then prosthetic material can be used. An end-to-end anastomosis is then performed between the conduit of choice and the renal artery using either a 6-0 or 7-0 polypropylene suture. The length of the arteriotomy needs to be at least three times the diameter of the renal artery to prevent anastomotic restenosis. If the surgeon plans to perform a side-to-side anastomosis between the conduit and the renal artery, then it is performed first, and the aortic anastomosis follows. Endarterectomy, either transrenal or transaortic, is an alternative to bypass for short ostial lesions, or in patients with multiple renal arteries. The transrenal endarterectomy is performed with a transverse longitudinal incision on the aorta that extends into the diseased renal artery. After the plaque removal, the arteriotomy is closed with a prosthetic patch. Transaortic endarterectomy is well suited for patients with multiple renal arteries and short ostial lesions. The aorta is opened longitudinally and aortic sleeve endarterectomy is performed, followed by eversion endarterectomy of the renal arteries. Adequate mobilization of the renal arteries is essential for a safe and complete endarterectomy. Hepatorenal and splenorenal bypass are alternative options of revascularizations for patients who might not tolerate aortic clamping, or for those with calcified aorta that precludes adequate control. For hepatorenal bypass, a right subcostal incision is used, and the hepatic artery is exposed with an incision in the lesser omentum. A Kocher maneuver is performed, the right renal vein is identified and mobilized, and the right renal artery is identified and controlled posteriorly to the vein. The greater saphenous vein is the conduit of choice. The anastomosis is performed end to side with the common hepatic artery, and end to end with the renal artery anterior to the inferior vena cava. The splenorenal bypass is performed via a left subcostal incision. The splenic artery is mobilized from the lesser sac, brought through a retropancreatic plane, and anastomosed end to end to the renal artery. Reimplantation of the renal artery is an attractive option of reconstruction in children, or in adults with ostial lesions. A redundant renal artery is a prerequisite for the procedure. After mobilization, the artery is transected and spatulated, eversion endarterectomy is performed, if necessary, and an end-to-side anastomosis with the aorta is created.

Clinical Results of Surgical Repair Results reflect the need for performance of renal artery bypass in high-volume and experienced centers. In a review from a large tertiary center, 92% of the patients with non-atherosclerotic vascular disease had good response to hypertension, but only 43% were completely cured and were taken off antihypertensives.8 9 Patients younger than 45 years old fare better with a cure rate of 68% and an improvement rate of 32%. In patients with atherosclerotic renal artery disease, the cure rate was even smaller (12%), and the overall response to hypertension rate was 85%. The operative mortality was 3.1% and 0% in the atherosclerotic and nonatherosclerotic groups, respectively. Renal function improvement occurs within the first week of the operation in approximately two thirds of the patients. A progressive decrease in the GFR is seen after this initial improvement, but the rate of decrease is less compared to the group of patients who did not respond at all to operative intervention. Up to three fourths of patients were permanently removed from dialysis in a large series.9 0 Favorable response of renal function to revascularization improves overall survival.

Endovascular Treatment

Endovascular treatment of renal artery occlusive disease was first introduced by Grntzig who successfully dilated a renal artery stenosis using a balloon catheter technique. This technique requires passage of a guidewire under fluoroscopic control typically from a femoral artery approach to across the stenosis in the renal artery. A balloondilating catheter is passed over the guidewire and positioned within the area of stenosis and inflated to produce a controlled disruption of the arterial wall. Alternatively, a balloon-mounted, expandable stent can be used to primarily dilate the renal artery stenosis. Completion angiography usually is performed to assess the immediate results. The technical aspect of an endovascular renal artery revascularization is discussed in Techniques of Renal Artery Angioplasty and Stenting below.

TECHNIQUES OF RENAL ARTERY ANGIOPLASTY AND STENTING Access to the renal artery for endovascular intervention is typically performed via a femoral artery approach, although a brachial artery approach can be considered in the event of severe aortoiliac occlusive disease, aortoiliac aneurysm, or severe caudal renal artery angulation. Once an introducer sheath is placed in the femoral artery, an aortogram is performed with a pigtail catheter placed in the suprarenal aorta. Additional oblique views are frequently necessary to more precisely visualize the orifice of the stenosed renal artery and thoroughly assess the presence of accessory renal arteries. Noniodinated contrast agents such as carbon dioxide and gadolinium can be used in endovascular renal intervention in patients with renal dysfunction or history of allergic reaction. After systemic heparinization, catheterization of the renal artery can be performed using a variety of selective angled catheters including the RDC, Cobra-2, Simmons I, or SOS Omni catheter (Boston Scientific/Meditech, Natick, Mass; Cook, Bloomington, Ind; Medtronic, Santa Rosa, Calif, Cordis, Warren, NJ; or AngioDynamics, Queensbury, NY). A selective renal angiogram is then performed to confirm position, and the lesion is crossed with either a 0.035-in or a 0.018- to 0.014-in guidewire. It is important to maintain the distal wire position without movement in the tertiary renal branches while guiding sheath placement to reduce the possibility of parenchymal perforation and spasm. A guiding sheath or a guiding catheter is then advanced at the orifice of the renal artery to provide a secure access for balloon and stent deployment. Balloon angioplasty is performed with a balloon sized to the diameter of the normal renal artery adjacent to the stenosis. Choosing a balloon with a 4-mm diameter is a reasonable first choice. The luminal diameter of the renal artery can be further assessed by comparing it to the fully inflated balloon. Such a comparison may provide a reference guide to determine whether renal artery dilatation with a larger diameter angioplasty balloon is necessary. Once balloon angioplasty of the renal artery is completed, an angiogram is performed to document the procedural result. Radiographic evidence of either residual stenosis or renal artery dissection constitutes suboptimal angioplasty results, which warrants an immediate renal artery stent placement. Moreover, atherosclerotic involvement of the very proximal renal artery that involves the vessel orifice typically requires stent placement. A balloon-expandable stent is typically used, and is positioned in such a way so that it protrudes into the aorta by 1 to 2 mm. The size of the stent is determined by the size of the renal artery, taking into account a desirable 10 to 20% oversizing. After the stent deployment, the angiogram is repeated and, upon a satisfactory result, the devices are withdrawn. It is critical to maintain the guidewire access across the renal lesion until satisfactory completion angiogram is obtained. Spasm of the branches of the renal artery will usually respond to nitroglycerin 100 to 200 mcg administered through the guiding sheath directly into the renal artery. While endovascular therapy of renal artery occlusive disease is considerably less invasive than conventional renal artery bypass operation, complications relating to this treatment modality can occur. In a study in which Guzman

and colleagues compared the complications following renal artery angioplasty and surgical revascularization, the authors noted that major complication rates following endovascular and surgical treatment were 17% and 31%, respectively. In contrast, significantly greater minor complications were associated with the endovascular cohort, which was 48%, in contrast to 7% in the surgical group.9 1 In a prospective randomized study that compared the clinical outcome of renal artery balloon angioplasty vs. stenting for renal ostial atherosclerotic lesion, comparable complications rates were found in the two groups, which were 39% and 43%, respectively. However, the incidence of restenosis rate at 6 months was significantly higher in the balloon angioplasty cohort than the stenting group, which was 48% in contrast to 14% at 6 months. This study underscores the clinical superiority of renal stenting compared to renal balloon angioplasty alone in patients with ostial stenosis.9 2 Deterioration in renal function, albeit transient, is a common complication following endovascular renal artery intervention. This is most likely the combined result of the use of iodinated contrast, and the occurrence of renal parenchymal embolism due to wire and catheter manipulation. In most cases, this is a temporary problem, as supportive care with adequate fluid hydration is sufficient to reverse the renal dysfunction. However, transient hemodialysis may become necessary in approximately 1% of patients. Other complications include vascular access complications (bleeding, hematoma, femoral nerve injury, arteriovenous fistula, and pseudoaneurysm), target vessel dissection, perinephric hematoma, early postoperative renal artery thrombosis, and extremity atheroembolism from thrombus in the aorta or the iliac arteries.

Clinical Results of Endovascular Interventions PERCUTANEOUS TRANSLUMINAL BALLOON ANGIOPLASTY FMD of the renal artery is the most common treatment indication for percutaneous, transluminal balloon angioplasty. Patients with symptomatic FM, such as hypertension or renal insufficiency, usually respond well to renal artery balloon angioplasty alone.9 3 In contrast, balloon angioplasty generally is not an effective treatment for patients with renal artery stenosis or proximal occlusive disease of the renal artery, due to the high incidence of restenosis with balloon angioplasty alone. In the latter group of patients, primary stent placement is the preferred endovascular treatment. The long-term benefit of renal artery balloon angioplasty in patients with FMD was reported by Surowiec and colleagues.9 3 They followed 14 patients who underwent 19 interventions on 18 renal artery segments. The technical success rate of balloon angioplasty for FMD was 95%. Primary patency rates were 81%, 69%, 69%, and 69% at 2, 4, 6, and 8 years, respectively. Assisted primary patency rates were 87%, 87%, 87%, and 87% at 2, 4, 6, and 8 years, respectively. The restenosis rate was 25% at 8 years. Clinical benefit, as defined by either improved or cured hypertension, was found in 79% of patients overall, with two thirds of patients having maintained this benefit at 8 years. The authors concluded that balloon angioplasty is highly effective in symptomatic FMD with excellent durable functional benefits.9 3 The utility of balloon angioplasty alone in the treatment of renovascular hypertension appears to be limited. Van Jaarsveld and associates performed a prospective study in which patients with renal artery stenosis were randomized to either drug therapy or balloon angioplasty treatment.9 4 A total of 106 patients with 50% diameter stenosis or greater plus hypertension or renal insufficiency were randomized in the study. At 3 months, there was no difference in the degree to which BP was controlled between the two groups. However, the degree and dose of antihypertensive medications was slightly lowered in the balloon angioplasty group. The above advantage of the angioplasty group completely disappeared at 12 months, making the authors conclude that, in the treatment of patients with hypertension and renal artery stenosis, percutaneous transluminal balloon angioplasty alone offers minimal advantage over antihypertensive drug therapy.

RENAL ARTERY STENTING Endovascular stent placement is the treatment of choice for patients with symptomatic or high-grade renal artery occlusive disease (Fig. 23-48). This is due in part to the high incidence of restenosis with balloon angioplasty alone, particularly in the setting of ostial stenosis. Renal artery stenting is also indicated for renal artery dissection caused by balloon angioplasty or other catheter-based interventions. Numerous studies have clearly demonstrated the clinical efficacy of renal artery stenting when compared to balloon angioplasty alone in patients with high-grade renal artery stenosis.

Fig. 23-48.

Renal artery stenting. A. Focal lesion in the renal artery (arrow ). B. Poststenting angiogram reveals a satisfactory result following a renal artery stenting placement (arrow ).

White and colleagues conducted a study to evaluate the role of renal artery stenting in patients with poorly controlled hypertension and renal artery lesions that did not respond well to balloon angioplasty alone.9 5 The technical success of the procedure was 99%. The mean BP values were 173 25/88 17 mmHg before stent implantation and 146 20/77 12 mmHg 6 months after renal artery stenting (P 20 cm, involving the popliteal artery) Chronic total occlusion of popliteal artery and proximal trifurcation vessels

CFA = common femoral artery; SFA = superficial femoral artery; TASC II = Trans-Atlantic Inter-Society Consensus. In a similar fashion, infrapopliteal arterial diseases are classified into four types based on TASC II guideline (Fig. 23-61). Type A lesions are single lesions 5.5 cm, with an acceptable perioperative mortality of less than 5%.

Pseudoxanthoma Elasticum Pseudoxanthoma elasticum is a rare inherited disorder of connective tissue that is characterized by an unbalanced elastic fiber metabolism and synthesis, resulting in fragmentation and calcification of the fibers. Clinical manifestations occur in the skin, ocular, GI, and cardiovascular systems. 206 Characteristic skin lesions are seen in the axilla, antecubital and popliteal fossae, and groin. The yellow, xanthoma-like papules occur in redundant folds of skin and are said to resemble plucked chicken skin. The inheritance pattern includes both autosomal dominant and recessive types and has a prevalence of one in 160,000 individuals.183 The ATP-binding cassette subfamily C member 6 (ABCC6) gene has been demonstrated to be responsible, and 43 mutations have been identified, all of which lead to calcification of the internal elastic laminae of medium-sized vessel walls.206 Cardiovascular features are common and include premature CAD, cerebrovascular disease, renovascular hypertension, diminished peripheral pulses, and restrictive cardiomyopathy. Symptom onset typically occurs in the second decade of life, with onset at an average age of 13 years. Patients should be counseled to reduce potential contributing factors for atherosclerosis such as tobacco use and high cholesterol levels. Calcium intake should be restricted in adolescents, as a positive correlation has been found between disease severity and calcium intake.206 Surgical management involves standard vascular techniques, with the exception that arterial conduits should not be used in cardiac bypass.

Kawasaki Disease Kawasaki disease was first described in 1967, as a mucocutaneous lymph node syndrome occurring in young children. In most studies, more than one half of the patients are younger than 2 years of age, with a higher prevalence in boys.207 Although originally described in Japan, the disease is found worldwide. An infectious agent may be causative; however, no specific agent has been identified. Immune activation with the contribution of cytokines, elastases, growth factors, and metalloproteinases is believed to be a mechanism for inflammation and aneurysm formation. Coronary artery aneurysms, the hallmark of the disease, histologically demonstrate a panarteritis with fibrinoid necrosis. Coronary arteriography may show occlusions, recanalization, and localized stenosis, in addition to multiple aneurysms. A variety of constitutional symptoms and signs resulting from systemic vasculitis are present in the acute phase of the illness.207 Medical therapy for Kawasaki disease clearly decreases the manifestations of coronary artery involvement. IV gamma globulin and aspirin therapy are most successful if begun within the first 10 days of illness. Up to 20% of untreated patients will develop coronary arterial lesions.207 A long-term, low-dose aspirin therapy regimen usually is recommended.

Inflammatory Arteritis and Vasculitis Chronic inflammatory arteritis and vasculitis (i.e., inflammatory changes within veins as well as arteries) include a

spectrum of disease processes caused by immunologic mechanisms. These terms signify a necrotizing transmural inflammation of the vessel wall associated with antigen-antibody immune complex deposition within the endothelium. These conditions show pronounced cellular infiltration in the adventitia, thickened intimal fibrosis, and organized thrombus.204 These disease processes may clinically mimic atherosclerosis, and most are treated by corticosteroid therapy or chemotherapeutic agents. Even so, it is important to recognize distinguishing characteristics of each disease to establish the course of treatment and long-term prognosis. A classification system of systemic vasculitis by vessel size is shown in Table 23-28.

Table 23-28 Classification of Vasculitis Based on Vessel Involvement Large vessel vasculitis Takayasu's arteritis Giant cell arteritis Behet's disease Medium-sized vessel vasculitis Polyarteritis nodosa Kawasaki disease Buerger's disease Small vessel vasculitis Hypersensitivity angiitis

Behet's Disease Behet's disease is a rare syndrome characterized by oral and genital ulcerations and ocular inflammation, affecting males in Japan and the Mediterranean. An HLA linkage has been found, indicating a genetic component to the etiology. Vascular involvement is seen in 7 to 38% of patients, and is localized to the abdominal aorta, femoral artery, and pulmonary artery.211 Vascular lesions also may include venous complications such as deep venous thrombosis or superficial thrombophlebitis. Arterial aneurysmal degeneration can occur; however, this is an uncommon, albeit potentially devastating, complication. Multiple true aneurysms and pseudoaneurysms may develop, and rupture of an aortic aneurysm is the major cause of death in patients with Behet's disease.212 Histologically, degeneration of the vasa vasorum with surrounding perivascular lymphocyte infiltration is seen, along with thickening of the elastic laminae around the tunica media.213 Aneurysm formation is believed to be associated with a loss of the nutrient flow and elastic component of the vessels, leading to progressive dilatation. Multiple aneurysms are relatively common, with a reported occurrence of 36% in affected Japanese patients.212 Furthermore, pseudoaneurysm formation after surgical bypass is common at anastomotic suture lines due to the vascular wall fragility and medial destruction. Systemic therapy with corticosteroids and immunosuppressive agents may diminish symptoms related to the inflammatory process; however, they have no effect on the rate of disease progression and arterial degeneration.212

Polyarteritis Nodosa Polyarteritis nodosa (PAN) is another systemic inflammatory disease process, which is characterized by a necrotizing inflammation of medium-sized or small arteries that spares the smallest blood vessels (i.e., arterioles and capillaries). This disease predominantly affects men more than women by a 2:1 ratio. PAN develops subacutely, with constitutional symptoms that last for weeks to months. Intermittent, low-grade fever, malaise, weight loss, and myalgia are common presenting symptoms. As medium-sized vessels lie within the deep dermis,

cutaneous manifestations occur in the form of livedo reticularis, nodules, ulcerations, and digital ischemia.214 Skin biopsies of these lesions may be sufficient for diagnosis. Inflammation may be seen histologically, with pleomorphic cellular infiltrates and segmental transmural necrosis leading to aneurysm formation. Neuritis from nerve infarction occurs in 60% of patients, and GI complications in up to 50%.215 Additionally, renal involvement is found in 40%, and manifests as microaneurysms within the kidney or segmental infarctions. Cardiac disease is a rare finding except at autopsy, where thickened, diseased coronary arteries may be seen, as well as patchy myocardial necrosis. Patients may succumb to renal failure, intestinal hemorrhage, or perforation. Endorgan ischemia from vascular occlusion or aneurysm rupture can be disastrous complications with high mortality rates. The mainstay of treatment is steroid and cytotoxic agent therapy. Up to 50% of patients with active PAN will experience remission with high dosing.215

Radiation-Induced Arteritis Radiation-induced arteritis results from progressive stenosis due to endothelial damage that leads to cellular proliferation and fibrosis. These are well-described complications of combined irradiation and chemotherapy for the treatment of head and neck malignancy. Arterial lesions are known complications of radiation and are similar to those found in atherosclerotic occlusive disease. A history of therapeutic irradiation to the neck can complicate the management of carotid artery occlusive disease. Radiation-induced damage to blood vessels has been well studied. The small capillaries and sinusoids are most susceptible to radiation effects, as endothelial cells are the most radiosensitive cells. The radiation effects on the medium and large-sized arteries include myointimal proliferation, with or without lipid deposits, and thrombosis. Characteristically, irregular, spindle-shaped cells are seen replacing the normal endothelial cells in the healing phase. Occlusive lesions develop in the irradiated carotid arteries, and are either the result of vessel wall fibrosis, or, more commonly, due to accelerated atherosclerosis. Neurologic complications related to radiation-induced carotid artery disease are similar to those due to nonirradiated atherosclerotic occlusive disease. Rupture of the carotid artery has been reported following neck irradiation, and is likely related to local wound complication and superimposed infection. The diagnosis of radiation arteritis is based on the clinical history and confirmation of the occlusive lesion by duplex ultrasound, MRA, CTA, or subtraction angiography. Irradiated lesions can be confined to the irradiated segment of the ICA with the remaining part of the vessel spared of disease. Characteristically, the radiation-induced atherosclerotic lesion does not involve the carotid bulb, unlike the nonradiated atherosclerotic lesions. The indications for intervention in radiation-induced carotid lesions are the same for atherosclerotic carotid occlusive lesions as previously discussed in the "Treatment of Carotid Occlusive Disease" section. However, asymptomatic irradiated carotid artery lesions should be considered for intervention because they can be more prone to progression and development of neurologic complications. Endovascular treatment with carotid angioplasty/stenting has become the treatment of choice for radiation-induced lesions, although surgical endarterectomy and bypass have been shown to be safe. The rate of recurrent stenosis is higher in radiation-induced carotid lesions, whether stented or surgically treated.

Raynaud's Syndrome First described in 1862 by Maurice Raynaud, the term Raynaud's syndrome applies to a heterogeneous symptom array associated with peripheral vasospasm, more commonly occurring in the upper extremities. The characteristically intermittent vasospasm classically follows exposure to various stimuli, including cold temperatures, tobacco, or emotional stress. Formerly, a distinction was made between Raynaud's "disease" and Raynaud's "phenomenon" for describing a benign disease occurring in isolation or a more severe disease secondary

to another underlying disorder, respectively. However, many patients develop collagen vascular disorders at some point after the onset of vasospastic symptoms; progression to a connective tissue disorder ranges from 11 to 65% in reported series.211,216 Therefore, the term Raynaud's syndrome is now used to encompass both the primary and secondary conditions. Characteristic color changes occur in response to the arteriolar vasospasm, ranging from intense pallor to cyanosis to redness as the vasospasm occurs. The digital vessels then relax, eventually leading to reactive hyperemia. The majority of patients are young women Chapter 24. Venous and Lymphatic Disease >

KEY POINTS 1. Deep vein thrombosis (DVT) and pulmonary embolism are frequent complications after major abdominal and orthopedic procedures. The risk is further increased in patients with malignancy and a history of venous thromboembolism. Options for DVT prophylaxis include intermittent pneumatic compression, use of graduated compression stockings, and administration of low-dose unfractionated heparin, low molecular weight heparin, fondaparinux, and vitamin K antagonists. However, prophylaxis should be stratified based on the patient's level of risk. 2. In patients with established DVT, unfractionated heparin, low molecular weight heparin, and fondaparinux are options for initial antithrombotic therapy. The duration and type of long-term anticoagulation should be stratified based on the provoked or unprovoked nature of the DVT, the location of the DVT, previous occurrence of DVT, and presence of concomitant malignancy. 3. Thrombolytic therapy, surgical thrombectomy, and placement of inferior vena cava filters are adjunctive treatments that may be indicated in patients with extensive and complicated venous thromboembolism. 4. Saphenous vein stripping, endovenous laser treatment, and radiofrequency ablation are effective therapies for patients with saphenous vein valvular insufficiency. Concomitant varicose veins may be managed with compression therapy, sclerotherapy (for smaller varices), and phlebectomy. 5. The mainstay of treatment for chronic venous insufficiency is compression therapy. Sclerotherapy, perforator vein ligation, and venous reconstruction may be indicated in patients in whom conservative management fails. 6. Lymphedema is categorized as primary (with early or delayed onset) or secondary. The goals of treatment are to minimize edema and prevent infection. Lymphatic massage, sequential pneumatic compression, use of compression garments, and limb elevation are effective forms of therapy.

VENOUS ANATOMY Veins are part of a dynamic and complex system that returns venous blood to the heart against the force of gravity in an upright individual. Venous blood flow is dependent on multiple factors such as gravity, venous valves, the cardiac and respiratory cycles, blood volume, and the calf muscle pump. Alterations in the intricate balance of these factors can result in venous pathology.

Structure of Veins Veins are thin-walled, highly distensible, and collapsible structures. Their structure specifically supports their two primary functions of transporting blood toward the heart and serving as a reservoir to prevent

intravascular volume overload. The venous intima is composed of a nonthrombogenic endothelium with an underlying basement membrane and an elastic lamina. The endothelium produces endothelium-derived relaxing factor and prostacyclin, which help maintain a nonthrombogenic surface through inhibition of platelet aggregation and promotion of platelet disaggregation.1 Circumferential rings of elastic tissue and smooth muscle located in the media of the vein allow for changes in vein caliber with minimal changes in venous pressure. When an individual is upright and standing still, the veins are maximally distended and their diameter may be several times greater than that in the supine position. Unidirectional blood flow is achieved with multiple venous valves. The number of valves is greatest below the knee and fewest in the more proximal veins. Each valve is made of two thin cusps consisting of a fine connective tissue skeleton covered by endothelium. Venous valves close in response to cephalad-to-caudal blood flow at a velocity of at least 30 cm/s.2 The inferior vena cava (IVC), common iliac veins, portal venous system, and cranial sinuses are valveless.

Lower Extremity Veins The nomenclature relating to venous anatomy recently has been revised. Lower extremity veins are divided into superficial, deep, and perforating veins. The superficial venous system lies above the uppermost fascial layer of the leg and thigh, and consists of the great saphenous vein (GSV) and small saphenous vein (SSV) and their tributaries. The GSV originates from the dorsal pedal venous arch and courses cephalad, anterior to the medial malleolus, entering the common femoral vein approximately 4 cm inferior and lateral to the pubic tubercle. The saphenous nerve accompanies the GSV medially and supplies cutaneous sensation to the medial leg and ankle. The SSV originates laterally from the dorsal pedal venous arch and courses cephalad in the posterior calf. Most often, it penetrates the popliteal fossa, between the medial and lateral heads of the gastrocnemius muscle, to join the popliteal vein. The termination of the SSV may be quite variable, however, with a proximal extension of the SSV (the vein of Giacomini) frequently connecting with the deep femoral vein or GSV. The sural nerve accompanies the SSV laterally along its course and supplies cutaneous sensation to the lateral malleolar region. The deep veins follow the course of major arteries in the extremities. In the lower leg, paired veins parallel the course of the anterior tibial, posterior tibial, and peroneal arteries, and join behind the knee to form the popliteal vein. Venous bridges connect the paired veins in the lower leg. The popliteal vein continues through the adductor hiatus to become the femoral vein. In the proximal thigh, the femoral vein joins with the deep femoral vein to form the common femoral vein, becoming the external iliac vein at the inguinal ligament. Multiple perforator veins traverse the deep fascia to connect the superficial and deep venous systems. Clinically important perforator veins are the Cockett and Boyd perforators. The Cockett perforator veins drain the medial lower leg and are relatively constant. They connect the posterior arch vein (a tributary to the GSV) and the posterior tibial vein. They may become varicose or incompetent in venous insufficiency states. The Boyd perforator veins connect the GSV to the deep veins approximately 10 cm below the knee and 1 to 2 cm medial to the tibia. Venous sinuses are thin-walled, large veins located within the substance of the soleus and gastrocnemius muscles. These sinuses are valveless and are linked by valved, small venous channels that prevent reflux. A large amount of blood can be stored in the venous sinuses. With each contraction of the calf muscle bed, blood is pumped out through the venous channels into the main conduit veins to return to the heart.

Upper Extremity Veins

As in the lower extremity, there are deep and superficial veins in the upper extremity. Deep veins of the upper extremity are paired and follow the named arteries in the arm. Superficial veins of the upper extremity are the cephalic and basilic veins and their tributaries. The cephalic vein originates at the lateral wrist and courses over the ventral surface of the forearm. In the upper arm, the cephalic vein terminates in the infraclavicular fossa, piercing the clavipectoral fascia to empty into the axillary vein. The basilic vein runs medially along the forearm and penetrates the deep fascia as it courses past the elbow in the upper arm. It then joins with the deep brachial veins to become the axillary vein. The median cubital vein joins the cephalic and the basilic veins on the ventral surface of the elbow. The axillary vein becomes the subclavian vein at the lateral border of the first rib. At the medial border of the scalenus anterior muscle, the subclavian vein joins with the internal jugular vein to become the brachiocephalic vein, with the subclavian vein coursing anterior to the scalenus anterior muscle. The left and right brachiocephalic veins join to become the superior vena cava, which empties into the right atrium.

EVALUATION OF THE VENOUS SYSTEM Clinical Evaluation The evaluation of the venous system begins with a detailed history and physical examination. Risk factors for acute and chronic venous disease are identified. They include increased age, history of venous thromboembolism (VTE), malignancy, trauma and spinal cord injury, hospitalization and immobilization, obesity, nephrotic syndrome, pregnancy and the recently postpartum state, oral contraceptive use or hormone replacement therapy, varicose veins, and hypercoagulable states, as well as the postoperative state. Venous pathology is often, but not always, associated with visible or palpable signs that can be identified during the physical examination. There is variation among individuals in the prominence of superficial veins when the person is standing. The superficial veins of a lean athletic person, even when normal, will appear large and easily visualized, but these veins will be far less obvious in the obese individual. Possible signs of superficial venous abnormalities are listed in Table 24-1. The deep veins cannot be directly assessed clinically, and abnormalities within them can only be inferred indirectly from changes found on clinical examination.

Table 24-1 Possible Signs of Superficial Venous Abnormalities Tortuosity Varicosity Venous saccule Distended subdermal venules (corona phlebectatica) Distended intradermal venules (spider angiomata) Warmth, erythema, tenderness (superficial thrombophlebitis) Chronic venous insufficiency (CVI) may lead to characteristic changes in the skin and subcutaneous tissues in the affected limb. CVI results from incompetence of venous valves, venous obstruction, or both. Most CVI involves venous reflux, and severe CVI often reflects a combination of reflux and venous obstruction. It is important to remember that although CVI originates with abnormalities of the veins, the target organ of CVI

is the skin. A typical leg affected by CVI will be edematous, with edema increasing over the course of the day (Fig. 24-1). The leg may also be indurated and pigmented with eczema and dermatitis. These changes are due to excessive proteinaceous capillary exudate and deposition of a pericapillary fibrin cuff that may limit nutritional exchange. In addition, an increase in white blood cell trapping within the skin microcirculation in CVI patients may lead to microvascular congestion and thrombosis. Subsequently, white blood cells may migrate into the interstitium and release necrotizing lysosomal enzymes, which results in tissue destruction and eventual ulceration.

Fig. 24-1.

Edematous left leg of a patient with chronic venous insufficiency.

Fibrosis occurs from impaired nutrition, chronic inflammation, and fat necrosis (lipodermatosclerosis). Hemosiderin deposition due to the exudation of red cells and subsequent lysis in the skin causes the characteristic pigmentation of chronic venous disease (Fig. 24-2). Ulceration can develop with longstanding venous hypertension and is associated with alterations in microcirculatory and cutaneous lymphatic anatomy

and function. The most common location of venous ulceration is approximately 3 cm proximal to the medial malleolus (Fig. 24-3).

Fig. 24-2.

Characteristic hyperpigmentation of chronic venous insufficiency.

Fig. 24-3.

Venous ulceration located proximal to the medial malleolus.

Trendelenburg's test is a clinical test that can help determine whether incompetent valves are present and in which of the three venous systems (superficial, deep, or perforator) the valves are abnormal. There are two components to this test. First, with the patient supine, the leg is elevated 45 degrees to empty the veins, and the GSV is occluded with the examiner's hand or with a rubber tourniquet. With the GSV still occluded, the patient stands and the superficial veins are observed for blood filling. Then compression on the GSV is released and the superficial veins are observed for increased filling with blood. A negative result, indicating no clinically evident venous reflux, is the gradual filling of the veins from arterial inflow. A positive result is the sudden filling of veins with standing in the first part of the test or with release of GSV compression in the second part of the test. The perforator veins are thought to be normal with competent valves if the result of the first component of the test is negative. If the result of this part of the test is positive, there are theoretically incompetent valves in both the deep and perforator veins. The GSV valves are competent if the second component of the test gives a negative result, and the GSV valves are incompetent if the second component of the test yields a positive result. Interpretation of the findings of Trendelenburg's test is obviously subjective. The test has therefore been largely supplanted by the more objective noninvasive vascular laboratory tests to localize sites of venous reflux.

NONINVASIVE EVALUATION Before the development of vascular ultrasound, noninvasive techniques to evaluate the venous system were based on plethysmographic techniques. Although a variety of plethysmographic techniques are used in the evaluation of both acute and chronic venous disease, they are all based on the detection of volume changes in the limb in response to blood flow.

Duplex ultrasonography (DUS) augmented by color flow imaging is now the most important noninvasive diagnostic method in the evaluation of the venous system. DUS has become standard for the detection of infrainguinal deep vein thrombosis (DVT), with near 100% sensitivity and specificity in symptomatic patients.3 It is also the preferred method of evaluation for upper extremity venous thrombosis and is useful in the evaluation of CVI by documenting the presence of valvular reflux and venous obstruction.

INVASIVE EVALUATION With the improved accuracy of noninvasive techniques for diagnostic purposes, the use of invasive procedures has become more selective. Venography is now primarily used as an adjunct to percutaneous or operative treatment of venous disorders. Because the pelvic veins often cannot be visualized with DUS because of overlying bowel gas or body habitus, venography is often used to evaluate iliofemoral vein thrombosis in preparation for endovascular treatment or open surgical treatment. Venography is performed by direct venipuncture with injection of contrast material. As with any invasive procedure, there are inherent risks associated with venography. Local effects include pain and local thrombosis at the puncture site and possible formation of a hematoma if larger veins are used for access. Pain is significantly lower with nonionic low-osmolality contrast media than with conventional contrast agents (with 18% vs. 44% of patients experiencing discomfort, respectively).4 Systemic effects of iodinated contrast media include allergic reaction and risk of renal failure. Postvenography venous thrombosis occurs distal to the puncture site in 1 to 9% of patients undergoing venography and results from vein intimal damage from the IV contrast agent.4

VENOUS THROMBOEMBOLISM Epidemiology Despite increased awareness and use of prophylactic modalities, DVT and pulmonary embolism (PE) remain important preventable sources of morbidity and mortality. The incidence of DVT ranges between 5 and 9 per 10,000 person-years in the general population, and the incidence of VTE (DVT and PE combined) is approximately 14 per 10,000 person-years.5,6 The resultant number of new cases of VTE may be over 275,000 per year in the United States.7 Not only does VTE pose an immediate threat to life, it also can cause long-term impairment due to resultant venous insufficiency. The 20-year cumulative incidence rates are 26.8 and 3.7% for the development of venous stasis changes and venous ulcers, respectively, after an episode of DVT.8

Risk Factors Three conditions, first described by Rudolf Virchow in 1862, contribute to VTE formation: stasis of blood flow, endothelial damage, and hypercoagulability. Of these risk factors, relative hypercoagulability appears most important in most cases of spontaneous DVT, whereas stasis and endothelial damage likely play a greater role in secondary DVT after immobilization, surgical procedures, and trauma. Identifiable risk factors for VTE relate to one of the conditions described by Virchow, and often more than one factor is present. Specific risk factors for VTE are listed in Table 24-2.

Table 24-2 Risk Factors for Venous Thromboembolism Acquired

Inherited

Advanced age

Factor V Leiden

Hospitalization/immobilization

Prothrombin 20210A

Hormone replacement therapy and oral contraceptive use

Antithrombin deficiency Protein C deficiency

Pregnancy and puerperium

Protein S deficiency

Prior venous thromboembolism

Factor XI elevation

Malignancy Major surgery

Dysfibrinogenemia Mixed Etiology

Obesity

Homocysteinemia

Nephrotic syndrome

Factor VII, VIII, IX, XI elevation

Trauma or spinal cord injury

Hyperfibrinogenemia

Long-haul travel (>6 h)

Activated protein C resistance without factor V Leiden

Varicose veins Antiphospholipid antibody syndrome Myeloproliferative disease Polycythemia The more common acquired risk factors include advanced age, hospitalization and immobilization, hormone replacement and oral contraceptive therapy, pregnancy and the recently postpartum state, prior VTE, malignancy, major surgery, obesity, nephrotic syndrome, trauma and spinal cord injury, long-haul travel (>6 hours), varicose veins, antiphospholipid syndrome, myeloproliferative disorders, and polycythemia. Heritable risk factors include factor V Leiden; prothrombin 20210A gene variant; antithrombin, protein C, and protein S deficiencies; and dysfibrinogenemias. In some patients, the cause of the thrombophilia may have both a heritable and an acquired component. These mixed causes include homocysteinemia; factor VII, VIII, IX, and XI elevation; hyperfibrinogenemia; and activated protein C resistance in the absence of factor V Leiden. 9 When multiple inherited and acquired risk factors are present in the same patient, a synergistic effect may occur, depending on the thrombophilia in question. For example, patients who are heterozygous for factor V Leiden are at only moderately increased risk for VTE (fourfold to eightfold). However, when this genetic risk is combined with the additional risk of oral contraceptive use, the risk for VTE increases approximately 35fold, the same order of magnitude as for someone who is homozygous for factor V Leiden. The interaction between other common risk factors also was demonstrated in the Women's Health Initiative investigation.1 0 The concomitant presence of obesity, advancing age, or factor V Leiden increased the thrombosis risk associated with hormone replacement therapy. However, not all risk factors have the same synergistic effect. Hyperhomocysteinemia and the most common genotype associated with elevated homocysteine levels (MTHFR 677TT) do not appear to interact with the presence of factor V Leiden to further increase the risk for

venous thrombosis. 1 1 Other factors associated with venous thrombosis include traditional cardiovascular risk factors (obesity, hypertension, diabetes), and there is a racial predilection for whites and African Americans, compared with Asians and Native Americans.12,13 Certain gene variants (single nucleotide polymorphisms) are associated with a mildly increased risk for DVT, and their presence may interact with other risk factors to increase the overall risk for venous thrombosis.1 4 However, testing for these polymorphisms is not common in clinical practice.

Diagnosis CLINICAL EVALUATION Early in the course of DVT development, venous thrombosis is thought to begin in an area of relative stasis, such as a soleal sinus vein or immediately downstream of the cusps of a venous valve in the axial calf veins. Isolated proximal DVT without tibial vein thrombosis is unusual. Early in the course of a DVT, there may be no or few clinical findings such as pain or swelling. Even extensive DVT may sometimes be present without signs or symptoms. History and physical examination are therefore unreliable in the diagnosis of DVT. In addition, symptoms and signs generally associated with DVT, such as extremity pain and/or swelling, are nonspecific. In large studies, DVT has been found by venography or DUS in =50% of patients in whom it was clinically suspected.15,16 Objective studies are therefore required to confirm a diagnosis of DVT or to exclude the presence of DVT. Clinical symptoms may worsen as DVT propagates and involves the major proximal deep veins. Massive DVT that obliterates the major deep venous channel of the extremity with relative sparing of collateral veins causes a condition called phlegmasia alba dolens (Fig. 24-4). This condition is characterized by pain, pitting edema, and blanching. There is no associated cyanosis. When the thrombosis extends to the collateral veins, massive fluid sequestration and more significant edema ensues, resulting in a condition known as phlegmasia cerulea dolens.1 7 Phlegmasia cerulea dolens is preceded by phlegmasia alba dolens in 50 to 60% of patients. The affected extremity in phlegmasia cerulea dolens is extremely painful, edematous, and cyanotic, and arterial insufficiency or compartment syndrome may be present. If the condition is left untreated, venous gangrene can ensue, leading to amputation.

Fig. 24-4.

Phlegmasia alba dolens of the right leg. Note the blanching and edema.

VASCULAR LAB AND RADIOLOGIC EVALUATION Duplex Ultrasound DUS is now the most commonly performed test for the detection of infrainguinal DVT, both above and below the knee, and has a sensitivity and specificity of >95% in symptomatic patients.3 DUS combines real-time Bmode ultrasound with pulsed Doppler capability. Color flow imaging is useful in more technically difficult examinations, such as in the evaluation of possible calf vein DVT. This combination offers the ability to noninvasively visualize the venous anatomy, detect occluded and partially occluded venous segments, and demonstrate physiologic flow characteristics using a mobile self-contained device. In the supine patient, normal lower extremity venous flow is phasic (Fig. 24-5), decreasing with inspiration in response to increased intra-abdominal pressure with the descent of the diaphragm and then increasing with expiration. When the patient is upright, the decrease in intra-abdominal pressure with expiration cannot overcome the hydrostatic column of pressure existing between the right atrium and the calf. Muscular contractions of the calf, along with the one-way venous valves, are then required to promote venous return to the heart. Flow also can be increased by leg elevation or compression and decreased by sudden elevation of intra-abdominal pressure (Valsalva's maneuver). In a venous DUS examination performed with the patient supine, spontaneous flow, variation of flow with respiration, and response of flow to Valsalva's maneuver are all assessed. However, the primary method of detecting DVT with ultrasound is demonstration of the lack of compressibility of the vein with probe pressure on B-mode imaging. Normally, in transverse section, the vein

walls should coapt with pressure. Lack of coaptation indicates thrombus.

Fig. 24-5.

Duplex ultrasound scan of a normal femoral vein with phasic flow signals.

The examination begins at the ankle and continues proximally to the groin. Each vein is visualized, and the flow signal is assessed with distal and proximal compression. Lower extremity DVT can be diagnosed by any of the following DUS findings: lack of spontaneous flow (Fig. 24-6), inability to compress the vein (Fig. 24-7), absence of color filling of the lumen by color flow DUS, loss of respiratory flow variation, and venous distention. Again, lack of venous compression on B-mode imaging is the primary diagnostic variable. Several studies comparing B-mode ultrasound to venography for the detection of femoropopliteal DVT in patients clinically suspected to have DVT report sensitivities of >91% and specificities of >97%. 18,19 The ability of DUS to assess isolated calf vein DVT varies greatly, with sensitivities ranging from 50 to 93% and specificities approaching 100%. 20,21

Fig. 24-6.

Duplex ultrasound of a femoral vein containing thrombus demonstrating no flow within the femoral vein.

Fig. 24-7.

B-mode ultrasound of the femoral vein in cross-section. The femoral vein does not collapse with external compression.

Impedance Plethysmography Impedance plethysmography (IPG) was the primary noninvasive method of diagnosing DVT before the widespread use of DUS but is infrequently used today. IPG is based on the principle that resistance to the flow of electricity between two electrodes, or electrical impedance, occurs as the volume of the extremity changes in response to blood flow. Two pairs of electrodes containing aluminum strips are placed circumferentially around the leg approximately 10 cm apart and a low-level current is delivered to the two outer electrodes. A pneumatic cuff is inflated over the thigh for venous outflow obstruction and then rapidly deflated. Changes in electrical resistance resulting from lower extremity blood volume changes are quantified. IPG is less accurate than DUS for the detection of proximal DVT, with an 83% sensitivity in symptomatic patients. It is a poor detector of calf vein DVT.2 2

Iodine 125 Fibrinogen Uptake Iodine 125 fibrinogen uptake (FUT) is a seldom used technique that involves IV administration of radioactive fibrinogen and monitoring for increased uptake in fibrin clots. An increase of 20% or more in one area of a limb indicates an area of thrombus.2 3 FUT can detect DVT in the calf, but high background radiation from the pelvis and the urinary tract limits its ability to detect proximal DVT. It also cannot be used in an extremity that has recently undergone surgery or has active inflammation. In a prospective study, FUT had a sensitivity of 73% and specificity of 71% for identification of DVT in a group of symptomatic and asymptomatic patients.2 2 Currently, FUT is primarily a research tool of historic interest.

Venography Venography is the most definitive test for the diagnosis of DVT in both symptomatic and asymptomatic patients. It is the gold standard to which other modalities are compared. This procedure involves placement of a small catheter in the dorsum of the foot and injection of a radiopaque contrast agent. Radiographs are obtained in at least two projections. A positive study result is failure to fill the deep system with passage of the contrast medium into the superficial system or demonstration of discrete filling defects (Fig. 24-8). A normal study result virtually excludes the presence of DVT. In a study of 160 patients with a normal venogram followed for 3 months, only two patients (1.3%) subsequently developed DVT and no patients experienced symptoms of PE.2 4

Fig. 24-8.

Venogram showing a filling defect in the popliteal vein (arrows).

Venography is not routinely used for the evaluation of lower extremity DVT because of the associated complications discussed previously. Currently, venography is reserved for imaging before operative venous

reconstruction and catheter-based therapy. It does, however, remain the procedure of choice in research studies evaluating methods of prophylaxis for DVT.

Treatment Once the diagnosis of VTE has been made, antithrombotic therapy should be initiated promptly. If clinical suspicion for VTE is high, it may be prudent to start treatment while the diagnosis is being objectively confirmed. The theoretic goals of VTE treatment are the prevention of mortality and morbidity associated with PE and the prevention of the postphlebitic syndrome. However, the only proven benefit of anticoagulant treatment for DVT is the prevention of death from PE. Treatment regimens may include antithrombotic therapy, vena caval interruption, catheter-directed or systemic thrombolytic therapy, and operative thrombectomy.

ANTITHROMBOTIC THERAPY Antithrombotic therapy may be initiated with IV or SC unfractionated heparin, SC low molecular weight heparin, or SC fondaparinux (a synthetic pentasaccharide). This initial therapy usually is continued for at least 5 days, while oral vitamin K antagonists are being simultaneously administered. The initial therapy typically is discontinued when the international normalized ratio (INR) is =2.0 for 24 hours.2 5 Unfractionated heparin (UFH) binds to antithrombin via a specific 18-saccharide sequence, which increases its activity over 1000-fold. This antithrombin-heparin complex primarily inhibits factor IIa (thrombin) and factor Xa and, to a lesser degree, factors IXa, XIa, and XIIa. In addition, UFH also binds to tissue factor pathway inhibitor, which inhibits the conversion of factor X to Xa, and factor IX to IXa. Finally, UFH catalyzes the inhibition of thrombin by heparin cofactor II via a mechanism that is independent of antithrombin. UFH therapy is most commonly administered with an initial IV bolus of 80 units/kg or 5000 units. Weightbased UFH dosages have been shown to be more effective than standard fixed boluses in rapidly achieving therapeutic levels.2 6 The initial bolus is followed by a continuous IV drip, initially at 18 units/kg per hour or 1300 units per hour. The half-life of IV UFH ranges from 45 to 90 minutes and is dose dependent. The level of antithrombotic therapy should be monitored every 6 hours using the activated partial thromboplastin time (aPTT), with the goal range of 1.5 to 2.5 times control values. This should correspond with plasma heparin anti-Xa activity levels of 0.3 to 0.7 IU/mL. Initial anticoagulation with UFH may be administered SC, although this route is less commonly used. Adjusted-dose therapeutic SC UFH is initiated with 17,500 units, followed by 250 units/kg twice daily, and dosing is adjusted to an aPTT goal range similar to that for IV UFH. Fixed-dose unmonitored SC UFH is started with a bolus of 333 units/kg, followed by 250 units/kg twice daily.2 5 Hemorrhage is the primary complication of UFH therapy. The rate of major hemorrhage (fatal, intracranial, retroperitoneal, or requiring transfusion of >2 units of packed red blood cells) is approximately 5% in hospitalized patients undergoing UFH therapy (1% in medical patients and 8% in surgical patients).2 7 For patients with UFH-related bleeding complications, cessation of UFH is required, and anticoagulation may be reversed with protamine sulfate. Protamine sulfate binds to UFH and forms an inactive salt compound. Each milligram of protamine neutralizes 90 to 115 units of heparin, and the dosage should not exceed 50 mg IV over any 10-minute period. Side effects of protamine sulfate include hypotension, pulmonary edema, and anaphylaxis. Patients with prior exposure to protamine-containing insulin (NPH) and patients with allergy to fish may have an increased risk of hypersensitivity, although no direct relationship has been established. The

protamine infusion should be terminated if any side effects occur. In addition to hemorrhage, heparin also has unique complications. Heparin-induced thrombocytopenia (HIT) results from heparin-associated antiplatelet antibodies (HAAbs) directed against platelet factor 4 complexed with heparin.2 8 HIT occurs in 1 to 5% of patients being treated with heparin.29,30 In patients with repeat heparin exposure (such as vascular surgery patients), the incidence of HAAb may be as high as 21%.3 1 HIT occurs most frequently in the second week of therapy and may lead to disastrous venous or arterial thrombotic complications. Therefore, platelet counts should be monitored periodically in patients receiving continuous heparin therapy. All forms of heparin should be stopped if there is a high clinical suspicion or confirmation of HIT [usually accompanied by an unexplained thrombocytopenia (90% after SC injection), longer half-lives (approximately 4 to 6 hours), and more predictable elimination rates. Weight-based once- or twice-daily SC LMWH injections, for which no monitoring is needed, provide a distinct advantage over continuous IV infusions of UFH for treatment of VTE. Most patients who receive therapeutic LMWH do not require monitoring. Patients who do require monitoring include those with significant renal insufficiency or failure, pediatric patients, obese patients of >120 kg, and patients who are pregnant. Monitoring may be performed using anti-Xa activity assays. However, the therapeutic anti-Xa goal range will depend on the type of LMWH and the frequency of dosing. Numerous LMWHs are commercially available. The various preparations differ in their anti-Xa and anti-IIa activities, and the treatment dosing for one LMWH cannot be extrapolated for use with another. The action of LMWHs may be partially reversed (approximately 60%) with protamine sulfate. Numerous well-designed trials comparing SC LMWH with IV and SC UFH for the treatment of DVT have been critically evaluated in several meta-analyses.32–34 The more recent studies demonstrate a decrease in thrombotic complications, bleeding, and mortality with LMWHs. LMWHs also are associated with a decreased rate of HAAb formation and HIT (1000 mm2) or were longstanding (>6 months). No evidence of rejection or sensitization has been reported in response to Apligraf application.

Apligraf skin graft material supplied as a disk on an agarose gel nutrient medium.

A prospective randomized study comparing multilayer compression therapy alone to treatment with Apligraf in addition to multilayered compression therapy has been performed to assess the efficacy of Apligraf in the treatment of venous ulcers.104 More patients treated with Apligraf had ulcer healing at 6 months (63% vs. 49%, P = .02). The median time to complete ulcer closure was significantly shorter in patients treated with Apligraf (61 days vs. 181 days, P = .003). The ulcers that showed the greatest benefit with the living skin construct were ones that were large and deep (>1000 mm2) or were longstanding (>6 months). No evidence of rejection or sensitization has been reported in response to Apligraf application.

Surgical Treatment of Chronic Venous Insufficiency PERFORATOR VEIN LIGATION Incompetence of the perforating veins connecting the superficial and deep venous systems of the lower extremities has been implicated in the development of venous ulcers. The classic open technique described by Linton in 1938 for perforator vein ligation has a high incidence of wound complications and has largely been abandoned.111 A minimally invasive technique termed subfascial endoscopic perforator vein surgery (SEPS) has evolved with the improvement in endoscopic equipment. DUS is performed preoperatively in patients undergoing SEPS to document deep venous competence and to identify perforating veins in the posterior compartment. The patient is positioned on the operating table with the affected leg elevated at 45 to 60 degrees. An Esmarch bandage and a thigh tourniquet are used to exsanguinate the limb. The knee is then flexed, and two small incisions are made in the proximal medial leg away from areas of maximal induration at the ankle. Laparoscopic trocars are then positioned, and the subfascial dissection is performed with a combination of blunt and sharp dissection. Carbon dioxide is then used to insufflate the subfascial space. The thigh tourniquet is inflated to prevent air embolism. The perforators are then identified and doubly clipped and divided. After completion of the procedure, the leg is wrapped in a compression bandage for 5 days postoperatively. In a report from a large North American registry of 146 patients undergoing SEPS112 (Fig. 24-20), healing was achieved in 88% of ulcers (75 of 85) at 1 year. Adjunctive procedures, primarily superficial vein stripping, were performed in 72% of patients. Ulcer recurrence was predicted to be 16% at 1 year and 28% at 2 years by life table analysis. The efficacy of the technique has not been confirmed in a randomized trial.

Fig. 24-20.

Trocar placement for subfascial endoscopic perforator vein surgery.

VENOUS RECONSTRUCTION In the absence of significant deep vein valvular incompetence, saphenous vein stripping and perforator vein ligation can be effective in the treatment of CVI. However, in patients with a combination of superficial and deep vein valvular incompetence, the addition of deep vein valvular reconstruction theoretically may improve ulcer healing. 113 Numerous techniques of deep vein valve correction have been reported. These techniques consist of repair of existing valves, transplant of venous segments from the arm, and transposition of an incompetent vein onto an adjacent competent vein. A method in which cryopreserved venous valve allografts are placed below incompetent vein segments surgically or percutaneously is currently in the early phases of development but does not seem effective.114 Successful long-term outcomes of 60 to 80% have been reported for venous valve reconstructions by internal suture repair. 113,115,116 However, among patients who initially had ulceration, 40 to 50% still had persistence or recurrence of ulcers in the long term.115,116 Valve transplantation involves replacement of a segment of incompetent femoral vein or popliteal vein with a segment of axillary or brachial vein with competent valves. Early results are similar to those for venous valve reconstruction.113,115,116 However, in the long term, the transplanted venous segments tend to develop incompetence, and long-term outcomes are poorer than those for venous valve reconstructions. The outcomes for venous transposition are similar to those for valve transplantation.

LYMPHEDEMA

Pathophysiology Lymphedema is extremity swelling that results from a reduction in lymphatic transport, with resultant pooling of lymph within the interstitial space. It is caused by anatomic problems such as lymphatic hypoplasia, functional insufficiency, or absence of lymphatic valves. The original classification system, described by Allen, is based on the cause of the lymphedema. Primary lymphedema is further subdivided into congenital lymphedema, lymphedema praecox, and lymphedema tarda. Congenital lymphedema may involve a single lower extremity, multiple limbs, the genitalia, or the face. The edema typically develops before 2 years of age and may be associated with specific hereditary syndromes (Turner syndrome, Milroy syndrome, Klippel-Trénaunay-Weber syndrome). Lymphedema praecox is the most common form of primary lymphedema, accounting for 94% of cases. Lymphedema praecox is far more common in women, with the gender ratio favoring women 10:1. The onset is during childhood or the teenage years, and the swelling involves the foot and calf. Lymphedema tarda is uncommon, accounting for Chapter 25. Esophagus and Diaphragmatic Hernia>

KEY POINTS 1. Objective esophageal physiology testing is cornerstone to making the diagnosis of benign esophageal disorders and in developing an individualized treatment plan for patients. 2. While most esophageal procedures can be performed using either a videoscopic or flexible endoscopic approach, the surgeon must be familiar with the surgical anatomy and open approaches to the esophagus along its entire length. 3. Laparoscopic cardiomyotomy is now considered the most effective treatment for achalasia and should include division of the gastric collar sling musculature. 4. While esophageal replacement is most commonly performed with the tubularized stomach, the surgeon should be familiar with the anatomy and techniques which enable the use of colon and jejunum. 5. Giant paraesophageal hernia should be repaired surgically in patients with symptoms, anemia, or signs of strangulation. 6. The cornerstone to esophageal cancer clinical staging includes the use of endoscopy, CT, PET, and endoscopic ultrasound. 7. In surgical candidates with esophageal cancer confined to the posterior mediastinum, esophagectomy represents the best possible chance for cure.

SURGICAL ANATOMY The esophagus is a muscular tube that starts as the continuation of the pharynx and ends as the cardia of the stomach. When the head is in a normal anatomic position, the transition from pharynx to esophagus occurs at the lower border of the sixth cervical vertebra. Topographically this corresponds to the cricoid cartilage anteriorly and the palpable transverse process of the sixth cervical vertebra laterally (Fig. 25-1). The esophagus is firmly attached at its upper end to the cricoid cartilage and at its lower end to the diaphragm; during swallowing, the proximal points of fixation move craniad the distance of one cervical vertebral body.

Fig. 25-1.

A. Topographic relationships of the cervical esophagus: (a ) hyoid bone, (b ) thyroid cartilage, (c ) cricoid cartilage, (d ) thyroid gland, (e ) sternoclavicular. B. Lateral radiographic appearance with landmarks identified as labeled in A . The location of C6 is also included (f ). [Reproduced with permission from Rothberg M, DeMeester TR: Surgical anatomy of the esophagus, in Shields TW (ed): General Thoracic Surgery , 3rd ed. Philadelphia: Lea & Febiger, 1989, p 77.]

The esophagus lies in the midline, with a deviation to the left in the lower portion of the neck and upper portion of the thorax, and returns to the midline in the midportion of the thorax near the bifurcation of the trachea (Fig. 252). In the lower portion of the thorax, the esophagus again deviates to the left and anteriorly to pass through the diaphragmatic hiatus.

Fig. 25-2.

Barium esophagogram. A. Posterior-anterior view. White arrow shows deviation to left. Black arrow shows return to midline. B. Lateral view. Black arrow shows anterior deviation. [Reproduced with permission from Rothberg M, DeMeester TR: Surgical anatomy of the esophagus, in Shields TW (ed): General Thoracic Surgery , 3rd ed. Philadelphia: Lea & Febiger, 1989, p 77.]

Three normal areas of esophageal narrowing are evident on the barium esophagogram or during esophagoscopy. The uppermost narrowing is located at the entrance into the esophagus and is caused by the cricopharyngeal muscle. Its luminal diameter is 1.5 cm, and it is the narrowest point of the esophagus. The middle narrowing is due to an indentation of the anterior and left lateral esophageal wall caused by the crossing of the left main stem bronchus and aortic arch. The luminal diameter at this point is 1.6 cm. The lowermost narrowing is at the hiatus of the diaphragm and is caused by the gastroesophageal sphincter mechanism. The luminal diameter at this point varies somewhat, depending on the distention of the esophagus by the passage of food, but has been measured at 1.6 to 1.9 cm. These normal constrictions tend to hold up swallowed foreign objects, and the overlying mucosa is subject to injury by swallowed corrosive liquids due to their slow passage through these areas. Figure 25-3 shows the average distance in centimeters measured during endoscopic examination between the

incisor teeth and the cricopharyngeus, aortic arch, and cardia of the stomach. Manometrically, the length of the esophagus between the lower border of the cricopharyngeus and upper border of the lower sphincter varies according to the height of the individual.

Fig. 25-3.

Important clinical endoscopic measurements of the esophagus in adults. [Reproduced with permission from Rothberg M, DeMeester TR: Surgical anatomy of the esophagus, in Shields TW (ed): General Thoracic Surgery , 3rd ed. Philadelphia: Lea & Febiger, 1989, p 78.]

The pharyngeal musculature consists of three broad, flat, overlapping fan-shaped constrictors (Fig. 25-4). The opening of the esophagus is collared by the cricopharyngeal muscle, which arises from both sides of the cricoid cartilage of the larynx and forms a continuous transverse muscle band without interruption by a median raphe. The fibers of this muscle blend inseparably with those of the inferior pharyngeal constrictor above and the inner circular

muscle fibers of the esophagus below. Some investigators believe that the cricopharyngeus is part of the inferior constrictor; that is, that the inferior constrictor has two parts, an upper or retrothyroid portion having diagonal fibers, and a lower or retrocricoid portion having transverse fibers. Keith in 1910 showed that these two parts of the same muscle serve totally different functions. The retrocricoid portion serves as the upper sphincter of the esophagus and relaxes when the retrothyroid portion contracts, to force the swallowed bolus from the pharynx into the esophagus.

Fig. 25-4.

External muscles of the pharynx. A. Posterolateral view. B. Posterior view. Dotted line represents usual site of myotomy. [Reproduced with permission from Rothberg M, DeMeester TR: Surgical anatomy of the esophagus, in Shields TW (ed): General Thoracic Surgery , 3rd ed. Philadelphia: Lea & Febiger, 1989, p 78.]

The cervical portion of the esophagus is approximately 5 cm long and descends between the trachea and the vertebral column, from the level of the sixth cervical vertebra to the level of the interspace between the first and second thoracic vertebrae posteriorly, or the level of the suprasternal notch anteriorly. The recurrent laryngeal nerves lie in the right and left grooves between the trachea and the esophagus. The left recurrent nerve lies somewhat closer to the esophagus than the right, owing to the slight deviation of the esophagus to the left, and the more lateral course of the right recurrent nerve around the right subclavian artery. Laterally, on the left and right sides of the cervical esophagus are the carotid sheaths and the lobes of the thyroid gland.

The thoracic portion of the esophagus is approximately 20 cm long. It starts at the thoracic inlet. In the upper portion of the thorax, it is in intimate relationship with the posterior wall of the trachea and the prevertebral fascia. Just above the tracheal bifurcation, the esophagus passes to the right of the aorta. This anatomic positioning can cause a notch indentation in its left lateral wall on a barium swallow radiogram. Immediately below this notch, the esophagus crosses both the bifurcation of the trachea and the left main stem bronchus, owing to the slight deviation of the terminal portion of the trachea to the right by the aorta (Fig. 25-5). From there down, the esophagus passes over the posterior surface of the subcarinal lymph nodes (LNs), and then descends over the pericardium of the left atrium to reach the diaphragmatic hiatus (Fig. 25-6). From the bifurcation of the trachea downward, both the vagal nerves and the esophageal nerve plexus lie on the muscular wall of the esophagus.

Fig. 25-5.

A. Cross-section of the thorax at the level of the tracheal bifurcation. B. Computed tomographic scan at same level viewed from above: (a ) ascending aorta, (b ) descending aorta, (c ) tracheal carina, (d ) esophagus, (e ) pulmonary artery. [Reproduced with permission from Rothberg M, DeMeester TR: Surgical anatomy of the esophagus, in Shields TW (ed): General Thoracic Surgery , 3rd ed. Philadelphia: Lea & Febiger, 1989, p 81.]

Fig. 25-6.

A. Cross-section of the thorax at the midleft atrial level. B. Computed tomographic scan at same level viewed from above: (a ) aorta, (b ) esophagus, (c ) left atrium, (d ) right atrium, (e ) left ventricle, (f ) right ventricle, (g ) pulmonary vein. [Reproduced with permission from Rothberg M, DeMeester TR: Surgical anatomy of the esophagus, in Shields TW (ed): General Thoracic Surgery , 3rd ed. Philadelphia: Lea & Febiger, 1989, p 82.]

Dorsally, the thoracic esophagus follows the curvature of the spine and remains in close contact with the vertebral bodies. From the eighth thoracic vertebra downward, the esophagus moves vertically away from the spine to pass through the hiatus of the diaphragm. The thoracic duct passes through the hiatus of the diaphragm on the anterior surface of the vertebral column behind the aorta and under the right crus. In the thorax, the thoracic duct lies dorsal to the esophagus between the azygos vein on the right and the descending thoracic aorta on the left. The abdominal portion of the esophagus is approximately 2 cm long and includes a portion of the lower esophageal sphincter (LES) (Fig. 25-7). It starts as the esophagus passes through the diaphragmatic hiatus and is surrounded by the phrenoesophageal membrane, a fibroelastic ligament arising from the subdiaphragmatic fascia as a continuation of the transversalis fascia lining the abdomen (Fig. 25-8). The upper leaf of the membrane attaches itself in a circumferential fashion around the esophagus, about 1 to 2 cm above the level of the hiatus. These fibers blend in with the elastic-containing adventitia of the abdominal esophagus and the cardia of the stomach. This portion of the esophagus is subjected to the positive-pressure environment of the abdomen.

Fig. 25-7.

Schematic drawing shows correlation between radial muscle thickness (left ) and three-dimensional manometric pressure image (right ) at human gastroesophageal junction. Muscle thickness across the gastroesophageal junction at the posterior gastric wall (PW), greater curvature (GC), anterior gastric wall (AW), and lesser curvature (LC) is shown in millimeters. Radial pressures at gastroesophageal junction (in millimeters of mercury) are plotted around an axis representing atmospheric pressure. (Reproduced with permission from Stein HJ, Liebermann-Meffert D, DeMeester TR, et al: Three-dimensional pressure image and muscular structure of the human lower esophageal sphincter. Surgery 117:692, 1995. Copyright Elsevier.)

Fig. 25-8.

Attachments and structure of the phrenoesophageal membrane. Transversalis fascia lies just above the parietal peritoneum. [Reproduced with permission from Rothberg M, DeMeester TR: Surgical anatomy of the esophagus, in Shields TW (ed): General Thoracic Surgery , 3rd ed. Philadelphia: Lea & Febiger, 1989, p 83.]

The musculature of the esophagus can be divided into an outer longitudinal and an inner circular layer. The upper 2 to 6 cm of the esophagus contains only striated muscle fibers. From there on, smooth muscle fibers gradually become more abundant. Most clinically significant esophageal motility disorders involve only the smooth muscle in the lower two thirds of the esophagus. When a surgical esophageal myotomy is indicated, the incision needs to extend only this distance. The longitudinal muscle fibers originate from a cricoesophageal tendon arising from the dorsal upper edge of the anteriorly located cricoid cartilage. The two bundles of muscle diverge and meet in the midline on the posterior wall of the esophagus about 3 cm below the cricoid (see Fig. 25-4). From this point on, the entire circumference of the esophagus is covered by a layer of longitudinal muscle fibers. This configuration of the longitudinal muscle fibers around the most proximal part of the esophagus leaves a V-shaped area in the posterior wall covered only with circular muscle fibers. Contraction of the longitudinal muscle fibers shortens the esophagus. The circular muscle layer of the esophagus is thicker than the outer longitudinal layer. In situ, the geometry of the circular muscle is helical and makes the peristalsis of the esophagus assume a worm-like drive, as opposed to segmental and sequential squeezing. As a consequence, severe motor abnormalities of the esophagus assume a corkscrew-like pattern on the barium swallow radiogram. The cervical portion of the esophagus receives its main blood supply from the inferior thyroid artery. The thoracic portion receives its blood supply from the bronchial arteries, with 75% of individuals having one right-sided and two left-sided branches. Two esophageal branches arise directly from the aorta. The abdominal portion of the esophagus receives its blood supply from the ascending branch of the left gastric artery and from inferior phrenic arteries (Fig. 25-9). On entering the wall of the esophagus, the arteries assume a T-shaped division to form a longitudinal plexus, giving rise to an intramural vascular network in the muscular and submucosal layers. As a

consequence, the esophagus can be mobilized from the stomach to the level of the aortic arch without fear of devascularization and ischemic necrosis. Caution should be exercised as to the extent of esophageal mobilization in patients who have had a previous thyroidectomy with ligation of the inferior thyroid arteries proximal to the origin of the esophageal branches.

Fig. 25-9.

Arterial blood supply of the esophagus. [Reproduced with permission from Rothberg M, DeMeester TR: Surgical anatomy of the esophagus, in Shields TW (ed): General Thoracic Surgery , 3rd ed. Philadelphia: Lea & Febiger, 1989, p 84.]

Blood from the capillaries of the esophagus flows into a submucosal venous plexus, and then into a periesophageal venous plexus from which the esophageal veins originate. In the cervical region, the esophageal veins empty into the inferior thyroid vein; in the thoracic region, they empty into the bronchial, azygos, or hemiazygos veins; and in the abdominal region, they empty into the coronary vein (Fig. 25-10). The submucosal venous networks of the

esophagus and stomach are in continuity with each other, and, in patients with portal venous obstruction, this communication functions as a collateral pathway for portal blood to enter the superior vena cava via the azygos vein.

Fig. 25-10.

Venous drainage of the esophagus. [Reproduced with permission from Rothberg M, DeMeester TR: Surgical anatomy of the esophagus, in Shields TW (ed): General Thoracic Surgery , 3rd ed. Philadelphia: Lea & Febiger, 1989, p 85.]

The parasympathetic innervation of the pharynx and esophagus is provided mainly by the vagus nerves. The constrictor muscles of the pharynx receive branches from the pharyngeal plexus, which is on the posterior lateral surface of the middle constrictor muscle, and is formed by pharyngeal branches of the vagus nerves with a small contribution from cranial nerves IX and XI (Fig. 25-11). The cricopharyngeal sphincter and the cervical portion of the esophagus receive branches from both recurrent laryngeal nerves, which originate from the vagus nerves—the right recurrent nerve at the lower margin of the subclavian artery and the left at the lower margin of the aortic arch. They are slung dorsally around these vessels and ascend in the groove between the esophagus and trachea, giving branches to each. Damage to these nerves interferes not only with the function of the vocal cords, but also

with the function of the cricopharyngeal sphincter and the motility of the cervical esophagus, predisposing the individual to pulmonary aspiration on swallowing.

Fig. 25-11.

Innervation of the esophagus. [Reproduced with permission from Rothberg M, DeMeester TR: Surgical anatomy of the esophagus, in Shields TW (ed): General Thoracic Surgery , 3rd ed. Philadelphia: Lea & Febiger, 1989, p 85.]

Afferent visceral sensory pain fibers from the esophagus end without synapse in the first four segments of the thoracic spinal cord, using a combination of sympathetic and vagal pathways. These pathways are also occupied by afferent visceral sensory fibers from the heart; hence, both organs have similar symptomatology. The lymphatics located in the submucosa of the esophagus are so dense and interconnected that they constitute a single plexus (Fig. 25-12). There are more lymph vessels than blood capillaries in the submucosa. Lymph flow in the submucosal plexus runs in a longitudinal direction, and, on injection of a contrast medium, the longitudinal spread is seen to be about six times that of the transverse spread. In the upper two-thirds of the esophagus, the

lymphatic flow is mostly cephalad, and, in the lower third, caudad. In the thoracic portion of the esophagus, the submucosal lymph plexus extends over a long distance in a longitudinal direction before penetrating the muscle layer to enter lymph vessels in the adventitia. As a consequence of this nonsegmental lymph drainage, a primary tumor can extend for a considerable length superiorly or inferiorly in the submucosal plexus. Consequently, free tumor cells can follow the submucosal lymphatic plexus in either direction for a long distance before they pass through the muscularis and on into the regional LNs. The cervical esophagus has a more direct segmental lymph drainage into the regional nodes, and, as a result, lesions in this portion of the esophagus have less submucosal extension and a more regionalized lymphatic spread.

Fig. 25-12.

Lymphatic drainage of the esophagus. (Reproduced with permission from DeMeester TR, Barlow AP: Surgery and current management for cancer of the esophagus and cardia: Part I. Curr Probl Surg 25:498, 1988. Copyright Elsevier.)

The efferent lymphatics from the cervical esophagus drain into the paratracheal and deep cervical LNs, and those from the upper thoracic esophagus empty mainly into the paratracheal LNs. Efferent lymphatics from the lower thoracic esophagus drain into the subcarinal nodes and nodes in the inferior pulmonary ligaments. The superior gastric nodes receive lymph not only from the abdominal portion of the esophagus, but also from the adjacent lower thoracic segment.

PHYSIOLOGY Swallowing Mechanism

The act of alimentation requires the passage of food and drink from the mouth into the stomach. One third of this distance consists of the mouth and hypopharynx, and two thirds is made up by the esophagus. To comprehend the mechanics of alimentation, it is useful to visualize the gullet as a mechanical model in which the tongue and pharynx function as a piston pump with three valves, and the body of the esophagus and cardia function as a worm-drive pump with a single valve. The three valves in the pharyngeal cylinder are the soft palate, epiglottis, and cricopharyngeus. The valve of the esophageal pump is the LES. Failure of the valves or the pumps leads to abnormalities in swallowing—that is, difficulty in food propulsion from mouth to stomach—or regurgitation of gastric contents into the esophagus or pharynx. Food is taken into the mouth in a variety of bite sizes, where it is broken up, mixed with saliva, and lubricated. Once initiated, swallowing is entirely a reflex act. When food is ready for swallowing, the tongue, acting like a piston, moves the bolus into the posterior oropharynx and forces it into the hypopharynx (Fig. 25-13). Concomitantly with the posterior movement of the tongue, the soft palate is elevated, thereby closing the passage between the oropharynx and nasopharynx. This partitioning prevents pressure generated in the oropharynx from being dissipated through the nose. When the soft palate is paralyzed, for example, after a cerebrovascular accident, food is commonly regurgitated into the nasopharynx. During swallowing, the hyoid bone moves upward and anteriorly, elevating the larynx and opening the retrolaryngeal space, bringing the epiglottis under the tongue (see Fig. 25-13). The backward tilt of the epiglottis covers the opening of the larynx to prevent aspiration. The entire pharyngeal part of swallowing occurs within 1.5 seconds.

Fig. 25-13.

Sequence of events during the oropharyngeal phase of swallowing. [Reproduced with permission from DeMeester TR, Stein HJ, Fuchs KH: Physiologic diagnostic studies, in Zuidema GD, Orringer MB (eds): Shackelford's Surgery of the Alimentary Tract , 3rd ed., Vol. I. Philadelphia: W.B. Saunders, 1991, p 95. Copyright Elsevier.]

During swallowing, the pressure in the hypopharynx rises abruptly, to at least 60 mmHg, due to the backward movement of the tongue and contraction of the posterior pharyngeal constrictors. A sizable pressure difference develops between the hypopharyngeal pressure and the less-than-atmospheric midesophageal or intrathoracic pressure (Fig. 25-14). This pressure gradient speeds the movement of food from the hypopharynx into the esophagus when the cricopharyngeus or upper esophageal sphincter relaxes. The bolus is both propelled by peristaltic contraction of the posterior pharyngeal constrictors and sucked into the thoracic esophagus. Critical to receiving the bolus is the compliance of the cervical esophagus; when compliance is lost due to muscle pathology, dysphagia can result. The upper esophageal sphincter closes within 0.5 second of the initiation of the swallow, with the immediate closing pressure reaching approximately twice the resting level of 30 mmHg. The postrelaxation contraction continues down the esophagus as a peristaltic wave (Fig. 25-15). The high closing pressure and the initiation of the peristaltic wave prevents reflux of the bolus from the esophagus back into the pharynx. After the peristaltic wave has passed farther down the esophagus, the pressure in the upper esophageal sphincter returns to its resting level.

Fig. 25-14.

Resting pressure profile of the foregut showing the pressure differential between the atmospheric pharyngeal pressure (P ) and the less-than-atmospheric midesophageal pressure (E ) and greater-than-atmospheric intragastric pressure (G ), with the interposed high pressure zones of the cricopharyngeus (C ) and distal esophageal sphincter (DES ). The necessity for relaxation of the cricopharyngeus and DES pressure to move a bolus into the stomach is apparent. Esophageal work occurs when a bolus is pushed from the midesophageal area (E ), with a pressure less than atmospheric, into the stomach, which has a pressure greater than atmospheric (G ). (Reproduced with permission from Waters PF, DeMeester TR: Foregut motor disorders and their surgical management. Med Clin North Am 65:1237, 1981. Copyright Elsevier.)

Fig. 25-15.

Intraluminal esophageal pressures in response to swallowing. (Reproduced with permission from Waters PF, DeMeester TR: Foregut motor disorders and their surgical management. Med Clin North Am 65:1238, 1981. Copyright Elsevier.)

Swallowing can be started at will, or it can be reflexively elicited by the stimulation of areas in the mouth and pharynx, among them the anterior and posterior tonsillar pillars or the posterior lateral walls of the hypopharynx.

The afferent sensory nerves of the pharynx are the glossopharyngeal nerves and the superior laryngeal branches of the vagus nerves. Once aroused by stimuli entering via these nerves, the swallowing center in the medulla coordinates the complete act of swallowing by discharging impulses through cranial nerves V, VII, X, XI, and XII, as well as the motor neurons of C1 to C3. Discharges through these nerves occur in a rather specific pattern and last for approximately 0.5 second. Little is known about the organization of the swallowing center, except that it can trigger swallowing after a variety of different inputs, but the response is always a rigidly ordered pattern of outflow. Following a cerebrovascular accident, this coordinated outflow may be altered, causing mild to severe abnormalities of swallowing. In more severe injury, swallowing can be grossly disrupted, leading to repetitive aspiration. The striated muscles of the cricopharyngeus and the upper one third of the esophagus are activated by efferent motor fibers distributed through the vagus nerve and its recurrent laryngeal branches. The integrity of innervation is required for the cricopharyngeus to relax in coordination with the pharyngeal contraction, and resume its resting tone once a bolus has entered the upper esophagus. Operative damage to the innervation can interfere with laryngeal, cricopharyngeal, and upper esophageal function, and predispose the patient to aspiration. The pharyngeal activity in swallowing initiates the esophageal phase. The body of the esophagus functions as a worm-drive propulsive pump due to the helical arrangement of its circular muscles, and is responsible for transferring a bolus of food into the stomach. The esophageal phase of swallowing represents esophageal work done during alimentation, in that food is moved into the stomach from a negative-pressure environment of –6 mmHg intrathoracic pressure, to a positive-pressure environment of 6 mmHg intra-abdominal pressure, or over a gradient of 12 mmHg (see Fig. 25-14). Effective and coordinated smooth muscle function in the lower one third of the esophagus is therefore important in pumping the food across this gradient. The peristaltic wave generates an occlusive pressure varying from 30 to 120 mmHg (see Fig. 25-15). The wave rises to a peak in 1 second, lasts at the peak for about 0.5 second, and then subsides in about 1.5 seconds. The whole course of the rise and fall of occlusive pressure may occupy one point in the esophagus for 3 to 5 seconds. The peak of a primary peristaltic contraction initiated by a swallow (primary peristalsis) moves down the esophagus at 2 to 4 cm/s and reaches the distal esophagus about 9 seconds after swallowing starts (see Fig. 25-15). Consecutive swallows produce similar primary peristaltic waves, but when the act of swallowing is rapidly repeated, the esophagus remains relaxed and the peristaltic wave occurs only after the last movement of the pharynx. Progress of the wave in the esophagus is caused by sequential activation of its muscles, initiated by efferent vagal nerve fibers arising in the swallowing center. Continuity of the esophageal muscle is not necessary for sequential activation if the nerves are intact. If the muscles, but not the nerves, are cut across, the pressure wave begins distally below the cut as it dies out at the proximal end above the cut. This allows a sleeve resection of the esophagus to be done without destroying its normal function. Afferent impulses from receptors within the esophageal wall are not essential for progress of the coordinated wave. Afferent nerves, however, do go to the swallowing center from the esophagus, because, if the esophagus is distended at any point, a contractual wave begins with a forceful closure of the upper esophageal sphincter and sweeps down the esophagus. This secondary contraction occurs without any movements of the mouth or pharynx. Secondary peristalsis can occur as an independent local reflex to clear the esophagus of ingested material left behind after the passage of the primary wave. Current studies suggest that secondary peristalsis is not as common as once thought. Despite the powerful occlusive pressure, the propulsive force of the esophagus is relatively feeble. If a subject attempts to swallow a bolus attached by a string to a counterweight, the maximum weight that can be overcome is

5 to 10 g. Orderly contractions of the muscular wall and anchoring of the esophagus at its inferior end are necessary for efficient aboral propulsion to occur. Loss of the inferior anchor, as occurs with a large hiatal hernia, can lead to inefficient propulsion. The LES provides a pressure barrier between the esophagus and stomach and acts as the valve on the worm-drive pump of the esophageal body. Although an anatomically distinct LES has been difficult to identify, microdissection studies show that, in humans, the sphincter-like function is related to the architecture of the muscle fibers at the junction of the esophageal tube with the gastric pouch (Fig. 25-16). The sphincter actively remains closed to prevent reflux of gastric contents into the esophagus and opens by a relaxation that coincides with a pharyngeal swallow (see Fig. 25-15). The LES pressure returns to its resting level after the peristaltic wave has passed through the esophagus. Consequently, reflux of gastric juice that may occur through the open valve during a swallow is cleared back into the stomach.

Fig. 25-16.

Wall thickness and orientation of fibers on microdissection of the cardia. At the junction of the esophageal tube and gastric pouch, there is an oblique muscular ring composed of an increased muscle mass inside the inner muscular layer. On the lesser curve side of the cardia, the muscle fibers of the inner layer are oriented transversely and form semicircular muscle clasps. On the greater curve side of the cardia, these muscle fibers form oblique loops that encircle the distal end of the cardia and gastric fundus. Both the semicircular muscle clasps and the oblique fibers of the fundus contract in a circular manner to close the cardia. [Reproduced with permission from DeMeester TR, Skinner DB: Evaluation of esophageal function and disease, in Glenn WWL

(ed): Thoracic and Cardiovascular Surgery , 4th ed. Norwalk, CT: Appleton-Century-Crofts, 1983, p 461.]

If the pharyngeal swallow does not initiate a peristaltic contraction, then the coincident relaxation of the LES is unguarded and reflux of gastric juice can occur. This may be an explanation for the observation of spontaneous lower esophageal relaxation, thought by some to be a causative factor in gastroesophageal reflux disease (GERD). The power of the worm-drive pump of the esophageal body is insufficient to force open a valve that does not relax. In dogs, a bilateral cervical parasympathetic blockade abolishes the relaxation of the LES that occurs with pharyngeal swallowing or distention of the esophagus. Consequently, vagal function appears to be important in coordinating the relaxation of the LES with esophageal contraction. The antireflux mechanism in human beings is composed of three components: a mechanically effective LES, efficient esophageal clearance, and an adequately functioning gastric reservoir. A defect of any one of these three components can lead to increased esophageal exposure to gastric juice and the development of mucosal injury.

Physiologic Reflux On 24-hour esophageal pH monitoring, healthy individuals have occasional episodes of gastroesophageal reflux. This physiologic reflux is more common when awake and in the upright position than during sleep in the supine position. When reflux of gastric juice occurs, normal subjects rapidly clear the acid gastric juice from the esophagus regardless of their position. There are several explanations for the observation that physiologic reflux in normal subjects is more common when they are awake and in the upright position than during sleep in the supine position. First, reflux episodes occur in healthy volunteers primarily during transient losses of the gastroesophageal barrier, which may be due to a relaxation of the LES or intragastric pressure overcoming sphincter pressure. Gastric juice can also reflux when a swallow-induced relaxation of the LES is not protected by an oncoming peristaltic wave. The average frequency of these "unguarded moments" or of transient losses of the gastroesophageal barrier is far less while asleep and in the supine position than while awake and in the upright position. Consequently, there are fewer opportunities for reflux to occur in the supine position. Second, in the upright position, there is a 12-mmHg pressure gradient between the resting, positive intra-abdominal pressure measured in the stomach and the most negative intrathoracic pressure measured in the esophagus at midthoracic level. This gradient favors the flow of gastric juice up into the thoracic esophagus when upright. The gradient diminishes in the supine position. Third, the LES pressure in normal subjects is significantly higher in the supine position than in the upright position. This is due to the apposition of the hydrostatic pressure of the abdomen to the abdominal portion of the sphincter when supine. In the upright position, the abdominal pressure surrounding the sphincter is negative compared with atmospheric pressure, and, as expected, the abdominal pressure gradually increases the more caudally it is measured. This pressure gradient tends to move the gastric contents toward the cardia and encourages the occurrence of reflux into the esophagus when the individual is upright. By contrast, in the supine position, the gastroesophageal pressure gradient diminishes, and the abdominal hydrostatic pressure under the diaphragm increases, causing an increase in sphincter pressure and a more competent cardia. The LES has intrinsic myogenic tone, which is modulated by neural and hormonal mechanisms. Alpha-adrenergic neurotransmitters or beta blockers stimulate the LES, and alpha blockers and beta stimulants decrease its pressure. It is not clear to what extent cholinergic nerve activity controls LES pressure. The vagus nerve carries both excitatory and inhibitory fibers to the esophagus and sphincter. The hormones gastrin and motilin have been shown to increase LES pressure; and cholecystokinin, estrogen, glucagon, progesterone, somatostatin, and secretin

decrease LES pressure. The peptides bombesin, l-enkephalin, and substance P increase LES pressure; and calcitonin gene-related peptide, gastric inhibitory peptide, neuropeptide Y, and vasoactive intestinal polypeptide decrease LES pressure. Some pharmacologic agents such as antacids, cholinergics, agonists, domperidone, metoclopramide, and prostaglandin F2 are known to increase LES pressure; and anticholinergics, barbiturates, calcium channel blockers, caffeine, diazepam, dopamine, meperidine, prostaglandin E1 and E2 , and theophylline decrease LES pressure. Peppermint, chocolate, coffee, ethanol, and fat are all associated with decreased LES pressure and may be responsible for esophageal symptoms after a sumptuous meal.

ASSESSMENT OF ESOPHAGEAL FUNCTION A thorough understanding of the patient's underlying anatomic and functional deficits before making therapeutic decisions is fundamental to the successful treatment of esophageal disease. The diagnostic tests, as presently used, may be divided into four broad groups: (a) tests to detect structural abnormalities of the esophagus; (b) tests to detect functional abnormalities of the esophagus; (c) tests to detect increased esophageal exposure to gastric juice; and (d) tests of duodenogastric function as they relate to esophageal disease.

Tests to Detect Structural Abnormalities RADIOGRAPHIC EVALUATION The first diagnostic test in patients with suspected esophageal disease should be a barium swallow including a full assessment of the stomach and duodenum. Esophageal motility can be assessed by observing several individual swallows of barium traversing the entire length of the organ, with the patient in the horizontal position. Hiatal hernias are best demonstrated with the patient prone because the increased intra-abdominal pressure produced in this position promotes displacement of the esophagogastric junction above the diaphragm. To detect lower esophageal narrowing, such as rings and strictures, fully distended views of the esophagogastric region are crucial. The density of the barium used to study the esophagus can potentially affect the accuracy of the examination. Esophageal disorders shown clearly by a full-column technique include circumferential carcinomas, peptic strictures, large esophageal ulcers, and hiatal hernias. A small hiatal hernia is usually not associated with significant symptoms or illness, and its presence is an irrelevant finding unless the hiatal hernia is large (Fig. 2517), the hiatal opening is narrow and interrupts the flow of barium into the stomach (Fig. 25-18), or the hernia is of the paraesophageal variety. Lesions extrinsic but adjacent to the esophagus can be reliably detected by the fullcolumn technique if they contact the distended esophageal wall. Conversely, a number of important disorders may go undetected if this is the sole technique used to examine the esophagus. These include small esophageal neoplasms, mild esophagitis, and esophageal varices. Thus, the full-column technique should be supplemented with mucosal relief or double-contrast films to enhance detection of these smaller or more subtle lesions.

Fig. 25-17.

Radiogram of an intrathoracic stomach. This is the end stage of a large hiatal hernia, regardless of its initial classification. [Reproduced with permission from DeMeester TR, Stein HJ, Fuchs KH: Physiologic diagnostic studies, in Zuidema GD, Orringer MB (eds): Shackelford's Surgery of the Alimentary Tract , 3rd ed, Vol. I. Philadelphia: W. B. Saunders, 1991, p 111. Copyright Elsevier.]

Fig. 25-18.

Radiographic barium study showing a primary esophageal wave propelling liquid barium into the supradiaphragmatic portion of the stomach in a patient with a hiatal hernia (A and B ). The diaphragmatic impingement on the stomach and the lack of contraction of the supradiaphragmatic stomach prevent passage of the bolus into the distal stomach (C ). As a consequence, the contents in the supradiaphragmatic portion of the stomach are regurgitated into the thoracic esophagus (D, E, and F ). The patient experiences dysphagia and regurgitation. On endoscopy, no anatomic abnormality other than a hiatal hernia was found, and on 24-hour pH monitoring, the patient had normal esophageal acid exposure. Symptoms of dysphagia and regurgitation were relieved by hiatal herniorrhaphy. (Reproduced with permission from Kaul BJ, DeMeester TR, Oka M, et al: The cause of dysphagia in uncomplicated sliding hiatal hernia and its relief by hiatal herniography. A roentgenographic manometric and clinical study. Ann Surg 211:409, 1990.)

Motion-recording techniques greatly aid in evaluating functional disorders of the pharyngoesophageal and esophageal phases of swallowing. The technique and indications for cine- and videoradiography will be discussed in the section entitled Video- and Cineradiography, as they are more useful to evaluate function and seldom used to detect structural abnormalities. The radiographic assessment of the esophagus is not complete unless the entire stomach and duodenum have been examined. A gastric or duodenal ulcer, partially obstructing gastric neoplasm, or scarred duodenum and

pylorus may contribute significantly to symptoms otherwise attributable to an esophageal abnormality. When a patient's complaints include dysphagia and no obstructing lesion is seen on the barium swallow, it is useful to have the patient swallow a barium-impregnated marshmallow, a barium-soaked piece of bread, or a hamburger mixed with barium. This test may bring out a functional disturbance in esophageal transport that can be missed when liquid barium is used.

ENDOSCOPIC EVALUATION In any patient complaining of dysphagia, esophagoscopy is indicated, even in the face of a normal radiographic study. A barium study obtained before esophagoscopy is helpful to the endoscopist by directing attention to locations of subtle change, and alerting the examiner to such potential danger spots as a cervical vertebral osteophyte, esophageal diverticulum, a deeply penetrating ulcer, or a carcinoma. Regardless of the radiologist's interpretation of an abnormal finding, each structural abnormality of the esophagus should be confirmed visually. For the initial endoscopic assessment, the flexible fiber-optic esophagoscope is the instrument of choice because of its technical ease, patient acceptance, and the ability to simultaneously assess the stomach and duodenum. Rigid endoscopy may be required in specific instances and should be part of the armamentarium of the endoscopist. The rigid esophagoscope may be an essential instrument when deeper biopsies are required or the cricopharyngeus and cervical esophagus need closer assessment. When GERD is the suspected diagnosis, particular attention should be paid to detecting the presence of esophagitis and Barrett's columnar-lined esophagus (CLE). When endoscopic esophagitis is seen, severity and the length of esophagus involved are recorded. Grade I esophagitis is defined as small, circular, nonconfluent erosions. Grade II esophagitis is defined by the presence of linear erosions lined with granulation tissue that bleeds easily when touched. Grade III esophagitis represents a more advanced stage, in which the linear erosions coalesce into circumferential loss of the epithelium and the mucosa may take a "cobblestone" appearance. Grade IV esophagitis is the presence of a stricture. Its severity can be assessed by the ease of passing a 36F endoscope. When a stricture is observed, the severity of the esophagitis above it should be recorded. The absence of esophagitis above a stricture suggests a chemical-induced injury or a neoplasm as a cause. The latter should always be considered and is ruled out only by evaluation of a tissue biopsy of adequate size. Barrett's esophagus (BE) is a condition in which the tubular esophagus is lined with columnar epithelium, as opposed to the normal squamous epithelium. Histologically, it appears as intestinal metaplasia (IM). It is suspected at endoscopy when there is difficulty in visualizing the squamocolumnar junction at its normal location, and by the appearance of a redder, more luxuriant mucosa than is normally seen in the lower esophagus. Its presence is confirmed by biopsy. Multiple biopsies should be taken in a cephalad direction to determine the level at which the junction of Barrett's epithelium with normal squamous mucosa occurs. BE is susceptible to ulceration, bleeding, stricture formation, and, most important, malignant degeneration. The earliest sign of the latter is severe dysplasia or intramucosal adenocarcinoma (Fig. 25-19). These dysplastic changes have a patchy distribution, so a minimum of four biopsy samples spaced 2 cm apart should be taken from the Barrett's-lined portion of the esophagus. Changes seen in one biopsy are significant. Nishimaki has determined that the tumors occur in an area of specialized columnar epithelium near the squamocolumnar junction in 85% of patients, and within 2 cm of the squamocolumnar junction in virtually all patients. Particular attention should be focused on this area in patients suspected of harboring a carcinoma.

Fig. 25-19.

Complications of reflux disease as seen on endoscopy. A. Linear erosion of grade II esophagitis. B. Cobblestone mucosa of grade III esophagitis. C. Stricture associated with grade III esophagitis. D. Uncomplicated Barrett's mucosa. E. Large ulcer in Barrett's mucosa. F. Adenocarcinoma arising in Barrett's mucosa.

Abnormalities of the gastroesophageal flap valve can be visualized by retroflexion of the endoscope. Hill has graded the appearance of the gastroesophageal valve from I to IV according to the degree of unfolding or deterioration of the normal valve architecture (Fig. 25-20). The appearance of the valve correlates with the presence of increased esophageal acid exposure, occurring predominantly in patients with grade III and IV valves.

Fig. 25-20.

A. Grade I flap valve appearance. Note the ridge of tissue that is closely approximated to the shaft of the retroflexed endoscope. It extends 3–4 cm along the lesser curve. B. Grade II flap valve appearance. The ridge is slightly less well defined than in grade I and it opens rarely with respiration and closes promptly. C. Grade III flap valve appearance. The ridge is barely present, and there is often failure to close around the endoscope. It is nearly always accompanied by a hiatal hernia. D. Grade IV flap valve appearance. There is no muscular ridge at all. The gastroesophageal valve stays open all the time, and squamous epithelium can often be seen from the retroflexed position. A hiatal hernia is always present. (Reproduced with permission from Hill LD, Kozarek RA, et al: The gastroesophageal flap valve. In vitro and in vivo observations. Gastrointest Endosc 44:541, 1996. Copyright Elsevier.)

A hiatal hernia is endoscopically confirmed by finding a pouch lined with gastric rugal folds lying 2 cm or more above the margins of the diaphragmatic crura, identified by having the patient sniff. A prominent sliding hiatal hernia frequently is associated with increased esophageal exposure to gastric juice. When a paraesophageal hernia (PEH) is observed, particular attention is taken to exclude a gastric ulcer or gastritis within the pouch. The intragastric retroflex or J maneuver is important in evaluating the full circumference of the mucosal lining of the herniated stomach. When an esophageal diverticulum is seen, it should be carefully explored with the flexible endoscope to exclude ulceration or neoplasia. When a submucosal mass is identified, biopsies are usually not performed. At the time of surgical resection, a submucosal leiomyoma or reduplication cyst can generally be dissected away from the intact mucosa, but if a biopsy sample is taken, the mucosa may become fixed to the underlying abnormality. This complicates the surgical dissection by increasing the risk of mucosal perforation.

Tests to Detect Functional Abnormalities In many patients with symptoms of an esophageal disorder, standard radiographic and endoscopic evaluation fails to demonstrate a structural abnormality. In these situations, esophageal function tests are necessary to identify a functional disorder.

STATIONARY MANOMETRY Esophageal manometry is a widely used technique to examine the motor function of the esophagus and its sphincters. Manometry is indicated whenever a motor abnormality of the esophagus is suspected on the basis of complaints of dysphagia, odynophagia, or noncardiac chest pain, and the barium swallow or endoscopy does not show a clear structural abnormality. Esophageal manometry is particularly necessary to confirm the diagnosis of specific primary esophageal motility disorders [i.e., achalasia, diffuse esophageal spasm (DES), nutcracker esophagus, and hypertensive LES]. It also identifies nonspecific esophageal motility abnormalities and motility disorders secondary to systemic disease such as scleroderma, dermatomyositis, polymyositis, or mixed connective tissue disease. In patients with symptomatic GERD, manometry of the esophageal body can identify a mechanically defective LES, and evaluate the adequacy of esophageal peristalsis and contraction amplitude. Manometry has become an essential tool in the preoperative evaluation of patients before antireflux surgery, allowing selection of the appropriate procedure based upon the patient's underlying esophageal function. Esophageal manometry is performed using electronic, pressure-sensitive transducers located within the catheter, or water-perfused catheters with lateral side holes attached to transducers outside the body. The traditional catheter consists of a train of five pressure transducers or five or more water-perfused tubes bound together. The transducers or lateral openings are placed at 5-cm intervals from the tip and oriented radially at 72 from each other around the circumference of the catheter. A special catheter assembly consisting of four lateral openings at the same level, oriented at 90 to each other, is of special use in measuring the three-dimensional vector volume of the LES. Other specially designed catheters can be used to assess the upper sphincter. As the pressure-sensitive station is brought across the gastroesophageal junction (GEJ), a rise in pressure above the gastric baseline signals the beginning of the LES. The respiratory inversion point is identified when the positive excursions that occur in the abdominal cavity with breathing change to negative deflections in the thorax. The respiratory inversion point serves as a reference point at which the amplitude of LES pressure and the length of the sphincter exposed to abdominal pressure are measured. As the pressure-sensitive station is withdrawn into the body of the esophagus, the upper border of the LES is identified by the drop in pressure to the esophageal

baseline. From these measurements, the pressure, abdominal length, and overall length of the sphincter are determined (Fig. 25-21). To account for the asymmetry of the sphincter (Fig. 25-22), the pressure profile is repeated with each of the five radially oriented transducers, and the average values for sphincter pressure above gastric baseline, overall sphincter length, and abdominal length of the sphincter are calculated.

Fig. 25-21.

Manometric pressure profile of the lower esophageal sphincter. The distances are measured from the nares. (Reproduced with permission from: Zaninotto G, DeMeester TR, et al: The lower esophageal sphincter in health and disease. Am J Surg 155:105, 1988. Copyright Elsevier.)

Fig. 25-22.

Radial configuration of the lower esophageal sphincter. A = anterior; L = left; LA = left anterior; LP = left posterior; P = posterior; R = right; RA = right anterior; RP = right posterior. (Reproduced with permission from Winans CS: Manometric asymmetry of the lower esophageal high pressure zone. Dig Dis 22:348, 1977. With kind permission from Springer Science+Business Media.)

Table 25-1 shows the values for these parameters in 50 normal volunteers without subjective or objective evidence of a foregut disorder. The level at which a deficiency in the mechanics of the LES occurs was defined by comparing the frequency distribution of these values in the 50 healthy volunteers with a population of similarly studied patients with symptoms of GERD. The presence of increased esophageal exposure to gastric juice was documented by 24-hour esophageal pH monitoring. Based on these studies, a mechanically defective sphincter is identified by having one or more of the following characteristics: an average LES pressure of 5 mmol/h and a maximal acid secretory capacity of more than 30 mmol/h.

CHOLESCINTIGRAPHY Scintigraphic hepatobiliary imaging is performed after IV injection of 5 Ci of such as disofenin

(99m

99m

Tc iminodiacetic acid derivatives

Tc-DISIDA). Gamma camera images of the upper abdomen, including the gallbladder and

stomach, are obtained at 5-minute intervals for 60 minutes. Imaging is continued for an additional 30 minutes after stimulation of gallbladder contraction with 20 mg/kg of synthetic C-terminal octapeptide of cholecystokinin. Duodenogastric reflux is demonstrated as an increase of radioactivity in the stomach in the sequential images. The clinical value of this test is limited due to its short duration and a relatively high false-positive rate in normal volunteers.

24-HOUR GASTRIC PH MONITORING Monitoring is performed over a complete circadian cycle with a pH electrode placed 5 cm below the manometrically located LES. The patient is fully ambulatory during the test and is encouraged to perform normal daily activity. The gastric pH profile is assessed separately for the meal, postprandial period, and fasting period. The latter is divided into the time spent upright and supine. The interpretation of continuous gastric pH recordings is more difficult than that of esophageal pH recordings. This is because the gastric pH environment is determined by a complex interplay of acid secretion; mucus secretion; ingested food; swallowed saliva; regurgitated duodenal, pancreatic, and biliary secretions; and the effectiveness of the mixing and evacuation of the chyme. Using 24-hour gastric pH monitoring to evaluate the gastric secretory state is based on studies that have shown that a good correlation exists between increased basal acid output on standard gastric acid analysis, and a left shift on the frequency distribution graph of gastric pH recordings during the supine fasting period. The evaluation of gastric emptying by 24-hour gastric pH monitoring is based on studies

demonstrating a good correlation between the emptying of a solid meal and the duration of the postprandial plateau and decline phase of the gastric pH record. Using 24-hour gastric pH monitoring to evaluate duodenogastric reflux is based on the observation that reflux of alkaline duodenal juice into the stomach can alkalinize the gastric pH environment. The measurement is not straightforward because of the effect of meals, and reduction in acid secretion can result in changes in gastric pH that mimic alkaline reflux episodes. To overcome this problem, computerized measurements of the number and height of alkalinizing peaks, the baseline pH, the postprandial pH plateau, and the pattern of pH decline from the plateau can be used to identify the probability of duodenogastric reflux. The results are presented as an overall score that indicates the likelihood of pathologic duodenogastric reflux. Initial data indicate that this approach has a higher sensitivity and specificity for the diagnosis of pathologic duodenogastric reflux than scintigraphic methods do. Combined 24-hour esophageal and gastric pH monitoring can identify excessive alkaline duodenogastric and alkaline gastroesophageal reflux in symptomatic patients. The combined tracings can often identify simultaneous gastric and esophageal alkalinization, suggesting a duodenal origin for the esophageal alkaline exposure (Fig. 2528).

Fig. 25-28.

A. Combined esophageal and gastric pH monitoring showing position of probes in relation to the lower esophageal sphincter. B. Combined ambulatory esophageal (upper tracing ) and gastric (lower tracing ) pH monitoring showing duodenogastric reflux (arrows ) with propagation of the alkaline juice into the esophagus of a patient with complicated Barrett's esophagus. The gastric tracing (lower ) is taken from a probe lying 5 cm below the upper esophageal sphincter. The esophageal tracing (upper ) is taken from a probe lying 5 cm above the lower esophageal sphincter. Note that in only a small proportion of time does duodenogastric reflux move the pH of the esophagus above the threshold of 7, causing the iceberg effect. [Reproduced with permission from DeMeester TR, Stein HJ, Fuchs KH: Physiologic diagnostic studies, in Zuidema GD, Orringer MB (eds): Shackelford's Surgery of the Alimentary Tract , 3rd ed., Vol. I. Philadelphia: W.B. Saunders, 1991, p 123. Copyright Elsevier.]

GASTROESOPHAGEAL REFLUX DISEASE GERD was not recognized as a significant clinical problem until the mid-1930s and was not identified as a precipitating cause for esophagitis until after World War II. In the early twenty-first century, it has grown to be a very common problem and now accounts for a majority of esophageal pathology. It is recognized as a chronic disease, and when medical therapy is required, it is often lifelong. Recent efforts at the development of various

endoscopic antireflux interventions, although innovative, have not been successful in consistently controlling gastroesophageal reflux. Antireflux surgery is an effective and long-term therapy and is the only treatment that is able to restore the gastroesophageal barrier. Despite the common prevalence of GERD, it can be one of the most challenging diagnostic and therapeutic problems in clinical medicine. A contributing factor to this is the lack of a universally accepted definition of the disease. The most simplistic approach is to define the disease by its symptoms. However, symptoms thought to be indicative of GERD, such as heartburn or acid regurgitation, are very common in the general population and many individuals consider them to be normal and do not seek medical attention. Even when excessive, these symptoms are not specific for gastroesophageal reflux. They can be caused by other diseases such as achalasia, DES, esophageal carcinoma, pyloric stenosis, cholelithiasis, gastritis, gastric or duodenal ulcer, and coronary artery disease. A thorough, structured evaluation of the patient's symptoms is essential before any therapy, particularly any form of esophageal surgery. The presence and severity of both typical symptoms of heartburn, regurgitation, and dysphagia, and atypical symptoms of cough, hoarseness, chest pain, asthma, and aspiration should be discussed with the patient in detail. Many of these atypical symptoms may not be esophageal related and hence will not improve and may even worsen with antireflux surgery. Heartburn is generally defined as a substernal burning-type discomfort, beginning in the epigastrium and radiating upward. It is often aggravated by meals, spicy or fatty foods, chocolate, alcohol, and coffee and can be worse in the supine position. It is commonly, although not universally, relieved by antacid or antisecretory medications. Epidemiologic studies have shown that heartburn occurs monthly in as many as 40 to 50% of the Western population. The occurrence of heartburn at night and its effect on quality of life have recently been highlighted by a Gallup poll conducted by the American Gastroenterologic Society (Table 25-4).

Table 25-4 American Gastroenterologic Association Gallup Poll on Nighttime Gastroesophageal Reflux Disease Symptoms 50 million Americans have nighttime heartburn at least 1/wk 80% of heartburn sufferers had nocturnal symptoms—65% both day & night 63% report that it affects their ability to sleep and impacts their work the next day 72% are on prescription medications Nearly half (45%) report that current remedies do not relieve all symptoms

Regurgitation, the effortless return of acid or bitter gastric contents into the chest, pharynx, or mouth, is highly suggestive of foregut pathology. It is often particularly severe at night when supine or when bending over and can be secondary to either an incompetent or obstructed GEJ. With the later, as in achalasia, the regurgitant is often bland, as if food was put into a blender. When questioned, most patients can distinguish the two. It is the regurgitation of gastric contents that may result in associated pulmonary symptoms, including cough, hoarseness, asthma, and recurrent pneumonia. Bronchospasm can be precipitated by esophageal acidification and cough by either acid stimulation or distention of the esophagus. Dysphagia , or difficulty swallowing , is a relatively nonspecific term but arguably the most specific symptom of foregut disease. It is often a sign of underlying malignancy and should be aggressively investigated until a diagnosis is established. Dysphagia refers to the sensation of difficulty in the passage of food from the mouth to the stomach and can be divided into oropharyngeal and esophageal etiologies. Oropharyngeal dysphagia is

characterized by difficulty transferring food out of the mouth into the esophagus, nasal regurgitation, and/or aspiration. Esophageal dysphagia refers to the sensation of food sticking in the lower chest or epigastrium. This may or may not be accompanied by pain (odynophagia) that will be relieved by the passage of the bolus. Chest pain, although commonly and appropriately attributed to cardiac disease, is frequently secondary to esophageal pathology as well. As early as 1982, DeMeester and associates showed that nearly 50% of patients with severe chest pain, normal cardiac function, and normal coronary arteriograms had positive 24-hour pH studies, implicating gastroesophageal reflux as the underlying etiology. Exercise-induced gastroesophageal reflux is well known to occur, and may result in exertional chest pain similar to angina. It can be quite difficult, if not impossible, to distinguish between the two etiologies, particularly on clinical grounds alone. Nevens and colleagues evaluated the ability of experienced cardiologists to differentiate pain of cardiac vs. esophageal origin. Of 248 patients initially seen by cardiologists, 185 were thought to have typical angina and 63 atypical chest pain. Forty eight (26%) of those thought to have classic angina had normal coronary angiograms and 16 of the 63 with atypical pain had abnormal angiogram. Thus, the cardiologists' clinical impression was wrong 25% of the time. Finally, Pope and associates investigated the ultimate diagnosis in 10,689 patients presenting to an emergency room with acute chest pain. Seventeen percent were found to have acute ischemia, 6% stable angina, 21% other cardiac causes and 55% had noncardiac causes. They concluded that the majority of people presenting to the emergency room with chest pain do not have an underlying cardiac etiology for their symptoms. Chest pain precipitated by meals, occurring at night while supine, nonradiating, responsive to antacid medication, or accompanied by other symptoms suggesting esophageal disease such as dysphagia or regurgitation should trigger the thought of possible esophageal origin. Further, the distinction between heartburn and chest pain is also difficult and largely dependent upon the individual patient. One person's heartburn is another's chest pain. The precise mechanisms accounting for the generation of symptoms secondary to esophageal pathology remain unclear. Considerable insight has been acquired, however. Investigations into the effect of luminal content, esophageal distention and muscular function, neural pathways, and brain localization have provided a basic understanding of the stimuli responsible for symptom generation. It is also clear that the visceroneural pathways of the foregut are complexly intertwined with that of the tracheobronchial tree and heart. This fact accounts for the common overlap of clinical presentations with diverse disease processes in upper GI, cardiac, and pulmonary systems.

The Human Antireflux Mechanism and the Pathophysiology of Gastroesophageal Reflux Disease There is a high-pressure zone located at the esophagogastric junction in humans. Although this is typically referred to as the lower esophageal "sphincter," there are no distinct anatomical landmarks which define its beginning and end. Architecturally speaking, there is a specialized thickening in this region that is made up of the collar sling musculature and the clasp fibers. The collar sling is located on the greater curvature side of the junction, and the clasp fibers are located on the lesser curvature side. These muscles remain in tonic opposition until the act of swallowing, whereupon receptive relaxation occurs allowing passage of a food bolus into the stomach. In addition, the LES will also open when the gastric fundus is distended with gas and liquid, thus resulting in an unfolding of the valve and enabling venting of gas (a belch). Whether physiologic or pathologic, the common denominator for most episodes of gastroesophageal reflux is the loss of the high-pressure zone and thus a decrease in the resistance it imparts to the retrograde flow of gastric juice into the esophageal body. The primary cause of GERD is secondary to the permanent attenuation of the collar sling musculature, with a resultant opening of the gastric cardia and loss of the high-pressure zone as measured with esophageal manometry.

THE LOWER ESOPHAGEAL SPHINCTER As defined by esophageal manometry, there are three characteristics of the LES that work in unison to maintain its barrier function. These characteristics include the resting LES pressure, its overall length, and the intra-abdominal length that is exposed to the positive pressure environment of the abdomen (Table 25-5). The resistance to gastroesophageal reflux is a function of both the resting LES pressure and length over which this pressure is exerted. Thus, as the sphincter becomes shorter, a higher pressure will be required in order to prevent a given amount of reflux (Fig. 25-29). Much like the neck of a balloon as it is inflated, as the stomach fills and distends, sphincter length decreases. Therefore, if the overall length of the sphincter is permanently short from repeated distention of the fundus secondary to large volume meals, then with minimal episodes of gastric distention and pressure, there will be insufficient sphincter length for the barrier to remain competent, and reflux will occur.

Table 25-5 Normal Manometric Values of the Distal Esophageal Sphincter, n = 50 Pressure (mmHg) 13 5.8 27.7 Overall length (cm) 3.6 2.1 5.6 Abdominal length (cm) 2 0.9 4.7 Parameter Median Value

Fig. 25-29.

2.5th Percentile

97.5th Percentile

As the esophageal sphincter becomes shorter, increased pressure is necessary to maintain competence. LES = lower esophageal sphincter.

A third characteristic of the LES that impacts its ability to prevent reflux is its position about the diaphragm. It is important that a portion of the total length of the LES be exposed to the effects of intra-abdominal pressure. That is, during periods of elevated intra-abdominal pressure, the resistance of the barrier would be overcome if pressure were not applied equally to both the LES and stomach simultaneously. Thus, in the presence of a hiatal hernia, the sphincter resides entirely within the chest cavity and cannot respond to an increase in intra-abdominal pressure because the pinch valve mechanism is lost and gastroesophageal reflux is more liable to occur. Therefore, a permanently defective sphincter is defined by one or more of the following characteristics: An LES with a mean resting pressure of less than 6 mmHg, an overall sphincter length of 30 mmHg) during meal periods in individual normal volunteers, patients (Pat) without dysphagia, and patients with nonobstructive dysphagia.

In patients selected for surgery, preoperative manometry is essential to determine the proximal extent of the esophageal myotomy. Most surgeons extend the myotomy distally across the LES to reduce outflow resistance.

Consequently, some form of antireflux protection is needed to avoid gastroesophageal reflux if there has been extensive dissection of the cardia. In this situation, most authors prefer a partial, rather than a full, fundoplication, in order not to add back-resistance that will further interfere with the ability of the myotomized esophagus to empty (Fig. 25-61). If the symptoms of reflux are present preoperatively, 24-hour pH monitoring is required to confirm its presence.

Fig. 25-61.

Esophageal (Eso.) diameter, dysphagia, and esophageal retention in patients with achalasia treated with myotomy and Nissen fundoplication, 10 years after treatment (Rx). (Based on Topart P, et al: Long-term effect of total fundoplication on the myotomized esophagus. Ann Thorac Surg 54:1046, 1992.)

The procedure may be performed either open or via thoracoscopy. The open technique is performed through a left thoracotomy in the sixth intercostal space (Fig. 25-62). An incision is made in the posterior mediastinal pleura over the esophagus, and the left lateral wall of the esophagus is exposed. The esophagus is not circumferentially dissected unless necessary. A 2-cm incision is made into the abdomen through the parietal peritoneum at the midportion of the left crus. A tongue of gastric fundus is pulled into the chest. This exposes the GEJ and its associated fat pad. The latter is excised to give a clear view of the junction. A myotomy is performed through all muscle layers, extending distally over the stomach 1 to 2 cm below the GEJ, and proximally on the esophagus over the distance of the manometric abnormality. The muscle layer is dissected from the mucosa laterally for a distance of 1 cm. Care is taken to divide all minute muscle ibands, particularly in the area of the GEJ. The gastric fundic tongue s sutured to the margins of the myotomy over a distance of 3 to 4 cm and replaced into the abdomen. This maintains separation of the muscle and acts as a partial fundoplication to prevent reflux.

Fig. 25-62.

Technique of long myotomy: A. Exposure of the lower esophagus through the left sixth intercostal space and incision of the mediastinal pleura in preparation for surgical myotomy. B. Location of a 2-cm incision made through the phrenoesophageal membrane into the abdomen along the midlateral border of the left crus. C. Retraction of tongue of gastric fundus into the chest through the previously made incision. D. Removal of the gastroesophageal fat pad to expose the gastroesophageal junction. E. A myotomy down to the mucosa is started on the esophageal body. F. Completed myotomy extending over the stomach for 1 cm. G. Reconstruction of the cardia after a myotomy, illustrating the position of the sutures used to stitch the gastric fundic flap to the margins of the myotomy. H. Reconstruction of the cardia after a myotomy, illustrating the intraabdominal position of the gastric tongue covering the distal 4 cm of the myotomy.

If an epiphrenic diverticulum is present, it is excised by dividing the neck with a stapler sized for the thickness of the diverticulum (2.0- to 4.8-mm staple leg length) followed by a closure of the muscle over the staple line, when possible. The myotomy is then performed on the opposite esophageal wall. If a midesophageal diverticulum is present, the myotomy is made so that it includes the muscle around the neck, and the diverticulum is suspended by attaching it to the paravertebral fascia of the thoracic vertebra above the level of the diverticular neck. Before performing any operation for an esophageal diverticulum, it is wise to endoscope the patient to wash all food and other debris from the diverticulum. The results of myotomy for motor disorders of the esophageal body have improved in parallel with the improved preoperative diagnosis afforded by manometry. Previous published series report between 40 and 92% improvement of symptoms, but interpretation is difficult due to the small number of patients involved and the varying criteria for diagnosis of the primary motor abnormality. When myotomy is accurately done, 93% of the patients have effective palliation of dysphagia after a mean follow-up of 5 years, and 89% would have the

procedure again, if it was necessary. Most patients gain or maintain rather than lose weight after the operation. Postoperative motility studies show that the myotomy reduces the amplitude of esophageal contractions to near zero and eliminates simultaneous peristaltic waves. If the benefit of obliterating the simultaneous waves exceeds the adverse effect on bolus propulsion caused by the loss of peristaltic waveforms, the patient's dysphagia is likely to be improved by the procedure. If not, the patient is likely to continue to complain of dysphagia and to have little improvement as a result of the operation. The thoracoscopic technique is complicated by the fact that it requires complete retraction of the lung anteriorly to expose the esophagus. Proper positioning of the patient is critical to achieving this exposure. A prone position is ideal, allowing the left lung to fall forward away from the esophagus. Because of the possibility of open thoracotomy, however, it is best to place the patient in the right lateral decubitus position with the left thorax up, and then to roll the patient anteriorly 45 toward prone. A beanbag secured to the table is used to hold the patient. The table can be rotated a further 30 to 40 so that the patient ends up nearly prone. Should thoracotomy become necessary, the table can be rotated back to the horizontal position and a thoracotomy performed without difficulty. Prone positioning is the key element in providing exposure for long myotomy. Four thoracoscopic ports in the left chest are used. With suitable lung retraction, the myotomy is performed through all esophageal muscle layers, extending distally to the endoscopic GEJ, and proximally over the distance of the manometric abnormality. Few reports exist concerning the minimally invasive technique for performing long esophageal myotomy. Cuschieri has reported a preliminary experience with a thoracoscopically performed long esophageal myotomy for the treatment of nutcracker esophagus. Three patients with symptoms of chest pain and high-amplitude esophageal contractions and peristaltic waveforms were operated on. No major morbidity was encountered. Nasogastric tubes were removed the first postoperative day and oral feeding was started on the second postoperative day. Two patients were discharged on postoperative day 4 and one patient on day 5. All had symptomatic relief on shortterm follow-up. Epiphrenic diverticula are more frequently addressed with laparoscopic access, in combination with a laparoscopic division of the LES (Heller myotomy) (Fig. 25-63). If the diverticulum can be completely mobilized through the hiatus, it may be safely excised from below. The neck of the diverticulum is transected with a GIA stapler after passage of a 48F dilator. Not infrequently, the diverticulum is sufficiently large that access to the neck of the diverticulum across the hiatus is quite difficult. Additionally, the inflammatory reaction to the diverticulum may further make the transhiatal dissection difficult. Under these circumstances, it is safer to perform the diverticulectomy through a right thoracoscopic approach either at the time of the initial procedure or at a later date, depending upon the frailty of the patient. Following diverticulectomy, it is critical that the esophageal staple line be treated with a great deal of care. Closure of the muscle over the staple line is preferable. Additionally, the patient kept NPO for 3 to 5 days and obtained a contrast study before initiating clear liquids. Solid foods are withheld for 2 weeks to decrease the likelihood of staple line leak. Buttressing or sealing the staple line with fibrin glue is also an attractive option.

Fig. 25-63.

A. Epiphrenic diverticula are situated above the lower esophageal sphincter on right side of esophagus. B. Stapler amputates neck of diverticulum. C. Muscle reapproximated over staple line, and Heller myotomy is performed.

Myotomy of the Lower Esophageal Sphincter (Heller Myotomy) Second only to reflux disease, achalasia is the most common functional disorder of the esophagus to require surgical intervention. The goal of treatment is to relieve the functional outflow obstruction secondary to the loss of relaxation and compliance of the LES. This requires disrupting the LES muscle. When performed adequately (i.e., reducing sphincter pressure to Chapter 26. Stomach>

KEY POINTS 1. Any patient admitted to a hospital because of peptic ulcer disease should be placed on lifelong acid suppression. 2. Patients who regularly take NSAIDs or aspirin should take concomitant acid suppressive medication if they are more than age 60 years old, or on anticoagulants, or if they have multiple medical comorbidities. 3. Lifelong acid suppressive medication may be equivalent to surgical vagotomy in preventing recurrent peptic ulcer or ulcer complications. 4. Gastric resection for peptic ulcer should be avoided in the asthenic or high-risk patient. 5. Many patients with locally advanced gastric cancer (T2b, T3, T4) are cured by an oncologically sound operation that includes wide margins and adequate lymphadenectomy. 6. Most patients with primary gastric lymphoma can be treated without gastric resection. 7. Gastric carcinoids should usually be removed either endoscopically or surgically. The surgeon should treat gastric carcinoid without hypergastrinemia (type 3) as if it were malignant. 8. Roux-en-Y gastrojejunostomy should be avoided unless more than half of the stomach has been removed. Otherwise marginal ulceration and/or gastric stasis (Roux syndrome) may become problematic.

HISTORY The stomach is a remarkable organ with important digestive, nutritional, and endocrine functions. The stomach stores and facilitates the digestion and absorption of ingested food, and it helps regulate appetite. Treatable diseases of the stomach are common, and it is accessible and relatively forgiving. Thus, the stomach is a favorite therapeutic target. To provide intelligent diagnosis and treatment, the physician and surgeon must understand gastric anatomy, physiology, and pathophysiology. This includes a sound understanding of the mechanical, secretory, and endocrine processes through which the stomach accomplishes its important functions. It also includes a familiarity with the common benign and malignant gastric disorders of clinical significance. The purpose of this chapter is to enhance the reader's current understanding and familiarity with these concepts and topics. Some important milestones in the history of gastric surgery1–6 are listed in Table 26-1.

Table 26-1 Historic Milestones in Gastric Surgery 350 B.C. – 201 A.D. Existence of gastric ulceration was acknowledged by Diocles of Carystos (350 A.D. ).

B.C.

), Celsus, and Galen (131–201

1363 Guy de Chauliac describes closure of gastric wound. 1586 Marcellus Donatus of Mantua describes gastric ulcer at autopsy. 1600–1700 Reports of surgeons cutting stomach to remove foreign bodies. 1688 Muralto describes duodenal ulcer at autopsy. 1737 Morgagni describes both gastric and duodenal ulcer at autopsy. 1833 William Beaumont reports data recorded during his care of Alexis St. Martin who developed a gastric fistula from a left upper quadrant musket wound. 1869 Maury reportedly performs feeding gastrostomy to palliate esophageal stricture following consultation with Samuel D. Gross. 1875 Sidney Jones in London publishes the first successful gastrostomy for feeding. 1879 Paen performed distal gastrectomy and gastroduodenostomy. The patient died 5 d later. 1880 Rydygier resected a distal gastric cancer, and the patient died 12 h later. 1880 Billroth resects distal gastric cancer and performs gastroduodenostomy (Billroth I). Patient Therese Heller recovers and survives 4 mo. 1881 Anton Wolfler performs loop gastrojejunostomy to palliate an obstructing distal gastric cancer. 1884 Rydygier reports an unsuccessful gastrojejunostomy for benign gastric outlet obstruction. 1885 Billroth performs a successful distal gastrectomy and gastrojejunostomy (Billroth II) for gastric cancer. 1886 Heineke performs pyloroplasty. 1888 Mikulicz performs similar operation. 1892 Jaboulay describes bypassing the intact pylorus with gastroduodenostomy. 1902 Finney from Baltimore describes pyloroplasty technique. 1891–1913 Different techniques of gastrostomy are described by Witzel (1891), Stamm (1894), and Janeway (1913). 1920–1950 Subtotal gastrectomy grows popular as an operation for peptic ulcer. Von Haberer and Finsterer proponents. 1943 Dragstedt and Owen describe transthoracic truncal vagotomy to treat peptic ulcer disease. By the early 1950s, it is well recognized that some patients developed gastric stasis after this procedure, and transabdominal truncal vagotomy and drainage (pyloroplasty or gastrojejunostomy) become a standard ulcer operation. 1952 Farmer and Smithwick describe good results with truncal vagotomy and hemigastrectomy for peptic ulcer.

1953 Edwards and Herrington (Nashville) describe truncal vagotomy and antrectomy for peptic ulcer. 1955 Zollinger and Ellison describe the eponymous syndrome. 1957 Griffith and Harkins (Seattle) describe parietal cell vagotomy (highly selective vagotomy) for the elective treatment of peptic ulcer disease. 1980–2000 Japanese surgeons and other surgical groups from East Asia demonstrate that more aggressive lymphadenectomy may improve survival in patients with gastric cancer. 1990–current Evolving role of laparoscopic techniques in the treatment of surgical gastric disease. 1995–current Dramatic increase in bariatric operations. 2000–current Development of natural orifice translumenal endoscopic surgery. Date

Event

ANATOMY Anatomic Relationships and Gross Morphology The stomach is readily recognizable as the asymmetrical, pear-shaped, most proximal abdominal organ of the digestive tract (Fig. 26-1).7 The part of the stomach attached to the esophagus is called the cardia. Just proximal to the cardia at the gastroesophageal (GE) junction is the anatomically indistinct but physiologically demonstrable lower esophageal sphincter. At the distal end, the pyloric sphincter connects the stomach to the proximal duodenum. The stomach is relatively fixed at these points, but the large midportion is quite mobile.

Fig. 26-1.

Anatomic regions of the stomach. [Reproduced with permission from Mercer DW, Liu TH, Castaneda A: Anatomy and physiology of the stomach, in Zuidema GD, Yeo CJ (eds): Shackelford's Surgery of the Alimentary Tract , 5th ed., Vol. II. Philadelphia: Saunders, 2002, p 3. Copyright Elsevier.]

The superior-most part of the stomach is the distensible floppy fundus, bounded superiorly by the diaphragm and laterally by the spleen. The angle of His is where the fundus meets the left side of the GE junction. Generally, the inferior extent of the fundus is considered to be the horizontal plane of the GE junction, where the body (corpus) of the stomach begins. The body of the stomach contains most of the parietal (oxyntic) cells, some of which are also present in the cardia and fundus. The body is bounded on the right by the relatively straight lesser curvature and on the left by the more curved greater curvature. At the angularis incisura, the lesser curvature turns rather abruptly to the right, marking the anatomic beginning of the antrum, which comprises the distal 25 to 30% of the stomach. The organs that commonly abut the stomach are the liver, colon, spleen, pancreas, and occasionally the kidney (Fig. 26-2). The left lateral segment of the liver usually covers a large part of the anterior stomach. Inferiorly, the stomach is attached to the transverse colon by the gastrocolic omentum. The lesser curvature is tethered to the liver by the hepatogastric ligament, also referred to as the lesser omentum or pars flaccida. Posterior to the stomach is the lesser omental bursa and the pancreas.

Fig. 26-2.

Anatomic relationships of the stomach. [Reproduced with permission from Mercer DW, Liu TH, Castaneda A: Anatomy and physiology of the stomach, in Zuidema GD, Yeo CJ (eds): Shackelford's Surgery of the Alimentary Tract , 5th ed., Vol. II. Philadelphia: Saunders, 2002, p 3. Copyright Elsevier.]

Arterial and Venous Blood Supply The stomach is the most richly vascularized portion of the alimentary tube. Both the quantity of blood delivered to the stomach and the richness of the intramural gastric vascular anastomotic network are impressive. The large majority of the gastric blood supply is from the celiac axis via four named arteries (Fig. 26-3). The left and right gastric arteries form an anastomotic arcade along the lesser curvature, and the right and left gastroepiploic arteries form an arcade along the greater gastric curvature. The consistently largest artery to the stomach is the left gastric artery, which usually arises directly from the celiac trunk and divides into an ascending and descending branch along the lesser gastric curvature. Approximately 15% of the time, the left gastric artery supplies an aberrant vessel that travels in the gastrohepatic ligament (lesser omentum) to the left side of the liver. Rarely, this is the only arterial blood supply to this part of the liver, and inadvertent ligation may lead to clinically significant hepatic ischemia in this unusual circumstance. The more common smaller aberrant left hepatic artery may usually be ligated without significant consequences.

Fig. 26-3.

Arterial blood supply to the stomach. a. = artery; v. = vein. [Reproduced with permission from Mercer DW, Liu TH, Castaneda A: Anatomy and physiology of the stomach, in Zuidema GD, Yeo CJ (eds): Shackelford's Surgery of the Alimentary Tract , 5th ed., Vol. II. Philadelphia: Saunders, 2002, p 3. Copyright Elsevier.]

The second largest artery to the stomach is the right gastroepiploic artery, which arises consistently from the gastroduodenal artery behind the first portion of the duodenum. The left gastroepiploic artery arises from the splenic artery, and, together with the right gastroepiploic artery, forms the rich gastroepiploic arcade along the

greater curvature. The right gastric artery usually arises from the hepatic artery near the pylorus and hepatoduodenal ligament, and runs proximally along the distal stomach. In the fundus along the proximal greater curvature, the short gastric arteries and veins arise from the splenic circulation. There also may be additional vascular branches to the proximal stomach from the phrenic and splenic circulation. The veins draining the stomach generally parallel the arteries. The left gastric (coronary vein) and right gastric veins usually drain into the portal vein, though occasionally the coronary vein drains into the splenic vein. The right gastroepiploic vein drains into the superior mesenteric vein near the inferior border of the pancreatic neck, and the left gastroepiploic vein drains into the splenic vein. The richness of the gastric blood supply and the extensiveness of the anastomotic connections have some important clinical implications. Erosion of a peptic ulcer or gastric cancer into a large perigastric vessel may cause life-threatening hemorrhage. Because of the rich venous interconnections in the stomach, a distal splenorenal shunt, which connects the distal end of the divided splenic vein to the side of the left renal vein, can effectively decompress esophagogastric varices in patients with portal hypertension.8 Finally, at least two of the four named gastric arteries may be occluded or ligated with impunity. This is done routinely when the stomach is mobilized and pedicled on the right gastric and right gastroepiploic vessels to reach into the neck as an esophageal replacement (see Chap. 25). 9

Lymphatic Drainage Generally speaking, the gastric lymphatics parallel the blood vessels (Fig. 26-4).1 0 The cardia and medial half of the corpus commonly drain to nodes along the left gastric and celiac axis. The lesser curvature side of the antrum usually drains to the right gastric and pyloric nodes, while the greater curvature half of the distal stomach drains to the nodes along the right gastroepiploic chain. The proximal greater curvature side of the stomach usually drains into nodes along the left gastroepiploic or splenic hilum. The nodes along both the greater and lesser curvature commonly drain into the celiac nodal basin. There is a rich anastomotic network of lymphatics that drain the stomach, often in a somewhat unpredictable fashion. Thus, a tumor arising in the distal stomach may give rise to positive lymph nodes in the splenic hilum. The rich intramural plexus of lymphatics and veins accounts for the fact that there can be microscopic evidence of malignant cells in the gastric wall at a resection margin that is several centimeters away from palpable malignant tumor. It also helps explain the not infrequent finding of positive lymph nodes which may be many centimeters away from the primary tumor, with closer nodes that remain negative.

Fig. 26-4.

Lymph node stations draining the stomach according to the Japanese Research Society for Gastric Cancer. Stations 3–6 are commonly removed with D1 gastrectomy. Stations 1, 2, and 7–12 are commonly removed with D2 gastrectomy. [Reproduced with permission from Hermanek P, et al (eds): TNM Atlas: Illustrated Guide to the TNM/pTNM Classification of Malignant Tumours , 4th ed. Berlin: Springer-Verlag, 1997, p 82–83. Copyright 1997, with kind permission of Springer Science + Business Media.]

Extensive and meticulous lymphadenectomy is considered by many surgeons to be an important part of the operation for gastric cancer. Surgeons and pathologists have numbered the primary and secondary lymph node groups to which the stomach drains (see Fig. 26-4).11,12

Innervation Both the extrinsic and intrinsic innervation of the stomach play an important role in gastric secretory and motor function.1 3 The vagus nerves provide the extrinsic parasympathetic innervation to the stomach, and acetylcholine is the most important neurotransmitter. From the vagal nucleus in the floor of the fourth cerebral ventricle, the vagus traverses the neck in the carotid sheath and enters the mediastinum, where it gives off the recurrent laryngeal nerve and divides into several branches around the esophagus. These branches come together again above the esophageal hiatus and form the l eft (a nterior) and ri ght (p osterior) vagal trunks (mnemonic LARP). Near the GE junction the anterior vagus sends a branch (or branches) to the liver in the gastrohepatic ligament, and continues along the lesser curvature as the anterior nerve of Latarjet (Fig. 26-5). Similarly, the posterior vagus sends branches to the celiac plexus and continues along the posterior lesser curvature. The nerves of Latarjet send segmental branches to the body of the stomach before they terminate near the angularis incisura as the "crow's foot," sending branches to the antropyloric region. There may be additional branches to the distal stomach and pylorus that travel near the right gastric and/or gastroepiploic arteries. In 50% of patients, there are more than two vagal nerves at the esophageal hiatus. The branch that the posterior vagus sends to the posterior fundus is termed the criminal nerve of Grassi . This branch typically arises above the esophageal hiatus and is easily missed during truncal or highly selective vagotomy (HSV). Vagal fibers originating in the brain synapse with neurons in Auerbach's myenteric plexus and Meissner's submucosal plexus. Although clinicians are accustomed to thinking about the vagus nerves as important efferent nerves (i.e., carrying stimuli to the viscera), it is important to consider the fact that fully 75% of the axons contained in the vagal trunks are afferent (i.e., carrying stimuli from the viscera to the brain).

Fig. 26-5.

Vagal innervation of the stomach. br. = branch; n. = nerve; rt. = right. [Reproduced with permission from Anatomy and physiology of the stomach, in Menguy R: Surgery of Peptic Ulcer. Philadelphia: Saunders, 1976, p 8. Copyright Elsevier.]

The extrinsic sympathetic nerve supply to the stomach originates at spinal levels T5 through T10 and travels in the splanchnic nerves to the celiac ganglion. Postganglionic sympathetic nerves then travel from the celiac ganglion to the stomach along the blood vessels. Neurons in the myenteric and submucosal plexuses constitute the intrinsic nervous system of the stomach. There may be more intrinsic gastric neurons than extrinsic neurons, but their function is poorly understood. It is obviously an oversimplification (and incorrect) to think exclusively of the vagus as the cholinergic system and the sympathetic system as the adrenergic system of innervation. Although acetylcholine is an important neurotransmitter mediating vagal function, and epinephrine is important in the sympathetic nerves, both systems (as well as the intrinsic neurons) have various and diverse neurotransmitters including cholinergic, adrenergic, and peptidergic (e.g., substance P and somatostatin).

Histology There are four distinct layers of the gastric wall: mucosa, submucosa, muscularis propria, and serosa (Fig. 26-6). 7

The inner layer of the stomach is the mucosa, which is lined with columnar epithelial cells of various types. Beneath the basement membrane of the epithelial cells is the lamina propria, which contains connective tissue, blood vessels, nerve fibers, and inflammatory cells. Beneath the lamina propria is a thin muscle layer called the muscularis mucosa , the deep boundary of the mucosal layer of the gut. The epithelium, lamina propria, and muscularis mucosa constitute the mucosa (Fig. 26-7).1 4 The epithelium of the gastric mucosa is columnar glandular. A scanning electron micrograph shows a smooth mucosal carpet punctuated by the openings of the gastric glands. The gastric glands are lined with different types of epithelial cells, depending upon their location in the stomach (Fig. 26-8, Table 26-2).15,16 There are also endocrine cells present in the gastric glands. Progenitor cells at the base of the glands differentiate and replenish sloughed cells on a regular basis. Throughout the stomach, the carpet consists primarily of mucus-secreting surface epithelial cells (SECs) that extend down into the gland pits for variable distances. These cells also secrete bicarbonate and play an important role in protecting the stomach from injury due to acid, pepsin, and/or ingested irritants. In fact, all epithelial cells of the stomach (except the endocrine cells) contain carbonic anhydrase and are capable of producing bicarbonate.

Fig. 26-6.

Layers of the gastric wall. [Reproduced with permission from The esophagus and stomach, in Fawcett DW: Bloom and Fawcett's Textbook of Histology , 11th ed. Philadelphia: Saunders, 1986, p 625. Copyright Elsevier.]

Fig. 26-7.

Gastric mucosa. (Reproduced with permission from Bloom W, Fawcett DW: A Textbook of Histology . Philadelphia: Saunders, 1975, p 639.)

Fig. 26-8.

Mammalian gastric gland from the body of the stomach.

[Reproduced with permission from Ito S, Winchester RJ: The fine structure of the gastric muscosa in the bat. J Cell Biol 16:541, 1963. By copyright permission of The Rockefeller University Press.]

Table 26-2 Epithelial Cells of the Stomach Surface-foveolar mucous cells Apical stippled granules up to 1 µm in diameter Production of neutral glycoprotein and bicarbonate to form a gel on the gastric luminal surface; neutralization of hydrochloric acida Mucous neck cell Heterogeneous granules 1–2 µm in diameter dispersed throughout the cytoplasm Progenitor cell for all other gastric epithelial cells; glycoprotein production; production of pepsinogens I and II Oxyntic (parietal) cell Surface membrane invaginations (canaliculi); tubulovesicle structures; numerous mitochondria Production of hydrochloric acid; production of intrinsic factor; production of bicarbonate Chief cell Moderately dense apical granules up to 2 m in diameter; prominent supranuclear Golgi apparatus; extensive basolateral granular endoplasmic reticulum Production of pepsinogens I and II, and of lipase Cardiopyloric mucous cell Mixture of granules like those in mucous neck and chief cells; extensive basolateral granular endoplasmic reticulum Production of glycoprotein; production of pepsinogen II Endocrine cells See Figure 26-11 Cell Type a

Distinctive Ultrastructural Features

Major Functions

Bicarbonate is probably produced by other gastric epithelial cells in addition to surface-foveolar mucous cells.

Source: From Antonioli et al,1 6 with permission. In the cardia, the gastric glands are branched and secrete primarily mucus and bicarbonate, but not much acid. In the fundus and body, the glands are more tubular and the pits are deep. Parietal and chief cells are common in these glands (Fig. 26-9). Histamine-secreting enterochromaffin-like (ECL) cells and somatostatin-secreting D cells are also found. Parietal cells secrete acid and intrinsic factor into the gastric lumen, and bicarbonate into the intercellular space. They have a characteristic ultrastructural appearance with secretory canaliculi (deep invaginations of the surface membrane), and cytoplasmic tubulovesicles containing the acid-producing apparatus H+ /K+ -ATPase (proton pump) (see Fig. 26-9). There are numerous mitochondria; in fact the parietal cell is the most mitochondria rich cell in the body. When the parietal cell is stimulated, the cytoplasmic tubulovesicles fuse with the membrane of the secretory canaliculus; when acid production ceases, the process is reversed. Arguably, parietal cells produce the only truly essential substance produced by the stomach (i.e., intrinsic factor). Parietal cells tend to occupy the midportion of the gastric glands found in the corpus of the stomach.

Fig. 26-9.

Ultrastructural features of the parietal (oxyntic) cell. SC = secretory canaliculus; M = mitochondria; TV = tubulovesicle. [Reproduced with permission from Antonioli DA, Madara JL: Functional anatomy of the gastrointestinal tract, in Ming S-C, Goldman H (eds): Pathology of the Gastrointestinal Tract , 2nd ed. Baltimore: Williams & Wilkins, 1998, p 13.]

Chief cells (also called zymogenic cells ) secrete pepsinogen I, which is maximally activated at a pH of 2.5. They tend to be clustered toward the base of the gastric glands and have a low columnar shape. Ultrastructurally, chief cells have the characteristics of protein-synthesizing cells: basal granular endoplasmic reticulum, supranuclear Golgi apparatus, and apical zymogen granules (Fig. 26-10). When stimulated, the chief cells produce two immunologically distinct proenzyme forms of pepsinogen: predominantly pepsinogen I and some pepsinogen II, most of which is produced by SECs. These proenzymes are activated in an acidic luminal environment.

Fig. 26-10.

Ultrastructural features of the chief (zymogenic) cell. GA = Golgi apparatus; GER = granular endoplasmic reticulum; ZG = zymogen granule. [Reproduced with permission from Antonioli DA, Madara JL: Functional anatomy of the gastrointestinal tract, in Ming S-C, Goldman H (eds): Pathology of the Gastrointestinal Tract , 2nd ed. Baltimore: Williams & Wilkins, 1998, p 13.]

In the antrum, the gastric glands are again more branched and shallow, parietal cells are rare, and gastrinsecreting G cells and somatostatin-secreting D cells are present. A variety of hormone-secreting cells are present in various proportions throughout the gastric mucosa (Fig. 26-11).1 7 Histologic analysis suggests that in the normal stomach, 13% of the epithelial cells are oxyntic (parietal) cells, 44% are chief (zymogenic) cells, 40% are mucous cells, and 3% are endocrine cells. In general, the antrum produces gastrin but not acid, and the proximal stomach produces acid but not gastrin. The border between the corpus and antrum migrates proximally with age (especially on the lesser curvature side of the stomach).

Fig. 26-11.

Endocrine cells of the stomach. D = d cell (somatostatin); EC = enterochrommafin cell; ECL = enterochrommafin-like cell (histamine); G = g cell (gastrin). [Reproduced with permission from Feldman M: Gastric secretion, in Feldman M, et al (eds): Sleisenger and Fordtran's Gastrointestinal and Liver Disease , 7th ed. Philadelphia: Saunders, 2002, p 715. Copyright Elsevier.]

Deep to the muscularis mucosa is the submucosa, which is rich in branching blood vessels, lymphatics, collagen, various inflammatory cells, autonomic nerve fibers, and ganglion cells of Meissner's autonomic submucosal plexus. The collagen-rich submucosa gives strength to GI anastomoses. The mucosa and submucosa are folded into the grossly visible gastric rugae, which tend to flatten out as the stomach becomes distended. Below the submucosa is the thick muscularis propria (also referred to as the muscularis externa ), which consists of an incomplete inner oblique layer, a complete middle circular layer (continuous with the esophageal circular muscle and the circular muscle of the pylorus), and a complete outer longitudinal layer (continuous with the longitudinal layer of the esophagus and duodenum). Within the muscularis propria is the rich network of autonomic ganglia and nerves that make up Auerbach's myenteric plexus. Specialized pacemaker cells, the interstitial cells of Cajal (ICC), also are present. The outer layer of the stomach is the serosa, also known as the visceral peritoneum . This layer provides significant tensile strength to gastric anastomoses. When tumors originating in the mucosa penetrate and breach the serosa, microscopic or gross peritoneal metastases are common, presumably from shedding of tumor cells that would not have occurred if the serosa had not been penetrated. In this way, the serosa may be thought of as an outer envelope of the stomach.

PHYSIOLOGY The stomach stores food and facilitates digestion through a variety of secretory and motor functions. Important secretory functions include the production of acid, pepsin, intrinsic factor, mucus, and a variety of GI hormones. Important motor functions include food storage (receptive relaxation and accommodation), grinding and mixing,

controlled emptying of ingested food, and periodic interprandial "housekeeping."

Acid Secretion Hydrochloric acid in the stomach hastens both the physical and (with pepsin) the biochemical breakdown of ingested food. In an acidic environment, pepsin and acid facilitate proteolysis. Gastric acid also inhibits the proliferation of ingested pathogens, which protects against both infectious gastroenteritides and intestinal bacterial overgrowth. Long-term acid suppression with proton pump inhibitors (PPIs) has been associated with an increased risk of community acquired Clostridium difficile colitis and other gastroenteritides, presumably because of the absence of this protective germicidal barrier.18,19

PARIETAL CELL The parietal cell is stimulated to secrete acid (Fig. 26-12) when one or more of three membrane receptor types is stimulated by acetylcholine (from vagal nerve fibers), gastrin (from D cells), or histamine (from ECL cells).7,20,21 The enzyme H + /K+ -ATPase is the proton pump. It is stored within the intracellular tubulovesicles and is the final common pathway for gastric acid secretion. When the parietal cell is stimulated, there is a cytoskeletal rearrangement and fusion of the tubulovesicles with the apical membrane of the secretory canaliculus. The heterodimer assembly of the enzyme subunits into the microvilli of the secretory canaliculus results in acid secretion, with extracellular potassium being exchanged for cytosolic hydrogen. Although electro-neutral, this is an energy requiring process because the hydrogen is secreted against a gradient of at least 1 million-fold, which explains why the parietal cell is packed with energy producing mitochondria. During acid production, potassium and chloride are also secreted into the secretory canaliculus through separate channels, providing potassium for the H+ /K+ -ATPase, and chloride for the secreted hydrogen.

Fig. 26-12.

Control of acid secretion in the parietal cell. ATP = adenosine triphosphate; cAMP = cyclic adenosine monophosphate; CCK = cholecystokinin; H 2 = histamine 2; IP 3 = inositol trisphosphate; PIP2 = phosphatidylinositol 4,5-bisphosphate; PLC = phospholipase C. [Reproduced with permission from Mercer DW, Liu TH, Castaneda A: Anatomy and physiology of the stomach, in Zuidema GD, Yeo CJ (eds): Shackelford's Surgery of the Alimentary Tract , 5th ed., Vol. II. Philadelphia: Saunders, 2002, p 3. Copyright Elsevier.]

The normal human stomach contains approximately 1 billion parietal cells, and total gastric acid production is proportional to parietal cell mass. The potent acid-suppressing PPI drugs irreversibly interfere with the function of the H+ /K+ -ATPase molecule. These agents must be incorporated into the activated enzyme to be effective, and thus work best when taken before or during a meal (when the parietal cell is stimulated). When PPI therapy is stopped, acid secretory capability gradually returns (within days) as new H+ /K+ -ATPase is synthesized. Gastrin, acetylcholine, and histamine stimulate the parietal cell to secrete hydrochloric acid (see Fig. 26-12). Gastrin binds to type B cholecystokinin (CCK) receptors, and acetylcholine binds to M 3 muscarinic receptors. Both stimulate phospholipase C via a G-protein–linked mechanism leading to increased production of inositol

trisphosphate from membrane bound phospholipids. Inositol trisphosphate stimulates the release of calcium from intracellular stores, which leads to activation of protein kinases and activation of H+ /K+ -ATPase. Histamine binds to the histamine 2 (H2 ) receptor, which stimulates adenylate cyclase, also via a G-protein–linked mechanism. Activation of adenylate cyclase results in an increase in intracellular cyclic adenosine monophosphate which activates protein kinases, leading to increased levels of phosphoproteins and activation of the proton pump. Somatostatin from mucosal D cells binds to membrane receptors and inhibits the activation of adenylate cyclase through an inhibitory G protein.

PHYSIOLOGIC ACID SECRETION Food ingestion is the physiologic stimulus for acid secretion (Fig. 26-13). The acid secretory response that occurs after a meal is traditionally described in three phases: cephalic, gastric, and intestinal.22,23 The cephalic or vagal phase begins with the thought, sight, smell, and/or taste of food. These stimuli activate several cortical and hypothalamic sites (e.g., tractus solitarius, dorsal motor nucleus, and dorsal vagal complex), and signals are transmitted to the stomach by the vagal nerves. Acetylcholine is released, leading to stimulation of ECL cells and parietal cells. Although the acid secreted per unit of time in the cephalic phase is greater than in the other two phases, the cephalic phase is shorter. Thus, the cephalic phase accounts for no more than 30% of total acid secretion in response to a meal. Sham feeding (chewing and spitting) stimulates gastric acid secretion only via the cephalic phase, and results in acid secretion that is about half of that seen in response to IV pentagastrin or histamine.

Fig. 26-13.

Physiologic control of acid secretion. ECL = enterochromaffin-like. [Reproduced with permission from Mercer DW, Liu TH, Castaneda A: Anatomy and physiology of the stomach, in Zuidema GD, Yeo CJ (eds): Shackelford's Surgery of the Alimentary Tract , 5th ed., Vol. II. Philadelphia: Saunders, 2002, p 3. Copyright Elsevier.]

When food reaches the stomach, the gastric phase of acid secretion begins. This phase lasts until the stomach is empty, and accounts for about 60% of the total acid secretion in response to a meal. The gastric phase of acid secretion has several components. Amino acids and small peptides directly stimulate antral G cells to secrete gastrin, which is carried in the bloodstream to the parietal cells and stimulates acid secretion in an endocrine fashion. In addition, proximal gastric distention stimulates acid secretion via a vagovagal reflex arc, which is abolished by truncal or HSV. Antral distention also stimulates antral gastrin secretion. Acetylcholine stimulates gastrin release and gastrin stimulates histamine release from ECL cells. The intestinal phase of gastric secretion is poorly understood. It is thought to be mediated by a hormone yet to be discovered that is released from the proximal small bowel mucosa in response to luminal chyme. This phase starts when gastric emptying of ingested food begins, and continues as long as nutrients remain in the proximal small

intestine. It accounts for about 10% of meal-induced acid secretion. Interprandial basal acid secretion is 2 to 5 mEq hydrochloric acid per hour, about 10% of maximal acid output (MAO), and it is greater at night. Basal acid secretion probably contributes to the relatively low bacterial counts found in the stomach. Basal acid secretion is reduced 75 to 90% by vagotomy or H2 receptor blockade. The pivotal role that ECL cells play in the regulation of gastric acid secretion is emphasized in Fig. 26-13. A large part of the acid stimulatory effects of both acetylcholine and gastrin are mediated by histamine released from mucosal ECL cells. This explains why the histamine 2 receptor antagonists (H2 RAs) are such effective inhibitors of acid secretion, even though histamine is only one of three parietal cell stimulants. The mucosal D cell, which releases somatostatin, is also an important regulator of acid secretion. Somatostatin inhibits histamine release from ECL cells and gastrin release from antral G cells. The function of D cells is inhibited by Helicobacter pylori infection, and this leads to an exaggerated acid secretory response (see below under Helicobacter pylori Infection).

Pepsinogen Secretion The most potent physiologic stimulus for pepsinogen secretion from chief cells is food ingestion; acetylcholine is the most important mediator. Somatostatin inhibits pepsinogen secretion. Pepsinogen I is produced by chief cells in acid producing glands, whereas pepsinogen II is produced by SECs in both acid producing and gastrin producing (i.e., antral) glands. Pepsinogen is cleaved to the active pepsin enzyme in an acidic environment and is maximally active at pH 2.5, and inactive at pH >5, although pepsinogen II may be activated over a wider pH range than pepsinogen I. Pepsin catalyzes the hydrolysis of proteins and is denatured at alkaline pH.

Intrinsic Factor Activated parietal cells secrete intrinsic factor in addition to hydrochloric acid. Presumably the stimulants are similar, but acid secretion and intrinsic factor secretion may not be linked. Intrinsic factor binds to luminal vitamin B12, and the complex is absorbed in the terminal ileum via mucosal receptors. Vitamin B1 2 deficiency can be life threatening, and patients with total gastrectomy or pernicious anemia (i.e., patients with no parietal cells) require B1 2 supplementation by a nonenteric route. Some patients develop vitamin B1 2 deficiency following gastric bypass, presumably because there is insufficient intrinsic factor present in the small proximal gastric pouch. Under normal conditions, a significant excess of intrinsic factor is secreted, and acid-suppressive medication does not appear to inhibit intrinsic factor production and release.

Gastric Mucosal Barrier The stomach's durable resistance to autodigestion by caustic hydrochloric acid and active pepsin is intriguing. Some of the important elements of gastric barrier function and cytoprotection are listed in Table 26-3.24,25 When these defenses break down, ulceration occurs. A variety of factors are important in maintaining an intact gastric mucosal layer. The mucus and bicarbonate secreted by SECs form an unstirred mucous gel with a favorable pH gradient. Cell membranes and tight junctions prevent hydrogen ions from gaining access to the interstitial space. Hydrogen ions that do break through are buffered by the alkaline tide created by basolateral bicarbonate secretion from stimulated parietal cells. Any sloughed or denuded SECs are rapidly replaced by migration of adjacent cells, a process known as restitution . Mucosal blood flow plays a crucial role in maintaining a healthy mucosa, providing nutrients and oxygen for the cellular functions involved in cytoprotection. "Back-diffused" hydrogen is buffered and rapidly removed by the rich blood supply. When "barrier breakers" such as bile or aspirin lead to increased backdiffusion of hydrogen ions from the lumen into the lamina propria and submucosa, there is a protective increase in mucosal blood flow. If this protective response is blocked, gross ulceration can occur. Important mediators of these

protective mechanisms include prostaglandins, nitric oxide, intrinsic nerves, and peptides (e.g., calcitonin generelated peptide, gastrin-releasing peptide [GRP], and gastrin). Misoprostol is a commercially available prostaglandin E analogue that has been shown to prevent gastric mucosal damage in chronic users of NSAIDs. More commonly used is sucralfate, which acts locally to enhance mucosal defenses. Some protective reflexes involve afferent sensory neurons, and can be blocked by the application of topical anesthetics to the gastric mucosa, or the experimental destruction of the afferent sensory nerves. In addition to these local defenses, there are important protective factors in saliva, duodenal secretions, and pancreatic or biliary secretions.

Table 26-3 Important Components and Mediators of Mucosal Defenses in the Stomach Components Mucous barrier Bicarbonate secretion Epithelial barrier Hydrophobic phospholipids Tight junctions Restitution Microcirculation (reactive hyperemia) Afferent sensory neurons Mediators Prostaglandins Nitric oxide Epidermal growth factor Calcitonin gene-related peptide Hepatocyte growth factor Histamine Gastrin-releasing peptide

Gastric Hormones GASTRIN Gastrin is produced by antral G cells and is the major hormonal stimulant of acid secretion during the gastric phase. Gastrin is also trophic to GI epithelial and enterochromaffin cells. A variety of molecular forms exist: big gastrin (34 amino acids; G 3 4 ), little gastrin (17 amino acids; G 1 7 ), and minigastrin (14 amino acids; G1 4 ). The large majority of gastrin released by the human antrum is G 1 7 . The biologically active pentapeptide sequence at the C-terminal end of gastrin is identical to that of CCK. Luminal peptides and amino acids are the most potent stimulants of gastrin release, and luminal acid is the most potent inhibitor of gastrin secretion. The latter effect is predominantly mediated in a paracrine fashion by somatostatin released from antral D cells. Gastrin-stimulated acid secretion is significantly blocked by H2 antagonists, suggesting that the principal mediator of gastrinstimulated acid production is histamine from mucosal ECL cells (see Fig. 26-13). In fact, chronic hypergastrinemia such as that seen with pernicious anemia or long-term use of potent acid suppressants or gastrinoma is associated with hyperplasia of gastric ECL cells and, rarely, gastric carcinoid. Gastrin also is trophic to gastric parietal cells and to other GI mucosal cells. Important causes of hypergastrinemia include pernicious anemia, acid-suppressive medication, gastrinoma, retained antrum following distal gastrectomy and Billroth II surgery, and vagotomy.

SOMATOSTATIN

Somatostatin is produced by D cells located throughout the gastric mucosa. The predominant form in humans is somatostatin 14, though somatostatin 28 is present as well. The major stimulus for somatostatin release is antral acidification; acetylcholine from vagal nerve fibers inhibits its release. Somatostatin inhibits acid secretion from parietal cells and gastrin release from G cells. It also decreases histamine release from ECL cells. The proximity of the D cells to these target cells suggests that the primary effect of somatostatin is mediated in a paracrine fashion, but an endocrine (i.e., bloodstream) effect also is possible.

GASTRIN-RELEASING PEPTIDE GRP is the mammalian equivalent of bombesin, a hormone discovered more than two decades ago in an extract of skin from a frog. In the antrum, GRP stimulates both gastrin and somatostatin release by binding to receptors on the G and D cells. There are nerve terminals ending near the mucosa in the gastric body and antrum, which are rich in GRP immunoreactivity. When GRP is given peripherally, it stimulates acid secretion, but when it is given centrally into the cerebral ventricles of animals, it inhibits acid secretion, apparently via a pathway involving the sympathetic nervous system. GRP is a mediator of gastroprotective increased mucosal blood flow in response to luminal irritants.

LEPTIN Leptin is a protein primarily synthesized in adipocytes. It is also made by chief cells in the stomach, the main source of leptin in the GI tract.2 6 Leptin works at least in part via vagally mediated pathways to decrease food intake in animals. Not surprisingly, leptin, a satiety signal hormone, and ghrelin, a hunger signal hormone, are both primarily synthesized in the stomach, an organ increasingly recognized as central to the mechanisms of appetite control.26,27

GHRELIN Ghrelin is a small peptide described in 1999 that is produced primarily in the stomach.2 8 Ghrelin is a potent secretagogue of pituitary growth hormone (but not adrenocorticotropic hormone, follicle-stimulating hormone, luteinizing hormone, prolactin, or thyroid-stimulating hormone). Ghrelin appears to be an orexigenic regulator of appetite (i.e., when ghrelin is elevated, appetite is stimulated, and when it is suppressed, appetite is suppressed). Resection of the primary source of this hormone (i.e., the stomach) may partly account for the anorexia and weight loss seen in some patients following gastrectomy (Fig. 26-14). 2 9 The gastric bypass operation, a very effective treatment for morbid obesity, has been shown by some investigators to be associated with suppression of plasma ghrelin levels (and appetite) in humans (Fig. 26-15A).3 0

Fig. 26-14.

Ghrelin levels are decreased after gastrectomy. (Reproduced with permission from Ariyasu H, Takaya K, Tagami T, et al: Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans. J Clin Endocrinol Metab 86:4753, 2001.)

Fig. 26-15.

A and B. Ghrelin secretion after bariatric surgery. Some investigators have suggested that ghrelin secretion is dramatically decreased after gastric bypass. Other groups have shown statistically insignificant changes in ghrelin levels after gastric bypass, but significant decreases after sleeve gastrectomy. A: green = gastric bypass; blue = obese controls; red = normal weight controls; B: blue = fasting; pink = postprandial. (Fig. 26-15A reproduced with permission from Cummings DE, et al: Plasma ghrelin levels after diet-induced weight loss or

gastric bypass surgery. N Engl J Med 346:1623, 2002. Copyright 2002 Massachusetts Medical Society. All rights reserved. Fig. 26-15B reproduced with permission from Karamanakos SN, et al: Weight loss, appetite suppression, and changes in fasting and postprandial ghrelin and peptide-YY levels after Roux-en-Y gastric bypass and sleeve gastrectomy: A prospective, double blind study. Ann Surg 247:401, 2008.)

Other groups have failed to show a significant decrease in ghrelin levels following gastric bypass but have found such decreases following sleeve gastrectomy, another effective weight loss operation (Fig. 26-15B).3 1 Obviously appetite control is complex with redundant and overlapping orexigenic and anorexigenic pathways and signals. 26,27

Gastric Motility and Emptying Gastric motor function has several purposes.32–34 Interprandial motor activity clears the stomach of undigested debris, sloughed cells, and mucus. When feeding begins, the stomach relaxes to accommodate the meal. Regulated motor activity then breaks down the food into small particles and controls the output into the duodenum. The stomach accomplishes these functions by coordinated smooth muscle relaxation and contraction of the various gastric segments (proximal, distal, and pyloric). Smooth muscle myoelectric potentials are translated into muscular activity, which is modulated by extrinsic and intrinsic innervation and hormones. The mechanisms by which gastric distention is translated into a neurohormonal satiety signal have only been partially elucidated.26,27

INTRINSIC GASTRIC INNERVATION The extrinsic parasympathetic and sympathetic gastric innervation was discussed above under Innervation. The intrinsic innervation consists of ganglia and nerves that constitute the enteric nervous system (Fig. 26-16).3 5 There are a variety of neurotransmitters, which are generally grouped as excitatory (augment muscular activity) and inhibitory (decrease muscular activity). Important excitatory neurotransmitters include acetylcholine, the tachykinins, substance P, and neurokinin A. Important inhibitory neurotransmitters include nitric oxide (NO) and vasoactive intestinal peptide (VIP). Serotonin has been shown to modulate both contraction and relaxation. A variety of other molecules affect motility, including GRP, histamine, neuropeptide Y, norepinephrine, and endogenous opioids.

Fig. 26-16.

Enteric nervous system. [Reproduced with permission from Chial HJ, Camilleri M: Motility disorders of the stomach and small intestine, in Friedman SL, McQuaid KR, Grendell JH (eds): Current Diagnosis and Treatment in Gastroenterology , 2nd ed. New York: McGraw-Hill, 2003, p 355.]

Specialized cells in the muscularis propria also are important modulators of GI motility. These cells, called interstitial cells of Cajal , are distinguishable histologically from neurons and myocytes, and appear to amplify both cholinergic excitatory and nitrergic inhibitory input to the smooth muscle of the stomach and intestine.3 6 They are thought either to share a common stem cell of origin with, or to be the cell of origin for, gastrointestinal stromal tumors (GISTs) which are the most common mesenchymal neoplasm in the GI tract.

SEGMENTAL GASTRIC MOTILITY In general, the proximal stomach serves as short-term food storage function and helps regulate basal intragastric tone, and the distal stomach mixes and grinds the food. The pylorus helps the latter process when closed, facilitating retropulsion of the solid food bolus back into the body of the stomach for additional breakdown. The pylorus opens intermittently to allow metered emptying of liquids and small solid particles into the duodenum. Most of the motor activity of the proximal stomach consists of slow tonic contractions and relaxations, lasting up to

5 minutes. This activity is the main determinant of basal intragastric pressure, an important determinant of liquid emptying. Rapid phasic contractions may be superimposed on the slower tonic motor activity. When food is ingested, intragastric pressure falls as the proximal stomach relaxes. This proximal relaxation is mediated by two important vagovagal reflexes: receptive relaxation and gastric accommodation. Receptive relaxation refers to the reduction in proximal gastric tone associated with the act of swallowing. This occurs before the food reaches the stomach, and can be reproduced by mechanical stimulation of the pharynx or esophagus. Gastric accommodation refers to the proximal gastric relaxation associated with distention of the stomach. Accommodation is mediated through stretch receptors in the gastric wall and does not require esophageal or pharyngeal stimulation. Because both of these reflexes are mediated by afferent and efferent vagal fibers, they are significantly altered by truncal and HSV. Both these operations result in decreased gastric compliance, shifting the volume/pressure curve to the left. That is, interference with normal receptive relaxation and/or accommodation results in decreased gastric compliance, such that for any given amount of food or liquid ingested, the intragastric pressure is greater. This may increase the rate of liquid emptying, perhaps contributing to dumping symptoms in some patients after vagotomy. NO and VIP are the principal mediators of proximal gastric relaxation. But a variety of other agents increase proximal gastric relaxation and compliance, including dopamine, gastrin, CCK, secretin, GRP, and glucagon. Proximal gastric tone also is decreased by duodenal distention, colonic distention, and ileal perfusion with glucose (ileal brake). The distal stomach breaks up solid food and is the main determinant of gastric emptying of solids. Slow waves of myoelectric depolarization sweep down the distal stomach at a rate of about three per minute. These waves originate from the proximal gastric pacemaker, high on the greater curvature. The pacing cells may be ICC, which have been shown to have a similar function in the small intestine and colon. Most of these myoelectric waves are below the threshold for smooth muscle contraction in the quiescent state, and thus are associated with negligible changes in pressure. Neural and/or hormonal input, which increases the plateau phase of the action potential, can trigger muscle contraction, resulting in a peristaltic wave associated with the electrical slow wave, and of the same frequency (three per minute) (Fig. 26-17). It is possible that implantable gastric pacemakers benefit some patients with gastroparesis by favorably impacting this myoelectric coupling.

Fig. 26-17.

The relationship between intracellular electrical activity and muscle cell contraction. Note that contractile activity is always associated with electrical activity, but the converse is not so. During mechanical quiescence, there are regular depolarizations that do not reach threshold. In the stimulated state, the threshold for contraction is reached, and motor activity is

demonstrable. [Reproduced with permission from Kim CH: Electrical activity of the stomach: clinical implications. Mayo Clin Proc 61:205, 1986.]

During fasting, distal gastric motor activity is controlled by the migrating motor complex (MMC), the "gastrointestinal housekeeper" (Fig. 26-18). The purported function of the MMC is to sweep along any undigested food, debris, sloughed cells, and mucus after the fed phase of digestion is complete. The MMC lasts approximately 100 minutes (longer at night, shorter during daytime) and is divided into four phases. Phase I (about half the length of the entire cycle) is a period of relative motor inactivity. High-amplitude muscular contractions do not occur in phase I of the MMC. Phase II (about 25% of the entire MMC cycle) consists of some irregular, highamplitude, generally nonpropulsive contractions. Phase III, a period of intense, regular, (about three per minute) propulsive contractions, only lasts about 5 to 10 minutes. Most phase III complexes of the GI MMC begin in the stomach, and the frequency approximates that of the myoelectric gastric slow wave. Phase IV is a transition period.

Fig. 26-18.

Migrating motor complex, the fasting pattern of GI activity. During phase III of the migrating motor complex, effective peristaltic waves progress from the stomach to the distal small intestine.

[Reproduced with permission from Rees WDW, et al: Human interdigestive and postprandial gastrointestinal motor and gastrointestinal hormone patterns. Dig Dis Sci 27(4):321, 1982. Copyright 1982, with kind permission of Springer Science + Business Media.]

Neurohormonal control of the MMC is poorly understood, but it appears that different phases are regulated by different mechanisms. For example, vagotomy abolishes phase II of the gastric MMC but has little influence on phase III. In fact, phase III persists in the autotransplanted stomach, totally devoid of extrinsic neural input. This suggests that phase III is regulated by intrinsic nerves and/or hormones. Indeed, the initiation of phase III of the MMC in the distal stomach corresponds temporally to elevation in serum levels of motilin, a hormone produced in the duodenal mucosa. Resection of the duodenum abolishes distal gastric phase III in dogs. Resection of the duodenum in humans (e.g., with pancreaticoduodenectomy, the Whipple procedure) commonly results in early postoperative delayed gastric emptying sometimes responsive to erythromycin, a motilin agonist.3 7 There are clearly motilin receptors on antral smooth muscle and nerves. Other modulators of gastric MMC activity include NO, endogenous opioids, intrinsic cholinergic and adrenergic nerves, and duodenal pH (MMC phase III does not occur if the duodenal pH is below 7). Feeding abolishes the MMC and leads to the fed motor pattern. The fed motor pattern of gastric activity starts within 10 minutes of food ingestion and persists until all the food has left the stomach. The neurohormonal initiator of this change is unknown, but CCK and the vagus appear to play some role: Sham feeding transiently induces antral motor activity resembling the fed motor pattern, and this is blocked by the CCK receptor antagonist loxiglumide. Gastric motility during the fed pattern resembles phase II of the MMC, with irregular but continuous phasic contractions of the distal stomach. During the fed state, about half of the myoelectric slow waves are associated with strong distal gastric contractions. Some are prograde and some are retrograde, serving to mix and grind the solid components of the meal. The magnitude of gastric contractions and the duration of the pattern is influenced by the consistency and composition of the meal. The pylorus functions as an effective regulator of gastric emptying and an effective barrier to duodenogastric reflux. Bypass, transection, or resection of the pylorus may lead to uncontrolled gastric emptying of food and the dumping syndrome (see below under Postgastrectomy Problems). Pyloric dysfunction or disruption may also result in uncontrolled entry of duodenal contents into the stomach. Perfusion of the duodenum with lipids, glucose, amino acids, hypertonic saline, or hydrochloric acid results in closure of the pylorus and decreased transpyloric flow. Ileal perfusion with fat has the same effect. A variety of neurohumoral pathways are involved with these physiologic responses, and there is evidence that different pathways may be involved for different stimuli. The pylorus is readily apparent grossly as a thick ring of muscle and connective tissue. The density of nerve tissue in the pyloric smooth muscle is severalfold higher than in the antrum, with increased numbers of neurons staining positive for substance P, neuropeptide Y, VIP, and galanin. ICC are more closely associated with pyloric myocytes, and the myoelectric slow wave of the pylorus has the same frequency as that seen in the distal stomach. The motor activity of the pylorus is both tonic and phasic. During phase III of the MMC, the pylorus is open as gastric contents are swept into the duodenum. During the fed phase, the pylorus is closed most of the time. It relaxes intermittently, usually in synchronization with lower-amplitude, minor antral contractions. The higher-amplitude, more major antral contractions are usually met with a closed pylorus, facilitating retropulsion and further grinding of food. Modulation of pyloric motor activity is complex. There is evidence of both inhibitory and excitatory vagal pathways. Some contractile vagal effects are mediated by opioid pathways, because they are blocked by naloxone. Electrical

stimulation of the duodenum causes the pylorus to contract, whereas electrical stimulation of the antrum causes pyloric relaxation. Generally, NO mediates pyloric relaxation; NO donors lead to pyloric relaxation and decreased resistance to flow in a variety of models, whereas NO synthetase inhibitors have the opposite effect. Other molecules that may play a physiologic role in controlling pyloric smooth muscle include serotonin, VIP, prostaglandin E1 , and galanin (pyloric relaxation); and histamine, CCK, and secretin (pyloric contraction).

GASTRIC EMPTYING The control of gastric emptying is complex. In general, gastric emptying is slowed by increasing caloric content or osmolarity, increased fat content, and increased particle size; liquid emptying is faster than solid emptying. Osmolarity, acidity, caloric content, and nutrient composition are important modulators. Stimulation of duodenal osmoreceptors, glucoreceptors, and pH receptors clearly inhibits gastric emptying by a variety of neurohumoral mechanisms. CCK has been consistently shown to inhibit gastric emptying at physiologic doses (Fig. 26-19). Recently, it has been noted that the anorexigenic hormone leptin, secreted mostly by fat but also by gastric mucosa, inhibits gastric emptying, perhaps through the same pathway as CCK (which also has properties of a satiety hormone). The orexigenic hormone ghrelin has the opposite effect.

Fig. 26-19.

Cholecystokinin (CCK) inhibits gastric emptying. [Reproduced with permission from Covasa M, Ritter RC: Adaptation to high-fat diet reduces inhibition of gastric emptying by CCK and intestinal oleate. Am J Physiol Regulatory Integrative Comp Physiol 278:R166, 2000.]

LIQUID EMPTYING The gastric emptying of water or isotonic saline follows first-order kinetics, with a half emptying time around 12

minutes. Thus, if one drinks 200 mL of water, about 100 mL enters the duodenum by 12 minutes, whereas if one drinks 400 mL of water, about 200 mL enters the duodenum by 12 minutes. This emptying pattern of liquids is modified considerably as the caloric density, osmolarity, and nutrient composition of the liquid changes (Fig. 2620). Up to an osmolarity of about 1 M, liquid emptying occurs at a rate of about 200 kcal per hour. Duodenal osmoreceptors and hormones (e.g., secretin and VIP) are important modulators of liquid gastric emptying. Generally, liquid emptying is delayed in the supine position.

Fig. 26-20.

Nutrient composition and caloric density affect liquid gastric emptying. Glucose solution (solid circles), the least calorically dense, emptied the fastest. Other more calorically dense solutions, such as milk protein (solid triangles) and peptide hydrolysates (open circles and solid triangles), emptied slower. [Reproduced with permission from Calbet JA, MacLean DA: Role of caloric content on gastric emptying in humans. J Physiol 498:533, 1997.]

Traditionally, liquid emptying has been attributed to the activity of the proximal stomach, but it is probably more complicated than previously thought. Clearly, receptive relaxation and gastric accommodation play a role in gastric emptying of liquids. Patients with a denervated (e.g., vagotomized), resected, or plicated (e.g., fundoplication) proximal stomach have decreased gastric compliance and may show accelerated gastric emptying of liquids. A swallowed liquid meal induces receptive relaxation, but the same meal delivered via nasogastric tube bypasses this reflex and is associated with a higher intragastric pressure and accelerated emptying.

Some observations suggest an active role for the distal stomach in liquid emptying. For instance even if the proximal intragastric pressure is lower than duodenal pressure, normal gastric emptying of liquids can occur. Also, diabetic patients may have normal proximal gastric motor function and profoundly delayed gastric emptying of liquids. Indeed, antral contractile activity does correlate with liquid gastric emptying, and this distal gastric activity appears to vary with the nutrient composition and caloric content of the liquid meal. Depending on the circumstances, distal gastric motor activity can promote or inhibit gastric emptying of liquids. Distal gastrectomy and pyloric stenting both obviously interfere with distal gastric motor activity, and both accelerate the initial rapid phase of liquid gastric emptying.

SOLID EMPTYING Normally, the half-time of solid gastric emptying is 2 cm in diameter. The mortality rate for surgery for bleeding peptic ulcer is 10 to 20%.

Fig. 26-42.

Algorithm for the treatment of bleeding peptic ulcer. ASA = acetylsalicylic acid; EGD = esophagogastroduodenoscopy; O.R. = operating room; PPI = proton pump inhibitor; PRBC = unit of packed red blood cells; PT = prothrombin time; PTT = partial thromboplastin time; Rx = treatment.

OPERATION FOR BLEEDING PEPTIC ULCER (FIG. 26-43) Fig. 26-43.

Algorithm for operation for bleeding peptic ulcer. BMI = body mass index; Bx = biopsy; PPI = proton pump inhibitor; proc = procedure; TV = truncal vagotomy; TV/A = truncal vagotomy and antrectomy; TV/D = truncal vagotomy and drainage.

The two operations most commonly used for bleeding duodenal ulcer are oversewing of the ulcer usually without vagotomy,7 0 or V+A. Oversewing alone results in a higher rebleeding rate but a lower operative mortality rate. When the mortality for reoperation for rebleeding is considered, the overall mortality is probably comparable for the two approaches. Patients who are in shock or medically unstable should not have gastric resection. An initial pyloromyotomy incision allows access to the bleeding posterior duodenal ulcer, and an expeditious Kocher maneuver allows the surgeon to control the hemorrhage with the left hand if necessary. Heavy suture material on a stout needle is used to place figure-of-eight sutures or a U-stitch to secure the bleeding vessel at the base of the posterior duodenal ulcer. Multiple sutures are usually necessary. Once the surgeon is unequivocally convinced that hemostasis is secure, a pyloroplasty can be performed. If the patient is stable, vagotomy may be added. If the patient is not a high operative risk and V+A is selected, smaller duodenal ulcers are resected with the specimen;

larger bleeding duodenal ulcers must often be left behind in the duodenal stump. In this situation, suture hemostasis must be attained and a secure duodenal closure accomplished. The anterior wall of the open duodenum can be sutured to either the proximal or distal lip of the posterior ulcer once the bleeding vessel has been sutured. The duodenal closure can be buttressed with omentum and the duodenum should be decompressed, either with a lateral duodenostomy or retrograde duodenostomy tube via the proximal jejunum or nasogastric route. Right upper quadrant closed suction peritoneal drainage is important. Use of a feeding jejunostomy is also considered. A Billroth II anastomosis is preferred. The initial management of bleeding gastric ulcers and the indications for operation are similar to those for bleeding duodenal ulcer. These lesions tend to occur in older and/or medically complicated patients, and this fact may increase the operative risk. Although this has been used by some as an excuse not to operate early on these patients, experience shows that planned surgery in a resuscitated patient results in a better operative survival rate than emergent operation in a patient who has rebled and is in shock. Distal gastric resection to include the bleeding ulcer is the procedure of choice for bleeding gastric ulcer. Second best is V+D with oversewing and biopsy of the ulcer to rule out cancer. Oversewing of the bleeder followed by long-term acid suppression is a reasonable alternative in high-risk or unstable patients.

Perforated Peptic Ulcer (Fig. 26-44) Perforation is the second most common complication of peptic ulcer. As with bleeding ulcer, NSAID and/or aspirin use have been inextricably linked with perforated PUD, especially in the elderly population.7 5 Well over 20% of patients over the age of 60 years old presenting with a perforated ulcer are taking NSAIDs at the time of perforation. Surgery is almost always indicated, although occasionally nonsurgical treatment can be used in the stable patient without peritonitis in whom radiologic studies document a sealed perforation. Patients with acute perforation and GI blood loss (either chronic or acute) should be suspected of having a second ulcer.

Fig. 26-44.

Algorithm for operation for perforated peptic ulcer. ASA = acetylsalicylic acid; BMI = body mass index; Bx = biopsy; HSV = highly selective vagotomy; Hx = history; PPI = proton pump inhibitor; Rx = treatment; TV/D = truncal vagotomy and drainage.

The options for surgical treatment of perforated duodenal ulcer are simple patch closure, patch closure and HSV, or patch closure and V+D. Simple patch closure alone should be done in patients with hemodynamic instability and/or exudative peritonitis signifying a perforation >24 hours old. In all other patients, the addition of HSV may be considered because numerous studies have reported a negligible mortality with this approach. 63,67 However, in the United States and Western Europe, there is clearly a trend away from definitive operation for perforated duodenal ulcer, probably because of the ready availability of PPI, and surgeon unfamiliarity with definitive operation in this setting. 7 0 Perforated gastric ulcer results in a higher mortality rate than perforated duodenal ulcer (10 to 40%) due to the following: patients' more advanced age, increased medical comorbidities, delay in seeking medical attention, and

the larger size of gastric ulcers. In the stable patient without multiple operative risk factors, perforated gastric ulcers are best treated by distal gastric resection. Vagotomy is usually added for type II and III gastric ulcers. Patch closure with biopsy; or local excision and closure; or biopsy, closure, truncal vagotomy, and drainage are alternative operations in the unstable or high-risk patient, or in the patient with a perforation in an inopportune location (e.g., juxtapyloric). All perforated gastric ulcers, even those in the prepyloric position, should be biopsied if they are not removed at surgery.

Obstructing Peptic Ulcer Currently, gastric outlet obstruction is the least common indication for operation in PUD. Acute ulcers associated with obstruction due to edema and/or motor dysfunction may respond to intensive antisecretory therapy and nasogastric suction. But most patients with significant obstruction from chronic ulceration will require some sort of more substantial intervention. Endoscopic balloon dilation can often transiently improve obstructive symptoms, but many of these patients ultimately fail and come to operation.7 6 The most common operations for obstructing PUD are V+A and V+D. HSV and gastrojejunostomy is comparable to V+A in this setting7 7 and is an appealing operation for obstruction, both because it can readily be done using laparoscopic techniques, and because it does not complicate future resection, should this be needed. However, potentially curable gastric or duodenal cancers can be missed with this approach.

Intractable or Nonhealing Peptic Ulcer This should indeed be a rare indication for surgery performed today. Arguably, the patient referred for surgical evaluation because of intractable PUD should raise red flags for the surgeon: Maybe the patient has a missed cancer; maybe the patient is noncompliant (not taking prescribed PPI, still taking NSAIDs, still smoking); maybe the patient has Helicobacter despite the presence of a negative test or previous treatment. Because acid secretion can be totally blocked and H. pylori eradicated with modern medication, the question remains: "Why does the patient have a persistent ulcer diathesis?" The surgeon should review the differential diagnosis of nonhealing ulcer before any consideration of operative treatment (Table 26-13).

Table 26-13 Differential Diagnosis of Intractability or Nonhealing Peptic Ulcer Disease Cancer Gastric Pancreatic Duodenal Persistent Helicobacter pylori infection Tests may be false-negative Consider empiric treatment Noncompliant patient Failure to take prescribed medication Surreptitious use of NSAIDs Motility disorder Zollinger-Ellison syndrome

Surgical treatment should be considered in patients with nonhealing or intractable PUD who have multiple recurrences, large ulcers (>2 cm), complications (obstruction, perforation, or hemorrhage), or suspected malignancy. Definitive operation, particularly gastric resection, should be considered most cautiously in the thin or

marginally nourished individual. It is important that the surgeon not fall into the trap of performing a large, irreversible operation on these patients, based on the unproven theory that if all other methods have failed to heal the ulcer, a large operation is required. Although there is a large quantity of very good data in the surgical literature suggesting that the large majority of patients do well after the larger elective ulcer operations, these data may not be particularly relevant to the modern patient.6 7 Candidates for ulcer operation today are different than those of three or four decades ago. One might argue that current medical care has healed the minor ulcers, and that patients presenting with true intractability or nonhealing will be more difficult to treat and are likely to have chronic problems after a major ulcer operation. If surgery is necessary, a lesser operation may be preferable. It is the practice of this author never to perform a gastrectomy as the initial elective operation for intractable duodenal ulcer in the thin or asthenic patient. Instead, the preferred operation for this group of patients is HSV. In patients with nonhealing gastric ulcer, wedge resection with HSV should be considered in thin or frail patients. Otherwise, distal gastrectomy (to include the ulcer) is recommended. It is unnecessary to add a vagotomy in patients with type I or type IV (juxtaesophageal) gastric ulcers because they are usually associated with acid hyposecretion. Type IV gastric ulcers may be difficult to resect as part of a distal gastrectomy, and a variety of surgical techniques have been described to treat these more proximal lesions (Fig. 26-45).

Fig. 26-45.

Operations for gastric ulcer. [Reproduced with permission from Seymour NE: Operations for peptic ulcer and their complications, in Feldman M, Sharschmidt BF, Sleisenger MH (eds): Gastrointestinal and Liver Disease , 6th ed. Philadelphia: Saunders, 1998, p 702. Copyright Elsevier.]

Zollinger-Ellison Syndrome78–81 ZES is caused by the uncontrolled secretion of abnormal amounts of gastrin by a duodenal or pancreatic neuroendocrine tumor (i.e., gastrinoma). Most cases (80%) are sporadic, but 20% are inherited. The inherited or familial form of gastrinoma is associated with multiple endocrine neoplasia type 1 (MEN1), which consists of parathyroid, pituitary, and pancreatic (or duodenal) tumors. Gastrinoma is the most common pancreatic tumor in patients with MEN I. Patients with MEN I usually have multiple gastrinoma tumors, and surgical cure is unusual. Sporadic gastrinomas are more often solitary and amenable to surgical cure. Currently, about 50 to 60% of gastrinomas are malignant, with lymph node, liver, or other distant metastases at operation. Five-year survival in

patients presenting with metastatic disease is approximately 40%. The larger the primary gastrinoma, the higher the likelihood of metastatic disease. More than 90% of patients with sporadically, completely resected gastrinoma will be cured. The most common symptoms of ZES are epigastric pain, GERD, and diarrhea. More than 90% of patients with gastrinoma have peptic ulcer. Most ulcers are in the typical location (proximal duodenum), but atypical ulcer location (distal duodenum, jejunum, or multiple ulcers) should prompt an evaluation for gastrinoma. Gastrinoma also should be considered in the differential diagnosis of recurrent or refractory peptic ulcer, secretory diarrhea, gastric rugal hypertrophy, esophagitis with stricture, bleeding or perforated ulcer, familial ulcer, peptic ulcer with hypercalcemia, and gastric carcinoid. The majority of patients with ZES have been symptomatic for several years before definitive diagnosis and, in general, patients with ZES and MEN1 are diagnosed in their 20s and 30s, while those with sporadic ZES more typically are diagnosed in their 40s and 50s. ZES is an important part of the differential diagnosis of hypergastrinemia (Fig. 26-46). All patients with gastrinoma have an elevated gastrin level, and hypergastrinemia in the presence of elevated BAO strongly suggests gastrinoma. Patients with gastrinoma usually have a BAO >15 mEq/h or >5 mEq/h if they have had a previous procedure for peptic ulcer. Acid secretory medications should be held for several days before gastrin measurement, because acid suppression may falsely elevate gastrin levels. Causes of hypergastrinemia can be divided into those associated with hyperacidity and those associated with hypoacidity (see Fig. 26-46). The diagnosis of ZES is confirmed by the secretin stimulation test. An IV bolus of secretin (2 U/kg) is given and gastrin levels are checked before and after injection. An increase in serum gastrin of 200 pg/mL or greater suggests the presence of gastrinoma. Patients with gastrinoma should have serum calcium and parathyroid hormone levels determined to rule out MEN1 and, if present, parathyroidectomy should be considered before resection of gastrinoma.

Fig. 26-46.

Algorithm for diagnosis and management of hypergastrinemia. BAO = basal acid output; B1 = Billroth 1; B2 = Billroth 2; Bx = biopsy; ECL = enterochromaffin-like; EGD = esophagogastroduodenoscopy; GJ = gastrojejunostomy; H2 RA = histamine 2 receptor antagonist; insuff = insufficiency; MEN1 = multiple endocrine neoplasia type 1; PPI = proton pump inhibitor; R/O = rule out; SB = small bowel; S/P = status post; TV = truncal vagotomy; TV and A = truncal vagotomy and antrectomy.

Eighty percent of primary tumors are found in the gastrinoma triangle (Fig. 26-47), and many tumors are small (2 cm in size and MRI is comparable. EUS is more sensitive than these other noninvasive imaging tests, but it still misses many of the smaller lesions, and may confuse normal lymph nodes for gastrinomas. Currently, the preoperative imaging study of choice for gastrinoma is somatostatin receptor

scintigraphy (the octreotide scan). When the pretest probability of gastrinoma is high, the sensitivity and specificity of this modality approach 100%. Gastrinoma cells contain type 2 somatostatin receptors that bind the indiumlabeled somatostatin analogue (octreotide) with high affinity, making imaging with a gamma camera possible (Fig. 26-48). Currently, angiographic localization studies are infrequently performed for gastrinoma. Both diagnostic angiography and transhepatic selective venous sampling of the portal system have been supplanted by selective secretin infusion, which helps to localize the tumor as inside or outside the gastrinoma triangle.

Fig. 26-47.

Gastrinoma triangle. [Reproduced with permission from Ritchie WP Jr.: Benign diseases of the stomach and duodenum, in Ritchie WP, Steele G, Dean RH (eds): General Surgery . Philadelphia: Lippincott, 1995, p 117.]

Fig. 26-48.

Positive octreotide scan in patient with gastrinoma. (Courtesy of Dr. Alan Maurer.)

In this test, an arterial catheter is selectively placed in a named vessel supplying the pancreas (e.g., gastroduodenal or splenic), and a venous catheter is placed in a hepatic vein. Secretin is injected into the visceral artery and gastrin is sampled in the hepatic vein. A significant elevation in hepatic venous gastrin indicates that the tumor is supplied by the injected artery. This test should be performed if pancreaticoduodenectomy is contemplated. Probably the most important means of locating gastrinomas is intraoperative exploration. All patients with sporadic (nonfamilial) gastrinoma should be considered for surgical resection and possible cure. The lesions should be located in 90% of patients, and the large majority is cured by extirpation of the gastrinoma(s). A thorough intraoperative exploration of the gastrinoma triangle and pancreas is essential, but other sites (i.e., liver, stomach, small bowel, mesentery, and pelvis) should be evaluated as part of a thorough intra-abdominal evaluation to find the primary tumor, which is usually solitary. The duodenum and pancreas should be extensively mobilized and intraoperative ultrasound should be used. Intraoperative EGD with transillumination should be considered. If the tumor cannot be located, generous longitudinal duodenotomy with inspection and palpation of the duodenal wall should be considered. Lymph nodes from the portal, peripancreatic, and celiac

drainage basins should be sampled. Ablation or resection of hepatic metastases should be considered. The management of gastrinoma in patients with MEN1 is controversial because the patients are rarely cured by operation, and the tumors tend to be small and multiple. If the tumor can be imaged preoperatively, operation by an experienced gastrinoma surgeon is reasonable. Acid hypersecretion in patients with gastrinoma can always be managed with high-dose PPIs. Highly selective vagotomy may make management easier in some patients and should be considered in those with surgically untreatable or unresectable gastrinoma. Gastrectomy for ZES is no longer indicated.

GASTRITIS AND STRESS ULCER Pathogenesis and Prevention Gastritis is mucosal inflammation. The gross endoscopic diagnosis of gastritis correlates poorly with histologic findings, and is thus relatively useless as a diagnosis without confirmatory biopsy. Additionally, there is poor correlation between symptoms and histologic gastritis. The most common cause of gastritis is H. pylori . Other causes of gastritis include alcohol, NSAIDs, Crohn's disease, tuberculosis, and bile reflux (primary or secondary). These agents cause injury by a variety of different mechanisms. In general, the infectious and inflammatory causes result in immune cell infiltration and cytokine production which damage mucosal cells. The chemical agents (alcohol, aspirin, and bile) generally work to disrupt the mucosal barrier, allowing mucosal damage by back diffusion of luminal hydrogen ions. Stress gastritis is a peculiar entity that has all but disappeared from the clinical (if not endoscopic) lexicon, largely due to better critical care and acid suppression or cytoprotective agents (e.g., sucralfate) in the intensive care unit (ICU). Stress gastritis and stress ulcer are probably due to inadequate gastric mucosal blood flow during periods of intense physiologic stress. Adequate mucosal blood flow is important to maintain the mucosal barrier, and to buffer any back-diffused hydrogen ions. When blood flow is inadequate, these processes fail and mucosal breakdown occurs. Modern intensive care, with emphasis on adequate tissue perfusion and oxygenation, has undoubtedly decreased the severity of gastric mucosal injury seen in the ICU today. Although it is still common to see small mucosal erosions when performing upper endoscopy in the ICU, it is rare for these lesions to coalesce into the larger bleeding erosions that plagued the ICU patient 30 to 40 years ago. The rationale for routine acid suppression in the ICU, supported by excellent data from clinical trials8 2 and the laboratory, 8 3 is that less mucosal injury will be caused in the potentially weakened gastric mucosa if there is less luminal acid. There are some studies suggesting that routine acid suppression leads to overgrowth of gastric bacteria, which increases the incidence and/or severity of aspiration pneumonia in the ICU. Nevertheless, acid suppression, particularly in the severely ill patient, remains an important part of clinical pathways in most ICUs.8 4 In the extraordinarily rare patient requiring operation today for hemorrhagic stress gastritis, the surgical options include V+D with oversewing of the major bleeding lesions, or near total gastrectomy. Angiographic embolization and endoscopic hemostatic treatment should be considered as well.

MALIGNANT NEOPLASMS OF THE STOMACH The three most common primary malignant gastric neoplasms are adenocarcinoma (95%), lymphoma (4%), and malignant GIST (1%) (Table 26-14). Other rare primary malignancies include carcinoid, angiosarcoma, carcinosarcoma, and squamous cell carcinoma. Occasionally the stomach is the site of hematogenous metastasis from other sites (e.g., melanoma or breast). More commonly, malignant tumors from adjacent organs invade the

stomach by direct extension (e.g., colon or pancreas) or by peritoneal seeding (e.g., ovary).

Table 26-14 Frequency of Gastric Tumors Malignant tumors 4199 93.0 Carcinoma 3970 87.9 Lymphoma 136 3.0 Leiomyosarcoma 77 1.7 Carcinoid 11 0.3 Others 5 0.1 Benign tumors 315 7.0 Polyp 140 3.1 Leiomyoma 92 2.0 Inflammatory lesions 30 0.7 Heterotopic pancreas 20 0.4 Others 33 0.8 Tumor Type

No. of Cases

Percent

Source: Modified with permission from Ming S-C (ed): Tumors of the Esophagus and Stomach, AFIP Atlas of Tumor Pathology, Second Series, Fascicle 7. Washington DC: American Registry of Pathology, 1973, p 82, Table VI.

Adenocarcinoma EPIDEMIOLOGY

In 1930 in the United States, gastric cancer was the leading cause of cancer death among men and the third leading cause of cancer death among women. Today, it is not even included among the top 10 causes. Over the past several decades, there has been a dramatic decrease in the gastric cancer incidence and death rate in the United States as well as in most Western industrialized countries (Fig. 26-49). This decrease has been mostly in the so-called intestinal form rather than in the diffuse form of gastric cancer. Worldwide, especially in Asia and Eastern Europe, gastric cancer remains a leading cause of cancer death. In 2007 in the United States, there were approximately 21,500 new cases of stomach cancer (13,190 in men and 8310 in women), and 10,848 deaths from this disease (6418 men and 4430 women.8 5 The estimated 5-year survival rate is 22%, up from about 15% in 1975.

Fig. 26-49.

Death rates for gastric cancer in different countries. [Reproduced with permission from Ming S-C, Hirota T: Malignant epithelial tumors of the stomach, in Ming S-C, Goldman H (eds): Pathology of the Gastrointestinal Tract , 2nd ed. Baltimore: Williams & Wilkins, 1998, p 607.]

In general, gastric cancer is a disease of the elderly, and it is twice as common in blacks as in whites. In younger patients, tumors are more often of the diffuse variety and tend to be large, aggressive, and more poorly differentiated, sometimes infiltrating the entire stomach (linitis plastic). Gastric cancer has a higher incidence in groups of lower socioeconomic status.

ETIOLOGY Gastric cancer is more common in patients with pernicious anemia, blood group A, or a family history of gastric cancer. When patients migrate from a high-incidence region to a low-incidence region, the risk of gastric cancer decreases in the subsequent generations born in the new region. This strongly suggests an environmental influence on the development of gastric cancer. Environmental factors appear to be more related etiologically to the intestinal form of gastric cancer than the more aggressive diffuse form. The commonly accepted risk factors for gastric cancer are listed in Table 26-15.

Table 26-15 Factors Increasing or Decreasing the Risk of Gastric Cancer Increase risk Family history Diet (high in nitrates, salt, fat) Familial polyposis Gastric adenomas Hereditary nonpolyposis colorectal cancer Helicobacter pylori infection Atrophic gastritis, intestinal metaplasia, dysplasia Previous gastrectomy or gastrojejunostomy (>10 y ago) Tobacco use Mntrier's disease Decrease risk Aspirin Diet (high fresh fruit and vegetable intake) Vitamin C

Diet and Drugs Typically, a starchy diet high in pickled, salted, or smoked food is found in many regions of high gastric cancer risk. Dietary nitrates have been impugned as a possible cause of gastric cancer. Gastric bacteria (more common in the achlorhydric stomach of patients with atrophic gastritis, a risk factor for gastric cancer) convert nitrate into nitrite, a proven carcinogen. A diet high in fresh fruits and vegetables and rich in vitamin C and E has been shown to decrease the population's risk of gastric cancer. The reduced consumption of nitrate-rich preserved foods seen with the growth of refrigeration has been suggested as a cause of the dramatic decrease in gastric cancer seen in North America and Western Europe. Tobacco use probably increases the risk of stomach cancer, and alcohol use probably has no effect. Regular aspirin use may be protective.

Helicobacter pylori 54,86 The risk of gastric cancer in patients with chronic H. pylori infection is increased about threefold. When compared to uninfected patients, patients with a history of gastric ulcer are more likely to develop gastric cancer (incidence ratio 1.8, 95% confidence interval 1.6 to 2.0), and patients with a history of duodenal ulcer are at decreased risk

for gastric cancer (incidence ratio 0.6, 95% confidence interval 0.4 to 0.7). As diagrammed in Fig. 26-50, this may be due to the fact that some patients develop antral-predominant disease (predisposing to duodenal ulcer and somehow protecting against gastric cancer), while other patients develop corpus-predominant gastritis, resulting in hypochlorhydria and somehow predisposing to gastric ulcer and gastric cancer. 8 7 The theoretical sequence for development of gastric adenocarcinoma is diagrammed in Fig. 26-51.54,87 Recently, it has been demonstrated that bone marrow–derived stem cells play a key role in the pathogenesis of gastric adenocarcinoma in patients with chronic H. pylori infection.5 4 However, it must be recognized that gastric adenocarcinoma is a multifactorial disease. Not all patients with gastric cancer have H. pylori , and there are some geographic areas with a high prevalence of chronic H. pylori infection and a low prevalence of gastric cancer (the "African enigma"). Finally, H. pylori –infected patients seem to be at decreased risk for the development of adenocarcinoma of the distal esophagus and cardia region.8 8 Perhaps the corporeal gastritis decreases acid secretion, creating a less damaging refluxate and thus reducing the risk for Barrett's esophagus, the precursor lesion for these tumors.

Fig. 26-50.

Helicobacter and gastritis, and the pathogenesis of duodenal ulcer (DU) or gastric cancer. [Reproduced with permission from Leung WK, Ng EKW, Sung JJY: Tumors of the stomach, in Yamada T et al (eds): Textbook of Gastroenterology , 4th ed. Philadelphia: Lippincott, Williams & Wilkins, 2003, p 1416.]

Fig. 26-51.

Gastric carcinogenesis. [Reproduced with permission from Leung WK, Ng EKW, Sung JJY: Tumors of the stomach, in Yamada T, et al (eds): Textbook of Gastroenterology , 4th ed. Philadelphia: Lippincott, Williams & Wilkins, 2003, p 1416.]

Epstein-Barr Virus About 10% of gastric adenocarcinomas carry the EBV virus. This amounts to about 50 to 75,000 cases worldwide. Recently it has been suggested that EBV infection is a rather late step in gastric carcinogenesis, since EBV transcripts are present in cancer cells but not in the metaplastic cells of precursor epithelium. 8 9

Genetic Factors A variety of genetic abnormalities have been described in gastric cancer (Table 26-16). Most gastric cancers are aneuploid. The most common genetic abnormalities in sporadic gastric cancer affect the p53 and COX-2 genes. Over two thirds of gastric cancers have deletion or suppression of the important tumor- suppressor gene p53 . Additionally, approximately the same proportion have overexpression of COX-2 . In the colon, tumors with upregulation of this gene have suppressed apoptosis, more angiogenesis, and higher metastatic potential. Gastric

tumors that overexpress COX-2 are more aggressive tumors. Recently, a germline mutation in the CDH1 gene encoding for E-cadherin was shown to be associated with hereditary diffuse gastric cancer. Prophylactic total gastrectomy should be considered in patients with these mutations.9 0

Table 26-16 Genetic Abnormalities in Gastric Cancer Deletion/suppression p53 60–70 FHIT 60 APC 50 DCC 50 E-cadherin 10 years

following the initial operation, and they usually arise in an area of chronic gastritis, metaplasia, and dysplasia. This is often near the stoma, but many of these tumors are quite large at presentation, and are equally divided between intestinal and diffuse subtypes. Most cases have been reported following Billroth II gastroenterostomy, but there also have been cases following Billroth I gastroduodenostomy. Whether simple loop gastrojejunostomy increases a patient's risk of gastric cancer, and whether a Roux-en-Y anastomosis following gastric resection lowers their risk of gastric cancer is unknown. Stage for stage, the prognosis for gastric stump cancer is similar to proximal gastric cancer.9 3

Other Premalignant States A mutated E-cadherin gene is associated with hereditary diffuse gastric cancer. Prophylactic total gastrectomy should be considered.9 0 Obviously, a myriad of genetic and environmental factors will affect members of the same family, and up to 10% of gastric cancer cases appear to be familial without a clear-cut genetic diagnosis. Firstdegree relatives of patients with gastric cancer have a two- to threefold increased risk of developing the disease. Patients with hereditary nonpolyposis colorectal cancer have a 10% risk of developing gastric cancer, predominantly the intestinal subtype. The mucous cell hyperplasia of Mntrier's disease is generally considered to carry a 5 to 10% risk of adenocarcinoma. Periodic surveillance EGD is prudent in all the above conditions. The glandular hyperplasia associated with gastrinoma is not premalignant, but ECL hyperplasia and/or carcinoid tumors can occur.

PATHOLOGY Dysplasia It is generally accepted that gastric dysplasia is the universal precursor to gastric adenocarcinoma. Patients with severe dysplasia should be considered for gastric resection if the abnormality is widespread or multifocal, or EMR if the severe dysplasia is localized. Patients with mild dysplasia should be followed with endoscopic biopsy surveillance, and Helicobacter eradication.

Early Gastric Cancer Early gastric cancer is defined as adenocarcinoma limited to the mucosa and submucosa of the stomach, regardless of lymph node status. The entity is common in the Orient, where gastric cancer is a common cause of cancer death, and where aggressive surveillance programs have therefore been established. Approximately 10% of patients with early gastric cancer will have lymph node metastases. There are several types and subtypes of early gastric cancer (Table 26-17 and Fig. 26-55). Approximately 70% of early gastric cancers are well differentiated, and 30% are poorly differentiated. The overall cure rate with adequate gastric resection and lymphadenectomy is 95%. In some Japanese centers, 50% of the gastric cancers treated are early gastric cancer. In the United States, less than 20% of resected gastric adenocarcinomas are early gastric cancer. Small intramucosal lesions can be treated with EMR.9 4

Table 26-17 Early Gastric Cancer Type I Exophytic lesion extending into the gastric lumen Type II Superficial variant IIA Elevated lesions with a height no more than the thickness of the adjacent mucosa IIB

Flat lesions IIC Depressed lesions with an eroded but not deeply ulcerated appearance Type III Excavated lesions that may extend into the muscularis propria without invasion of this layer by actual cancer cells

Fig. 26-55.

Pathologic types of early gastric cancer. [Reproduced with permission from Fenoglio-Preiser CM et al: Pathologic and phenotypic features of gastric cancer. Semin Oncol 23(3):292, 1996. Copyright Elsevier.]

Gross Morphology and Histologic Subtypes There are four gross forms of gastric cancer: polypoid, fungating, ulcerative, and scirrhous. In the first two, the

bulk of the tumor mass is intraluminal. Polypoid tumors are not ulcerated; fungating tumors are elevated intraluminally, but also ulcerated. In the latter two gross subtypes, the bulk of the tumor mass is in the wall of the stomach. Ulcerative tumors are self-descriptive; scirrhous tumors infiltrate the entire thickness of the stomach and cover a very large surface area. Scirrhous tumors (linitis plastica) have a particularly poor prognosis, and commonly involve the entire stomach. Although these latter lesions may be technically resectable with total gastrectomy, it is common for both the esophageal and duodenal margins of resection to show microscopic evidence of tumor infiltration. Death from recurrent disease within 6 months is common. The location of the primary tumor in the stomach is important in planning the operation. Several decades ago, the large majority of gastric cancers were in the distal stomach. Recently, there has been a proximal migration of tumors, so that currently, the distribution is closer to 40% distal, 30% middle, and 30% proximal.

Histology The most important prognostic indicators in gastric cancer are both histologic: lymph node involvement and depth of tumor invasion. Tumor grade (degree of differentiation: well, moderately, or poorly) is also important prognostically. There are several histologic classifications of gastric cancer. The World Health Organization recognizes several histologic types (Table 26-18). The Japanese classification is similar but more detailed. The commonly used Lauren classification separates gastric cancers into intestinal type (53%), diffuse type (33%), and unclassified (14%). The intestinal type is associated with chronic atrophic gastritis, severe intestinal metaplasia, and dysplasia, and tends to be less aggressive than the diffuse type. The diffuse type of gastric cancer is more likely to be poorly differentiated and is associated with younger patients and proximal tumors. The Ming classification also is useful and easy to remember, with only two types—expanding (67%) and infiltrative (33%).

Table 26-18 World Health Organization Histologic Typing of Gastric Cancer Adenocarcinoma Papillary adenocarcinoma Tubular adenocarcinoma Mucinous adenocarcinoma Signet-ring cell carcinoma Adenosquamous carcinoma Squamous cell carcinoma Small cell carcinoma Undifferentiated carcinoma Others

Source: Reproduced with permission from Ming S-C, Hirota T: Malignant epithelial tumors of the stomach, in Ming S-C, Goldman H (eds): Pathology of the Gastrointestinal Tract, 2nd ed. Baltimore: Williams & Wilkins, 1998.

Pathologic Staging Ultimately, prognosis is related to pathologic stage. The most widespread system for staging of gastric cancer is the tumor-node-metastasis (TNM) staging system based on depth of tumor invasion, extent of lymph node metastases, and presence of distant metastases. This system was developed by the American Joint Committee on Cancer and the International Union Against Cancer, and has undergone several modifications since it was originally conceived (Table 26-19).

Table 26-19 TNM Staging of Gastric Cancer by the International Union Against Cancer and American Joint Committee on Cancer T: Primary tumor Tis Carcinoma in situ; intraepithelial tumor without invasion of lamina propria T1 Tumor invades lamina propria or submucosa T2 Tumor invades muscularis propria or subserosa T3 Tumor penetrates serosa (visceral peritoneum) without invasion of adjacent structures T4 Tumor invades adjacent structures N: Regional lymph node N0 No regional lymph node metastasis N1 Metastasis in 1 to 6 regional lymph nodes N2 Metastasis in 7 to 15 lymph nodes N3 Metastasis in more than 15 regional lymph nodes M: Distant metastasis M0 No distant metastasis M1 Distant metastasis Stage grouping Stage T N M 0 Tis N0 M0 IA T1 N0 M0 IB T1 N1 M0 T2 N0 M0

II T1 N2 M0 T2 N1 M0 T3 N0 M0 IIIA T2 N2 M0 T3 N1 M0 T4 N0 M0 IIIB T3 N2 M0 IV T4 N1–3 M0 T1–3 N3 M0 Any T Any N M1

Source: Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Sixth Edition (2002) published by Springer Science and Business Media LLC, www.springerlink.com.

CLINICAL MANIFESTATIONS

Most patients who are diagnosed with gastric cancer in the United States have advanced stage III or IV disease at the time of diagnosis. The most common symptoms are weight loss and decreased food intake due to anorexia and early satiety. Abdominal pain (usually not severe and often ignored) also is common. Other symptoms include nausea, vomiting, and bloating. Acute GI bleeding is somewhat unusual (5%), but chronic occult blood loss is common and manifests as iron deficiency anemia and heme-positive stool. Dysphagia is common if the tumor involves the cardia of the stomach. Paraneoplastic syndromes such as Trousseau's syndrome (thrombophlebitis), acanthosis nigricans (hyperpigmentation of the axilla and groin), or peripheral neuropathy are rarely present. Physical examination usually is normal. Other than signs of weight loss, specific physical findings usually indicate incurability. A focused examination in a patient in whom gastric cancer is a likely part of the differential diagnosis should include an examination of the neck, chest, abdomen, rectum, and pelvis. Cervical, supraclavicular (on the left referred to as Virchow's node), and axillary lymph nodes may be enlarged, and today can be sampled in the office with fine-needle aspiration cytology. There may be a metastatic pleural effusion, or aspiration pneumonitis in a patient with vomiting and/or obstruction. An abdominal mass could indicate a large (usually T4 incurable) primary tumor, liver metastases, or carcinomatosis (including Krukenberg's tumor of the ovary). A palpable umbilical nodule (Sister Joseph's nodule) is pathognomonic of advanced disease, or there may be evidence on exam of malignant ascites. Rectal exam may reveal heme-positive stool and hard nodularity extraluminally and anteriorly, indicating so-called drop metastases , or rectal shelf of Blumer in the pouch of Douglas.

DIAGNOSTIC EVALUATION Distinguishing between peptic ulcer and gastric cancer on clinical grounds alone is usually impossible. Patients over the age of 45 years old who have new-onset dyspepsia, as well as all patients with dyspepsia and alarm symptoms (weight loss, recurrent vomiting, dysphagia, evidence of bleeding, or anemia) or with a family history of gastric cancer should have prompt upper endoscopy and biopsy if a mucosal lesion is noted. Essentially, all patients in whom gastric cancer is part of the differential diagnosis should have endoscopy and biopsy. If suspicion for cancer is high and the biopsy is negative, the patient should be re-endoscoped and more aggressively biopsied. In some patients with gastric tumors, upper GI series can be helpful in planning treatment. Although a good double-contrast barium upper GI examination is sensitive for gastric tumors (up to 75% sensitive), in most centers, endoscopy has become the gold standard for the diagnosis of gastric malignancy. Preoperative staging of gastric cancer is best accomplished with abdominal/pelvic CT scanning with IV and oral contrast. MRI is probably comparable. The best way to stage the tumor locally is via EUS, which gives fairly accurate (80%) information about the depth of tumor penetration into the gastric wall, and can usually show enlarged (>5 mm) perigastric and celiac lymph nodes. In some centers, if the tumor is transmural (T3) or involves lymph nodes (enlarged nodes can usually be needled under ultrasound guidance), preoperative (neoadjuvant) chemotherapy is given. However, there are limitations to tumor staging with EUS. It largely is operator dependent and may underestimate lymph node involvement because normal-sized nodes (Chapter 28. Small Intestine>

KEY POINTS 1. The small intestine performs a diverse set of functions. 2. Small bowel obstruction is one of the most common surgical diagnoses. 3. Most cases of small bowel obstruction are due to adhesions from previous surgery. 4. If, following surgical resection, less than 200 cm of small bowel remains, patients are at risk of developing short bowel syndrome. 5. Tumors and malignancies of the small bowel are rare and difficult to diagnose.

AN UNDERRATED ORGAN The small intestine is the raison d'tre of the GI tract as it is the principle site of nutrient digestion and absorption.1 The small intestine is also the body's largest reservoir of immunologically active and hormone-producing cells, and hence can be conceptualized as the largest organ of the immune and endocrine systems, respectively. It achieves this diversity of action through unique anatomical features that provide it with a massive surface area, a diversity of cell types, and a complex neural network to coordinate these functions. Despite its size and importance, diseases of the small intestine are relatively infrequent, and present diagnostic and therapeutic challenges. Treatments for common conditions such as postoperative ileus are hardly more effective than those used at the dawn of the last century. Mortality rates associated with acute mesenteric ischemia have not improved during the past 50 years. Despite the introduction of novel imaging techniques such as capsule endoscopy and double balloon endoscopy, diagnostic tests lack sufficient predictive power to definitively guide clinical decision making for individual patients. Furthermore, few high-quality, controlled data on the efficacy of surgical therapies for small bowel diseases are available. Therefore, sound clinical judgment and a thorough understanding of anatomy, physiology, and pathophysiology remain essential to the care of patients with intestinal disorders.

GROSS ANATOMY The small intestine is a tubular structure that extends from the pylorus to the cecum. The estimated length of this structure varies depending on whether radiologic, surgical, or autopsy measurements are made. In the living, it is thought to measure 4 to 6 m.2 The small intestine consists of three segments lying in series: the duodenum,

jejunum, and ileum. The duodenum, the most proximal segment, lies in the retroperitoneum immediately adjacent to the head and inferior border of the body of the pancreas. The duodenum is demarcated from the stomach by the pylorus and from the jejunum by the ligament of Treitz. The jejunum and ileum lie within the peritoneal cavity and are tethered to the retroperitoneum by a broad-based mesentery. No distinct anatomic landmark demarcates the jejunum from the ileum; the proximal 40% of the jejunoileal segment is arbitrarily defined as the jejunum and the distal 60% as the ileum. The ileum is demarcated from the cecum by the ileocecal valve. The small intestine contains mucosal folds known as plicae circulares or valvulae conniventes that are visible upon gross inspection. These folds are also visible radiographically and help in the distinction between small intestine and colon, which does not contain them, on abdominal radiographs. These folds are more prominent in the proximal intestine than in the distal small intestine. Other features evident on gross inspection that are more characteristic of the proximal than distal small intestine include a larger circumference, thicker wall, less fatty mesentery, and longer vasa recta (Fig. 28-1). Gross examination of the small intestinal mucosa also reveals aggregates of lymphoid follicles. Those follicles, located in the ileum, are the most prominent and are designated Peyer's patches .

Fig. 28-1.

Gross features of jejunum contrasted with those of ileum. Relative to the ileum, the jejunum has a larger diameter, thicker wall, more prominent plicae circulares, a less fatty mesentery, and longer vasa recta.

Most of the duodenum derives its arterial blood from branches of both the celiac and the superior mesenteric arteries. The distal duodenum, the jejunum, and the ileum derive their arterial blood from the superior mesenteric artery. Their venous drainage occurs via the superior mesenteric vein. Lymph drainage occurs through lymphatic vessels coursing parallel to corresponding arteries. This lymph drains through mesenteric lymph nodes to the cisterna chyli, then through the thoracic duct, and ultimately into the left subclavian vein. The parasympathetic and sympathetic innervation of the small intestine is derived from the vagus and splanchnic nerves, respectively.

HISTOLOGY

The wall of the small intestine consists of four distinct layers: mucosa, submucosa, muscularis externa, and serosa (Fig. 28-2).

Fig. 28-2.

Layers of wall of the small intestine. The individual layers and their prominent features are represented schematically.

The mucosa is the innermost layer and it consists of three layers: epithelium, lamina propria, and muscularis mucosae. The epithelium is exposed to the intestinal lumen and is the surface through which absorption from and secretion into the lumen occurs. The lamina propria is located immediately external to the epithelium and consists of connective tissue and a heterogeneous population of cells. It is demarcated from the more external submucosa by the muscularis mucosae, a thin sheet of smooth muscle cells. The mucosa is organized into villi and crypts (crypts of Lieberkhn). Villi are finger-like projections of epithelium and underlying lamina propria that contain blood and lymphatic (lacteals) vessels that extend into the intestinal lumen. Intestinal, epithelial cellular proliferation is confined to the crypts , each of which carries an average census of 250 to 300 cells. All epithelial cells in each crypt are derived from an unknown number of the yet uncharacterized multipotent stem cells located at or near the crypt's base. Their immediate descendants are amplified by undergoing several cycles of rapid division. These descendants then make a commitment to differentiate along one of four pathways that ultimately yield enterocytes and goblet , enteroendocrine , and Paneth cells. With the exception of Paneth cells, these lineages complete their terminal differentiation during an upward migration from each crypt to adjacent villi. The journey from the crypt to the villus tip is completed in 2 to 5 days and terminates with cells being removed by apoptosis and/or exfoliation. Thus, the small intestinal epithelium undergoes

continuous renewal, making it one of the body's most dynamic tissues. The high cellular turnover rate contributes to mucosal resiliency but also makes the intestine uniquely susceptible to certain forms of injury such as that induced by radiation and chemotherapy. Enterocytes are the predominant absorptive cell of the intestinal epithelium. Their apical (lumen-facing) cell membrane contains specialized digestive enzymes, transporter mechanisms, and microvilli that are estimated to increase the absorptive surface area of the small intestine by up to 40-fold. Goblet cells produce mucin believed to play a role in mucosal defense against pathogens. Enteroendocrine cells are characterized by secretory granules containing regulatory agents and are discussed in greater detail below in the Endocrine Function section. Paneth cells are located at the base of the crypt and contain secretory granules containing growth factors, digestive enzymes, and antimicrobial peptides. In addition, the intestinal epithelium contains microfold (M) cells and intraepithelial lymphocytes. These two components of the immune system are discussed below. The submucosa consists of dense connective tissue and a heterogeneous population of cells, including leukocytes and fibroblasts. The submucosa also contains an extensive network of vascular and lymphatic vessels, nerve fibers, and ganglion cells of the submucosal (Meissner's) plexus. The muscularis propria consists of an outer, longitudinally oriented layer and an inner, circularly oriented layer of smooth muscle fibers. Located at the interface between these two layers are ganglion cells of the myenteric (Auerbach's) plexus. The serosa consists of a single layer of mesothelial cells and is a component of the visceral peritoneum.

DEVELOPMENT The first recognizable precursor of the small intestine is the embryonic gut tube, formed from the endoderm during the fourth week of gestation. The gut tube is divided into foregut, midgut, and hindgut. Other than duodenum, which is a foregut structure, the rest of the small intestine is derived from the midgut. The gut tube initially communicates with the yolk sac; however, the communication between these two structures narrows by the sixth week to form the vitelline duct. The yolk sac and vitelline duct usually undergo obliteration by the end of gestation. Incomplete obliteration of the vitelline duct results in the spectrum of defects associated with Meckel's diverticula. Also, during the fourth week of gestation, the mesoderm of the embryo splits. The portion of mesoderm that adheres to the endoderm forms the visceral peritoneum, while the portion that adheres to the ectoderm forms the parietal peritoneum. This mesodermal division results in the formation of a coelomic cavity that is the precursor of the peritoneal cavity. At approximately the fifth week of gestation, the bowel begins to lengthen to an extent greater than that which can be accommodated by the developing abdominal cavity, resulting in the extracoelomic herniation of the developing bowel. The bowel continues to lengthen during the subsequent weeks and is retracted back into the abdominal cavity during the tenth week of gestation. Subsequently, the duodenum becomes a retroperitoneal structure. Coincident with extrusion and retraction, the bowel undergoes a 270 counterclockwise rotation relative to the posterior abdominal wall. This rotation accounts for the usual locations of the cecum in the right lower quadrant and the duodenojejunal junction to the left of midline (Fig. 28-3).

Fig. 28-3.

Developmental rotation of the intestine. A. During the fifth week of gestation, the developing intestine herniates out of the coelomic cavity and begins to undergo a counterclockwise rotation about the axis of the superior mesenteric artery. B and C. Intestinal rotation continues, as the developing transverse colon passes anterior to the developing duodenum. D. Final positions of the small intestine and colon resulting from a 270 counterclockwise rotation of the developing intestine and its return into the abdominal cavity.

The celiac and superior mesenteric arteries and veins are derived from the vitelline vascular system, which, in turn, is derived from blood vessels formed within the splanchnopleuric mesoderm during the third week of gestation. Neurons found in the small intestine are derived from neural crest cells that begin to migrate away from the neural tube during the third week of gestation. These neural crest cells enter the mesenchyme of the primitive foregut and subsequently migrate to the remainder of the bowel. During the sixth week of gestation, the lumen of the developing bowel becomes obliterated as bowel epithelial proliferation accelerates. Vacuoles form within the bowel substance during the subsequent weeks and coalesce to form the intestinal lumen by the ninth week of gestation. Errors in this recanalization may account for defects such as intestinal webs and stenoses. Most intestinal atresias, however, are believed to be related to ischemic episodes occurring after organogenesis has been completed rather than to errors in recanalization. During the ninth week of gestation, the intestinal epithelium develops intestine-specific features such as cryptvillus architecture. Organogenesis is complete by approximately the twelfth week of gestation. Elucidation of the fundamental mechanisms regulating patterned intestinal development is an area of active

investigation.

PHYSIOLOGY Digestion and Absorption The intestinal epithelium is the interface through which absorption and secretion occur. It has features characteristic of absorptive epithelia in general, including epithelial cells with cellular membranes possessing distinct apical (luminal) and basolateral (serosal) domains demarcated by intercellular tight junctions, and an asymmetric distribution of transmembrane transporter mechanisms that promotes vectorial transport of solutes across the epithelium. Solutes can traverse the epithelium by active or passive transport. Passive transport of solutes occurs through diffusion or convection and is driven by existing electrochemical gradients. Active transport is the energydependent net transfer of solutes in the absence of or against an electrochemical gradient. Active transport occurs through transcellular pathways (through the cell), whereas passive transport can occur through either transcellular or paracellular pathways (between cells through the tight junctions). Transcellular transport requires solutes to traverse the cell membranes through specialized membrane proteins, such as channels, carriers, and pumps. The molecular characterization of transporter proteins is evolving rapidly, with different transporter families, each containing many individual genes encoding specific transporters, now identified. Similarly, understanding of the paracellular pathway is evolving. In contrast to what was once believed, it is becoming apparent that paracellular permeability is substrate specific, dynamic, and subject to regulation by specific tight junction proteins.3

WATER AND ELECTROLYTE ABSORPTION AND SECRETION Eight to 9 L of fluid enter the small intestine daily. Most of this volume consists of salivary, gastric, biliary, pancreatic, and intestinal secretions. Under normal conditions, the small intestine absorbs over 80% of this fluid, leaving approximately 1.5 L that enters the colon (Fig. 28-4). Small intestinal absorption and secretion are tightly regulated; derangements in water and electrolyte homeostasis characteristic of many of the disorders discussed in this chapter play an important role in contributing to their associated clinical features.

Fig. 28-4.

Small intestinal fluid fluxes. Typical quantities (in volume per day) of fluid entering and leaving the small intestinal lumen in a healthy adult are shown.

Water absorption is believed to be driven by osmotic gradients created primarily by active transepithelial Na+ absorption. Intestinal water secretion, in contrast, is believed to be driven by osmotic gradients created primarily by transepithelial Cl– secretion. Most intestinal water transport is believed to occur through the transcellular pathway. 4 The specific transport mechanisms mediating water absorption are incompletely characterized. Aquaporins (water channels) are expressed in the intestinal epithelium; however, their contribution to overall intestinal water absorption appears to be relatively minor.5 The prevailing model for intestinal epithelial Na+ absorption is shown in Fig. 28-5. Activity of the Na + /K+ ATPase enzyme, which is located in the basolateral membrane and exchanges three intracellular Na+ for every two extracellular K+ in an energy-dependent process, generates the electrochemical gradient that drives the transport of Na+ from the intestinal lumen into the cytoplasm of enterocytes. Na+ ions traverse the apical membrane through several distinct transporter mechanisms including nutrient-coupled sodium transport (e.g., sodium-glucose cotransporter-1, SGLT1), sodium channels, and sodium-hydrogen exchangers. Absorbed Na + ions are then extruded from enterocytes through the Na+ /K+ ATPase located in the basolateral membrane. Similar mechanistic models that account for the transport of other common ions such as K+ and HCO3– also exist.

Fig. 28-5.

Model of transepithelial sodium (Na+ ) absorption. Na+ traverses the apical membrane of enterocytes through a variety of mechanisms, including nutrient-coupled Na+ transport, Na+ /H+ exchange, and Na + channels. Activity of the Na+ /K+ ATPase located on the basolateral membrane generates the electrochemical gradient that provides the driving force for Na+ absorption.

Substantial heterogeneity, with respect to both crypt-villus and craniocaudal axes, exist for intestinal epithelial transport mechanisms. For example, nutrient-coupled Na+ transporters are expressed in mature villus cells, but are absent in crypt cells. In contrast, the cystic fibrosis transmembrane regulator (a chloride channel) is expressed to a greater extent in crypt cells. This spatial distribution pattern is consistent with a model in which absorptive function resides primarily in the villus and secretory function in the crypt. Intestinal absorption and secretion are subject to modulation under physiologic and pathophysiologic conditions by a wide array of hormonal, neural, and immune regulatory mediators (Table 28-1).

Table 28-1 Regulation of Intestinal Absorption and Secretion Agents that stimulate absorption or inhibit secretion of water Aldosterone Glucocorticoids Angiotensin Norepinephrine Epinephrine Dopamine Somatostatin Neuropeptide Y Peptide YY

Enkephalin Agents that simulate secretion or inhibit absorption of water Secretin Bradykinin Prostaglandins Acetylcholine Atrial natriuretic factor Vasopressin Vasoactive intestinal peptide Bombesin Substance P Serotonin Neurotensin Histamine

CARBOHYDRATE DIGESTION AND ABSORPTION Approximately 45% of energy consumption in the average Western diet consists of carbohydrates, approximately one half of which is in the form of starch (linear or branched polymers of glucose) derived from cereals and plants. Other major sources of dietary carbohydrates include sugars derived from milk (lactose), fruits and vegetables (fructose, glucose, and sucrose), or purified from sugar cane or beets (sucrose). Processed foods contain a variety of sugars including fructose, oligosaccharides, and polysaccharides. Glycogen derived from meat contributes only a small fraction of dietary carbohydrate. Pancreatic amylase is the major enzyme of starch digestion, although salivary amylase initiates the process. The terminal products of amylase-mediated starch digestion are oligosaccharides, maltotriose, maltose, and alpha-limit dextrins (Fig. 28-6). These products, as well as the major disaccharides in the diet (sucrose and lactose), are unable to undergo absorption in this form. They must first undergo hydrolytic cleavage into their constituent monosaccharides; these hydrolytic reactions are catalyzed by specific brush border membrane hydrolases that are expressed most abundantly in the villi of the duodenum and jejunum. The three major monosaccharides that represent the terminal products of carbohydrate digestion are glucose, galactose, and fructose.

Fig. 28-6.

Carbohydrate digestion. Dietary carbohydrates, including starch and the disaccharides sucrose and lactose, must undergo hydrolysis into constituent monosaccharides glucose, galactose, and fructose before being absorbed by the intestinal epithelium. These hydrolytic reactions are catalyzed by salivary and pancreatic amylase and by enterocyte brush border hydrolases.

Under physiologic conditions, most of these sugars are absorbed through the epithelium via the transcellular route. Glucose and galactose are transported through the enterocyte brush border membrane via intestinal SGLT1 (Fig. 28-7). Fructose is transported through the brush border membrane by facilitated diffusion via glucose transporter5 (GLUT5, a member of the facilitative glucose transporter family). All three monosaccharides are extruded through the basolateral membrane by facilitated diffusion. Extruded monosaccharides diffuse into venules and ultimately enter the portal venous system.

Fig. 28-7.

Hexose transporters. Glucose and galactose enter the enterocyte through secondary active transport via the sodium-glucose cotransporter-1 (SGLT1) located on the apical (brush border) membrane. Fructose enters through facilitated diffusion via glucose transporter-5 (GLUT5). Glucose and galactose are extruded basolaterally through facilitated diffusion via glucose transporter-2 (GLUT2). Fructose is extruded basolaterally via GLUT5.

There is evidence of overexpression of hexose transporters, specifically SGLT1, in disease states such as diabetes.6 Several approaches aimed at down-regulation of these transporters are being investigated as a novel therapy for disease states such as diabetes and obesity.7

PROTEIN DIGESTION AND ABSORPTION Ten to 15% of energy consumption in the average Western diet consists of proteins. In addition to dietary proteins, approximately one half of the protein load that enters the small intestine is derived from endogenous sources including salivary and GI secretions and desquamated intestinal epithelial cells. Protein digestion begins in the stomach with action of pepsins. This is not, however, an essential step, because surgical patients who are achlorhydric, or have lost part or all their stomach, are still able to successfully digest proteins. Digestion continues in the duodenum with the actions of a variety of pancreatic peptidases. These enzymes are secreted as inactive proenzymes. This is in contrast to pancreatic amylase and lipase, which are secreted in their active forms. In response to the presence of bile acids, enterokinase is liberated from the intestinal brush border membrane to catalyze the conversion of trypsinogen to active trypsin; trypsin, in turn, activates itself and other proteases. The final products of intraluminal protein digestion consist of neutral and basic amino acids and peptides two to six amino acids in length (Fig. 28-8). Additional digestion occurs through the actions of peptidases that exist in the enterocyte brush border and cytoplasm. Epithelial absorption occurs for both single amino acids and di- or tripeptides via specific membrane-bound transporters. Absorbed amino acids and peptides then enter the portal venous circulation.

Fig. 28-8.

Protein digestion. Dietary proteins must undergo hydrolysis into constituent single amino acids and di- and tripeptides before being absorbed by the intestinal epithelium. These hydrolytic reactions are catalyzed by pancreatic peptidases (e.g., trypsin) and by enterocyte brush border peptidases.

Of all amino acids, glutamine appears to be a unique, major source of energy for enterocytes. Active glutamine uptake into enterocytes occurs through both apical and basolateral transport mechanisms.

FAT DIGESTION AND ABSORPTION Approximately 40% of the average Western diet consists of fat. Over 95% of dietary fat is in the form of long-chain triglycerides; the remainder includes phospholipids such as lecithin, fatty acids, cholesterol, and fat-soluble vitamins. Over 94% of the ingested fats are absorbed in the proximal jejunum. Because fats are normally water insoluble, key to successful digestion of ingested fats is solubilization of them into an emulsion by the mechanical actions of mastication and antral peristalsis. Although lipolysis of triglycerides to form fatty acids and monoglycerides is initiated in the stomach by gastric lipase, its principal site is the proximal intestine, where pancreatic lipase is the catalyst (Fig. 28-9).

Fig. 28-9.

Fat digestion. Long-chain triglycerides, which constitute the majority of dietary fats, must undergo lipolysis into constituent long-chain fatty acids and monoglycerides before being absorbed by the intestinal epithelium. These reactions are catalyzed by gastric and pancreatic lipases. The products of lipolysis are transported in the form of mixed micelles to enterocytes, where they are resynthesized into triglycerides, which are then packaged in the form of chylomicrons that are secreted into the intestinal lymph (chyle). Triglycerides composed of short- and medium-chain fatty acids are absorbed by the intestinal

epithelium directly, without undergoing lipolysis, and are secreted into the portal venous circulation.

Bile acids act as detergents that help in solubilization of the lipolysis by forming mixed micelles. These micelles are polymolecular aggregates with a hydrophobic core of fat, and a hydrophilic surface that act as shuttles, delivering the products of lipolysis to the enterocyte brush border membrane, where they are absorbed. The bile salts, however, remain in the bowel lumen and travel to the terminal ileum, where they are actively resorbed. They enter the portal circulation and are resecreted into bile, thus completing the enterohepatic circulation. Dissociation of lipids from the micelles occurs in a thin layer of water (50 to 500 m thick) with an acidic microenvironment immediately adjacent to the brush border called the unstirred water layer . Most lipids are absorbed in the proximal jejunum, whereas bile salts are absorbed in the distal ileum through an active process. Fatty acid binding proteins are a family of proteins located on the brush border membrane, facilitating diffusion of long-chain fatty acids across the brush border membrane. Cholesterol crosses the brush border membrane through an active process that is yet to be completely characterized. Within the enterocytes, triglycerides are resynthesized and incorporated into chylomicrons that are secreted into the intestinal lymphatics and ultimately enter the thoracic duct. In these chylomicrons, lipoproteins serve a detergent-like role similar to that served by bile salts in the mixed micelles. The steps described above are required for the digestion and absorption of triglycerides containing long-chain fatty acids. However, triglycerides containing short- and medium-chain fatty acids are more hydrophilic and are absorbed without undergoing intraluminal hydrolysis, micellular solubilization, mucosal re-esterification, and chylomicron formation. Instead, they are directly absorbed and enter the portal venous circulation rather than the lymphatics. This information provides the rationale for administering nutritional supplements containing mediumchain triglycerides to patients with GI diseases associated with impaired digestion and/or malabsorption of longchain triglycerides.

VITAMIN AND MINERAL ABSORPTION Vitamin B12 (cobalamin) malabsorption can result from a variety of surgical manipulations. The vitamin is initially bound by saliva-derived R protein. In the duodenum, R protein is hydrolyzed by pancreatic enzymes, allowing free cobalamin to bind to gastric parietal cell-derived intrinsic factor. The cobalamin-intrinsic factor complex is able to escape hydrolysis by pancreatic enzymes, allowing it to reach the terminal ileum, which expresses specific receptors for intrinsic factor. Subsequent events in cobalamin absorption are poorly characterized, but the intact complex probably enters enterocytes through translocation. Because each of these steps is necessary for cobalamin assimilation, gastric resection, gastric bypass, and ileal resection can each result in vitamin B1 2 insufficiency. Other water-soluble vitamins for which specific carrier-mediated transport processes have been characterized include ascorbic acid, folate, thiamine, riboflavin, pantothenic acid, and biotin. Fat-soluble vitamins A, D, and E appear to be absorbed through passive diffusion. Vitamin K appears to be absorbed through both passive diffusion and carrier-mediated uptake. Calcium is absorbed through both transcellular transport and paracellular diffusion. The duodenum is the major site for transcellular transport; paracellular transport occurs throughout the small intestine. A key step in transcellular calcium transport is mediated by calbindin, a calcium-binding protein located in the cytoplasm of enterocytes. Regulation of calbindin synthesis is the principal mechanism by which vitamin D regulates intestinal calcium absorption. Abnormal calcium levels are increasingly seen in surgical patients who have undergone a gastric bypass. Although usual calcium supplementation is in the form of calcium carbonate, which is cheap, in such

patients with low acid exposure, calcium citrate is a better formulation for replacement therapy. Iron and magnesium are each absorbed through both transcellular and paracellular routes. A divalent metal transporter capable of transporting Fe2+ , Zn 2+ , Mn 2+ , Co2+ , Cd2+ , Cu2+ , Ni2+ , and Pb2+ that has recently been localized to the intestinal brush border, may account for at least a portion of the transcellular absorption of these ions.8

Barrier and Immune Function Although the intestinal epithelium allows for the efficient absorption of dietary nutrients, it must discriminate between pathogens and harmless antigens such as food proteins and commensal bacteria and it must resist invasion by pathogens. Factors contributing to epithelial defense include immunoglobulin A (IgA), mucins, and the relative impermeability of the brush border membrane and tight junctions to macromolecules and bacteria. Recently described factors likely to play important roles in intestinal mucosal defense include antimicrobial peptides such as the defensins.9 The intestinal component of the immune system, known as the gut-associated lymphoid tissue (GALT), contains over 70% of the body's immune cells. The GALT is conceptually divided into inductive and effector sites. 1 0 Inductive sites include Peyer's patches, mesenteric lymph nodes, and smaller isolated lymphoid follicles scattered throughout the small intestine (Fig. 2810). Peyer's patches are macroscopic aggregates of B-cell follicles and intervening T-cell areas found in the lamina propria of the small intestine, primarily the distal ileum. Overlying Peyer's patches is a specialized epithelium containing M cells. These cells possess an apical membrane with microfolds rather than microvilli, which is characteristic of most intestinal epithelial cells. Using transepithelial vesicular transport, M cells transfer microbes to underlying professional antigen-presenting cells, such as dendritic cells. Dendritic cells, in addition, may sample luminal antigens directly through their dendrite-like processes that extend through epithelial tight junctions. Antigen-presenting cells interact with and prime nave lymphocytes, which then exit through the draining lymphatics to enter the mesenteric lymph nodes, where they undergo differentiation. These lymphocytes then migrate into the systemic circulation via the thoracic duct and ultimately accumulate in the intestinal mucosa at effector sites. Alternative induction mechanisms, such as antigen presentation within mesenteric lymph nodes, are also likely to exist.

Fig. 28-10.

Gut-associated lymphoid tissue. Select components of the gut-associated lymphoid tissue are schematically represented. Peyer's patches consist of a specialized follicle-associated epithelium (FAE) containing M cells, a subepithelial dome (SED) rich in dendritic cells (DC), and B-cell follicle containing germinal centers (GC). Plasma cells in the lamina propria produce immunoglobulin A (IgA), which is transported to the intestinal lumen where it serves as the first line of defense against pathogens. Other components of the gut-associated lymphoid tissue include isolated lymphoid follicles, mesenteric lymph nodes, and regulatory and effector lymphocytes. B = B cell; T = T cell.

Effector lymphocytes are distributed into distinct compartments. IgA-producing plasma cells are derived from B cells and are located in the lamina propria. CD4+ T cells are also located in the lamina propria. CD8+ T cells migrate preferentially to the epithelium, but are also found in the lamina propria. These T cells are central to immune regulation; in addition the CD8+ T cells have potent cytotoxic T lymphocyte activity. IgA is transported through the intestinal epithelial cells into the lumen, where it exists in the form of a dimer complexed with a secretory component. This configuration renders IgA resistant to proteolysis by digestive enzymes. IgA is believed to both help prevent the entry of microbes through the epithelium and to promote excretion of antigens or microbes that have already penetrated into the lamina propria. Ineffective resistance to invasion by pathogens is hypothesized to play an etiologic role in sepsis by allowing translocation of bacteria and/or toxins into the systemic circulation. In contrast, overexuberant immune sensitivity or lack of tolerance to dietary antigens or commensal bacteria is believed to contribute to the pathogenesis of chronic inflammatory disorders such as celiac disease and Crohn's disease. 1 0

Motility Myocytes of the intestinal muscle layers are electrically and mechanically coordinated in the form of syncytia. Contractions of the muscularis propria are responsible for small intestinal peristalsis. Contraction of the outer longitudinal muscle layer results in bowel shortening; contraction of the inner circular layer results in luminal narrowing. Contractions of the muscularis mucosa contribute to mucosal or villus motility, but not to peristalsis. Several distinctive patterns of muscularis propria activity have been observed to occur in the small intestine. These patterns include ascending excitation and descending inhibition in which muscular contraction occurs proximal to a stimulus, such as the presence of a bolus of ingested food, and muscular relaxation occurs distal to the stimulus (Fig. 28-11). These two reflexes are present even in the absence of any extrinsic innervation to the small intestine and contribute to peristalsis when they are propagated in a coordinated fashion along the length of the intestine. The fed or postprandial pattern begins within 10 to 20 minutes of meal ingestion and abates 4 to 6 hours afterward. Rhythmic segmentations or pressure waves traveling only short distances also are observed. This segmenting pattern is hypothesized to assist in mixing intraluminal contents and in facilitating their contact with the absorptive mucosal surface. The fasting pattern or interdigestive motor cycle (IDMC) consists of three phases. Phase I is characterized by motor quiescence, phase II by seemingly disorganized pressure waves occurring at submaximal rates, and phase III by sustained pressure waves occurring at maximal rates. This pattern is hypothesized to expel residual debris and bacteria from the small intestine. The median duration of the IDMC ranges from 90 to 120 minutes. At any given time, different portions of the small intestine can be in different phases of the IDMC.

Fig. 28-11.

Ascending excitation and descending inhibition. The presence of a food bolus within the intestinal lumen is sensed by a sensory neuron (SN) that relays signals to (a) excitatory motor neurons (EMN) that have projections to intestinal muscle cells located proximal to the food bolus and (b) inhibitory motor neurons (IMN) that have projections to intestinal muscle cells located distal to the food bolus. This stereotypical motor reflex is controlled by the enteric nervous system and occurs in the absence of extraintestinal innervations. It contributes to peristalsis.

The regulatory mechanisms driving small intestinal motility consist of both pacemakers intrinsic to the small intestine and external neurohumoral modulatory signals. The interstitial cells of Cajal are pleomorphic mesenchymal cells located within the muscularis propria of the intestine that generate the electrical slow wave

(basic electrical rhythm or pacesetter potential) that plays a pacemaker role in setting the fundamental rhythmicity of small intestinal contractions. The frequency of the slow wave varies along the longitudinal axis of the intestine: It ranges from 12 waves per minute in the duodenum to 7 waves per minute in the distal ileum. Smooth muscle contraction occurs only when an electrical action potential (spike burst) is superimposed on the slow wave. Thus, the slow wave determines the maximum frequency of contractions; however, not every slow wave is associated with a contraction. This intrinsic contractile mechanism is subject to neural and hormonal regulation. The enteric motor system (ENS) provides both inhibitory and excitatory stimuli. The predominant excitatory transmitters are acetylcholine and substance P, and the inhibitory transmitters include nitric oxide, vasoactive intestinal peptide, and adenosine triphosphate. In general, the sympathetic motor supply is inhibitory to the ENS; therefore, increased sympathetic input into the intestine leads to decreased intestinal smooth muscle activity. The parasympathetic motor supply is more complex, with projections to both inhibitory and excitatory ENS motor neurons. Correspondingly, the effects of parasympathetic inputs into intestinal motility are more difficult to predict.

Endocrine Function Endocrinology as a discipline was born with the discovery of secretin, an intestinal regulatory peptide that was the first hormone to be identified. The small intestine is now recognized to be the largest hormone-producing organ in the body, both with respect to the number of hormone-producing cells and the number of individual hormones produced.1 1 Over 30 peptide hormone genes have been identified as being expressed in the GI tract. Because of differential posttranscriptional and posttranslational processing, over 100 distinct regulatory peptides are produced. In addition, monoamines, such as histamine and dopamine, and eicosanoids with hormone-like activities are produced in the intestine. "Gut hormones" were previously conceptualized as peptides produced by the enteroendocrine cells of the intestinal mucosa that are released into the systemic circulation to reach receptors in target sites in the GI tract. Now it is clear that "gut hormone" genes are widely expressed throughout the body, not only in endocrine cells, but also in central and peripheral neurons.1 2 The products of these genes are general intercellular messengers that can act as endocrine, paracrine, autocrine, or neurocrine mediators. Thus, they may act as true blood-borne hormones as well as through local effects. There are notable homology patterns among individual regulatory peptides found in the GI tract. Based on these homologies, approximately one half of the known regulatory peptides can be classified into families.1 2 For example, the secretin family includes secretin, glucagon, and glucagon-like peptides, glucose-dependent insulinotropic peptide, vasoactive intestinal polypeptide, peptide histidine isoleucine, growth hormone releasing hormone, and pituitary adenylyl cyclase-activating peptide. Other peptide families include those named for insulin, epidermal growth factor, gastrin, pancreatic polypeptide, tachykinin, and somatostatin. Receptor subtype multiplicity and cell-specific expression patterns for these receptor subtypes that are characteristic of these regulatory mediators make definition of their actions complex. Detailed description of these actions is beyond the scope of this chapter; however, examples of regulatory peptides produced by enteroendocrine cells of the small intestinal epithelium and their most commonly ascribed functions are summarized in Table 28-2. Some of these peptides or their analogues are used in routine clinical practice. For example, therapeutic applications of octreotide, a long-acting analogue of somatostatin, include the amelioration of symptoms associated with neuroendocrine tumors (e.g., carcinoid syndrome), postgastrectomy dumping syndrome, enterocutaneous fistulas, and the initial treatment of acute hemorrhage due to esophageal varices. The

gastrin secretory response to secretin administration forms the basis for the standard test used to establish the diagnosis of Zollinger-Ellison syndrome. Cholecystokinin is used in evaluations of gallbladder ejection fraction, a parameter that may have use in patients who have symptoms of biliary colic but are not found to have gallstones. Of the peptides listed in Table 28-2, glucagon-like peptide 2 (GLP-2) has been identified as a specific and potent intestinotrophic hormone. GLP-2 both stimulates cellular proliferation and inhibits apoptosis in the intestinal epithelium. It has been demonstrated to induce intestinal regeneration and promote healing in numerous experimental models of intestinal disease. It is currently under clinical evaluation as an intestinotrophic agent in patients suffering from the short bowel syndrome, as discussed in the Short Bowel Syndrome section below.

Table 28-2 Representative Regulatory Peptides Produced in the Small Intestine Somatostatin D cell Inhibits GI secretion, motility, and splanchnic perfusion Secretin S cell Stimulates exocrine pancreatic secretion Stimulates intestinal secretion Cholecystokinin I cell Stimulates pancreatic exocrine secretion Stimulates gallbladder emptying Inhibits sphincter of Oddi contraction Motilin M cell Simulates intestinal motility Peptide YY L cell Inhibits intestinal motility and secretion Glucagon-like peptide 2 L cell Stimulates intestinal epithelial proliferation Neurotensin N cell Stimulates pancreatic and biliary secretion Inhibits small bowel motility Stimulates intestinal mucosal growth Hormone

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table indicates which enteroendocrine cell types located in the intestinal epithelium produce these peptides. These peptides are also widely expressed in nonintestinal tissues.

Intestinal Adaptation The small intestine has the capacity to adapt in response to varying demands imposed by physiologic and pathologic conditions. Of particular relevance to many of the diseases discussed in this chapter is the adaptation that occurs in the remnant intestine following surgical resection of a large portion of the small intestine (massive small bowel resection). Postresection intestinal adaptation has been studied extensively using animal models. Within a few hours after bowel resection, the remnant small intestine displays evidence of epithelial cellular hyperplasia. With additional time, villi lengthen, intestinal absorptive surface area increases, and digestive and absorptive functions improve. Postresection intestinal adaptation in human patients is less well studied, but seems to follow similar steps as that seen in experimental models, and takes 1 to 2 years to complete.1 3 The mechanisms responsible for inducing postresection intestinal adaptation are under active investigation. Several classes of effectors that stimulate intestinal growth include specific nutrients, peptide hormones and growth factors, pancreatic secretions, and some cytokines.1 4 Nutritional components with intestinal growth-stimulating effects include fiber, fatty acids, triglycerides, glutamine, polyamines, and lectins. Peptide growth factors reported to induce growth include epidermal growth factor, transforming growth factor alpha, insulin-like growth factors I and II, keratinocyte growth factor, hepatocyte growth factor, gastrin, peptide YY, neurotensin, and bombesin. Cytokines that stimulate growth include interleukin (IL)-11, IL-3, and IL-15. The most recently characterized stimulator of enterocyte proliferation is GLP-2, which has potent trophic activity that is specific for the intestinal epithelium. 1 5 As serum concentrations of GLP-2 rise following massive small bowel resection and GLP-2 immunoneutralization inhibits postresection intestinal adaptation, GLP-2 is a promising candidate mediator of this response. Postresection adaptation serves to compensate for the function of intestine that has been resected. Jejunal resection generally is better tolerated, as ileum shows better capacity to compensate. However, the magnitude of this response is limited. If enough small intestine is resected, a devastating condition known as the short bowel syndrome results. This condition is discussed in the Short Bowel Syndrome section at the end of this chapter.

SMALL BOWEL OBSTRUCTION Epidemiology Mechanical small bowel obstruction is the most frequently encountered surgical disorder of the small intestine. Although a wide range of etiologies for this condition exist, the obstructing lesion can be conceptualized according to its anatomic relationship to the intestinal wall as:

1. Intraluminal (e.g., foreign bodies, gallstones, or meconium) 2. Intramural (e.g., tumors, Crohn's disease–associated inflammatory strictures) 3. Extrinsic (e.g., adhesions, hernias, or carcinomatosis) Intra-abdominal adhesions related to prior abdominal surgery account for up to 75% of the cases of small bowel obstruction. Over 300,000 patients are estimated to undergo surgery annually to treat adhesion-induced small bowel obstruction in the United States.1 6 Less prevalent etiologies for small bowel obstruction include hernias, malignant bowel obstruction, and Crohn's disease. The frequency with which obstruction related to these conditions is encountered varies according to the

patient population and practice setting. Cancer-related small bowel obstructions are commonly due to extrinsic compression or invasion by advanced malignancies arising in organs other than the small bowel; few are due to primary small bowel tumors. The most commonly encountered etiologies of small bowel obstruction are summarized in Table 28-3. Although congenital abnormalities capable of causing small bowel obstruction usually become evident during childhood, they sometimes elude detection and are diagnosed for the first time in adult patients presenting with abdominal symptoms. For example, intestinal malrotation and midgut volvulus should not be forgotten when considering the differential diagnosis of adult patients with acute or chronic symptoms of small bowel obstruction, especially those without a history of prior abdominal surgery. A rare etiology of obstruction is the superior mesenteric artery syndrome, characterized by compression of the third portion of the duodenum by the superior mesenteric artery as it crosses over this portion of the duodenum. This condition should be considered in young asthenic individuals who have chronic symptoms suggestive of proximal small bowel obstruction.

Table 28-3 Small Bowel Obstruction: Common Etiologies Adhesions Neoplasms Primary small bowel neoplasms Secondary small bowel cancer (e.g., melanoma-derived metastasis) Local invasion by intra-abdominal malignancy (e.g., desmoid tumors) Carcinomatosis Hernias External (e.g., inguinal and femoral) Internal (e.g., following Roux-en-Y gastric bypass surgery) Crohn's disease Volvulus Intussusception Radiation-induced stricture Postischemic stricture Foreign body Gallstone ileus Diverticulitis Meckel's diverticulum Hematoma Congenital abnormalities (e.g., webs, duplications, and malrotation)

Pathophysiology With onset of obstruction, gas and fluid accumulate within the intestinal lumen proximal to the site of obstruction. The intestinal activity increases in an effort to overcome the obstruction, accounting for the colicky pain and the diarrhea that some experience even in the presence of complete bowel obstruction. Most of the gas that accumulates originates from swallowed air, although some is produced within the intestine. The fluid consists of swallowed liquids and GI secretions (obstruction stimulates intestinal epithelial water secretion). With ongoing gas and fluid accumulation, the bowel distends and intraluminal and intramural pressures rise. The intestinal motility is eventually reduced with fewer contractions. With obstruction, the luminal flora of the small bowel, which is usually sterile, changes and a variety of organisms have been cultured from the contents. Translocation of these bacteria to regional lymph nodes has been demonstrated, although the significance of this process is not well understood. If

the intramural pressure becomes high enough, intestinal microvascular perfusion is impaired, leading to intestinal ischemia, and, ultimately, necrosis. This condition is termed strangulated bowel obstruction . With partial small bowel obstruction , only a portion of the intestinal lumen is occluded, allowing passage of some gas and fluid. The progression of pathophysiologic events described above tends to occur more slowly than with complete small bowel obstruction , and development of strangulation is less likely. A particularly dangerous form of bowel obstruction is closed loop obstruction , in which a segment of intestine is obstructed both proximally and distally (e.g., with volvulus). In such cases, the accumulating gas and fluid cannot escape either proximally or distally from the obstructed segment, leading to a rapid rise in luminal pressure, and a rapid progression to strangulation.

Clinical Presentation The symptoms of small bowel obstruction are colicky abdominal pain, nausea, vomiting, and obstipation. Vomiting is a more prominent symptom with proximal obstructions than distal. Character of vomitus is important as with bacterial overgrowth, the vomitus is more feculent, suggesting a more established obstruction (Fig. 28-12). Continued passage of flatus and/or stool beyond 6 to 12 hours after onset of symptoms is characteristic of partial rather than complete obstruction. The signs of small bowel obstruction include abdominal distention that is most pronounced if the site of obstruction is in the distal ileum, and may be absent if the site of obstruction is in the proximal small intestine. Bowel sounds may be hyperactive initially, but in late stages of bowel obstruction, minimal bowel sounds may be heard. Laboratory findings reflect intravascular volume depletion and consist of hemoconcentration and electrolyte abnormalities. Mild leukocytosis is common.

Fig. 28-12.

Chronic partial small bowel obstruction. This patient presented with a several months' history of chronic abdominal pain, and

intermittent vomiting. The coronal computed tomographic image shows grossly dilated loops of proximal small bowel on the left side (wide arrow ), with decompressed loops of small bowel on the right side (narrow arrow ). The dilated segment shows evidence of feculization of bowel contents, consistent with the chronic nature of the obstruction. Patient's vomitus had characteristic feculent smell and quality. At exploratory laparotomy, adhesive bands were identified and divided.

Features of strangulated obstruction include abdominal pain often disproportionate to the degree of abdominal findings, suggestive of intestinal ischemia. Patients often have tachycardia, localized abdominal tenderness, fever, marked leukocytosis, and acidosis. Any of these findings should alert the clinician to the possibility of strangulation, and the need for early surgical intervention.

Diagnosis The diagnostic evaluation should focus on the following goals: (a) distinguish mechanical obstruction from ileus, (b) determine the etiology of the obstruction, (c) discriminate partial from complete obstruction, and (d) discriminate simple from strangulating obstruction. Important elements to obtain on history include prior abdominal operations (suggesting the presence of adhesions) and the presence of abdominal disorders (e.g., intra-abdominal cancer or inflammatory bowel disease) that may provide insights into the etiology of obstruction. Upon examination, a meticulous search for hernias (particularly in the inguinal and femoral regions) should be conducted. The stool should be checked for gross or occult blood, the presence of which is suggestive of intestinal strangulation. The diagnosis of small bowel obstruction is usually confirmed with radiographic examination. The abdominal series consists of (a) a radiograph of the abdomen with the patient in a supine position, (b) a radiograph of the abdomen with the patient in an upright position, and (c) a radiograph of the chest with the patient in an upright position. The finding most specific for small bowel obstruction is the triad of dilated small bowel loops (>3 cm in diameter), airfluid levels seen on upright films, and a paucity of air in the colon. The sensitivity of abdominal radiographs in the detection of small bowel obstruction ranges from 70 to 80%.1 7 Specificity is low because ileus and colonic obstruction can be associated with findings that mimic those observed with small bowel obstruction. False-negative findings on radiographs can result when the site of obstruction is located in the proximal small bowel and when the bowel lumen is filled with fluid but no gas, thereby preventing visualization of air-fluid levels or bowel distention. The latter situation is associated with closed-loop obstruction. Despite these limitations, abdominal radiographs remain an important study in patients with suspected small bowel obstruction because of their widespread availability and low cost. Computed tomographic (CT) scanning is 80 to 90% sensitive and 70 to 90% specific in the detection of small bowel obstruction.1 7 The findings of small bowel obstruction include a discrete transition zone with dilation of bowel proximally, decompression of bowel distally, intraluminal contrast that does not pass beyond the transition zone, and a colon containing little gas or fluid (Fig. 28-13). CT scanning may also provide evidence for the presence of closed-loop obstruction and strangulation. Closed-loop obstruction is suggested by the presence of a U-shaped or C-shaped dilated bowel loop associated with a radial distribution of mesenteric vessels converging toward a torsion point. Strangulation is suggested by thickening of the bowel wall, pneumatosis intestinalis (air in the bowel wall), portal venous gas, mesenteric haziness, and poor uptake of IV contrast into the wall of the affected bowel (Fig. 2814). CT scanning also offers a global evaluation of the abdomen and may therefore reveal the etiology of obstruction. This feature is important in the acute setting when intestinal obstruction represents only one of many diagnoses in patients presenting with acute abdominal conditions.

Fig. 28-13.

Small bowel obstruction. A computed tomographic scan of a patient presenting with signs and symptoms of bowel obstruction. Image shows grossly dilated loops of small bowel, with decompressed terminal ileum (I) and ascending colon (C), suggesting a complete distal small bowel obstruction. At laparotomy, adhesive bands from a previous surgery were identified and divided.

Fig. 28-14.

Intestinal pneumatosis. This computed tomographic scan shows intestinal pneumatosis (arrow ). The cause of this radiologic finding was intestinal ischemia. Patient was taken emergently to the operating room and underwent resection of an infarcted segment of small bowel.

The CT scan usually is performed after administration of oral water soluble contrast, or diluted barium. The water soluble contrast has been shown to have prognostic and therapeutic values too. Several studies and a subsequent meta-analysis have shown that appearance of the contrast in the colon within 24 hours is predictive of nonsurgical resolution of bowel obstruction.1 8 Although use of oral contrast did not alter the rate of surgical intervention, it did reduce the overall length of hospital stay in those presenting with small bowel obstruction. A limitation of CT scanning is its low sensitivity (Chapter 29. Colon, Rectum, and Anus>

KEY POINTS 1. Resection principles: The mesenteric clearance technique dictates the extent of resection and is determined by the nature of the primary pathology, the intent of resection, the location of the lesion, and the condition of the mesentery. 2. Minimally invasive resection: Laparoscopic and/or hand-assisted laparoscopy has been shown to be both safe and efficacious for colorectal resection. 3. Function after resection: Bowel function is often compromised after colorectal resection, especially after low anterior resection. For this reason, it is important to obtain a history of prior anorectal trauma and/or incontinence before considering a low anastomosis. 4. Ostomies: Preoperative marking for a planned stoma is critical for a patient's quality of life. Ideally, a stoma should be located within the rectus muscle, in a location where the patient can easily see and manipulate the appliance, and away from previous scars, bony prominences, or abdominal creases. 5. Inflammatory bowel disease: Both Crohn's disease and ulcerative colitis are associated with an increased risk of colorectal carcinoma. Risk depends upon the amount of colon involved and the duration of disease. 6. Pathogenesis of colorectal cancer: A variety of mutations have been identified in colorectal cancer. Mutations may cause activation of oncogenes (K-ras) and/or inactivation of tumor-suppressor genes [adenomatous polyposis coli (APC) < DCC (deleted in colorectal carcinoma), p53]. 7. Early rectal cancer: Optimal treatment of very early rectal cancer (T1NXMX) is controversial. Transanal excision alone has been associated with a very high rate of local recurrence. In patients who will tolerate and accept radical surgery, this approach is probably appropriate. Chemoradiation either before or after transanal excision can also be considered, but has not been prospectively studied. 8. Anal epidermoid carcinoma: Unlike rectal adenocarcinoma, anal epidermoid carcinoma is treated primarily with chemoradiation. Surgery is reserved for patients with persistent or recurrent disease. 9. Rectal prolapse: Rectal prolapse occurs most commonly in elderly women. Transabdominal repair (rectopexy with or without resection) offers more durability than perineal proctosigmoidectomy, but carries greater operative risk. 10. Hemorrhoids: Hemorrhoids are cushions of submucosal tissue containing venules, arterioles, and smooth muscle fiber. They are thought o play a role in maintaining continence. Resection is only indicated for refractory symptoms.

11. Fistula in ano: Treatment of fistula in ano depends upon the location of the fistula, amount of anal sphincter involved in the fistula, and the underlying disease process.

EMBRYOLOGY AND ANATOMY Embryology The embryonic GI tract begins developing during the fourth week of gestation. The primitive gut is derived from the endoderm and divided into three segments: foregut , midgut , and hindgut . Both midgut and hindgut contribute to the colon, rectum, and anus. The midgut develops into the small intestine, ascending colon, and proximal transverse colon, and receives blood supply from the superior mesenteric artery. During the sixth week of gestation, the midgut herniates out of the abdominal cavity, and then rotates 270 counterclockwise around the superior mesenteric artery to return to its final position inside the abdominal cavity during the tenth week of gestation. The hindgut develops into the distal transverse colon, descending colon, rectum, and proximal anus, all of which receive their blood supply from the inferior mesenteric artery. During the sixth week of gestation, the distal-most end of the hindgut, the cloaca , is divided by the urorectal septum into the urogenital sinus and the rectum. The distal anal canal is derived from ectoderm and receives its blood supply from the internal pudendal artery. The dentate line divides the endodermal hindgut from the ectodermal distal anal canal.

Anatomy The large intestine extends from the ileocecal valve to the anus. It is divided anatomically and functionally into the colon , rectum , and anal canal . The wall of the colon and rectum comprise five distinct layers: mucosa, submucosa, inner circular muscle, outer longitudinal muscle, and serosa. In the colon, the outer longitudinal muscle is separated into three teniae coli , which converge proximally at the appendix and distally at the rectum, where the outer longitudinal muscle layer is circumferential. In the distal rectum, the inner smooth muscle layer coalesces to form the internal anal sphincter. The intraperitoneal colon and proximal one third of the rectum are covered by serosa; the mid and lower rectum lack serosa.

COLON LANDMARKS The colon begins at the junction of the terminal ileum and cecum and extends 3 to 5 ft to the rectum. The rectosigmoid junction is found at approximately the level of the sacral promontory and is arbitrarily described as the point at which the three teniae coli coalesce to form the outer longitudinal smooth muscle layer of the rectum. The cecum is the widest diameter portion of the colon (normally 7.5 to 8.5 cm) and has the thinnest muscular wall. As a result, the cecum is most vulnerable to perforation and least vulnerable to obstruction. The ascending colon usually is fixed to the retroperitoneum. The hepatic flexure marks the transition to the transverse colon. The intraperitoneal transverse colon is relatively mobile, but is tethered by the gastrocolic ligament and colonic mesentery. The greater omentum is attached to the anterior/superior edge of the transverse colon. These attachments explain the characteristic triangular appearance of the transverse colon observed during colonoscopy. The splenic flexure marks the transition from the transverse colon to the descending colon. The attachments between the splenic flexure and the spleen (the lienocolic ligament) can be short and dense, making mobilization of this flexure during colectomy challenging. The descending colon is relatively fixed to the retroperitoneum. The sigmoid colon is the narrowest part of the large intestine and is extremely mobile. Although the sigmoid colon usually is located in the left lower quadrant, redundancy and mobility can result in a portion of the sigmoid colon

residing in the right lower quadrant. This mobility explains why volvulus is most common in the sigmoid colon and why diseases affecting the sigmoid colon, such as diverticulitis, may occasionally present as right-sided abdominal pain. The narrow caliber of the sigmoid colon makes this segment of the large intestine the most vulnerable to obstruction.

COLON VASCULAR SUPPLY The arterial supply to the colon is highly variable (Fig. 29-1). In general, the superior mesenteric artery branches into the ileocolic artery (absent in up to 20% of people), which supplies blood flow to the terminal ileum and proximal ascending colon, the right colic artery , which supplies the ascending colon, and the middle colic artery , which supplies the transverse colon. The inferior mesenteric artery branches into the left colic artery , which supplies the descending colon, several sigmoidal branches , which supply the sigmoid colon, and the superior rectal artery , which supplies the proximal rectum. The terminal branches of each artery form anastomoses with the terminal branches of the adjacent artery and communicate via the marginal artery of Drummond . This arcade is complete in only 15 to 20% of people.

Fig. 29-1.

Arterial blood supply to the colon. a. = artery.

Except for the inferior mesenteric vein , the veins of the colon parallel their corresponding arteries and bear the same terminology (Fig. 29-2). The inferior mesenteric vein ascends in the retroperitoneal plane over the psoas muscle and continues posterior to the pancreas to join the splenic vein. During a colectomy, this vein often is mobilized independently and ligated at the inferior edge of the pancreas.

Fig. 29-2.

Venous drainage of the colon. v. = vein. [Reproduced with permission from Bell RH, Rikkers LF, Mulholland M (eds): Digestive Tract Surgery: A Text and Atlas. Philadelphia: Lippincott Williams & Wilkins, 1996, p 1459.]

COLON LYMPHATIC DRAINAGE The lymphatic drainage of the colon originates in a network of lymphatics in the muscularis mucosa. Lymphatic vessels and lymph nodes follow the regional arteries. Lymph nodes are found on the bowel wall (epicolic), along the inner margin of the bowel adjacent to the arterial arcades (paracolic), around the named mesenteric vessels (intermediate), and at the origin of the superior and inferior mesenteric arteries (main). The sentinel lymph nodes are the first one to four lymph nodes to drain a specific segment of the colon, and are thought to be the first site of metastasis in colon cancer. The use of sentinel lymph node dissection and analysis in colon cancer remains controversial.

COLON NERVE SUPPLY The colon is innervated by both sympathetic (inhibitory) and parasympathetic (stimulatory) nerves, which parallel the course of the arteries. Sympathetic nerves arise from T6–T12 and L1–L3. The parasympathetic innervation to the right and transverse colon is from the vagus nerve; the parasympathetic nerves to the left colon arise from sacral nerves S2–S4 to form the nervi erigentes.

ANORECTAL LANDMARKS The rectum is approximately 12 to 15 cm in length. Three distinct submucosal folds, the valves of Houston , extend into the rectal lumen. Posteriorly, the presacral fascia separates the rectum from the presacral venous plexus and

the pelvic nerves. At S4, the rectosacral fascia (Waldeyer's fascia ) extends forward and downward and attaches to the fascia propria at the anorectal junction. Anteriorly, Denonvilliers' fascia separates the rectum from the prostate and seminal vesicles in men and from the vagina in women. The lateral ligaments support the lower rectum. The surgical anal canal measures 2 to 4 cm in length and generally is longer in men than in women. It begins at the anorectal junction and terminates at the anal verge. The dentate or pectinate line marks the transition point between columnar rectal mucosa and squamous anoderm. The 1 to 2 cm of mucosa just proximal to the dentate line shares histologic characteristics of columnar, cuboidal, and squamous epithelium and is referred to as the anal transition zone . The dentate line is surrounded by longitudinal mucosal folds, known as the columns of Morgagni , into which the anal crypts empty. These crypts are the source of cryptoglandular abscesses (Fig. 29-3).

Fig. 29-3.

The lining of the anal canal. [From Goldberg SM, Gordon PH, Nivatvongs S (eds): Essentials of Anorectal Surgery. Philadelphia: J.B. Lippincott Company, 1980, p 4. Reproduced with permission from Stanley M. Goldberg, MD.]

In the distal rectum, the inner smooth muscle is thickened and comprises the internal anal sphincter that is surrounded by the subcutaneous , superficial , and deep external sphincter . The deep external anal sphincter is an extension of the puborectalis muscle . The puborectalis , iliococcygeus , and pubococcygeus muscles form the levator ani muscle of the pelvic floor (Fig. 29-4).

Fig. 29-4.

The distal rectum and anal canal. m. = muscle.

ANORECTAL VASCULAR SUPPLY The superior rectal artery arises from the terminal branch of the inferior mesenteric artery and supplies the upper rectum. The middle rectal artery arises from the internal iliac; the presence and size of these arteries are highly variable. The inferior rectal artery arises from the internal pudendal artery, which is a branch of the internal iliac artery. A rich network of collaterals connects the terminal arterioles of each of these arteries, thus making the rectum relatively resistant to ischemia (Fig. 29-5).

Fig. 29-5.

Arterial supply to the rectum and anal canal.

The venous drainage of the rectum parallels the arterial supply. The superior rectal vein drains into the portal system via the inferior mesenteric vein. The middle rectal vein drains into the internal iliac vein. The inferior rectal vein drains into the internal pudendal vein, and subsequently into the internal iliac vein. A submucosal plexus deep to the columns of Morgagni forms the hemorrhoidal plexus and drains into all three veins.

ANORECTAL LYMPHATIC DRAINAGE Lymphatic drainage of the rectum parallels the vascular supply. Lymphatic channels in the upper and middle rectum drain superiorly into the inferior mesenteric lymph nodes. Lymphatic channels in the lower rectum drain both superiorly into the inferior mesenteric lymph nodes and laterally into the internal iliac lymph nodes. The anal canal has a more complex pattern of lymphatic drainage. Proximal to the dentate line, lymph drains into both the inferior mesenteric lymph nodes and the internal iliac lymph nodes. Distal to the dentate line, lymph primarily drains into the inguinal lymph nodes, but also can drain into the inferior mesenteric lymph nodes and internal iliac lymph nodes.

ANORECTAL NERVE SUPPLY Both sympathetic and parasympathetic nerves innervate the anorectum. Sympathetic nerve fibers are derived from L1–L3 and join the preaortic plexus. The preaortic nerve fibers then extend below the aorta to form the hypogastric plexus , which subsequently joins the parasympathetic fibers to form the pelvic plexus. Parasympathetic nerve fibers are known as the nervi erigentes and originate from S2–S4. These fibers join the sympathetic fibers to form the pelvic plexus. Sympathetic and parasympathetic fibers then supply the anorectum and adjacent urogenital organs.

The internal anal sphincter is innervated by sympathetic and parasympathetic nerve fibers; both types of fibers inhibit sphincter contraction. The external anal sphincter and puborectalis muscles are innervated by the inferior rectal branch of the internal pudendal nerve . The levator ani receives innervation from both the internal pudendal nerve and direct branches of S3 to S5. Sensory innervation to the anal canal is provided by the inferior rectal branch of the pudendal nerve . Although the rectum is relatively insensate, the anal canal below the dentate line is sensate.

Congenital Anomalies Perturbation of the embryologic development of the midgut and hindgut may result in anatomic abnormalities of the colon, rectum, and anus. Failure of the midgut to rotate and return to the abdominal cavity during the tenth week of gestation results in varying degrees of intestinal malrotation and colonic nonfixation. Failure of canalization of the primitive gut can result in colonic duplication. Incomplete descent of the urogenital septum may result in imperforate anus and associated fistulas to the genitourinary tract. Many infants with congenital anomalies of the hindgut have associated abnormalities in the genitourinary tract.

NORMAL PHYSIOLOGY Fluid and Electrolyte Exchanges The colon is a major site for water absorption and electrolyte exchange. Approximately 90% of the water contained in ileal fluid is absorbed in the colon (1000 to 2000 mL/d), and up to 5000 mL of fluid can be absorbed daily. Sodium is absorbed actively via a Na-K ATPase. The colon can absorb up to 400 mEq of sodium per day. Water accompanies the transported sodium and is absorbed passively along an osmotic gradient. Potassium is actively secreted into the colonic lumen and absorbed by passive diffusion. Chloride is absorbed actively via a chloride–bicarbonate exchange. Bacterial degradation of protein and urea produces ammonia. Ammonia is subsequently absorbed and transported to the liver. Absorption of ammonia depends, in part, upon intraluminal pH. A decrease in colonic bacteria (e.g., broad-spectrum antibiotic usage) and/or a decrease in intraluminal pH (e.g., lactulose administration) will decrease ammonia absorption.

Short-Chain Fatty Acids Short-chain fatty acids (acetate, butyrate, and propionate) are produced by bacterial fermentation of dietary carbohydrates. Short-chain fatty acids are an important source of energy for the colonic mucosa, and metabolism by colonocytes provides energy for processes such as active transport of sodium. Lack of a dietary source for production of short-chain fatty acids, or diversion of the fecal stream by an ileostomy or colostomy, may result in mucosal atrophy and "diversion colitis."

Colonic Microflora and Intestinal Gas Approximately 30% of fecal dry weight is composed of bacteria (101 1 to 102 bacteria/g of feces). Anaerobes are the predominant class of microorganism, and Bacteroides species are the most common (10 1 1 to 101 2 organisms/mL). Escherichia coli are the most numerous aerobes (108 to 101 0 organisms/mL). Endogenous microflora are crucial for the breakdown of carbohydrates and proteins in the colon and participate in the metabolism of bilirubin, bile acids, estrogen, and cholesterol. Colonic bacteria also are necessary for production of vitamin K. Endogenous bacteria also are thought to suppress the emergence of pathogenic microorganisms, such as Clostridium difficile . However, the high bacterial load of the large intestine may contribute to sepsis in critically

ill patients and may contribute to intra-abdominal sepsis, abscess, and wound infection following colectomy. Intestinal gas arises from swallowed air, diffusion from the blood, and intraluminal production. Nitrogen, oxygen, carbon dioxide, hydrogen, and methane are the major components of intestinal gas. Nitrogen and oxygen are largely derived from swallowed air. Carbon dioxide is produced by the reaction of bicarbonate and hydrogen ions, and by the digestion of triglycerides to fatty acids. Hydrogen and methane are produced by colonic bacteria. The production of methane is highly variable. The GI tract usually contains between 100 and 200 mL of gas and 400 to 1200 mL per day are released as flatus, depending upon the type of food ingested.

Motility, Defecation, and Continence MOTILITY Unlike the small intestine, the large intestine does not demonstrate cyclic motor activity characteristic of the migratory motor complex. Instead, the colon displays intermittent contractions of either low or high amplitude. Low-amplitude, short-duration contractions occur in bursts and appear to move the colonic contents both antegrade and retrograde. It is thought that these bursts of motor activity delay colonic transit and thus increase the time available for absorption of water and exchange of electrolytes. High-amplitude contractions occur in a more coordinated fashion and create "mass movements." Bursts of "rectal motor complexes" also have been described. In general, cholinergic activation increases colonic motility.

DEFECATION Defecation is a complex, coordinated mechanism involving colonic mass movement, increased intra-abdominal and rectal pressure, and relaxation of the pelvic floor. Distention of the rectum causes a reflex relaxation of the internal anal sphincter (the rectoanal inhibitory reflex) that allows the contents to make contact with the anal canal. This "sampling reflex" allows the sensory epithelium to distinguish solid stool from liquid stool and gas. If defecation does not occur, the rectum relaxes and the urge to defecate passes (the accommodation response ). Defecation proceeds by coordination of increasing intra-abdominal pressure via the Valsalva maneuver, increased rectal contraction, relaxation of the puborectalis muscle, and opening of the anal canal.

CONTINENCE The maintenance of fecal continence is at least as complex as the mechanism of defecation. Continence requires adequate rectal wall compliance to accommodate the fecal bolus, appropriate neurogenic control of the pelvic floor and sphincter mechanism, and functional internal and external sphincter muscles. At rest, the puborectalis muscle creates a "sling" around the distal rectum, forming a relatively acute angle that distributes intra-abdominal forces onto the pelvic floor. With defecation, this angle straightens, allowing downward force to be applied along the axis of the rectum and anal canal. The internal and external sphincters are tonically active at rest. The internal sphincter is responsible for most of the resting, involuntary sphincter tone (resting pressure). The external sphincter is responsible for most of the voluntary sphincter tone (squeeze pressure). Branches of the pudendal nerve innervate both the internal and external sphincter. Finally, the hemorrhoidal cushions may contribute to continence by mechanically blocking the anal canal. Thus, impaired continence may result from poor rectal compliance, injury to the internal and/or external sphincter or puborectalis, or nerve damage or neuropathy.

CLINICAL EVALUATION Clinical Assessment A complete history and physical examination is the starting point for evaluating any patient with suspected disease

of the colon and rectum. Special attention should be paid to the patient's past medical and surgical history to detect underlying conditions that might contribute to a GI problem. If patients have had prior intestinal surgery, it is essential that one understand the resultant GI anatomy. A history of anorectal surgery may be critical for patients with either abdominal or anorectal complaints. Obstetric history in women is essential to suspect occult pelvic floor and/or anal sphincter damage. A family history of colorectal disease, especially inflammatory bowel disease, polyps, and colorectal cancer, is crucial. In addition to family history of colorectal disease, history of other malignancies may suggest the presence of a genetic syndrome. Medication use must be detailed as many drugs cause GI symptoms. Before recommending operative intervention, the adequacy of medical treatment must be ascertained. In addition to examining the abdomen, visual inspection of the anus and perineum and careful digital rectal exam are essential.

Endoscopy ANOSCOPY The anoscope is a useful instrument for examination of the anal canal. Anoscopes are made in a variety of sizes and measure approximately 8 cm in length. A larger anoscope provides better exposure for anal procedures such as rubber band ligation or sclerotherapy of hemorrhoids. The anoscope, with obturator in place, should be adequately lubricated and gently inserted into the anal canal. The obturator is withdrawn, inspection of the visualized anal canal is done, and the anoscope should then be withdrawn. It is rotated 90 and reinserted to allow visualization of all four quadrants of the canal. If the patient complains of severe perianal pain and cannot tolerate a digital rectal examination, anoscopy should not be attempted without anesthesia.

PROCTOSCOPY The rigid proctoscope is useful for examination of the rectum and distal sigmoid colon and occasionally is used therapeutically. The standard proctoscope is 25 cm in length and available in various diameters. Most often, a 15or 19-mm diameter proctoscope is used for diagnostic examinations. The large (25-mm diameter) proctoscope is useful for procedures such as polypectomy, electrocoagulation, or detorsion of a sigmoid volvulus. A smaller "pediatric" proctoscope (11-mm diameter) is better tolerated by patients with anal stricture. Suction is necessary for an adequate proctoscopic examination.

FLEXIBLE SIGMOIDOSCOPY AND COLONOSCOPY Video or fiber-optic flexible sigmoidoscopy and colonoscopy provide excellent visualization of the colon and rectum. Sigmoidoscopes measure 60 cm in length. Full depth of insertion may allow visualization as high as the splenic flexure, although the mobility and redundancy of the sigmoid colon often limit the extent of the examination. Partial preparation with enemas usually is adequate for sigmoidoscopy and most patients can tolerate this procedure without sedation. Colonoscopes measure 100 to 160 cm in length and are capable of examining the entire colon and terminal ileum. A complete oral bowel preparation usually is necessary for colonoscopy and the duration and discomfort of the procedure usually require conscious sedation. Both sigmoidoscopy and colonoscopy can be used diagnostically and therapeutically. Electrocautery generally should not be used in the absence of a complete bowel preparation because of the risk of explosion of intestinal methane or hydrogen gases. Diagnostic colonoscopes possess a single channel through which instruments such as snares, biopsy forceps, or electrocautery can be passed; this channel also provides suction and irrigation capability. Therapeutic colonoscopes possess two channels to allow simultaneous suction/irrigation and the use of snares, biopsy forceps, or electrocautery.

CAPSULE ENDOSCOPY

Capsule endoscopy is an emerging technology that uses a small ingestible camera. After swallowing the camera, images of the mucosa of the GI tract are captured, transmitted by radiofrequency to a belt-held receiver, then downloaded to a computer for viewing and analysis. At present, capsule endoscopy largely has been used to detect small bowel lesions. However, it has been suggested that this technique might also be useful for diagnosing colorectal disease.1–3 At present, the use of capsule endoscopy in the evaluation of colorectal disease remains unproven.

Imaging PLAIN X-RAYS AND CONTRAST STUDIES Despite advanced radiologic techniques, plain x-rays and contrast studies continue to play an important role in the evaluation of patients with suspected colon and rectal diseases. Plain x-rays of the abdomen (supine, upright, and diaphragmatic views) are useful for detecting free intra-abdominal air, bowel gas patterns suggestive of small or large bowel obstruction, and volvulus. Contrast studies are useful for evaluating obstructive symptoms, delineating fistulous tracts, and diagnosing small perforations or anastomotic leaks. While Gastrografin cannot provide the mucosal detail provided by barium, this water-soluble contrast agent is recommended if perforation or leak is suspected. Double-contrast barium enema has been reported to be 70 to 90% sensitive for the detection of mass lesions greater than 1 cm in diameter.4 Detection of small lesions can be extremely difficult, especially in a patient with extensive diverticulosis. For this reason, a colonoscopy is preferred for evaluating nonobstructing mass lesions in the colon. Double-contrast barium enema has been used as a back-up examination if colonoscopy is incomplete.

COMPUTED TOMOGRAPHY Computed tomography (CT) is commonly used in the evaluation of patients with abdominal complaints. Its utility is primarily in the detection of extraluminal disease, such as intra-abdominal abscesses and pericolic inflammation, and in staging colorectal carcinoma, because of its sensitivity in detection of hepatic metastases. Extravasation of oral or rectal contrast also may confirm the diagnosis of perforation or anastomotic leak. Nonspecific findings such as bowel wall thickening or mesenteric stranding may suggest inflammatory bowel disease, enteritis/colitis, or ischemia. A standard CT scan is relatively insensitive for the detection of intraluminal lesions.

VIRTUAL COLONOSCOPY/COMPUTED TOMOGRAPHY COLOGRAPHY Virtual colonoscopy (CT colography) is a new radiologic technique that is designed to overcome some of the limitations of traditional CT scanning. This technology uses helical CT and three-dimensional reconstruction to detect intraluminal colonic lesions. Oral bowel preparation, oral and rectal contrast, and colon insufflation are used to maximize sensitivity. Early evaluation of virtual colonoscopy suggests that accuracy may approach that of colonoscopy for detection of lesions 1 cm in diameter or greater.

MAGNETIC RESONANCE IMAGING The main use of magnetic resonance imaging (MRI) in colorectal disorders is in evaluation of pelvic lesions. MRI is more sensitive than CT for detecting bony involvement or pelvic sidewall extension of rectal tumors. MRI accurately determines the extent of spread of rectal cancer into the adjacent mesorectum and can reliably predict difficulty achieving radial margin clearance of a rectal cancer by surgery alone. When the radial margin is threatened, neoadjuvant chemoradiation generally is indicated. MRI also can be helpful in the detection and delineation of complex fistulas in ano. The use of an endorectal coil may increase sensitivity.

POSITRON EMISSION TOMOGRAPHY

Positron emission tomography (PET) is used for imaging tissues with high levels of anaerobic glycolysis, such as malignant tumors.1 8 F-fluorodeoxyglucose is injected as a tracer; metabolism of this molecule then results in positron emission. PET has been used as an adjunct to CT in the staging of colorectal cancer and may prove useful in discriminating recurrent cancer from fibrosis. The combination of PET and CT technology recently has been introduced. By combining these modalities, anatomic correlation between regions of high isotope accumulation ("hot spots") on PET and abnormalities on CT can be determined. PET/CT increasingly is used to diagnose recurrent and/or metastatic colorectal cancer. However, the efficacy and use of this technology remains unproven.

ANGIOGRAPHY Angiography occasionally is used for the detection of bleeding within the colon or small bowel. To visualize hemorrhage angiographically, bleeding must be relatively brisk (approximately 0.5 to 1.0 mL per minute). If extravasation of contrast is identified, infusion of vasopressin or angiographic embolization can be therapeutic. CT and MR angiography also are useful for assessing patency of visceral vessels. This technique uses three dimensional reconstruction to detect vascular lesions. If an abnormality is found, more traditional techniques (angiography, surgery) may then be used to further define and/or correct the problem.

ENDORECTAL AND ENDOANAL ULTRASOUND Endorectal ultrasound is primarily used to evaluate the depth of invasion of neoplastic lesions in the rectum. The normal rectal wall appears as a five-layer structure (Fig. 29-6). Ultrasound can reliably differentiate most benign polyps from invasive tumors based upon the integrity of the submucosal layer. Ultrasound also can differentiate superficial T1–T2 from deeper T3–T4 tumors. Overall, the accuracy of ultrasound in detecting depth of mural invasion ranges between 81 and 94%.5 This modality also can detect enlarged perirectal lymph nodes, which may suggest nodal metastases; accuracy of detection of pathologically positive lymph nodes is 58 to 83%. Ultrasound may also prove useful for early detection of local recurrence after surgery.

Fig. 29-6.

A. Schematic of the layers of the rectal wall observed on endorectal ultrasonography. B. Normal endorectal ultrasonography. (A . Courtesy of Charles O. Finne III, MD, Minneapolis, MN.)

Endoanal ultrasound is used to evaluate the layers of the anal canal. Internal anal sphincter, external anal sphincter, and puborectalis muscle can be differentiated. Endoanal ultrasound is particularly useful for detecting sphincter defects and for outlining complex anal fistulas.

Physiologic and Pelvic Floor Investigations Anorectal physiologic testing uses a variety of techniques to investigate the function of the pelvic floor. These techniques are useful in the evaluation of patients with incontinence, constipation, rectal prolapse, obstructed defecation, and other disorders of the pelvic floor.

MANOMETRY Anorectal manometry is performed by placing a pressure-sensitive catheter in the lower rectum. The catheter is then withdrawn through the anal canal and pressures recorded. A balloon attached to the tip of the catheter also can be used to test anorectal sensation. The resting pressure in the anal canal reflects the function of the internal anal sphincter (normal: 40 to 80 mmHg), while the squeeze pressure , defined as the maximum voluntary

contraction pressure minus the resting pressure, reflects function of the external anal sphincter (normal: 40 to 80 mmHg above resting pressure). The high-pressure zone estimates the length of the anal canal (normal: 2.0 to 4.0 cm). The rectoanal inhibitory reflex can be detected by inflating a balloon in the distal rectum; absence of this reflex is characteristic of Hirschsprung's disease.

NEUROPHYSIOLOGY Neurophysiologic testing assesses function of the pudendal nerves and recruitment of puborectalis muscle fibers. Pudendal nerve terminal motor latency measures the speed of transmission of a nerve impulse through the distal pudendal nerve fibers (normal: 1.8 to 2.2 milliseconds); prolonged latency suggests the presence of neuropathy. Electromyography (EMG) recruitment assesses the contraction and relaxation of the puborectalis muscle during attempted defecation. Normally, recruitment increases when a patient is instructed to "squeeze," and decreases when a patient is instructed to "push." Inappropriate recruitment is an indication of paradoxical contraction (nonrelaxation of the puborectalis). Needle EMG has been used to map both the pudendal nerves and the anatomy of the internal and external sphincters. However, this examination is painful and poorly tolerated by most patients. Needle EMG has largely been replaced by pudendal nerve motor-latency testing to assess pudendal nerve function and endoanal ultrasound to map the sphincters.

RECTAL EVACUATION STUDIES Rectal evacuation studies include the balloon expulsion test and video defecography. Balloon expulsion assesses a patient's ability to expel an intrarectal balloon. Video defecography provides a more detailed assessment of defecation. In this test, barium paste is placed in the rectum and defecation is then recorded fluoroscopically. Defecography is used to differentiate nonrelaxation of the puborectalis, obstructed defecation, increased perineal descent, rectal prolapse and intussusception, rectocele, and enterocele. The addition of vaginal contrast and intraperitoneal contrast is useful in delineating complex disorders of the pelvic floor.

Laboratory Studies FECAL OCCULT BLOOD TESTING Fecal occult blood testing (FOBT) is used as a screening test for colonic neoplasms in asymptomatic, average-risk individuals. The efficacy of this test is based upon serial testing because the majority of colorectal malignancies will bleed intermittently. FOBT has been a nonspecific test for peroxidase contained in hemoglobin; consequently, occult bleeding from any GI source will produce a positive result. Similarly, many foods (red meat, some fruits and vegetables, and vitamin C) will produce a false-positive result. Patients were counseled to eat a restricted diet for 2 to 3 days before the test. Increased specificity is now possible by using immunochemical FOBT. These tests rely on monoclonal or polyclonal antibodies to react with the intact globin portion of human hemoglobin. Because globin does not survive in the upper GI tract, the immunochemical tests are more specific for identifying occult bleeding from the colon or rectum. Dietary restrictions are not necessary. Any positive FOBT mandates further investigation, usually by colonoscopy.

STOOL STUDIES Stool studies often are helpful in evaluating the etiology of diarrhea. Wet-mount examination reveals the presence of fecal leukocytes, which may suggest colonic inflammation or the presence of an invasive organism such as invasive E. coli or Shigella . Stool cultures can detect pathogenic bacteria, ova, and parasites. C. difficile colitis is diagnosed by detecting bacterial toxin in the stool. 6 Steatorrhea may be diagnosed by adding Sudan red stain to a stool sample.

SERUM TESTS Specific laboratory tests that should be performed will be dictated by the clinical scenario. Preoperative studies generally include a complete blood count and electrolyte panel. The addition of coagulation studies, liver function tests, and blood typing/cross-matching depends upon the patient's medical condition and the proposed surgical procedure.

TUMOR MARKERS Carcinoembryonic antigen (CEA) may be elevated in 60 to 90% of patients with colorectal cancer. Despite this, CEA is not an effective screening tool for this malignancy. Many practitioners follow serial CEA levels after curativeintent surgery to detect early recurrence of colorectal cancer. However, this tumor marker is nonspecific, and no survival benefit has yet been proven. Other biochemical markers (ornithine decarboxylase, urokinase) have been proposed, but none has yet proven sensitive or specific for detection, staging, or predicting prognosis of colorectal carcinoma.7

GENETIC TESTING Although familial colorectal cancer syndromes, such as familial adenomatous polyposis (FAP) and hereditary nonpolyposis colon cancer (HNPCC) are rare, information about the specific genetic abnormalities underlying these disorders has led to significant interest in the role of genetic testing for colorectal cancer.8 Tests for mutations in the adenomatous polyposis coli (APC) gene responsible for FAP, and in mismatch repair genes responsible for HNPCC, are commercially available and extremely accurate in families with known mutations. However, in the absence of an identified mutation, a negative result is uninformative. For individuals from high-risk families without an identified mutation, increased surveillance is recommended.9 Although many of these mutations also are present in sporadic colorectal cancer, the accuracy of genetic testing in average-risk individuals is considerably lower and these tests are not recommended for screening. Because of the potential psychosocial implications of genetic testing, it is strongly recommended that professional genetic counselors be involved in the care of any patient considering these tests.

Evaluation of Common Symptoms PAIN Abdominal pain is a nonspecific symptom with a myriad of causes. Abdominal pain related to the colon and rectum can result from obstruction (either inflammatory or neoplastic), inflammation, perforation, or ischemia. Plain x-rays and judicious use of contrast studies and/or a CT scan often can confirm the diagnosis. Gentle retrograde contrast studies (barium or Gastrografin enema) may be useful in delineating the degree of colonic obstruction. Sigmoidoscopy and/or colonoscopy performed by an experienced endoscopist can assist in the diagnosis of ischemic colitis, infectious colitis, and inflammatory bowel disease. However, if perforation is suspected, colonoscopy and/or sigmoidoscopy generally are contraindicated. Evaluation and treatment of abdominal pain from a colorectal source should follow the usual surgical principles of a thorough history and physical examination, appropriate diagnostic tests, resuscitation, and appropriately timed surgical intervention. Pelvic pain can originate from the distal colon and rectum or from adjacent urogenital structures. Tenesmus may result from proctitis or from a rectal or retrorectal mass. Cyclical pain associated with menses, especially when accompanied by rectal bleeding, suggests a diagnosis of endometriosis. Pelvic inflammatory disease also can produce significant abdominal and pelvic pain. The extension of a peridiverticular abscess or periappendiceal abscess into the pelvis may also cause pain. CT scan and/or MRI may be useful in differentiating these diseases.

Proctoscopy (if tolerated) also can be helpful. Occasionally, laparoscopy will yield a diagnosis. Anorectal pain is most often secondary to an anal fissure, perirectal abscess and/or fistula, or a thrombosed hemorrhoid. Physical examination usually can differentiate these conditions. Other, less common causes of anorectal pain include anal canal neoplasms, perianal skin infection, and dermatologic conditions. Proctalgia fugax results from levator spasm and may present without any other anorectal findings. Physical examination is critical in evaluating patients with anorectal pain. If a patient is too tender to examine in the office, an examination under anesthesia is necessary. MRI or other imaging studies may be helpful in select cases where the etiology of pain is elusive.

LOWER GASTROINTESTINAL BLEEDING The first goal in evaluating and treating a patient with GI hemorrhage is adequate resuscitation. The principles of ensuring a patent airway, supporting ventilation, and optimizing hemodynamic parameters apply and coagulopathy and/or thrombocytopenia should be corrected. The second goal is to identify the source of hemorrhage. Because the most common source of GI hemorrhage is esophageal, gastric, or duodenal, nasogastric aspiration should always be performed; return of bile suggests that the source of bleeding is distal to the ligament of Treitz. If aspiration reveals blood or nonbile secretions, or if symptoms suggest an upper intestinal source, esophagogastroduodenoscopy is performed. Anoscopy and/or limited proctoscopy can identify hemorrhoidal bleeding. A technetium-99–tagged red blood cell scan is extremely sensitive and is able to detect as little as 0.1 mL/h of bleeding; however, localization is imprecise. If the technetium-99–tagged red blood cell scan is positive, angiography can then be used to localize bleeding. Infusion of vasopressin or angioembolization may be therapeutic. Alternatively, a catheter can be left in the bleeding vessel to allow localization at the time of laparotomy. If the patient is hemodynamically stable, a rapid bowel preparation (over 4 to 6 hours) can be performed to allow colonoscopy. Colonoscopy may identify the cause of the bleeding, and cautery or injection of epinephrine into the bleeding site may be used to control hemorrhage. Colectomy may be required if bleeding persists despite these interventions. Intraoperative colonoscopy and/or enteroscopy may assist in localizing bleeding. If colectomy is required, a segmental resection is preferred if the bleeding source can be localized. "Blind" subtotal colectomy may very rarely be required in a patient who is hemodynamically unstable with ongoing colonic hemorrhage of an unknown source. In this setting, it is crucial to irrigate the rectum and examine the mucosa by proctoscopy to ensure that the source of bleeding is not distal to the resection margin (Fig. 29-7).

Fig. 29-7.

Algorithm for treatment of colorectal hemorrhage. NG = nasogastric;

99m

Tc = technetium-99; RBC = red blood cell.

[Reproduced with permission from Gordon PH, Nivatvongs S (eds): Principles and Practice of Surgery for the Colon, Rectum, and Anus, 2nd ed. New York: Marcel Dekker, Inc., 1999, p 1279.]

Occult blood loss from the GI tract may manifest as iron-deficiency anemia or may be detected with FOBT. Because colon neoplasms bleed intermittently and rarely present with rapid hemorrhage, the presence of occult fecal blood should always prompt a colonoscopy. Unexplained iron-deficiency anemia is also an indication for colonoscopy. Hematochezia commonly is caused by hemorrhoids or fissure. Sharp, knife-like pain and bright-red rectal bleeding with bowel movements suggest the diagnosis of fissure. Painless, bright-red rectal bleeding with bowel movements often is secondary to a friable internal hemorrhoid that is easily detected by anoscopy. In the absence of a painful, obvious fissure, any patient with rectal bleeding should undergo a careful digital rectal examination, anoscopy, and proctosigmoidoscopy. Failure to diagnose a source in the distal anorectum should prompt colonoscopy.

CONSTIPATION AND OBSTRUCTED DEFECATION Constipation is an extremely common complaint, affecting more than 4 million people in the United States. Despite

the prevalence of this problem, there is lack of agreement about an appropriate definition of constipation. Patients may describe infrequent bowel movements, hard stools, or excessive straining. A careful history of these symptoms often clarifies the nature of the problem. Constipation has a myriad of causes. Underlying metabolic, pharmacologic, endocrine, psychological, and neurologic causes often contribute to the problem. A stricture or mass lesion should be excluded by colonoscopy or barium enema. After these causes have been excluded, evaluation focuses on differentiating slow-transit constipation from outlet obstruction . Transit studies, in which radiopaque markers are swallowed and then followed radiographically, are useful for diagnosing slow-transit constipation. Anorectal manometry and EMG can detect nonrelaxation of the puborectalis, which contributes to outlet obstruction. The absence of an anorectal inhibitory reflex suggests Hirschsprung's disease and may prompt a rectal mucosal biopsy. Defecography can identify rectal prolapse, intussusception, rectocele, or enterocele. Medical management is the mainstay of therapy for constipation and includes fiber, increased fluid intake, and laxatives. Outlet obstruction from nonrelaxation of the puborectalis often responds to biofeedback.1 0 Surgery to correct rectocele and rectal prolapse has a variable effect on symptoms of constipation, but can be successful in selected patients. Subtotal colectomy is considered only for patients with severe slow-transit constipation (colonic inertia) refractory to maximal medical interventions. Although this operation almost always increases bowel movement frequency, complaints of diarrhea, incontinence, and abdominal pain are not infrequent, and patients should be carefully selected.1 1

DIARRHEA AND IRRITABLE BOWEL SYNDROME Diarrhea is also a common complaint and is usually a self-limited symptom of infectious gastroenteritis. If diarrhea is chronic or is accompanied by bleeding or abdominal pain, further investigation is warranted. Bloody diarrhea and pain are characteristic of colitis; etiology can be an infection (invasive E. coli , Shigella , Salmonella , Campylobacter , Entamoeba histolytica , or C. difficile ), inflammatory bowel disease (ulcerative colitis or Crohn's colitis), or ischemia. Stool wet-mount and culture often can diagnose infection. Sigmoidoscopy or colonoscopy can be helpful in diagnosing inflammatory bowel disease or ischemia. However, if the patient has abdominal tenderness, particularly with peritoneal signs, or any other evidence of perforation, endoscopy is contraindicated. Chronic diarrhea may present a more difficult diagnostic dilemma. Chronic ulcerative colitis, Crohn's colitis, infection, malabsorption, and short-gut syndrome can cause chronic diarrhea. Rarely, carcinoid syndrome and islet cell tumors (vasoactive intestinal peptide-secreting tumor, somatostatinoma, gastrinoma) present with this symptom. Large villous lesions may cause secretory diarrhea. Collagenous colitis can cause diarrhea without any obvious mucosal abnormality. Along with stool cultures, tests for malabsorption, and metabolic investigations, colonoscopy can be invaluable in differentiating these causes. Biopsies should be taken even if the colonic mucosa appears grossly normal. Irritable bowel syndrome is a particularly troubling constellation of symptoms consisting of crampy abdominal pain, bloating, constipation, and urgent diarrhea. Work-up reveals no underlying anatomic or physiologic abnormality. Once other disorders have been excluded, dietary restrictions and avoidance of caffeine, alcohol, and tobacco may help to alleviate symptoms. Antispasmodics and bulking agents may be helpful.

INCONTINENCE The incidence of fecal incontinence has been estimated to occur in 10 to 13 individuals per 1000 people older than age 65 years. Incontinence ranges in severity from occasional leakage of gas and liquid stool to daily loss of solid

stool. The underlying cause of incontinence is often multifactorial and diarrhea often is contributory. In general, causes of incontinence can be classified as neurogenic or anatomic . Neurogenic causes include diseases of the central nervous system and spinal cord along with pudendal nerve injury. Anatomic causes include congenital abnormalities, procidentia, overflow incontinence secondary to impaction or neoplasm, and trauma. The most common traumatic cause of incontinence is injury to the anal sphincter during vaginal delivery. Other causes include anorectal surgery, impalement, and pelvic fracture. After a thorough medical evaluation to detect underlying conditions that might contribute to incontinence, evaluation focuses on assessment of the anal sphincter and pudendal nerves. Pudendal nerve terminal motor latency testing may detect neuropathy. Anal manometry can detect low resting and squeeze pressures. Defecography can detect rectal prolapse. Endoanal ultrasound is invaluable in diagnosing sphincter defects (Fig. 29-8).

Fig. 29-8.

A. Endoanal ultrasonography showing the normal layers of the anal canal. B. Endoanal ultrasonography with anterior sphincter defect from birthing injury. EAS = external anal sphincter; IAS = internal anal sphincter. (Both images courtesy of Charles O. Finne III, MD, Minneapolis, MN.)

Therapy depends upon the underlying abnormality. Diarrhea should be treated medically (fiber, antidiarrheal agents). Even in the absence of frank diarrhea, the addition of dietary fiber may improve continence. Some patients may respond to biofeedback. Many patients with a sphincter defect are candidates for an overlapping sphincteroplasty. Innovative technologies that focus on stimulating the sacral nerve roots via an implantable nerve stimulator or replacing a damaged or poorly functioning sphincter with an artificial sphincter are proving useful in patients who fail other interventions.12,13 The delivery of radiofrequency energy to the anal canal (the Secca procedure) also has been proposed.1 4 Finally, a stoma can provide relief for severely incontinent patients who have failed or are not candidates for other interventions.1 5

GENERAL SURGICAL CONSIDERATIONS Colorectal resections are performed for a wide variety of conditions, including neoplasms (benign and malignant), inflammatory bowel diseases, and other benign conditions. Although the indication and urgency for surgery will

alter some of the technical details, the operative principles of colorectal resections, anastomoses, and use of ostomies are well established. These principles and general considerations for anesthesia and other operative preliminaries are outlined here.

Resections The mesenteric clearance technique dictates the extent of colonic resection and is determined by the nature of the primary pathology (malignant or benign), the intent of the resection (curative or palliative), the precise location(s) of the primary pathology, and the condition of the mesentery (thin and soft or thickened and indurated). In general, a proximal mesenteric ligation will eliminate the blood supply to a greater length of colon and require a more extensive "colectomy." Curative resection of a colorectal cancer usually is accomplished best by performing a proximal mesenteric vessel ligation and radical mesenteric clearance of the lymphatic drainage basin of the tumor site with concomitant resection of the overlying omentum (Fig. 29-9). Resection of a benign process does not require wide mesenteric resection and the omentum can be preserved, if desired.

Fig. 29-9.

Extent of resection for carcinoma of the colon. A. Cecal cancer. B. Hepatic flexure cancer. C. Transverse colon cancer. D. Splenic flexure cancer. E. Descending colon cancer. F. Sigmoid colon cancer.

EMERGENCY RESECTION Emergency resection may be required because of obstruction, perforation, or hemorrhage. In this setting, the bowel is almost always unprepared and the patient may be unstable. The surgical principles described above in Resections apply and an attempt should be made to resect the involved segment along with its lymphovascular supply. If the resection involves the right colon or proximal transverse colon (right or extended right colectomy), a primary ileocolonic anastomosis usually can be performed safely as long as the remaining bowel appears healthy and the patient is stable. For left-sided tumors, the traditional approach has involved resection of the involved bowel and end colostomy, with or without a mucus fistula. However, there is an increasing body of data to suggest that a primary anastomosis without a bowel preparation or with an on-table lavage, with or without a diverting ileostomy, may be equally safe in this setting. If the proximal colon looks unhealthy (vascular compromise, serosal tears, perforation), a subtotal colectomy can be performed with a small bowel to rectosigmoid anastomosis. Resection and diversion (ileostomy or colostomy) remains safe and appropriate if the bowel looks compromised or if the patient is unstable, malnourished, or immunosuppressed.

MINIMALLY INVASIVE TECHNIQUES OF RESECTION With advances in minimally invasive technology, many procedures that previously have required laparotomy can

now be performed laparoscopically or with hand-assisted laparoscopy . Potential advantages of laparoscopy include improved cosmetic result, decreased postoperative pain, and earlier return of bowel function. Moreover, some experimental data suggest that minimally invasive operations have less immunosuppressive impact on the patient and thus might improve postoperative outcome and even long-term survival. To date, most studies have demonstrated equivalence between laparoscopic and open resection in terms of extent of resection. However, laparoscopic colon resections are technically demanding and consistently require longer operative time than do open procedures. Return of bowel function and length of hospital stay are highly variable. Long-term outcome has yet to be determined; however, short-term quality of life appears to be improved by laparoscopy.1 6 As training in minimally invasive techniques improves, laparoscopic colon resection increasingly is gaining popularity. The most recent advances in minimally invasive surgery involves use of robotics and telemanipulation in which the surgeon operates from a console remote from the patient. Robotic colectomy has been performed and appears to be technically feasible.1 7 However, to date there has been no demonstrated advantage for robotic resection over laparoscopic resection.

COLECTOMY A variety of terms are used to describe different types of colectomy (Fig. 29-10).

Fig. 29-10.

Terminology of types of colorectal resections: A C Ileocecectomy; + A + B D Ascending colectomy; + A + B F Right hemicolectomy; + A + B G Extended right hemicolectomy; + E + F G + H Transverse colectomy; G I Left hemicolectomy; F I Extended left hemicolectomy; J + K Sigmoid colectomy; + A + B J Subtotal colectomy; + A + B K Total colectomy; + A + B L Total proctocolectomy. [Reproduced with permission from Fielding LP, Goldberg SM (eds): Rob & Smith's Operative: Surgery of the Colon, Rectum, and Anus. UK: Elsevier Science Ltd., 1993, p 349.]

Ileocolic Resection An ileocolic resection describes a limited resection of the terminal ileum, cecum, and appendix. It is used to remove disease involving these segments of the intestine (e.g., ileocecal Crohn's disease) and benign lesions or incurable cancers arising in the terminal ileum, cecum, and, occasionally, the appendix. If curable malignancy is suspected, more radical resections, such as a right hemicolectomy, generally are indicated. The ileocolic vessels are ligated and divided. A variable length of small intestine may be resected, depending upon the disease process. A primary anastomosis is created between the distal small bowel and the ascending colon. It is technically difficult to perform an anastomosis at or just proximal to the ileocecal valve; therefore, if the most distal ileum needs to be resected, the cecum generally also is removed.

Right Colectomy A right colectomy is used to remove lesions or disease in the right colon and is oncologically the most appropriate operation for curative intent resection of proximal colon carcinoma. The ileocolic vessels, right colic vessels, and right branches of the middle colic vessels are ligated and divided. Approximately 10 cm of terminal ileum usually are included in the resection. A primary ileal-transverse colon anastomosis is almost always possible.

Extended Right Colectomy An extended right colectomy may be used for curative intent resection of lesions located at the hepatic flexure or proximal transverse colon. A standard right colectomy is extended to include ligation of the middle colic vessels at their base. The right colon and proximal transverse colon are resected, and a primary anastomosis is created between the distal ileum and distal transverse colon. Such an anastomosis relies on the marginal artery of Drummond. If the blood supply is questionable, the resection is extended to include the splenic flexure and the anastomosis of ileum is to the descending colon.

Transverse Colectomy Lesions in the mid and distal transverse colon may be resected by ligating the middle colic vessels and resecting the transverse colon, followed by a colocolonic anastomosis. However, an extended right colectomy with an anastomosis between the terminal ileum and descending colon may be a safer anastomosis with an equivalent functional result.

Left Colectomy For lesions or disease states confined to the distal transverse colon, splenic flexure, or descending colon, a left colectomy is performed. The left branches of the middle colic vessels, the left colic vessels, and the first branches of the sigmoid vessels are ligated. A colocolonic anastomosis usually can be performed.

Extended Left Colectomy An extended left colectomy is an option for removing lesions in the distal transverse colon. In this operation, the left colectomy is extended proximally to include the right branches of the middle colic vessels.

Sigmoid Colectomy Lesions in the sigmoid colon require ligation and division of the sigmoid branches of the inferior mesenteric artery. In general, the entire sigmoid colon should be resected to the level of the peritoneal reflection and an anastomosis created between the descending colon and upper rectum. Full mobilization of the splenic flexure often is required to create a tension-free anastomosis.

Total and Subtotal Colectomy Total or subtotal colectomy occasionally is required for patients with fulminant colitis, attenuated FAP (AFAP), or synchronous colon carcinomas. In this procedure, the ileocolic vessels, right colic vessels, middle colic vessels, and left colic vessels are ligated and divided. The superior rectal vessels are preserved. If it is desired to preserve the sigmoid, the distal sigmoid vessels are left intact and an anastomosis is created between the ileum and distal sigmoid colon (subtotal colectomy with ileosigmoid anastomosis). If the sigmoid is to be resected, the sigmoidal vessels are ligated and divided, and the ileum is anastomosed to the upper rectum (total abdominal colectomy with ileorectal anastomosis). If an anastomosis is contraindicated, an end-ileostomy is created and the remaining sigmoid or rectum is managed either as a mucus fistula or a Hartmann pouch.

PROCTOCOLECTOMY Total Proctocolectomy In this procedure, the entire colon, rectum, and anus are removed and the ileum is brought to the skin as a Brooke ileostomy.

Restorative Proctocolectomy (Ileal Pouch Anal Anastomosis) The entire colon and rectum are resected, but the anal sphincter muscles and a variable portion of the distal anal canal are preserved. Bowel continuity is restored by anastomosis of an ileal reservoir to the anal canal. The original technique included a transanal mucosectomy and handsewn ileoanal anastomosis. Proponents of this technique argue that mucosectomy guarantees removal of all of the diseased mucosa, including the anal transition zone, and therefore decreases the risk of ongoing disease, dysplasia, and carcinoma.1 8 Opponents cite the increased risk of incontinence after mucosectomy and argue that even meticulous technique invariably leaves behind mucosal "islands" that are subsequently hidden under the anastomosis. Moreover, the "double-staple" technique using the circular stapling devices is considerably simpler than mucosectomy and a handsewn anastomosis (Fig. 29-11).1 9 Regardless of the anastomotic technique, many surgeons recommend that patients undergo annual surveillance of the anastomosis and/or anal transition zone by digital rectal exam and anoscopy or proctoscopy.

Fig. 29-11.

After a total colectomy and resection of the rectum (A ), the anal canal with a short cuff of transitional mucosa and sphincter muscles is preserved (B ). An ileal J-pouch has been constructed and is anastomosed to the anal canal using a double-staple technique (C ). [Reproduced with permission from Bell RH, Rikkers LF, Mulholland M (eds): Digestive Tract Surgery: A Text and Atlas. Philadelphia: Lippincott Williams & Wilkins, 1996, p 1527.]

The neorectum is made by anastomosis of the terminal ileum aligned in a "J," "S," or "W" configuration. Because functional outcomes are similar and because the J-pouch is the simplest to construct, it has become the most used configuration. With increasing experience in laparoscopic colectomy, some centers have begun performing total proctocolectomy with ileal pouch anal reconstruction using minimally invasive surgical techniques. Most surgeons

perform a proximal ileostomy to divert succus from the newly created pouch in an attempt to minimize the consequences of leak and sepsis, especially in patients who are malnourished or immunosuppressed (Fig. 29-12). The ileostomy is then closed 6 to 12 weeks later, after a contrast study confirms the integrity of the pouch. In lowrisk patients, however, there are reports of successful creation of an ileoanal pouch without diverting stoma.2 0

Fig. 29-12.

Ileal S-pouch anal anastomosis with temporary loop ileostomy. [Reproduced with permission from Bell RH, Rikkers LF, Mulholland M (eds): Digestive Tract Surgery: A Text and Atlas. Philadelphia: Lippincott Williams & Wilkins, 1996, p 1533.]

ANTERIOR RESECTION Anterior resection is the general term used to describe resection of the rectum from an abdominal approach to the pelvis with no need for a perineal, sacral, or other incision. Three types of anterior resection have been described.

High Anterior Resection A high anterior resection is the term used to describe resection of the distal sigmoid colon and upper rectum and is the appropriate operation for benign lesions and disease at the rectosigmoid junction such as diverticulitis. The

upper rectum is mobilized but the pelvic peritoneum is not divided and the rectum is not mobilized fully from the concavity of the sacrum. The inferior mesenteric artery is ligated at its base and the inferior mesenteric vein, which follows a different course than the artery, is ligated separately. A primary anastomosis (usually end-to-end) between the colon and rectal stump with a short cuff of peritoneum surrounding its anterior two thirds generally can be performed.

Low Anterior Resection A low anterior resection is used to remove lesions in the upper and midrectum. The rectosigmoid is mobilized, the pelvic peritoneum is opened, and the inferior mesenteric artery is ligated and divided either at its origin from the aorta or just distal to the takeoff of the left colic artery. The rectum is mobilized from the sacrum by sharp dissection under direct view within the endopelvic fascial plane. The dissection may be performed distally to the anorectal ring, extending posteriorly through the rectosacral fascia to the coccyx and anteriorly through Denonvilliers' fascia to the vagina in women or the seminal vesicles and prostate in men. The rectum and accompanying mesorectum are divided at the appropriate level, depending upon the nature of the lesion. A low rectal anastomosis usually requires mobilization of the splenic flexure and ligation and division of the inferior mesenteric vein just inferior to the pancreas. Circular stapling devices have greatly facilitated the conduct and improved the safety of the colon to extraperitoneal rectal anastomosis.

Extended Low Anterior Resection An extended low anterior resection is necessary to remove lesions located in the distal rectum, but several centimeters above the sphincter. The rectum is fully mobilized to the level of the levator ani muscle just as for a low anterior resection, but the anterior dissection is extended along the rectovaginal septum in women and distal to the seminal vesicles and prostate in men. After resection at this level, a coloanal anastomosis can be created using one of a variety of techniques described below in Anastomoses. Because the risk of an anastomotic leak and subsequent sepsis is higher when an anastomosis is created in the distal rectum or anal canal, creation of a temporary ileostomy should be considered in this setting. Although an anastomosis may be technically feasible very low in the rectum or anal canal, it is important to note that postoperative function may be poor. Because the descending colon lacks the distensibility of the rectum, the reservoir function may be compromised. Pelvic radiation, prior anorectal surgery, and obstetric trauma may cause unsuspected sphincter damage. Finally, a very low anastomosis may involve and compromise the upper sphincter. Creation of a colon J-pouch improves function during the first postoperative year. 2 1 A history of sphincter damage or any degree of incontinence is a relative contraindication for a coloanal anastomosis. In such patients, an end colostomy may be a more satisfactory option.

HARTMANN'S PROCEDURE AND MUCUS FISTULA Hartmann's procedure refers to a colon or rectal resection without an anastomosis in which a colostomy or ileostomy is created and the distal colon or rectum is left as a blind pouch. The term typically is used when the left or sigmoid colon is resected and the closed off rectum is left in the pelvis. If the distal colon is long enough to reach the abdominal wall, a mucus fistula can be created by opening the defunctioned bowel and suturing it to the skin.

ABDOMINOPERINEAL RESECTION An abdominoperineal resection (APR) involves removal of the entire rectum, anal canal, and anus with construction of a permanent colostomy from the descending or sigmoid colon. The abdominal-pelvic portion of this operation

proceeds in the same fashion as described for an extended low anterior resection. The perineal dissection can be performed with the patient in lithotomy position (often by a second surgeon) or in the prone position after closure of the abdomen and creation of the colostomy. For cancer, the perineal dissection is designed to excise the anal canal with a wide circumferential margin. Primary wound closure usually is successful but the large perineal defect, especially if radiation has been used, may require a vascularized flap closure in some patients. For benign disease, proctectomy may be performed using an intersphincteric dissection between the internal and external sphincters. This approach minimizes the perineal wound making it easier to close because the levator muscle remains intact.

Anastomoses Anastomoses may be created between two segments of bowel in a multitude of ways. The geometry of the anastomosis may be end-to-end , end-to-side , side-to-end , or side-to-side . The anastomotic technique may be handsewn (single or double layer ) or stapled (Fig. 29-13). The submucosal layer of the intestine provides the strength of the bowel wall and must be incorporated in the anastomosis to assure healing. The choice of anastomosis depends upon the operative anatomy and surgeon preference. Although many surgeons advocate one method over another, none has been proven to be superior. Accurate approximation of two well-vascularized, healthy limbs of bowel without tension in a normotensive, well-nourished patient almost always results in a good outcome. Anastomoses at highest risk of leak or stricture are those that are in the distal rectal or anal canal, involve irradiated or diseased intestine, or are performed in malnourished, ill patients.

Fig. 29-13.

A. Sutured end-to-end colocolic anastomosis. B. Sutured end-to-side ileocolic anastomosis. C. Stapled side-to-side, functional end-to-end ileocolic anastomosis. [Reproduced with permission from Bell RH, Rikkers LF, Mulholland M (eds): Digestive Tract Surgery: A Text and Atlas. Philadelphia: Lippincott Williams & Wilkins, 1996, pp 1473, 1475, and 1479.]

ANASTOMOTIC CONFIGURATION End-to-End An end-to-end anastomosis can be performed when two segments of bowel are roughly the same caliber. This technique most often is used in rectal resections, but may be used for colocolostomy or small bowel anastomoses.

End-to-Side An end-to-side configuration is useful when one limb of bowel is larger than the other. This most commonly occurs in the setting of chronic obstruction.

Side-to-End A side-to-end anastomosis is used when the proximal bowel is of smaller caliber than the distal bowel. Ileorectal anastomoses commonly make use of this configuration. A side-to-end anastomosis may have a less tenuous blood supply than an end-to-end anastomosis.

Side-to-Side A side-to-side anastomosis allows a large, well-vascularized connection to be created on the antimesenteric side of two segments of intestine. This technique is commonly used in ileocolic and small bowel anastomoses.

ANASTOMOTIC TECHNIQUE Hand-Sutured Technique Any of the configurations described above under Anastomotic Configuration may be created using a hand-sutured or stapled technique. Hand-sutured anastomoses may be single layer , using either running or interrupted stitches, or double layer . A double-layer anastomosis usually consists of a continuous inner layer and an interrupted outer layer. Suture material may be either permanent or absorbable. After distal rectal or anal canal resection, a transanal, handsewn coloanal anastomosis may be necessary to restore bowel continuity. This can be done in conjunction with an anal canal mucosectomy to allow the anastomosis to be at the dentate line.

Stapled Techniques Linear cutter stapling devices are used to divide the bowel and to create side-to-side anastomoses. The anastomosis may be reinforced with interrupted sutures if desired. Circular stapling devices can create end-to-end, end-to-side, or side-to-end anastomoses. These instruments are particularly useful for creating low rectal or anal canal anastomoses where the anatomy of the pelvis makes a handsewn anastomosis technically difficult or impossible. Following resection of the colorectum, a stapled end-to-end colorectal, coloanal canal, or ileal pouch anal canal anastomosis may be created by one of two techniques. With the open purse-string technique, the distal rectal stump pursestring is placed by hand and the assembled circular stapler is inserted into the anus and guided up to the rectal pursestring. The stapler is opened and the distal pursestring is tied. A pursestring is placed in the distal end of the proximal colon; the proximal colon is placed over the anvil and the pursestring tightened. The stapler is closed and fired (Fig. 29-14). With the alternative double-staple technique , the distal rectum or anal canal is closed with a transverse staple line. The circular stapler is inserted through the anus without its anvil until the cartridge effaces the transverse staple line. The stapler is opened, causing the trocar to perforate through the rectal stump adjacent to the transverse staple line. A pursestring is placed in the distal end of the proximal colon or the end of the ileal pouch. The stapler anvil is inserted into the proximal colon or ileal pouch and the pursestring is tightened around the anvil. The anvil is mated to the trocar and the stapler closed and fired (see Fig. 29-11). After firing and removing the stapler, the resulting anastomotic rings should be inspected to ensure that they are intact. A gap in an anastomotic ring suggests that the circular staple line is incomplete and the anastomosis should be reinforced with suture circumferentially, if technically feasible. A temporary proximal ileostomy may be indicated as well.

Fig. 29-14.

Technique of end-to-end colorectal anastomosis using a circular stapler. A. The patient is in modified lithotomy position. B. After resection of the rectosigmoid and placement of purse-string sutures proximally and distally, the stapler is inserted into the anal canal and opened. C. Rectal purse-string suture is tied to secure the rectal stump to the rod of the stapler, and the colonic pursestring is tied to secure the colon to the anvil of the stapler. D. The stapler is closed and fired. E. The stapler is removed, leaving a circular stapled end-to-end anastomosis.

Ostomies

Depending upon the clinical situation, a stoma may be temporary or permanent. It may be end-on or a loop. However, regardless of the indication for a stoma, placement and construction are crucial for function. A stoma should be located within the rectus muscle to minimize the risk of a postoperative parastomal hernia. It also should be placed where the patient can see it and easily manipulate the appliance. The surrounding abdominal soft tissue should be as flat as possible to ensure a tight seal and prevent leakage. Preoperative evaluation by an enterostomal therapy (ET) nurse to identify the ideal stoma site and to counsel and educate the patient is invaluable (Fig. 29-15).

Fig. 29-15.

Marking of an ideal site for ileostomy. [Reproduced with permission from Bell RH, Rikkers LF, Mulholland M (eds): Digestive Tract Surgery: A Text and Atlas . Philadelphia: Lippincott Williams & Wilkins, 1996, p 1273.]

For all stomas, a circular skin incision is created and the subcutaneous tissue dissected to the level of the anterior

rectus sheath. The anterior rectus sheath is incised in a cruciate fashion, the muscle fibers separated bluntly, and the posterior sheath identified and incised. The size of the defect depends upon the size of the bowel used to create the stoma, but should be as small as possible without compromising the intestinal blood supply (usually the width of two to three fingers). The bowel is then brought through the defect and secured. The abdominal incision is usually closed and dressed before maturing the stoma to avoid contaminating the wound. To make appliance use easier, a protruding nipple is fashioned by everting the bowel. Three or four interrupted absorbable sutures are placed through the edge of the bowel, then through the serosa, approximately 2 cm proximal to the edge, and then through the dermis (Brooke technique). After the stoma is everted, the mucocutaneous junction is sutured circumferentially with interrupted absorbable suture (Fig. 29-16).

Fig. 29-16.

Brooke ileostomy. A. Four sutures incorporating the cut end of the ileum, the seromuscular layer at the level of the anterior rectus fascia, and the subcuticular edge of the skin are placed at 90 to each other. B. The sutures are tied to produce stomal eversion, and (C ) simple sutures from the cut edge of the bowel to the subcuticular tissue complete the maturation of the ileostomy. [Reproduced with permission from Bell RH, Rikkers LF, Mulholland M (eds): Digestive Tract Surgery: A Text and Atlas. Philadelphia: Lippincott Williams & Wilkins, 1996, p 1278.]

ILEOSTOMY Temporary Ileostomy A temporary ileostomy often is used to "protect" an anastomosis that is at risk for leakage (low in the rectum, in an irradiated field, in an immunocompromised or malnourished patient, and in some emergency operations). In this setting, the stoma often is constructed as a loop ileostomy (see Fig. 29-12). A segment of distal ileum is brought through the defect in the abdominal wall as a loop. An enterotomy is created and the stoma matured as described above in Ostomies. The loop may be secured with or without an underlying rod. A divided loop may also be created by firing a linear cutter stapler across the distal limb of the loop flush with the skin followed by maturation of the proximal limb of the loop. This technique prevents incomplete diversion that occasionally occurs with a loop ileostomy. The advantage of a loop or divided loop ileostomy is that subsequent closure often can be accomplished without a formal laparotomy. An elliptical incision is created around the stoma and the bowel gently dissected free of the subcutaneous tissues and fascia. A handsewn or stapled anastomosis can then be created and the intestine returned to the peritoneal cavity. This avoids a long laparotomy incision and generally is well tolerated. Timing of ileostomy closure should take into account anastomotic healing as well as the patient's overall condition. A flexible endoscopy exam and a contrast enema (Gastrografin) are recommended before closure to ensure that the anastomosis has not leaked and is patent. A patient's nutritional status should be optimized. In cancer patients receiving adjuvant chemotherapy, ileostomy closure should be delayed until chemotherapy is completed.

Permanent Ileostomy A permanent ileostomy sometimes is required after total proctocolectomy or in patients with obstruction. An end ileostomy is the preferred configuration for a permanent ileostomy because a symmetric protruding nipple can be fashioned more easily than with a loop ileostomy (see Fig. 29-16). The end of the small intestine is brought through the abdominal wall defect and matured. Stitches often are used to secure the bowel to the posterior fascia.

Complications of Ileostomy Stoma necrosis may occur in the early postoperative period and usually is caused by skeletonizing the distal small bowel and/or creating an overly tight fascial defect. Limited mucosal necrosis above the fascia may be treated expectantly, but necrosis below the level of the fascia requires surgical revision. Stoma retraction may occur early or late, and may be exacerbated by obesity. Local revision may be necessary. The creation of an ileostomy bypasses the fluid absorbing capability of the colon, and dehydration with fluid and electrolyte abnormalities is not uncommon. Ideally, ileostomy output should be maintained at less than 1500 mL/d to avoid this problem. Bulk agents and opioids (Lomotil, Imodium, tincture of opium) are useful. The somatostatin analogue, Octreotide, has been used with variable success in this setting. Skin irritation also can occur, especially if the stoma appliance fits poorly. Skin protecting agents and custom pouches can help to solve this problem. Obstruction may occur intraabdominally or at the site where the stoma exits the fascia. Parastomal hernia is less common after an ileostomy than after a colostomy, but can cause poor appliance fitting, pain, obstruction, or strangulation. In general, symptomatic parastomal hernias should be repaired. Repair usually requires re-siting the stoma to the contralateral side of the abdomen. Prolapse is a rare, late complication and often is associated with a parastomal hernia. Valve slippage resulting in either leakage or obstruction is a common complication of a continent Kock pouch ileostomy.

COLOSTOMY

Most colostomies are created as end colostomies rather than loop colostomies (Fig. 29-17). The bulkiness of the colon makes a loop colostomy awkward for an appliance, and prolapse is more likely with this configuration. Most colostomies are created on the left side of the colon. An abdominal wall defect is created and the end of the colon mobilized through it. Because a protruding stoma is considerably easier to pouch, colostomies also should be matured in a Brooke fashion. The distal bowel may be brought through the abdominal wall as a mucus fistula or left intra-abdominally as a Hartmann's pouch . Tacking the distal end of the colon to the abdominal wall or tagging it with permanent suture can make identification of the stump easier if the colostomy is closed at a later date. Closure of a colostomy usually requires laparotomy. The stoma is dissected free of the abdominal wall and the distal bowel identified. An end-to-end anastomosis is then created.

Fig. 29-17.

Intraperitoneal end colostomy.

Complications of Colostomy Colostomy necrosis may occur in the early postoperative period and results from an impaired vascular supply (skeletonization of the distal colon or a tight fascial defect). Like ileostomy necrosis, limited suprafascial necrosis may be followed expectantly, but necrosis below the fascia requires surgery. Retraction may also occur, but is less problematic with a colostomy than with an ileostomy because the stool is less irritating to the skin than succus entericus . Obstruction is unusual, but may also occur. Parastomal hernia is the most common late complication of

a colostomy and requires repair if it is symptomatic. Prolapse occurs rarely. Dehydration is rare after colostomy and skin irritation is less common than with ileostomy.

Functional Results Function following segmental colonic resection and primary anastomosis generally is excellent. A small percentage of patients following subtotal or total colectomy and ileosigmoid or ileorectal anastomosis may experience diarrhea and bowel frequency. This is especially true if the patient is elderly, if significant length of small bowel has been resected, and if residual proctocolitis is poorly controlled. In general, the more distal the anastomosis, the more the risk of troublesome diarrhea and frequency. Function following anterior resection is highly dependent on the level of anastomosis, the use of pre- or postoperative pelvic radiation, and underlying sphincter function. Following low anterior or extended low anterior resection, some surgeons prefer to construct a short (8 to 10 cm) colon-J-pouch to anastomose to the distal rectum or anal canal. The reservoir lessens urgency, frequency, and incontinence, but some patients have difficulty initiating defecation after construction of a colon-J-pouch.2 1 The physical and psychological problems associated with a permanent Brooke ileostomy led to development of the continent Kock pouch ileostomy. Unfortunately, complications, especially complications related to valve slippage, are common. Despite variations of technique designed to improve the function of the continent ileostomy, most surgeons have abandoned this operation and instead perform restorative proctocolectomy with ileal pouch anal anastomosis. Although ileal pouch anal reconstruction is anatomically appealing, functional outcome is far from perfect.22,23 Patients should be counseled to expect eight to 10 bowel movements per day. Up to 50% have some degree of nocturnal incontinence. Pouchitis occurs in nearly 50% of patients, and small bowel obstruction is not uncommon. Other less common complications include difficulties with pouch evacuation, pouch–anal and/or pouch–vaginal fistula, and anal stricture. Pouch failure rate averages 5 to 10%. Patients who are subsequently diagnosed with Crohn's disease have a considerably higher pouch failure rate (approximately 50%), while patients with indeterminate colitis have an intermediate pouch failure rate (15 to 20%). Despite these drawbacks, the vast majority of patients are satisfied and prefer ileal pouch–anal reconstruction to permanent ileostomy. Pouchitis is an inflammatory condition that affects both ileoanal pouches and continent ileostomy reservoirs. Incidence of pouchitis ranges from 30 to 55%. Symptoms include increased diarrhea, hematochezia, abdominal pain, fever, and malaise. Diagnosis is made endoscopically with biopsies. Differential diagnosis includes infection and undiagnosed Crohn's disease. The etiology of pouchitis is unknown. Some believe pouchitis results from fecal stasis within the pouch but emptying studies are not confirmatory. Antibiotics (metronidazole ciprofloxacin) are the mainstays of therapy and most patients will respond rapidly to either oral preparations or enemas.24,25 Some patients develop chronic pouchitis that necessitates ongoing suppressive antibiotic therapy. Salicylate and corticosteroid enemas also have been used with some success. Reintroduction of normal flora by ingestion of probiotics has been suggested as a possible treatment in refractory cases. Occasionally, pouch excision is necessary to control the symptoms of chronic pouchitis.

Anesthesia Considerations LOCAL ANESTHESIA Many anorectal procedures can be performed with local anesthetic alone. IV sedation often is provided to calm the patient. Injection of 0.5% lidocaine (short acting) and 0.25% bupivacaine (long acting) into the perianal skin,

sphincter, and area around the pudendal nerves usually provides an adequate block. The addition of dilute epinephrine decreases bleeding and prolongs the anesthetic effect.

REGIONAL ANESTHESIA Epidural, spinal, and caudal anesthetics can be used for anorectal procedures and transanal resections. In patients with severe medical comorbidity, regional anesthesia occasionally may be used for laparotomy and colectomy. Postoperative epidural anesthesia provides excellent pain relief and improves pulmonary function.

GENERAL ANESTHESIA General anesthesia is required for the vast majority of intra-abdominal procedures. Patients should undergo a thorough preoperative cardiovascular evaluation. In patients with significant comorbid disease, preadmission and an anesthesia consultation may be appropriate.

POSITIONING Most abdominal colectomies can be performed in the supine position. Anterior and APRs require lithotomy positioning. Adequate padding should be provided for the patient's sacrum and care should be taken to avoid stirrup pressure on the peroneal nerves. Anorectal procedures may be performed in lithotomy but the prone jackknife position is preferred for most procedures, especially if the anterior quadrant needs to be seen well. Distal posterior lesions usually can be accessed from either position, but more proximal posterior lesions are better accessed in prone position.

Operative Preliminaries BOWEL PREPARATION The rationale for bowel preparation is that decreasing the bacterial load in the colon and rectum will decrease the incidence of postoperative infection. Mechanical bowel preparation uses cathartics to rid the colon of solid stool the night before surgery.2 6 The most commonly used regimens include polyethylene glycol (PEG) solutions or sodium phosphate. PEG solutions require patients to drink a large volume and may cause bloating and nausea. Sodium phosphate solutions generally are better tolerated, but are more likely to cause fluid and electrolyte abnormalities. PEG and sodium phosphate are equally efficacious in bowel cleansing. The preparatory formulations recently have been introduced in tablet form in an attempt to improve tolerance. However, these methods of bowel cleansing require ingestion of 40 or more tablets with water over several hours. To date, this has not proven superior to the more traditional products.2 7 Antibiotic prophylaxis also is recommended. The addition of oral antibiotics to the preoperative mechanical bowel preparation is thought to decrease postoperative infection by further decreasing the bacterial load of the colon. A combination of three doses of neomycin (1 g) and erythromycin base (1 g) is most commonly used. Some surgeons substitute metronidazole (500 mg) for erythromycin to avoid GI upset. Ciprofloxacin also has been used in this setting. It is important to note, however, that although the majority of surgeons use oral antibiotic prophylaxis, this practice has never been proven to decrease postoperative infectious complications.28,29 A broad-spectrum parenteral antibiotic(s) should be administered just before the skin incision. There is no proven benefit to using antibiotics postoperatively after an uncomplicated colectomy. Despite widespread use of mechanical bowel preparation, the necessity of bowel cleansing before colectomy has been questioned. European surgeons in particular have advocated abandoning this practice. Several small studies suggest that a mechanical bowel preparation does not decrease the risk of postoperative wound infection or anastomotic dehiscence.30–32 Larger prospective trials are needed to determine whether mechanical bowel

preparation before colectomy is a necessity or a source of added morbidity that can be avoided.

STOMA PLANNING The preoperative preparation of a patient who is expected to require a stoma should include a consultation with an enterostomal therapy nurse . ET nurses are specially trained and credentialed by the Wound, Ostomy and Continence Nurses Society. Preoperative planning includes counseling, education, and stoma siting. Postoperatively, the ET nurse assists with local skin care and pouching. Other considerations in stoma planning include evaluation of other medical conditions that may impact a patient's ability to manage a stoma (e.g., eyesight, manual dexterity). Preoperative stoma siting is crucial for a patient's postoperative function and quality of life. A poorly placed stoma can result in leakage and skin breakdown. Ideally, a stoma should be placed in a location that the patient can easily see and manipulate, within the rectus muscle, and below the belt line (see Fig. 29-15). Because the abdominal landmarks in a supine, anesthetized patient may be dramatically different from those in an awake, standing, or sitting patient, the stoma site should always be marked with a tattoo, skin scratch, or permanent marker preoperatively, if possible. In an emergency operation where the stoma site has not been marked, an attempt should be made to place a stoma within the rectus muscle and away from both the costal margin and iliac crest. In emergencies, placement high on the abdominal wall is preferred to a low-lying site.

URETERAL STENTS Ureteral stents may be useful for identifying the ureters intraoperatively and are placed via cystoscopy after the induction of general anesthesia and removed at the end of the operation. Stents can be invaluable in reoperative pelvic surgery or when there is significant retroperitoneal inflammation (such as complicated diverticulitis). Lighted stents may be helpful in laparoscopic resections. Patients often have transient hematuria postoperatively but major complications are rare.

MULTIDISCIPLINARY TEAMS Patients with complex colorectal disease often benefit from a multidisciplinary approach. Patients with pelvic floor disorders (especially incontinence) often require evaluation by both a colorectal surgeon and a urologist or urogynecologist. Preoperative evaluation of cancer patients by a medical oncologist and/or radiation oncologist is crucial for planning either neoadjuvant or adjuvant therapy. Intraoperatively, complex pelvic resections often require the involvement of not only a colorectal surgeon but also a urologist, gynecologic oncologist, neurosurgeon, and/or plastic surgeon. Radiation oncologists should be involved in the operation if brachytherapy catheters are to be placed for intracavitary radiation or if intraoperative radiation therapy is planned. Rarely, psychiatric disorders may manifest as colorectal problems (especially functional disorders and chronic pain) and involvement of a psychiatrist or psychologist may be beneficial.

INFLAMMATORY BOWEL DISEASE General Considerations EPIDEMIOLOGY Inflammatory bowel disease includes ulcerative colitis , Crohn's disease , and indeterminate colitis . Ulcerative colitis occurs in eight to 15 people per 100,000 in the United States and Northern Europe. The incidence is considerably lower in Asia, Africa, and South America, and among the nonwhite population in the United States. Ulcerative colitis incidence peaks during the third decade of life and again in the seventh decade of life. The

incidence of Crohn's disease is slightly lower, one to five people per 100,000 population. Crohn's disease also affects Northern European and white populations disproportionately. Crohn's disease has a similar bimodal incidence, with most cases occurring between ages 15 to 30 years and ages 55 to 60 years. In 15% of patients with inflammatory bowel disease, differentiation between ulcerative colitis and Crohn's colitis is impossible; these patients are classified as having indeterminate colitis .

ETIOLOGY Multiple etiologies for inflammatory bowel disease have been proposed, but none are proven. The consistent geographic differences in incidence suggest an environmental factor such as diet or infection. Smoking, alcohol, and oral contraceptive use also have been implicated. Family history may play a role because 10 to 30% of patients with inflammatory bowel disease report a family member with the same disease.3 3 Other theories focus on an autoimmune mechanism and/or a defect in the intestinal immune system. Although there is general agreement that interaction among the immune system, the mucosal barrier of the gut, and a variety of infectious agents is involved in the pathogenesis of inflammatory bowel disease, the mechanism(s) by which these interactions produce disease is poorly understood.3 4 Bacteria such as Mycobacterium paratuberculosis and Listeria monocytogenes , and viruses such as paramyxovirus and measles virus, have been suggested as etiologic agents in Crohn's disease. A defect in the gut mucosal barrier, which increases exposure to intraluminal bacteria, toxins, or proinflammatory substances, also has been suggested. Finally, an autoimmune mechanism has been postulated. Although there is no clear evidence linking an immunologic disorder to inflammatory bowel disease, the similarity of many of the extraintestinal manifestations to rheumatologic disorders has made this theory attractive. Regardless of the underlying cause of either ulcerative colitis or Crohn's disease, both disorders are characterized by intestinal inflammation and medical therapy is largely based upon reducing inflammation.

PATHOLOGY AND DIFFERENTIAL DIAGNOSIS Although ulcerative colitis and Crohn's colitis share many pathologic and clinical similarities, these conditions may be differentiated in 85% of patients. Ulcerative colitis is a mucosal process in which the colonic mucosa and submucosa are infiltrated with inflammatory cells. The mucosa may be atrophic and crypt abscesses are common. Endoscopically, the mucosa is frequently friable and may possess multiple inflammatory pseudopolyps. In longstanding ulcerative colitis, the colon may be foreshortened and the mucosa replaced by scar. In quiescent ulcerative colitis, the colonic mucosa may appear normal endoscopically and microscopically. Ulcerative colitis may affect the rectum (proctitis), rectum and sigmoid colon (proctosigmoiditis), rectum and left colon (left-sided colitis), or the rectum and entire colon (pancolitis). Ulcerative colitis does not involve the small intestine, but the terminal ileum may demonstrate inflammatory changes ("backwash ileitis"). A key feature of ulcerative colitis is the continuous involvement of the rectum and colon; rectal sparing or skip lesions suggest a diagnosis of Crohn's disease. Symptoms are related to the degree of mucosal inflammation and the extent of colitis. Patients typically complain of bloody diarrhea and crampy abdominal pain. Proctitis may produce tenesmus. Severe abdominal pain and fever raises the concern of fulminant colitis or toxic megacolon . Physical findings are nonspecific and range from minimal abdominal tenderness and distention to frank peritonitis. In the nonemergent setting, the diagnosis typically is made by colonoscopy and mucosal biopsy. In contrast to ulcerative colitis, Crohn's disease is a transmural inflammatory process that can affect any part of the GI tract from mouth to anus. Mucosal ulcerations, an inflammatory cell infiltrate, and noncaseating granulomas are characteristic pathologic findings. Chronic inflammation may ultimately result in fibrosis, strictures, and fistulas in either the colon or small intestine. The endoscopic appearance of Crohn's colitis is characterized by deep serpiginous ulcers and a "cobblestone" appearance. Skip lesions and rectal sparing are common. Symptoms of

Crohn's disease depend upon the severity of inflammation and/or fibrosis and the location of inflammation in the GI tract. Acute inflammation may produce diarrhea, crampy abdominal pain, and fever. Strictures may produce symptoms of obstruction. Weight loss is common, both because of obstruction and from protein loss. Perianal Crohn's disease may present with pain, swelling, and drainage from fistulas or abscesses. Physical findings are also related to the site and severity of disease. In 15% of patients with colitis from inflammatory bowel disease, differentiation of ulcerative colitis from Crohn's colitis proves impossible either grossly or microscopically (indeterminate colitis). These patients typically present with symptoms similar to ulcerative colitis. Endoscopic and pathologic findings usually include features common to both diseases. Further differential diagnoses include infectious colitides, especially Campylobacter jejuni , Entamoeba histolytica , C. difficile , Neisseria gonococcus , Salmonella , and Shigella species.

EXTRAINTESTINAL MANIFESTATIONS The liver is a common site of extracolonic disease in inflammatory bowel disease. Fatty infiltration of the liver is present in 40 to 50% of patients and cirrhosis is found in 2 to 5%. Fatty infiltration may be reversed by medical or surgical treatment of colonic disease, but cirrhosis is irreversible. Primary sclerosing cholangitis is a progressive disease characterized by intra- and extrahepatic bile duct strictures. Forty to 60% of patients with primary sclerosing cholangitis have ulcerative colitis. Colectomy will not reverse this disease, and the only effective therapy is liver transplantation. Pericholangitis also is associated with inflammatory bowel disease and may be diagnosed with a liver biopsy. Bile duct carcinoma is a rare complication of long-standing inflammatory bowel disease. Patients who develop bile duct carcinoma in the presence of inflammatory bowel disease are, on average, 20 years younger than other patients with bile duct carcinoma. Arthritis is also a common extracolonic manifestation of inflammatory bowel disease, and the incidence is 20 times greater than in the general population. Arthritis usually improves with treatment of the colonic disease. Sacroiliitis and ankylosing spondylitis are associated with inflammatory bowel disease, although the relationship is poorly understood. Medical and surgical treatment of the colonic disease does not impact symptoms. Erythema nodosum is seen in 5 to 15% of patients with inflammatory bowel disease and usually coincides with clinical disease activity. Women are affected three to four times more frequently than men. The characteristic lesions are raised, red, and predominantly on the lower legs. Pyoderma gangrenosum is an uncommon but serious condition that occurs almost exclusively in patients with inflammatory bowel disease. The lesion begins as an erythematous plaque, papule, or bleb, usually located on the pretibial region of the leg and occasionally near a stoma. The lesions progress and ulcerate, leading to a painful, necrotic wound. Pyoderma gangrenosum may respond to resection of the affected bowel in some patients. In others, this disorder is unaffected by treatment of the underlying bowel disease. Up to 10% of patients with inflammatory bowel disease will develop ocular lesions. These include uveitis, iritis, episcleritis, and conjunctivitis. They usually develop during an acute exacerbation of the inflammatory bowel disease. The etiology is unknown.

PRINCIPLES OF NONOPERATIVE MANAGEMENT Medical therapy for inflammatory bowel disease focuses on decreasing inflammation and alleviating symptoms, and many of the agents used are the same for both ulcerative colitis and Crohn's disease. In general, mild to moderate flares may be treated in the outpatient setting. More severe signs and symptoms mandate hospitalization.

Pancolitis generally requires more aggressive therapy than limited disease. Because ulcerative proctitis and proctosigmoiditis are limited to the distal large intestine, topical therapy with salicylate and/or corticosteroid suppositories and enemas can be extremely effective. Systemic therapy rarely is required in these patients.

Salicylates Sulfasalazine (Azulfidine), 5-ASA, and related compounds are first-line agents in the medical treatment of mild to moderate inflammatory bowel disease. These compounds decrease inflammation by inhibition of cyclooxygenase and 5-lipoxygenase in the gut mucosa. They require direct contact with affected mucosa for efficacy. Multiple preparations are available for administration to different sites in the small intestine and colon [sulfasalazine, mesalamine (Pentasa), Asacol, Rowasa, Canasa].

Antibiotics Antibiotics often are used to decrease the intraluminal bacterial load in Crohn's disease. Metronidazole has been reported to improve Crohn's colitis and perianal disease, but the evidence is weak. Fluoroquinolones also may be effective in some cases. In the absence of fulminant colitis or toxic megacolon, antibiotics are not used to treat ulcerative colitis.

Corticosteroids Corticosteroids (either oral or parenteral) are a key component of treatment for an acute exacerbation of either ulcerative colitis or Crohn's disease. Corticosteroids are nonspecific inhibitors of the immune system and 75 to 90% of patients will improve with the administration of these drugs. However, corticosteroids have a number of serious side effects and use of these agents should be limited to the shortest course possible. In addition, corticosteroids should be used judiciously in children because of the potential adverse effect on growth. Failure to wean corticosteroids is a relative indication for surgery. Because of the systemic effects of corticosteroids, an effort has been made to develop drugs that act locally and have limited systemic absorption. Newer agents such as budesonide, beclomethasone dipropionate, and tixocortol pivalate undergo rapid hepatic degradation that significantly decreases systemic toxicity. Budesonide is available as an oral preparation. Corticosteroid enemas provide effective local therapy for proctitis and proctosigmoiditis and have fewer side effects than systemic corticosteroids.

Immunosuppressive Agents Azathioprine and 6-mercaptopurine are antimetabolite drugs that interfere with nucleic acid synthesis and thus decrease proliferation of inflammatory cells. These agents are useful for treating ulcerative colitis and Crohn's disease in patients who have failed salicylate therapy or who are dependent upon or refractory to corticosteroids. It is important to note, however, that the onset of action of these drugs takes 6 to 12 weeks, and concomitant use of corticosteroids almost always is required.3 4 Cyclosporine is an immunosuppressive agent that interferes with T-cell function. Although cyclosporine is not routinely used to treat inflammatory bowel disease, up to 80% of patients with an acute flare of ulcerative colitis will improve with its use. However, the majority of these patients will ultimately require colectomy. Cyclosporine also occasionally is used to treat exacerbations of Crohn's disease and approximately two thirds of patients will note some improvement. Improvement generally is apparent within 2 weeks of beginning cyclosporine therapy. Long-term use of cyclosporine is limited by its significant toxicity. Methotrexate is a folate antagonist that also has been used to treat inflammatory bowel disease. Although the

efficacy of this agent is unproven, there are reports that more than 50% of patients will improve with administration of this drug.3 5 Infliximab (Remicade) is a monoclonal antibody against tumor necrosis factor alpha. IV infusion of this agent decreases inflammation systemically. More than 50% of patients with moderate to severe Crohn's disease will improve with infliximab therapy.3 6 This agent also has been useful in treating patients with perianal Crohn's disease. Recurrence is common, however, and many patients require infusions on a bimonthly basis. Infliximab has not been used as extensively for treatment of ulcerative colitis; however, there are reports of efficacy in this setting. 37,38 Other monoclonal antibody agents have been developed and are now being used in clinical trials in patients with inflammatory bowel disease.

Nutrition Patients with inflammatory bowel disease often are malnourished. Abdominal pain and obstructive symptoms may decrease oral intake. Diarrhea can cause significant protein loss. Ongoing inflammation produces a catabolic physiologic state. Parenteral nutrition should be strongly considered early in the course of therapy for either Crohn's disease or ulcerative colitis. The nutritional status of the patient also should be considered when planning operative intervention and nutritional parameters such as serum albumin, prealbumin, and transferrin should be assessed. In extremely malnourished patients, especially those who also are being treated with corticosteroids, creation of a stoma often is safer than a primary anastomosis.

Ulcerative Colitis Ulcerative colitis is a dynamic disease characterized by remissions and exacerbations. The clinical spectrum ranges from an inactive or quiescent phase to low-grade active disease to fulminant disease. The onset of ulcerative colitis may be insidious, with minimal bloody stools, or the onset can be abrupt, with severe diarrhea and bleeding, tenesmus, abdominal pain, and fever. The severity of symptoms depends upon the degree and extent of inflammation. Although anemia is common, massive hemorrhage is rare. Physical findings often are nonspecific. Diagnosis of ulcerative colitis almost always is made endoscopically. Because the rectum is invariably involved, proctoscopy may be adequate to establish the diagnosis. The earliest manifestation is mucosal edema, which results in a loss of the normal vascular pattern. In more advanced disease, characteristic findings include mucosal friability and ulceration. Pus and mucus also may be present. Although mucosal biopsy often is diagnostic in the chronic phase of ulcerative colitis, biopsy in the acute phase often will reveal only nonspecific inflammation. A complete evaluation with colonoscopy or barium enema during an acute flare is contraindicated because of the risk of perforation. Barium enema has been used to diagnose ulcerative colitis and to determine the extent of disease. However, this modality is less sensitive than colonoscopy and may not detect early disease. In long-standing ulcerative colitis, the colon is foreshortened and lacks haustral markings ("lead pipe" colon). Because the inflammation in ulcerative colitis is purely mucosal, strictures are highly uncommon. Any stricture diagnosed in a patient with ulcerative colitis must be presumed to be malignant until proven otherwise.

INDICATIONS FOR SURGERY Indications for surgery in ulcerative colitis may be emergent or elective. Emergency surgery is required for patients with massive life-threatening hemorrhage , toxic megacolon , or fulminant colitis who fail to respond rapidly to medical therapy. Patients with signs and symptoms of fulminant colitis should be treated aggressively with bowel rest, hydration, broad-spectrum antibiotics, and parenteral corticosteroids. Colonoscopy and barium enema are

contraindicated, and antidiarrheal agents should be avoided. Deterioration in clinical condition or failure to improve within 24 to 48 hours mandates surgery. Indications for elective surgery include intractability despite maximal medical therapy and high-risk development of major complications of medical therapy, such as aseptic necrosis of joints secondary to chronic steroid use. Elective surgery also is indicated in patients at significant risk of developing colorectal carcinoma. Risk of malignancy increases with pancolonic disease and the duration of symptoms is approximately 2% after 10 years, 8% after 20 years, and 18% after 30 years. Unlike sporadic colorectal cancers, carcinoma developing in the context of ulcerative colitis is more likely to arise from areas of flat dysplasia and may be difficult to diagnose at an early stage. For this reason, it is recommended that patients with long-standing ulcerative colitis undergo colonoscopic surveillance with multiple (40 to 50), random biopsies to identify dysplasia before invasive malignancy develops. However, the adequacy of this type of screening is controversial. Recently, magnifying chromoendoscopy has been used to improve sensitivity.39,40 This technique uses topical dyes that are applied to the colonic mucosa at the time of endoscopy (Lugol's solution, methylene blue, indigo carmine, and others). These dyes highlight contrast between normal and dysplastic epithelium, allowing more precise biopsy of suspicious areas.4 1 Surveillance is recommended annually after 8 years in patients with pancolitis, and annually after 15 years in patients with left-sided colitis. Although low-grade dysplasia was long thought to represent minimal risk, more recent studies show that invasive cancer may be present in up to 20% of patients with low-grade dysplasia. For this reason, any patient with dysplasia should be advised to undergo proctocolectomy. Controversy exists over whether prophylactic proctocolectomy should be recommended for patients who have had chronic ulcerative colitis for >10 years in the absence of dysplasia. Proponents of this approach note that surveillance colonoscopy with multiple biopsies samples only a small fraction of the colonic mucosa and dysplasia and carcinoma are often missed. Opponents cite the relatively low risk of progression to carcinoma if all biopsies have lacked dysplasia (approximately 2.4%). Neither approach has been definitively shown to decrease mortality from colorectal cancer.

OPERATIVE MANAGEMENT Emergent Operation In a patient with fulminant colitis or toxic megacolon, total abdominal colectomy with end ileostomy, rather than total proctocolectomy, is recommended. Although the rectum is invariably diseased, most patients improve dramatically after an abdominal colectomy, and this operation avoids a difficult and time-consuming pelvic dissection in a critically ill patient. Rarely, a loop ileostomy and decompressing colostomy may be necessary if the patient is too unstable to withstand colectomy. Definitive surgery may then be undertaken at a later date once the patient has recovered. Complex techniques such as an ileal pouch anal reconstruction generally are contraindicated in the emergent setting. However, massive hemorrhage that includes bleeding from the rectum may necessitate proctectomy and either a permanent ileostomy or ileal pouch anal anastomosis.

Elective Operation In the past, abdominal colectomy with ileorectal anastomosis often was recommended for patients with relatively quiescent rectal disease. The risk of ongoing inflammation, the risk of malignancy, and the availability of restorative proctocolectomy have led most surgeons to now recommend elective operations that include resection of the rectum. Abdominal colectomy with ileorectal anastomosis is still an appropriate operation for a patient with indeterminate colitis and rectal sparing. Total proctocolectomy with end ileostomy has been the "gold standard" for patients with chronic ulcerative colitis. This operation removes the entire affected intestine and avoids the functional disturbances associated with ileal pouch–anal reconstruction. Most patients function well physically and

psychologically after this operation. Total proctocolectomy with continent ileostomy (Kock's pouch ) was developed to improve function and quality of life after total proctocolectomy, but morbidity is significant and restorative proctocolectomy generally is preferred today. Since its reintroduction in 1980, restorative proctocolectomy with ileal pouch–anal anastomosis has become the procedure of choice for most patients who require total proctocolectomy but wish to avoid a permanent ileostomy (see Figs. 29-11 and 29-12).1 8

Crohn's Disease Like ulcerative colitis, Crohn's disease is characterized by exacerbations and remissions. Crohn's disease, however, may affect any portion of the intestinal tract, from mouth to anus. Diagnosis may be made by colonoscopy or esophagogastroduodenoscopy, or by barium small bowel study or enema, depending upon which part of the intestine is most affected. Skip lesions are key in differentiating Crohn's colitis from ulcerative colitis, and rectal sparing occurs in approximately 40% of patients. The most common site of involvement in Crohn's disease is the terminal ileum and cecum (ileocolic Crohn's disease), followed by the small bowel, and then by the colon and rectum. Perianal and anal canal Crohn's disease manifest by complex anal fistulas and/or abscesses, anal ulcers, and large skin tags may be the initial site of presentation in up to 4% of cases.

INDICATIONS FOR SURGERY Because Crohn's disease can affect any part of the GI tract, the therapeutic rationale is fundamentally different from that of ulcerative colitis. Ulcerative colitis may be cured by removal of the affected intestinal segment (the colon and rectum). In Crohn's disease, it is impossible to remove all of the at-risk intestine; therefore, surgical therapy is reserved for complications of the disease. Crohn's disease may present as an acute inflammatory process or as a chronic fibrotic process. During the acute inflammatory phase, patients may present with intestinal inflammation complicated by fistulas and/or intraabdominal abscesses. Maximal medical therapy should be instituted, including anti-inflammatory medications, bowel rest, and antibiotics. Parenteral nutrition should be considered if the patient is malnourished. Most intraabdominal abscesses can be drained percutaneously with the use of CT scan guidance. Although the majority of these patients will ultimately require surgery to remove the diseased segment of bowel, these interventions allow the patient's condition to stabilize, nutrition to be optimized, and inflammation to decrease before embarking upon a surgical resection. Chronic fibrosis may result in strictures in any part of the GI tract. Because the fibrotic process is gradual, free perforation proximal to the obstructing stricture is rare, and, instead, adjacent structures "wall off" the site of perforation. The result often is development of enteric and colonic internal fistulas to other segments of intestine and other viscera (bladder, uterus, vagina) and retroperitoneal sites. Chronic strictures almost never improve with medical therapy. Optimal timing for surgery should take into account the patient's underlying medical and nutritional status. Strictures may be treated with resection or stricturoplasty . Associated fistulas generally require resection of the segment of bowel with active Crohn's disease; the secondary sites of the fistula often are otherwise normal and generally do not require resection after division of the fistula. Simple closure of the secondary fistula site usually suffices. Once an operation is undertaken for Crohn's disease, several principles should guide intraoperative decision making. In general, a laparotomy for Crohn's disease should be done through a midline incision because of the possible need for a stoma. Laparoscopy also is increasingly used in this setting. Because many patients with Crohn's disease will require multiple operations, the length of bowel removed should be minimized . Bowel should be resected to an area with grossly normal margins ; frozen sections are not necessary. Finally, a primary

anastomosis may be safely created if the patient is medically stable, nutritionally replete, and taking few immunosuppressive medications. Creation of a stoma should be strongly considered in any patient who is hemodynamically unstable, septic, malnourished, or receiving high-dose immunosuppressive therapy and in patients with extensive intra-abdominal contamination.

ILEOCOLIC AND SMALL BOWEL CROHN'S DISEASE The terminal ileum and cecum are involved in Crohn's disease in up to 41% of patients; the small intestine is involved in up to 35% of patients. The most common indications for surgery are internal fistula or abscess (30 to 38% of patients) and obstruction (35 to 37% of patients). Psoas abscess may result from ileocolic Crohn's disease. Sepsis should be controlled with percutaneous drainage of abscess(es) and antibiotics, if possible. Parenteral nutrition may be necessary in patients with chronic obstruction. The extent of resection depends on the amount of involved intestine. Short segments of inflamed small intestine and right colon should be resected and a primary anastomosis created if the patient is stable, nutrition is adequate, and immunosuppression is minimal. Isolated chronic strictures also should be resected. In patients with multiple fibrotic strictures that would require extensive small bowel resection, stricturoplasty is a safe and effective alternative to resection. Short strictures are amenable to a transverse stricturoplasty, while longer strictures may be treated with a side-to-side small bowel anastomosis (Fig. 29-18).

Fig. 29-18.

Alternative stricturoplasty techniques. A. A short stricture is opened along the antimesenteric surface of the bowel wall. B. The enterotomy is closed transversely. C. A long stricture is opened along the antimesenteric surface of the bowel wall. D. The bowel is folded into an inverted "U." E. A side-to-side anastomosis is made. (Reproduced with permission from Corman ML: Colon & Rectal Surgery, 2nd ed. Philadelphia: Lippincott Williams & Wilkins, 1989, p 832.)

Risk of recurrence after resection for ileocolic and small bowel Crohn's disease is high. More than 50% of patients will experience a recurrence within 10 years, and the majority of these will require a second operation.

CROHN'S COLITIS Crohn's disease of the large intestine may present as fulminant colitis or toxic megacolon . In this setting, treatment is identical to treatment of fulminant colitis and toxic megacolon secondary to ulcerative colitis. Resuscitation and medical therapy with bowel rest, broad-spectrum antibiotics, and parenteral corticosteroids should be instituted. If the patient's condition worsens or fails to rapidly improve, total abdominal colectomy with end ileostomy is recommended. An elective proctectomy may be required if the patient has refractory Crohn's proctitis. Alternatively, if the rectum is spared, an ileorectal anastomosis may be appropriate once the patient has recovered. Other indications for surgery in chronic Crohn's colitis are intractability , complications of medical therapy , and risk of or development of malignancy . Unlike ulcerative colitis, Crohn's colitis may be segmental and rectal sparing often is observed. A segmental colectomy may be appropriate if the remaining colon and/or rectum appear normal. An isolated colonic stricture also may be treated by segmental colectomy. Although it was long thought that Crohn's disease did not increase the risk of colorectal carcinoma, it is now recognized that Crohn's colitis

(especially pancolitis) carries nearly the same risk for cancer as ulcerative colitis. Annual surveillance colonoscopy with multiple biopsies is recommended for patients with long-standing Crohn's colitis (>7 years duration). As in ulcerative colitis, dysplasia is an indication for total proctocolectomy. Ileal pouch–anal reconstruction is not recommended in these patients because of the risk for development of Crohn's disease within the pouch and the high risk of complications—fistula, abscess, stricture, pouch dysfunction, and pouch failure.

ANAL AND PERIANAL CROHN'S DISEASE Anal and perianal manifestations of Crohn's disease are very common. Anal or perianal disease occurs in 35% of all patients with Crohn's disease. Isolated anal Crohn's disease is uncommon, affecting only 3 to 4% of patients. Detection of anal Crohn's disease, therefore, should prompt evaluation of the remainder of the GI tract. The most common perianal lesions in Crohn's disease are skin tags that are minimally symptomatic. Fissures also are common. Typically, a fissure from Crohn's disease is particularly deep or broad and perhaps better described as an anal ulcer. They often are multiple and located in a lateral position rather than anterior or posterior midline as seen in an idiopathic fissure in ano. A classic appearing fissure in ano located laterally should raise the suspicion of Crohn's disease. Perianal abscess and fistulas are common and can be particularly challenging. Fistulas tend to be complex and often have multiple tracts (Fig. 29-19). Hemorrhoids are not more common in patients with Crohn's disease than in the general population, although many patients tend to attribute any anal or perianal symptom to "hemorrhoids."

Fig. 29-19.

Photograph of a patient with multiple perianal fistulas secondary to Crohn's disease. [Reproduced with permission from Hamilton SR, Borson BC: Crohn’s disease: Pathology, in Berk JE (ed): Bockus Gastroenterology, 4th ed. Philadelphia: Saunders, 1985, Fig. 127-5, p 2229. Copyright Elsevier.]

Treatment of anal and perianal Crohn's disease focuses on alleviation of symptoms. Perianal skin irritation from diarrhea often responds to medical therapy directed at small bowel or colonic disease. In general, skin tags and hemorrhoids should not be excised unless they are extremely symptomatic because of the risk of creating chronic, nonhealing wounds. Fissures may respond to local or systemic therapy; sphincterotomy is relatively contraindicated because of the risk of creating a chronic, nonhealing wound, and because of the increased risk of incontinence in a patient with diarrhea from underlying colitis or small bowel disease. Anal ulcers associated with Crohn's disease usually are not very painful unless there is an underlying abscess. Thus, in patients with significant anal pain, an examination under anesthesia is indicated to exclude an underlying abscess or fistula and to assess the rectal mucosa. In the absence of active Crohn's proctitis, one can proceed cautiously with a partial internal sphincterotomy if the examination under anesthesia reveals a classic-appearing posterior or anterior fissure and anal stenosis. Recurrent abscess(es) or complex anal fistulas should raise the possibility of Crohn's disease. Treatment focuses on

control of sepsis , delineation of complex anatomy , treatment of underlying mucosal disease , and sphincter preservation . Abscesses often can be drained locally, and mushroom catheters are useful for maintaining drainage. Endoanal ultrasound and pelvic MRI are useful for mapping complex fistulous tracts. Liberal use of setons can control many fistulas and avoid division of the sphincter. Many patients with anal Crohn's disease function well with multiple setons left in place for years. Endoanal advancement flaps may be considered for definitive therapy if the rectal mucosa is uninvolved. In 10 to 15% of cases, intractable perianal sepsis requires proctectomy. Rectovaginal fistula can be a particularly difficult problem in these patients. A rectal or vaginal mucosal advancement flap may be used if the rectal mucosa appears healthy and scarring of the rectovaginal septum is minimal. Occasionally, proctectomy is the best option for women with highly symptomatic rectovaginal fistula. Although proximal diversion often is used to protect complex perianal reconstruction, there is no evidence that diversion alone increases healing of anal and perianal Crohn's disease. Medical treatment of underlying proctitis with salicylate and/or corticosteroid enemas may be helpful; however, control of sepsis is the primary goal of therapy. Metronidazole also has been used with some success in this setting. Infliximab and other similar monoclonal antibody agents have shown some efficacy in healing chronic fistulas secondary to Crohn's disease. The success of infliximab has led to a concerted effort to identify other immunomodulators that might prove useful. Proinflammatory cytokines such as interleukin-12 and interferon- are potential targets. Inhibition of immune cell migration also has been suggested as an approach.4 2 However, it is of paramount importance to drain any and all abscesses before initiating immunosuppressive therapy such as corticosteroids or infliximab.

Indeterminate Colitis Approximately 15% of patients with inflammatory bowel disease manifest clinical and pathologic characteristics of both ulcerative colitis and Crohn's disease. Endoscopy, barium enema, and biopsy may be unable to differentiate ulcerative colitis from Crohn's colitis in this setting. The indications for surgery are the same as those for ulcerative colitis: intractability , complications of medical therapy , and risk of or development of malignancy . In the setting of indeterminate colitis in a patient who prefers a sphincter-sparing operation, a total abdominal colectomy with end ileostomy may be the best initial procedure. Pathologic examination of the entire colon may then allow a more accurate diagnosis. If the diagnosis suggests ulcerative colitis, an ileal pouch–anal anastomosis procedure can be performed. If the diagnosis remains in question, the safest surgical option is completion proctectomy with end ileostomy (similar to Crohn's colitis). Ileal pouch–anal reconstruction also may be considered with the understanding that the pouch failure rate is between 15 and 20%.

DIVERTICULAR DISEASE Diverticular disease is a clinical term used to describe the presence of symptomatic diverticula. Diverticulosis refers to the presence of diverticula without inflammation. Diverticulitis refers to inflammation and infection associated with diverticula. The majority of colonic diverticula are false diverticula in which the mucosa and muscularis mucosa have herniated through the colonic wall. These diverticula occur between the taeniae coli, at points where the main blood vessels penetrate the colonic wall (presumably creating an area of relative weakness in the colonic muscle). They are thought to be pulsion diverticula resulting from high intraluminal pressure. Diverticular bleeding can be massive, but usually is self limited. True diverticula , which comprise all layers of the bowel wall, are rare and are usually congenital in origin. Diverticulosis is extremely common in the United States and Europe. It is estimated that half of the population

older than age 50 years has colonic diverticula. The sigmoid colon is the most common site of diverticulosis (Fig. 29-20). Diverticulosis is thought to be an acquired disorder, but the etiology is poorly understood. The most accepted theory is that a lack of dietary fiber results in smaller stool volume, requiring high intraluminal pressure and high colonic wall tension for propulsion. Chronic contraction then results in muscular hypertrophy and development of the process of segmentation in which the colon acts like separate segments instead of functioning as a continuous tube. As segmentation progresses, the high pressures are directed radially toward the colon wall rather than to development of propulsive waves that move stool distally. The high radial pressures directed against the bowel wall create pulsion diverticula. A loss of tensile strength and a decrease in elasticity of the bowel wall with age also have been proposed etiologies. While none of these theories has been proven, a high-fiber diet does appear to decrease the incidence of diverticulosis. Although diverticulosis is common, most cases are asymptomatic and complications occur in the minority of people with this condition.

Fig. 29-20.

Diverticulosis of sigmoid colon on barium enema. [Reproduced with permission from Nivatvongs S, Becker ER: Colon, rectum and anal canal, in James EC, Corry RJ, Perry JCF Jr. (eds): Basic Surgical Practice. Philadelphia: Hanley & Belfus, 1987. Copyright Elsevier.]

Inflammatory Complications (Diverticulitis) Diverticulitis refers to inflammation and infection associated with a diverticulum and is estimated to occur in 10 to 25% of people with diverticulosis. Peridiverticular and pericolic infection results from a perforation (either macroscopic or microscopic) of a diverticulum, which leads to contamination, inflammation, and infection. The spectrum of disease ranges from mild, uncomplicated diverticulitis that can be treated in the outpatient setting, to free perforation and diffuse peritonitis that requires emergency laparotomy. Most patients present with left-sided abdominal pain, with or without fever, and leukocytosis. A mass may be present. Plain radiographs are useful for detecting free intra-abdominal air. CT scan is extremely useful for defining pericolic inflammation, phlegmon, or abscess. Contrast enemas and/or endoscopy are relatively contraindicated because of the risk of perforation. The differential diagnosis includes malignancy, ischemic colitis, infectious colitis, and inflammatory bowel disease.

UNCOMPLICATED DIVERTICULITIS Uncomplicated diverticulitis is characterized by left lower quadrant pain and tenderness. CT findings include pericolic soft tissue stranding, colonic wall thickening, and/or phlegmon. Most patients with uncomplicated diverticulitis will respond to outpatient therapy with broad-spectrum oral antibiotics and a low-residue diet. Antibiotics should be continued for 7 to 10 days. About 10 to 20% of patients with more severe pain, tenderness, fever, and leukocytosis are treated in the hospital with parenteral antibiotics and bowel rest. Most patients improve within 48 to 72 hours. Failure to improve may suggest abscess formation. CT can be extremely useful in this setting and many pericolic abscesses can be drained percutaneously (see below in Complicated Diverticulitits). Deterioration in a patient's clinical condition and/or the development of peritonitis are indications for laparotomy. Most patients with uncomplicated diverticulitis will recover without surgery, and 50 to 70% will have no further episodes. However, the risk of complications increases with recurrent disease. For this reason, elective sigmoid colectomy often is recommended after the second episode of diverticulitis, especially if the patient has required hospitalization. Resection often has been recommended after the first episode in very young patients and often is recommended after the first episode of complicated diverticulitis . These general guidelines have been questioned in recent years. Many surgeons now will not advise colectomy even after two documented episodes of diverticulitis assuming the patient is completely asymptomatic and that carcinoma has been excluded by colonoscopy. Immunosuppressed patients generally are still advised to undergo colectomy after a single episode of documented diverticulitis. Medical comorbidity should be considered when evaluating a patient for elective resection, and the risks of recurrent disease weighed against the risks of the operation. Because colon carcinoma may have an identical clinical presentation to diverticulitis (either complicated or uncomplicated), all patients must be evaluated for malignancy after resolution of the acute episode. Sigmoidoscopy or colonoscopy is recommended 4 to 6 weeks after recovery. Inability to exclude malignancy is another indication for resection. In the elective setting, a sigmoid colectomy with a primary anastomosis is the procedure of choice. The resection should always be extended to the rectum distally because the risk of recurrence is high if a segment of sigmoid colon is retained. The proximal extent of the resection should include all thickened or inflamed bowel; however, resection of all diverticula is unnecessary. Increasingly, laparoscopy is being used for elective sigmoid colectomy for diverticular disease.

COMPLICATED DIVERTICULITIS Complicated diverticulitis includes diverticulitis with abscess, obstruction, diffuse peritonitis (free perforation), or fistulas between the colon and adjacent structures. Colovesical, colovaginal, and coloenteric fistulas are long-term sequelae of complicated diverticulitis. The Hinchey staging system often is used to describe the severity of

complicated diverticulitis: Stage I includes colonic inflammation with an associated pericolic abscess; stage II includes colonic inflammation with a retroperitoneal or pelvic abscess; stage III is associated with purulent peritonitis; and stage IV is associated with fecal peritonitis. Treatment depends on the patient's overall clinical condition and the degree of peritoneal contamination and infection. Small abscesses (Chapter 30. The Appendix>

KEY POINTS 1. Appendectomy for appendicitis is the most commonly performed emergency operation in the world. 2. Despite the increased use of ultrasonography, computed tomographic scanning, and laparoscopy, the rate of misdiagnosis of appendicitis has remained constant (15.3%), as has the rate of appendiceal rupture. The percentage of misdiagnosed cases of appendicitis is significantly higher among women than among men. 3. Appendicitis is a polymicrobial infection, with some series reporting up to 14 different organisms cultured in patients with perforation. The principal organisms seen in the normal appendix, in acute appendicitis, and in perforated appendicitis are Escherichia coli and Bacteroides fragilis. 4. Antibiotic prophylaxis is effective in the prevention of postoperative wound infection and intra-abdominal abscess. Antibiotic coverage is limited to 24 to 48 hours in cases of nonperforated appendicitis. For perforated appendicitis, 7 to 10 days of treatment is recommended. 5. Compared with younger patients, elderly patients with appendicitis often pose a more difficult diagnostic problem because of the atypical presentation, expanded differential diagnosis, and communication difficulty. These factors contribute to the disproportionately high perforation rate seen in the elderly. 6. The overall incidence of fetal loss after appendectomy is 4% and the risk of early delivery is 7%. Rates of fetal loss are considerably higher in women with complex appendicitis than in those with negative appendectomy and those with simple appendicitis. Removing a normal appendix is associated with a 4% risk of fetal loss and 10% risk of early delivery. 7. Recent data on appendiceal malignancies from the Surveillance, Epidemiology, and End Results program identified mucinous adenocarcinoma as the most frequent histologic diagnosis, followed by adenocarcinoma, carcinoid, goblet cell carcinoma, and signet-ring cell carcinoma.

ANATOMY AND FUNCTION The appendix first becomes visible in the eighth week of embryologic development as a protuberance off the terminal portion of the cecum. During both antenatal and postnatal development, the growth rate of the cecum exceeds that of the appendix, so that the appendix is displaced medially toward the ileocecal valve. The relationship of the base of the appendix to the cecum remains constant, whereas the tip can be found in a retrocecal, pelvic, subcecal, preileal, or right pericolic position (Fig. 30-1). These anatomic considerations have significant clinical importance in the context of acute appendicitis. The three taeniae coli converge at the junction of the cecum with the appendix and can be a useful landmark to identify the appendix. The appendix can vary in

length from 30 cm; most appendices are 6 to 9 cm long. Appendiceal absence, duplication, and diverticula have all been described.1–4

Fig. 30-1.

Various anatomic positions of the vermiform appendix.

For many years, the appendix was erroneously viewed as a vestigial organ with no known function. It is now well recognized that the appendix is an immunologic organ that actively participates in the secretion of immunoglobulins, particularly immunoglobulin A. Although there is no clear role for the appendix in the development of human disease, recent studies demonstrate a potential correlation between appendectomy and the development of inflammatory bowel disease. There appears to be a negative age-related association between prior appendectomy and subsequent development of ulcerative colitis. In addition, comparative analysis clearly shows that prior appendectomy is associated with a more benign phenotype in ulcerative colitis and a delay in onset of disease. The association between Crohn's disease and appendectomy is less clear. Although earlier studies suggested that appendectomy increases the risk of developing Crohn's disease, more recent studies that carefully assessed the timing of appendectomy in relation to the onset of Crohn's disease demonstrated a negative

correlation. These data suggest that appendectomy may protect against the subsequent development of inflammatory bowel disease; however, the mechanism is unclear.4 Lymphoid tissue first appears in the appendix approximately 2 weeks after birth. The amount of lymphoid tissue increases throughout puberty, remains steady for the next decade, and then begins a steady decrease with age. After the age of 60 years, virtually no lymphoid tissue remains within the appendix, and complete obliteration of the appendiceal lumen is common.1–4

ACUTE APPENDICITIS Historical Background Although ancient texts have scattered descriptions of surgery being undertaken for ailments sounding like appendicitis, credit for performing the first appendectomy goes to Claudius Amyand, a surgeon at St. George's Hospital in London and Sergeant Surgeon to Queen Ann, King George I, and King George II. In 1736, he operated on an 11-year-old boy with a scrotal hernia and a fecal fistula. Within the hernial sac, Amyand found the appendix perforated by a pin. He successfully removed the appendix and repaired the hernia.5 The appendix was not identified as an organ capable of causing disease until the nineteenth century. In 1824, Louyer-Villermay presented a paper before the Royal Academy of Medicine in Paris. He reported on two autopsy cases of appendicitis and emphasized the importance of the condition. In 1827, Franois Melier, a French physician, expounded on Louyer-Villermay's work. He reported six autopsy cases and was the first to suggest the antemortem recognition of appendicitis.5 This work was discounted by many physicians of the era, including Baron Guillaume Dupuytren. Dupuytren believed that inflammation of the cecum was the main cause of pathology of the right lower quadrant. The term typhlitis or perityphlitis was used to describe right lower quadrant inflammation. In 1839, a textbook authored by Bright and Addison entitled Elements of Practical Medicine described the symptoms of appendicitis and identified the primary cause of inflammatory processes of the right lower quadrant.6 Reginald Fitz, a professor of pathologic anatomy at Harvard, is credited with coining the term appendicitis. His landmark paper definitively identified the appendix as the primary cause of right lower quadrant inflammation.7 Initial surgical therapy for appendicitis was primarily designed to drain right lower quadrant abscesses that occurred secondary to appendiceal perforation. It appears that the first surgical treatment for appendicitis or perityphlitis without abscess was carried out by Hancock in 1848. He incised the peritoneum and drained the right lower quadrant without removing the appendix. The first published account of appendectomy for appendicitis was by Krnlein in 1886. However, this patient died 2 days after operation. Fergus, in Canada, performed the first elective appendectomy in 1883.5 The greatest contributor to the advancement in the treatment of appendicitis was Charles McBurney. In 1889, he published his landmark paper in the New York State Medical Journal describing the indications for early laparotomy for the treatment of appendicitis. It is in this paper that he described the McBurney point as follows: "maximum tenderness, when one examines with the fingertips is, in adults, one half to two inches inside the right anterior spinous process of the ilium on a line drawn to the umbilicus."8 McBurney subsequently published a paper in 1894 describing the incision that bears his name.9 However, McBurney later credited McArthur with first describing this incision. Semm is widely credited with performing the first successful laparoscopic appendectomy in 1982.1 0 The surgical treatment of appendicitis is one of the great public health advances of the last 150 years. Appendectomy for appendicitis is the most commonly performed emergency operation in the world. Appendicitis is a disease of the young, with 40% of cases occurring in patients between the ages of 10 and 29 years.1 1 In 1886,

Fitz reported the associated mortality rate of appendicitis to be at least 67% without surgical therapy.7 Currently, the mortality rate for acute appendicitis with treatment is reported to be 80 years of age (Fig. 302).13,14

Fig. 30-2.

Rate of negative appendectomy by age group. (Adapted from Flum et al.13,14 )

Etiology and Pathogenesis

Obstruction of the lumen is the dominant etiologic factor in acute appendicitis. Fecaliths are the most common cause of appendiceal obstruction. Less common causes are hypertrophy of lymphoid tissue, inspissated barium from previous x-ray studies, tumors, vegetable and fruit seeds, and intestinal parasites. The frequency of obstruction rises with the severity of the inflammatory process. Fecaliths are found in 40% of cases of simple acute appendicitis, in 65% of cases of gangrenous appendicitis without rupture, and in nearly 90% of cases of gangrenous appendicitis with rupture. Traditionally the belief has been that there is a predictable sequence of events leading to eventual appendiceal rupture. The proximal obstruction of the appendiceal lumen produces a closed-loop obstruction, and continuing normal secretion by the appendiceal mucosa rapidly produces distention. The luminal capacity of the normal appendix is only 0.1 mL. Secretion of as little as 0.5 mL of fluid distal to an obstruction raises the intraluminal pressure to 60 cm H2 O. Distention of the appendix stimulates the nerve endings of visceral afferent stretch fibers, producing vague, dull, diffuse pain in the midabdomen or lower epigastrium. Peristalsis also is stimulated by the rather sudden distention, so that some cramping may be superimposed on the visceral pain early in the course of appendicitis. Distention increases from continued mucosal secretion and from rapid multiplication of the resident bacteria of the appendix. Distention of this magnitude usually causes reflex nausea and vomiting, and the diffuse visceral pain becomes more severe. As pressure in the organ increases, venous pressure is exceeded. Capillaries and venules are occluded, but arteriolar inflow continues, resulting in engorgement and vascular congestion. The inflammatory process soon involves the serosa of the appendix and in turn parietal peritoneum in the region, which produces the characteristic shift in pain to the right lower quadrant. The mucosa of the GI tract, including the appendix, is susceptible to impairment of blood supply; thus its integrity is compromised early in the process, which allows bacterial invasion. As progressive distention encroaches on first the venous return and subsequently the arteriolar inflow, the area with the poorest blood supply suffers most: ellipsoidal infarcts develop in the antimesenteric border. As distention, bacterial invasion, compromise of vascular supply, and infarction progress, perforation occurs, usually through one of the infarcted areas on the antimesenteric border. Perforation generally occurs just beyond the point of obstruction rather than at the tip because of the effect of diameter on intraluminal tension. This sequence is not inevitable, however, and some episodes of acute appendicitis apparently subside spontaneously. Many patients who are found at operation to have acute appendicitis give a history of previous similar, but less severe, attacks of right lower quadrant pain. Pathologic examination of the appendices removed from these patients often reveals thickening and scarring, suggesting old, healed acute inflammation. 15,16 The strong association between delay in presentation and appendiceal perforation supported the proposition that appendiceal perforation is the advanced stage of acute appendicitis; however, recent epidemiologic studies have suggested that nonperforated and perforated appendicitis may, in fact, be different diseases.1 7

Bacteriology The bacterial population of the normal appendix is similar to that of the normal colon. The appendiceal flora remains constant throughout life with the exception of Porphyromonas gingivalis. This bacterium is seen only in adults.1 8 The bacteria cultured in cases of appendicitis are therefore similar to those seen in other colonic infections such as diverticulitis. The principal organisms seen in the normal appendix, in acute appendicitis, and in perforated appendicitis are Escherichia coli and Bacteroides fragilis.

18–21

However, a wide variety of both facultative and

anaerobic bacteria and mycobacteria may be present (Table 30-1). Appendicitis is a polymicrobial infection, with some series reporting the culture of up to 14 different organisms in patients with perforation.1 8

Table 30-1 Common Organisms Seen in Patients with Acute Appendicitis Gram-negative bacilli Gram-negative bacilli Escherichia coli Bacteroides fragilis Pseudomonas aeruginosa Other Bacteroide s species Klebsiella species Fusobacterium species Gram-positive cocci Gram-positive cocci Streptococcus anginosus Peptostreptococcus species Other Streptococcu s species Gram-positive bacilli Enterococcus species Clostridium species Aerobic and Facultative

Anaerobic

The routine culture of intraperitoneal samples in patients with either perforated or nonperforated appendicitis is questionable. As discussed earlier, the flora is known, and therefore broad-spectrum antibiotics are indicated. By the time culture results are available, the patient often has recovered from the illness. In addition, the number of organisms cultured and the ability of a specific laboratory to culture anaerobic organisms vary greatly. Peritoneal culture should be reserved for patients who are immunosuppressed, as a result of either illness or medication, and for patients who develop an abscess after the treatment of appendicitis.20–22 Antibiotic prophylaxis is effective in the prevention of postoperative wound infection and intra-abdominal abscess.2 3 Antibiotic coverage is limited to 24 to 48 hours in cases of nonperforated appendicitis. For perforated appendicitis, 7 to 10 days of therapy is recommended. IV antibiotics are usually given until the white blood cell count is normal and the patient is afebrile for 24 hours. Antibiotic irrigation of the peritoneal cavity and the use of transperitoneal drainage through the wound are controversial.2 4

Clinical Manifestations SYMPTOMS Abdominal pain is the prime symptom of acute appendicitis. Classically, pain is initially diffusely centered in the lower epigastrium or umbilical area, is moderately severe, and is steady, sometimes with intermittent cramping superimposed. After a period varying from 1 to 12 hours, but usually within 4 to 6 hours, the pain localizes to the right lower quadrant. This classic pain sequence, although usual, is not invariable. In some patients, the pain of appendicitis begins in the right lower quadrant and remains there. Variations in the anatomic location of the appendix account for many of the variations in the principal locus of the somatic phase of the pain. For example, a long appendix with the inflamed tip in the left lower quadrant causes pain in that area. A retrocecal appendix may cause principally flank or back pain; a pelvic appendix, principally suprapubic pain; and a retroileal appendix, testicular pain, presumably from irritation of the spermatic artery and ureter. Intestinal malrotation also is responsible for puzzling pain patterns. The visceral component is in the normal location, but the somatic

component is felt in that part of the abdomen where the cecum has been arrested in rotation. Anorexia nearly always accompanies appendicitis. It is so constant that the diagnosis should be questioned if the patient is not anorectic. Although vomiting occurs in nearly 75% of patients, it is neither prominent nor prolonged, and most patients vomit only once or twice. Vomiting is caused by both neural stimulation and the presence of ileus. Most patients give a history of obstipation beginning before the onset of abdominal pain, and many feel that defecation would relieve their abdominal pain. Diarrhea occurs in some patients, however, particularly children, so that the pattern of bowel function is of little differential diagnostic value. The sequence of symptom appearance has great significance for the differential diagnosis. In >95% of patients with acute appendicitis, anorexia is the first symptom, followed by abdominal pain, which is followed, in turn, by vomiting (if vomiting occurs). If vomiting precedes the onset of pain, the diagnosis of appendicitis should be questioned.

SIGNS Physical findings are determined principally by what the anatomic position of the inflamed appendix is, as well as by whether the organ has already ruptured when the patient is first examined. Vital signs are minimally changed by uncomplicated appendicitis. Temperature elevation is rarely >1C (1.8F) and the pulse rate is normal or slightly elevated. Changes of greater magnitude usually indicate that a complication has occurred or that another diagnosis should be considered.2 5 Patients with appendicitis usually prefer to lie supine, with the thighs, particularly the right thigh, drawn up, because any motion increases pain. If asked to move, they do so slowly and with caution. The classic right lower quadrant physical signs are present when the inflamed appendix lies in the anterior position. Tenderness often is maximal at or near the McBurney point.8 Direct rebound tenderness usually is present. In addition, referred or indirect rebound tenderness is present. This referred tenderness is felt maximally in the right lower quadrant, which indicates localized peritoneal irritation.2 5 The Rovsing sign—pain in the right lower quadrant when palpatory pressure is exerted in the left lower quadrant—also indicates the site of peritoneal irritation. Cutaneous hyperesthesia in the area supplied by the spinal nerves on the right at T10, T11, and T12 frequently accompanies acute appendicitis. In patients with obvious appendicitis, this sign is superfluous, but in some early cases, it may be the first positive sign. Hyperesthesia is elicited either by needle prick or by gently picking up the skin between the forefinger and thumb. Muscular resistance to palpation of the abdominal wall roughly parallels the severity of the inflammatory process. Early in the disease, resistance, if present, consists mainly of voluntary guarding. As peritoneal irritation progresses, muscle spasm increases and becomes largely involuntary, that is, true reflex rigidity due to contraction of muscles directly beneath the inflamed parietal peritoneum. Anatomic variations in the position of the inflamed appendix lead to deviations in the usual physical findings. With a retrocecal appendix, the anterior abdominal findings are less striking, and tenderness may be most marked in the flank. When the inflamed appendix hangs into the pelvis, abdominal findings may be entirely absent, and the diagnosis may be missed unless the rectum is examined. As the examining finger exerts pressure on the peritoneum of Douglas' cul-de-sac, pain is felt in the suprapubic area as well as locally within the rectum. Signs of localized muscle irritation also may be present. The psoas sign indicates an irritative focus in proximity to that

muscle. The test is performed by having the patient lie on the left side as the examiner slowly extends the patient's right thigh, thus stretching the iliopsoas muscle. The test result is positive if extension produces pain. Similarly, a positive obturator sign of hypogastric pain on stretching the obturator internus indicates irritation in the pelvis. The test is performed by passive internal rotation of the flexed right thigh with the patient supine.

LABORATORY FINDINGS Mild leukocytosis, ranging from 10,000 to 18,000 cells/mm3 , usually is present in patients with acute, uncomplicated appendicitis and often is accompanied by a moderate polymorphonuclear predominance. White blood cell counts are variable, however. It is unusual for the white blood cell count to be >18,000 cells/mm3 in uncomplicated appendicitis. White blood cell counts above this level raise the possibility of a perforated appendix with or without an abscess. Urinalysis can be useful to rule out the urinary tract as the source of infection. Although several white or red blood cells can be present from ureteral or bladder irritation as a result of an inflamed appendix, bacteriuria in a urine specimen obtained via catheter generally is not seen in acute appendicitis.2 6

Imaging Studies Plain films of the abdomen, although frequently obtained as part of the general evaluation of a patient with an acute abdomen, rarely are helpful in diagnosing acute appendicitis. However, plain radiographs can be of significant benefit in ruling out other pathology. In patients with acute appendicitis, one often sees an abnormal bowel gas pattern, which is a nonspecific finding. The presence of a fecalith is rarely noted on plain films but, if present, is highly suggestive of the diagnosis. A chest radiograph is sometimes indicated to rule out referred pain from a right lower lobe pneumonic process. Additional radiographic studies include barium enema examination and radioactively labeled leukocyte scans. If the appendix fills on barium enema, appendicitis is excluded. On the other hand, if the appendix does not fill, no determination can be made. 2 7 To date, there has not been enough experience with radionuclide scans to assess their utility. Graded compression sonography has been suggested as an accurate way to establish the diagnosis of appendicitis. The technique is inexpensive, can be performed rapidly, does not require a contrast medium, and can be used even in pregnant patients. Sonographically, the appendix is identified as a blind-ending, nonperistaltic bowel loop originating from the cecum. With maximal compression, the diameter of the appendix is measured in the anteroposterior dimension. Scan results are considered positive if a noncompressible appendix =6 mm in the anteroposterior direction is demonstrated (Fig. 30-3). The presence of an appendicolith establishes the diagnosis. Thickening of the appendiceal wall and the presence of periappendiceal fluid is highly suggestive. Sonographic demonstration of a normal appendix, which is an easily compressible, blind-ending tubular structure measuring =5 mm in diameter, excludes the diagnosis of acute appendicitis. The study results are considered inconclusive if the appendix is not visualized and there is no pericecal fluid or mass. When the diagnosis of acute appendicitis is excluded by sonography, a brief survey of the remainder of the abdominal cavity should be performed to establish an alternative diagnosis. In females of childbearing age, the pelvic organs must be adequately visualized either by transabdominal or endovaginal ultrasonography to exclude gynecologic pathology as a cause of acute abdominal pain. The sonographic diagnosis of acute appendicitis has a reported sensitivity of 55 to 96% and a specificity of 85 to 98%.28–30 Sonography is similarly effective in children and pregnant women, although its application is somewhat limited in late pregnancy.

Fig. 30-3.

Sonogram of a 10-year-old girl who presented with nausea, vomiting, and abdominal pain. The appendix measured 10.0 mm in maximal anteroposterior diameter in both the noncompression (A ) and compression (B ) views.

Although sonography can easily identify abscesses in cases of perforation, the technique has limitations and results are user dependent. A false-positive scan result can occur in the presence of periappendicitis from surrounding inflammation, a dilated fallopian tube can be mistaken for an inflamed appendix, inspissated stool can mimic an appendicolith, and, in obese patients, the appendix may not be compressible because of overlying fat. Falsenegative sonogram results can occur if appendicitis is confined to the appendiceal tip, the appendix is retrocecal, the appendix is markedly enlarged and mistaken for small bowel, or the appendix is perforated and therefore compressible.3 1 Some studies have reported that graded compression sonography improved the diagnosis of appendicitis over clinical examination, specifically decreasing the percentage of negative explorations for appendectomies from 37 to 13%. 3 2 Sonography also decreases the time before operation. Sonography identified appendicitis in 10% of patients who were believed to have a low likelihood of the disease on physical examination.3 3 The positive and negative predictive values of ultrasonography have impressively been reported as 91 and 92%, respectively.

However, in a recent prospective multicenter study, routine ultrasonography did not improve diagnostic accuracy or rates of negative appendectomy or perforation compared with clinical assessment. High-resolution helical CT also has been used to diagnose appendicitis. On CT scan, the inflamed appendix appears dilated (>5 cm) and the wall is thickened. There is usually evidence of inflammation, with "dirty fat," thickened mesoappendix, and even an obvious phlegmon (Fig. 30-4). Fecaliths can be easily visualized, but their presence is not necessarily pathognomonic of appendicitis. An important suggestive abnormality is the arrowhead sign. This is caused by thickening of the cecum, which funnels contrast agent toward the orifice of the inflamed appendix. CT scanning is also an excellent technique for identifying other inflammatory processes masquerading as appendicitis.

Fig. 30-4.

Computed tomographic scans with findings positive for appendicitis. Note the thick-walled and dilated appendix (A ) and mesenteric streaking and "dirty fat" (B ).

Several CT techniques have been used, including focused and nonfocused CT scans and enhanced and nonenhanced helical CT scanning. Nonenhanced helical CT scanning is important, because one of the disadvantages of using CT scanning in the evaluation of right lower quadrant pain is dye allergy. Surprisingly, all of these techniques have yielded essentially identical rates of diagnostic accuracy: 92 to 97% sensitivity, 85 to 94% specificity, 90 to 98% accuracy, and 75 to 95% positive and 95 to 99% negative predictive values.34–36 The additional use of a rectally administered contrast agent did not improve the results of CT scanning. A number of studies have documented improvement in diagnostic accuracy with the liberal use of CT scanning in the work-up of suspected appendicitis. CT lowered the rate of negative appendectomies from 19 to 12% in one study, 3 7 and the incidence of negative appendectomies in women from 24 to 5% in another.3 8 The use of this imaging study altered the care of 24% of patients studied and provided alternative diagnoses in half of the patients with normal appendices on CT scan.3 9 Despite the potential usefulness of this technique, there are significant disadvantages. CT scanning is expensive, exposes the patient to significant radiation, and cannot be used during pregnancy. Allergy contraindicates the administration of IV contrast agents in some patients, and others cannot tolerate the oral ingestion of luminal dye, particularly in the presence of nausea and vomiting. Finally, not all studies have documented the utility of CT scanning in all patients with right lower quadrant pain.4 0

A number of studies have compared the effectiveness of graded compression sonography and helical CT in establishing the diagnosis of appendicitis. Although the differences are rather small, CT scanning has consistently proven superior. For example, in one study, 600 ultrasounds and 317 CT scans demonstrated sensitivity of 80 and 97%, specificity of 93 and 94%, diagnostic accuracy of 89 and 95%, positive predictive value of 91 and 92%, and negative predictive value of 88 and 98%, respectively.3 0 In another study, ultrasound positively impacted the management of 19% of patients, compared with 73% of patients for CT. Finally, in a third study, the negative appendix rate was 17% for patients studied by ultrasonography compared with a negative appendix rate of 2% for patients who underwent helical CT scanning.4 1 One concern about ultrasonography is the high intraobserver variability.4 2 One issue that has not been resolved is which patients are candidates for imaging studies.4 3 This question may be moot, because CT scanning routinely is ordered by emergency physicians before surgeons are even consulted. The concept that all patients with right lower quadrant pain should undergo CT scanning has been strongly supported by two reports by Rao and his colleagues at the Massachusetts General Hospital. In one, this group documented that CT scanning led to a fall in the negative appendectomy rate from 20 to 7% and a decline in the perforation rate from 22 to 14%, as well as establishment of an alternative diagnosis in 50% of patients.4 4 In the second study, published in the New England Journal of Medicine, Rao and associates documented that CT scanning prevented 13 unnecessary appendectomies, saved 50 inpatient hospital days, and lowered the per-patient cost by $447.4 5 In contrast, several other studies failed to prove an advantage of routine CT scanning, documenting that surgeon accuracy approached that of the imaging study and expressing concern that the imaging studies could adversely delay appendectomy in affected patients.46,47 The rational approach is the selective use of CT scanning. This has been documented by several studies in which imaging was performed based on an algorithm or protocol.4 8 The likelihood of appendicitis can be ascertained using the Alvarado scale (Table 30-2).4 9 This scoring system was designed to improve the diagnosis of appendicitis and was devised by giving relative weight to specific clinical manifestation. Table 30-2 lists the eight specific indicators identified. Patients with scores of 9 or 10 are almost certain to have appendicitis; there is little advantage in further work-up, and they should go to the operating room. Patients with scores of 7 or 8 have a high likelihood of appendicitis, whereas scores of 5 or 6 are compatible with, but not diagnostic of, appendicitis. CT scanning is certainly appropriate for patients with Alvarado scores of 5 and 6, and a case can be built for imaging for those with scores of 7 and 8. On the other hand, it is difficult to justify the expense, radiation exposure, and possible complications of CT scanning in patients whose scores of 0 to 4 make it extremely unlikely (but not impossible) that they have appendicitis.

Table 30-2 Alvarado Scale for the Diagnosis of Appendicitis Symptoms Migration of pain 1 Anorexia 1 Nausea and/or vomiting 1 Signs Right lower quadrant tenderness

2 Rebound 1 Elevated temperature 1 Laboratory values Leukocytosis 2 Left shift in leukocyte count 1 Total points 10 Manifestations

Value

Source: Reproduced with permission from Alvarado.4 9 Selective CT scanning based on the likelihood of appendicitis takes advantage of the clinical skill of the experienced surgeon and, when indicated, adds the expertise of the radiologist and his or her imaging study. Figure 30-5 proposes a treatment algorithm addressing the rational use of diagnostic testing.5 0

Fig. 30-5.

Clinical algorithm for suspected cases of acute appendicitis. If gynecologic disease is suspected, a pelvic and endovaginal ultrasound examination is indicated. (Reproduced with permission from Paulson et al.50 Copyright Massachusetts Medical Society. All rights reserved.)

Laparoscopy can serve as both a diagnostic and therapeutic maneuver for patients with acute abdominal pain and suspected acute appendicitis. Laparoscopy is probably most useful in the evaluation of females with lower abdominal complaints, because appendectomy is performed on a normal appendix in as many as 30 to 40% of these patients. Differentiating acute gynecologic pathology from acute appendicitis can be effectively accomplished using the laparoscope.

Appendiceal Rupture Immediate appendectomy has long been the recommended treatment for acute appendicitis because of the presumed risk of progression to rupture. The overall rate of perforated appendicitis is 25.8%. Children 65 years of age have the highest rates of perforation (45 and 51%, respectively) (Fig. 306).14,15,51 It has been suggested that delays in presentation are responsible for the majority of perforated appendices. There is no accurate way of determining when and if an appendix will rupture before resolution of the inflammatory process. Recent studies suggest that, in selected patients, observation and antibiotic therapy alone may be an appropriate treatment for acute appendicitis.17,52

Fig. 30-6.

Rate of appendiceal rupture by age group. (Personal communication from David Flum, MD.)

Appendiceal rupture occurs most frequently distal to the point of luminal obstruction along the antimesenteric border of the appendix. Rupture should be suspected in the presence of fever with a temperature of >39C (102F) and a white blood cell count of >18,000 cells/mm3 . In the majority of cases, rupture is contained and patients display localized rebound tenderness. Generalized peritonitis will be present if the walling-off process is ineffective in containing the rupture. In 2 to 6% of cases, an ill-defined mass is detected on physical examination. This could represent a phlegmon, which consists of matted loops of bowel adherent to the adjacent inflamed appendix, or a periappendiceal abscess. Patients who present with a mass have experienced symptoms for a longer duration, usually at least 5 to 7 days. Distinguishing acute, uncomplicated appendicitis from acute appendicitis with perforation on the basis of clinical findings is often difficult, but it is important to make the distinction because their treatment differs. CT scan may be beneficial in guiding therapy. Phlegmons and small abscesses can be treated conservatively with IV antibiotics; well-localized abscesses can be managed with percutaneous drainage; complex abscesses should be considered for surgical drainage. If operative drainage is required, it should be performed using an extraperitoneal approach, with appendectomy reserved for cases in which the appendix is easily accessible. Interval appendectomy performed at least 6 weeks after the acute event has classically been recommended for all patients treated either nonoperatively or with simple drainage of an abscess.53,54

Differential Diagnosis The differential diagnosis of acute appendicitis is essentially the diagnosis of the acute abdomen (see Chap. 35).

This is because clinical manifestations are not specific for a given disease but are specific for disturbance of a given physiologic function or functions. Thus, an essentially identical clinical picture can result from a wide variety of acute processes within the peritoneal cavity that produce the same alterations of function as does acute appendicitis. The accuracy of preoperative diagnosis should be approximately 85%. If it is consistently less, it is likely that some unnecessary operations are being performed, and a more rigorous preoperative differential diagnosis is in order. A diagnostic accuracy rate that is consistently >90% should also cause concern, because this may mean that some patients with atypical, but bona fide, cases of acute appendicitis are being "observed" when they should receive prompt surgical intervention. The Haller group, however, has shown that this is not invariably true.5 5 Before that group's study, the perforation rate at the hospital at which the study took place was 26.7%, and acute appendicitis was found in 80% of the patients undergoing operation. By implementing a policy of intensive inhospital observation when the diagnosis of appendicitis was unclear, the group raised the rate of acute appendicitis found at operation to 94%, but the perforation rate remained unchanged at 27.5%.5 5 The rate of false-negative appendectomies is highest in young adult females. A normal appendix is found in 32 to 45% of appendectomies performed in women 15 to 45 years of age.1 4 A common error is to make a preoperative diagnosis of acute appendicitis only to find some other condition (or nothing) at operation. Much less frequently, acute appendicitis is found after a preoperative diagnosis of another condition. The most common erroneous preoperative diagnoses—together accounting for >75% of cases—are, in descending order of frequency, acute mesenteric lymphadenitis, no organic pathologic condition, acute pelvic inflammatory disease, twisted ovarian cyst or ruptured graafian follicle, and acute gastroenteritis. The differential diagnosis of acute appendicitis depends on four major factors: the anatomic location of the inflamed appendix; the stage of the process (i.e., simple or ruptured); the patient's age; and the patient's sex.56–60

ACUTE MESENTERIC ADENITIS Acute mesenteric adenitis is the disease most often confused with acute appendicitis in children. Almost invariably, an upper respiratory tract infection is present or has recently subsided. The pain usually is diffuse, and tenderness is not as sharply localized as in appendicitis. Voluntary guarding is sometimes present, but true rigidity is rare. Generalized lymphadenopathy may be noted. Laboratory procedures are of little help in arriving at the correct diagnosis, although a relative lymphocytosis, when present, suggests mesenteric adenitis. Observation for several hours is in order if the diagnosis of mesenteric adenitis seems likely, because it is a self-limited disease. However, if the differentiation remains in doubt, immediate exploration is the safest course of action. Human infection with Yersinia enterocolitica or Yersinia pseudotuberculosis , transmitted through food contaminated by feces or urine, causes mesenteric adenitis as well as ileitis, colitis, and acute appendicitis. Many of the infections are mild and self limited, but they may lead to systemic disease with a high fatality rate if untreated. The organisms are usually sensitive to tetracyclines, streptomycin, ampicillin, and kanamycin. A preoperative suspicion of the diagnosis should not delay operative intervention, because appendicitis caused by Yersinia cannot be clinically distinguished from appendicitis due to other causes. Approximately 6% of cases of mesenteric adenitis are caused by Yersinia infection. Salmonella typhimurium infection causes mesenteric adenitis and paralytic ileus with symptoms similar to those of appendicitis. The diagnosis can be established by serologic testing. Campylobacter jejuni causes diarrhea and pain that mimics that of appendicitis. The organism can be cultured from stool.

GYNECOLOGIC DISORDERS Diseases of the female internal reproductive organs that may erroneously be diagnosed as appendicitis are, in approximate descending order of frequency, pelvic inflammatory disease, ruptured graafian follicle, twisted ovarian cyst or tumor, endometriosis, and ruptured ectopic pregnancy.

Pelvic Inflammatory Disease In pelvic inflammatory disease the infection usually is bilateral but, if confined to the right tube, may mimic acute appendicitis. Nausea and vomiting are present in patients with appendicitis, but in only approximately 50% of those with pelvic inflammatory disease. Pain and tenderness are usually lower, and motion of the cervix is exquisitely painful. Intracellular diplococci may be demonstrable on smear of the purulent vaginal discharge. The ratio of cases of appendicitis to cases of pelvic inflammatory disease is low in females in the early phase of the menstrual cycle and high during the luteal phase. The careful clinical use of these features has reduced the incidence of negative findings on laparoscopy in young women to 15%.

Ruptured Graafian Follicle Ovulation commonly results in the spillage of sufficient amounts of blood and follicular fluid to produce brief, mild lower abdominal pain. If the amount of fluid is unusually copious and is from the right ovary, appendicitis may be simulated. Pain and tenderness are rather diffuse. Leukocytosis and fever are minimal or absent. Because this pain occurs at the midpoint of the menstrual cycle, it is often called mittelschmerz.

Twisted Ovarian Cyst Serous cysts of the ovary are common and generally remain asymptomatic. When right-sided cysts rupture or undergo torsion, the manifestations are similar to those of appendicitis. Patients develop right lower quadrant pain, tenderness, rebound, fever, and leukocytosis. If the mass is palpable on physical examination, the diagnosis can be made easily. Both transvaginal ultrasonography and CT scanning can be diagnostic if a mass is not palpable. Torsion requires emergent operative treatment. If the torsion is complete or longstanding, the pedicle undergoes thrombosis, and the ovary and tube become gangrenous and require resection. Leakage of ovarian cysts resolves spontaneously, however, and is best treated nonoperatively.24,56–61

Ruptured Ectopic Pregnancy Blastocysts may implant in the fallopian tube (usually the ampullary portion) and in the ovary. Rupture of right tubal or ovarian pregnancies can mimic appendicitis. Patients may give a history of abnormal menses, either missing one or two periods or noting only slight vaginal bleeding. Unfortunately, patients do not always realize they are pregnant. The development of right lower quadrant or pelvic pain may be the first symptom. The diagnosis of ruptured ectopic pregnancy should be relatively easy. The presence of a pelvic mass and elevated levels of chorionic gonadotropin are characteristic. Although the leukocyte count rises slightly (to approximately 14,000 cells/mm3 ), the hematocrit level falls as a consequence of the intra-abdominal hemorrhage. Vaginal examination reveals cervical motion and adnexal tenderness, and a more definitive diagnosis can be established by culdocentesis. The presence of blood and particularly decidual tissue is pathognomonic. The treatment of ruptured ectopic pregnancy is emergency surgery.

ACUTE GASTROENTERITIS Acute gastroenteritis is common but usually can be easily distinguished from acute appendicitis. Gastroenteritis is characterized by profuse diarrhea, nausea, and vomiting. Hyperperistaltic abdominal cramps precede the watery

stools. The abdomen is relaxed between cramps, and there are no localizing signs. Laboratory values vary with the specific cause.

OTHER INTESTINAL DISORDERS Meckel's Diverticulitis Meckel's diverticulitis gives rise to a clinical picture similar to that of acute appendicitis. Meckel's diverticulum is located within the distal 2 ft of the ileum. Meckel's diverticulitis is associated with the same complications as appendicitis and requires the same treatment—prompt surgical intervention. Resection of the segment of ileum bearing the diverticulum with end-to-end anastomosis can nearly always be done through a McBurney incision, extended if necessary, or laparoscopically.

Crohn's Enteritis The manifestations of acute regional enteritis—fever, right lower quadrant pain and tenderness, and leukocytosis—often simulate acute appendicitis. The presence of diarrhea and the absence of anorexia, nausea, and vomiting favor a diagnosis of enteritis, but this is not sufficient to exclude acute appendicitis. In an appreciable percentage of patients with chronic regional enteritis, the diagnosis is first made at the time of operation for presumed acute appendicitis. In cases of an acutely inflamed distal ileum with no cecal involvement and a normal appendix, appendectomy is indicated. Progression to chronic Crohn's ileitis is uncommon.

Colonic Lesions Diverticulitis or perforating carcinoma of the cecum, or of that portion of the sigmoid that lies in the right side, may be impossible to distinguish from appendicitis. These entities should be considered in older patients. CT scanning is often helpful in making a diagnosis in older patients with right lower quadrant pain and atypical clinical presentations. Epiploic appendagitis probably results from infarction of the colonic appendage(s) secondary to torsion. Symptoms may be minimal, or there may be continuous abdominal pain in an area corresponding to the contour of the colon, lasting several days. Pain shift is unusual, and there is no diagnostic sequence of symptoms. The patient does not look ill, nausea and vomiting are unusual, and appetite generally is unaffected. Localized tenderness over the site is usual and often is associated with rebound without rigidity. In 25% of reported cases, pain persists or recurs until the infarcted epiploic appendage is removed.

OTHER DISEASES Diseases or conditions not mentioned in the preceding sections that must be considered in the differential diagnosis include foreign body perforations of the bowel, closed-loop intestinal obstruction, mesenteric vascular infarction, pleuritis of the right lower chest, acute cholecystitis, acute pancreatitis, hematoma of the abdominal wall, epididymitis, testicular torsion, urinary tract infection, ureteral stone, primary peritonitis, and Henoch-Schnlein purpura.

Acute Appendicitis in the Young The establishment of a diagnosis of acute appendicitis is more difficult in young children than in the adult. The inability of young children to give an accurate history, diagnostic delays by both parents and physicians, and the frequency of GI upset in children are all contributing factors. 6 2 In children the physical examination findings of maximal tenderness in the right lower quadrant, the inability to walk or walking with a limp, and pain with percussion, coughing, and hopping were found to have the highest sensitivity for appendicitis.6 3

The more rapid progression to rupture and the inability of the underdeveloped greater omentum to contain a rupture lead to significant morbidity rates in children. Children 38C (100.4F) and a shift to the left in leukocyte count of >76%, especially if they are male, are anorectic, or have had pain of long duration before admission.6 5 As a result of increased comorbidities and an increased rate of perforation, postoperative morbidity, mortality, and hospital length of stay are increased in the elderly compared with younger populations with appendicitis. Although no randomized trials have been conducted, it appears that elderly patients benefit from a laparoscopic approach to treatment of appendicitis. The use of laparoscopy in the elderly has significantly increased in recent years. In general, laparoscopic appendectomy offers elderly patients with appendicitis a shorter length of hospital stay, a reduction in complication and mortality rates, and a greater chance of discharge to home (independent of further nursing care or rehabilitation).6 7

Acute Appendicitis during Pregnancy Appendectomy for presumed appendicitis is the most common surgical emergency during pregnancy. The incidence is approximately 1 in 766 births. Acute appendicitis can occur at any time during pregnancy.6 8 The overall negative appendectomy rate during pregnancy is approximately 25% and appears to be higher than the rate seen in nonpregnant women.68,69 A higher rate of negative appendectomy is seen in the second trimester, and the lowest rate is in the third trimester. The diversity of clinical presentations and the difficulty in making the diagnosis of acute appendicitis in pregnant women is well established. This is particularly true in the late second trimester and the third trimester, when many abdominal symptoms may be considered pregnancy related. In addition, during

pregnancy there are anatomic changes in the appendix (Fig. 30-7) and increased abdominal laxity that may further complicate clinical evaluation. There is no association between appendectomy and subsequent fertility.

Fig. 30-7.

Location of the appendix during pregnancy. ASIS = anterior superior iliac spine. [Reproduced with permission from Metcalf A: The appendix, in Corson JD, Williamson RCN (eds): Surgery. London: Mosby, 2001.]

Appendicitis in pregnancy should be suspected when a pregnant woman complains of abdominal pain of new onset. The most consistent sign encountered in acute appendicitis during pregnancy is pain in the right side of the abdomen. Seventy-four percent of patients report pain located in the right lower abdominal quadrant, with no difference between early and late pregnancy. Only 57% of patients present with the classic history of diffuse periumbilical pain migrating to the right lower quadrant. Laboratory evaluation is not helpful in establishing the diagnosis of acute appendicitis during pregnancy. The physiologic leukocytosis of pregnancy has been defined as high as 16,000 cells/mm3 . In one series only 38% of patients with appendicitis had a white blood cell count of >16,000 cells/mm 3 . 6 8 Recent data suggest that the incidence of perforated or complex appendicitis is not

increased in pregnant patients.6 9 When the diagnosis is in doubt, abdominal ultrasound may be beneficial. Another option is magnetic resonance imaging, which has no known deleterious effects on the fetus. The American College of Radiology recommends the use of nonionizing radiation techniques for front-line imaging in pregnant women.7 0 Laparoscopy has been advocated in equivocal cases, especially early in pregnancy; however laparoscopic appendectomy may be associated with an increase in pregnancy-related complications. In an analysis of outcomes in California using administrative databases, laparoscopy was found to be associated with a 2.31 increased odds of fetal loss over open surgery.6 9 The overall incidence of fetal loss after appendectomy is 4% and the risk of early delivery is 7%. Rates of fetal loss are considerably higher in women with complex appendicitis than in those with a negative appendectomy and with simple appendicitis. It is important to note that a negative appendectomy is not a benign procedure. Removing a normal appendix is associated with a 4% risk of fetal loss and 10% risk of early delivery. Maternal mortality after appendectomy is extremely rare (0.03%). Because the incidence of ruptured appendix is similar in pregnant and nonpregnant women and because maternal mortality is so low, it appears that the greatest opportunity to improve fetal outcomes is by improving diagnostic accuracy and reducing the rate of negative appendectomy.68–71

Appendicitis in Patients with AIDS or HIV Infection The incidence of acute appendicitis in HIV-infected patients is reported to be 0.5%. This is higher than the 0.1 to 0.2% incidence reported for the general population.7 2 The presentation of acute appendicitis in HIV-infected patients is similar to that in noninfected patients. The majority of HIV-infected patients with appendicitis have fever, periumbilical pain radiating to the right lower quadrant (91%), right lower quadrant tenderness (91%), and rebound tenderness (74%). HIV-infected patients do not manifest an absolute leukocytosis; however, if a baseline leukocyte count is available, nearly all HIV-infected patients with appendicitis demonstrate a relative leukocytosis.72,73 The risk of appendiceal rupture appears to be increased in HIV-infected patients. In one large series of HIV-infected patients who underwent appendectomy for presumed appendicitis, 43% of patients were found to have perforated appendicitis at laparotomy. 7 4 The increased risk of appendiceal rupture may be related to the delay in presentation seen in this patient population. 72,74 The mean duration of symptoms before arrival in the emergency department has been reported to be increased in HIV-infected patients, with >60% of patients reporting the duration of symptoms to be longer than 24 hours.7 2 In early series, significant hospital delay also may have contributed to high rates of rupture.7 2 However, with increased understanding of abdominal pain in HIV-infected patients, hospital delay has become less prevalent.72,75 A low CD4 count is also associated with an increased incidence of appendiceal rupture. In one large series, patients with nonruptured appendices had CD4 counts of 158.75 47 cells/mm3 compared with 94.5 32 cells/mm3 in patients with appendiceal rupture. 7 2 The differential diagnosis of right lower quadrant pain is expanded in HIV-infected patients compared with the general population. In addition to the conditions discussed elsewhere in this chapter, opportunistic infections should be considered as a possible cause of right lower quadrant pain.72–75 Such opportunistic infections include cytomegalovirus (CMV) infection, Kaposi's sarcoma, tuberculosis, lymphoma, and other causes of infectious colitis. CMV infection may be seen anywhere in the GI tract. CMV infection causes a vasculitis of blood vessels in the submucosa of the gut, which leads to thrombosis. Mucosal ischemia develops, leading to ulceration, gangrene of the bowel wall, and perforation. Spontaneous peritonitis may be caused by opportunistic pathogens, including CMV, Mycobacterium avium-intracellulare complex, Mycobacterium tuberculosis , Cryptococcus neoformans , and

Strongyloides . Kaposi's sarcoma and non-Hodgkin's lymphoma may present with pain and a right lower quadrant mass. Viral and bacterial colitis occur with a higher frequency in HIV-infected patients than in the general population. Colitis should always be considered in HIV-infected patients presenting with right lower quadrant pain. Neutropenic enterocolitis (typhlitis) should also be considered in the differential diagnosis of right lower quadrant pain in HIV-infected patients. 73,75 A thorough history and physical examination is important when evaluating any patient with right lower quadrant pain. In the HIV-infected patient with classic signs and symptoms of appendicitis, immediate appendectomy is indicated. In those patients with diarrhea as a prominent symptom, colonoscopy may be warranted. In patients with equivocal findings, CT scan is usually helpful. The majority of pathologic findings identified in HIV-infected patients who undergo appendectomy for presumed appendicitis are typical. The negative appendectomy rate is 5 to 10%. However, in up to 25% of patients AIDS-related entities are found in the operative specimens, including CMV, Kaposi's sarcoma, and M. avium-intracellulare complex.72,74 In a retrospective study of 77 HIV-infected patients from 1988 to 1995, the 30-day mortality rate for patients undergoing appendectomy was reported to be 9.1%.7 2 More recent series report 0% mortality in this group of patients.7 5 Morbidity rates for HIV-infected patients with nonperforated appendicitis are similar to those seen in the general population. Postoperative morbidity rates appear to be higher in HIV-infected patients with perforated appendicitis. In addition, the length of hospital stay for HIV-infected patients undergoing appendectomy is twice that for the general population.72,75 No series has been reported to date that addresses the role of laparoscopic appendectomy in the HIV-infected population.

Treatment Despite the advent of more sophisticated diagnostic modalities, the importance of early operative intervention should not be minimized. Once the decision to operate for presumed acute appendicitis has been made, the patient should be prepared for the operating room. Adequate hydration should be ensured, electrolyte abnormalities should be corrected, and pre-existing cardiac, pulmonary, and renal conditions should be addressed. A large metaanalysis has demonstrated the efficacy of preoperative antibiotics in lowering the infectious complications in appendicitis.2 3 Most surgeons routinely administer antibiotics to all patients with suspected appendicitis. If simple acute appendicitis is encountered, there is no benefit in extending antibiotic coverage beyond 24 hours. If perforated or gangrenous appendicitis is found, antibiotics are continued until the patient is afebrile and has a normal white blood cell count. For intra-abdominal infections of GI tract origin that are of mild to moderate severity, the Surgical Infection Society has recommended single-agent therapy with cefoxitin, cefotetan, or ticarcillin-clavulanic acid. For more severe infections, single-agent therapy with carbapenems or combination therapy with a third-generation cephalosporin, monobactam, or aminoglycoside plus anaerobic coverage with clindamycin or metronidazole is indicated.2 4 The recommendations are similar for children. 7 6

OPEN APPENDECTOMY For open appendectomy most surgeons use either a McBurney (oblique) or Rocky-Davis (transverse) right lower quadrant muscle-splitting incision in patients with suspected appendicitis. The incision should be centered over either the point of maximal tenderness or a palpable mass. If an abscess is suspected, a laterally placed incision is imperative to allow retroperitoneal drainage and to avoid generalized contamination of the peritoneal cavity. If the diagnosis is in doubt, a lower midline incision is recommended to allow a more extensive examination of the peritoneal cavity. This is especially relevant in older patients with possible malignancy or diverticulitis. Several techniques can be used to locate the appendix. Because the cecum usually is visible within the incision, the

convergence of the taeniae can be followed to the base of the appendix. A sweeping lateral to medial motion can aid in delivering the appendiceal tip into the operative field. Occasionally, limited mobilization of the cecum is needed to aid in adequate visualization. Once identified, the appendix is mobilized by dividing the mesoappendix, with care taken to ligate the appendiceal artery securely. The appendiceal stump can be managed by simple ligation or by ligation and inversion with either a purse-string or Z stitch. As long as the stump is clearly viable and the base of the cecum is not involved with the inflammatory process, the stump can be safely ligated with a nonabsorbable suture. The mucosa is frequently obliterated to avoid the development of mucocele. The peritoneal cavity is irrigated and the wound closed in layers. If perforation or gangrene is found in adults, the skin and subcutaneous tissue should be left open and allowed to heal by secondary intent or closed in 4 to 5 days as a delayed primary closure. In children, who generally have little subcutaneous fat, primary wound closure has not led to an increased incidence of wound infection. If appendicitis is not found, a methodical search must be made for an alternative diagnosis. The cecum and mesentery should first be inspected. Next, the small bowel should be examined in a retrograde fashion beginning at the ileocecal valve and extending at least 2 ft. In females, special attention should be paid to the pelvic organs. An attempt also should be made to examine the upper abdominal contents. Peritoneal fluid should be sent for Gram's staining and culture. If purulent fluid is encountered, it is imperative that the source be identified. A medial extension of the incision (Fowler-Weir), with division of the anterior and posterior rectus sheath, is acceptable if further evaluation of the lower abdomen is indicated. If upper abdominal pathology is encountered, the right lower quadrant incision is closed and an appropriate upper midline incision is made.9

LAPAROSCOPIC APPENDECTOMY Semm first reported successful laparoscopic appendectomy several years before the first laparoscopic cholecystectomy.1 0 However, the laparoscopic approach to appendectomy did not come into widespread use until after the success of laparoscopic cholecystectomy. This may be due to the fact that appendectomy, by virtue of its small incision, is already a form of minimal-access surgery.7 7 Laparoscopic appendectomy is performed under general anesthesia. A nasogastric tube and a urinary catheter are placed before obtaining a pneumoperitoneum. Laparoscopic appendectomy usually requires the use of three ports. Four ports may occasionally be necessary to mobilize a retrocecal appendix. The surgeon usually stands to the patient's left. One assistant is required to operate the camera. One trocar is placed in the umbilicus (10 mm), and a second trocar is placed in the suprapubic position. Some surgeons place this second port in the left lower quadrant. The suprapubic trocar is either 10 or 12 mm, depending on whether or not a linear stapler will be used. The placement of the third trocar (5 mm) is variable and usually is either in the left lower quadrant, epigastrium, or right upper quadrant. Placement is based on location of the appendix and surgeon preference. Initially, the abdomen is thoroughly explored to exclude other pathology. The appendix is identified by following the anterior taeniae to its base. Dissection at the base of the appendix enables the surgeon to create a window between the mesentery and the base of the appendix (Fig. 30-8A). The mesentery and base of the appendix are then secured and divided separately. When the mesoappendix is involved with the inflammatory process, it is often best to divide the appendix first with a linear stapler and then to divide the mesoappendix immediately adjacent to the appendix with clips, electrocautery, Harmonic Scalpel, or staples (Fig. 30-8B and 30-8C). The base of the appendix is not inverted. The appendix is removed from the abdominal cavity through a trocar site or within a retrieval bag. The base of the appendix and the mesoappendix should be evaluated for hemostasis. The right lower quadrant should be irrigated. Trocars are removed under direct vision.78,79

Fig. 30-8.

Laparoscopic resection of the appendix. Occasionally, if the appendix and mesoappendix are extremely inflamed, it is easier to divide the appendix at its base before division of the mesoappendix. A. A window is created in the mesoappendix close to the base of the appendix. B. The linear stapler is then used to divide the appendix at its base. C. Finally the mesoappendix

can be easily divided using the linear stapler. [Reproduced with permission from Ortega JM, Ricardo AE: Surgery of the appendix and colon, in Moody FG (ed): Atlas of Ambulatory Surgery. Philadelphia: WB Saunders, 1999.]

The utility of laparoscopic appendectomy in the management of acute appendicitis remains controversial. Surgeons may be hesitant to implement a new technique because the conventional open approach already has proved to be simple and effective. A number of articles in peer-reviewed journals have compared laparoscopic and open appendectomy, including >20 randomized, controlled trials and 6 meta-analyses. 64,77,80–84 The overall quality of these randomized, controlled trials has been limited by the failure to blind patients and providers as to the treatment modality used. Furthermore, investigators have failed to perform prestudy sample size analysis for the outcomes studied.6 4 The largest meta-analysis comparing open to laparoscopic appendectomy included 47 studies, 39 of which were studies of adult patients. This analysis demonstrated that the duration of surgery and costs of operation were higher for laparoscopic appendectomy than for open appendectomy. Wound infections were approximately half as likely after laparoscopic appendectomy as after open appendectomy. However, the rate of intra-abdominal abscess was three times higher after laparoscopic appendectomy than after open appendectomy.6 4 A principal proposed benefit of laparoscopic appendectomy has been decreased postoperative pain. Patientreported pain on the first postoperative day is significantly less after laparoscopic appendectomy. However, the difference has been calculated to be only 8 points on a 100-point visual analogue scale. This difference is below the level of pain that an average patient is able to perceive.6 2 Hospital length of stay also is statistically significantly less after laparoscopic appendectomy. However, in most studies this difference is 95% of the bile salts secreted in bile are reabsorbed in the intestine and then excreted again by the liver (enterohepatic circulation). Bile salts, in conjunction with phospholipids, are responsible for the digestion and absorption of lipids in the small intestine. Bile salts are sodium and potassium salts of bile acids conjugated to amino acids. The bile acids are derivatives of cholesterol synthesized in the hepatocyte. Cholesterol, ingested from the diet or derived from hepatic synthesis, is converted into the bile acids cholic acid and chenodeoxycholic acid. These bile acids are conjugated to either glycine or taurine before secretion into the biliary system. Bacteria in the intestine can remove glycine and taurine from bile salts. They can also convert some of the primary bile acids into secondary bile acids by removing a hydroxyl group, producing deoxycholic from cholic acid, and lithocholic from chenodeoxycholic acid. Bile salts are amphipathic, containing both hydrophobic and hydrophilic domains. The amphipathic nature of bile salts allows for the emulsification of lipids, which results in the breakdown of fat globules into microscopic droplets. This greatly increases the surface area of lipids, which permits their digestion by lipases. Bile salts are also able to carry and solubilize lipids by forming micelles. Lipids collect in the micelles, with cholesterol in the hydrophobic center and amphipathic phospholipids with their hydrophilic heads on the outside and their hydrophobic tails in the center. The micelles play an important role in keeping lipids in solution and transporting them to the brush border of the intestinal epithelial cells, where they are absorbed. Bile salts secreted into the intestine are efficiently reabsorbed and reused. Approximately 90 to 95% of the bile salts are absorbed from the small intestine at the terminal ileum. The remaining 5 to 10% enters the colon and is converted to the secondary salts of deoxycholic acid and lithocholic acid. The mixture of primary and secondary bile salts and bile acids is absorbed primarily by active transport in the terminal ileum. The absorbed bile salts are transported back to the liver in the portal vein and re-excreted in the bile. Those lost in the stool are replaced by synthesis in the liver. The continuous process of secretion of bile salts in the bile, their passage through the intestine, and their subsequent return to the liver is termed the enterohepatic circulation.

10

Drug Metabolism The liver plays an important role in providing mechanisms for ridding the body of foreign molecules (xenobiotics) that are absorbed from the environment. In most cases, a drug is relatively lipophilic to ensure good absorption. The liver participates in the elimination of these lipid-soluble drugs by transforming them into more readily excreted hydrophilic products. There are two main reactions that can occur in the liver important for drug metabolism. Phase I reactions include oxidation, reduction, and hydrolysis of molecules that result in metabolites that are more hydrophilic than the original chemicals. The cytochrome P-450 system is a family of hemoproteins important for oxidative reactions involving drug and toxic substances. Phase II reactions, also known as

conjugation reactions, are synthetic reactions that involve addition of subgroups to the drug molecule. These subgroups include glucuronate, acetate, glutathione, glycine, sulfate, and methyl groups. These drug reactions occur mainly in the smooth endoplasmic reticulum of the hepatocyte. Many factors can affect drug metabolism in the liver. When the rate of metabolism of a pharmacologically active metabolite is increased (i.e., enzyme induction), the duration of the drug action will decrease. However, when the metabolism of a drug is decreased (i.e., enzyme inhibition), then the drug will be metabolically active for a longer period of time. It is important to note that some drugs may be converted to active products by metabolism in the liver. An example is acetaminophen when taken in larger doses. Normally, acetaminophen is conjugated by the liver to harmless glucuronide and sulfate metabolites that are water soluble and eliminated in the urine. During an overdose, the normal metabolic pathways are overwhelmed, and some of the drug is converted to a reactive and toxic intermediate by the cytochrome P-450 system. Glutathione can normally bind to this intermediate and lead to the excretion of a harmless product. However, as glutathione stores are diminished, the reactive intermediate cannot be detoxified and it combines with lipid bilayers of hepatocytes, which results in cellular necrosis. Thus, treatment of acetaminophen overdoses consists of replacing glutathione with sulfhydryl compounds such as acetylcysteine.

Liver Function Tests Liver function tests is a term frequently used to refer to measurement of the levels of a group of serum markers for evaluation of liver dysfunction. Most commonly, levels of aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (AP), -glutamyltranspeptidase (GGTP), and bilirubin are included in this panel. This term is a misnomer, however, because most of these tests measure not liver function but rather cell damage. More accurate measurement of the liver's synthetic function is provided by serum albumin levels and prothrombin time. Although measuring liver enzyme levels is important in the assessment of a patient's liver disease, these test results can be nonspecific. Thus, evaluation of patients with suspected liver disease should always involve careful interpretation of abnormalities in these liver test results in the context of a thorough history and physical examination. The approach to evaluating abnormal laboratory values can also be simplified by categorizing the type of abnormality that predominates (hepatocellular damage, abnormal synthetic function, or cholestasis).

Hepatocellular Injury Hepatocellular injury of the liver is usually indicated by abnormalities in levels of the liver aminotransferases AST and ALT. These enzymes participate in gluconeogenesis by catalyzing the transfer of amino groups from aspartic acid or alanine to ketoglutaric acid to produce oxaloacetic acid and pyruvic acid, respectively (these enzymes were formerly referred to as glutamic-oxaloacetic transaminase and glutamic-pyruvic transaminase ). AST is found in the liver, cardiac muscle, skeletal muscle, kidney, brain, pancreas, lungs, and red blood cells and thus is less specific for disorders of the liver. ALT is predominately found in the liver and thus is more specific for liver disease. Hepatocellular injury is the trigger for release of these enzymes into the circulation. Common causes of elevated aminotransferase levels include viral hepatitis, alcohol abuse, medications, genetic disorders (Wilson's disease, hemochromatosis, alpha1-antitrypsin deficiency), and autoimmune diseases. The extent of serum aminotransferase elevations can suggest certain etiologies of the liver injury. However, the levels of the enzymes in these tests correlate poorly with the severity of hepatocellular necrosis, because they may not be significantly elevated in conditions of hepatic fibrosis or cirrhosis. In alcoholic liver disease, an AST:ALT ratio of >2:1 is common. Mild elevations of transaminase levels can be found in nonalcoholic fatty liver disease, chronic viral infection, or medication-induced injury. Moderate increases in the levels of these enzymes are common in

acute viral hepatitis. In conditions of ischemic insults, toxin ingestions (i.e., acetaminophen), and fulminant hepatitis, AST and ALT levels can be elevated to the thousands.

Abnormal Synthetic Function Albumin synthesis is an important function of the liver and thus can be measured to evaluate the liver's synthetic function. The liver produces approximately 10 g of albumin per day. However, albumin levels are dependent on a number of factors such as nutritional status, renal dysfunction, protein-losing enteropathies, and hormonal disturbances. In addition, level of albumin is not a marker of acute hepatic dysfunction due to albumin's long halflife of 15 to 20 days. Most clotting factors (except factor VIII) are synthesized exclusively in the liver, and thus their levels can also be used as a measure of hepatic synthetic function. Measurements of the prothrombin time and international normalized ratio (INR) are one of the best tests of hepatic synthetic function. The prothrombin time measures the rate of conversion of prothrombin to thrombin. To standardize the reporting of prothrombin time and avoid interlaboratory variability, the INR was developed. The INR is the ratio of the patient's prothrombin time to the mean control prothrombin time. Because vitamin K is involved in the -carboxylation of factors used to measure prothrombin time (factors II, VII, IX, and X), values may be prolonged in other conditions such as vitamin K deficiency and warfarin therapy.

Cholestasis Cholestasis is a condition in which bile flow from the liver to the duodenum is impaired. Disturbances in bile flow may be due to intrahepatic causes (hepatocellular dysfunction) or extrahepatic causes (biliary tree obstruction). Cholestasis often results in the release of certain enzymes and thus can be detected by measuring the serum levels of bilirubin, AP, and GGTP, which will be abnormal. Bilirubin is a breakdown product of hemoglobin metabolism. Unconjugated bilirubin is insoluble and thus is transported to the liver bound to albumin. In the liver, it is conjugated to allow excretion in bile. Measured total bilirubin levels can be low, normal, or high in patients with significant liver disease because of the liver's reserve ability to conjugate significant amounts of bilirubin. Thus, to help aid in the diagnosis of hyperbilirubinemia, fractionation of the total bilirubin is usually performed to distinguish between conjugated (direct) and unconjugated (indirect) bilirubin. Indirect bilirubin is a term frequently used to refer to unconjugated bilirubin in the circulation because the addition of another chemical is necessary to differentiate this fraction from the whole. Normally, >90% of serum bilirubin is unconjugated. The testing process for conjugated bilirubin, in contrast, is direct without the addition of other agents. The direct bilirubin test measures the levels of conjugated bilirubin and delta bilirubin (conjugated bilirubin bound to albumin). The patterns of elevation of the different fractions of bilirubin provide important diagnostic clues as to the cause of cholestasis. In general, an elevated indirect bilirubin level suggests intrahepatic cholestasis and an elevated direct bilirubin level suggests extrahepatic obstruction. Mechanisms that can result in increases in unconjugated bilirubin levels include increased bilirubin production (hemolytic disorders and resorption of hematomas) or defects (inherited or acquired) in hepatic uptake or conjugation. The rate-limiting step in bilirubin metabolism is the excretion of bilirubin from hepatocytes, so conjugated hyperbilirubinemia can be seen in inherited or acquired disorders of intrahepatic excretion or extrahepatic obstruction. Conjugated bilirubin cannot be excreted and accumulates in the hepatocytes, which results in its secretion into the circulation. Because conjugated bilirubin is water soluble, it can be found in the urine of patients with jaundice. AP is an enzyme with a wide tissue distribution but is found primarily in the liver and bones. In the liver, it is expressed by the bile duct epithelium. In conditions of biliary obstruction, levels rise as a result of increased

synthesis and release into the serum. Because the half-life of serum AP is approximately 7 days, it may take several days for levels to normalize even after resolution of the biliary obstruction. GGTP is another enzyme found in hepatocytes and released from the bile duct epithelium. Elevation of GGTP is an early marker and also a sensitive test for hepatobiliary disease. Like AP elevation, however, it is nonspecific and can be produced by a variety of disorders in the absence of liver disease. Increased levels of GGTP can be induced by certain medications, alcohol abuse, pancreatic disease, myocardial infarction, renal failure, and obstructive pulmonary disease. For this reason, elevated GGTP levels are often interpreted in conjunction with other enzyme abnormalities. For example, a raised GGTP level with increased AP level supports a liver source.

Jaundice Jaundice refers to the yellowish staining of the skin, sclera, and mucous membranes with the pigment bilirubin. Hyperbilirubinemia is usually detectable as jaundice when blood levels rise above 2.5 to 3 mg/dL. Jaundice can be caused by a wide range of benign and malignant disorders. However, when present, it may indicate a serious condition, and thus knowledge of the differential diagnosis of jaundice and a systematic approach to the work-up of the patient is necessary. Work-up of a patient with jaundice is simplified by organizing the possible causes of the disorder into groups based on the location of bilirubin metabolism. As mentioned previously, bilirubin metabolism can take place in three phases: prehepatic, intrahepatic, and posthepatic. The prehepatic phase includes the production of bilirubin from the breakdown of heme products and its transport to the liver. The majority of the heme results from red blood cell metabolism and the rest from other heme-containing organic compounds such as myoglobin and cytochromes. In the liver, the insoluble unconjugated bilirubin is then conjugated to glucuronic acid to allow for solubility in bile and excretion. The posthepatic phase of bilirubin metabolism consists of excretion of soluble bilirubin through the biliary system into the duodenum. Dysfunction in any of these phases can lead to jaundice.1 0

PREHEPATIC Jaundice as a result of elevated levels of unconjugated bilirubin occurs from faulty prehepatic metabolism and usually arises from conditions that interfere with proper conjugation of bilirubin in the hepatocyte. Insufficient conjugation is often seen in processes that result in excessive heme metabolism. Subsequently, the conjugation system is overwhelmed, which results in unconjugated hyperbilirubinemia. Causes of hemolysis include inherited and acquired hemolytic anemias. Inherited hemolytic anemias include genetic disorders of the red blood cell membrane (hereditary spherocytosis), enzyme defects (glucose-6-phosphate dehydrogenase deficiency), and defects in hemoglobin structure (sickle cell anemia and thalassemias). Hemolytic anemias can also be acquired, and these can be further divided into those with immune-mediated and those with non–immune-mediated causes. Immune-mediated hemolytic anemias result in a positive finding on a direct Coombs' test and have a variety of autoimmune and drug-induced causes. In contrast, direct Coombs' test results are negative in nonimmune hemolytic anemias. The causes in this latter category are varied and include drugs and toxins that directly damage red blood cells, mechanical trauma (heart valves), microangiopathy, and infections. Prehepatic dysfunction of bilirubin metabolism can also result from failure in the transport of unconjugated bilirubin to the liver by albumin in any condition that leads to plasma protein loss. A poor nutritional state or excess protein loss as seen in burn patients can lead to elevated levels of unconjugated bilirubin in the circulation and jaundice.

INTRAHEPATIC Intrahepatic causes of jaundice involve the intracellular mechanisms for conjugation and excretion of bile from the hepatocyte. The enzymatic processes in the hepatocytes can be affected by any condition that impairs hepatic

blood flow and subsequent function of the liver (ischemic or hypoxic events). Furthermore, there are multiple inherited disorders of enzyme metabolism that can result in either unconjugated or conjugated hyperbilirubinemia. Gilbert syndrome is a genetic variant characterized by diminished activity of the enzyme glucuronyltransferase, which results in decreased conjugation of bilirubin to glucuronide. It is a benign condition that affects approximately 4 to 7% of the population. Typically, the disease results in transient mild increases in unconjugated bilirubin levels and jaundice during episodes of fasting, stress, or illness. These episodes are self limited and usually do not require further treatment. Another inherited disorder of bilirubin conjugation is Crigler-Najjar syndrome. It is a rare disease found in neonates and can result in neurotoxic sequelae from bilirubin encephalopathy. In addition to defects in conjugation, disorders in bilirubin excretion in the hepatocyte can also lead to jaundice. Rotor's syndrome and Dubin-Johnson syndrome are two uncommon genetic disorders that disrupt transport of conjugated bilirubin from the hepatocyte and result in conjugated hyperbilirubinemia. There are also multiple acquired conditions that result in inflammation and intrahepatic cholestasis by affecting hepatocyte mechanisms for conjugation and excretion of bile. Viruses, alcohol abuse, sepsis, and autoimmune disorders can all result in inflammation in the liver with subsequent disruption of bilirubin transport in the liver. In addition, jaundice can also occur from the cytotoxic effects of many medications, including acetaminophen, oral contraceptives, and anabolic steroids.

POSTHEPATIC Posthepatic causes of jaundice are usually the result of intrinsic or extrinsic obstruction of the biliary duct system that prevents the flow of bile into the duodenum. There is a wide spectrum of pathologies that may present with obstructive jaundice. Intrinsic obstruction can occur from biliary diseases, including cholelithiasis, choledocholithiasis, benign and malignant biliary strictures, cholangiocarcinoma, cholangitis, and papillary disorders. Extrinsic compression of the biliary tree is commonly due to pancreatic disorders. Patients with pancreatitis, pseudocysts, and malignancies can present with jaundice due to external compression of the biliary system. Finally, with the growing armamentarium of endoscopic tools and minimally invasive surgical approaches, surgical complications are becoming more frequent causes of extrahepatic cholestasis. Misadventures with surgical clips, retained stones, and inadvertent ischemic insults to the biliary system can result in obstructive jaundice recognized immediately postoperatively or many years later.

MOLECULAR SIGNALING PATHWAYS IN THE LIVER Acute Phase Reaction The liver is the site of synthesis of acute phase proteins that consist of a group of plasma proteins that are rapidly released in response to inflammatory conditions elsewhere in the body. The synthesis of these proteins in the liver is influenced by a number of inflammatory mediators. Cytokines such as tumor necrosis factor alpha (TNF- ), interferon- , interleukin-1 (IL-1), interleukin-6 (IL-6), and interleukin-8 (IL-8) are released by inflammatory cells into the circulation at sites of injury and modulate the acute phase response. In response to these cytokines, the liver increases synthesis and release of a wide variety of proteins, including ceruloplasmin, complement factors, Creactive protein, D-dimer protein, alpha1 -antitrysin, and serum amyloid A. There are proteins such as serum albumin and transferrin whose levels also decrease (negative acute phase proteins) in response to inflammation. The acute phase response of the liver can be initiated in reaction to infection, trauma, or malignancy. The purpose of the release of these proteins from the liver is to contain infectious processes, prevent further tissue damage, and

begin reparative and regeneration processes to restore body homeostasis. For example, products of the complement pathways can attach to microbes to allow for phagocytosis and act as chemoattractants to the areas of inflammation. C-reactive protein is an important acute phase protein that is also involved in the clearance of microorganisms by binding to their membranes and functioning as an opsonin to facilitate phagocytosis. Other proteins such as alpha1-antitrypsin are protease inhibitors and restrict the protease activity of enzymes of inflammatory cells. Thus, the secretion of acute phase proteins from the liver during the acute phase response is an early defense measure against harmful stimuli before the full activation of the immune response.1 1

Lipopolysaccharide Signaling The liver is a complex organ with an important function in immune surveillance and clearance of bacteria and their products. This function is facilitated by the fact that the liver receives all of the drainage of the GI tract via the portal blood flow, which makes it the last barrier preventing bacteria and their toxins from reaching the systemic circulation. The importance of preventing bacteria and their products from reaching the systemic bloodstream is evident in patients who are infected with gram-negative bacteria. Gram-negative bacterial infection produces an acute inflammatory reaction that can lead to septic shock and multiple organ failure. The complications of gramnegative sepsis are initiated by endotoxin (lipopolysaccharide, or LPS). LPS is a glycolipid constituent of the outer membranes of gram-negative bacteria composed of a hydrophilic polysaccharide portion and a hydrophobic domain called lipid A. The lipid A structure is the LPS component responsible for the biologic effects of LPS. Mere nanogram amounts of LPS injected into humans can result in the manifestations of septic shock. The profound effects of LPS are caused not only by the direct effect of LPS itself but also by activation of LPS-sensitive cells, which results in the excessive release of cytokines and other inflammatory mediators. Because sepsis from gram-negative bacterial infection continues to be a major cause of morbidity and mortality, significant efforts have been made to identify the molecules involved in LPS binding and signaling (Fig. 31-10). Lipopolysaccharide-binding protein (LBP), CD14, myeloid differentiation-2 (MD-2), and toll-like receptors all have been identified as important mediators in the pathway of LPS stimulation. LBP is an acute phase protein synthesized by hepatocytes that binds the lipid A moiety of LPS and forms a soluble LBP-LPS complex. This LBPLPS complex then interacts with CD14, a receptor identified as important in LPS recognition, which results in the release of inflammatory cytokines and mediators.1 2 Studies have shown that although LBP is important, it is not required for LPS to interact with CD14; however, its presence markedly decreases the concentration of LPS necessary for cellular activation. This may be important especially at the low concentrations of LPS found under physiologic conditions. CD14 exists in two forms: membrane form and soluble form. The interaction of LPS with membrane CD14 or soluble CD14 is important in host clearance of LPS. This interaction is also responsible for the toxic effects of LPS seen in the liver and systemic circulation after the release of inflammatory cytokines and mediators. Although membrane CD14 is a membrane protein found on the surface of cells of myeloid lineage and mediates the activation of these cells by LPS, soluble CD14 is found in the serum and enables responses to LPS by cells that do not express CD14. In addition to playing an important role in the release of LBP as an acute phase reactant during LPS-mediated inflammatory insults, the liver is also one of the major sources of release of soluble CD14 into the circulation.

Fig. 31-10.

Lipopolysaccharide (LPS) and toll-like receptor 4 (TLR4) signaling in the liver. Circulating LPS-binding protein (LBP) binds to LPS in the plasma and is recognized by CD14. LPS signaling requires the formation of a complex consisting of dimerized TLR4 receptors and the adaptor MD-2. Subsequent signals activated by TLR4 can be subdivided into those dependent on MyD88 and MAL and those independent of MyD88, which require the adaptors TRIF and TRAM. LPS signaling leads to the activation of multiple inflammatory pathways, including nuclear factor B (NF- B), interferon regulatory factor 3 (IRF-3), and mitogenactivated protein kinase kinase (MKK). I = inhibitor of B kinase; JNK = c-Jun N-terminal kinase; MAL = MyD88-adaptorlike; MD-2 = myeloid differentiation-2; MyD88 = myeloid differentiation factor 88; TBK1 = TANK-binding kinase 1; TIR = toll/interleukin-1 receptor; TRAF6 = tumor necrosis factor receptor–associated factor 6; TRAM = TRIF-related adaptor molecule; TRIF = TIR domain–containing adaptor-inducing interferon- .

The binding of the LBP-LPS complex to CD14 is not enough to transduce an intracellular LPS signal. 1 2 Membrane CD14 is a glycosylphosphatidylinositol-anchored protein without a membrane-spanning domain. Thus, signaling further downstream of LPS requires additional elements. In studies using chemically modified, radiolabeled LPS capable of cross-linking to nearby proteins, LPS has been shown to cross-link specifically to two other molecules, TLR4 and MD-2. TLR4 is a member of the family of proteins called toll-like receptors and has been identified as the transmembrane coreceptor to CD14. TLR4 was originally identified as the molecular sensor for bacterial LPS when studies demonstrated that mutations in the tlr4 gene were responsible for defective LPS signaling in mutant mice. Thus, initiation of the LPS signaling cascade requires the interaction of LPS directly with the heteromeric receptor complex of CD14, TLR4, and MD-2. Activation of this complex senses the presence of bacterial LPS at the cell surface and then transmits a signal into the cytoplasm through two distinct pathways. One pathway is dependent on an adaptor known as myeloid differentiation factor 88 (MyD88). The other pathway is MyD88 independent and

relies on an adaptor known as toll/IL-1 receptor domain–containing adaptor-inducing interferon-

(TRIF).

The liver is the main organ involved in the clearance of LPS from the bloodstream and so plays a critical role in the identification and processing of LPS.1 3 Kupffer cells are the resident macrophages of the liver and have been shown to participate in LPS clearance. Studies have demonstrated that the majority of radiolabeled LPS injected IV is quickly cleared from the circulation and found in the liver, primarily localized to the Kupffer cells.1 3 Kupffer cells also contribute to the inflammatory cascade by producing cytokines in response to LPS. Interestingly, hepatocytes, the parenchymal cells of the liver, also have all the components required for LPS recognition and signaling and can participate in the response to LPS and process LPS for clearance. Although the liver is essential in the host response to gram-negative bacterial infection by contributing to LPS clearance and to the LPS-induced inflammatory reaction, evidence reveals that LPS may actually have a reciprocal role in the pathogenesis of liver disorders. A relationship between LPS and liver disease is not a novel concept. Early studies showed a correlation between the presence or absence of gut-derived LPS and the development of liver injury.1 2 Attempts to eliminate gut-derived LPS have had protective effects in various animal models of liver injury, including models of alcohol-induced liver disease. 1 2 Other studies have shown the synergism between LPS and hepatotoxins in worsening liver injury. Strategies of endotoxin antagonism have been examined in animal models and clinical trials.1 4 In summary, the liver is essential in the clearance of LPS, but it can also contribute to the negative systemic effects seen in gram-negative bacterial sepsis by excessive activation of the LPS signaling pathway. In addition, there is evidence that this signaling pathway may participate in the pathogenesis of a variety of liver diseases. An understanding and characterization of the LPS pathway within the liver is an important step to understanding the molecular basis for the lethal effect of LPS during sepsis and liver disorders.

Nitric Oxide Nitric oxide (NO) is a diffusible, free-radical gas that was first identified in 1980 as endothelium-derived relaxing factor. Its physiologic and pathophysiologic importance in the cardiovascular system was discovered with the identification of its vital role as a vasodilator. However, its mediation of a variety of other diverse biologic activities has since been recognized. In the liver, the influence of NO in normal physiology as well as in states of disease has been extensively studied. The activation of inflammatory cascades in the liver almost universally includes the upregulation of the inducible or inflammatory isoform of nitric oxide synthase (iNOS) and subsequent NO production. The functions of iNOS and NO in the liver are complex, and a clear dichotomy in their roles in liver dysfunction, whether being protective or detrimental, has been demonstrated. NO can be produced by one of three nitric oxide synthases (NOSs): neuronal NOS (nNOS), iNOS, and endothelial NOS (eNOS) 1 5 (Fig. 31-11). These enzymes catalyze the conversion of l-arginine to NO and l-citrulline. The enzymes nNOS and eNOS are constitutively expressed in a wide range of tissues. The activity of iNOS and eNOS is primarily controlled by calcium-mediated signaling that results in transient activation of these enzymes to produce small amounts of NO. As its name implies, iNOS is not normally expressed in resting states in most tissues but is upregulated by gene transcription under conditions of stress. In contrast to nNOS and eNOS, iNOS produces a large and sustained amount of NO. Although iNOS was first identified in macrophages, it has been shown to be expressed in most cell types if appropriately stimulated. Interestingly, studies of the liver with hepatocytes provided the first evidence that parenchymal cells could express iNOS. It is now known that iNOS can be expressed in all cell types of the liver, but hepatocyte expression appears to be the most prominent. Studies have shown that many inflammatory mediators, including cytokines, microbial products, and oxidative stress, are all capable of

stimulating iNOS expression in the liver. 1 6

Fig. 31-11.

The L -arginine/nitric oxide synthase (NOS)/nitric oxide (NO) pathway. NO is implicated in a wide range of regulatory mechanisms as well as inflammatory processes. L -Arginine is converted to NO by the enzyme NOS. NO has been found to have a dichotomous action in various inflammatory settings, mediating both protective and deleterious effects.

The chemical action of NO in biologic systems has been difficult to study due to its short-lived nature. NO is highly reactive with other molecules due to its one unpaired electron. These interactions can result in either nitrosation or oxidation with subsequent varied effects on cellular processes. NO also can signal through cyclic nucleotides by activating the soluble isoform of guanylyl cyclase, which increases levels of cyclic guanosine monophosphate (cGMP). The functions of cGMP include acting as a second messenger that transmits signals by activating downstream kinases or cyclic nucleotide-gated channels. In addition to affecting cGMP signaling, NO also has been found to modulate the expression of many genes. The role of NO in inflammatory states of the liver is complex and is at times conflicting.1 6 Under physiologic conditions, NO is important in maintaining hepatic perfusion. However, under inflammatory conditions, such as ischemia/reperfusion (I/R), NO can play either a protective or harmful role depending on the enzymatic source (iNOS vs. eNOS) and the type of ischemia reperfusion (cold vs. warm). It appears that the low level of constitutively expressed eNOS-derived NO is primarily beneficial in models of I/R injury, with vasodilation and subsequent improvement in hepatic microcirculation as the proposed mechanism of protection. Interestingly,

activation of iNOS in similar models suggests a potentially harmful role for iNOS. NO, through its reaction with reactive nitrogen and oxygen intermediates generated in the course of reperfusion injury, can contribute to much of the hepatocellular damage, depending on the intracellular ratio of these intermediates to NO. The production of iNOS and NO are also closely tied to multiple other inflammatory mediators in the liver, and activation of these downstream signals may explain some of the detrimental effects of NO in I/R injury of the liver. Thus, given its diverse biologic effects as a signaling molecule, it is not surprising that NO plays both a protective and potentially harmful role in the setting of hepatic I/R injury. The final effect of NO varies in different liver diseases and depends on the overall hepatic environment. The potential use of NO pharmacologic manipulation to treat hepatic disease will require careful balance of the risks and benefits of this simple yet extremely complicated molecule.

Heme Oxygenase System Heme oxygenase (HO) is the rate-limiting enzyme in the degradation of heme to yield biliverdin, carbon monoxide (CO), and free iron (Fig. 31-12). The HO system, which is activated in response to multiple cellular stresses, has been shown to be an endogenous cytoprotectant in a variety of inflammatory conditions. Currently three HO isozymes have been identified. HO-1 is the inducible form of HO, whereas HO-2 and HO-3 are constitutively expressed. The function of HO in heme degradation is essential due to the potentially toxic effects of heme. An excess of heme can cause cellular damage from oxidative stress due to its production of reactive oxygen species. Thus, the HO system is an important defense mechanism against free heme-mediated oxidative stress.

Fig. 31-12.

Heme oxygenase 1 (HO-1) and carbon monoxide (CO) signaling. HO-1 is an enzyme involved in the degradation of heme. Its protective effects in settings of hepatic stress are mediated by the catalytic products of heme degradation: ferritin, bilirubin, and CO.

HO-1 has been shown to be induced in a variety of organs during diverse conditions such as hypoxia, endotoxemia, I/R, hyperthermia, and radiation exposure.1 7 HO-1 is involved in maintaining redox homeostasis during cellular

stress. In the liver, HO-1 is thought normally to modulate hepatic microvasculature tone through its generation of CO and, like NO, its activation of guanylyl cyclase. This important role is demonstrated in animal models of portal hypertension in which inhibition of HO-1 exacerbates hypertension. Because HO-1 is induced as a protective mechanism in response to various stimuli, targeted induction of HO-1 has been studied as a therapeutic strategy for protection against inflammatory processes. HO-1 overexpression exerts hepatoprotective effects in models of I/R injury, hemorrhagic shock and resuscitation, acetaminophen-induced hepatonecrosis, and sepsis-mediated liver injury.1 7 Although HO-1 has been shown to provide protective effects in a variety of inflammatory states, the specific mechanisms by which HO-1 mediates its protective effects remains to be fully elucidated.1 7 Originally thought to be only potentially toxic waste, the by-products generated during heme catabolism now appear to play important roles in protecting against cellular stress. The well-known hazardous effects of high doses of CO are attributable to its ability to bind hemoglobin and myoglobin, which prevents the release of oxygen to tissues. However, only recently have the physiologic and beneficial roles of CO been identified. CO is produced in injured tissues via induction of HO-1 and contributes to the attenuation of proinflammatory processes. Similar to NO, CO plays an important role in maintaining the microcirculation through its activation of soluble guanylyl cyclase and subsequent elevation of intracellular cGMP. The signaling activities of cGMP lead to smooth muscle relaxation and inhibition and platelet aggregation. In addition, CO also has been shown to inhibit proinflammatory cytokines (TNF- , IL-1) and chemokines while simultaneously inducing anti-inflammatory cytokines (IL-10). Exogenous low-dose CO has been shown to protect the liver from I/R injury and endotoxemia. Biliverdin and bilirubin are other metabolites of heme that also are recognized as possible mediators of HO-1's protective function (see Fig. 31-12). The cytosolic enzyme biliverdin reductase catalyzes the reduction of biliverdin to bilirubin. Both biliverdin and bilirubin have important endogenous antioxidant properties. Free iron, the third byproduct of heme oxidation, is known to be cytotoxic by catalyzing the production of hydroxyl radicals. However, HO-1 induction is associated with increased levels of ferritin, the free iron–sequestering protein. Thus, the increase in ferritin levels with the subsequent decrease in intracellular concentrations of free iron results in a net antioxidant effect. Importantly, both bilirubin and ferritin have been shown to protect against liver injury in a variety of I/R models.1 7 In summary, HO-1 is upregulated and protective in multiple conditions of hepatic stress. Until recently, the degradation products of the HO system were thought to be only potentially toxic waste. It now appears that CO, biliverdin and bilirubin, and ferritin are important in the maintenance of cellular redox homeostasis and may play a role in the mechanism of hepatoprotection in disease. Studies involving induction of HO-1 expression and use of its metabolic products hold therapeutic promise for novel agents to protect against disorders of hepatic inflammation.

Toll-Like Receptors The liver is a central regulator of the systemic immune response after acute insults to the body. Not only does it play a crucial role in modulating the systemic inflammatory response to infection or injury, it is also subject to injury and dysfunction from these same processes. Recent advances in the study of mechanisms for the activation of the innate immune system have pointed to the TLRs as a common pathway for immune recognition of microbial invasion and tissue injury.1 8 By recognizing either microbial products or endogenous molecules released from damaged sites, the TLR system is capable of alerting the host to danger by activating the innate immune system. Initially, this is manifested by the production of inflammatory mediators and the rapid uptake of invading microbes and their products. When excessive, this inflammatory response can contribute to organ damage and dysfunction.

To date, 13 TLRs have been described in mice and 10 in humans.1 8 TLRs are a family of proteins that are mammalian homologues to the Drosophila Toll, a protein that functions in development and immunity. The cytoplasmic portion of TLRs is similar to that of the IL-1 receptor (IL-1R) family and is called the toll/IL-1 receptor (TIR) domain. Unlike the IL-1R extracellular portion that consists of an immunoglobulin-like domain, the TLRs have leucine-rich repeats in their extracellular portion. The TLRs have many structural similarities, both extracellularly and intracellularly, but they differ from each other in ligand specificities and expression patterns, and show some variability in the signaling pathways they activate. The TLRs were initially identified as components of the innate immune system that acted as a front-line defense mechanism against infections. Their recognition of patterns on pathogens, such as microbial peptides, LPS, lipoteichoic acids, bacterial DNA, and single-stranded RNA, resulted in the activation of an inflammatory response meant for controlling the invading organisms. In situations of noninfectious inflammation such as seen in trauma, clinicians have long recognized similar activation of the same inflammatory pathways and systemic manifestations. This observation, among others, led to the hypothesis that the immune system is designed to recognize any threats, whether from pathogens or tissue damage, that may lead to disruption of homeostasis. Under conditions of sterile inflammation, the activation of immune cells is through the release of endogenous danger molecules, normal cell constituents released by damaged or dying cells, or components of the extracellular matrix, released by the action of proteases at the site of tissue damage. Recent observations show that both microbial products and endogenous danger molecules can be recognized through the TLR system. Perhaps more than any of the other TLR family members, TLR4 sits at the interface of microbial and sterile inflammation. Whereas the role of TLR4 in the recognition of LPS is well established, only recently has it become apparent that TLR4 also participates in the recognition of endogenous danger molecules1 8 (see Fig. 31-10). In vivo evidence for TLR4-mediated danger signaling comes from studies of acute tissue injury in hemorrhagic shock, trauma, and I/R models.1 9 In each case, TLR4-mutant animals exhibited reduced injury or inflammation compared with wild-type controls. In efforts to identify the ligands responsible for TLR4-dependent signaling in noninfectious insults, multiple molecules have been suggested. These include heat shock proteins, fibrinogen, hyaluronic acid, heparin sulfate, and high mobility group box 1 (HMGB1). Although a central role for TLR4 in recognizing tissue injury is building, studies are beginning to suggest that other TLR family members may also participate in the recognition of endogenous molecules released by tissue injury.1 9 The very recent realization that certain TLR family members also respond to endogenous molecules released from stressed or damaged tissues points to a molecular basis for a shared mechanism of innate immune activation by infection and injury.

RADIOLOGIC EVALUATION OF THE LIVER Ultrasound Abdominal ultrasound is a commonly applied imaging modality used to evaluate abdominal symptoms. Ultrasound technology is based on the pulse-echo principle. The ultrasound transducer converts electrical energy to highfrequency sound energy that is transmitted into tissue. Although some of the ultrasound waves are transmitted through the tissue, some are reflected back, and the ultrasound image is produced when the ultrasound receiver detects those reflected waves. This real-time gray scale (B-mode) imaging is augmented by Doppler flow imaging. Doppler ultrasound not only can detect the presence of blood vessels but also can determine the direction and velocity of blood flow. Ultrasonography is a useful initial imaging test of the liver because it is inexpensive, is widely available, involves no radiation exposure, and is well tolerated by patients. It is excellent for diagnosing biliary pathology and focal liver lesions. In addition, liver injury can be evaluated in trauma patients using the

focused abdominal sonography for trauma examination. Limitations of ultrasound include incomplete imaging of the liver, most often at the dome or beneath ribs on the surface, and incomplete visualization of lesion boundaries. Moreover, obesity and overlying bowel gas also can interfere with image quality. Thus, ultrasonographically detected masses usually require further evaluation by other imaging modalities due to the lower sensitivity and specificity of ultrasound compared with CT and MRI. The advent of contrast-enhanced ultrasound has improved the ability of this modality to differentiate among benign and malignant lesions. The injection of gas microbubble agents can increase the sensitivity and specificity of ultrasound in detecting and diagnosing liver lesions. Microbubbles are 3.5 g/dL 2.8–3.5 g/dL

90% of cases.

SURGICAL SHUNT The need for surgical shunts has been reduced since the introduction of the TIPS procedure and hepatic transplantation. At this time the recommendation is that surgical shunts be considered only in patients who have MELD scores of 90% of cases refractory to medical treatment, and should not affect subsequent hepatic transplantation. Possible complications include bleeding either intra-abdominally or via the biliary tree, infections, renal failure, decreased hepatic function, and hepatic encephalopathy, which occur in 25 to 30% of patients undergoing the TIPS procedure. After the TIPS procedure the hyperdynamic circulation of cirrhosis also can be worsened, and a patient with underlying cardiac problems can experience cardiac failure.

NONSHUNT SURGICAL MANAGEMENT OF REFRACTORY VARICEAL BLEEDING In the patient with extrahepatic portal vein thrombosis and refractory variceal bleeding, the Sugiura procedure may be considered. The Sugiura procedure consists of extensive devascularization of the stomach and distal esophagus along with transection of the esophagus, splenectomy, truncal vagotomy, and pyloroplasty. As with performance of surgical shunts, patient survival is dependent on hepatic reserve at the time of the surgical procedure. Experience in Western countries is somewhat limited, and a number of modifications have been made to the original Sugiura procedure over time.

Hepatic Transplantation Patients with cirrhosis, portal hypertension, and variceal bleeding usually die as a result of hepatic failure and not acute blood loss. Therefore, hepatic transplantation must be considered in the patient with ESLD, because it represents the patient's only chance for definitive therapy and long-term survival. Hepatic transplantation also can be considered for the patient with variceal bleeding refractory to all other forms of management. Survival after hepatic transplantation is not affected adversely by the previous performance of EVL, TIPS, or splenorenal or mesocaval shunts. Previous creation of an Eck fistula, however, does make hepatic transplantation much more

technically difficult, and therefore this procedure should be avoided in the transplantation candidate. In addition to saving the patient's life, hepatic transplantation reverses most of the hemodynamic and humoral changes associated with cirrhosis.

Budd-Chiari Syndrome Budd-Chiari syndrome (BCS) is an uncommon congestive hepatopathy characterized by the obstruction of hepatic venous outflow. Patients may present with acute signs and symptoms of abdominal pain, ascites, and hepatomegaly or more chronic symptoms related to long-standing portal hypertension. The obstruction may be thrombotic or nonthrombotic anywhere along the venous outflow system from the hepatic venules to the right atrium. Variations in the level of obstruction is one of the factors explaining the heterogeneity of the disease. The incidence of BCS is 1 in 100,000 of the general population worldwide.3 9 BCS is defined as primary when the obstructive process involves an endoluminal venous thrombosis. BCS is considered as a secondary process when the veins are compressed or invaded by a neighboring lesion originating outside the vein. A thorough evaluation demonstrates one or more thrombotic risk factors in approximately 75 to 90% of patients with primary BCS. Twenty-five percent of primary BCS patients have two or more risk factors. 3 9 BCS remains poorly understood, however, and primary myeloproliferative disorders account for approximately 35 to 50% of the primary cases of BCS. In most cases the myeloproliferative disorder can be classified as essential thrombocythemia or polycythemia rubra, but forms that are more difficult to classify also occur. In >90% of affected patients the myeloproliferative disorder was not diagnosed before the development of BCS. Most patients (80%) are women of a relatively young age (mean age is 30 years). The diagnosis of myeloproliferative disorder is made by demonstrating clusters of dystrophic megakaryocytes in a bone marrow biopsy specimen or by demonstrating formation of spontaneous colonies in cultures of erythroid progenitors on erythropoietin-poor media. All known inherited thrombophilias have been implicated in the development of BCS. Activated protein C resistance, generally related to heterozygous or homozygous factor V Leiden mutation, is seen in approximately 25% of patients with BCS. Factor V Leiden mutation is present in the majority of cases related to pregnancy or oral contraceptive use. Anticardiolipin antibodies and hyperhomocysteinemia are also risk factors for BCS. Protein S, protein C, and antithrombin III are all produced in the liver, and their levels are affected by liver dysfunction. Therefore, although levels of these proteins may be found to be low in patients with BCS, it is difficult to prove this as the causative factor. Oral contraceptive use has also been shown to be a risk factor for BCS.3 9 Clinically significant BCS is usually the result of obstruction of two or more of the major hepatic veins. The obstruction results in increased sinusoidal pressure and decreased sinusoidal blood flow. Therefore, liver congestion, right upper quadrant pain, and ascites may occur. In addition, liver perfusion via the portal vein is decreased, and 70% of affected patients have noninflammatory centrilobular necrosis on biopsy. Acute liver failure is rare, and most patients go on to develop chronic portal hypertension and ascites. Within a few weeks of obstruction centrilobular fibrosis begins and is followed by progressive fibrosis, nodular regeneration, and cirrhosis. Caudate lobe hypertrophy occurs in approximately 50% of cases and is due to the fact that the caudate lobe has direct venous drainage into the IVC. This caudate lobe hypertrophy can result in obstruction of the IVC. Abdominal ultrasonography is the initial investigation of choice and can demonstrate absence of hepatic vein flow, spiderweb hepatic veins, and collateral hepatic veins. 4 0 Abdominal ultrasonography has a sensitivity and specificity of approximately 85%. MRI of the abdomen also is capable of demonstrating hepatic vein thrombosis and evaluating the IVC but is limited in that it cannot show direction of blood flow. The definitive radiographic study to evaluate BCS is hepatic venography to determine the presence and extent of hepatic vein thrombus as well as IVC

pressures. Hepatic venography with measurement of IVC pressures should be performed before undertaking TIPS or a surgical shunt. Liver biopsy specimens demonstrate congestion, hepatocyte loss, and centrilobularfibrosis. Liver biopsy is necessary to differentiate BCS from veno-occlusive disease that is due to nonthrombotic obstruction of the hepatic venules by subendothelial swelling. Initial treatment consists of diagnosing and medically managing the underlying disease process and preventing extension of the hepatic vein thrombosis through systemic anticoagulation. The BCS-associated portal hypertension and ascites are medically managed in a manner similar to that in most cirrhotic patients. Thrombolytic therapy alone for acute thrombosis may be attempted. However, the risk:benefit ratio is still unknown. Hepatic decompression aims to decrease sinusoidal pressure by restoring the outflow of blood from the liver via either medical therapy, recanalization of the obstructed hepatic veins, or side-to-side portacaval shunt. Radiographic and surgical intervention should be reserved for those patients whose condition is nonresponsive to medical therapy. Percutaneous angioplasty and TIPS, in combination with thrombolytic therapy, are currently preferred to surgical shunt because the procedural mortality is low and caudate lobe hypertrophy does not affect the outcome of these procedures. Side-to-side portacaval shunt attempts to turn the portal vein into a hepatic outflow tract. Usually a venous or prosthetic interposition graft is necessary. Patients with a hemodynamically significant IVC stricture due to caudate lobe hypertrophy require preshunt IVC stenting. Most patients with portacaval shunt show improvement in hepatic function and fibrosis at 1 year without significant hepatic encephalopathy.4 0 However, the enthusiasm for this procedure has been curbed due to the relatively high rate of operative mortality and shunt dysfunction. Hepatic transplantation should be considered for patients with manifestations of ESLD and can be expected to produce a 10-year survival rate of 75%. Whether hepatic transplantation should be a primary treatment for BCS, should replace other hepatic decompressive treatment options, or should be used only as a rescue operation remains unclear and somewhat controversial. It must be noted that, irrespective of the nontransplantation treatment modality initially used, the manifestations of BCS may progress and ultimately require hepatic transplantation.

INFECTIONS OF THE LIVER The liver contains the largest portion of the reticuloendothelial system in the human body and is therefore able to handle the continuous low-level exposure to enteric bacteria that it receives through the portal venous system. Due to the high level of reticuloendothelial cells in the liver, nonviral infections are unusual.

Pyogenic Liver Abscess Pyogenic liver abscesses are the most common liver abscesses seen in the United States. Previously they were felt to be due to portal infection, often occurring in young patients secondary to acute appendicitis. However, with earlier diagnosis this cause of abscesses has decreased. Pyogenic liver abscesses also occur as a result of impaired biliary drainage, hematogenous infection arising from sources such as IV drug abuse and teeth cleaning, and local spread of infection (diverticulitis or Crohn's disease). Patients may also develop pyogenic abscess as a complication of subacute bacterial endocarditis and infected indwelling catheters. There appears to be an increasing incidence due to infection by opportunistic organisms among immunosuppressed patients, including transplant and chemotherapy recipients and the AIDS population. Pyogenic hepatic abscesses may be single or multiple and are more frequently found in the right lobe of the liver.4 1 The abscess cavities are variable in size and, when multiple, may coalesce to give a honeycomb appearance. Approximately 40% of abscesses are monomicrobial, an additional 40% are polymicrobial, and 20% are culture negative. The most common infecting agents are gram-negative organisms. Escherichia coli is found in two thirds, and Streptococcus faecalis, Klebsiella, and Proteus vulgaris are

also common. Anaerobic organisms such as Bacteroides fragilis are also seen frequently. Staphylococcus and Streptococcus are more common in patients with endocarditis and infected indwelling catheters. Patients usually are symptomatic with right upper quadrant pain and fever. Jaundice occurs in up to one third of affected patients. A thorough history and physical examination are necessary to attempt to localize the primary causative site. Leucocytosis, an elevated sedimentation rate, and an elevated alkaline phosphatase (AP) level are the most common laboratory findings. Significant abnormalities in the results of the remaining liver function tests are unusual. Blood cultures reveal the causative organism in approximately 50% of cases. Ultrasound examination of the liver reveals pyogenic abscesses as round or oval hypoechoic lesions with well-defined borders and a variable number of internal echoes. CT scan is highly sensitive in the localization of pyogenic liver abscesses. The abscesses are hypodense and may contain air-fluid levels indicating a gas-producing infectious organism as well as peripheral enhancement (Fig. 31-19). MRI of the abdomen also can detect pyogenic abscesses with a high level of sensitivity but plays a limited role because of its inability to be used for image-guided diagnosis and therapy.

Fig. 31-19.

Computed tomographic scan of pyogenic liver abscesses. Multiple hepatic abscesses are seen in a patient after an episode of diverticulitis. Note the loculated large central abscess as well as the left lateral segment abscess.

The current cornerstones of treatment include correction of the underlying cause, needle aspiration, and IV antibiotic therapy. On presentation, percutaneous aspiration and culture of the aspirate may be beneficial to guide subsequent antibiotic therapy. Initial antibiotic therapy needs to cover gram-negative as well as anaerobic organisms. Aspiration and placement of a drainage catheter is beneficial for only a minority of pyogenic abscesses,

because most are quite viscous and drainage is ineffective. Antibiotic therapy must be continued for at least 8 weeks. Aspiration and IV antibiotic therapy can be expected to be effective in 80 to 90% of patients. If this initial mode of therapy fails, the patients should undergo surgical therapy, including laparoscopic or open drainage. Anatomic surgical resection can be performed in patients with recalcitrant abscesses. It must be kept in mind throughout the evaluation and treatment of the presumed pyogenic abscess that a necrotic hepatic malignancy must not be mistaken for a hepatic abscess. Therefore, early diagnosis and progression to surgical resection should be advocated for patients who do not respond to initial antibiotic therapy.

Amebic Abscess Entamoeba histolytica is a parasite that is endemic worldwide, infecting approximately 10% of the world's population. Amebiasis is most common in subtropical climates, especially in areas with poor sanitation. E. histolytica exists in a vegetative form and as cysts capable of surviving outside the human body. The cystic form passes through the stomach and small bowel unharmed and then transforms into a trophozoite in the colon. Here it invades the colonic mucosa forming typical flask-shaped ulcers, enters the portal venous system, and is carried to the liver. Occasionally, the trophozoite will pass through the hepatic sinusoid and into the systemic circulation, which results in lung and brain abscesses. Amebae multiply and block small intrahepatic portal radicles with consequent focal infarction of hepatocytes. They contain a proteolytic enzyme that also destroys liver parenchyma. The abscesses formed are variable in size and can be single or multiple. The amebic abscess is most commonly located in the superior-anterior aspect of the right lobe of the liver near the diaphragm and has a necrotic central portion that contains a thick, reddish brown, puslike material. This material has been likened to anchovy paste or chocolate sauce. Amebic abscesses are the most common type of liver abscesses worldwide. Amebiasis should be considered in patients who have traveled to an endemic area and present with right upper quadrant pain, fever, hepatomegaly, and hepatic abscess.4 1 Leukocytosis is common, whereas elevated transaminase levels and jaundice are unusual. The most common biochemical abnormality is a mildly elevated AP level. Even though this disease process is secondary to a colonic infection, the presence of diarrhea is unusual. For most patients findings of the fluorescent antibody test for E. histolytica are positive, and results can remain positive for some time after a clinical cure. Amebiasis is unlikely to be present if the serologic test results are negative. Ultrasound and CT scanning of the abdomen are both very sensitive but nonspecific for the detection of amebic abscesses. 4 1 CT scanning also is useful in detecting extrahepatic involvement. Amebic abscesses usually appear as well-defined low-density round lesions that have enhancement of the wall. They also usually appear somewhat ragged in appearance with a peripheral zone of edema. The central cavity may have septations as well as fluid levels. Metronidazole 750 mg tid for 7 to 10 days is the treatment of choice and is successful in 95% of cases. Defervescence usually occurs in 3 to 5 days. The time necessary for the abscess to resolve depends on the initial size at presentation and varies from 30 to 300 days.4 1 Both ultrasound and CT of the liver can be used as follow-up after the initiation of medical therapy. Aspiration of the abscess is rarely needed and should be reserved for patients with large abscesses, abscesses that do not respond to medical therapy, abscesses that appear to be superinfected, and abscesses of the left lobe of the liver that may rupture into the pericardium.

Hydatid Disease Hydatid disease is due to the larval or cyst stage of infection by the tapeworm Echinococcus granulosus, which lives

in the dog.4 2 Humans, sheep, and cattle are intermediate hosts. The dog is infected by eating the viscera of sheep that contain hydatid cysts. Scolices, contained in the cysts, adhere to the small intestine of the dog and become adult taenia, which attach to the intestinal wall. Each worm sheds approximately 500 ova into the bowel. The infected ova-containing feces of the dog contaminate grass and farmland, and the ova are ingested by sheep, pigs, and humans. The ova have chitinous envelopes that are dissolved by gastric juice. The liberated ovum burrows through the intestinal mucosa and is carried by the portal vein to the liver, where it develops into an adult cyst. Most cysts are caught in the hepatic sinusoids, and 70% of hydatid cysts form in the liver. A few ova pass through the liver and are held up in the pulmonary capillary bed or enter the systemic circulation, forming cysts in the lung, spleen, brain, or bones. Hydatid disease is most common in sheep-raising areas, where dogs have access to infected offal. These include South Australia, New Zealand, Africa, Greece, Spain, and the Middle East. The disease is uncommon in Britain. Hydatid cysts commonly involve the right lobe of the liver, usually the anterior-inferior or posterior-inferior segments. The uncomplicated cyst may be silent and found only at autopsy or incidentally. Occasionally, the affected patient presents with dull right upper quadrant pain or abdominal distention. Cysts may become secondarily infected, involve other organs, or even rupture, which leads to an allergic or anaphylactic reaction. The diagnosis of hydatid disease is based on the findings of an enzyme-linked immunosorbent assay (ELISA) for echinococcal antigens, and results are positive in approximately 85% of infected patients.4 2 The ELISA results may be negative in an infected patient if the cyst has not leaked or does not contain scolices, or if the parasite is no longer viable. Eosinophilia of >7% is found is approximately 30% of infected patients. Ultrasonography and CT scanning of the abdomen are both quite sensitive for detecting hydatid cysts. The appearance of the cysts on images depends on the stage of cyst development. Typically, hydatid cysts are well-defined hypodense lesions with a distinct wall. Ring-like calcifications of the pericysts are present in 20 to 30% of cases. As healing occurs, the entire cyst calcifies densely, and a lesion with this appearance is usually dead or inactive. Daughter cysts generally occur in a peripheral location and are typically slightly hypodense compared with the mother cyst. MRI of the abdomen may be useful to evaluate the pericyst, cyst matrix, and daughter cyst characteristics. Unless the cysts are small or the patient is not a suitable candidate for surgical resection, the treatment of hydatid disease is surgically based because of the high risk of secondary infection and rupture. Medical treatment with albendazole relies on drug diffusion through the cyst membrane. The concentration of drug achieved in the cyst is uncertain but is better than that of mebendazole, and albendazole can be used as initial treatment for small, asymptomatic cysts. For most cysts surgical resection involving laparoscopic or open complete cyst removal with instillation of a scolicidal agent is preferred and usually is curative. If complete cystectomy is not possible, then formal anatomic liver resection can be used. During surgical resection caution must be exercised to avoid rupture of the cyst with release of protoscolices into the peritoneal cavity. Peritoneal contamination can result in an acute anaphylactic reaction or peritoneal implantation of scolices with daughter cyst formation and inevitable recurrence. Alveolar echinococcosis (caused by Echinococcus multilocularis ) occurs in the Northern Hemisphere, produces a more generalized granulomatous reaction, and can present in a manner similar to that of a malignancy. Resection is the treatment of choice.

Ascariasis Ascaris infection is particularly common in the Far East, India, and South Africa. Ova of the roundworm Ascaris lumbricoides arrive in the liver by retrograde flow in the bile ducts. The adult worm is 10 to 20 cm long and may lodge in the common bile duct, producing partial bile duct obstruction and secondary cholangitic abscesses. The

ascaris may be a nucleus for the development of intrahepatic gallstones. The clinical presentation in an affected patient may include any of the following: biliary colic, acute cholecystitis, acute pancreatitis, or hepatic abscess.4 3 Plain abdominal radiographs, abdominal ultrasound, and endoscopic retrograde cholangiography (ERCP) all can demonstrate the ascaris as linear filling defects in the bile ducts. Occasionally worms can be seen moving into and out of the biliary tree from the duodenum. Treatment consists of administration of piperazine citrate, mebendazole, or albendazole in combination with ERCP extraction of the worms. Failure of endoscopic extraction warrants surgical removal of the ascaris.

Schistosomiasis Schistosomiasis affects >200 million people in 74 countries. Hepatic schistosomiasis is usually a complication of the intestinal disease, because emboli of schistosomiasis ova reach the liver via the mesenteric venous system. Eggs excreted in the feces hatch in water to release free-swimming embryos, which enter snails and develop into forktailed cercariae. They then re-enter human skin during contact within infected water. They burrow down to the capillary bed, and at that point there is widespread hematogenous dissemination. Those entering the intrahepatic portal system grow rapidly, and a granulomatous reaction occurs. The degree of resultant portal fibrosis is related to the adult worm load. Schistosomiasis has three stages of clinical symptomatology: the first includes itching after the entry of cercariae through the skin; the second includes fever, urticaria, and eosinophilia; and the third involves hepatic fibrosis followed by presinusoidal portal hypertension. During this third phase the liver shrinks, the spleen enlarges, and the patient may develop complications of portal hypertension while hepatic function is maintained. Active infection is detected by stool examination. Serologic tests indicate past exposure without specifics regarding timing. A negative serologic test result rules out schistosomal infection. Serum levels of transaminases are usually normal, but the AP level may be mildly elevated. A decreased serum albumin level is usually the result of frequent GI bleeds and decreased nutrition. Medical treatment of schistosomiasis includes education regarding hygiene and the avoidance of infected water. Treatment with praziquantel 40 to 75 mg/kg as a single dose is the treatment of choice for all forms of schistosomiasis and produces few side effects. GI bleeding usually is controlled by endoscopic variceal ligation. However, in a patient with refractory GI portal hypertensive bleeding, distal splenorenal shunt or gastric devascularization and splenectomy need to be considered.

Viral Hepatitis The role of the surgeon in the management of viral hepatitis is somewhat limited. However, the disease entities of hepatitis A, B, and C need to be kept in mind during any evaluation for liver disease. The findings of hepatitis A in many cases will be acute, nonspecific, and similar to those associated with hepatic metastases, biliary obstruction, and cirrhosis. Hepatitis B and C can both lead to chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC). Current hepatitis B vaccination programs as well as treatment protocols involving nucleoside analogues and hepatitis B immunoglobulin have dramatically improved the treatment options for affected patients. The incidence of ESLD and HCC are both diminished by these protocols. Currently, the same therapeutic options are not available for hepatitis C, and although some patients do maintain a sustained viral response after interferon-based therapy, many either do not respond or have recurrences of their disease. The unraveling of the crystal structures of all three major hepatitis C viral enzymes involved in replication has led to the development of several novel drugs, including protease inhibitors, polymerase inhibitors, and hepatitis C vaccines. Although early results are encouraging, longer-term data are required to determine the effectiveness of these new treatment options.

WORK-UP OF AN INCIDENTAL LIVER MASS A liver mass often is identified incidentally during a radiologic imaging procedure performed for another indication. For example, a liver mass may be discovered during evaluation for gallbladder disease or kidney stones. In addition, with advances in imaging technology, previously undetected lesions are now identified. Although many of these lesions are benign and will require no further treatment, the concern for malignancy requires a thorough evaluation. Thus, an orderly approach should be taken to the work-up of an incidental liver lesion to minimize unnecessary testing.4 4 The evaluation of an incidental liver mass begins with a history and physical examination (Fig. 31-20). The patient should be asked about abdominal pain, weight loss, previous liver disease, cirrhosis, alcohol use, viral hepatitis, blood transfusions, tattoos, oral contraceptive use (in women), and personal or family history of cancer. On physical examination, jaundice, scleral icterus, hepatomegaly, splenomegaly, palpable mass, or stigmata of portal hypertension should be noted. After completion of the history and physical examination, blood work should be performed, including complete blood count; platelet count; measurement of levels of electrolytes, blood urea nitrogen, creatinine, glucose, and albumin; liver function tests; serum ammonia level; coagulation studies; hepatitis screen; and measurement of levels of the tumor markers carcinoembryonic antigen, alpha-fetoprotein, and cancer antigen 19-9.

Fig. 31-20.

Algorithm for diagnostic work-up of an incidental liver lesion. The evaluation includes history and physical examination, blood work, imaging studies, and liver biopsy (if needed). AFP = alpha-fetoprotein; BUN = blood urea nitrogen; CA 19-9 = cancer antigen 19-9; CEA = carcinoembryonic antigen; creat = creatinine; CBC = complete blood count; CT = computed

tomography; EGD = esophagogastroduodenoscopy; glu = glucose; Gyn = gynecologic; HTN = hypertension; MRI = magnetic resonance imaging; OCP = oral contraceptive pill; PAP = Papanicolaou; US = ultrasound.

The differential diagnosis for an incidental liver mass includes cysts, benign solid lesions, and primary or metastatic cancers (Table 31-7). Ultrasound or CT is commonly performed to evaluate respiratory or abdominal symptoms, and these scans are usually what leads to the discovery of an incidental liver lesion. Although hepatic ultrasound is inexpensive, technical limitations are often encountered due to interference by bowel gas, obesity, or overlying ribs; a mass seen on liver ultrasound should be further evaluated with a dedicated contrast helical CT or MRI scan.21,22 Additional imaging studies should be performed as indicated. For example, if the working diagnosis is a liver hemangioma and the CT scan findings are not classical for this diagnosis, then a contrast liver MRI should be performed. If the MRI is inconclusive, then an old-fashioned nuclear medicine tagged red blood cell scan can be helpful. If the radiologic imaging results are classic for a benign hemangioma or focal nodular hyperplasia (FNH), then a liver biopsy is not indicated (and actually risks hemorrhage, because both lesions are hypervascular) and observation is warranted as long as the patient is asymptomatic.

Table 31-7 Classification of Liver Lesions Benign Cyst Hemangioma Focal nodular hyperplasia Adenoma Biliary hamartoma Abscess Malignant Hepatocellular carcinoma Cholangiocarcinoma (bile duct cancer) Gallbladder cancer Metastatic colorectal cancer Metastatic neuroendocrine cancer (carcinoid) Other metastatic cancers

If all imaging studies are inconclusive, then an image-guided percutaneous liver biopsy should be considered. If the lesion is too small to biopsy or cannot be well visualized or targeted for percutaneous biopsy, then options are either close follow-up imaging (e.g., 3 to 6 months) to document stability or laparoscopic liver biopsy. Laparoscopic liver biopsy also is indicated in cases of cirrhosis with ascites and coagulopathy, in which the bleeding risk is excessive by percutaneous route. If liver biopsy findings demonstrate adenocarcinoma, then the differential diagnosis narrows to metastatic adenocarcinoma from an unknown or occult primary; a primary liver adenocarcinoma, which also is known as cholangiocarcinoma; or bile duct cancer (see "Malignant Liver Tumors"). Although pathologic staining can provide clues to the origin, a primary liver cholangiocarcinoma is usually a diagnosis of exclusion after an occult extrahepatic primary malignancy is ruled out. In these cases the work-up for an occult primary carcinoma should include colonoscopy; EGD (upper endoscopy); mammogram, gynecologic examination, and Papanicolaou smear (in women); and prostate-specific antigen testing and prostate evaluation (in men).

HEPATIC CYSTS Congenital Cysts The majority of hepatic cysts are asymptomatic. Hepatic cysts are usually identified incidentally and can occur at any time throughout life. The most common benign lesion found in the liver is the congenital or simple cyst. The exact prevalence of simple hepatic cysts in the U.S. population is not known, but the female:male ratio is approximately 4:1, and the prevalence is approximately 2.8 to 3.6%.4 5 Simple cysts are the result of excluded hyperplastic bile duct rests. Simple cysts usually are identified in hepatic imaging studies as thin-walled, homogeneous, fluid-filled structures with few to no septations. The cyst epithelium is cuboidal and secretes a clear nonbilious serous fluid. With the exception of large cysts, simple cysts are usually asymptomatic. Large simple cysts may cause abdominal pain, epigastric fullness, and early satiety. Occasionally the affected patient presents with an abdominal mass. Asymptomatic simple cysts are best managed conservatively. The preferred treatment for symptomatic cysts is ultrasound- or CT-guided percutaneous cyst aspiration followed by sclerotherapy. This approach is approximately 90% effective in controlling symptoms and ablating the cyst cavity. If percutaneous treatment is unavailable or ineffective, treatment may include either laparoscopic or open surgical cysts fenestration. The laparoscopic approach is being used more frequently and is 90% effective. The excised cyst wall is sent for pathologic analysis to rule out carcinoma, and the remaining cyst wall must be carefully inspected for evidence of neoplastic change. If such change is present, complete resection is required, either by enucleation or formal hepatic resection.

Biliary Cystadenoma Biliary cystadenomas are slow-growing, unusual, benign lesions that most commonly present as large lesions in the right lobe of the liver. Although these lesions are usually benign, they can undergo malignant transformation. Biliary cystadenomas usually present with abdominal pain. An abdominal mass occasionally can be identified on physical examination. In contrast to simple cysts, biliary cystadenomas have walls that appear thicker with soft tissue nodules and the cyst's septations usually enhance. The protein content of the fluid can be variable and can affect the radiographic images on CT and MRI. Surgical resection is the preferred mode of treatment.

Polycystic Liver Disease Adult polycystic liver disease (ADPCLD) occurs as an autosomal dominant disease and usually presents in the third decade of life. Some 44 to 76% of affected families are found to have mutations of PKD1 and approximately 75% have mutations of PKD2.4 6 The prevalence and number of hepatic cysts are higher in females and increase with advancing age and with increasing severity of renal cystic disease and renal dysfunction. At age 60 years, approximately 80% of ADPCLD patients will have hepatic cysts, with women having more and larger cysts. This gender difference may be due to the effects of estrogen. Patients with a small number of cysts or with small cysts (1, usually develop clinical symptoms, including abdominal pain, shortness of breath, and early satiety. Progressive ADPCLD will result in renal failure and the need for hemodialysis. In most patients, the liver parenchymal volume is preserved despite extensive cystic disease. Hepatic decompensation, variceal hemorrhage, ascites, and encephalopathy develop rarely in patients with ADPCLD and only in patients with massive cystic disease. The most common hepatologic complications associated with ADPCLD are intracystic hemorrhage, infection, and posttraumatic rupture. The most common abnormal biochemical test finding is a modestly elevated -glutamyltransferase level and the most useful imaging test is CT scanning of the abdomen,

which will demonstrate the characteristic polycystic appearance. Other conditions that may be associated with ADPCLD include cerebral aneurysm, diverticulosis, mitral valve prolapse, and inguinal hernia. There is no effective medical therapy for ADPCLD. Cyst aspiration and sclerosis may be considered if the patient has one or a few dominant cysts; however, most patients have multiple cysts and do not improve when this technique is used. Cyst fenestration via an open or laparoscopic approach can be attempted in symptomatic patients; however, approximately 50% of treated patients will have recurrence of their symptoms. 4 7 The only definitive therapy for patients with symptomatic ADPCLD is orthotopic liver transplantation. If the patient has renal involvement (polycystic kidney disease) with renal failure, consideration should be given to combined liver-kidney transplantation. Because of the genetic basis of ADPCLD, living-donor transplantation should be considered only if the presence of ADPCLD in the donor can be ruled out.

Caroli's Disease Caroli's disease is a syndrome of congenital ductal plate malformations of the intrahepatic bile ducts and is characterized by segmental cystic dilatation of the intrahepatic biliary radicals.4 8 Caroli's disease also is associated with an increased incidence of biliary lithiasis, cholangitis, and biliary abscess formation. Caroli's disease usually occurs in the absence of cirrhosis and is associated with cystic renal disease. 4 8 The most common presenting symptoms include fever, chills, and abdominal pain. Most patients present by the age of 30 years, and males and females are affected equally. Rarely, patients can present later in life with complications secondary to portal hypertension. Approximately 33% of affected patients develop biliary lithiasis and 7% develop cholangiocarcinoma. The diagnosis of Caroli's disease is made based on imaging studies. Magnetic resonance cholangiopancreatography, ERCP, and percutaneous transhepatic cholangiography provide more detailed imaging of the biliary tree and confirm communication of the intrahepatic cysts with the biliary tree, which is necessary to solidify the diagnosis. Treatment consists of biliary drainage, with ERCP and percutaneous transhepatic cholangiography serving as firstline therapeutic modalities. If the disease is limited to a single lobe of the liver, hepatic resection can be beneficial. Liver resection can be considered in the patient with hepatic decompensation or unresponsive recurrent cholangitis and possibly in the patient with a small T1 or T2 cholangiocarcinoma.

BENIGN LIVER LESIONS The liver is an organ that is commonly involved either primarily or secondarily with vascular, metabolic, infectious, and malignant processes. Many classification schemes are used to help narrow the differential diagnosis of liver lesions: solid or cystic, single or multiple, cell of origin (hepatocellular, cholangiocellular, or mesenchymal), and benign or malignant. The most common benign lesions are cysts, hemangiomas, FNH, and hepatocellular adenomas. Many of these lesions have typical features in imaging studies that help confirm the diagnosis.

Cyst Hepatic cysts are the most frequently encountered liver lesion overall and are described in detail in the section "Hepatic Cysts." Cystic lesions of the liver can arise primarily (congenital) or secondarily from trauma (seroma or biloma), infection (pyogenic or parasitic), or neoplastic disease. Congenital cysts are usually simple cysts containing thin serous fluid and are reported to occur in 5 to 14% of the population, with higher prevalence in women. In most cases, congenital cysts are differentiated from secondary cysts (infectious or neoplastic origin) in that they have no visible wall or solid component and are filled with homogeneous, clear fluid. For benign solid liver lesions, the differential diagnosis includes hemangioma, adenoma, FNH, and bile duct hamartoma (see Table 31-7).

Hemangioma

Hemangiomas (also referred to as hemangiomata ) are the most common solid benign masses that occur in the liver. They consist of large endothelial-lined vascular spaces and represent congenital vascular lesions that contain fibrous tissue and small blood vessels which eventually grow. They are more common in women and occur in 2 to 20% of the population. They can range from small (=1 cm) to giant cavernous hemangiomas (10 to 25 cm). The most common symptom is pain, which often occurs with lesions larger than 5 to 6 cm. Spontaneous rupture (bleeding) is rare, and the main indication for resection is pain. Surgical resection can be accomplished by enucleation or formal hepatic resection, depending on the location and involvement of intrahepatic vascular structures and hepatic ducts. The majority of hemangiomas can be diagnosed by liver imaging studies. On biphasic contrast CT scan, large hemangiomas show asymmetrical nodular peripheral enhancement that is isodense with large vessels and exhibit progressive centripetal enhancement fill-in over time (Fig. 31-21).2 1 On MRI, hemangiomas are hypointense on T1weighted images and hyperintense on T2-weighted images.4 9 With gadolinium enhancement, hemangiomas show a pattern of peripheral nodular enhancement similar to that seen on contrast CT scans. Caution should be exercised in ordering a liver biopsy if the suspected diagnosis is hemangioma because of the risk of bleeding from the biopsy site, especially if the lesion is at the edge of the liver.

Fig. 31-21.

Computed tomographic scans showing classic appearance of benign liver lesions. Focal nodular hyperplasia (FNH) is hypervascular on arterial phase, isodense to liver on venous phase, and has a central scar (upper panels ). Adenoma is hypovascular (lower left panel ). Hemangioma shows asymmetrical peripheral enhancement (lower right panel ).

Adenoma

Hepatic adenomas are benign solid neoplasms of the liver. They are most commonly seen in young women (aged 20 years to the forties) and are typically solitary, although multiple adenomas also can occur. Prior or current use of estrogens (oral contraceptives) is a clear risk factor for development of liver adenomas, although they can occur even in the absence of oral contraceptive use. On gross examination, they appear soft and encapsulated and are tan to light brown. Histologically, adenomas lack bile duct glands and Kupffer cells, have no true lobules, and contain hepatocytes that appear congested or vacuolated due to glycogen deposition. On CT scan, adenomas usually have sharply defined borders and can be confused with metastatic tumors. With venous phase contrast, they can look hypodense or isodense in comparison with background liver, whereas on arterial phase contrast subtle hypervascular enhancement often is seen (see Fig. 31-21). On MRI scans, adenomas are hyperintense on T1-weighted images and enhance early after gadolinium injection. On nuclear medicine imaging, they typically appear as "cold," in contrast with FNH. Hepatic adenomas carry a significant risk of spontaneous rupture with intraperitoneal bleeding. The clinical presentation may be abdominal pain, and in 10 to 25% of cases hepatic adenomas present with spontaneous intraperitoneal hemorrhage. Hepatic adenomas also have a risk of malignant transformation to a well-differentiated HCC. Therefore, it usually is recommended that a hepatic adenoma (once diagnosed) be surgically resected.4 4

Focal Nodular Hyperplasia FNH is another solid, benign lesion of the liver. Similar to adenomas, they are more common in women of childbearing age, although the link to oral contraceptive use is not as clear as with adenomas. A good-quality biphasic CT scan usually is diagnostic of FNH, on which such lesions appear well circumscribed with a typical central scar (see Fig. 31-21). They show intense homogeneous enhancement on arterial phase contrast images and are often isodense or invisible compared with background liver on the venous phase. On MRI scans, FNH lesions are hypointense on T1-weighted images and isointense to hyperintense on T2-weighted images. After gadolinium administration, lesions are hyperintense but become isointense on delayed images. The fibrous septa extending from the central scar are also more readily seen with MRI. If CT or MRI scans do not show the classic appearance, radionuclide sulfur colloid imaging may be used to diagnose FNH based on select uptake by Kupffer cells. Unlike adenomas, FNH lesions usually do not rupture spontaneously and have no significant risk of malignant transformation. The main indication for surgical resection is abdominal pain. Oral contraceptive or estrogen use should be stopped when either FNH or adenoma is diagnosed.

Bile Duct Hamartoma Bile duct hamartomas are typically small liver lesions, 2 to 4 mm in size, visualized on the surface of the liver at laparotomy. They are firm, smooth, and whitish yellow in appearance. They can be difficult to differentiate from small metastatic lesions, and excisional biopsy often is required to establish the diagnosis.

MALIGNANT LIVER TUMORS Malignant tumors in the liver can be classified as primary (cancers that originate in the liver) or metastatic (cancers that spread to the liver from an extrahepatic primary site) (see Table 31-7). Primary cancers in the liver that originate from hepatocytes are known as hepatocellular carcinomas (HCCs or hepatomas), whereas cancers arising in the bile ducts are known as cholangiocarcinomas. In the United States, approximately 150,000 new cases of colorectal cancer are diagnosed each year, and the majority of patients (approximately 60%) will develop hepatic metastases over their lifetime. Hence, the most

common tumor seen in the liver is metastatic colorectal cancer. This compares with approximately 18,000 new cases of HCC diagnosed annually in the United States. Interestingly, in a Western series of 1000 consecutive new liver cancer patients seen at a university medical center, 47% were HCC, 17% were colorectal cancer metastases, 11% were cholangiocarcinomas, 7% were neuroendocrine metastases, and 18% were other tumors.5 0 Although these figures do not reflect the incidence or prevalence of these liver cancers, they are indicative of referral patterns in a tertiary academic medical center with a large liver transplantation team and active hepatology clinic.

Hepatocellular Carcinoma HCC is the fifth most common malignancy worldwide, with an estimated 1,000,000 new cases diagnosed annually. Major risk factors are viral hepatitis (B or C), alcoholic cirrhosis, hemochromatosis, and nonalcoholic steatohepatitis. In Asia, the risk is as high as 30 to 65 per 100,000 persons per year, whereas in the United States the risk is only 2 per 100,000 persons per year.5 1 Although cirrhosis is not present in all cases, it has been estimated to be present 70 to 90% of the time. In a person with cirrhosis, the annual conversion rate to HCC is 3 to 6%. In patients with chronic hepatitis C virus infection, cirrhosis usually is present before the HCC develops; however, in cases of hepatitis C virus infection, HCC tumors can occur before the onset of cirrhosis. HCCs are typically hypervascular with blood supplied predominantly from the hepatic artery. Thus, the lesion often appears hypervascular during the arterial phase of CT studies (Fig. 31-22) and relatively hypodense during the delayed phases due to early washout of the contrast medium by the arterial blood. MRI imaging also is effective in characterizing HCC. HCC is variable on T1-weighted images and usually hyperintense on T2-weighted images. As with contrast CT, HCC enhances in the arterial phase after gadolinium injection because of its hypervascularity and becomes hypointense in the delayed phases due to contrast washout. HCC has a tendency to invade the portal vein, and the presence of an enhancing portal vein thrombus is highly suggestive of HCC.

Fig. 31-22.

Computed tomographic (CT) images of hepatocellular carcinoma (HCC) and peripheral cholangiocarcinoma. CT scans reveal a large (upper panel ) and small (middle panel ) hypervascular HCC. A hypovascular left lobe peripheral cholangiocarcinoma (Cholangio CA) is also shown (lower panel ).

The treatment of HCC is complex and is best managed by a multidisciplinary liver transplant team. A complete algorithm for the evaluation and management of HCC is shown (Fig. 31-23).

Fig. 31-23.

Algorithm for the management of hepatocellular carcinoma (HCC). The treatment algorithm for HCC begins with determining whether the patient is a resection candidate or liver transplant candidate. Bili = bilirubin level (in milligrams per deciliter); Child's = Child-Turcotte-Pugh class; lap = laparoscopic; LDLT = living-donor liver transplantation; LN = lymph node; MELD = Model for End-Stage Liver Disease; OLTx = orthotopic liver transplantation; Perc = percutaneous; RFA = radiofrequency ablation; TACE = transarterial chemoembolization; Tx = transplantation; UNOS = United Network for Organ Sharing; vasc. = vascular.

For patients without cirrhosis who develop HCC, resection is the treatment of choice. For those patients with Child's class A cirrhosis with preserved liver function and no portal hypertension, resection also is considered. If resection is not possible because of poor liver function and the HCC meets the Milan criteria (one nodule 60 years, disease-free interval of 50%). Hence, OLT is an appealing treatment, because it removes the cancer and the cirrhotic liver that leads to HCC. Approximately 6000 liver transplantations are performed each year in the United States, with 1-year survival rates approaching 90%. In April 2008, approximately 16,400 patients were on the waiting list for liver transplantation.9 5 Initial series of OLT for HCC reported in the 1990s included advanced cases of HCC, and the 5-year survival rates were only 20 to 50%.6 1 This compared poorly with overall 5-year survival rates of 70 to 75% for OLT in the Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) database. Mazzaferro and colleagues at Milan subsequently showed that survival rates were markedly improved when OLT was limited to patients with early-stage HCC (stage I or stage II) with one tumor 5 cm, or three tumors with the largest being 3 cm, along with an absence of gross vascular invasion or extrahepatic spre96,97 Multiple studies have validated these findings, although some groups have proposed an expansion of the Milan criteria.52,61,98 In 2002, OPTN/UNOS adopted the Model for End-Stage Liver Disease (MELD) score [a 6- to 40-point scale based on serum total bilirubin level, creatinine level, and international normalized ratio (INR)] for allocation of deceased donor liver organs in the United States. In an attempt to decrease the high mortality rate for patients with preserved liver function and progressive HCC, patients with stage II HCC were given priority points (currently 22 MELD points). This had a positive effect for HCC liver transplant candidates, leading to decreased waiting list

dropout and increased transplant rates with excellent long-term outcomes.9 9 The goal is to better equate death rates on the liver transplant waiting list for patients with stage II HCC with rates for patients with chronic liver disease without HCC.

Radiofrequency Ablation In 1891, d'Arsonval discovered that radiofrequency (RF) waves delivered as an alternating electric current (>10 kHz) could pass through living tissue without causing pain or neuromuscular excitation. The resistance of the tissue to the rapidly alternating current produced heat. This discovery contributed to the development of the surgical application of electrocautery. In 1908, Beer used RF coagulation to destroy urinary bladder tumors. Cushing and Bovie later applied RF ablation to intracranial tumors. In 1961, Lounsberry studied the histologic changes of the liver after RFA in animal models. He found that RF caused local tissue destruction with uniform necrosis. In the early 1990s, two groups proposed that RFA can be an effective method for destroying unresectable malignant liver tumors.100,101 Both groups found that RFA produced lesions with well-demarcated areas of necrosis without viable tumor cells present. Clinical reports after short-term follow-up suggested that RFA was safe and effective in the treatment of liver tumors.102–104 However, Abdalla and colleagues examined data for 358 consecutive patients with colorectal liver metastases treated with curative intent over a 10-year period (1992 to 2002).105 Liver-only recurrence after RFA was four times the rate after resection (44% vs. 11% of patients), and RFA alone or in combination with resection did not provide survival rates comparable to those with resection alone. Nonetheless, RFA remains a common procedure that can be performed by a percutaneous, minimally invasive laparoscopic, or open approach.106,107 It also has been used successfully to ablate small HCCs as a bridge to liver transplantation.108 Recently, results were reported for the first randomized clinical trial involving RFA treatment for HCC in 291 Chinese patients with three or fewer HCC tumors ranging in size from 3 to 7.5 cm.109 Patients were randomly assigned to treatment arms of RFA alone (n = 100), transarterial chemoembolization (TACE) alone (n = 95), or combined TACE plus RFA (n = 96). At a median follow-up of 28.5 months, median survival was 22 months in the RFA group, 24 months in the TACE group, and 37 months in the TACE plus RFA group. Patients treated with TACE plus RFA had significantly better overall survival than those treated with TACE alone (P Chapter 32. Gallbladder and the Extrahepatic Biliary System>

KEY POINTS 1. The physiology of the gallbladder and sphincter of Oddi are regulated by a complex interplay of hormones and neuronal inputs designed to coordinate bile release with food consumption. Dysfunctions related to this activity are linked to the development of gallbladder pathologies described in this chapter. 2. In Western countries, the most common type of gallstones are cholesterol stones. The pathogenesis of these stones relates to supersaturation of bile with cholesterol and subsequent precipitation. 3. The main risk factor for gallbladder disease in Western countries is cholelithiasis. The main complications include cholecystitis, choledocholithiasis, cholangitis, and biliary pancreatitis. In addition, cholelithiasis plays the role as the major risk factor for the development of gallbladder cancer. 4. Laparoscopic cholecystectomy has been demonstrated to be a safe and effective alternative to open cholecystectomy and has become the treatment of choice for symptomatic gallstones. Knowledge of the various anatomic anomalies of the cystic duct and artery is helpful in guiding the dissection of these structures as well as avoiding injury to the common bile duct during cholecystectomy. 5. Common bile duct injuries, although uncommon, can be devastating to patients. Proper exposure of Calot's triangle and careful identification of the anatomic structures are keys to avoiding these injuries. Once a bile duct injury is diagnosed, the best outcomes are seen at large referral centers with experienced biliary surgeons. 6. Carcinoma of the gallbladder and bile duct generally have a poor prognosis because patients usually present late in the disease process and have poor response to chemo and radiation therapies. Surgery offers the best chance for survival and has good long-term survival in patients with early-stage disease.

ANATOMY Gallbladder The gallbladder is a pear-shaped sac, about 7 to 10 cm long, with an average capacity of 30 to 50 mL. When obstructed, the gallbladder can distend markedly and contain up to 300 mL.1 The gallbladder is located in a fossa on the inferior surface of the liver. A line from this fossa to the inferior vena cava divides the liver into right and left liver lobes. The gallbladder is divided into four anatomic areas: the fundus, the corpus (body), the infundibulum, and the neck. The fundus is the rounded, blind end that normally extends 1 to 2 cm beyond the liver's margin. It contains most of the smooth muscles of the organ, in contrast to the body, which is the main storage area and contains most of the elastic tissue. The body extends from the fundus and tapers into the neck, a funnel-shaped area that connects with the cystic duct. The neck usually follows a gentle curve, the convexity of which may be

enlarged to form the infundibulum or Hartmann's pouch. The neck lies in the deepest part of the gallbladder fossa and extends into the free portion of the hepatoduodenal ligament (Fig. 32-1).

Fig. 32-1.

Anterior aspect of the biliary anatomy. a = right hepatic duct; b = left hepatic duct; c = common hepatic duct; d = portal vein; e = hepatic artery; f = gastroduodenal artery; g = left gastric artery; h = common bile duct; i = fundus of the gallbladder; j = body of gallbladder; k = infundibulum; l = cystic duct; m = cystic artery; n = superior pancreaticoduodenal artery. Note: the situation of the hepatic bile duct confluence anterior to the right branch of the portal vein, the posterior course of the right hepatic artery behind the common hepatic duct.

The same peritoneal lining that covers the liver covers the fundus and the inferior surface of the gallbladder. Occasionally, the gallbladder has a complete peritoneal covering, and is suspended in a mesentery off the inferior surface of the liver and, rarely, it is embedded deep inside the liver parenchyma (an intrahepatic gallbladder). The gallbladder is lined by a single, highly folded, tall columnar epithelium that contains cholesterol and fat globules. The mucus secreted into the gallbladder originates in the tubuloalveolar glands found in the mucosa lining the infundibulum and neck of the gallbladder, but are absent from the body and fundus. The epithelial lining of the gallbladder is supported by a lamina propria. The muscle layer has circular longitudinal and oblique fibers, but without well-developed layers. The perimuscular subserosa contains connective tissue, nerves, vessels, lymphatics, and adipocytes. It is covered by the serosa except where the gallbladder is embedded in the liver. The gallbladder differs histologically from the rest of the GI tract in that it lacks a muscularis mucosa and submucosa. The cystic artery that supplies the gallbladder is usually a branch of the right hepatic artery (>90% of the time). The course of the cystic artery may vary, but it nearly always is found within the hepatocystic triangle, the area bound by the cystic duct, common hepatic duct, and the liver margin (triangle of Calot). When the cystic artery reaches the neck of the gallbladder, it divides into anterior and posterior divisions. Venous return is carried either through small veins that enter directly into the liver or, rarely, to a large cystic vein that carries blood back to the portal vein. Gallbladder lymphatics drain into nodes at the neck of the gallbladder. Frequently, a visible lymph node overlies the insertion of the cystic artery into the gallbladder wall. The nerves of the gallbladder arise from the vagus and from sympathetic branches that pass through the celiac plexus. The preganglionic sympathetic level is T8 and T9. Impulses from the liver, gallbladder, and the bile ducts pass by means of sympathetic afferent fibers through the splanchnic nerves and mediate the pain of biliary colic. The hepatic branch of the vagus nerve supplies cholinergic fibers to the gallbladder, bile ducts, and the liver. The vagal branches also have peptide-containing nerves containing agents such as substance P, somatostatin, enkephalins, and vasoactive intestinal polypeptide.2

Bile Ducts The extrahepatic bile ducts consist of the right and left hepatic ducts, the common hepatic duct, the cystic duct, and the common bile duct or choledochus. The common bile duct enters the second portion of the duodenum through a muscular structure, the sphincter of Oddi. 3 The left hepatic duct is longer than the right and has a greater propensity for dilatation as a consequence of distal obstruction. The two ducts join to form a common hepatic duct, close to their emergence from the liver. The common hepatic duct is 1 to 4 cm in length and has a diameter of approximately 4 mm. It lies in front of the portal vein and to the right of the hepatic artery. The common hepatic duct is joined at an acute angle by the cystic duct to form the common bile duct. The length of the cystic duct is quite variable. It may be short or absent and have a high union with the hepatic duct, or long and run parallel, behind, or spiral to the main hepatic duct before joining it, sometimes as far as at the duodenum. Variations of the cystic duct and its point of union with the common hepatic duct are surgically important (Fig. 32-2). The segment of the cystic duct adjacent to the gallbladder neck bears a variable number of mucosal folds called the spiral valves of Heister . They do not have any valvular function but may make cannulation of the cystic duct difficult.

Fig. 32-2.

Variations of the cystic duct anatomy. A. Low junction between the cystic duct and common hepatic duct. B. Cystic duct adherent to the common hepatic duct. C. High junction between the cystic and the common hepatic duct. D. Cystic duct drains into right hepatic duct. E. Long cystic duct that joins common hepatic duct behind the duodenum. F. Absence of cystic duct. G. Cystic duct crosses posterior to common hepatic duct and joins it anteriorly. H. Cystic duct courses anterior to common hepatic duct and joins it posteriorly.

The common bile duct is about 7 to 11 cm in length and 5 to 10 mm in diameter. The upper third (supraduodenal

portion) passes downward in the free edge of the hepatoduodenal ligament, to the right of the hepatic artery and anterior to the portal vein. The middle third (retroduodenal portion) of the common bile duct curves behind the first portion of the duodenum and diverges laterally from the portal vein and the hepatic arteries. The lower third (pancreatic portion) curves behind the head of the pancreas in a groove, or traverses through it and enters the second part of the duodenum. There, the pancreatic duct frequently joins it. The common bile duct runs obliquely downward within the wall of the duodenum for 1 to 2 cm before opening on a papilla of mucous membrane (ampulla of Vater), about 10 cm distal to the pylorus. The union of the common bile duct and the main pancreatic duct follows one of three configurations. In about 70% of people, these ducts unite outside the duodenal wall and traverse the duodenal wall as a single duct. In about 20%, they join within the duodenal wall and have a short or no common duct, but open through the same opening into the duodenum. In about 10%, they exit via separate openings into the duodenum. The sphincter of Oddi, a thick coat of circular smooth muscle, surrounds the common bile duct at the ampulla of Vater (Fig. 32-3). It controls the flow of bile, and in some cases pancreatic juice, into the duodenum.

Fig. 32-3.

The sphincter of Oddi.

The extrahepatic bile ducts are lined by a columnar mucosa with numerous mucous glands in the common bile duct. A fibroareolar tissue containing scant smooth muscle cells surrounds the mucosa. A distinct muscle layer is not present in the human common bile duct. The arterial supply to the bile ducts is derived from the gastroduodenal and the right hepatic arteries, with major trunks running along the medial and lateral walls of the common duct (sometimes referred to as 3 o'clock and 9 o'clock). These arteries anastomose freely within the duct walls. The density of nerve fibers and ganglia increase near the sphincter of Oddi, but the nerve supply to the common bile duct and the sphincter of Oddi is the same as for the gallbladder.1,2

Anomalies The classic description of the extrahepatic biliary tree and its arteries applies only in about one third of patients. 4 The gallbladder may have abnormal positions, be intrahepatic, be rudimentary, have anomalous forms, or be duplicated. Isolated congenital absence of the gallbladder is very rare, with a reported incidence of 0.03%. Before the diagnosis is made, the presence of an intrahepatic bladder or anomalous position must be ruled out. Duplication of the gallbladder with two separate cavities and two separate cystic ducts has an incidence of about one in every 4000 persons. This occurs in two major varieties: the more common form in which each gallbladder has its own cystic duct that empties independently into the same or different parts of the extrahepatic biliary tree, and as two cystic ducts that merge before they enter the common bile duct. Duplication is only clinically important when some pathologic processes affect one or both organs. A left-sided gallbladder with a cystic duct emptying into the left hepatic duct or the common bile duct and a retrodisplacement of the gallbladder are both extremely rare. A partial or totally intrahepatic gallbladder is associated with an increased incidence of cholelithiasis. Small ducts (of Luschka) may drain directly from the liver into the body of the gallbladder. If present, but not recognized at the time of a cholecystectomy, a bile leak with the accumulation of bile (biloma) may occur in the abdomen. An accessory right hepatic duct occurs in about 5% of cases. Variations of how the common bile duct enters the duodenum are described in Bile Ducts above. Anomalies of the hepatic artery and the cystic artery are quite common, occurring in as many as 50% of cases.5 In about 5% of cases, there are two right hepatic arteries, one from the common hepatic artery and the other from the superior mesenteric artery. In about 20% of patients, the right hepatic artery comes off the superior mesenteric artery. The right hepatic artery may course anterior to the common duct. The right hepatic artery may be vulnerable during surgical procedures, in particular when it runs parallel to the cystic duct or in the mesentery of the gallbladder. The cystic artery arises from the right hepatic artery in about 90% of cases, but may arise from the left hepatic, common hepatic, gastroduodenal, or superior mesenteric arteries (Fig. 32-4).

Fig. 32-4.

Variations in the arterial supply to the gallbladder. A. Cystic artery from right hepatic artery, about 80–90%. B. Cystic artery from right hepatic artery (accessory or replaced) from superior mesenteric artery, about 10%. C. Two cystic arteries, one from the right hepatic, the other from the common hepatic artery, rare. D. Two cystic arteries, one from the right hepatic, the other from the left hepatic artery, rare. E. The cystic artery branching from the right hepatic artery and running anterior to the common hepatic duct, rare. F. Two cystic arteries arising from the right hepatic artery, rare.

PHYSIOLOGY Bile Formation and Composition The liver produces bile continuously and excretes it into the bile canaliculi. The normal adult consuming an average diet produces within the liver 500 to 1000 mL of bile a day. The secretion of bile is responsive to neurogenic, humoral, and chemical stimuli. Vagal stimulation increases secretion of bile, whereas splanchnic nerve stimulation results in decreased bile flow. Hydrochloric acid, partly digested proteins, and fatty acids in the duodenum stimulate the release of secretin from the duodenum that, in turn, increases bile production and bile flow. Bile flows from the liver through to the hepatic ducts, into the common hepatic duct, through the common bile duct, and finally into the duodenum. With an intact sphincter of Oddi, bile flow is directed into the gallbladder. Bile is mainly composed of water, electrolytes, bile salts, proteins, lipids, and bile pigments. Sodium, potassium, calcium, and chlorine have the same concentration in bile as in plasma or extracellular fluid. The pH of hepatic bile is usually neutral or slightly alkaline, but varies with diet; an increase in protein shifts the bile to a more acidic pH. The primary bile salts, cholate and chenodeoxycholate, are synthesized in the liver from cholesterol. They are conjugated there with taurine and glycine, and act within the bile as anions (bile acids) that are balanced by sodium. Bile salts are excreted into the bile by the hepatocyte and aid in the digestion and absorption of fats in the intestines.6 In the intestines, about 80% of the conjugated bile acids are absorbed in the terminal ileum. The remainder is dehydroxylated (deconjugated) by gut bacteria, forming secondary bile acids deoxycholate and lithocholate. These are absorbed in the colon, transported to the liver, conjugated, and secreted into the bile. Eventually, about 95% of the bile acid pool is reabsorbed and returned via the portal venous system to the liver, the so-called enterohepatic circulation . Five percent is excreted in the stool, leaving the relatively small amount of bile acids to have maximum effect. Cholesterol and phospholipids synthesized in the liver are the principal lipids found in bile. The synthesis of phospholipids and cholesterol by the liver is, in part, regulated by bile acids. The color of the bile is due to the presence of the pigment bilirubin diglucuronide, which is the metabolic product from the breakdown of hemoglobin, and is present in bile in concentrations 100 times greater than in plasma. Once in the intestine, bacteria convert it into urobilinogen, a small fraction of which is absorbed and secreted into the bile.

Gallbladder Function The gallbladder, the bile ducts, and the sphincter of Oddi act together to store and regulate the flow of bile. The main function of the gallbladder is to concentrate and store hepatic bile and to deliver bile into the duodenum in response to a meal.

ABSORPTION AND SECRETION In the fasting state, approximately 80% of the bile secreted by the liver is stored in the gallbladder. This storage is made possible because of the remarkable absorptive capacity of the gallbladder, as the gallbladder mucosa has the greatest absorptive power per unit area of any structure in the body. It rapidly absorbs sodium, chloride, and water

against significant concentration gradients, concentrating the bile as much as 10-fold and leading to a marked change in bile composition. This rapid absorption is one of the mechanisms that prevent a rise in pressure within the biliary system under normal circumstances. Gradual relaxation as well as emptying of the gallbladder during the fasting period also plays a role in maintaining a relatively low intraluminal pressure in the biliary tree. The epithelial cells of the gallbladder secrete at least two important products into the gallbladder lumen: glycoproteins and hydrogen ions. The mucosal glands in the infundibulum and the neck of the gallbladder secrete mucus glycoproteins that are believed to protect the mucosa from the lytic action of bile and to facilitate the passage of bile through the cystic duct. This mucus makes up the colorless "white bile" seen in hydrops of the gallbladder resulting from cystic duct obstruction. The transport of hydrogen ions by the gallbladder epithelium leads to a decrease in the gallbladder bile pH. The acidification promotes calcium solubility, thereby preventing its precipitation as calcium salts.6

MOTOR ACTIVITY Gallbladder filling is facilitated by tonic contraction of the sphincter of Oddi, which creates a pressure gradient between the bile ducts and the gallbladder. During fasting, the gallbladder does not simply fill passively. In association with phase II of the interdigestive migrating myenteric motor complex in the gut, the gallbladder repeatedly empties small volumes of bile into the duodenum. This process is mediated at least in part by the hormone motilin. In response to a meal, the gallbladder empties by a coordinated motor response of gallbladder contraction and sphincter of Oddi relaxation. One of the main stimuli to gallbladder emptying is the hormone cholecystokinin (CCK). CCK is released endogenously from the duodenal mucosa in response to a meal.7 When stimulated by eating, the gallbladder empties 50 to 70% of its contents within 30 to 40 minutes. Over the following 60 to 90 minutes, the gallbladder gradually refills. This is correlated with a reduced CCK level. Other hormonal and neural pathways also are involved in the coordinated action of the gallbladder and the sphincter of Oddi. Defects in the motor activity of the gallbladder are thought to play a role in cholesterol nucleation and gallstone formation.8

NEUROHORMONAL REGULATION The vagus nerve stimulates contraction of the gallbladder, and splanchnic sympathetic stimulation is inhibitory to its motor activity. Parasympathomimetic drugs contract the gallbladder, whereas atropine leads to relaxation. Neurally mediated reflexes link the sphincter of Oddi with the gallbladder, stomach, and duodenum to coordinate the flow of bile into the duodenum. Antral distention of the stomach causes both gallbladder contraction and relaxation of the sphincter of Oddi. Hormonal receptors are located on the smooth muscles, vessels, nerves, and epithelium of the gallbladder. CCK is a peptide that comes from epithelial cells of the upper GI tract and is found in the highest concentrations in the duodenum. CCK is released into the bloodstream by acid, fat, and amino acids in the duodenum.9 CCK has a plasma half-life of 2 to 3 minutes and is metabolized by both the liver and the kidneys. CCK acts directly on smooth muscle receptors of the gallbladder and stimulates gallbladder contraction. It also relaxes the terminal bile duct, the sphincter of Oddi, and the duodenum. CCK stimulation of the gallbladder and the biliary tree also is mediated by cholinergic vagal neurons. In patients who have had a vagotomy, the response to CCK stimulation is diminished and the size and the volume of the gallbladder are increased. Vasoactive intestinal polypeptide inhibits contraction and causes gallbladder relaxation. Somatostatin and its analogues are potent inhibitors of gallbladder contraction. Patients treated with somatostatin analogues and those with somatostatinoma have a high incidence of gallstones, presumably due to the inhibition of gallbladder contraction and emptying. Other hormones such as substance P and enkephalin affect gallbladder motility, but the

physiologic role is unclear.7

Sphincter of Oddi The sphincter of Oddi regulates flow of bile (and pancreatic juice) into the duodenum, prevents the regurgitation of duodenal contents into the biliary tree, and diverts bile into the gallbladder. It is a complex structure that is functionally independent from the duodenal musculature and creates a high-pressure zone between the bile duct and the duodenum. The sphincter of Oddi is about 4 to 6 mm in length and has a basal resting pressure of about 13 mmHg above the duodenal pressure. On manometry, the sphincter shows phasic contractions with a frequency of about four per minute and an amplitude of 12 to 140 mmHg.8 The spontaneous motility of the sphincter of Oddi is regulated by the interstitial cells of Cajal through intrinsic and extrinsic inputs from hormones and neurons acting on the smooth muscle cells.1 0 Relaxation occurs with a rise in CCK, leading to diminished amplitude of phasic contractions and reduced basal pressure, allowing increased flow of bile into the duodenum (Fig. 32-5). During fasting, the sphincter of Oddi activity is coordinated with the periodic partial gallbladder emptying and an increase in bile flow that occurs during phase II of the migrating myoelectric motor complexes.1 1

Fig. 32-5.

The effect of cholecystokinin on the gallbladder and the sphincter of Oddi. A. During fasting, with the sphincter of Oddi contracted and the gallbladder filling. B. In response to a meal, the sphincter of Oddi relaxed and the gallbladder emptying.

DIAGNOSTIC STUDIES A variety of diagnostic modalities are available for the patient with suspected disease of the gallbladder and the bile ducts. In 1924 the diagnosis of gallstones was improved significantly by the introduction of oral cholecystography by Graham and Cole. For decades it was the mainstay of investigation for gallstones. In the 1950s biliary scintigraphy was developed, as well as intrahepatic and endoscopic retrograde cholangiography (ERC), allowing imaging of the biliary tract. Later ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI) vastly improved the ability to image the biliary tract.1 2

Blood Tests When patients with suspected diseases of the gallbladder or the extrahepatic biliary tree are evaluated, a complete blood count and liver function tests are routinely requested. An elevated white blood cell (WBC) count may indicate or raise suspicion of cholecystitis. If associated with an elevation of bilirubin, alkaline phosphatase, and aminotransferase, cholangitis should be suspected. Cholestasis, an obstruction to bile flow, is characterized by an elevation of bilirubin (i.e., the conjugated form), and a rise in alkaline phosphatase. Serum aminotransferases may be normal or mildly elevated. In patients with biliary colic or chronic cholecystitis, blood tests will typically be normal.

Ultrasonography An ultrasound is the initial investigation of any patient suspected of disease of the biliary tree. 1 3 It is noninvasive, painless, does not submit the patient to radiation, and can be performed on critically ill patients. It is dependent

upon the skills and the experience of the operator, and it is dynamic (i.e., static images do not give the same information as those obtained during the ultrasound investigation itself). Adjacent organs can frequently be examined at the same time. Obese patients, patients with ascites, and patients with distended bowel may be difficult to examine satisfactorily with an ultrasound. Ultrasound will show stones in the gallbladder with sensitivity and specificity of >90%. Stones are acoustically dense and reflect the ultrasound waves back to the ultrasonic transducer. Because stones block the passage of sound waves to the region behind them, they also produce an acoustic shadow (Fig. 32-6). Stones move with changes in position. Polyps may be calcified and reflect shadows, but do not move with change in posture. Some stones form a layer in the gallbladder; others a sediment or sludge. A thickened gallbladder wall and local tenderness indicate cholecystitis. The patient has acute cholecystitis if a layer of edema is seen within the wall of the gallbladder or between the gallbladder and the liver in association with localized tenderness. When a stone obstructs the neck of the gallbladder, the gallbladder may become very large, but thin walled. A contracted, thickwalled gallbladder is indicative of chronic cholecystitis.

Fig. 32-6.

An ultrasonography of the gallbladder. Arrows indicate the acoustic shadows from stones in the gallbladder.

The extrahepatic bile ducts are also well visualized by ultrasound, except for the retroduodenal portion. Dilation of the ducts in a patient with jaundice establishes an extrahepatic obstruction as a cause for the jaundice. Frequently, the site and, sometimes, the cause of obstruction can be determined by ultrasound. Small stones in the common bile duct frequently get lodged at the distal end of it, behind the duodenum, and are, therefore, difficult to detect. A dilated common bile duct on ultrasound, small stones in the gallbladder, and the clinical presentation allow one to assume that a stone or stones are causing the obstruction. Periampullary tumors can be difficult to diagnose on ultrasound, but beyond the retroduodenal portion, the level of obstruction and the cause may be visualized quite well. Ultrasound can be helpful in evaluating tumor invasion and flow in the portal vein, an important guideline for resectability of periampullary and pancreatic head tumors.1 4

Oral Cholecystography Once considered the diagnostic procedure of choice for gallstones, oral cholecystography has largely been replaced by ultrasonography. It involves oral administration of a radiopaque compound that is absorbed, excreted by the liver, and passed into the gallbladder. Stones are noted on a film as filling defects in a visualized, opacified gallbladder. Oral cholecystography is of no value in patients with intestinal malabsorption, vomiting, obstructive jaundice, and hepatic failure.

Biliary Radionuclide Scanning (Hida Scan) Biliary scintigraphy provides a noninvasive evaluation of the liver, gallbladder, bile ducts, and duodenum with both anatomic and functional information.

99m

Technetium-labeled derivatives of dimethyl iminodiacetic acid (HIDA) are

injected intravenously, cleared by the Kupffer cells in the liver, and excreted in the bile. Uptake by the liver is detected within 10 minutes, and the gallbladder, the bile ducts, and the duodenum are visualized within 60 minutes in fasting subjects. The primary use of biliary scintigraphy is in the diagnosis of acute cholecystitis, which appears as a nonvisualized gallbladder, with prompt filling of the common bile duct and duodenum. Evidence of cystic duct obstruction on biliary scintigraphy is highly diagnostic for acute cholecystitis. The sensitivity and specificity for the diagnosis are about 95% each. False-positive results are increased in patients with gallbladder stasis, as in critically ill patients and in patients receiving parenteral nutrition. Filling of the gallbladder and common bile duct with delayed or absent filling of the duodenum indicates an obstruction at the ampulla. Biliary leaks as a complication of surgery of the gallbladder or the biliary tree can be confirmed and frequently localized by biliary scintigraphy.1 5

Computed Tomography Abdominal CT scans are inferior to ultrasonography in diagnosing gallstones. The major application of CT scans is to define the course and status of the extrahepatic biliary tree and adjacent structures. It is the test of choice in evaluating the patient with suspected malignancy of the gallbladder, the extrahepatic biliary system, or nearby organs, in particular, the head of the pancreas. Use of CT scan is an integral part of the differential diagnosis of obstructive jaundice (Fig. 32-7). Spiral CT scanning provides additional staging information, including vascular involvement in patients with periampullary tumors.1 6

Fig. 32-7.

Computed tomography scan of the upper abdomen from a patient with cancer of the distal common bile duct. The cancer obstructs the common bile duct as well as the pancreatic duct. 1 = the portal vein; 2 = a dilated intrahepatic bile duct; 3 = dilated cystic duct and the neck of the gallbladder; 4 = dilated common hepatic duct; 5 = the bifurcation of the common hepatic artery into the gastroduodenal artery and the proper hepatic artery; 6 = dilated pancreatic duct; 7 = the splenic vein.

Percutaneous Transhepatic Cholangiography Intrahepatic bile ducts are accessed percutaneously with a small needle under fluoroscopic guidance. Once the position in a bile duct has been confirmed, a guidewire is passed and, subsequently, a catheter is passed over the wire (Fig. 32-8). Through the catheter, a cholangiogram can be performed and therapeutic interventions done, such as biliary drain insertions and stent placements. Percutaneous transhepatic cholangiography (PTC) has little role in the management of patients with uncomplicated gallstone disease, but is particularly useful in patients with bile duct strictures and tumors, as it defines the anatomy of the biliary tree proximal to the affected segment. As with any invasive procedure, there are potential risks. For PTC, these are mainly bleeding, cholangitis, bile leak, and other catheter-related problems.1 5

Fig. 32-8.

Schematic diagram of percutaneous transhepatic cholangiogram and drainage for obstructing proximal cholangiocarcinoma. A. Dilated intrahepatic bile duct is entered percutaneously with a fine needle. B. Small guidewire is passed through the needle into the duct. C. A plastic catheter has been passed over the wire, and the wire is subsequently removed. A cholangiogram is

performed through the catheter. D. An external drainage catheter in place. E. Long wire placed via the catheter and advanced past the tumor and into the duodenum. F. Internal stent has been placed through the tumor.

Magnetic Resonance Imaging Available since the mid-1990s, MRI provides anatomic details of the liver, gallbladder, and pancreas similar to those obtained from CT. Many MRI techniques (i.e., heavily T2-weighted sequences, pulse sequences with or without contrast materials) can generate high resolution anatomic images of the biliary tree and the pancreatic duct. It has a sensitivity and specificity of 95 and 89%, respectively, at detecting choledocholithiasis.1 7 MRI with magnetic resonance cholangiopancreatography (MRCP) offers a single noninvasive test for the diagnosis of biliary tract and pancreatic disease1 8 (Fig. 32-9).

Fig. 32-9.

Magnetic resonance cholangiopancreatography. This view shows the course of the extrahepatic bile ducts (arrow ) and the pancreatic duct (arrowheads ).

Endoscopic Retrograde Cholangiography and Endoscopic Ultrasound

Using a side-viewing endoscope, the common bile duct can be cannulated and a cholangiogram performed using fluoroscopy (Fig. 32-10). The procedure requires IV sedation for the patient. The advantages of ERC include direct visualization of the ampullary region and direct access to the distal common bile duct, with the possibility of therapeutic intervention. The test is rarely needed for uncomplicated gallstone disease, but for stones in the common bile duct, in particular, when associated with obstructive jaundice, cholangitis, or gallstone pancreatitis, ERC is the diagnostic and often therapeutic procedure of choice. Once the endoscopic cholangiogram has shown ductal stones, sphincterotomy and stone extraction can be performed, and the common bile duct cleared of stones. In the hands of experts, the success rate of common bile duct cannulation and cholangiography is >90%. Complications of diagnostic ERC include pancreatitis and cholangitis, and occur in up to 5% of patients. 1 9 The development of small fiber-optic cameras that can be threaded through endoscopes used for endoscopic retrograde cholangiopancreatography (ERCP) has facilitated the development of intraductal endoscopy. By providing direct visualization of the biliary and pancreatic ducts, this technology has been shown to increase the effectiveness of ERCP in the diagnosis of certain biliary and pancreatic diseases.20,21 Intraductal endoscopy has been shown to have therapeutic applications that include biliary stone lithotripsy and extraction in high-risk surgical patients.2 2 As with most endoscopic procedures, intraductal endoscopy generally is considered safe, but there are no large trials that specifically address this issue. Typical complications such as bile duct perforation, minor bleeding from sphincterotomy or lithotripsy, and cholangitis have been described.2 3 Further refinement of this technology will enhance ERCP as a diagnostic and therapeutic tool.

Fig. 32-10.

Endoscopic retrograde cholangiography. A. A schematic picture showing the side-viewing endoscope in the duodenum and a catheter in the common bile duct. B. An endoscopic cholangiography showing stones in the common bile duct. The catheter has been placed in the ampulla of Vater (arrow ). Note the duodenal shadow indicated with arrowheads .

Endoscopic Ultrasound An endoscopic ultrasound requires a special endoscope with an ultrasound transducer at its tip. The results are operator dependent, but offer noninvasive imaging of the bile ducts and adjacent structures. It is of particular value in the evaluation of tumors and their resectability. The ultrasound endoscope has a biopsy channel, allowing needle biopsies of a tumor under ultrasonic guidance. Endoscopic ultrasound also has been used to identify bile duct stones, and although it is less sensitive than ERC, the technique is less invasive.

GALLSTONE DISEASE Prevalence and Incidence Gallstone disease is one of the most common problems affecting the digestive tract. Autopsy reports have shown a prevalence of gallstones from 11 to 36%.2 4 The prevalence of gallstones is related to many factors, including age, gender, and ethnic background. Certain conditions predispose to the development of gallstones. Obesity,

pregnancy, dietary factors, Crohn's disease, terminal ileal resection, gastric surgery, hereditary spherocytosis, sickle cell disease, and thalassemia are all associated with an increased risk of developing gallstones.8 Women are three times more likely to develop gallstones than men, and first-degree relatives of patients with gallstones have a twofold greater prevalence.2 5

Natural History Most patients will remain asymptomatic from their gallstones throughout life. For unknown reasons, some patients progress to a symptomatic stage, with biliary colic caused by a stone obstructing the cystic duct. Symptomatic gallstone disease may progress to complications related to the gallstones. 2 6 These include acute cholecystitis, choledocholithiasis with or without cholangitis, gallstone pancreatitis, cholecystocholedochal fistula, cholecystoduodenal or cholecystoenteric fistula leading to gallstone ileus, and gallbladder carcinoma. Rarely, complication of gallstones is the presenting picture. Gallstones in patients without biliary symptoms are commonly diagnosed incidentally on ultrasonography, CT scans, abdominal radiography, or at laparotomy. Several studies have examined the likelihood of developing biliary colic or developing significant complications of gallstone disease. Approximately 3% of asymptomatic individuals become symptomatic per year (i.e., develop biliary colic). Once symptomatic, patients tend to have recurring bouts of biliary colic. Complicated gallstone disease develops in 3 to 5% of symptomatic patients per year. Over a 20year period, about two thirds of asymptomatic patients with gallstones remain symptom free.2 7 Because few patients develop complications without previous biliary symptoms, prophylactic cholecystectomy in asymptomatic persons with gallstones is rarely indicated. For elderly patients with diabetes, for individuals who will be isolated from medical care for extended periods of time, and in populations with increased risk of gallbladder cancer, a prophylactic cholecystectomy may be advisable. Porcelain gallbladder, a rare premalignant condition in which the wall of the gallbladder becomes calcified, is an absolute indication for cholecystectomy.

Gallstone Formation Gallstones form as a result of solids settling out of solution. The major organic solutes in bile are bilirubin, bile salts, phospholipids, and cholesterol. Gallstones are classified by their cholesterol content as either cholesterol stones or pigment stones. Pigment stones can be further classified as either black or brown. In Western countries, about 80% of gallstones are cholesterol stones and about 15 to 20% are black pigment stones.2 8 Brown pigment stones account for only a small percentage. Both types of pigment stones are more common in Asia.

CHOLESTEROL STONES Pure cholesterol stones are uncommon and account for 70% cholesterol by weight. These stones are usually multiple, of variable size, and may be hard and faceted or irregular, mulberry-shaped, and soft (Fig. 32-11). Colors range from whitish yellow and green to black. Most cholesterol stones are radiolucent; 8 mm in diameter) on ultrasonography in a patient with gallstones, jaundice, and biliary pain is highly suggestive of common bile duct stones. Magnetic resonance cholangiography (MRC) provides excellent anatomic detail and has a sensitivity and specificity of 95 and 89%, respectively, at detecting choledocholithiasis >5 mm in diameter.1 8 Endoscopic cholangiography is the gold standard for diagnosing common bile duct stones. It has the distinct advantage of providing a therapeutic option at the time of diagnosis. In experienced hands, cannulation of the ampulla of Vater and diagnostic cholangiography are achieved in >90% of cases, with associated morbidity of 70 years old presenting with bile duct stones should have their ductal stones cleared endoscopically. Studies comparing surgery to endoscopic treatment have documented less morbidity and mortality for endoscopic treatment in this group of patients. 4 5 They do not need to be submitted for a cholecystectomy, as only about 15% will become symptomatic from their gallbladder stones, and such patients can be treated as the need arises by a cholecystectomy.4 6

Fig. 32-16.

Retained common bile duct stones. The patient presented 3 weeks after laparoscopic cholecystectomy. A. An ultrasound shows a normal or mildly dilated common bile duct with a stone. Note the location of the right hepatic artery anterior to the common hepatic duct (an anatomic variation). B. An endoscopic retrograde cholangiography from the same patient shows multiple stones in the common bile duct. Only the top one showed on ultrasound as the other stones lie in the distal common bile duct behind the duodenum.

CHOLANGITIS Cholangitis is one of the two main complications of choledochal stones, the other being gallstone pancreatitis. Acute cholangitis is an ascending bacterial infection in association with partial or complete obstruction of the bile ducts. Hepatic bile is sterile, and bile in the bile ducts is kept sterile by continuous bile flow and by the presence of antibacterial substances in bile, such as immunoglobulin. Mechanical hindrance to bile flow facilitates bacterial contamination. Positive bile cultures are common in the presence of bile duct stones as well as with other causes of obstruction. Biliary bacterial contamination alone does not lead to clinical cholangitis; the combination of both significant bacterial contamination and biliary obstruction is required for its development. Gallstones are the most common cause of obstruction in cholangitis; other causes are benign and malignant strictures, parasites, instrumentation of the ducts and indwelling stents, and partially obstructed biliary-enteric anastomosis. The most common organisms cultured from bile in patients with cholangitis include E. coli , Klebsiella pneumoniae , Streptococcus faecalis , Enterobacter, and Bacteroides fragilis . 4 7

Clinical Presentation Cholangitis may present as anything from a mild, intermittent, and self-limited disease to a fulminant, potentially life-threatening septicemia. The patient with gallstone-induced cholangitis is typically older and female. The most common presentation is fever, epigastric or right upper quadrant pain, and jaundice. These classic symptoms, well known as Charcot's triad , are present in about two thirds of patients. The illness may progress rapidly with septicemia and disorientation, known as Reynolds pentad (e.g., fever, jaundice, right upper quadrant pain, septic shock, and mental status changes). However, the presentation may be atypical, with little if any fever, jaundice, or pain. This occurs most commonly in the elderly, who may have unremarkable symptoms until they collapse with septicemia. Patients with indwelling stents rarely become jaundiced. On abdominal examination, the findings are indistinguishable from those of acute cholecystitis. 4 8

Diagnosis and Management Leukocytosis, hyperbilirubinemia, and elevation of alkaline phosphatase and transaminases are common and, when present, support the clinical diagnosis of cholangitis. Ultrasonography is helpful, as it will document the presence of gallbladder stones, demonstrate dilated ducts, and possibly pinpoint the site of obstruction; however, rarely will it elucidate the exact cause. The definitive diagnostic test is ERC. In cases in which ERC is not available, PTC is indicated. Both ERC and PTC will show the level and the reason for the obstruction, allow culture of the bile, possibly allow the removal of stones if present, and drainage of the bile ducts with drainage catheters or stents. CT scanning and MRI will show pancreatic and periampullary masses, if present, in addition to the ductal dilatation. The initial treatment of patients with cholangitis includes IV antibiotics and fluid resuscitation. These patients may require intensive care unit monitoring and vasopressor support. Most patients will respond to these measures. However, the obstructed bile duct must be drained as soon as the patient has been stabilized. About 15% of patients will not respond to antibiotics and fluid resuscitation, and an emergency biliary decompression may be required. Biliary decompression may be accomplished endoscopically, via the percutaneous transhepatic route, or surgically. The selection of procedure should be based on the level and the nature of the biliary obstruction. Patients with choledocholithiasis or periampullary malignancies are best approached endoscopically, with sphincterotomy and stone removal, or by placement of an endoscopic biliary stent.4 9 In patients in whom the obstruction is more proximal or perihilar, or when a stricture in a biliary-enteric anastomosis is the cause or the endoscopic route has failed, percutaneous transhepatic drainage is used. When neither ERC nor PTC is available, an emergent operation for decompression of the common bile duct with a T tube may be necessary and lifesaving. Definitive operative therapy should be deferred until the cholangitis has been treated and the proper diagnosis established. Patients with indwelling stents and cholangitis usually require repeated imaging and exchange of the stent over a guidewire. Acute cholangitis is associated with an overall mortality rate of approximately 5%. When associated with renal failure, cardiac impairment, hepatic abscesses, and malignancies, the morbidity and mortality rates are much higher.

BILIARY PANCREATITIS Gallstones in the common bile duct are associated with acute pancreatitis. Obstruction of the pancreatic duct by an impacted stone or temporary obstruction by a stone passing through the ampulla may lead to pancreatitis. The exact mechanism by which the obstruction of the pancreatic duct leads to pancreatitis is still not clear. An ultrasonogram of the biliary tree in patients with pancreatitis is essential. If gallstones are present and the pancreatitis is severe, an ERC with sphincterotomy and stone extraction may abort the episode of pancreatitis.

Once the pancreatitis has subsided, the gallbladder should be removed during the same admission. When gallstones are present and the pancreatitis is mild and self-limited, the stone has probably passed. For these patients, a cholecystectomy and an intraoperative cholangiogram or a preoperative ERC is indicated.

Cholangiohepatitis Cholangiohepatitis, also known as recurrent pyogenic cholangitis , is endemic to the Orient. It also has been encountered in the Chinese population in the United States, as well as in Europe and Australia. It affects both sexes equally and occurs most frequently in the third and fourth decades of life. Cholangiohepatitis is caused by bacterial contamination (commonly E. coli , Klebsiella species, Bacteroides species, or Enterococcus faecalis) of the biliary tree, and often is associated with biliary parasites such as Clonorchis sinensis , Opisthorchis viverrini , and Ascaris lumbricoides . Bacterial enzymes cause deconjugation of bilirubin, which precipitates as bile sludge. The sludge and dead bacterial cell bodies form brown pigment stones. The nucleus of the stone may contain an adult Clonorchis worm, an ovum, or an ascarid. These stones are formed throughout the biliary tree and cause partial obstruction that contributes to the repeated bouts of cholangitis. Biliary strictures form as a result of recurrent cholangitis and lead to further stone formation, infection, hepatic abscesses, and liver failure (secondary biliary cirrhosis). 5 0 The patient usually presents with pain in the right upper quadrant and epigastrium, fever, and jaundice. Recurrence of symptoms is one of the most characteristic features of the disease. The episodes may vary in severity but, without intervention, will gradually lead to malnutrition and hepatic insufficiency. An ultrasound will detect stones in the biliary tree, pneumobilia from infection due to gas-forming organisms, liver abscesses, and, occasionally, strictures. The gallbladder may be thickened, but is inflamed in about 20% of patients, and rarely contains stones. MRCP and PTC are the mainstays of biliary imaging for cholangiohepatitis. They can detect obstructions, define strictures and stones, and allow emergent decompression of the biliary tree in the septic patient. Hepatic abscesses may be drained percutaneously. The long-term goal of therapy is to extract stones and debris and relieve strictures. It may take several procedures and require a Roux-en-Y hepaticojejunostomy to establish biliary-enteric continuity. Occasionally, resection of involved areas of the liver may offer the best form of treatment. Recurrences are common and the prognosis is poor once hepatic insufficiency has developed.5 1

OPERATIVE INTERVENTIONS FOR GALLSTONE DISEASE Cholecystostomy A cholecystostomy decompresses and drains the distended, inflamed, hydropic, or purulent gallbladder. It is applicable if the patient is not fit to tolerate an abdominal operation.5 2 Ultrasound-guided percutaneous drainage with a pigtail catheter is the procedure of choice. The catheter is inserted over a guidewire that has been passed through the abdominal wall, the liver, and into the gallbladder (Fig. 32-17). By passing the catheter through the liver, the risk of bile leak around the catheter is minimized. 5 3 The catheter can be removed when the inflammation has resolved and the patient's condition improved. The gallbladder can be removed later, if indicated, usually by laparoscopy. Surgical cholecystostomy with a large catheter placed under local anesthesia is rarely required today.

Fig. 32-17.

Percutaneous cholecystostomy. A pigtail catheter has been placed through the abdominal wall, the right lobe of the liver, and into the gallbladder.

Cholecystectomy Cholecystectomy is the most common major abdominal procedure performed in Western countries. Carl Langenbuch performed the first successful cholecystectomy in 1882, and for >100 years, it was the standard treatment for symptomatic gallbladder stones. Open cholecystectomy was a safe and effective treatment for both acute and chronic cholecystitis. In 1987, laparoscopic cholecystectomy was introduced by Philippe Mouret in France and quickly revolutionized the treatment of gallstones. It not only supplanted open cholecystectomy, but also more or less ended attempts for noninvasive management of gallstones, such as extracorporeal shock wave and bile salt therapy. Laparoscopic cholecystectomy offers a cure for gallstones with a minimally invasive procedure, minor pain and scarring, and early return to full activity. Today, laparoscopic cholecystectomy is the treatment of choice for symptomatic gallstones. Absolute contraindications for the procedure are uncontrolled coagulopathy and end-stage liver disease. Rarely, patients with severe obstructive pulmonary disease or congestive heart failure (e.g., cardiac ejection fraction 1 cm proximal to the ampulla. This results in a long common channel that may allow free reflux of pancreatic secretions into the biliary tract, leading to inflammatory changes, increased biliary pressure, and cyst formation. Choledochal cysts are classified into five types (Fig. 32-22). The cysts are lined with cuboidal epithelium and can vary in size from 2 cm in diameter to giant cysts.

Fig. 32-22.

Classification of choledochal cysts. Type I, fusiform or cystic dilations of the extrahepatic biliary tree, is the most common type, making up >50% of the choledochal cysts. Type II, saccular diverticulum of an extrahepatic bile duct. Rare, 20% incidence of gallbladder carcinoma. These gallbladders should be removed, even if the patients are asymptomatic. Patients with choledochal cysts have an increased risk of developing cancer anywhere in the biliary tree, but the incidence is highest in the gallbladder. Sclerosing cholangitis, anomalous pancreaticobiliary duct junction, and exposure to carcinogens (azotoluene, nitrosamines) also are associated with cancer of the gallbladder.

PATHOLOGY Between 80 and 90% of the gallbladder tumors are adenocarcinomas. Squamous cell, adenosquamous, oat cell, and other anaplastic lesions occur rarely. The histologic subtypes of gallbladder adenocarcinomas include papillary, nodular, and tubular. Less than 10% are of the papillary type, but these are associated with an overall better outcome, as they are most commonly diagnosed while localized to the gallbladder. Cancer of the gallbladder spreads through the lymphatics, with venous drainage, and with direct invasion into the liver parenchyma. Lymphatic flow from the gallbladder drains first to the cystic duct node (Calot's), then the pericholedochal and hilar nodes, and finally the peripancreatic, duodenal, periportal, celiac, and superior mesenteric artery nodes. The gallbladder veins drain directly into the adjacent liver, usually segments IV and V, where tumor invasion is common (Fig. 32-25). The gallbladder wall differs histologically from the intestines in that it lacks a muscularis mucosa and submucosa. Lymphatics are present in the subserosal layer only. Therefore, cancers invading but not growing through the muscular layer have minimal risk of nodal disease. When diagnosed, about 25% of gallbladder cancers

are localized to the gallbladder wall, 35% have regional nodal involvement and/or extension into adjacent liver, and approximately 40% have distant metastasis.8 4

Fig. 32-25.

Computed tomography scan of a patient with gallbladder cancer. The image shown is at the level of the liver hilum. The portal vein is bifurcating into the left and right portal branch. The tumor has invaded segment IV of the liver (arrowheads ) and obstructed the common hepatic duct, resulting in intrahepatic ductal dilatation (arrows ).

CLINICAL MANIFESTATIONS AND DIAGNOSIS Signs and symptoms of carcinoma of the gallbladder are generally indistinguishable from those associated with cholecystitis and cholelithiasis. These include abdominal discomfort, right upper quadrant pain, nausea, and vomiting. Jaundice, weight loss, anorexia, ascites, and abdominal mass are less common presenting symptoms. More than one half of gallbladder cancers are not diagnosed before surgery. Common misdiagnoses include chronic cholecystitis, acute cholecystitis, choledocholithiasis, hydrops of the gallbladder, and pancreatic cancer. Laboratory findings are not diagnostic but, if abnormal, are most often consistent with biliary obstruction. Ultrasonography often reveals a thickened, irregular gallbladder wall or a mass replacing the gallbladder. Ultrasonography may visualize tumor invasion of the liver, lymphadenopathy, and a dilated biliary tree. The sensitivity of ultrasonography in detecting gallbladder cancer ranges from 70 to 100%. A CT scan is an important tool for staging

and may identify a gallbladder mass or local invasion into adjacent organs. In addition, a spiral CT scan can demonstrate vascular invasion; however, CT scan is a poor method for identifying nodal spread. In jaundiced patients, a percutaneous transhepatic or endoscopic cholangiogram may be helpful to delineate the extent of biliary tree involvement, and typically shows a long stricture of the common bile duct. With newer MRI techniques, MRCP has evolved into a single noninvasive imaging method that allows complete assessment of biliary, vascular, nodal, hepatic, and adjacent organ involvement.8 5 If diagnostic studies suggest that the tumor is unresectable, a CT scan or ultrasound-guided biopsy of the tumor can be obtained to provide a pathologic diagnosis.

TREATMENT Surgery remains the only curative option for gallbladder cancer as well as for cholangiocarcinoma. However, palliative procedures for patients with unresectable cancer and jaundice or duodenal obstruction remain the most frequently performed surgery for gallbladder cancers. Today, patients with obstructive jaundice can frequently be managed with either endoscopic or percutaneously placed biliary stents. There are no proven effective options for adjuvant radiation or chemotherapy for patients with gallbladder cancer. The pathologic stage of gallbladder cancer determines the operative treatment for patients with localized gallbladder cancer. Patients without evidence of distant metastasis warrant exploration for tissue diagnosis, pathologic staging, and possible curative resection. Tumors limited to the muscular layer of the gallbladder (T1) are usually identified incidentally, after cholecystectomy for gallstone disease. There is near universal agreement that simple cholecystectomy is an adequate treatment for T1 lesions and results in a near 100% overall 5-year survival rate. When the tumor invades the perimuscular connective tissue without extension beyond the serosa or into the liver (T2 tumors), an extended cholecystectomy should be performed.8 6 That includes resection of liver segments IVB and V, and lymphadenectomy of the cystic duct, and pericholedochal, portal, right celiac, and posterior pancreatoduodenal lymph nodes. One half of patients with T2 tumors are found to have nodal disease on pathologic examination. Therefore, regional lymphadenectomy is an important part of surgery for T2 cancers.8 7 For tumors that grow beyond the serosa or invade the liver or other organs (T3 and T4 tumors), there is a high likelihood of intraperitoneal and distant spread. If no peritoneal or nodal involvement is found, complete tumor excision with an extended right hepatectomy (segments IV, V, VI, VII, and VIII) must be performed for adequate tumor clearance. An aggressive approach in patients who will tolerate surgery has resulted in an increased survival for T3 and T4 lesions.

PROGNOSIS Most patients with gallbladder cancer have unresectable disease at the time of diagnosis. The 5-year survival rate of all patients with gallbladder cancer is 70% vs. 25 to 40%, respectively. Patients with advanced but resectable gallbladder cancer are reported to have 5-year survival rates of 20 to 50%. However, the median survival for patients with distant metastasis at the time of presentation is only 1 to 3 months. Recurrence after resection of gallbladder cancer occurs most commonly in the liver or the celiac or retropancreatic nodes. The prognosis for recurrent disease is very poor. Death occurs most commonly secondary to biliary sepsis or liver failure. The main goal of follow-up is to provide palliative care. The most common problems are pruritus and cholangitis associated with obstructive jaundice, bowel obstruction secondary to carcinomatosis, and pain.

Bile Duct Carcinoma Cholangiocarcinoma is a rare tumor arising from the biliary epithelium and may occur anywhere along the biliary tree. About two thirds are located at the hepatic duct bifurcation. Surgical resection offers the only chance for cure; however, many patients have advanced disease at the time of diagnosis. Therefore, palliative procedures aimed to provide biliary drainage to prevent liver failure and cholangitis are often the only therapeutic possibilities. Most patients with unresectable disease die within 1 year of diagnosis.8 9

INCIDENCE The autopsy incidence of bile duct carcinoma is about 0.3%. The overall incidence of cholangiocarcinoma in the United States is about 1.0 per 100,000 people per year, with about 3000 new cases diagnosed annually. The male to female ratio is 1.3:1, and the average age of presentation is between 50 and 70 years.

ETIOLOGY Risk factors associated with cholangiocarcinoma include primary sclerosing cholangitis, choledochal cysts, ulcerative colitis, hepatolithiasis, biliary-enteric anastomosis, and biliary tract infections with Clonorchis or in chronic typhoid carriers. Features common to most risk factors include biliary stasis, bile duct stones, and infection. Other risk factors associated with cholangiocarcinoma are liver flukes, dietary nitrosamines, Thorotrast, and exposure to dioxin.90,91

PATHOLOGY Over 95% of bile duct cancers are adenocarcinomas. Morphologically, they are divided into nodular (the most common type), scirrhous, diffusely infiltrating, or papillary. Anatomically, they are divided into distal, proximal, or perihilar tumors. Intrahepatic cholangiocarcinomas occur, but they are treated like hepatocellular carcinoma, with hepatectomy when possible. About two thirds of cholangiocarcinomas are located in the perihilar location. Perihilar cholangiocarcinomas, also referred to as Klatskin tumors, are further classified based on anatomic location by the Bismuth-Corlette classification (Fig. 32-26). Type I tumors are confined to the common hepatic duct, but type II tumors involve the bifurcation without involvement of the secondary intrahepatic ducts. Type IIIa and IIIb tumors extend into the right and left secondary intrahepatic ducts, respectively. Type IV tumors involve both the right and left secondary intrahepatic ducts.

Fig. 32-26.

Bismuth-Corlette classification of bile duct tumors.

CLINICAL MANIFESTATIONS AND DIAGNOSIS Painless jaundice is the most common presentation. Pruritus, mild right upper quadrant pain, anorexia, fatigue, and weight loss also may be present. Cholangitis is the presenting symptom in about 10% of patients, but occurs more commonly after biliary manipulation in these patients. Except for jaundice, physical examination is usually normal in patients with cholangiocarcinoma. Occasionally, asymptomatic patients are found to have cholangiocarcinoma while being evaluated for elevated alkaline phosphatase and -glutamyltransferase levels. Tumor markers such CA 125 and carcinoembryonic antigen can be elevated in cholangiocarcinoma but tend to be nonspecific because they also increase in other GI and gynecologic malignancies or cholangiopathologies. The tumor marker most commonly used to aid the diagnosis of cholangiocarcinoma is CA 19-9, which has a sensitivity of 79% and specificity of 98% if the serum value is >129 U/mL.9 2 However, mild elevations in CA 19-9 can be seen in cholangitis, other GI and gynecologic neoplasms, and in patients who lack the Lewis blood type antigen.9 3 The initial tests are usually ultrasound or CT scan. A perihilar tumor causes dilatation of the intrahepatic biliary tree, but normal or collapsed gallbladder and extrahepatic bile ducts distal to the tumor. Distal bile duct cancer leads to dilatation of the extra- and the intrahepatic bile ducts as well as the gallbladder. Ultrasound can establish

the level of obstruction and rule out the presence of bile duct stones as the cause of the obstructive jaundice (Fig. 32-27). It is usually difficult to visualize the tumor itself on ultrasound or on a standard CT scan. Either ultrasound or spiral CT can be used to determine portal vein patency. The biliary anatomy is defined by cholangiography. PTC defines the proximal extent of the tumor, which is the most important factor in determining resectability. ERC is used, particularly in the evaluation of distal bile duct tumors. For the evaluation of vascular involvement, celiac angiography may be necessary. With the newer types of MRI, a single noninvasive test has the potential of evaluating the biliary anatomy, lymph nodes, and vascular involvement, as well as the tumor growth itself.9 4

Fig. 32-27.

A. An endoscopic retrograde cholangiography from a patient with cancer of the common hepatic duct (arrowheads ). The common bile duct is of normal size as is the cystic duct (arrow ), but the proximal biliary tree is dilated. The gallbladder is not visualized because of tumor obstructing its neck. B. An ultrasound from the same patient showing dilated ducts and tumor obstructing the common hepatic duct (arrow ). The walls of the bile ducts adjacent to the obstruction are thickened by tumor infiltration (arrowheads ).

Tissue diagnosis may be difficult to obtain nonoperatively except in advanced cases. Percutaneous fine-needle aspiration biopsy, biliary brush or scrape biopsy, and cytologic examination have a low sensitivity in detecting malignancy. Patients with potentially resectable disease should, therefore, be offered surgical exploration based on radiographic findings and clinical suspicion.9 5

TREATMENT Surgical excision is the only potentially curative treatment for cholangiocarcinoma. In the past one to two decades, improvements in surgical techniques have resulted in lower mortality and better outcome for patients undergoing aggressive surgical excision for cholangiocarcinoma.9 6 Patients should undergo surgical exploration if they have no signs of metastasis or locally unresectable disease. However, despite improvements in ultrasonography, CT scanning, and MRI, more than one half of patients who are explored are found to have peritoneal implants, nodal or hepatic metastasis, or locally advanced disease that precludes resection. For these patients, surgical bypass for biliary decompression and cholecystectomy to prevent the occurrence of acute cholecystitis should be performed.9 7 For unresectable perihilar cholangiocarcinoma, Roux-en-Y cholangiojejunostomy to either segment II or III bile ducts or to the right hepatic duct can be performed. For curative resection, the location and local extension of the tumor dictates the extent of the resection. Perihilar

tumors involving the bifurcation or proximal common hepatic duct (Bismuth-Corlette type I or II) with no signs of vascular involvement are candidates for local tumor excision with portal lymphadenectomy, cholecystectomy, common bile duct excision, and bilateral Roux-en-Y hepaticojejunostomies. If the tumor involves the right or left hepatic duct (Bismuth-Corlette type IIIa or IIIb), right or left hepatic lobectomy, respectively, should also be performed. Frequently, resection of the adjacent caudate lobe is required because of direct extension into caudate biliary radicals or parenchyma.9 5 Distal bile duct tumors are more often resectable. They are treated with pylorus-preserving pancreatoduodenectomy (Whipple procedure). For patients with distal bile duct cancer found to be unresectable on surgical exploration, Roux-en-Y hepaticojejunostomy, cholecystectomy, and gastrojejunostomy to prevent gastric outlet obstruction should be performed. Nonoperative biliary decompression is performed for patients with unresectable disease on diagnostic evaluation. Percutaneous placement of expandable metal stents or drainage catheters is usually the appropriate approach for proximal tumors. However, for distal bile duct tumors, endoscopic placement is often the preferred approach (Fig. 32-28). There is a significant risk of cholangitis with internal and external drainage, and stent occlusion is not uncommon. However, although surgical bypass offers improved patency and fewer episodes of cholangitis, an operative intervention is not warranted in patients with metastatic disease.9 8

Fig. 32-28.

A through F. Percutaneous transhepatic cholangiography and placement of a biliary drainage catheter. The catheter has been passed through the tumor area (distal cholangiocarcinoma) that is obstructing the distal common bile duct and into the duodenum.

There is no proven role for adjuvant chemotherapy in the treatment of cholangiocarcinoma. Adjuvant radiation therapy has also not been shown to increase either quality of life or survival in resected patients. Patients with unresectable disease often are offered treatment with 5-fluorouracil alone or in combination with mitomycin C and doxorubicin, but the response rates are low, 20 different hormones are secreted by the islets, and the exact functions of this milieu are very complex. There is diversity among the islets depending on their location within the pancreas. In general, islets located closer to major arterioles are larger than islets located more deeply in the parenchyma of the pancreas. The

- and

-cells are evenly distributed throughout the pancreas, but

islets in the head and uncinate process (ventral anlage) have a higher percentage of PP cells and fewer whereas islets in the body and tail (dorsal anlage) contain the majority of

-cells,

-cells and few PP cells. This is clinically

significant because pancreatoduodenectomy removes 95% of the PP cells in the pancreas. This may partially explain the higher incidence of glucose intolerance after the Whipple procedure than after distal pancreatectomy. In addition, chronic pancreatitis, which disproportionately affects the pancreatic head, is associated with PP deficiency and pancreatogenic diabetes. 2 3 Control of islet secretion is complex and involves an interplay of neural signals, blood flow patterns, and autocrine, paracrine, and hormonal feedback loops. Although the pancreatic islets account for only 2% of the pancreatic mass, they receive about 20 to 30% of the pancreatic arteriolar flow. The manner in which the blood flows through an individual islet can affect islet function because the

-cells are located in the center and the other islet cells are

located mostly in the periphery. Blood can flow into the center of the islet and then to the periphery, from the periphery to the center, or from one pole of the islet to the other. In rodents, in vivo microscopy has demonstrated blood flow from one pole to the other. In addition, sphincters at the feeding arteriole were observed regulating blood flow to the periphery or center of the islet as it passed from pole to pole. The sphincters are actually bulging endothelial cells of the afferent capillary. These sphincters seemed to be regulated by blood glucose concentrations, neural impulses, and nitric oxide. The predominant pattern of blood flow through the islets in the human pancreas is still conjectural. However, the peptide products of individual islet cells affect neighboring islet cells in a paracrine fashion. Experiments using isolated perfused pancreas and monoclonal antibodies to specific islet peptides have demonstrated that somatostatin from the glucagon secretion from the

-cells inhibits insulin secretion from the

-cells,

-cells, and PP secretion from the PP cells. Somatostatin may have an important role

in intraislet control of islet cell secretions2 4 (Fig. 33-10). Islet hormone secretion also is regulated by endocrine feedback mechanisms. Insulin secretion, for example, is exquisitely sensitive to small increments in the arterial insulin concentration.

Fig. 33-10.

- to

-cell axis. Somatostatin from the

from the

-cells may play an important role in intraislet paracrine control of insulin secretion

-cells.

Although most of the blood supply to the exocrine pancreas comes directly from the pancreatic arterial flow, blood draining from the islet capillaries goes on to perfuse the exocrine pancreas. Perfusion of the acinar cells with venous blood from the islets allows the endocrine pancreas to influence the exocrine pancreas. For example, insulin release, stimulated by high levels of carbohydrates in the ingested meal, is thought to promote an amylase-rich exocrine secretion, which preferentially provides for digestion of starches and sugars.

ACUTE PANCREATITIS Definition and Incidence Acute pancreatitis is an inflammatory disease of the pancreas that is associated with little or no fibrosis of the gland. It can be initiated by several factors, including gallstones, alcohol, trauma, and infections, and, in some cases, it is hereditary. Very often, patients with acute pancreatitis develop additional complications such as sepsis, shock, and respiratory and renal failure, resulting in considerable morbidity and mortality.2 5 Approximately 300,000 cases occur in the United States each year, 10 to 20% of which are severe, leading to over 3000 deaths. Pancreatitis is a contributing factor in an additional 4000 deaths annually and inflicts a heavy economic burden, accounting for more than $2 billion in health costs annually in the United States.2 6 Despite the considerable amount of research under way relating to this disease, its pathophysiologic mechanisms remain incompletely understood. This can be attributed, in part, to the relative inaccessibility of clinical material for experimental studies, which has led to the development of several models of experimental pancreatitis with which its etiology, pathophysiology, and treatment regimens are being explored.

Etiology

The etiology of acute pancreatitis is a complex subject because many different factors have been implicated in the causation of this disease, and sometimes there are no identifiable causes (Table 33-3). Two factors, biliary tract stone disease and alcoholism, account for 80 to 90% of the cases. The remaining 10 to 20 % is accounted for either by idiopathic disease or by a variety of miscellaneous causes including trauma, surgery, drugs, heredity, infection and toxins.

Table 33-3 Etiologies of Acute Pancreatitis Alcohol Biliary tract disease Hyperlipidemia Hereditary Hypercalcemia Trauma External Surgical Endoscopic retrograde cholangiopancreatography Ischemia Hypoperfusion Atheroembolic Vasculitis Pancreatic duct obstruction Neoplasms Pancreas divisum Ampullary and duodenal lesions Infections Venom Drugs Idiopathic

Source: Reproduced with permission from Yeo CJ, Cameron JL: Exocrine pancreas, in Townsend CM et al (eds): Sabiston's Textbook of Surgery . Philadelphia: Saunders, 2000, p 1117. Copyright Elsevier.

BILIARY TRACT DISEASE Although acute pancreatitis is documented in association with acalculous biliary tract disease, bile duct stones (choledocholithiasis) represent the most common form of associated biliary abnormality. The mechanism by which a gallstone may cause pancreatitis is not entirely clear, although gallstones have been implicated ever since Opie made the seminal observation in 1901 of two patients who died of acute pancreatitis with stones impacted in their ampulla of Vater.2 7 This led him to propose the "common-channel hypothesis," in which a blockage below the junction of the biliary and pancreatic ducts would cause bile to flow into the pancreas, which could then be damaged by the detergent action of bile salts. Important objections to this theory include the anatomic reality that the majority of individuals have such a short common channel that a stone located there would block both the pancreatic and biliary ducts, effectively isolating the two systems. Furthermore, hydrostatic pressure in the biliary tract is lower than in the pancreas, a condition that would favor abnormal flow of pancreatic juice into the bile duct rather than in the opposite direction. These reservations are bolstered by the observation that, in experimental animals, the flow of normal bile through an

unobstructed pancreatic duct does not result in acute pancreatitis (although forceful retrograde injection of bile into the pancreas causes injury similar to that of acute pancreatitis). Another proposed mechanism of causation postulates that passage of a gallstone through the sphincter of Oddi renders it momentarily incompetent, permitting the reflux of duodenal juice containing activated digestive enzymes into the pancreatic ductal system. However, it is questionable whether the transit time through the sphincter of Oddi is long enough to cause sufficient incompetence. Finally, the observation remains that procedures designed to render the sphincter incompetent, such as sphincterotomy, do not routinely cause pancreatitis. Therefore, although it is reasonable to dismiss an incompetent sphincter of Oddi as an etiologic factor in acute pancreatitis, it is not as simple to dismiss the role of gallstones. A clinical study showed that 88% of patients with acute pancreatitis passed gallstones in their feces within 10 days of the attack. This is in contrast to only 11% of gallstone patients who did not have pancreatitis, suggesting that the process of passing a gallstone may be linked to the development of acute pancreatitis. This information justifies searching for a more likely causative factor than abnormal bile or duodenal juice backflow into the pancreas. A common phenomenon shared by gallstone disease and other conditions causing acute pancreatitis, such as helminthic infestation of the pancreatic duct or its blockage by tumors, is ductal hypertension resulting from ongoing exocrine secretion into an obstructed pancreatic duct. A simple mechanical explanation has been proposed whereby elevated intraductal pressure causes rupture of the smaller ductules and leakage of pancreatic juice into the parenchyma. Although the pancreatic duct fluid pH is maintained in the range of 8 to 9 by the secretion of bicarbonate, the interstitial pH of 7 within the pancreatic tissue favors activation of proteases when transductal extravasation of fluid occurs. Although pancreatic ductal obstruction and hypertension are likely initiating factors in the etiology of acute pancreatitis, the mechanism by which ductal hypertension initiates pancreatic injury remains under investigation.2 7 Although the mechanical factors that initiate the process are unclear, the colocalization theory of Steer and Saluja has gained acceptance as the cellular mechanism of acute pancreatitis.2 8 In the normal pancreas, the inactive digestive zymogens and the lysosomal hydrolases are found separately in discrete organelles. However, in response to ductal obstruction, hypersecretion, or a cellular insult, these two classes of substances become improperly colocalized in a vacuolar structure within the pancreatic acinar cell. A cascade has been postulated in which trypsinogen colocalizes with cathepsin B to produce activated trypsin, which, in turn, activates the other digestive zymogens. These active digestive enzymes then begin autodigestion within the pancreatic acinar cells, leading to pancreatitis.

ALCOHOL Although some patients show the symptoms of acute pancreatitis after little use or even a single exposure to alcohol, the disease commonly occurs in patients who have consumed alcohol for at least 2 years, and often much longer, up to 10 years. In a patient with an exposure history to ethanol and the total absence of other possible causative factors, a first attack of pancreatitis is considered alcohol-related acute pancreatitis. However, it is possible that a first attack of alcohol-related pancreatitis in the typical longstanding alcohol user is really the first manifestation of chronic pancreatitis. The disease can become recurrent with continued alcohol abuse. The nature of alcohol consumed (i.e., beer, wine, or hard liquor) is less significant than a daily intake of between 100 and 150 g of ethanol. Between 10 and 15% of individuals with this degree of alcohol intake go on to develop pancreatitis, while a similar proportion develop cirrhosis of the liver. Ethanol can induce pancreatitis by several methods. The "secretion with blockage" mechanism is possible because ethanol causes spasm of the sphincter of Oddi, and, more important, ethanol is a metabolic toxin to pancreatic

acinar cells, where it can interfere with enzyme synthesis and secretion. The initial effect of ethanol is a brief secretory increase followed by inhibition. This can lead to elevation of enzyme proteins that can precipitate within the pancreatic duct. Calcium then can precipitate within this protein matrix, causing multiple ductal obstructions, while continued secretion can cause pressure buildup. Ethanol also increases ductal permeability, making it possible for improperly activated enzymes to leak out of the pancreatic duct into the surrounding tissue. The inappropriate activation of trypsin by ethanol has been demonstrated in vitro. Ethanol also transiently decreases pancreatic blood flow, possibly causing focal ischemic injury to the gland.29,30 There is evidence that alcoholics who develop pancreatitis have a diet richer in protein and fat than those who do not. Ethanol can alter lipid metabolism, and a transient hyperlipidemic state is sometimes seen during an attack of alcoholic pancreatitis, although the etiologic significance of this observation remains uncertain.

TUMORS A tumor should be considered in a nonalcoholic patient with acute pancreatitis who has no demonstrable biliary tract disease. Approximately 1 to 2% of patients with acute pancreatitis have pancreatic carcinoma, and an episode of acute pancreatitis can be the first clinical manifestation of a periampullary tumor. In both conditions, the pancreatitis possibly results from blockage of secreted juice and its upstream consequences.

IATROGENIC PANCREATITIS Acute pancreatitis can be associated with a number of surgical procedures, most commonly those performed on or close to the pancreas, such as pancreatic biopsy, biliary duct exploration, distal gastrectomy, and splenectomy. Acute pancreatitis is associated postoperatively with Billroth II gastrectomy and jejunostomy, in which increased intraduodenal pressure can cause backflow of activated enzymes into the pancreas. However, pancreatitis also can occur in association with surgery that uses low systemic perfusion, such as cardiopulmonary bypass and cardiac transplantation. Acute pancreatitis has been reported to be associated with severe hypothermia, and the hypothermia associated with cardiopulmonary bypass may be similarly causative. It also is possible that atheromatous emboli or ischemia may cause pancreatic injury. Most commonly, endoscopic retrograde cholangiopancreatography (ERCP) results in pancreatitis in 2 to 10% of patients, due to direct injury and/or intraductal hypertension.

DRUGS For practical reasons, it often is difficult to implicate a drug as the cause of pancreatitis. Many drugs can produce hyperamylasemia and/or abdominal pain, and a drug is considered suspect if the pancreatitis-like illness resolves with its discontinuation. Ethical considerations generally rule out rechallenge with the suspect drug, so the connection often remains vague. However, despite these limitations, certain drugs are known to be capable of causing acute pancreatitis. These include the thiazide diuretics, furosemide, estrogens, azathioprine, Lasparaginase, 6-mercaptopurine, methyldopa, the sulfonamides, tetracycline, pentamidine, procainamide, nitrofurantoin, dideoxyinosine, valproic acid, and acetylcholinesterase inhibitors.

INFECTIONS Though mumps, coxsackievirus, and Mycoplasma pneumoniae are believed to be capable of inducing acute pancreatitis by infecting the acinar cells, none of these agents has been isolated from a diseased pancreas. The belief may have arisen from the observation that antibody titers to mumps and coxsackievirus are elevated in approximately 30% of patients with acute pancreatitis with no other identified cause. However, this elevation may be an anamnestic or nonspecific response to pancreatitis.

HYPERLIPIDEMIA It has been suggested that lipase can liberate large amounts of toxic fatty acids into the pancreatic microcirculation. This could lead to endothelial injury, sludging of blood cells, and consequent ischemic states. Patients with types I and V hyperlipoproteinemia often experience attacks of abdominal pain that are thought to indicate episodes of acute pancreatitis. These episodes are frequently associated with marked hypertriglyceridemia and lactescent serum and can be prevented by dietary modifications that restrict serum triglycerides.

MISCELLANEOUS CAUSES An episode of acute pancreatitis may be precipitated by several other factors. Hypercalcemic states arising from hyperparathyroidism can result in both acute and chronic pancreatitis; the mechanism most likely involves hypersecretion and the formation of calcified stones intraductally. Also implicated are infestations by Ascaris lumbricoides and the liver fluke Clonorchis sinensis , which is endemic to China, Japan, and Southeast Asia. These cause Oriental cholangitis, which is associated with cholangiocarcinoma obstructing the pancreatic duct. A dominant gene mutation following Mendelian inheritance is known to result in hereditary pancreatitis.3 1 Whitcomb and associates described several families from various parts of the world who have mutations in their cationic trypsinogen gene PRSS1 , which results in pancreatitis.3 2 Additionally, 20 to 45% of patients with pancreas divisum (unfused ducts of Wirsung and Santorini) develop pancreatitis, but the failure of procedures to improve drainage of the lesser papilla in reducing attacks of pancreatitis, as well as the observed lack of ductal dilatation in such patients, argues against pancreas divisum as an etiologic factor, rendering the role of this condition as yet unclear. Other implicated factors include azotemia, vasculitis, and the sting of the Trinidadian scorpion Tityus trinitatis . This scorpion's venom has been shown to cause neurotransmitter discharge from cholinergic nerve terminals, leading to massive production of pancreatic juice. Poisoning with antiacetylcholinesterase insecticides has a similar effect. Finally, no apparent cause can be ascribed to some episodes of acute pancreatitis, and these constitute the group referred to as idiopathic pancreatitis . Some of these patients are eventually found to have gallstone-related pancreatitis, which calls for caution in labeling any episode "idiopathic."

Pathophysiology Acute pancreatitis occurs in varying degrees of severity, the determinants of which are multifactorial. The generally prevalent belief today is that pancreatitis begins with the activation of digestive zymogens inside acinar cells, which cause acinar cell injury. Studies suggest that the ultimate severity of the resulting pancreatitis may be determined by the events that occur subsequent to acinar cell injury.3 3 These include inflammatory cell recruitment and activation, as well as generation and release of cytokines and other chemical mediators of inflammation (Fig. 3311).

Fig. 33-11.

Pathophysiology of acute pancreatitis.

INITIAL EVENTS LEADING TO THE ONSET OF PANCREATITIS Under physiologic conditions, the pancreas synthesizes a large amount of protein. A majority of these proteins

consist of digestive enzymes. Because the exocrine pancreas produces several enzymes that are potentially injurious to itself, it prevents autodigestion by intracellularly assembling the inactive precursors of these enzymes, called proenzymes or zymogens , which are then transported and secreted outside of the gland. Their activation occurs safely in the duodenum, where the brush-border enzyme enteropeptidase (or enterokinase) activates the trypsinogen, and the resulting trypsin then activates the other zymogens in a cascade reaction. To further protect the pancreas from these potentially harmful digestive enzymes, they are segregated from the cytoplasmic space within acinar cells by being enclosed within membrane-bound organelles, referred to as zymogen granules . Another layer of protection is provided by the synthesis of trypsin inhibitors, which are transported and stored along with the digestive enzyme zymogens. These are available to inhibit small amounts of prematurely activated trypsinogen within pancreatic acinar cells. It is generally theorized that acute pancreatitis occurs when this process goes awry and the gland is injured by the erroneously activated enzymes that it produces. There are three reasons for this theory: (a) the pancreas is digestible by the activated enzymes of the duodenum; (b) activated digestive enzymes are found within the pancreas during pancreatitis, and (c) the histology of pancreatitis is suggestive of a coagulative necrosis. However, the mechanism(s) of erroneous activation are not fully understood. Using several different models, recent research has focused intensively on the etiology of the activation mechanism. It was seen that the synthesis and intracellular transport of digestive enzymes are not affected during the development of pancreatitis, but that the secretory output of enzymes of the pancreas is markedly reduced.3 4 Very early in the development of the disease (shortly after the onset, but before morphologic or biochemical changes are apparent), digestive enzymes are localized in cytoplasmic vacuoles that also contain the lysosomal hydrolase cathepsin B, which is known to activate trypsinogen. Furthermore, intracellular trypsinogen activation was found synchronously with the colocalization phenomenon. Further support for this hypothesis is provided by findings that inhibition of cathepsin B activity by the highly specific inhibitor, CA-074me, protects against intraacinar cell trypsinogen activation and pancreatitis in two different models of experimental pancreatitis.3 5 These studies strongly suggest that trypsinogen is activated because it erroneously colocalizes in cytoplasmic vacuoles with cathepsin B. The opportunity is therefore created for autodigestion, however, the mechanism by which the prematurely activated trypsin causes acinar cell injury and death is not well understood. Recent studies suggest that trypsin, once activated inside the colocalized vacuoles (which appear to be similar to those recently described as autophagic vacuoles, 3 6 mediates the permeability of these organelles, and causes them to release their contents into the cytosol. Cathepsin B is one of the enzymes released into the cytosol during pancreatitis. Once in the cytosol, it initiates apoptotic cell death by permeabilizing mitochondrial membranes, which allows cytochrome C to be released into the cytosol. This initiates the apoptotic cascade and results in the apoptotic death of the acinar cells (Fig. 33-12).3 7

Fig. 33-12.

Schematic representation of the overall pancreatitis hypothesis. When acinar cells are pathologically stimulated, their lysosomal and zymogen contents colocalize, whereupon trypsinogen is activated to trypsin by cathepsin B. Increased cytosolic calcium is required for colocalization. The active trypsin mediates the permeability of these colocalized organelles. Once trypsin has permeabilized the cells, cathepsin B and other contents of these colocalized organelles are released into the cytosol. Once in the cytosol, cathepsin B activates apoptosis by causing cytochrome c to be released from the mitochondria. Cathepsin B–induced activation of the Bcl-2 family of proteins may help release cytochrome c from the mitochondria. Heat shock protein 70 (HSP70) overexpression attenuates cytosolic calcium (Cai 2+ ), thus preventing colocalization and the subsequent events that lead to acinar cell injury and death.

FACTORS DETERMINING THE SEVERITY OF PANCREATITIS Clinically, the severity of acute pancreatitis varies significantly. Some patients experience a mild form of the disease that is self-limiting, while others suffer a more severe and sometimes lethal attack. The factors determining the severity of pancreatitis are multifactorial, but their identification is of considerable therapeutic

importance, because their manipulation may decrease the morbidity and mortality associated with the disease. It generally is believed that pancreatitis begins with the intrapancreatic activation of digestive enzyme zymogens, acinar cell injury, and activation of transcription factors such as nuclear factor- B (NF- B) and activator protein 1.3 8 This, in turn, leads to the production of proinflammatory factors, acinar cell necrosis, systemic inflammatory response syndrome, and distant organ dysfunction, including lung injury that frequently manifests as the acute respiratory distress syndrome (ARDS). The ultimate severity of acute pancreatitis depends on the extent of the systemic inflammatory response, as well as several cytokines and chemokines and their receptors that play a critical role in the activation and migration of inflammatory cells to the affected site.3 9 In addition to the cells of the immune system such as the neutrophils, the pancreatic acinar cells are also a source of inflammatory mediators during pancreatitis. Over the past few years, the list of factors associated with pancreatitis and associated lung injury has grown rapidly to include tumor necrosis factor alpha, monocyte chemotactic protein-1, Mob1, interleukin-1 (IL-1 ), platelet activating factor (PAF), substance P, adhesion molecules [intercellular adhesion molecule-1 (ICAM-1) and selectins], IL-6, IL-8, IL-10, C5a, the CCR1 receptor and its ligands, granulocyte-macrophage colony-stimulating factor, macrophage migration inhibitory factor, COX-2, prostaglandin E1, nitric oxide, and reactive oxygen species.4 0 In addition, several studies have focused on the protective role played by heat shock proteins in pancreatitis.4 1 The ultimate severity of pancreatitis and associated lung injury depends on the balance between the pro- and anti-inflammatory factors. Several therapeutic regimens aimed at reducing the inflammatory response have been tested and include anti–tumor necrosis factor alpha antibody, IL-1 receptor antagonist, anti–ICAM-1 and anti-CD3 antibodies, IL-10, recombinant PAF acetylhydrolase, and the calcineurin antagonist FK506. Recent studies also indicate that Toll-like receptor 4 (TLR4) is significant in determining the severity of acute pancreatitis. The TLR4 initiates a complex signaling pathway when it interacts with lipopolysaccharides that result in a proinflammatory response. Mice in which TLR4 is genetically deleted have significantly reduced pancreatitis; this suggests that TLR4 is a significant promoter of proinflammation. However, this effect appears independently of lipopolysaccharides and is probably mediated by a hitherto unknown TLR4 agonist. It is likely that TLR4 antagonists would be a good therapy against pancreatitis.4 2 An alternate approach to prevent or reduce the severity of pancreatitis is to inhibit the two early events in pancreatitis, intrapancreatic trypsinogen and NF- B activation. Agents that specifically prevent an increase in trypsin activity, either by inhibiting trypsinogen activation and colocalization (e.g., low doses of wortmannin, water immersion, and thermal stress), or inhibiting the cathepsin B activity (E64d or CA074me), have been successful in reducing the severity of pancreatitis in experimental rodent models. Prior thermal (and arsenite) stress and water immersion stress, which upregulate heat shock proteins 70 and 60, respectively, not only prevent cerulein-induced trypsinogen activation, but also inhibit cerulein-induced NF- B activation in the pancreas and protect against pancreatitis.4 3 These studies await verification in a clinical setting.

Diagnosis The clinical diagnosis of pancreatitis is one of exclusion. The other upper abdominal conditions that can be confused with acute pancreatitis include perforated peptic ulcer, a gangrenous small bowel obstruction, and acute cholecystitis. Because these conditions often have a fatal outcome without surgery, urgent intervention is indicated in the small number of cases in which doubt persists. All episodes of acute pancreatitis begin with severe pain, generally following a substantial meal. The pain is usually epigastric, but can occur anywhere in the abdomen or lower chest. It has been described as "knifing" or "boring through" to the back, and may be relieved by the patient leaning forward. It precedes the onset of nausea and

vomiting, with retching often continuing after the stomach has emptied. Vomiting does not relieve the pain, which is more intense in necrotizing than in edematous pancreatitis. An episode of acute pancreatic inflammation in a patient with known chronic pancreatitis has the same findings. On examination, the patient may show tachycardia, tachypnea, hypotension, and hyperthermia. The temperature is usually only mildly elevated in uncomplicated pancreatitis. Voluntary and involuntary guarding can be seen over the epigastric region. The bowel sounds are decreased or absent. There are usually no palpable masses. The abdomen may be distended with intraperitoneal fluid. There may be pleural effusion, particularly on the left side. With increasing severity of disease, the intravascular fluid loss may become life-threatening as a result of sequestration of edematous fluid in the retroperitoneum. Hemoconcentration then results in an elevated hematocrit. However, there also may be bleeding into the retroperitoneum or the peritoneal cavity. In some patients (about 1%), the blood from necrotizing pancreatitis may dissect through the soft tissues and manifest as a bluish discoloration around the umbilicus (Cullen's sign) or in the flanks (Grey Turner's sign). The severe fluid loss may lead to prerenal azotemia with elevated blood urea nitrogen and creatinine levels. There also may be hyperglycemia, hypoalbuminemia, and hypocalcemia sufficient in some cases to produce tetany.

SERUM MARKERS Because pancreatic acinar cells synthesize, store, and secrete a large number of digestive enzymes (e.g., amylase, lipase, trypsinogen, and elastase), the levels of these enzymes are elevated in the serum of most pancreatitis patients. Because of the ease of measurement, serum amylase levels are measured most often. Serum amylase concentration increases almost immediately with the onset of disease and peaks within several hours. It remains elevated for 3 to 5 days before returning to normal. There is no significant correlation between the magnitude of serum amylase elevation and severity of pancreatitis; in fact, a milder form of acute pancreatitis is often associated with higher levels of serum amylase as compared with that in a more severe form of the disease. It is important to note that hyperamylasemia can also occur as a result of conditions not involving pancreatitis. For example, hyperamylasemia can occur in a patient with small bowel obstruction, perforated duodenal ulcer, or other intra-abdominal inflammatory conditions. In contrast, a patient with acute pancreatitis may have a normal serum amylase level, which could be due to several reasons. In patients with hyperlipidemia, values might appear to be normal because of interference by lipids with chemical determination of serum amylase. In many cases, urinary clearance of pancreatic enzymes from the circulation increases during pancreatitis; therefore, urinary levels may be more sensitive than serum levels. For these reasons, it is recommended that amylase concentrations also be measured in the urine. Urinary amylase levels usually remain elevated for several days after serum levels have returned to normal. In patients with severe pancreatitis associated with significant necrotic damage, the pancreas may not release large amounts of enzymes into the circulation. It is important to recognize that, in patients with severe pancreatitis, frequent measurement of serum enzymes is not needed. Patients with alcoholic pancreatitis, in general, have a smaller increase in serum amylase levels. Because hyperamylasemia can be observed in many extrapancreatic diseases, measuring pancreatic-specific amylase (p-amylase) rather than total amylase, which also includes salivary amylase, makes the diagnosis more specific (88 to 93%). Other pancreatic enzymes also have been evaluated to improve the diagnostic accuracy of serum measurements. Specificity of these markers ranges from 77 to 96%, the highest being for lipase. Measurements of many digestive enzymes also have methodologic limitations and cannot be easily adapted for quantitation in emergency labs. Because serum levels of lipase remain elevated for a longer time than total or p-amylase, it is the serum indicator

of highest probability of the disease.

ULTRASOUND Abdominal ultrasound (US) examination is the best way to confirm the presence of gallstones in suspected biliary pancreatitis. It also can detect extrapancreatic ductal dilations and reveal pancreatic edema, swelling, and peripancreatic fluid collections (PFCs). However, in about 20% of patients, the US examination does not provide satisfactory results because of the presence of bowel gas, which may obscure sonographic imaging of the pancreas. A CT scan of the pancreas is more commonly used to diagnose pancreatitis (Fig. 33-13). CT scanning is used to distinguish milder (nonnecrotic) forms of the disease from more severe necrotizing or infected pancreatitis in patients whose clinical presentation raises the suspicion of advanced disease.4 4

Fig. 33-13.

Nonnecrotizing acute pancreatitis. The computed tomographic image reveals edema (large arrow ) and fluid (small arrow ) but intact vascularization of the pancreas overall.

ASSESSMENT OF SEVERITY An early discrimination between mild edematous and severe necrotizing forms of the disease is of the utmost importance to provide optimal care to the patient. Several predictors of severity, including early prognostic signs, serum markers, and CT scans, are commonly used for this purpose.4 5

EARLY PROGNOSTIC SIGNS

In 1974, Ranson identified a series of prognostic signs for early identification of patients with severe pancreatitis. 4 6 Out of these 11 objective parameters, five are measured at the time of admission, whereas the remaining six are measured within 48 hours of admission (Table 33-4). Morbidity and mortality of the disease are directly related to the number of signs present. If the number of positive Ranson signs is less than two, the mortality is generally zero; with three to five positive signs, mortality is increased to 10 to 20%. The mortality rate increases to >50% when there are more than seven positive Ranson signs. Although prognostic signs are useful in determining the severity of pancreatitis, there are several limitations to the value of these signs. One has to measure all 11 signs to achieve the best predictability of prognosis, and two full days are needed to complete the profile. A delay of 48 hours after admission merely for assessment may squander a valuable opportunity to prevent a complication during this time. It is important to realize that Ranson's prognostic signs are best used within the initial 48 hours of hospitalization and have not been validated for later time intervals. Although several investigators (Imrie, Banks, Agarwal-Pitchumoni, and others) have proposed modifications to simplify these prognostic criteria throughout the years since their inception, Ranson's original 11 signs are still the most commonly used.

Table 33-4 Ranson's Prognostic Signs of Pancreatitis Criteria for acute pancreatitis not due to gallstones At admission During the initial 48 h Age >55 y Hematocrit fall >10 points WBC >16,000/mm3 BUN elevation >5 mg/dL Blood glucose>200 mg/dL Serum calcium 350 IU/L Arterial P O 2 250 U/dL Base deficit >4 mEq/L Estimated fluid sequestration >6 L Criteria for acute gallstone pancreatitis At admission During the initial 48 h Age >70 y Hematocrit fall >10 points WBC >18,000/mm3 BUN elevation >2 mg/dL Blood glucose>220 mg/dL Serum calcium 400 IU/L Base deficit >5 mEq/L Serum AST >250 U/dL Estimated fluid sequestration >4 L

AST = aspartate transaminase; BUN = blood urea nitrogen; LDH = lactate dehydrogenase; PO of oxygen; WBC = white blood cell count.

2

= partial pressure

Source: Data from Ranson JHC: Etiological and prognostic factors in human acute pancreatitis: A review. Am J Gastroenterol 77:633, 1982. From Macmillan Publishers Ltd. Ranson JH, Rifkind KM, Roses DF, et al: Prognostic signs and the role of operative management in acute pancreatitis. Surg Gynecol Obstet 139:69, 1974. Another set of criteria often used to assess the severity of pancreatitis is the a cute p hysiology a nd c hronic h ealth e valuation (APACHE-II) score. This grading system assesses severity on the basis of quantitative measures of abnormalities of multiple variables, including vital signs and specific laboratory parameters, coupled with the age and chronic health status of the patient. The main advantage of the APACHE-II scoring system is the immediate assessment of the severity of pancreatitis. A score of eight or more at admission is usually considered indicative of severe disease.4 7

BIOCHEMICAL MARKERS The ideal biochemical marker for prognosis of acute pancreatitis should not only have high specificity and sensitivity but also should be able to discriminate between mild (edematous) and severe (necrotic) disease on admission. Although serum enzymes such as amylase and lipase are helpful in the diagnosis of pancreatitis, these have no prognostic value. Several recent research studies have suggested additional markers that may have prognostic value, including acute phase proteins such as C-reactive protein (CRP), alpha2 -macroglobulin, polymorphonuclear neutrophil–elastase, alpha1-antitrypsin, and phospholipase A2. Although CRP measurement is commonly available, many of the others are not. Therefore, at this time, CRP seems to be the marker of choice in clinical settings. The measurement of IL-6 has recently been shown to distinguish patients with mild or severe forms of the disease. However, these tests have to undergo large-scale evaluations before they can be recommended for routine use. Another prognostic marker under evaluation is urinary–trypsinogen activation peptide (TAP). TAP is a five- to seven-amino acid peptide that is released from the N-terminus of trypsinogen during its activation. In studies, Neoptolemos and colleagues have shown a good correlation between the severity of pancreatitis and concentrations of TAP in urine.4 8 However, further testing and methodologic developments are needed before TAP can be used as a routine prognostic marker.

COMPUTED TOMOGRAPHY SCAN CT scanning with bolus IV contrast has become the gold standard for detecting and assessing the severity of pancreatitis. Although clinically mild pancreatitis is usually associated with interstitial edema, severe pancreatitis is associated with necrosis. In interstitial pancreatitis, the microcirculation of the pancreas remains intact, and the gland shows uniform enhancement on IV contrast-enhanced CT scan (see Fig. 33-13). In necrotizing pancreatitis, however, the microcirculation is disrupted; therefore, the enhancement of the gland on contrast-enhanced CT scan is considerably decreased. The presence of air bubbles on a CT scan is an indication of infected necrosis or pancreatic abscess (Fig. 33-14). Currently, IV (bolus) contrast-enhanced CT scanning is routinely performed on patients who are suspected of harboring severe pancreatitis, regardless of their Ranson's or APACHE scores.4 9

Fig. 33-14.

Necrotizing (infected) acute pancreatitis. The computed tomographic image reveals areas of nonperfusion and the presence of gas in the region of severe necrosis, which indicates infection.

Treatment The severity of acute pancreatitis covers a broad spectrum of illness, ranging from the mild and self-limiting to the life-threatening necrotizing variety. Regardless of severity, hospitalization of the patient with suspected acute pancreatitis for observation and diagnostic study is usually mandatory. Upon confirmation of the diagnosis, patients with moderate to severe disease should be transferred to the intensive care unit for observation and maximal support. The most important initial treatment is conservative intensive care with the goals of oral food and fluid restriction, replacement of fluids and electrolytes parenterally as assessed by central venous pressure and urinary excretion, and control of pain. In severe acute pancreatitis, or when signs of infection are present, most experts recommend broad-spectrum antibiotics (e.g., imipenem) and careful surveillance for complications of the disease (Table 33-5).4 9

Table 33-5 Complications of Acute Pancreatitis I. Local A. Pancreatic phlegmon B. Pancreatic abscess C. Pancreatic pseudocyst D. Pancreatic ascites E. Involvement of adjacent organs, with hemorrhage, thrombosis, bowel infarction, obstructive jaundice, fistula formation, or mechanical obstruction II. Systemic A. Pulmonary 1. Pneumonia, atelectasis

2. Acute respiratory distress syndrome 3. Pleural effusion B. Cardiovascular 1. Hypotension 2. Hypovolemia 3. Sudden death 4. Nonspecific ST-T wave changes 5. Pericardial effusion C. Hematologic 1. Hemoconcentration 2. Disseminated intravascular coagulopathy D. GI hemorrhage 1. Peptic ulcer 2. Erosive gastritis 3. Portal vein or splenic vein thrombosis with varices E. Renal 1. Oliguria 2. Azotemia 3. Renal artery/vein thrombosis F. Metabolic 1. Hyperglycemia 2. Hypocalcemia 3. Hypertriglyceridemia 4. Encephalopathy 5. Sudden blindness (Purtscher's retinopathy) G. Central nervous system 1. Psychosis 2. Fat emboli 3. Alcohol withdrawal syndrome H. Fat necrosis 1. Intra-abdominal saponification 2. Subcutaneous tissue necrosis

Source: Reproduced with permission from Greenberger NJ, Toskes PP, Isselbacher KJ: Acute and chronic pancreatitis, in Isselbacher KJ et al (eds): Harrison's Principles of Internal Medicine, 13th ed. New York: McGrawHill, 1994, p 1524.

MILD PANCREATITIS Pancreatitis is classified as mild when the patient has no systemic complications, low APACHE-II scores and Ranson's signs, sustained clinical improvement, and when a CT scan rules out necrotizing pancreatitis. The treatment then is mostly supportive and has the important aim of resting the pancreas through restriction of oral food and fluids. Nasogastric suction and H2 -blockers have routinely been used in this connection, based on the reasoning that even the smallest amount of gastric acid reaching the duodenum could stimulate pancreatic secretion. However, these measures are of little value. The following secretion-inhibiting drugs have also been tried without notable success: atropine, calcitonin, somatostatin, glucagon, and fluorouracil.5 0

Pancreatitis is also an autodigestive process, and various protease-inhibiting drugs, including aprotinin, gabexate mesylate, camostate, and phospholipase A2 inhibitors, as well as fresh frozen plasma, have been tested to prevent proteolysis, but with little success. Because a significant component of the patient's distress arises from the inflammatory aspect of pancreatitis, various methods have been tried to alleviate inflammation, including indomethacin and the prostaglandin inhibitors; but again, these have not proved to be of much value. Some recent studies examined a different strategy, namely the use of PAF antagonists such as PAF acetylhydrolase and Lexipafant. These showed promising results in experimental animals and in initial clinical studies, but did not live up to their promise in larger-scale clinical trials.5 1 The current principles of treatment are physiologic monitoring, metabolic support, and maintenance of fluid balance, which can become dangerously disturbed even in mild acute pancreatitis because of fluid sequestration, vomiting, and sudoresis. Because hypovolemia can result in pancreatic and other visceral ischemia, fluid balance should be assessed at least every 8 hours initially. The severe pain of acute pancreatitis prevents the patient from resting, and results in ongoing cholinergic discharge, which stimulates gastric and pancreatic secretion. Therefore, pain management is of great importance. Administration of buprenorphine, pentazocine, procaine hydrochloride, and meperidine are all of value in controlling abdominal pain. Morphine is to be avoided, due to its potential to cause sphincter of Oddi spasm. Antibiotic therapy has not proved to be of value in the absence of signs or documented sources of infection. Cautious resumption of oral feeding consisting of small and slowly increasing meals is permissible after the abdominal pain and tenderness have subsided, serum amylase has returned to normal, and the patient experiences hunger. This usually occurs within a week of the onset of an attack of mild acute pancreatitis. A low-fat, low-protein diet is advocated as the initial form of nutrition following an attack of acute pancreatitis.

SEVERE PANCREATITIS Pancreatitis can be classified as severe based on predictors such as APACHE-II scores and Ranson's signs, and any evidence that the condition is severe mandates care of the patient in the intensive care unit. Such evidence may take various forms, such as the onset of encephalopathy, a hematocrit >50%, urine output 25 g/L and a markedly elevated amylase level. Serum amylase may also be elevated, presumably from reabsorption across the parietal membrane. Serum albumin may be low, and patients may have coexisting liver disease. Paracentesis is therefore critical to differentiate pancreatic from hepatic ascites.

Fig. 33-43.

Pancreatic ascites. Computed tomographic scan of a patient with a ruptured pancreatic pseudocyst resulting in intraperitoneal pancreatic fluid. (Reproduced with permission from Lipsett et al.203 )

ERCP is most helpful to delineate the location of the pancreatic duct leak and to elucidate the underlying pancreatic ductal anatomy. Pancreatic duct stenting may be considered at the time of ERCP, but if nonsurgical therapy is undertaken and then abandoned, repeat imaging of the pancreatic duct is appropriate to guide surgical treatment.

Antisecretory therapy with the somatostatin analogue octreotide acetate, together with bowel rest and parenteral nutrition, is successful in more than half of patients.205 Reapposition of serosal surfaces to facilitate closure of the leak is considered a part of therapy, and this is accomplished by complete paracentesis. For pleural effusions, a period of chest tube drainage may facilitate closure of the internal fistula.202,205 Surgical therapy is reserved for those who fail to respond to medical treatment. If the leak originates from the central region of the pancreas, a Roux-en-Y pancreaticojejunostomy is performed to the site of duct leakage (Fig. 33-44). If the leak is in the tail, a distal pancreatectomy may be considered, or an internal drainage procedure can be performed. The results of surgical treatment are usually favorable if the ductal anatomy has been carefully delineated preoperatively.

Fig. 33-44.

Internal drainage for leaking pancreatic duct. A Roux-en-Y pancreaticojejunostomy is performed at the site of duct rupture to accomplish internal drainage of the pancreatic duct leak. (Reproduced with permission from Cameron.202 )

PANCREATIC-ENTERIC FISTULA The erosion of a pancreatic pseudocyst into an adjacent hollow viscus can result in a pancreatic-enteric fistula. The

most common site of communication is the transverse colon or splenic flexure. The fistula usually presents with evidence of GI or colonic bleeding and sepsis. If the fistula communicates with the stomach or duodenum, it may close spontaneously or persist as a pancreatic-enteric fistula. When the fistula involves the colon, operative correction is usually required.206

HEAD-OF-PANCREAS MASS In up to 30% of patients with advanced chronic pancreatitis, an inflammatory mass develops in the head of the pancreas.207 The clinical presentation includes severe pain, and frequently includes stenosis of the distal common bile duct, duodenal stenosis, compression of the portal vein, and stenosis of the proximal main pancreatic duct (Table 33-15). In a series of 279 patients with chronic pancreatitis treated surgically at the University of Ulm in Germany, patients with pancreatic head enlargement represented half of the total group. The subgroup with pancreatic head enlargement appeared to have a lower incidence of endocrine and exocrine insufficiency, but a higher expression of epidermal growth factor and the c-erb B-2 protooncogene.208 Mutations and polymorphisms of p53 were found in 3 and 8% of these patients, respectively, and a focus of ductular carcinoma was found in 3.7% of patients with pancreatic head enlargement. It was concluded that an accelerated transformation from hyperplasia to dysplasia exists in patients with pancreatic head enlargement, although the etiology for this process remains unclear. Treatment in the majority of cases consisted of the duodenum-preserving pancreatic head resection (DPPHR), with good results.

Table 33-15 Signs and Symptoms of Chronic Pancreatitis with and without a Pancreatic Head Mass Daily severe pain 67 40 Cholestasis 46 11 Slight to frequent pain 33 60 Duodenal obstruction 30 7 Diabetes mellitus 18 30 Vascular involvement 15 8 Signs and Symptoms

With Head Enlargement (n = 138) (%)

Source: Reproduced with permission from Beger et al.207

SPLENIC AND PORTAL VEIN THROMBOSIS

Without Head Enlargement (n = 141) (%)

Vascular complications of chronic pancreatitis are fortunately infrequent, because they are difficult to treat successfully. Portal vein compression and occlusion can occur as a consequence of an inflammatory mass in the head of the pancreas, and splenic vein thrombosis occurs in association with chronic pancreatitis in 4 to 8% of cases.209 Variceal formation can occur as a consequence of either portal or splenic venous occlusion, and splenic vein thrombosis with gastric variceal formation is referred to as left-sided or sinistral portal hypertension . Although bleeding complications are infrequent, the mortality risk of bleeding is >20%. When gastroesophageal varices are caused by splenic vein thrombosis, the addition of splenectomy to prevent variceal hemorrhage is prudent when surgery is otherwise indicated to correct other problems.

Treatment MEDICAL THERAPY The medical treatment of chronic or recurrent pain in chronic pancreatitis requires the use of analgesics, a cessation of alcohol use, oral enzyme therapy, and the selective use of antisecretory therapy. Interventional procedures to block visceral afferent nerve conduction or to treat obstructions of the main pancreatic duct are also an adjunct to medical treatment.

ANALGESIA Oral analgesics are prescribed as needed, alone or with analgesia-enhancing agents such as gabapentin. Adequate pain control usually requires the use of narcotics, but these should be titrated to achieve pain relief with the lowest effective dose. Opioid addiction is common, and the use of long-acting analgesics by transdermal patch together with oral agents for pain exacerbations slightly reduces the sedative effects of high-dose oral narcotics. It is essential for patients to abstain from alcohol. In addition to removing the causative agent, alcohol abstention results in pain reduction or relief in 60 to 75% of patients with chronic pancreatitis.210 Despite this benefit, roughly half of alcoholic chronic pancreatitis patients continue to abuse alcohol.

ENZYME THERAPY Pancreatic enzyme administration serves to reverse the effects of pancreatic exocrine insufficiency and may reduce or alleviate the pain experienced by patients. The choice of enzyme supplement and the dose should be selected based on whether malabsorption or pain (or both) are the indications for therapy211 (Table 33-16). Conventional (non–enteric-coated) enzyme preparations are partially degraded by gastric acid but are available within the duodenal and jejunal regions to bind to CCK-releasing peptide, and downregulate the release of CCK. This theoretically reduces the enteric signal for pancreatic exocrine secretion, which reduces the pressure within a partially or completely obstructed pancreatic duct.212,213 Enteric-coated preparations result in little to no pain relief, presumably due to their reduced bioavailability in the proximal gut.214 Due to the loss of pancreatic enzymes by acid hydrolysis and proteolysis, relatively large doses are required to achieve effective levels of enzyme within the proximal small bowel. Enteric-coated preparations are protected from acid degradation but are presumably not released in the critical proximal gut in sufficient quantity to inhibit the stimulus for endogenous pancreatic enzyme secretion. Nonalcoholic patients may experience more effective pain relief than alcoholic patients,211 but it is recommended that all patients with chronic pancreatitis pain begin a trial of non–enteric-coated enzyme supplements for 1 month. If pain relief is achieved, therapy is continued. If enzyme therapy fails, further investigation of the pancreatic ductal system by ERCP guides the therapy based on the presence or absence of large duct (obstructive) disease (Fig. 33-45).

Table 33-16 Pancreatic Enzyme Preparations

Conventional (non-enteric-coated) compounds b Viokase 8 tablets each time 8000/30,000 Ku-Zyme HP 8 tablets each time 8000/30,000 Enteric-coated compoundsc Creon 10 2–3 capsules each 10,000/37,500 Creon 20 2–3 capsules each 20,000/75,000 Pancrease MT 10 2–3 capsules each 10,000/30,000 Pancrease MT 16 2–3 capsules each 16,000/48,000 Name

a The

time

time

time

time Dosea

Lipase/Protease (USP Units)

dosing schedule is before meals; can also take a dose at night if patient experiences pain.

b

Conventional enzymes are the treatment of choice for pain relief. If no improvement occurs with conventional enzymes alone, add H2 -blockers or proton pump inhibitors to decrease peptic acid inhibition of the enzymes. c

Enteric-coated preparations are treatment of choice for steatorrhea. Acid-suppressive therapy should not be given with enteric-coated preparations. USP = United States Pharmacopeia.

Fig. 33-45.

Algorithm for the treatment of chronic pancreatitis pain. ERCP = endoscopic retrograde cholangiopancreatography; TPN = total parenteral nutrition. (Reproduced with permission from Amann et al.211 )

ANTISECRETORY THERAPY Somatostatin administration has been shown to inhibit pancreatic exocrine secretion and CCK release.215 The somatostatin analogue octreotide acetate has therefore been investigated for pain relief in patients with chronic pancreatitis.216,217 In a double-blind, prospective, randomized 4-week trial, 65% of patients who received 200 g of octreotide acetate subcutaneously three times daily reported pain relief, compared with 35% of placebo-treated subjects. Patients who had the best results were patients with chronic abdominal pain, suggestive of obstructive pancreatopathy. However, in another trial that used a 3-day duration of treatment, no significant pain relief was observed.218 None of the studies published thus far have examined the sustained-release formulation of octreotide, and it remains unclear what subgroups of patients, or what dose of octreotide, might be beneficial in the treatment of pain. Anecdotal reports suggest that severe pain exacerbations in chronic pancreatitis can benefit from a combination of octreotide therapy and TPN, and trials are currently underway to assess the effectiveness of the sustained-release form of octreotide that requires only once-monthly administration.

NEUROLYTIC THERAPY Celiac plexus neurolysis with alcohol injection has been an effective form of analgesic treatment in patients with pancreatic carcinoma. However, the use of radiologically- or endoscopically-guided celiac plexus blockade in chronic pancreatitis has been disappointing. Due to the risk of alcohol injury and the need for repeated injections, celiac plexus blockade in chronic pancreatitis has used short-acting analgesics or other drugs rather than 50% alcohol. A recent trial of EUS-guided celiac plexus blockade revealed successful pain relief in 55% of patients, but

the benefit lasted beyond 6 months in only 10% of patients.219 The procedure therefore appears safe, but the effect is short lived in those patients who obtain pain relief.

ENDOSCOPIC MANAGEMENT The techniques of endoscopic treatment of pancreatic duct obstruction, stone disease, pseudocyst formation, pancreatic duct leak, and for the diagnosis and management of associated pancreatic tumors have expanded greatly over the past 10 years. Newer endoscopes with expanded therapeutic capabilities have been introduced, and the role of EUS and EUS-guided needle and catheter insertion has expanded the ability of the therapeutic endoscopist in the diagnosis and treatment of chronic pancreatitis and its complications.220 Pancreatic duct stenting is used for treatment of proximal pancreatic duct stenosis, decompression of a pancreatic duct leak, and for drainage of pancreatic pseudocysts that can be catheterized through the main pancreatic duct (Fig. 33-46). Pancreatic duct stents can induce an inflammatory response within the duct, so prolonged stenting is usually avoided. Patients with sphincter of Oddi dyskinesia are at high risk for developing post-ERCP pancreatitis after biliary sphincterotomy, and a recent study demonstrated that the prophylactic placement of a pancreatic duct stent reduced the amylase level and development of pancreatitis after biliary sphincterotomy.221 Pancreatic duct leaks were seen in 37% of patients with acute pancreatitis, and pancreatic duct stenting appeared to facilitate the resolution of the leak.222 Similarly, pancreatic duct stenting has been used to treat postsurgical pancreatic duct leaks and posttraumatic leaks.95,223,224

Fig. 33-46.

Endoscopic decompression of a peripancreatic fluid collection through the pancreatic duct. Options for transpapillary placement include placement of the stent (A ) beyond the point of duct disruption, (B ) at the point of disruption, or (C ) proximal to the point of duct disruption. Each of these locations may facilitate decompression of a peripancreatic fluid collection or pseudocyst caused by duct disruption, analogous to this successful treatment of a cystic duct leak by a common bile duct stent. (Reproduced with permission from Hawes.199 )

Pancreas divisum (see Fig. 33-3) is thought to cause pain and chronic pancreatitis due to functional or mechanical obstruction of the dorsal duct draining exclusively, or predominantly, through the lesser papilla. A recent study from Marseille reported good long-term results in 24 patients after minor papilla sphincterotomy and dorsal duct stenting.225 The number of patients with chronic pain decreased from 83% before stenting to 29% after stenting, but pancreatitis or recurrent papillary stenosis occurred in 38%. Patients that responded best were those with intermittent pain, and this subset may be preferentially treated with endoscopic therapy. Idiopathic pancreatitis patients have been treated with endoscopic stenting, pancreatic duct sphincterotomy, and endoscopic stone removal with good results.220,226 In a prospective randomized trial, 53% of idiopathic recurrent pancreatitis patients in the control group experienced continued episodes of pancreatitis, although only 11% of the treated patients had continued symptoms.220 Extracorporeal shock wave lithotripsy (ESWL) has been used for pancreatic duct stones, together with endoscopic stenting and stone removal.227 A single ESWL session was used in 35 patients with pancreatic duct stones, together with 86 ERCP sessions to complete the stone removal process. After 2.4 years, 80% of patients had significant relief of symptoms (Fig. 33-47). However, due to the tendency for recurrent stone formation, the use of ESWL for long-term management of calcific pancreatitis remains uncertain.

Fig. 33-47.

Extracorporeal shock wave lithotripsy treatment of pancreatic duct stones. The endoscopic retrograde cholangiopancreatography images are shown (A ) before and (B ) after extracorporeal shock wave lithotripsy therapy of pancreatic duct obstruction due to calculus formation. (Reproduced with permission from Kozarek et al.227 )

SURGICAL THERAPY Indications and History The traditional approach to surgical treatment of chronic pancreatitis and its complications has maintained that surgery should be considered only when the medical therapy of symptoms has failed. Nealon and Thompson published a landmark study in 1993, however, that showed that the progression of chronic obstructive pancreatitis could be delayed or prevented by pancreatic duct decompression.228 No other therapy has been shown to prevent the progression of chronic pancreatitis, and this study demonstrated the role of surgery in the early management of the disease (Table 33-17). Small-duct disease or the absence of a clear obstructive component are causes for uncertainty over the choice of operation. Major resections have a high complication rate, both early and late, in chronic alcoholic pancreatitis, and lesser procedures often result in symptomatic recurrence. So the choice of operation and the timing of surgery are based on each patient's pancreatic anatomy, the likelihood (or lack thereof) that further medical and endoscopic therapy will halt the symptoms of the disease, and the chance that a good result will be obtained with the lowest risk of morbidity and mortality. Finally, preparation for surgery should include restoration of protein-caloric homeostasis, abstinence from alcohol and tobacco, and a detailed review of the risks and likely outcomes to establish a bond of trust and commitment between the patient and the surgeon.

Table 33-17 Effect of Surgical Drainage on Progression of Chronic Pancreatitis

Operated (n = 47) Mild to moderate 48 (87%); severe 6 (13%) Nonoperated (n = 36) Mild to moderate 8 (22%); severe 28 (78%) Treatment Group

24-Month Evaluation

Eighty-three patients with chronic pancreatitis were evaluated by exocrine, endocrine, nutritional, and endoscopic retrograde cholangiopancreatography studies, and all had mild to moderate disease and dilated pancreatic ducts. A Puestow-type duct decompression procedure was performed in 47 patients, and all subjects were restaged by the same methods 24 months later. Source: Reproduced with permission from Nealon et al.228 Historically, the surgery for chronic pancreatitis before the second half of the twentieth century was a true demonstration of trial and error, with little anatomic information available before operation. Excellent results before CT scans and ERCP were either the result of serendipity or due to the talent and creativity of the surgeon. In 1911, Link described an operation he devised on the spot, when a laparotomy in a young woman with abdominal pain revealed a fluctuant, obstructed pancreatic duct. After performing a dochotomy and evacuating multiple stones, he inserted a rubber tube, and exteriorized the pancreatostomy just above her navel.229 He later described the operation as having been a success for the next 30 years of the patient's life, during which the patient managed the care of the drainage tube without apparent problems. 230 With the demonstration in 1942 by Priestley that total pancreatectomy was technically feasible,231 and the report in 1946 by Whipple that proximal pancreatic resection was beneficial in (three) patients with chronic pancreatitis,232 the option of surgical resection as treatment for chronic pancreatitis was established. By the mid-1950s, however, growing disappointment with the high risk of resection and the lack of long-term benefit overshadowed the surgical treatment of chronic pancreatitis. The choice of resection vs. drainage was largely based on surgeon preference until the 1970s, when the widespread adoption of ERCP and CT scans provided the ability to preoperatively diagnose obstructive and sclerotic disease, and this resulted in the rational selection of operative procedures. During this period, the major drawbacks to surgical therapy remained the approximately 20% incidence of recurrent symptoms despite surgery, the corresponding development of an inflammatory (or malignant) mass in the undrained pancreatic head (Fig. 33-48), or the high morbidity and mortality of major resectional procedures that seemed to predispose the patients to a cascade of metabolic problems.

Fig. 33-48.

Head-of-pancreas mass after Puestow procedure. The computed tomographic appearance of an inflammatory mass occupying the head of the pancreas, which developed 2 years after Puestow decompression of the body and tail of pancreas.

Sphincteroplasty The sphincter of Oddi and the pancreatic duct sphincter serve as gatekeepers for the passage of pancreatic juice into the duodenum (Fig. 33-49). Stenosis of either sphincter (sclerosing papillitis), due to scarring from pancreatitis or from the passage of gallstones, may result in obstruction of the pancreatic duct and chronic pain.233 As gallstone pancreatitis became a popular diagnosis in the 1940s and 1950s, attention was focused on the ampullary region as a possible cause of chronic symptoms, and surgical sphincteroplasty was advocated. Although endoscopic techniques are now used routinely to perform sphincterotomy of either the common bile duct or pancreatic duct, a true (permanent) sphincteroplasty can only be performed surgically. Transduodenal sphincteroplasty with incision of the septum between the pancreatic duct and common bile duct appears to offer significant relief for patients with obstruction and inflammation isolated to this region234 (Fig. 33-50).

Fig. 33-49.

Schematic diagram of the ampullary, biliary, and pancreatic duct sphincters. The point of merger of the bile duct and pancreatic duct is highly variable, and a true sphincter of the pancreatic duct may be poorly developed. [After Simeone DM: Gallbladder and biliary tract, in Yamada T et al (eds): Textbook of Gastroenterology, 4th ed. Philadelphia: Lippincott Williams & Wilkins, 2003, p 2173, with permission.]

Fig. 33-50.

Operative sphincteroplasty of the biliary and pancreatic duct. The ampullary and bile duct sphincters are divided, as is the pancreatic duct sphincter, with suture apposition of the mucosal edges of the incision. (Adapted with permission from Moody et al. 234 )

Drainage Procedures After the early reports of success with pancreatostomy for the relief of symptoms of chronic pancreatitis,229 Cattell described pancreaticojejunostomy for relief of pain in unresectable pancreatic carcinoma. 235 Shortly thereafter, Duval,236 and separately, Zollinger and associates,237 described the caudal Roux-en-Y pancreaticojejunostomy for the treatment of chronic pancreatitis in 1954 (Fig. 33-51). The so-called Duval procedure was used for decades by some surgeons, but it almost invariably failed due to restenosis and segmental obstruction of the pancreas due to progressive scarring. In 1958, Puestow and Gillesby described these segmental narrowings and dilatations of the ductal system as a "chain of lakes," and proposed a longitudinal decompression of the body and tail of the pancreas into a Roux limb of jejunum238 (Fig 33-52). Four of Puestow and Gillesby's 21 initial cases were side-to-side anastomoses, and 2 years after their report, Partington and Rochelle described a much simpler version of the longitudinal, or side-to-side Roux-en-Y pancreaticojejunostomy that became universally known as the Puestow procedure 239 (Fig. 33-53).

Fig. 33-51.

Duval's caudal pancreaticojejunostomy. [Reproduced with permission from Greenlee HB: The role of surgery for chronic pancreatitis and its complications, in Nyhus LM (ed): Surg Annu , Vol 15. Norwalk, Connecticut: Appleton-Century-Crofts, 1983, p 289.]

Fig. 33-52.

Puestow and Gillesby's longitudinal pancreaticojejunostomy. Originally described as an invaginating anastomosis that drained the entire body and tail, the anastomosis was created after amputating the tail of the gland and opening the duct along the long axis of the gland. [Reproduced with permission from Greenlee HB: The role of surgery for chronic pancreatitis and its complications, in Nyhus LM (ed): Surg Annu , Vol 15. Norwalk, Connecticut: Appleton-Century-Crofts, 1983, p 290.]

Fig. 33-53.

Longitudinal dochotomy in obstructing calcific pancreatitis. A longitudinal pancreatotomy typically discloses segmental stenosis of the pancreatic duct and the presence of intraductal calculi in a patient with chronic calcific pancreatitis (A ). Following mobilization of a Roux limb of jejunum, a longitudinal pancreaticojejunostomy is performed to permit extensive drainage of the pancreatic duct system (B ). This technique, described by Partington and Rochelle, is the typical method used for the Puestow procedure. (Reproduced with permission from Partington et al.239 )

The effectiveness of decompression of the pancreatic duct is dependent on the extent to which ductal hypertension is the etiologic agent for the disease. Thus, the diameter of the pancreatic duct is a surrogate for the degree of ductal hypertension, and the Puestow procedure has been shown to be effective for pain relief when the maximum duct diameter is 6 mm. Results are less impressive in glands with smaller caliber ducts, although Izbicki and associates have described good results with a conization method that allows a longitudinal decompression of more normal caliber ducts.240 Successful pain relief after the Puestow-type decompression procedure has been reported in 75 to 85% of patients for the first few years after surgery, but pain recurs in >20% of patients after 5 years, 149 even in patients who are abstinent from alcohol. With the advent of therapeutic endoscopy and techniques for transluminal stone removal and lithotripsy, modern clinical series have reported the successful endoscopic treatment of pancreatic duct calculi, although the long-term outcomes of these efforts has been uneven.241–244 Endoscopic removal of pancreatic duct stones is usually coupled to prolonged pancreatic duct stenting, which carries the risk of further inflammation.245,246 Despite the risk of

perioperative complications, the surgical management of pancreatic duct stones and stenosis has been shown to be superior to endoscopic treatment in randomized clinical trials in which the long, side-to-side technique of pancreaticojejunostomy is used.247,248

Resectional Procedures Distal Pancreatectomy For patients with focal inflammatory changes localized to the body and tail, or in whom no significant ductal dilatation exists, the technique of partial (40 to 80%) distal pancreatectomy has been advocated (Fig. 33-54). Although distal pancreatectomy is less morbid than more extensive resectional procedures, the operation leaves untreated a major portion of the gland, and is therefore associated with a significant risk of symptomatic recurrence.140 It has been a more popular operation in British centers, where its success seems to be greater, perhaps due to the lower incidence of alcoholic chronic pancreatitis.249 However, long-term outcomes reveal good pain relief in only 60% of patients, with completion pancreatectomy required for pain relief in 13% of patients.

Fig. 33-54.

Distal (spleen-sparing) pancreatectomy. A distal pancreatectomy for chronic pancreatitis is usually performed with en bloc splenectomy. In the presence of minimal inflammation, a spleen-sparing version can be performed, as shown here. (Reproduced with permission from Bell.196 )

Laparoscopic distal pancreatectomy has been shown to be feasible for the removal of focal lesions of the distal pancreas250 but is more difficult in the setting of chronic pancreatitis.

Ninety-Five Percent Distal Pancreatectomy In 1965, Fry and Child proposed the more radical 95% distal pancreatectomy, which was intended for patients with sclerotic (small duct) disease, and which attempted to avoid the morbidity of total pancreatectomy by preserving the rim of pancreas in the pancreaticoduodenal groove, along with its associated blood vessels and distal common bile duct.233 The operation was found to be associated with pain relief in 60 to 77% of patients long term, but is accompanied by a high risk of brittle diabetes, hypoglycemic coma, and malnutrition.251 Although the operation was the first attempt to resect the pancreatic head while preserving the duodenum and distal bile duct, the extensive degree of pancreatic removal led to its failure as viable treatment for the symptoms of pancreatic sclerosis.

Proximal Pancreatectomy In 1946, Whipple reported a series of five patients treated with either pancreaticoduodenectomy or total pancreatectomy for symptomatic chronic pancreatitis, with one operative death. 232 Subsequently, proximal pancreatectomy or pancreaticoduodenectomy, with or without pylorus preservation (Fig. 33-55), has been widely used for the treatment of chronic pancreatitis. 145,206,252 In the three largest modern (circa 2000) series of the treatment of chronic pancreatitis by the Whipple procedure, pain relief 4 to 6 years after operation was found in 71 to 89% of patients. However, mortality ranged from 1.5 to 3%, and major complications occurred in 25 to 38% of patients at the Johns Hopkins Hospital,253 the Massachusetts General Hospital,254 and the Mayo Clinic.255 In followup, 25 to 48% of patients developed diabetes, and about the same percentage required exocrine therapy. Advocates of the Whipple procedure uniformly suggest that the high rate of symptomatic relief outweighs the metabolic consequences and the mortality risk of the procedure.

Fig. 33-55.

The pancreaticoduodenectomy (Whipple procedure) can be performed either with the standard technique, which includes distal gastrectomy (A ), or with preservation of the pylorus (B ). The pylorus-sparing version of the procedure is used most commonly. [Reproduced from Gaw JU, Andersen DK: Pancreatic surgery, in Wu GY, Aziz K, Whalen GF (eds): An Internist's Illustrated Guide to Gastrointestinal Surgery . Totowa, NJ: Humana Press, 2003, p 229, with permission.]

Total Pancreatectomy Priestley and associates first described successful total pancreatectomy in 1944 in a patient with hyperinsulinism,231 and two of Whipple's original five cases of chronic pancreatitis reported in 1946 were treated with total pancreatectomy.232 Subsequently, surgeons who used total pancreatectomy found that the operation produces no better pain relief for their patients than pancreaticoduodenectomy (about 80% to 85%). Moreover, the metabolic consequences of total pancreatectomy in the absence of islet cell transplantation are profound and lifethreatening. The patients have a "brittle" form of diabetes in which avoidance of hyper- and hypoglycemia is problematic.158,256–258 In addition, lethal episodes of hypoglycemia are common in severe apancreatic diabetes. These are due to hypoglycemic unresponsiveness, due to the absence of pancreatic glucagon, and to hypoglycemia unawareness, despite an ongoing need to treat with exogenous insulin.259 In a series of >100 patients treated with total pancreatectomy, Gall and colleagues showed that half of all the late deaths after this operation were due to (iatrogenic) hypoglycemia.260 Without adequate insulin treatment, patients with apancreatic diabetes become progressively more hyperglycemic and develop the same incidence of retinal and renal disease as type 1 diabetic

patients.157 Despite newer forms of insulin and insulin delivery systems, severe apancreatic diabetes is an adverse outcome, as complete prevention of the physiologic consequences of total pancreatectomy remains an unfulfilled goal.

Hybrid Procedures In 1980, Beger and associates described the DPPHR261 (Fig. 33-56), and published long-term results with DPPHR for the treatment of chronic pancreatitis in 1985,262 and more recently in 1999.263 In 388 patients who were followed for an average of 6 years after DPPHR, pain relief was maintained in 91%, mortality was 7 years, and found complete or substantial pain relief in 87% of patients. There was no operative mortality, but 22% of patients developed postoperative complications.266

Fig. 33-58.

Frey procedure. The local resection of the pancreatic head with longitudinal pancreaticojejunostomy (LR-LPJ) provides complete decompression of the entire pancreatic ductal system. Reconstruction is performed with a side-to-side Roux-en-Y pancreaticojejunostomy. (Reproduced with permission from Bell.196 )

Key steps in the performance of the LR-LPJ include preservation of the pancreatic neck as well as the capsule of the posterior pancreatic head. In the pancreaticoduodenectomy and the DPPHR, the pancreatic neck is freed up from the portal and superior mesenteric vein confluence and divided. In the LR-LPJ, the neck of the pancreas is preserved intact as are the body and tail of the pancreas. Not having to divide the pancreatic neck, as in the pancreaticoduodenectomy or DPPHR, reduces the risk of the operation, as it avoids intraoperative problems with the venous structures lying posterior to the gland. To reduce the risk of penetrating the posterior capsule of the

head, Frey recommended in his 1994 report that the posterior limit of resection be the back wall of the opened duct of Wirsung and duct to the uncinate (Fig. 33-59).

Fig. 33-59.

Operative view of excavated head of the pancreas during the Frey procedure. The main pancreatic duct is opened widely down to the level of the ampulla, and the head of the pancreas is excavated in a conical fashion so as to allow complete decompression of the chronically obstructed and inflamed pancreatic ducts. (Reproduced with permission from Aspelund G et al: Improved outcomes for benign disease with limited pancreatic head resection. J Gastrointest Surg 9:400, 2005. With kind permission from Springer Science + Business Media.)

Subsequent to Frey's own modification of the technique, other surgeons have described modifications of the extent or technique of the LR-LPJ. Andersen and Topazian advocated performing the LR-LPJ as it was originally described, in which the entirety of the ducts are excised from the head (Fig. 33-60), and described the use of the ultrasonic aspirator and dissector for this purpose.267 The use of this device permits precise removal of the ducts and adjacent tissue with good visualization and without complications. There is little pancreatic tissue behind these ducts and the pancreatic capsule is continuously palpated as the dissection proceeds to ensure a safe margin of resection. The intrapancreatic portion of the common bile duct is usually exposed, and avoiding injury to it is enhanced by the ultrasonic aspirator. The majority of the parenchyma of the uncinate process is spared, and the excavation of the pancreatic head is made contiguous with a generous dochotomy of the dorsal duct. Whether merely unroofing as opposed to removal of the proximal ducts contributes to better pain relief is not known and awaits a randomized trial to compare the two versions of the LR-LPJ. Izbicki and colleagues at the University of Hamburg also recommend a more extensive excavation of the pancreatic head, and use a technique that they refer to as the Hamburg modification of the LR-LPJ268 (Fig. 33-61). This wider excavation of the pancreatic head is created in continuity with the dorsal dochotomy, and is followed by a single, side-to-side pancreaticojejunostomy.

Fig. 33-60.

Complete excavation of the pancreatic head and distal pancreatic dochotomy. A true excavation and removal of the proximal ductal system is combined with a distal pancreatic dochotomy. Reconstruction is performed with a single side-to-side Rouxen-Y pancreaticojejunostomy. (Reproduced with permission from Andersen DK, Topazian MD: Pancreatic head excavation: A variation on the theme of duodenum-preserving pancreatic head resection. Arch Surg 139:375, 2004. Copyright 2004 American Medical Association. All rights reserved.)

Fig. 33-61.

The Hamburg modification of the local resection of the pancreatic head with longitudinal pancreaticojejunostomy. (From Izbicki JR, Yekebas EE, Mann O: Shackelford's Surgery of the Alimentary Tract . New York: Saunders, 2007, p 1310.)

In 2001, Ho and Frey subsequently described merely excavating the core of the pancreatic head, and draining the excavation with a Roux-en-Y pancreaticojejunostomy, but without any effort to include the dorsal duct269,270 (Fig. 33-62). In 2003, Farkas and colleagues described a similar excavation of the central portion of the pancreatic head without any effort to include the duct of the body in the lateral pancreaticojejunostomy,271 and reported excellent results of what they termed an organ-preserving pancreatic head resection (OPPHR) in a randomized comparison to the pylorus-preserving pancreaticoduodenectomy (PPPD).272

Fig. 33-62.

Excavation of pancreatic head without longitudinal pancreaticojejunostomy. (From Ho HS, Frey CF: Arch Surg 136:1353, 2001.)

This approach was advocated by Gloor and associates in Bern as an alternative to the DPPHR procedure in patients with portal hypertension,273 and was described as the Berne modification of the DPPHR (Fig. 33-63). Most recently, Kninger and colleagues in Heidelberg published a randomized, controlled trial of the "Berne" version of the excavation method compared to the "classic" Beger procedure. 274 Operative times and length of stay were shorter in the group undergoing excavation of the pancreatic head, while long-term outcomes and quality-of-life scores were identical over 2 years postoperatively.

Fig. 33-63.

The Berne modification of the local resection of the pancreatic head with longitudinal pancreaticojejunostomy. (From Gloor B, Friess H, Uhl W, et al: A modified technique of the Beger and Frey procedure in patients with chronic pancreatitis. Dig Surg 18:21, 2001.)

The common element of these variations on the theme of LR-LPJ remains the excavation or "coring out" of the central portion of the pancreatic head. It remains uncertain, however, whether and to what degree the dochotomy needs to be extended into the body and tail. The logical conclusion of all of these efforts is that the head of the pancreas is the nidus of the chronic inflammatory process in chronic pancreatitis, and that removal of the central portion of the head of the gland is the key to the successful resolution of pain long-term.

Complications Initial and long-term results of the LR-LPJ demonstrate pain relief that is equivalent to that of pancreaticoduodenectomy and the DPPHR.275–277 The observed mortality rate has thus far been zero, and therefore, less than with the Whipple procedure. Major complications were less with the LR-LPJ (16%) than with pancreaticoduodenectomy (40%) or DPPHR (25%) in one single-site series, and the incidence of new postoperative diabetes after LR-LPJ was 8% with an average follow-up of 3 years.185

Comparisons of the Three Operative Procedures: Pancreaticoduodenectomy, DPPHR (Beger

Procedure), and LR-LPJ (Frey Procedure) There has been considerable interest to apply evidence-based methods to the study of the three operations currently advocated for the treatment of chronic pancreatitis. The best studies, or level 1 data by the Strength of Recommendation Taxonomy, are prospective, randomized controlled trials comparing two or more operations from a single or multi-institutional study. Retrospective, cohort-based studies are regarded as level 2 data by the Strength of Recommendation Taxonomy criteria. To date, six published level 1 studies have examined various comparisons between these three operations, and one level 2 study has examined all three procedures at a single institution. In the level 1 study of 43 patients by Klempa and colleagues,278 DPPHR patients had a shorter hospital stay, greater weight gain, less postoperative diabetes, and exocrine dysfunction than standard Whipple patients over a 3- to 5-year follow-up. Pain control was similar between the two procedures. This was confirmed in a level 1 study of 40 patients by Buchler and associates,279 in which DPPHR patients reported better pain relief, glucose tolerance, and weight gain compared to pylorus-preserving pancreaticoduodenectomy (PPPD) patients, however the follow-up averaged 1000 pg/mL. Gastrin levels can be elevated in conditions other than ZES. Common causes of hypergastrinemia include pernicious anemia, treatment with proton pump inhibitors, renal failure, G-cell hyperplasia, atrophic gastritis, retained or excluded antrum, and gastric outlet obstruction. In equivocal cases, when the gastrin level is not markedly elevated, a secretin stimulation test is helpful. In 70 to 90% of patients, the primary gastrinoma is found in Passaro's triangle, an area defined by a triangle with points located at the junction of the cystic duct and common bile duct, the second and third portion of the duodenum, and the neck and body of the pancreas (Fig. 33-66). However, because gastrinomas can be found almost anywhere, whole-body imaging is required. The test of choice is SSTR (octreotide) scintigraphy in combination with CT. The octreotide scan is more sensitive than CT, locating about 85% of gastrinomas and detecting tumors Chapter 34. Spleen>

KEY POINTS 1. The human spleen plays a key immunologic role in defense against a number of organisms, particularly encapsulated bacteria. 2. The spleen can cause significant morbidity and/or hematologic disturbance if it becomes hyperfunctioning (hypersplenism) or hypertrophied (splenomegaly). 3. There is a broad spectrum of nontraumatic diseases for which elective splenectomy can be curative or palliative. They can be broadly categorized as red blood cell disorders and hemoglobinopathies, white blood cell disorders, platelet disorders, bone marrow disorders, infections and abscesses, cysts and tumors, storage diseases and infiltrative disorders, and miscellaneous conditions. 4. Partial splenectomy may be a suitable alternative to total splenectomy for certain conditions of hypersplenism or splenomegaly, particularly in children in whom preservation of splenic immunologic function is especially important. 5. Preoperative splenic artery embolization for elective splenectomy has benefits and disadvantages. It may be most suitable in cases of enlarged spleen. Conclusive evidence is lacking. 6. Overwhelming postsplenectomy infection (OPSI) is an uncommon but potentially grave disease. Children and those undergoing splenectomy for hematologic malignancy are at elevated risk. 7. Vaccination of the splenectomized patient remains the most effective prevention strategy against OPSI. Preoperative vaccination before elective splenectomy is most prudent. 8. Antibiotic prophylactic strategies against OPSI vary widely. Data regarding their use are lacking. 9. Laparoscopic splenectomy provides equal hematologic outcomes with decreased morbidity compared with the open operation. The laparoscopic approach has emerged as the standard for elective, nontraumatic splenectomy. 10. Inadvertent intraoperative splenic injury is a scenario for which every abdominal surgeon should be prepared. Availability of a predetermined algorithm, with emphasis on the patient’s condition, facilitates intraoperative decision making.

HISTORICAL BACKGROUND The spleen has had a remarkable number of attributes and functions ascribed to it throughout history. In 350

B.C

Aristotle described how the "hot character" of the spleen aided in digestion. Writings dating back to the first century variously describe the spleen as the seat of laughter and also as the source of black bile giving rise to melancholy. Thus the term spleen came to be associated with the derivative meaning of "ill temper." Historically,

.

credence was given to the idea of the spleen as a locus of conflicting emotions. In the midseventeenth century Blackmore characterized the spleen as the organ to which "Hypochondrial and Hysterical Affections" could be attributed. Throughout the centuries the spleen also has been considered an impediment to fleetness of foot for both man and beast. Until modern times, however, removal of the spleen usually resulted in the death of the patient. Anecdotal reports of splenic surgery began to emerge in the sixteenth century. By the end of the eighteenth century, the vast majority of splenectomies performed were partial, with the majority of patients requiring surgical attention for left upper quadrant stab wounds resulting in partial or total splenic prolapse. By 1877 only 50 splenectomies had ever been performed, with a mortality rate of >70%. Yet by 1900, large series of splenectomies were reported with an operative mortality rate that had already dropped to 1 kg or a pole-to-pole length of >15 cm generally qualifies as splenomegaly. Hypersplenism often is found in association with splenomegaly but is not synonymous with it. Hypersplenism is defined as the presence of one or more cytopenias in the context of a normally functioning bone marrow. Disorders causing hypersplenism can be categorized as either (a) those in which increased destruction of abnormal blood cells occurs in an intrinsically normal spleen (e.g., hemolytic anemias) or (b) primary disorders of the spleen resulting in increased sequestration and destruction of normal blood cells (e.g., infiltrative disorders). The life cycles of cellular elements vary widely in human blood. A neutrophil in circulation has a normal half-life of approximately 6 hours. The spleen's role in the normal clearance of neutrophils is not well established. It is clear that hypersplenism may result in neutropenia through sequestration of normal white blood cells or the removal of abnormal ones. Platelets, on the other hand, generally survive in the circulation for 10 days. Under normal circumstances a third of the total platelet pool is sequestered in the spleen. Thrombocytopenia may result from excessive sequestration of platelets as well as accelerated platelet destruction in the spleen. Splenomegaly may result in sequestration of up to 80% of the platelet pool. The spleen may also contribute to the immunologic alteration of platelets, which leads to thrombocytopenia in the absence of splenomegaly (e.g., idiopathic thrombocytopenic purpura, or ITP). The immunologic functions of the spleen are consistent with those of other lymphoid organs. It is a site of bloodborne antigen presentation and the initiation of T- and B-lymphocyte activities involved in humoral and cellular immune responses. Alteration of splenic immune function often gives rise to antibody production, which results in blood cell destruction. Although the spleen contributes to the process of erythrocyte maturation, in adult humans there is little evidence of normal hematopoietic function. The spleen does have a minor role in hematopoiesis in the fourth month in the human fetus, and reactivation can occur in childhood if the bone marrow fails to meet the hematologic needs. Splenic hematopoiesis giving rise to abnormal red blood cells is seen in adults with myeloproliferative disorders. In addition, in response to some anemias, elements of the red pulp may revert to hematopoiesis.

IMAGING FOR EVALUATION OF SIZE AND PATHOLOGY

Imaging of the spleen is performed most frequently to assess its size before elective splenectomy. Other indications for splenic imaging include trauma, investigations of left upper quadrant pain, characterization of splenic lesions such as tumors, cysts, and abscesses, and guidance for percutaneous procedures.10,11

Ultrasound Ultrasound is the least invasive mode of splenic imaging. It is rapid, easy to perform, and does not expose the patient to ionizing radiation. It is often the first imaging modality applied to the spleen during evaluation and resuscitation of the trauma patient, although questions of sensitivity and specificity remain.1 2 In the elective setting, such as for routine diagnostic purposes or for preoperative planning, the sensitivity of ultrasound for detecting textural lesions of the spleen can be quite good in experienced hands. Percutaneous ultrasound-guided procedures for splenic disease (e.g., cyst aspiration, biopsy), historically avoided due to the risk of hemorrhage and other complications, are becoming more common as the safety of these procedures is being increasingly demonstrated.10,11

Computed Tomography Computed tomography (CT) affords a high degree of resolution and detail of the splenic parenchyma. Modern-day CT is more automated and thus less operator dependent than ultrasound, which makes it the preferred imaging modality for many practitioners. CT has become an invaluable tool in the evaluation and management of the blunt trauma patient, and standardized scoring systems for splenic trauma based on CT images now aid in management decisions.1 3 In the nontrauma setting, CT is extremely useful for assessment of splenomegaly, identification of solid and cystic lesions, and guidance of percutaneous procedures. The use of iodinated contrast material adds diagnostic clarity to CT imaging of the spleen, although at the cost of the small but real risks of renal impairment or allergic reaction.

Plain Radiography Rarely is plain radiography used for primary splenic imaging. Plain films can indirectly provide an outline of the spleen in the left upper quadrant or suggest splenomegaly by revealing displacement of adjacent air-filled structures (e.g., the stomach or splenic flexure of the colon). Plain films may also demonstrate splenic calcifications. Splenic calcifications often are found in association with splenomegaly but are otherwise a nonspecific finding. Splenic calcifications can indicate a number of benign, neoplastic, or infectious processes, including phlebolith, splenic artery aneurysm, sickle cell changes, tumors (e.g., hemangioma, hemangiosarcoma, lymphoma), echinococcosis, or tuberculosis. 1 4

Magnetic Resonance Imaging Although magnetic resonance imaging offers excellent detail and versatility in abdominal imaging, it is more expensive than CT scanning or ultrasound and offers no obvious advantage for primary imaging of the spleen. Magnetic resonance imaging can be a valuable adjunct to the more commonly used imaging techniques when splenic disease is suspected but not definitively diagnosed.14,15

Angiography Angiography of the spleen most commonly refers to invasive arterial imaging, and when it is combined with therapeutic splenic arterial embolization (SAE), there are multiple applications for this procedure: localization and treatment of hemorrhage in select trauma patients1 6 ; delivery of a variety of therapies in patients with cirrhosis or portal and sinistral hypertension, and in transplant patients 1 7 ; and adjunct (or, more controversially, as an

alternative) to splenectomy for treatment of hematologic disorders such as ITP or hypersplenism.18,19 Preoperative or intraoperative SAE for elective splenectomy is also a common, although not universal, practice. Few prospective data have been published in the last 5 years on preoperative SAE. Preoperative SAE is purported not only to facilitate operation but also possibly to allow a laparoscopic approach in patients whose spleens had previously been considered too large for, or otherwise not amenable to, laparoscopic resection. Limited success in using partial SAE as an alternative to therapeutic splenectomy in chronic ITP has been previously reported. 18,19 Its detractors argue that the need for increased analgesics and occasional extended hospital stay preoperatively, the possibility of pancreatitis, and the well-described risks of invasive arteriography negate any presumed benefits of preoperative SAE.

Nuclear Imaging Radioscintigraphy with technetium Tc 99m sulfur colloid demonstrates splenic location and size. It may be especially helpful in locating accessory spleens after unsuccessful splenectomy for ITP and has recently proven useful in diagnosing splenosis.20,21 Unfortunately, no conclusive outcome benefit has been shown for preoperative technetium scanning before splenectomy.2 2

Splenic Index The splenic index (SI) is a useful concept, initially proposed by Cools and colleagues,2 3 expressing the volume of the spleen in milliliters. The SI is obtained by multiplying the spleen's length, width, and height as determined by a reliable imaging modality and using these values in a specific standard ellipsoid volume and linear regression formula.2 4 Normal values for SI range from 120 mL to 480 mL, and the normal ex vivo weight of the spleen is approximately 150 g.2 3

INDICATIONS FOR SPLENECTOMY Splenectomy is therapeutic for a large host of conditions, which can be divided into the following broad categories: splenic rupture (trauma), red blood cell disorders and hemoglobinopathies, white blood cell disorders, platelet disorders, bone marrow disorders (myeloproliferative disorders), cysts and tumors, infections and abscesses, storage diseases and infiltrative disorders, and a number of miscellaneous disorders and lesions (Table 34-1).

Table 34-1 Indications for and Expected Response to Splenectomy in Various Diseases and Conditions Hereditary spherocytosis Hemolytic anemia, recurrent transfusions, intractable leg ulcers Improves or eliminates anemia Hereditary elliptocytosis Limited role for splenectomy — Pyruvate kinase deficiency Only in severe cases, recurrent transfusions Decreased transfusion requirement, palliative only Glucose-6-phosphate dehydrogenase deficiency None — Warm-antibody autoimmune hemolytic anemia Failure of medical (steroid) therapy

60–80% response rate, recurrences common Sickle cell disease History of acute sequestration crisis, splenic symptoms or infarction (consider concomitant cholecystectomy) Palliative, variable response Thalassemia Excessive transfusion requirements, symptomatic splenomegaly or infarction Diminished transfusion requirements, relief of symptoms Acute myeloid leukemia (AML) Intolerable symptomatic splenomegaly Relief of abdominal pain and early satiety Chronic myeloid leukemia Symptomatic splenomegaly Relief of abdominal pain and early satiety Chronic myelomonocytic leukemia Symptomatic splenomegaly Relief of abdominal pain and early satiety Essential thrombocythemia Only for advanced disease (i.e., transformation to myeloid metaplasia or AML) with severe symptomatic splenomegaly Relief of abdominal pain and early satiety Polycythemia vera Only for advanced disease (i.e., transformation to myeloid metaplasia or AML) with severe symptomatic splenomegaly Relief of abdominal pain and early satiety Myelofibrosis (agnogenic myeloid metaplasia) Severe symptomatic splenomegaly 76% clinical response at 1 y, high risk of hemorrhagic, thrombotic, and infectious complications (26%) Chronic lymphocytic leukemia Cytopenias and anemia 75% response rate Hairy cell leukemia Cytopenias and symptomatic splenomegaly 40–70% response rate Hodgkin's disease Surgical staging in select cases — Non-Hodgkin's lymphoma Cytopenias, symptomatic splenomegaly Improved complete blood count values, relief of symptoms Idiopathic thrombocytopenic purpura Failure of medical therapy, recurrent disease 75–85% rate of long-term response Thrombotic thrombocytopenic purpura Excessive plasma exchange requirement Typically curative Abscesses of the spleen Therapy of choice Curative Symptomatic parasitic cysts

Therapy of choice Curative; exercise caution not to spill cyst contents Symptomatic nonparasitic cysts Partial splenectomy for small cysts; unroofing for large cysts Curative Gaucher's disease Hypersplenism Improves cytopenias; does not correct underlying disease Niemann-Pick disease Symptomatic splenomegaly Improves symptoms; does not correct underlying disease Amyloidosis Symptomatic splenomegaly Improves symptoms; does not correct underlying disease Sarcoidosis Hypersplenism or symptomatic splenomegaly Improves symptoms and cytopenias; does not correct underlying disease Felty's syndrome Neutropenia 80% durable response rate Splenic artery aneurysm Splenectomy best for distal lesions near splenic hilum Curative Portal hypertension Portal or sinistral hypertension due to splenic vein thrombosis Palliative Disease/Condition Indications for Splenectomy

Response to Splenectomy

Overall, the most common indication for splenectomy is trauma to the spleen, whether external trauma (blunt or penetrating) or iatrogenic injury (e.g., during operative procedures for other reasons). Inadvertent intraoperative injury to the spleen in the nontrauma patient is discussed in a later section. Management of splenic injury in the trauma patient is beyond the scope of this chapter. Regarding elective splenectomy, the most common indication in the past had been staging for Hodgkin's disease. More recent data suggest that ITP is now the most frequent indication for elective splenectomy.2,25

Red Blood Cell Disorders CONGENITAL Hereditary Spherocytosis Hereditary spherocytosis (HS) results from an inherited dysfunction or deficiency in one of the erythrocyte membrane proteins (spectrin, ankyrin, band 3 protein, or protein 4.2 ). The resulting destabilization of the membrane lipid bilayer allows a pathologic release of membrane lipids. The red blood cell assumes a more spherical, less deformable shape, and the spherocytic erythrocytes are sequestered and destroyed in the spleen. Hemolytic anemia ensues; in fact, HS is the most common hemolytic anemia for which splenectomy is indicated. 2 6 HS is inherited primarily in an autosomal dominant fashion; the estimated prevalence in Western populations is 1

in 5000. Patients with typical HS forms may have mild jaundice. Splenomegaly usually is present on physical examination. Laboratory examination reveals varying degrees of anemia: patients with mild forms of the disease may have no anemia; patients with severe forms may have hemoglobin levels as low as 4 to 6 g/dL. The mean corpuscular volume is typically low to normal or slightly decreased. For screening, a combined elevated mean corpuscular hemoglobin concentration and an elevated erythrocyte distribution width are an excellent predictor. Other laboratory indicators of HS include those providing evidence of rapid red blood cell destruction, including elevated reticulocyte count, elevated lactate dehydrogenase level, and increased level of unconjugated bilirubin. Spherocytes are readily apparent on peripheral blood film. Dramatic clinical improvement—even despite persistent hemolysis—often occurs after splenectomy in patients with severe disease. Because children can be affected with HS, the timing of splenectomy is important and is aimed at reducing the quite small possibility of overwhelming postsplenectomy sepsis. Delaying such an operation until the patient is between the ages of 4 and 6—unless the anemia and hemolysis accelerate—is recommended by most.2 6 Gallstones are more likely to develop in patients with HS, and over half of patients between the ages of 10 and 30 with HS have cholelithiasis. 2 7 For children with cholelithiasis prophylactic cholecystectomy is recommended at the time of splenectomy.2 8 Hereditary elliptocytosis (HE) merits brief discussion to distinguish it from HS. Both HS and HE are conditions of the red blood cell membrane that result from genetic defects in skeletal membrane proteins. With the HE defect, the red blood cell elongates as it circulates, so that far fewer red blood cells are sequestered or destroyed when transiting the splenic parenchyma. Unless >50% of red blood cells are affected (a scenario that could permit development of a clinical syndrome like HS) HE may be considered harmless.

Red Blood Cell Enzyme Deficiencies Red blood cell enzyme deficiencies associated with hemolytic anemia may be classified into two groups: deficiencies of enzymes involved in glycolytic pathways, such as pyruvate kinase (PK) deficiency, and deficiencies of enzymes needed to maintain a high ratio of reduced to oxidized glutathione in the red blood cell, protecting it from oxidative damage, such as glucose-6-phosphate dehydrogenase (G6PD) deficiency.

Pyruvate Kinase Deficiency The most common red blood cell enzyme deficiency to cause congenital chronic hemolytic anemia is PK deficiency.2 9 Its pathophysiology is unclear. PK deficiency affects people worldwide, with a slight preponderance among those of northern European or Chinese descent. Clinical manifestations of the disease vary widely, from transfusion-dependent severe anemia in early childhood to well-compensated mild anemia in adolescents or adults. Diagnosis is made either by a screening test or by detection of specific mutations at the complementary DNA or genomic level. Splenomegaly is common, and in severe cases splenectomy can alleviate transfusion requirements.5 As with other disorders that cause hemolytic anemia in children, splenectomy should be delayed if possible to at least 4 years of age to reduce the risk of postsplenectomy infection.

Glucose-6-Phosphate Dehydrogenase Deficiency The most common red blood cell enzyme deficiency overall is G6PD deficiency. It is far more prevalent than PK deficiency with >400 million people affected worldwide, although most experience only moderate health risks and no longevity reduction.3 0 Clinical manifestations—chronic hemolytic anemia, acute intermittent hemolytic episodes, or no hemolysis—depend on the variant of G6PD deficiency. The mainstay of therapy is avoidance of drugs known

to precipitate hemolysis in patients with G6PD deficiency. Transfusions are given in cases of symptomatic anemia. Conventional wisdom is that splenectomy is not indicated in this disease,5 and certainly the overwhelming majority of patients with G6PD deficiency will neither require nor benefit from splenectomy. However, one report described a small collection of cases of six symptomatic G6PD deficiency patients who had severe hemolytic anemia and required transfusion, all of whom were identified to share a common mutation at exon 10.3 0 All underwent splenectomy. A complete response occurred in four patients (transfusion requirement eliminated) and a partial response in one (transfusion requirement reduced); no follow-up data were provided for the remaining patient. This study indicates that for a carefully select group of patients with severe hemolytic anemia attributable to G6PD deficiency, splenectomy may be of benefit, although more data must be collected before such a recommendation can be made.

ACQUIRED Warm-Antibody Autoimmune Hemolytic Anemia Autoimmune hemolytic anemias (AIHAs) are characterized by the destruction of red blood cells, whose erythrocyte life span is diminished by autoantibodies leveled against antigens. AIHA is classified as either primary or secondary, depending on whether an underlying cause, such as a disease or toxin, is identified. AIHA is also divided into "warm" and "cold" categories, based on the temperature at which the autoantibodies exert their effect. In cold-agglutinin disease severe symptoms are uncommon and splenectomy is almost never indicated; therefore, this entity is not discussed further in this section. However, warm-antibody AIHA has clinical consequences with which the surgeon should be familiar. Warm-antibody AIHA, although occurring primarily in midlife, can affect individuals at all ages. The disorder is more common among women, and fully half of warm-antibody AIHA cases are idiopathic. Clinical presentation may be acute or gradual. Findings include mild jaundice and symptoms and signs of anemia. One third to one half of patients present with splenomegaly. Sometimes in such cases the spleen is palpable on physical examination. The diagnosis relies on demonstrating hemolysis as indicated by anemia, reticulocytosis, and/or products of red blood cell destruction, including bilirubin, in the blood, urine, and stool. A positive result on direct Coombs' test confirms the AIHA diagnosis by distinguishing autoimmune from other forms of hemolytic anemia. Treatment of AIHA depends on the severity of the disease and whether it is primary or secondary. Severe symptomatic anemia demands prompt attention, often requiring red blood cell transfusion. The mainstay treatment for both primary and secondary forms of symptomatic, unstable AIHA is corticosteroids. Therapy should continue until a response is noted by a rise in hematocrit and fall in reticulocyte count, which generally occurs within 3 weeks. Clinical response to splenectomy for AIHA varies, and the evidence from a number of small case series is conflicting. For example, one 2004 series reported a favorable response to splenectomy in patients with AIHA secondary to chronic lymphocytic leukemia, 3 1 whereas more recent series found no benefit from splenectomy in patients with AIHA secondary to systemic lupus erythematosus or inflammatory bowel disease.3 2 Favorable responses to splenectomy have been reported in patients with warm-antibody AIHA. Transient responses are more common, however, and many patients eventually experience hemolysis again despite splenectomy.31,32 The decision regarding splenectomy in the case of AIHA should be individualized based on careful consideration of the clinical history and frank discussion with the patient.

Hemoglobinopathies

Sickle cell disease is an inherited chronic hemolytic anemia that results from the mutant sickle cell hemoglobin (HbS) within the red blood cell and is inherited in an autosomal codominant fashion. Persons who inherit an HbS gene from one parent (heterozygous) are carriers; those who inherit an HbS gene from both parents (homozygous) have sickle cell anemia. In sickle cell disease the underlying abnormality is the mutation of adenine to thymine in the sixth codon of the globin gene, which results in the substitution of valine for glutamic acid as the sixth amino acid of the chain. Mutant

-

-globin

chains included in the hemoglobin tetramer create HbS. Deoxygenated HbS is insoluble and

becomes polymerized and sickled. The subsequent lack of deformability of the red blood cell, in addition to other processes, results in microvascular congestion, which may lead to thrombosis, ischemia, and tissue necrosis. The disorder is characterized by painful intermittent episodes. Sequestration occurs in the spleen, with splenomegaly resulting early in the disease course. In most patients subsequent infarction of the spleen and autosplenectomy occur at some later time.3 3 The most frequent indications for splenectomy in sickle cell disease are recurrent acute sequestration crises, hypersplenism, and splenic abscess.3 4 The occurrence of one major acute sequestration crisis, characterized by rapid painful enlargement of the spleen and circulatory collapse, generally is considered sufficient grounds for splenectomy. Preoperative preparation should include special attention to adequate hydration and avoidance of hypothermia. Splenectomy does not affect the sickling process, and therapy for sickle cell anemia remains largely palliative. Transfusions are indicated for anemia, for moderately severe episodes of acute chest syndrome (i.e., a new infiltrate on chest radiograph associated with new symptoms, such as fever, cough, sputum production, or hypoxia),3 5 and preoperatively before splenectomy. Patients experiencing stroke or a severe crisis may require hydration and an exchange transfusion, which may be performed manually or with automated apheresis equipment. Hydroxyurea is an oral chemotherapeutic agent that upregulates fetal hemoglobin, which interferes with polymerization of HbS and thus reduces the sickling process.

Thalassemia Thalassemia is the term for a group of inherited disorders of hemoglobin synthesis prevalent among people of Mediterranean extraction and classified according to the hemoglobin chain ( , , or ) affected. As a group the thalassemias are the most common genetic diseases known to arise from a single gene defect.3 6 Most forms of this disorder are inherited in Mendelian recessive fashion from asymptomatic carrier parents. In the so-called thalassemia belt that extends the shores of the Mediterranean as well as through the Arabian Peninsula, Turkey, Iran, India, and southeastern Asia the incidence of thalassemia is between 2.5 and 15%.3 7 However, thalassemias have been found in people of all ethnic origins.3 8 In all forms of thalassemia the primary defect is absent or reduced production of hemoglobin chains. From this abnormality two significant consequences arise: (1) reduced functioning of hemoglobin tetramers, yielding hypochromia and microcytosis; and (2) unbalanced biosynthesis of individual

and

subunits, which results in

insoluble red blood cells that cannot release oxygen normally and may precipitate with cell aging. Both underproduction of hemoglobin and excess production of unpaired hemoglobin subunits contribute to thalassemiaassociated morbidity and mortality. A diagnosis of thalassemia major (homozygous form) is made by demonstrating hypochromic microcytic anemia associated with randomly distorted red blood cells and nucleated erythrocytes (target cells) on peripheral blood smear.5 Elevated reticulocyte count and white blood cell count are among the associated findings. Because are needed to form both fetal hemoglobin and adult hemoglobin,

chains

-thalassemia becomes symptomatic in utero or

at birth. By contrast, -thalassemia becomes symptomatic at 4 to 6 months, because

chains are involved only in

adult hemoglobin synthesis. The clinical spectrum of the thalassemias is wide. Heterozygous carriers of the disease are usually asymptomatic. Homozygous individuals, on the other hand, typically present before 2 years of age with pallor, growth retardation, jaundice, and abdominal swelling due to liver and spleen enlargement. Among other characteristics of thalassemia major are intractable leg ulcers, head enlargement, frequent infections, and the need for periodic blood transfusions. Untreated individuals usually die in late infancy or early childhood from severe anemia.5 Treatment for thalassemia involves red blood cell transfusions to maintain a hemoglobin level of >9 mg/dL, along with intensive parenteral chelation therapy with deferoxamine. Splenectomy is indicated for patients with excessive transfusion requirements (>200 mL/kg per year), discomfort due to splenomegaly, or painful splenic infarction. 5,39 Careful assessment of the risk:benefit ratio is essential. Thalassemia patients are at high risk for pulmonary hypertension after splenectomy; the precise etiology of this sequela is under investigation.4 0 The increase in infectious complications is likely to be due to a coexisting immune deficiency, in large part brought about by iron overload, which may be associated both with the thalassemia itself and with transfusions. The disproportionately high rate of overwhelming postsplenectomy infection in thalassemia patients has led some investigators to consider partial splenectomy in children; some success in reducing mortality has been reported.4 1 However, splenectomy should be delayed until after the age of 4 years unless it is absolutely necessary.

White Blood Cell Disorders The role of splenectomy in patients with white blood cell disorders varies. As for the myelogenous diseases mentioned previously, splenectomy for white blood cell disorders can be effective therapy for symptomatic splenomegaly and hypersplenism, improving some clinical parameters but generally not altering the course of the underlying disease. Historically, splenectomy has played a role during surgical staging for Hodgkin's disease, although this practice has become less common with the advent of advanced imaging technologies and less extensive biopsy strategies. 4 2 Careful consideration of the intended benefits of splenectomy must be weighed against the significant perioperative and postsplenectomy risks in this often complex patient population.4 3

CHRONIC LYMPHOCYTIC LEUKEMIA The main characteristic of chronic lymphocytic leukemia (CLL) is a progressive accumulation of long-lived but nonfunctional lymphocytes. Symptoms of CLL are nonspecific and include weakness, fatigue, fever without illness, night sweats, and frequent bacterial and viral infections. The most frequent finding is lymphadenopathy. When the spleen is enlarged, it may be massive or barely palpable below the costal margin. Splenectomy is indicated to improve cytopenias and was shown to be 75% effective in a combined group of patients who had either CLL or nonmalignant Hodgkin's disease.4 4 Splenectomy may facilitate chemotherapy in patients whose cell counts were prohibitively low before spleen removal. Palliative splenectomy also is indicated for symptomatic splenomegaly.

HAIRY CELL LEUKEMIA Hairy cell leukemia (HCL) is an uncommon blood disorder, representing only 2% of all adult leukemias. HCL is characterized by splenomegaly, pancytopenia, and large numbers of abnormal lymphocytes in the bone marrow. These lymphocytes contain irregular hair-like cytoplasmic projections identifiable on the peripheral smear. Many HCL patients have few symptoms and require no specific therapy. Splenectomy does not correct the underlying disorder but does return cell counts to normal in 40 to 70% of patients and alleviates symptoms of splenomegaly.45,46

HODGKIN'S DISEASE Hodgkin's disease (HD) is a disorder of the lymphoid system characterized by the presence of Reed-Sternberg cells (which actually form the minority of the Hodgkin's tumor). More than 90% of patients with HD present with lymphadenopathy above the diaphragm. Lymph nodes can become particularly bulky in the mediastinum, which may result in shortness of breath, cough, or obstructive pneumonia. Lymphadenopathy below the diaphragm is rare on presentation but can arise with disease progression. The spleen is often an occult site of spread, but massive splenomegaly is not common. In addition, large spleens do not necessarily signify involvement. Four major histologic types exist: lymphocyte predominance type, nodular sclerosis type, mixed cellularity type, and lymphocyte depletion type. The histologic type, along with location of disease and symptomatology, influence survival for patients with HD. Stage I disease is limited to one anatomic region; stage II disease is defined by the presence of two or more contiguous or noncontiguous regions on the same side of the diaphragm; stage III disease involves disease on both sides of the diaphragm, but limited to lymph nodes, spleen, and Waldeyer's ring (the ring of lymphoid tissue formed by the lingual, palatine, and nasopharyngeal tonsils); stage IV disease includes involvement of the bone marrow, lung, liver, skin, GI tract, or any organ or tissue other than the lymph nodes or Waldeyer's ring.4 7 Staging laparotomy for HD is less commonly performed in the current era of minimally invasive surgery and advanced imaging techniques. More liberal use of chemotherapy for patients with HD has significantly reduced the indications for surgical staging. Current indications for surgical staging include clinical stage I or II disease of the nodular sclerosing type and no symptoms referable to HD.5 The surgical staging procedure for HD includes a biopsy of the liver, splenectomy, and the removal of representative nodes in the retroperitoneum, mesentery, and hepatoduodenal ligament. An iliac marrow biopsy generally is included. Unlike in non-Hodgkin's lymphoma, studies have concluded that surgical staging has altered clinical staging in as many as 42% of cases (26 to 37% upgraded, 7 to 15% downgraded).5 Staging information affects treatment, because patients with early-stage disease who have no splenic involvement may be candidates for radiotherapy alone. Those with splenic involvement generally require chemotherapy or multimodality therapy.

NON-HODGKIN'S LYMPHOMA Non-Hodgkin's lymphoma (NHL) encompasses all malignancies derived from the lymphoid system except classic HD. A proliferation of any one of the three predominant lymph cell types—natural killer cells, T cells, or B cells—may be included in the category of NHL. Because of the wide net cast by NHL, the clinical presentations of the disorders under its umbrella vary. The subentities of NHL may be clinically classified into nodal or extranodal, as well as indolent, aggressive, and very aggressive groups. Patients with indolent lymphomas may present with mild or no symptoms and seek medical attention for a swollen lymph node, whereas the aggressive and very aggressive lymphomas create easily noticeable symptoms, such as pain, swelling due to obstruction of vessels, fever, and night sweats. Surgical staging is no longer indicated for NHL, because the combination of history and physical examination, chest radiograph and abdominal/pelvic CT scan, biopsy of involved lymph nodes (including laparoscopically directed nodal and liver biopsies), and bone marrow biopsy is sufficient.5 Splenomegaly exists in some, but not all, forms of NHL, and splenectomy is indicated for management of symptoms related to an enlarged spleen as well as for improvement of cytopenias.

Platelet Disorders IDIOPATHIC THROMBOCYTOPENIC PURPURA

Idiopathic thrombocytopenic purpura (ITP), also called immune thrombocytopenic purpura , is an autoimmune disorder characterized by a low platelet count and mucocutaneous and petechial bleeding. The low platelet count stems from premature removal of platelets opsonized by antiplatelet immunoglobulin G autoantibodies produced in the spleen. This clearance occurs through the interaction of platelet autoantibodies with Fc receptors expressed on tissue macrophages, predominantly in the spleen and liver. The estimated incidence of ITP is 100 persons per million annually, about one half of whom are children.4 8 Adult-onset and childhood-onset ITP are strikingly different in their clinical course and management. Patients with ITP typically present with petechiae or ecchymoses, although some experience major bleeding from the outset. Bleeding may occur from mucosal surfaces in the form of gingival bleeding, epistaxis, menorrhagia, hematuria, or even melena. The severity of bleeding frequently corresponds to the deficiency in platelets: Patients with counts >50,000/mm3 usually present with incidental findings; those with counts between 30,000 and 50,000/mm3 often have easy bruising; those with platelet counts between 10,000 and 30,000/mm3 may develop spontaneous petechiae or ecchymoses; and those with counts 1

x

103 monocytes/mm3 ) and in the bone marrow. Splenomegaly occurs in one half of these

patients, and splenectomy can result in symptomatic relief.

ESSENTIAL THROMBOCYTHEMIA Essential thrombocythemia (ET) represents abnormal growth of the megakaryocyte cell line, resulting in increased levels of platelets in the bloodstream. The diagnosis is made after the exclusion of other chronic myeloid disorders such as CML, polycythemia vera, and myelofibrosis that may also present with thrombocytosis.5 7 Clinical manifestations of ET include vasomotor symptoms, thrombohemorrhagic events, recurrent fetal loss, and the transformation to myelofibrosis with myeloid metaplasia or AML. Hydroxyurea is used to reduce thrombotic events in ET but does not alter transformation to myelofibrosis or leukemia. Splenomegaly occurs in one third to one half of patients with ET. Splenectomy is not felt to be helpful in the early stages of ET and is best reserved for the later stages of disease, when myeloid metaplasia has developed.5 7 Even in these circumstances, candidates should be chosen selectively, because significant bleeding has been reported to complicate splenectomy in these patients.

POLYCYTHEMIA VERA

Polycythemia vera (PV) is a clonal, chronic, progressive myeloproliferative disorder characterized by an increase in red blood cell mass, frequently accompanied by leukocytosis, thrombocytosis, and splenomegaly. Patients with PV typically enjoy longer survival than those affected by hematologic malignancies but remain at risk for transformation to myelofibrosis or AML. The disease is rare, with an annual incidence of 5 to 17 cases per million population. 5 8 Physical findings include ruddy cyanosis, conjunctival plethora, hepatomegaly, splenomegaly, and hypertension. Treatment should be tailored to the risk status of the patient and ranges from phlebotomy and aspirin administration to the use of chemotherapeutic agents. As in ET, splenectomy is not helpful in the early stages of disease and is best reserved for patients with late-stage disease in whom myeloid metaplasia has developed and splenomegaly-related symptoms are severe.5 5

MYELOFIBROSIS (AGNOGENIC MYELOID METAPLASIA) The term myelofibrosis may be used to describe either the generic condition of fibrosis of the bone marrow (which may be associated with a number of benign and malignant disorders) or a specific, chronic, malignant hematologic disease associated with splenomegaly, the presence of red blood cell and white blood cell progenitors in the bloodstream, marrow fibrosis, and extramedullary hematopoiesis, otherwise known as agnogenic myeloid metaplasia (AMM). AMM also can be referred to as myelosclerosis, idiopathic myeloid metaplasia, and osteosclerosis. In this chapter the term myelofibrosis is synonymous with AMM. In AMM fibrosis of the bone marrow is believed to be a response to a clonal proliferation of hematopoietic stem cells. Marrow failure is common. The true incidence of AMM is unknown due to the scarcity of epidemiologic data, but one study estimated its U.S. incidence at 1.46 per 100,000 population.5 9 Excessive radiation exposure may play a role in the development of AMM, because persons within close proximity of the atomic bomb blasts in Japan, as well as those with a history of exposure to the contrast agent thorium dioxide (Thorotrast), have been shown to exhibit a higher incidence of AMM. The diagnosis is made by a careful examination of the peripheral blood smear and bone marrow. Nucleated red blood cells and immature myeloid elements in the blood are present in 96% of cases and strongly suggest the diagnosis. Teardrop poikilocytosis is another frequent finding. Care must be taken, however, to exclude a history of a primary neoplasm (such as lymphoma or adenocarcinoma of the stomach, lung, prostate, or breast) or tuberculosis, because patients with these conditions may develop secondary myelofibrosis. Treatment depends on symptoms: Asymptomatic patients are closely followed, whereas symptomatic patients undergo therapeutic intervention targeted to their symptoms.6 0 Splenomegaly-related symptoms are best treated with splenectomy. Although some chemotherapeutic agents (busulfan, hydroxyurea, interferon- ) and low-dose radiation can reduce splenic size, their discontinuation usually results in rapid splenic regrowth. A thorough preoperative work-up must precede splenectomy in patients with AMM. The candidate must possess acceptable cardiac, pulmonary, hepatic, and renal reserve for the operation. The coagulation system should be examined; testing should include measurement of coagulation factors V and VIII and fibrin split products, platelet count, and bleeding time. Low platelet counts may require administration of adrenal steroids and/or platelet transfusion at the time of surgery. Splenectomy provides durable, effective palliation for nearly all patients with AMM, although postoperative complications are more common in patients with AMM than in those with other hematologic indications.5 The Mayo Clinic recently published its 30-year experience with 314 myelofibrosis patients who underwent splenectomy: nearly half of the operations (49%) were performed to alleviate the mechanical symptoms of splenomegaly; the remainder were undertaken to manage anemia, thrombocytopenia, or portal hypertension. Response to splenectomy was 76% overall at 1 year; overall complication rate was 28%, including

21 perioperative deaths.6 1 Thrombosis, hemorrhage, and infection complications were common, with preoperative thrombocytopenia an independent predictor of mortality risk. These data underscore the severity of this malignancy and emphasize need for careful patient selection when considering splenectomy in AMM.

Infections and Abscesses Primary infections of the spleen are infrequently reported. However, the potential effects of certain systemic infections on the spleen merit close attention, mostly because of the potential risk of spontaneous splenic rupture. Infectious mononucleosis due to either Epstein-Barr virus or cytomegalovirus infection imparts a small but oftendiscussed risk of spontaneous splenic rupture in both adults and children. The true incidence may be underreported, however. Recent case reports abound in the literature regarding spontaneous splenic rupture due to a variety of infectious causes (malaria, Listeria infection, fungal infections, dengue, and Q fever, to name a few) as well as a variety of neoplastic and other noninfectious causes (lymphoma, angiosarcoma, amyloidosis, pregnancy). The presumed pathophysiologic mechanism is infiltration of the splenic parenchyma with inflammatory cells, which distorts the architecture and fibrous support system of the spleen and thins the splenic capsule. 6 2 In this setting, splenic rupture can occur spontaneously or after a seemingly minor external trauma or even a Valsalva maneuver.6 3 Abscesses of the spleen are uncommon, with an incidence of 0.14 to 0.7% based on autopsy findings.6 4 They occur more frequently in tropical locations, where they are associated with thrombosed splenic vessels and infarction in patients with sickle cell anemia. Five distinct mechanisms of splenic abscess formation have been described: (a) hematogenous infection; (b) contiguous infection; (c) hemoglobinopathy; (d) immunosuppression, including HIV infection and chemotherapy; and (e) trauma. Presentation frequently is delayed, with most patients enduring symptoms for 16 to 22 days before diagnosis. Clinical manifestations include fever, left upper quadrant pain, leukocytosis, and splenomegaly in about one third of patients. The diagnosis is confirmed by ultrasound or CT scan, which has a 95% sensitivity and specificity. Upon discovery of a splenic abscess, broad-spectrum antibiotics should be started, with adjustment to more specific therapy based on culture results and continuation of treatment for 14 days. Splenectomy is the operation of choice, but percutaneous and open drainage are options for patients who cannot tolerate splenectomy.5 Percutaneous drainage is successful for patients with unilocular disease.

Cysts and Tumors Splenic cysts can be categorized according to a number of criteria; one clinically relevant scheme is to characterize splenic cysts as either parasitic or nonparasitic. Parasitic infection is the most common cause of splenic cysts worldwide, and the majority are due to Echinococcus species. Such cysts are more commonly found in areas where the pathogen is endemic. Symptoms, when present, generally are related to the presence of a mass lesion in the left upper quadrant or a lesion that impinges on the stomach. Ultrasound can establish the presence of a cystic lesion and occasionally incidentally detect asymptomatic lesions as well. Serologic testing for echinococcal antibodies can confirm or exclude the cystic lesion as parasitic, an important piece of information when planning operative therapy. Symptomatic parasitic cysts are best treated with splenectomy. Avoidance of spillage of parasitic cyst contents into the peritoneal cavity to avoid the possibility of anaphylactic shock is an important principle in surgical management. Cysts resulting from trauma are termed pseudocysts due to their lack of cellular lining. Less common examples of nonparasitic cysts are dermoid, epidermoid, and epithelial cysts.6 5 The treatment of nonparasitic cysts depends on whether or not they produce symptoms. Asymptomatic nonparasitic cysts may be observed with close follow-up by ultrasound to exclude significant expansion. Patients should be advised of the risk of cyst rupture with even minor

abdominal trauma if they elect nonoperative management for large cysts. Small symptomatic nonparasitic cysts may be excised with splenic preservation, and large symptomatic nonparasitic cysts may be unroofed. Both of these operations may be performed laparoscopically.6 6 The most common primary tumor of the spleen is sarcoma. Autopsy studies reveal an approximately 0.6% rate of tumor metastasis to the spleen; most of these metastases are carcinomas.6 7 Lung cancer is the tumor that most commonly spreads to the spleen.

Storage Diseases and Infiltrative Disorders GAUCHER'S DISEASE Gaucher's disease is an inherited lipid storage disorder characterized by the deposition of glucocerebroside in cells of the macrophage-monocyte system. The underlying abnormality is a deficiency in the activity of a lysosomal hydrolase. Abnormal glycolipid storage results in organomegaly, particularly hepatomegaly and splenomegaly. 6 8 Patients with Gaucher's disease frequently experience symptoms related to splenomegaly, including early satiety and abdominal discomfort, and to hypersplenism, including thrombocytopenia, normocytic anemia, and mild leukopenia. These latter findings occur as a result of excessive sequestration of formed blood elements in the spleen. Other symptoms in patients with Gaucher's disease include bone pain, pathologic fractures, and jaundice. Splenectomy alleviates hematologic abnormalities in patients with hypersplenism but it does not correct the underlying disease process. Partial splenectomy has been shown to be effective in children to correct both hematologic problems and symptoms due to splenomegaly without incurring the risk of overwhelming postsplenectomy sepsis.

NIEMANN-PICK DISEASE Niemann-Pick disease is an inherited disorder of abnormal lysosomal storage of sphingomyelin and cholesterol in cells of the macrophage-monocyte system. Four types of the disease (A, B, C, and D) exist, with unique clinical presentations. Types A and B result from a deficiency in lysosomal hydrolase and are the forms most likely to demonstrate splenomegaly with its concomitant symptoms.

AMYLOIDOSIS Amyloidosis is a disorder of abnormal extracellular protein deposition. There are multiple forms of amyloidosis, each with its own individual clinical presentation, and the severity of disease may range from asymptomatic to multiorgan failure. Patients with primary amyloidosis, associated with plasma cell dyscrasia, have splenic involvement in approximately 5% of cases. Secondary amyloidosis, associated with chronic inflammatory conditions, also may present with an enlarged spleen. Symptoms of splenomegaly are relieved by splenectomy.

SARCOIDOSIS Sarcoidosis is an inflammatory disease of young adults characterized by noncaseating granulomas in affected tissues. Signs and symptoms of the disease range in severity and typically are nonspecific, such as fatigue and malaise. Any organ system may be involved. The most commonly involved organ is the lung, followed by the spleen. Splenomegaly occurs in approximately 25% of patients. Massive splenomegaly (>1 kg) is rare.6 9 Other affected tissues include the lymph nodes, eyes, joints, liver, spleen, and heart. When splenomegaly occurs and causes symptoms related to size or hypersplenism, splenectomy effectively relieves symptoms and corrects hematologic abnormalities such as anemia and thrombocytopenia. Spontaneous splenic rupture has been reported in sarcoidosis.7 0

Miscellaneous Disorders and Lesions SPLENIC ARTERY ANEURYSM Although splenic artery aneurysm is rare, it is the most common visceral artery aneurysm. Women are four times more likely to be affected than men. The aneurysm usually arises in the middle to distal portion of the splenic artery. In one series, mortality was significantly higher in patients with underlying portal hypertension (>50%) than in those without it (17%).7 1 Indications for treatment include presence of symptoms, pregnancy, intention to become pregnant, and presence of pseudoaneurysms associated with inflammatory processes. Aneurysm resection or ligation alone is acceptable for amenable lesions in the midsplenic artery, but distal lesions in close proximity to the splenic hilum should be treated with concomitant splenectomy. An excellent prognosis follows elective treatment. Splenic artery embolization has been used to treat splenic artery aneurysm, but painful splenic infarction and abscess may follow.

PORTAL HYPERTENSION Portal hypertension can result from numerous causes but is usually due to cirrhosis. Splenomegaly and splenic congestion often accompany portal hypertension, which leads to sequestration and destruction of circulating cells in the spleen. Splenectomy is not indicated for hypersplenism per se in patients with portal hypertension, however, because no correlation exists between the degree of pancytopenia and long-term survival in these patients.5 In rare circumstances in which splenectomy is required to reduce bleeding from esophageal varices exacerbated by thrombocytopenia, a concomitant splenorenal shunt procedure should be performed to decompress the portal system.5 Portal hypertension secondary to splenic vein thrombosis is potentially curable with splenectomy. Patients with bleeding from isolated gastric varices who have normal liver function test results, especially those with a history of pancreatic disease, should be examined for splenic vein thrombosis and treated with splenectomy if findings are positive.

FELTY'S SYNDROME The triad of rheumatoid arthritis, splenomegaly, and neutropenia is called Felty's syndrome. It exists in approximately 3% of all patients with rheumatoid arthritis, two thirds of whom are women. Immune complexes coat the surface of white blood cells, which leads to their sequestration and clearance in the spleen with subsequent neutropenia. This neutropenia (80% of patients showing a durable increase in white blood cell count. More than one half of patients who had infections before surgery did not have any infections after splenectomy.7 2 Besides symptomatic neutropenia, other indications for splenectomy include transfusion-dependent anemia and profound thrombocytopenia.

PREOPERATIVE CONSIDERATIONS Vaccination Splenectomy imparts a small (2900 patients generally supports these observations, although there was a suggestion that hemorrhagic complications may be higher with the laparoscopic approach.111 Questions of the cost effectiveness of LS persist, although analysis of this issue is hindered by a lack of universally accepted metrics as well as a paucity of recent objective data. Proponents of LS argue that the generally higher operating room charges are offset by the reduced hospital stay and presumably shorter time of lost productivity. 100 For those institutions with experienced personnel and technical capability, the laparoscopic approach has emerged as the standard for elective, nontraumatic splenectomy.

Overwhelming Postsplenectomy Infection Asplenic patients bear an increased susceptibility to infection for the remainder of their lives. Although the overwhelming majority of splenectomized patients experience no ill consequence from the absence of the spleen, the potentially catastrophic consequences of overwhelming postsplenectomy infection (OPSI) demand lifelong vigilance and intimate knowledge of the appropriate precautions and preventative measures. All involved—patient, family members, and physicians—need to play an active role.

CLINICAL FEATURES Sepsis in splenectomized patients is a medical emergency. Therefore, any clinical suggestion of infection, including seemingly isolated fevers, must be viewed with a high index of suspicion and treated empirically as thorough investigation proceeds. OPSI may begin with a relatively mild-appearing prodrome with nonspecific symptoms. In addition to fever, nonspecific symptoms such as malaise, myalgias, headache, vomiting, diarrhea, abdominal pain, and others should be viewed with alarm in the asplenic patient. Absent the spleen, the infectious process signaled by such symptoms can progress rapidly to fulminant bacteremic septic shock, with hypotension, anuria, and disseminated intravascular coagulation. The need for a high index of suspicion, prompt action, and aggressive education of the patient, family, and medical provider cannot be overstated. The true incidence of OPSI is not precisely known, because defining criteria vary among published series. Overall lifetime risk remains low, ranging from Chapter 35. Abdominal Wall, Omentum, Mesentery, and Retroperitoneum>

KEY POINTS 1. Musculoaponeurotic anatomic features of the abdominal wall layers differ superior to and inferior to the arcuate line on the posterior aspect of the rectus sheath. 2. Defects of the complex process of abdominal wall development in the fetus can occur in several ways resulting in persistent midgut herniation (omphalocele and gastroschisis) or vitelline duct remnant abnormalities (Meckel's diverticulum, or vitelline duct fistula or cyst). 3. The management of rectus sheath hematomas consists of reversal of any anticoagulation or coagulopathy and observation, unless either hemodynamic instability or enlargement necessitates surgical evacuation. 4. Incisional hernias of the anterior abdominal wall may occur in up to 10–20% of prior abdominal operations of all types. 5. Primary suture repair of abdominal wall incisional hernias is associated with an unacceptably high incidence of hernia recurrence, and has prompted the wide use of prosthetic mesh materials for hernia repair. 6. Laparoscopic incisional hernia repair offers important advantages over open repairs including reduced pain medication use, earlier return to normal function, and possibly superior protection from hernia recurrence. 7. Sclerosing mesenteritis is a poorly understood mesenteric process characterized by variable degrees of inflammation and fibrosis within mesenteric tissues of the small and large bowel, which frequently requires surgical biopsy to rule out neoplasm and to establish the correct diagnosis. 8. Retroperitoneal fibrosis is a primary or secondary fibroproliferative process in the retroperitoenum characterized by distortion of retroperitoneal structures, including the ureters and inferior vena cava. 9. Treatment of retroperitoneal fibrosis may include ureterolysis or ureteral stenting, and medical therapies such as corticosteroids or tamoxifen.

ABDOMINAL WALL General Considerations The abdominal wall is defined superiorly by the costal margins, inferiorly by the symphysis pubis and pelvic bones, and posteriorly by the vertebral column. It serves to support and protect abdominal and retroperitoneal structures, and its complex muscular functions enable twisting and flexing motions of the trunk. Surgical implications of abdominal wall structure become apparent during the course of managing primary abdominal wall diseases or gaining access to the peritoneal cavity. A surgeon must have a thorough understanding of the arrangement of

abdominal wall muscles and aponeuroses.

Surgical Anatomy The abdominal wall is an anatomically complex, layered structure with segmentally derived blood supply and innervation (Fig. 35-1). It is mesodermal in origin and develops as bilateral migrating sheets that originate in the paravertebral region and envelop the future abdominal area. The leading edges of these structures develop into the rectus abdominis muscles, which eventually meet in the midline of the anterior abdominal wall. The muscle fibers of the rectus abdominis are arranged vertically and are encased within an aponeurotic sheath, the anterior and posterior layers of which are fused in the midline at the linea alba. The rectus abdominis has insertions on the symphysis pubis and pubic bones, on the anteroinferior aspects of the fifth and sixth ribs, as well as on the seventh costal cartilages and the xiphoid process. The lateral border of the rectus muscles assumes a convex shape that gives rise to the surface landmark of the linea semilunaris. There usually are three tendinous intersections or inscriptions that cross the rectus muscles: one at the level of the xiphoid process, one at the level of the umbilicus, and one halfway between the xiphoid process and the umbilicus (see Fig. 35-1).

Fig. 35-1.

Anterior abdominal wall. The linea alba is the midline aponeurotic demarcation between the bellies of the rectus abdominis muscles. The rectus abdominis muscle and its tendinous intersections on the left are shown deep to the reflected anterior rectus sheath. Segmental cutaneous nerve branches also are shown. m. = muscle. [Reproduced with permission from Moore KL, Dailey AF (eds): Clinically Oriented Anatomy, 4th ed. Philadelphia: Lippincott Williams & Wilkins, 1999, p 181.]

Lateral to the rectus sheath are three muscular layers with oblique fiber orientations relative to one another (Fig. 35-2). These layers are derived from the laterally migrating mesodermal tissues during the sixth to seventh week of fetal development, before fusion of the developing rectus abdominis muscles in the midline. The external oblique muscle runs inferiorly and medially, arising from the margins of the lowest eight ribs and costal cartilages. The external oblique muscle originates laterally on the latissimus dorsi and serratus anterior muscles, as well as on the iliac crest. Medially it forms a tendinous aponeurosis, which is contiguous with the anterior rectus sheath. The inguinal ligament is the inferior-most edge of the external oblique aponeurosis, reflected posteriorly in the area between the anterior superior iliac spine and pubic tubercle. The internal oblique muscle lies immediately deep to the external oblique muscle and arises from the lateral aspect of the inguinal ligament, the iliac crest, and the thoracolumbar fascia. Its fibers course superiorly and medially and form a tendinous aponeurosis that contributes components to both the anterior and posterior rectus sheath. The lower medial and inferior-most fibers of the internal oblique course may fuse with the lower fibers of the transversus abdominis muscle (the conjoined area ). The inferior-most fibers of the internal oblique muscle are contiguous with the cremasteric muscle in the inguinal canal. These relationships are of critical significance in the management of inguinal hernia. The transversus abdominis muscle is the deepest of the three lateral muscles and, as its name implies, runs transversely from the bilateral lowest six ribs, the lumbosacral fascia, and the iliac crest to the lateral border of the rectus abdominis musculoaponeurotic structures.

Fig. 35-2.

The three muscular layers of the abdominal wall lateral to the rectus abdominis are the external oblique, internal oblique, and transversus abdominis muscles, shown here on the low abdomen, where the lower margin of the external oblique reflects posteriorly as the inguinal ligament. [Reproduced with permission from Moore KL, Dailey AF (eds): Clinically Oriented Anatomy, 4th ed. Philadelphia: Lippincott Williams & Wilkins, 1999, p 181.]

The complexities of the anterior and posterior aspects of the rectus sheath are best understood in their relationship to the arcuate line (semicircular line of Douglas), which lies roughly at the level of the anterior superior iliac spines (Fig. 35-3). Above the arcuate line, the anterior rectus sheath is formed by the external oblique aponeurosis and the external lamina of the internal oblique aponeurosis, whereas the posterior rectus sheath is formed by the internal lamina of the internal oblique aponeurosis, the transversus abdominis aponeurosis, and the transversalis fascia. Below the arcuate line, the anterior rectus sheath is formed by the external oblique aponeurosis, the laminae of the internal oblique aponeurosis, and the transversus abdominis aponeurosis. There is no aponeurotic posterior covering of this lower portion of the rectus muscles, although the transversalis fascia remains a contiguous structure on the posterior aspect of the abdominal wall in this area as well.

Fig. 35-3.

Cross-sectional anatomy of the abdominal wall above and below the arcuate line of Douglas. The lower right abdominal wall segment shows clearly the absence of an aponeurotic covering of the posterior aspect of the rectus abdominis muscle inferior to the arcuate line. Superior to the arcuate line, there are both internal oblique and transversus abdominis aponeurotic contributions to the posterior rectus sheath. [Reproduced with permission from Moore KL, Dailey AF (eds): Clinically Oriented Anatomy, 4th ed. Philadelphia: Lippincott Williams & Wilkins, 1999, p 185.]

The majority of the blood supply to the muscles of the anterior abdominal wall is derived from the superior and inferior epigastric arteries (Fig. 35-4). The superior epigastric artery arises from the internal thoracic artery, whereas the inferior epigastric artery arises from the external iliac artery. A collateral network of branches of the subcostal and lumbar arteries also contributes to the abdominal wall blood supply. The lymphatic drainage of the abdominal wall is predominantly to the major nodal basins in the superficial inguinal and axillary areas.

Fig. 35-4.

The superior and inferior epigastric arteries form an anastomosing network of vessels in and around the rectus sheath, with collateralization to subcostal and lumbar vessels situated more laterally on the abdominal wall. Lymphatic drainage is via axially or inguinal nodal basins. [Reproduced with permission from Moore KL, Dailey AF (eds): Clinically Oriented Anatomy, 4th ed. Philadelphia: Lippincott Williams & Wilkins, 1999, p 86.]

Innervation of the anterior abdominal wall is segmentally related to specific spinal levels. The motor nerves to the rectus muscles, the internal oblique muscles, and the transversus abdominis muscles run from the anterior rami of spinal nerves at the T6 to T12 levels. The overlying skin is innervated by afferent branches of the T4 to L1 nerve roots, with the nerve roots of T10 subserving sensation of the skin around the umbilicus (Fig. 35-5).

Fig. 35-5.

Dermatomal sensory innervation of the abdominal wall. [Reproduced with permission from Moore KL, Dailey AF (eds): Clinically Oriented Anatomy, 4th ed. Philadelphia: Lippincott Williams & Wilkins, 1999, p 188.]

Physiology The rectus muscles, the external oblique muscles, and the internal oblique muscles work as a unit to flex the trunk anteriorly or laterally. Rotation of the trunk is achieved by the contraction of the external oblique muscle and the contralateral internal oblique muscle. For example, rotation of the trunk to the right is produced by contraction of the left external oblique muscle and the right internal oblique muscle. In addition, all four muscle groups (i.e., rectus muscles, external oblique muscles, internal oblique muscles, and transversus abdominis muscles) are involved in raising intra-abdominal pressure. If the diaphragm is relaxed when the abdominal musculature is contracted, the pressure exerted by the abdominal muscles results in expiration of air from the lungs or a cough if this contraction is forceful. Thus, these abdominal muscles are the primary muscles of expiration. If the diaphragm is contracted when the abdominal musculature is contracted (Valsalva maneuver ) the increased abdominal pressure aids in processes such as micturition, defecation, and childbirth.

Abdominal Anatomy and Surgical Incisions

The abdominal wall can be viewed as a barrier to successful exposure of pathology in the deeper tissues. Surgeons must deal with this barrier every day to access sites of disease, and this engenders practical questions of where and how to make incisions. Structural characteristics of the abdominal wall are encountered with every abdominal incision used to gain entry to the peritoneal cavity or extraperitoneal tissues. Incisions for open surgery generally are located in proximity to the principal operative targets. Laparoscopic port site incisions might be remote from the site of interest and are carefully planned based on the anticipated instrument approach angles and necessary working distances both to the operative site and between ports. Orientation of the line of any incision may be determined based on expected quality of exposure; closure considerations, including cosmesis; avoidance of previous incision sites; and simple surgeon preference. In general, the incision for open peritoneal access can be longitudinal (in or off the midline), transverse (lateral to or crossing the midline), or oblique (directed either upward or downward toward the flank) (Fig. 35-6). Modifications of these general classes of incisions are numerous and can consist of various extensions that are intended to optimize exposure in specific clinical situations. In some infrequent situations, combinations of incision types may be used. For the majority of nonlaparoscopic procedures on the GI tract, midline incisions are used because of the flexibility offered by this approach in establishing adequate exposure. The incision in the fused midline aponeurotic tissue (linea alba) is simple and requires no division of skeletal muscle. Paramedian incisions are made longitudinally 3 cm off the midline, through the rectus abdominis sheath structures, and have largely been abandoned in favor of midline or nonlongitudinal access methods. Incisions lateral to the midline made with transverse or oblique orientations may divide the successive muscular layers or bluntly split them in the direction of their fibers. The latter muscle-splitting approach (exemplified by the classic McBurney incision for appendectomy) may be less destructive to tissue and thus allow healing with less scarring and tissue distortion but generally offers more limited exposure than other methods. Subcostal incisions on the right (Kocher incision for cholecystectomy) or left (for splenectomy) are archetypal muscle-dividing incisions that generally result in transection of some or all of the rectus abdominis muscle fibers and investing aponeuroses. These incisions generally are closed in two layers. The more superficial one incorporates the anterior aponeurotic sheath of the rectus muscle medially, transitioning to external oblique muscle and aponeurosis more laterally. The posterior, deeper layer consists of internal oblique and transversus abdominis muscle. The anatomic considerations are the same for closure of transverse muscle-dividing incisions, either lateral to or crossing the midline. The Pfannenstiel incision, used commonly for pelvic procedures, is distinguished by transverse skin and anterior rectus sheath incisions, followed by rectus muscle retraction and longitudinal incision of the peritoneum. Irrespective of the incision type, suture apposition of abdominal wall tissues during closure ideally is accomplished without great tension and with great precision. The surgeon must appreciate all necessary anatomic distinctions to minimize the opportunity for defective healing.

Fig. 35-6.

Various anterior abdominal wall incisions for exposure of peritoneal structures. A, Midline incision; B, paramedian incision; C, right subcostal incision and "saber slash" extension to costal margin (dashed line ); D, bilateral subcostal (also bucket handle, chevron, gable) incision, and "Mercedes Benz" extension (dashed line ); E, Rocky-Davis incision and Weir extension (dashed line ); F, McBurney incision; G, transverse incision and extension across midline (dashed line ); and H, Pfannenstiel incision.

Abdominal incisions are injuries inflicted under controlled circumstances that can lead to short- and long-term complications and patient disability. The question of how large an incision must be to allow safe operative maneuvers at the surgical site of interest has no simple answer. In general, it is prudent to make incisions no larger than is necessary to safely accomplish the operative goals. Efforts to deal with this issue have engendered surgical solutions intended both to reduce patient disability and to improve the overall ergonomics associated with smaller access sites. Laparoscopic surgery, and now natural orifice transluminal endoscopic surgery (NOTES), have owed their development largely to the belief that avoidance of surgical injury to the abdominal wall is of significant benefit to the patient. For open surgery, a variety of devices are available to retract the abdominal wall and facilitate peritoneal exposure without subjecting the patient to excessively large incisions or surgical personnel to exhausting retraction tasks (Fig. 35-7). Examples include the Bookwalter, Omni-Tract, and Thompson retractors.

Fig. 35-7.

Bookwalter retractor in use for exposure of peritoneal structures during abdominal surgery. Devices of this type are valuable exposure aids that reduce the physical demands on personnel in the operating room and allow more complete focus on the surgical site of interest.

Congenital Abnormalities The abdominal wall layers begin to form in the first weeks after conception. Prominent in the early embryonic abdominal wall is a large central defect through which pass the vitelline (omphalomesenteric) duct and allantois. The vitelline duct connects the embryonic and fetal midgut to the yolk sac. During the sixth week of development, the abdominal contents grow too large for the abdominal wall to completely contain and the embryonic midgut herniates into the umbilical cord. Although outside the confines of the developing abdomen, it undergoes a 270degree counterclockwise rotation and, at the end of the twelfth week, returns to the abdominal cavity. Defects in abdominal wall closure may lead to omphalocele or gastroschisis. In omphalocele, viscera protrude through an open umbilical ring and are covered by a sac derived from the amnion. In gastroschisis, the viscera protrude through a defect lateral to the umbilicus and no sac is present. During the third trimester, the vitelline duct regresses. Persistence of a vitelline duct remnant on the ileal border results in Meckel's diverticulum. Complete failure of the vitelline duct to regress results in a vitelline duct fistula, which is associated with drainage of small intestine contents from the umbilicus. If both the intestinal and umbilical ends of the vitelline duct regress into fibrous cords, a central vitelline duct (omphalomesenteric) cyst may occur. Persistent vitelline duct remnants between the GI tract and the anterior abdominal wall may be associated with small intestine volvulus in neonates. When diagnosed, vitelline duct fistulas and cysts should be excised along with any accompanying fibrous cord.

The urachus is a fibromuscular, tubular extension of the allantois that develops with the descent of the bladder to its pelvic position. Persistence of urachal remnants can result in cysts as well as fistulas to the urinary bladder with drainage of urine from the umbilicus. These are treated by urachal excision and closure of any bladder defect that may be present.

Acquired Abnormalities RECTUS ABDOMINIS DIASTASIS Rectus abdominis diastasis (or diastasis recti) is a clinically evident separation of the rectus abdominis muscle pillars. This results in a characteristic bulging of the abdominal wall in the epigastrium that is sometimes mistaken for a ventral hernia despite the fact that the midline aponeurosis is intact and no hernia defect is present. Diastasis may be congenital, as a result of a more lateral insertion of the rectus muscles to the ribs and costochondral junctions, but is more typically an acquired condition, occurring with advancing age, in obesity, or after pregnancy. In the postpartum setting, rectus diastasis tends to occur in women who are of advanced maternal age, who have a multiple or twin pregnancy, or who deliver a high-birth-weight infant. Diastasis is usually easily identified on physical examination (Fig. 35-8). Computed tomographic (CT) scanning provides an accurate means of measuring the distance between the rectus pillars and can differentiate rectus diastasis from a true ventral hernia if clarification is required. Surgical correction of rectus diastasis by plication of the broad midline aponeurosis has been described for cosmetic indications and for alleviation of impaired abdominal wall muscular function. However, these approaches introduce the risk of an actual ventral hernia and are of questionable value in addressing pathology.

Fig. 35-8.

Diastasis recti visible in the midepigastrium with Valsalva maneuver. The edges of the rectus abdominis muscle, rigid with voluntary contraction, are palpable along the entire length of the bulging area. This should not be mistaken for a ventral hernia.

RECTUS SHEATH HEMATOMA The terminal branches of the superior and inferior epigastric arteries course deep to the posterior aspect of the left and right rectus abdominis muscles and enter the posterior rectus sheath. Hemorrhage from any of the network of collateralizing vessels within the rectus sheath and muscles can result in a rectus sheath hematoma. Although a history of major or minor blunt trauma may be elicited, less obvious events also have been reported to cause this condition, such as sudden contraction of the rectus muscles with coughing, sneezing, or any vigorous physical activity. Spontaneous rectus sheath hematomas have been described in the elderly and in those receiving anticoagulation therapy. Patients frequently describe the sudden onset of unilateral abdominal pain that may be confused with lateralized peritoneal disorders such as appendicitis. Below the arcuate line, a hematoma may cross the midline and cause bilateral lower quadrant pain. History and physical examination alone may be diagnostic. Pain typically increases with contraction of the rectus muscles and a tender mass may be palpated. The ability to appreciate an intra-abdominal mass is ordinarily degraded with contraction of the rectus muscles. Fothergill's sign is a palpable abdominal mass that remains unchanged with contraction of the rectus muscles and is classically associated with rectus hematoma. Hemoglobin level and hematocrit should be measured and coagulation studies should be performed. Abdominal ultrasonography may show a solid or cystic mass within the abdominal wall depending on the chronicity of the bleeding. CT is the most definitive study to establish the correct diagnosis and to exclude other disorders (Fig. 35-9). Magnetic resonance imaging (MRI) also has been used for this purpose.

Fig. 35-9.

Computed tomographic scan showing a medium-sized right rectus sheath hematoma. The hematoma occurred in an elderly patient without a clear history of trauma who was receiving anticoagulation therapy. Because of its size and the patient's slender body habitus, this hematoma was palpable and could be followed clinically.

Specific treatment depends on the severity of the hemorrhage (Fig. 35-10). Small, unilateral, and stable hematomas may be observed without patient hospitalization. Bilateral or large hematomas will likely require hospitalization and possibly resuscitation. The need for transfusion or coagulation factor replacement is determined by the clinical circumstances. Reversal of warfarin (Coumadin) anticoagulation in the acute setting is frequently, but not always, necessary. Emergent operative intervention or angiographic embolization is required infrequently but may be necessary if hematoma enlargement, free bleeding, or clinical deterioration occur. Surgical therapy is used in the rare situations of failed angiographic treatment or hemodynamic instability that precludes any other options. The operative goals are evacuation of the hematoma and ligation of any bleeding vessel identified. Mortality from this condition is rare but has been reported in elderly patients requiring surgical treatment.

Fig. 35-10.

Management algorithm for rectus sheath hematoma. Most patients present with a mass and/or pain and are managed without intervention. The potential for a rare catastrophic bleeding event must be recognized, however. Surgical evacuation is reserved for those circumstances in which clinical evidence of ongoing bleeding makes any other management option untenable. CBC = complete blood count; CT = computed tomography; OR = operating room.

ABDOMINAL WALL HERNIAS Hernias of the anterior abdominal wall, or ventral hernias, represent defects in the parietal abdominal wall fascia and muscle through which intra-abdominal or preperitoneal contents can protrude. Ventral hernias may be congenital or acquired. Acquired hernias may develop through slow architectural deterioration of the muscular aponeuroses or they may develop from failed healing of an anterior abdominal wall incision (incisional hernia ). The most common finding is a mass or bulge on the anterior abdominal wall, which may increase in size with a Valsalva maneuver. Ventral hernias may be asymptomatic or cause a considerable degree of discomfort, and generally enlarge over time. Physical examination reveals a bulge on the anterior abdominal wall that may reduce spontaneously, with recumbency, or with manual pressure. A hernia that cannot be reduced is described as incarcerated and requires emergent surgical correction. Incarceration of an intestinal segment may be accompanied by nausea, vomiting, and significant pain. Should the blood supply to the incarcerated bowel be compromised, the hernia is described as strangulated, and the localized ischemia may lead to infarction and perforation.

Primary ventral hernias (nonincisional) are also termed true ventral hernias. These are more properly named according to their anatomic location. Epigastric hernias are located in the midline between the xiphoid process and the umbilicus. They are generally small, may be multiple, and at elective repair are usually found to contain omentum or a portion of the falciform ligament. These may be congenital and due to defective midline fusion of developing lateral abdominal wall elements. Umbilical hernias occur at the umbilical ring and may either be present at birth or develop gradually during the life of the individual. Umbilical hernias are present in approximately 10 percent of all newborns and are more common in premature infants. Most congenital umbilical hernias close spontaneously by age 5 years. If closure does not occur by this time, elective surgical repair usually is advised. Adults with small, asymptomatic umbilical hernias may be followed clinically. Surgical treatment is offered if a hernia is observed to enlarge, if it is associated with symptoms, or if incarceration occurs. Surgical treatment can consist of primary sutured repair or placement of prosthetic mesh for larger defects (>2 cm) using open or laparoscopic methods. Spigelian hernias can occur anywhere along the length of the Spigelian line or zone—an aponeurotic band of variable width at the lateral border of the rectus abdominis. However, the most frequent location of these rare hernias is at or slightly above the level of the arcuate line. These are not always clinically evident as a bulge and may come to medical attention because of pain or incarceration. Patients with advanced liver disease, ascites, and umbilical hernia require special consideration. Enlargement of the umbilical ring usually occurs in this clinical situation as a result of increased intra-abdominal pressure from uncontrolled ascites. The first line of therapy is aggressive medical correction of the ascites with diuretics, dietary management, and paracentesis for tense ascites with respiratory compromise. These hernias usually are filled with ascitic fluid, but omentum or bowel may enter the defect after large-volume paracentesis. Uncontrolled ascites may lead to skin breakdown on the protuberant hernia and eventual ascitic leak, which can predispose the patient to bacterial peritonitis. Patients with refractory ascites may be candidates for transjugular intrahepatic portocaval shunting or eventual liver transplantation. Umbilical hernia repair should be deferred until after the ascites is controlled.

INCISIONAL HERNIAS Approximately 4 million abdominal operations are performed every year and as many as 10 to 20% of these patients have been estimated to develop hernias at the abdominal incision sites. Any such occurrence is termed incisional hernia and can be regarded as a wound healing failure. The cause of incisional hernia in any given case can be difficult to determine, but obesity, primary wound healing defects, multiple prior procedures, prior incisional hernias, and technical errors during repair may all be contributory. Hernias can occur at sites of defective healing within the approximated incision or at the suture puncture sites created during the closure, or both. Repair of incisional hernias can be technically challenging, and a myriad of methods have been described. The most important distinctions in describing surgical management of incisional hernias are primary vs. mesh repair and open vs. laparoscopic repair. Primary repair methods for incisional hernia include both simple suture closure and components separation, and are open procedures. Simple suture approximation of fascial defect edges predictably results in a suture line under tension. Primary repair, even of small hernias (defects 2 years. Of the recurrences noted, the overwhelming majority were felt to be secondary to technical errors committed early in the surgeons' experience that were avoided during the later cases. Recently, investigators at Washington University examined pooled data from 45 different series of laparoscopic and open ventral hernia repair. Use of the laparoscopic technique was associated with statistically fewer wound complications, fewer overall complications, and a lower recurrence rate than use of the open technique. These benefits of the minimally invasive technique are achieved by eliminating the requisite large abdominal incision at a location where the abdominal wall blood supply has previously been compromised. In addition, with the laparoscopic technique, the entire undersurface of the abdominal wall can be examined, which often reveals multiple secondary defects that might not otherwise be appreciated. The technique of laparoscopic incisional hernia repair generally involves laterally placed ports for midline defects and contralaterally placed ports for lateral defects. All adhesions to the anterior abdominal wall are divided, with great care taken not to injure the intestine either directly or with thermal or electrical energy. The contents of the hernial sac are completely reduced, but in contrast to open repairs, the sac itself is left in situ. Once the area encompassing all fascial defects is defined, a mesh is fashioned to allow for sufficient overlap (minimum of 3 to 4 cm) under the healthy abdominal wall. After insertion into the abdomen, the mesh is fixed into position with transfascial sutures placed circumferentially around the mesh and spiral tacks placed according to surgeon preference (Fig. 35-11). It has been proposed that transfascial sutures contribute to excessive postoperative pain, and some surgeons have eliminated them from the aforementioned technique, relying solely on spiral tacks for the strength of the repair. LeBlanc reviewed the usefulness of transfascial sutures and cautiously recommended a minimum 5-cm overlap of mesh from defect edge if transfascial sutures are not used.

Fig. 35-11.

Intraperitoneal view of polytetrafluoroethylene mesh used for laparoscopic ventral incisional hernia repair. The mesh is in place on the posterior aspect of the abdominal wall without apparent laxity due to the ongoing CO2 insufflation. Once pneumoperitoneum is released, sufficient laxity is introduced to relieve any pull at the fixation points and to permit good apposition of mesh to the abdominal wall surface.

OMENTUM Surgical Anatomy The greater omentum and lesser omentum are fibro-fatty aprons that provide support, coverage, and protection for peritoneal contents. These structures begin to develop during the fourth week of gestation. The greater omentum develops from the dorsal mesogastrium, which begins as a double-layered structure. The spleen develops in between the two layers, and later in development the two layers fuse, giving rise to the intraperitoneal spleen and the gastrosplenic ligament. The fused layers then hang from the greater curvature of the stomach and drape over the transverse colon, to which their posterior surface becomes fixed. The gastrocolic ligament and the gastrosplenic ligament are those segments of the greater omental apron that connect the named structures. In the adult, the greater omentum lies in between the anterior abdominal wall and the hollow viscera, and usually extends into the pelvis to the level of the symphysis pubis. The lesser omentum, otherwise known as the hepatoduodenal and hepatogastric ligaments, develops from the mesoderm of the septum transversum, which connects the embryonic liver to the foregut. The common bile duct, portal vein, and hepatic artery are located in the inferolateral margin of the lesser omentum, which also forms the anterior margin of the foramen of Winslow. The blood supply to the greater omentum is derived from the right and left gastroepiploic arteries. The venous

drainage parallels the arterial supply to a great extent, with the left and right gastroepiploic veins ultimately draining into the portal system.

Physiology In the early twentieth century, the British surgeon Rutherford Morison noted that the omentum tended to wall off areas of infection and limit the spread of intraperitoneal contamination. He termed the omentum the abdominal policeman. Shortly after his description was published, several reports suggested intrinsic hemostatic characteristics of the omentum. In 1996, researchers in the Netherlands demonstrated that the concentration of tissue factor in omentum is over twice the amount per gram of that found in muscle. This facilitates activation of coagulation at sites of inflammation, ischemia, infection, or trauma within the peritoneal cavity. The consequent local production of fibrin contributes to the ability of the omentum to adhere to areas of injury or inflammation.

Omental Infarction Interruption of the blood supply to the omentum is a rare cause of an acute abdomen that may be secondary to torsion of the omentum around its vascular pedicle, thrombosis or vasculitis of the omental vessels, or omental venous outflow obstruction. Fewer than 100 cases have been reported, and the diagnosis is most likely to be made in male adults. Depending on the location of the infarcted omental tissue, this disease process may mimic appendicitis, cholecystitis, diverticulitis, perforated peptic ulcer, or ruptured ovarian cyst. Patients typically present with localized right lower quadrant, right upper quadrant, or left lower quadrant pain. Although a mild degree of nausea may be present, patients do not usually have concomitant intestinal symptoms. Physical examination typically reveals a mild tachycardia and a low-grade fever. Abdominal examination may demonstrate a tender, palpable mass associated with guarding and rebound tenderness. The diagnosis is rarely made before abdominal imaging studies are performed. Either abdominal CT or ultrasonography will show a localized, inflammatory mass of fat density. Treatment of omental infarction depends on the certainty with which the diagnosis is made. In patients who are not toxic and whose abdominal imaging results are convincing, supportive care is sufficient. However, many cases are indistinguishable from surgical conditions with immediate surgical implications, such as appendicitis. In these instances, laparoscopic exploration offers the opportunity to establish an accurate diagnosis and determine the most appropriate treatment. Resection of the infarcted tissue results in rapid resolution of symptoms.

Omental Cysts Cystic lesions of the omentum and mesentery are related disorders, likely resulting from either peritoneal inclusions or degeneration of lymphatic structures. Omental cysts are far less common than mesenteric cysts. Omental cysts may present as an asymptomatic abdominal mass or may cause abdominal pain with or without appreciable mass or distention. Physical examination may reveal a freely mobile intra-abdominal mass. Both CT and abdominal ultrasound reveal a well-circumscribed, cystic mass lesion arising from the greater omentum. Treatment involves resection of all symptomatic omental cysts. Resection of these benign lesions is readily accomplished using laparoscopic techniques.

Omental Neoplasms Primary tumors of the omentum are uncommon. Benign tumors of the omentum include lipomas, myxomas, and desmoid tumors. Primary malignant tumors of the omentum are considered mesodermally derived stromal tumors, in which some of the associated immunohistochemical characteristics of GI stromal tumors have been described, including c-kit immunopositivity. Metastatic tumors of the omentum are common, with metastatic ovarian cancer

showing the highest preponderance of omental involvement. Malignant tumors of the stomach, small intestine, colon, pancreas, biliary tract, uterus, and kidney may also metastasize to the omentum.

MESENTERY Surgical Anatomy The mesentery develops from mesenchyme that attaches the foregut, midgut, and hindgut to the posterior abdominal wall. During embryonic maturation, this mesenchyme forms the dorsal mesentery. In the region of the stomach, the dorsal mesentery becomes the greater omentum, whereas in the region of the jejunum and ileum the dorsal mesentery becomes the mesentery proper. In the region of the colon, the dorsal mesentery is known as the mesocolon. During embryonic development, after the 270-degree counterclockwise rotation of the herniated midgut, the reduced mesentery achieves its final fixation state. The segments at the duodenum, ascending colon, and descending colon become fixed to the retroperitoneum, whereas the small intestine mesentery, transverse colon mesentery, and, to a variable extent, the sigmoid colon mesentery remain mobile (Fig. 35-12). Defects in the normal developmental steps of intestinal rotation result in malrotation disorders.

Fig. 35-12.

Anatomic relationships of intestinal mesentery to the retroperitoneum after completion of intestinal rotation during fetal development. art. = artery; sup. = superior; transv. = transverse. [Reproduced with permission from Healey JE, Hodge J (eds): Surgical Anatomy, 2nd ed. Toronto: BC Decker, 1990, p 153.]

The root of the small intestine mesentery wall normally courses in an oblique direction, from the left upper quadrant at the ligament of Treitz to the right lower quadrant at the ileocecal valve and the fixed cecum. The small and large intestine mesenteries serve as the major pathway for arterial, venous, lymphatic, and neural structures coursing to and from the bowel. Anatomic anomalies of the mesentery related to rotational disorders can lead to paraduodenal or mesocolic hernias (Fig. 35-13), which can present as chronic or acute intestinal obstruction in children or adults.

Fig. 35-13.

Mesocolic hernia of small bowel into a retrocolic hernial sac posterior to the descending colon mesentery. Hernias of this type, as well as hernias into paraduodenal recesses, result from abnormal fixation of mesenteric structures during the course of intestinal rotation. a. = artery; v. = vein. [Reproduced with permission from Healey JE, Hodge J (eds): Surgical Anatomy, 2nd ed. Toronto: BC Decker, 1990, p 153.]

Sclerosing Mesenteritis Sclerosing mesenteritis, also referred to as mesenteric panniculitis or mesenteric lipodystrophy, is a chronic inflammatory and fibrotic process that involves a portion of the intestinal mesentery. There is no gender or race predominance, but the condition is most commonly diagnosed in individuals >50 years of age. The etiology of this process is unknown, but its cardinal feature is increased tissue density within the mesentery. This can be localized and associated with a discrete non-neoplastic mesenteric mass or more diffuse, sometimes involving large swaths of mesentery without well-defined borders. There may be varying relative degrees of fat tissue degeneration, inflammation, and fibrosis on histologic examination, which gives rise to the various terms used to describe this condition. Mesenteric lipodystrophy is used when the inflammatory and fibrotic components are small. Mesenteric panniculitis signifies an increased inflammatory component with replacement of degenerative fatty elements. Sclerosing mesenteritis signifies a major fibrotic component and is sometimes referred to as retractile mesenteritis to describe mesenteric retraction and shortening associated with scarring. It is not clear if these represent stages in a sequential process or variations in disease severity. A discrete mass may be up to 40 cm in diameter, and patients typically present with symptoms of a mass lesion. Abdominal pain is the most frequent presenting symptom, followed by the presence of a nonpainful mass or, more rarely, intestinal obstruction. However, many cases are discovered incidentally when imaging studies (most frequently abdominal CT scanning) are performed for unrelated reasons. This then raises diagnostic questions whose resolution is often pursued using invasive procedures.

CT of the abdomen can verify the presence of a mass lesion or area of the mesentery with a higher density than found in normal mesenteric tissue. This may frequently involve the vascular structures in the mesenteric root (Fig. 35-14). Although CT cannot definitively distinguish sclerosing mesenteritis from a primary or secondary mesenteric tumor, identification of a "fat ring sign" or hypodense zone around the mass area has been suggested as a means of distinguishing sclerosing mesenteritis from lymphoma. The presence of a hyperattenuating stripe also has been suggested as a radiologic finding that would favor a diagnosis of mesenteritis (Fig. 35-15).

Fig. 35-14.

Computed tomographic coronal section of a focus of sclerosing mesenteritis at the mesenteric root, straddling major proximal branches of the superior mesenteric artery. The location of the mass restricted surgical options to biopsy and confirmation of diagnosis.

Fig. 35-15.

Computed tomographic scan of sclerosing mesenteritis (mesenteric lipodystrophy). This condition cannot easily be distinguished from a neoplasm of the mesentery on radiologic study. In this case, the study showed "fatty mesenteric tumor with involvement of mesenteric vessels," and "mesenteric lipodystrophy" was demonstrated by biopsy findings at exploration. The finding of a hyperattenuating stripe around the lesion, as seen in this image, has been associated with the diagnosis of mesenteritis.

Surgery has been used most frequently to establish a diagnosis and to rule out a neoplastic process. The extent and location of mesenteric involvement defines, and in some cases limits, the options for surgical intervention. In addition to simple biopsy, bowel and mesenteric resection can be considered, particularly in cases in which it is technically feasible based on mass size and the ability to avoid injury to the small intestine blood supply (Fig. 3516). Often, however, the involvement of the vascular structures at the mesenteric root makes resection unfeasible. In rare cases, an ostomy of some type for fecal diversion in the face of obstruction can be considered. The recent use of positron emission tomography with CT scanning has proven effective in ruling out neoplasia for focal mesenteric masses, which leaves the sclerosing mesenteritis diagnosis as one of exclusion. However, it is not clear that use of this newer modality will eliminate the need to obtain tissue for diagnostic purposes.

Fig. 35-16.

Operative findings at the time of resection of what was believed to be a mesenteric tumor but which proved to be a focus of mesenteric lipodystrophy. In this case, the relatively small site of involvement and the peripheral location in the small intestine mesentery permitted management by resection en bloc with a segment of adjacent small bowel.

In most cases of sclerosing mesenteritis the process appears to be self-limited and may even demonstrate regression if followed with interval imaging studies. Clinical symptoms are very likely to improve without intervention, and therefore aggressive surgical treatments are generally not indicated. In clinically problematic cases that are not amenable to resection because of widespread mesenteric involvement or unfavorable location, medical treatment has been given to alleviate severe symptoms. Among the agents that have been used are corticosteroids, colchicine, tamoxifen, and cyclophosphamide.

Mesenteric Cysts Cysts of the mesentery are benign lesions with an incidence of Chapter 36. Soft Tissue Sarcomas>

KEY POINTS 1. Sarcomas are a heterogeneous group of tumors that can occur throughout the body and encompass more than 50 subtypes with distinct histologic lines of differentiation. 2. These rare tumors account for less than 1% of cancers in adults (estimated 10,000 cases per year in the United States) and represent 7% of cancers in children. 3. Approximately two thirds of soft tissue sarcomas arise in the extremities; the remaining one third are distributed between the retroperitoneum, trunk, abdomen, and head and neck. 4. The treatment algorithm for soft tissue sarcomas depends on tumor stage, site, and histology. 5. Multimodality treatment including surgical resection, radiation therapy and, in selected cases, systemic chemotherapy, has been applied to patients with locally advanced, high-grade, extremity sarcomas. 6. Overall 5-year survival rate for patients with all stages of soft tissue sarcoma is 50 to 60%. 7. Of the patients who die of sarcoma, most will succumb to metastatic disease in the lungs, which 80% of the time occurs within 2 to 3 years of the initial diagnosis. 8. Progress in the understanding of soft tissue sarcoma biology is crucial for the development of new therapeutic targets.

OVERVIEW Incidence Sarcomas are a heterogeneous group of tumors that arise predominantly from the embryonic mesoderm, but also can originate, as does the peripheral nervous system, from the ectoderm. In 2007, approximately 9220 new cases of soft tissue sarcoma were diagnosed in the United States with 3560 deaths attributable to disease.1 These rare tumors account for less than 1% of cancers in adults and represent 7% of cancers in children. Several distinct groups of sarcomas are recognized; soft tissue sarcomas, the largest of these groups, are the focus of this chapter. Other groups include bone sarcomas (osteosarcomas and chondrosarcomas), Ewing's sarcomas, and peripheral primitive neuroectodermal tumors. Soft tissue sarcomas can occur throughout the body and encompass more than 50 histiotypes (Table 36-1) with distinct histologic lines of differentiation. The most common histologic types of soft tissue sarcoma in adults (excluding Kaposi's sarcoma) are malignant fibrous histiocytoma (MFH, 28%), leiomyosarcoma (12%), liposarcoma (15%), synovial sarcoma (10%), and malignant peripheral nerve sheath tumors (6%). 2 Rhabdomyosarcoma is the

most common soft tissue sarcoma of childhood. Most primary soft tissue sarcomas originate in an extremity (50 to 60%); the next most common sites are the trunk, retroperitoneum, and head and neck.

Table 36-1 Relative Frequency of Histologic Subtypes of Soft Tissue Sarcoma2 Malignant fibrous histiocytoma 349 28 Liposarcoma 188 15 Leiomyosarcoma 148 12 Unclassified sarcoma 140 11 Synovial sarcoma 125 10 Malignant peripheral nerve sheath tumor 72 6 Rhabdomyosarcoma 60 5 Fibrosarcoma 38 3 Ewing's sarcoma 25 2 Angiosarcoma 25 2 Osteosarcoma 14 1 Epithelioid sarcoma 14 1 Chondrosarcoma 13 1 Clear-cell sarcoma 12 1 Alveolar soft part sarcoma 7

1 Malignant hemangiopericytoma 5 0.4 Histologic Subtypes

n

%

Source: Data from Coindre et al.2 During the past 25 years, a multimodality treatment approach has been applied to patients with extremity sarcomas, which had led to modest improvements in both survival and quality of life. However, patients with abdominal sarcomas continue to have high rates of recurrence and poor overall survival. Overall 5-year survival rate for patients with all stages of soft tissue sarcoma is 50 to 60%. Of the patients who die of sarcoma, most will succumb to metastatic disease, which 80% of the time occurs within 2 to 3 years of the initial diagnosis.

Epidemiology Except for malignant peripheral nerve sheath tumors in patients with neurofibromatosis, sarcomas do not seem to result from the progression or dedifferentiation of benign soft tissue tumors. Despite the variety of histologic subtypes, sarcomas have many common clinical and pathologic features. Overall, the clinical behavior of most soft tissue sarcomas is similar and is determined by anatomic location (depth), grade, and size. The dominant pattern of metastasis is hematogenous, primarily to the lungs. Lymph node metastases are rare (5 cm (T2), computed tomography (CT) of the chest should be considered. CT is the preferred technique for evaluating retroperitoneal sarcomas, whereas magnetic resonance imaging (MRI) often is favored for soft tissue sarcomas of the extremities.1 6 Both ultrasonography and CT can assist in guiding fine-needle aspiration, core biopsy for initial diagnosis, and at recurrence.

ULTRASONOGRAPHY Ultrasonography may have a diagnostic role for patients who cannot undergo MRI. Ultrasonography also can be a useful adjunct to MRI when findings are indeterminate and for delineating adjacent vascular structures.

COMPUTED TOMOGRAPHY Contrast-enhanced CT can assess the extent of soft tissue tumor burden and the proximity of the tumor to vital structures (Fig. 36-1). CT is the preferred imaging technique for evaluating retroperitoneal sarcomas.1 6 Current CT techniques can provide a detailed survey of the abdomen and pelvis and can delineate adjacent organs and vascular structures. For extremity sarcomas, CT may be useful if MRI is not available or cannot be used. CT of the abdomen and pelvis should be done when histologic assessment of an extremity sarcoma reveals a myxoid liposarcoma, because this subtype is known to metastasize to the abdomen.1 7

Fig. 36-1.

A 27-year-old man presented with symptoms of back pain. Computed tomography of the abdomen demonstrating a 4.1 x 3.3 cm hypodense mass in the retrocaval region involving the inferior vena cava. Subsequent biopsy of the tumor confirmed leiomyosarcoma.

MAGNETIC RESONANCE IMAGING MRI accurately delineates muscle groups and distinguishes among bone, vascular structures, and tumor. Sagittal and coronal views allow evaluation of anatomic compartments in three dimensions (Fig. 36-2). Soft tissue sarcomas of the extremities usually present on MRI as heterogeneous masses. Their signal intensity tends to be equal to or slightly higher than that of adjacent skeletal muscle on T1-weighted images and heterogeneous and high on T2-weighted images. Hemorrhagic, cystic, or necrotic changes also may be observed in the tumor. Special

MRI techniques, including magnetic resonance angiography, may be performed if adjacent vascular structures must be delineated.

Fig. 36-2.

A 55-year-old woman presented with right thigh pain and enlarging mass. Coronal image demonstrating an 18-cm mass within the adductor magnus musculature with evidence of necrosis and hemorrhage.

MRI has supplanted CT as the imaging technique of choice for evaluation of soft tissue sarcomas of the extremities. MRI also is valuable for assessing tumor recurrence after surgery (Fig. 36-3). A baseline image usually is obtained 3 months after surgery. Some clinicians believe that routine postoperative imaging of a primary extremity tumor site is not necessary for asymptomatic patients, citing the difficulties in detecting early recurrence in scarred, irradiated tissue.1 6 Others advocate routine imaging every 6 months for the first 2 years.

Fig. 36-3.

A 51-year-old woman, 30 months status postexcision of desmoid tumor of the left breast and chest wall. Magnetic resonance imaging of the chest demonstrating a 5.2 x 7.7 cm mass with both T2 signal and postcontrast T1 signal indicating a recurrent desmoid tumor in the anterior aspect of the left upper arm and shoulder.

MRI may be an important adjunct to cytologic analysis in distinguishing benign lesions such as lipomas, hemangiomas, schwannomas, neurofibromas, and intramuscular myxomas from their malignant counterparts. In the setting of preoperative chemotherapy, contrast-enhanced T1-weighted MRIs can be useful in evaluating intratumoral necrosis.

Biopsy Techniques FINE-NEEDLE ASPIRATION Fine-needle aspiration is an acceptable method of diagnosing most soft tissue sarcomas, particularly when the results correlate closely with clinical and imaging findings.1 8 However, fine-needle aspiration biopsy is indicated for primary diagnosis of soft tissue sarcomas only at centers where cytopathologists have experience with these types of tumors. Fine-needle aspiration biopsy is also the procedure of choice to confirm or rule out the presence of a metastatic focus or local recurrence. When tumor grading is essential for treatment planning, fine-needle aspiration biopsy is not the preferred technique. Superficial lesions often are subjected to fine-needle aspiration biopsies in the clinic setting. Deeper tumors may require an interventional radiologist to perform the technique under sonographic or CT guidance. The technique

generally involves the use of a 21- to 23-gauge needle that is introduced into the mass after appropriate cleansing of the skin and injection of local anesthetic. Negative pressure is applied, and the needle is pulled back and forth several times in various directions. After the negative pressure is released, the needle is withdrawn and the contents of the needle are used to prepare a smear.1 9 A cytopathologist then examines the slides to determine whether sufficient diagnostic material is present. When insufficient diagnostic material is obtained, a core needle biopsy should be performed. Diagnostic accuracy rates for fine-needle aspiration biopsy of primary tumors range from 60 to 96%. In general, the amount of material obtained from a fine-needle aspiration biopsy is small, and diagnostic accuracy clearly depends on the experience of the cytopathologist.

CORE NEEDLE BIOPSY Core needle biopsy is a safe, accurate, and economical procedure for diagnosing sarcomas. The tissue sample obtained from a core needle biopsy is usually sufficient for several diagnostic tests such as electron microscopy, cytogenetic analysis, and flow cytometry. The reported complication rate for core needle biopsy is less than 1%.2 0 CT guidance can enhance the positive yield rate of a core needle biopsy by more accurately pinpointing the location of the tumor. Precise localization in the tumor mass is particularly important to avoid sampling nondiagnostic necrotic or cystic areas of the tumor. CT guidance also permits access to tumors in otherwise inaccessible anatomic locations or when located near vital structures. Dupuy and associates examined the accuracy of core needle biopsy in 221 patients with musculoskeletal neoplasms. 2 0 Core needle biopsy had an accuracy of 93% compared with the diagnosis given at the time of definitive treatment. Only 8% of patients had nondiagnostic or insufficient specimens.

INCISIONAL BIOPSY Open biopsy is a reliable diagnostic method that allows adequate tissue to be sampled for definitive and specific histologic identification of bone or soft tissue sarcomas. When adequate tissue for diagnosis cannot be obtained by fine-needle aspiration biopsy or core biopsy, an incisional biopsy is indicated for deep tumors and for superficial soft tissue tumors >3 cm. Incisional biopsies usually are performed as a last resort when fine-needle aspiration or core biopsy specimens are nondiagnostic. Open biopsies should be performed only by surgeons experienced in the management of soft tissue sarcomas. In a series of 107 patients with soft tissue sarcomas, planned surgical treatments had to be changed due to prior, poorly oriented biopsies in 25% of the cases.2 1 Other series have reported complications in up to 16% of open biopsies.1 9 An open biopsy ideally should be performed in a designated treatment center and by the surgeon who will perform the definitive surgery. The biopsy incision should be oriented longitudinally along the extremity to allow a subsequent wide local excision that encompasses the biopsy site, scar, and tumor en bloc. A poorly oriented biopsy incision often mandates an excessively large surgical defect for a wide local excision. This, in turn, can result in a larger postoperative radiotherapy field to encompass all tissues at risk. Another mandate of surgical technique is that adequate hemostasis be achieved at the time of biopsy to prevent dissemination of tumor cells into adjacent tissue planes by hematoma. An incisional or open biopsy is the most reliable of the diagnostic methods, providing accurate histologic diagnosis and grading in >95% of soft tissue sarcomas. In addition, the amount of tissue obtained often is sufficient for additional diagnostic studies if necessary.

EXCISIONAL BIOPSY Excisional biopsy can be performed for easily accessible (superficial) extremity or truncal lesions 3 cm should be evaluated with radiologic imaging [ultrasonography or computed tomography (CT)] and a tissue diagnosis made by core needle biopsy. 2. Once a sarcoma diagnosis is established, obtain imaging (magnetic resonance imaging for extremity lesions and CT for other anatomic locations) and evaluation for metastatic disease with chest CT for intermediate/high-grade or T2 tumors. 3. A wide local excision with 2-cm margins is adequate therapy for low-grade lesions and T1 tumors. 4. Radiation therapy plays a critical role in the management of large (T2) tumors. 5. Patients with recurrent high-grade sarcomas or distant metastatic disease should be evaluated for chemotherapy. 6. An aggressive surgical approach should be taken in the treatment of patients with an isolated local recurrence or resectable distant metastases.

Surgery Small (15 cm. At most institutions the typical preoperative dose is 50 Gy, given in 25 fractions. Postoperative radiation therapy planning is based on tumor site, tumor grade, assessment of surgical margins, and on institutional preferences. The entire surgical scar and drain sites should be included in the field so that a near–full dose can be administered to the superficial skin. Metallic clips placed in the tumor bed during surgery can help define the limits of the resection and aid in radiation therapy planning. Doses of 60 to 70 Gy are usually necessary for postoperative treatment. Although postoperative radiation treatment of upper extremity sarcomas has been associated with a lower incidence of wound complications, the upper extremity site also is associated with a greater rate of local recurrence compared with the lower extremity.7 0 No consensus exists on the optimal sequence of radiation therapy and surgery. The available data come largely from single-institution, nonrandomized studies. Proponents of preoperative radiation therapy cite several advantages. Multidisciplinary planning with radiation oncologists, medical oncologists, and surgeons is facilitated early in the course of therapy if the tumor is in situ; moreover, lower doses of preoperative radiation can be delivered to an undisturbed tissue bed with improved tissue oxygenation. In addition, Nielsen and associates7 1 demonstrated that the size of preoperative radiation fields is smaller and the number of joints included on those fields is fewer than in postoperative radiation fields, which may result in improved functional outcome. Critics of preoperative radiation therapy cite as deterrents the difficulty of pathologic assessment of margins and the increased rate of wound complications.7 2 However, plastic surgery techniques with advanced tissue transfer procedures are being used more often in these high-risk wounds, and reportedly result in better outcomes. The only randomized comparison of preoperative and postoperative radiation therapy conducted to date was performed by the National Cancer Institute of Canada Clinical Trial Canadian Sarcoma Group.7 3 This trial was designed to compare complications and the functional outcome of patients treated with preoperative and postoperative external beam radiation therapy. The 190 patients enrolled from October 1994 to December 1997 were randomized to receive preoperative radiotherapy (50 Gy) or postoperative radiotherapy (66 Gy). With a median follow-up of 3.3 years, the recurrence and progression-free survival rates were similar between groups, with the only statistically significant difference being in the rates of wound complications. That is, the incidence of wound complications was 35% in the patients who received preoperative therapy but just 17% in the patients who received postoperative radiation therapy. 7 3 Late radiation toxicity was higher in the postoperative group compared to the preoperative radiation group (48.2 vs. 31.5%) with larger field sizes predicting greater rates of fibrosis, joint stiffness, and edema.7 4 Brachytherapy involves the placement of multiple catheters in the tumor resection bed. The primary benefit of

brachytherapy is the shorter overall treatment time of 4 to 6 days compared with pre- or postoperative radiation therapy regimens, that can last 4 to 6 weeks. Brachytherapy produces less radiation scatter in critical anatomic regions (e.g., gonads or joints) and potentially improved function. A cost-analysis comparison of brachytherapy vs. external beam irradiation showed that costs were lower to undergo adjuvant irradiation with brachytherapy for soft tissue sarcomas.7 5 Brachytherapy also can be used for recurrent disease previously treated with external beam radiation. Guidelines established at the Memorial Sloan-Kettering Cancer Center recommend spacing the afterloading catheters in 1-cm increments while leaving a 2-cm margin around the surgical bed.6 3 After adequate wound healing is established, usually after the fifth postoperative day, the catheters are loaded with seeds containing iridium-192 that deliver 42 to 45 Gy of radiation to the tumor bed over 4 to 6 days. The primary disadvantage of brachytherapy is that it requires an extended inpatient stay and bed rest. IMRT recently has been introduced as a radiation technique that delivers radiation more precisely to the tumor while sparing surrounding tissues. The proposed benefits of preoperative IMRT include treatment delivery to tumors while minimizing the dose to superficial tissues (i.e., skin), thereby reducing postoperative wound infections7 6 and underlying bone complications (i.e., femur) by achieving concave dose distributions.7 7 Theoretically, treatment with IMRT would result in a lower risk of long-term femur fractures. The long-term outcomes following IMRT have not yet been established. Local toxicity from radiation therapy varies according to radiation dose, field size, and timing (pre- or postoperative). With preoperative radiotherapy, the most frequent wound complications are wound dehiscence, wound necrosis, persistent drainage, infection, seroma formation, ulceration, and cellulitis.7 3 Postoperative radiation treatment of free flaps often is associated with wound complications, and patients should be advised that secondary surgical repair may be necessary. Wound complication rates of 13 to 37% have been reported for patients receiving preoperative radiation therapy as compared with 5 to 20% for patients receiving postoperative treatment.7 8 If catheters are loaded after the fifth postoperative day, rates of wound complications following brachytherapy are similar to those reported after postoperative radiation therapy. Long-term (chronic) effects of radiation therapy (those occurring more than 1 year after completion of therapy) generally are related to fibrosis/contracture, lymphedema, neurologic injury, osteitis, and fracture, all of which can cause substantial functional impairment.7 8 Variables associated with poorer functional outcome following radiation therapy include treatment of larger tumors, use of higher doses of radiation (>63 Gy), longer radiation fields (>35 cm), poor radiation technique, neural sacrifice, postoperative fractures, and wound complications. 74,79 Additionally, complications of any kind are less likely following treatment for upper extremity sarcoma. 72,73

Systemic Therapy Despite improvements in local control rates, metastasis and death remain significant problems for patients with high-risk soft tissue sarcomas. Patients considered at high risk of death from sarcoma include those presenting with metastatic disease, presenting with localized sarcomas at nonextremity sites, or presenting with sarcomas of intermediate- or high-grade histology >5 cm (T2). 27,63 Treatment of patients with high-risk localized or metastatic disease often includes chemotherapy. Results of conventional chemotherapy regimens have been poor for most patients with sarcoma. As a group, sarcomas include histologic subtypes that are responsive to cytotoxic chemotherapy and subtypes that are universally resistant to current agents. A spectrum of chemosensitivity has been demonstrated for various histologic subtypes. In particular, synovial sarcoma and fibrosarcoma have been noted to be highly sensitive to chemotherapy8 0 and liposarcoma and myxofibrosarcoma as having intermediate sensitivity to chemotherapy; and

GI stromal tumors and chondrosarcoma as being highly resistant to chemotherapy. Considering the variability of responses, it is not surprising that no overall survival benefit has been demonstrated. Historically, only three drugs—doxorubicin, dacarbazine, and ifosfamide—have consistently demonstrated response rates of 20% or more for advanced soft tissue sarcomas. Doxorubicin and ifosfamide are the two most active agents, with consistently reported response rates of 20% or greater, and both agents have demonstrated positive dose-response curves.81,82 Response rates to ifosfamide have been reported to range from 20 to 60% in singleinstitution series using higher-dose regimens or in combination with doxorubicin.8 2 Over the last 5 years, several additional chemotherapeutic agents have been noted to be active. Single-agent response rates to gemcitabine in patients with advanced sarcoma have been reported to be 18%8 3 except for the specific histologic subtype leiomyosarcoma, in which response rates as high as 53% have been reported both alone or in combination with docetaxel.83,84 Gemcitabine combined with vinorelbine also has been associated with clinical benefit in patients with advanced sarcomas.8 5 Other subtype-specific cytotoxic agents that have emerged include taxanes, docetaxel, and paclitaxel, which have been found to have specific activity in angiosarcomas. 86,87

Integrating Multimodality Therapy The primary objective of multimodality treatment is cure; when this endpoint is not possible, the goal is palliation of symptoms. Patients with a suspected diagnosis of soft tissue sarcoma should be referred to multidisciplinary centers that specialize in treating this disease.8 8 Patients with a deep soft tissue mass should be referred, even before a biopsy is performed, to a tertiary treatment center that offers care by a team of specialists. Such multidisciplinary teams typically include oncologists from several disciplines (medicine, pediatrics [if applicable], surgery, and radiation therapy), as well as a pathologist, radiologist, and ancillary staff. An analysis by Gutierrez and colleagues8 9 reported that soft tissue sarcoma patients treated at high-volume centers have significantly better survival and functional outcomes. They conclude that particularly those with large, high-grade, or truncal/retroperitoneal tumors should be treated exclusively at specialized centers.

ADJUVANT CHEMOTHERAPY The use of adjuvant chemotherapy for soft tissue sarcomas remains controversial. The average 5-year disease-free survival rate for patients initially presenting with localized disease is only about 50%. More than a dozen individual randomized trials of adjuvant chemotherapy have failed to demonstrate improvement in disease-free patients and overall survival in patients with soft tissue sarcomas. However, several limitations of these individual trials may explain the lack of observed improvement. First, the chemotherapy regimens used were suboptimal, relying on single-agent therapy (most commonly with doxorubicin) and insufficiently intensive dosing schedules. Second, the patient groups were not large enough to detect clinically significant differences in survival rates. Finally, most studies included patients at low risk of metastasis and death, namely those with small (10 cm (62 vs. 83% for surgery alone vs. neoadjuvant chemotherapy and surgery, respectively).9 4 Because the evidence addressing treatment of stage III disease is inconclusive, considerable variation still exists in treatment standards. It may be that there are subsets of high-risk patients based on tumor size or histology with extremity soft tissue sarcoma who derive significant benefit from systemic chemotherapy. Specifically, retrospective cohort analyses have noted a benefit in disease-specific survival in patients with large (T2), highgrade liposarcomas and synovial sarcomas of the extremity treated with combination ifosfamide and doxorubicin compared with patients who received no chemotherapy.9 5 A major deterrent to the use of adjuvant chemotherapy has been the risk of adverse toxic effects in patients who do not respond to therapy. To optimize the use of doxorubicin and ifosfamide, investigators have tried to escalate the drug doses with combination regimens with the aim of maximizing tumor-cell kill. The ultimate goal is to achieve an incremental response rate and improve the quality of response sufficiently to influence survival. However, the limits to this approach are becoming apparent even when treatment includes support with hematopoietic growth factors. The advent of growth factors like granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor has helped minimize the morbidity related to neutropenia; however, dose-limiting thrombocytopenia continues to pose a challenge for treatment. Use of high-dose doxorubicin has been limited by myelotoxicity, epithelial toxicity, painful hand-foot syndrome, and potentially severe cardiac toxicity. The toxicity profile for systemic regimens with gemcitabine has been mild, primarily related to hematologic toxicity. This regimen is of particular clinical interest for patients with limited options due to (a) prior exposure to full therapeutic doses of doxorubicin and ifosfamide, (b) advanced age, and (c) significant comorbidities.

NEOADJUVANT/PREOPERATIVE CHEMOTHERAPY

The rationale for using neoadjuvant and preoperative chemotherapy for soft tissue sarcomas is the belief that only 30 to 50% of patients will respond to standard (postoperative) chemotherapy. Neoadjuvant chemotherapy enables oncologists to identify patients whose disease responds to chemotherapy by assessing that response while the primary tumor is in situ. Patients whose tumors do not respond to short courses of preoperative chemotherapy are, thus, spared the toxic effects of prolonged postoperative or adjuvant chemotherapy. Treatment approaches that combine systemic chemotherapy with radiosensitizers and concurrent external beam radiation may improve disease-free survival by treating microscopic disease and enhancing the treatment of macroscopic disease. Concurrent chemoradiotherapy with doxorubicin-based regimens reportedly produces favorable local control rates for patients with sarcoma.9 5 Since those findings were published, several groups have attempted to evaluate the optimal route of administration, alternative chemotherapeutic agents, and the toxicity of combined therapies. Theoretical advantages of concurrent treatment notwithstanding, use of concurrent local and systemic therapy decreases the total treatment time for patients with high-risk sarcoma. This decrease represents a substantial advantage over current sequential combined-method treatment approaches, for which the total duration of treatment for radiation, chemotherapy, surgery, and rehabilitation frequently exceeds 6 to 9 months.

Surveillance In general, it is believed that early recognition and treatment of recurrent local or distant disease can prolong survival in patients with soft tissue sarcoma. This is primarily based on a few reports involving small numbers of patients that have indicated salvage after recurrent local disease is possible by performing radical re-excision with or without radiation therapy.96,97 Similarly, several groups have reported that survival can be prolonged after resection of pulmonary metastases. These limited data form the basis for use of aggressive surveillance strategies for all patients with soft tissue sarcoma. History and physical examination are the most useful components of follow-up in evaluating for local recurrence after definitive treatment. CT and MRI are useful for evaluating less accessible regions, such as the retroperitoneum, and in assessing equivocal changes on examination. Most recurrences of soft tissue sarcomas occur in the first 2 years after completion of therapy. Patients should be evaluated with a complete history and physical examination and chest radiography every 3 to 6 months during the 2- to 3-year period of highest risk. Most experts recommend that the tumor site should be evaluated every 6 months by performing MRI for extremity tumors or CT for intra-abdominal or retroperitoneal tumors. Guidelines have been established for using MRI to distinguish recurrences from typical postsurgical changes. A discrete nodule with low signal intensity on T1weighted images and higher signal intensity on T2-weighted images that enhances after administration of IV contrast is strongly suggestive of recurrence and should be sampled for biopsy. In some circumstances, ultrasonography can be used to assess recurrence of tumor in the extremities. Recurrence after surgery for abdominal soft tissue sarcomas is common. CT is useful for detecting recurrences at primary and distant anatomic sites in the abdomen and pelvis. After surgery, cross-sectional imaging every 3 to 6 months during the first 2 years and every 6 months for 3 years thereafter has been recommended. However, many experienced surgeons are advocating less aggressive imaging for asymptomatic patients, particularly after a second recurrence of retroperitoneal sarcoma arguing that no evidence exists to suggest that survival is improved by earlier detection. Because most metastases to distant sites occur within 2 to 3 years of initial diagnosis, general guidelines are that follow-up intervals can be lengthened to every 6 months, with annual imaging, for years 2 through 5. After 5 years,

patients should be evaluated and undergo chest radiography annually. Whooley and associates reviewed the efficacy of the surveillance strategy used at Roswell Park Cancer Institute for 174 patients with soft tissue sarcomas of the extremities. 9 8 Patients were evaluated every 3 months for the first 2 years, every 4 to 6 months during year 3, and every 6 months through year 5. Local recurrence occurred in 18% of patients at a median interval of 14 months, and all but one of the recurrences was detected by physical examination alone. Fifty-seven patients had distant recurrences (at a median of 18 months after treatment), of which 36 were asymptomatic and diagnosed by surveillance radiographic imaging. Those investigators determined that the positive predictive value of chest radiography in follow-up was 92%.9 8 However, evaluation of the primary site by CT or MRI and routine laboratory assessment was ineffective in detecting recurrences. The authors of this report cautioned that their study did not conclusively demonstrate that CT and MRI should not be used. Rather, patient characteristics, location of the primary tumor, previous treatment, and physician familiarity with changes after surgery and radiation therapy should all be considered in determining the need for radiographic imaging.

Recurrent Sarcoma The pattern of recurrence is related to the anatomic site of the primary tumor. Up to 20% of patients with extremity sarcoma develop locally recurrent disease. Patients with microscopically positive surgical margins are at increased risk of local recurrence. In a series of 179 patients with locally recurrent extremity soft tissue sarcoma at Memorial Sloan-Kettering Cancer Center, the median interval to local recurrence was noted to be 16 months; 65% developed a local recurrence by 2 years and 90% by 4 years.9 6 The majority of patients (89%) were treated with additional limb-sparing surgery, and 73% received additional adjuvant therapy with a disease-specific survival of 55% at 4 years. Independent prognostic factors for disease-specific survival after local recurrence included histologic tumor grade, local recurrence size, and local recurrence-free interval. These data indicate that surveillance of patients for the first 4 years after resection of their primary extremity sarcoma is warranted. An isolated local recurrence should be treated aggressively with margin-negative resection. For patients with extremity sarcomas, this frequently requires amputation. However, some patients with recurrent extremity sarcoma can undergo function-preserving resection combined with additional radiation therapy, with or without chemotherapy, with acceptable rates of local control.99–101 Nori and colleagues reported a local control rate of 69% among 40 patients with recurrent tumors treated with re-excision and brachytherapy to a median dose of 45 Gy.101 In a similar series, limb-sparing conservative surgery was possible in 24 of 36 patients (66%), and the 5-year local recurrence-free survival rate was 72%. 9 9 The primary determinant of survival in patients with soft tissue sarcoma is development of distant metastases. Patients with extremity sarcomas generally have recurrence as distant pulmonary metastases, whereas patients with retroperitoneal or intra-abdominal sarcomas tend to have local recurrences.9 8 Other less common sites of metastasis include bone (7%), liver (4%), 5 2 and lymph nodes.3 Myxoid liposarcoma of the extremity is known to metastasize to the abdomen and pelvis and requires staging CT of these regions before definitive local therapy.1 7

SURGICAL RESECTION FOR METASTATIC SARCOMA The most common initial site of metastasis of soft tissue sarcomas is the lung. Selected patients with a limited number of pulmonary nodules (fewer than four), long disease-free intervals, and no endobronchial invasion may become long-term survivors after pulmonary resection (Fig. 36-8); 15 to 40% of patients with complete resection of metastatic disease confined to the lung are long-term survivors. 98,102 In a retrospective multi-institutional study of 255 patients, the 5-year overall survival rate after metastasectomy was reported to be 38%.103 Favorable prognostic factors in that study included microscopically free margins, age younger than 40 years old, and grade I

or II tumors.103 For patients who are surgical candidates, pulmonary resection alone also has been shown to be the most cost-effective treatment strategy compared to no treatment, chemotherapy alone, and surgery combined with chemotherapy.104

Fig. 36-8.

A 58-year-old man with a history of a T2 unclassified sarcoma of the thigh developed a solitary lung metastasis 18 months following surgical resection.

CHEMOTHERAPY FOR METASTATIC SARCOMA The only available treatment for most patients with metastatic disease is chemotherapy. Historically, response rates for patients with stage IV soft tissue sarcoma have been low. Several prognostic factors have been defined for patients undergoing chemotherapy, including performance status, previous response to chemotherapy, younger age, absence of hepatic metastases, low-grade tumors, and long disease-free interval.105 Isolated liver metastases, if stable over several months, may be amenable to resection, radiofrequency ablation, or chemoembolization.

PALLIATIVE RADIATION THERAPY Definitive radiation therapy has been described as a treatment option to be considered in clinical situations where there is no acceptable surgical option available (e.g., patient with significant medical comorbidities). A window of

therapeutic radiation dose benefit has been reported in this clinical setting in the range of 63 Gy to 67 Gy; higher radiation doses (greater than 63 Gy) yielded superior tumor control while doses over 68 Gy yielded increased rates of major complications. 106

SPECIAL SITUATIONS Myxoid Liposarcomas Myxoid liposarcomas belong to the group of soft tissue sarcomas with lipomatous differentiation. However, these tumors have very distinct morphology with myxoid stroma and lipomatous differentiation and clinical behavior that differs from the other liposarcoma subtypes. Myxoid liposarcomas frequently present as slow-growing, deep tumors in the lower extremity. Distinct from other soft tissue sarcomas that metastasize to the lungs, metastases arising from myxoid liposarcoma often are detected in other soft tissue locations, including the retroperitoneum or extremities.107,108 For this reason, CT of the chest, abdomen, and pelvis are recommended for the adequate staging and surveillance of patients with myxoid liposarcoma. Specific chromosomal translocation has been identified in myxoid liposarcoma that consists of the fusion of the SUF and CHOP genes [(t12;16)(q13;p11)] in 90% of tumors and fusion of the EWS and CHOP [(t12;22)(q13;q12)] genes in greater than 5% of tumors.109 These translocations can be detected using polymerase chain reaction techniques for diagnostic purposes.

Retroperitoneal Sarcomas Most retroperitoneal tumors are malignant, and about one third are soft tissue sarcomas. Also included in the differential diagnosis are primary germ cell tumor, lymphoma, or metastatic testicular cancer. Ten to 15% of adult soft tissue sarcomas, or about 1000 new cases, of retroperitoneal sarcoma are diagnosed annually in the United States. The most common sarcomas occurring in the retroperitoneum are liposarcomas, MFHs, and leiomyosarcomas. In contrast to extremity sarcomas, many retroperitoneal sarcomas present as large tumor masses abutting or involving vital structures, making margin-free resection difficult. As a result, locoregional recurrence is common (72% at 5 years), and prognosis for patients with retroperitoneal sarcoma is poor with 5year survival estimated at 36 to 58%.110 Retroperitoneal sarcomas generally present as large masses; nearly 50% are >20 cm at the time of diagnosis. They typically do not produce symptoms until they grow large enough to compress or invade contiguous structures. The evaluation for a patient with a retroperitoneal mass begins with an accurate history that should exclude signs and symptoms associated with lymphoma (e.g., fever and night sweats). Complete physical examination, with particular attention to all nodal basins and testicular examination in men, is critically important. Laboratory assessment can be helpful; an elevated lactate dehydrogenase level may suggest lymphoma, and elevated beta human chorionic gonadotropin levels or alpha-fetoprotein levels can indicate a germ cell tumor. Radiologic assessment should include CT of the abdomen and pelvis to define the extent of the tumor and its relationship to surrounding structures, particularly vascular structures. Imaging should also encompass the liver for the presence of metastases, the abdomen for discontiguous disease, and the kidneys bilaterally for function. Angiography or magnetic resonance arteriography/venography also can be used to delineate vascular anatomy in selected patients when involvement of critical vascular structures is suspected. Thoracic CT is indicated to detect lung metastases. For patients presenting with an equivocal history, an unusual appearance of the mass, an unresectable tumor, or distant metastasis, CT guided core needle or laparoscopic biopsy is appropriate to obtain a sample for tissue diagnosis.

Complete surgical resection is the most effective treatment for primary or recurrent retroperitoneal sarcomas (Fig. 36-9). En bloc resections for these tumors often include sacrificing contiguous structures such as the small bowel, colon, kidney, inferior vena cava, and aorta. In a review of 141 patient who underwent resection of retroperitoneal sarcoma with major blood vessel involvement, postoperative morbidity and mortality were 36 and 4% respectively, and vessel patency rates were greater than 88% at a median follow-up of 19.3 months.111 With favorable rates of local control and survival reported in their cohort of patients with tumor-free resection margins, the authors concluded that vascular resection is the treatment of choice in sarcomas that involve major blood vessels in the retroperitoneum.111

Fig. 36-9.

A. Computed tomography image of the abdomen for a 50-year-old woman with a massive retroperitoneal tumor with anterior displacement of left kidney. B. Gross specimen, en bloc resection of retroperitoneal liposarcoma with spleen, left kidney, left adrenal gland, and transverse and sigmoid colon.

In several retrospective assessments of patients with retroperitoneal sarcoma, complete surgical excision was achieved in only 40 to 60% of patients.112,113 In an analysis of 500 patients with retroperitoneal soft tissue sarcomas treated at Memorial Sloan-Kettering Cancer Center, the median survival time for those who underwent complete resection was 103 months vs. 18 months for those who underwent incomplete resection, or observation without resection.114 In general, surgical resection should not be offered to patients unless radiographic evidence indicates the potential for complete resection, although palliative surgical procedures may be considered to reduce the symptoms of intestinal obstruction, pain, or bleeding.115 In particular, patients with atypical lipomatous tumors, also termed well-differentiated liposarcomas , may benefit symptomatically from repeated tumor debulking. Tumor stage at presentation, high histologic grade, unresectability, and grossly positive resection margins are strongly associated with rates of death from retroperitoneal sarcoma.114,116,117 Survival rates at 5 years are typically reported to be 40 to 50%. The best chance for long-term survival for patients with retroperitoneal sarcoma is achieved with a margin-negative resection, however, this often is not possible. In one series, the 5-year disease-free survival rate was 50% for patients who had margin-negative resection as compared with 28% for patients undergoing incomplete resection.112 In the series reported by Lewis and associates,114 about 75% of patients died of locally recurrent disease without distant metastasis. As is true for extremity lesions, tumor grade is also a significant predictor of outcome for patients with retroperitoneal sarcoma. In the series reported by Jaques

and colleagues,113 patients with high-grade tumors (n = 65) had a median survival time of only 20 months compared with 80 months for patients with low-grade tumors (n = 49).

ADJUVANT THERAPY Most studies have failed to show a survival advantage for adjuvant chemotherapy for retroperitoneal sarcomas. 118–120 However, adjuvant chemotherapy has been advocated for some of the more uncommon histologic variants of retroperitoneal sarcoma including dedifferentiated liposarcoma, MFHs, and primitive neuroectodermal tumors.121,122 Because of the high rates of local recurrence, adjuvant radiation therapy has been proposed as a potential means of treating microscopic residual disease following the surgical resection of retroperitoneal sarcomas. However, the optimal technique and timing of delivery continues to evolve as clinicians weigh the potential benefits with the increased risk of treatment-related toxicity. Treatment of retroperitoneal sarcomas is complex because tumors are usually large, requiring large fields, and due to the proximity of radiosensitive structures (i.e., bowel). Several techniques have been used, including preoperative and postoperative external beam radiation, intraoperative radiation therapy, and brachytherapy.123 Preoperative radiotherapy is emerging as a technique that is feasible and well tolerated. Toxicity may be lower with preoperative radiation given that (a) the tumor borders are definable, (b) the tumor acts as an expander, displacing radiosensitive viscera away from the treatment field, and (c) effective doses of radiation may be lower preoperatively.124 There are a number of studies that report favorable local control rates for intermediate and high-grade retroperitoneal sarcomas treated with preoperative radiotherapy plus complete resection compared to historical data.123 However, most studies have failed to show a survival benefit for such patients.125 This body of evidence prompted the initiation of a multicenter, randomized trial sponsored by the American College of Surgeon's Oncology Group to compare surgery alone with preoperative radiation therapy plus surgery (ACOSOG Z9031). Unfortunately, the study was closed prematurely in 2006 because of lack of patient accrual. There are no consensus guidelines for the use of radiation in patients with primary or recurrent retroperitoneal sarcomas. The optimal balance between acceptable radiation toxicity and effective local control is yet to be determined. Current recommendations for radiation therapy for patients with retroperitoneal sarcoma at MDACC are based on presentation of disease.117 For high-risk patients, defined as those with large, high-grade tumors or recurrent lowgrade tumors, 50-Gy preoperative radiation therapy followed by surgical resection is recommended. In the preoperative setting, the tumor often displaces the bowel out of the field of radiation and treatment may be delivered with less toxicity. Postoperative radiation is discouraged unless the resected tumor bed is clearly away from dose-limiting structures.

RECURRENCES Retroperitoneal sarcomas recur in two thirds of patients. In addition to recurring locally in the tumor bed and metastasizing to the lungs, retroperitoneal leiomyosarcomas frequently spread to the liver. Retroperitoneal sarcomas can also recur diffusely throughout the peritoneal cavity (sarcomatosis). The approach to resectable recurrent disease after the treatment of a retroperitoneal sarcoma is similar to the approach taken after the recurrence of an extremity sarcoma. However, the ability to resect a recurrent retroperitoneal sarcoma declines precipitously. In a large series of patients treated at Memorial Sloan-Kettering Cancer Center, the authors were able to resect recurrent tumors in 57% of patients with a first recurrence, but in only 20% after a second recurrence, and 10% after a third recurrence.3 5 Of note is that in as many as 25% of patients, well-differentiated liposarcoma may recur in a poorly differentiated form or develop areas of dedifferentiation. Dedifferentiated

retroperitoneal liposarcoma is more aggressive with a greater propensity for distant metastasis than its welldifferentiated precursor.

Gastrointestinal Sarcomas Patients with GI sarcomas most often present with nonspecific GI symptoms that are determined by the site of the primary tumor. In a series from Memorial Sloan-Kettering Cancer Center, early satiety and dyspepsia were noted in patients with upper GI tumors, whereas tenesmus and changes in bowel habits were common in those with tumors of the lower GI tract.126 In a series of 80 patients with various smooth muscle tumors of the GI tract, Chou and associates127 identified the most common presenting symptoms and signs as GI bleeding (44%), abdominal mass (38%), and abdominal pain (21%). Establishing the diagnosis of a GI sarcoma preoperatively is often difficult. Radiologic assessment, including CT of the abdomen or pelvis, is sometimes useful to determine the anatomic location, size, and extent of disease. Patients with localized disease frequently present with a large intra-abdominal mass but no radiographic evidence of the regional lymph node metastases that would be typical of an adenocarcinoma of comparable size and anatomic location. In patients with advanced disease, CT may demonstrate disseminated intra-abdominal masses with or without concomitant ascites and possible invasion of tissue planes. Endoscopy (esophagoduodenoscopy or colonoscopy) has become the mainstay for evaluating symptoms related to the GI tract. For tumors involving the stomach, upper endoscopy with endoscopic ultrasonography and biopsy are important diagnostic tests used to distinguish adenocarcinoma from GI sarcomas. This distinction is clinically significant because the extent of resection (local excision vs. gastrectomy) and the role of regional lymph node dissection differs for these two conditions. Lymphatic spread is not the primary route of metastasis for GI sarcomas. Consequently, lymphadenectomy is not routinely performed as part of resection. Based on published data and the primary pattern of distant (vs. local) failure, the general recommendation is to perform a marginnegative resection with a 2- to 4-cm margin of normal tissue. However, some cases may be technically challenging because of the tumor's anatomic location or size. For example, for gastric tumors located near the gastroesophageal junction, achieving adequate surgical margins may not be possible without a total or proximal subtotal gastrectomy. Similarly, large leiomyosarcomas arising from the stomach with invasion of adjacent organs should be resected together with the adjacent involved viscera en bloc. Segmental bowel resection is the standard treatment for sarcomas of the small or large intestine. For the jejunum, ileum, and colon, the tumor is excised en bloc with the involved segment of intestine and its mesentery; radical mesenteric lymphadenectomy is not attempted. For sarcomas originating in the rectum, the technique used for tumor resection is based on the anatomic location and size of the tumor. For small, low rectal lesions, it may be possible to achieve clear margins with a transanal excision. Large or locally invasive lesions may require more extensive operations for complete tumor extirpation.128,129 Meijer and colleagues129 reviewed the experience with 50 patients with primary colorectal sarcoma at Memorial Sloan-Kettering Cancer Center. In 32 cases, the primary tumor was located in the rectum, and 18 tumors involved the colon. Of the rectal lesions, 15 were treated with abdominoperineal resection and 12 were treated with local excision. Distant metastasis was the first recurrence in 11 of the 32 patients who underwent curative resection.129

GASTROINTESTINAL STROMAL TUMOR Gastrointestinal stromal tumors (GISTs), which constitute the majority of GI sarcomas, have distinctive molecular features of GISTs that have been characterized over the last decade. These tumors share phenotypic similarities with the intestinal pacemaker cell known as the interstitial cells of Cajal . 130 The interstitial cells of Cajal and GIST

cells express the hematopoietic progenitor cell marker CD34 and the growth factor receptor c-Kit (CD117).131 c-Kit is a transmembrane glycoprotein receptor with an internal tyrosine kinase component that, when activated, triggers a cascade of intracellular signals regulating cell growth and survival.132 The expression of the c-Kit gene protein product CD117 has emerged as an important defining feature of GISTs. Using these diagnostic criteria, the incidence of GIST has been estimated at 6–15 cases per 1 million population. 133–135 Kit mutation site has emerged as a prognostic factor of progression-free and overall survival in patients with GIST. Patients with Kit exon 11 mutation have a superior progression-free and overall survival on imatinib therapy compared to those patients whose tumors have an exon 9 mutation or wild-type Kit. Current clinical practice in many centers is to perform mutation analysis of the Kit gene in all new patients for both prognostic and therapeutic consideration.

RADIOLOGIC ASSESSMENT Positron emission tomography (PET) using

18

F-fluorodeoxyglucose has been reported as useful for preoperative

staging of GISTs, as it may reveal early metastases and establish baseline metabolic activity. PET has been shown to be highly sensitive in detecting early response to imatinib treatment and predicting long-term response in patients with metastatic GIST. Because PET imaging is still not widely available and, in some lesions, insensitive, and because glucose uptake is not sufficient, predictive criteria for assessment of GISTs using CT imaging also have been proposed.136

MANAGEMENT OF LOCALIZED DISEASE Surgery remains the only potentially curative treatment for patients with localized GISTs. Complete resection with negative margins, even of locally advanced tumors, is associated with improved survival.137 The extent of surgery required to produce a complete resection does not seem to influence survival. The 5-year survival rate for all patients with GISTs ranges from 20 to 44% and up to 75% for early-stage tumors that have been completely excised.137 However, a more recent analysis of 200 patients by DeMatteo and colleagues noted a disease-specific survival rate of only 54% for patients in whom a grossly complete resection of primary GISTs had been achieved, and the median survival duration for patients with metastatic disease was only 20 months.138 As with other soft tissue sarcomas, tumor size has consistently been identified as an important prognostic factor for GISTs. Mitotic activity also has been identified as an important prognostic factor and is generally categorized as Chapter 37. Inguinal Hernias>

KEY POINTS 1. A proficient understanding of groin anatomy is essential to successful inguinal hernia treatment. 2. Conservative management of asymptomatic inguinal hernias is acceptable. 3. Elective repair of inguinal hernias can be undertaken using a laparoscopic or open approach.

4. Laparoscopic inguinal hernia repair results in less pain and faster recovery, yet requires specialized training and equipment 5. The use of prosthetic mesh as a reinforcement significantly improves recurrence rates, whether the repair is open or laparoscopic. 6. Recurrence, pain, and quality of life are important outcome factors.

HISTORY

The treatment of inguinal hernias is integral to the history and current status of general surgery; evolution in the treatment o

inguinal hernias has paralleled technologic developments in the field. The most significant advances to impact inguinal hernia repair have been the addition of prosthetic materials to conventional repairs and the introduction of laparoscopy to general surgical procedures. Evidence of surgical repair of inguinal hernias can be traced back to civilizations of ancient Egypt and Greece.1 Early management of inguinal hernias involved a conservative approach using trusses; however, the inefficacy of this approach prompted the initiation of a surgical approach to the problem. As a consequence of the primitiveness of the techniques, the treatment was often worse than the disease itself. Surgery often involved routine excision of the testicle, and wounds were

closed with cauterization or left to granulate on their own. Considering these procedures were performed before the advent o the aseptic technique, it is safe to assume that mortality was quite high. For those that did survive the operation, recurrence the hernia was commonplace. Failure of these early techniques of hernia repair was based on inadequate knowledge of groin anatomy and poor understanding of the natural history of hernia formation. As the anatomy of the human body was described via dissection study, the anatomy of the groin became defined. From the late 1700s to the early 1800s, physicians such as Hasselbach,

Cooper, Camper, Scarpa, Richter, and Gimbernat identified vital components of the inguinal region, and their contributions ar reflected in the current nomenclature. The progress in anatomic understanding, coupled with the development of the aseptic technique, led surgeons such as Marcy, Kocher, and Lucas-Championnire to enter the inguinal canal and perform sac dissection, high ligation, and closure of the internal ring. Results had improved, but recurrence rates remained high with prolonged follow-up.

By demonstrating a comprehensive understanding of inguinal anatomy, Bassini (1844–1924) transformed inguinal hernia rep into a successful venture with minimal morbidity to the patient. His operation involved dissection of the layers of the inguinal

canal to the transversalis fascia and then a reconstruction of the floor of the inguinal canal in several layers. The success of th Bassini repair over any of its predecessors ushered in an era of tissue-based repairs. Modifications of the Bassini repair were manifest in the McVay repair, as well as the Shouldice repair. All three of these techniques are currently practiced: the Shouldice repair, namely at the institution that bears its name (Shouldice Hernia Centre) and the McVay and Bassini in situations when prosthetic materials are contraindicated.

The era of tissue-based repairs was supplanted by tension-free repairs with the widespread acceptance of prosthetic material for inguinal floor reconstruction. Initially described by Lichtenstein, the repair involved placement of a Marlex mesh over the entire floor of the inguinal canal. The repair capitalized on the concept of the myopectineal orifice of Fruchaud, which was based on the notion that whatever the type of inguinal hernia, the defect lay in the integrity of the transversalis fascia. This

was superior to previous tissue-based repairs in that the weakness of the transversalis fascia could be restored by bridging th defect with mesh, rather than placing tension between tissues to close the defect. Superior results could be achieved by

nonexpert hernia surgeons. The concept of prosthetic reconstruction of the inguinal floor was also furthered by Stoppa, Rives and Wantz, who developed a preperitoneal mesh placement over the transversalis fascia.

With the advent of minimally invasive surgery, inguinal hernia repair underwent its most recent transformation. Laparoscopic inguinal hernia repair has added to the armamentarium of the general surgeon, providing a technique that lessens postoperative pain and improves recovery. Since the initial description by Ger, the laparoscopic method of hernia repair has become significantly more sophisticated. Refinements in approach and technique have led to the development of the intraperitoneal onlay mesh (Fitzgibbons and Toy 1990), the transabdominal preperitoneal (TAPP) repair (Arregui 1991), and the totally extraperitoneal (TEP) repair (Duluq 1991). Furthermore, an array of prosthetic materials has been introduced to further lower recurrence rates and provide the patient with the utmost quality of life. Irrespective of the approach to hernia repair, be it open or laparoscopic, the current state of surgical treatment of inguinal hernia depends on a sound foundation of the inguinal anatomy. The application of current technologies to this anatomic knowledge has fostered successful treatment of inguinal hernias with minimal morbidity heretofore unknown to surgical practice.

EPIDEMIOLOGY Inguinal hernia repair is one of the cornerstones of a general surgery practice and is one of the most commonly performed procedures in the United States, owing to a significant lifetime incidence and variety of successful treatment modalities. Although there are no exact figures totaling the number of inguinal hernia repairs performed annually, it has been estimated that approximately 800,000 cases were performed in 2003, not including recurrent or bilateral hernias.2 A vast majority of these procedures were performed on an outpatient basis. Advancements in perioperative anesthesia and the increase in proportion of laparoscopic treatment of inguinal hernias have combined to increase the percentage of ambulatory inguinal

hernias. In a survey of 17 states in 2003, 89% of the total number of inguinal hernia repairs were performed on an outpatien basis.3 However, the preponderance of laparoscopic inguinal hernia repair is relatively low (14%) when compared to percentage of open inguinal hernia repair (86%).4 The majority of abdominal wall hernias occur in the groin, totaling approximately 75% of the total incidence. It is difficult to

estimate the exact prevalence of inguinal hernias in the population, but an overwhelming majority of inguinal hernias occur in

males vs. females. Of inguinal hernia repairs, 90% are performed in males and 10% in females. Approximately 70% of femor hernia repairs are performed on female patients; however, females undergo nearly five times the number of inguinal hernia repairs as femoral hernia repairs. The most common type of groin hernia presenting in females remains the indirect inguinal

hernia.5

Classical teaching has been that most unilateral hernias originate on the right side. However, it has been recognized that up t one third of patients that undergo unilateral inguinal hernia repair may develop a contralateral inguinal hernia. Physical examination, although dependable in confirming the presence of symptomatic hernias, is beset with limitations when a small hernia is present. Therefore, although patients were diagnosed with unilateral inguinal hernias, they may, in fact, have had bilateral hernias. With the advent of laparoscopic techniques, the contralateral side can be examined without additional incisions or trocars. In a study examining only patients with primary unilateral inguinal hernias, 22% were found to have an occult contralateral hernia during laparoscopic inguinal hernia repair.6 Although asymptomatic at time of diagnosis, these hernias have the potential to become clinically significant as the patient ages.

Incidence of inguinal hernias in males has a bimodal distribution with peaks before 1 year of age and then again after age 40

The age-dependence of inguinal hernias was demonstrated in an oft-cited study by Abramson. Males >25 years old (n = 1883 were studied and constituted 91% of the total males settled in western Jerusalem. Between the years 1969–71, the

participants were first interviewed regarding the presence of an inguinal hernia and subsequently examined by a physician. A total of 459 men with 637 hernias between them were identified. The results were limited to those that had not previously

undergone an inguinal hernia operation. The current prevalence rate was 18%, and the lifetime risk of developing an inguinal

hernia was 24%. When subdivided into age groups, those aged 25 to 34 years had a lifetime prevalence rate of 15% whereas

those aged 75 years and over had a rate of 47% (Table 37-1).7 In a later study of California males aged 14 to 62, significantl

decreased "current" prevalence rates were noted in most age groups; however, lifetime prevalence rates were largely similar between both studies. A notable drawback of this study was the reliance on self-reporting and the absence of physical examination to confirm findings.

Table 37-1 Inguinal Hernia Prevalence by Age Current prevalence (%) 12 15 20 26 29 34 Lifetime prevalence (%) 15 19 28 34 40 47 Age (Y)

25–34

35–44

45–54

55–64

65–74

75+

Current = repaired hernias excluded; Lifetime = repaired hernias included.

ETIOLOGY

Inguinal hernias may be considered congenital or acquired diseases. Although there is debate, in all likelihood, inguinal hernia

in the adult are acquired defects in the abdominal wall. A number of studies have attempted to delineate the precise causes o

inguinal hernia formation; however, the risk factors are likely multifactorial, the common denominator being a weakness in th abdominal wall musculature (Table 37-2). Congenital hernias, which make up the majority of pediatric hernias, can be considered an impedance of normal development, rather than an acquired weakness. During the normal course of development, the testes descend from the intra-abdominal space into the scrotum in the third trimester. Their descent is preceded by the gubernaculum and a diverticulum of peritoneum, which protrudes through the inguinal canal and ultimately becomes the processus vaginalis. Between 36 and 40 weeks, the processus vaginalis closes and eliminates the peritoneal

opening at the internal inguinal ring. 8 Failure of the peritoneum to close results in a patent processus vaginalis (PPV) and thu explains the high incidence of indirect inguinal hernias in preterm babies. It should be noted that the processus vaginalis continues to close as the child ages, with most closing within the first few months of life. Children with congenital indirect

inguinal hernias will present with a PPV; however, its presence does not necessarily indicate an inguinal hernia (Fig. 37-1). In

study of nearly 600 adults undergoing laparoscopy for reasons not related to inguinal hernia repair, bilateral inspection of the internal inguinal rings revealed an incidence of 12% of PPV. None of these patients had clinically significant symptoms of a

groin hernia.9 However, in a group of 300 patients undergoing unilateral laparoscopic inguinal hernia repair, 12% were found

have a contralateral PPV. Over the next 5 years, they developed inguinal hernias at a rate four times more than counterparts that had a closed ring.1 0

Table 37-2 Presumed Causes of Groin Herniation Coughing Chronic obstructive pulmonary disease Obesity Straining Constipation Prostatism Pregnancy Birthweight Chapter 38. Thyroid, Parathyroid, and Adrenal>

KEY POINTS 1. There has been a paradigm shift in the surgical management of Graves' disease with increased use of total or near-total thyroidectomy, rather than subtotal thyroidectomy. 2. Familial nonmedullary thyroid cancer is increasingly being recognized as a separate entity. Surgeons must be aware of the potential for false negative fine-needle aspiration biopsy in this setting. 3. Total thyroidectomy is the surgical treatment of choice for most thyroid cancers, provided complication rates are low. 4. The widespread use of positron emission tomography scanning for staging various malignancies and ultrasound for vascular screening is leading to an increased incidence of thyroid incidentalomas. Management should be based on assessment of the individual patient's risk following complete clinical and fine-needle aspiration biopsy evaluation. 5. Focused mini-incision parathyroidectomy, after appropriate localization, has become the procedure of choice for the treatment of sporadic primary hyperparathyroidism. 6. Parathyroidectomy has been shown to improve the classic and so-called nonspecific symptoms and metabolic complications of primary hyperparathyroidism. 7. Very high calcium and parathyroid hormone levels in a patient with primary hyperparathyroidism should alert the surgeon to the presence of a possible parathyroid carcinoma. 8. Subclinical Cushing's syndrome is characterized by subtle abnormalities in corticosteroid synthesis, and many of its manifestations appear to be treated by adrenalectomy. 9. Fine-needle aspiration biopsy has a very limited role in the evaluation of adrenal incidentalomas unless the patient has previously had a cancer and should only be performed after appropriate biochemical studies have been performed to rule out pheochromocytoma. 10. Adrenocortical cancer can be difficult to diagnose even on pathology examination so that continued follow-up of patients with resected seemingly benign tumors is advised.

THYROID Historical Background Goiters (from the Latin guttur, throat), defined as an enlargement of the thyroid, have been recognized since 2700

B.C.

even though the thyroid gland was not documented as such until the Renaissance period. In 1619, Hieronymus

Fabricius ab Aquapendente recognized that goiters arose from the thyroid gland. The term thyroid gland (Greek thyreoeides , shield-shaped) is, however, attributed to Thomas Wharton in his Adenographia (1656). In 1776, the thyroid was classified as a ductless gland by Albrecht von Haller and was thought to have numerous functions ranging from lubrication of the larynx to acting as a reservoir for blood to provide continuous flow to the brain, to beautifying women's necks. Burnt seaweed was considered to be the most effective treatment for goiters. The first accounts of thyroid surgery for the treatment of goiters were given by Roger Frugardi in 1170. In response to failure of medical treatment, two setons were inserted at right angles into the goiter and tightened twice daily until the goiter separated. The open wound was treated with caustic powder and left to heal. However, thyroid surgery continued to be hazardous with prohibitive mortality rates (>40%) until the latter half of the nineteenth century, when advances in general anesthesia, antisepsis, and hemostasis enabled surgeons to perform thyroid surgery with significantly reduced mortality and morbidity rates. The most notable thyroid surgeons were Emil Theodor Kocher (1841–1917) and C.A. Theodor Billroth (1829–1894), who performed thousands of operations with increasingly successful results. However, as more patients survived thyroid operations, new problems and issues became apparent. After total thyroidectomy, patients (particularly children) became myxedematous with cretinous features. Myxedema was first effectively treated in 1891 by George Murray using a subcutaneous injection of an extract of sheep's thyroid and later, Edward Fox demonstrated that oral therapy was equally effective. In 1909, Kocher was awarded the Nobel Prize for medicine in recognition "for his works on the physiology, pathology, and surgery of the thyroid gland."

Embryology The thyroid gland arises as an outpouching of the primitive foregut around the third week of gestation. It originates at the base of the tongue at the foramen cecum. Endoderm cells in the floor of the pharyngeal anlage thicken to form the medial thyroid anlage (Fig. 38-1) that descends in the neck anterior to structures that form the hyoid bone and larynx. During its descent, the anlage remains connected to the foramen cecum via an epithelial-lined tube known as the thyroglossal duct . The epithelial cells making up the anlage give rise to the thyroid follicular cells. The paired lateral anlages originate from the fourth branchial pouch and fuse with the median anlage at approximately the fifth week of gestation. The lateral anlages are neuroectodermal in origin (ultimobranchial bodies) and provide the calcitonin producing parafollicular or C cells, which thus come to lie in the superoposterior region of the gland. Thyroid follicles are initially apparent by 8 weeks, and colloid formation begins by the eleventh week of gestation.

Fig. 38-1.

Thyroid embryology—early development of the median thyroid anlage as a pharyngeal pouch. [Reproduced with permission from Embryology and developmental abnormalities, in Cady B, Rossi R (eds): Surgery of the Thyroid and Parathyroid Glands . Philadelphia: WB Saunders, 1991, p 6.]

Developmental Abnormalities THYROGLOSSAL DUCT CYST AND SINUS Thyroglossal duct cysts are the most commonly encountered congenital cervical anomalies. During the fifth week of gestation, the thyroglossal duct lumen starts to obliterate, and the duct disappears by the eighth week of gestation. Rarely, the thyroglossal duct may persist in whole, or in part. Thyroglossal duct cysts may occur anywhere along the migratory path of the thyroid although 80% are found in juxtaposition to the hyoid bone. They are usually asymptomatic but occasionally become infected by oral bacteria, prompting the patient to seek medical advice. Thyroglossal duct sinuses result from infection of the cyst secondary to spontaneous or surgical drainage of the cyst and are accompanied by minor inflammation of the surrounding skin. Histologically, thyroglossal duct cysts are lined by pseudostratified ciliated columnar epithelium and squamous epithelium, with heterotopic thyroid tissue present in 20% of cases. The diagnosis usually is established by observing a 1- to 2-cm, smooth, well-defined midline neck mass that moves upward with protrusion of the tongue. Routine thyroid imaging is not necessary although thyroid scintigraphy and ultrasound have been performed to document the presence of normal thyroid tissue in the neck. Treatment involves the "Sistrunk operation," which consists of en bloc cystectomy and excision of the central hyoid bone to minimize recurrence. Approximately 1% of thyroglossal duct cysts are found to contain cancer, which is usually

papillary (85%). The role of total thyroidectomy in this setting is controversial, but is advised in older patients with large tumors, particularly if there are additional thyroid nodules and evidence of cyst wall invasion or lymph node metastases.1 Squamous, Hrthle cell, and anaplastic cancers also have been reported but are rare. Medullary thyroid cancers (MTCs) are, however, not found in thyroglossal duct cysts.

LINGUAL THYROID A lingual thyroid represents a failure of the median thyroid anlage to descend normally and may be the only thyroid tissue present. Intervention becomes necessary for obstructive symptoms such as choking, dysphagia, airway obstruction, or hemorrhage. Many of these patients develop hypothyroidism. Medical treatment options include administration of exogenous thyroid hormone to suppress thyroid-stimulating hormone (TSH) and radioactive iodine (RAI) ablation followed by hormone replacement. Surgical excision is rarely needed but, if required, should be preceded by an evaluation of normal thyroid tissue in the neck to avoid inadvertently rendering the patient hypothyroid.

ECTOPIC THYROID Normal thyroid tissue may be found anywhere in the central neck compartment, including the esophagus, trachea, and anterior mediastinum. Thyroid tissue has been observed adjacent to the aortic arch, in the aortopulmonary window, within the upper pericardium, or in the interventricular septum. Often, "tongues" of thyroid tissue are seen to extend off the inferior poles of the gland and are particularly apparent in large goiters. Thyroid tissue situated lateral to the carotid sheath and jugular vein, previously termed lateral aberrant thyroid , almost always represents metastatic thyroid cancer in lymph nodes, and not remnants of the lateral anlage that had failed to fuse with the main thyroid, as previously suggested by Crile. Even if not readily apparent on physical examination or ultrasound imaging, the ipsilateral thyroid lobe contains a focus of papillary thyroid cancer (PTC), which may be microscopic.

PYRAMIDAL LOBE Normally the thyroglossal duct atrophies, although it may remain as a fibrous band. In about 50% of individuals, the distal end that connects to the thyroid persists as a pyramidal lobe projecting up from the isthmus, lying just to the left or right of the midline. In the normal individual, the pyramidal lobe is not palpable, but in disorders resulting in thyroid hypertrophy (e.g., Graves' disease, diffuse nodular goiter, or lymphocytic thyroiditis), the pyramidal lobe usually is enlarged and palpable.

Thyroid Anatomy The anatomic relations of the thyroid gland and surrounding structures are depicted in Fig. 38-2. The adult thyroid gland is brown in color and firm in consistency, and is located posterior to the strap muscles. The normal thyroid gland weighs approximately 20 g, but gland weight varies with body weight and iodine intake. The thyroid lobes are located adjacent to the thyroid cartilage and connected in the midline by an isthmus that is located just inferior to the cricoid cartilage. A pyramidal lobe is present in about 50% of patients. The thyroid lobes extend to the midthyroid cartilage superiorly and lie adjacent to the carotid sheaths and sternocleidomastoid muscles laterally. The strap muscles (sternohyoid, sternothyroid, and superior belly of the omohyoid) are located anteriorly and are innervated by the ansa cervicalis (ansa hypoglossi). The thyroid gland is enveloped by a loosely connecting fascia that is formed from the partition of the deep cervical fascia into anterior and posterior divisions. The true capsule of the thyroid is a thin, densely adherent fibrous layer that sends out septa that invaginate into the gland, forming pseudolobules. The thyroid capsule is condensed into the posterior suspensory or Berry's ligament near the cricoid cartilage and upper tracheal rings.

Fig. 38-2.

Anatomy of the thyroid gland and surrounding structures, viewed anteriorly (A ) and in cross-section (B ). a. = artery; m. = muscle; n. = nerve; v. = vein.

BLOOD SUPPLY The superior thyroid arteries arise from the ipsilateral external carotid arteries and divide into anterior and posterior branches at the apices of the thyroid lobes. The inferior thyroid arteries arise from the thyrocervical trunk shortly after their origin from the subclavian arteries. The inferior thyroid arteries travel upward in the neck posterior to the carotid sheath to enter the thyroid lobes at their midpoint. A thyroidea ima artery arises directly from the aorta or innominate in 1 to 4% of individuals to enter the isthmus or replace a missing inferior thyroid artery. The inferior thyroid artery crosses the recurrent laryngeal nerve (RLN), necessitating identification of the RLN before the arterial branches can be ligated. The venous drainage of the thyroid gland occurs via multiple small surface veins, which coalesce to form three sets of veins—the superior, middle, and inferior thyroid veins. The superior thyroid veins run with the superior thyroid arteries bilaterally. The middle vein or veins are the least consistent. The superior and middle veins drain directly into the internal jugular veins. The inferior veins often form a plexus, which drains into the brachiocephalic veins.

NERVES The left RLN arises from the vagus nerve where it crosses the aortic arch, loops around the ligamentum arteriosum, and ascends medially in the neck within the tracheoesophageal groove. The right RLN arises from the vagus at its crossing with the right subclavian artery. The nerve usually passes posterior to the artery before ascending in the neck, its course being more oblique than the left RLN. Along their course in the neck, the RLNs may branch, and pass anterior, posterior, or interdigitate with branches of the inferior thyroid artery (Fig. 38-3). The right RLN may be nonrecurrent in 0.5 to 1% of individuals and often is associated with a vascular anomaly.2 Nonrecurrent left RLNs are rare but have been reported in patients with situs inversus and a right-sided aortic arch. The RLN may branch in its course in the neck and identification of a small nerve should alert the surgeon to this possibility.

Identification of the nerves or their branches often necessitates mobilization of the most lateral and posterior extent of the thyroid gland, the tubercle of Zuckerkandl, at the level of the cricoid cartilage. The last segments of the nerves often course below the tubercle and are closely approximated to the ligament of Berry. Branches of the nerve may traverse the ligament in 25% of individuals, and are particularly vulnerable to injury at this junction. The RLNs terminate by entering the larynx posterior to the cricothyroid muscle.

Fig. 38-3.

Relationship of recurrent laryngeal nerve to the inferior thyroid artery—the superior parathyroid is characteristically dorsal to the plane of the nerve, whereas the inferior gland is ventral to the nerve.

The RLNs innervate all the intrinsic muscles of the larynx, except the cricothyroid muscles, which are innervated by

the external laryngeal nerves. Injury to one RLN leads to paralysis of the ipsilateral vocal cord, which comes to lie in the paramedian or the abducted position. The paramedian position results in a normal, but weak voice, whereas the abducted position leads to a hoarse voice and an ineffective cough. Bilateral RLN injury may lead to airway obstruction, necessitating emergency tracheostomy, or loss of voice. If both cords come to lie in an abducted position, air movement can occur, but the patient has an ineffective cough and is at increased risk of repeated respiratory tract infections from aspiration. The superior laryngeal nerves also arise from the vagus nerves. After their origin at the base of the skull, these nerves travel along the internal carotid artery and divide into two branches at the level of the hyoid bone. The internal branch of the superior laryngeal nerve is sensory to the supraglottic larynx. Injury to this nerve is rare in thyroid surgery, but its occurrence may result in aspiration. The external branch of the superior laryngeal nerve lies on the inferior pharyngeal constrictor muscle and descends alongside the superior thyroid vessels before innervating the cricothyroid muscle. Cernea and colleagues3 proposed a classification system to describe the relationship of this nerve to the superior thyroid vessels (Fig. 38-4). The type 2a variant, in which the nerve crosses below the tip of the thyroid superior pole, occurs in up to 20% of individuals and places the nerve at a greater risk of injury. Therefore, the superior pole vessels should not be ligated en masse, but should be individually divided, low on the thyroid gland and dissected lateral to the cricothyroid muscle. Injury to this nerve leads to inability to tense the ipsilateral vocal cord and hence difficulty "hitting high notes," projecting the voice, and voice fatigue during prolonged speech.

Fig. 38-4.

Relationship of the external branch of the superior laryngeal nerve and superior thyroid artery originally described by Cernea and colleagues.3 In type 1 anatomy, the nerve crosses the artery =1 cm above the superior aspect of the thyroid lobe. In type 2 anatomy, the nerve crosses the artery 95% 10-year survival rate. Several prognostic indicators have been incorporated into various staging systems, which enable patients to be stratified into low-risk and high-risk groups. Unfortunately, all of these classification systems rely on data that are not available preoperatively. In 1987, Hay and colleagues2 7 at the Mayo Clinic proposed the AGES scoring system, which incorporates A ge, histologic G rade, E xtrathyroidal invasion, and metastases and tumor S ize to predict the risk of dying from papillary cancer. Low-risk patients are young, with well-differentiated tumors, no metastases, and small primary lesions, whereas high-risk patients are older, with poorly differentiated tumors, local invasion, distant metastases, and large primary lesions. The MACIS scale is a postoperative system modified from the AGES scale. This scale

incorporates distant M etastases, A ge at presentation (40 years old), C ompleteness of original surgical resection, extrathyroidal I nvasion, and S ize of original lesion (in cm) and classifies patients into four risk groups based on their scores. Cady proposed the AMES system2 8 to classify differentiated thyroid tumors into low- and high-risk groups using A ge (men 70% of lung micrometastases that are detected by RAI scan in the presence of a normal chest x-ray, whereas the success rates drop to 30 mU/L are considered optimal, based on noncontrolled studies. 3 7 A low-iodine diet also is recommended during this 2-week period. The usual protocol involves administering a screening dose of 1 to 3 mCi of

123

I and measuring

uptake 24 hours later. After a total thyroidectomy, this value should be 2 ng/mL usually need another

131

I treatment after 6 to 12 months until one or two negative scans are obtained. The

follow-up scan can be done after hormone withdrawal or after recombinant TSH. The latter is more expensive but is preferred by patients. The maximum dose of radioiodine that can be administered at one time without performing dosimetry is approximately 200 mCi with a cumulative dose of 1000 to 1500 mCi. Up to 500 mCi can be given with proper pretreatment dosimetry. The early and delayed complications of RAI therapy are listed in Table 38-7.

Table 38-7 Complications of Radioactive Iodine Therapy (131 I) and Doses at Which They Are Observed Neck pain, swelling, and tenderness Hematologic Thyroiditis (if remnant present) Bone marrow suppression (>500 mCi) Sialadenitis (50–450 mCi), taste dysfunction Leukemia ( >1000 mCi) Hemorrhage (brain metastases) Fertility Cerebral edema (brain metastases, 200 mCi) Ovarian/testicular damage, infertility Vocal cord paralysis Increased spontaneous abortion rate Nausea and vomiting (50–450 mCi) Bone marrow suppression (200 mCi) Pulmonary fibrosis Chronic sialadenitis, nodules, taste dysfunction Increased risk of cancer Anaplastic thyroid cancer Gastric cancer Hepatocellular cancer Lung cancer Breast cancer (>1000 mCi) Bladder cancer Hypoparathyroidism

Acute

Long-Term

External Beam Radiotherapy and Chemotherapy External beam radiotherapy is occasionally required to control unresectable, locally invasive or recurrent disease4 4 and to treat metastases in support bones to decrease the risk of fractures. It also is of value for the treatment and control of pain from bony metastases when there is minimal or no RAIU. Single and multidrug chemotherapy has been used with little success in disseminated thyroid cancer, and there is no role for routine chemotherapy.3 7 Doxorubicin (Adriamycin) and paclitaxel (Taxol) are the most frequently used agents. The former acts as a radiation sensitizer and should be considered in patients undergoing external beam radiation.

Thyroid Hormone T4 is necessary not only as replacement therapy in patients after total or near-total thyroidectomy, but has the additional effect of suppressing TSH and reducing the growth stimulus for any possible residual thyroid cancer cells. TSH suppression reduces tumor recurrence rates. T4 should be administered to ensure that the patient remains euthyroid, with circulating TSH levels at about 0.1 U/L in low-risk patients, or 50%) bilateral. Total thyroidectomy is the treatment of choice for patients with MTC because of the high incidence of multicentricity, the more aggressive course, and the fact that

131

I therapy usually is not effective.

Central compartment nodes frequently are involved early in the disease process, so that a bilateral central neck node dissection should be routinely performed. In patients with palpable cervical nodes or involved central neck nodes, ipsilateral or bilateral, modified radical neck dissection is recommended. The role of prophylactic lateral neck dissection is controversial. However, in patients with tumors >1 cm, ipsilateral prophylactic modified radical neck dissection is recommended because >60% of these patients have nodal metastases. If ipsilateral nodes are positive, a contralateral node dissection should be performed. In the case of locally recurrent or metastatic disease, tumor debulking is advised not only to ameliorate symptoms of flushing and diarrhea, but also to decrease risk of death from recurrent central neck or mediastinal disease. External beam radiotherapy is controversial, but is recommended for patients with unresectable residual or recurrent tumor. There is no effective chemotherapy regimen. Various targeted therapies are being investigated for the treatment of MTC. A tyrosine kinase inhibitorSTI571 (imatinib) had shown promise in in vitro studies, but phase II clinical trials have been less encouraging.46,47 Another tyrosine kinase inhibitor with activity against the vascular endothelial growth factor receptor 2, ZD6474 (Zactima) was more effective in that phase II studies have shown partial responses in 27% of patients, with reduction in both calcitonin and CEA levels. An anti-CEA monoclonal antibody (labetuzumab) also has shown antitumor response in a small group of patients.4 8 Radiofrequency ablation done laparoscopically appears promising in the palliative treatment of liver metastases >1.5 cm. In patients who have hypercalcemia at the time of thyroidectomy, only obviously enlarged parathyroid glands should be removed. The other parathyroid glands should be preserved and marked in patients with normocalcemia, as only about 20% of patients with MEN2A develop HPT. When a normal parathyroid cannot be maintained on a vascular pedicle, it should be removed, biopsied to confirm that it is a parathyroid, and then autotransplanted to the forearm of the nondominant arm. Total thyroidectomy is indicated in RET mutation carriers once the mutation is confirmed. The procedure should be performed before age 6 in MEN2A patients and before age 1 year old in MEN2B patients.49,50 Central neck dissection can be avoided in children who are RET -positive and calcitoninnegative with a normal ultrasound examination. When the calcitonin is increased or the ultrasound suggests a thyroid cancer, a prophylactic central neck dissection is indicated.

Postoperative Follow-Up and Prognosis Patients are followed by annual measurements of calcitonin and CEA levels, in addition to history and physical examination. Other modalities used to localize recurrent disease include ultrasound, CT, MRI, and more recently, FDG PET scans. The latter have been reported to be superior to other radionuclide-based and routine morphologic

imaging by some investigators.5 1 Prognosis is related to disease stage. The 10-year survival rate is approximately 80% but decreases to 45% in patients with lymph node involvement. Survival also is significantly influenced by disease type. It is best in patients with non-MEN familial MTC, followed by those with MEN2A, and then those with sporadic disease. Prognosis is the worst (survival 35% at 10 years) in patients with MEN2B. Performing prophylactic surgery in RET oncogene mutation carriers not only improves survival rates but also renders most patients calcitonin free.

Anaplastic Carcinoma Anaplastic carcinoma accounts for approximately 1% of all thyroid malignancies in the United States and is declining in incidence. Women are more commonly affected, and the majority of tumors present in the seventh and eighth decade of life. The typical patient has a long-standing neck mass, which rapidly enlarges and may be painful. Associated symptoms such as dysphonia, dysphagia, and dyspnea are common. The tumor is large and may be fixed to surrounding structures or may be ulcerated with areas of necrosis (Fig. 38-21). Lymph nodes usually are palpable at presentation. Evidence of metastatic spread also may be present. Diagnosis is confirmed by FNAB revealing characteristic giant and multinucleated cells. Incisional biopsy occasionally is needed to confirm the diagnosis, and isthmusectomy with or without a tracheostomy may be needed to alleviate tracheal obstruction.

Fig. 38-21.

Magnetic resonance imaging scan of a patient with anaplastic thyroid cancer. Note heterogeneity consistent with necrosis.

Pathology On gross inspection, anaplastic tumors are firm and whitish in appearance. Microscopically, sheets of cells with marked heterogeneity are seen. Cells may be spindle shaped, polygonal, or large, multinucleated cells. Foci of more differentiated thyroid tumors, either follicular or papillary, may be seen, suggesting that anaplastic tumors arise from more well-differentiated tumors. One should confirm that the tumor is not a MTC or a small cell lymphoma because the prognosis varies considerably.

Treatment and Prognosis This tumor is one of the most aggressive thyroid malignancies, with few patients surviving 6 months beyond diagnosis. All forms of treatment have been disappointing. If anaplastic carcinoma presents as a resectable mass, thyroidectomy may lead to a small improvement in survival, especially in younger individuals. Combined radiation and chemotherapy in an adjuvant setting in patients with resectable disease has been associated with prolonged survival,5 2 although these agents are also being used in a neoadjuvant fashion. Tracheostomy may be needed to alleviate airway obstruction.

Lymphoma

Lymphomas account for 33). Urinary calcium levels need not be measured routinely, except in patients who have not had previously documented normocalcemia or have a family history of hypercalcemia to rule out FHH. In patients with FHH, 24-hour urinary calcium excretion is characteristically low (33) Magnesium Unchanged or decreased (in patients with osteitis fibrosa cystica) Uric acid Normal or increased Alkaline phosphatase Normal or increased (in the presence of high turnover bone disease) Acid-base status Mild hyperchloremic metabolic acidosis Calcium:creatinine ratio >0.02 (vs. 1 mg/dL above the upper limit of normal) and if BMD measured at any of three sites (radius, spine, or hip) is greater than 2.5 standard deviations below those of gender- and race-matched, not age-matched, controls (i.e., peak bone density or T score (rather than Z score) 1 mg/dL above the upper limits of normal Life-threatening hypercalcemic episode Creatine clearance reduced by 30% Kidney stones on abdominal x-rays Markedly elevated 24-h urinary calcium excretion (=400 mg/d) Substantially decreased bone mineral density at the lumbar spine, hip, or distal radius (>2.5 SD below peak bone mass, T score 80% for detection of parathyroid adenomas.7 3 Sestamibi (Cardiolite) initially was introduced for cardiac imaging and is concentrated in mitochondria-rich tissue. It was subsequently noted to be useful for parathyroid localization due to the delayed washout of the radionuclide from hypercellular parathyroid tissue compared to thyroid tissue. Sestamibi scans generally are complemented by neck ultrasound (Fig. 38-31B), which can identify adenomas with >75% sensitivity in experienced centers, 7 3 and is most useful in identifying intrathyroidal parathyroids. Single-photon emission computed tomography, particularly when used with CT, has been shown to be superior to other nuclear medicine–based imaging.7 4 Specifically, singlephoton emission computed tomography can indicate whether an adenoma is located in the anterior or posterior mediastinum (aortopulmonary window), thus enabling the surgeon to modify the operative approach accordingly.7 5 CT and MRI scans are less sensitive than sestamibi scans, but are helpful in localizing large paraesophageal and mediastinal glands. IOPTH was initially introduced in 1993 and is used to determine the adequacy of parathyroid resection (Fig. 38-32). 7 6 According to one commonly used criterion, when the PTH falls by 50% or greater 10 minutes after removal of a parathyroid tumor, as compared to the highest preremoval value, the test is considered positive, and the operation is terminated. IOPTH measurements, like localization studies, are less reliable in multiglandular disease.

Fig. 38-31.

A. Sestamibi scan in a patient with primary hyperparathyroidism showing persistent uptake suggesting a left lower hypercellular parathyroid gland. B. Neck ultrasound in a patient with primary hyperparathyroidism showing a left lower parathyroid adenoma.

Fig. 38-32.

Correlation of the 10-minute incubation time quick parathyroid hormone assay with the 24-hour immunoradiometric (irma) parathyroid hormone assay from 138 paired intraoperative samples from 38 patients undergoing parathyroidectomy. (Reproduced with permission from Irvin G, et al: Clinical usefulness of an intraoperative "quick parathyroid hormone" assay. Surgery 114:1020, 1993. Copyright Elsevier.)

Although preoperative localization studies and IOPTH have become widely used since their inception, the literature is lacking in studies directly comparing procedures performed with and without these studies. Furthermore, localization studies, including intraoperative PTH, are less sensitive and accurate when they are most necessary, such as in the presence of multiple gland parathyroid disease. Long-term outcome data and cost-effectiveness studies are needed before routine use of localization studies can be recommended; however, they should be used if a focused approach or reoperation is planned.7 0

Operative Approaches Unilateral parathyroid exploration was first carried out using intraoperative staining of a biopsy from the normal parathyroid gland with Sudan black dye to rule out a double adenoma. Initially, the choice of side to be explored was random, but the introduction of preoperative localization studies has enabled a more directed approach. In contrast, the focused approach identifies only the enlarged parathyroid gland, and no attempts are made to locate other normal parathyroid glands. Unilateral neck explorations have several advantages over bilateral neck exploration, including reduced operative times and complications, such as injury to the RLN and hypoparathyroidism. However, most existing studies comparing the two approaches are retrospective and do not analyze the results on an intention-to-treat basis. Another argument against a unilateral exploration is the risk of missing another adenoma on the opposite side of the neck. The incidence of double adenomas has been reported to range from 0 to 10%, with an increased incidence in elderly patients. The risk of missing a second adenoma is higher in populations with a higher incidence of multiple adenomas, such as those with familial HPT, MEN

syndromes, and the elderly. Another difficulty inherent with unilateral exploration is the inability to discern whether the combination of an abnormal gland and a normal gland on the initial side constitute a single adenoma or asymmetric hyperplasia. A recently published update on the 5-year results of a randomized trial comparing unilateral vs. bilateral neck exploration did not note any difference in the rates of recurrent or persistent disease in the two groups of patients.7 7 These issues will only be resolved by a large, prospective, multicenter study or improved molecular analytic techniques. Radio-guided parathyroidectomy takes advantage of the ability of parathyroid tumors to retain 99m Tc-sestamibi. One to two mCi of the isotope is injected before surgery and a hand-held gamma probe is used to guide the identification of the enlarged gland, taking care to ensure the equilibration of radioactivity counts in all quadrants. Reported advantages include easier localization, particularly in reoperative cases, and the ability to perform the procedure under local anesthetic or sedation using smaller incisions. Many studies demonstrated the feasibility of this technique; however, it is rarely used now, largely because it offers little advantage over preoperative sestamibi scans and is associated with increased operative times. Like preoperative scanning, it also has reduced accuracy in the presence of multiglandular disease. Endoscopic approaches include both video-assisted and total endoscopic techniques. Total endoscopic parathyroidectomy was first described by Gagner in 19967 8 and several other investigators have since reported on this technique. Although port placements are variable, as is the case with endoscopic thyroidectomy, they all involve creation of a working space in the neck using CO2 insufflation, with the reported advantages being superior cosmesis and excellent visualization. Although feasible, these techniques also have been associated with increased operating times, more personnel, and greater expense, and have, in general, not been useful for patients with multiglandular disease, a large thyroid mass, or previous neck surgery and irradiation. Their greatest use has been in patients with tumors at ectopic sites such as the mediastinum where thoracoscopic parathyroidectomy is an excellent alternative to sternotomy. Studies have shown that if both sestamibi scan and neck ultrasound studies independently identify the same, enlarged parathyroid gland, and no other gland, it is indeed the abnormal gland in approximately 95% of cases. These patients with sporadic PHPT are candidates for a focused neck exploration, an approach that is most commonly referred to as minimally invasive parathyroidectomy and has been reported to be the method of choice for members of the International Association of Endocrine Surgeons preferring a minimal-access approach.7 2 A standard bilateral neck exploration is planned if parathyroid localization studies or IOPTH are not available; if the localizing studies fail to identify any abnormal parathyroid gland or identify multiple abnormal glands, in patients with a family history of PHPT, MEN1, or MEN2A; or a concomitant thyroid disorder requires bilateral exploration. In addition, finding a minimally abnormal parathyroid gland on the side indicated by localization studies during focal exploration should prompt a bilateral exploration or at least the identification of a normal parathyroid gland on the same side. In patients with MEN1, HPT should be corrected before treatment of gastrinomas because gastrin levels decline after parathyroidectomy.

Conduct of Parathyroidectomy (Standard Bilateral Exploration) An experienced parathyroid surgeon with a thorough knowledge of parathyroid anatomy and embryology and meticulous technique is crucial for the best surgical results. The procedure usually is performed under general anesthesia. The patient is positioned supine on the operating table with the neck extended. For a bilateral exploration, the neck is explored via a 3- to 4-cm incision just caudal to the cricoid cartilage. The initial dissection and exposure is similar to that used for thyroidectomy. After the strap muscles are separated in the midline, one side of the neck is chosen for exploration. In contrast to a thyroidectomy, the dissection during a

parathyroidectomy is maintained lateral to the thyroid, making it easier to identify the parathyroid glands and not disturb their blood supply.

Identification of Parathyroids A bloodless field is important to allow identification of parathyroid glands. The middle thyroid veins are ligated and divided, thus enabling medial and anterior retraction of the thyroid lobe, with the aid of a peanut sponge or placement of 2 to 0 silk sutures into the thyroid. The space between the carotid sheath and thyroid is then opened by gentle sharp and blunt dissection, from the cricoid cartilage superiorly to the thymus inferiorly and the RLN is identified. Approximately 85% of the parathyroid glands are found within 1 cm of the junction of the inferior thyroid artery and RLNs. The upper parathyroid glands usually are superior to this junction and dorsal (posterior) to the nerve, whereas the lower glands are located inferior to the junction and ventral (anterior) to the recurrent nerve. Because parathyroid glands are partly surrounded by fat, any fat lobule at typical parathyroid locations should be explored because the normal or abnormal parathyroid gland may be concealed in the fatty tissue. The thin fascia overlying a "suspicious" fat lobule should be incised using a sharp curved hemostat and scalpel. This maneuver often causes the parathyroid gland to "pop" out. Alternatively, gentle, blunt peanut sponge dissection between the carotid sheath and the thyroid gland often reveals a "float" sign, suggesting the site of the abnormal parathyroid gland. Normal parathyroids are light beige and only slightly darker or brown compared to adjacent fat. Parathyroid tissue needs to be distinguished from normal or brown fat tissue, thyroid nodules, lymph nodes, and ectopic thymus. Lymph nodes generally are light beige to whitish gray in color, glassy, and multiple in number, whereas thyroid nodules generally are more vascular, firm, dark or reddish brown in color, and have a more variegated appearance. Intraoperatively, a suspicious nodule may be aspirated using a fine needle attached to a syringe containing 1 cc of saline. Very high PTH levels in the aspirate have been shown to be diagnostic in the intraoperative identification of parathyroid glands. Several characteristics such as size (>7 mm), weight, and color are used to distinguish normal from hypercellular parathyroid glands. Hypercellular glands generally are darker, more firm, and more vascular than normocellular glands. No single method is 100% reliable, and, therefore, the parathyroid surgeon must rely on experience and, at times, advice from a pathologist to help distinguish normal from hypercellular glands. Although several molecular studies have shown use in distinguishing parathyroid adenomas from hyperplasia, this determination also must be made by the surgeon intraoperatively by documenting the presence of a normal parathyroid gland.

Location of Parathyroid Glands The majority of lower parathyroid glands are found in proximity to the lower thyroid pole (Fig. 38-33A). If not found at this location, the thyrothymic ligament and thymus should be mobilized. The upper end of the cervical thymus is gently grasped with a right angle clamp, and the distal portion is bluntly dissected from perithymic fat with a peanut sponge. One can then "walk down" the thymus with successive right-angle clamps (Fig. 38-33B). Applying light tension along with a "twisting" motion helps to free the upper thymus. The carotid sheath also should be opened from the bifurcation to the base of the neck if the parathyroid tumor cannot be found. If these maneuvers are unsuccessful, an intrathyroidal gland should be sought by using intraoperative ultrasound, incising the thyroid capsule on its posterolateral surface or by performing an ipsilateral thyroid lobectomy and "breadloafing" the thyroid lobe. Preoperative or intraoperative ultrasonography can be useful for identifying intrathyroidal parathyroid glands. Rarely, the third branchial pouch may maldescend and be found high in the neck (undescended parathymus), anterior to the carotid bulb, along with the missing parathyroid gland. Upper parathyroid glands are more consistent in position and usually are found near the junction of the upper and middle thirds of the gland, at the level of the cricoid cartilage (Fig. 38-33C). Ectopic upper glands may be found in carotid sheath,

tracheoesophageal groove, retroesophageal, or in the posterior mediastinum. The locations of ectopic upper and lower parathyroid glands are shown in Fig. 38-34. Every attempt must be made to identify all four glands. Treatment depends upon the number of abnormal glands.

1. A single adenoma is presumed to be the cause of a patient's PHPT if only one parathyroid tumor is identified and the other parathyroid glands are normal, a situation present in about 80% of patients with PHPT. Adenomas typically have an atrophic rim of normal parathyroid tissue but this characteristic may be absent. The adenoma is dissected free of surrounding tissue, taking care to stay immediately adjacent to the tumor, without fracturing it. The vascular pedicle is clamped, divided, and ligated. Care should be taken to not rupture the parathyroid gland to decrease the risk of parathyromatosis. If there is any question about the presumed normal glands, one of them should be biopsied and examined by frozen section. 2. If two abnormal and two normal glands are identified, the patient has double adenomas. Triple adenomas are present if three glands are abnormal and one is normal. Multiple adenomas are more common in older patients with an incidence of up to 10% in patients >60 years old. The abnormal glands should be excised, provided the remaining glands are confirmed as such, thus excluding asymmetric hyperplasia after biopsy and frozen section. 3. If all parathyroid glands are enlarged or hypercellular, patients have parathyroid hyperplasia that has been shown to occur in about 15% of patients in various series. These glands are often lobulated, usually lack the rim of normal parathyroid gland seen in adenomas, and may be variable in size. It often is difficult to distinguish multiple adenomas from hyperplasia with variable gland size. Hyperplasia may be of the chief cell (more common), mixed, or clear-cell type. Patients with hyperplasia may be treated by subtotal parathyroidectomy or by total parathyroidectomy and autotransplantation, with the choice of procedure being determined by rates of recurrence, postoperative hypocalcemia, and failure rates of autotransplanted tissue. Initial studies demonstrated equivalent cure rates and postoperative hypocalcemia for the two techniques, with the latter having the added advantage of avoiding recurrence in the neck. However, autotransplanted tissue may fail to function in about 5% of cases.

Fig. 38-33.

Conduct of parathyroidectomy. A. Exposure of the lower parathyroid gland near the inferior pole of the thyroid gland and anterior to the recurrent laryngeal nerve. B. A thymectomy may be necessary if the lower parathyroid cannot be found in its usual location, or if the patient has familial primary hyperparathyroidism or secondary hyperparathyroidism. C. Exposure of the upper parathyroid gland near the insertion of the recurrent laryngeal nerve at the level of the cricothyroid muscle. a. = artery; Inf. = inferior; n. = nerve.

Fig. 38-34.

Location of ectopic upper and lower parathyroid glands. (Reproduced with permission from Akerstrm G, et al: Surgical anatomy of human parathyroid glands. Surgery 95:15, 1984. Copyright Elsevier.)

All four parathyroid glands are identified and carefully mobilized. For patients with hyperplasia, a titanium clip is placed across the most normal gland, leaving a 50-mg remnant and taking care to avoid disturbing the vascular pedicle and that the gland is resected with a sharp scalpel. If possible, it is preferable to subtotally resect an inferior gland, which is more easily accessible in case of recurrence due to its anterior location with respect to the RLN. The resected parathyroid tissue is confirmed by frozen section or PTH assay. If the remnant appears to be viable, the remaining glands are resected. If there is any question as to the viability of the initially subtotally resected gland, another gland is chosen for subtotal resection and the initial remnant is removed. Whenever multiple parathyroids are resected, it is preferable to cryopreserve tissue, so that it may be autotransplanted should the patient become hypoparathyroid. Parathyroid tissue usually is transplanted into the nondominant forearm. A horizontal skin incision is made overlying the brachioradialis muscle a few centimeters below the antecubital fossa. Pockets are made in the belly of the muscle and one to two pieces of parathyroid tissue measuring 1 mm each are placed into each pocket. A total of 12 to 14 pieces are transplanted. Autotransplanted

tissue also has been reported to function when transplanted into fat.

Indications for Sternotomy A sternotomy is usually not recommended at the initial operation, unless the calcium level is >13 mg/dL. Rather, it is preferred to biopsy the normal glands and subsequently close the patient's neck and obtain localizing studies, if they were not obtained previously. Intraoperative PTH assay during the operation from large veins may be helpful. Using highly selective venous catheterization postoperatively also may be needed when noninvasive localization studies are negative, equivocal, or conflicting. Lower parathyroid glands tend to migrate into the anterior mediastinum in the thymus or perithymic fat and usually can be approached via a cervical incision. A sternotomy is needed to deliver these tumors in approximately 5% of cases. Generally, the gland can be approached by a partial sternotomy to the third intercostal space. The midline sternotomy can be extended to the left or right side as required. Upper glands tend to migrate to the posterior mediastinum in the tracheoesophageal groove. Mediastinal glands also may be found in the aortopulmonary window or pericardium, or attached to the ascending aorta, aortic arch, or its branches.

Special Situations Parathyroid Carcinoma Parathyroid cancer accounts for approximately 1% of PHPT cases. It may be suspected preoperatively by the presence of severe symptoms, serum calcium levels >14 mg/dL, significantly elevated PTH levels (5

x

normal), and

a palpable parathyroid gland. Local invasion is most common; approximately 15% of patients have lymph node metastases and 33% have distant metastases at presentation. Intraoperatively, parathyroid cancer is suggested by the presence of a large, gray-white to gray-brown parathyroid tumor that is adherent to or invasive into surrounding tissues like muscle, thyroid, RLN, trachea, or esophagus. Enlarged lymph nodes also may be present. Accurate diagnosis necessitates histologic examination that reveals local tissue invasion, vascular or capsular invasion, trabecular or fibrous stroma, and frequent mitoses. Treatment of parathyroid cancer consists of bilateral neck exploration, with en bloc excision of the tumor and the ipsilateral thyroid lobe. Modified radical neck dissection is recommended in the presence of lymph node metastases. Prophylactic neck dissection is not advised because it is associated with an increased risk of complications and does not appear to have a significant impact on survival. If the diagnosis is made postoperatively, a decision must be made regarding the adequacy of initial surgery based on a review of operative notes, pathology reports, localization studies, and calcium and PTH levels. If any question exists, histologic review by another experienced pathologist can be helpful. Additional procedures can then be performed accordingly. Reoperation is indicated for locally recurrent or metastatic disease to control hypercalcemia. Radiation and chemotherapy may be considered in patients with unresectable disease. Bisphosphonates have shown some effectiveness in treating hypercalcemia associated with parathyroid carcinoma. Cinacalcet hydrochloride, a calcimimetic, can reduce PTH levels by directly binding to the CASR cells on the parathyroid gland and has been shown to be useful in controlling hypercalcemia in patients with refractory parathyroid carcinoma.7 9

Familial Hyperparathyroidism PHPT may occur as a component of various inherited syndromes such as MEN1 and MEN2A. Inherited PHPT also can occur as isolated familial HPT (non-MEN), or familial HPT with jaw tumors. The diagnosis of familial HPT is known or suspected in approximately 85% of patients preoperatively. Furthermore, patients with hereditary HPT generally have a higher incidence of multiglandular disease, supernumerary glands, and recurrent or persistent disease. Therefore, these patients warrant a more aggressive approach and are not candidates for various focused surgical

approaches. Although not absolutely necessary, preoperative sestamibi scan and ultrasound can be obtained in patients with inherited HPT to identify potential ectopic glands. A standard bilateral neck exploration is performed, along with a bilateral cervical thymectomy, regardless of the results of localization studies. Both subtotal parathyroidectomy and total parathyroidectomy with autotransplantation are appropriate and parathyroid tissue also should be cryopreserved. If an adenoma is found in patients with familial HPT, the adenoma and the ipsilateral normal parathyroid glands are resected. The normal-appearing glands on the contralateral side are biopsied and marked, so that only one side of the neck will need to be explored in the event of recurrence. Patients with MEN2A require total thyroidectomy and central neck dissection for prevention/treatment of MTC, a procedure that places the parathyroids at risk. Moreover, HPT is less aggressive in these patients. Hence, only abnormal parathyroid glands need to be resected at neck exploration. The other normal parathyroid glands should be marked with a clip.

Neonatal Hyperparathyroidism Infants with neonatal HPT present with severe hypercalcemia, lethargy, hypotonia, and mental retardation. This disorder is associated with homozygous mutations in the CASR gene. Urgent total parathyroidectomy (with autotransplantation and cryopreservation) and thymectomy is indicated. Subtotal resection is associated with high recurrence rates.

Parathyromatosis Parathyromatosis is a rare condition characterized by the finding of multiple nodules of hyper-functioning parathyroid tissue throughout the neck and mediastinum, usually following a previous parathyroidectomy. The true etiology of parathyromatosis is not known. It is postulated to arise either from overgrowth of congenital parathyroid rests (ontogenous parathyromatosis) or seeding at surgery from rupture of parathyroid tumors or subtotal resection of hyperplastic glands. Parathyromatosis represents a rare cause of persistent or recurrent HPT8 0 and can be identified intraoperatively. Aggressive local resection of these deposits can result in normocalcemia but is rarely curative. Some studies suggest that these patients have low-grade carcinoma because of invasion into muscle and other structures distant from the resected parathyroid tumor.

Postoperative Care and Follow-Up Patients who have undergone parathyroidectomy are advised to undergo calcium level checks 2 weeks postoperatively, at 6 months, and then annually. Recurrence rates are rare (norepinephrine>>isoproterenol; and

2

1

receptors—isoproterenol > epinephrine >> norepinephrine.

Table 38-16 Catecholamine Hormone Receptors and Effects They Mediate 1

receptors

receptors—isoproterenol >epinephrine = norepinephrine;

Blood vessels Contraction Gut Decreased motility, increased sphincter tone Pancreas Decreased insulin and glucagon release Liver Glycogenolysis, gluconeogenesis Eyes Pupil dilation Uterus Contraction Skin Sweating 2

Synapse (sympathetic) Inhibits norepinephrine release Platelet Aggregation 1

Heart Chronotropic, inotropic Adipose tissue Lipolysis Gut Decreased motility, increased sphincter tone Pancreas Increased insulin and glucagon release 2

Blood vessels Vasodilation Bronchioles Dilation

Uterus Relaxation Receptor

Tissue

Function

Disorders of the Adrenal Cortex HYPERALDOSTERONISM Hyperaldosteronism may be secondary to stimulation of the renin-angiotensin system from renal artery stenosis and to low-flow states such as congestive heart failure and cirrhosis. Hyperaldosteronism resulting from these conditions is reversible by treatment of the underlying cause. Primary hyperaldosteronism results from autonomous aldosterone secretion which, in turn, leads to suppression of renin secretion. Primary aldosteronism usually occurs in individuals between the ages of 30 to 50 years old and accounts for 1% of hypertension cases. It is associated with hypokalemia; however, more patients with Conn's syndrome are being diagnosed with normal potassium levels. Most cases result from a solitary functioning adrenal adenoma (~70%) and idiopathic bilateral hyperplasia (30%). Adrenocortical carcinoma and glucocorticoid suppressible hyperaldosteronism are rare, each accounting for 6 cm in diameter.8 8 The sensitivity, specificity, and likelihood ratio of tumor size in predicting malignancy (based on Surveillance; Epidemiology, and End Results program data) was recently reported as 96%, 51%, and 2 for tumors =4 cm; and 90%, 78%, and 4.1 for tumors =6 cm.8 9 Other CT imaging characteristics suggesting malignancy include tumor heterogeneity, irregular margins, and the presence of hemorrhage and adjacent lymphadenopathy or liver metastases. Moderately bright signal intensity on T2 -weighted images (adrenal mass to liver ratio 1.2:2.8), significant lesion enhancement, and slow washout after injection of gadolinium contrast also indicate malignancy, as does evidence of local invasion into adjacent structures such as the liver, blood vessels (IVC), and distant metastases. Once adrenal cancer is diagnosed, CT scans of the chest and pelvis are performed for staging. The tumor-node-metastasis (TNM) staging system for adrenocortical carcinoma is depicted in Table 38-19. Up to 70% of patients present with stage III or IV disease.

Fig. 38-45.

Computed tomography scan of the abdomen showing a left adrenocortical cancer with synchronous liver metastasis.

Table 38-19 TNM Staging for Adrenocortical Cancer29 I T1, N0, M0 II T2, N0, M0 III T3, N0, M0T1–2, N1, M0 IV T3–4, N1, M0 Any T, any N, M1 Stage

TNM Class

Primary tumor (T): T1, size =5 cm without local invasion; T2, size >5 cm without local invasion; T3, any size with local invasion but no involvement of adjacent organs; T4, any size with involvement of adjacent organs. Nodes (N): N0, no involvement of regional nodes; N1, positive regional lymph nodes. Metastasis (M): M0, no known distal metastases, M1, distant metastases present.

Source: Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Sixth Edition (2002) published by Springer Science and Business Media LLC, www.springerlink.com.

Pathology Most adrenocortical cancers are large, weighing between 100 and 1000 g. On gross examination, areas of hemorrhage and necrosis often are evident. Microscopically, cells are hyperchromatic and typically have large nuclei and prominent nucleoli. It is very difficult to distinguish benign adrenal adenomas from carcinomas by histologic examination alone. Capsular or vascular invasion is the most reliable sign of cancer. Weiss and associates studied a combination of nine criteria for their usefulness in distinguishing malignant from benign adrenal tumors: nuclear grade III or IV; mitotic rate greater than 5/50 high-power fields; atypical mitoses; clear cells comprising 25% or less of the tumor; a diffuse architecture; microscopic necrosis; and invasion of venous, sinusoidal, and capsular structure. Tumors with four or more of these criteria were likely to metastasize and/or recur.9 0 Rarely, the diagnosis of malignancy of a completely resected adrenal tumor is often only made in retrospect by the finding of metastatic disease many years later.

Treatment The most important predictor of survival in patients with adrenal cancer is the adequacy of resection. Patients who undergo complete resection have 5-year actuarial survival rates ranging from 32 to 48%, whereas median survival is 90% of cases of CAH. This deficiency prevents the production of 11-deoxycortisol and 11-DOC from progesterone precursors. Deficiency of glucocorticoids and aldosterone leads to elevated ACTH levels and overproduction of adrenal androgens and corticosteroid precursors such as 17-hydroxyprogesterone and

4

-

androstenedione. These compounds are converted to testosterone in the peripheral tissues, thereby leading to virilization. Complete deficiency of 21-hydroxylase presents at birth with virilization, diarrhea, hypovolemia, hyponatremia, hyperkalemia, and hyperpigmentation. Partial enzyme deficiency may present at birth or later with virilizing features. These patients are less prone to the salt-wasting that characterizes complete enzyme deficiency. 11 -hydroxylase deficiency is the second most common form of CAH and leads to hypertension (from 11-DOC accumulation), virilization, and hyperpigmentation. Other enzyme deficiencies include 3 -hydroxydehydrogenase and 17-hydroxylase deficiency. Congenital adrenal lipoid hyperplasia is the most severe form of CAH, which is caused by cholesterol desmolase deficiency. It leads to the disruption of all steroid biosynthetic pathways, thus resulting in a fatal salt-wasting syndrome in phenotypic female patients.

Diagnostic Tests The particular enzyme deficiency can be diagnosed by karyotype analysis and measurement of plasma and urinary steroids. The most common enzyme deficiency, absence of 21-hydroxylase, leads to increased plasma 17-

hydroxyprogesterone and progesterone levels, because these compounds cannot be converted to 11-deoxycortisol and 11-deoxycorticosterone, respectively. 11 -hydroxylase deficiency is the next most common disorder and results in elevated plasma 11-DOC and 11-deoxycortisol. Urinary 17-hydroxyprogesterone, androgens, and 17ketosteroids also are elevated. The dexamethasone suppression test (2 to 4 mg divided qid for 7 days) can be used to distinguish adrenal hyperplasia from neoplasia. CT, MRI, and iodocholesterol scans generally are used to localize the tumors.

Treatment Patients with CAH traditionally have been managed medically, with cortisol and mineralocorticoid replacement to suppress the hypothalamic-pituitary-adrenal axis. However, the doses of steroids required often are supraphysiologic and lead to iatrogenic hypercortisolism. More recently, bilateral laparoscopic adrenalectomy has been proposed as an alternative treatment for this disease and has been successfully performed in a limited number of patients for various forms of CAH.

Disorders of the Adrenal Medulla PHEOCHROMOCYTOMAS Pheochromocytomas are rare tumors with prevalence rates ranging from 0.3 to 0.95% in autopsy series and approximately 1.9% in series using biochemical screening. They can occur at any age with a peak incidence in the fourth and fifth decades of life and have no gender predilection. Extra-adrenal tumors, also called functional paragangliomas, may be found at sites of sympathetic ganglia in the organ of Zuckerkandl, neck, mediastinum, abdomen, and pelvis. Pheochromocytomas often are called the 10 percent tumor because 10% are bilateral, 10% are malignant, 10% occur in pediatric patients, 10% are extra-adrenal, and 10% are familial. Pheochromocytomas occur in families with MEN2A and MEN2B, in approximately 50% of patients. Both syndromes are inherited in an autosomal dominant fashion and are caused by germline mutations in the RET proto-oncogene. Another syndrome with an increased risk of pheochromocytomas is von Hippel-Lindau (VHL) disease, which also is inherited in an autosomal dominant manner. This syndrome also includes retinal angioma, hemangioblastomas of the central nervous system, renal cysts and carcinomas, pancreatic cysts, and epididymal cystadenomas. The incidence of pheochromocytomas in the syndrome is approximately 14%. The gene causing VHL has been mapped to chromosome 3p and is a tumor-suppressor gene. Pheochromocytomas also are included within the tumor spectrum of neurofibromatosis type 1 (NF1 gene) and other neuroectodermal disorders (Sturge-Weber syndrome and tuberous sclerosis), Carney's syndrome (gastric epithelioid leiomyosarcoma, pulmonary chondroma, and extraadrenal paraganglioma), MEN1 syndrome, and the familial paraganglioma and pheochromocytoma syndrome caused by mutations in the succinyl dehydrogenase family of genes (SDHB, SDHC, and SDHD).9 2

Symptoms and Signs Headache, palpitations, and diaphoresis constitute the "classic triad" of pheochromocytomas. Symptoms such a anxiety, tremulousness, paresthesias, flushing, chest pain, shortness of breath, abdominal pain, nausea, vomiting, and others are nonspecific and may be episodic in nature. Cardiovascular complications such as myocardial infarction and cerebrovascular accidents may ensue. These symptoms can be incited by a range of stimuli including exercise, micturition, and defecation. The most common clinical sign is hypertension. Pheochromocytomas are one of the few curable causes of hypertension and are found in 0.1 to 0.2% of hypertensive patients. Hypertension related to this tumor may be paroxysmal with intervening normotension, sustained with paroxysms or sustained hypertension alone. Sudden death may occur in patients with undiagnosed tumors who undergo other surgeries or

biopsy.

Diagnostic Tests Biochemical Studies Pheochromocytomas are diagnosed by testing 24-hour urine samples for catecholamines and their metabolites as well as by determining plasma metanephrine levels. Urinary metanephrines are 98% sensitive and also are highly specific for pheochromocytomas, whereas VMA measurements are slightly less sensitive and specific. False-positive VMA tests may result from ingestion of caffeine, raw fruits, or medications ( -methyldopa). Fractionated urinary catecholamines (norepinephrine, epinephrine, and dopamine) also are very sensitive but less specific for pheochromocytomas. Because extra-adrenal sites lack phenylethanolamine N -methyltransferase, these tumors secrete norepinephrine whereas epinephrine is the main hormone secreted from adrenal pheochromocytomas. Many physiologic and pathologic states can alter the levels of plasma catecholamines. Hence, they often are thought to be less accurate than urinary tests. Both epinephrine and norepinephrine should be measured, as tumors often secrete one or the other hormone. Sensitivities of 85% and specificities of 95% have been reported using cutoff values of 2000 pg/mL for norepinephrine and 200 pg/mL for epinephrine. Clonidine is an agent that suppresses neurogenically mediated catecholamine excess but not secretion from pheochromocytomas. A normal clonidine suppression test is defined by a decrease of basal catecholamine levels to 5 cm) lesions. This technique is being increasingly used for small adenomas causing hyperaldosteronism. The patient is placed in the prone-jackknife position, and the operating table is flexed at the waist to open the space between the posterior costal margin and the pelvis. Palpation is used to identify the position of the twelfth rib. Percutaneous ultrasound is performed to determine the outline of the underlying kidney and adrenal. When done laparoscopically, the surgeon stands on the side of the adrenal to be removed and the assistant stands on the opposite side. A 1.5-cm incision is placed 2 cm inferior and parallel to the twelfth rib, laterally at the level of the

inferior pole of the kidney. Gerota's space is entered under direct vision using a 12-mm direct viewing trocar with a 0 laparoscope through the muscle layers of the posterior abdominal wall. Alternatively, blunt dissection with the surgeon's finger also can identify the space behind Gerota's fascia. The trocar is then replaced by a dissecting balloon, which is manually inflated using a hand pump under direct vision through the laparoscope. A 12-mm trocar is then reinserted into this space and CO2 is insufflated to 12 to 15 mmHg pressure. The 0 laparoscope is replaced by a 45 laparoscope. Two additional 5- or 10-mm trocars are placed, one each on either side of the first port. Laparoscopic ultrasound then is used to help locate the adrenal gland and vessels. The adrenal dissection is begun at the superior pole and then proceeds to the lateral and inferior aspect. The medial dissection usually is performed last, and the vessels are identified and divided as described in Lateral Transabdominal Approach above.

OPEN ADRENALECTOMY Open adrenalectomy may be performed via four approaches, each with specific advantages and disadvantages. The anterior approach allows examination of the abdominal cavity and resection of bilateral tumors via a single incision. The posterior approach avoids the morbidity of a laparotomy incision, especially in patients with cardiopulmonary disease and those prone to wound complications (Cushing's syndrome) and avoids abdominal adhesions in patients who have undergone previous abdominal surgery. Recovery time is also quicker and hospitalization shorter. However, the retroperitoneal exposure is difficult, particularly in obese patients and the small working space makes it unsuitable for tumors >6 cm in diameter. The lateral approach is best for obese patients and for large tumors because it provides a bigger working space. The thoracoabdominal approach is most useful for en bloc resection of large (>10 cm), malignant lesions. However, it is associated with significant morbidity and should be used selectively.

Anterior Approach The adrenals may be removed via a midline incision or bilateral subcostal incision (Fig. 38-50). The former allows adequate infraumbilical exposure for examination of extra-adrenal tumors, whereas the latter provides better superior and lateral exposure. For the right side, the hepatic flexure of the colon in mobilized inferiorly, the triangular ligament is incised to retract the liver medially and superiorly. A generous Kocher maneuver is used to mobilize the duodenum anteriorly and expose the retroperitoneal fat and the IVC (Fig. 38-51A). Gerota's fascia is incised, and the gland is freed of surrounding fibro-fatty tissue and the kidney inferiorly. The lateral and superior surfaces usually are mobilized first. Then, the short, right adrenal vein is dissected, ligated, and divided, taking care not to injure the hepatic veins and IVC. On the left side, the adrenal is located cephalad to the pancreatic tail and just lateral to the aorta. For large tumors, the adrenal is best approached by medial visceral rotation to mobilize the spleen, colon, and pancreas toward the midline (Fig. 38-51B). An alternative approach is to enter the lesser sac by division of the gastrocolic ligament. The pancreas is mobilized superiorly by incision of its inferior peritoneal attachments, thus exposing the left kidney and adrenal. The gland is then mobilized as on the right side.

Fig. 38-50.

Incisions for open adrenalectomy. Anterior approach (A ), posterior approach (B ), and thoracoabdominal approach (C ).

Fig. 38-51.

Technique of open adrenalectomy. Exposure of the right adrenal is facilitated by a Kocher maneuver to mobilize the duodenum and upward retraction of the liver (A ). The left adrenal can be exposed by medial visceral rotation of the spleen and pancreas (B ). v. = vein.

Posterior Approach The patient is placed prone on the operating table, similar to the laparoscopic approach. A hockey stick or curvilinear incision may be used, and extended through the latissimus dorsi and sacrospinous fascia. The twelfth rib generally is excised at its base and the eleventh rib is retracted superiorly to reveal the pleura and the lateral arcuate ligament of the liver on the right side. The pleura also is mobilized cephalad, and the adrenal and kidney are identified. The superior aspect of the gland is dissected first, and the superior vessels are identified and ligated. This prevents superior retraction of the adrenal gland. The remainder of the gland is then dissected and the adrenal gland and tumor removed. The resulting space generally is filled with perinephric fat and closed in layers. A chest x-ray is obtained postoperatively to rule out a pneumothorax.

Lateral Approach The patient is placed in a lateral position with the table flexed and an incision is made between the eleventh and twelfth ribs or subcostally. The dissection then is performed as indicated previously in Anterior Approach.

COMPLICATIONS OF ADRENAL SURGERY Patients with Cushing's syndrome are more prone to infectious (incisional and intra-abdominal abscess) and thrombotic complications. Creation of pneumoperitoneum may result in injury to various organs from Veress needle and trocar insertion, subcutaneous emphysema, pneumothorax, and hemodynamic compromise. Excessive retraction and dissection may lead to bleeding from injury to the IVC and renal vessels, or from injury to

surrounding organs such as the liver, pancreas, spleen, and stomach. Postoperative hemodynamic instability may be evident in patients with pheochromocytomas, and patients are at risk of adrenal insufficiency after bilateral adrenalectomy and sometimes after unilateral adrenalectomy (unrecognized Cushing's syndrome or, very rarely, Conn's syndrome). Long-term morbidity results mainly from injury to nerve roots during trocar insertion, which can lead to chronic pain syndromes or muscle weakness, although this is more of an issue in case of open procedures. Approximately 30% of patients who undergo bilateral adrenalectomy for Cushing's disease are at risk of developing Nelson's syndrome from progressive growth of the pre-existing pituitary tumor. This leads to increased ACTH levels, hyperpigmentation, visual field defects, headaches, and extraocular muscle palsies. Transsphenoidal pituitary resection is the initial mode of therapy and external beam radiotherapy is used in patients with residual tumor or extrasellar invasion.

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53. de Perrot M, Fadel E, Mercier O, et al: Surgical management of mediastinal goiters: When is a sternotomy required? Thorac Cardiovasc Surg 55:39, 2007. 54. Chan WF, Lang BH, Lo CY: The role of intraoperative neuromonitoring of recurrent laryngeal nerve during thyroidectomy: A comparative study on 1000 nerves at risk. Surgery 140:866; discussion 72, 2006. 55. Akerstrm G, Malmaeus J, Bergstrom R: Surgical anatomy of human parathyroid glands. Surgery 95:14, 1984. 56. Gilmour J: The gross anatomy of the parathyroid glands. J Pathol 46:133, 1938. 57. Raue F, Haag C, Schulze E, et al: The role of the extracellular calcium-sensing receptor in health and disease. Exp Clin Endocrinol Diabetes 114:397, 2006. [PMID: 17039419] 58. Awad SS, Miskulin J, Thompson N: Parathyroid adenomas versus four-gland hyperplasia as the cause of primary hyperparathyroidism in patients with prolonged lithium therapy. World J Surg 27:486, 2003. [PMID: 12658498] 59. Doherty GM. Multiple endocrine neoplasia type 1. J Surg Oncol 89:143, 2005. [PMID: 15719382] 60. Balogh K, Racz K, Patocs A, et al: Menin and its interacting proteins: Elucidation of menin function. Trends Endocrinol Metab 17:357, 2006. [PMID: 16997566] 61. Shattuck TM, Valimaki S, Obara T, et al: Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma. N Engl J Med 349:1722, 2003. [PMID: 14585940] 62. Talpos GB, Bone HG 3rd, Kleerekoper M, et al: Randomized trial of parathyroidectomy in mild asymptomatic primary hyperparathyroidism: Patient description and effects on the SF-36 health survey. Surgery 128:1013; discussion 20, 2000. 63. Greutelaers B, Kullen K, Kollias J, et al: Pasieka Illness Questionnaire: Its value in primary hyperparathyroidism. ANZ J Surg 74:112, 2004. [PMID: 14996155] 64. Vestergaard P, Mollerup CL, Frokjaer VG, et al: Cardiovascular events before and after surgery for primary hyperparathyroidism. World J Surg 27:216, 2003. [PMID: 12616440] 65. Hedback G, Tisell LE, Bengtsson BA, et al: Premature death in patients operated on for primary hyperparathyroidism. World J Surg 14:829; discussion 36, 1990. 66. Wermers RA, Khosla S, Atkinson EJ, et al: Survival after the diagnosis of hyperparathyroidism: A population-based study. Am J Med 104:115, 1998. [PMID: 9528728] 67. Scholz DA, Purnell DC: Asymptomatic primary hyperparathyroidism. 10-year prospective study. Mayo Clin Proc 56:473, 1981. [PMID: 7266058] 68. Silverberg SJ, Shane E, Jacobs TP, et al: A 10-year prospective study of primary hyperparathyroidism with or without parathyroid surgery. N Engl J Med 341:1249, 1999. [PMID: 10528034] 69. Proceedings of the NIH Consensus Development Conference on diagnosis and management of asymptomatic primary hyperparathyroidism. Bethesda, Maryland, October 29–31, 1990. J Bone Miner Res 6:S1, 1991. 70. Bilezikian JP, Potts JT Jr., Fuleihan Gel H, et al: Summary statement from a workshop on asymptomatic primary hyperparathyroidism: A perspective for the 21st century. J Clin Endocrinol Metab 87:5353, 2002. [PMID: 12466320] 71. Sheldon DG, Lee FT, Neil NJ, et al: Surgical treatment of hyperparathyroidism improves health-related quality of life. Arch Surg 137:1022; discussion 6, 2002.

72. Sackett WR, Bambach CP: Bilateral subtotal laparoscopic adrenalectomy for phaeochromocytoma. ANZ J Surg 73:664, 2003. [PMID: 12887546] 73. Johnson NA, Tublin ME, Ogilvie JB: Parathyroid imaging: Technique and role in the preoperative evaluation of primary hyperparathyroidism. AJR Am J Roentgenol 188:1706, 2007. [PMID: 17515397] 74. Lavely WC, Goetze S, Friedman KP, et al: Comparison of SPECT/CT, SPECT, and planar imaging with single- and dual-phase (99m)Tc-sestamibi parathyroid scintigraphy. J Nucl Med 48:1084, 2007. [PMID: 17574983] 75. Fujii H, Kubo A: Sestamibi scintigraphy for the application of minimally invasive surgery of hyperfunctioning parathyroid lesions. Biomed Pharmacother 56:7s, 2002. 76. Sharma J, Milas M, Berber E, et al: Value of intraoperative parathyroid hormone monitoring. Ann Surg Oncol 15:493, 2008. [PMID: 18355302] 77. Westerdahl J, Bergenfelz A: Unilateral versus bilateral neck exploration for primary hyperparathyroidism: Five-year follow-up of a randomized controlled trial. Ann Surg 246:976, 2007. [PMID: 18043099] 78. Gagner M: Endoscopic subtotal parathyroidectomy in patients with primary hyperparathyroidism. Br J Surg 83:875, 1996. [PMID: 8696772] 79. Silverberg SJ, Rubin MR, Faiman C, et al: Cinacalcet hydrochloride reduces the serum calcium concentration in inoperable parathyroid carcinoma. J Clin Endocrinol Metab 92:3803, 2007. [PMID: 17666472] 80. Carpenter JM, Michaelson PG, Lidner TK, et al: Parathyromatosis. Ear Nose Throat J 86:21, 2007. [PMID: 17315827] 81. Caron NR, Sturgeon C, Clark OH: Persistent and recurrent hyperparathyroidism. Curr Treat Options Oncol 5:335, 2004. [PMID: 15233910] 82. Elder GJ: Parathyroidectomy in the calcimimetic era. Nephrology 10:511, 2005. [PMID: 16221104] 83. Triponez F, Kebebew E, Dosseh D, et al: Less-than-subtotal parathyroidectomy increases the risk of persistent/recurrent hyperparathyroidism after parathyroidectomy in tertiary hyperparathyroidism after renal transplantation. Surgery 140:990; discussion 7, 2006. 84. Schirpenbach C, Reincke M: Primary aldosteronism: Current knowledge and controversies in Conn's syndrome. Nat Clin Pract Endocrinol Metab 3:220, 2007. [PMID: 17315030] 85. Rossi GP: New concepts in adrenal vein sampling for aldosterone in the diagnosis of primary aldosteronism. Curr Hypertens Rep 9:90, 2007. [PMID: 17442218] 86. Pecori Giraldi F, Ambrogio AG, De Martin M, et al: Specificity of first-line tests for the diagnosis of Cushing's syndrome: Assessment in a large series. J Clin Endocrinol Metab 92:4123, 2007. 87. Rodgers SE, Evans DB, Lee JE, et al: Adrenocortical carcinoma. Surg Oncol Clin N Am 15:535, 2006. [PMID: 16882496] 88. Copeland PM: The incidentally discovered adrenal mass. Ann Surg 199:116, 1984. [PMID: 6691725] 89. Sturgeon C, Shen WT, Clark OH, et al: Risk assessment in 457 adrenal cortical carcinomas: How much does tumor size predict the likelihood of malignancy? J Am Coll Surg 202:423, 2006. [PMID: 16500246] 90. Aubert S, Wacrenier A, Leroy X, et al: Weiss system revisited: A clinicopathologic and immunohistochemical study of 49 adrenocortical tumors. Am J Surg Pathol 26:1612, 2002. [PMID: 12459628] 91. Terzolo M, Angeli A, Fassnacht M, et al: Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med 356:2372, 2007.

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KEY POINTS 1. In infants with Bochdalek type congenital diaphragmatic hernia the severity of pulmonary hypoplasia and the resultant pulmonary hypertension are key determinants of survival. Barotrauma and hypoxia should be avoided. 2. During initial management of an infant with esophageal atresia and distal tracheoesophageal fistula, every effort should be made to avoid distending the gastrointestinal tract, especially when using mechanical ventilation. The patient should be evaluated for components of the VACTERL (vertebral, anorectal, cardiac, tracheoesophageal, renal, limb) anomalies. Timing and extent of surgery is dictated by the stability of the patient. 3. Although malrotation with midgut volvulus occurs most commonly within the first few weeks of life, it should always be considered in the differential diagnosis in a child with bilious emesis. Volvulus is a surgical emergency; therefore in a critically ill child, prompt surgical intervention should not be delayed for any reason. 4. When evaluating a newborn infant for vomiting, it is critical to distinguish between proximal and distal causes of intestinal obstruction utilizing both prenatal and postnatal history, physical examination and abdominal radiographs. 5. Risk factors for necrotizing enterocolitis (NEC) include prematurity, formula feeding, bacterial infection, and intestinal ischemia. Critical to the management of infants with advanced (Bell stage III) or perforated NEC is timely and adequate source control of peritoneal contamination. Early sequelae of NEC include perforation, sepsis, and death. Later sequelae include short-bowel syndrome and stricture. 6. In patients with intestinal obstruction secondary to Hirschsprung’s disease a leveling ostomy or endorectal pull through should be performed using ganglionated bowel, proximal to the transition zone between ganglionic and aganglionic intestine. 7. Prognosis of infants with biliary atresia is directly related to age at diagnosis and timing of portoenterostomy. Infants with advanced age at the time of diagnosis or infants who fail to demonstrate evidence of bile drainage after portoenterostomy usually require liver transplantation. 8. Infants with omphaloceles have greater associated morbidity and mortality than infants with gastroschisis due to a higher incidence of congenital anomalies and pulmonary hypoplasia. Gastroschisis can be associated with intestinal atresia, but not with other congenital anomalies. An intact omphalocele can be repaired electively, while gastroschisis requires urgent intervention to protect the exposed intestine. 9. Prognosis for children with Wilms’ tumor is defined by the stage of disease at the time of diagnosis and

the histologic type (favorable vs. unfavorable). Preoperative chemotherapy is indicated for bilateral involvement, a solitary kidney, or tumor in the inferior vena cava above the hepatic veins. Gross tumor rupture during surgery automatically changes the stage to 3 (at a minimum). 10. Injury is the leading cause of death in children older than 1 year of age. Blunt mechanisms account for the majority of pediatric injuries. The central nervous system is the most commonly injured organ system and the leading cause of death in injured children.

INTRODUCTION In his classic 1953 textbook titled The Surgery of Infancy and Childhood, Dr. Robert E. Gross summarized the essential challenge of pediatric surgery as follows: "Those who daily operate on adults, even with the greatest of skill, are sometimes appalled—or certainly are not at their best—when called upon to operate on and care for a tiny patient. Something more than diminutive instruments or scaled-down operative manipulations are necessary to do the job in a suitable manner." To this day, surgical residents and other trainees often approach the pediatric surgical patient with the same mix of fear and anxiety, yet generally complete their pediatric surgical experience with genuine respect for the resilience of children and for the precision required in their care both in the operating room and during the perioperative period. Over the decades, the specialty of pediatric surgery has evolved considerably. Our ability to care for the smallest of patients with surgical disorders has increased dramatically, so that even in utero surgery is now an option in certain circumstances. Similarly, our mastery of the pathophysiology of the diseases that pediatric surgeons face has increased to the point that many of these diseases are now understood at the level of molecular or cellular signaling pathways. Pediatric surgery provides the opportunity to intervene positively in a wide array of diseases and to exert a long-lasting impact on the lives of children and their grateful parents. The scope of diseases encountered in the standard practice of pediatric surgery is immense, with patients ranging in age from fetus to 18-year-olds, and includes anomalies of the head and neck, thoracic, GI, and genitourinary areas. This chapter is not designed to cover the entire spectrum of diseases a pediatric surgeon is expected to master; rather, it presents a synopsis of a handful of pediatric surgical conditions that a practicing general surgeon is likely to encounter over the course of his or her career.

PEDIATRIC SURGICAL THEMES: PITFALLS AND PEARLS This chapter focuses on the unique considerations in the diagnosis and management of surgical diseases in the pediatric population. Many surgical trainees approach the surgical care of children with some degree of fear and trepidation. As any pediatric caregiver will attest, the surgical management of infants and children requires careful and professional interactions with their parents. The stress that the parents of sick children experience in the hospital setting can, at times, be overwhelming. It is due, in part, to the uncertainty regarding a particular prognosis, the feeling of helplessness that evolves when one is unable to care for one's child, and, in certain cases, the guilt or remorse that one feels for not seeking medical care earlier or for consenting to a particular procedure. Management of the sick child and his or her family therefore requires not only a certain set of skills but also a unique knowledge base. This section is included to summarize some important general principles in accomplishing this task. 1. Children are not little adults, but they are little people. In practical terms, this often-heard refrain implies that children have unique fluid, electrolyte, and medication needs. Thus, the dosage of medications and the administration of IV fluids should be based

1.

on the child's weight. The corollary of this point is that infants and young children are extremely sensitive to perturbations in their normal physiology and, because of this, may be easily tipped into fluid overload or dehydration. 2. Children whisper before they shout. Children with surgical diseases can deteriorate very quickly. But before they deteriorate, they often manifest subtle physical findings. These findings—referred to as whispers—may include signs such as tachycardia, bradycardia, hypothermia, fever, recurrent emesis, or feeding intolerance. Meticulous attention to these subtle findings may unmask the development of potentially serious, life-threatening physiologic disturbances. 3. Always listen to the mother and the father. Surgical diseases in children can be very difficult to diagnose because children are often minimally communicative and the information they do communicate may be confusing, conflicting, or both. In all cases, it is wise to listen to the child's parents, who have closely observed their child and know him or her best. 4. Children experience pain after surgery. Careful and adequate pain management must accompany surgical interventions. 5. Pediatric tissue must be handled delicately.

GENERAL CONSIDERATIONS Fluid and Electrolyte Balance In management of the pediatric surgical patient, an understanding of fluid and electrolyte balance is critical, because the margin between dehydration and fluid overload is rather small. This is particularly true in infants, who have little reserve. Failure to pay meticulous attention to their hydration status can result in significant fluid overload or dehydration. Several surgical diagnoses, such as gastroschisis and short-bowel syndrome, are characterized by a predisposition to fluid loss. Others require judicious restoration of intravascular volume to prevent cardiac failure, as is the case in patients with congenital diaphragmatic hernia and associated pulmonary hypertension. The infant's physiologic day is approximately 8 hours in duration. Accordingly, careful assessment of the individual patient's fluid balance, including fluid intake and output for the previous 8 hours, is essential to prevent dehydration or fluid overload. Clinical signs of dehydration include tachycardia, decreased urine output, reduced skin turgor, a depressed fontanelle, absent tears, lethargy, and poor feeding. Fluid overload is often manifested by a new requirement for oxygen and the onset of respiratory distress, tachypnea, and tachycardia. The physical assessment of the fluid status of each child must include a complete head-to-toe evaluation, with emphasis on determining whether perturbations in normal physiology are present. At 12 weeks' gestation, the total body water of a fetus is approximately 94 mL/kg. By the time the fetus reaches full term, the total body water has decreased to approximately 80 mL/kg. Total body water drops an additional 5% within the first week of life, and by 1 year of life, total body water approaches adult levels, 60 to 65 mL/kg. Parallel to the drop in total body water is the reduction in extracellular fluid. These changes are

accelerated in the preterm infant, who may face additional fluid losses due to coexisting congenital anomalies or surgery. The volume of normal daily maintenance fluids for most children can be estimated using the following formula: 100 mL/kg for the first 10 kg, plus 50 mL/kg for 11 to 20 kg, plus 25 mL/kg for each additional kilogram of body weight thereafter. Because IV fluid orders are written as milliliters per hour, this can be conveniently converted to 4 mL/kg per hour up to 10 kg, plus 2 mL/kg per hour for 11 to 20 kg, and an additional 1 mL/kg per hour for each additional kilogram of body weight thereafter. For example, a 26-kg child has an estimated maintenance fluid requirement of (10

x

4) + (10

x

2) + (6

x

1) = 66 mL/h in the

absence of massive fluid losses or shock. A newborn infant with gastroschisis will manifest significant evaporative losses from the exposed bowel, so that fluid requirements will be in the range of 150 to 180 mL/kg per day. Precise management of a neonate's fluid status requires an understanding of changes in the glomerular filtration rate (GFR) and tubular function of the kidney. The full-term newborn's GFR is approximately 21 mL/min per square meter compared with 70 mL/min per square meter in an adult. Within the first year GFR increases steadily to the point that it essentially reaches adult levels by the end of the first year of life. The capacity to concentrate urine is very limited in preterm and term infants. In comparison with an adult who can concentrate urine to 1200 mOsm/kg, infants can concentrate urine at best to 600 mOsm/kg. Although infants are capable of secreting antidiuretic hormone, the aquaporin water channel–mediated osmotic water permeability of the infant's collecting tubules is severely limited compared with that of an adult, which leads to insensitivity to antidiuretic hormone. Sodium requirements range from 2 mEq/kg per day in term infants to 5 mEq/kg per day in critically ill preterm infants as a consequence of salt wasting. Potassium requirements range from 1 to 2 mEq/kg per day. Calcium and magnesium supplementation of IV fluids is essential to prevent laryngospasm, dysrhythmias, and tetany.

Acid-Base Equilibrium Acute metabolic acidosis usually implies inadequate tissue perfusion and is a serious disorder in children. Potentially life-threatening causes that are specific for the pediatric population must be sought. They include intestinal ischemia from necrotizing enterocolitis (in the neonate), midgut volvulus, and incarcerated hernia. Other causes include chronic bicarbonate loss from the GI tract and acid accumulation as in chronic renal failure. Respiratory acidosis implies hypoventilation, the cause of which should be apparent. Treatment of acute metabolic acidosis should be aimed at restoring tissue perfusion by addressing the underlying abnormality first. For severe metabolic acidemia in which the serum pH is 2.5 kg and a gestational age of >34 weeks has been used to select patients for ECMO, although success has been achieved in infants with weights as low as 1.8 kg. It must be emphasized that, although ECMO may allow successful treatment of a population of neonates with refractory pulmonary hypertension, the use of this technique remains controversial. On decannulation, a decision should be made regarding whether to repair the carotid artery or not. In instances in which the child is cannulated for a brief period (=5 days) this may be feasible. A recent study failed to show any benefit from repairing the carotid artery, although this finding remains controversial. A strategy that does not involve the use of ECMO but instead emphasizes the use of permissive hypercapnia and the avoidance of barotrauma may provide equal overall outcome in patients with CDH. This likely reflects the fact that mortality is related to the degree of pulmonary hypoplasia and the presence of congenital anomalies, neither of which is correctable by ECMO.

The timing of diaphragmatic hernia repair remains controversial, particularly when the infant is supported on ECMO. In patients who are not placed on ECMO, repair should be performed once the hemodynamic status has been optimized. In neonates who are on ECMO, some surgeons perform early repair on bypass; others wait until the infant's lungs are fully recovered and the pulmonary hypertension has subsided, repair the diaphragm, and discontinue bypass within hours of surgery. Still others repair the diaphragm only after the infant is off bypass. Repair of the diaphragmatic hernia may be accomplished by either an abdominal or a transthoracic approach and can be performed using open or minimally invasive techniques. In the abdominal approach, through a subcostal incision, the abdominal viscera are withdrawn from the chest to expose the defect in the diaphragm. Care must be taken when reducing the spleen and liver, because bleeding from these structures can be fatal. The anterior margin is often apparent, whereas the posterior muscular rim is attenuated. If the infant undergoes heparinization on bypass, minimal dissection of the muscular margins is performed. Electrocautery is used liberally to minimize postoperative bleeding. Most infants who require ECMO support before hernia repair have large defects, often lacking the medial and posterior margins. Before the availability of ECMO therapy, most of these infants died. In about three fourths of infants who undergo repair on bypass, the use of prosthetic material is required to patch the defect, and it is sutured to the diaphragmatic remnant or around ribs or costal cartilages for large defects. If there is adequate muscle for closure, a single layer of nonabsorbable horizontal mattress suture is used to close the defect. Just before the repair is complete, a chest tube may be positioned in the thoracic cavity. The authors tend to reserve the use of chest tubes for patients who are repaired while on ECMO, because these patients are at risk for developing a hemothorax, which can significantly impair ventilation. Anatomic closure of the abdominal wall may be impossible after reduction of the viscera. Occasionally a prosthetic patch may be sutured to the fascia to facilitate closure. The patch can be removed at a later time, and the ventral hernia can be closed at that time or subsequently. In patients who are deemed to be candidates for a minimally invasive approach (stable condition, >2 kg, no pulmonary hypertension), a thoracoscopic repair may be safely performed. If the diaphragm has been repaired with the patient on ECMO, weaning and decannulation are accomplished as soon as possible. All infants are ventilated postoperatively to maintain preductal arterial oxygenation of 80 to 100 mmHg. Very slow weaning from the ventilator is necessary to avoid recurrent pulmonary hypertension.

Congenital Lobar Emphysema Congenital lobar emphysema (CLE) is a condition manifested during the first few months of life as a progressive hyperexpansion of one or more lobes of the lung. It can be life-threatening in the newborn period, but in the older infant it causes less respiratory distress. Air entering during inspiration is trapped in the lobe. On expiration, the lobe cannot deflate and progressively overexpands, which causes atelectasis of the adjacent lobe or lobes. This hyperexpansion eventually shifts the mediastinum to the opposite side and compromises the other lung. CLE usually occurs in the upper lobes of the lung (left more often than right), followed next in frequency by the right middle lobe; however, it can occur in the lower lobes as well. It is caused by intrinsic bronchial obstruction from poor bronchial cartilage development or extrinsic compression. Approximately 14% of children with this condition have cardiac defects, with an enlarged left atrium or a major vessel causing compression of the ipsilateral bronchus. Symptoms range from mild respiratory distress to full-fledged respiratory failure with tachypnea, dyspnea, cough, and late cyanosis. These symptoms may be static or they may progress rapidly or result in recurrent pneumonia. Occasionally, infants with CLE present with failure to thrive, which likely reflects the increased work associated with the overexpanded lung. A hyperexpanded hemithorax on the ipsilateral side is

pathognomonic for CLE. Diagnosis is typically confirmed by chest radiograph, which shows a hyperlucent affected lobe with adjacent lobar compression and atelectasis. As a consequence of mass effect, the mediastinum may be shifted to the contralateral side, resulting in compression and atelectasis of the contralateral lung (Fig. 39-4). Although a chest radiograph is usually sufficient, it is sometimes important to obtain a CT scan of the chest to clearly establish the diagnosis of CLE. This should be done only in patients in stable condition. Unless foreign body or mucus plugging is suspected as a cause of hyperinflation, bronchoscopy is not advisable, because it can lead to more air trapping and cause life-threatening respiratory distress in an infant in stable condition. Treatment is resection of the affected lobe, which can be safely performed using either an open or thoracoscopic approach. Unless symptoms necessitate earlier surgery, resection can usually be performed after the infant is several months of age. The prognosis is excellent. Ongoing lung development in pediatric patients results in the generation of new alveoli in the remaining lung tissue, unlike in adult patients.

Fig. 39-4.

Congenital lobar emphysema of the left upper lobe in a 2-week-old boy. Mediastinal shift is present.

Congenital Pulmonary Airway Malformation

Congenital pulmonary airway malformation (CPAM) consists of cystic proliferation of the terminal airway, which produces cysts lined by mucus-producing respiratory epithelium and elastic tissue in the cyst walls without cartilage formation. There may be a single cyst with a wall of connective tissue containing smooth muscle. Formerly known as congenital cystic adenomatoid malformation, CPAM may consist of a single large cyst or multiple cysts (type I), may be characterized by smaller and more numerous cysts (type II), or may resemble fetal lung without macroscopic cysts (type III). CPAMs frequently occur in the left lower lobe. However, this lesion can occur in any lobe or may occur in both lungs simultaneously. In the left lower lobe, a type I CPAM may be confused at birth with a CDH. Clinical symptoms may range from none at all to severe respiratory failure at birth. Both single and multiple cysts can produce air trapping and may be confused with CLE, pneumatoceles, or even pulmonary sequestrations. The cysts also can be involved with repeated infections and produce fever and cough in older infants and children. The diagnosis often can be made by chest radiograph. In certain cases, ultrasonographic or CT scan may be definitive (Fig. 39-5). Prenatal ultrasonography may suggest the diagnosis. In the newborn period, ultrasonography may also be useful, especially to distinguish between CPAM and CDH. Resection is curative and may need to be performed urgently in the infant with severe respiratory distress. Long term, there is a risk of malignant degeneration to pulmonary blastoma. As a result, resection of the affected lobe is usually required (Fig. 39-6). Prognosis is excellent.

Fig. 39-5.

Computed tomographic scan of the chest showing a congenital pulmonary airway malformation of the left lower lobe.

Fig. 39-6.

Intraoperative photograph showing left lower lobe congenital pulmonary airway malformation seen in Fig. 39-5.

Pulmonary Sequestration In pulmonary sequestration, a mass of lung tissue, usually in the left lower chest, lacks the usual connections to the pulmonary artery or tracheobronchial tree and its blood supply is derived directly from the aorta. There are two kinds of sequestration. In extralobar sequestration a small area of nonaerated lung is separated from the main lung mass, has a systemic blood supply, and usually is located immediately above the left diaphragm. It is commonly found in cases of CDH. Intralobar sequestration more commonly occurs within the parenchyma of the left lower lobe but also can occur on the right. There is no major connection to the tracheobronchial tree, but a secondary connection may be established, perhaps through infection or via adjacent intrapulmonary shunts. The blood supply frequently originates from the aorta below the diaphragm; multiple vessels may be present (Fig. 39-7). Venous drainage of both types can be systemic or pulmonary. The cause of sequestration is unknown but most probably involves an abnormal budding of the developing lung that picks up a systemic blood supply and never becomes connected with the bronchus or pulmonary vessels. Sequestrations may, in some cases, exhibit mixed pathology showing components consistent with CPAMs. Extralobar sequestration is asymptomatic and is usually discovered incidentally on chest radiograph. If the diagnosis can be confirmed, for example by CT scan, resection is not necessary unless the sequestration becomes symptomatic. Diagnosis of intralobar sequestration may be made prenatally and confirmed on postnatal CT scan. Alternatively, the diagnosis of intralobar sequestration may be established

after repeated infections manifested by cough, fever, and consolidation in the posterior basal segment of the left lower lobe. Increasingly the diagnosis is being made in the early months of life by ultrasonography. Color Doppler ultrasonography often can be helpful in delineating the systemic arterial supply. Removal of the entire left lower lobe is usually necessary, because the diagnosis often is made late after multiple infections. Occasionally segmental resection of the sequestered part of the lung can be performed using an open, or ideally a thoracoscopic, approach. If an open approach is used, it is important to open the chest through a low intercostal space (sixth or seventh), to gain access to the vascular attachments to the aorta. These attachments may insert into the aorta below the diaphragm; in these cases division of the vessels as they traverse the thoracic cavity is essential. Prognosis is generally excellent. However, failure to obtain adequate control of these vessels may result in their retraction into the abdomen and lead to uncontrollable hemorrhage.

Fig. 39-7.

Arteriogram showing large systemic artery supply to an intralobar sequestration of the left lower lobe.

Bronchogenic Cyst

Bronchogenic cysts can occur anywhere along the respiratory tract from the neck to the lung parenchyma. They are probably embryonic rests of foregut origin that have been pinched off from the main portion of the developing tracheobronchial tree and are closely associated in causation with other foregut duplication cysts arising from the esophagus. For purists, foregut duplication cysts are named by their origin rather than their mucosal tissue type, therefore bronchogenic cysts may contain GI epithelium. However, although foregut duplication cyst is the correct terminology, it is not generally used. Bronchogenic cysts can present at any age. They may be seen on prenatal ultrasonographic scan but are discovered most often incidentally on postnatal chest radiograph. Histologically, they are hamartomatous and usually consist of a single cyst lined with respiratory epithelium, containing cartilage and smooth muscle. Although they may be completely asymptomatic, bronchogenic cysts may produce symptoms that depend on their anatomic location. In the paratracheal region of the neck they can produce airway compression and respiratory distress. In the lung parenchyma, they may become infected and present with fever and cough. In addition, they may cause obstruction of the bronchial lumen with distal atelectasis and infection. They may also cause mediastinal compression. Rarely, rupture of the cyst can occur. Chest radiograph usually shows a dense mass, and CT scan or magnetic resonance imaging (MRI) delineates the precise anatomic location of the lesion. Treatment consists of resection of the cyst, which may need to be undertaken in emergency circumstances because of airway or cardiac compression. Resection can be performed either as an open procedure or, more commonly, using a thoracoscopic approach.

Bronchiectasis Bronchiectasis is an abnormal and irreversible dilatation of the bronchi and bronchioles associated with chronic suppurative disease of the airways. Usually the children have an underlying congenital pulmonary anomaly, cystic fibrosis, or immune deficiency. Bronchiectasis also can result from chronic infection secondary to a neglected bronchial foreign body. The symptoms include a chronic cough, often productive of purulent secretions; recurrent pulmonary infection; and hemoptysis. The diagnosis is suggested by a chest radiograph that shows increased bronchovascular markings in the affected lobe. Chest CT delineates bronchiectasis with excellent resolution. The preferred treatment for bronchiectasis is medical, consisting of antibiotics, postural drainage, and bronchodilator therapy, because many children with the disease show signs of airflow obstruction and bronchial hyperresponsiveness. Lobectomy or segmental resection is indicated for localized disease that has not responded appropriately to medical therapy. In severe cases, lung transplantation may be required to replace the terminally damaged, septic lung.

Foreign Bodies The inherent curiosity of children and their innate propensity to place new objects into their mouths to fully explore them place them at great risk for aspiration. Ingested objects can be found in the airway or in the esophagus; in both cases the results can be life-threatening.

ASPIRATION Aspiration of foreign bodies most commonly occurs in the toddler age group. Peanuts are the object most frequently aspirated, although other materials (popcorn, for instance) may also be involved. A solid foreign body often will cause air trapping, with hyperlucency of the affected lobe or lung seen especially on expiration. Oil from a peanut is very irritating and may cause pneumonia. Delay in diagnosis can lead to atelectasis and infection. The most common anatomic location for a foreign body is the right main stem bronchus or the right lower lobe. The child usually will cough or choke while eating but may then become

asymptomatic. Total respiratory obstruction may occur with a tracheal foreign body; however, respiratory distress is usually mild if present at all. A unilateral wheeze is often heard on auscultation. This wheeze often leads to an inappropriate diagnosis of asthma and may delay the correct diagnosis for some time. A chest radiograph will show a radiopaque foreign body, but in the case of nuts, seeds, or plastic toy parts, the only clue may be hyperexpansion of the affected lobe on an expiratory film or fluoroscopy. Bronchoscopy confirms the diagnosis and allows removal of the foreign body. It may be a very simple procedure or it may be extremely difficult, especially with a smooth foreign body that cannot be grasped easily or one that has been retained for some time. A rigid bronchoscope should be employed in all cases, and use of optical forceps facilitates grasping of the inhaled object. Epinephrine may be injected into the mucosa when the object has been present for a long period of time to minimize bleeding. Bronchiectasis may be seen as an extremely late phenomenon after repeated infections of the poorly aerated lung and may require partial or total resection of the affected lobe. The differential diagnosis of a bronchial foreign body includes an intraluminal tumor (i.e., carcinoid, hemangioma, or neurofibroma).

CAUSTIC INGESTION AND ESOPHAGEAL INJURY The most common foreign body in the esophagus is a coin, followed by small toy parts. Toddlers are most frequently affected. The coin is retained in the esophagus at one of three locations: the cricopharyngeus, the area of the aortic arch, or the gastroesophageal junction, all areas of normal anatomic narrowing. Symptoms are variable depending on the anatomic position of the foreign body and the degree of obstruction. There is often a relatively asymptomatic period after ingestion. The initial symptoms are GI symptoms and include dysphagia, drooling, and vomiting. The longer the foreign body remains in the esophagus, the greater the incidence of respiratory symptoms, which include cough, stridor, and wheezing. These findings may be interpreted as signs of upper respiratory tract infections. Objects that are present for a long period of time—particularly in children who have underlying neurologic impairment—may manifest as chronic dysphagia. The chest radiograph is diagnostic in the case of an ingested coin. A contrast swallow evaluation may be required for nonradiopaque foreign bodies. Coins lodged in the upper esophagus for 10 kg. There are three viable options for the definitive pullthrough procedure that are currently used. Although individual surgeons may advocate one procedure over another, studies have demonstrated that the outcome after each type of operation is similar. For each of the operations that is performed, the principles of treatment include confirming the location in the bowel where the transition zone between ganglionic and aganglionic bowel exists, resecting the aganglionic segment of bowel, and performing an anastomosis of ganglionated bowel to either the anus or a cuff of rectal mucosa (Fig. 39-23).

Fig. 39-23.

Three operations for surgical correction of Hirschsprung's disease. A. The Duhamel procedure leaves the rectum in place and brings ganglionic bowel into the retrorectal space. B. Swenson's procedure is a resection with end-to-end anastomosis performed by exteriorizing bowel ends through the anus. C. In the Soave operation endorectal dissection is performed and mucosa is removed from the aganglionic distal segment. The ganglionic bowel is then brought down to the anus within the seromuscular tunnel.

It is now well established that a primary pull-through procedure can be performed safely, even in the newborn period. This approach follows the same treatment principles as a staged procedure and saves the patient from an additional operation. Many surgeons perform the intra-abdominal dissection using the laparoscope. This approach is especially useful in the newborn period, because it provides excellent visualization of the pelvis. In children with significant colonic distention, it is important to allow for a period of decompression using a rectal tube if a single-staged pull-through is to be performed. In older children with a very distended, hypertrophied colon, it may be prudent to perform a colostomy to allow the bowel to decompress, before performing a pull-through procedure. However, one should emphasize that there is no upper age limit for performing a primary pull-through. Of the three pull-through procedures performed for Hirschsprung's disease, the first is the original Swenson's procedure. In this operation, the aganglionic rectum is dissected in the pelvis and removed down to the anus. The ganglionic colon is then anastomosed to the anus via a perineal approach. In the Duhamel procedure, dissection outside the rectum is confined to the retrorectal space, and the ganglionic colon is anastomosed posteriorly just above the anus. The anterior wall of the ganglionic colon and the posterior wall of the aganglionic rectum are anastomosed using a stapler. Although both of these procedures are extremely effective, they are limited by the possibility of damage to the parasympathetic nerves that are adjacent to the rectum. To circumvent this potential problem, the Soave procedure calls for dissection entirely within the rectum. The rectal mucosa is stripped from the muscular sleeve, and the ganglionic colon is brought through this sleeve and anastomosed to the anus. This operation may be performed completely from below. In all cases, it is critical that the level at which ganglionated bowel exists be determined. Most surgeons believe that the anastomosis should be performed at least 5 cm from the point at which ganglion cells are found.

This avoids performing a pull-through in the transition zone, which is associated with a high incidence of complications due to inadequate emptying of the pull-through segment. Up to one third of patients who undergo a transition zone pull-through will require a reoperation. The main complications of all procedures include postoperative enterocolitis, constipation, and anastomotic stricture. As mentioned earlier, long-term results for the three procedures are comparable and are generally excellent in experienced hands. These three procedures also can be adapted for total colonic aganglionosis in which the ileum is used for the pull-through segment.

ANORECTAL MALFORMATIONS Anatomic Description Anorectal malformations are a spectrum of congenital anomalies that include imperforate anus and persistent cloaca. Anorectal malformations occur in approximately 1 in 5000 live births and affect males and females almost equally. The embryologic basis includes failure of descent of the urorectal septum. The level to which this septum descends determines the type of anomaly that is present, which subsequently influences the surgical approach. In patients with imperforate anus, the rectum fails to descend through the external sphincter complex. Instead, the rectal pouch ends blindly in the pelvis, above or below the levator ani muscle. In most cases, the blind rectal pouch communicates more distally with the genitourinary system or with the perineum through a fistulous tract. Traditionally, the anatomic description of imperforate anus has characterized it as either "high" or "low" depending on whether the rectum ends above the levator ani muscle complex or partially descends through this muscle (Fig. 39-24). Based on this classification system, in male patients with high imperforate anus the rectum usually ends as a fistula into the membranous urethra. In females, high imperforate anus often occurs in the context of a persistent cloaca. In both males and females, low lesions are associated with a fistula to the perineum. In males, the fistula connects with the median raphe of the scrotum or penis. In females, the fistula may end within the vestibule of the vagina, which is located immediately outside the hymen, or at the perineum.

Fig. 39-24.

Low imperforate anus in a male. Note the well-developed buttocks. The perineal fistula was found at the midline raphe.

Because this classification system is somewhat arbitrary, Peña proposed a classification system that specifically and unambiguously describes the location of the fistulous opening. In males the fistula may communicate with (a) the perineum (cutaneous perineal fistula), (b) the lowest portion of the posterior urethra (rectourethral bulbar fistula), (c) the upper portion of the posterior urethra (rectourethral prostatic fistula), or (d) the bladder neck (rectovesicular fistula). In females, the urethra may open to the perineum between the female genitalia and the center of the sphincter (cutaneous perineal fistula) or into the vestibule of the vagina (vestibular fistula) (Fig. 39-25). In both sexes, the rectum may end in a completely blind fashion (imperforate anus without fistula). In rare cases, patients may have a normal anal canal yet there may be total atresia or severe stenosis of the rectum.

Fig. 39-25.

Imperforate anus in a female. A catheter has been placed into the fistula, which is in the vestibule of the vagina.

In males the most frequent defect is imperforate anus with rectourethral fistula, followed by rectoperineal fistula, then rectovesicular or recto–bladder neck fistula. In females, the most frequent defect is rectovestibular defect, followed by cutaneous perineal fistula. The third most common defect in females is persistent cloaca. The latter lesion represents a wide spectrum of malformations in which the rectum, vagina, and urinary tract meet and fuse into a single common channel. On physical examination, a single perineal orifice is observed, located at the place where the urethra normally opens. Typically, the external genitalia are hypoplastic.

Associated Malformations Approximately 60% of patients with an anorectal malformation have another associated malformation. The most common is a urinary tract defect, which occurs in approximately 50% of patients. Skeletal defects are also seen, and the sacrum is most commonly involved. Spinal cord anomalies, especially tethered cord, are common, particularly in children with high lesions. GI tract anomalies occur, most commonly esophageal atresia. Cardiac anomalies may be noted, and occasionally patients present with a constellation of defects as part of the VACTERL syndrome (described earlier).

Management of Patients with Imperforate Anus Patients with imperforate anus are usually in stable condition, and the diagnosis is readily apparent. Despite

the obstruction, the abdomen initially is not distended, and there is rarely any urgency to intervene. The principles of management center around diagnosing the type of defect that is present (high vs. low) and evaluating for the presence of associated anomalies. It may take up to 24 hours before the presence of a fistula on the skin is noted, and thus the neonate should be observed for some period before definitive surgery is undertaken. All patients should therefore have an orogastric tube placed and should be monitored for the appearance of meconium in or around the perineum, or in the urine. Investigation for associated defects should include ultrasonography of the abdomen to assess for the presence of a urinary tract anomaly. Other tests should include an echocardiogram and spinal radiographs. Ultrasonography of the spine should be performed to look for the presence of a tethered cord. To further classify the location of the fistula as either high or low, a lateral abdominal radiograph can be obtained with a radiopaque marker on the perineum. Placing the infant in the inverted position allows the distance between the most distal extent of air in the rectum and the perineal surface to be measured. This study is imprecise, however, and may add little to the overall management of these patients. The surgical management of infants with imperforate anus is determined by the anatomic defect. In general, when a low lesion is present, only a perineal operation is required without a colostomy. Infants with a high lesion require a colostomy in the newborn period, followed by a pull-through procedure at approximately 2 months of age. When a persistent cloaca is present, the urinary tract needs to be carefully evaluated at the time of colostomy formation to ensure that normal emptying can occur and to determine whether the bladder needs to be drained by means of a vesicostomy. If there is any doubt about the type of lesion, it is safer to perform a colostomy rather than jeopardize the infant's long-term chances for continence by an injudicious perineal operation. The type of pull-through procedure favored by most pediatric surgeons today is the posterior sagittal anorectoplasty, as described by Peña and DeVries. In this procedure, the patient is placed in the prone jackknife position, the levator ani and external sphincter complex is divided in the midline posteriorly, the communication between the GI tract and the urinary tract is divided, and the rectum is brought down after sufficient length is achieved. The muscles are then reconstructed and sutured to the rectum. The outcome for 1192 patients who underwent this procedure was recently reviewed by Peña and Hong. Seventy-five percent of patients were found to have voluntary bowel movements, and nearly 40% were considered totally continent. As a rule, the incidence of incontinence is increased in patients with high lesions, whereas those with low lesions are more likely to be constipated. Management of the patient with high imperforate anus can be greatly facilitated by the use of a laparoscopically assisted approach, in which the patient is operated on in the supine position and the rectum is mobilized down to the fistulous connection to the bladder neck. This fistulous connection is then divided, and the rectum is completely mobilized to below the peritoneal reflection. The operation then proceeds at the perineum, and the location of the muscle complex is determined using a nerve stimulator. A Veress needle is then advanced through the skin at the indicated site, with the laparoscope providing guidance to the exact intrapelvic orientation. Dilators are then placed over the Veress needle, the rectum is pulled through this peritoneal opening, and an anoplasty is performed.

JAUNDICE Approach to the Jaundiced Infant Jaundice is present during the first week of life in 60% of term infants and 80% of preterm infants. There is usually an accumulation of unconjugated bilirubin, but there may also be deposition of direct bilirubin. During

fetal life, the placenta is the principal route of elimination of unconjugated bilirubin. In the newborn infant, bilirubin is conjugated through the activity of glucuronyl transferase. In the conjugated form, bilirubin is water soluble, which results in its excretion into the biliary system and then into the GI tract. Newborns have a relatively high level of circulating hemoglobin and relative immaturity of the conjugating machinery. This results in a transient accumulation of bilirubin in the tissues, which is manifested as jaundice. Physiologic jaundice is evident by the second or third day of life and usually resolves within approximately 5 to 7 days. By definition, jaundice that persists beyond 2 weeks is considered pathologic. Pathologic jaundice may be due to biliary obstruction, increased hemoglobin load, or liver dysfunction. The work-up of the jaundiced infant therefore should include a search for the following possibilities: (a) obstructive disorders, including biliary atresia, choledochal cyst, and inspissated bile syndrome; (b) hematologic disorders, including ABO incompatibility, Rh incompatibility, and spherocytosis; (c) metabolic disorders, including alpha1-antitrypsin deficiency, galactosemia, and pyruvate kinase deficiency; and (d) congenital infection, including syphilis and rubella.

Biliary Atresia PATHOGENESIS Biliary atresia is a rare disease associated with significant morbidity and mortality. This disease is characterized by a fibroproliferative obliteration of the biliary tree that progresses toward hepatic fibrosis, cirrhosis, and end-stage liver failure. The incidence of this disease is approximately 1 in 5000 to 1 in 12,000. The etiology of biliary atresia is likely multifactorial. In the classic textbook Abdominal Surgery of Infancy and Childhood, Ladd and Gross described the cause of biliary atresia as an "arrest of development during the solid stage of bile duct formation." Previously proposed theories of the cause of biliary atresia have focused on defects in hepatogenesis, prenatal vasculogenesis, immune dysregulation, infectious agents, and exposure to toxins. More recently, genetic mutations in the cfc1 gene, implicated in left-right axis determinations, were identified in patients with biliary atresia–splenic malformation syndrome. In addition, the finding of a higher incidence of maternal microchimerism in the livers of males with biliary atresia has led to the suggestion that consequent expression of maternal antigens may lead to an autoimmune process that results in inflammation and obliteration of the biliary tree. Recent animal studies strongly implicate perinatal exposure to reovirus or rotavirus. Such viral exposure may lead to periportal inflammation mediated by interferon- and other cytokines.

CLINICAL PRESENTATION Infants with biliary atresia present with jaundice at birth or shortly thereafter. The diagnosis of biliary atresia is frequently not entertained by pediatricians, in part because physiologic jaundice of the newborn is so common and biliary atresia is so uncommon. For this reason, a delay in diagnosis is not unusual. However, infants with biliary atresia characteristically have acholic, pale gray stools, secondary to obstructed bile flow. With further passage of time, these infants manifest progressive failure to thrive and, if untreated, develop stigmata of liver failure and portal hypertension, particularly splenomegaly and esophageal varices. The obliterative process of biliary atresia involves the common duct, cystic duct, one or both hepatic ducts, and the gallbladder, in a variety of combinations. Histopathologic findings for patients with biliary atresia include inflammatory changes in the parenchyma of the liver as well as fibrous deposition at the portal plates observed on trichrome staining of frozen tissue sections. In certain cases, bile duct proliferation may be seen, a relatively nonspecific marker of liver injury. Approximately 25% of patients with biliary atresia have

coincidental malformations that are often associated with polysplenia and may include intestinal malrotation, preduodenal portal vein, and intrahepatic vena cava.

DIAGNOSIS In general, the diagnosis of biliary atresia is made using a combination of studies, because no single test is sufficiently sensitive or specific. Fractionation of the serum bilirubin is performed to determine if the associated hyperbilirubinemia is conjugated or unconjugated. Work-up commonly includes the analysis of TORCH (toxoplasmosis, other infections, rubella, cytomegalovirus infection, and herpes simplex) infection titers as well as tests for viral hepatitis. Typically ultrasonography is performed to assess for the presence of other causes of biliary tract obstruction, including choledochal cyst. The absence of a gallbladder is highly suggestive of the diagnosis of biliary atresia. However, the presence of a gallbladder does not exclude the diagnosis of biliary atresia, because in approximately 10% of biliary atresia patients, the distal biliary tract is patent and a gallbladder may be visualized, even though the proximal ducts are atretic. One should note that the intrahepatic bile ducts are never dilated in patients with biliary atresia. In many centers, a nuclear medicine scan using technetium TC 99m disofenin, performed after pretreatment of the patient with phenobarbital, has proven to be an accurate and reliable study. If radionuclide appears in the intestine, the biliary tree is patent and the diagnosis of biliary atresia is excluded. If radionuclide is concentrated by the liver but is not excreted despite treatment with phenobarbital, and results of the metabolic screen, particularly alpha1-antitrypsin level, are normal, the presumptive diagnosis is biliary atresia. Percutaneous liver biopsy findings might potentially distinguish between biliary atresia and other sources of jaundice such as neonatal hepatitis. When the results of these tests point to or cannot exclude the diagnosis of biliary atresia, surgical exploration is warranted. At surgery, a cholangiogram may be performed if possible, using the gallbladder as a point of access. This may be accomplished using a laparoscope. The cholangiogram demonstrates the anatomy of the biliary tree, reveals whether extrahepatic bile duct atresia is present, and indicates whether there is distal bile flow into the duodenum. The cholangiogram may demonstrate hypoplasia of the extrahepatic biliary system. This condition is associated with hepatic parenchymal disorders that cause severe intrahepatic cholestasis, including alpha1-antitrypsin deficiency and biliary hypoplasia (Alagille syndrome). Alternatively, a cursory assessment of the extrahepatic biliary tree may clearly delineate the atresia.

Inspissated Bile Syndrome The term inspissated bile syndrome is applied to patients with normal biliary tracts who have persistent obstructive jaundice. Increased viscosity of bile and obstruction of the canaliculi are implicated as causes. The condition has been seen in infants receiving parenteral nutrition, but it is also encountered in patients with disorders associated with hemolysis and in patients with cystic fibrosis. In some instances, no etiologic factors can be defined. Cholangiography is both diagnostic and therapeutic in inspissated bile syndrome.

Neonatal Hepatitis Neonatal hepatitis may present in a similar fashion to biliary atresia. This disease is characterized by persistent jaundice due to acquired biliary inflammation without obliteration of the bile ducts. There may be a viral cause. The disease is usually self-limited.

TREATMENT If the diagnosis of biliary atresia is confirmed intraoperatively, then surgical treatment is undertaken during

the same procedure. Currently, first-line therapy consists of creation of a hepatoportoenterostomy, as described by Kasai. The purpose of this procedure is to promote bile flow into the intestine. The procedure is based on Kasai's observation that the fibrous tissue at the porta hepatis invests microscopically patent biliary ductules that, in turn, communicate with the intrahepatic ductal system (Fig. 39-26). Transecting this fibrous tissue at the portal plate, which is invariably encountered cephalad to the bifurcating portal vein, opens these channels and establishes bile flow into a surgically constructed intestinal conduit, usually a Roux-en-Y limb of jejunum (Fig. 39-27). Some authors believe that an intussuscepted antireflux valve is useful in preventing retrograde bile reflux, although the data suggest that it does not influence outcome. A liver biopsy is performed at the time of surgery to determine the degree of hepatic fibrosis that is present. The diameter of bile ducts at the portal plate is predictive of the likelihood of long-term success of biliary drainage through the portoenterostomy. Numerous studies also suggest that the likelihood of surgical success is inversely related to the age at the time of portoenterostomy. Infants treated before 60 days of age are more likely to achieve successful and long-term biliary drainage than are older infants. Although the outlook is less favorable for patients after the twelfth week, it is reasonable to proceed with surgery even beyond this point, because the alternative is certain liver failure. It is noteworthy that a significant number of patients have had favorable outcomes after undergoing portoenterostomy despite advanced age at the time of diagnosis.

Fig. 39-26.

Intraoperative photograph showing a Kasai portoenterostomy. Arrows denote the site of the anastomosis. Note the engorged liver.

Fig. 39-27.

Schematic illustration of the Kasai portoenterostomy for biliary atresia. An isolated limb of jejunum is brought to the porta hepatis and anastomosed to the transected ducts at the liver plate.

Bile drainage is anticipated when the operation is carried out early; however, bile flow does not necessarily imply cure. Approximately one third of patients remain symptom free after portoenterostomy; the remainder require liver transplantation due to progressive liver failure. Independent risk factors that predict failure of the procedure include bridging liver fibrosis at the time of surgery and postoperative cholangitic episodes. A recent review of the data of the Japanese Biliary Atresia Registry, which includes the results for 1381 patients, showed that the 10-year survival rate was 53% without transplantation and 66.7% with transplantation. A common postoperative complication is cholangitis. There is no effective strategy to completely eliminate this complication, and the effectiveness of long-term prophylactic antibiotics has not been fully resolved. In 2002, the National Institutes of Health–supported multicenter Biliary Atresia Research Consortium (BARC) was established to investigate the etiology of biliary atresia and to identify factors that affect outcome after portoenterostomy. BARC has previously reported that rapid normalization of serum

bilirubin levels and weight gain are predictive of survival with the native liver. In a prospective randomized controlled trial, BARC is currently analyzing the efficacy of corticosteroids in promoting sustained bile flow after hepatoportoenterostomy.

Choledochal Cyst CLASSIFICATION The term choledochal cyst refers to a spectrum of congenital biliary tract disorders that were previously grouped under the name idiopathic dilatation of the common bile duct. Based on the classification system proposed by Alonso-Lej, five types of choledochal cyst are described. Type I cysts are characterized by fusiform dilatation of the bile duct. This type is the most common and is found in 80 to 90% of cases. Type II choledochal cysts appear as an isolated diverticulum protruding from the wall of the common bile duct. The cyst may be joined to the common bile duct by a narrow stalk. Type III choledochal cysts arise from the intraduodenal portion of the common bile duct and are also known as choledochoceles. Type IVA cysts consist of multiple dilatations of the intrahepatic and extrahepatic bile ducts. Type IVB choledochal cysts are multiple dilatations involving only the extrahepatic bile ducts. Type V cysts (Caroli's disease) consist of multiple dilatations limited to the intrahepatic bile ducts. Choledochal cyst is most appropriately considered the predominant feature in a constellation of pathologic abnormalities that can occur within the pancreatobiliary system. Frequently associated with choledochal cyst is an anomalous junction of the pancreatic and common bile ducts. The etiology of choledochal cyst is controversial. Babbit proposed an abnormal pancreatic and biliary duct junction, with the formation of a "common channel" into which pancreatic enzymes are secreted. This process results in weakening of the bile duct wall by gradual enzymatic destruction, which leads to dilatation, inflammation, and finally cyst formation. Not all patients with choledochal cyst demonstrate an anatomic common channel, which raises questions regarding the accuracy of this model.

CLINICAL PRESENTATION Choledochal cyst is more common in females than in males (4:1). Typically these cysts present in children beyond the toddler age group. The classic symptom triad consists of abdominal pain, mass, and jaundice. However, this complex is actually encountered in fewer than half of patients. The more usual presentation is that of episodic abdominal pain, often recurring over the course of months or years and generally associated with only minimal jaundice that may escape detection. If the disorder is left undiagnosed, patients may develop cholangitis or pancreatitis. Cholangitis may lead to the development of cirrhosis and portal hypertension. Choledochal cyst can present in the newborn period, with symptoms very similar to those of biliary atresia. Often neonates have an abdominal mass at presentation.

DIAGNOSIS Choledochal cyst is frequently diagnosed in the fetus during screening prenatal ultrasonography. In the older child or adolescent, abdominal ultrasonography may reveal a cystic structure arising from the biliary tree. CT will confirm the diagnosis. These studies show the dimensions of the cyst and define its relationship to the vascular structures in the porta hepatis, as well as the intrahepatic ductal configuration. Endoscopic retrograde cholangiopancreatography is reserved for cases in which confusion remains regarding the diagnosis after evaluation by less invasive imaging modalities. Magnetic resonance cholangiopancreatography may provide a more detailed depiction of the anatomy of the cyst and its

relationship to the bifurcation of the hepatic ducts and to the pancreatic duct.

TREATMENT The cyst wall is composed of fibrous tissue and is devoid of mucosal lining. As a result, the treatment of choledochal cyst is surgical excision followed by biliary-enteric reconstruction. There is no role for internal drainage by cystenterostomy, which leaves the cyst wall intact and leads to the inevitable development of cholangitis. Rarely, choledochal cyst can lead to the development of a biliary tract malignancy. This provides a further rationale for complete cyst excision. Resection of the cyst requires circumferential dissection. The posterior plane between the cyst and portal vein must be carefully dissected to accomplish removal. The pancreatic duct, which may enter the distal cyst, is vulnerable to injury during distal cyst excision but can be prevented by avoiding entry into the pancreatic parenchyma. In cases in which the degree of pericystic inflammation is dense, it may be unsafe to attempt complete cyst removal. In this instance, it is reasonable to dissect within the posterior wall of the cyst, which allows the inner lining of the back wall to be dissected free from the outer layer that directly overlies the portal vascular structures. The lateral and anterior cyst, as well as the internal aspect of the back wall, is removed, but the outer posterior wall remains behind. Cyst excision is accomplished, and the proximal bile duct is anastomosed to the intestinal tract, typically via a Roux-en-Y limb of jejunum. More recently, laparoscopically assisted resections of choledochal cysts have been described. In these cases, the end-toside jejunojejunostomy is performed extracorporeally, but the remainder of the procedure is completed using minimally invasive techniques. The prognosis for children who have undergone complete excision of choledochal cyst is excellent. Complications include anastomotic stricture, cholangitis, and intrahepatic stone formation. These complications may develop a long time after surgery has been completed.

DEFORMITIES OF THE ABDOMINAL WALL Embryology of the Abdominal Wall The abdominal wall is formed by four separate embryologic folds—cephalic, caudal, and right and left lateral folds—each of which is composed of somatic and splanchnic layers. Each of the folds develops toward the anterior center portion of the coelomic cavity, joining to form a large umbilical ring that surrounds the two umbilical arteries, the vein, and the yolk sac or omphalomesenteric duct. These structures are covered by an outer layer of amnion, and the entire unit composes the umbilical cord. Between the fifth and tenth weeks of fetal development the intestinal tract undergoes rapid growth outside the abdominal cavity within the proximal portion of the umbilical cord. As development is completed, the intestine gradually returns to the abdominal cavity. Contraction of the umbilical ring completes the process of abdominal wall formation. Failure of the cephalic fold to close results in sternal defects such as congenital absence of the sternum. Failure of the caudal fold to close results in exstrophy of the bladder and, in more extreme cases, exstrophy of the cloaca. Interruption of central migration of the lateral folds results in omphalocele. Gastroschisis, originally thought to be a variant of omphalocele, probably results from a fetal accident in the form of intrauterine rupture of a hernia of the umbilical cord.

Umbilical Hernia Failure of the umbilical ring to close results in a central defect in the linea alba. The resulting umbilical hernia

is covered by normal umbilical skin and subcutaneous tissue, but the fascial defect allows protrusion of abdominal contents. Hernias less than a centimeter in size at the time of birth usually will close spontaneously by 4 years of life. Sometimes the hernia is large enough that the protrusion is disfiguring and disturbing to both the child and the family. In such circumstances early repair may be advisable (Fig. 39-28).

Fig. 39-28.

Umbilical hernia in a 1-year-old female.

Umbilical hernias are generally asymptomatic protrusions of the abdominal wall. They are generally noted by parents or physicians on physical examination, and these patients are referred for a surgical opinion due to concern for possible incarceration. Although incarceration is rarely seen in an umbilical hernia, it can happen. Children present with abdominal pain, bilious emesis, and a tender, hard mass protruding from the umbilicus. This constellation of symptoms mandates immediate exploration and repair of the hernia. In these cases, a knuckle of ischemic or necrotic bowel may be found that requires resection. More commonly, the child is asymptomatic and treatment is governed by the size of the defect, the age of the patient, and the concerns of the child and family regarding the cosmetic appearance of the abdomen. When the defect is

small and spontaneous closure is likely, most surgeons will delay surgical correction until 4 or 5 years of age. If closure does not occur by this time, it is reasonable to repair the hernia. If a younger child has an extremely large hernia, or if the family or child is bothered by the cosmetic appearance, then repair is indicated. Repair of uncomplicated umbilical hernia is performed under general anesthesia as an outpatient procedure. A small curved incision that fits into the skin crease of the umbilicus is made, and the sac is dissected free from the overlying skin. The fascial defect is repaired with permanent or long-lasting absorbable, interrupted sutures that are placed in a transverse plane. The cosmetic appearance of the umbilicus is restored by tacking the undersurface of the umbilical skin to the reapproximated fascia. The skin is closed using subcuticular sutures. The postoperative recovery is typically uneventful, and recurrence is rare.

Patent Urachus During the development of the coelomic cavity, there is free communication between the urinary bladder and the abdominal wall through the urachus, which exits adjacent to the omphalomesenteric duct. Persistence of this tract results in a communication between the bladder and the umbilicus. The first sign of a patent urachus is moisture or urine flow from the umbilicus. Recurrent urinary tract infection can result. The urachus may be partially obliterated, with a remnant remaining beneath the umbilicus in the extraperitoneal position as an isolated cyst that may be identified by ultrasonography. Such a cyst usually presents as an inflammatory mass inferior to the umbilicus. Initial treatment is drainage of the infected cyst followed by cyst excision as a separate procedure once the inflammation has resolved. In the child with a persistently draining umbilicus, a diagnosis of patent urachus should be considered. The differential diagnosis includes an umbilical granuloma, which generally responds to local application of silver nitrate. The diagnosis of patent urachus is confirmed by umbilical exploration. The urachal tract is excised and the bladder is closed. A patent vitelline duct may also present with umbilical drainage. In this circumstance, there is a communication with the small intestine, often at the site of Meckel's diverticulum. Treatment includes umbilical exploration with resection of the involved bowel (Fig. 39-29).

Fig. 39-29.

Patent vitelline duct. Note the communication between the umbilicus and the small bowel at the site of a Meckel's diverticulum.

Omphalocele PRESENTATION Omphalocele refers to a congenital defect of the abdominal wall in which the bowel and solid viscera are covered by peritoneum and amniotic membrane (Fig. 39-30). The umbilical cord inserts into the sac. The abdominal wall defect measures =4 cm in diameter. Omphalocele has an incidence of approximately 1 in 5000 live births and occurs in association with special syndromes such as exstrophy of the cloaca (vesicointestinal fissure), the Beckwith-Wiedemann constellation of anomalies (macroglossia, macrosomia, hypoglycemia, visceromegaly, and omphalocele) and the Cantrell pentalogy (lower thoracic wall malformations such as cleft sternum, ectopia cordis, epigastric omphalocele, anterior midline diaphragmatic hernia, and cardiac anomalies). The defect may be very small or large enough that it contains most of the abdominal viscera. There is a 60 to 70% incidence of associated anomalies, especially cardiac anomalies (20 to 40% of cases) and chromosomal abnormalities. Chromosomal anomalies are more common in children with smaller defects. Omphalocele is associated with prematurity (10 to 50% of cases) and intrauterine growth restriction (20% of cases).

Fig. 39-30.

Giant omphalocele in a newborn male.

TREATMENT Immediate treatment of an infant with omphalocele consists of attending to the vital signs and maintaining body temperature. The omphalocele should be covered with saline-soaked gauze and the trunk should be wrapped circumferentially. No pressure should be placed on the omphalocele sac in an effort to reduce its contents, because this maneuver may increase the risk of rupture of the sac or may interfere with abdominal venous return. Prophylactic antibiotics should be administered in case of rupture. The subsequent treatment and outcome are determined by the size of the omphalocele. In general, small- to medium-sized defects have a significantly better prognosis than extremely large defects in which the liver is present. In these cases, not only is the management of the abdominal wall defect a significant challenge, but these patients often have concomitant pulmonary insufficiency that can lead to significant morbidity and mortality. Whenever possible, a primary repair of the omphalocele should be undertaken. This involves resection of the omphalocele membrane and closure of the fascia. A layer of prosthetic material may be required to achieve

closure. In infants with a giant omphalocele (defect >7 cm in diameter, liver present within the sac), the defect cannot be closed primarily because there is simply no room to reduce the viscera into the abdominal cavity (see Fig. 39-30). Other infants may have associated congenital anomalies that complicate surgical repair. Under these circumstances, a nonoperative approach can be used. The omphalocele sac can be treated with desiccating substances such as povidone-iodine (Betadine), silver sulfadiazine (Silvadene), or sulfasalazine. Typically 2 to 3 months are required before re-epithelialization occurs. In the past, mercury compounds were used, but their use has been discontinued because of associated systemic toxicity. After epithelialization has occurred, attempts should be made to achieve closure of the anterior abdominal wall. Such procedures typically require extensive measures to achieve skin closure, including the use of biosynthetic materials. It is noteworthy that the abdominal vasculature is typically easily mobilized, due to the absence of adhesions to the sac. In cases of giant omphalocele, prolonged hospitalization is typical.

Gastroschisis PRESENTATION Gastroschisis is a congenital anomaly characterized by a defect in the anterior abdominal wall through which the intestinal contents freely protrude. Unlike with omphalocele, there is no overlying sac and the size of the defect is much smaller (5 cm in diameter because of the perceived risk of ovarian torsion. It has now become apparent from serial ultrasonographic examinations that many of these lesions will resolve spontaneously. Therefore, asymptomatic, simple cysts may be observed, and surgery can be performed only when the cysts fail to decrease in size or become symptomatic. Typically, resolution occurs

by approximately 6 months of age. A laparoscopic approach is preferable when simple cysts must be removed. By contrast, complex cysts of any size require surgical intervention at presentation.

Ambiguous Genitalia EMBRYOLOGY Normal sexual differentiation occurs in the sixth fetal week. In every fetus, wolffian (male) and müllerian (female) ducts are present until the onset of sexual differentiation. Normal sexual differentiation is directed by the sex-determining region of the Y chromosome (SRY). This is located on the distal end of the short arm of the Y chromosome. SRY provides a genetic switch that initiates gonadal differentiation in the mammalian urogenital ridge. Secretion of müllerian inhibiting substance (MIS) by the Sertoli cells of the seminiferous tubules results in regression of the müllerian duct, the anlage of the uterus, fallopian tubes, and upper vagina. The result of MIS secretion therefore is a phenotypic male. In the absence of SRY in the Y chromosome, MIS is not produced, and the müllerian duct derivatives are preserved. Thus, the female phenotype prevails. For the male phenotype to develop, the embryo must have a Y chromosome, the SRY must be normal without point mutations or deletions, testosterone and MIS must be produced by the differentiated gonad, and the tissues must respond to these hormones. Any disruption of the orderly steps in sexual differentiation may be reflected clinically as variants of the intersex syndromes, which are currently referred to as disorders of sex development (DSDs). DSDs may be classified as (a) ovotesticular DSD (with both ovarian and testicular gonadal tissue present; previously known as true hermaphroditism); (b) 46,XY DSD, characterized by undervirilization or undermasculinization of an XY male (only testicular tissue present; previously known as male pseudohermaphroditism); (c) 46,XX DSD, characterized by overvirilization or masculinization of an XX female (ovarian tissue only; female pseudohermaphroditism); and (d) 46,XY complete gonadal dysgenesis (usually underdeveloped or imperfectly formed gonads).

OVOTESTICULAR DISORDER OF SEX DEVELOPMENT (TRUE HERMAPHRODITISM) Ovotesticular DSD is the rarest form of ambiguous genitalia. Patients have both normal male and normal female gonads, with an ovary on one side and a testis on the other. Occasionally, an ovotestis is present on one or both sides. The majority of these patients have a 46,XX karyotype (46,XX testicular DSD). Both the testis and the testicular portion of the ovotestis should be removed.

46,XY DISORDER OF SEX DEVELOPMENT (MALE PSEUDOHERMAPHRODITISM) The condition of 46,XY DSD occurs in infants with an XY karyotype but deficient masculinization of the external genitalia. Bilateral testes are present, but the duct structures differentiate partly as phenotypically female. The causes of the disorder include inadequate testosterone production due to biosynthetic error, inability to convert testosterone to dihydrotestosterone due to 5 -reductase deficiency, or deficiencies in androgen receptors. The latter disorder is termed testicular feminization syndrome. Occasionally, the diagnosis in these children is made during routine inguinal herniorrhaphy in a phenotypic female, at which time testes are found. The testes should be resected due to the risk of malignant degeneration, although this should be done only after a full discussion with the family has occurred.

46,XX DISORDER OF SEX DEVELOPMENT (FEMALE PSEUDOHERMAPHRODITISM) The syndrome of 46,XX DSD is characterized by overvirilization or masculinization of an XX female. The most common cause of this female condition is congenital adrenal hyperplasia. These children have a 46,XX karyotype but have been exposed to excessive androgens in utero. Common enzyme deficiencies include 21hydroxylase deficiency, 11 -hydroxylase deficiency, and 3 -hydroxysteroid dehydrogenase deficiency. These deficiencies lead to overproduction of intermediary steroid hormones, which results in masculinization of the external genitalia of the XX fetus. These patients are unable to synthesize cortisol. In 90% of cases, deficiency of 21-hydroxylase causes adrenocorticotropic hormone to stimulate the secretion of excessive quantities of adrenal androgen, which masculinizes the developing female (Fig. 39-36). These infants are prone to salt loss and require cortisol replacement. Those with mineralocorticoid deficiency also require fludrocortisone replacement.

Fig. 39-36.

Ambiguous genitalia manifest as enlarged clitoris and labioscrotal folds in an infant with adrenogenital syndrome.

MIXED GONADAL DYSGENESIS

Mixed gonadal dysgenesis is characterized by dysgenetic gonads and retained müllerian structures. The typical karyotype is mosaic, usually 45XO,46XY. The incidence of malignant tumors in the dysgenetic gonads, most commonly gonadoblastoma, is high. Therefore, they should be removed.

MANAGEMENT In the differential diagnosis of patients with DSD, the following diagnostic steps are necessary: (a) evaluation of the genetic background and family history; (b) assessment of the anatomic structures by physical examination and/or ultrasonography; (c) chromosome analysis; (d) determination of biochemical factors in serum and urine to evaluate for the presence of an enzyme defect; and (e) laparoscopy for gonadal biopsy. Treatment should include correction of electrolyte and volume losses in cases of congenital adrenal hyperplasia and replacement of hormone deficiency. Surgical assignment of gender should never be done at the first operation. Although historically female gender had been assigned, there is abundant and convincing evidence that raising a genotypic male as a female has devastating consequences, not only anatomically but also psychosocially. This is particularly relevant given the role of prenatal and postnatal hormones on gender imprinting and identity. In general, surgical reconstruction should be performed after a full genetic work-up and with the involvement of pediatric endocrinologists, pediatric plastic surgeons, and ethicists with expertise in gender issues. Discussion with the family also plays an important role. This approach reduces the anxiety associated with these disorders and helps to ensure the normal physical and emotional development of these patients.

PEDIATRIC MALIGNANCY Cancer is the second leading cause of death in children after trauma and accounts for approximately 11% of all pediatric deaths in the United States. Several features distinguish pediatric from adult cancers, including the presence of tumors that are predominantly seen in children, such as neuroblastomas and germ cell tumors, and the favorable response to chemotherapy observed for many pediatric solid malignancies, even in the presence of metastases.

Wilms' Tumor CLINICAL PRESENTATION Wilms' tumor is the most common primary malignant tumor of the kidney in children. Approximately 500 new cases are seen annually in the United States, and most are diagnosed in children between 1 and 5 years of age with the peak incidence at age 3. Advances in the care of patients with Wilms' tumor have resulted in an overall cure rate of roughly 90%, even in the presence of metastatic spread. The tumor usually develops in otherwise healthy children as an asymptomatic mass in the flank or upper abdomen. Frequently, the mass is discovered by a parent while bathing or dressing the child. Other symptoms include hypertension, hematuria, obstipation, and weight loss. Occasionally the mass is discovered after blunt abdominal trauma.

GENETICS OF WILMS' TUMOR Wilms' tumor can arise from both germline and somatic mutations, and can occur in the presence or absence of a family history. Nearly 97% of Wilms' tumors are sporadic in that they occur in the absence of a heritable or congenital cause or risk factor. When a heritable risk factor is identified, the affected children often present at an earlier age and the disease is frequently bilateral. Most of these tumors are associated with germline mutations. It is well established that there is a genetic predisposition to Wilms' tumor in the WAGR

syndrome, which consists of Wilms' tumor, aniridia, genitourinary abnormalities, and mental retardation. In addition, there is an increased incidence of Wilms' tumor in certain overgrowth conditions, particularly Beckwith-Wiedemann syndrome and hemihypertrophy. WAGR syndrome has been shown to result from the deletion of one copy each of the Wilms' tumor gene WT1 and the adjacent aniridia gene PAX6 on chromosome band 11p13. Beckwith-Wiedemann syndrome is an overgrowth syndrome that is characterized by visceromegaly, macroglossia, and hyperinsulinemic hypoglycemia. It arises from mutations at the 11p15.5 locus. There is evidence to suggest that analysis of the methylation status of several genes in the 11p15 locus could predict the individual risk for the development of Wilms' tumor. Importantly, however, most patients with Wilms' tumor do not have mutations at these genetic loci.

SURGICAL TREATMENT Before operation, all patients suspected of having Wilms' tumor should undergo abdominal and chest CT. These studies characterize the mass, identify the presence of metastases, and provide information on the opposite kidney (Fig. 39-37). CT scanning also reveals the presence of nephrogenic rests, which are precursor lesions to Wilms' tumor. Abdominal ultrasonography should be performed to evaluate for the presence of renal vein or vena caval extension.

Fig. 39-37.

Wilms' tumor of the right kidney (arrow) in a 3-year-old girl.

The management of patients with Wilms' tumor has been carefully analyzed within the context of large studies involving thousands of patients. These studies have been coordinated by the National Wilms Tumor Study Group (NWTSG) in North America and by the International Society of Paediatric Oncology (SIOP),

mainly in European countries. Significant differences in the approach to patients with Wilms' tumor have been highlighted by these studies. The NWTSG supports a strategy of surgery followed by chemotherapy in most instances, whereas the SIOP approach is to shrink the tumor using preoperative chemotherapy. In some circumstances preoperative chemotherapy is supported by both groups, including in cases of bilateral involvement or inferior vena cava involvement that extends above the hepatic veins and involvement of a solitary kidney by Wilms' tumor. The NWTSG proponents argue that preoperative therapy in other instances results in a loss of important staging information and therefore places patients at higher risk for recurrence or, alternatively, may lead to overly aggressive treatment in some cases and greater morbidity. However, the overall survival rates are no different for patients treated using the NWTSG and SIOP approaches. The goal of surgery is complete removal of the tumor. It is crucial to avoid tumor rupture or injury to contiguous organs. A sampling of regional lymph nodes should be included, and all suspicious nodes should be excised or biopsied. Typically a transverse abdominal incision is made, and a transperitoneal approach is used. The opposite side is carefully inspected to ensure that no disease is present. Although historically this involved the complete mobilization of the contralateral kidney, current evidence indicates that preoperative high-resolution CT scanning is sufficiently accurate to detect clinically significant lesions if they are present. Provided only unilateral disease is present, a radical nephroureterectomy is then performed with control of the renal pedicle as an initial step. If there is spread above the hepatic veins, an intrathoracic approach may be required. If bilateral disease is encountered, chemotherapy is administered, followed by a nephronsparing procedure. Biopsy may be required if the patient does not respond to the initial chemotherapy.

CHEMOTHERAPY After nephroureterectomy for Wilms' tumor, the need for chemotherapy and/or radiation therapy is determined by the histologic features and clinical stage of the tumor. Essentially, patients who have disease confined to one kidney that is completely excised surgically receive a short course of chemotherapy, and for this group a 97% 4-year survival is expected, with tumor relapse rare after that time. Patients who have more advanced disease or tumors with unfavorable histologic features receive more intensive chemotherapy and radiation therapy. Even in patients with stage IV disease, cure rates of 80% are achieved. The survival rates are worse in the small percentage of patients whose tumors are considered to be of unfavorable histologic type.

Neuroblastoma CLINICAL PRESENTATION Neuroblastoma is the third most common pediatric malignancy and accounts for approximately 10% of all childhood cancers. The overwhelming majority of patients have advanced disease at the time of presentation, and unlike in patients with Wilms' tumor, the overall survival rate is 5 cm and/or regional node involvement.

Stage 4

Metastatic disease at diagnosis.

Source: From Lawrence W Jr., Gehan EA, Hays DM, et al: Prognostic significance of staging factors of the UICC staging system in childhood rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma

Study (IRS-II). J Clin Oncol 5:46, 1987; and Lawrence W Jr., Anderson JR, Gehan EA, et al: Pretreatment TNM staging of childhood rhabdomyosarcoma: A report of the Intergroup Rhabdomyosarcoma Study Group. Children's Cancer Study Group. Pediatric Oncology Group. Cancer 80:1165, 1997.

PROGNOSIS The prognosis for rhabdomyosarcoma is related to the site of origin, resectability, presence of metastases, number of metastatic sites, and histopathologic features. Primary sites associated with more favorable prognoses include the orbit and nonparameningeal head and neck, paratestis and vagina (nonbladder, nonprostate genitourinary), and the biliary tract. Patients with tumors 1 year of age. In fact, trauma is responsible for almost half of all pediatric deaths—more than cancer, congenital anomalies, pneumonia, heart disease, homicide, and meningitis combined. Death from unintentional injuries accounts for 65% of all injury-related deaths in children Chapter 40. Urology >

KEY POINTS 1. In the surgical treatment of invasive bladder cancer, a thorough lymph node dissection is essential. 2. Patients with testicular cancer without radiographic evidence of metastasis often harbor microscopic deposits of disease and require either adjuvant treatment or very close surveillance. 3. Nephrectomy is the mainstay of treatment for localized renal cell carcinoma, and it also provides a survival benefit in the setting of metastatic disease. 4. The vast majority of renal trauma can be treated conservatively, with early surgical intervention reserved for persistent bleeding or renal vascular injuries. 5. Distal ureteral injuries should only be treated with bladder reimplantation because of the high failure rate of distal uretero-ureterostomies. 6. Extraperitoneal bladder ruptures can be treated conservatively but intraperitoneal ruptures typically require surgical repair. 7. Nearly all episodes of acute urinary retention can be treated with conservative measures such as decreasing narcotic usage and increasing ambulation. 8. Testicular torsion is an emergency where successful testicular salvage is inversely related to the delay in repair, so cases with a high degree of clinical suspicion should not wait for a radiologic diagnosis. 9. Fournier's gangrene is a potentially lethal condition that requires aggressive débridement and close followup due to the frequent need for repeat débridement. 10. Most small ureteral calculi will pass spontaneously, but larger stones (>6 mm) are better treated with ureteral stenting and lithotripsy.

ANATOMY The anatomic structures that fall under the purview of genitourinary surgery are the kidneys, adrenals, ureters, bladder, prostate, seminal vesicles, urethra, vas deferens, and testes. They are situated mainly outside the peritoneum, but urologic surgery frequently involves intraperitoneal approaches to the kidney, bladder, and retroperitoneal lymph nodes. Furthermore, urologists must be familiar with the techniques of intestinal surgery for the purposes of urinary diversion and bladder augmentation.

Kidney and Adrenal The kidneys are paired retroperitoneal organs that are invested in a fibro-fatty layer: Gerota's fascia. Posterolaterally, the kidneys are bordered by the quadratus lumborum and posteromedially by the psoas

muscle. Anteriorly they are confined by the posterior layer of the peritoneum. On the left, the spleen lies superolaterally, separated from the kidney and Gerota's fascia by the peritoneum. On the right, the liver is situated superiorly and anteriorly and also is separated by the peritoneum. The second portion of the duodenum is in close proximity to the right renal vessels and, during right renal surgery, it must be reflected anteromedially (Kocherized) to achieve vascular control. The renal arteries, in the typical configuration, are single vessels extending from the aorta that branch into several segmental arteries before entering the renal sinus. The right renal artery passes posterior to the vena cava and is significantly longer than the left renal artery. Occasionally, the kidney is supplied by a second renal artery, typically to the lower pole. Within the kidney, there is essentially no anastomotic arterial flow, so the kidneys are prone to infarction when branch vessels are interrupted. The renal veins, which course anteriorly to the renal arteries, drain to the vena cava. The left renal vein passes anteriorly to the aorta and is much longer than the right renal vein. The left vein is in continuity with the left gonadal vein, the left inferior adrenal vein, and a lumbar vein. These veins provide adequate drainage for the left kidney in the event that drainage to the vena cava is interrupted. The right renal vein has no such collateral venous drainage. The collecting system of the kidney is composed of several major and minor calyces that coalesce into the renal pelvis. The renal pelvis can have either a mainly intrarenal or extrarenal position. The renal pelvis tapers into the ureteropelvic junction (UPJ) where it joins with the ureter. The adrenal glands lie superomedially to the kidneys within Gerota's fascia. There is a layer of Gerota's fascia between the adrenal and the kidney. However, in the presence of a tumor or inflammatory process, the adrenal can become very adherent to the kidney, and separation can be difficult. The arterial supply of the adrenals derives from the aorta and small branches from the renal arteries. The venous drainage on the left is mainly through the inferior phrenic vein and through the left renal vein via the inferior adrenal vein. On the right, the adrenal is drained by a very short (Chapter 41. Gynecology>

KEY POINTS 1. The general gynecology examination must incorporate the whole physical examination to adequately diagnosis and treat gynecologic disorders. 2. Gynecologic causes of acute abdomen include: pelvic inflammatory disease and tubo-ovarian abscess, ovarian torsion, ruptured ectopic pregnancy, and septic abortion. Pregnancy must be ruled out early in assessment of reproductive age patients presenting with abdominal or pelvic pain. 3. Pregnancy confers important changes to both the cardiovascular system and the coagulation cascade. Trauma in pregnancy must be managed with these changes in mind. 4. Pelvic floor dysfunction (pelvic organ prolapse, urinary and fecal incontinence) is common; 11% of women will undergo a reconstructive surgical procedure at some point in their lives. 5. It is critical that abnormal lesions of vulva, vagina, and cervix are biopsied for diagnosis before any treatment is planned; postmenopausal bleeding should always be investigated to rule out malignancy. Early-stage cervical cancer is managed surgically whereas chemoradiation is preferred for stages IB and above. 6. Risk-reducing salpingo-oophorectomy should be considered in women with BRCA1 or BRCA2 mutations; riskreducing salpingo-oophorectomy and complete hysterectomy should be considered in women with hereditary nonpolyposis coli cancer. 7. Complete debulking for epithelial ovarian cancer is a critical element in patient response and survival. The preferred primary therapy for optimally debulked advanced-stage ovarian epithelial ovarian cancer in women without significant intra-abdominal adhesions is intraperitoneal chemotherapy.

PATHOPHYSIOLOGY AND MECHANISMS OF DISEASE The female reproductive tract is a unique component of the body with a multitude of tightly regulated functions. Many of the activities normally ongoing, such as angiogenesis and physiologic invasion, are necessary for the reproductive organs to fulfill their purpose, and are usurped in disease. Immune surveillance is modified by multiple mechanisms under investigation, regulated in a different fashion, to allow implantation, placentation, and development of the fetus. How this potential disruption of the normal immune barriers is involved in pathologic events is incompletely understood. The ongoing rupture, healing, angiogenesis, and regrowth of the ovarian capsule and endometrium during the menstrual cycle uses the same series of biologic and biochemical events that are also active in pathologic events such as endometriosis and endometriomas, mature teratomas, dysgerminomas, and progression to malignancy. Genetic abnormalities, both germline and somatic, that may cause

competence and/or promote disease are now being uncovered, especially in the progression to malignancy, in pharmacogenomics, and in surgical risks such as bleeding and clotting. Incorporation of genetic and genomic information in disease diagnosis and assessment is a wave for the near future and may alter how we consider who is at risk, how diseases are diagnosed and followed, and even what drugs or therapies we use for an individual patient. These points will be incorporated with surgical approaches into discussions of anatomy, diagnostic workup, infection, surgical and medical aspects of the obstetric patient, pelvic floor dysfunction, and neoplasms.

ANATOMY The outlet of the bony pelvis is defined by the ischiopubic ramus anteriorly and the coccyx and sacrotuberous ligaments posteriorly.1 This outlet can be subdivided into anterior and posterior triangles, which share a common base via a line between the ischial tuberosities. The soft tissues of the anterior triangle are layered in a fashion similar to the anterior abdominal wall. The most superficial layer is a skin and adipose layer (vulva) that overlies a fascial layer (perineal membrane) that is, in turn, superficial to a muscular layer (levator ani).

Vulva The labia majora form the cutaneous boundaries of the lateral vulva and represent the female homologue of the male scrotum (Fig. 41-1). The labia majora are fatty folds covered by hair-bearing skin in the adult. They fuse anteriorly over the anterior prominence of the symphysis pubis, the mons pubis. The deeper portions of the adipose layers are called Colles' fascia and insert onto the inferior margin of the perineal membrane, limiting spread of superficial hematomas inferiorly. Adjacent and medial to the labia majora are the labia minora , smaller folds of connective tissue covered laterally by non–hair-bearing skin and medially by vaginal mucosa. The anterior fusion of the labia minora forms the prepuce and frenulum of the clitoris ; posteriorly, the labia minora fuse to create the fossa navicularis and posterior fourchette. The term vestibule refers to the area medial to the labia minora bounded by the fossa navicularis and the clitoris. Both the urethra and the vagina open into the vestibule. Skene's glands lie lateral and inferior to the urethral meatus. Cysts, abscesses, and neoplasms may arise in these glands.

Fig. 41-1.

External genitalia. (Reproduced with permission from Rock J, Jones HW: TeLinde's Operative Gynecology , 9th ed. Philadelphia, PA: Lippincott, Williams & Wilkins, 2003, Fig. 5-1, p 70.)

Erectile tissues and associated muscles are in the space between the perineal membrane and the vulvar subcutaneous tissues (Fig. 41-2). The clitoris is formed by two crura and is suspended from the pubis. Overlying the crura are ischiocavernosus muscles that run along the inferior surfaces of the ischiopubic rami. Extending medially from the inferior end of the ischiocavernosus muscles are the superficial transverse perinei muscles. These terminate in the midline in the perineal body, caudal and deep to the posterior fourchette. Vestibular bulbs lie just deep to the vestibule and are covered laterally by bulbocavernosus muscles. These originate from the perineal body and insert into the body of the clitoris. At the inferior end of the vestibular bulbs are Bartholin's glands, which connect to the vestibular skin by ducts.

Fig. 41-2.

Superficial compartment and perineal membrane. (Reproduced with permission from Rock J, Jones HW: TeLinde's Operative Gynecology , 9th ed. Philadelphia, PA: Lippincott, Williams & Wilkins, 2003, Fig. 5-2, p 71.)

Musculature of the Pelvic Floor The opening of the pelvis is spanned by the muscles of the pelvic diaphragm (Fig. 41-3). These muscles contract tonically. Most anatomy textbooks fail to give a true picture of the horizontal nature of the pelvic floor musculature (due to embalming artifact). These muscles include, from anterior to posterior, bilaterally, the pubococcygeus , puborectalis , iliococcygeus , and coccygeus muscles. The first two of these muscles contribute fibers to the fibromuscular perineal body. The urogenital hiatus is bordered laterally by the pubococcygeus muscles and anteriorly by the symphysis pubis . It is through this muscular defect that the urethra and vagina pass, and it is the focal point for the study of disorders of pelvic support such as cystocele, rectocele, and uterine prolapse.

Fig. 41-3.

Deeper muscles and nerves of the pelvic floor.

Nerves of the Pelvic Floor The pudendal nerve arises from S2 to S4, travels laterally, exiting the greater sciatic foramen, hooking around the ischial spine and sacrospinous ligament, and returning via the greater sciatic foramen (Fig. 41-4). It travels through Alcock's canal and becomes the sensory and motor nerve of the perineum. The motor neurons originate in Onuf's nucleus in the sacral spinal cord and serve the tonically contracting urethral and anal sphincter. Direct branches from the S2 to S4 nerves serve the levator ani muscles. During childbirth and other excessive straining, this tethered nerve (along with the levator ani muscles) is subject to stretch injury, and at least partially responsible for many female pelvic floor disorders.

Fig. 41-4.

The nerve supply of the female pelvis.

Internal Genitalia Figure 41-5 is a view of the internal genitalia as one would approach the pelvis from a midline abdominal incision. The central uterus and uterine cervix are supported by the pelvic floor muscles. They are suspended by the lateral fibrous cardinal, or Mackenrodt's ligament and the uterosacral ligaments, which insert into the paracervical fascia medially and into the muscular sidewalls of the pelvis laterally. Posteriorly, the uterosacral ligaments provide support for the vagina and cervix as they course from the sacrum lateral to the rectum and insert into the paracervical fascia.

Fig. 41-5.

Internal pelvic anatomy, from above.

The bilateral fallopian tubes arise from the upper lateral cornua of the uterus and course posterolaterally. Each widens in the distal third, or ampulla . The ovaries are attached to the uterine cornu by the proper ovarian ligaments . Emanating from the uterine cornu and traveling through the inguinal canal are the round ligaments, eventually attaching to the subcutaneous tissue of the mons pubis. The ovaries are suspended from the lateral pelvis by their vascular pedicles, the infundibulopelvic ligaments . The peritoneum enfolding the adnexa (tube, round ligament, and ovary) is referred to as the broad ligament , although it is no more ligamentous than the peritoneum overlying the ovarian artery and vein. The peritoneal recesses in the pelvis anterior and posterior to the uterus are referred to as the anterior and posterior cul-de-sacs . The latter is also called the pouch or cul-de-sac of Douglas . On transverse section, several avascular, and therefore important, surgical planes can be identified (Fig. 41-6). These include the lateral paravesical and pararectal spaces, and from anterior to posterior, the retropubic or prevesical space of Retzius and the vesicovaginal, rectovaginal, and retrorectal or presacral spaces. The pelvic brim demarcates the obstetric, or true, from the false pelvis contained within the iliac crests.

Fig. 41-6.

The avascular spaces of the female pelvis.

The muscles of the pelvic sidewall include the iliacus, the psoas, and the obturator internus muscle (Fig. 41-7). Except for the middle sacral artery originating at the aortic bifurcation, and the ovarian arteries originating from the abdominal aorta, the blood supply to the pelvis arises from the internal iliac arteries. The internal iliac, or hypogastric arteries divide into anterior and posterior branches. The latter supply lumbar and gluteal branches. From the anterior division of the hypogastric arteries arise the obturator, uterine, pudendal, middle rectal, along with superior and middle vesical arteries. The nerves found in the pelvis are the sciatic, obturator, and femoral nerves (see Fig. 41-4). Sympathetic fibers course along the major arteries and parasympathetics form the superior and inferior pelvic plexus. The ureters enter the pelvis as they cross the distal common iliac arteries laterally and then course inferior to the ovarian arteries and veins until crossing under the uterine arteries just lateral to the cervix. After traveling to the cervix, the ureters course downward and medially over the anterior surface of the vagina before entering the base of the bladder.

Fig. 41-7.

The muscles and vasculature of the pelvis.

DIAGNOSIS Elements of Gynecologic History A complete history is a seminal part of any assessment (Table 41-1). Many gynecologic diseases can present with broad constitutional symptoms, occur secondary to other conditions, or be related to medications. A full history should include particular attention to family history, organ system history, including breast, GI, and urinary tract symptoms, and a careful anesthesia and surgical history. The key elements of a focused gynecologic history include the following: Age at menarche and menopause Present and past menstrual status Obstetrical history History of pelvic assessments, including cervical smear results History of pelvic infections and HIV status if indicated, and Prior gynecologic surgery(s).

Table 41-1 Key Elements of the Gynecologic History

Menstrual history Age at menarche, menopause Identifies abnormal patterns related to endocrine, structural, infectious, and oncologic etiologies Bleeding pattern, postmenopausal bleeding, spotting between periods Any medications (Coumadin, heparin, aspirin, herbals, others) or personal or family history that might lead to prolonged bleeding times Obstetrical history Number of pregnancies, dates, type of deliveries, pregnancy loss, abortion, complications Identifies predisposing pregnancy for gestational trophoblastic disease, possible surgical complications Infectious diseases Sexually transmitted diseases and treatment and/or testing for these Also need to explore history of other GI diseases that may mimic sexually transmitted diseases (Crohn's, diverticulitis) Contraceptive history Present contraception if appropriate, prior use, type, and duration Concurrent pregnancy with procedure or complications of contraceptives Cytologic screening Frequency, results (normal, prior abnormal Papanicolaou), any prior surgery or diagnoses, human papillomavirus testing history Prolonged intervals increase risk of cervical cancer. Relationship to anal, vaginal, vulvar cancers. Prior gynecologic surgery Type (laparoscopy, vaginal, abdominal); diagnosis (endometriosis?, ovarian cysts?, tubo-ovarian abscess?); actual pathology if possible. Assess present history against this background (for example, granulosa cell pathology, is it now recurrent?) Pain history Site, location, relationship (with urination, with menses, with intercourse at initiation or deep penetration?, with bowel movements?), referral? Assesses relationship to other organ systems, and potential involvement of these with process. Common examples presenting as pelvic pain, ureteral stone, endometriosis with bowel involvement, etc. Issue

Elements to Explore

Associated Issues

Gynecologic Examination Many women use their gynecologist as their primary care physician. When that is the case, it is necessary that a full medical and surgical history be taken and that, in addition to the pelvic examination, a minimum additional examination should include: thyroid, breast, cardiac, and pulmonary examinations. The pelvic examination starts with a full abdominal examination. Inguinal node evaluation is performed before placing the patient's legs in the dorsal lithotomy position (in stirrups). A flexible, focused light source is essential and vaginal instruments including speculums of variable sizes and shapes including pediatric sizes (Graves and Pederson) are required to assure that the patient's anatomy can be fully and comfortably viewed. The external genitalia are inspected, noting the distribution of pubic hair, the skin color and contour, the Bartholin's and Skene's glands, and perianal area. Abnormalities are documented, and a map with measurements of abnormalities drawn. A warmed lubricated speculum is inserted into the vagina and gently opened to identify the

cervix if present, or the vaginal apex if not. If there is a concern that a malignancy is present, careful digital assessment of a vaginal mass and location may be addressed before speculum placement to avoid abrading a vascular lesion and inducing hemorrhage. The speculum would then be inserted just short of the length to the mass to view that area directly before advancing. An uncomplicated speculum examination includes examination of the vaginal sidewalls, assessment of secretions including culture if necessary, and collection of the cervical cytologic specimen. Cervical cytology is performed by use of a brush placed into the cervical os, rotation of the brush, and then placement of the brush into liquid medium or spread and fixed on a glass slide, depending on the evaluation methods in use. A bimanual examination is performed by placing two fingers in the vaginal canal; one finger may be used if patient has had prior radiation with stenosis or chemo- or other therapy with associated vaginal atrophy (Fig. 41-8). Carefully and sequentially assess the size and shape of the uterus by moving it against the abdominal hand, the adnexa by carefully sweeping the abdominal hand down the side of the uterus. The rectovaginal examination, one finger in the vagina and one in the rectal vault, is used to further examine and characterize the location, shape, fixation, size, and complexity of the uterus, adnexa, cervix, and anterior and posterior cul de sacs. The rectovaginal exam also allows examination of the uterosacral ligaments from the back of the uterus sweeping lateral to the rectal finger to the sacrum.

Fig. 41-8.

Bimanual abdominovaginal palpation of the uterus.

It is critical that presurgical assessment include a full general examination. This is particularly important with potentially oncologic diagnoses or infectious issues to assure that the proposed surgery is both safe and appropriate. Complications such as sites of metastatic cancer or infection, associated bleeding and/or clotting

issues and history, and drug exposure, allergies, and current medications must be addressed.

Screening Procedures CERVICAL CYTOLOGY The present guidelines for cervical cytology recommend annual evaluation for all sexually active women up to the age of 30 years old. After age 30, cervical cytology may be extended to every 2 to 3 years if cytology has remained negative and/or testing for human papillomavirus (HPV) high-risk types have been negative. This can be achieved with either liquid techniques or the older smear technique, recognizing that the accepted approach is moving to liquid techniques as they allow for reflex testing of HPV high-risk subtypes as appropriate. It is beyond the scope of the chapter to describe in detail the complex patterns that vary by age and prior history for following abnormal cytology findings. These must be addressed before any surgery, other than diagnostic, involving the cervix is planned. The diagnostic approach for abnormal Pap smears is detailed in Fig. 41-9.

Fig. 41-9.

Diagnostic approach for cervical dysplasia. AGC = atypical glandular cells; ASCUS = atypical cells of undetermined significance; HGSIL = high-grade squamous intraepithelial lesion; HPV = human papillomavirus; LGSIL = low-grade

squamous intraepithelial lesion; Pap = Papanicolaou.

HUMAN PAPILLOMAVIRUS TESTING If liquid-based cytology is used, HPV testing for high-risk types can be done using the same specimen collected for cervical cytology.2 HPV testing is useful to triage atypical cells of undetermined significance cytology results to either colposcopy or observation in patients beyond adolescence. Approximately half of atypical cells of undetermined significance cases will test positive for high-risk HPV subtypes and need colposcopy; those with negative tests can be followed routinely with cervical cytology. HPV testing is indicated in particular for planning intervals of cervical screening after age 30 years old. In these patients, if HPV testing is combined with cytology and both test negative, screening intervals can be spaced to every 3 years. Patients with low-grade squamous intraepithelial lesions have a high likelihood of testing positive, and as such high-risk HPV testing is not cost effective for triage; all should go to colposcopy.

VAGINAL DISCHARGE AND CULTURES See section on Lower Genital Tract Infections.

BETA HUMAN CHORIONIC GONADOTROPHIN TESTING Quantitative urinary pregnancy tests for beta human chorionic gonadotrophin (beta-hCG) are standard before any surgery in a woman of reproductive age and potential, regardless of contraception history. In addition, serum betahCG testing is appropriate for evaluation of suspected ectopic pregnancy, gestational trophoblastic disease (GTD), or ovarian mass in a young woman. In the case of ectopic pregnancy, serial levels are required when a pregnancy cannot be identified in the uterine cavity. As a general rule, there should be at least a 66% rise in the beta-hCG level over 48 hours if there is a viable intrauterine pregnancy.

Common Office Procedures for Diagnosis VULVAR BIOPSY Any abnormal lesion including skin color changes, raised lesions, or ulcerations should be biopsied. Local infiltration of a longer acting anesthetic is followed by punch biopsy appropriate to the lesion. The specimen is elevated with Adson forceps and cut from its base with iris scissors.

VAGINAL BIOPSY This biopsy follows the same principles as vulvar biopsy but often is difficult to perform because of the angle of the lesion. After injection with local anesthetic, traction of the area with Allis forceps and direct resection of the lesion with a Metzenbaum scissors or cervical biopsy instrument (Schubert, Kevorkian, etc.) can achieve an adequate biopsy. Cervical biopsy topical 4% lidocaine may be adequate for the many cervical biopsies that can be done without a tenaculum. The maintenance of sharp cervical biopsy forceps is critical to success. A loop electrosurgical excision procedure (LEEP) can be performed if the lesion is more extensive or vascular and allows the ball tip to be used for cautery. Cauterization of all of the above lesions can be performed with silver nitrate, Monsel's solution, or direct electrical cauterization as required. If not adequate, suture should suffice to provide hemostasis.

ENDOMETRIAL BIOPSY

An endometrial sampling should be performed before planned hysterectomy if there is a history of abnormal bleeding, defined as bleeding between periods, spotting other than midcycle, heavy bleeding, frequent bleeding, or postmenopausal bleeding. A patient with the potential for pregnancy should have a pregnancy test before the procedure. Topical 4% lidocaine can be applied under direct visualization to the anterior cervix where a tenaculum might be placed, and then in the endocervical canal with a cotton-tipped applicator. A Pipelle is inserted after cervical cleaning and the depth noted; a tenaculum is placed if the cervix is too mobile or the uterus too flexed. The specimen is obtained by pulling on the central end, creating a small amount of suction in the uterine cavity, and moving it within the cavity to access all sides.3 Additional passes may be made if the specimen is not initially adequate.

EVALUATION FOR FISTULAE Common office procedures to evaluate for the presence of vesicovaginal fistulae include placement of a vaginal tampon before the procedure, and then insertion of sterile milk or sterile dye into the bladder through a transurethral catheter. Evaluation of suspected ureteral fistula is best done with radiologic imaging, and when confirmed, IV injection of dye may allow for direct visualization if the site is not obvious. Rectal fistula can be identified in a similar fashion using a large Foley catheter placed in the distal rectum through which dye may be injected or with the use of an oral charcoal slurry and timed examination. Common areas for fistulae are at the vaginal apex, at the site of a surgical incision, or around the site of a prior episiotomy or perineal repair after a vaginal delivery.

GYNECOLOGIC INFECTIONS Lower Genital Tract Infections Vulvovaginal symptoms are extremely common, accounting for >10 million office visits per year in the United States. The causes of vaginal complaints are commonly infectious in origin but they include a number of noninfectious causes, such as chemicals or irritants, hormone deficiency, foreign bodies, systemic diseases, and malignancy. Symptoms are commonly nonspecific and include abnormal vaginal discharge, pruritus, irritation, burning, odor, dyspareunia, bleeding, and ulcers.

CULTURES The two most important cultures of vaginal secretions are for gonorrhea and chlamydia. A purulent discharge from the cervix should always raise suspicion of these infections even in the absence of pelvic pain or other signs. These cultures are obtained by removing ectocervical discharge or blood and then with a sterile swab obtaining an endocervical swab that is then placed in carrier media for later culture on Thayer-Martin medium, and/or for enzyme linked immunosorbent assay or direct fluorescent antibody testing.

Vaginitis Normal vaginal discharge is white or transparent, thick, and mostly odorless. It increases during pregnancy, with use of estrogen-progestin contraceptives, or at midcycle around the time of ovulation. Complaints of foul odor and abnormal vaginal discharge should be investigated. Candidiasis, bacterial vaginosis (BV), and trichomoniasis account for 90% of cases of vaginitis (Table 41-2). The initial work-up includes pelvic examination, vaginal pH testing, microscopy, and, less commonly, vulvovaginal and cervical cultures.4 The pH of the normal vaginal secretions is 3.8 to 4.4, which is hostile to growth of pathogens. pH of 4.9 or greater is indicative of a bacterial or protozoal infection. Vaginal pH is obtained by dipping a pH tape into vaginal secretions collected on the speculum.

Microscopy requires preparing wet and potassium hydroxide (KOH) mounts by adding a drop of normal saline or 10% KOH solutions to a specimen of the discharge. Microscopic examination of the wet mount may reveal motile trichomonads indicative of trichomoniasis or the characteristic clue cells of BV. KOH lyses cellular material and allows the clinician to appreciate the presence of mycelia characteristic of candidiasis. Treatment of vaginal infection before anticipated surgery is appropriate, particularly for BV, which may be associated with a higher risk for vaginal cuff infections. Figure 41-10 summarizes the diagnostic and treatment approach for common causes of vulvovaginitis.

Table 41-2 Features of Common Causes of Vaginitis Pathogen Anaerobic organisms Candida albicans Trichomonas vaginalis % of Vaginitis 40 30 20 pH >4.5 4.5 Signs and symptoms Malodorous, adherent discharge White discharge, vulvar erythema, pruritus, dyspareunia Malodorous purulent discharge, vulvovaginal erythema, dyspareunia Wet mount Clue cells Pseudohyphae or budding yeasts in 40% of cases Motile trichomonads KOH mount Pseudohyphae or budding yeasts in 70% of cases Amine test + – – Treatment Metronidazole 500 mg bid x 7 d or 2 g single dose, metronidazole or clindamycin vaginal cream Oral fluconazole 150 mg single dose, vaginal antifungal preparations Metronidazole 2 g single dose and treatment of partner Bacterial Vaginosis

Vulvovaginal Candidiasis

+ = positive; – = negative; KOH = potassium hydroxide.

Fig. 41-10.

Trichomoniasis

Treatment algorithm for vulvovaginitis. KOH = potassium hydroxide.

BACTERIAL VAGINOSIS BV is the most common cause of vaginal discharge, accounting for 50% of cases. It results from reduction in concentration of the normally dominant lactobacilli and increase in concentration of anaerobic organisms like Gardnerella vaginalis , Mycoplasma hominis , Bacteroides spp, and others.5,6 Patient presentation, symptoms, cause, diagnostics, and interventions are shown in Table 41-2. Diagnosis is made by microscopy and involves recognition of clue cells, which are epithelial cells studded with adherent bacteria causing their margins to be obliterated. The discharge typically produces a fishy odor upon addition of KOH (amine or Whiff test).

VULVOVAGINAL CANDIDIASIS Vulvovaginal candidiasis is the most common cause of vulvar pruritus. It generally is caused by Candida albicans and occasionally by other Candida spp. It is common in pregnancy, in diabetics, in patients taking antibiotics, and in the immunocompromised. Seventy-five percent of women will experience one episode, with 40 to 50% having two or more. Diagnosis is confirmed by observation of pseudohyphae or yeasts on microscopy.

TRICHOMONAS VAGINALIS Trichomonas vaginalis causes primarily a vaginal infection; however, the copious discharge results in a secondary

vulvitis. Diagnosis is made with saline wet mount demonstrating motile protozoans.

Genital Ulcer Syndromes The frequency of the infectious etiologies of genital ulcers varies by geographic location. In the United States, the most common causes of sexually transmitted genital ulcers in young adults are, in descending order of prevalence: herpes simplex virus (HSV), syphilis, and chancroid.7 Others infectious causes of genital ulcers include lymphogranuloma venereum and granuloma inguinale. Noninfectious etiologies include Behet's disease, neoplasms, and trauma. Establishing a diagnosis requires knowledge of the characteristics of genital ulcer syndromes and a rational approach to the evaluation of patients to guide therapy at the time of the initial encounter (Table 41-3). Confirmation of the established diagnosis requires the use of appropriate diagnostic tests.8

Table 41-3 Clinical Features of Genital Ulcer Syndromes Pathogen HSV type II and, less commonly, HSV type I Treponema palladium Haemophilus ducreyi Chlamydia trachomatis L1–L3 Calymmatobacterium granulomatis Incubation period 2–7 d Typically 2–4 wk (can range from 1–12 wk) 1–14 d 3 d–6 wk 1–4 wk (up to 6 mo) Primary lesion Vesicle Papule Papule or pustule Papule, pustule, or vesicle Papule Number of lesions Multiple, may coalesce Usually one Usually multiple, may coalesce Usually one Variable Diameter (mm) 1–2 5–15 2–20 2–10 Variable Edges Erythematous Sharply demarcated, elevated, round, or oval Undermined, ragged, irregular Elevated, round, or oval Elevated, irregular

Depth Superficial Superficial or deep Excavated Superficial or deep Elevated Base Serous, erythematous Smooth, nonpurulent Purulent Variable Red and rough ("beefy") Induration None Firm Soft Occasionally firm Firm Pain Common Unusual Usually very tender Variable Uncommon Lymphadenopathy Firm, tender, often bilateral Firm, nontender, bilateral Tender, may suppurate, usually unilateral Tender, may suppurate, loculated, usually unilateral Pseudoadenopathy Treatment Acyclovir 400 mg PO tid x 7–10 d for primary infection and 400 mg PO tid x 5 d for episodic management Primary, secondary, and early latent (1 y) and latent of unknown duration: benzathine PCN-G 2.4 million units IM qwk x 3 Ciprofloxacin 500 mg PO bid x 3 d or Erythromycin base 500 mg PO tid x 7 d Suppression Acyclovir 400 mg PO bid for those with frequent outbreak — — — —

Herpes Syphilis Chancroid Lymphogranuloma Venereum

Granuloma Inguinale (Donovanosis)

HSV = herpes simplex virus; PCN-G = penicillin. Source: Adapted from Stenchever M, Droegemueller W, Herbst A, et al: Comprehensive Gynecology , 4th ed. St Louis: Mosby, 2001.

GENITAL HERPES Herpes is a recurrent, incurable, sexually transmitted disease that has reached epidemic proportions. At least one in five individuals has had genital herpes in the United States. Herpes simplex infection is highly contagious and is caused by HSV-II and, less commonly, by HSV-I. Primary infection is a genital and systemic disease. Patients usually present with multiple painful vesicles that coalesce to form shallow superficial ulcers involving the vulva, vagina, and cervix.9 Other possible symptoms include dysuria, fever, malaise, tender inguinal lymphadenopathy, and headaches. Less commonly, the infection can be subclinical and entirely asymptomatic. Once a patient is infected, there is a tendency for outbreaks at various intervals for life. Between outbreaks, the herpes virus resides dormant in the dorsal root ganglia of S2–4. Recurrent genital herpes is a local disease and characteristically less severe than the primary infection and of shorter duration. A common feature of recurrence is as prodromal phase of vulvar burning, tenderness, and pruritus lasting from a few hours up to a few days. Diagnosis is made by simple inspection of the lesions, cytology is helpful (Tzanck smear), and culture is confirmatory. Treatment is outlined in Table 41-3; alternative antiviral medications include famciclovir and valacyclovir. Vaginal delivery is contraindicated in pregnant patients presenting in labor with active genital herpes. Cesarean section is indicated and aims to prevent a potentially devastating neonatal infection.10,11

SYPHILIS Syphilis is a chronic, systemic, sexually transmitted disease and is the second most common cause of genital ulcers and is caused by Treponema pallidum , an anaerobic spirochete.1 2 In the United States, >36,000 cases of syphilis were reported in 2006, including 9756 cases of primary and secondary syphilis. The incidence was highest in women 20 to 24 years of age. Clinically, syphilis is divided into primary, secondary, tertiary, and congenital. The primary stage is marked by the appearance of a single ulcer (chancre). The chancre usually is firm, round, painless, may be accompanied by regional adenopathy, and develops at the site of entry of the bacterium. It lasts 3 to 6 weeks, and it heals without treatment. However, without treatment, the primary infection progresses to secondary syphilis and eventually to tertiary disease in 30% of cases, after a variable latent phase that usually lasts for years. During pregnancy, syphilis can be transmitted to the fetus and may result in the varied manifestations of congenital syphilis syndrome, which may results in fetal hydrops and intrauterine fetal demise. The diagnosis of syphilis is typically made by examination and serologic testing. Nonspecific nontreponemal tests such as rapid plasma reagin and Venereal Disease Research Laboratories are used for screening, and specific treponemal tests such as fluorescent-labeled treponema antibody absorption and microhemagglutination assay for antibodies to T. pallidum are used for confirmation.

CHANCROID Chancroid is a contagious sexually transmitted ulcerative disease of the vulva caused by Haemophilus ducreyi , small gram-negative rods that exhibit parallel alignment on Gram's staining ("school of fish").1 3 After a short incubation period, the patient usually develops multiple painful soft ulcers on the vulva, mainly on the labia majora and, less commonly, on the labia minora or involving the perineal area. The chancroid ulcer has ragged, irregular

borders and a base that bleeds easily and is covered with grayish exudates. Approximately half the patients will develop painful inguinal lymphadenitis within 2 weeks of an untreated infection, which may undergo liquefaction and presents as buboes.1 4 These may rupture and discharge pus. Diagnosis is made by Gram's stain and, less commonly, by culture.

LYMPHOGRANULOMA VENEREUM Lymphogranuloma venereum (LVG) is a sexually transmitted infection of lymphatic tissue caused by Chlamydia trachomatis serotypes L1, L2, and L3. LVG is rare in the United States.1 5 In its primary stage, a genital ulcer develops at the site of inoculation after an incubation period of 3 to 30 days. The primary ulcer heals within a few days without therapy. The secondary phase of LVG develops 2 to 4 weeks later and is precipitated by direct spread to inguinal and perirectal lymph nodes. These painful, enlarged lymph nodes may result in the classic inguinal "groove sign" (double genitocrural fold) and may form buboes and rupture. Without adequate therapy, the patient will progress to the third stage marked by extensive inflammation and scarring. Clinical diagnosis is confirmed by serologic testing and culture. Complications include genital elephantiasis and colorectal fistulae and strictures. Treatment cures the infection and prevents ongoing tissue damage. Buboes occasionally require aspiration or incision and drainage.

GRANULOMA INGUINALE Granuloma inguinale, donovanosis, is an ulcerative bacterial infection of the vulva and perianal area that is transmitted via sexual contact in the majority of cases. It is caused by the intracellular gram-negative bacterium Klebsiella granulomatis . It is endemic in some tropical areas but is rarely seen in the United States. After a variable incubation period, the infection manifests as multiple nodules that ulcerate resulting in "beefy-red" ulcers covered with granulation tissue. These ulcers bleed easily and may coalesce, resulting in destruction of the vulvar architecture. The causative organism is difficult to culture, and diagnosis requires visualization of Donovan bodies on tissue crush preparation or biopsy. Donovan bodies are intracytoplasmic clusters of bacteria found in macrophages.

Molluscum Contagiosum Molluscum contagiosum is a localized viral infection of the skin that typically spares the palms and soles. It can involve the genital area, and the lesions usually are small shiny papules with central umbilication. The condition is self-limited and resolves spontaneously. Genital lesions can be treated to prevent sexual transmission. Treatment options include curettage, cryotherapy, and laser ablation.

Bartholin's Cysts and Abscesses Bartholin's glands (great vestibular glands) are located at the vaginal orifice at the 4 and 8 o'clock positions and they are rarely palpable in normal patients. They are lined with cuboidal epithelium and secrete mucoid material to keep the vulva moist. Their ducts are lined with transitional epithelium and their obstruction secondary to inflammation may lead to the development of a Bartholin's cyst or abscess. Bartholin's cysts range in size from 1 to 3 cm, and are detected on examination or recognized by the patient. They occasionally result in discomfort and dyspareunia and require treatment. Cysts and ducts can become infected and form abscesses. Infections are often polymicrobial; however, sexually transmitted Neisseria gonorrhea and C. trachomatis are sometimes implicated. Abscesses usually present as acutely inflamed, exquisitely tender masses. Treatment consists of incision and drainage and placement of a Word catheter, a small catheter with a balloon tip, for 2 to 3 weeks to allow for formation and epithelialization of a new duct. Appropriate antibiotic therapy should be instituted and modified

based upon culture results. Recurrent cysts or abscesses are usually marsupialized, but on occasion necessitate excision of the whole gland. Marsupialization is done by incising the cyst or abscess wall and securing its lining to the skin edges with interrupted sutures.1 6 Cysts or abscesses that fail to resolve after drainage and those occurring in patients >40 years of age should be biopsied to exclude malignancy.

Vulvar Condylomas Condylomata acuminata (anogenital warts) are viral infections caused by HPV.2 Genital infection with HPV is the most common sexually transmitted infection in the United States today. It is estimated that approximately 1% of sexually active adults currently have genital warts. There are more than 100 different types of HPV, and they differ in terms of the type of epithelium they infect. More than 30 types infect the anogenital epithelium, including the cervix, vagina, vulva, urethra, rectum, and anus. These are divided into low- and high-risk types. HPV 6 and 11 are the most common low-risk types and are implicated in 90% of cases of genital warts.1 7 High-risk types can be found in association with invasive cancers. Genital warts are skin colored or pink and range from smooth, flattened papules to verrucous, papilliform lesions. Lesions may be single or multiple and extensive. Diagnosis is made by simple inspection and should be confirmed with biopsy as verrucous and other vulvar cancers can be mistaken for condylomata.1 8 Treatment modalities range from patient-applied ointments, physician-applied agents, and office procedures, to outpatient surgery. Patients may be prescribed 5% imiquimod cream to apply once at bedtime and wash off in the morning, three times a week, for up to 16 weeks. Trichloroacetic acid is a commonly used caustic agent for in office application and can be repeated weekly as necessary. Surgical modalities include cryotherapy, laser ablation, cauterization, and surgical excision depending on the severity and extent of the lesions.

Upper Genital Tract Infections Pelvic inflammatory disease (PID) is an infection of the upper female genital tract involving the uterus, fallopian tubes, and ovaries, resulting in endometritis, salpingitis, and oophoritis. It often involves contiguous pelvic organs resulting in peritonitis, tubo-ovarian abscesses, and occasionally perihepatitis (Fitz-Hugh–Curtis syndrome). Longterm sequelae include infertility, chronic pelvic pain, and increased risk of ectopic pregnancy.19,20 PID is mostly a sexually transmitted, ascending infection caused by N. gonorrhea and/or C. trachomatis , but numerous other organisms have been implicated, including normal vaginal flora. Screening for concomitant HIV infection is strongly recommended. Less commonly, PID may result from extension of other pelvic and abdominal infections such as appendicitis and diverticulitis, or may be precipitated by medical procedure, such as hysterosalpingography, endometrial biopsy, or dilation and curettage. Risk factors for PID include age 6 cm in diameter that are fragile and generally should be followed without any surgical intervention as they resolve with removal or treatment of the GTD. Metastatic GTD can present on the cervix, vagina, liver, or lung and should not be managed surgically, as chemotherapy is the primary therapy and the incidence of bleeding complications is significant. Primary surgery for diagnosis and initial therapy is a suction dilatation and curettage. Oxytocin is started either before anesthesia or immediately as the cervix is being dilated. The largest suction catheter possible (12 mm preferred) is gently inserted through the cervix and suction turned on, to allow the tissue to be removed and the uterus to rapidly decrease, with less blood loss. Following this, a sharp curettage of the uterus is done with a larger curette associated with a higher risk for perforation. Following diagnosis, beta-hCG is followed weekly until normal

for 3 weeks, then monthly for at least 6 months. Any increase in beta-hCG may trigger further evaluation and consideration of chemotherapy.

PELVIC FLOOR DYSFUNCTION Pelvic floor disorders can be categorized, from a urogynecologic perspective, into three main topics: female urinary incontinence and voiding dysfunction, pelvic organ prolapse, and disorders of defecation.3 3 Approximately 11% of women will undergo surgery for incontinence or prolapse.3 4 The normal functions of support, storage, and evacuation can be altered by derangements in neuromuscular function both centrally and peripherally, and through acquired changes in connective tissue. Reconstructive surgeons aim to repair or compensate for many of these losses.

Evaluation Diagnostic evaluations, in addition to the history and examinations described above under Gynecologic Examination, can aid in the diagnosis of many pelvic floor disorders. Cystoscopy, multichannel urodynamics, and/or fluoroscopic evaluation of the urinary tract can be obtained for patients with urinary incontinence or voiding dysfunction.3 5 Defecography, anal manometry, and endorectal ultrasound may be useful for diagnosis of defecatory dysfunction. A standardized examination called the pelvic organ prolapse quantification

35

helps to clarify which

vaginal compartment, and therefore, which specific structure, has lost its anatomic integrity in women with uterovaginal prolapse. Finally, dynamic magnetic resonance imaging (MRI) and pelvic floor electromyography have growing use for all three disorders.

SURGERY FOR PELVIC ORGAN PROLAPSE Vaginal Procedures36 Many factors are important in determining which reconstructive operation is optimal for a given patient with pelvic organ prolapse. Surgical decisions often are based on case series and expert opinions that may not have universal applicability. However, the few reports with the highest level of evidence suggest that failure rates for prolapse reconstruction may be twice as high using the vaginal approach when compared with the abdominal route.36,37

COLPORRHAPHY Anterior colporrhaphy begins with incision of the anterior vaginal epithelium in a midline sagittal direction. The epithelium is dissected away from the underlying vaginal muscularis. Although many surgical descriptions refer to plication of the "endopelvic" or "pubocervical" fascia, such structures have not been shown to exist as histologically distinct layers. The vaginal muscularis is plicated with interrupted delayed absorbable stitches, after which the epithelium is trimmed and reapproximated. The vaginal canal is therefore shortened and narrowed proportionately to the amount of removed epithelium. Posterior colporrhaphy is performed in a similar manner, often including the distal pubococcygeus muscles in the plication. In addition to the vaginal shortening and neuropathy that may be induced by these dissections, levator plication is associated with a significant risk of postoperative dyspareunia. These factors influence the selection of appropriate patients for colporrhaphy procedures.

SACROSPINOUS FIXATION The sacrospinous ligament is used as a unilateral fixation point for the vaginal apex. The procedure begins with entry into the rectovaginal space, usually by incising the posterior vaginal wall at its attachment to the perineal body. The space is developed to the level of the vaginal apex, and the rectal pillar is penetrated to gain access to

the pararectal space. The sacrospinous ligament is found embedded in and continuous with the coccygeus muscle, which extends from the ischial spine to the lateral surface of the sacrum. A long-ligature carrier is used to place sutures medial to the ischial spine, through the substance of the ligament-muscle complex. Structures at risk in this procedure include the pudendal neurovascular bundle, the inferior gluteal neurovascular bundle, lumbosacral plexus, and sciatic nerve. After the stitches are placed, the free ends are sewn to the undersurface of the vaginal cuff. The sacrospinous stitches are tied to firmly approximate the vagina to the ligament without suture bridging. The epithelial incision is closed.

UTEROSACRAL LIGAMENT SUSPENSION Both sacrospinous fixation and suspension of the vaginal apex to the uterosacral ligaments may be performed immediately following vaginal hysterectomy or applied to posthysterectomy vaginal vault prolapse. The procedure is based on the concept that the natural support structures for the apical vagina and cervix are the uterosacral ligaments. When using the uterosacral ligaments for repair of prolapse, it is important to recall that these structures are not "ligaments" in the true sense of the word, but rather condensations of smooth muscle, collagen, and elastin. The integrity and strength of these structures may vary greatly from patient to patient. The repair uses the middle third of the ligament, which allows firm tissue-to-tissue approximation to the vagina and does not divert the ureter medially. Several support stitches are placed, such that the lateral-most portion of the vaginal cuff is attached to the distal-most part of the ligament and the medial cuff to the proximal ligament. Intraoperative evaluation of the lower urinary tract is important to confirm the absence of ureteral compromise.

COLPOCLEISIS A colpocleisis removes part or all of the vaginal epithelium. This obliterates the vaginal vault, leaving the external genitalia unchanged. Colpocleisis is reserved for patients who are elderly, who do not wish to retain coital ability, and for whom there is good reason not to perform a more extensive reconstructive operation. The main benefits of colpocleisis operations are their simplicity, speed, and high efficacy. The LeFort colpocleisis technique, done for complete uterovaginal prolapse, involves denudation of a rectangular portion of vaginal epithelium on both the anterior and posterior walls followed by suture reapproximation of the exposed submucosal surfaces. The uterus is left in situ. Lateral drainage canals remain for drainage of uterine secretions. By contrast, total colpocleisis involves hysterectomy, if applicable, followed by excision of the entire anterior and posterior epithelium. Successive pursestring sutures through the vaginal muscularis are used to reduce the prolapsed organs to above the level of the levator plate. The bladder neck is displaced posteriorly by the repair, placing the patient at risk for postoperative stress incontinence; a concomitant procedure to stabilize the urethrovesical junction is recommended. This may involve plication of the anterior vaginal muscularis (Kelly plication), pubourethral ligament plication, or a sling procedure, depending on preoperative urodynamic findings.

Abdominal Procedures SACROCOLPOPEXY Pelvic reconstructive surgery by the abdominal approach has, as its main advantage, the use of graft material for support of the vaginal apex. The natural apical support structure, the cardinal–uterosacral ligament complex, is often damaged and attenuated. The use of graft material to compensate for defective vaginal support structures is well described.3 8 Apical support defects rarely exist in isolation. Therefore, the sacrocolpopexy may be modified to include the anterior and posterior vaginal walls as well as the perineal body in the suspension. Sacrocolpopexies can be performed via laparotomy as well as via laparoscopy. Like rectopexies and low anterior resections, deep pelvic access is needed. Significant suturing at varied angles is required. The advent of the da Vinci robotic

laparoscopic system has made visualization and adequate placement of the mesh and sutures easier to perform when using the minimally invasive approach. A rigid stent is placed into the vagina to facilitate its dissection from the overlying bladder and rectum, and to allow the graft material to be spread evenly over its surface. A strip of synthetic mesh is fixed to the anterior and posterior vaginal wall. The peritoneum overlying the presacral area is opened, extending to the posterior cul-desac. The sigmoid colon is retracted medially and the anterior surface of the sacrum is skeletonized. Two to four permanent sutures are placed through the anterior longitudinal ligament in the midline, starting at the S2 level and proceeding distally. The sutures are passed through the graft at an appropriate location to support the vaginal vault without tension. The peritoneum is then closed with an absorbable running suture. The most dangerous potential complication of sacrocolpopexy is life-threatening sacral hemorrhage.

SURGERY FOR STRESS URINARY INCONTINENCE There are a multitude of studies addressing the efficacy of different surgical procedures for urinary incontinence. The interpretation of this literature is often difficult because of a lack of standardized definitions or standardized procedures. Stress incontinence is believed to be caused by lack of urethrovaginal support (urethral hypermobility) or intrinsic sphincter deficiency (ISD). ISD is a term applied to a subset of stress-incontinent patients who have particularly severe symptoms, including urine leakage with minimal exertion. This condition often is recognized clinically as the low pressure or "drainpipe" urethra. The urethral sphincter mechanism in these patients is severely damaged, limiting coaptation of the urethra. There are no set specific or objective criteria that define ISD, although urodynamic criteria often are used to support it. Standard surgical procedures used to correct stress incontinence share a common feature: partial urethral obstruction that achieves urethral closure under stress. Despite older literature to the contrary, this objective does not require that the bladder neck be "elevated to a high retropubic location."3 9

Needle Suspension The transvaginal needle suspension was first described in 1959 by Pereyra.4 0 Variations on this technique include the Stamey, Gittes, and Raz procedures. After an anterior colpotomy is made, the vaginal epithelium is dissected and mobilized to the level of the descending pubic rami. The space of Retzius is entered bilaterally using a blunt clamp or closed heavy Mayo scissors to penetrate the perineal membrane along the inferior aspect of the descending pubic ramus. A long, angled needle is passed through a small transverse suprapubic incision, through the rectus fascia, through the space of Retzius, to bring up the ends of a suture that has been secured to the periurethral vaginal muscularis. Variations exist in the way in which the suture is attached to the periurethral tissue and the method of abdominal wall fixation. Long-term studies of needle procedures have shown evidence of steadily increasing failure rates, likely a result of suture pullout from the periurethral vaginal tissue.

Retropubic Colposuspension The space of Retzius is approached extraperitoneally, from an abdominal approach, allowing the bladder to be mobilized from the surrounding adipose tissue and lateral pelvis. Overlying fat and blood vessels in the area of the vesical neck are cleared away.

MARSHALL-MARCHETTI-KRANTZ PROCEDURE In the Marshall-Marchetti-Krantz procedure, a permanent suture is placed lateral to the urethra bilaterally and tied to the periosteum of the pubic ramus or perichondrium of the symphysis pubis. The surgical objective is to appose

the urethra to (or within 1 to 2 cm of) the posterior surface of the symphysis pubis. Osteitis pubis is a rare, but serious, potential complication that can result from trauma and devascularization of the symphysis. This and suture pullout from the symphysis has prompted the search for improved techniques.

BURCH PROCEDURE The most quoted description of the Burch procedure is that of Tanagho in 1976.4 1 Two pairs of large-caliber delayed-absorbable suture are placed through the periurethral vaginal wall, one pair at the midurethra and one at the urethrovesical junction. Each stitch is then anchored to the ipsilateral Cooper's (iliopectineal) ligament. The sutures are tied with the operator's nondominant hand placed vaginally to give preferential support to the urethrovesical junction relative to the anterior vaginal wall without overcorrection. Long-term outcome studies up to 10 years have shown the Burch procedure yields cure rates of 80 to 85%.

Suburethral Sling A variety of organic and synthetic graft materials have been used to construct suburethral slings. Synthetic materials fell out of favor after a high incidence of postoperative urinary retention and urethral damage were found to be associated with their use. Currently, the most commonly used sling materials include autografts of rectus fascia and processed cadaveric allografts (fascia lata). The procedure is performed by a combined abdominovaginal approach, using a small transverse suprapubic skin incision. The anterior vaginal epithelium is incised in the midline from the midurethra to just proximal to the urethrovesical junction, as identified by the bulb of an indwelling urethral catheter. The epithelium is dissected from the underlying muscularis using sharp dissection bilaterally. The space of Retzius is entered using a blunt clamp or closed heavy Mayo scissors to penetrate the perineal membrane along the inferior aspect of the descending pubic ramus. Maintenance of the proper angle of penetration is important to minimize the risk of injury to the obturator neurovascular bundle or ilioinguinal nerve laterally, and urethra or bladder medially. A Bozeman clamp or long-angled ligature carrier is used to perforate the rectus fascia two fingerbreadths superior to the pubic bone just medial to the pubic tubercle, and the instrument is guided along the back of the pubic bone through the space of Retzius and into the vaginal incision to retrieve one arm of the sling. After bringing up the other side of the sling, and confirming the absence of urinary tract injury, the sling arms are tied. Most often the sling arms are sutured to the rectus fascia or to one another, although procedures using pubic bone anchors also have been described. The base of the sling is positioned at the urethrovesical junction. Cure rates range from 75 to 95% for the many different types of sling procedures. Slings are associated with higher complication rates than most other incontinence procedures, most frequently involving voiding dysfunction, urinary retention, new-onset urge incontinence, and foreign-body erosion.

Tensionless Sling The tension-free vaginal tape is a modified sling that uses a strip of polypropylene mesh. Unlike traditional sling procedures, the mesh is positioned at the midurethra, not the urethrovesical junction, and is not sutured or otherwise fixed into place. Advantages of tension-free vaginal tape include the ability to perform the procedure under local anesthesia and on an outpatient basis. Small subepithelial tunnels are made bilaterally to the descending pubic rami through an anterior vaginal wall incision. A specialized conical metal needle coupled to a handle is used to drive one end of the sling through the perineal membrane, space of Retzius, and through one of two small suprapubic stab incisions. The tape is set in place without any tension after bringing up the other end of the tape through the other side. Recently, multiple modifications have been made to carry the tape through the bilateral medial portions of the obturator space. Risks of the procedure include visceral injury from blind introduction of the needle, bleeding, and nerve and muscle injury in the obturator space. Additionally, voiding

dysfunction and delayed erosion of mesh into the bladder or urethra has been seen.

Collagen Bulking agent injection is indicated for patients with urodynamically proven stress incontinence that meets criteria for ISD, but is negative for urethral hypermobility. Glutaraldehyde cross-linked bovine dermal collagen has since become the most widely used injectable agent. Use of other materials, including silicone polymers (Macroplastique) and carbon-coated zirconium beads (Durasphere), also has been described. Anesthesia is easily obtained by using intraurethral 2% lidocaine jelly and/or transvaginal injection of the periurethral tissues with 5 mL of 1% lidocaine. A transurethral or periurethral technique may be used, using a 30 operating female cystourethroscope to directly visualize the injection. The material is injected underneath the urethral mucosa at the bladder neck and proximal urethra, usually at the 4 and 8 o'clock positions, until mucosal apposition is seen. Patients must demonstrate a negative reaction to a collagen skin test before injection. The long-term cure rate is 20 to 30%, with an additional 50 to 60% of patients demonstrating improvement.3 1 Repeat injections frequently are necessary because of migration and dissolution of the collagen material.

PELVIC NEOPLASMS Vulvaginal Lesions BENIGN VULVAR LESIONS Many women suffer with undiagnosed symptoms of vulvar disease. They endure vulvar itching and pain and eventually seek medical help only to be commonly misdiagnosed and treated with repeated courses of antifungals. Vulvar conditions like contact dermatitis, atrophic vulvovaginitis, lichen sclerosis, lichen planus, lichen chronicus simplex, Paget's disease, Bowen's disease, and invasive vulvar cancer are not uncommon. Systemic disease like psoriasis, eczema, Crohn's disease, Behet's disease, vitiligo, and seborrheic dermatitis may also involve the vulvar skin. Patients presenting with chronic vulvar symptoms should be carefully interviewed, examined, and a vulvar biopsy obtained whenever the diagnosis is in question, the patient is not responding to treatment, or premalignant and malignant disease is suspected.

Atrophic Vulvovaginitis This is common in postmenopausal patients and causes thinning and atrophy of the vaginal mucosa and vulvar skin secondary to inadequate estrogenation. Patients may be asymptomatic or present with vulvar itching, burning, and/or dyspareunia. This condition is commonly managed with vaginal estrogen preparations used once or twice weekly.

Vulvar Contact Dermatitis This dermatitis is a common cause of acute or chronic vulvar pruritus and can be irritant or allergic.4 2 Irritant dermatitis usually results from overzealous hygiene habits such as the use of harsh soaps and frequent douching, but is also common in patients with urinary or fecal incontinence, especially the elderly and the disabled. Allergic vulvar dermatitis is caused by a variety of allergens such as fragrances and topical antibiotics. The mainstay of treatment is to identify and discontinue the offending agent or practice, or providing a skin barrier in the case of incontinence.

Leukoplakias There are three types of leukoplakia, a flat white abnormality. Lichen sclerosis is the most common cause of

leukoplakia.4 2 It affects women 30 to 40 years of age. Classically, it results in a figure-of-eight pattern of white epithelium around the anus and vulva, resulting in variable scarring and itching, and, less commonly, pain. Diagnosis is confirmed with biopsy and treatment consists of steroids such as clobetasol 0.05% ointment daily for up to 12 weeks. Lichen planus is a cause of leukoplakia with an onset in the fifth and sixth decade of life. Lichen planus, in contrast to lichen sclerosis, which is limited to the vulva and perianal skin, can involve the vagina and oral mucosa, and erosions occur in the majority of patients leading to a variable degree of scarring. Patients usually have a history of dysuria and dyspareunia and complain of a burning vulvar pain. Histology is not specific, and biopsy is recommended. Treatment is with steroid ointments. Systemic steroids are indicated for severe and/or unresponsive cases. Lichen simplex chronicus is the third cause of leukoplakia, but is distinguished from the other lichen diseases by epidermal thickening, absence of scarring, and a severe intolerable itch.4 2 Intense scratching is not uncommon and contributes to the severity of the symptoms and predisposes the cracked skin to infections. Treatment consists of cessation of the scratching that sometimes requires sedation, elimination of any allergen or irritant, suppression of inflammation with potent steroid ointments, and treatment of any coexisting infections.

Paget's Disease of the Vulva Paget's disease of the vulva is an intraepithelial disease of unknown etiology that affects mostly white postmenopausal women in their sixth decade of life. It causes chronic vulvar itching and is sometimes associated with an underlying invasive vulvar adenocarcinoma or invasive cancers of the breast, cervix, or GI tract. Grossly, the lesion is variable but usually confluent, raised, erythematous to violet, and waxy in appearance. Biopsy is required for diagnosis; the disease is intraepithelial and characterized by Paget's cells with large pale cytoplasm. Treatment is assessment for other potential concurrent adenocarcinomas and then surgical removal by wide local resection of the involved area with a 2-cm margin. Free margins are difficult to obtain because the disease usually extends beyond the clinically visible area.43,44 Intraoperative frozen section of the margins can be done to ensure complete resection. Unfortunately, Paget's vulvar lesions have a high likelihood of recurrence even after securing negative resection margins.

VULVAR INTRAEPITHELIAL NEOPLASIA Vulvar intraepithelial neoplasia (VIN) is similar to its cervical intraepithelial neoplasia (CIN) counterpart and is graded on the degree of epithelial involvement as mild (VIN I), moderate (VIN II), severe (VIN III), or vulvar carcinoma in situ (Bowen's disease).4 5 Risk factors include HPV infection, prior VIN, HIV infection, immunosuppression, smoking, vulvar dermatoses such as lichen sclerosis, CIN, and cervical cancer. VIN can be unifocal or multifocal. Unifocal lesions commonly affect postmenopausal women and lack a clear association with HPV, while multifocal disease mostly affects younger reproductive age females and has a strong association with HPV infection. Fifty percent of patients are asymptomatic, with vulvar pruritus being the most common complaint in those with symptoms. Lesions may be vague or raised, and velvety with sharply demarcated borders. Diagnosis is made with a vulvar skin biopsy and multiple biopsies are sometimes necessary. Colposcopy with application of 5% acetic acid and identification of the acetowhite lesions of VIN is a valuable diagnostic tool for subtle lesions and will help guide the biopsy. Evaluation of the perianal and anal area is important as the disease may involve these areas, particularly in immunocompromised and nicotine-addicted women. Once invasive disease is ruled out, treatment usually involves wide surgical excision; however, the initial treatment approach may include 5% imiquimod cream, carbon dioxide laser ablation, or cavitational ultrasonic surgical aspiration and depends on the number of lesions and their severity. When laser ablation is used, a 1-mm depth in hair-free areas is usually sufficient, while hairy lesions require ablation to a 3-mm depth because the hair follicles' roots can reach a depth of 2.5 mm. Unfortunately, VIN tends to recur in up to 30% of cases and high-grade lesions (VIN III, carcinoma in

situ) progress to invasive disease in approximately 10% of patients if left untreated.4 6

VULVAR CANCER Vulvar cancer is the fourth most common gynecologic cancer and is responsible for 4% of the female reproductive cancers and 0.6% of all cancers in women.4 7 It mostly affects postmenopausal women, and the mean age at diagnosis is 65 years old. Risks factors are similar to those for VIN with persistent infection with high-risk HPV types being responsible for the majority of cases. Patients usually present with a vulvar ulcer or mass. Pruritus is a common complaint, and vulvar bleeding or enlarged inguinal lymph nodes are signs of advanced disease. Careful evaluation of the patient is necessary to rule out concurrent lesions of the vagina and cervix. Biopsy is required and should be sufficient to allow evaluation of the extent of stromal invasion. Vulvar carcinomas are squamous in 90% of cases. Other less common histologies include melanoma (5%), basal cell carcinoma (2%), and soft tissue sarcomas (1 to 2%). Spread of the vulvar carcinomas is by direct local extension and via lymphatic microembolization. Hematogenous spread is uncommon except for vulvar melanoma. Lymphatic spread seems to follow a stepwise, predictable pattern (Fig. 41-13): (a) the superficial inguinal lymph nodes, which lie in the subcutaneous tissue overlying the inguinal ligament; (b) the deep inguinal lymph nodes, which lie along the course of the round ligament in the inguinal canal; (c) the superficial femoral lymph nodes, grouped around the saphenous vein just superficial to the fossa ovalis; (d) the deep femoral lymph nodes, including the most cephalad node of Cloquet or Rosenmller; and ultimately, (e) the external iliac lymph nodes.48–50 The node of Cloquet is an important sentinel node situated in the route of spread to the pelvic lymph nodes. Vulvar cancer is staged surgically with the inguinofemoral lymph node status being the most important prognostic factor. The International Federation of Gynecology and Obstetrics staging system for vulvar cancer is widely used and provides a schema in which prognosis and therapy are closely linked to stage (Table 41-6).5 1 Patients with early-stage disease have a favorable prognosis with approximately 90% 5-year survival rates for stage I disease; stages III and IV disease carry a poor prognosis with 5-year survival rates ranging from 15 to 30%. The exception is melanoma for which the pathologic staging by depth of invasion of the primary tumor and then known metastases is more likely to identify risk for recurrence.

Fig. 41-13.

Lymphatic drainage of the vulva delineated by Stanley Way. v. = vein.

Table 41-6 International Federation of Gynecology and Obstetrics Staging of Vulvar Carcinoma 0 Carcinoma in situ, intraepithelial carcinoma IA Tumor confined to the vulva or perineum, =2 cm in greatest dimension, negative nodes, stromal invasion =1 mm IB Tumor confined to the vulva or perineum, =2 cm in greatest dimension, negative nodes, stromal invasion >1 mm II Tumor confined to the vulva and/or perineum, >2 cm in greatest dimension, negative nodes III Tumor of any size with adjacent spread to the lower urethra or anus and/or unilateral regional lymph node metastasis IVA Tumor invades any of the following: upper urethra, bladder or rectal mucosa, pelvic bone, or bilateral regional node metastasis IVB Any distant metastasis including pelvic lymph nodes Stage

Treatment is individualized, especially with early-stage disease. Surgical resection is the mainstay of treatment for early stages. The most conservative procedure should be performed in view of the high morbidity of aggressive

surgical management.48–50 The historical single-stage en bloc radical vulvectomy championed by Way and Taussig (Fig. 41-14) has been largely abandoned and replaced by the modified radical vulvectomy and bilateral inguinofemoral lymphadenectomy performed through three separate incisions. Stage IA can be adequately treated with an excisional biopsy with a 1-cm disease-free margin. Stages IB and II disease require radical wide excision with a 2-cm margin, but modified radical hemivulvectomy also is used (Fig. 41-15).

Fig. 41-14.

En bloc radical vulvectomy outlined by Way and Taussig.

Fig. 41-15.

Extent of modified radical hemivulvectomy for stages I and II squamous cancer of the vulva.

Treatment options for stage III and IV disease include: (a) chemoradiation followed by limited resection if needed, (b) radical vulvectomy, and (c) radical vulvectomy coupled with pelvic exenteration. Recently, external beam radiotherapy combined with radiosensitizing chemotherapy of cisplatin and 5-fluorouracil is emerging as the preferred initial management of advanced disease followed by limited surgical resection of residual disease. 52,53 Reconstruction of the vulva and groin, if needed, can be accomplished by using myocutaneous flaps based on the gracilis, sartorius, or tensor fasciae latae muscles. The need for inguinal lymphadenectomy (Figs. 41-16 and 41-17) is dictated by the extent of the disease and is essential for planning therapy to provide a better opportunity for cure. Nodal involvement is rare in stage IA, and hence, lymphadenectomy is not needed. Inguinal lymphadenectomy is indicated beyond stage IA and unilateral is recommended for lateralized lesions or bilateral for central lesions that cross the midline or those involving the periclitoral area. The extent of dissection varies from superficial in the case of clinically negative nodes, resection of gross-only disease, to full groin dissection. Vulvar sentinel lymph node biopsy is under investigation by the Gynecologic Oncology Group (GOG). This concept is widely used in breast cancer and melanoma and involves peritumor injection of isosulfan blue dye, a radioactive tracer, or a combination of both to facilitate intraoperative identification of involved sentinel nodes in the majority of patients. Preliminary data are encouraging and may allow patients with negative sentinel nodes to avoid complete groin dissection and its attendant morbidity such as lower extremity lymphedema.

Fig. 41-16.

Superficial inguinal lymphadenectomy. a. = artery; m. = muscle; n. = nerve.

Fig. 41-17.

Incision recommended for superficial inguinal lymphadenectomy. v. = vein.

Nodal failure in the groin and pelvis is difficult to treat successfully, and attention to primary management of these areas is key. Postoperative adjuvant inguinal and pelvic radiotherapy is indicated when inguinal lymph nodes are positive, and is superior to pelvic lymphadenectomy, which has been largely abandoned. It also is indicated when

the vulvectomy margins are positive or close positive for disease and further surgical management is not anatomically feasible.

VAGINAL CANCER Vaginal carcinoma is a rare gynecologic malignancy and accounts for only about 2 to 3% of cancers affecting the female reproductive system.5 4 Squamous cell carcinomas account for 85 to 90% of cases, while adenocarcinomas, malignant melanomas, and soft tissue sarcomas make up the remaining 10 to 15%. More than two thirds of vaginal cancers are diagnosed in women 60 years of age or older. Risk factors include vaginal intraepithelial neoplasia (VAIN), persistent HPV infection with high-risk types, VIN, CIN and cervical cancer, diethylstilbestrol (DES) exposure in utero, smoking, HIV infection, and immunosuppression. Patients with vaginal cancer usually present with postmenopausal and/or postcoital bleeding and may also complain of vaginal discharge, vaginal mass, dysuria, hematuria, rectal bleeding, or pelvic pain which may be indicative of advanced disease. Diagnosis is made via biopsy of suspicious lesions, which may require colposcopic guidance. DES is a drug used in the past in the management of patients with recurrent miscarriages. It was removed from the market in 1971 secondary to reports linking its in utero exposure to the development of clear-cell adenocarcinoma of the cervix and vagina in the exposed daughters, as well as a variety of vaginal, cervical, and uterine anomalies.55,56 The risk of clear-cell adenocarcinoma is one in 1000 of those exposed with an average age at diagnosis of 19 years (7 to 33 years). The incidence of vaginal clear-cell adenocarcinoma is in decline as most DES-exposed daughters are now older than 35 years, and beyond the risk range.

Vaginal Intraepithelial Neoplasia VAIN is similar to VIN and is classified based on the degree of epithelial involvement as mild (I), moderate (II), severe (III), or carcinoma-in-situ.4 5 Upward of 65 to 80% of VAIN or vaginal cancers are associated with HPV infection. The majority of lesions are located in the upper one third of the vagina. Lesions are usually asymptomatic and found incidentally on cytologic screening. Diagnosis is made via guided biopsy of acetowhite lesions at the time of colposcopy. Lesions may appear flat or raised white with sharply demarcated borders and may show vascular changes. The presence of aberrant vessels with marked branching is suggestive of invasive disease. VAIN is treated with laser ablation, surgical excision, or topical 5-fluorouracil therapy.

Vaginal Carcinoma Vaginal cancer is staged clinically by pelvic exam, chest x-ray, cystoscopy, and proctoscopy (Table 41-7).5 1 Studies such as IV pyelogram, barium enema, and CT scans also may be used as needed to define the extent of disease. Vaginal cancer spreads by local extension to adjacent pelvic structures, by lymphatic embolization to regional lymph nodes, and, less commonly, via the hematogenous route to distant organs such as the lungs and liver. Lesions in the upper vagina drain directly into the pelvic lymph nodes and onto the para-aortic nodes, while lesions involving the lower third drain initially to the inguinofemoral lymph nodes from which they then spread to the pelvic nodes.

Table 41-7 International Federation of Gynecology and Obstetrics Staging of Vaginal Carcinoma 0 Carcinoma in situ; intraepithelial neoplasia grade 3 I Tumor limited to the vaginal wall

II Tumor has involved the subvaginal tissue but has not extended to the pelvic wall III Tumor extends to the pelvic wall IV Tumor has extended beyond the true pelvis or has involved the mucosa of the bladder or rectum IVA Tumor invades bladder and/or rectal mucosa and/or direct extension beyond the true pelvis IVB Distant metastasis Stage

Treatment of stage I disease, involving the upper vagina, may be achieved with surgery or via intracavitary radiation therapy.48–50 Surgery consists of a radical hysterectomy, upper vaginectomy, and bilateral pelvic lymphadenectomy. Stage I disease in the mid- to lower vagina usually is treated with radiation and concurrent chemotherapy. External beam pelvic radiation is the mainstay of treatment for stages II–IV and may be followed by intracavitary and/or interstitial brachytherapy. With treatment, prognosis for early-stage disease is excellent with >90% 5-year survival rates. Advanced-stage disease, however, carries a poor prognosis with only 15 to 40% 5-year survival rates for stage III–IV disease.

Lesions of the Cervix BENIGN CERVICAL LESIONS Benign lesions of the cervix include endocervical polyps, nabothian cysts (clear, fluid-filled cysts with smooth surfaces), posttrauma (such as delivery-related cervical tear, or prior cervical surgery) malformation of the cervix, and cervical condylomata. If small, office biopsy is appropriate if the diagnosis is not clear. For endocervical polyps, exploration of the base of the polyp with a cotton swab tip to identify that it is cervical and not uterine, and to identify the stalk characteristics, can help identify the appropriate surgical approach. If small, and the base is identified, simply grasping it with ring forceps and slowly rotating it until separated from the base may be adequate. Use of LEEP is appropriate for larger lesions or for specimens of areas identified as abnormal by colposcopy or visual inspection. For condylomata proven by biopsy, LEEP or laser ablation is appropriate.

CERVICAL CANCER Cervical cancer accounts for about 17,000 cases per year and over 5000 deaths in the United States. It is a major killer worldwide with 250,000 deaths annually. Cervical screening is correlated with early identification and treatment of preinvasive disease.5 7 Cervical cancer is most common in women with long intervals between screening, or with no prior screening. The presence of inherited genetic variations that increase the likelihood of developing cervical cancer when exposed to oncogenic subtypes of HPV is likely and under active investigation. The oncogenes of high-risk HPV are both initiating and promoting for cervical cancer. Other correlates with disease include concurrent active HIV infection with immunosuppression, smoking, and probably other genetic factors. It is anticipated that early vaccination, before infection, will function as primary prevention for cervical cancer. It is expected to reduce both the risk and frequency of high-grade CIN, but also translate to marked reduction in actual invasive cancer, requiring 20 to 40 years to see full impact. However, not all high-risk HPV subtypes are covered in the two vaccines available in 2009. Thus, vaccination will likely prevent approximately 70% of cancers in the

United States, depending on regional area distribution of oncogenic subtypes. Vaccines are approved for girls ages 9 to 26, but are recommended preferentially for the younger girls as there was a stronger immunologic response seen.

Staging and Management The diagnosis of cervical cancer is made by cervical biopsy, either of a gross lesion or a colposcopically identified lesion. The majority of the histology is squamous, with adenocarcinoma comprising about 20% of cases, and occasional rare and aggressive variants such as neuroendocrine tumors. Staging is clinical, not surgical, and follows the International Federation of Gynecology and Obstetrics guidelines, which mesh with TNM staging. Staging and management options are outlined in Table 41-8.

Table 41-8 International Federation of Gynecology and Obstetrics Cervical Cancer Staging and Management Options 0 Carcinoma-in-situ Adenocarcinoma in situ: hysterectomy, although some may be followed for preservation if all margins negative on cone Squamous-in-situ: local excision with loop electrosurgical excision procedure or cone or laser ablation I Confined to the cervix A1 and some A2: fertility preservation through large cone followed by close monitoring, followed by hysterectomy A1: minimal invasion A2: 185 mmHg are among the contraindications to tPA therapy. Patients not eligible for tPA require hemodynamic optimization and neurologic monitoring. Admit such patients to the ICU stroke service for blood pressure management and frequent neurologic checks. Permissive hypertension allows for maximal cerebral perfusion. Systolic blood pressure >180 mmHg may require treatment, but the optimal mean arterial pressure goal is between 100 to 140 mmHg. Give normal saline solution without glucose (which could injure neurons in the penumbra), and aim for normovolemia. A stroke patient who worsens clinically should undergo repeat head CT to evaluate for hemorrhage or increasing mass effect from swelling, which typically peaks 3 to 5 days after the stroke. Significant swelling from an MCA or cerebellar strokes may cause herniation and brain stem injury. A decompressive hemicraniectomy or suboccipital craniectomy can be a life-saving intervention for these select stroke patients.

Hemorrhagic Diseases Intracranial hemorrhage from abnormal or diseased vascular structures accounts for approximately 15% of acute cerebrovascular events. Hypertension and amyloid angiopathy account for most intraparenchymal hemorrhages, although AVMs, aneurysms, venous thrombosis, tumors, hemorrhagic conversion of ischemic infarct, and fungal infections also may be the cause. The term intracranial hemorrhage frequently is used to mean intraparenchymal hemorrhage and will be used here. Intracranial hemorrhage causes local neuronal injury and dysfunction and also may cause global dysfunction due to mass effect if sufficiently large. AVM or aneurysm rupture results in SAH because the major cerebral and cortical blood vessels travel in the subarachnoid space, between the pia and the arachnoid membrane. SAH can cause immediate concussive-like neuronal dysfunction by exposure of the brain to intra-arterial pressure pulsations during the hemorrhage; it can cause delayed ischemia from cerebral arterial vasospasm. Patients presenting with intracranial hemorrhages that do not follow typical patterns should undergo angiography or MRI to evaluate for possible underlying lesions, such as AVM or tumor. Hemorrhagic stroke typically occurs within the basal ganglia or cerebellum. The patient is usually hypertensive on admission and has a history of poorly controlled hypertension. Such patients are more likely to present with lethargy or obtundation, compared to those who suffer an ischemic stroke. Depressed mental status results from brain shift and herniation secondary to mass effect from the hematoma in deep structures. Ischemic stroke does

not cause mass effect acutely; and therefore, patients are more likely to present with normal consciousness and a focal neurologic deficit. Hemorrhagic strokes tend to present with a relatively gradual decline in neurologic function as the hematoma expands, rather than the immediately maximal symptoms caused by ischemic stroke. Table 42-3 provides a listing of relative incidences of intracranial hemorrhage by anatomic distribution.

Table 42-3 Anatomic Distribution of Intracranial Hemorrhages and Correlated Symptoms 50 Basal ganglia (putamen, globus pallidus), internal capsule Contralateral hemiparesis 15 Thalamus Contralateral hemisensory loss 10–20 Cerebral white matter (lobar) Depends on location (weakness, numbness, partial loss of visual field) 10–15 Pons Hemiparesis; may be devastating 10 Cerebellum Lethargy or coma due to brain stem compression and/or hydrocephalus 1–6 Brain stem (excluding pons) Often devastating % of Intracranial Hemorrhages

Location Classic Symptoms

HYPERTENSION Hypertension increases the relative risk of intracranial hemorrhage by approximately fourfold, likely due to chronic degenerative vasculopathy. Hypertensive hemorrhages often present in the basal ganglia, thalamus, or pons, and result from breakage of small perforating arteries that branch off of much larger parent vessels (Fig. 42-15).

Fig. 42-15.

A. Head computed tomography scan of a patient with left-sided weakness and progressive lethargy reveals a right basal ganglia hemorrhage (arrowhead ). The blood clot is bright white. Hypodensity around the clot represents cerebral edema. There is blood within the ventricular system. B. Another patient with intraventricular extension of a basal ganglia hemorrhage. The patient developed right-sided weakness and then lethargy. Head computed tomography indicated hydrocephalus. A ventriculostomy was placed for cerebrospinal fluid drainage (arrowhead indicates cross-sectional view of the catheter entering the anterior horn of the right lateral ventricle).

Most hypertensive hemorrhages should be medically managed. The hematoma often contains intact, salvageable axons because the blood dissects through and along neural tracts, and surgical clot evacuation destroys these axons. Factors potentially favoring surgery include: superficial clot location, young age, nondominant hemisphere, rapid deterioration, and significant mass effect. However, the most comprehensive randomized clinical trials to date did not show an overall improved outcome in surgically evacuated intracranial hemorrhage, except for the subgroup of patients with clot 10% of such injuries. The incidence of wound infection is high as are nonunion of the distal fragments. Posttraumatic arthritic joints are distressingly common.

Fractures of the Tibial Shaft Fractures of the tibial shaft usually result from direct blows or torsional mechanisms.7 The nearly subcutaneous position of the bone means that open fractures are commonly seen. Thus, inspection of the skin, particularly the anterior leg, is critically important. Fractures that result from a direct blow usually result in a transverse or oblique tibia injury often sparing the fibula. Torsional injury (frequent in skiers) will often lead to a spiral fracture of the tibia, often with associated fibular injury at the knee or the ankle. High-energy trauma to the limb can lead to comminuted fracture and extensive soft tissue injury. Management of tibial shaft fracture can be accomplished by a simple closed reduction and long leg cast immobilization. Advancing the patient to a functional brace within 4 to 6 weeks often is recommended. Nonunion of

fractures managed closed is a significant problem, and cast immobilization, when used, usually is necessary for approximately 3 to 4 months. Intramedullary nailing of the tibia is now commonly performed and, indeed, is the preferred form of treatment more often than not. An intramedullary nail is inserted across the fracture site, proceeding proximal to distal. Small diameter nails ("nonreamed nails") can be impacted across the fracture site directly. Another alternative, particularly with more unstable fractures, is a rigid intramedullary nail where reaming devices of graduated diameter are passed across the fracture site, before inserting a larger nail. These larger nails often are manufactured with screw holes positioned distal and proximal to accept transfixing distal and proximal interlocking screws to assist in controlling length and rotation.

Fractures of the Tibia Plateau The upper surface of the tibia, which articulates with the condyles of the femur, has a relatively flat surface and is usually referred to as the tibia plateau . 8 Fractures of this large articular surface can represent a challenge. The weightbearing demands of this surface are high, and the fractures are often accompanied by crushing and impaction of the cartilage menisci and the underlying cancellous bone, making reconstruction particularly challenging as several of the many pieces of this three dimensional puzzle can be partially crushed (Fig. 43-13). Fractures can involve the medial or the lateral plateau or both and often are accompanied by a significant angular deformity. Minimally displaced fractures can be managed nonoperatively with a cast or a brace. Criteria for nonoperative treatment include 40 years of age, and often is associated with a tight heel cord. Tendinosis can be disabling and generally is treated with immobilization and rest, stretching of the gastrocsoleus and Achilles region, and shoe modification. When severe and persistent, this condition is treated operatively by dbridement of the tendon involved. If the tendon insertional

area on the calcaneus is severely attenuated, operative reconstruction of the tendon may be necessary.

SPORTS MEDICINE Athletic injury can, of course, encompass many areas in the musculoskeletal system. The orthopedic subspecialty of "sports medicine" has developed in response to a very high incidence of soft tissue injuries (ligament, tendon, and cartilage) in patients who are active in exercise and athletics. The most problematic joints in this regard are the knee and the shoulder. Orthopedic treatment for such injuries involves careful history, physical examination, and close attention to the need and desires of the individual patient. Surgical intervention for ligament and cartilage injuries in such patients most frequently is done using arthroscopic technique.

Anatomy of the Knee The principal mechanical function of the knee is that of a hinge joint, but the knee does bear tremendous axial loads as well as torsional and sheer forces. The major stabilizing structures within the knee unfortunately are frequently injured. The anterior cruciate ligament (ACL) is a very stout ligament that is situated centrally within the knee. Its mechanical functions are complex, but the most important is to restrain the tibia from forward excursion below the femur. The posterior cruciate ligament (PCL) lies immediately behind the ACL. The PCL undoubtedly has multiple functions, the most important and most easily assessed is its function to restrain posterior sliding movements of the tibia beneath the femur. The medial collateral ligament (MCL) is located outside of the joint capsule and restrains the knee from bending in a valgus direction. The lateral collateral ligament is analogous to the MCL and joins the lateral femoral epicondyle to the fibular head. The function of the lateral collateral ligament is to restrain the joint from varus angulation. All of these ligaments are vulnerable to injury.

Menisci Within the joint, the two large articular surfaces of the condyles articulate with the cartilage of the tibial plateau. Crescent-shaped fibrocartilage menisci lie medially and laterally within the joint and serve to guide the femoral condyles' motion and to more evenly distribute loads across the joint. The menisci are important stabilizing structures. The fibrocartilaginous menisci are vascularized only in their outer third. Because of their significant mechanical function, they are subject to both acute traumatic tears (acute tears) as well as progressive degeneration (degenerative tears). The medial meniscus is torn more frequently than the lateral. Tears of either the medial or the lateral meniscus may be clinically silent or they may cause significantly disabling symptoms. Tears of the menisci have been reported in virtually all portions of the meniscus. Radial and longitudinal tears are common. 2 5 A special type of a longitudinal tear is the "bucket handle tear," which parallels the C-shaped contour of the meniscus and can create a significant and problematic flap if it displaces. Symptoms caused by a meniscal tear can include local pain and intermittent swelling of the knee, as well as pain on weightbearing. Displaced meniscal tears may cause interference with joint motion and, on some occasions, can frankly prevent the knee from full extension, a so-called locked knee . The locked knee joint does occasionally yield to manipulation to reduce the meniscal tear. More frequently, such patients require timely surgery to excise or repair the flap. Options for treatment of a meniscal tear include resection and reshaping of the torn area, generally preferred for small tears (Fig. 43-24).2 6 Very large tears in young active patients usually are treated by primary meniscal repair, generally using arthroscopic technique (Fig. 43-25). Complete excision of a torn meniscus, once quite popular, is

now recommended only rarely because of loss of the meniscal load distributing function that can accelerate osteoarthritic change in the knee.2 7 On some occasions, badly injured menisci in young active patients can be successfully treated by allograft replacement of the meniscus from a cadaver source. The long-term results of this approach are not yet clear.

Fig. 43-24.

Arthroscopic images of a tear of the medial meniscus of the knee before (top ) and after (bottom ) arthroscopic dbridement. (Courtesy of Dr. David Green.)

Fig. 43-25.

Arthroscopic images of a horizontal tear of the medial meniscus. The tear is repaired using a "buried suture" technique. (Courtesy of Dr. David Green.)

Ligamentous Injuries of the Knee MCL injury will occur after excessive valgus stress of the knee. Unfortunately, it is sometimes associated with a meniscal injury. Nonoperative treatment is preferred for an isolated MCL injury. In most cases, full return of function is anticipated. Lateral collateral ligament injuries are much less common than MCL ligament injuries. Similarly, however, they are most often managed nonoperatively. ACL injuries can be isolated injuries, but often are seen in combination with MCL rupture and medial or lateral meniscal tear. The triad of MCL, medial meniscus, and ACL tears is most common in contact sports (e.g., football) or jumping sports (e.g., basketball).

Anterior Cruciate Ligament Injury A functioning ACL is not necessary for most individual's activities and daily living.2 6 Indeed, many competitive athletes can function at a high level of competition with an ACL deficient knee as well, presumably due to secondary soft tissue constraints, muscle activities, and individual effort. Unfortunately, many individuals with an

ACL-deficient knee due to traumatic failure of the ligament find themselves unable to compete because of instabilities of the knee. Accordingly, in patients for whom athletic endeavor is an important part of their life, reconstruction of the intercruciate ligament is a useful procedure that has prolonged many patients' athletic participation (Fig. 43-26).2 8

Fig. 43-26.

Arthroscopic images of a patient with a rupture of the anterior cruciate ligament before (top ) and after (bottom ) reconstruction with a tendon graft. (Courtesy of Dr. David Green.)

Evaluation of the patient for possible ACL injury involves a Lachman test: manual passive assessment of the AP stability of the knee, which is held in slight extension. Diagnosis of the ACL rupture and other associated internal joints of the knee usually is confirmed by an MRI image of the affected joint. Various techniques for the reconstruction of the cruciate ligament are described, which generally involve autograft or allograft tissues placed through tunnels within the tibia and the femur.2 9 A central slip of the patellar tendon, including a portion of the bony attachment from both the tibial eminence and of the patella itself, is popular, as are woven grafts from

hamstring tendons. Other graft sources also have found favor. Accurate placement of the bony tunnels for the graft and proper tensioning of the graft are critical portions of this procedure. Following the procedure, a lengthy rehabilitation process generally is necessary. The PCL is less frequently injured than the ACL. A rupture of the PCL is, in general, better tolerated than is an ACLdeficient knee. A useful examination maneuver to test for PCL function is a posterior drawer test, which is essentially the reverse of the Lachman test where a slightly flexed knee is tested for the stability of the tibia beneath the femur by passive manipulation. PCL reconstruction is less commonly performed than ACL reconstruction, although, when functional deficits result from this injury, surgical treatment may be rewarding for athletic patients.3 0 Chronic PCL-deficient knees are thought to have an increased incidence of osteoarthritis, particularly in the patellofemoral and medial knee compartments.

THE SHOULDER Shoulder Dislocation and Shoulder Instability The glenohumeral joint is a ball and socket joint. Some stability for the very shallow socket of the glenoid is provided by the glenoid labrum, but this very mobile large joint is the most frequently dislocated joint in the human body. Dislocations can result from major or minor trauma. Although the dislocation can occur in the posterior or inferior directions, the most common direction for dislocation is anterior. A patient with an anterior dislocation will complain of local pain and will present with an internally rotated shoulder. The anterior position of the humeral head in such dislocation can make the radiographic diagnosis challenging. An AP x-ray, a glenoid (axillary) view, and a Y view of the shoulder is recommended in assessing this injury. Associated neurovascular injury is possible but rare. When carefully assessed, it often is found to be a transient axillary nerve palsy ( 30%). Relocation of the shoulder is generally accomplished with the patient supine by subjecting the arm to gentle traction in a position of slight abduction. Some sedation before the maneuver is helpful. After relocation of shoulder dislocation, the patient generally is provided a sling for comfort. Prolonged immobilization of the shoulder (as was done in years past) is not recommended.3 1 Prolonged immobilization will often lead to substantial stiffness in the shoulder and does not appreciably decrease the redislocation rate. Unfortunately, after an anterior dislocation, many patients will experience recurrent dislocations.3 2 When these become multiple events, surgical stabilization of the shoulder is considered. Numerous procedures for reconstructing and tightening the shoulder capsule are described, many of which now are accomplished arthroscopically.

Impingement Syndromes After minor trauma, repetitive injury, and sometimes without an identifiable inciting event, many patients experience symptoms of shoulder pain. Pain from a shoulder impairment syndrome often is reported in the anterior shoulder and is exacerbated by abduction of the shoulder, which can be due to irritation of the tissues in the subacromial space. Shoulder impingement syndromes represent a broad spectrum of disease ranging from simple bursitis to tendonitis of the long head of the biceps or supraspinatus tendon.3 3 In many cases, this impingement syndrome can progress to a frank tear of the supraspinatus tendon, the most cephalad of the rotator cuff tendons. The diagnosis is confirmed by documenting leakage of contrast in a shoulder arthrogram. MRI imaging also can be definitive, and ultrasonography is readily available and quite accurate. Interestingly, patients with rotator cuff tears frequently are asymptomatic, and many have excellent use of the shoulder without apparent pain or difficulty. On the other hand, many patients with such tears report with severe

disabling pain, and many are unable to pursue sporting activities as a result. Accordingly, surgical repair of a rotator cuff injury is often indicated to restore function. Primary repair of the rotator cuff is accomplished, in most cases, arthroscopically.3 4 The procedure sometimes is accompanied by a bony resection of the inferior portion of the acromion.

The Acromioclavicular Joint The acromioclavicular joint is stout and not very mobile. This joint is vulnerable to ligament injuries (sprains), particularly in athletic endeavors where blows to the shoulder or falls onto the shoulder are common. Such injuries range from simple partial thickness injures (grade 1 sprains) to frank tearing of the acromial-clavicular and acromioclavicular coracoacromial ligaments causing displacement of the joint. Such injuries are common in contact sports such as football, and are particularly common in athletes playing ice hockey. An acromioclavicular sprain is referred to as a shoulder separation and is not to be confused with a glenohumeral dislocation. Treatment for such a shoulder separation (acromial-clavicular sprain) usually is symptomatic. Significantly displaced injuries involving frank tearing of the coracoclavicular ligaments sometimes are reconstructed surgically.

THE SPINE Spinal Trauma The treatment of spinal trauma is one of the most challenging areas in orthopedic surgery. Situations at times are extremely challenging because many patients who have sustained significant spinal trauma also have concomitant visceral and other musculoskeletal injuries as well. Prioritizing treatment in these situations can be challenging. In patients with an isolated spinal cord injury, the major concerns for the treating orthopedic surgeon are the neurologic status of the patient, the possible presence of ongoing spinal cord compression, and the stability of the spine and the possible need for stabilization.3 5 Assessment of the neurologic status of the patient is covered in Chap. 42 on Neurosurgery. A detailed physical examination in search for other injuries as well as the thorough assessment for any neurologic deficits should be done early in the evaluation of these patients.3 6 Priorities of care follow the primary concerns of airway, ventilation, and circulation. If the patient is neurologically intact, then the primary concern is assessment of the spinal stability to know whether or not mobilization of the patient (often necessary for other treatments) is safe and whether successful healing of the spinal injury is likely without surgical intervention. In patients with significant neurologic deficits, the immediate question is asked whether or not there is ongoing compression of the spinal cord or the nerve root for which a decompressive procedure would be indicated. In most spinal cord injury situations, prompt decompression of ongoing neural compression is performed whenever possible. Unfortunately, the true benefits of such interventions are very difficult to objectively assess. There is a growing body of evidence that suggests that prompt decompression in spinal cord injury can make a detectable and measurable difference in the acute and semiacute neurologic function. Whether patients so treated are truly better 6 months or a year after their injury is a question that is still debated. Extensive laboratory investigation using animal models with spinal cord injury suggested that very prompt decompression of a localized spinal cord leads to objective and measurable differences in recovery. The optimal time for this decompression in humans is not yet known. A body of animal data suggests that early intervention is better than late intervention.

Occipital Cervical Dislocation

Dislocation of the occiput on the occipital condyles of the atlas (C1) is a common injury after high-energy trauma, particularly motor vehicle trauma. Unfortunately, only a tiny fraction of the patients with this injury survive, as it is almost always accompanied by a high cervical spine or brain stem injury. For the rare patients who survive this injury, traction on the spine is contraindicated. Definitive treatment consists of stabilization and fusion in situ using a screw-plate or rod screw device spanning from the occiput to the midcervical spine.3 7

Fractures of C1 (Jefferson Fracture) The Jefferson fracture, eloquently discussed by Dr. Jefferson in 1920, is a fracture of the C1 ring.3 8 The C1 vertebra does not have a true anterior body as do all of the rest of the vertebrae. The rather thin anterior and posterior rings are subject to fracture, particularly with axial load injuries. The Jefferson fracture results in a lateral spread of the lateral masses of C1, which are visible on an AP (through the mouth) x-ray image of the upper cervical spine. This injury actually results in an increase in the size of the spinal canal, and thus, rarely is associated with neurologic injury. Fortunately, the bony fractures heal quite reliably. The treatment of choice in Jefferson fractures is bracing with either a cervicothoracic orthosis or a halo ring and vest.

Fractures of C2 (Odontoid Fracture) The odontoid is a peg of bone that arises off the central body of the C2 vertebra and articulates with the anterior ring of the C1 vertebra. The articulation between the odontoid (or dens) in the C1 vertebra and the atlantoaxial facet joint is the site where half of normal cervical rotational movement occurs. The odontoid is a relatively small structure, however, and it is vulnerable to fracture. The types of odontoid fracture are eloquently discussed by Anderson and D'Alonzo in their classic paper, which describes a generally benign "type I" fracture that consists of an avulsion fracture off the very tip of the odontoid.3 9 These type I fractures are thought to arise from the alar ligaments that span from the tip of the odontoid to the skull (bypassing the C1 vertebra). Such isolated avulsion fractures, although they may be painful, do not represent any danger to the patient. Type I fractures generally are managed symptomatically with expected satisfactory outcomes. A fracture through the base of the odontoid, at the level of the articular surfaces of the facet joints, is classified as a "type II" injury in the Anderson and D'Alonzo classification scheme (Fig. 43-27). These fractures result from oblique or lateral loading forces on the odontoid. The rather small fracture surface created by this and the small surface of cancellous bone within the odontoid may be reasons why this particular variety of odontoid fracture heals poorly. When such fractures are immobilized in cervicothoracic orthosis or halo vest, nonunion rates ranging from 20 to 80% have been reported. Accordingly, treatment of a type II odontoid fracture is most usually operative. Stabilization of the fracture can be accomplished through an anterior approach by directly transfixing the odontoid with a screw initiated at the anterior/inferior border of the C2 body and inserted across the fracture site and up into the odontoid. This is a technically demanding screw placement and is only done with the availability of excellent intraoperative imaging techniques. An alternative to direct fixation of this fracture is a posterior stabilization and fusion of C1 on C2. This can be done by sublaminar wiring cable techniques or by posterior screw fixation. The anterior odontoid screw fixation does allow the potential for continued rotational movement between C1 and C2. The posterior fusion of C1 and C2, while restoring safety and stability, also results in a markedly diminished range of motion of the cervical spine.

Fig. 43-27.

X-ray images of a displaced fracture of the odontoid process of C2, before and after reduction and internal fixation. Transverse fracture at the bone of the odontoid (type II) has a high nonunion rate when managed nonoperatively.

Anderson and D'Alonzo type III fractures are described as those that extend into the body of C2, below the bone of the odontoid. The fractures' surfaces are large and well vascularized. Type III fractures heal reliably with halo brace, or other brace designs. Surgical intervention rarely is needed.

Hangman's Fractures of C2 Hangman's fractures or traumatic spondylolisthesis of C2 are fractures that occur through the pars interarticularis of C2 (the segment of the posterior elements between the superior and inferior facets of C2). This fracture results from sudden extension forces on the neck causing a fracture through this area of C2, which is one of the thinner portions of the posterior elements of this vertebra. This fracture, in most cases, does not result in any narrowing of the spinal canal. The overwhelming majority of patients with minimally displaced hangman's fractures are neurologically intact. Treatment for this injury is almost always nonoperative employing simple immobilization using a cervicothoracic orthosis or a halo vest. With higher-energy injuries (such as those intentionally created in judicial hangings), more severe extension forces can create dislocation of the C2–3 facet complex and injury of the C2–3 disc. Such displaced fractures can and do compromise the spinal canal. When significant displacement occurs, death can result due to compromise of respiration. Infrequently encountered are neurologically intact patients who have significantly displaced hangman's fractures. These patients are managed by internal fixation and bone grafting between C2 and C3 (Fig. 43-28).

Fig. 43-28.

Preoperative computed tomography images and a postoperative X-ray of a patient with a displaced hangman's fracture of C2 (traumatic spondylolisthesis). Most hangman's fractures are managed nonoperatively, but in severely displaced fractures, reduction and stabilization with bone grafting is indicated. This can be done with either an anterior or (as shown) posterior procedure.

Compression Fracture of the Cervical Spine Compression fractures of the cervical spine refer to an axial load injury with failure of the end plate, but preservation of the posterior cortex of the vertebral body. This will occur in the vertebrae of C3 to C7 and may or may not be associated with a fracture of the anterior cortex. In either case, with the posterior cortex of the vertebral body intact, no compromise of the neural elements results. The healing potential for these fractures is very high, and such patients generally are managed nonoperatively. Analgesics are prescribed as is a cervical brace for comfort.

Burst Fractures of the Cervical Spine

Burst fractures of the cervical spine arise as a result of failure under axial loads. Unrestrained motor vehicle occupants striking a windshield and diving accidents are common injury mechanisms. The burst fracture is distinct from the compression fracture, however, in that the posterior cortex of the vertebral body is fractured. This frequently results in displacement (retropulsion) of bony fragments into the canal, which can cause neurologic injury and dysfunction. Very high-energy burst fractures can result in fractures of the posterior elements as well; however, this is less commonly seen. A burst fracture noted in the neurologically intact patient can be managed conservatively by bed rest and traction. This can be appropriate treatment for a cooperative teenage patient who has potential to heal a fracture within a very short interval. Far more commonly, these occur in adult patients, for whom prolonged bed rest is not only inconvenient but risky. Accordingly, the overwhelming majority of such patients are managed operatively by anterior dbridement of the fracture (necessary should there be neurologic compromise) and reconstruction using a bone graft strut and the application of a screw and plate device. Plate fixation after strut grafting and decompression generally will allow immediate mobilization of the patient. Patients are restrained from rigorous activities until after fracture healing is confirmed in 6 to 15 weeks.

Unilateral and Bilateral Facet Dislocation A forceful flexion with distraction forces (such as can happen in an automobile accident with a restrained driver) can result in forward subluxation of the cervical vertebrae on a subjacent neighbor with dislocation of one or both of the facet joints. Interestingly, the diagnosis usually can be made with confidence by examination of a lateral xray image, as dislocation of one facet joint predictably will result in an anterior displacement of precisely 50% of the AP diameter of the involved vertebral body. Bilateral facet dislocation typically is caused by an anterior displacement of 50%. On occasion, fractures of the facet joint occur in association with the dislocation. A unilateral facet dislocation rarely results in spinal cord injury; however, bilateral facet dislocations frequently do. Radicular symptoms following unilateral or bilateral dislocation are common, as the dislocated facet can narrow the exit foramen and impinge the intervening nerve roots. Treatment for this injury consists of axial traction, usually exerted after placement of cranial tongs, followed by graduated application of weight and periodic x-rays. This always is done with the patient awake because of safety concerns. When successful reduction is attained, the risk of recurrent dislocation is so high that most patients are then taken to surgery for posterior fusion procedures of the involved vertebrae. This can be done with interspinous process wiring or by a screw-plate or screw-rod device, with screws inserted into the lateral masses. Postoperative stabilization with a cervical collar is at the discretion of the treating surgeon. Excellent long-term results are generally expected.

Clay Shoveler's Injury Clay shoveler's injury is a common, but often missed injury to the spinous process of a lower cervical vertebra or the upper thoracic vertebrae. It is most common at the levels of C6, C7, T1, and T2, and is the result of avulsion fracture of the spinous process by the paraspinal muscle forces. The injury was originally described in convicts involved with shoveling clay and soil. This is most commonly seen today after motor vehicle trauma. These fractures are at times difficult to see on x-ray images (because of the density shadow cast by the patient's shoulder). The fracture itself generally requires only symptomatic treatment (analgesics with or without a soft collar for comfort); however, it behooves the treating physician to look for such injuries when they are suspected.

FRACTURES OF THE THORACIC AND LUMBAR SPINE Thoracic Lumbar Spine Injury

Thoracic and lumbar fractures generally are discussed together because the mechanism fracture of these distinct anatomic areas is similar. Fractures of the thoracic spine are generally more stable than similar injuries in the lumbar spine because of the stability afforded by the ribs. Also, of course, neurologic injury patterns are different in the thoracic and proximal lumbar spine because of the presence of the spinal cord, which normally ends at the L2 level. Accordingly, injuries that compromise the spinal canal are more likely to cause neurologic deficits in the thoracic spine than in the lumbar spine. Nonetheless, general patterns of injury and their treatments are very similar.

Compression Fracture Acute compression fracture in the thoracic and lumbar spine is a relatively common event. Traumatic compression fractures in patients with normal bone densities may involve a fracture of the superior or, less frequently, inferior end plate with or without associated posterior cortical failure. The zone of injury for the compression fracture is confined to the "anterior column" as defined by Dr. Francis Denis4 0 in his classic paper in 1983 (Fig. 43-29). Isolated injuries to the anterior column do not result in neurologic deficit, because the posterior cortex of the vertebral body, and thus, the borders of the spinal canal remain intact; these injuries are not at all likely to lead to instability. Treatment is generally symptomatic with the use of braces for comfort and analgesics. In most cases, the fracture is noted to have successfully healed with resolution of pain within 4 to 10 weeks.

Fig. 43-29.

The spine can be thought of as three columns. Two of three can maintain stability.

Burst Fracture Burst fracture, caused by more severe axial load forces, is common following falls and motor vehicle trauma. A burst fracture involves fracture of one or both end plates and the anterior cortex of a thoracal lumbar vertebra with an associated failure of the posterior cortex. Frequently, the posterior cortical fracture results in retropulsion of bone into the canal, which can cause compromise of the neural elements and acute neurologic deficit. The

retropulsed fragment in a burst fracture injury typically has a trapezoidal shape, which reflects the trabecular anatomy in the area at the base of the pedicles where failure occurs.4 1 On occasion, with even more severe injury loads, posterior element fractures can occur, most frequently, the vertical fracture of the lamina caused by forces exerted through the facet causing a spreading force on the posterior elements. Such vertical lamina fractures are particularly important because, quite frequently, this fracture will contain an invaginated segment of the dura mater, sometimes with accompanying nerve roots. Surgical intervention posteriorly on such fracture can result in an iatrogenic dural tear and/or root injury. Neurologically intact patients with burst fractures usually are managed quite successfully by nonoperative means using a rigid orthosis and analgesics. When significant neurologic injury is noted, surgical treatment usually is recommended. Most commonly, this consists of an anterior exposure of the fractured vertebrae and removal of the fractured anterior elements. This procedure is called a corpectomy . Concomitant with this (as in cervical spine burst fractures), both adjacent discs are excised to expose the bony end plates. A strut graft is placed; this can be either autograft or allograft or manufactured struts of titanium or ceramic. Generally, a laterally placed rod or plate system also is inserted to afford stability. The anterior approach allows direct decompression of the spinal canal and removal of any retropulsed fragments. Another alternative is the posterior approach to the spine, which may or may not involve laminectomy and direct exposure of the neural elements. Because the offending compression is directed anteriorly, good visualization of the intraspinal fragments can be difficult from this approach, and usually, decompression is sought by distraction instrumentation. Hooks and screws are placed into vertebrae above and below the fractured segment and longitudinal stretching forces are applied through an attached rod. This usually results in partial reduction of the neurologic compression. When the posterior longitudinal ligament becomes tight, it will exert a corrective force encouraging the fragments in the canal to migrate back closer to their normal anatomic position. Predictable decompression of the spinal canal using posterior distracting techniques is not absolute. On average, this will result in improvement of the canal diameter, but in some cases, despite a technically well performed procedure, ongoing compression may persist.

Seatbelt Injuries (Flexion Distraction Injuries) Flexion distraction injuries result from distractive forces on the spine. The mechanism for this is acute forward flexion of the trunk and anterior restraint such as a lap belt type seat belt. As the pelvis and upper torso moves forward, a fulcrum is created that can create a failure of the spine under tension beginning with the posterior elements and extending through the spine. Failure can take place through the soft tissues with tearing of the dorsal fascia, the interspinous ligament, dislocation of the facets, and tearing of the discs. It also may occur through the bone with frank failure in tension of the bone of the spinous process, the lamina, the pedicles, and the body. This "all bone" variant carries the name Chance fracture , named not for its unique morphology, but in deference to Dr. Chance who first described this injury in 1958.4 2 Fortunately, flexion distraction injuries usually do not result in neurologic injury as the spinal neural elements are generally much more tolerant of distractive forces than they are of compression. Unfortunately, when the flexion distraction injury occurs predominantly through soft tissue, reliable healing of the soft tissue is not expected and posterior stabilization using internal fixation and an associated bone graft generally is indicated to restore stability to the spine. Interestingly, because of the rough irregular surfaces of the bone, fractures of the all bone variant (Chance fracture) are usually quite stable. Bracing is recommended, but the "all bone" Chance injury generally is quite

successfully managed nonoperatively.

Fracture Dislocations of the Spine Fracture dislocations of the spine are severe injuries associated with displaced injury of the bony elements, with either a translational or rotational component. By necessity, the presence of a translational or rotational deformity will result in canal compromise. The majority of patients sustaining these severe injuries do have a neurologic deficit, which is frequently profound (Fig. 43-30).

Fig. 43-30.

Preoperative computed tomography images and postoperative x-ray images of a patient with fractures of T5 and T6 and an "incomplete" spinal cord injury. The spinal canal was decompressed and the fractures stabilized using pedicle screw instrumentation.

Reduction of the displaced bones generally is indicated and is usually the best way to improve the canal dimensions. The prognosis for neurologic recovery in a patient with a neurologically complete injury is dismal. Patients with partial preservation of function often can make remarkable neurologic recoveries. Patients with fracture dislocations of the spine are essentially always managed operatively to stabilize the spine, to safeguard any neurologic function that might remain, or to allow mobilization of the patient and early initiation of rehabilitation.

Disc Herniation Disc herniation is an extremely common event generally seen between the ages of 20 and 50 years old. It can occur in the cervical, thoracic, or the lumbar spine. It consists of a tear or an attritional failure of the annulus of the intervertebral disc, allowing the nucleus pulposus material to penetrate through the annulus and enter the canal. The incidence of this phenomenon is impressive. Fortunately, the majority of such events are minimally symptomatic. A majority of the population will have a disc herniation during a normal lifetime. Classically, disc herniations present with axial pain either in the neck or in the lumbar area, which over 1 to 14 days progresses to include a radicular pain in the upper or lower extremity. Nerve root impingements can occur, depending on the

location of the herniation, of traversing nerve root or the exiting nerve root at any given level. Large herniations may impinge both of these nerve roots. In the cervical spine, potential for spinal cord compression also is noted, although this is not particularly common. When a disc herniation is causing myelopathic symptoms, it should be treated aggressively. The expected natural history of disc herniations is that of spontaneous resolution of symptoms. This is presumed to occur through natural accommodation of the nerve root to the compression and to the resolution of the acute inflammatory process that may accompany the acute annular injury. Several studies have demonstrated that the extruded nucleus pulposus material actually undergoes a significant amount of resorption over time as well. Accordingly, at least approximately 90% of radiculopathies due to disc herniation do resolve or substantially improve within 8 weeks. Thus, surgical intervention even for severe radiculopathies is not recommended in this initial 6- to 8-week interval.4 3 Should significant symptoms persist beyond this point in time, the decision is made between the surgeon and the patient about options for surgery. Should surgery be elected, excision of the involved disc and decompression of the nerve roots can be performed with an excellent prognosis. Thus, the great majority of patients express satisfaction with the results. Surgical treatment for a cervical disc herniation usually consists of an anterior approach to the spine with dissection through a transverse incision on the anterior neck. Dissection is carried lateral to the trachea and esophagus and medial to the carotid sheath to expose the bones and discs of the anterior cervical spine. The disc is removed in total from anterior to posterior; this allows direct visualization of the dura and the extruded disc. In most cases, the disc space is then bone grafted to effect a fusion between the involved vertebrae. In most cases, a low profile titanium plate is then affixed to the involved vertebrae by locking screws. The advantage of the anterior approach is that it allows visualization of the disc material, including any central component. An alternative surgical approach is a posterior decompression and laminectomy. Dissection is carried through the midline to expose the posterior elements of the spine. A portion of the lamina at the involved level is removed to allow access into the canal. This is an excellent option for foraminal impingements or for very lateral disc herniations. It is not possible from a posterior approach to visualize an exposed central disc herniation because of the presence of the spinal cord, which cannot be safely touched or manipulated. An advantage to the posterior approach is that this can be done without the need for fusion or instrumentation. The surgical approach for a disc herniation of the lumbar spine is similar to the posterior approach just described in the cervical spine. A midline incision is created with exposure of the posterior elements of the spine. Portions of the lamina are removed until good visualization of the lateral recess is possible. Unlike the cervical spine, gentle retraction of the dura is possible in the lower lumbar spine, allowing visualization of the traversing nerve roots as well as of the disc fragment. Thus, even a central disc fragment can be removed under excellent direct visualization of the lumbar spine. This can be done from a very small incision, and in nearly every case, without the need for fusion or instrumentation.

Spinal Stenosis Spinal stenosis is an acquired narrowing of the spinal canal and can occur in the cervical, thoracic, or lumbar spines. This generally is due to a combination of degenerative changes in the spine , loss of disc height, and bulging of both of the annular tissue as well as the ligamentum flavum; both will contribute to narrowing of the canal. The larger culprit is often hypertrophic changes in the facet joints with osteophyte formation, which can contribute to significant nerve impingement. Cervical stenosis can cause progressive myelopathic symptoms of hyperreflexia, ataxia, balance problems, and four quadrant weakness. On occasion, concomitant root compression

also can cause upper extremity radicular pains. In the lumbar spine, a more common picture is that of "neurogenic claudication." Patients are asymptomatic at rest, but with ambulation, they experience progressive discomfort, weakness, and at times, numbness in the lower extremities. The lower extremity symptoms, resulting from lumbar spinal stenosis, generally resolve very promptly with sitting or forward flexion of the body. It can be demonstrated that increasing lumbar lordosis (as with standing or walking) will cause further narrowing of the canal due to bulging of the ligamentum flavum and positioning of the arthritic facets. Temporary relief for spinal stenosis in both the cervical and lumbar spine can result from epidural administration of corticosteroids. Definitive treatment for disabling symptoms consists of decompressive surgery, specifically removal of the offending laminae and resection of hypotrophic bone from the involved facets.4 4 If extensive bony resection is performed, particularly in the cervical spine, stabilization using bone grafts and internal fixation (rods or plates) may be indicated. Spinal stenosis is a clinical entity most common in patients >50 years of age and occasionally, substantially older. Unfortunately, the same patient group often has acquired spinal deformities of degenerative spondylolisthesis or degenerative scoliosis.4 5 The presence of significant symptoms of spinal stenosis in the presence of a deformity such as spondylolisthesis or scoliosis can create a difficult management problem. Simple decompression in the face of a spondylolisthesis or a significant scoliosis may lead to abrupt, precipitous, and problematic progression of the patient's spinal deformity. Accordingly, when decompressive procedures are planned for patients with deformity, in most cases, concomitant fusion procedures with instrumentation are recommended. Unfortunately, these are large and potentially morbid surgical procedures that often are contraindicated for patients with debilitating comorbidities.

Back Pain and Degenerative Disc Disease Causes for low back pain are myriad, and unfortunately, for many patients, such pains become chronic and disabling. Complaints of low back pain should always alert the physician to the possibility of a dire process such as a malignancy. Metastatic disease is present in the spine with a frightening frequency. Degenerative disease of the spine is common and clearly can cause disabling low back pain. One enduring mystery, thus far, has been the limited correlation between degenerative disease demonstrated on imaging studies and levels of clinical back pain. Many patients with severe degenerative changes have no pain at all, while others with only mild degenerative disease on imaging studies complain of disabling symptoms. Evaluation and treatment of these patients remains an area of great controversy. One option in the management of disabling low back pain in the presence of degenerative disease is to consider fusion operations of the spine. Fusion procedures for painful degenerative osteoarthritic joints have historically been very successful in the extremities. Although fusion of the hip and knee for these indications has largely been supplanted by joint replacement procedures, it is recognized that knee fusion and hip fusion, as well as wrist, elbow, and shoulder fusion, can represent very effective pain relieving procedures. Unfortunately, the observed clinical results when fusion operations are applied to the spine are clearly less successful. Complicating issues of secondary gain, psychiatric issues, and the difficult diagnostic questions of which portions of the axial elements are causing the pain fuel the controversy. Many surgeons advocate the use of discography , a provocative test done on an awake patient wherein a needle is inserted percutaneously into a disc space and contrast is injected. Flow of the contrast through the disc and

annulus in an abnormal way is interpreted to document degenerative changes within the disc. Simultaneous provocation of "typical" pain by the injection is thought to confirm the anatomic location of the offending pain. Unfortunately, even with the use of discography, the success rate with such fusion procedures is controversial at best. Documentation of small numbers of unmyelinated nerve fibers within the outer annulus of the disc has been widely accepted by many as the true source of such back pain. Recently, the documentation of extensive innervation of the epidural space, and indeed of the vertebral bone itself, has raised other questions about possible pain sources in these patients. Work on this subject is continuing. A newer option for the management of degenerative disc disease is the use of an intervertebral disc replacement prosthesis. Several designs are now in use throughout the world. Substantial controversy surrounds their use, having to do with their true effectiveness, their potential for loosening, the potential creation of wear debris, and the difficulty associated with a future revision surgery. These prostheses are placed in close proximity to the contents of the spinal canal and to the great vessels. Future management of this challenging clinical problem is presently unclear.

Scoliosis Scoliosis is a term used to describe a lateral curve of the bones of the spine. This can easily be documented on xray images. Because of the anatomy of the spine, lateral bending deformity will always be accompanied by an associated rotational deformity as well, a phenomenon called coupling . Thus, the scoliosis curve will always have a rotational component. Scoliosis is a three-dimensional entity. The description of scoliotic curves is the topic for extensive mechanical and anatomic study, and several good schemes to measure and define the curves are in use. The most common one and most convenient is the Cobb method, after Dr. Cobb's description in 1948. 4 6 Lines are drawn along the end plates of the vertebral bodies at either end of the curve and the angle from where these lines intersect is taken as the "magnitude" of the curve. This technique does not take into account the rotational component of the deformities, which are measured by other means. Scoliosis curves are not only classified by their magnitude, but by their etiology. Scoliotic curves are classified as congenital (developmental abnormal shapes of the involved bones), degenerative (a curve caused by degenerative changes in the joints of the spine), metabolic (caused by generalized genetic metabolic disease such as mucopolysaccharidosis), neurogenic (spinal deformities caused by primary neurologic insult such as cerebral palsy or spinal cord injury), and myogenic curves (those curves associated with primary muscle problems). Such myogenic curves commonly are seen in muscular dystrophy patients. Idiopathic curves are the most common form of scoliosis. It is now emerging that idiopathic scoliosis actually represents a spectrum of genetic disease due to several different genes with variable penetrance. This chapter will limit the majority of discussion to degenerative curves and idiopathic curves. Degenerative curves generally are seen in patients over the age of 50 years old. At times, it is impossible to distinguish a primary degenerative curve from an idiopathic curve with associated degenerative disease. In any event, adults with scoliosis and progressive painful arthritic spines often have disabling symptoms, not only of axial pain, but of imbalance in posture due to these curves. Symptomatic measures using medications, therapy, and activity modification are, at times, rather unsatisfying. In severe cases, where objective deformity is noted and the patient's medical condition warrants, surgical intervention to apply corrective forces by the use of internal fixation with rod and screw constructs can result in substantial improvement and quality of life. These operations are undertaken only after careful forethought, meticulous informed consent, patient education, and careful

preoperative and perioperative medical attention. These are challenging surgical procedures with a high rate of complication.

Idiopathic Scoliosis Idiopathic scoliosis has infantile, juvenile, and adolescent forms. The overwhelming majority of the patients acquire their curves during adolescence. These curves, apparently due to a spectrum of genetic disorders with variable penetrance, generally manifested during early adolescence and may progress rapidly during periods of skeletal growth. Generally speaking, significant progression of these curves is arrested after skeletal maturity. During active skeletal growth, however, rapidly progressive deformity can arise. Initial management may consist of simple observation. Curves that are progressing at a rate likely to lead to significant deformity often are treated by the use of braces. Braces are applied to the trunk to hold the spine in a corrected position. Braces cannot result in permanent correction of a curve, but often are effective in slowing or arresting progression of a curve. Brace treatment for a patient with idiopathic scoliosis is generally most effective for curves between 20 and 40 as measured by the Cobb technique. If bracing is ineffective, or for patients with large curves, surgical intervention may be appropriate. Surgical treatment consists of using rods for instrumentation of the spine in an improved position with grafting and fusion, and can result in dramatic correction of these curves (Fig. 43-31). Such procedures also have the potential for significant complications and always result in markedly diminished truncal motion. The decision for surgery in an adolescent with scoliosis is always carefully considered and generally is undertaken only in the presence of unabated progression. It is a combined decision among the surgeon, parents, and patient.

Fig. 43-31.

Preoperative and postoperative images of a 13-year-old patient with progressive idiopathic scoliosis that was not controlled by bracing. Excellent correction was obtained with posterior instrumentation and fusion. (Courtesy of Dr. Darrell Hanson.)

Neuromuscular Scoliosis Scoliosis due to neurogenic cause generally is noted early in life. There are hundreds of neurologic conditions that can lead to scoliosis, such as polio and cerebral palsy. Such curves are usually uncompensated, meaning that the patient is unable to lean with his upper body to restore balance. Accordingly, these curves often make standing, and even sitting, unbalanced (Fig. 43-32). Nonambulatory patients often undergo scoliosis correction surgery to facilitate sitting balance and to avoid skin breakdown caused by pelvic obliquity.

Fig. 43-32.

Pre- and postoperative images of a 14-year-old patient with a progressive scoliosis associated with cerebral palsy. This curve was causing progressive problems with sitting balance that were successfully overcome with surgical correction and fusion. (Courtesy of Dr. Darrel Hanson.)

ORTHOPEDIC PATHOLOGY AND ONCOLOGY Orthopedic Pathology and Oncology: Introduction The orthopedic surgeon quite frequently is asked to deal with both benign and malignant tumors. Given the complexity of these entities, an approach to diagnosing and treating these lesions requires the collaboration of the

surgeon, radiologist, and pathologist; ideally with discussion both before and after biopsy and definitive treatment among all three. Failure to allow for adequate communication between all concerned often leads to misdiagnosis or worse. The most commonly encountered tumor problem facing orthopedic surgeons is that of metastatic disease to the bone. Many carcinomas, most notably lung, prostate, thyroid, breast, and kidney, quite frequently metastasize to the bone. Such skeletal metastases are often painful and may weaken the bone to the point where a pathologic fracture occurs. Unfortunately, the orthopedist is quite frequently the physician who makes the initial diagnosis of metastatic disease, as such painful lesions or associated fractures can be the presenting event for many patients with such cancer. When first evaluating a patient with a bony lesion, the orthopedist will use imaging studies, always to include plain x-ray images, and often other imaging techniques such at MRI, CT scan, and bone scan. Laboratory studies and patient history also are always considered. Bone lesions are notoriously challenging to identify. The possibility of malignancy or infection must be kept in mind in approaching any abnormal tissue in the bone. The orthopedic oncologist should always consider the possibility that the lesion in question could be a metastatic focus with a distant primary, may represent a focus of infection, may represent a non-neoplastic or developmental lesion, may represent a benign lesion, or may represent a lymphoma or myeloma. Finally, it could represent a primary malignancy of the mesenchymal tissues (a sarcoma). In patients with suspected metastatic disease, laboratory studies, x-rays, physical examination, and history will quite frequently reveal a primary source of tumor. Generally, the treatment rendered for the osseous metastases is nonsurgical. Unfortunately, a large metastatic lesion within the bone will frequently weaken the bone to the point of fracture. If a fracture has already occurred at the time of presentation, surgical treatment for stabilization and palliation of pain usually is indicated. Prevention is often recommended, as bone healing in the phase of metastatic disease is reliable. Restoring function to the patient is a high priority in such lesions that are frequently treated by internal fixation and sometimes with bone grafting. There are a number of non-neoplastic lesions of bone that mimic neoplasms. In the majority of cases, the first concern is that of accurate diagnosis. A malignant bone neoplasm, if misdiagnosed, can lead to disaster. Benign non-neoplasms of the bone are relatively common. They must be differentiated from malignant lesions. Benign lesions may be indolent, but some benign neoplasms are locally aggressive and destructive. Certain aggressive benign lesions, when occurring in difficult locations such as the spine, may result in paralysis or death.

Bone Neoplasms Sarcomas are the result of malignant transformation of cells of mesenchymal lineage. Some sarcomas are slow growing, while others are rapidly progressive. They are discussed here individually.

Metastatic Diseases Unfortunately, pathologic fractures are common. Any surgery on a lesion of this kind will be accompanied by an intraoperative biopsy of the abnormal tissue. Another frequently encountered problem is that of patients with metastatic disease that have large bony lesions that have not yet resulted in fracture.4 7 Recognizing these lesions can be surprisingly difficult. As much as 50% of a long bone substance may be destroyed by tumor before such lesions are visible on routine x-rays (Fig. 43-33). A large lesion occupying a significant portion of the shaft or long bone should be considered for prophylactic internal fixation. Procedures often can be done without opening the fracture site by inserting rods or nails from a distal site to traverse the lesion. Such internal fixation procedures can

actually protect the bone from fracture and can spare the patient a much more involved surgery.

Fig. 43-33.

Impending fracture of the proximal femur (arrow ) from metastatic breast carcinoma. Internal fixation using an intramedullary device (Zickel nail) with subsequent radiation therapy allows local control of the tumor and healing of the fracture.

Management of Patients with Sarcomas of the Bone The initial step in managing patients with bone sarcomas is a complete medical evaluation, including laboratory studies, investigation of the chest for possible metastatic lesions, and an assessment for other possible bony lesions (Fig. 43-34). In almost every case, initial biopsy is performed as a separate step before any surgical intervention.4 8 It is imperative that surgical planning and procedures be executed by an experienced tumor surgeon. The biopsy incision is carefully planned to traverse a minimum number of tissue planes so that the entire area of the biopsy dissection including the skin incision may be excised should the patient subsequently undergo a definitive resection of the tumor.49,50 Accordingly, incisions are as small as possible and oriented longitudinally. 51,52 Discussion of the biopsy with the interpreting pathologist is strongly encouraged before performing the biopsy.5 3

Whenever possible, biopsy tissue is obtained for "permanent" pathology analysis as well as culture and frozen section (Fig. 43-35). The frozen section is performed intraoperatively whenever possible.5 4 The purpose of the frozen section is not to provide a diagnosis; indeed, frozen section examination of sarcoma lesions is rarely definitive. The purpose of the frozen section is to ensure that the obtained tissue represents a reasonable sampling of the abnormal tissue. The critical information sought with the frozen section analysis is to ensure that the biopsy has been taken "within the lesion." Following this, the incision is closed. No further surgical treatment is undertaken until the final diagnosis has been established.

Fig. 43-34.

Staging algorithms for (A ) bone tumors and (B ) soft tissue tumors. Abd = abdomen; CT = computed tomography; CXR = chest x-ray; H&P = history and physical examination; MRI = magnetic resonance imaging. [Modified with permission from Kasser JR (ed): Orthopaedic Knowledge Update 5 . Rosemont, IL: American Academy of Orthopaedic Surgeons, 1996, p 136.]

Fig. 43-35.

Definitions of surgical margins for bone and soft tissue sarcomas. (Modified with permission from Enneking WF et al: A system for the surgical staging of musculoskeletal sarcoma. Clin Orthop 153:106, 1980.)

Metastatic Sarcomas Metastases from sarcomas can arise in many different tissues, but the most common site of initial metastatic disease is the lung. When a sarcoma is suspected, physical examination and imaging of the chest is an early and important consideration.

Chemotherapy in the Treatment of Sarcomas Use of chemotherapy before definitive surgical resection neoadjuvant treatment is now commonly a part of the management of many, if not most, sarcomas.5 5 Effective therapeutic agents have been developed over the last 30 years that are often effective in causing a reduction in the size of the malignant lesions. Chemotherapy alone is not

successful in affecting a cure of any sarcoma; however, combined combinations of chemotherapy and surgery can lead to gratifying long-term survival rates and cures.

Bone-Forming Tumors—Osteoid Osteoma (Benign) Osteoid osteoma is a benign bone-forming lesion of uncertain etiology that presents with a central radiolucent nidus (1.5 cm and has histologic features identical to the nidus of the osteoid osteoma. Although these lesions can occur anywhere, they have a propensity to develop in the posterior elements of the spine where they can mimic a malignancy radiologically. The radiologic appearance is of a purely lytic lesion with occasional internal matrix production. In smaller or thinner bones, the osteoblastoma will often "break out" into the surrounding soft tissue mimicking a malignant lesion. Histologically, an osteoblastoma will show new bone formation in irregular distributions with a rich fibrovascular stroma. Mitotic figures can be noted, especially if the lesion has been fractured or during pregnancy, but malignant transformation is rare. Osteoblastomas generally are managed by excision or local curettage.

Osteogenic Sarcoma Osteogenic sarcomas are malignant. There are an array of subtypes of osteogenic sarcomas that display varying degrees of potential for metastases. Osteogenic sarcoma tumors are distinguished by the direct synthesis of osteoid by the tumor cells. A low-grade variant of the osteogenic sarcoma is the periosteal osteogenic sarcoma. This is a slow-growing tumor and predictably occurs on the external surface of a long bone cortex. It is very common on the posterior aspect of the distal femur. Periosteal osteogenic sarcoma generally appears to be a large, circumscribed, densely sclerotic mass arising from the cortex. It generally is adherent to or continuous with the bone. Treatment for a periosteal osteogenic sarcoma (after confirmation by a carefully planned biopsy) is surgical excision with a wide margin. Adjunctive radiation therapy or chemotherapy may be indicated for periosteal osteogenic sarcomas with good levels of cure. Long-term survival from a periosteal osteogenic sarcoma after a

successful wide local excision can be >90%.

Classic Osteosarcoma (Malignant) High-grade osteogenic sarcomas generally take origin from within the medullary cavity of the bone and are the most common type of osteogenic sarcoma (Fig. 43-36). It is the most common bone malignancy in children and is especially common in the distal femur, proximal tibia, and proximal humerus. Osteogenic sarcomas may contain focal areas of cartilage formation; occasionally other mesenchymal tissues such as fat or muscle may be seen. The presence of any bone formation by the tumor cells, however, establishes the diagnosis of osteogenic sarcoma.

Fig. 43-36.

Low-power photomicrograph reveals cartilage matrix that entraps and destroys bone. The myxoid nature to the matrix suggests a grade II lesion.

Treatment for high-grade osteogenic sarcomas nearly always involves preoperative and postoperative chemotherapy as well as a wide excision of the lesion.5 6 Frequently, this necessitates amputation. In some cases, it is possible to resect large segments of a long bone, such as the tibia or the fibula, and reconstruct the limb. This is a highly specialized area of orthopedic surgery with the use of specific protheses (generally custom designed). The use of large osteochondral allografts often can be very helpful to preserve function in these patients. Chemotherapy and local radiation is frequently used. Long-term survival after the successful local resection of a high-grade osteogenic sarcoma can be >60%. Osteosarcoma, although predominantly seen in young patients, can be seen in older patients as a result of previous radiation or chemotherapy or underlying conditions such as Paget's disease. Unfortunately, the osteosarcomas that arise in these conditions are uniformly high grade.

CARTILAGE-FORMING TUMORS Cartilage-Forming Neoplasms Cartilage-forming neoplasms are another clinical challenge. As one might expect, there are both benign and malignant cartilage-forming tumors that present in the bone. When there is any possibility that the orthopedic surgeon is dealing with a malignant lesion, it is obligatory to work the patient up adequately for possible metastases before undertaking any definitive biopsy or treatment. As with bone-forming lesions, special attention is placed on ruling out other sites of bone involvement and possible metastatic foci in the lungs. General principles for biopsy of a cartilage containing lesion are identical with those discussed previously (Fig. 43-44) for boneforming lesions. Care is taken to plan a small incision, which can be easily incorporated entirely into a large debulking or extralesional excision procedure. As with the treatment of bone-forming lesions, it is strongly recommended that the biopsy procedure be performed by a surgeon who is trained and comfortable with the definitive surgical management as well. Preoperative consultation with the pathologist and intraoperative frozen section to ensure that an adequate specimen is obtained are important steps.

Fig. 43-44.

A. Magnetic resonance imaging of the hips demonstrates a large, soft tissue mass anterior to the right hip with heterogeneous signal and a sharp demarcation from the surrounding tissue. B. A medium-power photomicrograph demonstrates cartilage and bone maturing in an endochondral mechanism with delicate vessels that merges with the surrounding soft tissue (hematoxylin-eosin, original magnification x 100).

Benign Cartilage Lesions Chondromas are benign cartilage-forming tumors. When they occur centrally on the bone, they are referred to as enchondromas . When these lesions occur in the cortical bone, they are referred to as periosteal chondromas . Both forms of chondromas are most commonly seen in the long bones. They are particularly common in the bones of the hand, where they can cause pathologic fracture. Other common sites for chondromas are the proximal femur and humerus. Most enchondromas are identified as incidental findings on x-ray taken for other purposes. The radiographic appearance of an enchondroma is that of a generally round or oval-shaped lesion within the bone without significant bony reaction. All cartilage-forming tumors can contain areas of calcification. Microscopic analysis of an enchondroma reveals normal appearing cartilage. The lesion generally contains a small number of cartilage cells that do not show proliferation or pleiomorphism. The enchondroma frequently has such a familiar and benign appearance on x-ray imaging that management often consists of simple observation. In cases where lesions are large, painful, or display any atypical radiographic features, careful investigation and work-up for biopsy are indicated. On many occasions, biopsy (always accompanied by culture) is accompanied by curettage and bone grafting. The clinical syndrome of Ollier's disease refers to patients with multiple enchondromas. This condition also can be called multiple enchondromatosis . The related Maffucci's syndrome is used to describe patients with multiple enchondromas and multiple soft tissue angiomas. Patients with Maffucci's syndrome or Ollier's disease are at risk for malignant transformation of their enchondromas and therefore do require ongoing periodic evaluations

throughout their lives (see Fig. 43-7). Endochondromas may involve any bone that originates in cartilage. They are frequently seen in the bones of the hands and feet but can be seen in the long bones and the pelvis. Endochondromas are thought to arise from islands of cartilage that are left behind as the growth plate moves away from them. These islands can grow independently and slowly increase in size. The longer they are present, the more they will mature through endochondral ossification and calcify, which appears as arcs and rings on plain films. In the hands and feet, endochondromas can thin the cortex, increasing the chance for fracture.

Osteochondroma Osteochondromas are benign cartilage-forming lesions that arise within the cortex of the bone, usually in the metaphyseal region. The lesions arise from abnormalities in the epiphysial growth plate. Lesions have a cartilage "cap" that proliferates and can form a substantial-sized mass beneath the cartilage in histologically normal bone. Osteochondromas may be broad based (sessile), or on some occasions, have a defined, discrete stalk. Such osteochondromas are called pedunculated . For lesions with a characteristic appearance, observation alone can suffice. In some patients, however, the lesions can become painful, usually because of mechanical problems. In such cases, they can be surgically resected. Any painful osteochondroma should be taken seriously, however, as there is a described incidence (approximately 1%) of malignant transformation.

Chondroblastoma Chondroblastomas are benign cartilage-forming tumors nearly always found in the epiphysis area of a young patient usually before skeletal maturity. It is common for patients with chondroblastomas to present with pain. Generally, plain x-ray images of the joint reveal a focus of bone lysis or resorption surrounded by a rim of sclerotic, reactive bone (Fig. 43-37). Proliferating cells are seen within the lytic portion of the lesion and may represent chondroblasts. A small, but significant percentage of chondroblastomas are capable of metastases. Generally, they are managed by curettage and bone grafting.

Fig. 43-37.

Benign chondroblastoma (Codman's tumor) of the humerus.

Chondrosarcomas Chondrosarcoma is a malignant neoplasm of cartilage (Figs. 43-38 and 43-39). It is most common in adults and is commonly seen in the pelvis, spine, proximal humerus, and the knee. Most frequently, the presenting symptom is that of local pain. X-ray images show an expansive destructive lesion of the bone frequently with focal areas of calcification within the tumor (Figs. 43-40 and 43-41). It is important to differentiate the x-ray finding of calcification within cartilage tumors from that of ossification within a bone-forming tumor such as osteogenic sarcoma. The cartilage present in a chondrosarcoma is visualized on an x-ray as a disorganized density without cortication or trabecularization. Chondrosarcomas too often present challenging problems with management. Many of the tumors are within the spine or pelvis skeleton, making ablative surgery or amputation difficult or impossible. Further, many, if not most, chondrosarcomas are slow growing and are, thus, often less susceptible to chemotherapy and radiation therapy than many other sarcomas.

Fig. 43-38.

Medium power photomicrograph demonstrates an atypical bone-producing lesion with spindled cells.

Fig. 43-39.

High-power photomicrograph demonstrates the increased cellularity of a grade III chondrosarcoma.

Fig. 43-40.

Plain film of the proximal humerus demonstrates a metaphyseal matrix-producing lesion with arc- and ring-like formations consistent with cartilage formation. The lateral aspect of the lesion shows destruction of the cortex with soft tissue mass in keeping with the diagnosis of dedifferentiated chondrosarcoma.

Fig. 43-41.

Plain film of the proximal humerus demonstrates an ivory-like lesion of the proximal diaphysis with sunburst type periosteal reaction.

Treatment of a chondrosarcoma generally consists of a wide surgical resection alone.

FIBROUS LESIONS OF THE BONE Aneurysmal Bone Cysts An aneurysmal bone cyst is a reactive condition not thought to represent a neoplasm, which consists of a cyst. It can present after a pathologic fracture or due to complaints of local pain with an associated mass. Histology reveals large, blood-filled spaces with a true endothelial lining, foreign-body–type giant cells, and occasional woven bone formation. Care must be taken to examine the lesion adequately as secondary aneurysmal change is quite common and many lesions diagnosed as aneurysmal bone cyst are actually caused by another lesion with associated extensive cyst formation. Small lesions may be followed with simple observation, however, because risk of pathologic fracture means that the majority is treated by local curettage and bone grafting.

Unicameral Bone Cyst Unicameral bone cyst is a benign lesion, most commonly found in the metaphyseal regional of long bones (frequently the humerus of growing children). This lesion can present after pathologic fracture, but also is occasionally noted due to local pain or a mass. The cause for this condition is unknown. Radiographic appearance is generally that of a large, single, cystic structure within the bone. The histologic appearance of the lesion is that of a fluid-filled cystic area within the bone. The lining of the unicameral bone cyst is composed of fibrous tissue with occasional giant cells. Small lesions may be managed by simple observation, whereas larger lesions, in which fracture risk is significant, are managed by a local curettage and bone grafting.

Fibrous Dysplasia (Fibro-Osseous Dysplasia)

Fibrous dysplasia is a commonly seen lesion in children. It is usually an isolated, slow-growing hematoma consisting of mixed bone and fibrous tissue. Fibrous dysplasia is a lesion composed of a spindle-shaped, mononuclear stroma with woven bone formation. This lesion may involve one bone (monostotic) or multiple bones (polystotic). The radiologic features usually demonstrate areas of radiolucency with a hazy and diffuse internal matrix production often termed ground glass . The histologic features show a bland spindle cell proliferation with irregularly shaped woven bone formation. The bone arises directly out of the background stroma. Occasional giant cells, hemorrhage, and myxoid degeneration can occur, especially if the lesion is fractured. It most frequently is asymptomatic but, unfortunately in some patients, large metaphyseal lesions can lead to focal growth disturbance and bone deformity. Pathologic fracture also is sometimes seen. In the absence of fracture or deformity, the lesions usually are painless and asymptomatic and they are most commonly diagnosed as incidental findings on radiographs. When present in the proximal femur, successive fracture events may lead to a characteristic "Shepherd's crook" appearance to the proximal femur. Plain radiographs often are diagnostic and small lesions may be managed by simple observation. When lesions cause significant symptoms or when pathologic fracture is considered likely, curettage and internal fixation bone grafting often are offered as treatment.

Non-Ossifying Fibroma Non-ossifying fibroma is one of the most common bone lesions and can be found commonly as incidental lesions and in autopsy series. It presents as an eccentrically located, radiolucent lesion of the metaphysis with a lobulated or soap-bubble appearance. These proliferations have a dense peripheral sclerosis and may or may not have a fracture associated with it. Histologically, these lesions are composed of bland spindle stromal cells in a storiform pattern with admixed giant cells and xanthoma cells. Hemosiderin can be noted if the lesion is fractured. These lesions usually are treated conservatively. If a fracture is present, it can be curetted and grafted.

VASCULAR LESIONS OF BONE Hemangiomas of Bone Hemangiomas of bone are benign conditions that represent foci of dilated vascular venous structures within the bone. Hemangiomas are not neoplasms. Hemangiomas are commonly seen in the vertebral bodies where characteristic appearance of sclerosis is accompanied by coarse vertical striations within the bone. This characteristic appearance generally is adequate to establish the diagnosis. Hemangiomas rarely require treatment.

Tumors of Hematopoetic Tissue Tumors of the hematopoietic tissues include lymphomas and myelomas. Surgical treatment of lymphomas are discussed in Chap. 10. Myeloma is a malignancy that results from the transformation of cells of the plasma-cell lineage. Multiple myeloma is usually a systemic disease. Proliferating, malignant, antibody-producing plasma cells infiltrate the marrow in multiple bones. This can result in focal areas of bone resorption, often with a patchy distribution, creating an appearance of "moth-eaten" bones. Frequently, the process is diffuse and systemic, leading to diffuse nonfocal loss of bone in a condition that nearly exactly mimics osteoporosis in its radiographic presentation. Presenting symptoms are often systemic complaints such as weakness, lethargy, or weight loss. Commonly, the condition may manifest as a pathologic fracture. Myeloma is most common in patients >50 years of age and can present in patients in their eighth and ninth decades of life. On this basis, any patient with clinical signs of diminished mineral density, particularly those who

sustain a fracture, may have an underlying multiple myeloma. The diagnosis most commonly is made by laboratory studies. Plasma cells will produce a monoclonal spike on serum protein electrophoresis in the majority of cases. The presence of a characteristic monoclonal spike may establish the diagnosis. In some patients, the secreted antibody [which may be from any antibody group—immunoglobulin (IG) G, IgA, IgM] may be apparent and rapidly cleared from the blood and can almost always be seen on a urine protein electrophoresis study. Frequently in such patients, the erythrocyte sedimentation rate is elevated as the result of the altered serum protein composition.

Solitary Myeloma (Plasmacytoma) In some patients, the presence of a myeloma is limited to a single solitary osseous lesion: a plasmacytoma. When a patient evaluation indicates the likelihood that a solitary bone lesion is the sole focus of the myeloma, local radiation may be appropriate. Treatment for all of these myelomas generally centers around chemotherapy, often using multiple agents.

Chordoma Chordomas are slow-growing malignancies derived from embryonic notochord cells. Chordomas nearly always arise in the axial skeleton and most commonly involve the occiput or the sacrum. They can be found in the vertebrae. Chordomas are not found in the extremities. About one third of these tumors arise intracranially (skull base), about half are found in the sacrum, with the rest in the spine. Radiographically, cranial chordomas occur in the midline of the base of the skull and produce destruction of the spheno-occipital and hypophyseal areas. Sacrococcygeal chordomas take on an oval or circular appearance as they break out of the sacrum and grow into the pelvis. Microscopically, the hallmark is the large physaliferous cell, whose vacuolated cytoplasm gives it a soap-bubble appearance. These lesions are biphasic with the second population of polyhedral cells with an eosinophilic cytoplasm. Chordoma patients usually present with local pain and, given their proximity to the spine, often present with radicular or myelopathic symptoms. Sacral tumors may present rectal or urinary sphincter dysfunction, and occasionally, GI obstructive symptoms. Plain radiographs will often, but certainly not always, reveal the lesion. A central area of bony destruction with a soft tissue mass is characteristic. Chordomas are frequently fatal, however, because without local control, these centrally located tumors can threaten vital functions. The mainstay of treatment is wide local resection with a wide surgical margin. On rare occasions, radiation therapy may be indicated. In general, chordomas are not responsive to chemotherapy. Chordomas are malignant tumors that are slow growing, locally destructive and invasive, and late to metastasize.

Giant Cell Tumor of Bone Giant cell tumor of bone is a benign neoplasm of bone that can be very aggressive and destructive locally. The cellular origin for this tumor is unknown. Giant cell tumor of bone is most frequently seen in the long bones and is rare in children. Diagnosis is generally made following patient complaints of local pain. X-ray images reveal a lytic expansile lesion of the bone that is most frequently localized in the metaphysis of a long bone. Histologic analysis shows a mixture of round, oval, and spindle-shaped cells and numerous multinucleic giant cells. Treatment of giant cell tumor of bone involves aggressive and complete local resection. An incomplete resection frequently results in recurrence and may result in significant functional impairment and even amputation. Giant cell tumors of bone are locally aggressive and destructive lesions that arise in the metaphysic of long bones

in skeletally mature individuals. Giant cell tumors of bone are commonly found around the knee but can be seen in many locations. Plain films will show an eccentrically located metaphyseal lesion that is radiolucent. Most of the lesions will show cortical breakout with an associated soft tissue mass. Morphologically, these lesions consist of rounded mononuclear cells with admixed giant cells, hemosiderin, and new bone formation. These lesions have a high tendency to recur.

Ewing's Sarcoma of Bone Ewing's sarcoma of bone, or Ewing's tumor, is a small, round cell sarcoma most common in children and younger adults. Ewing's sarcoma is most common in the long bones, especially the metaphyseal regions of the femur, tibia, and humerus. Patients present with complaints of local pain, interestingly, often accompanied by fever. Ewing's sarcoma is an undifferentiated tumor occurring in children and primarily involves the diaphysis of long bones. Radiographically the early Ewing's tumor may be relatively inconspicuous. The tumor appears as an illdefined area of "moth-eaten" osteolytic destruction. It becomes more pronounced as the tumor progresses and often will show an aggressive periosteal reaction. The usual microscopic picture is that of sheets and geographic areas of small round blue cells with pale nuclei. There is no matrix production within these tumors unless there is an associated fracture. These cells are loaded with glycogen and a periodic acid–Schiff histochemical stain will be positive. These tumors have a characteristic 11:22 translocation that can be very helpful in making the correct diagnosis (Fig. 43-42).

Fig. 43-42.

A. Plain film of the elbow shows a permeative lesion of the ulna with a periosteal response in an "onion skin" pattern. B. A medium power photomicrograph reveals bland, small, round, blue cells and vessels characteristic of Ewing's sarcoma (hematoxylin-eosin, original magnification x 40).

Treatment of Ewing's sarcoma begins with a carefully planned biopsy. Definitive treatment may or may not involve surgical resection, but multiagent chemotherapy and radiation are the mainstays of treatment.

Subungual Exostosis Subungual exostosis is a subperiosteal, osteochondral proliferation usually in the distal toes, but it can be located in the fingers. The x-ray will show a mineralized formation, usually the distal phalanx with a soft tissue swelling and occasionally ulcer formation. Additionally, there is no communication with the underlying medullary canal that separates this from a true osteochondroma. Histologically, these lesions are composed of chondro-osseous matrix that emerges into the surrounding soft tissue. The cellular proliferation can be quite reactive and misinterpreted as a more aggressive process. Definitive treatment is surgical resection. These lesions often can recur if the overlying fibrous cap is not entirely removed (Figs. 43-43 and 43-44).

Fig. 43-43.

Medium-power photomicrograph shows maturing bone intimately associated with soft tissue (hematoxylin-eosin, original magnification x 100).

Myositis Ossificans Myositis ossificans is the result of posttraumatic ossification of a hematoma in the soft tissue. It most often occurs in muscle but can occur in fascia, tendon, joint capsule, and occasionally, fat. In cases of myositis ossificans, the endochondral bone formation follows essentially the same process as that of fracture callus formation. The damaged soft tissue is removed and the hematoma begins to organize with mesenchymal cells that differentiate into chondroblastic, osteoblastic, and vascular-type cells. Radiologically, these lesions are noted in the soft tissue and show an arrangement of bone and cartilage at the periphery of the lesion and interior soft tissue. This results in an "egg shell" calcification/ossification. Histologically, the features are bone and cartilage at the periphery of the lesion and a fibrovascular core. Over time, the outer endochondral ring will remodel to lamellar bone with an interior fibro-fatty center.

Paget's Disease Paget's disease is a relatively common condition of bone, most frequently seen in patients >40 years of age. Paget's disease may be mono-ostotic, or it may be seen in multiple bones. It is most commonly seen in the pelvis and spine but may also frequently occur in the humerus, femur, and tibia. The lesion results from abnormalities in the bone in the remodeling process, felt to be due to abnormalities in the osteoclasts. X-ray images of pagetic bone show characteristic sclerosis with coarsened trabeculae, cortical thickening, and often, cortical expansion of the bone. The appearance of the bone may also contain lytic as well as sclerotic areas. Microscopic appearance of pagetic bone shows broad irregular trabeculae, often with visible lines (indicating incomplete mineralization). On occasion, the striking appearance of "mosaic bone" is seen, which refers to large areas of incompletely mineralized bone that creates an appearance reminiscent of mosaic tile. The critical histologic feature of Paget's disease is not the partial mineralized bone, however; it is the presence of large osteoclasts with

abnormally large numbers of nuclei. Normal osteoclasts will have from two to four nuclei, in pagetic bone it is common to see osteoclasts with from five to 50 or more nuclei. It is speculated that the large abnormal osteoclasts result from late effects of a pre-existing paramyxovirus infection. It is believed that increased bony resorption by these abnormal osteoclasts causes local lysis of bone. The rapid healing process that follows leads to the disorganized and coarse bony texture. Bones involved with advanced Paget's disease can be subject to pathologic fracture. Bony abnormalities surround joints and often lead to accelerated arthritic change. Paget's disease is common in the spine, particularly in the lumbar spine. The characteristic bony expansion and arthritic change in the spine frequently results in the clinical syndrome of spinal stenosis. Treatment of Paget's disease generally is nonsurgical with the use of antiresorptive medicine such as bisphosphonates and/or calcitonin. Such medical treatment is usually sufficient for most patients with Paget's disease. Neglected Paget's or resistant cases will occasionally go to surgery for lumbar decompressive laminectomy (for spinal stenosis) or for joint replacement. Surgical treatment for patients with Paget's disease must be preceded by antiresorptive therapy as arteriovenous shunting in pagetic bone is frequently encountered. Bone bleeding can be a major problem in Paget's patients who are not medically treated.

Stress Fracture Stress fractures are a result of an active remodeling as a result of stress that most often is noticed in an episode of sudden increase in physical activity. This is very common in military recruits during basic training, but this can be seen in anyone with a sudden increase in athletic activity. Localized pain and tenderness is typical, and the skin can be locally red. X-ray examination may be unrevealing early on; however, subsequent films may show a periosteal reaction to increase suspicion for this condition. The most common location for stress fractures is the proximal tibia, but they can occur anywhere. As the fracture develops, films will show a lucent line perpendicular to the long axis of the involved bone. Histologically, this process is composed of aggregates of the osteoclasts removing bone with paucity of osteoblastic response and a variable amount of periosteal response.

JOINT RECONSTRUCTION The Surgical Treatment of Arthritis One of the most challenging problems facing the orthopedic surgeon is the treatment of degenerative and inflammatory diseases of joints. In all cases, the primary objectives are to relieve pain and to preserve motion and function. In the treatment of any joint complaint, a thorough evaluation of the patient's symptoms, history, and a thorough physical examination are essential. The orthopedic surgeon must distinguish between inflammatory disease and degenerative disease. The laboratory and imaging studies are also tremendously useful. It is always hoped that a nonsurgical means can be used to help the patient. Medications, physical therapy, rest, braces, and time are often all that is needed to assist the patient with an arthritic joint. On frequent occasion, however, more invasive treatments are necessary.

Injection of Joints For several decades, the treatment options for painful joints have included the injection of various substances. Local anesthetic agents can be injected into a joint for diagnostic purposes. Corticosteroids are frequently injected into joints for symptomatic relief (this can be done for both inflammatory disease and osteoarthritis). The use of intra-articular corticosteroid injections is controversial. This often provides short-term relief of pain and swelling

symptoms; however, the long-term consequences of this technique are debated. More recently, injections of high-molecular-weight, polysaccharide molecules such as hyaluronic acid have become popular in the treatment of degenerative disease of large joints. The utility of this technique is not yet quite clear in the evidence-based literature, but it does appear that at least some patients get substantial and somewhat lasting relief from these techniques.

Synovectomy Synovectomy is the surgical removal of substantial portions of the synovial lining of a joint. This is another procedure that can, on occasion, help a patient. The technique frequently has been applied to joints damaged by hemophilia. In severely symptomatic disease, intra-articular synovectomy also can be of benefit to patients with inflammatory disease such as rheumatoid arthritis.

Periarticular Osteotomy Arthritic joints often develop angular deformities. This can be from selective loss of cartilage from areas of high wear. It also can be from malalignments, either congenital or acquired after injury. It is quite common, for example, for osteoarthritis of the knee to be severe in the medial tibial-femoral portion of the joint and relatively mild in the lateral compartment. An osteotomy of the proximal tibia to selectively transfer weight to the healthier cartilage can often provide a prolonged period of relief to such patients. In a similar way, young adults with malaligned hips can often benefit from osteotomies of the proximal femur to create better femoral acetabular articulation.

Fusion Many arthritic joints can be surgically treated by bony arthrodesis fusion instead of joint replacement. This is most frequently performed in joints where motion is not critical. Fusion of certain joints of the foot (including painful degenerative arthritis of the first metacarpal and numerous bones of the midfoot) can be satisfactorily managed by applying bone grafts across the involved joint, transfixing the joint with internal fixation, screws, or periarticular plates. The arthritic wrist frequently is managed by fusion procedures, as the mobility of the shoulder, elbow, and fingers will usually allow preservation of excellent useful function. Arthrodesis of the shoulders is less frequently performed than arthroplasty of the shoulder, but it is an established and reasonably successful procedure. Nonetheless, fusion of the glenohumeral joints often allows satisfactory function, particularly in heavy laborers because of the compensatory motion of the trunk, scapulothoracic joints, elbow, and wrist.

Joint Arthroplasty—(Joint Replacement) Patients with severe intractable joint pain can be treated with prosthetic replacement of the diseased joint with an artificial joint composed of metal and plastic. This technique was successfully introduced by Sir John Charnley in the 1960s who successfully developed and first performed total joint replacement procedures on the hip. The genius of Dr. Charnley has been amply demonstrated as this procedure continues to remain one of the most successful operative interventions.5 7 A joint prosthesis, in nearly all cases, involves a mobile surface, most commonly composed of high-molecularweight polyethylene (the original material chosen by Dr. Charnley), which is affixed to metal components that are

anchored to the involved native bone. The metal components of a joint prosthesis can be affixed to native bone by precise carpentry and impaction (impaction fit). Such metal implants often are surfaced with porous metals that allow bony ingrowth (porous coated implants). In Dr. Charnley's original procedure, a polymer of methylmethacrylate was used to cement the metal components in place. Polymethylmethacrylate cement material continues in common use today, although the majority of hip and knee replacements are now performed with noncemented technique.

Total Hip Arthroplasty Images of a total hip replacement procedure are displayed in Figs. 43-6, 43-13, 43-33, 43-45, 43-46, 43-47, 4348, 43-49, and 43-50. The patient has a severely arthritic joint surface with sclerosis and cystic changes in both the femoral and acetabular articular surfaces. The patient was experiencing severe pain with essentially all activities of daily living and had lost the ability to move about normally. After the failure of conservative care to improve function, the patient can be taken to surgery for replacement of the hip.

Fig. 43-45.

Pathologic fracture of the femoral neck (arrow ), treated by femoral head excision and endoprosthetic hip replacement. In cases with acetabular involvement, the acetabulum must also be replaced.

Fig. 43-46.

Range of motion is measured in degrees. Each joint has a normal range and, when examining a patient with a joint or extremity disorder, the involved joint's range of motion should be measured and recorded.

Fig. 43-47.

A mortise view of a normal ankle. This view allows visualization of the relationship between the distal tibia and fibula.

Fig. 43-48.

Primary osteoarthritis of the knee. Anteroposterior and lateral radiographs showing varus deformity of the knee with joint space narrowing and osteophyte production on medial, lateral, and posterior aspects of the tibia, on anterior aspects of the femoral condyles, and on upper and lower poles of the patella. There is minimal cyst formation and sclerosis of subchondral bone of the medial joint space.

Fig. 43-49.

Coronal magnetic resonance imaging of a knee. The meniscus is easily seen as a dark (no signal) triangular structure between the femoral condyle and tibia. The medial collateral ligament is disrupted. Magnetic resonance imaging is a valuable tool to evaluate injuries to the soft tissues of the extremities.

Fig. 43-50.

Anteroposterior radiograph of a patient with chronic osteomyelitis. The patient had a compound (open) fracture of his tibia treated with an open reduction and internal fixation. He has developed a chronic infection. The plate that was on his tibia has been removed. The bone is denser than normal, and the medullary canal cannot be seen well. This suggests that there is sequestered (necrotic) bone that needs to be dbrided if the infection is to be controlled.

The hip joints can be exposed through a variety of surgical approaches. The most commonly performed is the posterior approach to the hip. The incision is made through the skin and fascia of the lateral proximal thigh, and dissection is continued deeper to expose the posterolateral portion of the proximal femur, the greater trochanter, and associated muscles. The short rotators are dissected away from the proximal trochanter, and the femoral neck is exposed by entering the hip capsule. Removal of the femoral head is accomplished by transecting the femoral neck with a power saw and dislocating the femoral head. The proximal femur is prepared by successive removal of bone from the medullary cavity. Specially shaped reamers and rasps are inserted to create an appropriate space for the stem of the femoral prosthesis. Similarly, any remaining articular cartilage is removed from the acetabulum using sequentially sized reamers to the level of good cancellous bone. The acetabular portion of the prosthesis, which contains the high–molecular-weight polyethylene articular surface, is attached to a metal cup. The prosthesis (usually metal or ceramic) is then impacted into place. The joint is then relocated, and the wound is closed. Great care is taken during the performance of this surgery to attain a functional anatomic position for both the femoral and acetabular components. Malposition of either component can lead to rotational deformity, premature

wear, or dislocation. As is readily apparent, during the surgical exposure, many of the intrinsic stabilizers of the hip joint are divided during the dissection needed to perform the surgery. Accordingly, following a total hip replacement procedure, restrictions are placed on the patient's range of motion until an adequate amount of scar is formed to help preserve long-term stability of the joint.

Total Knee Arthroplasty Total knee replacement involves resecting the native articular surface and subchondral bone from the femur, tibia, and the patella. Analogous to hip replacements, the distal femur generally is reconstructed with a large metal weightbearing surface shaped to mimic the femoral condyles. The tibial plateau is replaced by a high-molecularweight polyethylene surface usually attached to a flat metal surface, which is then affixed to the distal tibia by a stem, or screws, or both. The patella surface generally is reconstructed with a high-molecular-weight polyethylene articular surface. As with the hip, these components may be affixed to the bone using polymethylmethacrylate cement, although press fit components using various surface treatments to promote adhesion and bone ingrowth also are commonly used. A total knee replacement generally is accomplished through an anterior peripatellar approach, with the knee widely exposed; the articular surfaces are resected using precise saw cuts, guided by templates and jigs. Appropriate alignment of the components is essential for a successful result. Also critical is ligamentous balancing of the knee, such that medial and lateral stabilizing ligaments and the patellar tendon can function normally. Knee replacements can be performed with implants designed to make use of the normal cruciate ligaments. Other total knee designs accommodate these stabilizing functions as well and involve resection of these ligaments.

Complications of Total Joint Arthroplasty Artificial joints are used to replace worn out and damaged natural joints. Sadly, the artificial joints themselves are also subject to wear and damage and can fail by a variety of mechanisms. Total joint replacement components can loosen, fracture, or disassemble. Artificial joints can be damaged by virtue of corrosion or simply "wear out." Other complications include infection (acute, delayed, or chronic), contracture, and periprosthetic fracture. As arthritis and osteoporosis are both disease processes most common in older patients, they often occur together. Insertion of a prosthetic joint in a patient with osteoporosis requires special care to prevent intraoperative fractures. The purpose of an artificial joint creates a stress riser at the interface between prosthesis and bone. Unfortunately, fractures adjacent to total joint implants are not uncommon. Treatment for this problem is individualized and may involve internal fixation, replacement of the prosthesis, or both.

Corrosion, Wear, and Osteolysis Osteolysis is a major concern to the total knee replacement surgeon. The term osteolysis can be used to describe virtually any form of bony resorption, including that associated with metastatic disease or infection. In joint replacement, it generally refers to one of two unwanted phenomena. Osteolysis is a term that is used to describe focal bony resorption at the immediate interface between the prosthesis and the bone or the cement mantle and the bone. The motion of a loose implant on the bone prosthesis interface is such that bony resorption can occur, and unfortunately, without surgical revision, there is frequent progression of bone resorption to the point where mechanical symptoms of hip pain or knee pain result. The presence of an increasing zone of osteolysis in the

periprosthetic region becomes a strong relative indication for revision of the implant. A more serious and problematic form of osteolysis is that caused by a noninfectious inflammatory reaction to wear debris. Wear of the high-molecular-weight polyethylene articular surface can generate and disperse microscopic particles of high-molecular-weight polyethylene, which often cause a focal tissue inflammatory reaction. Reticuloendothelial cell proliferation and the action of other inflammatory cells may result at times in very aggressive rates of bony resorption. The process often is painful. When extensive osteolysis of this type is allowed to proceed for substantial lengths of time, serious and problematic loss of periarticular bone can result, adding additional difficulty to revision surgery. Particulate methylmethacrylate cement debris also can play a role in this form of osteolysis. Due to this problem of osteolysis, joint prosthesis designers have focused a great deal of attention on precisely engineering the articular surfaces and exploring options for other bearing surfaces materials. Metal on metal bearing surfaces and the use of other plastics or ceramics are areas of intense ongoing study. All total joint replacement prostheses have the potential to wear out or loosen. Accordingly, they are rarely indicated for young active patients, who will place a high mechanical demand on the prosthetic joint, although joint replacement may be very appropriate for "low demand" patients with systemic inflammatory disease. Revision or replacement of a loose infected or "worn out" joint prosthesis is an involved and technically challenging procedure. Such surgeries often involve extensive and difficult cement removal, and may involve the need for extensive bone grafting. For some difficult clinical challenges, custom-made revision prosthesis is used.

PEDIATRIC ORTHOPEDIC SURGERY The treatment of musculoskeletal pathology in pediatric patients is different in many ways from the treatment of adult patients. The orthopedic surgeon treating pediatric patients must be aware of numerous congenital and developmental conditions. Further, the skeletal system is growing. Preservation of normal growth is a significant priority in the management of this patient group. The pediatric orthopedic surgeon must be able to recognize and treat a large number of inherited congenital conditions, which include inherited metabolic disorders, inherited neurologic conditions, and inherited musculoskeletal anatomic abnormalities. The diagnosis and treatment of these inherited syndromes and disorders are beyond the scope of this chapter.

Birth Injuries Causing Neurologic Impairment BRACHIAL PLEXUS PALSY Injury of the brachial plexus during delivery was once a commonly encountered management problem. Patient with associated plexus injuries can present with mild, moderate, or severe impairment of the involved upper extremity, which can, on occasion, involve upper or lower roots and trunks of the plexus. Modern obstetrical practice has markedly decreased the incidence of this problem, which unfortunately still occurs in approximately 0.2% of all births. Such injuries are associated with large birth weight, forceps delivery, breech presentation, and prolonged labor. A plexus injury may represent a stretch injury or, on some occasions, a frank avulsion of nerve roots. In most patients, nonsurgical management is pursued with aggressive therapy and passive exercise to preserve motor motion in the shoulder while awaiting return of neurologic function. In unusual cases, surgical repair of injured roots and trunks of the plexus is performed.

CEREBRAL PALSY Cerebral palsy is a nonprogressive neuromuscular disorder, which usually is recognized before age 2 years old. It is considered to take origin from an injury to the developing brain. Usually, the specific cause is not identifiable. There is a wide variation in the consequences for cerebral palsy that may or may not be associated with mental impairment. Cerebral palsy is classified in physiologic and anatomic categories as spastic (the most common), athetotic, ataxic, and mixed. The majority of cerebral palsy patients are hyperreflexic with increased muscle tone and spasm. Such patients also are classified as having hemiplegia (upper and lower extremities) or diplegia where low extremity problems are greater than those in the upper extremity. Patients with cerebral palsy frequently develop spinal deformities, which is discussed separately in the Scoliosis section. Orthopedic treatments center on maintaining function and preserving range of motion. Tendon lengthening procedures, release of contractures, and tendon transfers can be helpful both in upper and lower extremities. Gait disorders are the focus of a great deal of attention, and often, major improvements in walking ability can be accomplished by well-planned tendon lengthening procedures and contracture releases. Because of unbalanced muscle forces due to associated spasticity, hip dysfunction, unfortunately, which frequently leads to hip dislocation or subluxation, is a significant problem for many cerebral palsy patients. Initial treatment often consists of abductor tendon releases that can be very rewarding. In some cases where a diagnosis is made late, or where soft tissue releases are unsuccessful, tendon balancing procedures may be combined with open reduction of a hip joint, sometimes augmented by acetabular reconstruction or osteotomy of the proximal femur. Knee contracture due to hamstring tightness is another commonly seen problem. Hamstring lengthening and other muscular tendon releases can be helpful. Foot and ankle deformities can also result from a cerebral palsy and usually are treated, even in nonambulatory patients, to facilitate shoe wear. Maintaining normal foot anatomy is essential in an ambulatory patient. The most common foot deformity caused by cerebral palsy is an equinovalgus foot, which is caused by heel cord contracture and peroneal spasm. Tendon balancing can be helpful. In severe cases, bony reconstruction also can be indicated.

Skeletal Growth Acquired musculoskeletal disorders in the pediatric patient cover a wide spectrum of disease, which includes injury, inflammatory disease, and developmental disorders. In all of these conditions, the treating surgeon must remember that immature bones are actively growing; preserving bone growth is a high priority of treatment (Fig. 43-51). In addition, the immature skeleton is incompletely ossified. Accurate diagnosis of an injury or musculoskeletal condition can be much more difficult because large portions of the skeleton are still cartilaginous and may be invisible radiographically with plain film. As can be seen, the epiphysis, generally containing an articular surface, is positioned at the ends of the long bone with an intervening physis or growth plate. The normal epiphysis is the site of longitudinal growth of a long bone. It is wide enough to be readily visible on clinical x-rays. The physis has specific layers or zones defined histologically adjacent to the epiphyseal bone known as the reserve zone of pluripotential cells. Proceeding from the reserve zone is the zone of differentiation , where differentiation of cartilage is first demonstrated. Below the zone of differentiation is the zone of proliferation , characterized by extensive cell division. Beneath the zone of proliferation is the zone of maturation , where more mature chondrocyte morphology is manifest. Beneath the zone of maturation is the hypertrophic zone where cells increase in size. Cell death and calcification of the cartilage matrix then occurs in the zone of calcification .

Fig. 43-51.

Structure and function relationships of the growth plate. Calcified cartilage bars form scaffold for osteoblasts to deposit new bone; osteoclast-like cells reabsorb calcified cartilage through remodeling. FGF = fibroblast growth factor; Gr. = growth; IGFI = insulin-like growth factor I; PTHrP = parathyroid hormone-related peptide; TGF

= transforming growth factor beta.

Preservation of normal growth in this area is important. Injury or insult to the growth plate can lead to premature growth arrest or angular deformity of the limb and a significant cosmetic and functional problem. Surrounding the metaphyseal and diaphyseal bone is the periosteal layer. The periosteum in immature individuals is far more thick and cellular than in adults. This metabolically active periosteum is responsible for the synthesis of new bone onto the diaphyseal and metaphyseal bone and is responsible for the circumferential growth of the bones. In very young patients, the metaphysis and epiphysis may be completely unossified. Ossification centers in the epiphysis and will appear in a very predictable order. An understanding of the expected sequence of ossification and its expected chronology are critical for the appropriate treatment of young patients. It must also be noted that some bones, particularly those of the spine, normally manifest multiple distinct ossification centers.

General Considerations in Pediatric Fractures The treatment of a fractured bone in a pediatric patient involves all of the issues present in adult injuries. In a child, however, treating physicians and surgeons are also much concerned with the status of the growth plate. Unfortunately, the epiphyseal growth plate is a very common site of fracture, as this unossified area of the bone is naturally weak and prone to fracture. Careful treatment of the injured growth plate is a high priority of treatment, and it must be kept in mind that reduction of fracture fragments through and across the growth plate must be done with great care.

Classification of Growth Plate Injuries Classification of growth plate injuries has important implications as doctors communicate about the treatment of a patient. The exact type of physeal injury is important for the prognosis and treatment of the fracture. Salter and

Harris described a very useful classification of growth plate injuries.5 8 A type I injury is a simple transverse failure of the physis without involvement of the ossified epiphysis or metaphysis. A Salter-Harris type II fracture contains a component of fracture through the growth plate in continuity with a fracture of the metaphysis. Salter-Harris type III fracture occurs partially through the epiphysis and partially through the growth plate. These fractures are essentially always intra-articular. A Salter-Harris type IV injury is one which has a fracture line extending through the physis extending from the metaphysis through into the epiphysis. Finally, a Salter-Harris type V injury is a subtle injury where the physis itself is injured but not displaced. Treatment of pediatric injuries that involve the growth plate are centered around precise and accurate reduction of the fragments and growth plate. Internal fixation of growth plate injuries is performed with great care to assist in the accurate positioning of the fragments for optimal healing. When possible, effort is made to avoid placing hardware that extends through the growth plate for fear of increasing the chance of premature growth plate closure.

Diaphyseal Injuries in a Pediatric Patient Fractures of the diaphysis of the long bones of pediatric patients are often treated closed. Interestingly, precise and accurate reduction of such fractures is, at times, less critical in pediatric patients than it is in adult patients because of the extensive remodeling that pediatric patients are capable of. An angular deformity within the plane of an adjacent joint is often completely remodeled by the accommodating growth of the child. When internal fixation of a diaphyseal fracture is performed on a child, the physis is avoided whenever possible.

Fractures of the Pediatric Hip Pediatric hip fractures carry a high potential for growth arrest and deformity. Very young patients with hip fractures are frequently treated by casting. A large cast encompassing the abdomen, lower back, pelvis, and lower limb is often a good choice. Such "spica" casts are well tolerated by very young patients, to some degree, because the period of immobilization can be relatively short in a very young patient because of their rapid healing potential. Displaced fractures of the hip in somewhat older patients are frequently managed operatively. If the displacement is mild, it may be managed with a spica cast. In some cases, a screw is inserted through a very small skin incision through the trochanteric region of the femur and traverse to fracture physis and engage the femoral head. It is necessary to do this with direct fluoroscopic image guidance. Careful attention to the screw position in these two planes is essential to make sure there is no penetration of the femoral head.

Fractures of the Intratrochanteric Region in the Pediatric Hip In very young patients, this injury may be managed with a spica cast. In older patients, internal fixation may also be used.

Fractures of the Femoral Shaft In children, femur fractures are usually low-energy injuries in contrast to adult femur fractures. Fractures of the femoral shaft in pediatric patients 6 years of age can be managed by limited internal fixation (Fig. 43-52). Flexible intramedullary nails are popular in the treatment of this injury.5 9 A patient who is approaching skeletal maturity (14 years or older) may be managed by a rigid intramedullary reamed nail, much as would be used in an adult. Extra-articular fractures of the distal femur or of the proximal tibia are generally managed in a long leg cast, unless there is excessive displacement or

angulation.

Fig. 43-52.

A spiral fracture of the shaft of the femur in a child. A and B document the displaced fracture. C and D demonstrate the x-ray appearance after closed reduction and the insertion of flexible rods. E and F demonstrate the healed bone, after hardware removal, with preservation of the growth plate.

Fractures of the Pediatric Ankle Fractures of the ankle in pediatric patients virtually always involve the growth plate. Salter-Harris I and II injuries (without physeal fractures) are generally managed by simple casting (Fig. 43-53). Intra-articular fractures (SalterHarris III or IV) are usually managed by closed reduction and internal fixation using percutaneous pins or screw fixation. In general, smooth nonthreaded pins are used, and care is taken not to traverse the physis unless absolutely necessary for stability.

Fig. 43-53.

Anteroposterior and lateral x-ray images of a Salter-Harris type II fracture of the distal tibia in a child. The displaced fracture involving the physis was reduced and immobilized in a cast.

Usually, the medial portion of the distal tibial physis fuses before the lateral. In such patients, an interesting fracture called a juvenile Tillaux fracture can occur. This Salter-Harris type II fracture involves a fracture through the lateral epiphysis and lateral physis. For these patients with the growth plate in the process of closing, open

reduction and precise internal fixation generally is recommended. Another challenging physeal injury in pediatric patients is the so-called triplane fracture . This is a complex Salter-Harris type IV fracture involving fractures to the physis, metaphysis, and epiphysis. Usually the three fractures occur in three orthogonal planes. This injury is usually managed by closed reduction with or without percutaneous pinning. This fracture often requires CT imaging to assess degree of joint line displacement.

Fractures of the Pediatric Elbow Fractures of the pediatric elbow create a special anxiety in the treating orthopedic surgeon. The elbow is a complex joint with articulation between the distal humerus and both the radius and ulna. In addition, there are separate ossification centers for the radial head: the olecranon as well as the medial and lateral epiphysis of the humerus. In very young patients, a fracture through the distal humeral epiphysis is often mistaken for a dislocation of the elbow (an injury that is extremely rare) (Fig. 43-54). A complete understanding of the ossification centers of the elbow as well as the timing of their appearance is essential to the confident diagnosis of the exact injury. Such fractures that also involve injury to the shafts of the radius or ulna are the pediatric equivalent of the Monteggia and Galeazzi fractures described previously in Fractures of the Ulnar Radius. Reduction and accurate alignment of the articular surfaces and accurate positioning of the radial head (often dislocated in these injuries) are high priorities in treatment. In general, closed reduction and percutaneous pin placement (often by necessity traversing the growth plate) is usually the most appropriate treatment option.6 0

Fig. 43-54.

A displaced supracondylar fracture in a child is shown before and after reduction and percutaneous pin fixation.

In assessment and treatment to these injuries, great attention must be placed to the neurovascular anatomy about the elbow. Associated injury to the brachial artery, to the traversing radial ulna and medial nerves are common. Assessment of the neurovascular function is essential before, during, and after treatment. Even after successful closed reduction, pinning, and immobilization, close meticulous follow-up for maintenance of reduction and of

neurovascular status of the limb is important.

DEVELOPMENTAL DISEASE IN CHILDREN Developmental Dysplasia of the Hip Developmental dysplasia of the hip (DDH) was previously called congenital dysplasia of the hip . The disorder is characterized by instability of the developing hip and may progress to frank, chronic dislocation of the hip. DDH is seen most frequently in newborns with a positive family history, who have breech positioning in utero, who are female, or who are firstborn.61–63 The disorder does not appear to have a strong genetic component. The most unfortunate situation in patients with DDH is in those who are diagnosed late. A chronically dislocated hip is a challenging problem for clinical management. Such untreated dislocations lead eventually to contracted hip musculature, a dysplastic acetabulum, and the formation of a fibrous "pulvinar," which can occupy the acetabulum and prevent reduction. As these are potential serious consequences, effort is put into early diagnosis of DDH. Newborns, generally within the first 3 days of life, are examined for hip instability. Two maneuvers are performed, one of which is Ortolani's test, which consists of gentle elevation and abduction of the femur. With the abduction maneuver, a palpable click or pop will signify the relocation of a dislocated hip. Another maneuver, Barlow's test, is performed by gentle adduction and depression of the femur (posterior pressure), which can cause a similar palpable click or pop as a hip in its normal position slips into a dislocated position. It is important that these maneuvers be performed gently and only after proper training. Infants with a dislocated or dislocatable hip will sometimes seem to have leg discrepancies of the femur when the hip is positioned in 90. It also is possible to make a tentative diagnosis based on the appearance of the skinfolds of the buttock. X-ray images can be helpful, but in the case of newborn children, the relevant portions of the acetabulum and femoral head are not yet ossified and xray diagnosis is a bit unreliable. More helpful is the use of ultrasound to image the hips. A skilled ultrasonographer can often demonstrate an impressive amount of detail in a dislocated or dislocatable hip. When the diagnosis is made promptly, treatment can, in most cases, result in an essentially normal hip joint. If the diagnosis is made later, prognosis may not be as favorable. Treatment of undiagnosed patients after they attain walking age (9 to 14 months) can be very challenging.

Treatment of Developmental Dysplasia of the Hip Treatment of a newborn who has a dislocated or dislocatable hip generally is based on achieving proper positioning of the femoral head in the acetabulum and maintaining a concentric reduction. In most cases with a dislocatable hip, the child is placed in a Pavlik harness, which maintains the hips in flexion and mild abduction. Extremes of abduction must be avoided, as maintaining hip in significant abduction can lead to avascular necrosis of the head (Fig. 43-55). With 1 to 3 months of treatment, the Pavlik harness is generally successful. In some patients, with more severe disease, selective tenotomies of some of the adductor muscles may be indicated.

Fig. 43-55.

Pavlik harness used to treat newborns with hip dysplasia. (Reproduced with permission from http://www.musckids.com/health_library/hrnewborn/ddh.htm.)

In neglected or undiagnosed DDH, when the patient reaches walking age without achieving a stable hip, open reduction is often necessary (Fig. 43-56). In such cases, an anterior approach to the hip generally is performed. Any pulvinar within the acetabulum is removed, and the femoral head is located. Often, these procedures are combined with capsular releases and adductor tenotomies. In cases with significant muscular contraction, femoral shortening (osteotomy to shortening of the femur) may be indicated. Following open reduction of osteonecrosis of the femoral head can occur. Restoration of the full pain-free motion of the hip is not always possible. In rare cases where open reduction does not produce a stable hip, some patients with severe DDH may be managed by pelvic osteotomy, where acetabular reconstruction or the creation of an acetabular shelf is performed.6 3 In some cases, a varus osteotomy of the proximal femur also may be considered.

Fig. 43-56.

X-ray images of a child with developmental dysplasia of the hip. Note that the right hip is dislocated and that the right acetabulum is shallow and malformed.

Legg-Calv-Perthes Disease Legg-Calv-Perthes disease , also known as coxa plana , is a condition of the pediatric hip characterized by a flattened, misshapen femoral head.6 4 The etiology of the problem is related to osteonecrosis of the proximal femoral epiphysis and is thought to result from vascular compromise.6 5 Legg-Calv-Perthes disease generally presents in children, usually males, between the ages of 4 and 8 years old. Presenting symptoms generally include groin or knee pain, decreased hip range of motion, and a limp. The Trendelenburg gait (tilting of the pelvis) is also commonly seen. Symptomatic treatment with traction, physical therapy, abduction exercise, crutches, and occasionally, femoral and pelvic osteotomies, are all offered as treatments. Unfortunately, a good solution for Legg-Calv-Perthes disease has been elusive thus far.

Slipped Capital Femoral Epiphysis A slipped capital femoral epiphysis (SCFE) is an acquired disorder of the epiphysis thought to be associated with weakness in the perichondrial ring of the growth plate.6 6 Children within the ages of 10 to 16 years old are noted to have the displacement of the epiphysis on the femoral neck. In most cases, there is no identifiable trauma history. It is not known whether this is acquired insidiously or acutely (Fig. 43-57). It is associated with African American heritage, obesity, and is somewhat more common in boys than in girls. Twenty-five percent of cases are bilateral. SCFE usually is diagnosed in patients who complain of pain. It is important to know that the pain caused by this pathology is usually located in the groin and proximal anterior thigh. It is also quite common for patients to complain of pain about the knee. In pediatric patients with complaints of knee pain, an effort should always be made to assess the ipsilateral hip as well.

Fig. 43-57.

Radiographic images of a young patient with a slipped capital femoral epiphysis, before (A ) and after (B ) screw fixation.

Treatment for virtually all SCFE patients is percutaneous screw fixation. The procedure is done through a small skin incision; a screw is inserted through the femoral neck to engage the epiphysis. Reduction of the slipped epiphysis is contraindicated because of an increased risk of avascular necrosis. Most practitioners find one screw to be adequate to prevent further slip.

Lower Extremity Rotational Abnormalities The pediatric patients with lower extremity rotational abnormalities present with abnormal rotation of the lower extremities often resulting in "intoeing" stance and gait. The diagnosis of femoral anteversion, tibial torsion, and metatarsus adductus are used to describe rotational abnormalities at these respective anatomic locations. It should be noted that most children do have a mild degree of intoeing as a normal developmental stage. Excessive rotation in internal rotation in the femur, most commonly seen in children age 3 to 7 years old, will usually correct by age 8. Severe degrees of rotation with functional impairment that do not correct after age 10 or 11 years old may be managed by rotational femoral osteotomy. Tibial torsion is the most common cause of an intoeing gait. This is most frequently noted in 1- and 2-year-old

children. This is often bilateral. Although occasionally intoeing can be marked, pediatric tibial torsion will completely resolve without treatment in almost every case. Metatarsus adductus is a condition of forefoot adduction, generally seen in infants. Of note, this may be associated with DDH of the hip. As with most rotational abnormalities, the overwhelming majority of these cases also resolve spontaneously.

Congenital Talipes Equinovarus Congenital talipes equinovarus, unfortunately frequently called club foot , is a common problem in pediatric orthopedic surgery (Fig. 43-58).6 7 In involved patients, this disorder, which is slightly more common in males than females, is associated with contractures of the medial tendons of the foot, often associated with a tight Achilles tendon.6 8 Contractures of the joint capsules of the ankle, hindfoot, and midfoot are also noted. Such feet are evaluated by radiographs before, during, and after treatment.6 9 In most cases, the problem can be corrected by meticulous sequential corrective casting of the foot. A successful program of casting may be complete in from 1 to 5 months and can often yield an essentially normal foot before walking age. In patients with more severe disease or in those who initiate treatment later, surgical release of contracted soft tissues may be necessary.7 0 In most cases, such surgical releases are not contemplated before 6 to 8 months of age.7 1

Fig. 43-58.

Characteristic deformities of talipes equinovarus, or club foot.

Osgood-Schlatter Disease Osgood-Schlatter disease is a very common problem most often seen in athletically active adolescents. This

disorder is characterized by ossification in the distal patellar tendon at the point of its insertion onto the tibial apophysis. This disorder is thought to result from mechanical stress on the tendinous insertional area. X-ray views of the involved knee show a characteristic irregularity in the insertional area and often show separately discrete ossicles within the tendon itself. The disease will present with severe local pain and exquisite tenderness in the area of the tibial tubercle. Effective treatment for the disease can be obtained by activity restriction, which is generally quite unwelcomed by the patient. If the symptoms are improved, athletic participation can be reasonable. In almost every case, symptoms do regress after skeletal maturity or the discontinuance of active athletic participation. In rare cases, persistive symptoms into adulthood can occur. Moderate success can be obtained by surgical excision of ossicles within the tendon of adults.

The Future of Orthopedic Surgery The treatment of musculoskeletal disease is progressing at a rapid pace. There is a very strong trend toward the use of less invasive surgical techniques, and the technology necessary for minimally invasive surgery is advancing rapidly. During the next decade, application of molecular medicine techniques to numerous musculoskeletal problems are likely. The use of molecular genetic techniques to enhance or even replace many of our present surgical treatments.

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Am 73:1263, 1991. [PMID: 1890132] 56. Enneking WF, Spanier SS, et al: A system for the surgical staging of musculoskeletal sarcoma. Clin Orthop 153:106, 1980. [PMID: 7449206] 57. Charnley J: Low Friction Arthroplasty: Theory and Practice . London: Churchill-Livingstone, 1979. 58. Salter RB, Harris WR: Injuries involving the epiphyseal plate. J Bone Joint Surg Am 45:587, 1963. 59. Bone LB, Johnson KD, Weigelt J, et al: Early vs. delayed stabilization of femoral fractures. A prospective randomized study. J Bone Joint Surg Am 71:336, 1989. [PMID: 2925704] 60. Skaggs DL, et al: Operative treatment of supracondylar fractures of the humerus in children. The consequences of pin placement. J Bone Joint Surg Am 3:735, 2001. 61. Weinstein SL, Mubarak SJ, Wenger DR: Developmental hip dysplasia and dislocation. Part I. J Bone Joint Surg Am 85:1824, 2003. 62. Weinstein SL, Mubarak SJ, Wenger DR: Developmental hip dysplasia and dislocation. Part II. J Bone Joint Surg Am 85:2024, 2003. 63. Willis RB: Developmental dysplasia of the hip: Assessment and treatment before walking age. Instr Course Lect 50:541, 2001. [PMID: 11372357] 64. Herring JS, Neustadt JB, William JJ, et al: The lateral pillar classification of Legg-Calv-Perthes disease. J Pediatr Orthop 12:143, 1992. [PMID: 1552014] 65. Catterall A: The natural history of Perthes' disease. J Bone Joint Surg Br 53:37, 1971. [PMID: 5578764] 66. Crawford AH: Current concepts review: Slipped capital femoral epiphysis. J Bone Joint Surg Am 70:1422, 1988. [PMID: 3053724] 67. Lichtblau S: A medial and lateral release operation for clubfoot: A preliminary report. J Bone Joint Surg Am 55:1377, 1973. [PMID: 4758710] 68. Cummings RJ, Davidson RS, Armstrong PF, et al: Congenital clubfoot. J Bone Joint Surg Am 84:290, 2002. [PMID: 11861737] 69. Ponseti IV: Congenital Clubfoot. Fundamentals for Treatment . Oxford: Oxford University Press, 1996. 70. Turco VJ: Surgical correction of the resistant clubfoot: One-stage posteromedial release with internal fixation: A preliminary report. J Bone Joint Surg Am 53:477, 1971. [PMID: 5580007] 71. Cummings, RJ, Davidson RS, Armstrong PF, et al: Congenital clubfoot. Instr Course Lect 51:385, 2002.

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KEY POINTS 1. Surgery of the hand is a regional specialty, integrating components of neurologic, orthopedic, plastic, and vascular surgery. 2. Understanding hand anatomy is the key to proper diagnosis of injury, infection, and degenerative disease of the hand. 3. After evaluation and/or treatment, patients should be splinted to protect the injured digits and keep the collateral ligaments of the injured joints on tension (metacarpophalangeal joints flexed, interphalangeal joints extended). 4. Clinical examination, particularly noting the area of greatest tenderness and/or inflammation, is the most useful diagnostic tool for hand infections. 5. If a patient managed conservatively for "cellulitis" does not improve within 24 to 48 hours of appropriate IV antibiotics, abscess must be suspected. 6. Vascular injuries producing warm ischemia (incomplete amputations or direct vessel trauma with compromised distal perfusion) must be addressed urgently to prevent irreversible tissue loss. 7. Healing of an injured or diseased structure in the hand is not the endpoint of treatment; the goal of any intervention must be to obtain structural healing, relief of pain, and maximization of function.

TREATMENT PRINCIPLES The highly mobile, functional, and strong hand is a major distinguishing point between human beings and the nonhuman primates. The hand is an essential participant for activities of daily living, vocation, and recreational activities. The hand is even adaptable enough to read for the blind and speak for the mute. The underlying goal of all aspects of hand surgery is to maximize mobility, sensibility, stability, and strength while minimizing pain. These goals are then maximized to the extent possible given the patient's particular pathology.

Bones The hand is highly mobile in space to allow maximum flexibility in function. As such, a number of directions particular to the hand are necessary to properly describe position, motion, etc.1 Palmar (or volar) refers to the anterior surface of the hand in the anatomic position; dorsal refers to the posterior surface in the anatomic position. The hand can rotate at the wrist level; rotation to bring the palm down is called pronation , to bring the palm up is called supination . Because the hand can rotate in space, the terms medial and lateral are avoided.

Radial and ulnar are used instead as these terms do not vary with respect to the rotational position of the hand. Abduction and adduction, when used on the hand, refer to movement of the digits away from and toward the middle finger, respectively (Fig. 44-1).

Fig. 44-1.

Terminology of common hand motions. [Reproduced with permission from American Society for Surgery of the Hand (ed): The Hand: Examination and Diagnosis , 3rd ed. Copyright Elsevier, 1990.]

The hand is comprised of 19 bones arranged in five rays.2 A ray is defined as a digit (finger or thumb) from the metacarpal (MC) base to the tip of the digit (Fig. 44-2A). The rays are numbered 1 through 5, beginning with the thumb. By convention, however, they are referred to by name: thumb, index, middle, ring, and small. There are five metacarpals, comprising the visible palm of the hand. Each digit has a proximal and a distal phalanx, but only the fingers have a middle phalanx as well. The metacarpophalangeal (MP) joint typically allows 90 of flexion with a small amount of hyperextension. In addition, the fingers can actively abduct (move away from the middle finger) and adduct (move toward the middle finger). The thumb, in contrast, moves principally in the flexion-extension arc at the MP joint. Although there can be laxity in the radial and ulnar direction, the thumb cannot actively move in

these directions at the MP level. The proximal interphalangeal (PIP) joint is the critical joint for finger mobility. Normal motion is 0 to 95 (full extension to flexion). The distal interphalangeal (DIP) joint also moves only in a flexion-extension plane from 0 to 90 on average. The thumb interphalangeal (IP) joint also moves only in a flexionextension plane. Its normal motion is highly variable between individuals, but averages 0 to 80.

Fig. 44-2.

Bony architecture of the hand and wrist. A. Bones of the hand and digits. All rays have metacarpophalangeal (MP) joints. The fingers have proximal and distal interphalangeal (PIP and DIP) joints, but the thumb has a single IP joint. B. Bones of the wrist: the proximal row consists of the scaphoid, lunate, and capitate. The distal row bones articulate with the metacarpals: the trapezium with the thumb, the trapezoid with the index, the capitate with the middle, and the hamate with the ring and small. The pisiform bone is a sesamoid within the flexor carpi ulnaris tendon. It overlaps the triquetrum and hamate but does not contribute to a carpal row. CMC = carpometacarpal; TFCC = triangular fibrocartilage complex.

Each of the MP and IP joints has a radial and ulnar collateral ligament to support it. The IP joint collateral ligaments are on tension with the joint fully extended. For the fingers, the MP joint collateral ligaments are on tension with the joint bent 90. Collateral ligaments have a tendency to contract when not placed on tension; this becomes relevant when splinting the hand (see Trauma section on splinting below). The wrist consists of eight carpal bones divided into two rows (see Fig. 44-2B).2 The proximal row consists of the scaphoid, lunate, and triquetrum. The lunate is the principal axis of motion of the hand onto the forearm. It bears approximately 35% of the load of the wrist onto the forearm. The scaphoid is an oddly shaped bone, which bears 55% of the load of the hand onto the forearm, but also serves as the principal link between the proximal and distal rows, allowing for motion while maintaining stability. Both the scaphoid and the lunate articulate with the radius. The triquetrum resides ulnar to the lunate. It does not interact with the ulna proximally; rather it interacts with a cartilage suspended between the ulnar styloid and the distal radius called the triangular fibrocartilage complex (see Fig. 44-2B). The remaining 10% of load of the hand onto the forearm is transmitted through the triangular fibrocartilage complex.3 The distal row consists of four bones. The trapezium resides between the scaphoid and the thumb MC. Distally, it has a saddle-shaped surface, which interacts with a reciprocally saddle-shaped base of the thumb MC to allow for

high mobility of the thumb carpometacarpal (CMC) joint in radial-ulnar and palmar-dorsal directions and opposition (see Fig. 44-1B). The trapezoid rests between the scaphoid and the index finger MC. The capitate, the largest carpal bone and first to ossify in a child, lies between the lunate and the middle finger MC but also interacts with the scaphoid on its proximal radial surface. The index and middle finger CMC joints are highly stable and have minimal mobility. The hamate is the ulnar-most bone in the distal row, sitting between the triquetrum proximally and the ring and small finger metacarpals distally. The ring and small finger CMC joints are mobile, but principally in the flexion-extension direction. The pisiform is a carpal bone only by geography. It is a sesamoid bone within the flexor carpi ulnaris (FCU) tendon (see below under Muscles Affecting the Hand and Wrist). It does not bear load, and can be excised, when necessary, without consequence.

Muscles Affecting the Hand and Wrist The wrist is moved by multiple tendons that originate from the forearm and elbow. The digits of the hand are moved by both intrinsic (originating within the hand) and extrinsic (originating proximal to the hand) muscles. All of these muscles are innervated by the median, radial, or ulnar nerves (or their branches) (Fig. 44-3).

Fig. 44-3.

Cross-section of the wrist at the midcarpal level. The relative geography of the neurologic and tendinous structures can be seen. The transverse carpal ligament (TCL) is the roof of the carpal tunnel, passing volar to the median nerve and long flexor tendons. The TCL is also the floor of the ulnar tunnel, or Guyon's canal, passing dorsal to the ulnar artery and nerve. The wrist and digital extensor tendons are also seen, distal to their compartments on the distal radius and ulna. Bones: C = capitate; H = hamate; P = pisiform; S = scaphoid. Tendons (flexor digitorum superficialis is volar to flexor digitorum

profundus within the carpal tunnel): 2 = index finger; 3 = middle finger; 4 = ring finger; 5 = small finger. A = artery; APL = abductor pollicis longus; ECRB = extensor carpi radialis brevis; ECRL = extensor carpi radialis longus; ECU = extensor carpi ulnaris; EDC = extensor digitorum communis; EDQ = extensor digiti quinti; EIP = extensor indices proprius; EPB = extensor pollicis brevis; EPL = extensor pollicis longus; FCR = flexor carpi radialis; FPL = flexor pollicis longus; N = nerve.

Three muscles flex the wrist, all of which originate from the medial epicondyle of the humerus. The flexor carpi radialis (FCR, median nerve) inserts on the base of the volar index finger MC. The FCU (ulnar nerve) also originates from the proximal ulna and inserts on the volar base of the small finger MC. The palmaris longus tendon does not insert on a bone; it inserts on the palmar fascia, located deep to the skin in the central proximal palm, and is absent in up to 15% of patients. The FCR tends also to deviate the wrist radially, the FCU ulnarly. All three wrist extensors are innervated by the radial nerve or its branches. The extensor carpi radialis longus (ECRL) originates from the distal shaft of the humerus and inserts on the dorsal base of the index finger MC. The extensor carpi radialis brevis (ECRB) originates from the lateral epicondyle of the humerus and inserts on the dorsal base of the middle finger MC. The extensor carpi ulnaris (ECU) originates from the lateral epicondyle of the humerus and inserts on the dorsal base of the small finger MC. The ECRL tends to deviate the wrist radially; the ECU ulnarly. The long flexors of the fingers all originate from the medial epicondyle of the humerus. The flexor digitorum superficialis (FDS) inserts on the base of the middle phalanx of each finger and primarily flexes the PIP joint. The flexor digitorum profundus (FDP) inserts on the base of the distal phalanx and primarily flexes the DIP joint. The flexor pollicis longus (FPL) originates more distally, from the ulna, radius, and interosseous membrane between them in the forearm. It inserts on the base of the distal phalanx of the thumb and primarily flexes the IP joint. All of these tendons can also flex the more proximal joint(s) in their respective rays. All of these muscles are innervated by the median nerve (or its branches) except the FDP to the ring and small finger, which are innervated by the ulnar nerve. The extrinsic extensors of the fingers and thumb are all innervated by the PIN (branch of the radial nerve). The extensor digitorum communis (EDC) originates from the lateral epicondyle of the humerus and extends the MP joints of the fingers. It is somewhat unusual in its insertion in that it does not insert on the dorsal base of the proximal phalanx, but rather into a soft tissue sling called the sagittal hood that surrounds the proximal phalanx base and pulls up on the volar surface in a hammock-like manner. More distally in the dorsal forearm, the extensor indices proprius (EIP) and extensor digiti quinti (EDQ) originate from the ulna, radius, and posterior interosseous membrane and insert on the sagittal hood of the index and small fingers, respectively. The thumb has three separate extrinsic extensors. All of these originate from the dorsal ulna in the mid-forearm and are innervated by the PIN. The abductor pollicis longus (APL) inserts on the radial base of the thumb MC to produce some extension, but mostly abduction. The extensor pollicis brevis (EPB) inserts on the base of the thumb proximal phalanx. The extensor pollicis longus (EPL) inserts on the base of the thumb distal phalanx. The intrinsic muscles of the hand are what allow human beings fine, subtle movements of the hand. Microsurgery, typing, and even video gaming would be difficult, if not impossible, without them. The thenar muscles originate from the volar radial surface of the scaphoid and trapezium and the flexor retinaculum. The abductor pollicis brevis inserts on the radial base of the thumb proximal phalanx and abducts the thumb in a radial and volar direction. The opponens pollicis (OP) inserts on the radial distal aspect of the thumb MC and draws the thumb across the palm toward the small finger. The flexor pollicis brevis (FPB) inserts on the base of

the thumb proximal phalanx and flexes the thumb MP joint. The abductor pollicis brevis, OP, and superficial head of the FPB are all innervated by the thenar motor branch of the median nerve. The lumbrical muscles are unique in the body in that they originate from a tendon. Each finger's lumbrical originates from the FDP tendon in the palm. The lumbrical tendon passes along the radial aspect of the digit to flex the MP and extend the IP joints. The index and middle lumbricals are median nerve innervated, and the ring and small finger lumbricals are ulnar nerve innervated. The hypothenar muscles originate from the pisiform, hamate, and flexor retinaculum and insert on the ulnar base of the small finger proximal phalanx. The abductor digiti quinti abducts the small finger. The opponens digiti quinti brings the small finger across the palm in reciprocal motion to the OP. The flexor digiti quinti flexes the small finger MC. All these muscles are innervated by the ulnar nerve. The interosseous muscles occupy the space between the MC bones. Their tendons insert on the bases of the proximal phalanges. All act to flex the MP joints and extend the IP joints. The three palmar interosseous muscles adduct the fingers. The four dorsal interosseous muscles abduct the fingers. The adductor pollicis originates from the middle finger MC and inserts on the ulnar base of the thumb proximal phalanx. It acts to adduct the thumb. All of these muscles, as well as the deep head of the FPB, are innervated by the ulnar nerve.

Tendons and Pulleys Multiple pulleys pass over or surround the extrinsic tendons en route to or within the hand. Their purpose is to prevent bow stringing of the tendon, which would decrease the efficiency of its force transmission. The most well known of the wrist level pulleys is the flexor retinaculum, also known as the transverse carpal ligament . It attaches to the scaphoid tubercle and trapezium radially, and the hook of the hamate bone and pisiform ulnarly. Deep to this ligament, between the scaphoid (radially) and the hamate (ulnarly), pass the FDS, FDP, and FPL tendons as well as the median nerve. This area is also known as the carpal tunnel (see Fig. 44-3). On the dorsum of the wrist, the extensor retinaculum is divided into six compartments. Beginning on the radial aspect of the radius, the first compartment contains the APL and EPB tendons. The second holds the ECRL and ECRB tendons. The EPL passes through the third compartment. The fourth compartment contains the EIP and EDC tendons; the fifth, the EDQ, and the sixth, the ECU. The sixth compartment is located on the ulnar aspect of the distal ulna. Although the compartments end at the radiocarpal/ulnocarpal joints, the relative geography of the tendons is preserved over the carpal bones (see Fig. 44-3). In the hand, the pulleys maintain the long flexor tendons in close apposition to the fingers and thumb. There are no extensor pulleys within the hand. Each finger has five annular and three cruciate pulleys (Fig. 44-4). The second and fourth (A2 and A4) pulleys are the critical structures that prevent bowstringing of the finger. 4 The remaining pulleys can be divided as needed for surgical exposure or to relieve a stricture area.

Fig. 44-4.

Drawing of anteroposterior and lateral view of the pulley system.

Vascular Two major arteries serve the hand. The radial artery travels under the brachioradialis muscle in the forearm. At the junction of the middle and distal thirds of the forearm, the artery becomes superficial and palpable, passing just radial to the FCR tendon. At the wrist level, the artery splits into two branches. The smaller, superficial branch passes volarly into the palm to contribute to the superficial palmar arch. The larger branch passes dorsally over the scaphoid bone, under the EPL and EPB tendons (known as the anatomic snuffbox ), and back volarly between the proximal thumb and index finger metacarpals to form the superficial palmar arch. The ulnar artery travels deep to the FCU muscle in the forearm. When the FCU becomes tendinous, the ulnar artery

resides deep and slightly radial to it. At the wrist, the artery travels between the hamate and pisiform bones superficial to the transverse carpal ligament (known as Guyon's canal ) into the palm. The larger, superficial branch forms the superficial palmar arch. The deeper branch contributes to the deep palmar arch (Fig. 44-5A). In 97% of patients, at least one of the deep or superficial palmar arches is intact, allowing for the entire hand to survive on the radial or ulnar artery.5

Fig. 44-5.

Arteries of the hand and finger. A. Relative position of the superficial and deep palmar arches to the bony structures and each other; note the radial artery passes dorsal to the thumb metacarpal base, through the first web space, and anterior to the index metacarpal base as it forms the deep arch. B. The neurovascular bundles lay volar to the midaxis of the digit with the artery dorsal to the nerve; Grayson's ligament (volar) and Cleland's ligament (dorsal) connect the bone to the skin surrounding the bundle.

Each digit receives a radial and ulnar digital artery. For the thumb, the radial digital artery may come from the deep palmar arch or the main body of the radial artery. The larger ulnar digital artery comes off the deep arch as either a single unit, the princeps pollicis artery, or less frequently, as the first common digital artery, which then splits into the radial digital artery to the index finger and the ulnar digital artery to the thumb. The second, third, and fourth digital arteries typically branch off the superficial palmar arch and pass between the index/middle, middle/ring, and ring/small fingers respectively, ultimately dividing into two proper digital arteries each. The ulnar digital artery of the small finger comes off as a separate branch from the superficial arch. Within the finger, the proper digital arteries travel lateral to the bones and tendons, just palmar to the midaxis of the digit, but dorsal to the proper digital nerves (see Fig. 44-5B).

Nerve Three principal nerves serve the forearm, wrist, and hand: the median, radial, and ulnar nerves. The most critical of these from a sensory standpoint is the median nerve. The median nerve begins as a terminal branch of the medial and lateral cords of the brachial plexus. It receives fibers from C5–T1. The palmar cutaneous branch of the median nerve serves the proximal, radial-sided palm. The main body of the median nerve splits into several branches after the carpal tunnel: a radial digital branch to the thumb, an ulnar digital nerve to the thumb, and a

radial digital nerve to the index finger (sometimes beginning as a single first common digital nerve); the second common digital nerve that branches into the ulnar digital nerve to the index finger and the radial digital nerve to the middle finger; and a third common digital nerve that branches into the ulnar digital nerve to the middle finger and a radial digital nerve to the ring finger. The digital nerves provide volar-sided sensation from the MC head level to the tip of the digit. They also, through their dorsal branches, provide dorsal-sided sensation to the digits from the midportion of the middle phalanx distally via dorsal branches. The thenar motor branch of the median nerve most commonly passes through the carpal tunnel and then travels in a recurrent fashion back to the thenar muscles. Less commonly, the nerve passes through or proximal to the transverse carpal ligament en route to its muscles. In the forearm, the median nerve gives motor branches to all of the flexor muscles except the FCU, and the ring and small finger portions of the FDP. Distal median motor fibers (with the exception of those to the thenar muscles) are carried through a large branch called the anterior interosseous nerve . The ulnar nerve is a terminal branch of the medial cord of the brachial plexus. It receives innervation from C8 and T1 roots. The FCU and FDP (ring/small) receive motor fibers from the ulnar nerve. In the distal forearm, 5 cm above the head of the ulna, the nerve gives off a dorsal sensory branch. Once in the hand, the nerve splits into the motor branch and sensory branches. The motor branch curves radially at the hook of the hamate bone to innervate the intrinsic muscles as described above in Muscles Affecting the Hand and Wrist. The sensory branches become the ulnar digital nerve to the small finger and the fourth common digital nerve which splits into the ulnar digital nerve to the ring finger and the radial digital nerve to the small finger. The sensory nerves provide distal dorsal sensation similar to the median nerve branches. The radial nerve is the larger of two terminal branches of the posterior cord of the brachial plexus. It receives fibers from C5–T1 nerve roots. It innervates all of the extensor muscles of the forearm and wrist, principally through its PIN branch. The major exception to this is the ECRL, which is innervated by the main body of the radial nerve in the distal upper arm. Unlike on the flexor surface, there is no ulnar nerve contribution to extension of the wrist, thumb, or finger MP joints. As noted above in Muscles Affecting the Hand and Wrist, the ulnar innervated intrinsic hand muscles are the principal extensors of the finger interphalangeal joints, although the long finger extensors (EDC, EIP, EDQ) make a secondary contribution to this function. In the proximal dorsal forearm, the superficial radial nerve (SRN) is the other terminal branch of the radial nerve. It travels deep to the brachioradialis muscle until 6 cm proximal to the radial styloid, where it becomes superficial. The SRN provides sensation to the dorsal hand and the radial three and one half digits up to the level of the midmiddle phalanx (where the dorsal branches of the proper digital nerves take over, as described earlier in this section). The dorsal branch of the ulnar nerve provides sensation to the ulnar one and one half digits and dorsal hand in complement to the SRN.

HAND EXAMINATION Emergency Room/Inpatient Consultation A common scenario in which the hand surgeon will be introduced to the patient is in trauma or other acute situations. The patient is evaluated by inspection, palpation, and provocative testing. Upon inspection, one should first note the position of the hand. The resting hand has a normal cascade of the fingers, with the small finger flexed most and the index finger least (Fig. 44-6). Disturbance of this suggests a tendon or skeletal problem. Also note any gross deformities or wounds, and what deeper structures, if any, are visible in such wounds. Observe for

abnormal coloration of a portion or all of the hand (this can be skewed by ambient temperature or other injuries), gross edema, and/or clubbing of the fingertips.

Fig. 44-6.

In the normal resting hand, the fingers assume a slightly flexed posture from the index finger (least) to the small finger (most).

Palpation typically begins with the radial and ulnar artery pulses at the wrist level. Pencil Doppler examination can supplement this and evaluate distal vessels. A pulsatile signal is normally detectable by pencil Doppler in the pad of the finger at the center of the whorl of creases. Discrepancies between digits should be noted. If all other tests are inconclusive, pricking the involved digit with a 25-gauge needle should produce bright red capillary bleeding. If an attached digit demonstrates inadequate or absent blood flow (warm ischemia), the urgency of completing the evaluation and initiating treatment markedly increases. Sensation must be evaluated before any administration of local anesthetic. At a minimum, light and sharp touch sensation should be documented for the radial and ulnar aspects of the tip of each digit. Beware of writing "sensation intact" at the conclusion of this evaluation. Medicolegally, intact means perfect and can be a liability if the sensation is measured more thoroughly after an intervention and noted not to be perfect. Rather, one should document what was tested (e.g., "light and sharp touch sensation present and symmetric to the tips of all digits of the injured hand"). In the setting of a sharp injury, sensory deficit implies a lacerated structure until proven otherwise. Once sensation has been evaluated and documented, the injured hand can be anesthetized for patient comfort during the remainder of the examination (see below under Local Anesthesia). Ability to flex and extend the wrist and digital joints is typically examined next. At the wrist level, the FCR and FCU tendons should be palpable during flexion. The wrist extensors are not as readily palpated due to the extensor retinaculum. Ability to flex the DIP joint (FDP) is tested by blocking the finger at the middle phalanx level. To test the FDS to each finger, hold the remaining three fingers in slight hyperextension and ask the patient to flex the involved digit (Fig. 44-7). This maneuver makes use of the fact that the FDP tendons share a common muscle

belly. Placing the remaining fingers in extension prevents the FDP from firing, and allows on the FDS, which has a separate muscle belly for each tendon, to fire. Strength in grip, finger abduction, and thumb opposition is tested and compared to the uninjured side. Range of motion (ROM) for the wrist, MP, and IP joints should be noted and compared to the opposite side.

Fig. 44-7.

The examiner holds the untested fingers in full extension, preventing contracture of the flexor digitorum profundus. In this position, the patient is asked to flex the finger, and only the flexor digitorum superficialis will be able to fire.

If there is suspicion for closed space infection, the hand should be evaluated for erythema, swelling, fluctuance, and localized tenderness. The dorsum of the hand does not have fascial septae, thus dorsal infections can spread more widely than palmar ones. The epitrochlear and axillary nodes should be palpated for enlargement and tenderness. Findings for specific infectious processes will be discussed in the Infections section. Additional examination maneuvers and findings, such as those for office consultations, will be discussed with each individual disease process covered later in this chapter.

HAND IMAGING

Plain X-Rays Almost every hand evaluation should include plain x-rays of the injured/affected part. A standard, anteroposterior, lateral, and oblique view of the hand or wrist (as appropriate) is rapid, inexpensive, and usually provides sufficient information about the bony structures to achieve a diagnosis in conjunction with the symptoms and findings.6 Lucencies within the bone should be noted. Most commonly, these represent fractures, but they can, on occasion, represent neoplastic or degenerative processes. Great care should be taken to evaluate the entire x-ray, typically beginning away from the area of the patient's complaint. Additional injuries can be missed that might affect the treatment plan selected and eventual outcome. Congruency of adjacent joints also should be noted. The MP and IP joints of the fingers should all be in the same plain on any given view. Incongruency of the joint(s) of one finger implies fracture with rotation. At the wrist level, the proximal and distal edge of the proximal row and proximal edge of the distal row should be smooth arcs,7 known as Gilula's arcs (Fig. 44-8A). Disruption of these implies ligamentous injury or possibly dislocation (see Fig. 44-8B).

Fig. 44-8.

Gilula's arcs are seen shown in this normal patient (A ) and in a patient with a scaphoid fracture and perilunate dislocation (B ).

Computed Tomography CT scanning of the hand and wrist can provide additional bony information when plain x-rays are insufficient. Comminuted fractures of the distal radius can be better visualized for number and orientation of fragments. Scaphoid fractures can be evaluated for displacement and comminution preoperatively as well as for the presence of bony bridging postoperatively (Fig. 44-9). CT scans are also useful for CMC fractures of the hand where overlap on a plain x-ray lateral view may make diagnosis difficult.

Fig. 44-9.

A. Preoperative images demonstrate a nonunion of a scaphoid fracture sustained 4 years earlier. B. Postoperatively, crosssectional imaging with a computed tomography scan in the coronal plan demonstrates bone crossing the previous fracture line. This can be difficult to discern on plain x-rays due to overlap of bone fragments.

Unlike the trunk and more proximal extremities, CT scans with contrast are less useful to demonstrate abscess cavities.

Ultrasonography Ultrasonography has the advantages of being able to demonstrate soft tissue structures and being available on nights and weekends. Unfortunately, it is also highly operator dependent. In the middle of the night, when magnetic resonance imaging (MRI) is not available, ultrasound may be able to demonstrate a large deep infection in the hand but is rarely more useful than a thorough clinical examination.

Magnetic Resonance Imaging MRI provides the best noninvasive visualization of the soft tissue structures. With contrast, MRI can demonstrate an occult abscess. Unfortunately, it usually is not available on nights and weekends when this information is often needed. MRI also can demonstrate soft tissue injuries such as cartilage or ligament tears or tendonitis (usually by

demonstrating edema in the area in question). It can demonstrate occult fractures that are not sufficiently displaced to be seen on x-ray or CT (again, by demonstrating edema). MRI also can demonstrate vascular disturbance of a bone, as with the patient with avascular necrosis of the scaphoid shown in Fig. 44-10.

Fig. 44-10.

T1-weighted magnetic resonance imaging (seen here) shows perfused bone as white . In this patient, there is the absence of whiteness where the scaphoid should be (dashed circle ), consistent with avascular necrosis.

Angiography Angiography of the upper extremity is rarely used. Magnetic resonance angiography and computed tomography angiography in many centers provide sufficient resolution of the vascular structures to make it necessary. Also, primary vascular disease of the upper extremity is relatively uncommon. In the trauma setting, vascular disturbance usually mandates exploration and direct visualization of the structures in question, and angiography is thus obviated. For a patient with vascular disease of the upper extremity, angiography of the upper extremity is usually performed through a femoral access much like with the leg. An arterial catheter can be used to deliver thrombolytic drugs to treat an occlusive process.

TRAUMA The upper extremity–injured patient may have additional injuries to other parts of the body. All injured patients should receive an appropriate trauma survey to look for additional injuries. Although the hand provides critical function to the patient, treatment of life or more proximal limb-threatening injuries takes precedence.

The patient with upper extremity trauma is evaluated as described in the Hand Examination section. Perform an appropriate sensory examination early. Once sensory status has been documented, administration of local anesthesia can provide comfort to the patient during the remainder of the evaluation and subsequent treatment. Patients should receive tetanus toxoid for penetrating injuries if more than 5 years have passed since the last vaccination.

Local Anesthesia Anesthetic blockade can be administered at the wrist level, digital level, or with local infiltration, as needed. Keep in mind that all local anesthetics are less effective in areas of inflammation. The agents most commonly used are lidocaine and bupivacaine. Lidocaine has the advantage of rapid onset while bupivacaine has the advantage of long duration (average 6 to 8 hours).8 Although bupivacaine can produce irreversible heart block in high doses, this is rarely an issue given the amounts typically used in the hand. For pediatric patients, the tolerated dose is 2.5 mg/kg. This can be easily remembered by noting that when using 0.25% bupivacaine, 1mL/kg is acceptable dosing. A commonly held axiom is that epinephrine is unacceptable to be used in the hand. Several recent large series have dispelled this myth.9 Epinephrine should not be used in the fingertip, and not in concentrations higher than 1:100,000 (i.e., what is present in commercially available local anesthetic with epinephrine). Beyond that, its use is acceptable and may be useful in an emergency room (ER) where tourniquet control may not be available. Also, as most ER procedures are done under pure local anesthesia, many patients will not tolerate the discomfort of the tourniquet beyond 30 minutes.1 0 Not only will epinephrine provide hemostasis, it also prolongs the effect of the local anesthetic. Simple lacerations, particularly on the dorsum of the hand, can be anesthetized with local infiltration. This is performed in the standard fashion. Blocking of the digital nerves at the MC head level is useful for volar injuries distal to this point and for dorsal injuries beyond the midpoint of the middle phalanx (via dorsal branches of the proper digital nerves). Fingertip injuries are particularly well anesthetized by this technique. There are two principal ways to anesthetize a digit (Fig. 44-11A and 44-11B). The flexor sheath technique introduces the needle in the slightly more sensitive volar skin at the MC head level; the intermetacarpal technique introduces the needle in the slightly less sensitive web space skin, but requires two injections for a single digit.

Fig. 44-11.

Local anesthesia can be administered at the digital or the wrist level. A. A single injection into the flexor tendon sheath at the

metacarpal head level provides complete anesthesia for the digit. B. Alternatively, one can inject from a dorsal approach into the web space on either side. C. The superficial radial nerve is blocked by infiltrating subcutaneously over the distal radius from the radial artery pulse to the distal radioulnar joint. The dorsal sensory branch of the ulnar nerve is blocked in similar fashion over the distal ulna. D. To block the ulnar nerve, insert the needle parallel to the plane of the palm and deep to the flexor carpi ulnaris tendon; aspirate to confirm the needle is not in the adjacent ulnar artery. E. To block the median nerve, insert the needle just ulnar to the palmaris longus tendon into the carpal tunnel. One should feel two points of resistance: one when piercing the skin, the second when piercing the antebrachial fascia.

Blocking one or more nerves as they cross the wrist can provide several advantages: anesthesia for multiple injured digits, avoiding areas of inflammation where the local anesthetic agent may be less effective, and avoiding injection where the volume of fluid injected may make treatment harder (such as fracture reduction). Four major nerves cross the wrist: the median nerve, SRN, ulnar nerve, and dorsal sensory branch of the ulnar nerve (see Fig. 44-11C, 44-11D, and 44-11E). When blocking the median and ulnar nerves, beware of intraneural injection, which can cause irreversible neural scarring. If the patient complains of severe paresthesias with injection, or high resistance is encountered, the needle should be repositioned.

Fractures and Dislocations For dislocations and displaced fractures, a visible deformity is often present. Nondisplaced fractures may not show a gross deformity, but will have edema and tenderness to palpation at the fracture site. The fracture should be described for its displacement, rotation, and angulation. The fracture should also be described in terms of comminution, the number and complexity of fracture fragments. Displacement is described as a percentage of the diameter of the bone; rotation is described in degrees of supination or pronation with respect to the rest of the hand; angulation is described in degrees. To avoid confusion, it is useful to describe in which direction the angle of the fracture points. All injuries should be evaluated for nearby wounds (open) that may introduce bacteria into the fracture site or joint space (Fig. 44-12).

Fig. 44-12.

Schematic representation of types of fractures by presence/absence of nearby wound, location within the bone, complexity, and orientation. [Reproduced with permission from American Society for Surgery of the Hand (ed): The Hand: Examination and Diagnosis , 3rd ed. Copyright Elsevier 1990.]

Once the initial force on the fracture ceases, the tendons passing beyond the fracture site provide the principal deforming force. Their force is directed proximally and, to a lesser extent, volarly. Based on this, the stability of a fracture can be determined by the orientation of the fracture with respect to the shaft of the bone. Transverse fractures are typically stable. Oblique fractures typically shorten. Spiral fractures typically rotate as they shorten and thus require surgical treatment. Fractures of the tuft of the distal phalanx are commonly seen. Slamming of a finger in a door is a common causative mechanism. These fractures are often nondisplaced and do not require treatment beyond protection of the distal phalanx from additional trauma while the fracture heals.

Displaced transverse fractures of the phalanges can usually be reduced with distraction. The distal part is pulled away from the main body of the hand, then pushed in the direction of the proximal shaft of the finger, then distraction is released. Postreduction x-rays should always be performed to document satisfactory reduction. Oblique and spiral fractures usually are unstable after reduction. The involved digit(s) should be splinted until appropriate surgical intervention can be performed. Articular fractures of the interphalangeal and MPs are worrisome because they may compromise motion. Chip fractures must be evaluated for instability of the collateral ligaments. If the joint is stable, the patient should initially be splinted for comfort. Motion therapy should be instituted early (ideally within the first week) to prevent stiffness. For larger fractures, the patient should be splinted until surgical treatment can be performed. In surgery, the fracture is typically internally fixated to allow for early motion, again with the goal of preventing stiffness.1 1 Dislocations of the PIPs produce traction on the neurovascular structures but usually do not lacerate them. In general, the patient should not be sent home with a joint that remains dislocated. Most commonly, the distal part is dorsal to the proximal shaft and sits in a hyperextended position. For this patient, the examiner gently applies pressure to the base of the distal part until it passes beyond the head of the proximal phalanx. Once there, the relocated PIP joint is gently flexed, confirming the joint is, in fact, reduced. The joint is splinted in slight flexion to prevent redislocation. On occasion, the head of the proximal phalanx may pass between the two slips of the FDS tendon. For these patients, the joint cannot be reduced in a closed fashion. Angulated fractures of the small finger MC ("boxer's fracture") are another common injury seen in the ER. Typical history is that the patient struck another individual or rigid object with a hook punch. These often are stable after reduction using the Jahss maneuver (Fig. 44-13).

Fig. 44-13.

The Jahss maneuver. The surgeon fully flexes the patient's small finger into the palm and secures it in his distal hand. The proximal hand controls the wrist and places the thumb on the patients fracture apex (the most prominent dorsal point). The examiner distracts the fracture, pushes dorsally with the distal hand (up arrow ) and resists dorsal motion with the proximal hand (down arrow ).

Fractures of the base of the thumb MC base often are unstable. The Bennett fracture displaces the volar-ulnar base of the bone. The remainder of the articular surface and the shaft typically dislocate dorsoradially and shorten. The thumb often appears grossly shortened, and the proximal shaft of the MC may reside at the level of the trapezium or even the scaphoid on x-ray. In a Rolando fracture, a second fracture line occurs between the remaining articular surface and the shaft. These fractures nearly always require open reduction and internal fixation. In general terms, most nondisplaced fractures do not require surgical treatment. The scaphoid bone of the wrist is a notable exception to this rule. Due to peculiarities in its vascular supply, particularly vulnerable at its proximal end, nondisplaced scaphoid fractures can fail to unite in up to 20% of patients, even with appropriate immobilization. Recent developments in hardware and surgical technique have allowed stabilization of the fracture with minimal surgical exposure. One prospective randomized series of scaphoid waist fractures demonstrated shortening of time to union by up to 6 weeks in the surgically treated group, but no difference in rate of union.1 2 Surgical treatment for nondisplaced scaphoid fractures is not indicated for all patients, but may be useful in the younger, more active patient who would benefit from an earlier return to full activity. Ligament injuries of the wrist can be difficult to recognize. Patients often present late and may not be able to localize their pain. In severe cases, the ligaments of the wrist can rupture to the point of dislocation of the capitate

off the lunate, or even the lunate off the radius. Mayfield and colleagues classified the progression of this injury into four groups.1 3 In the most severe group, the lunate dislocates off the radius into the carpal tunnel. In some circumstances, the scaphoid bone may break rather than the scapholunate ligament rupturing. Attention to the congruency or disruption of Gilula's arcs will help the examiner to recognize this injury. For patients with the type 4 (most severe) and some with the type 3 injury, the examiner should also evaluate for sensory disturbance in the median nerve distribution, as this may indicate acute carpal tunnel syndrome (CTS) and necessitate more urgent intervention. After reduction of fractures and dislocations (as well as after surgical repair of these and many other injuries), the hand must be splinted in a protected position. For the fingers, MP joints should be splinted 90, the IPs at 0 (called the intrinsic plus position ). The wrist is generally splinted at 20 extension, as this puts the hand in a more functional position. This keeps the collateral ligaments on tension and helps prevent secondary contracture. In general, one of three splints should be used for the ER patient (Fig. 44-14). The ulnar gutter splint uses plaster around the ulnar border of the hand. It is generally appropriate for small finger injuries only. Dorsal plaster splints can be used for injuries of any of the fingers. Plaster is more readily contoured to the dorsal surface of the hand than the volar surface, particularly in the setting of trauma-associated edema. For thumb injuries, the thumb spica splint is used to keep the thumb radially and palmarly abducted from the hand. For injuries involving the thumb MP joint or distal, the IP joint should be included in the splint. For more proximal injuries, it need not be included.

Fig. 44-14.

Common splints used for hand injuries/surgeries. A. Ulnar gutter splint. The ring and small fingers are included. The surgeon pushes on the dorsum of the fingers with the distal hand to produce interphalangeal (IP) joint extension and metacarpophalangeal joint flexion to 90 while the proximal hand controls wrist position. B. Dorsal four-finger splint. As with the ulnar gutter splint, finger metacarpophalangeal joints are flexed to 90 with IP joints kept fully extended. C. Thumb spica splint. One easy method to fabricate is to place one slab of plaster radially over the wrist and thumb with a second square of

plaster over the thenar eminence that joins the first. In this patient the IP joint was not included. For injuries at, or distal to, the metacarpophalangeal joint, the IP should be included in the splint.

Tendons Injuries to the flexor and extensor tendons compromise the mobility and strength of the digits. On inspection, injury normally is suspected by loss of the normal cascade of the fingers. The patient should be examined as described above in Emergency Room/Inpatient Consultation to evaluate for which tendon motion is deficient. If the patient is unable to cooperate, extension of the wrist will produce passive flexion of the fingers and also demonstrate a deficit. This is referred to as the tenodesis maneuver . Flexor tendon injuries are described based on zones (Fig. 44-15). Up until 40 years ago, zone 2 injuries were always reconstructed and never repaired primarily due to concern that the bulk of repair within the flexor sheath would prevent tendon glide. The work of Dr. Kleinert and colleagues at the University of Louisville changed this "axiom" and established the principle of primary repair and early controlled mobilization postoperatively.1 4 Flexor tendon injuries should always be repaired in the OR. Although they do not need to be repaired on the day of injury, the closer to the day of injury they are repaired, the easier it will be to retrieve the retracted proximal end. The laceration should be washed out and closed at the skin level only using permanent sutures. The hand should be splinted as described above in Fractures and Dislocations; one notable difference is that the wrist should be splinted at slight flexion (about 20) to help decrease the retracting force on the proximal cut tendon end.

Fig. 44-15.

The zones of flexor tendon injury: I . Flexor digitorum superficialis insertion to the flexor digitorum profundus insertion. II . Start of the A1 pulley to the flexor digitorum superficialis insertion. III . End of the carpal tunnel to the start of the A1 pulley. IV . Within the carpal tunnel. V . Proximal to the carpal tunnel.

Extensor tendons do not pass through a sheath in the fingers. As such, bulkiness of repair is less of a concern. With proper supervision/experience and equipment, primary extensor tendon repair can be performed in the ER. Very distal extensor injuries near the insertion on the dorsal base of the distal phalanx may not have sufficient distal tendon to hold a suture. Closed injuries, called mallet fingers , can be treated with extension splinting of the DIP joint for 6 continuous weeks. For patients with open injuries, a dermatotenodesis suture is performed. A 2-0 or 3-0 suture is passed through the distal skin, tendon remnant, and proximal tendon as a mattress suture. Be sure to use a suture of a different color than the skin closing sutures to help prevent removing the dermatotenodesis suture(s) too soon. The DIP joint is splinted in extension. More proximal injuries are typically repaired with a 3-0 braided polyester suture. Horizontal mattress or figure-ofeight sutures should be used, two per tendon if possible. Great care should be used to ensure matching the appropriate proximal and distal tendon ends. The patient is splinted with IP joints in extension and the wrist in extension per usual. MP joints should be splinted in 45 flexion, sometimes less. Although this position is not ideal

for MP collateral ligaments, it is important for taking tension off the tendon repairs. The patient should be seen within 1 week of repair to initiate hand therapy.

Nerve Injuries In the setting of a sharp injury, a sensory deficit implies a nerve laceration until proven otherwise. For blunt injuries, even displaced fractures and dislocations, nerves often are contused but not lacerated and are managed expectantly. Nerve repairs require appropriate microsurgical equipment and suture; they should not be performed in the ER. As with tendons, nerve injuries do not require immediate exploration. However, earlier exploration will allow for easier identification of structures. Earlier exploration also will allow for less scar tissue to be present; the nerve must be resected back to healthy nerve fascicle before repair. Delay between injury and repair can thus make a difference between the ability to repair a nerve primarily or the need to use a graft. The injured hand should be splinted with MPs at 90 and IPs at 0, as described above in Fractures and Dislocations.

Vascular Injuries Vascular injuries have the potential to be limb or digit threatening. A partial laceration of an artery at the wrist level can potentially even cause exsanguinating hemorrhage. Consultations for these injuries must be evaluated urgently. Initial treatment for an actively bleeding wound should be direct local pressure for no less than 10 continuous minutes. If this is unsuccessful, an upper extremity tourniquet inflated to 100 mmHg above the systolic pressure should be used. It should be noted that one should keep this tourniquet time to 40 years with good results.4 4 The silicone implant acts as a spacer between proximal and distal bone, rather than as a true resurfacing arthroplasty. The radial collateral ligament must be repaired to appropriate length to correct the preoperative ulnar deviation of the MP joint. Extensor tendon centralization is then performed, as needed, at the end of the procedure. For MP joint and PIP joint disease, fusion is an option. However, because RA usually affects multiple joints, fusion is typically avoided due to impaired function of adjacent joints, which would leave a severe motion deficit to the finger. Failure of the support ligaments of the distal radio-ulnar joint (DRUJ) leads to the caput ulnae posture of the wrist with the ulnar head prominent dorsally. As this dorsal prominence becomes more advanced, the ulna head, denuded of its cartilage to act as a buffer, erodes into the overlying extensor tendons. Extensor tenosynovitis, followed ultimately by tendon rupture, begins ulnarly and proceeds radially. Rupture of the ECU tendon may go unnoticed due to the intact ECRL and ECRB tendons to extend the wrist. EDQ rupture may go unnoticed if a sufficiently robust EDC tendon to the small finger exists. Once the fourth compartment (EDC) tendons begin to fail, the motion deficit is unable to be ignored by the patient. Surgical solutions must address the tendon ruptures as well as the DRUJ synovitis and instability and ulna head breakdown that led to them.4 3 Excision of the ulna head removes the bony prominence. The DRUJ synovitis also must be resected. Finally, the remaining distal ulna must be stabilized. Multiple techniques have been described using portions of FCU, ECU, wrist capsule, and combinations thereof. The ruptured extensor tendons typically are degenerated over a significant length. Primary repair is almost never possible, and the frequent occurrence of multiple tendon ruptures makes repair with graft less desirable due to the need for multiple graft donors. Feldon and colleagues4 3 recommend the following for increasing numbers of extensor tendon ruptures: for a single finger tendon rupture (most commonly to the small finger), EIP transfer; for two fingers (ring and small fingers), EIP transfer to the small finger and end-to-side repair of the ring finger to the intact middle finger extensor; for three fingers, EIP transfer to ring and small with middle finger end-to-side to the index or FDS (middle or ring finger) transfer to ring and small (if EIP unavailable) and middle finger end-to-side to

the index; for rupture of all four finger extensors, FDS (ring) is transferred to the ring and small extensors and FDS (middle) is transferred to the index and middle extensors. Strict compliance with postoperative therapy is essential to maximizing the surgical result. Due to the chronic inflammation associated with RA, tendon and ligament repairs will be slower to achieve maximal tensile strength. Prolonged nighttime splinting, usually for months, helps prevent recurrence of extensor lag. Finally, the disease may progress over time. Reconstructions that were initially adequate may stretch out or fail over time.

DUPUYTREN'S CONTRACTURE In 1614, a Swiss surgeon named Felix Plater first described contracture of multiple fingers due to palpable, cordlike structures on the volar surface of the hand and fingers. The disease state he described would ultimately come to be known as Dupuytren's contracture . Dupuytren's name came to be associated with the disease after he performed an open fasciotomy of a contracted cord before a class of medical students in 1831. 4 5 The palmar fascia consists of collagen bundles in the palm and fingers. These are primarily longitudinally oriented, and reside as a layer between the overlying skin and the underlying tendons and neurovascular structures. There are also connections from this layer to the deep structures below and the skin above. Much is known about the progression of these structures from their normal state (called bands) to their contracted state, but little is known about how or why this process begins. The Dupuytren's nodule represents the basic unit of disease.4 6 Increased collagen deposition leads to a palpable nodule in the palm. Over time, there is increased deposition distally into the fingers. This collagen becomes organized and linearly oriented. These collagen bundles, with the aid of myofibroblasts, contract down to form the cords that are the hallmark of the symptomatic patient. Detail of the molecular and cellular biology of Dupuytren's disease is beyond the scope of this chapter, but is available in multiple hand surgery texts.4 7 Most nonoperative management techniques will not delay the progression of disease. Corticosteroid injections may soften nodules and decrease discomfort associated with them, but are ineffective against cords. Splinting similarly has been shown not to retard disease progression. Injectable clostridial collagenase has shown promise in clinical trials4 8 but has not yet been reported in large or long-term series. It also is not yet commercially available. For patients with advanced disease, including contractures of the digits that limit function, surgery is the mainstay of therapy. Although rate of progression should weigh heavily in the decision of whether or not to perform surgery, general guidelines are MP contracture of 30 or more and/or PIP contracture of 20 or more.4 9 Surgery consists of an open approach through the skin down to the involved cords. Skin is elevated off the underlying cords. Great care must be taken to preserve as much as possible of the subdermal vascular plexus with the elevated skin flaps to minimize postoperative skin necrosis. All nerves, tendons, and blood vessels in the operative field should be identified. Once this is done, the involved cord is resected while keeping the critical deeper structures under direct vision. Skin is then closed, with local flap transpositions as needed, to allow for full extension of the fingers that have been released (Fig. 44-19).

Fig. 44-19.

Dupuytren's disease. A. This patient has cords affecting the thumb, middle, ring, and small fingers. B. The resected specimens are shown. C. Postoperatively, the patient went on to heal all his incisions and, with the aid of weeks of hand therapy, recovered full motion.

Dermatofasciectomy is an alternative to simple fasciectomy as described in the preceding paragraph. In dermatofasciectomy, overlying skin is resected along with the Dupuytren's cord. The wound is then typically closed with a skin graft. Dermatofasciectomy should only be performed if the skin cannot be separated from the underlying cords. Skin grafting should only be performed if the remaining skin after resection cannot be rearranged with local flaps to cover the wounds without the need for skin grafting. In the past, some authors have advocated total fasciectomy of the hand with the idea that recurrence/extension of disease could be prevented. Unfortunately, recurrences still occurred in these patients, and revision surgery became much more difficult. Complications of surgical treatment of Dupuytren's disease occur as often as 17%.5 0 Problems include: digital nerve laceration, digital artery laceration, buttonholing of the skin, hematoma, swelling, and pain including some patients with CRPS (see above section on Regional Pain Syndromes). Digital nerve injury can be quite devastating, producing annoying numbness at best or a painful neuroma in worse situations. Although the surgeon goes into the

operation knowing that he/she must identify the nerves and other critical structures, a fascial cord can be mistaken for a nerve and vice versa. It is best to identify the nerve proximal to the area involved with Dupuytren's disease and track it distally into the affected area. The hand is splinted in full extension at the end of surgery. Hand therapy typically is instituted within 1 week of surgery to begin mobilization of the fingers and edema control. The therapist also can identify any early wound problems as he/she will see the patient more frequently than the surgeon. Extension hand splinting is maintained for 4 to 6 weeks with nighttime splinting continued for an additional 6 to 8 weeks. After this point, the patient is serially followed for evidence of recurrence or extension of disease.

TENDONITIS/TENOSYNOVITIS Trigger Finger Stenosing tenosynovitis of the flexor tendon sheath, also known as trigger finger (TF), is one of the most common upper limb problems to be encountered in hand surgery practice. The condition starts with discomfort in the palm during movements of the involved digits. Gradually, the flexor tendon causes painful popping or snapping as the patient flexes and extends the digit. The patient often will present with a digit locked in a flexed position, which may require gentle passive manipulation to regain full extension. The phenomenon is due to a difference in size of the affected flexor tendon and the retinacular pulley. The mismatch is due to formation of a nodule in the FDS tendon, where it passes under the A1 pulley in the region of the MC head (see Fig. 44-4). In rare instances, a nodule distal to it in the tendon of the FDP also can be responsible. The most common etiology of TF is idiopathic formation of a nodule on the flexor tendon that obstructs gliding underneath the A1 pulley. The differential diagnosis includes localized swelling due to a partially lacerated flexor tendon catching against the A1 pulley, a nodule in the FDS that catches against the A3 pulley, locking caused by abnormal MC head shape preventing normal collateral ligament motion (staghorn lesion), foreign body in the MP joint, ganglion cyst of the tendon sheath, and sagittal band rupture causing the EDC to subluxate off the MC head and snap back in extension. Several studies demonstrate a correlation between TF and activities that require exertion of pressure in the palm while performing powerful grip or repetitive forceful digital flexion. Proximal phalangeal flexion in power-grip activities causes high loads at the distal edge of the A1 pulley.5 1 Some have suggested that bunching of the interwoven flexor tendon fibers causes the reactive intratendinous nodule observed at surgery.5 2 Stenosing tenosynovitis is much more common in women than men.5 1 In several series, peak incidence of trigger digit occurred in the fifth to sixth decades of life. The dominant hand is more affected, and involvement of several fingers is not unusual. The most commonly affected digit is the thumb, followed by the ring, long, small, and index fingers.5 3 Signs and symptoms include palpable popping, clicking or snapping sensation over the A1 pulley, locking in flexion (in later stages, passive manipulation is needed to extend the digit), stiffness of the digit, tenderness over the A1 pulley, flexion deformity or joint contracture in late presentations, especially the PIP joint. The goal of treatment for trigger digits is to eliminate the locking and allow full movement of the finger or thumb without discomfort. Swelling around the flexor tendon and tendon sheath must be reduced to allow smooth gliding of the tendon.

Nonoperative treatment includes limiting the activities that aggravate the condition. Splinting and/or oral antiinflammatory medication may help. If symptoms continue, a corticosteroid injection into the tendon sheath at the pulley is often effective in relieving the trigger digit. The authors prefer triamcinolone acetonide (40 mg/mL) mixed with 0.5% plain bupivacaine. The needle is inserted at the MC head, advanced until bone is encountered, and then withdrawn approximately 0.5 mm until resistance gives way, allowing the medication to be injected. Approximately 1 mL is deposited in the tendon sheath. The needle is withdrawn and pressure is applied. Fingers with irreducible flexion contractures should be treated with surgery, not steroid injection. Several studies advocate the use of percutaneous trigger release, in which the bevel of a needle is used to section the A1 pulley in an office procedure. This technique has been reported to be a safe alternative to open techniques.5 4 Gilberts and associates compared the results from open vs. percutaneous technique and found similar efficacy but quicker recovery in the percutaneous group.5 5 No serious complications have been reported with this technique, although there is a risk of incomplete pulley release, especially in severe cases. The use of this technique is not recommended in the thumb. If nonsurgical forms of treatment do not relieve the symptoms, surgery is indicated. This surgery is performed as an outpatient, usually with simple local anesthesia. The goal of surgery is to divide the A1 pulley at the base of the finger so that the tendon can glide more freely. A 10- to 15-mm incision is made over the affected MC head. Blunt dissection is used to spread the subcutaneous tissue and palmar fascia to expose the flexor tendon and sheath. The A1 pulley is identified and sharply transected longitudinally. Care should be taken to identify the demarcation between the A1 and A2 pulleys so that the A2 pulley is not violated. At completion, the finger is ranged to ensure that there is no residual triggering. Gentle traction on the flexor tendons also confirms that the A1 pulley has been completely released. Occasionally, a reduction tenoplasty may need to be performed if a large nodule is present (e.g., in RA). The skin incision is closed and a soft dressing is applied. Active motion of the finger generally begins immediately after surgery. Normal use of the hand usually can be resumed once comfort and pain control permits. Occasionally, hand therapy is required after surgery to regain better use. Nonoperative management is felt to be very safe without the risk of major complications. With the open technique, prolonged tenderness over the incision may occur. Infrequent complications include nerve injury, recurrence, and bowstringing of the flexor tendons due to sectioning of the A2 pulley.

De Quervain's Tenosynovitis De Quervain's disease, described in 1895 by Swiss surgeon Fritz de Quervain, is a stenosing tenosynovitis that causes tendon entrapment of the first dorsal compartment of the wrist. It is a common cause of wrist and hand pain, particular during thumb motion. The tendons of APL and EPB muscles pass through the first dorsal compartment. These tendons are secured tightly against the radial styloid by the extensor retinaculum. Frequent abduction of the thumb with ulnar deviation of the wrist is thought to create tension and eventual friction along the tendon sheath surrounding the APL and EPB. This friction leads to irritation and swelling of the sheath as well as thickening of the tendon that resists gliding. The differential diagnosis includes: ganglion of the extensor retinaculum, osteoarthritis of thumb CMC joint, degenerative arthritis at the radioscaphoid joint, CTS, SRN neuropathy at the wrist, scaphoid fracture, and intersection syndrome (see the Intersection Syndrome section). The average age of presentation is in the fifth and sixth decades, and the condition has been reported to be up to

six times more common in women than men.5 1 The disease also seems to affect pregnant or recently postpartum women and is thought to be due to repetitive lifting of infants. The wrist is usually affected bilaterally.5 6 De Quervain's also is seen in association with inflammatory conditions such as rheumatoid disease. Patients usually present with complaints of pain, several weeks to months in duration, along the radial aspect of the wrist aggravated by thumb motion. The most common symptoms are pain when grasping or pinching and tenderness at the first dorsal compartment, where the abductor policis longus and extensor policis brevis pass over the wrist joint (see Fig. 44-3). In some patients, a lump or thickened mass can be felt in the area 1 to 2 cm proximal to the radial styloid. Severe, sharp pain can be elicited by having the patient flex the thumb across the palm, make a fist, and then ulnarly deviate the wrist (Finkelstein's test) (Fig. 44-20).5 7 There should be no tenderness in the forearm proximal to the first dorsal compartment. Axial loading of the thumb should not elicit tenderness and pain, unless there is concomitant CMC joint arthritis.

Fig. 44-20.

Finkelstein's test. The patient places the thumb in the palm and makes a loose fist. The examiner then ulnarly deviates the patient's wrist (as indicated by the arrow ). Pain at the first dorsal compartment with this maneuver is a positive response.

If treated early, some cases improve with short periods of rest in a thumb spica splint, followed by stretching exercises designed to improve tendon gliding. The patient should also modify activity to avoid motions that trigger symptoms. Compliance with splinting can be an issue; symptoms tend to recur after the splint is removed and the causative activities are resumed. Oral NSAID medications are of some benefit. If splinting and NSAIDs fail, corticosteroid injection is the next line of treatment. The technique is similar to that used in TF. Injection into the tendon sheath of the first dorsal compartment has been shown to reduce tendon

thickening and inflammation.5 8 Corticosteroid injection has been reported to be effective in 50 to 80% of patients after one to two injections.5 1 With corticosteroid injections, possible complications of note include: transient anesthesia of the SRN at the first web space of the dorsal hand, direct injection injury to the radial nerve causing persistent pain (cheiralgia paresthetica), skin hypopigmentation in dark-skinned individuals, subcutaneous tissue atrophy, tendon weakening, and rupture (rare). More severe cases or those that do not respond to conservative treatment may require surgery to release the first dorsal compartment. In this procedure, a transverse incision is made over the first dorsal compartment approximately 1 cm proximal to the radial styloid. Longitudinal blunt dissection is used to expose the roof of the first dorsal compartment. Sharp or transverse dissection in this area increases the likelihood of injury to the SRN, which runs superficial to the ligament. The ligament covering the compartment is then sharply opened longitudinally along its dorsal margin. Attention must be paid to the variant anatomy in this region. 5 9 Frequently, there is a septum between the EPB and APL tendons;6 0 if this septum is identified, it must also be released, or symptoms will not be relieved. The skin incision is closed and a soft dressing is applied. Although the surgical management of de Quervain's tenosynovitis is straightforward, complications can be bothersome. Persistent symptoms from an incompletely released first dorsal compartment can necessitate surgical re-exploration. Volar or dorsal subluxation of the tendons is possible; if symptomatic, reconstruction of the sheath with a slip of brachioradialis or a strip of adjacent dorsal retinaculum can be performed. Injury to the SRN is a rare, but serious complication. Laceration or retraction injury to the nerve can cause neuritis or a painful neuroma. The complication is avoided by careful blunt dissection and gentle retraction. Controversy still exists regarding the optimal management of an iatrogenic lacerated radial sensory nerve.

Intersection Syndrome Intersection syndrome is tenosynovitis in which the tendons in the second dorsal compartment, radial wrist extensors ECRL and ECRB, cross over the tendons of the first dorsal compartment, EPB and APL. Intersection syndrome is characterized by pain in the distal dorsoradial forearm due to irritation of the affected tendons. The pain is proximal and ulnar to that of de Quervain's tenosynovitis and may be associated with localized swelling.6 1 Although this condition occurs at the intersection of the tendons of the first and second extensor compartments (proximal to the extensor retinaculum), many contend that the condition is a tenosynovitis of the ECRL and ECRB tendons. Intersection syndrome also can be caused by direct trauma to the second dorsal compartment. The differential diagnosis includes de Quervain's tenosynovitis, thumb CMC arthritis, radial sensory nerve irritation (Wartenberg's syndrome), and EPL tendonitis. Intersection syndrome is thought to be associated with activities that require repetitive wrist flexion and extension. Weightlifters, rowers, and other athletes are particularly prone to this condition. Patients with intersection syndrome complain of dorsal radial wrist or forearm pain. Symptoms are exacerbated by repetitive wrist flexion and extension associated with thumb motion. On examination, a focal swelling at the area of intersection often is present. Active or passive wrist motion may produce a characteristic crepitus in severe cases. Conservative treatment includes immobilization, activity modification, and pharmacologic intervention. A thumb spica splint effectively immobilizes the wrist extensors and thumb extensors. Several weeks of immobilization, followed by gradual splint weaning, usually is recommended. Activity modification at home and/or work also is critical. NSAIDs help alleviate pain and inflammation.

In recalcitrant cases, a corticosteroid injection into the second dorsal compartment is effective. Once the symptoms are under control, a program of supervised hand therapy leads to long-term recovery. Surgery can be effective in cases that do not respond to conservative measures. The second extensor compartment is approached through a dorsal longitudinal incision, beginning over the wrist and continuing proximally 3 to 4 cm to the inflamed area.6 2 The dorsal forearm fascia is divided longitudinally. Branches of the radial sensory nerve are identified and protected. The ECRL and ECRB tendons are released by longitudinally incising the extensor retinaculum over the second dorsal compartment. A thorough tenosynovectomy may be performed while elevating and protecting the tendons. The extensor retinaculum is not repaired. Skin is closed routinely, and the hand is placed in a volar thumb spica splint, maintaining the wrist at 15 to 20 of extension for 1 week. This is followed by early wrist ROM exercises. No large series documenting treatment outcomes exist in the literature. There are reports that approximately 60% of patients respond to conservative management while 100% of patients who require surgery obtain long-term symptomatic relief.6 2 Release of the second dorsal compartment could theoretically lead to bowstringing of the ECRL and ECRB tendons in extreme wrist extension; however, this complication has not been reported in the literature.

INFECTIONS The most common cause of hand infections is trauma. Other predisposing conditions include diabetes and neuropathies. Ninety percent of infections are caused by gram-positive organisms Staphylococcus aureus , Streptococcus viridans , Group A Streptococcus , and S. epidermis . Infection in the hand, as in most areas of the body, can be localized by five cardinal signs: rubor (redness), calor (heat), tumor (swelling), dolor (pain), and loss of function. Treatment of any hand infection focuses on drainage, antibiotics, splint immobilization, and elevation.6 3

Cellulitis Cellulitis of the hand is a nonsuppurative inflammation of the subcutaneous tissues. It is characterized by erythema, swelling, induration and warmth, and pain and tenderness. The most common pathogenic organisms are Staphylococcus and Streptococcus . Mainstays of treatment are elevation, splint immobilization, and judicious use of antibiotics. By definition, a diagnosis of cellulitis means that no purulence is present. If the patient does not improve within 24 to 48 hours, an abscess must be suspected.

Paronychia Paronychia is an infection of the nail bed or the periungual soft tissue. It sometimes begins as a hangnail and often presents as a small collection of purulent material at the side of the nail bed. In acute paronychia, the causative organisms are usually S. aureus or streptococci, less commonly Pseudomonas or Proteus species. Organisms enter through a break in the epidermis frequently due to nail biting or aggressive manicuring. In chronic paronychia, infection (usually Candida species) enters via the hand receiving prolonged exposure to a moist environment, such as those used as dishwashers. Paronychia develops along the nail margin (lateral and proximal nail folds), manifesting over hours to days with pain, warmth, redness, and swelling. Pus usually develops along the nail margin, less commonly beneath the nail. Rarely, infection penetrates deep into the finger and may produce infectious flexor tenosynovitis (FTS). Early treatment is warm compresses or soaks and an antistaphylococcal antibiotic. First-generation cephalosporins have traditionally been used, but the increasing prevalence of methicillin-resistant S. aureus

64

has led the authors

to begin empiric treatment with vancomycin. Fluctuant swelling or visible pus should be drained with a Freer elevator or the bevel of an 18-gauge needle inserted between the nail and nail fold (Fig. 44-21). If the abscess resides under the eponychial fold, then a proximally based flap of eponychium can be reflected up to allow for better drainage. An abscess that extends below the nail necessitates partial removal of the nail plate. A thin gauze wick should be inserted for 24 to 48 hours to maintain patency of the drainage tract.

Fig. 44-21.

Paronychia. A. Fluctuance in the nail fold is the hallmark of this infection. B. Technique of drainage between the nail plate and nail fold.

Felon A felon is a closed-space, purulent infection of the fingertip pulp. It is usually extremely painful, and if left untreated, can lead to ischemia and necrosis. The thumb and index finger are the most commonly affected digits. The fingertip pulp is divided into numerous small compartments by vertical septa that connect the distal phalanx bone to the overlying skin. Infection in these compartments can lead to abscess formation, tremendous edema, and rapid development of increased pressure in a closed space. The increased pressure may compromise blood flow and lead to necrosis of the skin and pulp. Wooden splinters or minor cuts are common predisposing causes; however, in half of patients, the condition is idiopathic. Initial minor injury causes inflammation, which is first confined by the tough fibrous septa within the pulp. Early infection causes pain and tenderness. At this stage, infection may resolve spontaneously with antibiotics. If resolution does not occur, increasing swelling and throbbing pain herald abscess formation. Felons are characterized by marked throbbing pain, tension, and edema of the fingertip pulp. S. aureus is the most common causative organism. More and more community-acquired methicillin-resistant S. aureus infections are being reported. Gram-negative organisms have been reported in immunosuppressed patients and diabetics. Fingertip blood glucose measurements have been implicated as an etiology. Eikenella corrodens infections have been reported in persons with diabetes who bite their fingernails.6 3 Adequate early treatment can prevent abscess formation. Tetanus should be updated. Antibiotics with activity against staphylococcal and streptococcal organisms should be administered. In cases where significant tension is present, the fingertip must be decompressed to preserve venous flow, whether or not a frank abscess has formed. The drained fluid should be sent for culture. The procedure to drain a felon is straightforward (Fig. 44-22). A digital block is performed. This is followed by a short skin incision. Only the skin is incised. Pus is evacuated using a blunt instrument to decrease the chance of severing a digital nerve or entering the tendon sheath. Gauze is loosely packed into the wound to prevent skin closure. A loose dressing and finger splint is applied. The hand is elevated and splinted.

Fig. 44-22.

A and B. The area of purulence in a felon is located in the pad of the distal phalanx as shown. B. A longitudinally oriented incision is made over the area of maximal fluctuance; this incision should not cross the distal interphalangeal joint crease. See text for additional details.

There is some debate regarding the choice of incision. A longitudinal incision over the area of maximal fluctuance (see Fig. 44-22) is effective and avoids the serious iatrogenic complications associated with other described incisions such as a transverse incision or an incision on the lateral aspect of the finger. The incision should not cross the DIP flexion crease to prevent formation of a flexion contracture. Probing is not carried out proximally to avoid extension of infection into the flexor tendon sheath. Lateral incisions, volar transverse incisions, and hockey stick and fish-mouth incisions have been suggested; however, these incisions offer no benefit and increase the potential for serious injury. In particular, the traditional lateral incision can causes ischemia and anesthesia by injuring one or both neurovascular bundles. The fish-mouth incision can lead to an unstable painful fingertip. Untreated or incompletely treated infections can lead to osteomyelitis, tenosynovitis, and septic arthritis.

Bites Human bites to the hand may lead to serious infections from any of the numerous organisms found in the oral cavity. Inoculation typically occurs during an altercation in which the skin and tendons over the MP and/or PIP joints are abraded and lacerated from an opponent's tooth. The initial clinical appearance of these "fight bites"

often is deceptively benign, leading to delays in seeking care and more severe infection on presentation. Human bites require aggressive evaluation and treatment. It is important to understand the mechanism of injury: the skin and joint capsule are trapped between a tooth and underlying bone. A 3-mm penetration can inoculate a joint in the hand. Treatment of these penetrating injuries includes irrigation and dbridement of any purulence or devitalized structure(s). The hand should be immobilized and elevated. The patient should be placed on broadspectrum antibiotics to cover Staphylococcus , Streptococcus, and anaerobic bacteria, such as amoxicillin/clavulanic (again recent trends in sensitivities have made penicillins less effective against Staphylococcus ). E. corrodens is an organism commonly isolated from human fight bites. Skin lacerations should be left open to heal secondarily. Dog, cat, and other animal bites are treated similarly.

HERPETIC WHITLOW Herpetic whitlow is a self-limited herpes simplex virus (HSV) infection of the distal finger. In the United States, HSV infection of the hand occurs in 2.4 cases per 100,000 population per year.6 5 It is the most common viral infection of the hand and infections by HSV1 or HSV2 are clinically indistinguishable. Direct inoculation of the virus into a wound is usually the mechanism of infection. Herpetic whitlow often is found in adult women with genital herpes, children with coexistent herpetic gingivostomatitis, and health care workers exposed to orotracheal secretions. The infection usually involves a single finger that is painful, erythematous, and swollen. It is characterized by vesicles early in the disease process. After about 2 weeks, the vesicles coalesce, and the infection may be mistaken for a paronychia or felon. Diagnosis usually is made by a careful history and physical. On examination, tenderness is present but is less severe than that found in bacterial infections. The distinction is very important to make because performing an incision and drainage on a herpetic whitlow can lead to secondary bacterial infection as well as spread of the herpes virus. If the vesicle is unroofed, fluid obtained can be sent for a Tzanck smear and/or viral culture to confirm the diagnosis. Most commonly, however, diagnosis can be made without intervention on the involved digit. Herpetic whitlow usually resolves spontaneously in 2 to 3 weeks. The main goals of treatment are to prevent both oral inoculation and spread of the infection, as well as to obtain symptomatic relief. The involved digit should be kept covered with a dry dressing. Some authors recommend treatment with oral acyclovir for 10 days if the diagnosis is made early in symptom onset, although acyclovir has not been demonstrated to shorten the course of this self-limited infection. Stronger evidence exists to recommend oral acyclovir for recurrent infections during the prodromal stage, as well as in immunocompromised patients. Infection can recur in 30 to 50% of patients, but the initial infection is typically the most severe.

FLEXOR TENOSYNOVITIS FTS is a severe pathophysiologic state causing disruption of normal flexor tendon function in the hand. A variety of etiologies are responsible for this process. Most acute cases of FTS are due to purulent infection. FTS also can occur secondary to chronic inflammation as a result of diabetes, RA, crystalline deposition, overuse syndromes, amyloidosis, psoriatic arthritis, systemic lupus erythematosus, and sarcoidosis. Suppurative FTS has the ability to rapidly destroy a finger's functional capacity and is considered a surgical emergency. Much of the original work on infectious FTS was done in the early 1900s. 6 6 In the 1940s, postoperative sheath

irrigation was suggested.6 7 Besser, Carter, Burman, and Nevaiser have described multiple techniques of closed continuous irrigation and/or dbridement as early as the 1960s.6 8 Suppurative FTS results from bacteria multiplying in the closed space of the flexor tendon sheath and culture-rich synovial fluid medium. Natural immune response mechanisms cause swelling and migration of inflammatory cells and mediators. The septic process and this inflammatory reaction within the tendon sheath quickly erode the paratenon, leading to adhesions and scarring. The ultimate consequences are tendon necrosis, disruption of the tendon sheath, and digital contracture. The primary mechanism of infectious FTS usually is penetrating trauma. Most infections are caused by skin flora, including both Staphylococcus and Streptococcus species. Bacteria involved vary by etiology of the infection: bite wounds (Pasteurella multocida —cat, E. corrodens —human); Bacteroides , Fusobacterium , Haemophilus species, gram-negative organisms—diabetic patients; hematogenous spread (Mycobacterium tuberculosis , Neisseria gonorrhea ); water-related punctures (Vibrio vulnificus , M. marinum ). Infection in any of the fingers may spread proximally into the wrist, carpal tunnel, and forearm, also known as Parona's space . 6 9 With the accumulation of purulence in the flexor tendon sheath, pressure can increase within the closed space and inhibit the inflammatory response. The increased pressure also inhibits blood flow and adds to the destructive process. Tendon ischemia increases the likelihood of tendon necrosis and rupture. Patients with infectious FTS present with complaints of pain, redness, and fever. Physical examination reveals Kanavel's "cardinal" signs of flexor tendon sheath infection,6 6 which are finger held in slight flexion, fusiform swelling, tenderness along the flexor tendon sheath, and pain over the flexor sheath with passive extension of the digit (Fig. 44-23A).

Fig. 44-23.

Suppurative flexor tenosynovitis of the ring finger. A. The finger demonstrates fusiform swelling and flexed posture. B. Proximal exposure for drainage. C. Distal drainage incision.

Kanavel's signs may be absent in patients who are immunocompromised, have early manifestations of infection, have recently received antibiotics, or have a chronic, indolent infection. The differential diagnosis includes inflammatory (nonsuppurative) FTS, herpetic whitlow, pyogenic arthritis, gout, fracture, degenerative arthritis or RA, sesamoiditis, and angiolipoma (found in case reports masquerading as FTS). If a patient presents with suspected infectious FTS, empiric IV antibiotics should be initiated. Prompt medical therapy in early cases may prevent the need for surgical drainage. For healthy individuals, empiric antibiotic therapy should cover Staphylococcus and Streptococcus . For immunocompromised patients (including diabetics) or infections associated with bite wounds, empiric treatment should include coverage of gram-negative organisms as well. Adjuncts to antibiotics include splint immobilization (intrinsic plus position preferred) and elevation until infection is under control. Hand rehabilitation (i.e., ROM exercises and edema control) should be initiated once pain and inflammation are under control.

If medical treatment alone is attempted, then inpatient observation for a minimum of 48 hours is indicated. Surgical intervention is necessary if no obvious improvement has occurred within 12 to 24 hours. In addition, for patients who are immunocompromised or have diabetes, surgery is warranted. Several surgical approaches can be used to drain infectious FTS. The method used is based upon the extent of the infection. Michon developed a classification scheme7 0 that can be useful in guiding surgical treatment: Stage I. Findings: Increased fluid in sheath, mainly a serous exudate Treatment: Catheter irrigation

Stage II. Findings: Purulent fluid, granulomatous synovium Treatment: Minimal invasive drainage indwelling catheter irrigation

Stage III. Findings: Necrosis of the tendon, pulleys, or tendon sheath Treatment: Extensive open dbridement and possible amputation

Current recommendations for stage and I and II infections advocate proximal and distal incisions for adequate drainage and irrigation. A proximal incision is made over the A1 pulley (see Fig. 44-23B). In the digit, either a volar zigzag (Brunner) incision or a midaxial incision may be used distally. This distal incision is made over the region of the A5 pulley (see Fig. 44-23C). A Brunner incision allows better initial exposure but may yield difficulties with tendon coverage if skin necrosis occurs. If used, the midaxial incision should be dorsal to the neurovascular bundle. A 16-gauge catheter or 5F pediatric feeding tube then is inserted into the tendon sheath through the proximal incision. The sheath is copiously irrigated with normal saline. Excessive fluid extravasation into the soft tissue of the digit should be avoided because the resulting increase in tissue pressure can lead to necrosis of the digit. The catheter is removed after irrigation. A small drain is placed in the distal incision, and the wounds are left open. Some surgeons prefer a continuous irrigation technique for a period of 24 to 48 hours. The catheter is sewn in place, and a small drain is placed at the distal incision site. Continuous or intermittent irrigation every 2 to 4 hours with sterile saline can then be performed through the indwelling catheter. Indications for open tendon sheath dbridement include stage III infections, chronic infections, or infections caused by atypical mycobacteria. To expose the tendon sheath, a Brunner incision or a longitudinal midaxial incision is made along the length of the digit. The thumb and small fingers are approached from the radial side, and the remaining digits are approached from the ulnar side. The incision begins distally at the level of the A5 pulley, or just beyond the distal flexion crease, and is extended proximally to the web space. For extensive infections, the sheath is opened at all of the cruciate pulleys while preserving the A2 and A4 pulleys. The purulent fluid should be sent for aerobic, anaerobic, fungal, acid-fast bacilli, and atypical acid-fast bacilli cultures. In cases of known mycobacterial infection, extensive tenosynovectomy may be necessary. If the small finger or thumb is involved and there is evidence of palmar bursae involvement, an additional incision proximal to the transverse carpal ligament is made to ensure adequate drainage of the radial and ulnar bursae. The sheath is copiously irrigated, and the wounds are left open with drains in place. After surgery, an intrinsic plus splint is applied, the hand is elevated, and the appropriate empiric antibiotic coverage is instituted while awaiting culture results. The hand is re-examined the following day. Whirlpool therapy

and ROM are begun. Drains are removed before discharge from the hospital. The wounds are left open to heal by secondary intention. In severe cases, repeat irrigation and operative dbridement may be required. The length of IV antibiotic treatment is determined by the culture and sensitivity results and specific patient factors. The transition from IV to oral antibiotics should be based not only on the culture results but also on the clinical progress. Oral antibiotics should be continued for 7 to 14 days. Follow-up should continue until the infection has resolved, all wounds are closed, and pain-free full motion has returned. Patients with infectious FTS that present early and have no comorbidities have a good prognosis. Patients that present with fulminant infection, have chronic infections, or are immunocompromised have increased risks of longterm complications and impairment. The most common complication is finger stiffness secondary to intrasheath adhesions. If loss of functional motion persists, tenolysis is considered 4 months postoperatively. The second major complication is soft tissue necrosis, which is more commonly seen in patients who have diabetes7 1 or who present late in the disease process.

Joint Space Infections The joints of the fingers are easily violated by penetrating trauma. Dorsally, they are only covered by skin and extensor tendon, and laterally, the collateral ligaments lie directly beneath the skin. As a result, sharp objects can readily inoculate the joint with infectious organisms. The common cause of septic arthritis is human or animal bite injuries to the MP joints. Septic arthritis can occur after trauma to the joint with teeth, needles, or thorns, or concomitant with tenosynovitis or osteitis. The symptoms are localized pain, tenderness, and swelling of the joint. Passive movement and axial loading of the joint are very painful. In the early stage, x-rays may demonstrate a slightly widened joint space. Joint destruction may be detected several weeks later. In these cases, osteomyelitis is most likely present. Early surgical treatment is most important to drain the infection and prevent the sequelae of septic arthritis. Treatment of septic arthritis depends on which joint is involved. For the IP joints, the surgeon incises dorsally and opens the joint just lateral to the terminal extensor tendon (DIP joints) or between the central slip and a lateral band (PIP joints). The joint is irrigated and the skin is left open. For the MP joints, a dorsal incision is made. The extensor tendon is split longitudinally. The joint capsule is incised and partially resected, and the joint irrigated thoroughly. The capsule and skin are left open, but the extensor tendon is closed with a running, locking, absorbable suture. Even in patients treated early, arthritis and fibrous ankylosis cannot always be avoided. In patients suspected of pyogenic wrist arthritis vs. crystalline arthropathy, arthrocentesis can be attempted before considering surgical intervention. Lister's tubercle (the bony prominence on the dorsal distal radius that serves as a pulley for the EPL) is palpated. An 18-gauge needle is inserted approximately 1 cm distal to this, angled 10 proximal (rather than true perpendicular) to the skin. Aspirated fluid should be sent for Gram's stain, crystal analysis, and culture. If a "dry tap" yields no fluid, 3 mL of sterile saline should be instilled and then aspirated, and sent for the same studies. If Gram's stain or culture comes back positive, or the patient's clinical course is compelling for intervention, surgical drainage of the wrist is performed. A longitudinal incision is made between the tendons of the third (EPL) and fourth (EDC and EIP) compartments. The wrist capsule is opened at the scapholunate interval over the radiocarpal joint. Great care is taken to avoid injuring the ligament connecting the scaphoid and lunate bones. A Penrose drain is placed and the skin is left open. The wrist is splinted and the hand elevated. Whirlpool and ROM therapy are begun on postoperative day 1.

Web Space Infections The second, third, and fourth web spaces are potential sites for infection. Within the web lies a fascial support structure called the natatory ligament . This can become contracted in Dupuytren's disease, but in the case of a web space infection, it serves as a partial separation between the volar and dorsal web space. Infection typically occurs as dorsal and volar pus pockets with a narrow connection through the natatory ligament, thus the term collar button abscess . On examination, patients typically have pain, swelling, and fluctuance on the palmar and/or dorsal web space surface. The adjacent fingers rest in abduction (Fig. 44-24A) and forced adduction causes pain. These infections are drained through separate dorsal and volar incisions. Great care is taken to leave a skin bridge >1 cm intact in the web. A Penrose drain is placed across both incisions (see Fig. 44-24B) and is removed before discharge from the hospital.

Fig. 44-24.

A. The fingers surrounding the involved (second) web space rest in greater abduction than the other fingers. B. Dorsal and volar drainage incision are made, separated by a bridge of intact web skin; a Penrose drain prevents the skin from closing too early.

Palmar Space Infections The deep palmar spaces may develop abscesses after puncture wounds. These infections may cause erythema, fluctuance, and pain. The deep fascial spaces of the hand are potential spaces and consist of the hypothenar, midpalmar, and thenar spaces. The hypothenar space begins at the radial border of the hypothenar muscle fascia and passes over the ulnar border of the hand. The midpalmar space is demarcated by the palmar interosseous muscles dorsally and the flexor tendons of the fingers volarly. Lastly, the thenar space consists of the area between the adductor pollicis muscle dorsally and the flexor tendon of the second digit ventrally. In some patients, thenar space infection may spread distally to the first web and then dorsally over the first dorsal interosseous muscle, referred to as a pantaloon abscess . These compartments are susceptible to infection by direct penetrating trauma, spread from a neighboring compartment, or hematogenous seeding. Because of the dorsal location of the hand lymphatics, erythema and swelling commonly appear over the dorsum of the hand, even when the injury is of palmar origin. Treatment involves careful incision and drainage and the usual postoperative modalities. For pantaloon abscesses, a second incision is necessary dorsal to the web space. A bridge of web skin must be left intact to prevent the risk of postoperative web space contracture. A Penrose drain is used similar to treatment for a collar button abscess. For the patient with inflammation of the hand and suspicion for infection, clinical examination is the most useful

diagnostic tool. Plain x-rays are useful to exclude fracture and foreign body. For each abscess location, clinical examination findings can be used to support or exclude a particular diagnosis (Fig. 44-25).

Fig. 44-25.

Diagnostic algorithm. Diagnostic work-up for a patient with hand inflammation to evaluate for infection. See text for details about particular infectious diagnoses. Abx = antibiotics; FTS = flexor tenosynovitis; IF MC = index finger metacarpal; MRI = magnetic resonance imaging; SF MC = small finger metacarpal.

TUMORS Abnormal lumps and bumps, considered to be tumors, are extremely common on the hand. They may vary from benign growths that are simply unsightly to malignant masses that require urgent treatment. Fortunately, most tumors on the hand are benign. Diagnosis usually can be made from the history given by the patient and examination of the lesion. Pathologic examination of tissue provides the final diagnosis.

Tumors may arise from any of the bones or soft tissues. The majority of lesions can be cured by removal but this often can be difficult for anatomic reasons. Tumors can lie close to important structures in the hand, such as nerves and vessels, which must be identified and carefully protected intraoperatively. Tumors in the hand can be broadly categorized as being benign or malignant; the most common lesions are described below in Benign Lesions and Malignant Tumors.

Benign Lesions Ganglion cysts are the most common soft tissue tumors in the hand.7 2 These lesions can be painful and usually are found on the dorsal wrist, followed by the volar wrist, flexor tendon sheath, and the dorsal DIP joint (the mucous cyst). These non-neoplastic, mucinous, fluid-filled pseudocysts arise from synovial linings of irritated and inflamed joints, ligaments, and tendon sheaths. As they have no epithelial lining, the focus of treatment is the site of production or leakage of the synovial fluid, rather than the cyst itself. Cysts may be aspirated; the sudden decrease in cyst pressure may allow the two sides of the stalk to coapt and close. Definitive therapy is surgical excision of the stalk and dbridement of the synovial origin. In the common dorsal wrist ganglion, dbridement of the dorsal wrist capsule over the scapholunate ligament is felt to be the most important aspect in achieving a low recurrence rate. Volar wrist ganglions arise at the radioscaphocapitate ligament along the radioscaphoid joint. Excision requires complete dissection and protection of the adjacent radial artery and branches of the SRN. For excision of ganglions arising from the flexor tendon sheath, the underlying annular pulleys and adjacent proper digital neurovascular bundles must be protected during dissection. Lipomas are very common tumors of the body. However, despite their benign nature, the growth of lipomas in the hand can cause neurologic changes by compressing nearby peripheral nerves. They can compress the median nerve and cause symptoms similar to that seen in CTS. Lipomas also can cause sensory deficits from compression of the ulnar nerve and SRN in the hand.7 3 Enchondromas arise from cartilage and are the most common primary bone tumors of the hand.7 4 These lesions account for >90% of bone tumors seen in the hand.7 5 The proximal phalanges are the most common sites of occurrence, followed by the MC bones. On radiographs, an enchondroma usually is seen as a well-defined radiolucent lesion in the diaphysis or metaphysis and also may have a well-defined sclerotic rim. Although these tumors are benign, local bony destruction can lead to pathologic fracture. Giant cell tumor of the tendon sheath is the second most common tumor of the hand. This tumor arises from the tendon sheath and includes discrete, nodular, or polypoid masses that affect the digits. The etiology is generally unknown, although a widely accepted explanation describes a reactive hyperplasia associated with an inflammatory process.7 6 The tumor is usually painless and asymptomatic, except for occasional distal numbness if it compresses a nearby digital nerve. Typically, these masses occur along the volar aspect of the hand and fingers and are most commonly adjacent to the DIP joint. The tumors are firm, lobulated, slow-growing masses that are firmly fixed to the underlying structures. The overlying skin often is freely mobile over proximal masses in the fingers. Pressure exerted by the tumors can cause cortical erosion of adjacent bony structures. The treatment of choice is marginal excision of the giant cell tumor. Giant cell tumor of bone most frequently is found in patients in their second to fourth decades of life. Jaffe provided the current clinical description and grading system used today.7 7 It is characterized by the pathologic presence of multinucleated giant cells. Pain is frequently the primary symptom.7 8 An expanding mass, primarily in the epiphysis, leads to cortical destruction and eventual pathologic fracture. Giant cell tumors are seen in the distal radius, and less commonly, in the phalanges. Nonsurgical treatment includes radiation and embolization. Surgical

options include intralesional curettage, although this has been associated with a significant rate of recurrence. Currently, adjuvant therapy such as cryosurgery and bone cement packing has decreased the rate of recurrence following intralesional curettage.7 9 Pyogenic granulomas may occur in the skin as solitary, raised lesions with hyperemic and ulcerated features. Trauma with superimposed infection and/or inflammation is considered to be the most probable cause of these lesions, which are not true neoplasms. Vascular causes have also been described.8 0 Definitive treatment of pyogenic granulomas involves excision with a generous margin of surrounding normal tissue. An alternative effective treatment is to shave off the lesion flush with the skin and coagulate the base.

Malignant Tumors Squamous cell carcinoma (SCC) is the most common primary malignant tumor of the hand, accounting for 75 to 90% of malignancies.8 1 It is two to five times more prevalent in males. Risk factors include sun exposure, x-ray exposure, chronic ulcers, immunosuppression, xeroderma pigmentosa, and actinic keratosis. Solar radiation is the most modifiable risk factor for SCC. Ulcers that develop within old burn or traumatic scars may undergo malignant change (Marjolin's ulcers), representing a more aggressive SCC. Transplant patients on immunosuppressive therapy have a fourfold increased risk of developing skin cancer while patients with xeroderma pigmentosum have a 1000-fold increase in the development of nonmelanotic SCC. These cancers often manifest as small, firm nodules or plaques with indistinct margins. The surface of the lesions may have various irregularities ranging from smooth to verruciform to ulcerated (Fig. 44-26). Scaling, bleeding, and crusting are often seen. Typically, SCC is only locally invasive; however, metastatic rates of up to 20% have been reported in radiation beds and burn scars. Treatment options include curettage and electrodesiccation, cryotherapy, and radiotherapy. Standard treatment is excision with 0.5- to 1-cm margins.8 1

Fig. 44-26.

Squamous cell cancer on the dorsal hand. A. The patient had a previous excision of squamous cell carcinoma with recurrence along the incision. B. Intraoperative defect after resection with 1-cm margins. Paratenon is intact. The wound was temporarily covered with allograft; once final margins were negative, a split-thickness sheet skin was placed.

Basal cell carcinoma (BCC) accounts for 3 to 12% of hand malignancies. Risk factors are similar to those for SCC and include chronic sun exposure, light complexion, and immunosuppression. Other associated conditions include inorganic arsenic exposure and Gorlin's syndrome. BCC classically presents on the hand as a small, well-defined nodule with a translucent, pearly border with overlying telangiectasias. Metastasis are extremely rare. Treatment options for BCC include curettage with electrodesiccation, cryosurgery, and radiation. Standard therapy is surgical excision with 0.5-cm margins. Although performed routinely for facial BCC, Mohs micrographic surgery rarely is indicated for lesions of the hand. Melanoma accounts for approximately 3% of primary malignant hand tumors, although this incidence is rising.8 2 Risk factors include long-term sun exposure, previous dysplastic nevi, fair complexion, family history of melanoma, and congenital nevi. Lesions with increased growth, change in color or shape, irregular borders, and accelerated growth are suggestive of melanoma. A pigmented lesion under the nail bed must be aggressively pursued with biopsy because of the concern for subungual melanomas. Survival is related to the Breslow thickness of the lesion. The principal treatment is surgical excision or amputation, with 1-cm margins for lesions up to 1 mm in depth, and 2-cm margins for thicker lesions.8 3 Clinically palpable nodes should be removed to allow staging. Although there is little role for elective lymph node dissections, sentinel lymph node status has been shown to be a valuable prognostic factor. Isolated limb perfusion may offer hope for salvage therapy of metastatic disease. Subungual

melanomas are treated with amputation at the level of the DIP joint. Studies have reported a 5-year survival rate of 66% in patients with subungual melanoma.8 4

BURNS Even though the palm of the hand comprises only 1% of total body surface area, burns of the hand can represent a serious short- or long-term disability. Hand burns are considered to be severe injuries requiring specialized treatment at a burn center. The management of hand burns is multidisciplinary and requires the expertise of hand surgeons, nurses, and occupational therapists. The multidisciplinary treatment of hand burns begins on the day of injury and may be carried out simultaneously with resuscitation and other treatment. Management objectives include edema control, avoidance of prolonged immobilization, prevention of infection, preservation of viable tissue, and prevention of contractures.

Acute Management After airway and breathing concerns are addressed in the primary survey, circulation to the hand needs to be assessed. Evaluation of radial, ulnar, and palmar arch pulses should be undertaken by palpation or Doppler ultrasound at initial evaluation and frequently thereafter. Objective evidence of inadequate perfusion (i.e., deteriorating clinical examination with changes in or loss of pulse or Doppler signal) indicates the need for escharotomy, especially in the setting of full-thickness circumferential hand and/or arm burns. Escharotomy may be performed at bedside using a scalpel or electrocautery under local anesthesia and/or IV sedation. In the forearm, axially oriented midradial and midulnar incisions are made for the entire extent of the full-thickness burn. Escharotomy should progress distally (wrist, hand, then digits) as necessary to restore perfusion. Digital escharotomies are achieved via midaxial incisions over the radial aspects of the thumb and small finger, and the ulnar aspect of the index, middle, and ring fingers. 8 5 This incision location on the digits is preferred to avoid scars that may be painful on the pinch and contact surfaces of the digits. Edema formation in burned hands hinders motion and may be a factor in later contracture formation. The hands must be elevated above the level of the heart to minimize edema formation. This is the most important initial step in the management of hand burns and can be done in any sized burn without hindering resuscitation, pulmonary, or other critical care management. After initial dbridement of devitalized tissue, burned hands should be cleansed twice daily. Burns that are clearly partial to full thickness may be managed with silver sulfadiazine cream. Some centers also use mafenide acetate in conjunction with silver sulfadiazine. A number of dressings are available for the treatment of clean partial-thickness burns. Allograft (human cadaver skin), although expensive, provides an excellent temporary dressing. Another option is Biobrane biosynthetic wound dressing (Bertek Pharmaceuticals, Morgantown, WVa), a bilayer semisynthetic dressing consisting of an elastic nylon fabric bonded to a semipermeable silastic membrane and coated with collagen polypeptides. Gloves manufactured from this material are available in a variety of sizes and are ideal dressings for clean partial-thickness burns of the hands. Cultured autologous keratinocytes also have been found to be useful in wound coverage. A burned hand that is not properly positioned, splinted, or ranged will develop debilitating contractures. These contractures represent major disabilities that are difficult to correct with subsequent reconstructive surgery. A typical contracture is an "intrinsic minus" position where the MP joints are fixed in hyperextension and the PIP joints are fixed in a position of flexion.8 6 The collateral ligaments of the MP joint are the most important structures of the burned hand. For this reason, positioning of the burned hand should place the MP joints at maximum flexion

to maximally stretch these collateral ligaments. The ideal anatomic position for splinting is the intrinsic plus position with the thumb fully abducted. An orthoplastic splint may be fashioned and secured to the forearm over burn dressings; Velcro straps allow the splint to be loosened to compensate for progressive edema. In special cases, burned hands can be maintained in a safe functional position by temporary Kirshner wire arthrodesis of unstable MP and IP joints. Occupational therapy has a major impact on hand function following burn injury. Early attention from occupational therapy can minimize the need for later reconstruction.8 7 Re-establishment of function is the ultimate goal for the patient and is directly dependent upon patient effort expended during occupational therapy sessions. Some clinicians feel that the function present at 1-year postinjury represents that plateau of rehabilitation potential. In many cases, with good wound care, skin will heal spontaneously without the need for operative intervention. In other cases, surgical excision of the burn with split-thickness skin grafting will be necessary. Grafting should be undertaken as soon as it becomes obvious that wound healing will not be complete by postburn day 14. Considerable controversy surrounds the need, timing, and method of grafting of burned hands. Several prospective studies show that final surgical management vs. nonoperative care does not impact functional outcome of burned hands. Likewise, function is not affected by the choice of sheet graft over meshed graft, and some claim that cosmetic result is similar with meshed and unmeshed grafts to the hands. The timing of hand graft application is also controversial. For burn patients, the first goal of skin grafting is survival, the second is function, and the third is aesthetics.8 8 This should be taken into account when planning skin grafting to the burned hand. The complete coverage of two burned hands with sheet grafts will likely require harvest of several large autografts. These same autografts, when meshed, could cover a larger area on the trunk, thereby reducing the total burn size. However, it makes little sense to leave a burn survivor with nonfunctional hands because grafting was deferred until the remainder of the skin was healed. A balance between survival and function must be struck.8 9 Tangential excision of burned hands should be performed under tourniquet to minimize potentially significant blood loss. Skin grafts are secured with skin staples, suture, or fibrin glue. Some surgeons will place the hand into a splint before grafting is commenced to minimize shearing. The splint is removed within 1 week, and gentle therapy is initiated. The patient is encouraged to use the hands for activities of daily living, and active ROM exercises are prescribed. Vacuum-assisted closure devices (V.A.C., KCI, San Antonio, Tex) have advanced wound care, in general, and have particular usefulness in the hand. A sponge specifically designed for the hand is available and is currently used at many centers in the treatment of hand burns (Fig. 44-27). Studies are underway that investigate whether burn progression is limited and edema is reduced by the early application of vacuum therapy. The hand V.A.C. sponge also provides an excellent method of splinting the burned hand in a position of function.

Fig. 44-27.

V.A.C. GranuFoam Hand Dressing. (Courtesy of KCI Licensing, Inc., 2008, used with permission.)

Reconstruction The most common upper extremity deformities requiring reconstruction after burns are dorsal hand and web space contractures. Ideally, proper positioning prevents dorsal hand contractures. If the initial excision was tangential rather than fascial, such that some remnant dorsal subcutaneous fat remains, a scar release can be performed. The released scar will slide distally, and a skin graft can fill in the defect created behind it. Any release must result in complete ROM of the MP joints. Web space contractures can be minimized by proper early surgery and compression gloves supplemented with web space conformers. In the normal web space, the leading edge of the volar aspect of the web is distal to the dorsal aspect. In the typical dorsal web space contracture, this is reversed, with dorsal syndactyly. When severe, abduction of the digits is limited. Repair can be achieved with local flaps and Z-plasties (Fig. 44-28).

Fig. 44-28.

Z-plasty release of web space contracture. A. First web space burn contracture. B. Immediate postoperative result.

When burns of the hands are deep, initial dbridement may result in exposure of viable tendon or joints. Flap coverage is then required. A local flap of choice is the reversed radial forearm flap. Extensive injury may require free-tissue transfer such as a free anterolateral thigh flap (Fig. 44-29) or free lateral arm flap. In cases where local flaps are unavailable due to extent of injury and free tissue transfer is contraindicated because of overall medical condition or vascular insufficiency, other pedicle flaps have been used, such as the groin flap. Recently, dermal substitutes have been used when a flap or full-thickness skin graft would have been necessary but was unavailable or unwise for the patient.9 0

Fig. 44-29.

Free anterolateral thigh flap reconstruction of a large dorsal hand wound. Once wound coverage is stable, this flap will need to be surgically revised to achieve proper contour.

Special Situations Chemical burns of the hands are continuously flushed with water until the pain significantly decreases or stops. Acid burns may require 20 minutes of irrigation while alkali burns may require several hours of irrigation. Hydrofluoric acid burns are a special consideration. This type of burn is marked by slow onset of severe pain as the compound reaches deeper tissues. Hydrofluoric acid avidly binds tissue and circulating calcium, resulting in hypocalcemia that can lead to cardiac arrhythmia and arrest. Following water irrigation, a mixture of calcium gluconate in an aqueous jelly is placed into a surgical glove, which is then used to cover the burned hand. Effectiveness of treatment is assessed by relief of pain. If topical therapy does not relieve pain, then locally injected intra-arterial calcium may be necessary.9 1 As electrical current passes through tissue, heat is generated in the intervening muscle and bone, leading to damage and necrosis of these tissues. The skin itself tends to dissipate heat externally and may remain uninjured. The examiner must have a high index of suspicion for deeper pathology, including compartment syndrome and rhabdomyolysis of the forearm muscles. Criteria for performing fasciotomy are similar for other circumstances of compartment syndrome, although some surgeons perform fasciotomy empirically based on mechanism of injury. In the upper extremity, fasciotomy should include the volar, mobile wad, and dorsal compartments of the forearm via two incisions placed 180 to each other. Carpal tunnel release is performed as part of the forearm release. Fasciotomy of the thenar, hypothenar, and interosseous compartments of the hand also may be performed depending on site of current entry and clinical examination.

VASCULAR DISEASE Vascular disorders encompass a broad spectrum of pathophysiologic states that results in aberrant microvascular

perfusion, potentially threatening the viability of the hand or digits. Vascular disorders of the upper extremity and hand can be classified into acute or chronic categories. Acute vascular injury to the hand can be due to trauma or iatrogenic causes. Traumatic vascular injury is discussed earlier in this chapter under Vascular Injuries. Iatrogenic causes include radial artery catheterization or drug injection. Acute vessel thrombosis may ensue, which may produce distal ischemia. The hand is assessed for perfusion within the injured adequacy of perfusion distally. Clinical examination and pencil Doppler evaluation may provide sufficient information. When these do not, contrast angiography remains the gold standard evaluation for vessel patency. It also can be used to direct localized thrombolytic therapy or as guidance for balloon embolectomy or vascular bypass, when indicated. Chronic vascular disorders tend to develop more slowly and are seen in an older population. This category includes atherosclerosis, progressive thrombosis (including hypothenar hammer syndrome), thromboangiitis obliterans (Buerger's disease), embolism, and vasospastic disease. Atherosclerosis of the brachial, radial, or ulnar artery with acute thrombosis may require surgical exploration, thrombectomy, and possible saphenous vein interposition grafting. Although angioplasty is often used to treat atherosclerotic lesions in other vascular beds, radial and ulnar artery arteriosclerosis is best treated by surgery. Frequently, both radial and ulnar arteries are affected by disease, and hence, the patient presents with symptoms. The presence of a complete palmar arterial arch with good distal runoff may allow good results with repair of only the radial or the ulnar artery. Atherosclerotic changes in the hand and finger arteries are difficult to treat and often associated with severe systemic disease and diabetes. Distal vessels that can receive a bypass graft must be present on angiography to consider a bypass procedure. Amputation may be the best option in cases where pain or gangrene is sufficiently severe. Aneurysms can be resected and repaired primarily with interpositional vein grafts.

Hypothenar Hammer Syndrome Aneurysmal thrombosis of the ulnar artery at the hook of the hamate is a common type of vascular occlusion in the hand. It is known as hypothenar hammer syndrome because it is often the result of repetitive trauma to the ulnar side of the palm associated with pounding as performed by laborers.9 2 Symptoms present may include pain, numbness and tingling, weakness of grip, discoloration of the fingers, and even gangrene or ulcers of the fingertips. Thrombosis of the ulnar artery can dislodge, leading to embolism in the palmar arch or digital vessels. If acute in onset, proximal occlusions may be embolectomized with a balloon catheter, or sometimes, under direct vision via an arteriotomy. Very distal embolism may require infusion of thrombolytics to dissolve clots and allow reperfusion. Large-vessel acute embolism and reperfusion may result in edema and compartment syndrome, requiring fasciotomy. A high index of suspicion must be maintained. For the more common scenario of chronic, progressive occlusion, the involved segment of ulnar artery should be resected. There is disagreement in the literature regarding whether simple ligation and excision is sufficient for patients with sufficient distal flow or if all patients should undergo vascular reconstruction.9 3 The authors' personal preference is to reconstruct all patients.

Vasospastic Disease Raynaud's phenomenon results from excessive sympathetic nervous system stimulation. Perfusion is diminished and fingers often become cyanotic. Although the onset of the symptoms is benign, chronic episodes can result in atrophic changes and painful ulceration or gangrene of the digits. Raynaud's disease is present when Raynaud's phenomenon occurs without another associated disease. This disease predominately affects young women and is

often bilateral. In contrast, Raynaud's syndrome occurs when Raynaud's phenomenon is associated with an underlying connective tissue disorder, such as scleroderma. Arterial stenosis is present due to disease changes in blood vessels as a result of the specific medical disorder. Scleroderma is an autoimmune connective tissue disorder resulting in fibrosis and abnormal collagen deposition in tissue. Many organs can be affected, with the skin most commonly and noticeably involved. In this disease, blood vessels are injured by intimal fibrosis leading to microvascular disease. The vessels become subject to Raynaud's phenomenon and patients develop painful, ulcerated, and sometimes necrotic digits. Sympathectomy can provide pain relief and healing of ulcers for patients with scleroderma and Raynaud's phenomenon. In this procedure, adventitia is stripped from the radial artery, ulnar artery, superficial palmar arch, and digital arteries in various combinations based on which digits are most affected. The decrease in sympathetic tone allows for vasodilation and increased blood flow. Patients being considered for sympathectomy typically undergo a trial of lidocaine infiltration near the vessels one intends to sympathectomize. If the patient notes significant distal pain relief and/or previously ischemic tissue improves in color, sympathectomy may provide the same results in a long-term fashion.9 4

CONGENITAL DIFFERENCES Congenital differences in a newborn can be particularly disabling as the child learns to interact with the environment through the use of his/her hands. The degree of anomaly can range from minor, such as a digital disproportion, to severe, such as total absence of a bone. In recent years, increasing knowledge of the molecular basis of embryonic limb development has significantly enhanced the understanding of congenital differences. Congenital hand differences have an incidence of 1:1500 births. The two most common differences encountered are syndactyly and polydactyly.9 5 There are numerous classification systems for hand differences. The Swanson classification, adopted by the American Society for Surgery of the Hand, delineates seven groups (headers in bold below), organized based on anatomic parts affected by types of embryonic failures.9 6

Failure of Formation of Parts The failure of the formation of parts is a group of congenital differences that forms as a result of a transverse or longitudinal arrest of development. Conditions in this group include radial club hand, a deformity that involves some or all of the tissues on the radial side of the forearm and hand, or ulnar club hand, which involves underdevelopment or absence of the ulnar-sided bones.

Failure of Separation of Parts The failure of the separation of parts comprises conditions where the tissues of the hand fail to separate during embryogenesis. Syndactyly, in which two or more fingers are fused together, is the most common congenital hand deformity. Syndactyly occurs in seven out of every 10,000 live births. There is a familial tendency to develop this deformity. This deformity often involves both hands, and males are more often affected than females. Surgical release of syndactyly requires the use of local flaps to create a floor for the interdigital web space and to partially surface the adjacent sides of the separated digits (Fig. 44-30). Residual defects along the sides of the separated fingers are covered with full-thickness skin grafts. Surgery is indicated when the webbing occurs distal to the usual point of separation of the fingers and the webbing prohibits full use of the fingers. Surgery usually is performed at 6 to 12 months of age.

Fig. 44-30.

Syndactyly. Hand of a 1-year-old patient with complex syndactyly between the long and ring finger. Complex syndactyly refers to fingers joined by bone or cartilaginous union, usually in a side-to-side fashion at the distal phalanges. The syndactyly is divided with interdigitating full-thickness flaps, a dorsal trapezoidal-shaped flap to resurface the floor of the web space, and full-thickness skin grafts. Note the skin grafts on the ulnar and radial sides of the new web space.

Duplications of Parts Duplication of digits is also known as polydactyly . Radial polydactyly is usually manifest as thumb duplication. Wassel described a classification system for thumb duplications based on the level of bifurcation.9 7 When two thumbs are present in the same hand, they are rarely both normal in size, alignment, and mobility. In the most common form of thumb duplication, a single broad MC supports two proximal phalanges, each of which support a distal phalanx. Optimal reconstruction requires merging of elements of both component digits. Usually the ulnar thumb is maintained. If the duplication occurs at the MP joint, the radial collateral ligament is preserved with the MC and attached to the proximal phalanx of the ulnar thumb. Surgery is usually performed at 6 to 12 months of age. Ulnar-sided polydactyly, may usually be treated by simple excision.

Overgrowth of Parts Overgrowth of digits also is known a macrodactyly , which causes an abnormally large digit. In this situation, the hand and the forearm also may be involved. In this rare condition, all parts of a digit are affected; however, in most cases, only one digit is involved, and it is usually the index finger. This condition is more commonly seen in males. Surgical treatment of this condition is complex, and the outcomes may be less than desirable. Sometimes, amputation of the enlarged digit is recommended.

Undergrowth of Parts Underdeveloped fingers or thumbs are associated with many congenital hand deformities. Surgical treatment is not always required to correct these deformities. Underdeveloped fingers may include the following: small digits (brachydactyly), missing muscles, underdeveloped or missing bones, or absence of a digit.

Constriction Band Syndrome Constriction band syndrome is a set of congenital differences that occurs when a tissue band forms around the digit(s) arm in utero, causing problems that can affect blood flow and normal growth. This condition may be associated with other problems such as clubfoot, cleft lip, cleft palate, or other craniofacial anomalies. The cause of the ring constrictions is unknown. Some theories suggest that folds or bands in the amniotic membrane may be responsible for this condition.

Generalized Skeletal Problems and Syndromes This is a rare and complex group of unclassified problems.

Treatment In addition to the managements described above, treatments for congenital anomalies may include limb manipulation and stretching, splinting of the affected limbs, tendon transfers, external appliances (to help realign misshapen digits or hands), physical therapy (to help increase the strength and function of the hand), correction of contractures, skin grafts, and prosthetics.9 8

REFERENCES Entries Highlighted in Bright Blue Are Key References. 1. American Society for Surgery of the Hand, in: The Hand: Examination and Diagnosis , 3rd ed. New York: Churchill Livingstone, 1990, p 5. 2. Moore KL: The upper limb, in Moore KL (ed): Clinically Oriented Anatomy , 3rd ed. Baltimore, Md: Williams & Wilkins, 1992, p 501. 3. Schuind F, Cooney WP, Linscheid RL, et al: Force and pressure transmission through the normal wrist. A theoretical two-dimensional study in the posteroanterior plane. J Biomech 28:587, 1995. [PMID: 7775494] 4. Doyle JR: Anatomy of the flexor tendon sheath and pulley system: A current review. J Hand Surg [Am] 14:349, 1989. [PMID: 2732428] 5. Dumanian GA, Segalman K, Buehner JW, et al: Analysis of digital pulse-volume recordings with radial and ulnar artery compression. Plast Reconstr Surg 102:1993, 1998. [PMID: 9810996] 6. Green DP: General principles, in Green DP, Hotchkiss RN, Pedersen WC, et al (eds): Green's Operative Hand Surgery , 5th ed. Philadelphia, Pa: Churchill Livingstone, 2005, p 3. 7. Gilula LA: Carpal injuries: Analytic approach and case exercises. AJR Am J Roentgenol 133:503, 1979. [PMID: 111512] 8. Cousins MJ, Mather LE: Clinical pharmacology of local anaesthetics. Anaesth Inten Care 8:257, 1980. [PMID: 6999936] 9. Lalonde D, Bell M, Benoit P, et al: A multicenter prospective study of 3,110 consecutive cases of elective epinephrine use in the fingers and hand: The Dalhousie Project clinical phase. J Hand Surg [Am] 30:1061, 2005. [PMID: 16182068] 10. Yousif NJ, Grunert BK, Forte RA, et al: A comparison of upper arm and forearm tourniquet tolerance. J Hand Surg [Br] 18:639, 1993. [PMID: 8294833]

11. Hastings H 2nd, Carroll C 4th: Treatment of closed articular fractures of the metacarpophalangeal and interphalangeal joints. Hand Clin 4:203, 1988. 12. Bond CD, Shin AY, McBride MT, et al: Percutaneous screw fixation or cast immobilization for nondisplaced scaphoid fractures. J Bone Joint Surg [Am] 83:483, 2001. [PMID: 11315775] 13. Mayfield JK, Johnson RP, Kilcoyne RF: The ligaments of the wrist and their functional significance. Anat Rec 186:417, 1976. [PMID: 999035] 14. Kleinert HE, Kutz JE, Atasoy E, et al: Primary repair of flexor tendons. Orthop Clin North Am 4:865, 1973. [PMID: 4598164] 15. Komatsu S, Tamai S: Successful replantation of a completely cut-off thumb: Case report. Plast Reconstr Surg 42:374, 1968. 16. Lifchez SD, Marchant-Hanson J, Matloub HS, et al: Functional improvement with digital prosthesis use after multiple digit amputations. J Hand Surg [Am] 30:790, 2005. [PMID: 16039373] 17. Frandsen PA: V-Y plasty as treatment of finger tip amputations. Acta Orthop Scand 49:255, 1978. [PMID: 356514] 18. Moberg E: The treatment of mutilating injuries of the upper limb. Surg Clin North Am 44:1107, 1964. [PMID: 14198141] 19. Melone CP Jr., Beasley RW, Carstens JH Jr.: The thenar flap—an analysis of its use in 150 cases. J Hand Surg [Am] 7:291, 1982. [PMID: 7086099] 20. Johnson RK, Iverson RE: Cross-finger pedicle flaps in the hand. J Bone Joint Surg Am 53:913, 1971. [PMID: 4934075] 21. Bekler H, Gokce A, Beyzadeoglu T, et al: The surgical treatment and outcomes of high-pressure injection injuries of the hand. J Hand Surg Eur Vol 32:394, 2007. [PMID: 17399870] 22. Mubarak SJ, Hargens AR: Acute compartment syndromes. Surg Clin North Am 63:539, 1983. [PMID: 6346542] 23. Gulgonen A: Compartment syndrome, in Green DP, Hotchkiss RN, Pedersen WC, et al (eds): Green's Operative Hand Surgery , 5th ed. Philadelphia, Pa: Churchill Livingstone, 2005, p 1985. 24. Wray RC Jr., Glunk R: Treatment of delayed union, nonunion, and malunion of the phalanges of the hand. Ann Plast Surg 22:14, 1989. [PMID: 2923403] 25. Munk B, Larsen CF: Bone grafting the scaphoid nonunion: A systematic review of 147 publications including 5,246 cases of scaphoid nonunion. Acta Orthop Scand 75:618, 2004. [PMID: 15513497] 26. Curtis RM: Capsulectomy of the interphalangeal joints of the fingers. J Bone Joint Surg Am 36:1219, 1954. [PMID: 13211714] 27. Nath RK, Mackinnon SE: Management of neuromas of the hand. Hand Clin 12:745, 1996. [PMID: 8953293] 28. Stanton-Hicks M, Jnig W, Hassenbusch S, et al: Reflex sympathetic dystrophy: Changing concepts and taxonomy. Pain 63:127, 1997. 29. Schrmann M, Zaspel J, Lhr P, et al: Imaging in early posttraumatic complex regional pain syndrome: A comparison of diagnostic methods. Clin J Pain 23:449, 2007. [PMID: 19488457] 30. Mackinnon SE: Pathophysiology of nerve compression. Hand Clin 18:231, 2002. [PMID: 12371026] 31. http://www.cdc.gov/niosh/docs/97-141/ergotxt5a.html: National Institutes for Occupational Safety and Health. Hand/Wrist Musculoskeletal disorders (Carpal Tunnel Syndrome, Hand/Wrist Tendinitis, and Hand/Arm Vibration Syndrome): Evidence for WorkRelatedness. NIOSH Publication No. 97-141 [accessed Feb. 11, 2009].

32. Williams TM, Mackinnon SE, Novak CB, et al: Verification of the pressure provocative test in carpal tunnel syndrome. Ann Plast Surg 29:8, 1992. [PMID: 1497301] 33. Green DP: Diagnostic and therapeutic value of carpal tunnel injection. J Hand Surg [Am] 9:850, 1984. [PMID: 6512200] 34. Trumble TE, Diao E, Abrams RA, et al: Single-portal endoscopic carpal tunnel release compared with open release: A prospective, randomized trial. J Bone Joint Surg Am ; 84:1107, 2002. [PMID: 12107308] 35. Mackinnon SE, Novak CB: Compression neuropathies, in Green DP, Hotchkiss RN, Pedersen WC, et al (eds): Green's Operative Hand Surgery , 5th ed. Philadelphia, Pa: Churchill Livingstone, 2005, p 999. 36. Swanson AB: Implant resection arthroplasty of the proximal interphalangeal joint. Orthop Clin North Am 4:1007, 1973. [PMID: 4598161] 37. Branam BR, Tuttle HG, Stern PJ, et al: Resurfacing arthroplasty versus silicone arthroplasty for proximal interphalangeal joint osteoarthritis. J Hand Surg [Am] 32:775, 2007. [PMID: 17606054] 38. Burton RI, Pellegrini VD Jr.: Surgical management of basal joint arthritis of the thumb. Part II. Ligament reconstruction with tendon interposition arthroplasty. J Hand Surg [Am] 11:324, 1986. [PMID: 3711604] 39. Gray KV, Meals RA: Hematoma and distraction arthroplasty for thumb basal joint osteoarthritis: minimum 6.5 year follow-up evaluation. J Hand Surg [Am] 32:23, 2007. [PMID: 17218172] 40. Watson HK, Ballet FL: The SLAC wrist: Scapholunate advanced collapse patter of degenerative arthritis. J Hand Surg [Am] 9:358, 1984. [PMID: 6725894] 41. Stern PJ, Agabegi SS, Kiefhaber TR, et al: Proximal row carpectomy. J Bone Joint Surg Am 87:166, 2005. [PMID: 16140792] 42. Goldfarb CA, Stern PJ, Kiefhaber TR: Palmar midcarpal instability: The results of treatment with 4-corner arthrodesis. J Hand Surg [Am] 29:258, 2004. [PMID: 15043899] 43. Feldon P, Terrono AL, Nalebuff EA, et al: Rheumatoid arthritis and other connective tissue disorders, in Green DP, Hotchkiss RN, Pedersen WC, et al (eds): Green's Operative Hand Surgery , 5th ed. Philadelphia, Pa: Churchill Livingstone, 2005, p 2049. 44. Swanson AB: Finger joint replacement by silicone rubber implants and the concept of implant fixation by encapsulation. Ann Rheum Dis 28:47, 1969. [PMID: 5379851] 45. Elliot D, Ragoowansi R: Dupuytren's disease secondary to acute injury, infection or operation distal to the elbow in the ipsilateral upper limb—a historical review. J Hand Surg [Br] 30:148, 2005. [PMID: 15757767] 46. Luck JV: Dupuytren's contracture: A new concept of the pathogenesis correlated with surgical management. J Bone Joint Surg Am 41:635, 1959. [PMID: 13664703] 47. McGrouther DA. Dupuytren's contracture, in Green DP, Hotchkiss RN, Pedersen WC, et al (eds): Green's Operative Hand Surgery , 5th ed. Philadelphia, Pa: Churchill Livingstone, 2005, p 159. 48. Badalamente MA, Hurst LC: Efficacy and safety of injectable mixed collagenase subtypes in the treatment of Dupuytren's contracture. J Hand Surg [Am] 32:767, 2007. [PMID: 17606053] 49. Saar JD, Grothaus PC: Dupuytren's disease: An overview. Plast Reconstr Surg 106:125, 2000. [PMID: 10883625] 50. Prosser R, Conolly WB: Complications following surgical treatment for Dupuytren's contracture. J Hand Ther 9:344, 1996. [PMID: 8994009] 51. Wolfe SW: Tenosynovitis, in: Green DP, Hotchkiss RN, Pederson WC, et al (eds): Green's Operative Hand Surgery , 5th ed.

Philadelphia, Pa: Churchill Livingstone, 2005, p 2137. 52. Hueston JT, Wilson WF: The aetiology of trigger finger explained on the basis of intratendinous architecture. Hand 4:257, 1972. [PMID: 5083965] 53. Fahey JJ, Bollinger JA: Trigger-finger in adults and children. J Bone Joint Surg Am 36:1200, 1954. [PMID: 13211713] 54. Eastwood DM, Gupta KJ, Johnson DP: Percutaneous release of the trigger finger: An office procedure. J Hand Surg [Am] 17:114, 1992. [PMID: 1538091] 55. Gilberts EC, Beekman WH, Stevens HJ, et al: Prospective randomized trial of open versus percutaneous surgery for trigger digits. J Hand Surg [Am] 26:497, 2001. [PMID: 11418913] 56. Moore JS: De Quervain's tenosynovitis: Stenosing tenosynovitis of the first dorsal compartment. J Occup Environ Med 39:990, 1997. [PMID: 9343764] 57. Finkelstein H: Stenosing tendovaginitis at the radial styloid process. J Bone Joint Surg 12:509, 1930. 58. Weiss AP, Akelman E, Tabatabai M: Treatment of de Quervain's disease. J Hand Surg [Am] 19:595, 1994. [PMID: 7963313] 59. Jackson WT, Viegas SF, Coon TM: Anatomical variations in the first extensor compartment of the wrist. A clinical and anatomical study. J Bone Joint Surg [Am] 68:923, 1986. [PMID: 3733780] 60. Littler JW, Freedman DM, Malerich MM: Compartment reconstruction for de Quervain's disease. J Hand Surg [Br] 27:242, 2002. [PMID: 12074610] 61. Hanlon DP, Luellen JR: Intersection syndrome: A case report and review of the literature. J Emerg Med 17:969, 1999. [PMID: 10595881] 62. Grundberg AB, Reagan DS: Pathologic anatomy of the forearm: Intersection syndrome. J Hand Surg [Am] 10:299, 1985. [PMID: 3980951] 63. Hausman MR, Lisser SP: Hand infections. Orthop Clin North Am 23:171, 1992. [PMID: 1729665] 64. Bach HG, Steffin B, Chhadia AM, et al: Community-associated methicillin-resistant Staphylococcus aureus hand infections in an urban setting. J Hand Surg [Am] 32:380, 2007. [PMID: 17336847] 65. Gill MJ, Arlette J, Buchan KA: Herpes simplex virus infection of the hand. A profile of 79 cases. Am J Med 84:89, 1988. [PMID: 2827469] 66. Kanavel AB: The treatment of acute suppurative tenosynovitis—discussion of technique, in: Infections of the Hand; A Guide to the Surgical Treatment of Acute and Chronic Suppurative Processes in the Fingers, Hand, and Forearm , 5th ed. Philadelphia: Lea and Farbinger, 1925, p 985. 67. Dickson-Wright A: Tendon sheath infections. Proc Roy Soc Med 37:504, 1943. 68. Gosain AK, Markison RE: Catheter irrigation for treatment of pyogenic closed space infections of the hand. Br J Plast Surg 44:270, 1991. [PMID: 1647830] 69. Boles SD, Schmidt CC: Pyogenic flexor tenosynovitis. Hand Clin 14:567, 1998. [PMID: 9884895] 70. Michon J: Phlegmon of the tendon sheaths. Ann Chir 28:277, 1974. [PMID: 4839194] 71. Kour AK, Looi KP, Phone MH, et al: Hand infections in patients with diabetes. Clin Orthop Relat Res 331:238, 1996. [PMID: 8895645]

72. Nelson CL, Sawmiller S, Phalen GS: Ganglions of the wrist and hand. J Bone Joint Surg [Am] 54:1459, 1972. [PMID: 4653631] 73. Leffert RD: Lipomas of the upper extremity. J Bone Joint Surg [Am] 54:1262, 1972. [PMID: 4652058] 74. Athanasian EA: Principles of diagnosis and management of musculoskeletal tumors, in Green DP, Hotchkiss RN, Pederson WC, et al (eds): Green's Operative Hand Surgery , 3rd ed. New York, NY: Churchill Livingstone, 1993, p 2206. 75. Bauer RD, Lewis MM, Posner MA: Treatment of enchondromas of the hand with allograft bone. J Hand Surg [Am] 13:908, 1988. [PMID: 3066817] 76. Jaffe HL, Lichtenstein HL, Elsutro CJ: Pigmented villonodular synovitis, bursitis, and tenosynovitis. Arch Pathol 31:731, 1941. 77. Jaffe HL, Lichtenstein L, Portis RB: Giant cell tumor of bone. Its pathologic appearance, grading, supposed variants and treatment. Arch Pathol 30:993, 1940. 78. Campanacci M: Giant cell tumor, in: Bone and Soft Tissue Tumors: Clinical Features, Imaging, Pathology and Treatment , 2nd ed. New York, NY: Springer-Verlag, 1999, p 99. 79. Cottalorda J, Bourelle S, Stephan JL, et al: Radiologic case study. Giant-cell tumor of the wrist in a skeletally immature girl. Orthopedics 25:550, 2002. 80. Witthaut J, Steffens K, Koob E: Reliable treatment of pyogenic granuloma of the hand. J Hand Surg [Br] 19:791, 1994. [PMID: 7706889] 81. TerKonda SP, Perdikis G: Non-melanotic skin tumors of the upper extremity. Hand Clin 20:293, 2004. [PMID: 15275688] 82. Glat PM, Shapiro RL, Roses DF, et al: Management considerations for melanonychia striata and melanoma of the hand. Hand Clin 11:183, 1995. [PMID: 7635880] 83. Balch CM, Soong SJ, Smith T, et al: Long-term results of a prospective surgical trial comparing 2 cm vs. 4 cm excision margins for 740 patients with 1-4 mm melanomas. Ann Surg Oncol 8:101, 2001. [PMID: 11258773] 84. Heaton KM, El-Naggar A, Ensign LG, et al: Surgical management and prognostic factors in patients with subungual melanoma. Ann Surg 219:197, 1994. [PMID: 8129491] 85. Sheridan RL: Acute hand burns in children: Management and long-term outcome based on a 10-year experience with 698 injured hands. Ann Surg 229:558, 1999. [PMID: 10203090] 86. Robson MC, Smith DJ: Burned hand, in Jurkiewicz MJ (ed): Plastic Surgery: Principles and Practices . St Louis, Mo: C.V. Mosby Co, 1990. 87. Achauer BM: Burn Reconstruction . New York, NY: Thieme Medical Publishers, 1991. 88. Sheridan RL: Comprehensive management of burns. Curr Prob Surg 38:641, 2001. 89. Goodwin CW, McGuire MS, McManus WF, et al: Prospective study of burn wound excision of the hands. J Trauma 23:510, 1983. [PMID: 6345800] 90. Haslik W, Kamolz LP, Nathschlger G, et al: First experiences with the collagen-elastin matrix Matriderm as a dermal substitute in severe burn injuries of the hand. Burns 33:364, 2007. [PMID: 17240532] 91. Hatzifotis M, Williams A, Muller M, et al: Hydrofluoric acid burns. Burns 30:156, 2004. [PMID: 15019125] 92. Conn J Jr., Bergan JJ, Bell JL: Hypothenar hammer syndrome: Posttraumatic digital ischemia. Surgery 68:1122, 1970. [PMID: 5483245]

93. Zimmerman NB, Zimmerman SI, McClinton MA, et al: Long-term recovery following surgical treatment for ulnar artery occlusion. J Hand Surg [Am] 19:17, 1994. [PMID: 8169363] 94. Ruch DS, Holden M, Smith BP, et al: Periarterial sympathectomy in scleroderma patients: Intermediate-term follow-up. J Hand Surg [Am] 27:258, 2002. [PMID: 11901385] 95. Giele H, Giele C, Bower C, et al: The incidence and epidemiology of congenital upper limb anomalies: A total population study. J Hand Surg [Am] 26:628, 2001. [PMID: 11466636] 96. Swanson AB: A classification for congenital limb malformations. J Hand Surg [Am] 1:8, 1976. [PMID: 1021591] 97. Wassel HD: The results of surgery for polydactyly of the thumb. A review. Clin Orthop Relat Res 64:175, 1969 [PMID: 4898399] 98. McCarroll HR: Congenital anomalies: A 25-year overview. J Hand Surg [Am] 25:1007, 2000. [PMID: 11119659]

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Print CloseWindow Note: Large images and tables on this page may necessitate printing in landscape mode. Copyright The McGraw-Hill Companies.All rights reserved. Schwartz's Principles of Surgery >Chapter 45. Plastic and Reconstructive Surgery>

KEY POINTS 1. Plastic surgery is the field of surgery that addresses congenital and acquired defects, striving to return form and function. 2. Children diagnosed with cleft and craniofacial anomalies benefit from interdisciplinary care at a specialized center focusing on team care. Long-term follow-up during growth and development is critical for optimal outcomes. 3. Reconstructive surgery attempts to restore form and function through techniques that include skin grafting, use of muscle flaps, bone grafting, tissue expansion, free tissue transfer with microsurgery, and replantation. 4. Aesthetic surgery is surgery performed to reshape the normal structure of the body to improve the patient's appearance and self-esteem. Patients undergoing aesthetic surgery present a unique challenge. The most important outcome parameter is patient satisfaction, and therefore a thorough understanding of the patient's motivations, goals, and expectations is critical. 5. Plastic surgery has been a field of innovation. The future of the specialty likely includes advancements in the areas of regenerative medicine, fetal surgery, and reconstructive transplantation with composite tissue allotransplants.

HISTORICAL BACKGROUND The field of plastic surgery focuses on the restoration of form and function to those who have congenital and acquired deformities. Plastic surgery routinely addresses new problems and challenges; therefore, the plastic surgeon must have an expert knowledge of anatomy and surgical technique to address new challenges. The word plastic is derived from the Greek plastikos, meaning "to mold." Although the term plastic surgery can be found in several medical writings from the eighteenth and nineteenth centuries, it was John Staige Davis who established the name of the specialty with the 1919 publication of his book Plastic Surgery—Its Principles and Practice. Certainly, for centuries plastic surgery operations have been performed. One of the earliest accounts of reconstructive surgery can be found in the Sushruta Samhita, an early text from the sixth or seventh century

B .C

.

by the practitioner Sushruta. In this writing, the reconstruction of an amputated nose with a pedicled forehead flap and the reconstruction of the ear with cheek flaps was described. In addition, in the first century

A .D

., the Roman

physicians Aulus Cornelius Celsus and Paulus Aegineta described operations for traumatic injuries of the face. The first textbook of plastic surgery is believed to be Gaspara Tagliacozzi's 1597 publication De Curtorum Chirurgia

per Insitionem. This text describes the reconstruction of the nose with a pedicled arm flap. The nineteenth century saw advances in reconstructive surgery, including Giuseppe Baronio's successful grafting of sheepskin. The techniques for perfecting human skin grafting followed in the later part of the century. Great advances in plastic surgery occurred as a result of the first and second world wars. Out of the fields of dental surgery, otolaryngology, ophthalmology, and general surgery, the discipline of plastic surgery was established. The founders of the field include Sir Harold Gillies, an otolaryngologist, who established a center for the treatment of maxillofacial injuries in England; V. H. Kazanjian, a dental surgeon from Boston, who established a center in France for the treatment of facial injuries incurred in World War II; and Vilray P. Blair, from St. Louis, who established centers for the treatment of soft tissue and maxillofacial reconstruction for the U.S. Army. With the onset of World War II, centers of excellence for hand reconstruction appeared as well. In the last 50 years, advances in the field of plastic surgery have included the transplantation of both autologous and allogeneic tissue, tissue expansion, techniques of moving tissues regionally within the body as muscle and myocutaneous flaps, the distant transfer of free flaps using microsurgery, replantation of traumatically amputated extremities and digits, and the emergence of the field of craniofacial surgery. The future of plastic surgery will likely see further advances in the realms of regenerative medicine, fetal surgery, and reconstructive transplantation with composite tissue allotransplants.

GENERAL PRINCIPLES Skin Incisions Human skin exists in a state of tension created by internal and external factors. Externally, skin and underlying subcutaneous tissue are acted on by gravity and clothing. Internally, skin is subjected to forces generated by underlying muscles, joint extension and flexion, and tethering of fibrous tissues from zones of adherence. As a result, when skin is incised linearly it gapes to variable degrees. When a circular skin excision is performed, the skin defect assumes an elliptical configuration paralleling the lines of greatest tension. Carl Langer, an anatomist from Vienna, first fully described these tension lines in the mid-1800s based on his studies of fresh cadavers.1 A. F. Borges described another set of skin lines that, different from Langer's lines, reflect the vectors of relaxed skin tension.2 Although the term Langer's lines often is used interchangeably with the term relaxed skin tension lines, the former lines describe skin tension vectors observed in the stretched integument of cadavers exhibiting rigor mortis, whereas the latter lines lay perpendicular to and more accurately reflect the action of underlying muscle.2 Kraissl's lines, which run along natural wrinkles and skin creases, tend also to follow the relaxed skin tension lines (Fig. 45-1). Relaxed skin tension lines may be exploited to create incisions and reconstructions that minimize anatomic distortion and improve cosmesis. In areas of anatomic mobility, such as the neck or over joints, incisions are oriented less for aesthetic reasons and more with the goal of avoiding scar contractures and subsequent functional compromise. In general, incisions are placed perpendicular to the action of the joint.

Fig. 45-1.

Relaxed skin tension lines. (Reprinted with permission from Wilhelmi et al. 1 )

There are situations, however, in which the direction of the incision has been pre-established, as in acute lacerations, burns, or old contracted and distorting scars. In these circumstances the principles of proper incision placement can be combined with simple surgical techniques to reorient the scar and lessen the deformity. The Zplasty technique uses the transposition of random skin flaps both to break up a linear scar and to release a scar contracture through lengthening (Fig. 45-2; Table 45-1).

Fig. 45-2.

Schematic of the Z-plasty technique. Top : Simple Z-plasty. Middle : Four-flap Z-plasty. Bottom : Five-flap Z-plasty. (Modified with permission from Hudson DA: Some thoughts on choosing a Z-plasty: The Z made simple. Plast Reconstr Surg 106:665, 2000.)

Table 45-1 Tissue Lengthening with Z-Plasty Simple 45-degree 50 Simple 60-degree 75 Simple 90-degree 100 Four-flap with 60-degree angles 150 Double-opposing 75 Five-flap 125

Source: Modified with permission from Hudson DA: Some thoughts on choosing a Z-plasty: The Z made simple. Plast Reconstr Surg 106:665, 2000.

Type of Z-Plasty

Increase in Length of Central Limb (%)

Source: Modified with permission from Hudson DA: Some thoughts on choosing a Z-plasty: The Z made simple. Plast Reconstr Surg 106:665, 2000. W-plasty is the technique of scar excision and reconstruction in zigzag fashion to camouflage the resulting scar. In areas where pressure or shearing forces are expected, as in weightbearing areas, incision planning should be performed carefully to minimize the effect of antagonistic forces on the healing incision. This point is discussed further in "Pressure Sore Treatment."

Wound Healing The fundamentals of plastic surgery are based on wound-healing physiology. Wound repair consists of an exquisitely regulated symphony of molecular and cellular instruments that act in concert to restore the local tissue environment to prewound conditions. Metabolic imbalances in the wound milieu drive this orchestration and continue to direct it until healing resolves the mechanical and metabolic problems. Although a detailed review of wound physiology is presented elsewhere in this text, it is useful to emphasize several points. Tissue injury, be it mechanical or metabolic, profoundly and instantly disrupts the tissue microenvironment and sets into motion a cascade of events that combine to re-establish the environmental status quo. Disrupted blood vessels fill the wound space with red blood cells and plasma. Injured cells release factor III (thromboplastin), which accelerates the clotting cascade. Clotting factors in the plasma are activated, and the coagulation cascade forms thrombin and eventually fibrin. Simultaneously, the complement system activates and produces chemoattractive complement protein fragments. Platelets, activated by thrombin and exposed collagen, release a number of growth factors and cytokines. Traumatized vessels contract in response to both direct physical stimulation (mediated by the autonomic nervous system) and prostaglandins released by platelets. Intact local microvasculature vasodilates and leaks plasma in response to inflammatory mediators such as histamine, kinins, and serotonin. These early events, and others, establish hemostasis and inflammation.3 Platelet activation initiates the first major escalation in the inflammatory response. Within minutes platelets release a number of signaling molecules from their

-granules to attract macrophages, polymorphonuclear cells (PMNs),

fibroblasts, and vascular endothelial cells. Within a few hours of injury, PMNs and macrophages invade the wound space and begin to remove tissue debris, coagulation proteins, and bacteria. Although both PMNs and macrophages begin to marginate early, PMNs dominate during the first few days. PMNs also constitute the primary defense against invading organisms that have breached the epithelial barrier. PMNs and macrophages, in concert with the complement system, form the basis of "natural" or "nonspecific" immunity. If there is no infection or foreign material, the neutrophil population quickly diminishes by the second day, whereas macrophages continue to amass.3 Macrophages become the major population by the third day after injury. These cells then dominate the wound region for days to weeks. Macrophages are thought to be the "masterminds" behind the complicated and finely tuned array of repair events that characterizes the proliferative phase of healing. Like neutrophils, activated macrophages continue the task of wound dbridement. They are a rich source of degradative enzymes that process the extracellular matrix to make room for remodeling. Tightly coordinated release of the many growth factors, colony-stimulating factors, interleukins, interferons, and cytokines gives the macrophage the ability to regulate migration, proliferation, and specific protein synthesis of multiple cell lines. Macrophages lead the characteristic procession of new tissue into the wound dead space. Immature, replicating fibroblasts follow the macrophages.

Mature fibroblasts then advance into the wound space and are, in turn, followed by newly forming capillary buds, the last cells in the procession.3 As previously mentioned, injury perturbs the microenvironment and leads to the autoamplifying inflammatory phase. As a result of these processes, three changes occur in the wound: the environment becomes hypoxic, acidotic, and hyperlactated. There is at least one biochemical pathway by which this low redox potential state can signal cells to take biologic action—the adenosine diphosphoribose (ADPR) system. Specifically, recent evidence has shown that alterations of the polyADPR system affect regulation of collagen and vascular endothelial growth factor (VEGF) transcription.3 Thus, the metabolic state that is so deranged in the wound microenvironment is intimately linked to altered cellular function, which leads to reparative cell phenotypes. After inflammation has begun, fibroblasts are attracted by many stimuli and then proliferate and migrate into the site of injury. Fibroblasts are the major producers of collagen in the repair response. Substances that increase collagen deposition and maturation include lactate, oxygen, and growth factors. Lack of these agents and steroid treatments decrease collagen in wounds. Macrophages also usher along angiogenesis, largely through the release of VEGF. VEGF production is upregulated by the same wound metabolic environment that stimulates collagen production. Also like collagen synthesis, VEGF release is increased by hyperoxia. As neovascularization takes place, many of the conditions that signaled the start of the inflammatory and proliferative phases are resolved, and the wound-healing response recedes. Epidermal cells are attracted to the healing wound by the same cytokines that attract other wound cells. Epithelialization proceeds best in a moist environment with high oxygen tension. 3 Preoperative, intraoperative, and postoperative interventions may be taken by the surgeon to minimize infection and optimize wound healing (Tables 45-2, 45-3, and 45-4). These measures all draw on what we understand of the physiologic wound-healing process.

Table 45-2 Preoperative Management Assess and optimize cardiopulmonary function; correct hypertension. Treat vasoconstriction: attend to blood volume, thermoregulatory vasoconstriction, pain, and anxiety. Assess recent nutrition and provide treatment as appropriate. Treat existing infection. Assess wound risk using the SENIC index. Start administration of vitamin A in patients taking glucocorticoids. Maintain tight blood glucose control. SENIC = Study on the Efficacy of Nosocomial Infection Control. Source: Modified with permission from Hunt TK, Hopf HW: Wound healing and wound infection: What surgeons and anesthesiologists can do. Surg Clin North Am 77:587, 1997. Copyright Elsevier.

Table 45-3 Intraoperative Management Administer appropriate prophylactic antibiotics at start of procedure. Keep antibiotic levels high during long operations. Keep patient warm. Maintain gentle surgical technique with minimal use of ties and cautery. Keep wounds moist.

Perform irrigation in cases of contamination. Elevate tissue oxygen tension by increasing the level of inspired oxygen. Delay closure of heavily contaminated wounds. Use appropriate sutures (and skin tapes). Use appropriate dressings.

Source: Modified with permission from Hunt TK, Hopf HW: Wound healing and wound infection: What surgeons and anesthesiologists can do. Surg Clin North Am 77:587, 1997. Copyright Elsevier.

Table 45-4 Postoperative Management Keep patient warm. Provide analgesia to keep patient comfortable, if not pain free. Keep up with third-space losses. Remember that fever increases fluid losses. Assess perfusion and react to abnormalities. Avoid diuresis until pain is gone and patient is warm. Assess losses (including thermal losses) if wound is open. Assess need for parenteral/enteral nutrition and respond. Continue to control hypertension and hyperglycemia. Source: Modified with permission from Hunt TK, Hopf HW: Wound healing and wound infection: What surgeons and anesthesiologists can do. Surg Clin North Am 77:587, 1997. Copyright Elsevier.

Skin Grafts and Skin Substitutes Discussion of skin grafting requires a basic review of skin anatomy. Skin is comprised of 5% epidermis and 95% dermis. The dermis contains sebaceous glands, whereas sweat glands and hair follicles are located in the subcutaneous tissue. The dermal thickness and concentration of skin appendages vary widely from one location to another on the body. The skin vasculature is superficial to the superficial fascial system and parallels the skin surface. The cutaneous vessels branch at right angles to penetrate subcutaneous tissue and arborize in the dermis, finally forming capillary tufts between dermal papillae. 4 Skin grafting dates back >3000 years to India, where forms of the technique were used to resurface nasal defects in thieves who were punished for their crimes with nose amputation. Modern skin grafting methods include splitthickness grafts, full-thickness grafts, and composite tissue grafts (Table 45-5). Each technique has advantages and disadvantages. Selection of a particular technique depends on the requirements of the defect to be reconstructed, the quality of the recipient bed, and the availability of donor site tissue.

Table 45-5 Classification of Skin Grafts Split thickness Thin (Thiersch-Ollier) 0.006–0.012 Intermediate (Blair-Brown) 0.012–0.018 Thick (Padgett) 0.018–0.024

Full thickness Entire dermis (Wolfe-Krause) Variable Composite tissue Full-thickness skin with additional tissue (subcutaneous fat, cartilage, muscle) Variable Type

Description

Thickness (in)

Source: Modified with permission from Andreassi A, Bilenchi R, Biagioli M, et al: Classification and pathophysiology of skin grafts. Clin Dermatol 23:332, 2005. Copyright Elsevier.

SPLIT-THICKNESS GRAFTS Split-thickness skin grafting represents the simplest method of superficial reconstruction in plastic surgery. Many of the characteristics of a split-thickness graft are determined by the amount of dermis present. Less dermis translates into less primary contraction (the degree to which a graft shrinks in dimensions after harvesting and before grafting), more secondary contraction (the degree to which a graft contracts during healing), and better chance of graft survival. Thin-split grafts have low primary contraction, high secondary contraction, and high reliability of graft take, often even in imperfect recipient beds. Thin grafts, however, tend to heal with abnormal pigmentation and poor durability compared with thick-split grafts and full-thickness grafts. Thick-split grafts have more primary contraction, show less secondary contraction, and may take less hardily. Split grafts may be meshed to expand the surface area that can be covered. This technique is particularly useful when a large area must be resurfaced, as in major burns. Meshed grafts usually also have enhanced reliability of engraftment, because the fenestrations allow for egress of wound fluid and excellent contour matching of the wound bed by the graft. The fenestrations in meshed grafts re-epithelialize by secondary intention from the surrounding graft skin. The major drawbacks of meshed grafts are poor cosmetic appearance and high secondary contraction. Meshing ratios used usually range from 1:1.5 to 1:6, with higher ratios associated with magnified drawbacks.

FULL-THICKNESS GRAFTS By definition full-thickness skin grafts include the epidermis and the complete layer of dermis from the donor skin. The subcutaneous tissue is carefully removed from the deep surface of the dermis to maximize the potential for engraftment. Full-thickness grafts are associated with the least secondary contraction upon healing, the best cosmetic appearance, and the highest durability. Because of this, they are frequently used in reconstructing superficial wounds of the face and the hands. These grafts require pristine, well-vascularized recipient beds without bacterial colonization, previous irradiation, or atrophic wound tissue.

GRAFT TAKE Skin graft take occurs in three phases, imbibition, inosculation, and revascularization. Plasmatic imbibition refers to the first 24 to 48 hours after skin grafting, during which time a thin film of fibrin and plasma separates the graft from the underlying wound bed. It remains controversial whether this film provides nutrients and oxygen to the graft or merely a moist environment to maintain the ischemic cells temporarily until a vascular supply is reestablished. After 48 hours a fine vascular network begins to form within the fibrin layer. These new capillary buds interface with the deep surface of the dermis and allow for transfer of some nutrients and oxygen. This phase, called inosculation, transitions into revascularization, the process by which new blood vessels either directly invade the graft or anastomose to open dermal vascular channels and restore the pink hue of skin. These phases are

generally complete by 4 to 5 days after graft placement. During these initial few days the graft is most susceptible to deleterious factors such as infection, mechanical shear forces, and hematoma or seroma.4

COMPOSITE GRAFTS Composite tissue grafts are donor tissue containing more than just epidermis and dermis. They commonly include subcutaneous fat, cartilage and perichondrium, and muscle. Although less common than skin grafts, grafts of this type are particularly useful in select cases of nasal reconstruction. Excision of the thick skin of the nasal lobule may create too deep a defect to reconstruct with a full-thickness skin graft. The ear lobe composite graft provides thicker coverage with good color match and a fairly inconspicuous donor site (Fig. 45-3). Similarly, the root of the helix of the ear may be used to reconstruct the alar rim, providing skin coverage, cartilaginous support, and internal lining in a single technique.

Fig. 45-3.

Composite graft reconstruction of nasal lobule. A. Scarred lobule from previous lesion excision. B. Scar excision markings. C. Insetting of composite ear lobe skin and subcutaneous fat graft. D. Postoperative day 3; note the pink hue of revascularization. E. Appearance at 5 weeks postoperatively. F. Donor site at 5 weeks postoperatively.

Flaps A flap is a vascularized block of tissue that is mobilized from its donor site and transferred to another location, adjacent or remote, for reconstructive purposes. The difference between a graft and a flap is that a graft brings no vascular pedicle and derives its blood flow from recipient site revascularization, whereas a flap arrives with its blood supply intact.

RANDOM PATTERN FLAPS Random pattern flaps have a blood supply based on small, unnamed blood vessels in the dermal-subdermal plexus, as opposed to the discrete, well-described, directional vessels of axial pattern flaps (Fig. 45-4). Random flaps are typically used to reconstruct relatively small, full-thickness defects that are not amenable to skin grafting. Unlike axial pattern flaps, random flaps are limited by their geometry. The generally accepted reliable length:width ratio for a random flap is 3:1. Exceptions to this rule abound, however. There are many different types of random

cutaneous flaps that differ in geometry and mobility. A transposition flap is rotated about a pivot point into an adjacent defect (Fig. 45-5). A Z-plasty is a type of transposition flap in which two flaps are rotated, each into the donor site of the other, to achieve central limb lengthening (see Fig. 45-2). Another common transposition flap is the rhomboid (Limberg) flap (Fig. 45-6). The bipedicle flap is comprised of two mirror-image transposition flaps that share their distal, undivided margin. Rotational flaps are similar to transpositional flaps but differ in that they are semicircular (Fig. 45-7). Advancement flaps slide forward or backward along the flap's long axis. Two common variants include the rectangular advancement flap and the V-Y advancement flap (Fig. 45-8). Like transposition flaps, interpolation flaps rotate about a pivot point. Unlike transposition flaps, they are inset into defects near, but not adjacent, to the donor site. An example of an interpolation flap is the thenar flap for fingertip reconstruction (Fig. 45-9).

Fig. 45-4.

Random pattern flap architecture. a. = artery. (Reproduced with permission from Aston et al. 5 )

Fig. 45-5.

Random pattern transposition flap.

Fig. 45-6.

A and B. Random pattern transposition flap, the rhomboid flap. (Photographs reproduced with permission from M. Gimbel.)

Fig. 45-7.

Random pattern rotational flap. (Reproduced with permission from Aston et al. 5 )

Fig. 45-8.

Random pattern advancement flap. A. Rectangular advancement flap with Burow's triangle excision. B. V-Y advancement flap. (Reproduced with permission from Aston et al. 5 )

Fig. 45-9.

Random pattern interpolation flap—the thenar flap. A. Middle fingertip injury with exposed bone and tendon. B. Elevation of distally based random pattern thenar flap. C. Insetting. D and E. Function and form at 3 months, after skin grafting of donor site. (Photographs reproduced with permission from M. Gimbel.)

Fasciocutaneous and Myocutaneous Flaps The composition of a flap is its tissue components. For example, a cutaneous flap contains skin and a variable amount of subcutaneous tissues. A fasciocutaneous flap contains skin, fascia, and intervening subcutaneous tissues. A muscle flap contains muscle only, whereas a myocutaneous flap contains muscle with its overlying skin and intervening tissues. An osseous flap contains vascularized bone only, whereas an osteomyocutaneous flap contains in addition muscle, skin, and subcutaneous tissues. The contiguity of a flap describes its source. Local flaps are transferred from a position adjacent to the defect. Regional flaps are from the same anatomic region of the body as the defect (e.g., the lower extremity region or the head and neck region). Distant flaps are transferred from a different anatomic region to the defect. Local, regional, and distant flaps may be pedicled, in that they remain attached to the blood supply at their source. Distant flaps may also be transferred as free flaps by microsurgical techniques; these are completely detached from the body,

and their blood supply is reinstated by anastomoses to recipient vessels close to the defect. Axial pattern flaps are based on an anatomically defined configuration of vessels.6 Arising from the aorta are arteries that supply the internal viscera and other deep vessels that divide to form the main arterial supplies to the trunk, head, and extremities. They ultimately feed interconnecting vessels that supply the vascular plexuses of the fascia, subcutaneous tissue, and skin. These interconnecting vessels reach the skin via either fasciocutaneous (also called septocutaneous ) vessels that traverse fascial septae, musculocutaneous perforators that penetrate muscle bellies, or direct cutaneous vessels that traverse neither muscle bellies nor fascial septae.7 Axial pattern flaps, incorporating suprafascial tissues, are supplied by these fasciocutaneous (septocutaneous), musculocutaneous, or direct cutaneous arteries. The internal viscera are also a source of axial pattern flaps, such as the jejunum flap and omentum flap. The circulation of bone- and muscle-containing flaps also is mainly axial in pattern. It also is possible to design local flaps, such as V-Y advancements and rhomboid flaps, as axial pattern flaps. The volume of tissue reliably supplied by the arterial input (and venous drainage) of an axial pattern flap defines its limits, not length:breadth ratios. This can be clarified conceptually. The arterial tree can be described in terms of angiosomes, territories (anatomic, dynamic, and potential), and choke vessels.8 Each artery supplies a block of tissue called an angiosome; neighboring angiosomes overlap. The anatomic territory of an artery is defined by the limits of its ramifications, where it forms anastomoses with neighboring anatomic territories. The vessels that pass between anatomic territories are called choke vessels. The dynamic territory of an artery is the volume of tissue stained by an intravascular administration of fluorescein into that artery. The potential territory of an artery is the volume of tissue that can be included in a flap that has undergone conditioning. Both the dynamic and potential territories extend beyond the anatomic territory of an artery. Although these territories of the artery supplying an axial pattern flap provide some guidance to the limits of such a flap harvest, there remains no quantifiable method to predict these safe limits exactly. By virtue of their defined blood supply, the contiguity of axial pattern flaps, unlike that of random pattern flaps, may be local, regional, or distant, and pedicled or free. Axial pattern flaps may also possess some areas with random pattern circulation, usually located at the flap periphery. Conditioning refers to any procedure that increases the reliability of a flap. Invoking the delay phenomenon, for example, has improved the survival of flaps whose use is frequently complicated by unpredictable partial necrosis, such as the pedicled transverse rectus abdominis myocutaneous (TRAM) flap. The procedure can be particularly useful in patients at higher risk, such as those who are obese, smoke, or have received radiotherapy. One method of delay for the pedicled TRAM flap is to divide a major portion of its blood supply, the deep inferior epigastric artery on both sides, approximately 2 weeks before transfer. In response, blood from the anatomic angiosome of the superior epigastric artery appears to flow into that of the interrupted deep inferior epigastric artery via intervening choke vessels. As a result, the flap becomes conditioned to rely on the superior epigastric artery. The TRAM flap can then be transferred based on the superior epigastric artery with less risk of its distal portions' becoming ischemic and possibly necrotic. Several theories have been proposed to explain the delay phenomenon, including metabolic compensatory responses to relative ischemia and dilatation of choke vessels; however, its mechanisms remain incompletely understood.9 Further subclassifications of flap circulation have been introduced for muscular and fasciocutaneous flaps.1 0 Individual muscles have been classified by Mathes and Nahai into five types (I to V) according to their blood supply (Table 45-6). This classification is also applied to the respective myocutaneous flaps. Fasciocutaneous flaps also have been classified by Nahai and Mathes into types A, B, and C (Table 45-7). The inclusion of muscle in a flap may serve to increase flap bulk (so as to obliterate dead space) or to provide a functioning component with the harvest of its motor nerve for coaptation to a recipient motor nerve. The purported advantages of muscle-containing flaps

over fasciocutaneous flaps for use in previously infected tissue beds or for fracture healing have been debated.

Table 45-6 Mathes-Nahai Classification of Muscular Flaps Type I One vascular pedicle Gastrocnemius Type II Dominant and minor pedicles (the flap cannot survive based only on the minor pedicles) Gracilis Type III Two dominant pedicles Rectus abdominis Type IV Segmental pedicles Sartorius Type V One dominant pedicle with secondary segmental pedicles (the flap can survive based only on the secondary pedicles) Pectoralis major Classification

Vascular Supply

Example

Table 45-7 Nahai-Mathes Classification of Fasciocutaneous Flaps Type A Direct cutaneous vessel that penetrates the fascia Temporoparietal fascial flap Type B Septocutaneous vessel that penetrates the fascia Radial artery forearm flap Type C Musculocutaneous vessel that penetrates the fascia Transverse rectus abdominis myocutaneous flap Classification

Vascular Supply

Example

With progressive advancements in flap transfer techniques and an understanding of microvascular flap anatomy, plastic surgeons have steadily increased the number and variety of available flaps, thereby improving the results of flap reconstructions. In addition, this knowledge has reduced the morbidity associated with flap harvest. Perhaps the most important advancement in flap surgery within the last two decades has been the introduction of the perforator flap. 1 1 Perforator flaps evolved from the observation that the muscle component of myocutaneous flaps served only as a passive carrier of blood supply to the overlying fasciocutaneous tissues (fascia, skin, and intervening subcutaneous tissues). Previous to this, it had been deemed necessary to include the muscle for reliable harvest of fasciocutaneous tissues supplied by its musculocutaneous perforators, even if it was not necessary to include that muscle for the reconstruction. This unfortunately caused an unnecessary muscular deficit at the donor site, and for this reason these flaps were sometimes abandoned. The introduction of intramuscular retrograde dissection techniques, however, allowed the skeletonization of a musculocutaneous perforator from its

encasement within a muscle belly, which spared that muscle from flap harvest and preserved its donor site function.7,11 Further refinement of this concept gave rise to the harvest of cutaneous flaps based on any vessel that penetrated the fascia, which preserved the muscle (when the vessel was a musculocutaneous perforator) as well as the fascia (by suprafascial dissection). Within the last decade, free-style flap harvest has also been introduced.1 2 With a handheld Doppler ultrasound probe, the surgeon is able to identify an arterial supply to almost any area of skin with the desired reconstructive characteristics and trace that pedicle in retrograde fashion along whatever direction it takes, preserving donor site fascia and muscle as necessary. Although the exact definition of what a perforator flap is remains contentious, its advantages remain clear: reduced donor site morbidity, reduced flap bulk, and increased flexibility in choosing desired flap components for reconstruction. The circulation of perforator flaps is axial in pattern; consequently, they can be transferred as pedicled island flaps or by microvascular free tissue transfer.

Free Tissue Transfer A free tissue transfer (or transplantation), often referred to as a free flap procedure, is an autogenous transplantation of vascularized tissues. Any axial pattern flap with pedicle vessels of a suitable diameter can be transferred as a free flap. This involves three main steps: (a) complete detachment of the flap, with devascularization, from the donor site; (b) revascularization of the flap with anastomoses to blood vessels in the recipient site; and (c) an intervening period of flap ischemia. Flap circulation must be restored within a tolerable ischemia time. Given the small diameter of most flap pedicle vessels (usually between 0.8 and 4.0 mm), these anastomoses are usually performed using an operative microscope that provides dedicated illumination and between 6x and 40 magnification. Any surgery performed with the aid of an operative microscope is termed microsurgery; such anastomoses are therefore termed microvascular anastomoses. High-magnification surgical loupes are usually used for flap harvest, especially for dissecting the flap pedicle, because they allow greater operator freedom. Aside from microvascular anastomosis, microsurgical techniques include microneural coaptation, microlymphatic anastomosis, and microtubular anastomosis. The first successful free tissue transfer in humans was transfer of a jejunal free flap for cervical esophagus reconstruction performed in 1957; however, the surgeons did not use microvascular surgery for the anastomoses. The first microvascular free tissue transfers in humans were carried out during the late 1960s and early 1970s. Free flaps were initially considered to be a last-resort option to reconstruct the most complex defects. However, as a result of improved microsurgical techniques and microinstrumentation, as well as proper patient and free flap selection and effective postoperative monitoring methods, the success rates have increased to exceed 95%.1 3 Today, free tissue transfer is often the first-choice treatment for many defects and is no longer considered the lastditch effort. It is now ubiquitously used in appropriate patients by reconstructive plastic surgeons worldwide. The predetermining factor in free flap failure is occlusion of its anastomotic lifeline blood supply due to thrombosis. As enumerated by Virchow's triad, any factors that alter normal laminar blood flow, cause endothelial damage, or change the constitution of blood (producing hypercoagulability) increase the risk of thrombosis (Table 45-8).1 4 Avoidance of this complication therefore begins with a thorough patient evaluation for the presence of acquired or inherited thrombophilic tendencies. The patient's hemodynamic status influences that of the free flap and should be optimized. The effect of tobacco smoking on free flap success has been debated, with some larger retrospective studies reporting no difference in thromboembolic complications; however, smoking is well known to affect wound healing.13,15 Smoking, and the use of potentially vasoconstrictive agents, such as caffeine, should be avoided for

several weeks before a free flap procedure. The restoration of normal laminar blood flow and avoidance of endothelial damage are addressed principally by careful flap insetting and meticulous microvascular surgical technique.

Table 45-8 Thrombogenic Factors That Can Affect Free Flap Pedicles and Anastomoses Tension or intimal malalignment at the anastomosis site; twisting, kinking, compression, or vasospasm of pedicle vessels Iatrogenic damage (e.g., back-walled anastomotic suture, poor vessel handling, too many sutures) Acquired thrombophilic tendency (e.g., pregnancy, paraneoplastic Trousseau's syndrome, antiphospholipid antibody syndromes) Nearby intraluminal structures (e.g., atherosclerotic plaque, venous valves, back-walled anastomotic suture) Previous vessel damage (e.g., atherosclerosis, trauma) Hereditary thrombophilias (e.g., activated protein C resistance, protein C/protein S deficiency, hyperhomocysteinemia) Altered Laminar Blood Flow

Endothelial Damage

Hypercoagulability

Planning a free flap goes beyond a simple calculation of matching flap and defect dimensions and tissue characteristics. The surgeon must, in addition, consider several important technicalities: what flap pedicle length and size are required (affected by flap choice), which recipient vessels to use, how to orient anastomoses (end to end or end to side), how to deal with mismatched donor and recipient vessel dimensions, how to overcome unhealthy donor and/or recipient vessels (e.g., traumatic dissection, scarred surgical field due to previous operation or radiotherapy), how to inset flap tissues (to maximize functional and cosmetic results without detriment to flap circulation), how to route the pedicle (to restore normal blood flow without pedicle kinking, twisting, or compression), how to position the patient (especially if the flap is to be inset over mobile soft tissue or joints), how to place postoperative dressings (so as to produce no compression of the flap or pedicle), and what donor site morbidity will likely result (there is a risk-benefit decision between defect severity and flap choice).1 6 In addition, the surgeon must have a suitable backup plan to overcome intraoperative troubles; for example, insufficient pedicle length can be addressed with an interpositional vein graft adjoining the donor and recipient vessels, and iatrogenic vessel injury or severely aberrant anatomy may necessitate use of a backup flap or backup recipient vessels.1 3 A clear understanding of the blood supply to the free flap and its tissue components is a prerequisite to harvesting a viable free flap. Pedicle vessels must be identified and protected, and handled minimally and atraumatically to avoid thrombogenic factors (see Table 45-8). Meticulous technique also reduces the risk of vasospasm, but the latter can be ameliorated by topical lidocaine or papaverine should it occur. Critical vessels connecting flap components must also be recognized and preserved. Under microscope magnification, the donor and recipient vessels should be dissected back to health. The presence of, for example, venous valves, atherosclerotic plaques, intimal trauma, and intraluminal prolapse of adventitial tissue at or adjacent to the anastomosis site increases the risk of thrombosis. The vessel ends should be cleared of periadventitial tissues for 3 to 5 mm with sharp dissection under the microscope. Periadventitial dissection should be limited to this extent, so as to avoid potential devascularization of the vessel wall by removal of the vasa vasorum and prevent the subsequent delayed development of a perianastomotic pseudoaneurysm. Adventitiectomy also helps relieve vasospasm by increasing compliance of the vessel wall and by inducing a local sympathectomy effect. The vessel ends usually are stabilized with a double approximating microvascular clamp for anastomosis. Interrupted sutures or, less commonly, continuous sutures can accomplish the anastomosis. The microneedle typically has a three eighths circle curvature

and is between 30 and 150 m in size. Its monofilament microsuture is usually between 9-0 and 11-0 caliber. The dimensions of the vessels to be anastomosed define the choice of microneedle and microsuture. Less commonly, suture alternatives such as fibrin adhesives or laser welding (these remain largely experimental) and mechanical anastomotic devices (e.g., venous couplers) may be used. Triangulating or bisecting suturing techniques can help to achieve an even placement of sutures. Normally, each suture should include the full thickness of both vessel walls, none should catch the opposite vessel wall (which causes disastrous luminal occlusion and intimal trauma), and the size of each bite should approximate the vessel wall thickness. The configuration of the anastomosis can be either end to end (Fig. 45-10), if the distal circulation can be adequately preserved, or end to side (Fig. 45-11) if the distal circulation must be preserved, as in the case of an arterially compromised extremity supplied by one dominant vessel. An end-to-side orientation may also be useful to overcome dramatically mismatched donorrecipient vessel dimensions. Whatever the method chosen, microanatomic differences between the vessels should be respected so as to achieve accurately approximated intimal surfaces in a tension-free anastomosis, devoid of redundancy that might promote kinking.1 3

Fig. 45-10.

A through D. End-to-end anastomosis.

Fig. 45-11.

A through E. End-to-side anastomosis.

The clinical monitoring of a free flap should start during flap harvest, especially before its pedicle is divided. A free flap that is struggling to maintain normal perfusion characteristics during harvest most likely has insufficient circulation, which may be due to arterial or venous compromise, or a combination of both (Table 45-9). Flap compromise may be due to reversible factors such as pedicle kinking, tensioning, or twisting; patient hemodynamic compromise; or an overly large flap harvest for the chosen pedicle vessels. If poor flap perfusion continues despite the absence or correction of all these factors, an inherent flap problem or a critical vascular injury to the flap or its pedicle must be considered, and it may not be safe to continue its harvest. This is one clear example of a situation in which a backup plan may require execution.

Table 45-9 Clinical Signs of Arterial and Venous Compromise in a Free Flapa Color Becoming paler Increasingly reddish or purplish Temperature Becoming cooler Becoming warmer Tissue turgor Reducing Increasing

Capillary refill time Becoming slower Becoming faster Pinprick bleeding Increasingly sluggish Quickening (and darkening) Clinical Sign a Note

Arterial Compromise

Venous Compromise

that venous and arterial compromise may coexist, and one may lead to the other.

Clinical flap monitoring continues after successful restoration of arterial inflow and venous outflow. The mainstay of postoperative free flap monitoring is clinical assessment (see Table 45-9), although supplementary instrument monitoring also can be helpful. Doppler ultrasound assessment of arterial and venous signals is useful for monitoring buried or concealed flaps. If flap perfusion was healthy before division of its donor site pedicle, then poor perfusion after anastomoses is likely due to either a technical error or insufficient systemic hemodynamics. The latter usually is correctable by ensuring that the patient and the patient's environment are suitably warm and by initiating IV colloid challenge or, if indicated, blood transfusion. Numerous potential technical errors, which have been described in the earlier paragraphs on planning and anastomosis technique, may occur. Routine postoperative patient monitoring includes measurement of total fluid inputs, urinary catheter output (which should be >1 mL/kg per hour), core temperature, and arterial blood pressure (systolic pressure should be >100 mmHg), as well as pulse oximetry. The patient and free flap are best monitored in an intensive care setting by experienced staff until both are stable enough for routine ward assessments.1 3 Occlusion of the anastomosis most commonly arises from internal thrombosis or from external compression of the pedicle, such as from surrounding tissues, fluid accumulation (e.g., hematoma and tissue edema), or overly tight dressings or skin sutures. Because there is a threshold of ischemia beyond which a flap will sustain irreversible tissue and/or microcirculatory damage, it is important that the early signs of flap circulatory compromise be recognized as quickly as possible and the underlying problem diagnosed and corrected promptly if flap health is to be restored successfully. Different tissues tolerate differing durations of ischemia in correlation with their tissuespecific basal metabolic rate. Although cooling free flaps (to reduce basal metabolic rate) has a variably protective effect in experimental settings, it appears that this practice contributes little to improving free flap success in the clinical setting as long as warm ischemia times are kept to 2 weeks generally require surgical treatment.2 8 There are many approaches to the orbital floor, including the transconjunctival, subciliary, and lower blepharoplasty incisions. All provide access to the orbital floor and allow for repair with a multitude of different autogenous and synthetic materials. Late complications include persistent diplopia, enophthalmos, ectropion, and entropion. Lateral and inferior orbital rim fractures also are not uncommon and are often associated with the zygomaticomaxillary complex fracture pattern, as discussed later. Special mention should be made of two uncommon complications after orbital fracture. Superior orbital fissure syndrome results from compression of structures contained in the superior orbital fissure in the posterior orbit. These include cranial nerves III, IV, and VI, and the first sensory division of cranial nerve V. Compression of these structures leads to symptoms of eyelid ptosis, globe proptosis, paralysis of the extraocular muscles, and anesthesia in the cranial nerve V1 distribution. If the optic nerve (cranial nerve II) is also involved, symptoms include blindness and the syndrome is dubbed orbital apex syndrome. Both of these syndromes are medical emergencies, and steroid therapy or surgical decompression is considered.

ZYGOMA AND ZYGOMATICOMAXILLARY COMPLEX FRACTURES The zygoma forms the lateral and inferior borders of the orbit. It articulates with the sphenoid bone in the lateral orbit, the maxilla medially and inferiorly, the frontal bone superiorly, and the temporal bone laterally (Fig. 45-28). Zygoma fractures may involve the arch alone or many of its bony relationships. Isolated arch fractures manifest as a flattened, wide face with associated edema and ecchymosis. Nondisplaced fractures may be treated nonsurgically, whereas displaced and comminuted arch fractures may be reduced and stabilized indirectly (Gilles approach) or, for more complicated fractures, directly through a coronal incision.

Fig. 45-28.

Facial bone anatomy. (Reproduced with permission from Hollier et al. 28 )

The zygomaticomaxillary complex (ZMC) fracture involves disruption of the zygomatic arch, the inferior orbital rim buttress, the zygomaticomaxillary buttress, the lateral orbital wall, and the zygomaticofrontal buttress. The fracture segment tends to rotate laterally and inferiorly, creating an expanded orbital volume, limited mandibular excursion, an inferior cant to the palpebral fissure, and a flattened malar eminence. ZMC fractures are almost always accompanied by numbness in the infraorbital nerve distribution and subconjunctival hematoma. Displaced fractures are treated by exposure through multiple incisions to gain access to all of the buttresses requiring fixation. These include the upper eyelid incision (zygomaticofrontal buttress and lateral orbital wall), the subtarsal or transconjunctival incision (orbital floor and infraorbital rim), and the maxillary gingivobuccal sulcus incision (zygomaticomaxillary buttress). Again, significantly complex zygomatic fractures require wide exposure through a coronal approach.5

NASO-ORBITAL-ETHMOID FRACTURES Naso-orbital-ethmoid (NOE) fractures are often part of a constellation of panfacial fractures and intracranial injuries. Anatomically, the fracture pattern involves the medial orbits, nasal bones, nasal processes of the frontal bone, and frontal processes of the maxilla. These injuries result in severe functional deficit and cosmetic deformity from collapse of the nose, ethmoids, and medial orbits; displacement of medial canthal ligament fixation; and nasolacrimal apparatus disruption. Telecanthus is produced by splaying apart of the nasomaxillary buttresses to which the medial canthal ligaments are attached. Treatment typically involves plating or wiring all bone fragments meticulously, potentially with primary bone grafting, to restore their normal configuration. Key to the successful

repair of an NOE fracture is the careful re-establishment of the nasomaxillary buttress and restoration of the pretrauma fixation points of the medial canthal ligaments. If comminution is severe, this may be achievable using transnasal wiring of the ligaments.

FRONTAL SINUS FRACTURES The region of the frontal sinus is a relatively weak structural point in the upper face. For this reason, it is a common location for fracture in facial trauma. The paired sinuses each have an anterior bony table that determines the contour of the forehead and a posterior table that separates the sinus from the dura. Each sinus drains through the medial floor into its frontonasal duct, which empties into the middle meatus within the nose. Treatment of a frontal sinus fracture depends on the fracture characteristics (Fig. 45-29).

Fig. 45-29.

Algorithm for the treatment of frontal sinus fracture. CSF = cerebrospinal fluid; CT = computed tomography; NF = nasofrontal; ORIF = open reduction, internal fixation.

NASAL FRACTURES The nose is the most common facial fracture site due to its prominent location, and such fracture can involve the cartilaginous nasal septum, the nasal bones, or both. It is important to perform an intranasal examination to determine whether a septal hematoma is present. If present, a septal hematoma must be incised, drained, and

packed to prevent pressure necrosis of the nasal septum and long-term midvault collapse. Closed reduction of nasal fractures may be performed under local or general anesthesia. Unfortunately, many, if not most, show some deformity upon final healing, requiring rhinoplasty if airway obstruction is present or if improved appearance is desired.

PANFACIAL FRACTURES Fractures of multiple bones in various locations fall into the category of panfacial fracture. These may involve frontal and maxillary sinus fractures, NOE fractures, orbital and ZMC fractures, palatal fractures, and complex mandible fractures. The difficulty in the repair of these injuries lies not in the technical aspects of fixation but in the re-establishment of normal relationships between facial features in the absence of all pretraumatic reference points. Without proper correction of bony fragment relationships, facial width is exaggerated and facial projection is lost. The key point in approaching the patient with a panfacial fracture is first to reduce and repair the zygomatic arches and frontal bar to establish the frame and width of the face. The nasomaxillary and zygomaticomaxillary buttresses may then be repaired within this correct frame. Next, the maxilla may be reduced to this framework, followed by palatal fixation if needed. Finally, now that the midface relationships have been corrected, maxillarymandibular fixation can be applied with the mandible in correct occlusion followed by plating of any mandibular fractures.2 9

Ear Reconstruction Acquired defects of the auricle have many causes, and many different choices for reconstruction are available. Reconstructive approach often is determined by the size and location of the defect. Small helical lesions may be simply excised as a wedge and closed primarily. Larger defects of the upper and middle thirds of the ear may use antihelical and conchal cartilage reduction patterns to reduce the circumference of the helix to allow primary closure. When helical defects are too large for this solution, local flaps may be used to close or re-create the missing tissue. Postauricular flaps created in staged procedures may be manipulated to create a skin tube mimicking the furled helix and bridging the gap of a defect. Alternatively, use of an Antia-Buch chondrocutaneous advancement flap combined with cartilaginous reduction allows for closure of defects3 0 (Fig. 45-30). Even larger defects of the upper and middle thirds of the ear may be reconstructed with large local skin flaps combined with contralateral cartilage grafts or contralateral composite grafts. Although ear lobe defects are relatively simple to close primarily, lower third auricular defects that involve more than just the lobe are complex and require cartilaginous support, often combined with local skin flaps.

Fig. 45-30.

Modified Antia-Buch ear reconstruction. A. Superior helix lesion. B. Excision pattern and reconstruction markings. C. Defect, flap elevation, and cartilage reduction. D. V-Y advancement of the flap. E. Flap insetting. F. Appearance at 1 month after surgery. (Photographs reproduced with permission from M. Gimbel.)

Nasal Reconstruction Reconstruction of the nose requires appreciation of the nine aesthetic subunits that are defined by normal anatomic contours and lighting patterns (Fig. 45-31). In general, if a defect involves =50% of a subunit, the remainder of the subunit should be excised and included in the reconstruction. The nose can be thought of as being composed of three layers: skin cover, structural support, and mucosal lining. When a defect or anticipated defect is evaluated, it is useful to consider what layers of tissue will be missing so that a reconstruction can be devised that replaces each layer. Nasal reconstruction methods draw on the full arsenal of reconstructive techniques. Healing by secondary intention is successfully used in concavities such as the alar groove. Split- or full-thickness skin grafts may be used for superficial defects of the nasal dorsum or sidewall. Composite grafts may be used for the nasal tip or alar rim (see Fig. 45-3). Local random pattern flaps are useful in closing small defects of the dorsum and tip, and may be combined with cartilage grafts if structural support is needed. Axial pattern flaps are commonly used for larger

defects. These flaps have the advantage of being able to cover and revascularize underlying cartilage grafts and enjoy a close color match to surrounding skin. Workhorse flaps often used in nasal reconstruction include the nasolabial flap and the paramedian forehead flap (Fig. 45-32). Even larger defects may require scalping flaps or free radial forearm flaps. Split calvarial cantilever bone grafts may provide the nasal dorsum support. Lining is generally achieved with scar tissue turnover flaps, mucoperichondrial flaps from within the nasal vestibule, or skin grafting of the underside of transposed flaps.

Fig. 45-31.

Nasal aesthetic subunits. (Photograph reproduced with permission from M. Gimbel.)

Fig. 45-32.

Nasal reconstruction with axial pattern flaps. Top row: Nasolabial flap reconstruction of an alar defect. Bottom row: Paramedian forehead flap reconstruction of the nasal lobule. (Photographs reproduced with permission from M. Gimbel.)

Lip Reconstruction The lips are important for articulate speech, eating and maintenance of oral competence, facial expression, and aesthetic harmony of the lower face. Three layers of tissue form the upper and lower lips: skin, muscle, and mucosa. Blood supply is through the facial artery and its branches to the lip, the superior and inferior labial arteries. Lip defects can arise from trauma, burns, neoplasms, congenital lesions, clefts, or infection. The most common malignancy in the upper lip is basal cell carcinoma, and the most common in the lower lip is squamous cell carcinoma. As with almost all types of reconstruction, choice of technique is heavily dependent on defect size, location, and deficient structures. The goals of lip reconstruction are restoration of the competent oral sphincter with vermilion apposition, preservation of sensation, and avoidance of microstomia, all while preserving a nearnormal static and dynamic appearance. In the upper and lower lip, vermilion-only defects can be corrected with advancement of the labial mucosa, often called a lip shave. In defects of less than one third the horizontal length, enough redundancy is present to allow primary closure. More complex decisions must be made for defects that are between one third and two thirds of the total lip length. The two categories of lip flap technique are transoral crosslip flaps and circumoral advancements flaps. Cross-lip flaps include the Abb flap and the Estlander flap. The Abb

flap was originally designed to reconstruct central upper lip (tubercle) defects with lower lip full-thickness tissue vascularized by one of the labial arteries (Fig. 45-33). The technique requires a second-stage procedure for division of the pedicle. The Estlander flap is similar in principle but is based laterally at the oral commissure and is used to reconstruct lateral upper or lower lip lesions. Both the Estlander and Abb flaps are denervated, but sensation and perhaps even motor function return over months.3 1 The Karapandzic technique is an advancement-rotation flap technique designed for central lower lip defects. Although good function, sensation, and mobility are preserved, a side effect is reduction in the size of the oral aperture. The Webster-Bernard technique uses cheek tissue advancement flaps to replace defects with full-thickness or partial-thickness cheek incisions extended laterally from the commissure (Fig. 45-34). When performed bilaterally, both the Karapandzic and the Webster-Bernard methods can be used to reconstruct a complete upper or lower lip.

Fig. 45-33.

Abb flap upper lip reconstruction. A. Defect and flap design. B. Rotation of the flap and primary closure of the donor site. C. Division of the pedicle (after 2 to 3 weeks) and final insetting.

Fig. 45-34.

Webster-Bernard lip reconstruction technique. (Reproduced with permission from Closmann JJ, Pogrel A, Schmidt BL: Reconstruction of perioral defects following resection for oral squamous cell carcinoma. J Oral Maxillofac Surg 64:367, 2006. Copyright Elsevier.)

In addition, microvascular free tissue transfer reconstruction may be necessary in cases where there is no remaining lip. The radial forearm free flap is the most commonly used for this purpose, usually transferred with the palmaris longus tendon for lip support.

Eyelid Reconstruction The eyelids protect the eye from exposure and are another crucial aesthetic structure of the face. They consist of an anterior lamella (skin and orbicularis oculi muscle) and a posterior lamella (tarsus and conjunctiva). The eyelid blood supply is robust, and ischemia is rarely a concern in reconstruction.

UPPER EYELID Defects comprising 3 cm below the IMF. Pseudoptosis or bottoming out is a term used to describe the descent of the breast tissue below the nipple and is a potential longterm complication of breast reduction. In addition to classification of nipple ptosis, a thorough preoperative evaluation also includes measurement of the distance from sternal notch to nipple bilaterally, as well as measurement of the distance from nipple to IMF. The base width of the breast should also be considered. Many patients are found to have significant baseline asymmetries in these measurements. Preoperative breast cancer screening consistent with current American Cancer Society guidelines should be performed for all patients undergoing elective breast reshaping surgery. The planned new nipple position should be symmetrical at the IMF along the breast meridian. There are many technical variations of the breast reduction procedure, but nearly all of them have common elements of reshaping the skin envelope in three dimensions and moving the nipple to a new location on a vascularized tissue pedicle. The pedicle is de-epithelialized to preserve the subdermal vascular plexus. Figure 45-60 shows the classic "keyhole" Wise pattern reduction technique. The skin resection is designed to create a conical shape, and the nipple is transposed on an inferiorly based pedicle.8 1 This results in an inverted T–shaped scar. Figure 45-61 shows a patient treated using this technique. All breast reduction techniques keep the scars on the lower half of the breast so they are covered by clothing. Techniques have been designed to minimize scar length and even eliminate the horizontal component in the IMF. Figure 45-62 depicts a vertical scar skin resection pattern with the nipple preserved on a superior pedicle.82,83 For excessively large breasts, the required pedicle length may be too long to provide adequate blood supply to the nipple. In such cases, the nipple is removed and replaced onto a viable tissue bed as a full-thickness skin graft. Complications of breast reduction include decreased nipple sensation, nipple loss (rare), skin necrosis, hematoma, and fat necrosis. This last complication can result in a firm mass of scar within the breast that may need careful evaluation and follow-up to distinguish it from a neoplastic mass. Long-term complications include inability to breastfeed and pseudoptosis, as mentioned earlier.

Fig. 45-60.

Inferior pedicle reduction mammaplasty. A. Markings for Wise pattern reduction. B. Purple area is region to be deepithelialized. C. Dark blue region is area to be resected. A segment of the inferior pedicle is de-epithelialized. The inferior pedicle is dissected straight down to the chest wall, with maintenance of an 8- to 10-cm pedicle width. Lateral and medial segments are resected. After this is accomplished, the superior flap is dissected to the clavicle. Breast subcutaneous tissue and parenchyma are resected from the superior pole. The vertical limbs are brought together and to the meridian of the inframammary fold. The nipple is then set in its new superior position. D. T-shaped incision on final closure.

Fig. 45-61.

A and B. Preoperative photos of a 25-year-old woman with symptoms of upper back pain, bra strap grooving, and rashes under the folds of her breasts treated with a Wise pattern inferior pedicle reduction. C and D. Patient 6 months after surgery.

Fig. 45-62.

Vertical reduction mammaplasty, Lejour technique. A. Markings for vertical reduction. B. Purple area is region to be deepithelialized. C. Dark blue region represents inferior pole to be resected. The shaded regions are the lateral and medial segments that are to be undermined; these areas can also be liposuctioned. The superior pedicle is de-epithelialized and dissected to the chest wall. The tissue and parenchyma from the inferior pole are resected. The pillars from the lateral and medial segments are sewn together. The nipple is transposed on its pedicle to its new position. D. Closure of the vertical mammaplasty. There is bunching up of skin and tissue along the vertical limb that will resolve over time; in addition, the new inframammary fold will declare itself superior to the original one.

Mastopexy In contradistinction to breast reduction, in which patients are treated for symptoms related to heavy breasts, mastopexy is a three-dimensional reshaping of the breast performed with no or minimal volume removal. The principles are the same, however: The skin envelope is contoured and the nipple location optimized. Because the degree of ptosis may be less severe than in breast reduction cases, the patterns of skin resection can vary widely. Minimal patterns may involve excision of just a crescent of skin from above the areola or a periareolar ("donut") resection. The Wise keyhole pattern can be used for larger skin excisions.

Augmentation Mammaplasty Although the use of prosthetic implants can successfully increase breast size, the surgeon must fully understand

both the risks of the biomaterials and the way in which a specific implant of given shape and size can be surgically integrated into the existing breast mound to achieve the desired result.8 4 To address the latter point, the surgeon must first consider the possible surgical approaches for implant placement. The three commonly used incisions for placement of cosmetic breast implants are inframammary, periareolar, and axillary (Fig. 45-63).8 5 A transumbilical breast augmentation technique has been advocated by some surgeons more recently, but critics of this approach point out that there is poor control over the dissection of the implant pocket and that direct access to the tissues of the breast is inadequate to control bleeding vessels. In addition, only saline implants can be used with transumbilical breast augmentation because the prefilled silicone implants are too large to pass through the incision and narrow tunnel. The implants may be placed in a subglandular or subpectoral position (Fig. 45-64). Many surgeons prefer the subpectoral placement because it provides greater soft tissue coverage in the upper pole of the breast and can hide contour irregularities related to the implant. This soft tissue coverage is especially important with saline implants, because visible rippling can occur. The next issue to consider is existing nipple position. If a patient has mild ptosis, the sheer volume of the implant may raise the nipple to an acceptable level. For more severe ptosis, a concurrent mastopexy is necessary. Some surgeons advocate performing the mastopexy as a second stage after the implant has settled into position.

Fig. 45-63.

Incisions for augmentation mammaplasty. A, Inframammary; B, axillary; C, periareolar.

Fig. 45-64.

Placement of breast implant. A. Subglandular. B. Subpectoral.

Potential complications related to the implant itself are numerous, and the patient must be fully informed of these possibilities before undergoing surgery. One important point is that there is a high likelihood that the patient will require a second operation to address an implant problem. The implant complications are essentially all local. Although there was concern in the past that implants might be associated with systemic connective tissue disorders, large epidemiologic studies have not supported such a link. The fears over implant safety were so strong that the Food and Drug Administration (FDA) declared a moratorium on the use of silicone gel implants in 1992. At that time, saline-filled implants were still allowed for general cosmetic use. Data were compiled on silicone gel implants, and these devices were approved by the FDA for general use in 2006.8 6 Potential implant complications include rupture of the device. For saline implants, this results in rapid deflation. For silicone gel implants, the rupture may be not be obvious and can be confirmed by MRI. Another complication is capsular contracture, which results in a tight envelope of scar that can distort the shape of the implant and cause pain in severe cases. A complication more common to saline devices is the appearance of rippling in the upper pole of the device. Implant malposition can also distort the breast shape and require reoperation. Safety data printed on the official FDAapproved package insert from one of the device manufacturers show the incidence of reoperation to be 29.9% over 7 years in a study of 901 women undergoing primary breast augmentation with saline-filled implants (postapproval study). The rate of severe capsular contracture (grade 3 or 4 on a 4-point scale) was 15.7%, and the rate of implant rupture was 9.8%.8 7 For silicone gel–filled implants, the reoperation rate was observed to be 23.5% over 4 years in a study of 455 women undergoing primary breast augmentation. The rate of severe capsular contracture (grade 3 or 4 on a 4-point scale) was 13.2%, and the rate of implant rupture (evaluated by MRI) was 2.7%. The three most common reasons for operation, in order, were capsular contracture (28.9%), implant malposition (15.6%), and ptosis (14.1%). For secondary augmentation, complication rates were much higher, with the

reoperation rate over 4 years rising to 35.2%. The rate of capsular contracture was 17.0%, and the rate of implant rupture was 4.0%.8 8 Another concern regarding breast implants is the issue of whether adequate mammography can be performed after augmentation. Displacement techniques can be used by the mammographer to view the breast tissue. Although patients are advised that implants may affect mammography, a study surveying women who did and did not undergo breast augmentation found no statistical difference in survival or detection of carcinoma between the two cohorts.8 9

Gynecomastia Male breast excess or gynecomastia can be caused by a host of medical diseases and pharmacologic agents. Medical conditions associated with gynecomastia include liver dysfunction, endocrine abnormalities, Klinefelter's syndrome, renal disease, testicular tumors, adrenal or pituitary adenomas, secreting lung carcinomas, and male breast cancer. Causative pharmacologic agents include marijuana, digoxin, spironolactone, cimetidine, theophylline, diazepam, and reserpine. Although these numerous causes must be considered, a majority of patients present with either idiopathic enlargement of the breast parenchyma (more common in teenagers) or simple skin ptosis and excess adipose deposits on the chest wall (considered pseudogynecomastia; more common in adult males). To obtain a flat chest, both liposuction and/or skin excision techniques can be used.9 0

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KEY POINTS 1. Emergency surgery in the elderly carries a mortality rate that is 3–4 times that seen after elective surgery. 2. Physiologic age, not chronologic age, is the consequence of diminished functional reserve due to comorbid conditions, and is the major predictor of perioperative morbidity and mortality in the elderly. 3. Impaired cardiac function is responsible for more than half of the postoperative deaths in elderly patients, so careful attention must be paid to intravascular volume status in the perioperative period. 4. In addition to cardiac impairment, deficiencies in pulmonary, renal, nutritional, and cognitive function are major factors in the development of postoperative complications in the elderly. 5. In elderly patients with acute appendicitis or acute cholecystitis, one third lack fever, one third lack an elevated white blood cell count, and one third lack physical findings of peritonitis. 6. Laparoscopic approaches to surgical management, including the use of exploratory laparoscopy to rule out surgical disease, is associated with fewer complications and more rapid recovery in the elderly. 7. Analgesic doses should be reduced and titrated carefully in the elderly to avoid delirium; meperidime (Demerol R) should not be used for pain control in elderly patients. 8. The goal of palliative care is to relieve symptoms and preserve physical and mental well-being.

GENERAL CONSIDERATIONS The old pediatric surgery adage that children are not just "small people" holds true for the other end of the age spectrum, the growing geriatric surgery population. With the aging and expanding U.S. population, a dramatic increase is anticipated in the number of geriatric patients that will require various surgical interventions. By 2030, people >65 years of age will account for 20% of the overall population.1 Furthermore, half of all Americans currently alive can expect to reach the ninth decade of life.2 Elderly patients represent a unique surgical challenge due to the complexity of comorbid conditions and physiologic changes that occur with aging. These physiologic changes, inherent to the aging process, result in decline of physiologic reserve, development of cognitive and functional impairments, and, not uncommonly, development of multiple comorbid conditions. Physiologic age is of greater importance in perioperative management of elderly surgical patients than chronologic age because it takes into account the burden of comorbid disease. It is, therefore, an accurate predictor of postoperative morbidity and mortality. The hallmark of physiologic aging or "senescence" is decreased functional reserve of critical organ systems, resulting in the decreased ability of these systems to cope with challenge, with surgical stress being a

prime example. The age of 70 years typically is accepted as the start of senescence because age-related organ dysfunction and development of comorbid conditions sharply increases between ages 70 and 75 years. 3 With improved technologies and expanded criteria for surgical interventions in extremely aged patients, increased awareness of the special needs of this population is required to ensure a comprehensive preoperative assessment, delivery of optimal surgical care, and minimization of postoperative complications. Most importantly, the ability to perform an intervention must be balanced with retention of postoperative physical and cognitive function. It is, therefore, crucial to deliver quality surgical care to an elderly patient using a multidisciplinary approach involving the patient and their family, geriatric medical physician, surgeon, and at times, intensivists. It is estimated that, by the year 2030, there will be 70 million people >65 years old, a stark increase over the 35 million in 2000.4 This ever growing elderly population will increasingly require surgical consultation and intervention. Patients >65 years old account for approximately 60% of the current general surgeon's workload. 5 Patients >65 years old account for approximately 50% of all emergent operations and 75% of operative mortality.4 These statistics challenge a surgeon to have an in-depth understanding of the careful perioperative evaluation required in elderly patients and the tailoring of surgical interventions based on unique changes in physiologic reserve of the patients and comorbid conditions that make elderly patients more susceptible to postoperative complications. After all, elderly patients may tolerate the surgical interventions but not the complications. Therefore, the careful perioperative assessment will lead to improved outcomes in progressively older age cohorts, thereby increasing the upper age limits of surgical candidacy. The importance of this chapter is to highlight salient management strategies for aged surgical patients to provide optimal care and reduce postoperative complications. A particular problem in the elderly population is the potential delay in surgical treatment either from missing a diagnosis secondary to atypical presentations or postponing elective operations because of the misconception that elderly patients will suffer increased complications and poor outcomes as a result of advanced age alone. For example, elective inguinal and umbilical hernia repairs are often postponed due to age bias; these can lead to potentially devastating consequences of bowel ischemia, gangrene, and perforation, to which elderly patients respond poorly (Fig. 46-1). Emergency hernia repairs are one of the most common procedures performed in older patients. Approximately 40% of hernia repairs are performed for incarceration or bowel obstruction in patients >65 years old. 5 Emergency repair of hernias is associated with an increased morbidity rate of approximately 50% and a mortality rate ranging between 8 to 14%; a significant increase from the 2% mortality rate following elective repair.5 One can argue that proper preoperative assessment and timely intervention would have prevented the complicated course that is marked by a need for intensive care resuscitation for intra-abdominal sepsis, a prolonged hospital course, and a requirement for physical rehabilitation secondary to progressive debilitation from prolonged immobilization. This chapter explores the physiologic changes associated with aging and the importance of the perioperative assessment and the tailored management of specific surgical diseases in this population.

Fig. 46-1.

Timely surgical intervention for a medically optimized elderly surgical candidate cannot be overemphasized. Elective procedures can be carried out safely in elderly patients avoiding the potentially devastating consequences of emergency surgery: ischemia, perforation, or death. This is an example of an umbilical hernia resulting in bowel strangulation in an elderly patient with devastating consequences. (Courtesy of David Ford, M.D.)

PHYSIOLOGY OF AGING Elderly surgical patients are a heterogeneous cohort with varying degrees of functional impairments and comorbid burdens. The "young old patient" may lead an active lifestyle with few, if any, comorbid conditions. But even for this seemingly healthy group, it is crucial to remember that there are inherent physiologic changes that occur with aging and affect every organ system. These physiologic changes may become more apparent and clinically consequential with the additional stressor of major illness and operative interventions. Therefore, chronologic age is rarely an accurate predictor of morbidity and mortality from surgical interventions. It is, however, an accurate marker for declining physiologic reserve and the presence of comorbid conditions. These, in turn, place elderly patients at higher risk because of impaired cardiac, pulmonary, renal, and neurological reserves, thereby increasing the morbidity and mortality of surgical interventions. Physiologic age, in addition to comorbid conditions, more accurately predicts surgical outcomes in the elderly than chronologic age. The physiologic changes of aging are summarized in Table 46-1.

Table 46-1 Physiologic Limitations of Aging, Their Clinical Consequences, and "Best Practices" in the Elderly Surgical Patient Body composition Significantly decreased muscle mass, accounting for much of decreased lean tissue mass Erosion of muscle mass during acute illness may result in strength rapidly falling below important clinical thresholds (e.g., impaired coughing, decreased mobility, increased risk of venous thrombosis) Maintain physical function through effective pain relief, avoiding tubes, drains, and other "restraints," early

mobilization, and assistance with mobilization. Increased fat mass

Minimize fasting, provide early nutritional supplementation or support (both protein-calorie and micronutrient). Altered volumes of drug distribution Adjust drug dosages for volume of distribution. Respiratory Decreased vital capacity Less effective cough Provide early mobilization, assumption of upright rather than supine position. Increased closing volume Predisposition to aspiration Decreased airway sensitivity and clearance Increased closure of small airways during tidal respiration, especially postoperatively and when supine, leading to increased atelectasis and shunting Ensure effective pain relief to allow mobilization, deep breathing. Decreased partial pressure of oxygen Provide routine supplemental oxygen in the immediate postoperative period, and then, as needed. Predisposition to hypoxemia Minimize use of nasogastric tubes. Cardiovascular Decreased maximal heart rate, cardiac output, ejection fraction Greater reliance on ventricular filling and increases in stroke volume (rather than ejection fraction) to achieve increases in cardiac output Use vigorous fluid resuscitation to achieve optimal ventricular filling. Reliance on increased end-diastolic volume to increase cardiac output Nonvasoconstricting inotropes and afterload reduction may be more effective, if pharmacologic support is required. Intolerant of hypovolemia Slowed ventricular filling, increased reliance on atrial contribution Intolerant of tachycardia, dysrhythmias, including atrial fibrillation Use active measures to maintain normothermia during surgical procedures and to rewarm after trauma: warmed IV fluids, humidified gases, warm air. Decreased baroreceptor sensitivity Predisposition to hypothermia (e.g., decline in body temperature during surgery is more marked unless preventive measures are taken) Thermoregulation Diminished sensitivity to ambient temperature and less efficient mechanisms of heat conservation, production, and dissipation If there is hypothermia, shivering may result, associated with marked increases in oxygen consumption and cardiopulmonary demands. Maintaining intraoperative normothermia reduces wound infections, adverse cardiac events, and length of hospital stay. Febrile responses to infection may be blunted in frail or malnourished elderly and those at extreme old age.

Fever may be absent despite serious infection, especially in frail elderly. Be aware of hypothermia in trauma resuscitation. Renal function, fluid-electrolyte homeostasis Decreased sensitivity to fluid, electrolyte perturbations Predisposition to hypovolemia Pay meticulous attention to fluid and electrolyte management. Predisposition to electrolyte disorders, (e.g., hyponatremia) Decreased efficiency of solute, water conservation, and excretion Recognize that a "normal" serum creatinine value reflects decreased creatinine clearance because muscle mass (i.e., creatinine production) is decreased concurrently. Predisposition to hyperglycemia Decreased renal mass, renal blood flow, and glomerular filtration rate Predisposition to hyperosmolar states Increased renal glucose threshold Select drugs carefully: Avoid those that may be nephrotoxic (e.g., aminoglycosides) or adversely affect renal blood flow (e.g., NSAIDs). Adjust drug dosages as appropriate for altered pharmacokinetics. Age-Related Changes

Clinical Consequences

Best Practices

Source: Reproduced with permission from Watters JM: Surgery in the elderly. Can J Surg 45:106, 2002.

SURGERY IN THE ELDERLY It is critical in the assessment of an elderly surgical candidate to evaluate physiologic age and to maintain a high index of suspicion for surgical pathology, keeping in mind that elderly patients often present with atypical symptoms and can present with vague abdominal examinations that may effectively mask intra-abdominal catastrophe. This is worsened by coexistent medical problems and altered mentation that may be the result of organic brain disease such as dementia, drugs, infection, or dehydration. Acute appendicitis and acute cholecystitis are examples of common acute surgical pathologies with which elderly patients present late or have delayed diagnosis or misdiagnosis. This often leads to higher rates of perforation and complications that adversely affect morbidity and mortality.6 In fact, biliary tract disease, including acute cholecystitis, is the most common indication for surgical intervention in the elderly. This is likely related to age-related changes within the biliary system, specifically increased lithogenicity of bile and increased prevalence of cholelithiasis.7 Delayed diagnosis may lead to complications such as ascending cholangitis and gallstone ileus. Elderly patients may not present with typical symptoms of acute abdominal pain, fever, or leukocytosis, likely secondary to depressed immune response of elderly patients. A careful assessment is crucial to timely operative intervention. In fact, in older patients presenting with acute appendicitis, the initial diagnosis is correct in less than half of the patients.7 Assessment of an elderly patient presenting with abdominal pain should begin with assuring stable hemodynamics and initiating appropriate resuscitation, as these patient are often profoundly dehydrated. As with most initial evaluations, airway, breathing, and circulation are initial priorities. A careful history and physical examination

should follow and provide invaluable clues to the underlying disease process. The chief complaint should be elicited as well as a history of previous admissions, which may alert to recurrent diseases such as acute diverticulitis or previous operations that may draw focus to adhesive small-bowel obstruction. It is also important to obtain a detailed history regarding comorbid conditions and current medications. Initial evaluation may include electrocardiogram to rule out coronary ischemia and chest x-ray to rule out congestive heart failure (CHF) or pneumonia. Basic laboratory evaluation will help to rule out common medical etiologies for abdominal pain, such as coronary ischemia, acute pancreatitis, hepatitis, or urinary tract infections. Then careful referral for radiographic imaging will help to confirm the diagnosis and allow timely operative intervention. Regardless, the importance of a high degree of clinical suspicion cannot be overemphasized.

PREOPERATIVE ASSESSMENT Surgical risk increases with advancing age as a consequence of physiologic decline and the development of comorbid conditions that make the elderly surgical patient more susceptible to postoperative complications. These complications are, in turn, poorly tolerated because of decreased physiologic reserve. Comorbid illness serves as the basis for the American Society of Anesthesiologists' (ASA's) physical status classification8 (Table 46-2). This is a valuable tool for identifying elderly patients who are at high risk for postoperative complications because it is based on organ system dysfunction and severity of functional impairment. It helps to identify subgroups of patients in whom appropriate measures should be taken to reduce the risk of adverse outcomes. Importantly, it also identifies emergency surgery as a dangerous risk factor for perioperative morbidity and mortality. The physiologic changes that occur with normal aging result in increased risks associated with anesthesia and surgery, but careful assessment of potential problems in the perioperative period combined with implementation of preventative measures can significantly reduce complications associated with general anesthesia in the elderly patient.9 Adequate control and understanding of the potential negative impact of comorbid conditions on surgical outcomes allows an appropriate preoperative evaluation that, in turn, leads to acceptable morbidity and mortality. A useful algorithm for the preoperative assessment of an elderly surgical patient is provided in Fig. 46-2.

Table 46-2 American Society of Anesthesiologists' Physical Status Classification ASA Risk Stratification of Anesthetic/Surgical Risk Class 1 Healthy patient Class 2 Mild systemic disease Class 3 Severe (but not incapacitating) systemic disease Class 4 Severe systemic disease posing a constant threat to life Class 5 Moribund with life expectancy 65 years old are found to be malnourished in an outpatient setting. This increases to 12 to 50% and 25 to 60% in the acute inpatient hospital setting and chronic institutional settings, respectively.1 7 The cycle of frailty that occurs with chronic undernutrition or malnutrition can lead to progressive functional decline, loss of muscle mass, and decreased oxygen consumption and metabolic rate among several other potentially debilitating consequences to this population.1 7 Therefore, adequate assessment of nutritional status of these patients preoperatively and the prompt institution of nutritional support is of utmost importance. This is an integral component of the preoperative assessment, considering that nutritional status is a proven independent predictor of surgical outcomes. Allowing a patient's nutritional state to deteriorate throughout the perioperative period leads to adverse outcomes, specifically increased nosocomial infections, multiorgan system dysfunction, poor wound healing, and impaired functional recovery. Therefore, nutritional assessment and support, if necessary, not only gives patients additional reserve to minimize postoperative complications, it aids in appropriate wound healing, functional recovery, and rehabilitation. Protein energy malnutrition (PEM) also can result from keeping surgical patients who may already have inadequate

nutritional reserve NPO. This may occur in a short period in the elderly, malnourished surgical patient in a hypermetabolic state induced by stress of illness and surgery. The physiologic consequences of PEM are multiple and include anorexia, hepatic dysfunction, decreased mucosal proliferation, and sarcopenia. 1 7 A good marker of PEM is hypoalbuminemia , also shown to be an extremely accurate predictor of surgical outcomes. The incidence of postoperative complications was increased in patients with serum albumin levels 10% weight loss and serum albumin level 70 years old. In addition, CDS was less likely to occur with patients found to have lung, esophagus, stomach, liver, or pancreatic cancer. 1 A careful assessment of the general and cancer-related condition of the patient is crucial to planning the best surgical intervention and postoperative adjuvant therapy.

Fig. 46-6.

A useful treatment algorithm to illustrate the effectiveness of oncologic surgery depends on the balance between achieving cure and maintaining functional quality of life (QOL). (Reproduced with permission from Balducci L, Beghe C: Cancer Control: Journal of the Moffitt Cancer Center 6:466, 1999.)

Formulating a comprehensive, multimodal treatment plan for an elderly patient with a malignancy amendable to surgical intervention is based on careful consideration of the patient's expected life span, specifically if the life span is expected to exceed survival from the malignancy. Additionally, considerations include the patient's ability to tolerate the surgery and any complications that may ensue, as well as the likelihood that the patient would suffer a complication from the cancer which would adversely impact quality of life.2 7 There is an ongoing international study that is titled "Preoperative Assessment of Cancer in the Elderly (PACE)" that is attempting to determine a scoring system that aids in assessing the oncogeriatric patient for surgical intervention. The PACE study incorporates several validated instruments that assess the functional and physiologic status of patients including the Mini Mental State Examination, ADL, Geriatric Depression Scale, and the ASA classification among other useful instruments. Interestingly, the PACE assessment also includes The Physiological and Operative Severity Score for enumeration of Mortality and Morbidity, which has been shown to predict morbidity and postoperative mortality in general

surgery and in patients with lung and colorectal malignancy. This score factors in the age of the patient and gives consideration to operative factors, including the type of surgical procedure used, the presence and extent of malignancy, and the timing of the operation (i.e., planned elective procedure or an emergency intervention).1 0 Palliative interventions are a part of the therapeutic armamentarium; however, a surgeon must weigh these variables carefully to determine if surgical intervention is appropriate.

Breast It is projected that there will be a 72% increase in the number of elderly women diagnosed with breast cancer in the United States by 2025. Furthermore, 50% of breast cancers occur after the age of 65 years old and 25% after the age of 75 years old.2 8 The estimated risk for development of new breast cancer is one in 14 women aged 60 to 79 years old compared to one in 24 in women aged 40 to 59 years old.2 8 Mortality rates following breast cancer surgery in elderly women is 80 years of age, with cardiovascular disease, diabetes, and previous cancer being most common.2 9 As expected, the resulting 5-year survival rate was lower in patients with two or more comorbid conditions. A recent study on risk factors for breast cancer in patients >75 years of age showed similarity to younger women and included obesity, nulliparity, family history, and advanced age at menopause.3 0 Interestingly, although breast cancer presentation in elderly patients may be diagnosed at more advanced stages, both clinical and pathologic data demonstrate less aggressive disease in elderly women with more favorable biologic characteristics. Elderly breast cancer patients are more likely to have estrogen-positive tumors and increasing endocrine responsiveness.3 0 Large percentages of elderly women are not offered conventional therapies for breast cancer, and the management of the axilla is frequently omitted. For example, elderly patients who are offered breast conservation surgery for breast cancer are less likely to have axillary dissection, postoperative radiation, and chemotherapy. This will undoubtedly influence surgical outcomes in elderly patients with breast cancer considering that local recurrence rates after conservative surgery without radiotherapy are reported from as low as 3% to as high as 47%. Advancing age has been demonstrated to be an independent predictor of concordance with treatment guidelines for definitive surgical therapy and adjuvant chemotherapy, as well as hormonal therapy. A study demonstrated that the odds of receiving a recommendation for chemotherapy decreased by 22% for each year of advancing patient age.2 6 The concept of nonsurgical management of breast cancer in elderly patients is falling out of favor because there is currently no rationale for denying surgical therapy for elderly breast cancer patients. Surgery and hormonal therapy were the best options for overall survival, breast cancer–specific survival, and disease-free survival. A Cochrane Review concluded that treatment with tamoxifen alone is not the best option because of higher local progression of disease; 81% compared to 38% with surgical intervention. Furthermore, the response rate only lasts for approximately 18 to 24 months.2 6 The final conclusion is that surgery remains the standard of care for elderly patients with breast cancer. Alternative therapies should be reserved for patients who have multiple comorbid conditions leading to poor candidacy for operative intervention, those who are frail, or those who refuse surgery. A timely study comparing the mortality after breast-conserving surgery (BCS) alone, BCS plus radiation therapy, mastectomy, and the receipt of adjuvant tamoxifen in elderly breast cancer patients determined less than standard treatment for these patients resulted in increased mortality. Elderly women receiving BCS without radiotherapy have more than twice the rate of breast cancer mortality compared to women undergoing mastectomy. In addition,

in older women with estrogen receptor and progesterone receptor positive tumors receiving tamoxifen, the rate of breast cancer death increased substantially with the decreasing duration of tamoxifen use.3 1 The standard of treatment for elderly patients with breast cancer should be the same as younger patients; BCS plus radiotherapy when indicated. If patients decline postoperative radiotherapy or are medically unfit for radiotherapy, mastectomy should be performed. Furthermore, elderly patients with tumor size 70 years old. In fact, inhospital mortality for patients >85 years old undergoing surgery for colorectal malignancy is estimated to be ninefold greater than for younger patients.3 3 Furthermore, elderly patients often have decreased cancer-specific survival when compared to younger patients. It has been proven that the 5year cancer-specific survival for CRC is similar among the age cohorts. Therefore, age is not an independent factor accounting for the decreased survival among elderly patients. It is rather a consequence of comorbid conditions and impaired physical capacity necessary for recovery from perioperative physiological stress.3 3 This leads to bias regarding poorer outcomes in elderly patients. For this reason, many elderly patients are receiving suboptimal cancer therapy and limited resections resulting in decreased survival rates and poorer outcomes. With the ever aging population, this must be addressed and clinical modifications implemented to improve outcomes of elderly patients undergoing surgical interventions for colorectal malignancies. Elderly patients should have continued, aggressive screening for colorectal malignancy and strict adherence to accepted surgical and adjuvant treatment guidelines. One of the most important aspects to delivering appropriate care to elderly patients with CRC is to consider the patient's wishes as well as expectations from the surgical intervention. In this respect, functional outcomes and quality of life take precedence in treating elderly patients, especially the aged elderly. Of patients >75 years old who underwent elective surgery, few demonstrated protracted decline in ADL and most experienced significant improvement in quality of life. 3 4 Approximately 10% of elderly patients >80 years old have protracted postoperative disability. Estimation of physical ability and surgical stress is useful for predicting decline in ADL and postoperative disability. It has been shown that, in patients 80 years old, avoidance of a stoma becomes paramount. These are important considerations for the geriatric surgeon.3 3

A prospective study was recently undertaken to specifically evaluate the epidemiology and risk of surgical intervention for CRC in elderly patients. A large cohort of 47,455 patients was divided based on age 75 years old.3 3 It was determined that a significant portion of elderly CRC patients are female, with multiple comorbidities leading to advanced ASA levels of 3 and above. The study determined that elderly patients underwent surgical interventions less often than younger patients (81% vs. 88% respectively, P 70 years old, and elderly patients are still presenting far too commonly with surgical emergencies resulting from obstruction and perforation in up to 40% of the cases.1 1 In addition, elderly patients had higher postoperative mortality than younger patients (10.6% vs. 3.8%, respectively). Right-sided resections, Hartmann's procedures, transanal endoscopic microsurgery, and transanal resection of tumors were more common in elderly patients, whereas formal resections, including low anterior and abdominoperineal resections, were more common in younger patients.3 3 Elderly patients are less likely to undergo CDS; with each half a decade increase in age >70 years old, the odds of receiving cancer-directed surgery were reduced by 44%. Interestingly, many of these patients presented with lower-stage Duke classification lesions. However, this was not secondary to earlier presentations as one might assume, but rather secondary to understaging from surgical treatment. Accurate staging may not be possible with local resections, limiting the number of lymph nodes available for proper staging. 3 5 Elderly patients also are less likely to undergo preoperative irradiation and neoadjuvant chemotherapy, reducing the likelihood of curative resection.3 3 Liver resection for CRC liver metastases in properly selected elderly patients 70 years of age or greater is feasible with older patients having similar operative survival to younger patients. Palliative surgery remains a viable option for elderly patients with disseminated CRC and should be aimed at the reduction of symptoms such as pain, obstruction, or hemorrhage. Bowel obstruction can be relieved with intestinal bypass or a diverting colostomy. The most common site of disseminated disease is the liver, and uncontrolled liver metastases are responsible for pain, abdominal distention, jaundice, and inferior vena caval obstruction. Elderly patients with metastatic disease who are not candidates for curative resection may be considered for ablation of the lesions by local destruction, cryotherapy, or radiofrequency ablation. More traditional means such as chemotherapy, which can be administered via the hepatic artery or radiation, also may be used.3 6 Similar to breast cancer, an upper age limit for CRC has not been clearly established. Screening for CRC may not lead to an observed survival benefit until 5 years or longer after screening had occurred. This would limit the benefit of screening in aged populations with limited life expectancy. An interesting way of looking at this controversy is from a recent study that determined that the number of screening colonoscopies needed to prevent one CRC-related death (NNS) increased as with increasing age and comorbidities. For example, in healthy men and women aged 75 to 79 years old, the NNS was 50. The corresponding NNS in patients 90 years and older was 279 in women and 482 in men.3 7 Consideration for continued screening in very elderly patients should take into account age and predicted life expectancy, comorbid burden, expected duration of the protective effect of screening, risk for cancer, results of previous screening colonoscopies, and patient preference.3 7

Lung Lung cancer is the leading cause of cancer-related deaths in the United States for patients >70 years old. National Cancer Institute statistics show that the peak incidence of lung cancer is between 75 and 79 years of age. Elderly lung cancer patients also have a higher mortality rate, and therefore, the peak mortality rate is between ages 75 and 84 years.3 8 Non–small cell lung cancer accounts for roughly 80% of all lung cancer cases, and >50% of these

patients are >65 years of age. Interestingly, approximately 30% of these patients are 70 years or older at diagnosis.3 9 Lung cancer is highly prevalent among elderly patients, so much so that a 2-cm, asymptomatic, solitary pulmonary nodule in a 70-year-old male smoker has a >70% chance of being an occult lung cancer. 2 Squamous cell carcinomas are more common among elderly patients than among younger patients, and these tumors are associated with a higher incidence of local disease, tend to have lower recurrence rates, and have longer survival times than nonsquamous cancers.3 8 In cases of resectable primary lung cancer, surgery remains the treatment of choice independent of age.1 1 The estimated life expectancy of untreated lung cancer is approximately 9 months. This can increase to as high as 18 months with palliative chemotherapy and radiation. However, the life expectancy of an elderly patient who has undergone a successful operative resection is estimated to be as high as 31 months, making this the preferred option when feasible.1 3 However, despite this and the fact that more elderly patients present with stage I disease, elderly patients are offered curative surgery less frequently than younger counterparts. The same holds true for chemotherapy and radiation. Advanced age is an independent risk factor for death after thoracotomy, with significantly increased mortality after age 65. These reasons are multifactorial partly due to the physiologic debilitation that occurs with division of the intrathoracic muscles that aid in respiratory function and the loss of lung volume after resections.1 3 One study demonstrated that patients 70 years of age or older who underwent thoracotomy for lung cancer had an operative mortality rate of 14%, which is directly related to the extent of the pulmonary resection. In one of the largest prospective, multi-institutional trials conducted, The Lung Cancer Study Group, increasing age led to a significant increase in 30-day mortality for patients undergoing thoracotomy and lung resection.1 3 They found overall mortality to be approximately 3.5% in patients 65 years old. 4 2 With the expanding elderly population, this will be an increasing source of morbidity and mortality; the risk of death after major trauma with multi-system and life-threatening injuries rises steeply after age 45 years old and doubles by age 75 years old. In contrast to what is observed for abdominal and thoracic surgery, even after controlling for injury severity and pre-existing medical conditions, patients aged 65 years and older sustaining traumatic injury were 4.6 times more likely to die than younger patients.4 2 Of note, there are several interesting aspects of care of the acutely injured elderly patient that must be kept in mind. First, physiologic reserve can be challenged by trauma. For example, previously unknown disease such as cardiac impairment may be acutely unmasked. Secondly, medications common to elderly patients, such as beta blockers and anticoagulation, can not only inhibit the physiologic response to stress but may even worsen injury. Finally, elderly patients with impaired functional status posttrauma are more likely to lose their ability to function independently without the support of a nursing home. Elderly patients are particularly susceptible to trauma due to changes that occur with aging, specifically, gait instability, decreased hearing and visual acuity, presence of confusion or dementia, underlying comorbid conditions, and poor reserve to tolerate the physiologic stress of traumatic injuries. Pre-existing medical conditions increase the risk of death after trauma significantly (up to threefold).4 0 This is worsened when combined with an elderly patient's decreased functional reserve for handling physiologic abnormalities accompanying major trauma, such as hypotension and hypoxia. It is important to consider a trauma patient's age, as patients aged 65 to 80 years old have a 6.6% overall mortality rate after traumatic injury, which rises to 10% in patients 80 years or older.4 2 Despite the increased risk of morbidity and mortality after traumatic injury, it is interesting to note that there is currently an under-triaging of elderly patients to level 1 trauma centers despite high injury severity scores. 4 2 In one study, elderly patients >65 years old were five times more likely to be under-triaged to nondesignated trauma hospitals than younger counterparts.4 2 However, a reduction in morbidity and mortality and posttraumatic complications as well as faster rehabilitation can result from better triaging practices. In one particular study involving acutely injured octogenarians with injury severity scores between 21 to 45, inhospital survival was as high as 56% in trauma centers, and this dramatically decreased to 8% in those treated at nontrauma hospitals.4 2 It is important to determine the medication regimen of elderly trauma patients. Medications such as beta blockers, calcium channel blockers, diuretics, and afterload reduction agents may impair critical augmentation of myocardial

function in trauma patients, especially if they are hypovolemic. Approximately 20% of the elderly population with coronary artery disease and 10% of those with hypertension are currently on beta blocker therapy.4 2 Therefore, tachycardia, one of the most valued signs of continued hypovolemia from either ongoing blood volume loss or underresuscitation, is lost in the elderly patient on beta blocker therapy. This makes interpretation of hemodynamic parameters in elderly patients inaccurate and, at times, misleading, which could lead to delays in appropriate interventions and resuscitation. However, it is important to keep in mind that, to date, evidence supporting early hemodynamic monitoring in elderly patients is lacking. The other medication class that can be detrimental to an elderly, acutely injured patient is anticoagulation, ranging from aspirin and clopidogrel (Plavix) to warfarin, which may, at times, be supratherapeutic. Massive intracranial hemorrhages resulting from minor falls from standing in elderly patients are demonstrated in Fig. 46-7. Both patients subsequently had extremely poor prognosis. Warfarin therapy may be used in patients with atrial fibrillation, DVT, and prosthetic heart valves. The mortality rate of elderly patients on warfarin with a traumatic intracranial hemorrhage was 48% compared with 10% in an age-matched cohort not on anticoagulation therapy.4 2 One of the most important caveats to treating elderly patients on anticoagulation with blunt head injury is the potential for significant, life-threatening intracranial hemorrhage despite initial normal head (computed tomography) CT scans. In one study, >70% of patients with minor mechanisms and negative CT scan, admitted for observation subsequently, clinically deteriorated within 12 hours of admission with a Glasgow Coma Scale of 75 years old, presence of shock on admission, severe head injury, and development of infectious complications.

Fig. 46-7.

Massive intracranial hemorrhage resulting from seemingly minor trauma. The importance of immediate reversal of anticoagulation in elderly patients cannot be overestimated.

A particular concern in elderly patients sustaining blunt trauma is pelvic and extremity fractures (Fig. 46-8). Elderly patients are particularly susceptible to these injuries secondary to underlying medical conditions such as osteoporosis. Furthermore, these injuries, in particular, can not only increase the mortality of elderly trauma patients but also can predispose them to complications resulting from immobility leading to pneumonia and atelectasis, DVT, and pulmonary embolism. These injuries also predispose to functional impairment. Pelvic fractures are the most serious skeletal injury in the elderly.4 3 Timely surgical intervention for extremity fractures in elderly patients is crucial to prompt recovery and helps to minimize mortality and morbidity from such injuries. In one study, a delay in providing surgical treatment for hip fractures by more than 2 days was associated with greater than double the risk of death within the first postoperative year.4 2

Fig. 46-8.

Elderly patients are extremely susceptible to long bone fractures due to underlying medical conditions such as osteoporosis, leading to death or debilitation. Interestingly, this patient who suffered a traumatic long bone fracture had previously undergone a hip replacement a few months prior following a simple fall.

MINIMALLY INVASIVE SURGERY Laparoscopy Open abdominal procedures may require more intensive postoperative care, longer hospital stays, and an increased need for postoperative rehabilitation and possible institutionalization for elderly patients with limited reserve. However, the increasing experience with laparoscopic techniques, combined with minimized pain, decreased length of hospital stay, and low morbidity and mortality rates, has led to the increased use of minimal access procedures among elderly patients. It has expanded from cholecystectomies to more complex procedures including colon resections, gastrectomies, and cardiac surgery. Laparoscopic surgery reduces common postoperative complications such as atelectasis, GI ileus, and wound infections. In elderly surgical patients, these complications easily progress to pneumonia, DVT, and metabolic and electrolyte disturbances.4 3 Decreased postoperative pain from smaller incisions leads to faster return to a

preoperative level of functioning including early ambulation, which decreases complications from prolonged bed rest, such as DVT and pneumonia from compromised pulmonary mechanics. The latter is especially important for elderly patients because deconditioning occurs with long hospital stays, which depresses their ability to return to preoperative functional status. Laparoscopic surgery also provides the added benefit of reduction of the inflammatory, hormonal, and metabolic stress induced by major open surgical operations. However, these benefits must be balanced against the potential adverse effects of carbon dioxide (CO2 ) insufflation and hemodynamic alterations induced by pneumoperitoneum and increased intra-abdominal pressure with concomitant decrease in venous return.4 4 Therefore, decisions to perform minimal access procedures in the elderly must be individualized to the patient with careful consideration of the impact of comorbid conditions and the potential for poor cardiopulmonary reserves. This helps to provide the optimal circumstance for intervention resulting in improved surgical outcomes. The cardiopulmonary effects induced by pneumoperitoneum are secondary to CO2 insufflation and increased intraabdominal pressure.4 4 CO2 insufflation is associated with hypercarbia and acidosis, both of which are proven direct myocardial depressants.4 4 Hypercarbia is reported to be problematic in patients with pre-existing pulmonary disease with chronic CO2 retention, but this is rarely observed. In patients without pre-existing disease, these alterations can be minimized by increasing minute ventilation during the procedure. The increased intra-abdominal pressure during insufflation can lead to increased afterload, increased peripheral vascular resistance and mean systemic pressure, and decreased preload.4 4 This can result in depressed myocardial function, which is of potentially serious consequence in an elderly patient with poor physiologic reserve. It is important to maintain tight control over the intra-abdominal pressure applied during the laparoscopic procedure. For example, pressures up to 20 mmHg are associated with increased filling pressures and cardiac output. However, further increased elevations result in decreased central venous pressures and cardiac output, which can be life threatening in a patient with pre-existing cardiac dysfunction and poor functional reserve. Although the occurrence of these serious consequences are rare, adequate preoperative knowledge of the physiologic changes induced by laparoscopic techniques, as well as the changes that occur with advancing age, leads to better control of the variables that lead to adverse outcomes. Maintenance of adequate preload (i.e., adequate IV fluid administration) and intraoperative volume control, and careful mechanical ventilation to control hypercarbia and acidosis are basic concepts that allow the safe application of minimally invasive techniques in the elderly. It also is important to remember that elderly patients undergoing laparoscopic procedures must be closely monitored for any evidence of respiratory or hemodynamic compromise resulting from the pneumoperitoneum. If such changes do occur, it is crucial to immediately decompress the abdomen and allow the patient time to recover. Studies have demonstrated that both advanced age >70 years old and an ASA classification of 3 or 4 are associated with higher conversion rates for laparoscopic cholecystectomy to open cholecystectomy. 4 5 These additional challenges, however, are not a contraindication to attempting the less invasive approach because conversion to an open procedure does not adversely impact the overall morbidity and mortality of the patient. A particularly useful application of minimally invasive techniques is to rule out a surgical abdomen in an elderly patient presenting with acute abdominal pain. Vague, poorly localized pain, further obscured by several underlying confounding comorbid conditions, as is the case with ischemic colitis and mesenteric ischemia, may subject an elderly patient with poor reserve to the risk of general anesthesia and a negative exploratory laparotomy. Analysis of several studies directed at the application of laparoscopic techniques for the patient with acute abdominal pain demonstrated that approximately 41% had pathology necessitating open laparotomy, 10% had pathology

amendable to laparoscopic intervention (i.e., acute cholecystitis), and 48% had nonsurgical disease that was subsequently managed nonoperatively, avoiding a negative exploration.4 5 Therefore, laparoscopic evaluation of abdominal pain in the critically ill elderly patient may prove to be a valuable tool.

ENDOVASCULAR SURGERY Abdominal aortic aneurysm (AAA) is a disease that primarily affects the elderly male patient. With increasing use of screening abdominal CT scans and ultrasounds for evaluation of various abdominal complaints, AAAs are being identified with greater frequency, most of which are diagnosed in elderly patients, given the increased prevalence of AAA with increasing age. In fact, the percentage of AAA rises from about 1% at age 55 to 60 years to approximately 10% in patients 80 years of age or older.4 6 Elderly patients, and octogenarians in particular, were deemed poor operative candidates for the traditional open repair given the frequent presence of comorbid conditions and limited cardiopulmonary reserve to tolerate a major operation or the many hours of required operative time and general anesthesia. Elderly patients had an increased perioperative morbidity and mortality following open aortic surgery in comparison to younger cohorts. However, the introduction of endovascular techniques for repair of AAA has shifted the risk-benefit ratio for operative intervention, allowing greater life expectancy for the elective repair of this potentially life-threatening condition with the benefits of minimally invasive techniques as described above. Studies have demonstrated that endovascular aortic repair (EVAR) is feasible and efficacious in elderly patients, including those previously considered unfit for open repair. EVAR is a minimally invasive technique in which a prosthetic graft is introduced into the aortic lumen via the common femoral artery to exclude the aortic aneurysm sac. EVAR significantly reduces operative and anesthesia times, blood loss, intensive care needs, length of stays, and major postoperative morbidity associated with open AAA repair. The most common complication following EVAR in elderly patients is renal impairment. Typically, patients are discharged 1 to 2 days following surgery and the graft is deployed via small bilateral groin incisions, obviating the need for a major laparotomy incision. Figure 46-9 demonstrates the endovascular repair of AAA and right iliac artery aneurysm via bilateral groin access in an 82-year-old man who was discharged from the hospital on postoperative day 2. This procedure also can be done using epidural anesthesia for high-risk candidates who may tolerate general anesthesia poorly. Endovascular repair has even been described under local anesthesia in patients at extreme high risk of rupture and death or after rupture and hemodynamic instability precluding the ability to tolerate general anesthesia.4 7 This was a reportable circumstance and obviously not the current standard of care.

Fig. 46-9.

Endovascular repair of abdominal aortic aneurysms (AAAs) is gaining favor for suitable elderly patients to prevent rupture. Through minimal groin incisions, this 82-year-old patient underwent repair of an AAA and right iliac artery aneurysm and was discharged on postoperative day 2.

Careful consideration of the life expectancy and the risk of rupture dictate the necessity for intervention. EVAR remains a viable option in elderly patients. Nonoperative management is justified in frail elderly patients with multiple comorbidities and reduced life expectancy whose operative risks outweigh the risk of rupture and in those who are unlikely to survive long enough to benefit from the repair.

THYROID AND PARATHYROID SURGERY The prevalence of thyroid disease increases with advancing age. The etiologies, risk factors, and presentations of thyroid disease are similar across all ages, and therefore, are not discussed in detail. Of note, however, is that elderly patients more often present with cardiac manifestations of hyperthyroidism, such as atrial fibrillation, than do their younger counterparts. A common finding requiring evaluation in elderly patients is the presence of a thyroid nodule, usually detected by physical examination. These nodules usually are single and four times more common in women, making them a particular concern for postmenopausal elderly women. Indications for surgical

intervention for thyroid nodules are dependent on the characteristics of the nodule (i.e., whether it is benign or malignant, or whether the patient is euthyroid or thyrotoxic). In addition, surgical intervention becomes necessary if the nodule enlarges, producing compressive symptoms. Papillary carcinoma in elderly patients tends to be sporadic with a bell-shaped distribution of age at presentation, occurring primarily in patients aged 30 to 59 years old. The incidence of papillary carcinoma decreases in patients >60 years of age.4 8 However, patients >60 years of age have increased risk of local recurrence and for the development of distant metastases. Metastatic disease may be more common in this population secondary to delayed referral for surgical intervention because of the misconception that the surgeon will be unwilling to operate on an elderly patient with thyroid disease. Age is also a prognostic indicator for patients with follicular carcinoma. There is a 2.2 times increased risk of mortality from follicular carcinoma per 20 years of increasing age.4 9 Therefore, prognosis for elderly patients with differentiated thyroid carcinomas is worse when compared to younger counterparts. The higher prevalence of vascular invasion and extracapsular extension among older patients is, in part, responsible for the poorer prognosis in geriatric patients. Advancing age leads to increased mortality risk for patients with thyroid cancer and is demonstrated by the AMES (a ge, m etastases, e xtent of primary tumor, and s ize of tumor) classification system developed by the Lahey Clinic. Anaplastic carcinoma is a highly aggressive form of thyroid carcinoma with dismal prognosis. It accounts for approximately 1% of all thyroid malignancies; however, it occurs primarily in elderly patients.5 0 This poorly differentiated tumor rapidly invades local structures, leading to clinical deterioration and eventually tracheal obstruction. These patients may present with a painful, rapidly enlarging neck mass accompanied by dysphagia and cervical tenderness. This leads to respiratory compromise and impingement of the airway. Unfortunately, because of the aggressive nature of the disease and the dismal prognosis, surgical resection of the tumor is not attempted for cure. Furthermore, radiation therapy and chemotherapy offer little benefit. Airway blockage, however, may necessitate surgical palliation or permanent tracheostomy to alleviate symptoms of respiratory distress.

PARATHYROID SURGERY Approximately 2% of the geriatric population, including 3% of women 75 years of age or older, will develop primary hyperparathyroidism.5 1 Geriatric patients are usually referred to surgery only when advanced disease is present because of concerns regarding the risks of surgery, but low rates of morbidity and negligible mortality combined with high cure rates of approximately 95 to 98% make parathyroidectomy safe and effective. Convincing evidence of the benefit of surgery is the usual marked symptomatic improvement, which greatly improves the quality of life for most patients. The National Institutes of Health Consensus Development Statement recommends curative therapy after diagnosis of primary hyperthyroidism is established in a patient regardless of age. Specific indications for operative intervention regardless of age include a 30% decrease in creatinine clearance, 24-hour urinary calcium excretion >400 mg, and decreased bone density.52,53 Elderly patients are especially prone to developing mental manifestations of hyperparathyroidism that may be severe enough to produce a dementia-like state. There often is a significant improvement in mental status after parathyroidectomy. Another specific symptom of hyperparathyroidism that may easily be mistaken for osteoporosis and can be present in postmenopausal, elderly women is orthopedic disease; specifically back pain, and possibly, the occurrence of vertebral fractures. This pain can be of moderate intensity, leading to impaired mobility and severely affecting the quality of life of elderly patients. The decreased bone density observed in elderly patients with hyperparathyroidism tends to improve during the first 2 years after successful parathyroid surgery. Limited parathyroidectomies with minimal dissection in geriatric patients are an effective alternative. This is a

viable option in patients with multiple comorbid conditions in whom the increased risk of surgical intervention or general anesthesia remains a concern. One study demonstrated that preoperative localization of the hyperfunctioning gland with the aid of

99m

Tc-sestamibi nuclear scanning, as well as intraoperative parathyroid

hormone (PTH) assays to rapidly confirm that all hypersecreting glands have been removed, allows limited parathyroidectomy to be performed with accuracy in elderly patients (Fig. 46-10).5 1 This procedure is described as "limited" because bilateral neck dissection for identification and biopsy of the remaining glands to determine if they are hypersecreting becomes unnecessary. The half-life of intact PTH is approximately 3 to 4 minutes. Therefore, a drop in the intraoperative PTH level at approximately 10 minutes after resection of the suspect hypersecreting gland suggests a 98% probability that the patient will return to normocalcemic levels postoperatively.5 1

Fig. 46-10.

Parathyroid adenoma in an elderly patient with high calcium levels and elevated parathyroid hormone levels. A. Sestamibi scan showed right-upper-gland adenoma facilitating a directed incision. B. One-g pituitary adenoma was easily identified intraoperatively (white arrow ). Black arrow points to the recurrent laryngeal nerve.

PALLIATIVE SURGERY Palliative surgery is defined as surgical intervention targeted to alleviate a patient's symptoms, thus improving the patient's quality of life despite minimal impact on the patient's survival (see Chap. 48).5 4 With an increasing number of aging surgical patients who often present with advanced disease, surgeons must be familiar with the concept of palliation to control disease. This concept focuses on providing the maximal benefit to the patient using the least-invasive intervention. Ultimately, this leads to symptom relief and preservation of the quality of life in terminal disease states. The uses of palliative surgery can range from extensive debulking operations aimed at aiding in the effectiveness of chemotherapy and radiation, to less complex operations to alleviate symptoms such as intractable vomiting, severe pain, cachexia, and anorexia that are common to terminal disease states. The success of palliative surgery is a careful balance between achieving symptom relief while ensuring that the development of new symptoms from the palliative intervention itself does not occur. Palliative care in the treatment of advanced disease often is associated with age bias; older patients are more prone to be offered palliative care in comparison to younger patients. In a recent survey, two surgical scenarios were presented to a panel of surgeons.3 5 The first patient was an 85-year-old woman with excellent functional status presenting for evaluation of back pain, jaundice, weight loss, and vomiting. Appropriate studies were completed with CT scan that demonstrated a mass in the head of the pancreas with invasion into the portal vein.

The patient in the second scenario experienced identical symptoms, but was significantly younger. Most of the surgeons selected major surgical intervention for the younger patient, while only one third of the panel offered the same intervention for the older patient. The majority offered only palliative care for the older patient. It is important to note that those surgeons who offered operative intervention based their decision on the functional status of the patient preoperatively. When transitioning from curative therapy to palliation, the risks and benefits of the proposed surgical intervention should be examined, as well as the intended impact to the patient's quality of life. There currently is no evidence to support that palliative surgery is less effective for elderly patients with surgically unresectable disease. Younger patients undergoing palliative interventions do not have a demonstrated improved outcome when compared to disease-matched older patients. Therefore, it is important to recognize that age is not a limitation to surgical intervention, and that all interventions should be individualized based on the severity of symptoms and the predicted benefit. Surgical palliative care can range from nonoperative management of malignant obstructions by percutaneous methods (Fig. 46-11) to laparoscopic surgery for the treatment of life-threatening illness by minimally invasive technique (Fig. 46-12). An interesting challenge in palliative care is the determination of the actual cause of a patient's symptoms to offer the most beneficial, but least invasive, intervention. Treatment of malignant pleural effusions, for example, should be tailored to the source of the symptoms, not the effusion. Effusions should be treated only when they cause significant distress for patients with terminal disease.3 5 Dyspnea in a terminal patient can be the result of chest wall restriction, pulmonary fibrosis from previous radiation treatment, infiltration of the primary cancer, or early airway obstruction from mediastinal spread of the primary tumor.3 5 If it is determined that a patient's dyspnea is largely secondary to a malignant pleural effusion, the goal of palliative intervention is lung expansion, preferably with permanent pleurodesis. Permanent control can be achieved via thoracoscopy or by more invasive thoracotomy with chemical pleurodesis.3 5 The latter intervention is highly effective for permanent resolution, and therefore, may be more invasive than necessary for patients with late-stage terminal disease. In these patients, medical pleurodesis with intrapleural injection of a sclerosant via thoracostomy tube placement is a better alternative. 3 5 For surgical therapy, minimally invasive procedures such as VATS may be an appropriate method to assess the apposition of pleural surfaces and may allow for talc pleurodesis or insertion of a pleuroperitoneal shunt. 3 5

Fig. 46-11.

Palliative care in an 82-year-old woman with obstructive jaundice from unresectable cholangiocarcinoma. Computed tomography scan showed metastatic disease to the liver. A. A percutaneous drainage of the biliary system with a stent placed across the obstruction from the hilum to the distal common bile duct. B. Two days later, a covered permanent metallic wall stent was placed across the obstruction.

Fig. 46-12.

An 85-year-old man with dementia presenting with a bleeding GI stromal tumor in the fundus of the stomach, treated with laparoscopic gastrectomy. A. The upper GI series delineating the tumor. B. Laparoscopic division of short gastric artery with harmonic scalpel. C. Division of stomach with Endo-GIA stapler. D. Resection of the mass before removal from abdomen via an endobag.

Palliative intervention for symptom relief and prevention of complications can be demonstrated in the management of terminal pancreatic cancer and metastatic CRC. Two thirds of patients with pancreatic cancer present with advanced disease, which often is diagnosed after evaluation of obstructive jaundice. Despite advanced disease, surgical intervention improves quality of life through relief of biliary obstruction. Percutaneous transhepatic stenting has emerged as a viable alternative to surgical bypass, achieving similar results and lowering mortality rates with the occurrence of fewer early complications. Endoscopic stenting is yet another option. If a patient does not have multiple comorbidities with good functional status, surgical intervention then can provide a definitive diagnosis and permanent biliary decompression and gastric drainage. In addition, an important palliative intervention that can be provided to patients with the open procedure is chemical splanchnicectomy, which is infiltration of the celiac plexus with an agent such as alcohol for effective relief of intractable pain from tumor invasion of the celiac plexus.3 5 A gastroenterostomy drainage procedure is effective protection against gastric outlet obstruction, which inevitably develops in 30% of patients. Palliative surgery for disseminated CRC should be aimed at the reduction of symptoms such as pain, obstruction, or hemorrhage. Bowel obstruction can be relieved with intestinal bypass or a diverting colostomy. The most common site of disseminated disease is the liver. Uncontrolled liver metastasis is responsible for pain, abdominal distention, jaundice, and inferior vena caval obstruction. Many patients with liver metastasis are not candidates for resection,

and therefore may be considered for ablation of the lesions by local destruction, cryotherapy, or radiofrequency ablation. More traditional means, such as chemotherapy, which can be administered via the hepatic artery or radiation, also may be used. Systemic corticosteroid therapy can be used in patients with advanced metastatic disease to reduce pain caused by swelling of the liver capsule. If bone metastases are present, pain may be controlled by irradiation, and prophylactic fixation of long bones may be considered to decrease pain as well as morbidity from pathologic fractures.3 5 Similarly, cerebral irradiation and high-dose steroid therapy may help to decrease intracranial pressure from metastatic disease as well as delay the onset of neurologic symptoms and cognitive impairment, which are essential to maintain quality of life of the patient.3 5

SPECIFIC SYMPTOM MANAGEMENT Gastrointestinal Disturbances The distressing symptoms often faced by terminally ill patients either result from the disease process or as a side effect of treatment. The causes of nausea and vomiting in terminally ill patients are multifactorial and can be attributed to various medications or chemotherapy treatments, gastric stasis, obstruction of the GI tract, mesenteric metastases, irritation of the GI tract, raised intracranial pressure from cerebral metastasis, or anxietyinduced emesis. Treatment should be focused on prevention of dehydration and malnutrition from poor oral intake. Antiemetics may be administered for control of nausea and vomiting. The oral route of administration is the best option for prophylaxis before chemotherapy treatments. However, other preparations such as suppositories or injections can be appropriate for patients who are unable to tolerate oral medications. Diarrhea and constipation also are common GI disturbances in terminal patients. Constipation is particularly common in patients receiving chronic narcotic medications. Constipation also can be caused by such events as tumor invasion leading to intestinal obstruction, metabolic abnormalities such as hypercalcemia from metastatic disease, and dehydration. Because constipation may be worsened by dehydration, adequate fluid intake often helps to alleviate symptoms. Constipation can lead to fecal impaction, nausea, and colicky abdominal pain. If there is difficulty distinguishing between constipation and early bowel obstruction, diagnostic tests are useful, but should be kept to a minimum in terminal patients. Patients can be treated with stool softeners and stimulant agents. Laxatives with peristalsis-stimulating action, such as senna or bisacodyl, should be used with caution because of the potential for causing intestinal colic. The occurrence of diarrhea also is multifactorial and can be caused by medications, overload incontinence with fecal impaction, from the disease process itself, malignant bowel obstruction, or improper laxative therapy. Radiation therapy can cause diarrhea by damage of the intestinal mucosa, which results in the release of prostaglandins and the malabsorption of bile salts that increases peristalsis. Once the underlying causes are identified and appropriately managed, patients can be given bulk-forming agents and opiate derivatives to aid in symptomatic improvement.

DEPRESSION AND ASTHENIA Asthenia is a condition of reduced energy levels accompanied by fatigue and generalized weakness without the presence of physical or mental exertion.5 5 In a study by Hinshaw and associates, asthenia was present in approximately 90% of patients and was more prevalent than pain, leading to the potential for impaired quality of life.5 5 Both of these symptoms commonly affect the terminally ill patient. However, if identified, appropriate interventions can be provided in an effort to improve quality of life and enhance the patient's functional status. In cancer patients, overactivity of the hypothalamic-pituitary-adrenal axis and elevation of interleukin-6 levels have

been reported in patients suffering with depression. Natural killer cell activity has been demonstrated to decline in patients with depression, causing an immunosuppressive effect and weakening the patient's response to tumor. 5 5 Poorly controlled pain and complications from disease progression also can cause terminal patients to develop depression. These complications include somnolence and depression that can occur with hypercalcemia from bony metastases with lung and breast cancer. These must be controlled as much as possible before the consideration of pharmacologic therapy to alleviate symptoms of depression. Appropriate therapy for depression and asthenia must be individualized. If a patient has good functional status with a predicted survival time of several months, the initiation of standard antidepressants is appropriate. However, if there is an expected short survival period with progression of depressive symptoms impairing quality of life, then a psychostimulant is more appropriate because of its immediate effect, better short-term efficacy, and the tendency for development of tolerance, usually within 3 months.5 5 Psychostimulants such as amphetamine and methylphenidate also increase appetite at lower doses and help to reduce sedation that may result from treatment with narcotic medications for pain management. 5 5 Psychostimulants also are effective in the management of asthenia, which shares a common clinical presentation with depression. However, pharmacologic therapy for asthenia should be provided only after treatable causes of this symptom, such as medications (including narcotics), the presence of pain, anemia, dehydration, and infection, as well as metabolic abnormalities, such as hyponatremia, hypokalemia, and hypercalcemia, have been assessed and corrected.5 5

Cachexia and Anorexia Cachexia refers to catabolic changes associated with progressive wasting that is present in patients with advanced illness; prominent symptoms include anorexia, weight loss, and asthenia.5 6 A subsequent loss of muscle and fat leading to anemia, hypoalbuminemia, and hypoproteinemia also is common. This is a chronic form of malnutrition and is not reversible with short-term nutritional support and hyperalimentation.5 6 Malnourished cancer patients with cachexia have reduced response to antineoplastic medications, radiation, and chemotherapy, as well as decreased survival rates.3 5 The mechanism of cachexia is poorly understood, but hypotheses include actions of interleukin-6, tumor necrosis factor, and interferon-mediating metabolic changes in chronic illness.5 6 Management of cachexia begins with the identification of correctable causes. Patients may have underlying metabolic derangements, as well as dehydration, that must be appropriately treated. Poorly controlled pain, anemia, and sleep disturbances also may exacerbate symptoms of cachexia, leading to malnutrition and wasting. Patients with terminal disease additionally often suffer from GI disturbances, such as constipation and nausea, which may lead to anorexia. Malabsorption is common in patients with pancreatic cancer, and supplementation of pancreatic enzymes may improve absorption and help to improve nutritional status. Nausea and vomiting should be appropriately managed. It is important to rule out mechanical causes of malnutrition that can effectively be treated with nonoperative management such as bowel rest and nasogastric tube compression or operative intervention. If no underlying correctable abnormalities are identified, patients may benefit from pharmacologic intervention with dexamethasone and prednisone, which increase appetites in patients with advanced cancer, leading to improved quality of life.5 6 The onset of effect is rapid but short-lived, and thus should be reserved for patients at terminal stages of disease. Other agents, such as progestational drugs, namely megestrol acetate (Megace), also stimulate appetite and cause weight gain in cachexia patients.5 6

Malignant Bowel Obstruction Patients with malignant bowel obstruction typically present with cramping abdominal pain, nausea, and vomiting,

which may be a common complication of advanced terminal disease secondary to GI malignancy or from extrinsic compression of bowel loops from progressive tumor burden. Conservative management can be effective and includes NPO, IV hydration, and nasogastric decompression. However, long-term management often is difficult. Medical management with pharmacologic agents such as somatostatin analogues to decrease GI output may also be considered for symptom alleviation, along with analgesics and antiemetics. Octreotide effectively decreases the volume of GI secretions via inhibition of intestinal hormones and growth hormone and is 70% effective in patients suffering with bowel obstruction with the added effect of decreasing colic and nausea.5 6 However, surgical palliation via bypass procedures, decompressing, or diverting ostomies may be required. Surgical intervention may provide permanent alleviation of obstruction and eliminate the need for repeated nasogastric decompressions that can limit patient comfort. In one study, approximately 40 to 70% of patients reported relief of symptoms of obstruction after surgical intervention. 5 6 This must be balanced against the risk of perioperative mortality from surgical intervention, which ranges from approximately 12 to 20%, as well as the potential for mortality from wound infection, poor wound healing, and fistula formation.5 6 Patients in whom the risk of surgical intervention outweighs the benefit of palliation include patients who have ascites or multiple sites of obstruction accompanied by poor functional status and poor nutrition with serum albumin levels 25,000 diplomates. Certificates in Anesthesia Pain Management and Anesthesia Critical Care Medicine are granted to those completing additional postgraduate training. The ASA has >35,000 members, and its official journal, Anesthesiology , has a monthly circulation of 40,000 worldwide.

BASIC PHARMACOLOGY Pharmacokinetics Pharmacokinetics or the time dependency of a drug describes the relationship between the dose of a drug and its plasma or tissue concentration. It is what the body does to the drug. It relates to absorption, distribution, metabolism, and elimination. The route of administration, metabolism, protein binding, and tissue distribution all affect the pharmacokinetics of a particular drug.

ADMINISTRATION, DISTRIBUTION, METABOLISM, AND ELIMINATION Administration of a drug affects its pharmacokinetics, as there will be different rates of drug entry into the circulation. For example, the oral and IV routes are subject to first-pass effect of the portal circulation; this can be bypassed with the nasal or sublingual route. Other routes of drug administration include transdermal, intramuscular, subcutaneous, or inhalation. Distribution is the delivery of a drug from the systemic circulation to the tissues. Once a drug has entered the systemic circulation, the rate at which it will enter the tissues depends on several factors: Molecular size of the drug, capillary permeability, polarity, and lipid solubility. Small molecules will pass more freely and quickly across cell membranes than large ones, but capillary permeability is variable and results in different diffusion rates. Renal glomerular capillaries are permeable to almost all non–protein-bound drugs; capillaries in the brain are fused (i.e., they have tight junctions) and are relatively impermeable to all but the tiniest molecules (the blood-brain barrier). Un-ionized molecules pass more easily across cell membranes than charged molecules; diffusibility also increases with increasing lipid solubility. Plasma protein and tissue binding. Many drugs bind to circulating proteins like albumin, glycoproteins, and globulins. Disease, age, and the presence of other drugs will affect the amount of protein binding; drug distribution is affected because only the unbound free portion of the drug can pass across the cell membrane. Drugs also bind reversibly to body tissues; if they bind with high affinity, they are said to be sequestered in that tissue (e.g., heavy metals are sequestered in bone).1 1 The fluid volume in which a drug distributes is termed the volume of distribution (Vd). This mathematically

derived value gives a rough estimation of the overall physical distribution of a drug in the body. A general rule for volume distribution is that the greater the Vd, the greater the diffusibility of the drug. Because drugs have variable ionization rates and bind differently to plasma proteins and tissues, the Vd is not a good predictor of the actual concentration of the drug after administration. Determining the apparent Vd (dose/concentration) is an attempt to more accurately ascertain the drug dose administered and its final concentration. Metabolism is the permanent breakdown of original compounds into smaller metabolites. Drug elimination varies widely; some drugs are excreted unchanged by the body, some decompose via plasma enzymes, and some are degraded by organ-based enzymes in the liver. Many drugs rely on multiple pathways for elimination (i.e., metabolized by liver enzymes then excreted by the kidney). When a drug is given orally, it reaches the liver via the portal circulation and is partially metabolized before reaching the systemic circulation. This is why an oral dose of a drug often must be much higher than an equally effective IV dose. Some drugs (e.g., nitroglycerine) are hydrolyzed presystemically in the gut wall and must be administered sublingually to achieve an effective concentration. It is important to remember that the response to drugs varies widely. The disposition of drugs is affected by age; weight; sex; pregnancy; disease states; and the concomitant use of alcohol, tobacco, and other licit and illicit drugs. Genetic polymorphism, or variations in genes which cause differing drug effects, is another explanation of varying drug response. This will be discussed later in the Future Direction of Anesthesia section on proteomics. This as yet unpredictable response to drugs underscores the importance of the most important monitor in the operating room—the anesthesiologist, who continuously assesses the patient's vital signs and adjusts the doses of anesthetic agents to match the surgical stimulus.

Pharmacodynamics Pharmacodynamics , or how the plasma concentration of a drug translates into its effect on the body, depends on biologic variability, receptor physiology, and clinical evaluations of the actual drug. It is what the drug does to the body. An agonist is a drug that causes a response. A full agonis t produces the full tissue response, and a partial agonist provokes less than the maximum response induced by a full agonist. An antagonist is a drug that does not provoke a response itself, but blocks agonist-mediated responses. An additive effect means that a second drug acts with the first drug and will produce an effect that is equal to the algebraic summation of both drugs. A synergistic effect means that two drugs interact to produce an effect that is greater than expected from the two drugs' algebraic summation.1 2 Hyporeactivity means a larger than expected dose is required to produce a response, and this effect is termed tolerance , desensitization , or tachyphylaxis . Tolerance usually results from chronic drug exposure, either through enzyme induction (e.g., alcohol) or depletion of neurotransmitters (e.g., cocaine).

Potency, Efficacy, Lethal Dose, and Therapeutic Index The potency of a drug is the dose required to produce a given effect, such as pain relief or a change in heart rate. The average sensitivity to a particular drug can be expressed through the calculation of the effective dose; ED5 0 would have the desired effect in 50% of the general population. The efficacy of any therapeutic agent is its power to produce a desired effect. Two drugs may have the same efficacy but different potencies. The difference in potency of the two drugs is described by the ratio ED5 0 b /ED 5 0 a , where a is the less potent drug. If the ED5 0 b equals 4 and the ED5 0 a equals 0.4, then drug a is 10 times as potent as drug b . For example, 10 mg of morphine produces analgesia equal to that of 1 mg of hydromorphone. They are equally effective, but hydromorphone is 10 times as potent as morphine.

Dose-response curves show the relationship between the dose of a drug administered (or the resulting plasma concentration) and the pharmacologic effect of the drug. The pharmacologic effect might be secretion of a hormone, a change in heart rate, or contraction of a muscle. Between 20 and 80% of the maximum effect, the logarithm of the dose and its response has a linear relationship. The term dose only applies to the amount administered and not the actual concentration. If the concentration of an antagonist is increased (in the presence of a fixed concentration of agonist), the dose-response curve will be shifted to the right, and a higher agonist concentration will be required to achieve the desired effect. A basic dose-response curve is shown in Fig. 47-1.

Fig. 47-1.

Basic dose-response curve.

The lethal dose (LD 5 0 ) of a drug produces death in 50% of animals to which it is given. The ratio of the lethal dose and effective dose, LD5 0 /ED 5 0 , is the therapeutic index . A drug with a high therapeutic index is safer than a drug with a low or narrow therapeutic index.

ANESTHETIC AGENTS Anesthesia can be local , regional , or general (Table 47-1). Local anesthesia is accomplished using a local anesthetic drug that can be injected intradermally and is used for the removal of small lesions or to repair traumatic injuries. Local anesthesia is the most frequent anesthetic administered by surgeons and may be accompanied by IV sedation to improve patient comfort.

Table 47-1 Anesthetic Agents, Their Actions, and Their Clinical Uses Unconsciousness Electroencephalogram Benzodiazepines

Sevoflurane Nitrous oxide —c Amnesia Clinical signs Midazolam Desflurane Anxiolysis Diazepam Isoflurane Lorazepam Enflurane Barbiturates Halothane Propofol Etomidate Ketaminea Analgesia Heart rate Opioids Sevoflurane Nitrous oxide Amides Esters Blood pressure Morphine Desflurane Lidocaine Cocaine Respiratory rate Meperidine Isoflurane Bupivacaine Procaine Clinical signs Hydromorphone Enflurane Mepivacaine Chloroprocaine

Fentanyl Halothane Prilocaine Tetracaine NSAIDs Ropivacaine Benzocaine Ketorolac Regional peripheral nerve blocks Parecoxib Muscle relaxation Nerve stimulator Depolarizing agent Sevoflurane —b Brachial plexus Paralysis Tidal volume Succinylcholine Desflurane Sciatic Hand grip Nondepolarizing agents Isoflurane Femoral 5-second head lift Enflurane Cervical plexus Clinical signs Pancuronium Halothane Regional central nerve blocks Vecuronium Rocuronium Spinal Atracurium Epidural Cis -atracurium

Mivacurium Effect Monitor IV Drugs

Potent Gases

Weak Gases

Local Anesthetics

a Note

that the IV agents are quite specific in their effects, except for ketamine, which has both amnestic and analgesic qualities. b

The potent inhalational anesthetics contribute to all three components of anesthesia, but nitrous oxide has weak amnestic and analgesic properties and provides no muscle relaxation at all. c

The local anesthetics produce excellent analgesia and muscle relaxation, but contribute nothing to amnesia or anxiolysis; these anesthetics must be supplemented with an IV sedative. General anesthesia entails all three elements of anesthesia (amnesia, analgesic, and muscle relaxation).

Local Anesthetics Local anesthetics are divided into two groups based on their chemical structure: the amides and the esters. In general, the amides are metabolized in the liver and the esters are metabolized by plasma cholinesterases, which yield metabolites with slightly higher allergic potential than the amides (Table 47-2).

Table 47-2 Biologic Properties of Commonly Used Local Anesthetics Esters Procaine 2 50 Plasma Chloroprocaine 2 45 Plasma Tetracaine 0.25 175 Plasma Amides Prilocaine 1 100 Liver/lung Lidocaine 1 100 Liver Mepivacaine 1 100 Liver

Bupivacaine 0.25 175 Liver Ropivacaine 0.3 150 Liver Etidocaine 0.25 200 Liver Agent Equianesthetic Concentration (%) Approximate Anesthetic Duration (min)

Site of Metabolism

Source: Reproduced with permission from Rosenberg et al.8 0

AMIDES Lidocaine, bupivacaine, mepivacaine, prilocaine, and ropivacaine have in common an amide linkage between a benzene ring and a hydrocarbon chain that, in turn, is attached to a tertiary amine. The benzene ring confers lipid solubility for penetration of nerve membranes, and the tertiary amine attached to the hydrocarbon chain makes these local anesthetics water soluble. Lidocaine has a more rapid onset and is shorter acting than bupivacaine; however, both are widely used for tissue infiltration, regional nerve blocks, and spinal and epidural anesthesia. Ropivacaine is the most recently introduced local anesthetic. It is clinically similar to bupivacaine in that it has a slow onset and a long duration, but is less cardiotoxic. All amides are 95% metabolized in the liver, with 5% excreted unchanged by the kidneys.

ESTERS Cocaine, procaine, chloroprocaine, tetracaine, and benzocaine have an ester linkage in place of the amide linkage mentioned above in the Amides section. Unique among local anesthetics, cocaine occurs in nature, was the first used clinically, produces vasoconstriction [making it useful for topical application (e.g., for intranasal surgery)], releases norepinephrine from nerve terminals resulting in hypertension, and is highly addictive. Cocaine is a Schedule II drug. Procaine, synthesized in 1905 as a nontoxic substitute for cocaine, has a short duration and is used for infiltration. Tetracaine has a long duration and is useful as a spinal anesthetic for lengthy operations. Benzocaine is for topical use only. The esters are hydrolyzed in the blood by pseudocholinesterase. Some of the metabolites have a greater allergic potential than the metabolites of the amide anesthetics, but true allergies to local anesthetics are rare. The common characteristic of all local anesthetics is a reversible block of the transmission of neural impulses when placed on or near a nerve membrane. Local anesthetics block nerve conduction by stabilizing sodium channels in their closed state, preventing action potentials from propagating along the nerve. The individual local anesthetic agents have different recovery times based on lipid solubility and tissue binding, but return of neural function is spontaneous as the drug is metabolized or removed from the nerve by the vascular system. Toxicity of local anesthetics results from absorption into the bloodstream or from inadvertent direct intravascular injection. Toxicity manifests first in the more sensitive central nervous system (CNS), and then the cardiovascular

system.

CENTRAL NERVOUS SYSTEM As plasma concentration of local anesthetic rises, symptoms progress from restlessness to complaints of tinnitus. Slurred speech, seizures, and unconsciousness follow. Cessation of the seizure via administration of a benzodiazepine or thiopental and maintenance of the airway is the immediate treatment. If the seizure persists, the trachea must be intubated with a cuffed endotracheal tube to guard against pulmonary aspiration of stomach contents.

CARDIOVASCULAR SYSTEM With increasingly elevated plasma levels of local anesthetics, progression to hypotension, increased P-R intervals, bradycardia, and cardiac arrest may occur. Bupivacaine is more cardiotoxic than other local anesthetics. It has a direct effect on ventricular muscle, and because it is more lipid soluble than lidocaine, it binds tightly to sodium channels (it is called the fast-in, slow-out local anesthetic ). Patients who have received an inadvertent intravascular injection of bupivacaine have experienced profound hypotension, ventricular tachycardia and fibrillation, and complete atrioventricular heart block that is extremely refractory to treatment. The toxic dose of lidocaine is approximately 5 mg/kg; that of bupivacaine is approximately 3 mg/kg. Calculation of the toxic dose before injection is imperative. It is helpful to remember that for any drug or solution, 1% = 10 mg/mL. For a 50-kg person, the toxic dose of bupivacaine would be approximately 3 mg/kg, or 3

x

50 =

150 mg. A 0.5% solution of bupivacaine is 5 mg/mL, so 150 mL/5 mg/mL = 30 mL as the upper limit for infiltration. For lidocaine in the same patient, the calculation is 50 kg

x

5 mg/mL = 250 mg toxic dose. If a 1%

solution is used, the allowed amount would be 250 mg/10 mg/mL = 25 mL.

ADDITIVES Epinephrine has one physiologic and several clinical effects when added to local anesthetics. Epinephrine is a vasoconstrictor, and by reducing local bleeding, molecules of the local anesthetic remain in proximity to the nerve for a longer time period. Onset of the nerve block is faster, the quality of the block is improved, the duration is longer, and less local anesthetic will be absorbed into the bloodstream, thereby reducing toxicity. Although epinephrine 1:200,000 (5 g/mL) added to a local anesthetic for infiltration will greatly lengthen the time of analgesia, epinephrine-containing solutions should not be injected into body parts with end-arteries, such as toes or fingers, as vasoconstriction may lead to ischemia or loss of a digit. When added to the local anesthetic, sodium bicarbonate will raise the pH, favoring the non-ionized uncharged form of the molecule. This speeds the onset of the block, especially in local anesthetics that are mixed with epinephrine. The pH of such solutions is around 4.5; therefore, the addition of sodium bicarbonate results in a relatively large increase in pH.1 3

Regional Anesthesia PERIPHERAL Local anesthetic can be injected peripherally , near a large nerve or plexus, to provide anesthesia to a larger region of the body. Examples include the brachial plexus for surgery of the arm or hand, blockade of the femoral and sciatic nerves for surgery of the lower extremity, ankle block for surgery of the foot or toes, intercostal block for analgesia of the thorax postoperatively, or blockade of the cervical plexus, which is ideal for carotid endarterectomy. Risks of peripheral regional nerve blocks are dependent on their location. For example, nerve blocks injected into the neck risk puncture of the carotid or vertebral arteries, intercostal nerves are in close proximity to the vascular bundle and have a high rate of absorption of local anesthetic, and nerve blocks of the

thorax run the risk of causing pneumothorax. All peripheral nerve blocks may be supplemented intraoperatively with IV sedation and/or analgesics.

CENTRAL Local anesthetic injected centrally near the spinal cord—spinal or epidural anesthesia—provides anesthesia for the lower half of the body. This is especially useful for genitourinary, gynecologic, inguinal hernia, or lower-extremity procedures. Spinal and epidural anesthesia block the spinal nerves as they exit the spinal cord. Spinal nerves are mixed nerves; they contain motor, sensory, and sympathetic components. The subsequent block will cause sensory anesthesia, loss of motor function, and blockade of the sympathetic nerves from the level of the anesthetic distally to the lower extremities. Subsequent vasodilation of the vasculature from sympathetic block may result in hypotension, which is treatable with IV fluids and/or pressors.

SPINAL ANESTHESIA Local anesthetic is injected directly into the dural sac surrounding the spinal cord. The level of injection is usually below L1 to L2, where the spinal cord ends in most adults. Because the local anesthetic is injected directly into the cerebrospinal fluid surrounding the spinal cord, only a small dose is needed, the onset of anesthesia is rapid, and the blockade thorough. Lidocaine, bupivacaine, and tetracaine are commonly used agents of differing durations; the block wears off naturally via drug uptake by the cerebrospinal fluid, bloodstream, or diffusion into fat. Epinephrine as an additive to the local anesthetic will significantly prolong the blockade. Possible complications include hypotension, especially if the patient is not adequately prehydrated; high spinal block requires immediate airway management; and postdural puncture headache sometimes occurs. Spinal headache is related to the diameter and configuration of the spinal needle, and can be reduced to approximately 1% with the use of a small 25- or 27-gauge needle. Cauda equina syndrome is injury to the nerves emanating distal to the spinal cord resulting in bowel and bladder dysfunction, and lower-extremity sensory and motor loss. It has mainly been seen in cases in which indwelling spinal microcatheters and high (5%) concentrations of lidocaine were used. Indwelling spinal catheters are no longer used.

EPIDURAL ANESTHESIA Epidural anesthesia could also be called extradural anesthesia , because local anesthetics are injected into the epidural space surrounding the dural sac of the spinal cord. Much greater volumes of anesthetic are required than with spinal anesthesia, and the onset of the block is longer—10 to 15 minutes. As in spinal anesthesia, local anesthetic bathes the spinal nerves as they exit the dura; the patient achieves analgesia from the sensory block, muscle relaxation from blockade of the motor nerves, and hypotension from blockade of the sympathetic nerves as they exit the spinal cord. Note that regional anesthesia, whether peripheral or central, provides only two of the three major components of anesthesia—analgesia and muscle relaxation. Anxiolysis, amnesia, or sedation must be attained by supplemental IV administration of other drugs (e.g., the benzodiazepines or propofol infusion). Complications are similar to those of spinal anesthesia. Inadvertent injection of local anesthetic into a dural tear will result in a high block, manifesting as unconsciousness, severe hypotension, and respiratory paralysis requiring immediate aggressive hemodynamic management and control of the airway. Indwelling catheters are often placed through introducers into the epidural space, allowing an intermittent or continuous technique, as opposed to the single-shot method of spinal anesthesia. By necessity, the epidural-introducing needles are of a much larger diameter (17- or 18-gauge) than spinal needles, and accidental dural puncture more often results in a severe

headache that may last up to 10 days if left untreated.

General Anesthesia General anesthesia describes a triad of three major and separate effects: unconsciousness (and amnesia), analgesia, and muscle relaxation (see Table 47-1). IV drugs usually produce a single, discrete effect, while most inhaled anesthetics produce elements of all three. General anesthesia is achieved with a combination of IV and inhaled drugs, each used to its maximum benefit. The science and art of anesthesia is a dynamic process. As the amount of stimulus to the patient changes during surgery, the patient's vital signs are used as a guide and the quantity of drugs is adjusted, maintaining an equilibrium between stimulus and dose. General anesthesia is what patients commonly think of when they are to be "put under," and can be a cause of considerable preoperative anxiety. 1 4

INTRAVENOUS AGENTS Unconsciousness and Amnesia The IV agents that produce unconsciousness and amnesia are frequently used for the induction of general anesthesia. They include barbiturates, benzodiazepines, propofol, etomidate, and ketamine. Except for ketamine, the following agents have no analgesic properties, nor do they cause paralysis or muscle relaxation.

Barbiturates The most common barbiturates are thiopental, thiamylal, and methohexital. The mechanism of action is at the aminobutyric acid (GABA) receptor, where they inhibit excitatory synaptic transmission. They produce a rapid, smooth induction within 60 seconds, and wear off in about 5 minutes. In higher doses and in patients with intravascular depletion, they cause hypotension and myocardial depression. The barbiturates are anticonvulsants and protect the brain during neurosurgery by reducing cerebral metabolism.

Propofol Propofol is an alkylated phenol that inhibits synaptic transmission through its effects at the GABA receptor. With a short duration, rapid recovery, and low incidence of nausea and vomiting, it has emerged as the agent of choice for ambulatory and minor general surgery. Additionally, propofol has bronchodilatory properties that make its use attractive in asthmatic patients and smokers. Propofol may cause hypotension, and should be used cautiously in patients with suspected hypovolemia and/or coronary artery disease (CAD), the latter of which may not tolerate a sudden drop in blood pressure. It can be used as a continuous infusion for sedation in the intensive care unit setting. Propofol is an irritant and frequently causes pain on injection.

Benzodiazepines The most important uses of the benzodiazepines are for reduction of anxiety and to produce amnesia. Frequently used IV benzodiazepines are diazepam, lorazepam, and midazolam. They all inhibit synaptic transmission at the GABA receptor, but have differing durations of action. The benzodiazepines can produce peripheral vasodilatation and hypotension, but have minimal effects on respiration when used alone. They must be used with caution when given with opioids; a synergistic reaction causing respiratory depression is common. The benzodiazepines are excellent anticonvulsants and only rarely cause allergic reactions.

Etomidate Etomidate is an imidazole derivative used for IV induction. Its rapid and almost complete hydrolysis to inactive

metabolites results in rapid awakening. Like the above IV agents, etomidate acts on the GABA receptor. It has little effect on cardiac output and heart rate, and induction doses usually produce less reduction in blood pressure than that seen with thiopental or propofol. Etomidate is associated with pain on injection and more nausea and vomiting than thiopental or propofol.

Ketamine Ketamine differs from the above IV agents in that it produces analgesia as well as amnesia. Its principal action is on the N -methyl-D -aspartate receptor; it has no action on the GABA receptor. It is a dissociative anesthetic, producing a cataleptic gaze with nystagmus. Patients may associate this with delirium and hallucinations while regaining consciousness. The addition of benzodiazepines has been shown to prevent these side effects. Ketamine can increase heart rate and blood pressure, which may cause myocardial ischemia in patients with CAD. Ketamine is useful in acutely hypovolemic patients to maintain blood pressure via sympathetic stimulation, but is a direct myocardial depressant in patients who are catecholamine depleted. Ketamine is a bronchodilator, making it useful for asthmatic patients, and rarely is associated with allergic reactions.

ANALGESIA The IV analgesics most frequently used in anesthesia today have little effect on consciousness, amnesia, or muscle relaxation. The most important class is the opioids , so called because they were first isolated from opium, with morphine, codeine, meperidine, hydromorphone, and the fentanyl family being the most common. The most important nonopioid analgesics are ketamine (discussed above in the Ketamine section) and ketorolac, an IV NSAID.

Opioid Analgesics The commonly used opioids—morphine, codeine, oxymorphone, meperidine, and the fentanyl-based compounds—act centrally on -receptors in the brain and spinal cord. The main side effects of opioids are euphoria, sedation, constipation, and respiratory depression, which also are mediated by the same -receptors in a dosedependent fashion. Although opioids have differing potencies required for effective analgesia, equianalgesic doses of opioids result in equal degrees of respiratory depression . Thus, there is no completely safe opioid analgesic. The synthetic opioids fentanyl, and its analogues sufentanil, alfentanil, and remifentanil, are commonly used in the operating room. They differ pharmacokinetically in their lipid solubility, tissue binding, and elimination profiles, and therefore have differing potencies and durations of action. Remifentanil is remarkable in that it undergoes rapid hydrolysis that is unaffected by sex, age, weight, or renal or hepatic function, even after prolonged infusion. Recovery is within minutes, but there is little residual postoperative analgesia. Naloxone and the longer-acting naltrexone are pure opioid antagonists . They can be used to reverse the side effects of opioid overdose (e.g., respiratory depression), but the analgesic effects of the opioid also will be reversed.

Nonopioid Analgesics Ketamine , an N -methyl-D -aspartate receptor antagonist, is a potent analgesic, but is one of the few IV agents that also causes significant sedation and amnesia. Unlike the -receptor agonists, ketamine supports respiration. It can be used in combination with opioids, but the dysphoric effects must be masked with the simultaneous use of sedatives, usually a benzodiazepine like midazolam. Ketorolac is a parenteral NSAID that produces analgesia by reducing prostaglandin formation via inhibition of the enzyme cyclooxygenase (COX). Intraoperative use of ketorolac reduces postoperative need for opioids. Two forms

of COX have been identified: COX-1 is responsible for the synthesis of several prostaglandins as well as prostacyclin, which protects gastric mucosa, and thromboxane, which supports platelet function. COX-2 is induced by inflammatory reactions to produce more prostaglandins. Ketorolac (as well as many oral NSAIDs, aspirin, and indomethacin) inhibits both COX-1 and COX-2, which causes the major side effects of gastric bleeding, platelet dysfunction, and hepatic and renal damage. Parecoxib is a parenteral COX-2 NSAID now being tested that would presumably produce analgesia and reduce inflammation without causing GI bleeding or platelet dysfunction.

NEUROMUSCULAR BLOCKING AGENTS Neuromuscular blocking agents have no amnestic, hypnotic, or analgesic properties; patients must be properly anesthetized before and in addition to the administration of these agents. A paralyzed but unsedated patient will be aware, conscious, and in pain, yet be unable to communicate their predicament. Inappropriate administration of a neuromuscular blocking agent to an awake patient is one of the most traumatic experiences imaginable. Neuromuscular blockade is not a substitute for adequate anesthesia, but is rather an adjunct to the anesthetic. Depth of neuromuscular blockade is best monitored with a nerve stimulator to ensure patient immobility intraoperatively, and to confirm a lack of residual paralysis postoperatively.1 5 Unlike the local anesthetics, which affect the ability of nerves to conduct impulses, the neuromuscular blockers have no effect on either nerves or muscles, but act primarily on the neuromuscular junction . There is one commonly used depolarizing neuromuscular blocker—succinylcholine. This agent binds to acetylcholine receptors on the postjunctional membrane in the neuromuscular junction and causes depolarization of muscle fibers. Although the rapid onset (1 No histamine release Tachycardia; slow onset; long duration Vecuronium 0.6 MAC) cause dilation of the cerebral vasculature, decreasing cerebral vascular resistance. CBF is therefore increased in a dose-dependent fashion, despite decreases in CMRO2 . 1 2 Propofol decreases CBF, ICP, and CMRO2 . 4 6 Propofol may also decrease systemic blood pressure, resulting in a decrease in cerebral perfusion pressure; however, propofol does not alter the autoregulation of CBF.4 7 Etomidate is a potent cerebral vasoconstrictor that reduces CBF and ICP and should be used with caution in patients with epilepsy due to its excitatory effects seen on electroencephalograms. 4 8 Opioids decrease CBF and may also decrease ICP under certain conditions. However, Sperry and associates have reported increases in ICP with the administration of fentanyl in head trauma patients.4 9 Additionally, opioids have a depressant effect on consciousness and ventilation that may increase ICP if accompanied by an increase in partial pressure of arterial CO2 ; opioids should be used with caution in head trauma patients. Regardless of the drugs or technique selected, maintenance of stable hemodynamics is optimal. Recovery from anesthesia should be smooth, avoiding pain, coughing, and straining, all of which can increase blood pressure and ICP and cause bleeding at the surgical site. Fluid therapy can increase cerebral edema and ICP when administered in large quantities, resulting in hypervolemia. Euvolemia should be the goal in head trauma patients, while hypervolemia may be beneficial for patients with intracranial aneurysms, to reduce vasospasm.

INTRAOPERATIVE MANAGEMENT Induction of General Anesthesia During induction of anesthesia, the patient becomes unconscious and rapidly apneic, myocardial function is usually depressed, and vascular tone abruptly changes. The induction of general anesthesia is the most critical component of practicing anesthesia, as the majority of catastrophic anesthetic complications occur during this phase. There are several different techniques used for the induction of general anesthesia, each with significant advantages and disadvantages (Fig. 47-3). Each patient must be carefully evaluated during the preoperative period to ensure that the most efficacious and safe technique is used.

Fig. 47-3.

Techniques for the induction of general anesthesia.

IV induction, used primarily in adults, is smooth and is associated with a high level of patient satisfaction. The addition of opioids will blunt the response of laryngoscopy and intubation to avoid hypertension and tachycardia. In a patient with a full stomach, the standard induction technique may result in vomiting and pulmonary aspiration of stomach contents. The goal of rapid sequence induction is to achieve secure protection of the airway with a cuffed endotracheal tube while preventing vomiting and aspiration. Rapid sequence induction is performed as follows: Proceed only after evaluation of the airway predicts an uncomplicated intubation. Preoxygenate the patient. Rapidly introduce an IV induction agent (e.g., propofol). An assistant to the anesthesiologist presses firmly down on the cricoid cartilage to block any gastric contents from being regurgitated into the trachea, and A muscle relaxant is injected, and the trachea is quickly intubated. The assistant is instructed not to release

pressure on the cricoid cartilage until the cuff of the endotracheal tube is inflated and the position of the tube is confirmed. Patients undergoing inhalation induction progress through three stages: (a) awake, (b) excitement, and (c) surgical level of anesthesia. Adult patients are not good candidates for this type of induction, as the smell of the inhalation agent is unpleasant and the excitement stage can last for several minutes, which may cause hypertension, tachycardia, laryngospasm, vomiting, and aspiration. Children, however, progress through stage 2 quickly and are highly motivated for inhalation induction as an alternative to the IV route. The benefit of postinduction IV cannulation is the avoidance of many presurgical anxieties, and inhalation induction is the most common technique for pediatric surgery.

Management of the Airway After induction of anesthesia, the airway may be managed in several ways, including by face mask, with a laryngeal mask airway (LMA), or, most definitively, by endotracheal intubation with a cuffed endotracheal tube. Nasal and oral airways can help establish a patent airway in a patient being ventilated with a mask by creating an air passage behind the tongue (Fig. 47-4).

Fig. 47-4.

From left to right: two nasal airways and three oral airways.

The LMA is a cuffed oral airway that sits in the oropharynx. It is passed blindly, and the cuff is inflated to push the soft tissues away from the laryngeal inlet. Because it does not pass through the vocal cords, it does not fully protect against aspiration. It should not be used in patients with a full stomach (Fig. 47-5; lower left).

Fig. 47-5.

(Top ) Laryngoscopes with curved straight blades; (Bottom ) laryngomask airway, intubating laryngomask airway, and Bullard rigid fiberoptic laryngoscope.

The accurate placement of an endotracheal tube requires skill and proper equipment and conditions. Usually, the patient is unconscious and immobile (including paralysis of the muscles of respiration). Intubation is typically performed under direct visualization by looking through the mouth with a laryngoscope directly at the vocal cords (direct laryngoscopy), and watching the endotracheal tube pass through the cords into the trachea. To obtain a direct line of sight, the patient is placed in the sniffing position. The neck is flexed at the lower cervical spine and extended at the atlanto-occipital joint. This flexion and extension are amplified during laryngoscopy. Laryngoscope handles contain batteries and can be fitted with curved (Macintosh) or straight (Miller) blades (see Fig. 47-5, top row). Some patients have physical characteristics or a history suggesting difficulty in placing an endotracheal tube. A short neck, limited neck mobility, small interincisor distance, short thyromental distance, and Mallampati class IV may all represent a challenge to endotracheal intubation. Several devices have been developed to assist in management of the difficult airway. The Bullard rigid fiberoptic laryngoscope is a self-contained device that can be passed through a mouth with a narrow opening (Fig. 47-6). The head and neck also can be kept in a neutral

position, as a direct line of sight needed with a standard laryngoscope is not necessary. Another new intubating device is the Glide scope, which allows visualization of the vocal cords on a screen (Fig. 47-7).

Fig. 47-6.

The Bullard rigid fiberoptic laryngoscope with endotracheal tube.

Fig. 47-7.

Video laryngoscope.

The intubating laryngeal mask airway (ILMA) is an advanced form of LMA designed to maintain a patent airway as well as facilitate tracheal intubation with an endotracheal tube. The ILMA can be placed in anticipated or unexpectedly difficult airways as an airway rescue device and as a guide for intubating the trachea. An endotracheal tube can be passed blindly through the ILMA into the larynx, or the ILMA can be used as a conduit for a flexible fiberoptic scope (Fig. 47-8).

Fig. 47-8.

Intubating laryngeal mask airway with endotracheal tube.

The flexible fiberoptic intubation scope is the gold standard for difficult intubation. It is indicated in difficult or compromised airways where neck extension is not desirable, or in cases with risk of dental damage. The scope is constructed of fiberoptic bundles and cables encased in a sheath. The cables permit manipulation of the tip of the scope by adjustments made at the operating end of the device. There is a port for suction and/or insufflation of O 2 . The scope gives excellent visualization of the airway with minimal hemodynamic stress when used properly. It can be used nasally or orally in an awake, spontaneously ventilating patient, whose airway has been treated with topical anesthetic. It requires skill for proper use, is expensive, and requires careful maintenance (Fig. 47-9).

Fig. 47-9.

Flexible fiberoptic intubation scope with endotracheal tube.

The ASA has developed algorithms for management of the difficult airway.5 0 These are shown in Figs. 47-10 and 47-11.

Fig. 47-10.

American Society of Anesthesiologists airway management algorithm, Part I. CO2 = carbon dioxide. (Reproduced with permission from Practice guidelines for management of the difficult airway: An updated report by the American Society of Anesthesiologists Task Force on Management of the Difficult Airway. Anesthesiology 98:1269, 2003)

Fig. 47-11.

American Society of Anesthesiologists airway management algorithm, Part II. CO2 = carbon dioxide. (Reproduced with permission from Practice guidelines for management of the difficult airway: An updated report by the American Society of Anesthesiologists Task Force on Management of the Difficult Airway. Anesthesiology 98:1269, 2003.)

Fluid Therapy Numerous preparations of IV fluid are available for the replacement of perioperative fluid losses in patients undergoing surgery. Different fluid preparations may influence clinical parameters (e.g., platelet function) and may also affect postoperative outcome. Traditionally, IV fluids have been classified according to whether they are crystalloid or colloid in nature. Crystalloid fluids comprise electrolyte solutions with or without a bicarbonate precursor such as acetate or lactate. The colloids contain a complex sugar or protein suspended in an electrolyte solution. A further distinction between IV fluid types may be based on the nature of the solution. Normal saline-based (0.9% sodium chloride) preparations (crystalloid or colloid) contain no electrolytes other than sodium and chloride. In contrast, balanced salt-based fluids such as lactated Ringer's solution contain other electrolytes, with or without a bicarbonate precursor. Several types of colloids are available, but three are most commonly used—hydroxyethyl starch (HES), gelatin, and albumin. The HES preparations differ from one another according to their concentration, molecular weight, and extent of hydroxyethylation or substitution, with resultant varying physiochemical properties. HES solutions most often are described according to their weight-averaged mean molecular weight in kilodaltons (kDa): highmolecular-weight (450 kDa), middle-molecular-weight (200 kDa, 270 kDa), and low-molecular-weight (130 kDa, 70 kDa). HES 450 kDa solutions are available in a normal saline solution (HES 450/NS) and in a lactated, balanced salt solution (HES 450/BS). Although all of these colloids are used in Europe, gelatins are not available in the

United States, and the only HES preparations approved by the U.S. Food and Drug Administration are the 6% highmolecular-weight (450 kDa) formulations. The administration of a large volume of any type of IV fluid will cause dilution of platelets and coagulation factors and may lead to coagulopathy (i.e., dilutional coagulopathy). In addition, fluids can have a direct impact on blood clotting through effects on circulating components of the coagulation cascade or by altering platelet function. Recent evidence suggests that the nature of the solution itself may influence coagulation and bleeding. HES 450/NS may be associated with more bleeding than other fluids. HES 450 in a balanced salt solution appears to be equivalent to 5% albumin with respect to bleeding outcomes.51–53 Waters and colleagues reported that patients undergoing abdominal aortic aneurysm repair who received lactated Ringer's solution received smaller volumes of platelets and had less blood product exposure than those treated with normal saline.5 4 It is possible that certain fluids may induce hypercoagulability that may be reflected not only by less bleeding, but also by an increased incidence of postoperative thrombotic complications (e.g., deep vein thrombosis and cerebrovascular accident). There are laboratory data5 5 to suggest that IV fluid administration may induce a hypercoagulable state, but the clinical significance of this remains unclear. The type of fluid administered intraoperatively to a patient can have a significant impact on renal function. The administration of HES/NS or normal saline to critically ill patients or elderly patients undergoing major surgery was associated with the development of renal dysfunction.56–58 The administration of adequate IV fluids during the perioperative period results in a lower incidence of nausea, vomiting, and antiemetic use after minor or day case surgery.5 9 In major noncardiac surgical patients, the administration of HES 450 (in a BS or NS solution, or a combination of balanced crystalloid and colloid) has been associated with less postoperative nausea, vomiting, and antiemetic use, and earlier return of postoperative bowel function as reflected by first consumption of solid food, than the administration of 5% albumin, lactated Ringer's solution, or normal saline alone.6 0 Studies of patients undergoing ambulatory surgery have shown that perioperative IV fluid administration decreases the incidence of dizziness, drowsiness, thirst, and headache.6 1 In a randomized crossover study of healthy volunteers, subjective deterioration in mental status (lassitude and difficulty in abstract thinking) was reported only by individuals who received 0.9% sodium chloride, and not by those who received lactated Ringer's solution.6 2 The possible effect of different IV fluid preparations on CNS function has not yet been fully explored. The relative impact of crystalloids and/or colloids on pulmonary function has been the subject of long-standing debate. No difference in postoperative pulmonary function was seen in cardiac surgery patients, orthopedic patients, or urologic surgery patients treated intraoperatively with different colloids.56,63,64 In a number of studies in major surgical patients that compared crystalloid (lactated Ringer's solution) with colloid (HES 130/NS, HES 450/NS, 5% albumin/BS),65–67 no difference was seen in the incidence or duration of mechanical ventilation or other indices of respiratory function. These findings suggest that the intraoperative administration of crystalloids does not have a detrimental effect on pulmonary function compared with the administration of colloids.

Transfusion of Red Blood Cells ABO BLOOD GROUPS There are four different ABO groups, which are determined by whether or not an individual's red blood cells (RBCs) carry the A antigen, the B antigen, both A and B, or neither. From early in childhood, normal healthy individuals

make antibodies against A or B antigens that are not expressed on their own cells. People who are group A have anti-B antibodies in their plasma, people who are group B have anti-A antibodies, people who are group O have anti-A and anti-B antibodies, and people who are group AB have neither of these antibodies. These naturally occurring antibodies are mainly immunoglobulin M that attack and rapidly destroy RBCs. Anti-A antibodies attack RBCs of group A (or AB), and anti-B antibodies attack RBCs of group B (or AB).

ABO-INCOMPATIBLE RED CELL TRANSFUSION If RBCs of the wrong group are transfused, in particular if group A RBCs are infused into a recipient who is group O, the recipient's anti-A antibodies bind to the transfused cells. This activates the complement pathways, which damages the red cell membranes and lyses the RBCs. Hb released from the damaged RBCs is toxic to the kidneys, while the fragments of ruptured cell membranes activate the blood-clotting pathways. The patient suffers acute renal failure and disseminated intravascular coagulation.

BASICS OF RED BLOOD CELL COMPATIBILITY Ensuring that the right blood group is transfused is imperative. It is essential to ensure that no ABO-incompatible RBC transfusion is ever given. This avoidable accident is likely to kill or harm the patient. Procedures in which compatibility is determined by establishing both transfusion recipient and donor blood ABO types via crossmatch analysis have evolved over years of clinical and laboratory experience to minimize the risk of this disastrous error. These procedures will continue to evolve as improved computerized systems are introduced to help staff avoid errors in blood administration.

Rhesus D Antigen and Antibody In a white population, about 15% will lack the Rhesus D (Rh D) antigen, and are termed Rh D negative . Antibodies to Rh D antigen occur only in individuals who are Rh D negative, and as a consequence of transfusion or pregnancy. Even small amounts of Rh D positive cells entering the circulation of an Rh D negative person can stimulate the production of antibodies to Rh D, usually immunoglobulin G.

PHYSIOLOGIC RESPONSE AND TOLERANCE OF ANEMIA O2 is carried in blood in two distinct forms: bound to Hb within the RBC and dissolved in the plasma. The actual oxygen content of arterial blood (CaO saturation of Hb (Sa O

2

2

) is determined by the concentration of Hb in the blood, the arterial oxygen

), the O2 -binding capacity of Hb, the PaO

2

, and the O2 solubility of plasma. These

variables are interrelated and can be expressed in the following equation:

Adult Hb consists of four protein chains, each carrying one heme group. One mole of Hb is able to bind to a maximum of 4 moles of O2 . O2 -binding capacity per gram of Hb is 1.39 g/mL. The relationship between PaO Hb O2 saturation is shown in Fig. 47-12. The steep part of this curve [partial pressure of oxygen (PO mmHg] facilitates O2 release from Hb. Tissue PO

2

and

values of different organs are also shown in Fig. 47-12 and lie on

this steep part of the curve, facilitating O2 release from Hb.

Fig. 47-12.

2

2

) 20 to 40

Oxygen hemoglobin dissociation curve. O2 = oxygen; PO

2

= partial pressure of oxygen.

Mild anemia is compensated by a shift in the Hb-O2 dissociation curve. The impact of more severe anemia may be physiologically modulated by an increase in cardiac output, which will increase tissue perfusion and cause a decrease in peripheral vascular resistance and decreases in whole blood viscosity.68,69 Anemia not only decreases the O2 content of blood but also decreases blood viscosity, promoting an increase in regional blood flow. Moreover, this increase in blood flow augments the perfused capillary area by an increase in filling pressures and microvasculature vasodilation that results in an increase in O2 uptake by the tissue beds.7 0 The effects of blood transfusion on O2 uptake are not as optimal as increasing blood flow, because the rise in hematocrit increases blood viscosity, which alters regional microvascular blood flow (i.e., perfusion).5 5 In normal animals undergoing acute hemodilution, cardiovascular function is maintained until the Hb level reaches between 3 and 5 g/dL, at which point ischemic changes then begin to appear on endocardial electrocardiogram leads (i.e., ST-segment changes).71,72

HEMODILUTION AND CRITICAL HEMATOCRIT The intentional dilution of blood volume often is referred to as acute normovolemic hemodilution (ANH) anemia . ANH is a technique in which whole blood is removed from a patient, while the circulating blood volume is maintained with acellular fluid. Blood is collected via central lines with simultaneous infusion of crystalloid or colloid

solutions. Collected blood is reinfused after major blood loss has ceased, or sooner, if indicated. Blood units are reinfused in the reverse order of collection. Under conditions of ANH, the increased plasma compartment becomes an important source of O2 , which is delivered to the tissues. Oxygenation is maintained by increased cardiac output and increased O2 extraction by the tissues, and when these compensatory mechanisms fail to match the O2 needs of the tissues, the "critical hematocrit" is said to have been reached. The critical hematocrit has been a source of debate for many years. A theoretical model was developed that describes the relation between hematocrit, myocardial O2 demand, and the required coronary blood flow during progressive hemodilution.7 3 Using this model, the determinants of critical hematocrit and the limits of ANH can be calculated based on the limits of coronary reserve. Because the critical hematocrit varies with O2 consumption and degree of CAD, a fixed critical hematocrit as a transfusion trigger is not appropriate in most patients. Rather, the indication for blood transfusions must individually take into account the specific circumstances of the patient, such as expected blood loss and required O2 transport capacity reserves, hemodynamic stability, CAD, and systemic O2 consumption.

RECOVERY FROM ANESTHESIA Reversal of Neuromuscular Blockade The elimination of neuromuscular blocking agents from the body and subsequent resumption of neuromuscular transmission takes a considerable amount of time, even with drugs such as vecuronium that have relatively short half-lives. Additionally, it is time consuming to wait for complete spontaneous recovery at the end of a surgical procedure. Therefore, it has become routine to antagonize the neuromuscular block pharmacologically with the use of reversal agents. Reversal agents raise the concentration of the neurotransmitter acetylcholine to a higher level than that of the neuromuscular blocking agent. This is accomplished by the use of anticholinesterase agents, which reduce the breakdown of acetylcholine. The most commonly used agents are neostigmine, pyridostigmine, and edrophonium. The common side effects of these three anticholinesterase agents are bradycardia, bronchial and intestinal smooth muscle contractions, and excessive secretions from salivary and bronchial glands. These effects are primarily mediated by effects on muscarinic receptors, which are effectively blocked by the concomitant use of antimuscarinic drugs such as atropine or glycopyrrolate. To ensure adequate ventilation postoperatively, it is important that the neuromuscular blocking agents are fully reversed, as assessed by monitoring twitch strength with a nerve stimulator and clinically correlating this with signs such as grip strength or 5-second head lift.

The Postanesthesia Care Unit It is of primary importance that all patients awakening from anesthesia are followed in a recovery room, as approximately 10% of all anesthetic accidents occur in the recovery period. As more serious surgeries are performed on older and sicker patients, the number of patients requiring postoperative ventilation and medications to support their circulation increases with age. The new trend for postoperative pain control with continuous epidural administration of local anesthetics and narcotics demands close observation, because respiratory depression can occur. In most hospitals, the number of intensive care beds is too small to accommodate the increasing number of these patients. What originally began as the recovery room now must function as an intensive care unit setting for short stays. The name "recovery room" has been changed to postanesthetic care unit (PACU). A variety of physiologic disorders that can affect different organ systems need to be diagnosed and treated in the PACU during emergence from anesthesia and surgery. Postoperative nausea and vomiting (PONV), airway support,

and hypotension requiring pharmacologic support have been observed to be the most frequent complications in the PACU.7 4 However, abnormal bleeding, hypertension, dysrhythmia, myocardial infarction, and altered mental status are not uncommon.7 4

Postoperative Nausea and Vomiting PONV typically occurs in 20 to 30% of surgical cases,7 5 with considerable variation in frequency reported between studies (range 8 to 92%).7 6 PONV is generally considered a transient, unpleasant event carrying little long-term morbidity; however, aspiration of emesis, gastric bleeding, and wound hematomas may occur with protracted or vigorous retching or vomiting. Troublesome PONV can prolong recovery room stay and hospitalization, and is one of the most common causes of hospital admission following ambulatory surgery. Published evidence suggests that prophylactic administration of antiemetics is not cost-effective in the surgical setting.7 7 Recent consensus guidelines using data from systematic reviews, randomized trials and studies, and data from logistic regression models have been published.7 7 An algorithm showing these guidelines is shown in Fig. 47-13.

Fig. 47-13.

Algorithm for the management of postoperative nausea and vomiting (PONV). (Reproduced with permission from Gan TJ, Meyer T, Apfel CC, et al: Consensus guidelines for managing postoperative nausea and vomiting. Anesth Analg 97:62, 2003.)

Agents usually administered for PONV are the serotonin receptor antagonists ondansetron, dolasetron, granisetron, and tropisetron. The safety and efficacy of the compounds, when given at the end of surgery, are virtually identical.77,78 Metoclopramide, when used in the standard dose of 10 mg, is ineffective for PONV.7 9 Although some studies have shown higher doses (20 mg) to have some effect on PONV, most evidence suggests that the serotonin

receptor antagonists are the most efficacious choice.

Pain: The Fifth Vital Sign Analgesic research methodology has been enhanced since the 1960s through the use of graduated and visual analog scales, tools that permit the standardization of pain scores. One frequently used graduated scale is a fourpoint measure of pain intensity (0 = no pain, 1 = mild pain, 2 = moderate pain, and 3 = severe pain) and a fivepoint measure of relief (0 = no relief, 1 = a little relief, 2 = some relief, 3 = a lot of relief, and 4 = complete relief). Acute postoperative pain and its treatment (or prophylaxis) are significant challenges for the health care professional. Despite the recent development of new nonnarcotic analgesics and a better understanding of the side effects associated with pain medication of all types, acute postoperative pain remains a significant concern for patients and represents an extremely negative experience for patients undergoing surgery. Many patients experience pain in the postoperative period despite the use of potent techniques such as patient-controlled analgesia, epidural analgesia, and regional anesthesia. The culture of acceptance of postoperative pain is changing. The American Pain Society has advocated the assessment of pain as the fifth vital sign, along with temperature, pulse, blood pressure, and respiratory rate. The four vital signs provide a quick snapshot of a patient's general condition, but pain management advocates claim the picture is not complete without including pain as the fifth vital sign. This approach may improve the efficacy of pain treatment. Many departments of anesthesiology support an active pain service and provide consultation for postoperative pain relief, including the administration of nerve blocks (Fig. 47-14).

Fig. 47-14.

Popliteal ultrasound.

MALIGNANT HYPERTHERMIA MH is a life-threatening, acute disorder, developing during or after general anesthesia. The clinical incidence of MH is about 1:12,000 in children and 1:40,000 in adults. A genetic predisposition and one or more triggering agents are necessary to evoke MH. Triggering agents include all volatile anesthetics (e.g., halothane, enflurane, isoflurane, sevoflurane, and desflurane), and the depolarizing muscle relaxant succinylcholine. Volatile anesthetics and/or succinylcholine cause a rise in the myoplasmic calcium concentration in susceptible patients, resulting in persistent muscle contraction. The classic MH crisis entails a hypermetabolic state, tachycardia, and the elevation of end-tidal CO2 in the face of constant minute ventilation. Respiratory and metabolic acidosis and muscle rigidity follow, as well as rhabdomyolysis, arrhythmias, hyperkalemia, and sudden cardiac arrest. A rise in temperature is often a late sign of MH. Treatment must be aggressive and begin as soon as a case of MH is suspected: Call for help. Stop all volatile anesthetics and give 100% O2 . Hyperventilate the patient up to three times the calculated minute volume. Begin infusion of dantrolene sodium, 2.5 mg/kg IV. Repeat as necessary, titrating to clinical signs of MH.

Continue dantrolene for at least 24 hours after the episode begins. Give bicarbonate to treat acidosis if dantrolene is ineffective. Treat hyperkalemia with insulin, glucose, and calcium. Avoid calcium channel blockers Continue to monitor core temperature. Call the MH hotline to report the case and get advice: 1-888-274-7899.

FUTURE DIRECTION OF ANESTHESIA The general mantra of "gene therapy is the future of medicine" must be more specifically related to how those genes create, shape, and regulate proteins. The study of how proteins manifest their activity and/or concentration, is called proteomics (from proteome—a fusion of "protein" and "genome"). As the technology advances to biologically identify individual proteins, studies of individual levels of proteomes will allow the study of disease processes on the molecular level, directly aiding diagnosis and therapeutics.8 1 Specifically to the field of anesthesiology, the technology of proteomics will be used to elucidate the actual mechanism of action of our anesthetic drugs and how these drugs have differing effects on different individuals. There will be a day when a buccal swab in the preoperative clinic will become routine; the results telling us which opioids carry the fewest side effects for that particular patient, for example, or which antiemetics are most effective, or which postoperative analgesics to use—a tailored anesthetic. Recent studies in mice have examined the

5 subunit of the GABA receptor, which appears to regulate memory. The human genome is polymorphic for

the

5 gene; because each variant may manifest in different amounts of memory/amnesia, proteomics may

someday lead to tests that determine the propensity of a particular patient to experience awareness and allow us to tailor the anesthetic even further.8 2

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31. Eldridge AJ, Sear JW: Peri-operative management of diabetic patients. Any changes for the better since 1985? Anaesthesia 51:45, 1996. [PMID: 8669566] 32. McAnulty GR, Robertshaw HJ, Hall GM: Anaesthetic management of patients with diabetes mellitus. Br J Anaesth 85:80, 2000. [PMID: 10927997] 33. Risum O, Abdelnoor M, Svennevig JL, et al: Diabetes mellitus and morbidity and mortality risks after coronary artery bypass surgery. Scand J Thorac Cardiovasc Surg 30:71, 1996. [PMID: 8857678] 34. Zacharias A, Habib RH: Factors predisposing to median sternotomy complications. Deep vs. superficial infection. Chest 110:1173, 1996. [PMID: 8915216] 35. Halter JB, Pflug AE: Effects of anesthesia and surgical stress on insulin secretion in man. Metabolism 29:1124, 1980. [PMID: 7001179] 36. Thorell A, Nygren J, Hirshman MF, et al: Surgery-induced insulin resistance in human patients: Relation to glucose transport and utilization. Am J Physiol 276:E754, 1999. 37. Das UN: Is insulin an endogenous cardioprotector? Crit Care 6:389, 2002. [PMID: 12398773] 38. Das UN: Insulin and inflammation: Further evidence and discussion. Nutrition 18:526, 2002. [PMID: 12044830] 39. Das UN: Insulin and the critically ill. Crit Care 6:262, 2002. [PMID: 12133190] 40. Hall GM: The anaesthetic modification of the endocrine and metabolic response to surgery. Ann R Coll Surg Engl 67:25, 1985. [PMID: 2857077] 41. Weinberg AD, Brennan MD, Gorman CA, et al: Outcome of anesthesia and surgery in hypothyroid patients. Arch Intern Med 143:893, 1983. [PMID: 6679233] 42. Murkin JM: Anesthesia and hypothyroidism: A review of thyroxine physiology, pharmacology, and anesthetic implications. Anesth Analg 61:371, 1982. [PMID: 7039417] 43. Adams JP, Murphy PG: Obesity in anaesthesia and intensive care. Br J Anaesth 85:91, 2000. [PMID: 10927998] 44. Rosenbaum M, Leibel RL, Hirsch J: Obesity. N Engl J Med 337:396, 1997. [PMID: 9241130] 45. Bouillon T, Shafer SL: Does size matter? Anesthesiology 89:557, 1998. [PMID: 9743389] 46. Pinaud M, Lelausque JN, Chetanneau A, et al: Effects of propofol on cerebral hemodynamics and metabolism in patients with brain trauma. Anesthesiology 73:404, 1990. [PMID: 2118315] 47. Strebel S, Kaufmann M, Guardiola PM, et al: Cerebral vasomotor responsiveness to carbon dioxide is preserved during propofol and midazolam anesthesia in humans. Anesth Analg 78:884, 1994. [PMID: 8160985] 48. Reddy RV, Moorthy SS, Dierdorf SF, et al: Excitatory effects and electroencephalographic correlation of etomidate, thiopental, methohexital, and propofol. Anesth Analg 77:1008, 1993. [PMID: 8214699] 49. Sperry RJ, Bailey PL, Reichman MV, et al: Fentanyl and sufentanil increase intracranial pressure in head trauma patients. Anesthesiology 77:416, 1992. [PMID: 1306051] 50. Practice guidelines for management of the difficult airway: An updated report by the American Society of Anesthesiologists Task Force on Management of the Difficult Airway. Anesthesiology 98:1269, 2003.

51. Bennett-Guerrero EFR, Mets B, Manspeizer HE, et al: Impact of normal saline based versus balanced salt intravenous fluid replacement on clinical outcomes: A randomized blinded trial. Anesth Analg 95:A147, 2001. 52. Gan T: Randomized comparison of coagulation profile when Hextend or 5% albumin is used for intraoperative fluid resuscitation. Anesth Analg 95:A193, 2001. 53. Petroni KG, Brimingham S: Hextend is a safe alternative to 5% albumin for patients undergoing elective cardiac surgery. Anesth Analg 95:A198, 2001. 54. Waters JH, Gottlieb A, Schoenwald P, et al: Normal saline versus lactated Ringer's solution for intraoperative fluid management in patients undergoing abdominal aortic aneurysm repair: An outcome study. Anesth Analg 93:817, 2001. [PMID: 11574339] 55. Gan TJ, Bennett-Guerrero E, Phillips-Bute B, et al: Hextend, a physiologically balanced plasma expander for large volume use in major surgery: A randomized phase III clinical trial. Hextend Study Group. Anesth Analg 88:992, 1999. [PMID: 10320157] 56. Gallandat Huet RC, Siemons AW, Baus D, et al: A novel hydroxyethyl starch (Voluven) for effective perioperative plasma volume substitution in cardiac surgery. Can J Anaesth 47:1207, 2000. 57. Cittanova ML, Leblanc I, Legendre C, et al: Effect of hydroxyethylstarch in brain-dead kidney donors on renal function in kidneytransplant recipients. Lancet 348:1620, 1996. [PMID: 8961992] 58. Schortgen F, Lacherade JC, Bruneel F, et al: Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: A multicentre randomised study. Lancet 357:911, 2001. [PMID: 11289347] 59. Elhakim M, el-Sebiae S, Kaschef N, et al: Intravenous fluid and postoperative nausea and vomiting after day-case termination of pregnancy. Acta Anaesthesiol Scand 42:216, 1998. [PMID: 9509206] 60. Gan TJ, Soppitt A, Maroof M, et al: Goal-directed intraoperative fluid administration reduces length of hospital stay after major surgery. Anesthesiology 97:820, 2002. [PMID: 12357146] 61. Yogendran S, Asokumar B, Cheng DC, et al: A prospective randomized double-blinded study of the effect of intravenous fluid therapy on adverse outcomes on outpatient surgery. Anesth Analg 80:682, 1995. [PMID: 7893018] 62. Williams EL, Hildebrand KL, McCormick SA, et al: The effect of intravenous lactated Ringer's solution versus 0.9% sodium chloride solution on serum osmolality in human volunteers. Anesth Analg 88:999, 1999. [PMID: 10320158] 63. Vogt NH, Bothner U, Lerch G, et al: Large-dose administration of 6% hydroxyethyl starch 200/0.5 total hip arthroplasty: Plasma homeostasis, hemostasis, and renal function compared to use of 5% human albumin. Anesth Analg 83:262, 1996. [PMID: 8694303] 64. Vogt N, Bothner U, Brinkmann A, et al: Peri-operative tolerance to large-dose 6% HES 200/0.5 in major urological procedures compared with 5% human albumin. Anaesthesia 54:121, 1999. [PMID: 10215706] 65. Lang K, Boldt J, Suttner S, et al: Colloids versus crystalloids and tissue oxygen tension in patients undergoing major abdominal surgery. Anesth Analg 93:405, 2001. [PMID: 11473870] 66. Marik PE, Iglesias J, Maini B: Gastric intramucosal pH changes after volume replacement with hydroxyethyl starch or crystalloid in patients undergoing elective abdominal aortic aneurysm repair. J Crit Care 12:51, 1997. [PMID: 9165412] 67. Virgilio RW, Rice CL, Smith DE, et al: Crystalloid vs. colloid resuscitation: Is one better? A randomized clinical study. Surgery 85:129, 1979. [PMID: 419454] 68. Murray JF, Escobar E, Rapaport E: Effects of blood viscosity on hemodynamic responses in acute normovolemic anemia. Am J Physiol 216:638, 1969. [PMID: 5765616] 69. Woodson RD, Auerbach S: Effect of increased oxygen affinity and anemia on cardiac output and its distribution. J Appl Physiol

53:1299, 1982. [PMID: 7174422] 70. Messmer K: Blood Rheology Factors and Capillary Blood Flow . Berlin: Springer-Verlag, 1991, p 312. 71. Wilkerson DK, Rosen AL, Sehgal LR, et al: Limits of cardiac compensation in anemic baboons. Surgery 103:665, 1988. [PMID: 3375993] 72. Hagl S, Heimisch W, Meisner H, et al: The effect of hemodilution on regional myocardial function in the presence of coronary stenosis. Basic Res Cardiol 72:344, 1977. [PMID: 901378] 73. Hoeft A, Wietasch JK, Sonntag H, et al: Theoretical limits of "permissive anemia." Zentralbl Chir 120:604, 1995. [PMID: 7571892] 74. Hines R, Barash PG, Watrous G, et al: Complications occurring in the postanesthesia care unit: A survey. Anesth Analg 74:503, 1992. [PMID: 1554116] 75. Watcha MF, White PF: Postoperative nausea and vomiting. Its etiology, treatment, and prevention. Anesthesiology 77:162, 1992. [PMID: 1609990] 76. Camu F, Lauwers MH, Verbessem D: Incidence and aetiology of postoperative nausea and vomiting. Eur J Anaesthesiol 9:25, 1992. 77. Gan TJ, Meyer T, Apfel CC, et al: Consensus guidelines for managing postoperative nausea and vomiting. Anesth Analg 97:62, 2003. [PMID: 12818945] 78. Sun R, Klein KW, White PF: The effect of timing of ondansetron administration in outpatients undergoing otolaryngologic surgery. Anesth Analg 84:331, 1997. [PMID: 9024023] 79. Henzi I, Walder B, Tramer MR: Metoclopramide in the prevention of postoperative nausea and vomiting: A quantitative systematic review of randomized, placebo-controlled studies. Br J Anaesth 83:761, 1999. [PMID: 10690140] 80. Rosenberg PH, Kytta J, Alila A: Absorption of bupivacaine, etidocaine, lignocaine and ropivacaine into n-heptane, rat sciatic nerve, and human extradural and subcutaneous fat. Br J Anaesth 58:310, 1986. [PMID: 3947493] 81. Atkins JH, Johansson JS: Technologies to shape the future: Proteomics applications in anesthesiology and critical care medicine. Anesth Analg 102:1207, 2006. [PMID: 16551925] 82. Orser BA, Mazer CD, Baker AJ: Awareness during anesthesia. CMAJ 178:185, 2008. [PMID: 18073268]

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KEY POINTS 1. The physician should document that the patient or surrogate has the capacity to make a medical decision. 2. The physician discloses to the patient details regarding the diagnosis and treatment options sufficient for the patient to make an informed consent. 3. Living wills are written to anticipate treatment options and choices in the event that a patient is rendered incompetent by a terminal illness. 4. The durable power of attorney for health care identifies surrogate decision makers and invests them with the authority to make health care decisions on a patient's behalf in the event that patients are unable to speak for themselves. 5. Surgeons should encourage their patients to clearly identify their surrogates early in the course of treatment. 6. Seven requirements for the ethical conduct of clinical trials have been articulated: value, scientific validity, fair subject selection, favorable risk-benefit ratio, independent review, informed consent, and respect for enrolled subjects. 7. The Association of American Medical Colleges stresses three key points regarding potential conflict of interest: full disclosure, aggressive monitoring, and misconduct management. 8. Disclosure of error is consistent with recent ethical advances in medicine toward more openness with patients and the involvement of patients in their care.

WHY ETHICS MATTER Dedicated to the advancement of surgery along its scientific and moral side. June 10, 1926, dedication on the Murphy Auditorium, the first home of the American College of Surgeons Ethical concerns involve not only the interests of patients, but also the interests of surgeons and society. Surgeons choose among the options available to them because they have particular opinions regarding what would be good (or bad) for their patients. Aristotle described practical wisdom (Greek: phronesis) as the capacity to choose the best option from among several imperfect alternatives (Fig. 48-1).1 Frequently, surgeons are confronted with clinical or interpersonal situations in which there is incomplete information, uncertain outcomes, and/or complex personal and familial relationships. The capacity to choose wisely in such circumstances is the challenge of surgical practice.

Fig. 48-1.

Bust of Aristotle. Marble, Roman copy after a Greek bronze original by Lysippos from 330

B.C.

[From http://en.wikipedia.org/wiki/File:Aristotle_Altemps_Inv8575.jpg: Ludovisi Collection, Accession number Inv. 8575, Palazzo Altemps, Location Ground Floor, Branch of the National Roman Museum. Photographer/source Jastrow (2006) from Wikipedia (accessed March 8, 2009).]

DEFINITIONS Biomedical ethics is the system of analysis and deliberation dedicated to guiding surgeons toward the "good" in the practice of surgery. One of the most influential ethical "systems" in the field of biomedical ethics is the principlist approach as articulated by Beauchamp and Childress.2 In this approach to ethical issues, moral dilemmas are deliberated by using four guiding principles: autonomy, beneficence, nonmaleficence, and justice.2 The principle of autonomy respects the capacity of individuals to choose their own destiny, and it implies a right for individuals to make those choices. It also implies an obligation for physicians to permit patients to make autonomous choices about their medical care. Beneficence requires that proposed actions aim at and achieve something good whereas nonmaleficence aims at avoiding concrete harm: primum non nocere.* Justice requires a fairness where both the benefits and burdens of a particular action are distributed equitably. *"First do no harm."

BIOMEDICAL ETHICS: AN OVERVIEW The history of medical ethics has its origins in antiquity. The Hippocratic Oath along with other professional codes has guided the actions of physicians for thousands of years (Fig. 48-2). The modern practice of medicine is therefore rooted in the Hippocratic tradition, but the growing technical powers of modern medicine raise new questions that were inconceivable in previous generations. Life support, dialysis, and modern drugs, as well as organ and cellular transplantation, have engendered new moral and ethical dilemmas. As such, the ethical challenges faced by the surgeon have become more complex and require greater attention.

Fig. 48-2.

Twelfth-century Byzantine manuscript. The Hippocratic oath was written out in the form of a cross from the Folio Biblioteca Vaticana. [From http://en.wikipedia.org/wiki/File:HippocraticOath.jpg: Rutkow IM: Surgery: An Illustrated History 1993, p 27, from Wikipedia (accessed March 8, 2009).]

The case-based paradigm for bioethics is used when a difficult clinical situation confronts the clinical team and questions with apparently conflicting values or principles are raised (Fig. 48-3). The first step is to clarify the relevant principles (e.g., autonomy, beneficence, nonmaleficence, and justice) and values (e.g., selfdetermination, quality of life, etc.) at stake. After identifying the principles and values that are affecting the situation, a proposed course of action is considered given the circumstances.

Fig. 48-3.

The four principles of the care-based paradigm.

Much of the discourse in bioethics adopts this "principlist" approach in which the relevant principles are identified, weighted and balanced, and then applied to formulate a course of action. This approach to bioethics is a powerful technique for thinking through moral problems, as the four principles define the dimensions of the ethical dilemma and provide a means for assessing the impact or extent of each value and principle at stake. The concept of virtue ethics was born with Socrates (Fig. 48-4) and raised in Plato's Republic where the four cardinal virtues of courage, justice, temperance, and practical wisdom are discussed.3–5 Practical wisdom is developed and acquired through experience. As such, the apprenticeship model of surgical residency teaches much more than technical mastery but moral training as well. In fact, the sociologist Charles Bosk argues that the "postgraduate training of surgeons is above all things an ethical training."6

Fig. 48-4.

Portrait of Socrates. Marble, Roman artwork (1st century), speculated to be a copy of a lost bronze statue made by Lysippos. [From http://en.wikipedia.org/wiki/File:Socrates_Louvre.jpg: Old fund. Accession number Ma 59 (MR 652) Location Department of Greek, Etruscan and Roman Antiquities, Sully wing, ground floor, room 17. Photographer/source Eric Gaba (User:Sting), July 2005. Wikipedia (accessed March 8, 2009). The photographer has licensed this photo under the Creative Commons Attribution ShareAlike 2.5 License. Official license: http://creativecommons.org/licenses/bysa/2.5/]

SPECIFIC ISSUES IN SURGICAL ETHICS Informed Consent Although a relatively recent development, the doctrine of informed consent is one of the most widely established tenets of modern biomedical ethics. During the nineteenth and early twentieth centuries, most physicians practiced a form of benign paternalism whereby patients were rarely involved in the decision-

making process regarding their medical care, relying instead on the beneficence of the physician. Consensus among the wider public eventually changed such that surgeons are now expected to have an open discussion about diagnosis and treatment with the patient to obtain informed consent. In the United States, the legal doctrine of simple consent dates from the 1914 decision in Schloendorff v The Society of New York Hospital regarding a case in which a surgeon removed a diseased uterus after the patient had consented to an examination under anesthesia, but with the express stipulation that no operative excision should be performed. The physician argued that his decision was justified by the beneficent obligation to avoid the risks of a second anesthetic. However, Justice Benjamin Cardozo stated: Every human being of adult years and sound mind has a right to determine what shall be done with his body; and a surgeon who performs an operation without his patient's consent commits an assault, for which he is liable in damages . . . except in cases of emergency, where the patient is unconscious, and where it is necessary to operate before consent can be obtained.7 Having established that patients have the right to determine what happens to their bodies, it took some time for the modern concept of informed consent to emerge from the initial doctrine of simple consent. The initial approach appealed to a professional practice standard whereby physicians were obligated to disclose to patients the kind of information that experienced surgeons customarily disclosed.8 However, this disclosure was not always adequate for patient needs. In another landmark case, Canterbury v Spence, the court rejected the professional practice standard in favor of the reasonable person standard whereby physicians are obliged to disclose to patients all information regarding diagnosis, treatment options, and risks that a "reasonable patient" would want to know in a similar situation. Rather than relying on the practices or consensus of the medical community, the reasonable person standard empowers the public (reasonable persons) to determine how much information should be disclosed by physicians to ensure that consent is truly informed. The court did recognize, however, that there are practical limits on the amount of information that can be communicated or assimilated.8 Subsequent litigation has revolved around what reasonable people expect to be disclosed in the consent process to include the nature and frequency of potential complications, the prognostic life expectancy,9 and the surgeon-specific success rates.7 Despite the litigious environment of medical practice, it is difficult to prosecute a case of inadequate informed consent so long as the clinician has made a concerted and documented effort to involve the patient in the decision-making process. Adequate informed consent entails at least four basic elements: (a) The physician documents that the patient or surrogate has the capacity to make a medical decision; (b) The surgeon discloses to the patient details regarding the diagnosis and treatment options sufficiently for the patient to make an informed choice; (c) The patient demonstrates understanding of the disclosed information before (d) authorizing freely a specific treatment plan without undue influence (Fig. 48-5). These goals are aimed at respecting each patient's prerogative for autonomous self-determination. To accomplish these goals, the surgeon needs to engage in a discussion about the causes and nature of the patient's disease, the risks and benefits of available treatment options, as well as details regarding what patients can expect after an operative intervention.10–17

Fig. 48-5.

Algorithm for navigating the process of informed consent. (From Childers R, Lipsett A, Pawlik T: Informed consent and the surgeon. J Am Coll Surg E-pub Jan. 21, 2009. Copyright 2009, with permission from Elsevier.)

Informed consent can be challenging in certain clinical settings. For example, obtaining consent for emergency surgery, where decisions are often made with incomplete information, can be difficult. Emergency consent requires the surgeon to consider if and how possible interventions might save a patient's life, and if successful, what kind of disability might be anticipated. Surgical emergencies are one of the few instances where the limits of patient autonomy are freely acknowledged, and surgeons are empowered by law and ethics to act promptly in the best interests of their patients according to the surgeon's judgment. Most applicable medical laws require physicians to provide the standard of care to incapacitated patients, even if it entails invasive procedures without the explicit consent of the patient or surrogate. If at all possible,

surgeons should seek the permission of their patients to provide treatment, but when emergency medical conditions render patients unable to grant that permission, and when delay is likely to have grave consequences, surgeons are legally and ethically justified in providing whatever surgical treatment the surgeon judges necessary to preserve life and restore health.7 This justification is based on the social consensus that most people would want their lives and health protected in this way, and this consensus is manifest in the medical profession's general orientation to preserve life. It may be that subsequent care may be withdrawn or withheld when the clinical prognosis is clearer, but in the context of initial resuscitation of injured patients, incomplete information makes clear judgments about the patient's ultimate prognosis or outcome impossible. The process of consent can also be challenging in the pediatric population. For many reasons, children and adolescents cannot participate in the process of giving informed consent in the same way as adults. Depending on their age, children may lack the cognitive and emotional maturity to participate fully in the process. In addition, depending on the child's age, their specific circumstances, as well as the local jurisdiction, children may not have legal standing to fully participate on their own independent of their parents. The use of parents or guardians as surrogate decision makers only partially addresses the ethical responsibility of the surgeon to involve the child in the informed consent process. The surgeon should strive to augment the role of the decision makers by involving the child in the process. Specifically, children should receive age-appropriate information about their clinical situation and therapeutic options so that the surgeon can solicit the child's "assent" for treatment. In this manner, while the parents or surrogate decision makers formally give the informed consent, the child remains an integral part of the process. Certain religious practices can present difficulties in treating minor children in need of life-saving blood transfusions; however, case law has made clear the precedent that parents, regardless of their held beliefs, may not place their minor children at mortal risk. In such a circumstance, the physician should seek counsel from the hospital medicolegal team, as well as from the institutional ethics team. Legal precedent has, in general, established that the hospital or physician can proceed with providing all necessary care for the child. Obtaining "consent" for organ donation deserves specific mention.1 8 Historically, discussion of organ donation with families of potential donors was performed by transplant professionals, who were introduced to families by intensivists after brain death had been confirmed and the family had been informed of the fact of death. In other instances, consent might be obtained by intensivists caring for the donor, as they were assumed to know the patient's family and could facilitate the process. However, issues of moral "neutrality" as part of end-of-life care in the intensive care unit have caused a shift in how obtaining "consent" for organ donation is handled. Responsibility for obtaining consent from the donor family is now vested in trained "designated requestors" (or "organ procurement coordinators")1 9 or by "independent" intensivists who do not have a therapeutic clinical relationship with the potential donor.2 0 In this way, the donor family can be allowed to make the decision regarding donation in a "neutral" environment without erosion of the therapeutic relationship with the treating physician. The process of informed consent also can be limited by the capacity of patients to assimilate information in the context of their illness. For example, despite the best efforts of surgeons, evidence suggests that patients rarely retain much of what is disclosed in the consent conversation, and they may not remember discussing details of the procedure that become relevant when postoperative complications arise. 2 1 It is important to recognize that the doctrine of informed consent places the most emphasis on the principle of autonomy precisely in those clinical situations when, because of their severe illness or impending death,

patients are often divested of their autonomy.

The Boundaries of Autonomy: Advanced Directives and Powers of Attorney Severe illness and impending death can often render patients incapable of exercising their autonomy regarding medical decisions. One approach to these difficult situations is to make decisions in the "best interests" of patients, but because such decisions require value judgments about which thoughtful people frequently disagree, ethicists, lawyers. and legislators have sought a more reliable solution. Advanced directives of various forms have been developed to carry forward into the future the autonomous choices of competent adults regarding health care decisions. Furthermore, the courts often accept "informal" advanced directives in the form of sworn testimony about statements the patient made at some time previous to their illness. When a formal document expressing the patient's advanced directives fails to exist, surgeons should consider the comments patients and families make when asked about their wishes in the setting of debilitating illness. Living wills are written to anticipate treatment options and choices in the event that a patient is rendered incompetent by a terminal illness. In the living will, the patient indicates which treatments she wishes to permit or prohibit in the setting of terminal illness. The possible treatments addressed often include mechanical ventilation, cardiopulmonary resuscitation, artificial nutrition, dialysis, antibiotics, or transfusion of blood products. Unfortunately, living wills are often too vague to offer concrete guidance in complex clinical situations, and the language ("terminal illness," "artificial nutrition") can be interpreted in many ways. Furthermore, by limiting the directive only to "terminal" conditions, it does not provide guidance for common clinical scenarios like advanced dementia, delirium, or persistent vegetative states where the patient is unable to make decisions, but is not "terminally" ill. Perhaps even more problematic is the evidence that demonstrates that healthy patients cannot reliably predict their preferences when they are actually sick. For example, the general public estimates the health-related quality of life (HRQoL) score of patients on dialysis at 0.39, although dialysis patients themselves rate their HRQoL at 0.56.2 2 Similarly, patients with colostomies rated their HRQoL at 0.92, compared to a score of 0.80 given by the general public for patients with colostomies.2 2 For these and other reasons, living wills are often unable to provide the extent of assistance they promise.2 3 An alternative to living wills is the durable power of attorney for health care in which patients identify surrogate decision makers and invest them with the authority to make health care decisions on their behalf in the event that they are unable to speak for themselves. Proponents of this approach hope that the surrogate will be able to make decisions that reflect the choices that the patients themselves would make if they were able. Unfortunately, several studies demonstrate that surrogates are not much better than chance at predicting the choices patients make when the patient is able to state a preference. 7,23,24 These data reveal a flaw in the guiding principle of surrogate decision making: Surrogates do not necessarily have privileged insight into the autonomous preferences of patients. However, the durable power of attorney at least allows patients to choose the person who will eventually make prudential decisions on their behalf and in their best interests; therefore, respecting the judgment of the surrogate is a way of respecting the selfdetermination of the incapacitated patient. 2 5 There is continuing enthusiasm for a wider use of advanced directives. In fact, the 1991 Patient Self Determination Act requires all U.S. health care facilities to (a) inform patients of their rights to have

advanced directives, and (b) to document those advanced directives in the chart at the time any patient is admitted to the health care facility.7 However, only a minority of patients in U.S. hospitals have advanced directives despite concerted efforts to teach the public of their benefits. For example, the ambitious SUPPORT trial used specially trained nurses to promote communication between physicians, patients, and their surrogates to improve the care and decision making of critically ill patients. Despite this concerted effort, the intervention demonstrated "no significant change in the timing of do not resuscitate (DNR) orders, in physician-patient agreement about DNR orders, in the number of undesirable days (patients experiences), in the prevalence of pain, or in the resources consumed."2 6 Some of the reluctance around physician-patient agreement about DNR orders may reflect patient and family anxiety that DNR orders equate to "do not treat." Patients and families should be assured, when appropriate, that declarations of DNR/do not intubate will not necessarily result in a change in ongoing routine clinical care. The issue of temporarily rescinding DNR/do not intubate orders around the time of an operative procedure may also need to be addressed with the family. Patients should be encouraged to clearly identify their surrogates, both formally and informally, early in the course of treatment, and before any major elective operation. Often, around the time of surgery or at the end of life, there are limits to patient autonomy in medical decision making. Seeking an advanced directive or surrogate decision maker requires time that is not always available when the clinical situation deteriorates. As such, these issues should be clarified as early as possible in the patient-physician relationship.

Withdrawing and Withholding Life-Sustaining Therapies The implementation of various forms of life support technology raise a number of legal and ethical concerns about when it is permissible to withdraw or withhold available therapeutic technology. There is general consensus among ethicists that there are no philosophic differences between withdrawing (stopping) or withholding (not starting) treatments that are no longer beneficial.2 7 However, the right to refuse, withdraw, and withhold beneficial treatments was not established before the landmark case of Karen Ann Quinlan. In 1975, Ms. Quinlan lapsed into a persistent vegetative state requiring ventilator support. After several months without clinical improvement, Ms. Quinlan's parents asked the hospital to withdraw ventilator support. The hospital refused, fearing prosecution for euthanasia. The case was appealed to the New Jersey Supreme Court where the justices ruled that it was permissible to withdraw ventilator support.2 8 This case established a now commonly recognized right to withdraw "extraordinary" life-saving technology if it is no longer desired by the patient or the patient's surrogate. The difference between "ordinary" and "extraordinary" care, and whether there is an ethical difference in withholding or withdrawing "ordinary" vs. "extraordinary" care, has been an area of much contention. The 1983 Nancy Cruzan case highlighted this issue. In this case, Ms. Cruzan had suffered severe injuries in an automobile crash that rendered her in a persistent vegetative state. Ms. Cruzan's family asked that her tube feeds be withheld, but the hospital refused. The case was appealed to the U.S. Supreme Court, which ruled that the tube feeding could be withheld if her parents demonstrated "clear and convincing evidence" that the incapacitated patient would have rejected the treatment.2 9 In this ruling, the court essentially ruled that there was no legal distinction between "ordinary" vs. "extraordinary" life-sustaining therapies.3 0 In allowing the feeding tube to be removed, the court accepted the principle that a competent person (even through a surrogate decision maker) has the right to decline treatment under the Fourteenth Amendment of the U.S.

Constitution. The court noted, however, that there has to be clear and convincing evidence of the patient's wishes (principle of autonomy) and that the burdens of the medical intervention should outweigh its benefits (consistent with the principles of beneficence and nonmaleficence). In deliberating the issue of withdrawing vs. withholding life-sustaining therapies, the principle of "double effect" is often mentioned. According to the principle of "double effect," a treatment (e.g., opioid administration in the terminally ill) that is intended to help and not harm the patient (i.e., relieve pain) is ethically acceptable even if an unintended consequence (side effect) of its administration is to shorten the life of the patient (e.g., by respiratory depression). Under the principle of double effect, a physician may withhold or withdraw a life-sustaining therapy if the surgeon's intent is to relieve suffering, not to hasten death. The classic formulation of double effect has four elements (Fig. 48-6).

Fig. 48-6.

The four elements of the double effect principle: 1) The good effect is produced directly by the action and not by the bad effect. 2) The person must intend only the good effect, even though the bad effect may be foreseen. 3) The act itself must not be intrinsically wrong, or needs to be at least neutral. 4) The good effect is sufficiently desirable to compensate for allowing the bad effect.

Withholding or withdrawing of life-sustaining therapy is ethically justified under the principle of double effect if the physician's intent is to relieve suffering, not to kill the patient. Thus, in managing the distress of the

dying, there is a fundamental ethical difference between titrating medications rapidly to achieve relief of distress and administering a very large bolus with the intent of causing apnea. It is important to note, however, that although the use of opioids for pain relief in advanced illness is frequently cited as the classic example of the double effect rule, opioids can be used safely without significant risk. In fact, if administered appropriately, in the vast majority of instances the rule of double effect need not be invoked when administering opioids for symptom relief in advanced illness.3 1 In accepting the ethical equivalence of withholding and withdrawing of life-sustaining therapy, surgeons can make difficult treatment decisions in the face of prognostic uncertainty.2 7 In light of this, some important principles to consider when considering withdrawal of life-sustaining therapy include: (a) Any and all treatments can be withdrawn. If circumstances justify withdrawal of one therapy (e.g., IV pressors, antibiotics), they may also justify withdrawal of others. (b) Be aware of the symbolic value of continuing some therapies (e.g., nutrition, hydration) even though their role in palliation is questionable. (c) Before withdrawing life-sustaining therapy, ask the patient and family if a spiritual advisor (e.g., pastor, imam, rabbi, or priest) should be called. (d) Consider requesting an ethics consult. Although the clinical setting may seem limited, a range of options usually exists with respect to withdrawing or withholding treatment, allowing for an incremental approach, for example (a) continuing the current regimen without adding new interventions or tests; (b) continuing the current regimen but withdrawing elements when they are no longer beneficial; and (c) withdrawing and withholding all treatments that are not targeted to relieve symptoms and maximize patient comfort.3 2 The surgeon might consider discussing the clinical situation with the patient or proxy decision maker, identify the various therapeutic options, and delineate the reasons why withholding or withdrawing life-sustaining therapy would be in the patient's best interest. If the patient (or designated proxy decision maker) does not agree with withholding or withdrawing life-sustaining therapy, the surgeon should consider or recommend a second medical opinion. If the second opinion corroborates that life-sustaining therapy should be withheld or withdrawn but the patient/family continues to disagree, the surgeon should consider assistance from institutional resources such as the ethics committee and hospital administration. Although the surgeon is not ethically obligated to provide treatment that he or she believes is futile, the surgeon is responsible for continued care of the patient, which may involve transferring the patient to a surgeon who is willing to provide the requested intervention.2 7

PALLIATIVE CARE General Principles of Palliative Care Palliative care is a coordinated, interdisciplinary effort that aims to relieve suffering and improve quality of life for patients and their families in the context of serious illness.3 3 It is offered simultaneously with all other appropriate medical treatment, and its indication is not limited to situations associated with a poor prognosis for survival. Palliative care strives to achieve more than symptom control, but it should not be confused with noncurative treatment. The World Health Organization defines palliative care as "an approach that improves the quality of life of patients and their families facing the problems associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial, and spiritual."3 4 Palliative care is both a philosophy of

care and an organized, highly structured system for delivering care. Palliative care includes the entire spectrum of intervention for the relief of symptoms and the promotion of quality of life. No specific therapy, including surgical intervention, is excluded from consideration. Therefore, surgeons have valuable contributions to make to palliative care. Furthermore, surgical palliative care can be defined as the treatment of suffering and the promotion of quality of life for seriously or terminally ill patients under the care of surgeons.3 5 The standard of palliative treatment lies in the agreement between patient and physician that the expected outcome is relief from distressing symptoms, lessening of pain, and improvement of quality of life. The decision to intervene is based on the treatment's ability to meet the stated goals, rather than its impact on the underlying disease. The fundamental elements of palliative care consist of pain and nonpain symptom management, communication among patients, their families, and care providers, and continuity of care across health systems and through the trajectory of illness. Additional features of system-based palliative care are teambased planning that includes patient and family; close attention to spiritual matters; and psychosocial support for patients, their families, and care providers, including bereavement support. Indications for palliative care consultation in surgical practice include: (a) patients with conditions that are progressive and life-limiting, especially if characterized by burdensome symptoms, functional decline, and progressive cognitive deficits; (b) assistance in clarification or reorientation of patient/family goals of care; (c) assistance in resolution of ethical dilemmas; (d) situations in which a patient/surrogate declines further invasive or curative treatments with stated preference for comfort measures only; (e) patients who are expected to die imminently or shortly after hospital discharge; and (f) provision of bereavement support for patient care staff, particularly after loss of a colleague under care3 5 (Table 48-1).

Table 48-1 Indications for Palliative Care Consultation Patients with conditions that are progressive and life-limiting, especially if characterized by burdensome symptoms, functional decline, and progressive cognitive deficits Assistance in clarification or reorientation of patient/family goals of care Assistance in resolution of ethical dilemmas Situations in which patient/surrogate declines further invasive or curative treatments with stated preference for comfort measures only Patients who are expected to die imminently or shortly after hospital discharge Provision of bereavement support for patient care staff, particularly after loss of a colleague under care

Palliative Care: History and Philosophy Palliative care, by virtue of its diverse goals, practices, and practitioners, has many origins, but it would not have emerged as a comprehensive philosophy of care without the seminal contributions of Dame Cicely Saunders (Fig. 48-7). Her life's work began at the bedside of an individual patient, but it ultimately led to the modern hospice movement, spawned a new medical specialty, initiated extensive scientific and social research, and has changed the perception of death and dying for millions of patients and families.

Fig. 48-7.

Dame Cicely Mary Strode Saunders. (Courtesy of St. Christopher's Hospice.)

Saunders was a registered nurse, a medical social worker, and ultimately, a physician who was inspired by the needs of suffering soldiers in World War II. Her mentor, thoracic surgeon Howard Barrett, ultimately convinced her to become a physician to increase the credibility of her ideas in the physician-dominated health care system of that time. Saunders made three seminal contributions to the emerging field of palliative care: (a) She observed that the quality of life for patients with pain from advanced cancer is improved with scheduled dosing of opioids; (b) she developed the concept of Total Pain4 1 to include physiologic, spiritual, and existential dimensions of pain; and (c) she founded St. Christopher's Hospice in 1967. Each of these contributions illustrates principles that have become the salient themes of all palliative care: the emphasis on symptom control that correlates with enhanced quality of life, the recognition of the spiritual and existential dimensions of health and illness, and the insistence on teamwork as the operational

model for delivery of care. Nathan Cherny (Fig. 48-8), another pioneer of palliative care, echoes these themes in his definition of palliative care: "[it] is concerned with three things: the quality of life, the value of life, and the meaning of life." 3 3 Therefore, it is existence, not death, that is the focus of palliative care.

Fig. 48-8.

Nathan Cherny, a pioneer for palliative care.

Surgeons have had an integral role in palliative care as it has evolved, and surgical procedures have been part of the armamentarium for symptom relief. For example, although mastectomy, gastrectomy, pancreaticoduodenectomy, and the Blalock-Taussig shunt are thought of as curative, or at least definitive, operations, the initial rationale for developing these procedures was their efficacy as palliative treatment.37,38 The official report from Massachusetts General Hospital of its experience treating victims of the Coconut Grove fire presciently identified psychologic and social care as major components for the total care the burn victims received.3 9

In addition to developing procedures with palliative utility, surgeons have also made important contributions to the philosophy of palliative care. For example, in 1975, shortly after the hospice concept was established, the distinguished surgeon-educator J. Englebert Dunphey addressed the concept of nonabandonment of terminally ill patients in a landmark lecture that deeply shaped the developing specialty of palliative care.4 0 The term palliative care was coined by a Canadian surgeon, Balfour Mount (Fig. 48-9), in 1975 on the opening of the first hospital-based palliative care program in North America. Surgeons were active in the establishment of many community hospice programs in the United States and have contributed popular professional and lay books on the subject.41–43

Fig. 48-9.

Balfour Mount. [Reproduced with permission from Canadian Broadcasting Company (Tracking number 22910).]

Over the past decade, the American College of Surgeons has issued several statements of principles outlining standards of palliative and end-of-life care in addition to its support of programs disseminating information to surgeons about the principles and practices of palliative care.44–46 The Royal College of Surgeons has acknowledged palliative care as a domain of expected competence for Fellowship for over a decade, and since 2002, the American Board of Surgery has included palliative care as a domain of expected knowledge for its qualifying exam. Over the last 40 years, hospice and palliative care have become established components of health care

systems in varying degrees in most countries of the world. Table 48-2 shows a comparison of palliative care and hospice. Both have received repeated endorsements by the World Health Organization,4 7 medical societies,4 4 and medical specialty boards.4 8 More than just a philosophy of care, hospice and palliative care have emerged as a medical specialty that provides a standard medical practice to patients in institutional settings and in patient homes. Palliative medicine was recognized as a medical subspecialty by the Royal College of Medicine in 1987 and by the American Board of Medical Specialties in 2006. Many insurers now reimburse these services as a standard benefit, and in the United States, the Medicare hospice benefit provides a per diem in support of nursing, social services, nurse aides, physician oversight, volunteers, chaplain support, durable medical equipment, and the cost of medications for symptom control.

Table 48-2 Comparison of Palliative and Hospice Care Palliative Care Eligibility

May be initiated by physician referral at time of diagnosis of any serious illness regardless of prognosis No renewal criteria because of lack of prognosis requirement

Hospice (Medicare Benefit) Patient is eligible for Medicare Part A Patient certified (two physicians) to have probable survival of 6 mo or less if disease, untreated, pursues its natural course Patient (surrogate if patient not competent) must sign form electing hospice benefit Eligibility may be renewed as long as patient continues to meet admission criteria

All illnesses, ages

All terminal illnesses Medicare benefit does not require Do Not Resuscitate for eligibility Medicare benefit does not require primary caregiver in the home Hospice care must be provided by a Medicare-certified hospice program

Venues of service

Hospitals including Veteran's Administration hospitals

Majority cared for at home Hospitals, including Veteran's Administration hospitals

Health care clinics

Assisted living facilities

Assisted living facilities

Nursing homes

Nursing homes Home Treatments

Insurance

Palliative and disease-directed therapies such as chemotherapy and dialysis

Some treatments and

Palliative only Some hospice programs will authorize continued dialysis, total parenteral nutrition, tube feedings, and chemotherapy More defined and comprehensive than palliative care

Insurance

Palliative Care Some treatments and medications covered by Medicare, Medicaid, and private insurers

Hospice (Medicare Benefit) More defined and comprehensive than palliative care reimbursement Medicare covers all expenses related to hospice care: medications, procedures, consultant's fees, durable medical equipment, home nursing visits, bereavement services up to 1 y after the date of death Medicaid benefit similar to Medicare in almost all states Most insurance plans have a hospice benefit

Team composition

Interdisciplinary Composition flexible depending on clinical setting

Interdisciplinary Medicare requires physician, nurse, social worker, and a volunteer as core team members Patient may retain primary physician or be followed by hospice medical director

Although all patients, regardless of prognosis, may benefit from the services of a palliative care physician with expertise in relieving intractable symptoms, hospice care4 9 is a specific form of palliative care intended for patients who have an estimated prognosis of 6 months or less to live, usually certified by two physicians (the attending physician and hospice medical director). Initially, there are two certification periods of 3 months each, followed by recertification every 60 days thereafter. Continued services may continue well beyond the original 6 months of estimated survival, and they are based on ongoing disease progression, further functional decline, and persistent symptom burden. The goal of hospice is to provide holistic care at the end of life focused on relief of the patient's suffering. Most Americans indicate a preference to die at home, but nearly 75% die in an institutional setting (half in acute hospitals and another one fourth in nursing homes). Of the one fourth that do die at home, hospice services can help make that experience better for both patient and surviving loved ones. Earlier referral and wider use of the hospice benefit may help more patients achieve their goal of dying at home.

Concepts of Suffering, Pain, Health, and Healing Palliative care addresses specifically the individual patient's experience of suffering due to illness. Indeed, the philosophical origins of palliative care began with attention to suffering and the existential questions suffering engenders. More than mere technologic evolution in the management of symptoms, the early proponents of palliative care sought a revolution in the moral foundations of medicine that challenged the assumptions that so often seemed to result in futile invasive intervention, and identified many of the problems that were subsequently taken up by medical ethicists. This reorientation of the goals of medical care from a focus on disease and its management to the patient's experience of illness focuses attention on the purpose of medicine and the meaning of health and healing. Over the past half century, several concepts and theories about the nature of pain, suffering, and health have been proposed in service of the evolving conceptual framework of palliative care. For example, while considering the differences between disease-oriented and illness-oriented approaches to the care of seriously ill patients, psychiatrist Arthur Kleinman wrote, "There is a moral core to healing in all societies. [Healing] is the central purpose of medicine . . . the purpose of medicine is both control of disease processes and care for

the illness experience. Nowhere is this clearer than in the relationship of the chronically ill to their medical system: For them, the control of disease is by definition limited; care for the life problems created by the disorder is the chief issue."5 0 The relief of pain has been the clinical foundation for hospice and palliative care. It has been defined by the International Association for the Study of Pain as "An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage."5 1 For purposes of interdisciplinary palliative care, Saunders's concept of "Total Pain"3 6 is a more useful definition and is frequently used as the basis for palliative assessments. Total Pain is the sum total of four principal domains of pain: physical, psychologic, social or socioeconomic, and spiritual. Each of these contributes to, but is not synonymous with, suffering. Persons suffer when their individual integrity or personhood is threatened: "Bodies do not suffer, only persons do."5 2 Personhood entails a transcendent dimension that often can frame the existential threat of death in some broader sense of meaning. As such, issues related to a person's past history and future legacy become compellingly more central as physical decline becomes increasingly pronounced. As argued by Cassell, if physicians understand suffering in only its physical dimension (attention to laboratory values, xrays, etc.), they may ignore the psychologic and spiritual pain that accompanies dying; such neglect may not only fail to relieve suffering, but actually compound it.5 2 Saunders's taxonomy of pain and Cassell's portrayal of the mechanism of suffering collectively represent the structure and function of the human psyche in the context of life-threatening illness. Frankl5 3 contributed to the philosophy of palliative care the notion that the willingness to survive is related to the capacity to make sense out of suffering, giving suffering a sense of meaning. Brody described suffering as the sense of anguish that besets an individual near the end of his life when his personal narrative is fragmented to the point of incoherence. This fragmentation prevents the individual from transforming his personal narrative into a legacy that will endure after death. Brody challenges physicians caring for severely ill patients to consider how their participation in the care of patients might best assist those patients in transforming a "broken story" into a "transcendent legacy."5 4 Finally, the developmental framework for the end of life proposed by Byock5 5 views the last phases of life not so much as an arena for suffering, but as a natural phase of life with its own developmental tasks, which, when achieved, result in deeply satisfying personal growth that reciprocates with the growth of those sharing this experience. Byock's four developmental tasks of the dying include: (a) renewal of a sense of personhood and meaning, (b) bringing closure to personal and community relationships, (c) bringing closure to worldly affairs, and (d) acceptance of the finality of life.

Effective Communication and Negotiating the Goals of Care Changing the goals of care from cure to palliation near the end of life is both emotionally and clinically challenging, and it depends on a clear prognosis and effective communication. Unfortunately, prognostication can be notoriously difficult and inaccurate in advanced illness, and Christakis has argued that, to a large degree, physicians have abdicated their traditional responsibility to provide clear prognosis regarding incurable disease and approaching death.5 6 However, there are validated tools for prognosis in critical illness (APACHE, MODS, etc.), and with most advanced diseases, functional status is the most powerful predictor of survival. For example, patients with advanced metastatic cancer who are resting/sleeping for 50% or more of normal waking hours and require some assistance with activities of daily living (ADL) have a projected

survival of weeks, and patients who are essentially bedfast and dependent for ADL have a projected survival of days to a week or two at best. Table 48-3 shows a simple prognostic tool to aid clinicians in recognizing patients nearing the end of life.

Table 48-3 Simple Prognostication Tool in Advanced Illness (Especially Cancer) Functional Level

Performance Status (ECOG)

Prognosis

Able to perform all basic ADLs independently and some IADLs 2

Months

Resting/sleeping up to 50% or more of waking hours and requiring some assistance with basic ADLs

3

Weeks to a few months

Dependent for basic ADLs and bed to chair existence

4

Days to a few weeks at most

These observations apply to patients with advanced, progressive, incurable illnesses (e.g., metastatic cancer refractory to treatment). Basic ADL = activities of daily living (e.g., transferring, toileting, bathing, dressing, and feeding oneself); IADL = instrumental activities of daily living (e.g., more complex activities such as meal preparation, performing household chores, balancing a checkbook, shopping, etc.); ECOG = Eastern Cooperative Oncology Group functional (performance) status. Alternatively, the Karnofsky Performance Scale is a scale of functional status ranging from 100 (high level of function) to 0 (death). It is commonly used in palliative care to roughly assess patient anticipated needs as well as prognosis. The Palliative Performance Scale5 7 is a validated5 8 expansion of the Karnofsky Performance Scale that includes five palliative-focused domains, including ambulation, activity level, selfcare, intake, and level of consciousness, in addition to evidence of disease. The Missoula-Vitas Quality of Life Index is a 25-question scale specifically for palliative care and hospice patients that scores symptoms, function, interpersonal relationships, well being, and spirituality. Updates and Spanish versions are available. 5 5 Regardless of the prognostic tool used, the prognosis should be conveyed to the patient and family. If done well, communication and negotiation with patients and families about advanced terminal illnesses can potentially avoid great psychologic harm and help make a difficult transition easier. To communicate effectively and compassionately, it is helpful to pursue an organized process similar to the structured history and physical central to the evaluation of any patient. One such structured approach to delivering unfavorable news proposes six steps that can be easily learned by clinicians: (a) getting started by selection of the appropriate setting, introductions, and seating; (b) determining what the patient or family knows; (c) determining what the patient or family wants to know; (d) giving the information; (e) expressing empathy; and (f) establishing expectations, planning, and aftercare (Table 48-4).5 9 Success with this approach to breaking bad news is critically dependent upon the clinician's ability to empathically respond to the patient's (and family's) reaction to the news.6 0 The empathic response does not require the surgeon to share the same emotions of the patient, but it does require the surgeon to identify the patient's emotion and accurately reflect that awareness back to the patient. Patient assessment in these conversations should give the highest priority to identifying and responding to the most immediate source of distress. Relieving a pressing symptom is prerequisite for a more thorough search for other potential sources of suffering, and the

assessment process, itself, can be therapeutic if conducted in a respectful and gentle manner.

Table 48-4 Communicating Unfavorable News: Important Principles Setting: Find a quiet, private place to meet. Sit down close to the patient. Listen: Clarify the patient's and/or the family's understanding of the situation. "Warning shot": Prepare patient and family and obtain their permission to communicate bad news (e.g., "I'm afraid I have bad news."). Silence: Pause after giving bad news. Allow patient/family to absorb/react to the news. Encourage: Convey hope that is realistic and appropriate to the circumstances (e.g., patient will not be abandoned; symptoms will be controlled).

CARE AT THE END OF LIFE The process of dying and the care of a patient at the time of death is a distinct clinical entity that demands specific skills from physicians. The issues specific to dying and the available tools for compassionate care at the end of life are addressed in this section.

The Syndrome of Imminent Demise32,61 In a patient who has progressed to the terminal stage of an advanced illness (e.g., cancer), a number of signs provide evidence of imminent death. As terminally ill patients progress toward death, they become increasingly bedbound, requiring assistance for all basic ADL. There is a steady decrease in desire and requests for food and fluids. More distressing to the dying patient is a progressively dry mouth that may be confused by the treating team as thirst. It is often exacerbated by anticholinergic medications, mouth breathing, and supplemental oxygen (O2) administered without humidification. With progressive debility, fatigue, and weight loss, it is common for terminally ill patients to experience increasing difficulty swallowing. This may result in aspiration episodes and an inability to swallow tablets, requiring alternative routes for medication administration (e.g., IV, SC, PR, sublingual, buccal, or transdermal). In addition to the increased risk of aspiration, patients near death develop great difficulty clearing oropharyngeal and upper airway secretions, leading to noisy breathing or the so-called "death rattle." As death approaches, the respiratory pattern may change to increasingly frequent periods of apnea often following a Cheyne-Stokes pattern of rapid, progressively longer breaths leading up to an apneic period. As circulatory instability develops near death, patients may exhibit cool and mottled extremities. Periods of confusion are often accompanied by decreasing urine output and episodes of fecal and urinary incontinence. A number of cognitive changes occur as death approaches. Patients who are in the last days of life may demonstrate some signs of confusion or delirium. Agitated delirium is a prominent feature of a difficult death. Other cognitive changes that may be seen include a decreased interest in social interactions, increased somnolence, reduced attention span, disorientation to time (often with altered sleep-wake cycles), and an altered dream life, including vivid "waking dreams" or visual hallucinations. Reduced hearing and visual acuity may be an issue for some patients; however, patients who appear comatose may still be aware of their surroundings. Severely cachectic patients may lose the ability to keep their eyes closed during sleep

because of loss of the retro-orbital fat pad.

Common Symptoms at the End of Life and Their Management32,61,62 The three most common, major symptoms that threaten the comfort of dying patients in their last days are respiratory distress, pain, and cognitive failure. General principles that are applicable to symptom management in the last days of life include: (a) anticipating symptoms before they develop; (b) minimizing technologic interventions (usually manage symptoms with medications); and (c) planning alternative routes for medications in case the oral route fails. It may be possible to cautiously reduce the dose of opioids and other medications as renal clearance decreases near the end of life, but it is important to remember that increased somnolence and decreasing respirations are prominent features of the dying process independent of medication side effects. Sudden cessation of opioid analgesics near the end of life could precipitate withdrawal symptoms, and therefore, medications should not be stopped for increasing somnolence or slowed respirations. The principles of pharmacotherapy for pain and nonpain symptoms in the palliative care setting are outlined in Table 48-5. The World Health Organization, 3 4 the United States Agency for Health Care Policy and Research,6 3 the Academy of Hospice and Palliative Medicine,6 4 and many other agencies have endorsed a "step ladder" approach to cancer pain management that can predictably result in satisfactory pain control in most patients (Table 48-6). More refractory pain problems require additional expertise, and occasionally, more invasive approaches (Tables 48-7 and 48-8).

Table 48-5 Principles of Pharmacotherapy in Palliative Care Believe patient report of symptoms. Modify pathologic process when possible and appropriate. In terminally ill, avoid medications not directly linked to symptom control. Use a multidisciplinary approach. Consider nonpharmacologic approaches whenever possible. Engage participation of clinical pharmacist in treatment plan. Select drugs that can multitask (i.e., use haloperidol for agitated delirium and nausea). For pain, use adjuvant medications when possible (see Table 48-8). When using opioids, spare when possible (adjuvant medication, local or regional anesthetics, surgical interventions, etc.). Avoid fixed combination drugs. Avoid excessive cost. Select agents with minimum side effects. Anticipate and prophylax against side effects. For the elderly, the hypoproteinemic, the azotemic: "Start low and go slow." Oral route whenever possible and practical. No IM injections.

Scheduled dosing, not prn, for persistent symptoms. Stepwise approach. (See the World Health Organization Analgesic Ladder for pain. See Table 48-6.) Reassess continuously and titrate to effect. Use equianalgesic doses when changing opioids (see Table 48-6). Assess patient/family's comprehension of management plan.

Table 48-6 The World Health Organization Three-Step Ladder for Control of Cancer Pain34 Step 1 mild pain (visual analogue scale, 1–3) Nonopioid ± adjuvant medication Step 2 moderate pain (visual analogue scale, 4–6) Opioid for mild to moderate pain and nonopioid ± an adjuvant Step 3 severe pain (visual analogue scale, 7–10) Opioid for moderate to severe pain ± nonopioid ± an adjuvant

Table 48-7 Analgesics for Persistent Pain Drug

Initial Dosing (Adult, >60 kg)

Comments

Mild persistent pain, visual analogue scale (VAS) 1–3 Acetaminophen (Tylenol)

Maximum = 3200 mg/24 h

Use 60 kg)

Comments

5 mg PO q4h

Sold as single agent or compounded with aspirin or acetaminophen. Slow release form available (Oxycontin)

Severe persistent pain, VAS 7–10 Morphine

10 mg PO q2–4h2–4 mg IV q4h

Standard drug for comparison to alternative opioids. Avoid or caution when giving to the elderly, patients with diminished glomerular filtration rate, or liver disease. Slow release PO form available (MS Contin).

Hydromorphone

1–3 mg PO, PR q4h1 mg IV, SC q4h

Suppository form available Oral dose forms limited to 4 mg maximum

Fentanyl, transdermal Methadone

12 g/h patch q72h

Not for acute pain management. Do not use on opioid-naive patients. Absorption unpredictable in cachectic patients.

Consultation with pain management, clinical pharmacists, or palliative care/ hospice services skilled in methadone use is recommended for those inexperienced in prescribing methadone.

Not a first-line agent, although very effective, especially for pain with a neuropathic component Very inexpensive Can be given PO, IV, SC, PR, sublingually, and vaginally Its long half-life makes dosing more difficult than alternative opioids and close monitoring is required when initiating Numerous medications, alcohol, and cigarette smoking can alter its serum levels Physicians who write methadone prescriptions for pain should specify this indication. Methadone use for drug withdrawal treatment requires special licensure.

Risk factors for NSAID-induced nephropathy include: advanced age, decreased glomerular filtration rate, congestive heart failure, hypovolemia, pressors, hepatic dysfunction, concomitant nephrotoxic agents. Dose reduction and hydration reduce risk. Opioids compounded with aspirin or acetaminophen are limited to treatment of moderate persistent pain because of dose-limiting toxicities of acetaminophen and aspirin. Slow-release preparations of morphine and oxycodone may be given rectally. Timed-release tablets or patches should never be crushed or cut. Opioid analgesics are the agents of choice for severe cancer-related pain. Sedation is a common side effect when initiating opioid therapy. Tolerance to this usually develops within a few days. If sedation persists

beyond a few days, a stimulant (methylphenidate 2.5–5 mg PO bid) can be given. Initiate bowel stimulant prophylaxis for constipation when prescribing opioids unless contraindicated. Adjuvant or coanalgesic agents are drugs that enhance analgesic efficacy of opioids, treat concurrent symptoms that exacerbate pain, or provide independent analgesia for specific types of pain (e.g., a tricyclic antidepressant for treatment of neuropathic pain). Coanalgesics can be initiated for persistent pain at any visual analogue scale level. Gabapentin is commonly used as an initial agent for neuropathic pain. No place for meperidine (Demerol), propoxyphene [Darvon, Darvocet, or mixed agonist-antagonist agents (Stadol, Talwin)] in management of persistent pain. Always consider alternative approaches (axial analgesia, operative approaches, etc.) when managing severe persistent pain. NOTE: These are not recommendations for specific patients. The inter- and intraindividual variability to opioids requires individualizing dosing and titration to effect. Source: Adapted, with permission from Dunn GP: Surgical palliative care, in Cameron JL (ed): Current Surgical Therapy, 9th ed. Philadelphia: Elsevier, 2008. Copyright Elsevier.

Table 48-8 Examples of Adjuvant Medications for Treatment of Neuropathic, Visceral, and Bone Paina Drug Class

Initial Dosing (Adult, >60 kg)

Comments

Tricyclic antidepressants

Amitriptyline 10–25 mg PO qhs

Sedating properties may be useful for relief of other concurrent symptoms. Side effects may precede benefit. Avoid in the elderly due to anticholinergic side effects.

Best for continuous burning or tingling pain and allodynia

Efficacy for pain not due to antidepressant effect Dose generally less than that required for antidepressant effect

Nortriptyline Less 10–25 mg PO qd anticholinergic effect

Drug Class

Initial Dosing (Adult, >60 kg)

Dose titrated up every few days until effect. Pain may respond to alternative antidepressants if no response to initial agent.

Doxepin 10–25 mg PO qhs

Imipramine 10–25 mg PO qd

Anticonvulsants For shooting, stabbing pain

Comments

. Gabapentin 100–300 mg PO qd. Titrate up rapidly as needed. Max: 1800 mg qd

Commonly used first-line agent. Generally well tolerated. Does not require blood level monitoring.

Carbamazepine Effective. Well 200 mg PO q12h studied. Requires blood monitoring. Valproic acid 250 mg PO tid Local anesthetics

Lidocaine transdermal patch 5%. Apply Systemic use to painful areas. requires Max: 3 monitoring. simultaneous Nebulized local patches over 12 anesthetics h (each patch (lidocaine, contains 700 mg bupivacaine) can lidocaine). be used for severe, refractory cough.

Systemic toxicity can result from Lidocaine/prilocaine applying more topical. Apply to than painful areas. recommended Miscellaneous Bisphosphonates number per (pamidronate, unit time and in zoledronic acid) patients with liver failure. Effective for postherpetic neuralgia.

Calcitonin nasal spray Dexamethasone

For bone pain,

For bone pain and reduced incidence of skeletal complications secondary to malignancy—best results in myeloma and breast cancer. Contraindicated in renal failure. Refractory bone pain

Drug Class

Initial Dosing (Adult, >60 kg) Dexamethasone

Comments

Radionuclides (Sr-89)

For malignant bone pain secondary to osteoclastic activity. 4–6 wk delay in benefit. Requires adequate bone marrow reserve. For prognosis of more than 3 mo.

Octreotide

Reduces GI secretions that contribute to visceral pain

For bone pain, acute nerve compression, visceral pain secondary to tumor infiltration or luminal obstruction by reducing inflammatory component of tumor

aRecommendations

are based on experience of practitioners of hospice and palliative medicine and in some instances do not reflect current clinical trials. Source: Adapted, with permission from Dunn GP: Surgical palliative care, in Cameron JL (ed): Current Surgical Therapy, 9th ed. Philadelphia: Elsevier, 2008. Copyright Elsevier. The primary treatment of dyspnea (air hunger) in the dying is opioids, which should be cautiously titrated to increase comfort and reduce tachypnea to a range of 15 to 20 breaths/min. Air movement across the face generated by a fan can sometimes be quite helpful. If this is not effective, empiric use of supplemental O2 by nasal cannula (2 to 3 L/min) may bring some subjective relief, independent of observable changes in pulse oximetry. Supplemental O 2 should be humidified to avoid exacerbation of dry mouth. Typical starting doses of an immediate release opioid for breathlessness should be one half to two thirds of a starting dose of the same agent for cancer pain. For patients already on opioids for pain, a 25 to 50% increment in the dose of

the current immediate release agent for breakthrough pain often will be effective in relieving breathlessness in addition to breakthrough pain. The availability and variety of drugs should not prevent consideration of nonpharmacologic therapy. Massage therapy, music therapy, art therapy, guided imagery, hypnosis, physical therapy, pet therapy, and others play a constructive role not only for the relief of symptoms, but for promoting a sense of hope through improving function, aesthetic pleasure, and social connectedness. Talents and capacities neglected during the treatment and progression of disease can be recovered even in the most advanced stages of illness. Pain is often less of a problem in the last days of life because the reduced activity level is associated with lower incident pain. This, combined with lower renal clearance of opioids, may result in greater potency of the prescribed agents. Severe pain crises are fortunately rare, but when they are inadequately addressed, can cause great and lasting distress (complicated grief) for loved ones who witness the final hours or days of agony. Such situations may require continuous administration of parenteral opioids. As death approaches and patients become less verbal, it is important to assess pain frequently, including the use of close observation for nonverbal signs of distress (e.g., grimacing, increased respiratory rate). Adequate dosing of opioid analgesics may require alternate route(s) of administration as patients become more somnolent or develop swallowing difficulties. Opioids should not be stopped abruptly, even if the patient becomes nonresponsive because sudden withdrawal can cause severe distress.65,66 Cognitive failure at the end of life is manifested in most patients by increasing somnolence and delirium. Gradually increasing somnolence can be accompanied by periods of disorientation and mild confusion, and it may respond to the reassuring presence of loved ones and caregivers with minimal need for medications. A more distressing form of delirium also can develop, manifested by increasing agitation that may require the use of neuroleptic medications. Increasing amounts of opioids and/or benzodiazepines may exacerbate the delirium (especially in the elderly).

Pronouncing Death67 If the body is hypothermic or has been hypothermic, such as a drowning victim pulled from the water in the winter, the physician should not declare death until warming attempts have been made. In the hospital, hospice, or home setting, the declaration of death becomes part of the medical or legal record of the event. There are a number of physical signs of death a physician should look for in confirming the patient's demise: complete lack of responsiveness to verbal or tactile stimuli, absence of heart beat and respirations, fixed pupils, skin color change to a waxen hue as blood settles, gradual poikilothermia, and sphincter relaxation with loss of urine and feces. For deaths in the home with patients who have been enrolled in hospice, the hospice nurse on call should be contacted immediately. In some states, deaths at home may require a brief police investigation and report. For deaths in the hospital, the family must be notified (in person, if possible). A coroner or medical examiner may need to be contacted under specific circumstances (e.g., deaths in the operating room), but most deaths do not require their services. However, the pronouncing physician will need to complete a death certificate according to local regulations. Survivors may also be approached, if appropriate, regarding potential autopsy and organ donation. Finally, it is important to accommodate religious rituals that may be important to the dying patient or the family. Bereavement is the experience of loss by death of a person to whom one is attached. Mourning is the process of adapting to such a loss in the thoughts, feelings, and behaviors that one experiences after the loss. 6 8 Although grief and mourning are accentuated in the immediate period around death, it is important to note that patients and families may

begin the process of bereavement well before the time of death as patients and families grieve incremental losses of independence, vitality, and control. In addition to the surviving loved ones, it is important to acknowledge that caregivers also experience grief for the loss of their patients.69,70

PROFESSIONAL ETHICS: CONFLICT OF INTEREST, RESEARCH, AND CLINICAL ETHICS Conflict of Interest Conflicts of interest for surgeons can arise in many situations in which the potential benefits or gains to be realized by the surgeon are, or are perceived to be, in conflict with the responsibility to put the patient's interests before the surgeon's own. Conflicts of interest for the surgeon can involve actual or perceived situations in which the individual stands to gain monetarily by his or her role as a physician or investigator. In the academic community, monetary gain may not be the primary factor. Instead, motivators such as power, tenure, or authorship on a publication may serve as potential sources of conflict of interest. For example, the accrual of subjects in research studies or patients in surgical series may ensure surgeons better authorship or more financial gains. The dual-role of the surgeon-scientist therefore needs to be considered because the duty as surgeon can conflict with the role of scientist or clinical researcher.

Research Ethics Over the last three decades in the United States, the ethical requirements for the conduct of human subject research have been formalized and widely accepted. Although detailed informed consent is a necessary condition for the conduct of ethically good human subject research, other factors also determine whether research is designed and conducted ethically. Emanuel and colleagues7 1 described seven requirements for all clinical research studies to be ethically sound: (a) value—enhancement(s) of health or knowledge must be derived from the research; (b) scientific validity—the research must be methodologically rigorous; (c) fair subject selection—scientific objectives, not vulnerability or privilege, and the potential for and distribution of risks and benefits, should determine communities selected as study sites and the inclusion criteria for individual subjects; (d) favorable risk-benefit ratio—within the context of standard clinical practice and the research protocol, risks must be minimized, potential benefits enhanced, and the potential benefits to individuals and knowledge gained for society must outweigh the risks; (e) independent review—unaffiliated individuals must review the research and approve, amend, or terminate it; (f) informed consent—individuals should be informed about the research and provide their voluntary consent; and (g) respect for enrolled subjects—subjects should have their privacy protected, the opportunity to withdraw, and their well-being monitored.7 1

Special Concerns in Surgical Research A significant issue for clinical surgical research is that it is often analyzed in a retrospective manner and not commonly undertaken in a prospective double-blind, randomized fashion. For a randomized trial to be undertaken, the researchers should be in a state of equipoise—that is, there must be a state of genuine uncertainty on the part of the clinical investigator or the expert medical community regarding the comparative therapeutic merits of each arm in a trial.7 2 To randomize subjects to receive two different treatments, a researcher must believe that the existing data are not sufficient to conclude that one treatment strategy is better than another. In designing surgical trials, surgeons usually have biases that one treatment is better than another and often have difficulty maintaining the state of equipoise. As such, it is

frequently difficult to demonstrate that a randomized trial is necessary or feasible, and treatment options that question the validity of clinical tenets are difficult to accept. Meakins has suggested that a slightly different hierarchy of evidence applies to evidence-based surgery.7 3 A second major issue for surgical trials is whether it is ethically acceptable to have a placebo-controlled surgical trial. Some commentators have argued that sham surgery is always wrong because, unlike a placebo medication that is harmless, every surgical procedure carries some risk.7 4 Others have argued that sham operations are essential to the design of a valid randomized clinical trial because, without a sham operation, it is not possible to know if the surgical intervention is the cause of improvement in patient symptoms or whether the improvement is due to the effect of having surgery.75,76 Most surgeons readily agree that designing an appropriately low-risk sham surgical procedure would create problems for the surgeon-patient relationship in that the surgeon would need to keep the sham a secret.7 7 In this sense, a sham surgical arm of a trial is very different from a placebo medication in that there cannot be blinding of the surgeon as to which procedure was undertaken. As a result, to have a sham surgery arm in a clinical trial, the interactions between the surgeon and the subject must be limited and the surgeon performing the procedure should not be the researcher who follows the subject during the trial. Despite difficulties with designing a surgical trial in which the surgeon could ethically perform a sham operation, there are specific circumstances that allow for placebo operations to be conducted, so long as certain criteria are met and are analyzed on a case by case basis.78,79

Surgical Innovation and Surgical Research An important issue is whether surgical innovation should be treated as research or as standard of care. Many of the advances in surgical technique and surgical technology have resulted from the innovations that individual surgeons have discovered or created during the course of challenging operations. As every patient is different and the surgeon is always trying to determine the best way to complete an operation, innovations have developed that have often moved the field of surgery forward.8 0 In the Korean and Vietnam wars, the military guidelines for the treatment of vascular injuries recommended ligation and amputation rather than interposition grafting of vascular injuries. Individual surgeons chose to ignore those guidelines and subsequently demonstrated the value of reconstructive techniques that ultimately became the standard of care. It is debated whether modifications in an accepted surgical technique based on the circumstances of an individual patient and the skill and judgment of an individual surgeon should require the same type of prior approval that enrollment in a clinical trial would warrant.8 1 However, if a surgeon decides to use a new technique on several occasions and to study the outcomes, Institutional Review Board approval and all other ethical requirements for research are necessary. These situations require strict oversight as well as explicit consent by the patient.8 2 In particular, when developing new and innovative techniques, the surgeon should work in close consultation with his or her senior colleagues, including the chairperson of the department. Frequently, more senior individuals can provide sage ethical advice regarding what constitutes minor innovative changes in a technique vs. true novel research. When compared to the formalized process for new drug approval by the Food and Drug Administration, the process for a surgeon developing an innovative operation is relatively unregulated and unsupervised.

Clinical Ethics: Disclosure of Errors Disclosure of error—either in medical or research matters—is important, but often difficult (see Chap. 12). Errors of judgment, errors in technique, and system errors are responsible for most errors that result in

complications and deaths. Hospitals are evaluated based on the number of complications and deaths that occur in surgical patients, and surgeons traditionally review their complications and deaths in a formal exercise known as the mortality and morbidity conference, or M&M. The exercise places importance on the attending surgeon's responsibility for errors made, whether he or she made them themselves, and the value of the exercise is related to the effect of "peer pressure"—the entire department knows about the case—on reducing repeated occurrences of such an error. Although a time-honored ritual in surgery, the M&M conference is nonetheless a poor method for analyzing causes of error and for developing methods to prevent them. Moreover, the proceedings of the M&M conference are protected from disclosure by the privilege of "peer review," and the details are rarely shared with patients or those outside of the department. A report from the United States Institute of Medicine titled "To Err Is Human" highlighted the large number of medical errors that occur and encouraged efforts to prevent patient harm. 8 3 Medical errors are generally considered to be "preventable adverse medical events."8 4 Given that medical errors clearly occur with some frequency, the question becomes what and how should patients be told of medical errors and what is the surgeon's ethical responsibility for this disclosure.8 5 Disclosure of error is consistent with the ethical tenets of openness with patients and the involvement of patients in their care. In contrast, failing to disclose errors to patients undermines public trust in medicine and potentially compromises the treatment of the consequences of errors. In addition, failure to self-disclose medical errors can be construed as a breach of professional ethics, as it is a failure to act solely for the patient's best interests. Patients require information regarding medical errors so that additional harm can be avoided. In addition, information regarding a medical error may be needed so that patients can make independent and well-informed decisions about future aspects of their care. The principles of autonomy and justice dictate that surgeons need to respect individuals by being fair in providing accurate information about all aspects of their care—even the medical errors. Disclosing one's own errors is therefore part of the ethical standard of honesty and putting the patient's interests above one's own. Disclosing the errors of others is more complicated and may require careful consideration and consultation. Surgeons sometimes discover that a prior operation has included an apparent error; an injured bile duct or a stenotic anastomosis may lead to the condition for which the surgeon is now treating the patient. Declaring a finding as an "error" may be inaccurate, however, and a nonjudgmental assessment of the situation is usually advisable. When clear evidence of a mistake is at hand, the surgeon's responsibility is defined by his or her obligation to act as the patient's agent.

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19. Williams MA, Lipsett PA, Rushton CH, et al: The physician's role in discussing organ donation with families. Crit Care Med 31:1568, 2003. [PMID: 12771634] 20. Pearson IY, Zurynski Y: A survey of personal and professional attitudes of intensivists to organ donation and transplantation. Anaesth Intensive Care 23:68, 1995. [PMID: 7778751] 21. Sulmasy DP, Lehmann LS, Levine DM, et al: Patients' perceptions of the quality of informed consent for common medical procedures. J Clin Ethics 5:189, 1994. [PMID: 7857407] 22. Ubel PA, Loewenstein G, Jepson C: Whose quality of life? A commentary exploring discrepancies between health state evaluations of patients and the general public. Qual Life Res 12:599, 2003. [PMID: 14516169] 23. Schneider CE: After autonomy. Wake Forest Law Review 41:411, 2006. 24. Sulmasy DP, Terry PB, Weisman CS, et al: The accuracy of substituted judgments in patients with terminal diagnoses. Ann Intern Med 128:621, 1998. [PMID: 9537935] 25. Sulmasy DP, Hughes MT, Thompson RE, et al: How would terminally ill patients have others make decisions for them in the event of decisional incapacity? A longitudinal study. J Am Geriatr Soc 55:1981, 2007. [PMID: 18031490] 26. SUPPORT Principle Investigators. A controlled trial to improve care for seriously ill hospitalized patients. The study to understand prognoses and preferences for outcomes and risks of treatments (SUPPORT). The SUPPORT Principal Investigators. JAMA 274:1591, 1995. 27. Pawlik TM: Withholding and withdrawing life-sustaining treatment: A surgeon's perspective. J Am Coll Surg 202:990, 2006. [PMID: 16735214] 28. In re Quinlan. 355 A2d 647 (JN). Vol 429 US 9221976. 29. Cruzan vs. Director, Missouri Dept of Health, 497(1990). 30. Annas GJ: Nancy Cruzan and the right to die. N Engl J Med 323:670, 1990. [PMID: 2385271] 31. Sykes N, Thorns A: The use of opioids and sedatives at the end of life. Lancet Oncol 4:312, 2003. [PMID: 12732169] 32. Nelson KA, Walsh D, Behrens C, et al: The dying cancer patient. Semin Oncol 27:84, 2000. [PMID: 10697024] 33. Doyle D, Hanks G: Introduction, in Oxford Textbook of Palliative Medicine, 3rd ed. New York: Oxford University Press, 2004.

34. www.who.int/cancer/palliative/definition/en/print.html: WHO Definition of Palliative Care, 2008, World Health Organization [accessed March 25, 2009]. 35. Dunn G: Surgical palliative care, in Mosby (ed): Current Surgical Therapy, 9th ed. Philadelphia: Elsevier, 2008. 36. Saunders C: The challenge of terminal care, in Symington T, Carter R (eds): Scientific Foundations of Oncology. London: Heineman, 1976 p 673. 37. Billroth T: Open letter to Dr. L Wittleshöfer. Wiener Medizinische Wochenschrift 31:162, 1881. 38. Whipple A: Present day surgery of the pancreas. N Engl J Med 226:515, 1942. 39. Aub JC, Beecher HK, Cannon B, et al: Management of the Coconut Grove Burns at the Massachusetts General Hospital. Philadelphia, PA: JB Lippincott Co, 1943. 40. Dunphy JE: Annual discourse—on caring for the patient with cancer. N Engl J Med 295:313, 1976. [PMID: 934211] 41. Zimmerman J: Hospice—Complete Care for the Terminally Ill. Baltimore: Urban and Schwarzenberg, 1981. 42. Nuland S: How We Die: Reflections on Life's Final Chapter. New York: Alfred A. Knopf, 1994. 43. Chen P: Final Exam. New York: Alfred K. Knopf, 2007. 44. Task Force on Surgical Palliative Care, Committee on Ethics: Statement of principles of palliative care. Bull Am Coll Surg 90:34, 2005. 45. American College of Surgeons: Principles guiding care at end of life. Bull Am Coll Surg 83:46, 1998. 46. Surgeons Palliative Care Workgroup: Report from the Field. J Am Coll Surg 197:661, 2003. 47. Cancer pain relief and palliative care. Report of a WHO Expert Committee. World Health Organ Tech Rep Ser 804:1, 1990. 48. American Board of Internal Medicine Committee on Evaluation of Clinical Competence. Caring for the Dying: Identification and Promotion of Physician Competency—Education Resource Document. Philadelphia: American Board of Internal Medicine, 1996. 49. Storey P, Knight C: UNIPAC One: The Hospice/Palliative Medicine Approach to End-of-Life Care. American Academy of Hospice and Palliative Medicine. Dubuque, IA: Kendall/Hunt Publishing Co, 1998.

50. Kleinman A: The Illness Narratives. Suffering, Healing & the Human Condition. New York: Basic Books, 1988. 51. International Association for the Study of Pain, Subcommittee on Taxonomy. Part II. Pain Terms: A current list with definitions and notes on usage. Pain 6:249, 1979. 52. Cassell E: The Nature of Suffering and the Goals of Medicine. New York: Oxford University, 1991. 53. Frankl V: Man's Search for Meaning. New York: Washington Square Press, 1985. 54. Brody H: "My story is broken; can you help me fix it?" Medical ethics and the joint construction of narrative. Lit Med 13:79, 1994. [PMID: 8007732] 55. Byock IR, Merriman MP: Measuring quality of life for patients with terminal illness: The Missoula-VITAS quality of life index. Palliat Med 12:231, 1998. [PMID: 9743822] 56. Christakis NA, Lamont EB: Extent and determinants of error in doctors' prognoses in terminally ill patients: Prospective cohort study. BMJ 320:469, 2000. [PMID: 10678857] 57. Anderson F, Downing GM, Hill J, et al: Palliative performance scale (PPS): A new tool. J Palliat Care 12:5, 1996. [PMID: 8857241] 58. Morita T, Tsunoda J, Inoue S, et al: Validity of the palliative performance scale from a survival perspective. J Pain Symptom Manage 18:2, 1999. [PMID: 10439564] 59. Buckman R: How to Break Bad News. A Guide for Health Care Professionals. Baltimore: Johns Hopkins University Press, 1992. 60. Kubler-Ross E: On Death and Dying. London: Routledge, 1973. 61. Twycross R, Lichter I: The terminal phase, in Doyle D, Hanks G, MacDonald N (eds): Oxford Textbook of Palliative Medicine. New York, NY: Oxford University Press, 1998, p 977. 62. Hinshaw DB: Spiritual issues in surgical palliative care. Surg Clin North Am 85:257, 2005. [PMID: 15833470] 63. Jacox A, Carr D, Payne R, et al: Management of cancer pain. AHCPR Publication No. 94-052: Clinical Practice Guideline No. 9. Rockville, MD: US Department of Health and Human Services, Public Health Service, 1994. 64. Storey P, Knight C: UNIPAC Three: Assessment and Treatment of Pain in the Terminally Ill, 2nd ed. New York, NY: Mary Ann Liebert, Inc, 2003.

65. Rubenfeld GD, Crawford SW: Principles and practice of withdrawing life-sustaining treatment in the ICU, in Curtis JR, Rubenfeld GD (eds): Managing Death in the Intensive Care Unit. New York: Oxford University Press, 2001. 66. Rousseau P: Existential distress and palliative sedation. Anesth Analg 101:611, 2005. [PMID: 16037198] 67. The EPEC-O Project, Educating Physicians in End-of-Life Care-Oncology: Module 6: Last Hours of Living. Bethesda, MD: National Cancer Institute, 2007. 68. Worden J: Bereavement Care. Philadelphia: Lippincott Williams and Wilkins, 2002. 69. Bishop JP, Rosemann PW, Schmidt FW: Fides ancilla medicinae: On the ersatz liturgy of death in biopsychosociospiritual medicine. The Heythrop Journal 49:20, 2008. 70. Schroeder-Sheker T: Transitus: A Blessed Death in the Modern World. Mt. Angel, Oregon: St. Dunstan's Press, 2001. 71. Emmanuel EJ, Wendler D, Grady C: What makes clinical research ethical? JAMA 283:2701, 2000. 72. Freedman B: Equipoise and the ethics of clinical research. N Engl J Med 317:141, 1987. [PMID: 3600702] 73. Meakins J: Innovation in surgery: The rules of evidence. Am J Surg 183:399, 2002. [PMID: 11975927] 74. Lefering R, Neugebauer E: Problems of randomized controlled trials in surgery. Paper presented at: Nonrandomized Comparative Clinical Studies 1997, Heidelberg. 75. Flum DR: Interpreting surgical trials with subjective outcomes: Avoiding UnSPORTsmanlike conduct. JAMA 296:2483, 2006. [PMID: 17119146] 76. Moseley JB, O'Malley K, Petersen NJ, et al: A controlled trial of arthroscopic surgery for osteoarthritis of the knee. N Engl J Med 347:81, 2002. Summary for patients in: J Fam Pract 51:813, 2002. 77. Angelos PA: Sham surgery in research: A surgeon's view. Am J Bioeth 3:65, 2003. [PMID: 14744340] 78. Miller FG: Sham surgery: An ethical analysis. Sci Eng Ethics 10:157, 2004. [PMID: 14986782] 79. Angelos P: Sham surgery in clinical trials. JAMA 297:1545; author reply 1546, 2007. 80. Riskin DJ, Longaker MT, Gertner M, et al: Innovation in surgery: A historical perspective. Ann Surg 244:686, 2006. [PMID: 17060760] 81. Biffl WL, Spain DA, Reitsma AM, et al: Responsible development and application of surgical innovations: A position statement of the Society of University Surgeons (draft statement of 2/19/08).

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CHAPTER 1 5. http://www.acgme.org/acWebsite/downloads/RRC_progReq/440generalsurgery01012008.pdf: ACGME Program Requirements for Graduate Medical Education in Surgery, 2007, Accreditation Council for Graduate Medical Education [accessed January 15, 2008]. 14. Scott DJ, Dunnington GL: New ACS/APDS skills curriculum: Moving the learning curve out of the operating room. J Gastrointest Surg 12:213, 2008. Epub October 10, 2007. 17. Dunnington GL, Williams RG: Addressing the new competencies for residents' surgical training. Acad Med 78:14, 2003. [PMID: 12525404] 93. http://www.acgme.org/acwebsite/portfolio/cbpac_faq.pdf: ACGME Learning Portfolio: A Professional Development Tool, 2008, Accreditation Council for Graduate Medical Education [accessed June 18, 2008].

CHAPTER 2 2. Lowry SF: Human endotoxemia: A model for mechanistic insight and therapeutic targeting. Shock 24 Suppl 1:94, 2005. 3. Borovikova LV, Ivanova S, Zhang M, et al: Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405:458, 2000. [PMID: 10839541] 8. Dellinger RP, Levy MM, Carlet JM, et al: Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 36:296, 2008. [PMID: 18158437] 41. Agnese DM, Calvano JE, Hahm SJ, et al: Human toll-like receptor 4 mutations but not CD14 polymorphisms are associated with an increased risk of gram-negative infections. J Infect Dis 186:1522, 2002. [PMID: 12404174] 82. Lowry SF: A new model of nutrition influenced inflammatory risk. J Am Coll Surg 205(4 Suppl):S65, 2007.

CHAPTER 3 29. Lucas CE: The water of life: A century of confusion. J Am Coll Surg 192:86, 2001. [PMID: 11192929] 42. Shires GT, Williams J, Brown F: Acute changes in extracellular fluids associated with major surgical procedures. Ann Surg 154:803, 1961. [PMID: 13912109] 43. Shires GT, Jackson DE: Postoperative salt tolerance. Arch Surg 84:703, 1962. [PMID: 13912108] 44. Shires GT III, Peitzman AB, Albert SA, et al: Response of extravascular lung water to intraoperative fluids. Ann Surg 197:515, 1983. [PMID: 6847271]

CHAPTER 4 7. Baldwin ZK, Spitzer AL, Ng VL, et al: Contemporary standards for the diagnosis and treatment of heparininduced thrombocytopenia (HIT). Surgery 143:305, 2008. [PMID: 18291250] 23. Brohi K, Cohen MJ, Ganter MT, et al: Acute coagulopathy of trauma: Hypoperfusion induces systemic anticoagulation and hyperfibrinolysis. J Trauma 64:1211, 2008. [PMID: 18469643] 34. Kearon C, Hirsh J: Management of anticoagulation before and after elective surgery. N Engl J Med 336:1506, 1997. [PMID: 9154771] 57. Herbert PC, Wells GW, Blajchman MA, et al: A multicenter, randomized, controlled clinical trial of transfusion requirement in critical care. N Engl J Med 340:409, 1999. 73. Holcomb JB, Wade CE, Michalek JE, et al: Increased plasma and platelet to RBC ratios improve outcome in 466 massively transfused civilian trauma patients. Ann Surg 248:447, 2008. [PMID: 18791365]

CHAPTER 5 20. Nathan C: Points of control in inflammation. Nature 420:846, 2002. [PMID: 12490957] 62. Holcomb JB: Damage control resuscitation. J Trauma 62(6 Suppl):S36, 2007. 71. Borgman MA, Spinella PC, Perkins JG, et al: The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat support hospital. J Trauma 63:805, 2007. [PMID: 18090009] 78. Dellinger RP, Levy MM, Carlet JM, et al: Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock. Crit Care Med 36:296, 2008. [PMID: 18158437]

CHAPTER 6 28. Chastre J, Wolff M, Fagon JY, et al: Comparison of 8 vs 15 days of antibiotic therapy for ventilatorassociated pneumonia in adults: A randomized trial. JAMA 290:2588, 2003. [PMID: 14625336] 30. Stone HH, Bourneuf AA, Stinson LD: Reliability of criteria for predicting persistent or recurrent sepsis. Arch Surg 120:17, 1985. [PMID: 3966872] 57. Solomkin JS, Mazuski JE, Baron EJ, et al: Infectious Diseases Society of America: Guidelines for the selection of anti-infective agents for complicated intra-abdominal infections. Clin Infect Dis 37:997, 2003. [PMID: 14523762] 66. Nathens AB, Curtis JR, Beale RJ, et al: Management of the critically ill patient with severe acute pancreatitis. Crit Care Med 32:2524, 2004. [PMID: 15599161] 87. Dellinger RP, Levy MM, Carlet JM, et al: Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 36:296, 2008. [PMID: 18158437]

CHAPTER 7 3. Feliciano DV, Mattox KL, Moore EE (eds): Trauma, 6th ed. New York: McGraw-Hill, 2008. 6. American College of Surgeons: Advanced Trauma Life Support, 7th ed. Chicago: American College of Surgeons, 2004. 13. Brain Trauma Foundation, American Association of Neurological Surgeons, Congress of Neurological Surgeons: Guidelines for the management of severe traumatic brain injury. J Neurotrauma 24(Suppl):S1, 2007.

CHAPTER 8

1. Baxter CR, Shires T: Physiological response to crystalloid resuscitation of severe burns. Ann N Y Acad Sci 150:874, 1968. [PMID: 4973463] 5. Klein MB, Nathens AB, Emerson D, et al: An analysis of the long-distance transport of burn patients to a regional burn center. J Burn Care Res 28:49, 2007. [PMID: 17211200] 41. Friedrich JB, Sullivan SR, Engrav LH, et al: Is supra-Baxter resuscitation in burn patients a new phenomenon? Burns 30:464, 2004. [PMID: 15225912] 95. Curreri PW, Richmond D, et al: Dietary requirements of patients with major burns. J Am Diet Assoc 65:415, 1974. [PMID: 4213656] 118. Engrav LH, Heimbach DM, Reus JL, et al: Early excision and grafting vs. nonoperative treatment of burns of indeterminant depth: A randomized prospective study. J Trauma 23:1001, 1983. [PMID: 6355500]

CHAPTER 9 40. Thornton FJ, Barbul A: Healing in the gastrointestinal tract. Surg Clin North Am 77:549, 1997. [PMID: 9194880] 86. Hopf HW, Ueno C, Aslam R, et al: Guidelines for the treatment of arterial insufficiency ulcers. Wound Repair Regen 14:693, 2006. [PMID: 17199834] 87. Hopf HW, Ueno C, Aslam R, et al: Guidelines for the prevention of lower extremity arterial ulcers. Wound Repair Regen 16:175, 2008. [PMID: 18318803] 88. Robson MC, Cooper DM, Aslam R, et al: Guidelines for the treatment of venous ulcers. Wound Repair Regen 14:649, 2006. [PMID: 17199831] 89. Flour M: Venous ulcer management: Has research led to improved healing for the patient? in Cherry G (ed): The Oxford European Wound Healing Course Handbook. Oxford: Positif Press, 2002, p 33. 91. Steed DL, Attinger C, Colaizzi T, et al: Guidelines for treatment of diabetic ulcers. Wound Repair Regen 14:680, 2006. [PMID: 17199833] 94. Steed DL, Attinger C, Brem H, et al: Guidelines for the prevention of diabetic ulcers. Wound Repair Regen 16:169, 2008. [PMID: 18318802] 95. Whitney J, Phillips L, Aslam R, et al: Guidelines for the treatment of pressure ulcers. Wound Repair Regen 14:663, 2006. [PMID: 17199832] 96. Eaglstein WH, Falanga V: Chronic wounds. Surg Clin North Am 77:689, 1997. [PMID: 9194887]

101. Mustoe TA: Evolution of silicone therapy and mechanism of action in scar management. Aesthetic Plast Surg 32:82, 2008. [PMID: 17968615]

CHAPTER 10 1. Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2007. CA Cancer J Clin 57:43, 2007. [PMID: 17237035] 4. Hanahan D, Weinberg RA: The hallmarks of cancer. Cell 100:57, 2000. [PMID: 10647931] 6. Fearon ER, Vogelstein B: A genetic model for colorectal tumorigenesis. Cell 61:759, 1990. [PMID: 2188735] 70. http://monographs.iarc.fr/ENG/Classification/index.php: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Complete List of Agents Evaluated and Their Classification, International Agency for Research on Cancer (IARC) [accessed January 16, 2008]. 74. http://monographs.iarc.fr/ENG/Classification/crthgr01.php: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Overall Evaluations of Carcinogenicity to Humans: Group 1: Carcinogenic to Humans, International Agency for Research on Cancer (IARC) [accessed January 16, 2008]. 83. Smith RA, Cokkinides V, Brawley OW. Cancer screening in the United States, 2009: a review of current American Cancer Society guidelines and issues in cancer screening. CA Cancer J Clin 59:27, 2009. Review.

CHAPTER 11 6. Murray JE, Merrill JP, Harrison JH, et al: Prolonged survival of human-kidney homografts by immunosuppressive drug therapy. N Engl J Med 268:1315, 1963. [PMID: 13936775] 15. Matas AJ, Kandaswamy R, Gillingham K, et al: Prednisone free maintenance immunosuppression—a 5 year experience. Am J Transplant 5:2473, 2005. [PMID: 16162197] 59. Sutherland DE, Gruessner RW, Dunn DL, et al: Lessons learned from more than 1000 pancreas transplants at a single institution. Am Surg 233:463, 2001. [PMID: 11303130] 62. Freeman RB Jr., Wiesner RH, Roberts JP, et al: Improving liver allocation: MELD and PELD. Am J Transplant 4 Suppl 9:114, 2004. 95. Patel R, Paya CV: Infections in solid-organ transplant recipients: Clin Microbiol Rev 10:86, 1997. [PMID: 8993860]

CHAPTER 12 3. Kohn KT, Corrigan JM, Donaldson MS: To Err Is Human: Building a Safer Health System. Washington, DC: National Academy Press, 1999. 17. Christian CK, Gustafson ML, Roth EM, et al: A prospective study of patient safety in the operating room. Surgery 139:159, 2006. [PMID: 16455323] 18. Makary MA, Sexton JB, Freischlag JA, et al: Operating room teamwork among physicians and nurses: Teamwork in the eye of the beholder. J Am Coll Surg 202:746, 2006. [PMID: 16648014] 20. Makary MA, Mukherjee A, Sexton JB, et al: Operating room briefings and wrong-site surgery. J Am Coll Surg 204:236, 2007. [PMID: 17254927] 41. Michaels RK, Makary MA, Dahab Y, et al: Achieving the National Quality Forum's "Never Events": Prevention of wrong site, wrong procedure, and wrong patient operations. Ann Surg 245:526, 2007. [PMID: 17414599] 113. Van den Berghe G, Wouters P, Weekers F, et al: Intensive insulin therapy in the critically ill patients. N Engl J Med 345:1359, 2001.

CHAPTER 13 13. Gattinoni L, Brazzi L, Pelosi P, et al: A trial of goal-oriented hemodynamic therapy in critically ill patients. SVo2 Collaborative Group. N Engl J Med 333:1025, 1995. [PMID: 7675044] 15. Rivers EP, Ander DS, Powell D: Central venous oxygen saturation monitoring in the critically ill patient. Curr Opin Crit Care 7:204, 2001. [PMID: 11436529] 30. Shah MR, Hasselblad V, Stevenson LW, et al: Impact of the pulmonary artery catheter in critically ill patients: Meta-analysis of randomized clinical trials. JAMA 294:1664, 2005 [PMID: 16204666] 35. Shoemaker WC, Appel PL, Kram HB, et al: Prospective trial of supranormal values of survivors as therapeutic goals in high-risk surgical patients. Chest 94:1176, 1988. [PMID: 3191758] 76. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 342:1301, 2000.

CHAPTER 14 80. Marescaux J, Dallemagne B, Perretta S, et al: Surgery without scars: Report of transluminal cholecystectomy in a human being. Arch Surg 142:823; discussion 826, 2007. 88. Fleshman J, Sargent DJ, Green E, for The Clinical Outcomes of Surgical Therapy Study Group: Laparoscopic colectomy for cancer is not inferior to open surgery based on 5-year data from the COST Study Group trial. Ann Surg 246:655; discussion 662, 2007. 89. Fried GM, Clas D, Meakins JL: Minimally invasive surgery in the elderly patient. Surg Clin North Am 74:375, 1994. [PMID: 8165473] 95. Anvari M: Telesurgery: Remote knowledge translation in clinical surgery. World J Surg 31:1545, 2007. [PMID: 17534550]

CHAPTER 15 1. Alberts B, Johnson A, Lewis J, et al: Molecular Biology of the Cell, 4th ed. New York: Garland Science, 2002. 2. Watson JD, Crick FH: Molecular structure of nucleic acids; a structure for deoxyribose nucleic acid. Nature 171:737, 1953. [PMID: 13054692] 5. Wolfsberg TG, Wetterstrand KA, Guyer MS, et al: A user's guide to the human genome. Nature Genetics Supplement, 2002. (Also see the Nature website: http://www.nature.com/nature/supplements/collections/humangenome/.) 22. Mullis K, Faloona F, Scharf S, et al: Specific enzymatic amplification of DNA in vitro: The polymerase chain reaction. Cold Spring Harb Symp Quant Biol 51:263, 1986. [PMID: 3472723] 26. Hannon GJ: RNAi, A Guide To Gene Silencing. New York: Cold Spring Harbor Laboratory Press, 2003.

CHAPTER 16 3. Nemes Z, Steinert PM: Bricks and mortar of the epidermal barrier. Exp Mol Med 31:5, 1999. [PMID: 10231017] 60. Marler JJ, Mulliken JB: Vascular anomalies: Classification, diagnosis, and natural history. Facial Plast Surg Clin North Am 9:495, 2001. [PMID: 17590938] 74. Balch CM, Buzaid AC, Soong SJ, et al: Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 16:3635, 2001.

CHAPTER 17 71. Saslow D, et al: American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin 57:75, 2007. [PMID: 17392385] 99. Breast, in Greene FL, et al (eds): AJCC Cancer Staging Manual, 6th ed. New York: Springer-Verlag, 2002, p 223. 128. Paik S, et al: A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351:2817, 2004. [PMID: 15591335] 136. Effects of radiotherapy and surgery in early breast cancer. An overview of the randomized trials. Early Breast Cancer Trialists' Collaborative Group. N Engl J Med 333:1444, 1995. 160. Krag DN, et al: Technical outcomes of sentinel-lymph-node resection and conventional axillary-lymphnode dissection in patients with clinically node-negative breast cancer: Results from the NSABP B-32 randomised phase III trial. Lancet Oncol 8:881, 2007. [PMID: 17851130] 201. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 365:1687, 2005.

CHAPTER 18 8. Lanza DC, Kennedy DW: Adult rhinosinusitis defined. Otolaryngol Head Neck Surg 117:S1, 1997. 66. Wolf GT, Hong WK, Fischer SG, et al: Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med 324:1685, 1991. 80. Eicher SA, Weber RS: Surgical management of cervical lymph node metastases. Curr Opin Oncol 8:215, 1996. [PMID: 8804818] 90. Urken ML, Buchbinder D, Costantino PD, et al: Oromandibular reconstruction using microvascular composite flaps: Report of 210 cases. Arch Otolaryngol Head Neck Surg 124:46, 1998. [PMID: 9440780]

CHAPTER 19 13. Swanson SJ, Herndon JE 2nd, D'Amico TA, et al: Video-assisted thoracic surgery lobectomy: Report of CALGB 39802—a prospective, multi-institution feasibility study. J Clin Oncol 25:4993, 2007. [PMID: 17971599] 14. Demmy TL, James TA, Swanson SJ, et al: Troubleshooting video-assisted thoracic surgery lobectomy. Ann Thorac Surg 79:1744; discussion 1753, 2005. 48. Colice GL, Shafazand S, Griffin JP, et al: Physiologic evaluation of the patient with lung cancer being considered for resectional surgery: ACCP evidenced-based clinical practice guidelines (2nd edition). Chest 132(3 Suppl):161S, 2007. 52. Groome PA, Bolejack V, Crowley JJ, et al: The IASLC Lung Cancer Staging Project: Validation of the proposals for revision of the T, N, and M descriptors and consequent stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol 2:694, 2007. [PMID: 17762335] 85. Ilowite J, Spiegler P, Chawla S: Bronchiectasis: New findings in the pathogenesis and treatment of this disease. Curr Opin Infect Dis 21:163, 2008. [PMID: 18317040] 179. Tremblay A, Michaud G: Single-center experience with 250 tunnelled pleural catheter insertions for malignant pleural effusion. Chest 129:362, 2006. [PMID: 16478853]

CHAPTER 20 20. Kouchoukos NT, Blackstone EH, Doty DB, et al: Congenital aortic stenosis, in Kouchoukos NT, Blackstone EH, Doty DB, et al (eds): Kirklin/Barrat-Boyes Cardiac Surgery, 3rd ed. Philadelphia: Churchill Livingstone, 2003, p 1269 27. Ross DN: Replacement of aortic and mitral valves with a pulmonary autograft. Lancet 57:956, 1967 52. Karamlou T, Bernasconi A, Jaeggi E, et al: Factors associated with arch reintervention and growth of the aortic arch after coarctation repair in neonates weighing less than 2.5 kg. J Thorac Cardiovasc Surg, 2009 (in press). 57. McCrindle BW, Jones TK, Morrow WR, et al: Acute results of balloon angioplasty of native coarctation versus recurrent aortic obstruction are equivalent. Valvuloplasty and Angioplasty of Congenital Anomalies (VACA) Registry Investigators. J Am Coll Cardiol 28:1810, 1996. [PMID: 8962571] 83. Karamlou T, Gurofsky R, Al Sukhni E, et al: Factors associated with mortality and reoperation in 377 children with total anomalous pulmonary venous connection. Circulation 115:1591, 2007. [PMID: 17353446]

95. deLeval MR, Kilner P, Gerwillig M, et al: Total cavopulmonary connection: A logical alternative to atriopulmonary connection for complex Fontan operations. J Thorac Cardiovasc Surg 96:682, 1988 148. Karamlou T, McCrindle BW, Williams WG: Surgery insight: Late complications following repair of tetralogy of Fallot and related surgical strategies for management. Nature Cardiovasc Med 3:611, 2006. [PMID: 17063166]

CHAPTER 21 1Libby P. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 8th ed. Philadelphia: Saunders Elsevier, 2007. 7. Eleven-year survival in the Veterans Administration randomized trial of coronary bypass surgery for stable angina. The Veterans Administration Coronary Artery Bypass Surgery Cooperative Study Group. N Engl J Med 311:1333, 1984. 13. Comparison of coronary bypass surgery with angioplasty in patients with multivessel disease. The Bypass Angioplasty Revascularization Investigation (BARI) Investigators. N Engl J Med 335:217, 1996. 17. Hannan EL, Racz MJ, Walford G, et al: Long-term outcomes of coronary-artery bypass grafting versus stent implantation. N Engl J Med 352:2174, 2005. [PMID: 15917382] 33. Jamieson WR, von Lipinski O, Miyagishima RT, et al: Performance of bioprostheses and mechanical prostheses assessed by composites of valve-related complications to 15 years after mitral valve replacement. J Thorac Cardiovasc Surg 129:1301, 2005. [PMID: 15942570] 40. Carpentier A. Cardiac valve surgery--the "French correction." J Thorac Cardiovasc Surg 86:323, 1983. [PMID: 6887954] 41. Bonow RO, Carabello BA, Kanu C, et al: ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): Developed in collaboration with the Society of Cardiovascular Anesthesiologists: Endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. Circulation 114:e84, 2006. 50. Mohty D, Orszulak TA, Schaff HV, et al: Very long-term survival and durability of mitral valve repair for mitral valve prolapse. Circulation 104:I1, 2001. 85. Acker MA, Bolling S, Shemin R, et al: Mitral valve surgery in heart failure: Insights from the Acorn Clinical Trial. J Thorac Cardiovasc Surg 132:568, 577.e1, 2006.

89. Athanasuleas CL, Stanley AW Jr., Buckberg GD, et al: Surgical anterior ventricular endocardial restoration (SAVER) in the dilated remodeled ventricle after anterior myocardial infarction. RESTORE group. Reconstructive Endoventricular Surgery, returning Torsion Original Radius Elliptical Shape to the LV. J Am Coll Cardiol 37:1199, 2001. [PMID: 11300423] 96. Rose EA, Gelijns AC, Moskowitz AJ, et al: Long-term mechanical left ventricular assistance for end-stage heart failure. N Engl J Med 345:1435, 2001. [PMID: 11794191]

CHAPTER 22 1. Johnston KW, Rutherford RB, Tilson MD, et al: Suggested standards for reporting on arterial aneurysms. Subcommittee on Reporting Standards for Arterial Aneurysms, Ad Hoc Committee on Reporting Standards, Society for Vascular Surgery and North American Chapter, International Society for Cardiovascular Surgery. J Vasc Surg 13:452, 1991. [PMID: 1999868] 2. Bickerstaff LK, Pairolero PC, Hollier LH, et al: Thoracic aortic aneurysms: A population-based study. Surgery 92:1103, 1982. [PMID: 7147188] 25. Elefteriades JA: Natural history of thoracic aortic aneurysms: Indications for surgery, and surgical versus nonsurgical risks. Ann Thorac Surg 74:S1877, 2002. 43. Gott VL, Cameron DE, Alejo DE, et al: Aortic root replacement in 271 Marfan patients: A 24-year experience. Ann Thorac Surg 73:438, 2002. [PMID: 11845856] 71. Coselli JS, LeMaire SA, Köksoy C, et al: Cerebrospinal fluid drainage reduces paraplegia after thoracoabdominal aortic aneurysm repair: Results of a randomized clinical trial. J Vasc Surg 35:631, 2002. [PMID: 11932655]

CHAPTER 23 24. Kita MW: Carotid endarterectomy in symptomatic carotid stenosis: NASCET comparative results at 30 months of follow-up. J Insur Med 24:42, 1992. [PMID: 10147825] 25. Warlow CP: Symptomatic patients: The European Carotid Surgery Trial (ECST). J Mal Vasc 18:198, 1993. [PMID: 8254241] 52. Greenhalgh RM, Brown LC, Kwong GP, et al: 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. Lancet 364:843, 2004. [PMID: 15351191] 53. Prinssen M, Verhoeven EL, Buth J, et al: A randomized trial comparing conventional and endovascular repair of abdominal aortic aneurysms. N Engl J Med 351:1607, 2004. [PMID: 15483279]

90. Hansen KJ, Cherr GS, Craven TE, et al: Management of ischemic nephropathy: Dialysis-free survival after surgical repair. J Vasc Surg 32:472; discussion 481, 2000. 106. Dormandy JA, Rutherford RB: Management of peripheral arterial disease (PAD). TASC Working Group. TransAtlantic Inter-Society Concensus (TASC). J Vasc Surg 31:S1, 2000.

CHAPTER 24 25. Kearon C, Kahn SR, Agnelli G, et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 133:454S, 2008. 67. Geerts WH, Bergqvist D, Pineo GF, et al: Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 133:381S, 2008. 60. Eklof B, Kistner RL, Masuda EM: Surgical treatment of acute iliofemoral deep venous thrombosis, in Gloviczki P, Yao JST (eds): Handbook of Venous Disorders. New York: Arnold, 2001, p 202. 112. Gloviczki P, Bergan JJ, Rhodes JM, et al: Mid-term results of endoscopic perforator vein interruption for chronic venous insufficiency: Lessons learned from the North American Subfascial Endoscopic Perforator Surgery registry. The North American Study Group. J Vasc Surg 29:489, 1999. [PMID: 10069914]

CHAPTER 25 Akiyama H, Tsurumaru M: Radical lymph node dissection for cancer of the thoracic esophagus. Ann Surg 220:364, 1994. [PMID: 8092902] Bonavina L, Nosadinia A, et al: Primary treatment of esophageal achalasia: Long-term results of myotomy and Dor fundoplication. Arch Surg 127:222, 1992. [PMID: 1540102] Castel DW, Richter J (eds): The Esophagus. Boston: Little, Brown & Co., 1999. Chang EY, Morris CD, Seltman AK, et al: The effect of antireflux surgery on esophageal carcinogenesis in patients with Barrett's esophagus: A systematic review. Ann Surg 246:11, 2007. [PMID: 17592284] Clark GW, Ireland AP, Peters JH, et al: Short segments of Barrett's esophagus: A prevalent complication of gastroesophageal reflux disease with malignant potential. J Gastrointest Surg 1:113, 1997. [PMID: 9834337] Csendes A, Braghetto I, et al: Late results of a prospective randomized study comparing forceful dilatation and oesophagomyotomy in patients with achalasia. Gut 30:299, 1989. [PMID: 2651226] Cunningham D, Allum WH, Stenning SP, et al: Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 6;355:11, 2006.

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CHAPTER 26 26. Cummings DE, Overduin J: Gastrointestinal regulation of food intake. J Clin Invest 117:13, 2007. [PMID: 17200702] 54. Fox JG, Wang TC: Inflammation, atrophy, and gastric cancer. J Clin Invest 117:60, 2007. [PMID: 17200707] 67. Harbison SP, Dempsey DT: Peptic ulcer disease. Curr Probl Surg 42:346, 2005. [PMID: 15988415] 98. Dicken BJ, Bigam DL, Cass C, et al: Gastric adenocarcinoma: Review and considerations for future directions. Ann Surg 241:27, 2005. [PMID: 15621988] 108. Gold JS, DeMatteo RP: Combined surgical and molecular therapy: The gastrointestinal stromal tumor model. Ann Surg 244:176, 2006. [PMID: 16858179]

CHAPTER 27 36. Nguyen NT, Goldman C, Rosenquist CJ, et al: Laparoscopic versus open gastric bypass: A randomized study of outcomes, quality of life, and costs. Ann Surg 234:279, 2001. [PMID: 11524581] 54. Dixon JB, O'Brien PE, Playfair J, et al: Adjustable gastric banding and conventional therapy for type 2 diabetes. A randomized controlled trial. JAMA 299:316, 2008. [PMID: 18212316] 58. Buchwald H, Avidor Y, Braunwald E, et al: Bariatric surgery. A systematic review and meta-analysis. JAMA 292:1724, 2004. [PMID: 15479938] 74. Schauer PR, Ikramuddin S, Gourash W, et al: Outcomes after laparoscopic Roux-en-Y gastric bypass for morbid obesity. Ann Surg 232:515, 2000. [PMID: 10998650] 80. Christou NV, Sampalis JS, Liberman M, et al: Surgery decreases long-term mortality, morbidity, and health care use in morbidly obese patients. Ann Surg 240:416, 2004. [PMID: 15319713] 107. Sjostrom L, Narbro K, Sjostron CD, et al: Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med 357:741, 2007. [PMID: 17715408]

108. Adams TD, Gress RE, Smith SC, et al: Long-term mortality after gastric bypass surgery. N Engl J Med 357:753, 2007. Another important article documenting that bariatric surgery decreases mortality in the severely obese population. 109. Rubino F, Marescaux J: Effect of duodenal-jejunal exclusion in a nonobese animal model of type 2 diabetes: A new perspective for a old disease. Ann Surg 239:1, 2004. [PMID: 14685093]

CHAPTER 28 3. Thomson ABR, Keelan M, Thiesen A, et al: Small bowel review: Normal physiology part 2. Dig Dis Sci 46:2588, 2001. [PMID: 11768248] 23. Foster NM, McGory ML, Zingmond DS, et al: Small bowel obstruction: A population-based appraisal. J Am Coll Surg 203:170, 2006. [PMID: 16864029] 44. Evenson AR, Shrikhande G, Fischer JE: Abdominal abscess and enteric fistula, in Zinner MJ, Ashley SW (eds): Maingot's Abdominal Operations, 11th ed. New York: McGraw Hill, 2007, p 184.

CHAPTER 29 9. Lynch HT, Lynch JF, Lynch PM, et al: Hereditary colorectal cancer syndromes: Molecular genetics, genetic counseling, diagnosis and management. Fam Cancer 7:27, 2008. [PMID: 17999161] 15. Tjandra JJ, Dykes SL, Kumar RR, et al: Practice parameters for the treatment of fecal incontinence. Dis Colon Rectum 50:1497, 2007. [PMID: 17674106] 75. Sauer R, Becker H, Hohenberger W, et al: Preoperative versus postoperative chemoradiation for rectal cancer. N Engl J Med 351:1731, 2004. [PMID: 15496622]

CHAPTER 30 4. Radford-Smith GL, Edwards JE, Purdie DM, et al. Protective role of appendicectomy on onset and severity of ulcerative colitis and Crohn's disease. Gut 51:808, 2002. [PMID: 12427781] 92. Yamini D, Vargas H, Klein S, et al: Perforated appendicitis: Is it truly a surgical urgency? Am Surg 64:970, 1998. [PMID: 9764704] 93. Owen A, Moore O, Marven S, et al: Interval laparoscopic appendectomy in children. J Laparoendosc Adv Surg Tech A 16:308, 2006. [PMID: 16796448]

CHAPTER 31 51. Schwartz M, Roayaie S, Konstadoulakis M: Strategies for the management of hepatocellular carcinoma [review]. Nat Clin Pract Oncol 4:424, 2007. [PMID: 17597707] 76. Pawlik TM, Schulick RD, Choti MA: Expanding criteria for resectability of colorectal liver metastases [review]. Oncologist 13:51, 2008. [PMID: 18245012] 95. Mazzaferro V, Chun YS, Poon RT, et al: Liver transplantation for hepatocellular carcinoma [review]. Ann Surg Oncol 15:1001, 2008. [PMID: 18236119] 159. Adam R, Miller R, Pitombo M, et al: Two-stage hepatectomy approach for initially unresectable colorectal hepatic metastases. Surg Oncol Clin N Am 16:525, 2007. [PMID: 17606192] 174. Koffron AJ, Auffenberg GB, Kung RD, et al: Evaluation of 300 minimally invasive liver resections at a single institution: Less is more. Ann Surg 246:385; discussion, 392, 2007.

CHAPTER 32 10. Woods CM, Mawe GM, Saccone GTP: The sphincter of Oddi: Understanding its control and function. Neurogastroenterol Motil 17(Supp 1):31, 2005. 57. Hunter JG: Acute cholecystitis revisited: Get it while it's hot. Ann Surg 227:468, 1998. [PMID: 9563530] 75. Way LW, Stewart L, Gantert W, et al: Causes and prevention of laparoscopic bile duct injuries: Analysis of 252 cases from a human factors and cognitive psychology perspective [Comment]. Ann Surg 237:460, 2003. [PMID: 12677139] 96. Mulholland MW, Yahanda A, Yeo CJ: Multidisciplinary management of perihilar bile duct cancer. J Am Coll Surg 193:440, 2001. [PMID: 11584972]

CHAPTER 33 25. Pandol SJ, Saluja AK, Imrie CW, et al: Acute pancreatitis: Bench to the bedside. Gastroenterology 133:1056 e1, 2007. 31. Whitcomb DC, Gorry MC, Preston RA, et al: Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet 14:141, 1996. [PMID: 8841182] 149. Lankisch PG, Lohr-Happe A, Otto J, et al: Natural course in chronic pancreatitis. Pain, exocrine and endocrine pancreatic insufficiency and prognosis of the disease. Digestion 54:148, 1993. [PMID: 8359556]

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CHAPTER 34 80. Cassar K, Munro A: Iatrogenic splenic injury. J R Coll Surg Edinb 47:731, 2002. [PMID: 12510965] 111. Winslow E, Brunt M: Perioperative outcomes of laparoscopic versus open splenectomy: A meta-analysis with an emphasis on complications. Surgery 134:647, 2003. [PMID: 14605626] 112. Taylor MD, Genuit T, Napolitano LM: Overwhelming postsplenectomy sepsis and trauma: Time to consider revaccination? J Trauma 59:1482, 2005. [PMID: 16394926]

CHAPTER 35 Anthony T, Bergen PC, Kim LT, et al: Factors affecting recurrence following incisional herniorrhaphy. World J Surg 24:95, 2000. [PMID: 10594211] Duchene DA, Winfield HN, Cadeddu JA, et al: Multi-institutional survey of laparoscopic ureterolysis for retroperitoneal fibrosis. Urology 69:1017, 2007. [PMID: 17572177] Kelly JK, Hwang WS: Idiopathic retractile (sclerosing) mesenteritis and its differential diagnosis. Am J Surg Pathol 13:513, 1989. [PMID: 2658633] Luijendijk RW, Hop WC, van den Tol MP, et al: A comparison of suture repair with mesh repair for incisional hernia. N Engl J Med 343:392, 2000. [PMID: 10933738] Pierce RA, Spitler JA, Frisella MM, et al: Pooled data analysis of laparoscopic vs. open ventral hernia repair: 14 years of patient data accrual. Surg Endosc 21:378, 2007. [PMID: 17180261] Saborido BP, Romero CJ, Medina ME, et al: Idiopathic segmental infarction of the greater omentum as a cause of acute abdomen. Report of two cases and review of the literature. Hepatogastroenterology 48:737, 2001.

CHAPTER 36 51. Rosenberg SA, Tepper J, Glatstein E, et al: The treatment of soft-tissue sarcomas of the extremities: Prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg 196:305, 1982. [PMID: 7114936] 62. Yang JC, Chang AE, Baker AR, et al: Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 16:197, 1998. [PMID: 9440743] 73. O'Sullivan B, Davis AM, Turcotte R, et al: Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: A randomised trial. Lancet 359:2235, 2002. [PMID: 12103287] 90. Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: Meta-analysis of individual data. Sarcoma Meta-analysis Collaboration. Lancet 350:1647, 1997.

CHAPTER 37 19. Rutkow IM, Robbins AW: "Tension-free" inguinal herniorrhaphy: A preliminary report on the "mesh plug" technique. Surgery 114:3, 1993. [PMID: 8356522] 37. Fitzgibbons RJ Jr, Giobbie-Hurder A, Gibbs JO, et al: Watchful waiting vs repair of inguinal hernia in minimally symptomatic men: A randomized clinical trial. JAMA 295:285, 2006. [PMID: 16418463] 41. Lichtenstein IL, Shulman AG, Amid PK: Use of mesh to prevent recurrence of hernias. Postgrad Med 87:155, 160. 1990. 47. Neumayer L, Giobbie-Hurder A, Jonasson O, et al: Open mesh versus laparoscopic mesh repair of inguinal hernia. N Engl J Med 350:1819, 2004. [PMID: 15107485] 53. Collaboration EH: Laparoscopic compared with open methods of groin hernia repair: Systematic review of randomized controlled trials. Br J Surg 87:860, 2000. [PMID: 10931019]

CHAPTER 38 33. Mazzaferri EL, Jhiang SM: Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 97:418, 1994. [PMID: 7977430] 37. Cooper DS, Doherty GM, Haugen BR, et al: Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 16:109, 2006. [PMID: 16420177] 70. Bilezikian JP, Potts JT Jr., Fuleihan Gel H, et al: Summary statement from a workshop on asymptomatic primary hyperparathyroidism: A perspective for the 21st century. J Clin Endocrinol Metab 87:5353, 2002. [PMID: 12466320]

CHAPTER 39 Bell MJ, Ternberg JL, Feigin RD, et al: Neonatal necrotizing enterocolitis: Therapeutic decisions based upon clinical staging. Ann Surg 187:1, 1978. [PMID: 413500] Bouchard S, Johnson MP, et al: The EXIT procedure: Experience and outcome in 31 cases. J Pediatr Surg 37:418, 2002. [PMID: 11877660] DeRusso PA, Ye W, Shepherd R, et al: Growth failure and outcomes in infants with biliary atresia: A report from the Biliary Atresia Research Consortium. Hepatology 46:1632, 2007. [PMID: 17929308] Grant D, Abu-Elmagd K, Reyes J, et al: 2003 Report of the intestine transplant registry: A new era has dawned. Ann Surg 241:607, 2005. [PMID: 15798462] Grikscheit TC, Vacanti JP: The history and current status of tissue engineering: The future of pediatric surgery. J Pediatr Surg 37:277, 2002. [PMID: 11877635] Gross RE, Ladd WE: The Field of Children's Surgery, in: Gross RE (ed): The Surgery of Infancy and Childhood: Its Principles and Techniques. W. B. Saunders: Philadelphia, 1953, p 1. Hackam DJ, Potoka D, et al: Utility of radiographic hepatic injury grade in predicting outcome for children after blunt abdominal trauma. J Pediatr Surg 37:386, 2002. [PMID: 11877653] Hackam DJ, Reblock K, et al: The influence of Down's syndrome on the management and outcome of children with Hirschsprung's disease. J Pediatr Surg 38:946, 2003. [PMID: 12778399] Hackam DJ, Superina R, et al: Single-stage repair of Hirschsprung's disease: A comparison of 109 patients over 5 years. J Pediatr Surg 32:1028, 1997 [PMID: 9247227] Harrison MR: Fetal surgery: Trials, tribulations, and turf. J Pediatr Surg 38:275, 2003. [PMID: 12632335]

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CHAPTER 40

3. Stein JP, Cai J, Groshen S, et al: Risk factors for patients with pelvic lymph node metastases following radical cystectomy with en bloc pelvic lymphadenectomy: Concept of lymph node density. J Urol 170:35, 2003. [PMID: 12796639] 12. Flanigan RC, Salmon SE, Blumenstein BA, et al: Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal cell cancer. N Engl J Med 345:1655, 2001. [PMID: 11759643] 14. Huang WC, Levey AS, Serio AM, et al: Chronic kidney disease after nephrectomy in patients with renal cortical tumors: A retrospective cohort study. Lancet Oncol 7:735, 2006. [PMID: 16945768] 19. Bill-Axelson A, Holmberg L, Filen F, et al: Radical prostatectomy versus watchful waiting in localized prostate cancer: The Scandinavian Prostate Cancer Group-4 Randomized Trial. J Natl Cancer Inst 100:1144, 2008. [PMID: 18695132] 22. Buckley JC, McAninch JW: Selective management of isolated and nonisolated grade IV renal injuries. J Urol 176:2498, 2006. [PMID: 17085141] 55. Curhan GC, Willett WC, Rimm EB, et al: A prospective study of dietary calcium and other nutrients and the risk of symptomatic kidney stones. N Engl J Med 328:833, 1993. [PMID: 8441427]

CHAPTER 41 23. Gabbe S, Niebyl J, Simpson J: Obstetrics: Normal and Problem Pregnancies, 4th ed. Philadelphia: Churchill Livingstone, 2002. 33. Walters M, Karram M: Urogynecology and Reconstructive Pelvic Surgery, 3rd ed. Philadelphia: Mosby, 2007. 48. Berek J, Hacker N: Practical Gynecologic Oncology, 4th ed. Philadelphia: Lippincott, Williams and Wilkins, 2004. 50. Hoskins W, Perez C, Young R. Principles and Practice of Gynecologic Oncology. Philadelphia: Lippincott, Williams and Wilkins, 2000. 59. Stenchever M, Droegemueller W, Herbst A, et al: Comprehensive Gynecology, 4th ed. St Louis: Mosby, 2001.

CHAPTER 42 5. Brain Trauma Foundation, American Association of Neurological Surgeons, Congress of Neurological Surgeons. Guidelines for the management of severe traumatic brain injury. J Neurotrauma 24:S1, 2007. 18. Denis F: The three column spine and its significance in the classification of acute thoracolumbar spinal injuries. Spine 8:817, 1983. [PMID: 6670016] 24. Anonymous. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators [see comment]. N Engl J Med 325:445, 1991. 27. Molyneux A, Kerr R, Stratton I, et al: International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: A randomised trial [see comment] [reprint in J Stroke Cerebrovasc Dis 11:304, 2002]. Lancet 360:1267, 2002. [PMID: 12414200] 30. Patchell RA, Tibbs PA, Walsh JW, et al: A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 322:494, 1990. [PMID: 2405271]

CHAPTER 43 1. Gustilo RB, Anderson JT: Prevention of infection in the treatment for one thousand and twenty-five open fractures of long bones. J Bone Joint Surg Am 58:453, 1976. [PMID: 773941] 40. Denis F: The three column spine and its significance in the classification of acute thoracolumbar spinal injuries. Spine 8:817, 1983. [PMID: 6670016] 43. Weinstein JN, Tosteson TD, Lurie JD, et al: Surgical vs nonoperative treatment for lumbar disk herniation. JAMA 296:2441, 2006. [PMID: 17119140] 58. Salter RB, Harris WR: Injuries involving the epiphyseal plate. J Bone Joint Surg Am 45:587, 1963. 63. Willis RB: Developmental dysplasia of the hip: Assessment and treatment before walking age. Instr Course Lect 50:541, 2001. [PMID: 11372357]

CHAPTER 44 1. American Society for Surgery of the Hand, in: The Hand: Examination and Diagnosis, 3rd ed. New York: Churchill Livingstone, 1990, p 5. 6. Green DP: General principles, in Green DP, Hotchkiss RN, Pedersen WC, et al (eds): Green's Operative Hand Surgery, 5th ed. Philadelphia, Pa: Churchill Livingstone, 2005, p 3. 9. Lalonde D, Bell M, Benoit P, et al: A multicenter prospective study of 3,110 consecutive cases of elective epinephrine use in the fingers and hand: The Dalhousie Project clinical phase. J Hand Surg [Am] 30:1061, 2005. [PMID: 16182068]

CHAPTER 45 13. Wei FC, Souminen S: Principles and techniques of microvascular surgery, in Mathes SJ (ed): Plastic Surgery, 2nd ed. Philadelphia: Elsevier, 2006, p 507. 16. Lutz BS, Wei FC: Microsurgical workhorse flaps in head and neck reconstruction. Clin Plast Surg 32:421, 2005. [PMID: 15979480] 25. Whitaker LA, Barlett SP: Craniofacial anomalies, in Jurkiewicz MJ, Krizek TJ, Mathes SJ, et al (eds): Plastic Surgery: Principles and Practice, vol. 1. St. Louis: Mosby, 1990, p 99. 38. Wei FC, Chen HC, Chuang CC, et al: Fibular osteoseptocutaneous flap: Anatomic study and clinical application. Plast Reconstr Surg 78:191, 1986. [PMID: 3523559] 53. Rohrich RJ, Lowe JB, Hackney FL, et al: An algorithm for abdominal wall reconstruction. Plast Reconstr Surg 105:202, 2000. [PMID: 10626993]

CHAPTER 46

24. Rao PS, Merion RM, Ashby VB, et al: Renal transplantation in elderly patients older than 70 years of age: Results from the Scientific Registry of Transplant Recipients. Transplantation 83:1069, 2007. [PMID: 17452897] 26. Giordano SH, Hortobagyi GN, Kau SC, et al: Breast cancer treatment guidelines in older women. J Clin Oncol 23: 783, 2005. [PMID: 15681522] 30. Gennari R: Breast cancer in elderly women. Optimizing the treatment. Breast Cancer Res Treat 110:199, 2008. [PMID: 17851758] 38. Mery CM, Pappas AN, Bueno R et al: Similar long-term survival of elderly patients with non-small cell lung cancer treated with lobectomy or wedge resection within the surveillance, epidemiology and end results database. Chest 28:237, 2005. 39. Cattaneo SM, Park BJ, Wilton AS, et al: Use of video-assisted thoracic surgery for lobectomy in the elderly results in fewer complications. Ann Thoracic Surg 85:231, 2008. [PMID: 18154816] 42. Chang TT, Schecter WP: Injury in the elderly and end-of-life decisions. Surg Clin North Am 87:229, 2007. [PMID: 17127130]

CHAPTER 47 11. Hull CJ: Principles of pharmacokinetics, in Hemmings H, Hopkins PM (eds): Foundations of Anesthesia. London: Mosby, 2000, p 77. 12. Stoelting RD, Dierdorf SF: Stoelting's Anesthesia and Co-Existing Disease, 5th ed. Philadelphia: Saunders, 2008. 50. Practice guidelines for management of the difficult airway: An updated report by the American Society of Anesthesiologists Task Force on Management of the Difficult Airway. Anesthesiology 98:1269, 2003. 77. Gan TJ, Meyer T, Apfel CC, et al: Consensus guidelines for managing postoperative nausea and vomiting. Anesth Analg 97:62, 2003. [PMID: 12818945] 80. Atkins JH, Johansson JS: Technologies to shape the future: Proteomics applications in anesthesiology and critical care medicine. Anesth Analg 102:1207, 2006. [PMID: 16551925]

CHAPTER 48 2. Beauchamp TL, Childress JF: Principles of Biomedical Ethics, 3rd ed. New York: Oxford University Press, 1989. 8. Faden RR, Beauchamp TL: A History and Theory of Informed Consent. New York: Oxford University Press, 1986. 35. Dunn G: Surgical palliative care, in Mosby (ed): Current Surgical Therapy, 9th ed. Philadelphia: Elsevier, 2008. 36. Saunders C: The challenge of terminal care, in Symington T, Carter R (eds): Scientific Foundations of Oncology. London: Heineman, 1976 p 673. 37. Billroth T: Open letter to Dr. L Wittleshöfer. Wiener Medizinische Wochenschrift 31:162, 1881. 46. Surgeons Palliative Care Workgroup: Report from the Field. J Am Coll Surg 197:661, 2003. 47. Cancer pain relief and palliative care. Report of a WHO Expert Committee. World Health Organ Tech Rep Ser 804:1, 1990. 62. Hinshaw DB: Spiritual issues in surgical palliative care. Surg Clin North Am 85:257, 2005. [PMID: 15833470] 63. Jacox A, Carr D, Payne R, et al: Management of cancer pain. AHCPR Publication No. 94-052: Clinical Practice Guideline No. 9. Rockville, MD: US Department of Health and Human Services, Public Health Service, 1994.

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