Surgery: Basic Science and Clinical Evidence

Surgery Second Edition Surgery Basic Science and Clinical Evidence Second Edition Edited by Jeffrey A. Norton, MD, ...

Author: Jeffrey A. Norton | Philip S. Barie | Ralph R. Bollinger | Alfred E. Chang | Stephen Lowry | Sean J. Mulvihill | Harvey I. Pass | Robert W. Thompson

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Surgery Second Edition

Surgery

Basic Science and Clinical Evidence Second Edition

Edited by Jeffrey A. Norton, MD, FACS

Robert L. and Mary Ellenburg Professor, Department of Surgery; Chief, Divisions of Surgical Oncology and General Surgery, Department of Surgery, Stanford University Medical Center, Stanford, California

Philip S. Barie, MD, MBA, FCCM, FACS

Professor, Departments of Surgery and Public Health; Chief, Division of Critical Care and Trauma, NewYork-Presbyterian Hospital/Weill Cornell Medical College, New York, New York

R. Randal Bollinger, MD, PhD, FACS

Professor, Departments of Surgery and Immunology, Duke University Medical Center, Durham, North Carolina

Alfred E. Chang, MD, FACS

Chief, Division of Surgical Oncology, Hugh Cabot Professor of Surgery, Department of Surgery, University of Michigan, Comprehensive Cancer Center, Ann Arbor, Michigan

Stephen F. Lowry, MD, MBA, FACS

Professor and Chairman, Department of Surgery, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, New Jersey

Sean J. Mulvihill, MD, FACS

Professor and Chair, Department of Surgery; Senior Director of Clinical Affairs, Huntsman Cancer Institute; The University of Utah, Salt Lake City, Utah

Harvey I. Pass, MD, FACS

Professor, Departments of Cardiothoracic Surgery and Surgery, New York University Medical Center, New York, New York

Robert W. Thompson, MD, FACS

Professor of Surgery (Section of Vascular Surgery), Radiology, and Cell Biology and Physiology; Vice-Chairman for Research, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri

~ Springer

Jeffrey A. Norton, MD, FACS Robert L. and Mary Ellenburg Professor, Department of Surgery; Chief, Divisions of Surgical Oncology and General Surgery, Department of Surgery, Stanford University Medical Center, Stanford, CA, USA Philip S. Batie, MD, MBA, FCCM, FACS Professor, Departments of Surgery and Public Health; Chief, Division of Critical Care and Trauma, NewYork-Presbyterian Hospital/Weill Cornell Medical College, New York, NY, USA R. Randal Bollinger, MD, PhD, FACS Professor, Departments of Surgery and Immunology, Duke University Medical Center, Durham, NC, USA Alfred E. Chang, MD, FACS Chief, Division of Surgical Oncology, Hugh Cabot Professor of Surgery, Department of Surgery, University of Michigan, Comprehensive Cancer Center, Ann Arbor, MI, USA Stephen F. Lowry, MD, MBA, FACS Professor and Chairman, Department of Surgery, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NT, USA Sean J. Mulvihill, MD, FACS Professor and Chair, Department of Surgery; Senior Director of Clinical Affairs, Huntsman Cancer Institute; The University of Utah, Salt Lake City, UT, USA Harvey 1. Pass, MD, FACS Professor, Departments of Cardiothoracic Surgery and Surgery, New York University Medical Center, New York, NY, USA Robert W. Thompson, MD, FACS Professor of Surgery (Section of Vascular Surgery), Radiology, and Cell Biology and Physiology; Vice-Chairman for Research, Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA

ISBN: 978-0-387-30800-5 e-ISBN: 978-0-387-68113-9 DOl: 10.1007/978-0-387-68113-9 Library of Congress Control Number: 20079218816 © 2008 Springer Science+Business Media, LLC

All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper 9 8 765 432 1 springer.com

To our families

Preface When the first edition of Surgery: Basic Science and Clinical Practice published, evidence-based medicine principles were just starting to be embraced by the surgery community. Our second edition comes at a critical time in surgical care when surgeons are expected to use the best available evidence to support their every day decisions in patient care, citing critical scientific evidence to support their decisions. No longer is it acceptable to simply say, "We do it this way because we always do it this way." The practice of surgery has evolved from considering the principles of evidence-based medicine to actively incorporating those principles into practice. We have taken great care to ensure that Surgery meets the needs of both students and clinicians, providing the scientific background, the clinical decision-making skills, and the surgical techniques to provide the best possible patient care. For this new edition, the editorial board has recruited a new member of the team. In order to provide the necessary emphasis on trauma and critical care, we asked Dr. Philip S. Barie to work with Dr. Stephen F. Lowry to thoroughly expand and improve those topics. The reader will quickly see the added depth and scope of coverage-a marked improvement over the previous edition. We have thoroughly revised every chapter and sharpened the focus on our evidence-based approach, including EBM tables and enhanced figures in every chapter. New chapters discuss transfusion therapy, intraabdominal and nosocomial infections, severe sepsis and shock, mechanical ventilation, imaging in critical care patients, bums and inhalation injury, vascular trauma, traumatic injury of the spine, and surgical rehabilitation. We have identified particular patient populations that require specialized care, including the elderly, neonates, children, and obese patients. We also discuss the needs of pregnant and immunocompromised patients, who require variations in surgical management and care. These chapters are well-illustrated and packed with important evidence to allow enlightened choices. We have included new chapters on vascular access for dialysis, chemotherapy and nutritional support, thoracic infections, and video-assisted thoracic surgery. The transplant section has been brought up to date and expanded to include transplantation of the intestine. Fundamentals of cancer genomics and proteomics and fundamentals of cancer cell biology and molecular targeting are essential to changes in cancer patient care and treatment, so we have expanded those topics in the oncology section. Finally, there is a new section on biomaterials, energy transfer, and robotics that provide the busy practicing surgeon with new methods and innovative perspectives for modem surgical care. In summary, the book has been thoroughly updated with recent advances in both scientific evidence and clinical practice, including 28 new chapters discussing exciting new areas in surgery. We have focused on current references and evidence to give the reader the most up-to-date information possible. We hope you will agree that this book, with its consistent and long-established EBM focus, is different from other surgical textbooks. The contributing authors are all clinically active experts who have written comprehensive, current chapters. We believe the chapters on emerging topics strike a balance describing both the current status of practice and the possibilities on the horizon. The chapters have been carefully edited to provide a smooth, readable text. As in previous editions, the evidence-based tables provide information that is consistently formatted and carefully rated, based on the quality of the study design and conduct. We will soon be embracing the changes in both learning and practice brought on by the ubiquity of computers in medicine. In addition to the print version of this book, we will bring together the timely content of journal articles with the authoritative content of a traditional textbook. At our soon-to-be launched web portal, users will be able to call up topics by book chapter, by general subject, or through a search function. (Similarly, journal readers will be able to access the content of Surgery when reading articles in a linked journal.) From this portal, users can navigate easily and seamlessly between book chapters, journal articles, and, where available, videoclips. An online image library, references linked to online databases with full text retrieval (when available), and related clinical and biomedical data will also be available. In addition, an e-book version of Surgery: Basic Science and Clinical Evidence is now available, in combination with the print book or as a stand-alone digital resource.

vii

viii

PREFACE

In short, Surgery: Basic Science and Clinical Evidence continues to be different and exciting. We have strived to combine the past and present, with an optimistic eye to the future. Surgery represents the state of the art and science of the full range of surgical practice as we now know it. We hoped to expand on our past success and create a key reference source for residents and students. We hope readers are as excited about this edition as we are and we invite you to send your comments. Please let us hear from you, as we want to update the book frequently, continuing to improve upon it and make it more reader friendly. We wish you good reading. Jeffrey A. Norton, MD, FACS Philip S. Barie, MD, MBA, FCCM, FACS R. Randal Bollinger, MD, PhD, FACS Alfred E. Chang, MD, FACS Stephen F. Lowry, MD, MBA, FACS Sean J. Mulvihill, MD, FACS Harvey I. Pass, MD, FACS Robert W. Thompson, MD, FACS January 2008

Acl<nowledgments

The Editorial Board wishes to thank both the editorial and production staff at Springer for their support and encouragement, Mary Shirazi, whose wonderful medical illustrations appear throughout the book, and Barbara Chernow and Kathy Jackson-Cleghorn of Chernow Editorial Services for their outstanding work in coordinating the production of this text. I personally would also like to thank my family members for their continued help and support, specifi-

cally Cathy, John, Meg, Pat, and Tim.

Jeffrey A. Norton, MD

This book is dedicated to all who thirst for knowledge, and strive to improve the care of the surgical patient. Philip S. Batie, MD, MBA The untiring support and encouragement of my wife, Monika Bollinger is gratefully acknowledged. I sincerely appreciate the superb work of each author who contributed to the transplantation section and especially the participation of my former colleagues and trainees, Drs. Duane Davis, Douglas Farmer, Bob Harland, Allan Kirk, Stuart Knechtle, Christine Lau, Brian Lima, and Betsy Tuttle-Newhall. R. Randal Bollinger, MD, PhD To my wife, Lana, for her support in this effort.

Alfred E. Chang, MD

To Susette, Alex, Lorna, and Kate, who make the "day job" all the more meaningful, and to Debbie, Micki, and Lynn, who help make the "day job" a pleasure. To my mentors, Dick Kraft, Frank Moody, Murray Brennan, and Tom Shires, who instilled a love of surgery and imparted (hopefully) a modicum of their great wisdom. Stephen F. Lowry, MD To the surgical trainees who will use this reference for inspiring me with their commitment to excellence, to my own mentor, Haile Oebas, MO, for his teaching, advice, and support, and to my wife Kim and sons Michael, Jeffrey, and Timothy for bringing joy to my life. Sean J. Mulvihill, MD To my family, Helen, Eric, and Ally Pass, for their constant support.

Harvey 1. Pass, MD

To my surgical mentors, Norm Thompson (dad), John Mannick, Ron Stoney, and Greg Sicard, for their inspiration and instruction. To my students, residents, and fellows, who keep me challenged, and to Della for keeping it all in order. To my wonderful wife Michelle and the joy of our lives, Taylor Alexandra, who makes it all worthwhile. Robert W. Thompson, MD

ix

Contents

Preface. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii Acknowledgments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xix Evidence-Based Tables xxxiii

Section One

Fundamentals of Surgical Care

Origins of Modem Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ira M. Rutkow

3

2

Evidence-Based Surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Robin S. McLeod

21

3

Cell Structure, Function, and Genetics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Siobhan A. Corbett and Ramsey A. Foty

37

4

Mediators of Inflammation and Injury. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stephen F. Lowry, Edward Lin, and Steve E. Calvano

75

5

Substrate Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Edward Lin and Stephen F. Lowry

101

6

Nutrition.................................................................... Kenneth A. Kudsk and Danny O. Jacobs

III

7

Perioperative Fluids and Electrolytes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Avery B. Nathens and Ronald V. Maier

139

8

Hemostasis and Coagulation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Marcel Levi and Tom van der Poll

149

9

Transfusion Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lena M. Napolitano

167

10 Wounds: Biology, Pathology, and Management. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . H. Peter Lorenz and Michael T. Longaker

191

11 Diagnosis and Treatment of Infection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . David L. Dunn

209

12 Infections of Skin and Soft Tissue. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Philip S. Batie and Soumitra R. Eachempati

237

13 Intraabdominal Infections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Michael A. West and Michael B. Shapiro

259

xi

xii

CONTENTS

14 Nosocomial Infections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pamela A. Lipsett

273

15 Severe Sepsis and Septic Shock. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Steven M. Opal

287

16 Shock and Resuscitation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Avery B. Nathens and Ronald V. Maier

305

17 Perioperative Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Philip S. Barie

323

18 Anesthesia................................................................... Joseph D. Tobias and Russell Wall

353

19 Management of Perioperative Pain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Susannah S. Wise

381

Section Two Biology and Practice of Trauma and Critical Care 20 Development of Trauma and Critical Care. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . G. Tom Shires t

397

21

Trauma Systems, Triage, and Disaster Management. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jeffrey Hammond

403

22 Monitoring of Cardiovascular and Respiratory Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Philip S. Barie and Soumitra R. Eachempati

409

23 Imaging of the Critically III Patient. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Amy D. Wyrzykowski and Grace S. Rozycki

423

24

Risk Prediction, Disease Stratification, and Outcome Description in Critical Surgical Illness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . John C. Marshall

25

Bums and Inhalation Injury. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Roger W. Yurt

447

26 Traumatic Brain Injury. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kyle Chapple and Roger Hartl

461

27

Trauma to the Torso. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Deborah M. Stein and Thomas M. Scalea

471

28

Trauma to the Pelvis and Extremities. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dean G. Lotich, Michael J. Gardner, and David L. Helfet

505

29 Vascular Trauma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Peter P. Lopez and Enrique Ginzberg

521

30

Traumatic Injury of the Spine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Justin F. Fraser, John Boockvar, and Roger Hartl

545

31

Multiple Organ Dysfunction Syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Donald E. Fry

563

32

Mechanical Ventilation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . David J. Dries and John F. Perry, Jr.

577

'Deceased

433

CONTENTS

xiii

33

Renal Replacement Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . John C.L. Wang, Roxana M. Bologa, and Stuart D. Saal

597

34

Open Abdomen. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Claudia E. Goettler and Michael F. Rotondo

613

35

Principles of Surgical Rehabilitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Michael W. O'Dell and Tammy Noren

631

Section Three Care of Unique Populations 36

Pediatric Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Russell K. Woo and Craig T. Albanese

649

37

Surgery in the Immunocompromised Patient. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . John Mihran Davis and Kathleen King Casey

697

38

Evidence-Based Bariatric Surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . John Morton

709

39

Surgical Care of the Pregnant Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Erika J. Lu and Myriam J. Curet

729

40

Palliative and End-of-Life Care. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sharon M. Weinstein and Olivia Walton

737

Section Four Gastrointestinal and Abdominal Surgery 41

History of Surgery of the Gastrointestinal Tract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sean J. Mulvihill and Haile T. Debas

743

42

Assessment of Acute Abdominal Symptoms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . William P. Schecter

759

43

Principles of Minimally Invasive Surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Theodore N. Pappas and Alison M. Fecher

771

44A

Esophagus: Benign Diseases of the Esophagus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Daniel Smith and David A. McClusky III

791

44B

Malignant Tumors of the Esophagus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gail Darling

827

45

Stomach and Duodenum. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Robert E. Glasgow and Michael D. Rollins

841

46

Pancreas.................................................................... Robert E. Glasgow and Sean J. Mulvihill

875

47

Biliary System. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hobart W. Harris

911

48

Liver....................................................................... Courtney Scaife

943

49

Small Intestine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Richard A. Hodin and Jeffrey B. Matthews

963

50

Appendix.................................................................... David Soybel

991

xiv

CONTENTS

51

Colon, Rectum, and Anus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Mark L. Welton, Andrew A. Shelton, George J. Chang, and Madhulika G. Varma

1011

52

Spleen...................................................................... Alan T. Lefor and Edward H. Phillips

1111

53

Hernias and Abdominal Wall Defects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Daniel J. Scott and Daniel B. Jones

1133

Section Five Endocrine Surgery 54

History of Endocrine Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Jeffrey A. Norton

1181

55

Parathyroid.................................................................. Matthew B. Bloom and Jeffrey A. Norton

1189

56

Thyroid..................................................................... Ronald J. Weigel

1211

57

Adrenal..................................................................... Robert Udelsman

1229

58

Neuroendocrine Tumors of the Pancreas and Gastrointestinal Tract and Carcinoid Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. David A. Peterson, James P. Dolan, and Jeffrey A. Norton

59

Multiple Endocrine Neoplasia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Terry C. Lairmore

1249 1285

Section Six Vascular Surgery 60

History of Vascular Surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Jesse E. Thompson

1299

61

Pathobiology of Vascular Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Bryan W. Tillman and Randolph L. Geary

1317

62

Cerebrovascular Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Peter L. Faries, Sheela T. Patel, and K. Craig Kent

1337

63

Diseases of the Thoracic Aorta. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Marineh Yagubian and Thoralf M. Sundt

1359

64

Diseases of the Great Vessels and the Thoracic Outlet. . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Spencer J. Melby and Robert W. Thompson

1375

65

Abdominal Aortic Aneurysms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. B. Timothy Baxter and Brad A. Winterstein

1397

66

Arterial Disease of the Lower Extremity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Michael A. Golden

1413

67

Venous Disease and Pulmonary Embolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Gregory L. Moneta and Mathew 1. Foley

1429

68

Vascular Access for Dialysis, Chemotherapy, and Nutritional Support. . . . . . . . . . . . . . . .. R. Randal Bollinger and Stuart J. Knechtle

1457

CONTENTS

Section Seven

xv

Thoracic Surgery

69 History of Cardiac Surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Larry W. Stephenson

1471

70 Preoperative and Postoperative Care of the Thoracic Surgery Patient. . . . . . . . . . . . . . . . .. Jessica Scott Donington

1481

71 Lung Neoplasms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Frank C. Detterbeck, Scott N. Gettinger, and Mark A. Socinski

1491

72 Thoracic and Pulmonary Infections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Frank A. Baciewicz, Jr.

1525

73 Video-Assisted Thoracic Surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Matthew J. Schucbett, James D. Luketich, and Hitan C. Fernando

1535

74 Pleura: Anatomy, Physiology, and Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Joseph S. Friedberg and John C. Kucharczuk

1551

75 Mediastinum................................................................. Mark 1. Block

1571

76 Congenital Heart Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Carl L. Backer and Constantine Mavroudis

1601

77 Adult Heart Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Todd K. Rosengart, William de Bois, Edgar Chedrawy, and Malica Vukovic

1621

78 Cardiac Replacement Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Benjamin C. Sun

1669

Section Eight Transplantation Surgery 79 History of Clinical Transplantation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Thomas E. Starzl

1681

80 Immunology of Transplantation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Allan D. Kirk and Eric A. Elster

1705

Rejection.................................................................... J. Richard Thistlethwaite and David Bruce

1 737

82 Principles of Organ Preservation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Brian Lima and J.E. Tuttle-Newhall

1747

83 Kidney Transplantation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Stuart J. Knechtle

1759

84 Pancreas and Islet Transplantation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Robert C. Harland and Marc R. Garfinkel

1773

85 Liver Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Douglas W. Han to, Scott R. Johnson, Seth J. Karp, and Khalid Khwaia

1787

86 Transplantation of the Intestine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Fady M. Kaldas and Douglas G. Farmer

1827

Lung Transplantation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Christine L. Lau, G. Alexander Patterson, and R. Duane Davis

1839

81

87

xvi

CONTENTS

88 Heart Transplantation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Catherine Sudarshan, DanielKreisel. and Bruce R. Rosengard

1861

Section Nine Cancer Surgery 89

History of Surgical Oncology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Walter Lawrence, Jr.

1889

90

Genetics of Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. John E. Phay and Jeffrey F. Moley

1901

91

Fundamentals of Cancer Genomics and Proteomics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Jimmy C. Sung, Alice Y. Lee, and Timothy J. Yeatman

1925

92

Fundamentals of Cancer Cell Biology and Molecular Targeting. . . . . . . . . . . . . . . . . . . . . .. Steven N. Hochwald, David Bloom, Vita Golubovskaya, and William G. Cance

1933

93

Immunology of Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Craig L. Slingluff, Jr.

1947

94

Principles of Cancer Surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. John H. Donohue

1965

95

Radiation as an Adjunct to Surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Barbara-Ann Millar and Laura A. Dawson

1985

96

Benign and Malignant Diseases of the Breast . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Helen A. Pass

2005

97 Melanoma and Other Cutaneous Malignancies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 2037 Vernon K. Sondak, Eric H. Jensen, and Kim A. Margolin 98

Soft Tissue Sarcoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Peter W. T. Pisters

2061

99

Gastrointestinal Stromal Tumors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Jason S. Gold and Ronald P. DeMatteo

2087

100 Head and Neck Malignancies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Jeffrey S. Moyer and Carol R. Bradford

2097

101 Surgical Emergencies in the Cancer Patient. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Jeffrey J. Sussman

2117

102 Nutritional Care of Cancer Patients. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. David A. August and Maureen B. Huhmann

2123

103 Regional Therapy of Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Douglas L. Fraker

2151

Section Ten Associated Disciplines 104 Urology..................................................................... Joseph C. Presti, Jr.

2175

105 Gynecology.................................................................. Hillary B. Boswell, Janet S. Rader, and David E. Cohn

2197

CONTENTS

106 Neurosurgery................................................................ Philip Starr

xvii 2217

107 Orthopaedic Surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 2233 David W. Lowenberg and Andrew Fang 108 Plastic Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 2263 W. Thomas Lawrence and Adam Lowenstein

Section Eleven Modern Practice of Surgery Technology, the Surgeon, and Surgical Innovation: An Introduction. . . . . . . . . . . . . . . . . .. 2289 Michael E. Gertner and Thomas Krummel 109 Biomaterials and the Evolution of Hernia Repair I: The History of Biomaterials and the Permanent Meshes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 2291 Raul A. Cortes, Edward Miranda, Hanmin Lee, and Michael E. Gertner 110 Biomaterials and the Evolution of Hernia Repair II: Composite Meshes. . . . . . . . . . . . . . .. 2305 Raul A. Cortes, Edward Miranda, Hanmin Lee, and Michael E. Gertner 111 Biomaterials and the Evolution of Hernia Repair III: Biologically Derived Prosthetic Meshes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 231 7 Raul A. Cortes, Edward Miranda, Hanmin Lee, and Michael E. Gertner 112 Injectable Biomaterials in Surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 2325 Bilal Shaii, Carlos Mery, Gary Binyamin, Joseph Knight, and Michael E. Gertner 113 Energy Transfer in the Practice of Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 2345 Tames Wall and Michael E. Gertner 114 Robot-Assisted Surgery: Technology and Current Clinical Status .. . . . . . . . . . . . . . . . . . .. 2355 Russell K. Woo, David A. Peterson, David Le, Michael E. Gertner, and Thomas Krummel Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 2373

Contributors

Craig T. Albanese, MD Professor, Pediatrics and Obstetrics and Gynecology, Department of Surgery, Stanford University Medical Center; Chief, Division of Pediatric Surgery and Director of Surgical Services, Lucile Packard Children's Hospital, Stanford, CA, USA David A. August, MD Associate Professor, Chief, Division of Surgical Oncology, Department of Surgery, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, and the Cancer Institute of New Jersey, New Brunswick, NT, USA Frank A. Baciewicz, Jr., MD Associate Professor, Department of Cardio-Thoracic Surgery, Wayne State University/Harper Hospital, Detroit, MI, USA Carl L. Backer, MD A. C. Buehler Professor, Division of Cardiovascular-Thoracic Surgery, Department of Surgery, Children's Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Philip S. Batie, MD, MBA Professor, Departments of Surgery and Public Health; Chief, Division of Critical Care and Trauma, NewYork-Presbyterian Hospital/Weill Cornell Medical College, New York, NY, USA B. Timothy Baxter, MD Professor, Department of Surgery, University of Nebraska Medical Center and the Methodist Hospital, Omaha, NE, USA Gary Binyamiti, PhD Surgical Innovation Fellow, Department of Surgery, Stanford University, James H. Clark Center, Stanford, CA, USA Mark 1. Block, MD Director, Department of Thoracic Oncology, Memorial Regional Cancer Center, Hollywood, FL, USA David Bloom, PhD Postdoctoral Associate, Department of Surgery, University of Florida College of Medicine, Gainesville, FL, USA Matthew B. Bloom, MD Resident, Department of Surgery, Stanford University, Stanford, CA, USA R. Randal Bollinger, MD, PhD Professor, Departments of Surgery and Immunology, Duke University Medical Center, Durham, NC, USA Roxana M. Bologa, MD Assistant Professor, Departments of Clinical Medicine and Surgery, Weill Cornell Medical College; Co-Director, Peritoneal Dialysis, The Rogosin Institute, New York, NY, USA

xx

CONTRIBUTORS

John Boockvar, MD Alvina and Willis Murphy Assistant Professor, Departments of Neurological Surgery, and Surgery, Weill Cornell Medical College, New York, NY, USA Hillary B. Boswell, MD Staff Physician, The Women's Specialists of Houston, General Obstetrics and Adult Gynecology, Pediatric and Adolescent Gynecology, St. Luke's Medical Tower, Houston, TX, USA Carol R. Bradford, MD, FACS Medical Director, Head and Neck Cancer Clinic; Professor, Department of Otolaryngology/Head and Neck Surgery, University of Michigan, UM Comprehensive Cancer Center, Ann Arbor, MI, USA David Bruce, MD, FACS Transplant Surgeon, Department of Transplant Surgery, LifeLink Healthcare Institute, Tampa, FL, USA Steve E. Calvano, PhD Associate Professor, Department of Surgery, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NT, USA William G. Cance, MD Professor and Chairman, Department of Surgery, University of Florida College of Medicine, Gainesville, FL, USA Kathleen King Casey, MD Chief, Infectious Disease, Department of Medicine, Jersey Shore University Medical Center, Neptune, NJ, USA George f. Chang, MD Assistant Professor, Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA Kyle Chapple, MD Resident, Department of Neurological Surgery, Weill Cornell Medical College, New York, NY, USA Edgar Chedtawy, MD Assistant Professor, Department of Surgery, University of Illinois at Chicago, Chicago, IL, USA David E. Cohn, MD Associate Professor, Divisions of Gynecologic Oncology, Departments of Obstetrics and Gynecology, The Ohio State University College of Medicine and Public Health, Columbus, OH, USA Siobhan A. Corbett, MD Associate Professor, Department of Surgery, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Clinical Academic Building, New Brunswick, NT, USA Raul A. Cortes, MD Clinical Fellow, Department of Surgery, University of California, San Francisco, San Francisco, CA, USA Myriam J. Curet, MD, FACS Associate Professor, Department of Surgery, Stanford University, Stanford, CA, USA Gail Darling, MD, FACS, FRCSC Associate Professor, Department of Thoracic Surgery, University Health Network, Toronto, Ontario, Canada John Mihran Davis, MD Professor, Department of Surgery, Jersey Shore University Medical Center, Neptune, NT, USA R. Duane Davis, MD Professor, Division of Cardiothoracic Surgery, Department of Surgery, Duke University Medical Center, Durham, NC, USA

CONTRIBUTORS

xxi

Laura A. Dawson, MD Assistant Professor, Department of Radiation Oncology, University of Toronto/Princess Margaret Hospital, Toronto, Ontario, Canada Haile T. Debas, MDt Executive Director, UCSF Global Health Sciences; Maurice Galante Distinguished Professor, Dean Emeritus, School of Medicine, Vice Chancellor Emeritus, Medical Affairs, Chancellor Emeritus, Department of Surgery, University of California, San Francisco, San Francisco, CA, USA William de Bois, MD Fellow, Department of Surgery, Heart Center at Stony Brook, Stony Brook University, Stony Brook, NY, USA Ronald P. DeMatteo, MD Vice Chair, Department of Surgery; Head, Division of General Surgical Oncology; Director, General Surgical Oncology Fellowship Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Frank C. Detterbeck, MD Professor; Section Chief; Surgical Director, Department Thoracic Oncology; Associate Director, Department for Clinical Affairs, Yale Cancer Center, Yale-New Haven Hospital, New Haven, CT, USA James P. Dolan, MD Lieutenant Colonel, USAF, MC, Chief, Department of General Surgery, Keesler Medical Center, Biloxi, MI, USA Jessica Scott Donington, MD Assistant Professor, Department of Cardiothoracic Surgery, Stanford University Medical Center, Stanford, CA, USA John H. Donohue, MD Professor, Department of Surgery, Mayo Medical School; Consultant, Division of Gastroenterologic and General Surgery, Mayo Clinic, Rochester, MN, USA David J. Dries, MSE, MD Assistant Medical Director, Department of Surgical Care, HealthPartners Medical Group; John F. Perry, Jr. Professor, Department of Surgery, University of Minnesota, St. Paul, MN, USA David L. Dunn, MD, PhD Vice President for Health Sciences, Professor, Department of Surgery, University at Buffalo/SUNY, Buffalo, NY, USA Soumitra R. Eachempati, MD Associate Professor, Departments of Surgery and Public Health, Weill Cornell Medical College; Associate Attending Surgeon, NewYork-Presbyterian Hospital, New York, NY, USA Eric A. Elster, MD Assistant Professor, Department of Surgery, Uniformed Services University; Transplantation Branch, National Institutes of Health, Bethesda, MD, USA Andrew Fang, MD Attending, Department of Orthopedics, South San Francisco Medical Center, San Francisco, CA, USA Peter L. Faries, MD Chief, Departments of Endovascular Surgery and Surgery, Cornell University, Weill Cornell Medical College, Columbia University College of Physicians and Surgeons, New York, NY, USA Douglas G. Farmer, MD Associate Professor, Department of Surgery, David Geffen School of Medicine at UCLA; Director, Intestinal Transplant Program, Director, Pediatric Liver Transplant Program, Co-Director, Intestinal Failure Center, Division of Liver and Pancreas Transplantation, Dumont UCLA Transplant Center, Los Angeles, CA, USA

xxii

CONTRIBUTORS

Alison M. Fecher, MD Fellow, Department of Surgery, Duke University Medical Center, Durham, NC. USA Hiran C. Fernando, MBBS Associate Professor, Department of Cardiothoracic Surgery, Boston University, Boston, MA, USA Mathew 1. Foley, MD Vascular Surgeon, Legacy Columbia Vascular and Endovascular Division, Legacy Emanuel Hospital and Health Center, Portland, OR, USA Ramsey A. Foty, PhD Assistant Professor, Department of Surgery, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ, USA Douglas L. Fraker, MD Jonathon Rhoads Professor, Department of Surgery; Vice-Chairman, Clinical Affairs, Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA Justin F. Fraser, MD Resident, Department of Neurological Surgery, NewYork-Presbyterian Hospital, New York, NY, USA Joseph S. Friedberg, MD Associate Professor, Chief, Division of Thoracic Surgery, Department of Surgery, University of Pennsylvania Medical Center at Presbyterian, Philadelphia, PA, USA Donald E. Fry, MD Adjunct Professor, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Michael J. Gardner, MD Senior Clinical Associate, Department of Orthopaedic Surgery, Hospital for Special Surgery, New York, NY, USA Marc R. Garfinkel, MD Assistant Professor, Department of Surgery, University of Chicago Medical Center, Center for Advanced Medicine, Chicago, IL, USA Randolph L. Geary, MD Professor, Department of General Surgery, Wake Forest University School of Medicine, Winston-Salem, NC, USA Michael E. Gertner, MD Consulting Assistant Professor, Department of Surgery, Stanford University, Stanford, CA, USA Scott N. Gettinger, MD Assistant Professor, Department of Medicine, Yale Medical Oncology, New Haven, CT, USA Enrique Ginzberg, MD Professor, DeWitt Daughtry Family, Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA Robert E. Glasgow, MD Assistant Professor, Department of Surgery, University of Utah, S.alt Lake City, UT, USA Claudia E. Goettler, MD Assistant Professor, Traumatology and Surgical Critical Care, Department of Surgery, Brody School of Medicine, East Carolina University, Greenville, NC, USA Jason S. Gold, MD Staff Surgeon, Surgical Service VA Boston Healthcare System, West Roxbury MA; Lecturer, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA

CONTRIBUTORS

xxiii

Michael A. Golden, MD Chief, Division of Vascular Surgery and Endovascular Therapy, Department of Surgery, Penn Presbyterian Medical Center, Philadelphia, PA, USA Vita Golubovskaya, PhD Research Assistant Professor, Department of Surgery, University of Florida College of Medicine, Gainesville, FL, USA Jeffrey Hammond, MD, MBA, MPH Professor, Department of Surgery, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ, USA Douglas W. Hanto, MD, PhD Lewis Thomas Professor, Department of Surgery, Harvard Medical School; Chief, Division of Transplantation, Beth Israel Deaconess Medical Center, Boston, MA, USA Robert C. Harland, MD Associate Professor, Departments of Surgery and Medicine, Director, Kidney and Pancreas Transplantation, Comer Children's Hospital, University of Chicago, Center for Advanced Medicine, Chicago, IL, USA Hobart W. Harris, MD, MPH Professor and Chief, Division of General Surgery, Vice-Chair, Department of Surgery, University of California, San Francisco, CA, USA Roger Hartl, MD Assistant Professor, Neurological Surgery, Weill Cornell Medical College, New York, NY, USA David L. Helfet, MD Professor, Department of Orthopaedic Surgery, Weill Cornell Medical Center, Director, Orthopedic Trauma Service, Hospital for Special Surgery/NewYork-Presbyterian Hospital, New York, NY, USA Steven N. Hochwald, MD Assistant Professor, Department of Surgical Oncology, Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL, USA Richard A. Hodin, MD Associate Professor, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Maureen B. Huhmann, MS, RD Instructor, Department of Primary Care, University of Medicine and Dentistry of New Jersey, New Brunswick, NT, USA Danny O. Jacobs, MD, MPH Professor and Chairman, Department of Surgery, Duke University Medical Center, Durham, NC, USA Eric H. Jensen, MD Fellow, Department of Surgical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA Scott R. Johnson, MD Instructor, Department of Surgery, Harvard Medical School; Surgical Director of Kidney Transplantation, Beth Deaconess Medical Center, Boston, MA, USA Daniel B. Jones, MD Associate Professor, Harvard Medical School; Chief, Minimally Invasive Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA Fady M. Kaldas, MD Surgical Research Fellow, Department of Surgery, University of California, Los Angeles, CA, USA

xxiv

CONTRIBUTORS

Seth J. Karp, MD Assistant Professor, Department of Surgery, Harvard Medical School; Division of Transplantation, Beth Israel Deaconess Medical Center, Boston, MA, USA K. Craig Kent, MD Chief, Combined Columbia and Cornell Division of Vascular Surgery, NewYork-Presbyterian Hospital, New York, NY; Professor, Department of Surgery, Columbia University College of Physicians and Surgeons, New York; Greenberg-Starr Professor, Department of Surgery, Weill Cornell Medical College, New York, NY, USA Khalid Kbwaia, MD Instructor, Department of Surgery, Harvard Medical School; Surgical Director of Pancreas Transplantation, Beth Israel Deaconess Medical Center, Boston, MA, USA Allan D. Kirk, MD, PhD Chief, Transplantation Branch, National Institutes of Health, Bethesda, MD, USA Stuart J. Knechtle, MD Ray D. Owen Professor, Departments of Transplantation and Surgery, University of Wisconsin Medical School, Madison, WI, USA Joseph Knight, MS Biodesign Innovation Fellow, Department of Cardiovascular Medicine, Stanford University, Stanford, CA,USA Daniel Kreisel, MD, PhD Assistant Professor, Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA Thomas Krummel, MD Emile Holman Professor and Chair, Department of Surgery, Division of Pediatric Surgery, Stanford University, Stanford, CA, USA John C. Kuchaiczuk, MD Assistant Professor, Department of Cardiothoracic Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA Kenneth A. Kudsk, MD Professor, Department of Surgery, Vice Chairman of Surgical Research, University of WisconsinMadison, Madison, WI, USA Terry C. Lairmore, MD Director, Division of Surgical Oncology, Scott and White Memorial Hospital and Clinic, Texas A&.M University System Health Science Center, Temple, TX, USA ChristineL.Lau,MD Fellow, Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA W. Thomas Lawrence, MD, MPH Professor and Chief, Department of Plastic Surgery, University of Kansas Medical Center, Sutherland Institute, Kansas City, KS, USA

Walter Lawrence, Jr., MD Professor Emeritus, Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University College of Medicine, Richmond, VA, USA David Le, MD Resident, Department of Surgery, Stanford University Medical Center, Stanford, CA, USA Alice Y. Lee, MS Computation Biologist, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

CONTRIBUTORS

xxv

Hanmin Lee, MD Associate Professor, Department of Surgery, Pediatrics, and OB-Gyn and Reproductive Services, University of California, San Francisco, San Francisco, CA, USA Alan T. Lefor, MD, MPH Professor, Department of Surgery, Iichi Medical University, Center for Graduate Medical Education, Shimotsuke, Tochigi, Japan Marcel Levi, MD, PhD Professor, Department of Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Brian Lima, MD Research Fellow, Department of Cardiothoracic Surgery, Duke University, Durham, NC, USA Edward Lin, MD Assistant Professor, Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA Pamela A. Lipsett, MD Professor, Department of Surgery, Anesthesiology/Critical Care Medicine, Johns Hopkins University Schools of Medicine and Nursing, Baltimore, MD, USA Michael T. Longaker, MD, MBA Deane P. and Louise Mitchell Professor, Department of Surgery (Plastic and Reconstructive); Director, Children's Surgical Research, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA, USA Peter P. Lopez, MD Assistant Professor, DeWitt Daughtry Family, Department of Surgery, Miller School of Medicine, University of Miami, Ryder Trauma Center, Jackson Memorial Medical Center, Miami, FL, USA H. Peter Lorenz, MD Associate Professor, Department of Surgery (Plastic and Reconstructive); Investigator, Children's Surgical Research Program, Stanford University School of Medicine, Stanford, CA, USA

Dean G. Lorich, MD Assistant Professor, Department of Orthopedic Surgery, Weill Cornell Medical Center; Associate Director, Orthopaedic Trauma Service, Hospital for Special Surgery/NewYork-Presbyterian Hospital, New York, NY, USA David W. Lowenberg, MD Chairman, Department of Orthopedic Surgery, California Pacific Medical Center, San Francisco, CA, USA Adam Lowenstein, MD Private Practice, Mendacito Center for Aesthetic Plastic Surgery, Santa Barbara, CA, USA Stephen F. Lowry, MD, MBA Professor and Chairman, Department of Surgery, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NT, USA Erika J. Lu, MD Resident, Department of Surgery, Stanford University Medical Center, Stanford, CA, USA Tames D. Luketich, MD Professor, Department of Surgery; Chief, Division of Thoracic and Foregut Surgery, University of Pittsburgh, Pittsburgh, PA, USA Ronald V. Maier, MD Jane and Donald D. Trunkey Professor, Vice Chair, Department of Surgery; Surgeon-in-Chief, Department of Surgery, Harborview Medical Center, Seattle, WA, USA

xxvi

CONTRIBUTORS

Kim A. Margolin, MD Associate Director for Clinical Research, Division of Medical Oncology and Therapeutics Research; Professor, Division of Hematology and Hematopoietic Cell Transplantation; Staff Physician, Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA John C. Marshall, MD Professor, Department of Surgery, Critical Care Medicine, University of Toronto/St. Michael's Hospital, Toronto, Ontario, Canada Jeffrey B. Matthews, MD Christian R. Holmes Professor, Chairman, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA Constantine Mavroudis, MD Willis J. Potts Professor, Department of Surgery; Surgeon-in-Chief, Division of Cardiovascular-Thoracic Surgery, Children's Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL, USA David A. McClusky, III, MD Chief Resident, Department of Surgery, Emory University Hospital, Atlanta, GA, USA Robin S. McLeod, MD, FRCSC Professor, Department of Surgery, University of Toronto; Head, Division of General Surgery, Mount Sinai Hospital, Toronto, Ontario, Canada Spencer J. Melby, MD Senior Resident, Department of General Surgery, Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, MO, USA Carlos Mery, MD, MPH Surgical Innovation Fellow, Department of Surgery, Stanford University, Mountain View, CA, USA Barbara-Ann Millar, MBChB Assistant Professor, Department of Radiation Oncology, University of Toronto/Princess Margaret Hospital, Toronto, Ontario, Canada Edward Miranda, MD Attending Surgeon, Department of Plastic and Reconstructive Surgery, California-Pacific Medical Center, San Francisco, CA, USA Jeffrey F. Moley, MD Professor, Division of General Surgery, Department of Surgery; Chief, Cancer and Endocrine Surgery Section; Associate Director, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA Gregory L. Moneta, MD Professor and Chief, Department of Vascular Surgery, Oregon Health and Science University, Portland, OR, USA John Morton, MD, MPH Director, Department of Bariatric Surgery, Stanford School of Medicine, Stanford, CA, USA Jeffrey S. Moyer, MD Assistant Professor, Department of Otolaryngology, Director of Medical Student Education, University of Michigan, A. Alfred Taubman Health Care Center, Ann Arbor, MI, USA Sean J. Mulvihill, MD Professor and Chair, Department of Surgery; Senior Director of Clinical Affairs, Huntsman Cancer Institute; The University of Utah, Salt Lake City, UT, USA

CONTRIBUTORS

xxvii

Lena M. Napolitano, MD Professor, Department of Surgery; Chief, Surgical Critical Care; Program Director, Surgical Critical Care Fellowship; Associate Chair, Department of Critical Care, University of Michigan School of Medicine, Ann Arbor, MI, USA Avery B. Nathens, MD, PhD, MPH Associate Professor, Director, Surgical Critical Care, Department of Surgery, University of Washington/ Harborview Medical Center, Seattle, WA, USA Tammy Noren, PT, MSPT Assistant Chief Physical Therapist, Department of Rehabilitation Medicine, NewYork-Presbyterian Hospital, Weill Cornell Medical Center, New York, NY, USA Jeffrey A. Norton, MD Robert L. and Mary Ellenburg Professor, Department of Surgery, Chief, Divisions of Surgical Oncology and General Surgery, Department of Surgery, Stanford University Medical Center, Stanford, CA, USA Michael W. O'Dell, MD Acting Chief and Professor, Department of Rehabilitation Medicine, New York, NY, USA Steven M. Opal, MD Professor, Infectious Disease Division, Department of Medicine, Brown Medical School, Providence, RI, USA Theodore N. Pappas, MD Professor and Vice President, Department of Administration and Surgery; Executive Medical Director, Private Diagnostic Clinic, Duke University Medical Center, Durham, NC, USA Helen A. Pass, MD Assistant Professor, Department of Clinical Surgery, Columbia University; Assistant Attending Surgeon, NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, NY, USA Sheela T. Patel, MD Resident, Department of Surgery, Weill Cornell Medical College, Columbia University College of Physicians and Surgeons, New York, NY, USA G. Alexander Patterson, MD Joseph C. Bancroft Professor, Department of Surgery; Chief, Division of Cardiothoracic Surgery, Department of General Thoracic Surgery, Washington University School of Medicine, St. Louis, MO, USA

John F. Perry, ti., MD Professor, Department of Surgery, University of Minnesota, Minneapolis, MN, USA David A. Peterson, MD Resident, Department of Surgery, Stanford University Medical Center, Stanford, CA, USA John E. Phay, MD Assistant Professor, Divisions of Surgical Oncology, Department of Surgery, Vanderbuilt University Medical Center, Nashville, TN, USA Edward H. Phillips, MD Director, Center for Minimally Invasive Surgery, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA Peter W. T. Pisters, MD Professor, Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA Joseph C. Presti, [t., MD Associate Clinical Professor, Department of Urology, University of California, San Francisco, San Francisco, CA, USA

xxviii

CONTRIBUTORS

Janet S. Rader, MD Professor, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology; Associate Professor, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA Michael D. Rollins, MD Assistant Professor, Department of Surgery, University of Utah, Salt Lake City, UT, USA Bruce R. Rosengard, MD Associate Professor, Department of Surgery, Cardiac Surgical Unit, Massachusetts General Hospital, Boston, MA, USA Todd K. Rosengart, MD Chief, Cardiothoracic Surgery, Co-Director of the Heart Center at Stony Brook, Stony Brook University, Stony Brook, NY, USA Michael F. Rotondo, MD Professor, Chairman, Department of Surgery, Brody School of Medicine, East Carolina University, Greenville, NC, USA Grace S. Rozycki, MD, MBA Professor, Department of Surgery; Director, Trauma and Surgical Critical Care, Emory University School of Medicine, Grady Memorial Hospital, Atlanta, GA, USA Ira M. Rutkow, MD Clinical Professor, Department of Surgery, University of Medicine and Dentistry of New Jersey, Newark, NJ, USA Stuart D. Saal, MD Professor, Departments of Clinical Medicine and Surgery, Weill Cornell Medical College; Vice President for Hospital Affairs; Medical Director, Transplantation Program; Co-Director, Renal Consultation Service; Co-Director, Apheresis, The Rogosin Institute, New York, NY, USA Courtney Scaife, MD Assistant Professor, Department of Surgery, University of Utah, Salt Lake City, UT, USA Thomas M. Scalea, MD Physician-in-Chief, R Adams Cowley Shock Trauma Center; Director, Program in Trauma, University of Maryland School of Medicine, Baltimore, MD, USA William P. Schecter, MD Professor, Department Clinical Surgery, University of California, San Francisco, University of California, San Francisco, San Francisco, CA, USA Matthew J. Schuchert, MD Instructor, Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA Daniel J. Scott, MD Associate Professor and William Henderson Chair, Director, Tulane Center for Minimally Invasive Surgery, Tulane University School of Medicine, New Orleans, LA, USA BilalShafi,MD,MSE Surgical Innovation Fellow, Departments of Surgery and Cardiovascular Medicine, Stanford University, Palo Alto, CA, USA Michael B. Shapiro, MD Associate Professor, Department of Surgery, Trauma and Critical Care, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Andrew A. Shelton, MD Assistant Professor, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA

CONTRIBUTORS

xxix

G. Tom Shires, MDt Professor, Department of Surgery, University of Nevada School of Medicine, Las Vegas, NV, USA

Craig L. Slingluff, Jr., MD Joseph Helms Farrow Professor, Department of Surgery, University of Virginia, Charlottesville, VA, USA C. Daniel Smith, MD Professor and Chair, Department of Surgery, Mayo Clinic Jacksonville, Jacksonville, FL, USA

Mark A. Socinski, MD Associate Professor, Department of Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA VernonK. Sondak, MD Chief, Division of Cutaneous Oncology; Professor, Departments of Surgery and Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA David Soybel, MD Senior Staff Surgeon, Division of General and Gastrointestinal Surgery, Brighams and Women's Hospital, Brigham and Women's Hospital, Division of General and Gastrointestinal Surgery, Boston, MA, USA Philip Starr, MD, PhD Associate Professor, Dolores Cakebread Endowed Chair, Co-Director, Functional Neurosurgery Program, Department of Neurological Surgery, University of California, San Francisco; Surgical Director, Parkinson's Disease Research, Education and Care Center (PADRECC) at San Francisco Veteran's Affairs Medical Center, San Francisco, CA, USA Thomas E. Starzl, MD, PhD Professor, Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA Deborah M. Stein, MD, MPH Assistant Professor, Department of Surgery, R Adams Cowley Shock Trauma Center, University of Maryland School of Medicine, Baltimore, MD, USA Larry W. Stephenson, MD Ford-Webber Professor, Department of Surgery; Professor and Chief, Cardiothoracic Surgery, Wayne State University, School of Medicine, Detroit, MI, USA Catherine Sudarshan, FRAS Attending, Cardiothoracic Division, Papworth Hospital, Cambridge, United Kingdom Benjamin C. Sun, MD Associate Professor and Director, Departments of Cardiac Transplantation and Mechanical Support and Surgery, The Ohio State University Medical Center, Columbus, OH, USA Thoralf M. Sundt, MD Professor, Department of Surgery, Mayo Clinic, Rochester, MN, USA Jimmy C. Sung, MD, JD Senior Resident, Department of Surgery, University of South Florida, Tampa, FL, USA Teffrey f. Sussman, MD Assistant Professor, Department of Surgery, University of Cincinnati/VAMC Cincinnati, Cincinnati, OH, USA

J.

Richard Thistlethwaite, MD, PhD Professor, Department of Surgery; President, Medical Staff, The University of Chicago Medical Center, Chicago, IL, USA "Deceased

xxx

CONTRIBUTORS

Jesse E. Thompson, MD Professor, Department of Surgery, Baylor University Medical Center, Dallas, TX, USA Robert W. Thompson, MD Professor, Departments of Surgery (Section of Vascular Surgery), Radiology, and Cell Biology and Physiology; Vice-Chairman for Research, Department of Surgery; Attending Surgeon, Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, MO, USA Bryan W. Tillman, MD, PhD Assistant Instructor, Department of Surgery, Wake Forest University Medical Center, Winston-Salem, NC, USA Joseph D. Tobias, MD Vice-Chairman, Department of Anesthesiology; Russell and Mary Shelden Chair, Department of Pediatric Intensive Care; Chief, Division of Pediatric Anesthesiology; Professor, Department of Pediatrics and Anesthesiology, University of Missouri, Columbia, MO, USA f.E. Tuttle-Newhall, MD Assistant Professor, Department of Surgery, Duke University, Durham, NC, USA Robert Udelsman, MD, MBA Professor and Chairman, Department of Surgery, Yale University School of Medicine, New Haven, CT, USA Tom van der Poll, MD, PhD Professor, Laboratory of Experimental Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Madbulika G. Varma, MD Attending, UCSF Center for Colorectal Surgery, University of California, San Francisco, Medical Center, San Francisco, CA, USA Malica Vukovic, MD Instructor, Department of Medicine, Evanston Hospital, Evanston, IL, USA James Wall, MD Resident, Department of Surgery, University of California, San Francisco, San Francisco, CA, USA Russell Wall, MD Director, Resident Education, Department of Anesthesia, Georgetown University, Washington, DC, USA Olivia Walton, PA-C Physicians Assistant, Department of Anesthesiology, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, USA John C.L. Wang, MD, PhD Professor, Departments of Clinical Medicine and Surgery, Weill Cornell Medical College; Vice President for Out-Patient Services; Director, Jack J. Dreyfus Clinic of Rogosin Kidney Center; Director, Adoptive Immunotherapy Program; Director, Nephrology; Co-Director, Renal Consultation Service, The Rogosin Institute, New York, NY, USA Ronald f. Weigel, MD, PhD Professor and Head, Department of Surgery, University of Iowa Roy J. and Lucille A. Carver College of Medicine and University of Iowa Hospitals and Clinics, Iowa City, lA, USA Sharon M. Weinstein, MD Associate Professor, Department of Anesthesiology, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, USA Mark L. Welton, MD Associate Professor, Department of Surgery, Stanford University Medical Center, Stanford, CA, USA

CONTRIBUTORS

xxxi

Michael A. West, MD, PhD Professor, Department of Surgery, Trauma/Critical Care, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA Brad A. Winterstein, MD Assistant Professor, Department of Surgery, University of Nebraska Medical Center and the Methodist Hospital, Omaha, NE, USA Susannah S. Wise, MD Instructor, Department of Surgery, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NT, USA Russell K. Woo, MD General Surgery Resident, Department of Surgery, Stanford University Medical Center, Stanford, CA, USA Amy D. Wyrzyk a wski, MD Assistant Professor, Department of Surgery, Emory University School of Medicine, Grady Memorial Hospital, Atlanta, GA, USA Marineh Yagubiati, MD Resident, Department of Surgery, Mayo Clinic, Rochester, MN, USA Timothy J. Yeatman, MD Associate Center Director, Department of Clinical Investigations; Professor, Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA Roger W. Yurt, MD Johnson and Johnson Distinguished Professor and Vice Chairman, Department of Surgery; Director, William Randolph Hearst Bum Center, Weill Cornell Medical College, NewYork-Presbyterian Hospital, New York, NY, USA

Evidence-Based Tables All evidence-based tables are indicated in the text by an TABLE 6.1.

Perioperative and Early Feeding Studies with Substantial Number of Well-Nourished or Moderately Malnourished Patients . . . . . . . . . . . . . . . . . . .

114

TABLE 6.2.

Enteral Versus Parenteral or Delayed Feeding in Trauma Patients . . . . . . . . . . .

115

TABLE 6.3.

Enteral Versus Parenteral or Other Therapy in General Surgical Patients. . . . .

116

TABLE 6.4.

Immune-Enhancing Diets Versus Standard Diet. . . . . . . . . . . . . . . . . . . . . . . . . .

119

TABLE 6.5.

Carbohydrate Versus Lipid as Primary Nonprotein Calorie Source. . . . . . . . . . .

121

TABLE 8.1.

Summary of Randomized Controlled Trials on the Efficacy and Safety of Low Molecular Weight Heparin in the Prevention of Postoperative Venous Thromboembolism in Patients Undergoing General Surgery, Major Orthopedic Surgery (Total Hip Replacement and Total Knee Replacement), and Trauma Surgery (Level I Evidence )

152

TABLE 9.5.

Indications for Cryoprecipitate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

170

TABLE 9.6.

Results of Epidemiological Studies on Anemia and Blood Transfusion in Critical Care. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

172

TABLE 12.2.

Recent Prospective Trials of Antibiotic Therapy for Complicated Skin and Skin Structure Infections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

241

TABLE 12.4.

Recent Prospective Trials of Antibiotic Therapy for Complicated Skin and Skin Structure Infections of the Foot in Patients with Diabetes Mellitus . . . . .

243

TABLE 12.11.

Systemic Antimicrobial Prophylaxis in Colorectal Surgery: Systematic Review of Randomized Controlled Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

247

TABLE 12.13.

Antibiotic Prophylaxis for Reduction of Surgical Site Infection Following Clean Surgery: Two Meta-Analyses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

248

TABLE 12.14.

Meta-Analysis of Measures to Prevent Infection Following Arterial Reconstruction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

248

TABLE 13.1.

Bacteria Isolated from Clinical Intraabdominal Infect ion (% of Patients in Whom a Particular Organism Was Recovered) . . . . . . . . . . . . . . . . . . . . . . . . .

260

TABLE 13.3.

Adjunctive (Nonantibiotic) Measures to Prevent Infection . . . . . . . . . . . . . . . . . .

262

TABLE 13.4.

Use of Perioperative Antibiotic Prophylaxis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

264

TABLE 13.5.

Open Appendectomy (OA) Versus Laparoscopic Appendectomy (LA) for Acute Appendicitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

265

TABLE 13.6.

Single-Stage Versus Two-Stage Operation for Complicated Acute Diverticulitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

266

TABLE 13.7.

Antibiotics for Abdominal Trauma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

268

TABLE 17.4.

Guidelines to Perioperative Cardiovascular Evaluation of Noncardiac Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

330

xxxiii

xxxiv

LIST OF EVIDENCE-BASED TABLES

TABLE 17.5.

Evidence-Based Pulmonary Risk Stratification for Noncardiothoracic Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

331

TABLE 17.6.

Evidence-Based Strategies to Reduce Pulmonary Risk for Noncardiothoracic Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

332

TABLE 17.9.

Summary of Evidence-Based Guidelines for Prevention of Venous Thromboembolic Disease in Surgical Patients from Fifth American College of Chest Physicians Consensus Conference on Antithrombotic Therapy, 1998

333

TABLE 17.13.

Summary of Evidence-Based Guidelines for Red Blood Cell Transfusions for Acute Blood Loss. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

338

TABLE 17.14.

Summary of Evidence-Based Guidelines for Red Blood Cell and Plasma Transfusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

338

TABLE 17.17.

Evidence-Based Practice Management Guideline for the Evaluation of Fever in Critically III Adult Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

344

TABLE 17.18.

Summary of Evidence-Based Clinical Guidelines for the Prevention of Nosocomial Bacterial Pneumonia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

346

TABLE 19.2.

Preoperative Versus Postoperative Analgesia. . . . . . . . . . . . . . . . . . . . . . . . . . . . .

384

TABLE 19.3.

Local Infusion Pump Versus Systemic Opioids . . . . . . . . . . . . . . . . . . . . . . . . . . .

386

TABLE 19.4.

Minimally Invasive Surgery Versus Open Surgery. . . . . . . . . . . . . . . . . . . . . . . . .

387

TABLE 19.7.

Epidural Versus Intravenous Opioid Postoperative Analgesia. . . . . . . . . . . . . . . .

389

TABLE 22.5.

Evidence for Utility of Pulmonary Artery Catheter in Perioperative Patients. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

417

TABLE 22.6.

Evidence for Utility of Pulmonary Artery Catheter in Monitoring Critically III Patients. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

418

TABLE 25.2.

Management of Inhalation Injury. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

450

TABLE 25.4.

Bum Shock Resuscitation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

451

TABLE 25.7.

Reports on Mortality in Patients with Thermal Injury in the Past Decade............................................................

456

TABLE 27.1.

Representative Clinical Experience with CT Scan for the Diagnosis of Penetrating Torso Trauma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

474

TABLE 27.2.

Representative Clinical Experience with CT Scan for the Diagnosis of Blunt Chest Trauma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

478

TABLE 27.3.

Representative Clinical Experience with CT Scan for the Diagnosis of Blunt Abdominal Trauma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

480

TABLE 27.4.

Representative Clinical Experience with Ultrasound for the Diagnosis of Torso Trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

482

TABLE 27.5.

Representative Clinical Experience with Nonoperative Management of Blunt Hepatic Injuries. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

487

TABLE 27.6.

Representative Clinical Experience with Nonoperative Management of Blunt Splenic Injuries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

490

TABLE 28.2.

Therapeutic Angiographic Embolization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

509

TABLE 28.4.

Prospective Evaluation of the Effect of a Damage Control Approach Versus Early Intramedullary Nailing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

512

TABLE 28.5.

Plate Fixation to Reamed Intramedullary Nailing in Chest Injury. . . . . . . . . . .

514

TABLE 28.6.

Early Fracture Stabilization and Worse Neurological Outcomes. . . . . . . . . . . . .

515

TABLE 28.7.

Early Fixation of Fractures in the Brain-Injured Patient with Good Outcomes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

516


TABLE 31.3.

xxxv

Published Reports of Studies of Corticosteroids in the Management of Patients with Sepsis/Systemic Inflammatory Response Syndrome (SIRS)/MODS. All Studies Were Prospective, Randomized Trials (Class 1 Evidence) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

569

Five Randomized, Prospective Trials that Studied Lower Tidal Volumes Versus Conventional Tidal Volumes in Patients Requiring Ventilator Support. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

569

TABLE 31.5.

Studies Designed to Neutralize or Bind Endotoxin in the Management of Patients with Sepsis, Septic Shock, and Organ Failure. . . . . . . . . . . . . . . . . . .

571

TABLE 31.6.

Clinical Trials that Have Attempted to Block or Modulate the Vasoactive Phase (Phase I) of the Systemic Inflammatory Response. All Interventions Were Prospective and Placebo-Controlled. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

572

TABLE 31.7.

Platelet-Activating Factor (PAF). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

572

TABLE 31.8.

Clinical Trials that Have Attempted to Modulate the Cytokine Response of Phase 2 of the Inflammatory Response. All Trials Were Prospective and Placebo Controlled (Class 1 Evidence) in Patients with the Clinical Diagnosis of Sepsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

573

TABLE 32.3.

Major Contemporary Trials Comparing Ventilator Weaning Modes. . . . . . . . . .

583

TABLE 32.6.

Overview of Ventilatory Strategies for Acute Lung Injury and the Acute Respiratory Distress Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

589

TABLE 32.7.

Summary of Randomized Trials of Low Tidal Volume Ventilatory Strategies in Treatment of Adult Patients with ALI/ARDS. . . . . . . . . . . . . . . . . . . . . . . . . .

590

TABLE 33.9.

Prospective Trials of Renal Replacement Therapy for Acute Renal Failure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

609

TABLE 34.3.

Intraabdominal Pressure (lAP) Effects on the Cardiovascular System. . . . . . . . .

617

TABLE 34.4.

Intraabdominal Pressure Effects on the Pulmonary System. . . . . . . . . . . . . . . . .

618

TABLE 34.5.

Intraabdominal Pressure Effects on the Renal System . . . . . . . . . . . . . . . . . . . . .

618

TABLE 34.6.

lAP Effects on the Splanchnic Circulation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

619

TABLE 34.7.

Effect of lAP on Intracranial Pressure (ICP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

620

TABLE 34.8.

lAP Effect on Abdominal Wall. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

620

TABLE 34.9.

lAP Effect on Endocrine and Cytokine Function. . . . . . . . . . . . . . . . . . . . . . . . . .

621

TABLE 35.4

Selected Evidence-Based Trials for Medications Management in Acquired Brain Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

637

TABLE 36.12.

Large (More Than 100 patients) Published Series of Pediatric Laparoscopic Fundoplication for Gastroesophageal Reflux Disease (GERD) . . . . . . . . . . . . . . .

667

TABLE 36.13.

Published Data Comparing Laparotomy (LAP) to Primary Peritoneal Drainage (PPD) for the Treatment of Perforated Necrotizing Enterocolitis (NEC)

674

TABLE 36.21.

Prospective Randomized Clinical Trials in Fetal Surgery for Severe Congenital Diaphragmatic Hernia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

693

TABLE 38.1.

Comparative Surgical Trials, 1977-1989. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

712

TABLE 38.2.

Comparative Surgical Trials, 1989-2006. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

712

TABLE 38.3.

Medical Versus Surgical Treatment of Obesity. . . . . . . . . . . . . . . . . . . . . . . . . . .

712

TABLE 38.8.

Cost-Effectiveness of Bariatric Surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

718

TABLE 38.10.

Gastric Bypass Techniques. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

720

TABLE 38.11.

Gastric Bypass Practice Patterns. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

720

TABLE 38.12.

Adjustable Gastric Banding Technique Trials. . . . . . . . . . . . . . . . . . . . . . . . . . . .

721

TABLE 31.4.

xxxvi


TABLE 38.13.

Sleeve Gastrectomy Trials. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

722

TABLE 38.14.

Intragastric Balloon Trials. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

722

TABLE 38.15.

Pacing Trials. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

722

TABLE 39.3.

Reported Cases of Laparoscopic Biliary Tract Surgeries During Pregnancy Trimester . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

733

TABLE 39.4.

Reported Cases of Laparoscopic Appendectomy During Pregnancy Trimesters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

734

TABLE 43.3.

Prospective Clinical Studies (Level II Evidence) of Hemodynamic Responses to Carbon Dioxide Pneumoperitoneum in Healthy Adults Compared to a Control Group Postinduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

774

Prospective Clinical Studies (Level II Evidence) of Hemodynamic Responses to Carbon Dioxide Pneumoperitoneum in Adults with Cardiopulmonary Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

775

TABLE 43.5.

Randomized Controlled Animal Studies (Level I Evidence) of Hemodynamic Responses to Laparoscopy Compared to Postinduction Control. . . . . . . . . . . . .

776

TABLE 43.6.

Level II Human Studies on the Metabolic and Immune Responses to Laparoscopic Versus Open Cholecystectomy. . . . . . . . . . . . . . . . . . . . . . . . . . . . .

781

TABLE 43.7.

Vascular and Bowel Injuries During 77,604 Laparoscopic Cholecystectomies (Level III Evidence) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

783

TABLE 44A.8.

Selective Review of Cited Experiences Using >80U Botulinum Toxin (Botox) for Treatment of Adults with Achalasia (Studies with 20 or More Subjects) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

800

TABLE 44A.9.

Review of Cited Experience with Operative Myotomy After Prior Endoscopic Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

801

TABLE 44A.I0.

Review of Cited Experience Using Balloon Dilation Versus Operative Myotomy for Treatment of Achalasia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

801

TABLE 44A.ll.

Review of Studies Evaluating Antireflux Procedure After Heller Myotomy (>20 patients, >12 month follow-up) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

803

TABLE 44A.15.

Summary of Results in Managing Pharyngoesophageal Diverticula. . . . . . . . . .

805

TABLE 44A.17.

Healing Rates of Esophagitis: PPI Versus H 2RA . . . . . . . . . . . . . . . . . . . . . . . . . . .

808

TABLE 44A.18.

Review of Cited Reports of Surgical Revision After Failed Fundoplication. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

812

TABLE 44A.19.

Cited Cohort Studies Evaluating Endoscopic Endoluminal Therapies. . . . . . . . .

813

TABLE 44A.20.

Cited Randomized Controlled Sham Trials Regarding Endoscopic Endoluminal Therapy for Gastroesophageal Reflux. . . . . . . . . . . . . . . . . . . . . . . .

813

TABLE 44A.22.

Medical Versus Surgical Treatment of Barrett's Esophagus. . . . . . . . . . . . . . . . .

814

TABLE 44A.23.

Antireflux Surgery and Regression of Barrett's Esophagus. . . . . . . . . . . . . . . . . .

815

TABLE 44A.24.

Antireflux Surgery and Progression of Barrett's to Dysplasia or Adenocarcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

815

TABLE 44B.4.

Operative Mortality, Morbidity, and Survival for Esophagectomy for Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

829

TABLE 44B.5.

Morbidity of Esophagectomy for Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

829

TABLE 44B.8.

Randomized Trials of Preoperative Chemotherapy Versus Surgery Alone. . . . .

833

TABLE 44B.9.

Randomized Trials of Neoadjuvant Chemoradiation and Surgery Versus Surgery Alone ..............................................

835

TABLE 44B.I0.

Comparison of Treatment Alternatives by Meta-analyses. . . . . . . . . . . . . . . . . .

836

TABLE 45.7.

Randomized, Double-Blinded, Placebo-Controlled, Crossover Trials of Octreotide Treatment for Severe Dumping Syndrome . . . . . . . . . . . . . . . . . . .

857

TABLE 43.4.


xxxvii

TABLE 45.11.

Comparison of 5-Year Survival from the Dutch Study to American and Japanese Results ...........................................

863

TABLE 45.12.

Reconstructive Options Following Distal Gastrectomy (Level I Evidence) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

864

TABLE 45.13.

Reconstructive Options Following Total Gastrectomy (Level I Evidence) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

864

TABLE 46.7.

Randomized, Controlled Clinical Trials of Early Endoscopic Sphincterotomy in Gallstone Pancreatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

884

TABLE 46.9.

Randomized, Controlled Clinical Trials of Prophylactic Antibiotic Therapy in Necrotizing Pancreatitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

885

TABLE 46.10.

Results of Longitudinal Pancreaticojejunostomy for Chronic Pancreatitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

889

TABLE 46.11.

Results of Pancreatic Resection for Chronic Pancreatitis. . . . . . . . . . . . . . . . . . .

890

TABLE 46.13.

Randomized, Controlled Clinical Trials Comparing Pylorus-Preserving Pancreaticoduodenectomy (PPPD) Versus Standard Whipple Procedure for Pancreatic Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

897

TABLE 46.14.

Randomized, Controlled Trials of Adjuvant Therapy Following Potentially Curative Pancreaticoduodenectomy for Pancreatic Adenocarcinoma . . . . . . . . .

898

TABLE 46.15.

Survival Following Pancreaticoduodenectomy for Pancreatic Adenocarcinoma: Recent Trials. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

900

TABLE 47.4.

Clinical Trials Comparing Early Versus Delayed Surgery for Acute Cholecystitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

924

TABLE 47.9.

Global Results of Laparoscopic Cholecystectomy. . . . . . . . . . . . . . . . . . . . . . . . .

933

TABLE 47.16.

Results of Aggressive Surgical Resection of Hilar Cholangiocarcinoma (1996-1998). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

938

TABLE 48.5.

Review of Regional Therapies for Hepatic Neoplasms. . . . . . . . . . . . . . . . . . . . .

952

TABLE 49.3.

Success Rates for Standard (Short) Versus Long Intestinal Tubes in Patients with Small-Bowel Obstruction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

971

TABLE 50.6.

Advantages of Laparoscopic Versus Conventional Open Appendectomy. . . . ..

1004

TABLE 50.7.

Quantitative Comparison: Laparoscopic (L) Versus Conventional Open (0) Appendectomy: Summary of Information in the Cochrane Database of Systematic Reviews. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

1004

TABLE 51.3.

Results After Strictureplasty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

1023

TABLE 51.11.

Impact of Fecal Occult Blood Testing on Mortality from Colorectal Malignancy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

1052

TABLE 51.12.

Impact of Sigmoidoscopy on Mortality from Colorectal Malignancy. . . . . . . ..

1052

TABLE 51.20.

Results for Selected Recent Series of Local Excision of Rectal Cancer Alone with Intent to Cure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

1066

TABLE 51.21.

Results for Selected Recent Series of Local Excision of Rectal Cancer with Postoperative Adjuvant Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

1067

TABLE 51.22.

Results of Randomized Trials of Preoperative Radiotherapy (Level I Evidence). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

1071

TABLE 51.23.

Results of Randomized Trials of Postoperative Radiotherapy (Level I Evidence). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

1071

TABLE 51.24.

Results of Randomized Trials of Combined Chemoradiation (Level I Evidence). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

1072

TABLE 51.28.

Results for Sigmoid Resection with Rectopexy for Rectal Prolapse. . . . . . . . . ..

1090

TABLE 51.29.

Results of the Delorme Procedure for Rectal Prolapse. . . . . . . . . . . . . . . . . . . ..

1091

xxxviii


TABLE 51.30.

Results for the Altemeier Procedure for Rectal Prolapse

.

1092

TABLE 52.5.

Adult Matched Retrospective Studies of Laparoscopic Versus Open Splenectomy for Disease (Level II Evidence)

.

1123

TABLE 52.6.

Adult Nonmatched Retrospective Studies

.

1124

TABLE 52.7.

Nonmatched Retrospective Study of Laparoscopic Splenectomy for Idiopathic Thrombocytopenia Purpura (LSI) Versus Laparoscopic Splenectomy for Other Diseases (LSO) (Level III Evidence) .

1124

TABLE 52.8.

Adult Matched Restrospective Study of Laparoscopic Versus Open Splenectomy for Idiopathic Thrombocytopenia Purpura (Level n Evidence)....

1124

TABLE 52.9.

Adult Nonmatched Retrospective Studies of Laparoscopic Versus Open Splenectomy for Disease (Level ill Evidence)

.

1124

TABLE 52.10.

Pediatric Matched Retrospective Study of Laparoscopic Versus Open Splenectomy for Disease (Level II Evidence)

.

1125

TABLE 52.11.

Pediatric Nonmatched Retrospective Study of Laparoscopic Versus Open Splenectomy for Disease (Level III Evidence)

.

1126

TABLE 52.12.

Nonmatched Retrospective Study of Laparoscopic Versus Open Splenectomy for Splenomegaly (Level ill Evidence) .

1126

TABLE 52.13.

Nonmatched Retrospective Studies of Laparoscopy Performed for Benign and . Malignant Diseases (Level ill Evidence)

1127

TABLE 53.4.

Select Prospective Randomized Trials Comparing Laparoscopic and Open Inguinal Hernia Repairs (Level I Evidence)

.

1149

TABLE 53.5.

Trials Comparing Different Types of Laparoscopic Repairs

.

1155

TABLE 53.6.

Trials Comparing Laparoscopic and Open Ventral Hernia Repairs

.

1166

TABLE 53.7.

Cohort Trials for Laparoscopic Ventral Hernia Repair

.

1169

TABLE 55.2.

Imaging Modalities Before Initial Operations for Primary Hyperparathyroidism (PHPT) .

1193

TABLE 55.3.

Imaging Modalities in Reoperative Parathyroidectomies: Overall Results

.

1195

TABLE 55.6.

Overall Results of Initial Operations for Primary Hyperparathyroidism

.

1199

TABLE 55.7.

Surgical Outcome for Reoperative Surgery

.

1202

TABLE 55.9.

Overall Results of Initial Operations for Secondary Hyperparathyroidism

.

1203

TABLE 56.3.

Proponents Supporting Less Than Total Thyroidectomy (Level II Evidence)

.

1219

TABLE 56.4.

Proponents Supporting Total Thyroidectomy (Level II Evidence)

.

1220

TABLE 57.12.

Laparoscopic Versus Open Adrenalectomy

.

1242

TABLE 58.6.

Outcome of Various Preoperative Localization Studies for Neuroendocrine Tumors

.

1257

TABLE 58.9.

Outcome of Surgical Management of Insulinoma and Gastrinoma and Survival After Gastrinoma Resection

.

1263

TABLE 58.11.

Incidence, Metastatic Disease, and 5-Year Survival for Carcinoid Tumors at Different Anatomic Sites

.

1275

TABLE 59.5.

Development of a Contralateral Pheochromocytoma After Unilateral Adrenalectomy (Level II Evidence)

.

1292

TABLE 59.6.

Results of Operation for Hyperparathyroidism in Patients with MEN 2A (Level II Evidence)

.

1293

TABLE 60.1.

First Carotid Reconstructions for Cerebrovascular Insufficiency in Chronological Order . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1309

TABLE 61.1.

Primary Prevention of Atherosclerosis in High Risk Patients (Level 1 Evidence)

1323

.


xxxix

TABLE 61.2.

Secondary Prevention of Atherosclerosis in Patients with Established Atherosclerotic Vascular Disease (Levell Evidence). . . . . . . . . . . . . . . . . . . . . ..

1323

TABLE 62.1.

Influence of the Technique of Carotid Endarterectomy on Rates of Perioperative Stroke/Death and Restenosis . . . . . . . . . . . . . . . . . . . . . . . . . . ..

1343

TABLE 62.2.

Influence of Anesthetic Technique on Perioperative Complications in Patients Undergoing CEA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

1344

TABLE 62.3.

Influence of Method of Arteriotomy Closure on Perioperative Complications and Restenosis in Patients Undergoing CEA . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

1346

TABLE 62.4.

Series of Carotid Angioplasty and Stenting (Level II Evidence) . . . . . . . . . . . . ..

1348

TABLE 63.1.

Management of Acute Aortic Syndromes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

1362

TABLE 63.2.

Prevention of Spinal Cord Infarction During Thoracic and Thoracoabdominal Aortic Aneurysm Repair. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

1368

TABLE 64.1.

Results of Innominate Artery Reconstruction (Level III Evidence) . . . . . . . . . ..

1377

TABLE 64.7.

Results for Transaxillary First Rib Resection (Level III Evidence) . . . . . . . . . . ..

1392

TABLE 64.8.

Results for Supraclavicular Scalenectomy/First Rib Resection (Level III Evidence) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

1393

TABLE 65.1.

Randomized Controlled Trials of Ultrasound Screening for Abdominal Aortic Aneurysm (AAA). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

1398

TABLE 65.2.

Randomized Controlled Trials of AAA Intervention. . . . . . . . . . . . . . . . . . . . . ..

1399

TABLE 65.7.

Randomized Trials of Renal Artery Stenosis Treatment Options. . . . . . . . . . ..

1407

TABLE 66.1.

Above-Knee Femoropopliteal Grafts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

1417

TABLE 66.2.

Below-Knee Femoropopliteal Grafts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

1417

TABLE 66.3.

Infrapopliteal Grafts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

1418

TABLE 66.4.

Percutaneous Transluminal Angioplasty Patency. . . . . . . . . . . . . . . . . . . . . . . ..

1419

TABLE 67.7.

Recommendations for Venous Thromboembolism Prophylaxis. . . . . . . . . . . . ..

1434

TABLE 67.8.

PIOPED Central Scan Interpretation Categories and Criteria. . . . . . . . . . . . . . ..

1437

TABLE 67.11.

Randomized Trials of LMWH versus UFH for Treatment of Deep Venous Thrombosis (DVT) (Level I Evidence) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1440

TABLE 68.1.

Vascular Access for Hemodialysis: Complication-Free Function (Level III Evidence) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

1459

TABLE 68.2.

Trials Comparing Surgical to Endovascular Management of Stenosis or Thrombosis of Dialysis Access Grafts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

1465

TABLE 68.3.

Patency Rates of Various Types of Vascular Access for Chronic Hemodialysis (Level III Data) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

1466

TABLE 69.1.

First Year of Successful Intracardiac Repairs Using Cardiopulmonary Bypass or Cross-Circulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

1474

TABLE 70.2.

Randomized Controlled Trials Examining the Impact of Perioperative Beta-Blockade on Patients with Cardiac Risk Factors. . . . . . . . . . . . . . . . . . . . ..

1482

TABLE 70.4.

Prospective Randomized Double-Blind Trials Addressing the Use of Prophylactic Antibiotics in Elective Pulmonary Resections. . . . . . . . . . . . ..

1484

TABLE 70.5.

Prospective Randomized Trials Comparing Suction to Water Seal Following Pulmonary Resections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

1486

TABLE 70.6.

Trials Evaluating Incidence and Prophylaxis for Deep Venous Thrombosis (DVT) in Thoracic Surgery Patients. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

1486

TABLE 70.7.

Randomized Trials with Placebo Control for the Prophylactic Use of Medication for the Prevention of Postoperative Atrial Fibrillation in General Thoracic Surgery Patients. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

1487

xl


TABLE 71.5.

Surgery and Adjuvant Radiotherapy

.

1500

TABLE 71.6.

Surgery and Platin-Based Chemotherapy

.

1502

TABLE 71.7.

Surgery and UFT-Based Chemotherapy

.

1502

TABLE 71.8.

Results of Resection of Patients with T4 Involvement from NSCLC

.

1504

TABLE 71.9.

Results of Traditional Chemoradiotherapy for Stage III NSCLC

.

1506

TABLE 71.10.

Randomized Trial of Sequential Versus Concurrent Chemoradiotherapy for Stage III NSCLC

.

1506

TABLE 71.12.

Randomized Trials of Chemotherapy Versus Basic Supportive Care in Advanced NSCLC

.

1508

TABLE 73.1.

VATS Lobectomy: Morbidity and Mortality

.

1536

TABLE 73.2.

VATS Lobectomy: Recurrence and Survival

.

1537

TABLE 73.3.

VATS Lobectomy: Perioperative Outcomes Data

.

1538

TABLE 73.4.

Comparison of Staging Modalities

.

1541

TABLE 73.5.

Minimally Invasive Esophagectomy: Surgical Outcomes

.

1544

TABLE 73.6.

Minimally Invasive Esophagectomy: Recurrence and Survival

.

1545

TABLE 75.1.

Comparison of Treatment Options for Postoperative Mediastinitis (Retrospective Studies, Level III Evidence)

.

1574

TABLE 75.8.

Prevalence of Thymoma in Patients with Myasthenia Gravis (MG)

.

1586

TABLE 75.9.

Results of Thymectomy for Myasthenia Gravis (Level III Evidence)

.

1587

TABLE 75.11.

Prevalence of Myasthenia Gravis (MG) in Patients with Thymoma

.

1588

TABLE 75.13.

Multimodality Treatment for Invasive Thymoma (Phase II Trials, Level II Evidence)

.

1589

TABLE 75.14.

Combination Chemotherapy for Advanced or Recurrent Thymic Tumors (Level II Evidence)

.

1590

TABLE 77.2.

Coronary Artery Bypass Trials. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1632

TABLE 77.3.

CABG Versus Percutaneous Transluminal Coronary Angioplasty (PTCA) Multivessel Disease Trials

.

1632

TABLE 77.4.

CABG Versus Percutaneous Coronary Intervention (PCI) with Stent Trials

.

1633

TABLE 77.5.

CABG Versus Medical Treatment

.

1633

TABLE 77.7.

Outcomes of CABG Versus PCI

.

1640

TABLE 77.8.

Selected Series of Surgical Repair of Free Wall Rupture of LV, LV Pseudoaneurysm, and LV Aneurysm

.

1643

TABLE 77.9.

Selected Series of Surgical Repair of Postinfarction Ventricular Septal Defect (VSD) and Acute Mitral Insufficiency

.

1644

TABLE 77.13.

Selected Series of Mitral Valve Replacements

.

1662

TABLE 77.14.

Mitral Valve Repair

· ..

1662

TABLE 79.3.

Kidney Transplantation with 6 Months or More Survival as of March

1963

.

1685

TABLE 80.3.

Immunosuppression Approaches

.

1723

TABLE 80.4.

Results of Recent Tolerance and Minimization Trials

.

1728

TABLE 80.5.

Preclinical Tolerance

.

1729

TABLE 80.6.

Xenotransplantation

· ..

1731

TABLE 81.2.

Studies of Calcineurin Inhibitor Withdrawal or Avoidance

.

1738


xli

TABLE 81.3.

Studies of Alemtuzumab [Campath] for Induction . . . . . . . . . . . . . . . . . . . . . . ..

1739

TABLE 81.4.

Studies of Anti-IL2R (Anti-CD25) Antibodies. . . . . . . . . . . . . . . . . . . . . . . . . . ..

1740

TABLE 81.5.

Effects of Positive Flow or B-Cell Crossmatch on Transplant Outcome... . .. .

1742

TABLE 82.4.

Optimal Cold Ischemia Time for Different Organs Based on Class of Evidence

1752

TABLE 85.12.

Liver Transplantation from Donors After Cardiac Death. . . . . . . . . . . . .. . . . ..

1800

TABLE 85.14.

Adult/Adult Split Liver Transplantation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

1807

TABLE 85.15.

Routine Use of T Tubes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

1809

TABLE 85.19.

Prevention of CMV Disease in Liver Transplant Recipients. . . . . . . . . . . . . . ..

1818

TABLE 86.2.

Patient Survival. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

1833

TABLE 86.3.

Graft Survival. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

1834

TABLE 86.5.

Nutritional Autonomy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

1836

TABLE 92.3.

Phase II Studies Evaluating Tyrosine Kinase Inhibitors in Solid Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

1941

TABLE 93.3.

Responses to High-Dose IL-2 Therapy in Human Trials. . . . . . . . . . . . . . . . . . ..

1950

TABLE 94.3.

Comparison of Mastectomy and Breast Conservation Therapy for Early-Stage Breast Carcinoma: Prospective Trials. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

1974

TABLE 94.4.

Effect of Regional Lymph Node Dissection: Prospective Trials. . . . . . . . . . . . ..

1975

TABLE 94.5.

Comparison of Biliary Decompression Techniques in Cancer Patients. . . . . . ..

1979

TABLE 95.2.

Randomized Trials of Mastectomy Compared to Breast-Conserving Surgery and Radiotherapy (Level I Evidence) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

1988

TABLE 95.3.

Randomized Trials of Breast-Conserving Surgery Compared to Breast-Conserving Therapy and Radiotherapy (Level I Evidence). . . . . . . . . . . ..

1989

TABLE 95.4.

Randomized Trials of Postoperative Adjuvant Radiation and Chemotherapy for Rectal Cancer (Level I Evidence) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

1992

TABLE 95.5.

Randomized Trials of Preoperative Adjuvant Radiation for Resectable Rectal Cancer (Level I Evidence) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

1993

TABLE 95.6.

Preoperative Radiation and Chemotherapy for Resectable Esophageal Cancer Randomized Trials (Level I Evidence) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

1995

TABLE 95.7.

Randomized Trials for Organ Preservation in Head and Neck Cancer. . . . . . ..

1997

TABLE 96.7.

Randomized Trial of Mastectomy Versus Breast Conservation (Level I Evidence). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2025

TABLE 96.9.

Sentinel Lymph Node (SLN) Mapping Trials. . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2027

TABLE 97.4.

Current Recommendations for Excision Margins for Cutaneous Melanomas. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2045

TABLE 97.5.

Randomized Trials of Elective Node Dissection in Clinically Localized Cutaneous Melanoma (Level I Evidence) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2046

TABLE 97.6.

Published Randomized Trials of Adjuvant Interferon Therapy in Resected Cutaneous Melanoma (Level I Evidence) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2050

TABLE 98.3.

Results of Surgery Alone for Selected Patients with Soft Tissue Sarcoma. . . ..

2067

TABLE 98.4.

Local Control with Surgery and Radiotherapy for Localized Soft Tissue Sarcoma: Randomized Phase III Trials and Selected Nonrandomized Retrospective Reviews (Level I and Level III Evidence). . . . . . . . . . . . . . . . . . . ..

2068

Phase III Trials of Adjuvant Radiotherapy for Localized Extremity and Trunk Sarcomas Stratified by Grade (Level I Evidence) . . . . . . . . . . . . . . . . . . . . . . . . ..

2068

TABLE 98.5.

xlii


TABLE 98.6.

Randomized Trials of Adjuvant Chemotherapy Versus Observation in Soft Tissue Sarcoma (Level I Evidence). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2070

TABLE 98.7.

Sarcoma Meta-Analysis Collaboration Group Meta-Analysis of Randomized Doxorubucin-Based Postoperative Chemotherapy in Soft Tissue Sarcoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2071

TABLE 98.8.

Survival Following Complete Resection of Pulmonary Metastases from Soft Tissue Sarcoma in Adults. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2075

TABLE 98.9.

Randomized Phase III Trials with Ifosfamide-Containing Treatment Arms in Advanced Soft Tissue Sarcoma (Level I Evidence) . . . . . . . . . . . . . . . . . . . . . . . ..

2077

TABLE 98.10.

Resectability Rates for Retroperitoneal Sarcomas in Selected Series. . . . . . . . ..

2078

TABLE 99.1.

Trials of Imatinib Mesylate in Metastatic Gastrointestinal Stromal Tumor (GIST). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2089

TABLE 99.2.

Response Rates to Chemotherapy in Patients with Metastatic GIST (Level III Evidence) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2091

TABLE 99.3.

Outcome of Complete Surgical Resection of Primary Localized GIST. . . . . . ..

2093

TABLE 100.3.

Patterns of Failure in the Department of Veterans Affairs Laryngeal Cancer Group Trial (Level I Evidence) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2103

TABLE 100.4.

Survival Rates for Larynx Preservation Trials Using Neoadjuvant Chemotherapy (Level I Evidence) .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2104

TABLE 100.5.

Meta-Analysis of Chemotherapy (CT) According to Timing of Chemotherapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2104

TABLE 102.6.

Pharmacological Treatments for Weight Loss. . . . . . . . . . . . . . . . . . . . . . . . . . ..

2128

TABLE 102.10.

Prospective, Randomized Trials Involving 20 or More Subjects of Perioperative Specialized Nutrition Support in Cancer Patients (Level 1 Evidence) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2132

TABLE 102.11.

Prospective, Randomized Trials Involving 30 or More Subjects of Specialized Nutrition Support in Stem Cell Transplantation. . . . . . . . . . . . . . . . . . . . . . . . ..

2134

TABLE 102.12.

Prospective, Randomized Trials Involving 30 or More Subjects of Specialized Nutrition Support in Cancer Patients Undergoing Chemotherapy. . . . . . . . . ..

2135

TABLE 102.14.

Prospective, Randomized Trials Involving 20 or More Subjects of Immune-Supplemented Enteral Nutrition Support in Cancer Patients (Level 1 Evidence) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2138

TABLE 103.5.

Prospective Randomized Trials of Adjuvant Isolated Limb Perfusion (ILP) for Resected High-Risk Primary or In-Transit Melanoma. . . . . . . . . . . . . . . . . . . . ..

2156

TABLE 103.7.

Results of ILP Trials Using TNF to Treat In-Transit Melanoma of the Extremity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2157

TABLE 103.8.

Response Rates and Limb Salvage in Phase II Trials of ILP to Treat Unresectable Soft Tissue Sarcomas of the Extremity. . . . . . . . . . . . . . . . . . . . ..

2158

TABLE 103.10.

Randomized Trials of Intraarterial Chemotherapy for Colorectal Metastases to the Liver. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2161

TABLE 103.11.

Phase II and III Trials of Adjuvant Intraarterial Chemotherapy After Resection of Colorectal Metastases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2162

TABLE 103.12.

Results of Clinical Trials with Isolated Hepatic Perfusion for Metastatic Cancers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2162

TABLE 103.13.

Phase 1/11 Trial of Continuous Hyperthermic Peritoneal Perfusion for Advanced Peritoneal Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2164

TABLE 104.1.

Mechanism and Site of Ureteral Injuries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2184

TABLE 104.2.

Urinalysis and Intravenous Urography in the Diagnosis of Ureteral Injuries. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2184


xliii

TABLE 104.4.

Results of Watchful Waiting Series for Prostate Cancer. . . . . . . . . . . . . . . . . . ..

2188

TABLE 105.2.

Studies Evaluating Ultrasonography in Pelvic Inflammatory Disease (Level II Evidence) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2201

TABLE 105.5.

Studies Evaluating the Surgical Approach to Hemodynamically Stable Ectopic Pregnancy (Level I Evidence) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2203

TABLE 105.6.

Studies Evaluating Radical Versus Conservative Surgical Management of Ectopic Pregnancy (Level II Evidence). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2203

TABLE 105.8.

Studies Evaluating the Use of Color Doppler Sonography in the Diagnosis and Management of Ovarian Torsion (Level II Evidence). . . . . . . . . . . . . . . . . . . . . ..

2205

TABLE 105.10.

Laparoscopic Management of Suspicious Adnexal Masses (Level II Evidence) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2206

TABLE 106.2.

Techniques for Controlling Elevated Intracranial Pressure (ICP) (Level II and Level ITI Evidence)

2220

TABLE 106.6.

Class I Evidence in Functional Neurosurgery (Epilepsy, Pain, and Movement Disorders) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2230

TABLE 109.1.

Seminal Studies and Reports Describing the Use of Polypropylene Mesh..............................................................

2294

TABLE 109.2.

Seminal Articles Describing the Use of Polyester and Polyester-Derived Meshes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2294

TABLE 109.3.

Seminal Articles Describing the Use of ePTFE and ePTFE-Derived Meshes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2295

TABLE 111.2.

Summary of Major Clinical Studies of Porcine Small Intestinal Submucosa (SIS) Used in Herniorrhaphy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2319

TABLE 111.3.

Summary of Major Clinical Studies of AlloDerm (Acellular Dermal Matrix) Used in Herniorrhaphy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2322

TABLE 112.2.

Selected Clinical Studies of Vertebroplasty and Balloon Kyphoplasty. . . . . . . ..

2328

TABLE 112.3.

Selected Clinical Trials for Bioglue" . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2331

TABLE 112.4.

Selected Clinical Trials for Hydrogels. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2333

TABLE 112.5.

Selected Clinical Trials for Fibrin Glues. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2335

TABLE 112.6.

Selected Clinical Trials for Dermal Fillers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2337

TABLE 112.7.

Selected Clinical Studies of "Miscellaneous Biomaterials." . . . . . . . . . . . . . . . ..

2339

TABLE 113.1.

Argon Beam Coagulator (ABC): Studies Supporting Use of the ABC in Tissue Coagulation of Solid Organs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2348

TABLE 113.2.

Radiofrequency Ablation (RFA) Can Treat Disease as Well as Assisting in Surgical Procedures: Clinical Outcomes Can Be Measured as Shown Here. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2349

TABLE 113.3.

Majority of Bipolar Sealing Data Are from Animal Studies: Similar Results Seen Across Various Platforms . . . . . . . ..

2350

TABLE 113.4.

Tissue Link: Limited Clinical Studies: In Animals, the Saline-Modulated Electrosurgical Device (SMED) Appears Efficacious in Controlling Vessels Below Organ Surface. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2350

TABLE 113.5.

Results with Harmonic Scalpel Show Equivalence and Superior Results in Some Cases to Electrocautery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2352

TABLE 114.2.

Clinical Trials Comparing Robot-Assisted Cholecystectomy to Standard Laparoscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2360

TABLE 114.3.

Clinical Trials Comparing Robot-Assisted Nissen Fundoplication to Standard Laparoscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

2362

xliv


TABLE 114.4.

Clinical Trials Comparing Robot-Assisted Colon Resection to Standard Laparoscopy

.

2363

TABLE 114.5.

Published Experience with Robot-Assisted Aortic Surgery

.

2367

TABLE 114.6.

Pediatric Clinical Experience with the Zeus" and da Vinci® Robotic Systems

.

2368

Surgery Second Edition

SECTION ONE

Fundamentals of Surgical Care

Origins of Modern Surgery Ira M. Rutkow Ancient Civilizations The Middle Ages The Renaissance The 17th Century

3 5 6 8

I

t remains a rhetorical question whether an understanding of surgical history is important to the maturation and continued education and training of a surgeon . Conversely, it is hardly necessary to dwell on the heuristic value that an appreciation of history provides in developing adjunctive humanistic, literary, and philosophical tastes. Clearly, medi cine is a lifelong learning process that should be an enjoyable and rewarding experience. For a surgeon, the study of surgical history contributes greatly toward making this learning process more pleasurable and is invigorating. To trace the evolution of what one does on a daily basis and to understand it from a historical perspective are enviable goals. It reality, there is no way to separate present-day surgery and one's own practice from the experiences of all the surgeons in all the preceding years. For the budding surgeon, it is a magnificent adventure to appreciate what he or she is currently learning within the context of past and present cultural, economic, political, and social institutions. The active practitioner will find that the study of the profession, dealing as it rightly must with all aspects of human society, affords an excellent avenue to the appreciation of previous ideas and concepts. As this chapter is titled "Origins of Modem Surgery," by definition it is concerned primarily with events prior to the 20th century, a time during which surgery evolved into its current status of respected profession.

Ancient Civilizations Although there is no way of knowing when the earliest surgical operations were performed, it is not unreasonable to assume that frequent attempts at surgery were completed by our most distant prehistorical ancestors. The attempt to remedy day-to-day external discomforts by manual manipulations must have been among the ongoing evolutionary efforts of the human species . Presumably, the earliest attempts at surgery were mainly devoted to the treatment of injuries and included procedures to alleviate nuisances, such as removing splinters, piercing boils or blisters, treating bums, and excis-

The 18th Century The 19th Century The 20th Century Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

10 12 18 19

ing traumatized tissue. Accordingly, surgery by default necessarily preceded internal medicine regarding the rational treatment of human disease. Speculations by the ancients about bodily "humors," "fluxes," "vital spirits," and other nonsensical doctrines did little to relieve human suffering. Instead, it was the" surgeon ," or at least the individual who wielded the knife or treated injuries, who was better equipped to handle diseases and wounds. The clearest example of this is that trephination remains the earliest example of actual major surgery . That prehistorical humans, using the most rudimentary surgical instruments, were able to bore open a human skull-and that th e patient survived-is an incredible medical accomplishment. When and how skull boring originated are matters of scientific conjecture. However, skulls from the Mesolithic cultural period have been found with round depressions suggestive of primitive trephination skills, which would date initial efforts at such operations at 10,000 to 5000 Be. Why would Stone Age humans resort to trephination? There is little archeological or other scientific evidence to suggest that this practice was used for the treatment of diseases such as osteomyelitis or syphilitic lesions of the cranium; most trephinations were performed on intact skulls with no prior signs of violence . It is more likely that trephinations were carried out for spiritual or magical reasons and used in cases of epilepsy, headache, or mental illness. From the Fertile Crescent in the Middle East, several ancient civilizations have provided some of the earliest known examples of surgical writings. The complex culture of AssyroBabylonia left the important Code of Hammurabi. Many of the rules in the code concern the outcome of operations (If a physician shall make a severe wound with the bronze operating-knife and kill the patient, or shall open a growth with a bronze operating-knife and destroy his eye, the physician's hands shall be cut off). Thus, despite the lack of archeological evidence regarding surgical tools, it can be assumed that surgical therapies were carried out. Closely connected in spirit and substance with Assyro-Babylonian and Sumerian-Semitic surgery is the surgery of the ancient Jews. A rich collection of surgical lore is found in the Talmud. The text discusses 3

4

CHAPTER 1

various surgical procedures, including how to suture wounds and clean traumatized edges, methods for dealing with imperforate anus, the advantages of lessening pain during a surgical procedure, reduction of dislocations, amputations and the use of wooden prostheses, cesarean section, and even veterinary procedures . From ancient Egypt, the Edwin Smith papyrus, written around 1600 BC, addresses strictly surgical problems. Unfortunately, the work , systematically arranged like a textbook of surgery, remains incomplete. The anatomical observations are descriptive, and terms were created to designate structures. This work provides the following information for dealing with the surgical problems: In the case of a skull in jury, the pulse is recorded, and a digital exploration of the wound is attempted to ascertain whether there is a depressed fracture of the skull. Feeble pulse and fever are noted in cases of hopeless head injuries. The traumatized skin edges are placed close together, and bandages soaked in a type of glue hold them in position. Fresh meat, perhaps for its hemostyptic value, is the usual dressing for the first day. The first allusions to surgical subjects in Greek civilization are found in the Homeric poems the Iliad and the Od yssey, which are generally accepted as dating from 800 to 700 BC. More than 100 passages give realistic descriptions of battle wounds, spearing, sword thrusts, arrow wounds, slingshot injuries, and their treatment. Numerous "schools" of medicine (associations of philosophers, priest-physicians, practitioners, and students) were beginning to develop throughout Greece. The two most important were located at Cnidos and Cos. It was on the latter that the "father of modem medicine," Hippocrates (Fig. 1.1) was said to have been born. He was able to disassociate medicine permanently

FIGURE 1.1. Hippocrates. (Courtesy of Jeremy Norman & Co., San Francisco.)

from the religious mysticism that previously coexisted with it; through his abilities as a teacher, he crystallized the existing knowledge of the Cnidian and Coan schools into a systematic science, and most important, he made physicians understand the high moral inspiration under which they practiced medicine. A collection of 72 medical works has become known as the Corpus Hippocraticum . Undoubtedly, the works of others were included in the Corpus, so when the writings of Hippocrates are discussed, it is reasonable to presume more than one author. The surgical texts , including "Wounds and Ulcers," "Hemorrhoids," "Fistulas," "Injuries of the Head," "Fractures," "Articulations," and "Mochlicus" (meaning Bones, Their Injuries and Displacements, and Instruments of Reduction) are the most lucid and brilliant sections of the entire work. Early Roman surgery is poorly understood because little remains of written information. However, it was believed to have been strongly influenced by Greek medicine and in most aspects reflected the Greek healing traditions. Surgery in Rome was practiced almost entirely by Greek physicians, yet the most erudite accounting of it was written by Cornelius Celsus (25 BC to AD 50), a Roman nobleman. Because he wrote in Latin, not Greek, and because he was not a physician, his works exerted little professional influence during his own time. Even in the handwritten manuscripts of the Middle Ages, his name is mentioned only a few times. When first printed during the Renaissance, however, his books on med icine became highly valued for their purity and precision in style and informative value. Celsus's De Medicina is the oldest important medical document after the Corpus Hippocraticum and provides a cumulative knowledge of medicine and surgery from the time of Hippocrates to the dawn of the Christian era. This work consists of eight sections or books; the last two discuss diseases considered strictly surgical. In particular, Celsus is best remembered for his description of the characteristics of inflammations: redness, swelling, heat, and pain (rubor, tumor, calor, and dolor, respectively). The most famous physician of the Roman period is Galen (AD 129-199), who is considered second only to Hippocrates as the most important physician of antiquity. His views dominated European medicine for almost 15 centuries, until the time of the Renaissance. Unlike Hippocrates, about whom little is known, Galen provided much autobiographical information. Born in Pergamum, he later served as chief surgeon to the Roman gladiators. Because human dissection was not permitted, Galen conducted well-publicized anatomical dissections on apes and pigs and drew much human anatomical data from animals rather than Homo sapiens. This necessity resulted in the perpetuation of countless errors throughout the medical literature until the 16th century. Despite Galen's overbearing personality and ill-formed mis conceptions, the breadth and depth of his writings are staggering. Viewed as a talented technical surgeon, he wrote extensively on the use of various surgical instruments. Most scholars consider his treatise on pathological swellings his foremost contribution to surgery because of its exacting discussion of inflammation and tumors. Due to his pugnacious personality, Galen never acquired any true disciples . However, because the coming Middle Ages were a scientifically and culturally unsettled era, there was a need for certainty and authority in medicine. Galen's answers provided the church

ORIGINS OF MODERN SURGERY

and lay leaders with their desire for an absolute truth, regardless of its veracity.

The Middle Ages The Middle Ages, or the medieval age, is most commonly delineated as beginning with the fall of Rome to the Goths in 476 and concluding with the fall of Constantinople to the Turks in 1453. The early Middle Ages (476-814) is often referred to as the Dark Ages because it is considered a time of widespread ignorance and lack of social progress. The classical thinking of Greco-Roman times, which viewed surgery as an invaluable adjunct to internal medicine, was completely obliterated during the Dark Ages. The clergy carried to the extreme Galen's belief that surgery was "a mode of treatment" by treating surgeons themselves as lackeys and underlings. Through the influence of the Arabian commentators, there was a genuine belief that it was unclean and unholy to touch another human body with one's hands. It must be understood that the medieval surgeon, whether renowned scholar or roving rogue, stood in jeopardy of life or limb if he operated unsuccessfully on any of the feudal lords. Consequently, the greatest surgeons of the time shrewdly advised their professional brethren to avoid or evade all difficult cases. However, when in the 12th century a number of edicts were issued by the church declaring that the shedding of blood was incompatible with a cleric's holy office, the "educated" class was clearly restricted from performing any type of surgical practice. In so doing, the church totally abandoned the surgical crafts to the secular arm of medieval society. Because monks were forbidden to perform surgical operations, this skill fell mostly to the "barbers," who had previously assisted the monks in their surgical therapies and in particular had been frequenting monasteries since 1092, when beards were banned. The barbers helped shave the monks and cut their hair in the particular styles of specific religious orders. These barbers soon widened the scope of their professional activities and became specialists. For instance, one operated for hernia, another for bladder calculi, and a third for cataract, with the knowledge handed down from father to son. By the 13th and 14th centuries, surgical techniques were beginning to mature at the hands of barber-surgeons. These faithful and mostly obscure followers of the craft of surgery, although continuously ostracized by clerical bigots, ensured the ultimate survival of surgery. Despite the church's ban on surgery, via its edict abhorring bloodshed, the craft of surgery steadily advanced. Even more surprising, much of this change was accomplished by surgeons affiliated with religious orders. Prominent among these individuals was Hugh of Lucca (1160-1257) and his major disciple, Theodoric (1205-1296). The Cbirurgia of Theodoric was completed in 1266 but is most important for providing excellent examples of the overall decline of surgery from its previous Greco-Roman sophistication. Basic surgical precepts had become buried in unintelligible jargon. Yet, despite its many shortcomings, the Chirutgia is an important milestone in the history of surgery; it demonstrated the beginnings of independence of thought and observation in surgical therapy. A noteworthy Italian contemporary of Hugh and Theodoric was William of Saliceto (1210-1277). A member of

5

the medical faculty at Bologna, his monumental effort, the Ciroxia (1270), stands out as a landmark in the history of surgery because it does not separate surgical diagnosis from internal medicine and even includes a remarkable collection of case histories. A resurgence of medical and surgical education in western Europe first occurred at the School of Salerno, situated near Naples on the Gulf of Paestum. From this school was authored the most important of early medieval surgical manuscripts, the Bamberg Surgery. Covering wounds and fractures of the skull, general wounds of the body, surgical lesions of eye and ear, diseases of the skin, fractures and dislocations, hemorrhoids, herniorrhaphy, bloodletting, and cautery, the work is pragmatic, especially concerning operative surgery. About 20 years after the Bamberg Surgery was written, a markedly different type of surgical manuscript appeared at Salerno. Roger of Salerno (circa late 12th century) authored an original, systematic text called the Surgery of Master Roger. With topics arranged in sequence from head to lower extremity, it was the preeminent surgical manuscript of the Salernitan school and is the first known independent surgical work in the Western world. By the end of the 1200s, Italian leadership in surgical education had substantially declined. Among the reasons for this declination was the civil war rampant throughout the country. These difficulties are particularly evident in the career of Lanfranc of Milan (?-1315). Having become involved in the political strife of his native country, Lanfranc resettled in France and became associated with a gathering of surgeons called the Confraternity of Saints Cosmas and Damian. According to popular tradition, Cosmas and his twin, Damian, had been traveling physicians who gave their services freely to those in need. During that earlier era's persecution of Christians, Cosmas and Damian were tortured and beheaded (circa AD 300). They were soon given sainthood for what were regarded as miraculous surgical cures and over the intervening centuries became recognized as the patron saints of surgery. Little is known about the early organization of the confraternity. However, by the beginning of the 14th century, a guild of Parisian barber -surgeons also existed. In general, these individuals were not permitted to use a knife, and as a result great jealousy existed between them and the confraternity. Noting the chaotic state of affairs, the king of France issued an edict in 1311; only individuals who underwent an examination administered from a royally authorized source should be allowed, according to the edict, to practice surgery in Paris. In this instance, the confraternity assumed the royal order and began academic testing. Those who passed the required examination were to be known as "masters of surgery." By this royal statute, the existence and autonomy of the surgeons were officially recognized. Paralleling the surgeons' ambitions to attain university status were the barber-surgeons' aspirations to gain entry into the surgeons' ranks. Unwelcome in the confraternity, the barber-surgeons obtained their own special royal charter (1372), legalizing their professional ambitions and the designation barber-surgeon. In addition to barbering, they were now entitled to treat carbuncles, bruises, boils, and any other nonmortal open wounds. Into this ever-changing political environment moved Lanfranc, who became one of the founders of modern French surgery. He became a bitter critic of the

6

CHAPTER 1

nonclerical and essentially uneducated barber-surgeons and soon wrote Chirutgia Magna (12961, the foundation of French surgical teaching for many years. A contemporary of Lanfranc was Henri de Mondeville (1260-13201, considered the first great French master of surgery. Mondeville's prominence lies entirely in his Cbiiutgie and early opposition to surgical quackery and empiricism. He declared that surgery must belong to all of medicine and twitted the church and its hierarchy to explain how its phys ician-clerks were supposed to learn surgery without permission to touch a human body. At the same time that Mondeville's career was coming to an end, the university at Montpellier was beginning to rival the university at Paris as the center of European medical and surgical education. The most prominent of its graduates and th e individual destined to become the preeminent European surgeon of the late Middle Ages was Guy de Chauliac (13001368). His massive Latin manuscript, Inventorium Seu Collectorium Cyrurgie (1363), would become the most important medical book then printed in France (La Grande Chirurgie, 1478).His methods dominated surgery in France and, to some degree, England for the next 2 centuries. English surgery during the Middle Ages was not nearly as developed as in France or Italy, but certain individuals did manage to become prominent. The most important was John of Arderne (1306-1390). Settling in London, Arderne joined the Guild of Military Surgeons. In 13th- and 14th-century London, guilds or companies were established to control various types of trades. Initially, barber-surgeons were allowed almost exclusive control over the practice of surgery in the city, which did nothing but political and financial harm to the smaller number of military surgeons. The barber-surgeons fought fierce economic and political battles with the military surgeons for the total right of supervision over anyone who practiced surgery. The London city corporation sided sometimes with one group, sometimes with the other, and indecision was always present.

was showing some signs of weakness as several popes approved the right to study the human body. Accordingly, by the early 16th century there were no further major hindrances to either dissection or autopsy. Few individuals have had an influence as overwhelming on the history of surgery as Andreas Vesalius (1514-1564 ) (Fig. 1.2). Deeply devoted to the study of human anatomy and proficient in human dissection, Vesalius served as professor of anatomy and public prosector at the University of Padua in Italy . The 7 years he spent in Padua left an indelible mark on the evolution of medicine and surgery. His public lectures drew great attendance, and he was in constant demand to provide anatomical discourses and demonstrations in other Italian cities. The indefatigable efforts of Vesalius culminated in the publication of his magnificent De Humani Corporis Fabrica (15431. The effect of this work was immediate and self-sustaining, with its many splendid woodcuts demonstrating innumerable peculiarities and minor variations in structures encountered in dissection. Although the Fabrica was written in Latin, its impact ultimately extended to individuals who spoke or understood only the vernacular, the everyday language of ordinary people . Galenic errors were boldly swept aside, permitting the emergence of modem medicine and surgery. Among Vesalius's greatest contributions was his research on the vascular system and the question of the circulation of blood. Even more radical than his criticism of past authorities was Vesalius's assertion that anatomical dissection must be completed by the physician/surgeon himselfa direct renunciation of the long-standing doctrine that dissection was a grisly and loathsome task to be performed only by a diener-like individual while from on high the learned physician lectured utilizing orthodox texts. This prin-

The Renaissance The European Renaissance, the great revival of learning via the arts, humanities, and growth of scientific thought, occurred from the late 14th to the 15th century. It began in northern Italy, spread gradually to other countries, and marked the transition from the medieval world to modem civilization. Renaissance society began to hold a worldly rather than a religious point of view, with this new attitude called humanism. Humans, not God, became the center of reference . There was a gradual transference of wealth and its attendant political power from the Christian church to various princes. These men assumed an avid interest in learning, and a new age of classicism developed . As a consequence, the all-pervasive religious character of medieval education and governance had become untenable. The unfettered flowering of surgery during the Renaissance was directly related to fundamental changes in the study of human anatomy. By the end of the Middle Ages, it had become apparent to physicians that further progress in the knowledge of medicine, specifically surgery, could not be attained unless scientific studies of human anatomy were made . By that time, the church's ban on human vivisection

FIGURE 1.2. Andreas Vesalius . (Courtesy of Jeremy Norman & Co., San Prancisco.]

ORIGIN S O F MODERN SUR GERY

ciple of "hands-on" education would remain Vesalius's most important and long-lasting contribution to the teaching of anatomy. During the Renaissance, each European country began to develop its own recognizable practice of surgery. Both Germany and Switzerland lagged far behind in the awakening of medicine and surgery during the late Middle Ages and in the great surgical renaissance. A number of reasons accounted for this, including the sorry state of university education in central Europe. In the particular case of Germanic surgery, most individuals who practiced the art of surgery were simple craftsmen who, like other artisans, joined together in guilds . It was thought no more suitable for a surgeon to study books than for a carpenter or a blacksmith to do so. Because German surgeons usually had no formal education, the y could neither speak nor read Latin . Although not as learned as their foreign colleagues, the German surgeons were well versed in the surgery of war. They were widely experienced in the growing field of military surgery, the subject of their earliest surgical works . These surgical texts were intended as practical handbooks or manuals for the use of their fellow craftsmen. Th ey were written in the vernacular and were concerned almost entirely with the treatment of wounds. Heinrich von Pfolspeundt was a 15th-c entury Bavarian army surgeon and the earliest known German surgical writer. He composed his Buch der Biindth-Ertznei in 1460, although it remained in manuscript form until 1868, when it was rediscovered, edited, and published. As was typical of the wound surgeon, he had no skill in major operations and did not know how to treat fractures and dislocations. He left minor surgery to the barbers and the larger operative procedures to the cutters. His text was largely limited to discussion of the management of wounds and other injuries . Within a quarter century of Pfolspeundt lived another, more literate German surgeon, Hieronymus Brunschw ig (1450-1512). His Dis ist Das Buch det Cirutgia Hantwirckung der Wundartzney (1497) is a remarkable publication, the first important printed surgical treatise in German. The last of the famous early German wound surgeons was Hans von Gersdorff (1480-1540). His Feldtbu ch der Wundartzn ey (1517), in vernacular German, is particularly valuable for its many important illustrations. Gersdorff is best remembered for his claim to have performed mor e than 200 amputations for gangrene or erysipelas . Other renowned Germanic surgeons of this era included Paracelsus (1493- 1541), Walter Hermann Ryff (circa first half of the 16th century) , Caspar Stromayr (circa 16th century), and Felix Wurtz (1 518-1 574). The first great book on eye surgery, Ophthalmaladauleia das ist Augendient (1 583), was written in vernacular German by George Bartisch (1535-1606). Bartisch, considered the founder of modem ophthalmology, was the first to practice the extirpation of the globe in cancer of the eye. Italian surgeons, unlike their generally illiterate Germanic-speaking counterparts, were often university educated and sometimes attained academic distinction. The vigorous rivalry between the itinerant barber-surgeons and their more sophisticated surgical peers was not readily apparent. Giovanni de Vigo (1460-1525) was the first Italian Renaissance surgeon to write an account of gunshot injuries and their treatment. As an outstanding compiler of surgical works , his Practica in Arte Cbirutgica Copiosa Cantinens Navem

7

Libras (1514) provides the most detailed portrait of European surgery as it existed at the end of the 15th century. Guido Guidi (1508-1569 ) followed de Vigo as the leading surgeon during the Italian Renaissance. His memory is particularly preserved in the names of several anatomical structures he described, such as the Vidian artery, canal, nerve, and vein. Mariano Santo of Barletta (1490-1550) achieved fame as a lithotomist. Giovanni Andrea della Crose (1514-1575) propagated many concepts of de Vigo and Guidi in his Chirurgiae Libti Septem (1573) and Chirurgiae Universalis Opus Absolutum (15731. Gaspare Tagliacozzi (1547-1599) has been called the father of plastic surgery. In his De Curtarum Cbinugia per Institianem (15971, he described in exacting detail specific operative methods for treating mutilating injuries, especially nasal defects. The last great Italian Renais sance surgeon was Hieronymus Fabricius ab Aquapendente (1 533-1620). As professor of anatomy and surgery at Padua, Fabricius had so many pupils that at his own expense he built in Padua the first known permanent anatomical amphitheater. The most important Spanish surgeon of this era was Francisco Arceo (1493-1573), but little information is available about his schooling and professional life. Dionisio Daza Chacon (1503-1580)wrote the most exhaustive Spanish work on surgery during this period, Practica y Teotica de Cinugia (1600). Bartolome Hidalgo de Aguero (1531 -1597) is commonly acknowledged as the father of modem Spanish surgery. He was lecturer on surgery at Seville and gained wide experience in the treatment of battlefield wounds. European surgery during the Renaissance owed much to France, primarily through the efforts of Pierre Franco (15001561)and Ambroise Pare (1510-1590)(Fig. 1.3),whos e achievements were especially impressive because both men rose from poverty , and neither was university educated. In the highly stratified society of the time, the lack of university

FIGURE 1.3. Ambrois e Pare. [Courtesy of Jeremy Norman & Co., San Francisco.]

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education usually prevented individuals from obtaining important standing in medicine or surgery. Franco was trained mostly by itinerant lithotomists, cataract couchers, and herniotomists, whereas Pare emerged from the ranks of the barber-surgeons. During the 16th century, the French barber-surgeons had clearly moved beyond the legal limitations that had earlier been placed on their clinical practice. They came to be known euphemistically as the "surgeons of the short gowns," in contradistinction to the "long-gown" or academic surgeons of the College of St. Come. The barber-surgeons guild grew much more rapidly than the College of St. Come, probably because the elitist, exclusive attitude of the college restricted its own membership. For the average Parisian, the barbersurgeon of the short gown was a much more accessible, pleasant, and familiar figure than his academic long-gown counterpart. Eventually, although the barber-surgeons did not have equivalent social status or academic rank, the public recognized their superior skills. It was during this period that Jean Canappe (1495-1552) translated Guy de Chauliac's works from Latin into French, thus allowing non-Latin-educated barber-surgeons access to printed surgical teachings. Canappe's avowed purpose was to aid the barber-surgeons against the opposition of the more educated university surgeons. Another French academic surgeon who authored a work expressly for the barber-surgeon was Jacques Dalechamps (1513-1588), the Chiturgie Francoise (1569). The controversies in France among itinerant surgeons, barber-surgeons, and university-educated surgeons and between physicians and surgeons were more intense than in any other European country. That Dalechamps could recognize Pare, a barber-surgeon, as the foremost surgeon in France, with Franco, an upstart itinerant, not far behind, was an important step in the eventual decision of the universities to make a university education available to men of the lower classes. It was obvious, at least to Dalechamps, that a positive future for French surgery depended on the outstanding barbersurgeons and occasional itinerant. The most famous of the French "incisors" was Franco. Although he rose from the ranks of the incisors, he was adamant in his attempts to remove operative surgery from the domain of the charlatans, itinerant quacks, and cutters and place it under the auspices of the regular practitioners (the surgeons of the short and long gowns). Franco accepted the physician's supervision of the surgeon, but he was unrelenting in his attacks on those who abused the true art of surgery. He became especially influential as a result of his writings in the vernacular and the fact that he eagerly operated on patients with hernias and bladder stones, unlike many well-known educated surgeons of France, who shied away from such technical feats. Pare's position in the history of surgery remains of supreme importance. He played the major role in reinvigorating and modernizing Renaissance surgery. Pare represents the severing of the final link between the surgical thought and techniques of the ancients and the push toward the modem era. His ability to articulate his findings in both written word and clinical practice brought him lasting fame. In 1541, realizing the importance of proper credentials, he presented himself for and successfully passed a required examination to become a master barber-surgeon and a member of that guild. Pare's

reputation became so great that he was begrudgingly made a member of the College of St. Come (1554). Despite at first being refused admission because he had been a barber's apprentice and spoke not in Latin but in the vernacular, Pare gave his inaugural lecture in French and was duly mocked by the envious. However, his membership, championed by Dalechamps, helped bring about a later union of the barber-surgeons and the surgeons of St. Come. It is a tribute to Pare's remarkable career that he became chief surgeon to four successive kings of France. Most important, he demonstrated true humility in his work with his patients and in the world of healing, a humility most evident in his well-remembered statement, "I treated him. God cured him." In England, the number of military surgeons had long remained constant, whereas the various barber-surgeons' companies grew more powerful. In 1540, a momentous event in English surgical history occurred. Under the aegis of Henry VIll, Parliament passed a statute uniting the previously chartered Guild or Company of Barber-Surgeons with the small, exclusive Guild of Military Surgeons. This new Royal Commonality of Barber-Surgeons received all the previous powers granted under past British sovereigns and more. The new charter declared that members who practiced surgery should no longer perform barber activities, and that barbers should not undertake any surgery except dental work. As a result of the new royal charter, a vigorous attempt was made to improve educational work. The surgical examiners instituted a series of licensing examinations, which culminated in the student receiving the Grand Diploma as a master in surgery and anatomy. The new company was entitled to receive the bodies of four executed criminals each year for the purpose of dissection. Thus, the Act of 1540 succeeded in creating for London an active educational and licensing body for the practice of surgery. Henry VIII's personal surgeon, Thomas Vicary (1495-1561), was elected first master of the united companies. Vicary was a recognized leader in the profession, although he left behind few memorable written works. Other English surgeons of note were Thomas Gale (1507-1587),William Bullein (?-1576), William Clowes (1540-1604), John Banister (15331610), and Peter Lowe (1550-1612). By the end of the 16th century, the craft of surgery in Europe had attained a tenuous but accepted and respected position within the world of medicine. Although surgeons continued to be viewed askance by their follow physicians, the importance of a surgeon's clinical skills could no longer be blithely dismissed. Admittedly, large areas of medical and surgical practice remained bound with superstition, herb therapy, and quackery. However, the true greatness of the many renowned surgeons during this era is reflected in their increasing scorn for quacks and charlatans and their application of rational empirical observations to daily practices. In essence, the humanism of the Renaissance provided surgeons with their first substantive opportunities to become respected members of the healing profession.

The 17th Century The scientific revolution of the 17th century represented a turning point in the history of medicine. Emphasis shifted dramatically from speculation to experimentation, with remarkable advances made in the basic sciences. However,


the teaching of medicine and surgery was still heavily influenced by ancient philosophies. Initially, supporters of older influences continued to outnumber the more progressive thinkers and scientists, but by the end of the century, the latter group had an overwhelming influence on the craft of surgery. The great centers of medical education in 17thcentury Europe were Leyden, Montpellier, Padua, and Paris, but the condition of medicine was vastly improved by the ambitions of royalty to establish small universities and by the formation of scientific societies. Specific advances in anatomy, physiology, and medical instrumentation aided this flowering of medicine. The most astonishing and influential of these progressive changes was the discovery and fundamental understanding of the anatomy and physiology of the circulation of blood by William Harvey (1578-1657). His Exercitatio Anatomica De Motu Cordis Et Sanguinis In Anima1ibus (1628) has been called the most important book in the history of medicine. Harvey used inductive logic to demonstrate that the heart acts as a muscular pump in propelling the blood along the arteries, and that the blood's motion is continuous and leads back to the heart via veins to form a cycle or circle. Although from the modem perspective medicine and surgery as practiced during this era hardly appear advanced, it was an era of remarkable innovation. New therapeutic modalities were introduced that would have an enormous impact on the future development of surgical operations. The most important of these were the concept of exhaustive treatment, including bleeding and purging, and the use of intravenous injection of drugs and transfusion of blood. Bloodletting in particular became a source of considerable remuneration for the surgeon. Exactly when the bleeding came into serious vogue remains historical conjecture. However, 11 Barbiere (1626), the earliest book specifically devoted to barber-surgery, contained engravings detailing bloodletting, including portraits of two female barber-surgeons considered especially adept at the procedure. In Paris, one of the major functions of surgical house officers was to bleed patients. This chore, said to consume an hour's time every afternoon, probably explains why there were more surgical interns than physician interns at the Hotel Dieu. The cultural and social aspects of 17th-century medicine and surgery suggest it to have been a time of individual scientific endeavor rather than of concerted advancement of science. Most surgeons were not well compensated, although certain prominent individuals were well off. The medieval custom of paying a lifetime annuity for a successful operation remained somewhat in vogue. Surgery in the 17th century did not keep pace with progress in anatomy and physiology. In comparison to the extensive development of medical literature, the literature of surgery seems meager. Surgeons had not yet achieved the social and academic status of physicians, and bitter antagonisms were still apparent in particular countries. The 17th century was a time of great political instability in England. As the country became increasingly isolated socially and politically from the rest of western Europe, and consequently from the western European universities, English surgeons had to rely on the teaching organized by various barber-surgeon companies and English universities. The activity of these barber-surgeon companies was reaching its zenith, exemplified by the London barber-surgeon company that

9

obtained an act of Parliament in 1604 and a new charter in 1629, which mandated that no one could practice surgery in that city until the person had passed an examination given in the presence of two or more master barber-surgeons. Still, quarrels continued to arise between surgeons who were not members of the company but instead were attached to hospitals and their medical schools. Bythe middle of this century, it was becoming evident that an English surgeon, if sufficiently educated and devoted to his craft, could reach a position of equality with the best physicians in the community. In many respects, this changing attitude was brought about by the increasing numbers of well-respected English surgeons and their erudite writings. Included within this group were John Woodall (1556-1643), Alexander Read (1586-1641), and the renowned Richard Wiseman (1620-1676). In Germany, the overriding societal event was the Thirty Years' War (1618-1648). The barber-surgeons in Germany continued to reign supreme; their various guilds contained men of ability and independent thought. The most prominent 17th-century German surgeon was Wilhelm Fabry von Hilden (1560-1634). Initiated into the art of surgery by a thorough apprenticeship under a succession of skilled and experienced wound surgeons and barber-surgeons, von Hilden authored the first book, De Combustionibus (1607), devoted entirely to bums. Another important German surgeon was Johannes Scultetus (1595-1645). Like increasing numbers of 17th-century surgeons, he was liberal in his indications for surgical intervention, as is evident in his famous Armamentarium Cbiiuigicum (1653), which became the most popular surgical text of that era. Although published posthumously by his nephew, the work was brought out in numerous editions and translations in practically every European country. Among other German surgeons, Matthaeus Purmann (1649-1711) was also well known. In France, the official status of the guild of barber-surgeons in Paris had greatly improved by the first portion of the 17th century. In 1603, the government of that city authorized the title of the guild to use the words barber-surgeons rather than simply barbers. Concurrently, master barber-surgeons were given the legal right to treat all kinds of wounds. Three decades later, Louis XITI reaffirmed the enabling statutes of his "dear community of master barber-surgeons" and recognized the community as "the principal source of the knowledge and practice of this art in all our kingdom." Surprisingly, some master barber-surgeons left the guild to join the ranks of the Confraternity of St. Come. However, most barber-surgeons did not wish to give up their barber's work in exchange for admission to the more elite organization. In 1613, revolutionary-minded members of both the confraternity and the guild attempted to unite the two companies, and the royal government gave its tacit approval. However, a majority of the academic surgeons of St. Come disavowed the union, thereby ending the agreement. More than 40 years later, the same plan for unification was proposed and met a far warmer reception from the academic surgeons. In 1655, the surgeons of both the long gown and short gown put aside their centuries-old rivalry and signed a contract of union. In joining forces with the barber-surgeons, the academic surgeons had an obvious economic incentive. As the membership of the prosperous guild of barber-surgeons increased, the

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guild threatened the viability of the much smaller confraternity of academic surgeons. The inescapable fact was that it was difficult to make a living by practicing only surgery. Without the mix of barber's work, such as bloodletting and wound care, the economic stability of practicing surgeons was seriously threatened. On a more practical level, barber-surgeons commanded much higher fees than did their academic counterparts. During the second half of the century, strengthening of the united surgical guild was evident. There was a marked increase in its prestige in the eyes of the public as a new surgical amphitheater was constructed in Paris (1694) to offer public anatomy and operative courses to large audiences. More important, several prominent surgeons, including Pierre Dionis (1643-1718) and Charles- Francois Felix (1650-1703), were regarded with much favor by Parisian society. Despite this growing prestige, few Paris surgeons actually performed major operations. In the 1690s, of the approximately 400 to 500 master surgeons, perhaps 50/0 practiced the bold, oftennew procedures, such as lithotomy. Most surgeons earned a livelihood by completing minor surgery, which included treating abscesses; applying external medications to various skin ailments, bruises, and cuts; reducing incarcerated hernias; setting fractures; and treating skin tumors, venereal diseases, and ulcers. Realistically, this kind of work was not sufficient to provide a livelihood for the entire surgical community. By the end of the century, certain surgeons had a growing disdain for what they regarded as socially demeaning work, so surgeons in Paris increasingly began to tum to the practice of "internal medicine." Because French surgery was in confusion, little progress was achieved until the end of the 17th century. More important, by the final years of the era it was evident that Paris barbers and surgeons were going their separate ways. The departure of the barbers reflected tangible alterations in the nature of surgery, which would become more evident in the next century.

The 18th Century The close relationship that had been established between surgeons and anatomical research continued during most of the 18th century. Thus, many of the period's outstanding anatomical and surgical discoveries were made by so-called surgeon-anatomists. Among the most important of these individuals were William Cheselden (1688-1752); the Monrosfather Alexander (primus) (1697-1767), son Alexander (secundus) (1733-1817), and grandson Alexander (tertius) (1773-1859); Percival Pott (1714-1788); William Hunter (1718-1783); the Meckels-father Johann (1724-1774), son Philipp (1756-1803), and two grandsons, Johann (1781-1833) and his younger brother August (1790-1829); Pierre-Joseph Desault (1744-1795); and Antonio Scarpa (1747-1832). Through their combined efforts, the role of surgery in the rise of modem medical thought would be ensured. By the end of the century, surgeons as a group had begun to rise above their traditional social status as technicians or craftsmen to receive acceptance as professionals on a par with physicians. Clearly, surgeons had become scientific as well as technical innovators. European surgery achieved great prominence in France in the 18th century. At the beginning of the century, new pat-

terns of surgical education and training were apparent. Two kinds of apprenticeships were available. The first was a formal arrangement for a period of 2 years consecutively, during which the apprentice's family and the master surgeon agreed to a legal contract, or brevet. The young man would provide certain services and obedience to his mentor; the surgeon agreed to provide education as well as food, shelter, and other basic needs. For families unable to afford a brevet apprenticeship, another, known as garcons cbituigiens or setviteurs cbiruigiens, existed. This type of apprentice was in a much more menial position than was the brevet apprentice and had less freedom to attend hospital and public lectures. More important, a master surgeon could have only one brevet apprentice at a time but was not restricted as to the number of garcons. Regardless of educational tract, neither the brevet apprentice nor the garcon was likely to learn how to perform major operations from the average Parisian master surgeon. Therefore, several renowned Paris surgeons offered practical training beyond minor surgical operations. These surgeons received fee-paying students, or pensionnaires, in addition to the one apprentice permitted them. The pensionnaire differed from the apprentice in that he did not enter into a binding agreement with the master surgeon and did not hope to fulfill an entrance requirement of one of the surgical guilds. He was simply allowed to accompany the distinguished master surgeon in his daily routines. The pensionnaires tended to be wealthy students from outside Paris and from foreign countries. Most were already graduates of medical school and came to Paris to strengthen their surgical training. Once a brevet apprentice or a garcon had completed his service, he began the final stage of surgical training, the journeyman or compagnon stage, which usually lasted for 7 years. Most compagnons hoped to become eligible for a mastership but were not allowed to practice surgery on their own. Those who chose not to move to the provinces, where a surgical mastership could be acquired with much greater ease, usually left their masters after a few years and commenced independent practices illegally in Paris. None of these individuals could realistically hope to become a Paris master surgeon unless he were a son or son-in-law of such a master or had political connections in the royal court or a hospital. The actual transformation of French surgeons from practitioners of guild mentality to well-educated professionals can be traced to 1715. In that year, Georges Mareschal (16581736), surgeon to Louis XIV, began a formal public campaign to improve the status of the Paris surgical community. Within 15 years, two important events would firmly place the surgeons on an equal social and scientific level with their physician peers. First, in 1731 Mareschal and Francois La Peyronie (1678-1747) petitioned the king to establish a society that would meet once a week to hear and discuss presentations of papers on surgical topics. This society became known as the Royal Academy or College of Surgery and consisted of the 70 leading master surgeons in Paris. A second major step in the evolutionary process of 18th-century French surgery concerned the Royal Declaration of 1743, which declared that henceforth Paris master surgeons were forbidden to work as barbers. Conversely, barber's work would be considered an inferior profession and would belong solely to the barber-wig-


makers. Therefore, when the last few Paris barber-surgeons retired from practice, such an occupation would become extinct. The transformation of French surgery from a craft guild to a liberal guild profession was complete in 1750, particularly as the French public finally viewed surgeons as on the same societal level as physicians. In the second half of the 18th century, Paris would showcase the talents of its surgeons, and that city became the mecca for surgeons from throughout the civilized world who sought further education and training. The Paris College of Surgery commenced a dissection school with practical instruction in anatomy and surgical operations, and a clinical research and teaching hospital was constructed. The leading French scientific surgeon of the first half of the 18th century was Jean-Louis Petit (1674-1750). His reputation as a bold, skillful surgeon attracted large numbers of students to his home, where he organized a private school. Petit was the originator of many important surgical methods and invented the screw tourniquet. The most renowned of Petit's pupils was Dominique Anel (1678-1725). Among other prominent French surgeons of this period were Nicolas Andry (1658-1742), Henri Le Dran (1685-1773), and Claude-Nicolas Le Cat (1700-1768). The French Revolution played such a tremendous part in reshaping the lives of French citizens that, not unexpectedly, surgeons and surgical thinking were also profoundly affected by the upheaval. From 1780 to 1793, politics was thought to hold the key to health. Accordingly, physicians flocked to the side of the revolutionaries. The concept of professional unification as a way to create a new health care delivery system became a subject of lively debate. In late 1790, one of the revolutionary councils decided that physicians and surgeons should be given the same education and undergo the same examinations. Neither the old guard of Paris surgeons nor the medical faculty had much chance to prevent unification. The surgical institutions of the old regime in Paris were so closely linked to the discredited monarchy that there was no possibility of their remaining in an unaltered state. In 1792, a law passed by the legislative assembly abolished simultaneously the Faculty of Medicine and the College of Surgery. Public instruction at the Paris College of Surgery persisted through 1794, but the college became a shell of its former self. The effect of all these laws would prove to be catastrophic to French surgeons. With the abolition of degrees in medicine and surgery and the dissolution of all academic colleges, the creation of the Ecole De Sante in 1794 marked the total unification of medicine and surgery in France. Educational requirements for the practice of either medicine or surgery were to be identical, and only one degree, Doctor of Medicine, would be awarded. With the opening of the new school, the destinies of the disciples of St. Come and the medical faculty of Paris became inextricably intertwined. Pierre-Joseph Desault, a surgeonanatomist, provided most of the dynamism of late 18thcentury French surgery. His greatest impact on the evolution of surgical education and training resulted from his introduction of the clinical surgical lesson. Despite his outstanding reputation, Desault provided little in the way of a written legacy except for his editing of the world's first surgical periodical, the Journal de Chirurgie (1791-1794).

11

In Great Britain, the barber-surgeon companies were in full power at the beginning of the century. In many instances, the surgeons in the various companies were increasingly involved in the financial management, which caused discontentment among the nonsurgical members. As long as the legal monopoly ofbarber-surgical practice continued, however, both parties were forced to resolve their petty differences in amicable ways. The London Company of Barber-Surgeons had controlled surgery in the metropolis for almost 2 centuries, but changes were taking place within its ranks that would have enormous historical repercussions. Although at the beginning of the century the barbers outnumbered the surgeons 20 to I, the greater part of the company's income was coming from the surgeons. As the number of British hospitals increased, so did the number, and correspondingly the importance, of surgeons. The two sections of the company had obviously diverged in status and interests, and their separation was inevitable. At the beginning of the 18th century, little competent surgical instruction was available in England or Scotland; the best was in London. The London Company of Barber-Surgeons acted as the bellwether for most of the country, and its dissolution had an enormous impact on the future of British surgery. The final divorce between the London barbers and surgeons was orchestrated primarily by two men, William Cheselden (1688-1752) and John Ranby (1703-1773). Cheselden was the leading English surgeon during the first half of this era, and his clinical work and administrative expertise ushered that country's surgical education and training into a new period. In London, the surgical educational system was gradually improving, and the demand for better anatomical teaching had been answered through a system of private schools. Because hospital appointments were difficult to obtain and practices slow to develop, Cheselden began providing a private course in anatomy in 1711. The success of Cheselden's anatomical lectures brought him into direct conflict with the company. He was accused of teaching anatomy in his home at times that conflicted with public dissection at the company hall. In 1738, Cheselden became a member of the court of assistants of the Company of Barber-Surgeons. Six years later, he became a junior warden, and it was during his tenure in office that the surgeons announced without any prior warning that they wished to separate permanently from the barbers. Parliament appointed a committee to consider the matter; the committee was chaired by Cheselden's son-in-law, with Cheselden himself donating £550 toward payment of the expenses incurred by the proceedings. Not unexpectedly, the committee upheld the petition of the surgeons, and in 1745, Parliament passed a bill forming an independent Company or Corporation of Surgeons. This formal separation was greatly aided by Ranby, who served as sergeant surgeon to the British monarch and was able to perform some persuasive lobbying. Although the company had a wonderful chance to advance the cause of British surgery, such was not the case. The act of Parliament entitled those who had satisfied a Court of Examiners to practice without hindrance anywhere in Great Britain, and apprenticeship was no longer specifically required. Many foreign nationals who were practicing surgery in London were admitted to the new company without inquiry regarding

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their training. Thus, it became impossible to ensure that a young surgeon would acquire surgical training in a systematized fashion based on some type of apprenticeship. The company dragged on in an uninspired existence for almost a half century. Early difficulties led to financial and administrative irregularities that were not readily overcome. The control of the company had gradually passed into the hands of the 10 members of the Court of Assistants, who were also examiners. In most instances, these examiners were appointed for life and were the only regular attendants at meetings. Realistically, during its first 50 years of existence the Company of Surgeons was nothing more than a bloated, inefficient examining body. Clearly, the individualistic attitude of most company surgeons resulted in petty quarrels, tardy publications, and a general lack of cohesiveness and created an untenable educational environment. Nonetheless, the art of surgery, existing outside the company, continued to be consolidated and advanced by careful clinical observations and superb teachers in private settings. Because the Company of Surgeons failed to adequately organize surgical education, effective licensing was nonexistent. Two types of programs assumed much of the responsibility for education. First were the private schools of anatomical and surgical instruction. In the absence of any great public medical institution, these schools provided excellent instruction but were decidedly transient and had no licensing powers. The many new hospitals and the schools of medicine and surgery that were evolving with them represented the second type of educational institution for surgeons. The surgeons attached to these hospitals had the opportunity to take their apprentices with them while performing surgical operations. In this way, the initial efforts to provide systematic teaching, including bedside instruction, were made. Schools naturally evolved from such individual entrepreneurship, and the emerging surgical educational system was enormously beneficial to the student. The apprentice's physical presence in a hospital also helped increase the overall efficiency of the institution's patient care. Although there were many teachers of surgery in 18thcentury London, the two most outstanding individuals were Percivall Pott (1713-1788) and John Hunter (1728-1793). Hunter particularly stands out because of the volume of his written work and the quality of his research. Considered a dexterous surgeon, he was primarily interested in the pathophysiology of surgical diseases. Ultimately, Hunter's voluminous research and clinical work resulted in a collection of more than 13,000 specimens, which became one of his most important legacies to the world of surgery. By the last decade of the century, Great Britain, especially London, had displaced Paris as the center for European surgical education and training. Well-known surgeons such as Cheselden, Pott, Hunter, and many others contributed to that success. Among the most prominent of these other surgeons were Samuel Sharp (1700-1780), John Pringle (1707-1782), William Bromfield (1712-1792), William Blizard (1743-1835), Henry Cline (1750-1827), Everard Home (1756-1832), John Abernethy (1764-1831), and William Hey (1736-1819). In an environment of military and socioeconomic strife, the condition of German surgical practice was decidedly unstable. Formalized surgical education and training were limited. Most individuals obtained surgical treatment from local barbers or itinerant quacks. The populace was over-

whelmingly superstitious and ignorant of medical facts. Despite repeated edicts by the kings, nobles, and city authorities to improve conditions for the physicians and surgeons, the unsettled times limited surgical progress. The first surgeon of importance in the 18th century was Lorenz Heister (16831758). His Chitutgie in Welcher Alles was zur Wund-Artzney Gehoret (1718) became one of the most popular surgical texts of the era and was published in numerous editions and was translated into Latin, English, Spanish, French, Italian, and Dutch. During the last half of the century, the principal German surgeons were Carl Siebold (1736-1807) and August Richter (1742-1812). In North America, medicine and surgery made few credible advances from 1600 to 1750. There were few actual physicians or surgeons of note, and most of the medical needs of the growing populace were served by three classes of health care providers: governors, clerics, and a wide range of selfeducated "physicians," secular preachers, and schoolmasters. By the late 18th century, American medicine began to be distinguished from that of earlier years by the higher regard in which physicians were held by society and the increasing numbers of Americans obtaining medical degrees in Europe and returning to the colonies with valuable clinical acumen and technical skills. Names that recur most commonly in the accounts of surgery in revolutionary times are John Bard (1716-1799); John Jones (1729-1791), who authored the first major surgical work written by an American, Plain Concise Practical Remarks on the Treatment of Wounds and Fractures (1775); Samuel Bard (1742-1821); William Baynham (1749-1814); and John Warren (1753-1815). At the end of the 1700s, the necessary role of surgery within the context of overall medicine had become clearer. There was an increasing interdependence of internal medicine and surgery, which had been cultivated in the common ground of 18th-century pathological anatomy and experimental physiology. At long last, physicians and surgeons had knowledge in areas that were essential to both disciplines. For thousands of years, surgeons had attempted to rely on an objective anatomical diagnosis. With the advent of pathology, physicians were able to regard disease from a perspective that had long been prevalent among surgeons. However, because surgery, to make its most impressive gains, still awaited the advent of anesthesia and antisepsis, 18th-century internal medicine appeared to yield more dramatic results, for example, in diagnosis and treatment.

The 19th Century During the 19th century, the organized advancement of medical sciences began, and the surgeon emerged as a specialist and a respected medical practitioner. Yet, the era began unobtrusively as a direct continuation of the medical and surgical development of the 18th century. Through the first half of the 19th century, the scope of surgery remained limited. Surgeons, whether university educated or trained in apprenticeships, treated only simple fractures, dislocations, and abscesses and performed amputations with dexterity but high mortality rates. They managed to ligate major arteries for common and accessible aneurysms and made heroic attempts to excise external tumors. Some specialized in the treatment of anal fistulas, hernias, cataracts, and bladder

ORIGINS O F MODERN SURGERY

stones. Compound fractures of the limbs with attendant sepsis remained mostly unmanageable, and staggering morbidity and mortality could be anticipated. Although a few bold surgeons endeavored to incise the abdomen in a hope to divide obstructing bands and adhesions, abdominal surgery was virtually unknown. Within just a few years, the practice of surgery would be altered more abruptly than in all its previous history. Startling new developments rendered the surgery of the 1850s and beyond a scientific profession markedly different from the surgery of the past . Among the most salient of these changes were the discovery and employment of anesthetics, the establishment of antiseptic and aseptic surgery, the improvement on old practices and the advent of radically new operative procedures, the use of roentgen rays, the development of more effective methods of hemostasis, and the evolution of practical blood transfusion. In addition, the total removal of any restrictions on the study of human anatomy and pathology, distinct and far-reaching changes in the methods of educating and training surgeons, the reform of medical care as a result of the rise of nursing as a profession, the formation of national and international surgical societies, and more rapid transfer of information via periodicals and other forms of communication all contributed to this progress. So great were the innovations and so inclusive was the domain of surgery that the foundation of basic operative procedures to be performed throughout the 20th century was laid by the time World War I was concluded (1918). Numerous efforts had been made throughout history to relieve by various measures the discomfort of surgical operations, and the epoch of ultimate conquest of pain is one of the most important in the evolution of surgery. Soporific, narcotic, and analgesic agents such as hashish, mandrake, and opium had been put to use for thousands of years. Alcoholic beverages also had been used to render a patient sufficiently oblivious to pain to permit the performance of surgical procedures on the surface of the body or on the bones . However, as anatomical knowledge and surgical techniques improved, the search for safer methods to prevent pain became more pressing. By the early 1830s, ether, nitrous oxide, and chloroform had been discovered. In the United States, "laughing gas" parties and "ether frolics" were in vogue. Young people were amusing themselves with the pleasant side effects of these compounds. Throughout the 1830s and 1840s, itinerant "professors" of chemistry travel ed to villages, towns, and cities to lecture on these new gases and demonstrate their exhilarating effects. Often, the most important part of such presentations consisted of having young members of the audience inhale ether vapor or nitrous oxide. These individuals lost their sense of equilibrium, felt little pain, and acted with an apparent loss of inhibition. It became obvious to various American physicians and dentists that the pain-relieving qualities of ether and nitrous oxide could be applicable to surgical operations. By December 1844, Horace Wells (1815-1848), a dentist from Connecticut, had grasped the concept of inhalation anesthesia and shared his findings with another dentist, William Morton (18191868). The latter settled in Boston and in October 1846 gave the first public demonstration of the effects of sulfuric ether anesthesia on a surgical patient, from whom John Collins Warren (1778-1856), professor of surgery at Harvard Medical School, removed a vascular tumor of the neck . After the

13

operation, Warren, greatly impressed with the new discovery, uttered his famous words: "Gentlemen, this is no humbug." News of the momentous event spread rapidly throughout the United States and Europe: a new epoch in the history of surgery had begun . Despite the introduction of general anesthesia, the evolution of surgery could not proceed smoothly until the grave problem of postoperative and hospital-acquired infection was resolved . Without a clear understanding of bacteriology and the sources of infection, however, most surgeons could do little more than provide high standards of surgical cleanliness, adequate hemostasis, and open-wound management. In many respects, the recognition of antisepsis and asepsis was a more important event in the evolution of surgical history than the advent of inhalation anesthesia. There was no arguing that the deadening of pain permitted a surgical operation to be conducted in a more efficacious manner. Haste was no longer of prime concern. However, if anesthesia had never been conceived, a surgical operation could still have been performed, albeit with much difficulty. Such was not the case with listerism. Without antisepsis and asepsis, major surgical procedures more than likely ended in death rather than just pain. Clearly, surgery needed both anesthesia and antisepsis, but in terms of overall importance, antisepsis proved of greater singular impact. In the long evolution of surgery, the contributions of few individuals are preeminent. Joseph Lister (1827-1912) (Fig. 1.4) can be placed in such an elite list because of his monumental efforts to introduce systematic, scientifically

FIGURE 1.4. Joseph Lister. (Courtesy of Jeremy Norman &. Co., San Francisco.)

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based antisepsis in the treatment of wounds and the performance of surgical operations. Lister pragmatically applied Louis Pasteur's (1822-1895) bacteriological research to human disease. Because infection was now known to be caused by a microscopic living body carried in the air, Lister devised a means of prevention and secured its adoption by a skeptical profession. Although the use of a carbolic acid spray remains his best-remembered detail, it was eventually abandoned in favor of other substances. Lister not only used carbolic acid in the wound but also sprayed it into the atmosphere around the operative field and table. Lister did not emphasize hand scrubbing but merely dipped his fingers into a solution of phenol and corrosive sublimate. A second important contribution that Lister made to sur gical technique was the development of sterile absorbable sutures. He was concerned that much of the deep suppuration found in wounds was created by previously contaminated silk ligatures. Lister evolved a carbolized catgut ligature better than any previously produced (1869). He was able to cut short the ends of his suture, thereby closing the wound tightly and eliminating the necessity of bringing the ends of the suture out through the wound. Over the years, Lister's principles of antisepsis gave way to those of asepsis, the complete elimination of bacteria. Asepsis was especially promulgated by Ernst von Bergmann (1836-1907), who merged the corrosive sublimate method into steam sterilization (1886) and eventually into the elaborate concept of general asepsis (1891). Any lingering doubts about the validity and significance of the momentous concepts Lister had put forth were eliminated on the battlefields of World War I. There, the importance of plain antisepsis became an invaluable lesson for surgeons around the world. Once antiseptic and aseptic techniques had been finally accepted as part of routine surgical practice, it was inevitable that other elaborate antiseptic rituals would similarly take hold . The use of gloves, face masks, operating gowns, and hats would soon naturally evolve. By the mid-1890s, surgeons were becoming fully satisfied with their antiseptic methods and the attendant results. Wound infection was becoming less of a concern, although difficulties still existed. Equally prominent among the 19th-century discoveries that had an enormous impact on the evolution of surgery was the research conducted by Wilhelm Roentgen (1845-1923) and his elucidation of x-rays in late 1895. Surgeons immediately applied the new discovery to the diagnosis and location of fractures, dislocations, and removal of foreign bodies. Far-reaching changes in the manner and methods of educating and training surgeons were among the most important organization advances in surgery during this era. The haphazard education of surgeons that had held sway for more than 2000 years became a well-defined system, as first promulgated in Germany, Austria, and the United States. By the mid -19th century, Germany and Austria had supplanted England and France as the centers of European surgical knowledge, a success in large measure attributable to the German system of surgical training. The German "pyramid" plan was soon adopted by William Halsted (1852-1922) (Fig. 1.5) in his program at the Johns Hopkins Hospital. Although Halsted has long been recognized for his original contributions to the science of surgery, the most far-reaching of his concepts lay in the education, training, and inspiration of a school of sur-

FIGURE 1.5. William Halst ed. (Courtesy of Jeremy Norman & Co., San Francisco.)

geons imbued with his principles of thought and action. The "Halsted tradition" remains the sine qua non of modem surgical residencies. Although textbooks, monographs, and treatises had always been the foundation of medical writing, the introduction of journals to the surgeon's written armamentarium had a tremendous impact on the development of surgery in the 19th century. Albrecht von Graefe's (1828-1870) [outnal der Chirurgie und Augen-Heilkunde (1820), Joseph Malgaigne's (1806-1865) loumal de Chirurgie (1843), Bernard Langenbeck's (1810-1887) Archiv fUr Klini sche Chirutgie (1860), and Lewis Pilcher's (1844-1917) Annals of Surgery (18851 were particularly renowned. London had displaced Paris as the center of international surgical excellence, partially because of the manner in which surgical practice and the education of surgeons had been organized. By 1797, the old Company of Surgeons had ceased to be an effective managerial body, and plans were under way to organize a more responsive institution, the Royal College of Surgeons. In 1800, the Royal College of Physicians, the Royal College of Surgeons, and the Society of Apothecaries controlled the three types of practice, which officially remained mutually exclusive. The members of the Royal College of Physicians were few and had minimal influence outside London. The larger membership of the Royal College of Surgeons included about 400 to 500 individuals trained to practice only surgery. The apothecaries, theoretically under the control of the Royal College of Physicians, were permitted to advise on medical cases but were not allowed to charge for that advice unless they prescribed a medicine. When a surgeon was called in to operate, an apothecary frequently was required to attend the patient afterward or to dress the wound, but he could receive no fee unless he induced the patient to take potions and dressings.


Because there were so few physicians, the requirement for more personnel fell to the apothecaries and members of the Royal College of Surgeons. To better care for patients, the apothecaries, who knew little surgery, joined the college to learn surgery . The typical surgeon, conversely, knew little about pharmaceutical medicine and was forced to obtain an apothecary's license. It became apparent that this new class of general practitioner or surgeon-apothecary needed a comprehensive, regulated form of training. In 1815, the apothecaries obtained an act of Parliament that enabled them to hold an examination for all who practiced in England and to prosecute unqualified practitioners, the first statute in Great Britain to impose penalties on unlicensed practitioners. Within a few years of the passage of the Act of 1815, the Royal College of Surgeons began to define more clearly its educational requirements and made them complementary to those required by the Society of Apothe caries. Thus, candidates who intended to enter general practice usually obtained both licenses, and a Master of the Royal College of Surgeons, Licentiate of the Society of Apothecaries (MRCS, LSA!, became the common qualification. The Royal College of Surgeons became a licensing body and during the course of the 19th century gradually assumed increasing responsibility for the education of surgeons. Its license, however, was purely optional, and anyone could practice without restriction. In 1843, the college charter was again re-formed: the name was legally changed to the Royal College of Surgeons of England, and the Fellowship of Surgeons was created. During the 19th century, the most prominent English surgeons included Astley Cooper (1768-1841) (Fig. 1.6), Charles Bell (1774-1842), Benjamin Brodie (1783-1862), William Lawrence (1783-1867), Benjamin Travers (1783-

FIGURE 1.6. Astley Cooper. (Courtesy of the New York Academy of Medicine Library.]

15

1858), George Guthrie (1785-1856), Robert Liston (17941847), James Syme (1799-1870), John Hilton (1804-18781, James Paget (1814-1899), John Erichsen (1818-1896), Jonathan Hutchinson (1828-1913), Hugh Owen Thomas (18341891),Robert Lawson Tait (1845-1899), and William Macewen (1848-1924). The ascendancy of German medicine and surgery did not occur until the latter half of the 19th century. Surgical education and training persisted in an undeveloped state in the German-speaking countries longer than in most other regions in western Europe. Undoubtedly, a major reason for the delay was that at the beginning of the century Germany was a conglomeration of divided, independent political units, with no one central city representing the focus of governmental organization. The 19th-century German unification process under Prussia presented unlimited opportunities for surgery and its surgeons. As the new Germany began to showcase itself to the international markets, it looked to its universities for image building. In Prussia, a system of medical study had been arranged in 1825. It provided both for physicians who studied at the universities and for surgeons, who were delineated into first and second classes . The surgeons of the first class were required to study at either a university or a "medicochirurgical school" for 3 years. Unlike the physicians, however, they were not required to know Latin, an indication, perhaps, that surgery was thought of as the more practical craft. Surgeons of the second class were educated only through an apprenticeship with a practicing second-class surgeon. At midcentury, the Prussian government decreed that there should be but a single class of doctors , and that more than a medical degree was necessary before doctors could obtain the right to practice. As the German-speaking empire grew, a great scholastic achievement was coming to fruition in the form of the richly endowed state university-highly organized, academically free, crowded with laboratories, and ever growing. The national achievements of Germany soon became international, and from the 1860s through World War I, its educational system attracted aspiring students, including physicians and surgeons, from all over the world. In a mighty academic upsurge of less than 40 years, German surgeons wrenched the world surgical stage away from their European neighbors and asserted their own dominance. In 1872, the Deutsche Gesellschaft fur Chirurgie was formed. This national organization soon began to hold annual meetings, during which papers were read and criticized. In effect, it acted as a gathering place for the free interchange of new German surgical ideas. The reasons for the rapid development of surgery in Germany are not easily defined, but it was undoubtedly related to political and economic changes, as well as to the general cultural and scientific climate. The multiplication in the number of chairs of surgery at the universities, the unification of the disparate branches of the healing art, and the organization of learned societies with journals to publicize their proceedings can be counted among the most important factors. Few surgeons of distinction practiced in Germany during the early part of the century. Franz Hesselbach (1759-1816) and Vincenz von Kern (1760-1829) were among the best known. By the fourth and fifth decades of the 19th century a

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growing number of German surgeons were achieving prominence . Although their influence would be the catalyst that later propelled Germany toward world prominence, most of them did not live to see the heights to which German surgery rose. Among these individuals were Conrad Langenbeck (1776-1851); Johann Meckel, the younger; Johann Friedrich Dieffenbach (1792- 1847); Georg Stromeyer (1804-1876); and Edward Zeis (1807- 1868). During the 1860s, German surgery began its rapid climb to world prominence. In most instances, it fell to the surgeons born during and after the second decade of the century to help showcase the astounding medical and surgical advances and superb technical achievements of German-speaking surgeons . Within this group were Karl Thiersch (1822-1895), Friedrich von Esmarch (1823-1908), Albrech von Graefe (1828-1870), Theodor Billroth (1928-1894), Richard von Volkmann (18301889), Ernst von Bergmann (1836-1907), Theodor Kocher (1841-1917) (Fig. 1.7),Vincenz Czerny (1842-1916), and Friedrich Trendelenburg (1844-1924). Following the midpoint of the 19th century, another group of surgeons would lead German domination of the world surgical stage through the tragic lessons of World War I. Included were Johann von Mikulicz-Radecki (1850-19051, Paul Kraske (1851-1930), Anton von Eiselsberg (1860-1939), Hermann pfannenstiel (1862-19091, Max Wilms (1867-19181, Fritz de Quervain (1868-1940), and George Perthes (1868-1927). In France, the new Paris medical school was basically the old College of Surgery with the addition of a few physicians. Although surgeons did not literally replace physicians, most physicians of the revolutionary era and the early 19th century had strong surgical backgrounds. In a matter of great symbol-

FIGURE 1.7. Theodor Kocher. [Courtesy of Historical Collections, Library of the College of Physicians of Philadelphia.)

FIGURE 1.8. Guillaume Dupuytren. (Courtesy of Historical Collections, Library of the College of Physicians of Philadelphia.]

ism, the new Paris medical school was provided a home within the spacious facilities of the former College of Surgery. The reform of hospital training for young doctors also indicated the strength of Parisian surgeons . In the 19th century, hospital service became an integral aspect of overall medical training. Consequently, such features as th e com petitive examinations, known as concours, and the division of nonresident students [externs] and resident students (interns) were throwbacks to earlier surgical precedents. Many chores that had previously been assigned to young surgeons (wound dressing, phlebotomy, minor surgery) were now undertaken by medical students. Thus, French physicians had a strong surgical inclination, even if they were not actually going to specialize in surgery . Prelisterian 19th.century French surgery falls into four natural periods: the first, or Napoleonic, era (1800-1814); the second era, from 1815 to 1835, which closely parallels developments in the career of Guillaume Dupuytren (1778-1835) (Fig. 1.8); a preanesthetic period, from Dupuytren's death until 1847; and a fourth period, which lasted until the mid1870s, when listerian techniques were finally accepted by most French surgeons . Among the well-known French surgeons of the 19th century and the beginning of the 20th century were Dominique Jean Larrey (1766-1842) (Fig. 1.9), Jacques Delpech (1777-1832), Jean Marjolin (1780-1850), Jules Cloquet (1790-1883), Jacques Lisfranc (1790-1847), Alfred Velpeau (1795-1867), Auguste Nelaton (1807-1873), Paul Broca (1824-1880), Jules Pean (1830-1898), Just LucasChampioniere (1843-1913), Henri Hartmann (1860-195 2), and Mathieu [aboulay (1860-1913 ). Although the mantle of surgical leadership had been assumed by French and German surgeons during this century, other European surgeons of note dotted the medical landscape. Names that should be mentioned include Antonio Scarpa (1752-1832), Adolf Callis en (1787-1866), Christian


FIGURE 1.9. Dominique Larrey. [Courtesy of Historical Collections, Library of the College of Physician s of Philadelphia.)

Tilanus (1796-1883), Nikolai Pirogoff (1810-1881), Eduardo Bassini (1844-1924), Carl Reyher (1846-1890), Niels Rovsing (1862-1927), and Leonardo Gigli (1863-1908). The practice of surgery in the United States during the 19th century consisted of several distinct periods, each characterized by conditions sufficiently different to constitute separate surgical eras. The initial decades (1800-18251 were in most respects an extension of medicine as it had developed in the 13 colonies. Few physicians or surgeons in early 19thcentury America had become qualified to practice through a systematic course of education because academic facilities in the United States were limited and an extensive medical education generally required attendance at a European medical school. To meet existing conditions, most future practitioners were compelled to become apprentices to practicing physicians in America and to "read medicine and surgery " while working in the physician's office. During the earliest periods of the century, surgery remained merely a technical mode of medical treatment: there was little to suggest that it had become a branch of scientific medicine. In contrast to Europe, there were virtually no individuals in America who could be considered scientific surgeons . However, several developments during the early part of the century indicated progress toward the professionalizing of American surgery. Increasing numbers of young Americans were beginning to matriculate at leading European medical centers, especially those in Great Britain. Americans who managed to study abroad came to form a considerable proportion of the leading surgeons in sparsely settled America. Among these individuals were Wright Post (1766-1822), Valentine Mott (1785-1865), and J. Kearny Rodgers (1793-1851) of New York City. The Philadelphia surgeons Philip Syng Physick (1768-1837), his nephew John Syng Dorsey (17831818), and William Gibson (1788-1868) took lengthy periods of training in London and Edinburgh, and both Ephraim McDowell (1771-1830) and Benjamin Winslow Dudley (1785-

17

1870) returned, after studying in the latter city, to practice in the wilds of Kentucky. The years from the mid-1820s to 1846, when ether anesthesia was introduced, can also be considered a distinct period in the history of American surgery . During that time, because of the vast proliferation of medical schools throughout the country, nearly every important physician and surgeon in the United States initially studied at an American medical school. From the few scattered 18th-century institutions in Boston, New York City, and Philadelphia to the myriad schools that were opened during the 19th century, medical education became widely available. From 1847 through 1860, a third era in 19th-century American surgery occurred, a period dominated by the increasing use of surgical anesthesia and tempered by the continued inability to control infection. The surgeon's technical expertise regarding operations also changed markedly. Whereas the trademark of the bold surgeon had always been operative speed (e.g., completing an amputation in less than 60 seconds], the advent of anesthesia enabled the operator to remove his focus from speed alone and to be more precise in his methods. Numbers of surgical operations were beginning to increase, and some surgeons were beginning to pursue scientific investigation. The foremost example of the new type of American surgeons was Samuel Gross (1805-1884). He was adamant in his use of animal models to understand surgical diseases and therapies. Of unquestioned importance in the development of an American profession of surgery was the tragic experience of the Civil War (1861-1865). This armed struggle produced a huge number of casualties, and the concomitant need for surgical care constituted a unique era in the development of surgery in this country during the 19th century. The contributions to surgical treatment that developed during the Civil War have never been fully appreciated, probably because antiseptic techniques remained unknown, and more deaths and suffering resulted from infectious processes than from battlefield injury. The most important direct effect of the Civil War was the great number of physicians who were introduced to basic principles of surgery . Literally thousands on thousands of the most difficult surgical cases imaginable were handled in a short time; so many cases would not have occurred in many years of peace . These new "surgeons" learned about new ideas and standards of care and became familiar with anesthetic agents. After this on-site surgical education and training, American surgical practice evolved rapidly . A fifth era of American surgery took place from 1865 through the late 1870s. Rapid advances were made in medical sciences despite the growing presence of various medical sects, including homeopaths, botanies, and eclectics. During the 1870s, for the first time, a substantial number of surgical textbooks and monographs by American surgeons were published. That American surgery had reached a new level of sophistication was evident both in the growth of surgical literature and in the number of well-respected practitioners. However, there still remained no clear delineation between physician and surgeon, and the defining of an American surgeon had become a particularly difficult task. Clearly, there was a difference between the European concept of a surgeon and his American counterpart. The European medical community had an established history of groups of physicians who performed little but surgical operations,

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CHAPTER 1

whereas such specialization would not be attained in America until after the 1880s. Therefore, it is likely that most surgeons practicing in the United States through the 1870s practiced more nonsurgical medicine and derived greater income from their medical therapies than their surgical operations. Only toward the end of the 19th century was surgery in the United States increasingly performed by those who considered themselves specialists in surgery. Although most general practitioners continued to perform minor surgical operations (such as those for simple fractures, minor skin trauma, and hernia), the more difficult procedures such as abdominal operations were completed by these new specialists in surgery. This distinction between surgeon and physician was most evident in the large urban areas of the country. In rural America, the tum toward specialists in surgery would not occur until well into the 20th century. A major part of this delay can be attributed to the large number of rural physicians who received surgical training during the Civil War and to their desire to remain physician/surgeons as a means of augmenting their income. In addition, physicians in rural America were in short supply, and these general practitioner/surgeons were obligated to provide the only surgical expertise available for many miles. By the conclusion of the 1870s, surgery was practiced with about equal success on both sides of the Atlantic Ocean. The major difference between the two continents was that in most instances any evidence of advanced scientific research was still concentrated in the older, more established European university and hospital centers, not in the United States. The penultimate evolutionary stage of American surgery in the 19th century, including the existence of well-supported and adequately supplied hospitals and research institutions, occurred during the decades of the 1880s and 1890s. These years brought about a final acceptance of the germ theory in America and with it the introduction of crude antiseptic and aseptic techniques into many of the country's operating rooms. For various reasons, Lister found widespread enthusiastic support for his beliefs among the surgeons of the European continent. In his own country, however, and in the United States, surgeons turned to listerian techniques slowly and, at times, with reluctance. Before the 1880s, there was less infection in America's spacious general hospitals than in the exceptionally crowded charity hospitals of Europe. Consequently, the clinical need for listerian principles was not as great in the United States as in Europe. During the late 1880s, several surgical texts appeared that brought about the final acceptance of Lister's techniques in the United States. The most important of these American publications was Arpad Gerster's (1848-1923) The Rules of Aseptic and Antiseptic Surgery (1888)and Nicholas Senn's (1844-1908) Surgical Bacteriology (1889). Two other events during the 1880s were also crucial in the professionalizing of American surgery. In 1880, the American Surgical Association, the country's first surgical organization' was formed. Three years later, the initial volumes of the Annals of Surgery were published. For the surgeon, the Annals represented the most influential and important of all American medical journals of the 19th century. It was the first American periodical devoted solely to the practice of surgery, and its pages recorded the advancement of American surgery more accurately than did any other written source. By having their own society and journal, American surgeons

finally achieved some measure of the social and political organization that European surgeons had experienced for almost a century. By the beginning of the 1890s, it was evident that both American and European surgery had been affected more profoundly than any other area of 19th-century medical practice by achievements in the medical sciences. The discovery of useful anesthetics and the development of a method to prevent wound infection revolutionized surgical practice. From a crude and dangerous art, surgery rapidly became an influential, prestigious medical specialty in the 19th century. American surgery had finally begun to achieve its status as a distinct medical specialty. The last developmental era began in 1889, when William Halsted initiated his work in the newly opened Johns Hopkins Hospital in Baltimore. Although other surgeons had more international reputations, it was Halsted who set the tone for the final period of development. His work reveals the beginnings of a new American surgery based as much on physiology as on anatomy. Halsted moved surgery from the heroics of the operating "theater" to the relative sterility of the operating room and the privacy of the research laboratory. American surgery was becoming a true science, and the recognition of surgery's true therapeutic powers would soon follow. By the end of the 19th century, American surgery had sufficiently matured to acquire a professionalism of its own. Great surgical centers were being constructed in every section of the country, and the practice of surgery was proliferating and progressing. What American surgeons lacked was a cohesiveness brought about by some type of educational organization similar to the Royal Colleges in Great Britain or the Academy of Surgery in France. Although such societies as the American Medical Association (1847), the American Surgical Association, and various surgical specialty groups had begun to be established, they held no overt regulatory powers. They were primarily educational alliances with no control over licensure. Lack of an organized system of surgical education, training, and licensure would plague American surgery well into the 20th century. Like their European counterparts, 19th-century American surgeons were great individual achievers. Among the most prominent were John Rhea Barton (1794-1871), Nathan Ryno Smith (1797-1877), Willard Parker (1800-1884), Joseph Pancoast (1805-1882), Gurdon Buck (1807-1877), Frank Hamilton (1813-1886), J. Marion Sims (1813-1883), Henry Bigelow (1818-1890), D. Hayes Agnew (1818-1892), Lewis Sayre (1820-1900), Thomas Addis Emmet (1828-1919), William Tod Helmuth (1833-1902), Hunter Holmes McGuire (18351900), William W. Keen (1837-1932), Henry Marcy (18371924),CharlesMcBumey(1845-1913),JohnWyeth(1845-1922), Roswell Park (1852-1914), Franklin Martin (1857-1935), Howard Kelly (1858-1943), William Mayo (1861-1939), George Crile (1864-1943), Charles Mayo (1865-1939), and Harvey Cushing (1869-1939).

The 20th Century Three phases of surgical development are noted during the 20th century-from 1900 to 1918, from 1919 to 1945, and from 1946 to the present. Within each period, significant events have transpired that have affected the history of


surgery. The first 20 years represent a direct continuation of the tremendous revolution that had occurred within the surgical sciences during the last quarter of the 19th century. Many advances in surgery have been made during armed conflict. Not unexpectedly, therefore, World War I provided a signpost for surgery during the remainder of the 20th century. At the beginning of this era, a certain sense of social discomfort on the part of surgeons led to continued mockery by "scientific" physicians, who often disqualified surgeons as nonthinkers and surgery as an inferior craft. By 1900, surgeons had basically explored all the cavities of the body. Nonetheless, operative surgery had not yet been accepted by physicians who were not oriented to surgery or, most importantly, by patients and society. Even in the late 1990s, the immediate consequences of surgical operations, such as discomfort and associated complications, often were of more concern to patients than the positive knowledge that surgery can eliminate potentially devastating disease processes. By the early 20th century, it was becoming evident that research models, theoretical concepts, and valid applications would be necessary to demonstrate the scientific basis of surgery to the public, and that to devise new operative methods, experimental surgery was necessary. Most important, a scientific basis for therapeutic surgical recommendations consisting of empirical data collected and analyzed according to internationally accepted rules and set apart from individual authoritative appreciations would have to be developed. Surgeons needed to allay society's fear of the surgical unknown and present surgery as an accepted part of the established medical armamentarium. The most consequential achievement for 20th-century surgeons was the eventual social acceptability of surgery. Among the difficulties in studying 20th-century surgery is the abundance of famous names and important written and clinical contributions. It becomes a difficult and invidious task to attempt any selection of representative personalities, particularly after World War I, when the evolution of surgery became affected more than ever before by socioeconomic events and technological advances rather than by unique individual clinical achievements. The vast social transformation of surgery and medicine has begun to control the fate of the individual practitioner in the late 20th and beginning of the 21st century to a much greater extent than the clinicians as a collective force are able to control it by their attempts to direct their own profession. For American surgeons, the years just before World War I were a time of active coalescence into various social and educational organizations. The most important of these soci-

19

eties was the American College of Surgeons, founded by Franklin Martin in 1914. Patterned after the Royal Colleges of Surgeons of England, Ireland, and Scotland, the American College of Surgeons established professional, ethical, and moral standards for every authorized graduate in medicine who practiced surgery. From 1919 to 1945, the maturation process for surgical specialties gathered tremendous momentum. This clarion call became a vital stage in the evolution of world surgery and constituted the most significant aspect of surgical history during that period. Ironically, the United States, which had been much slower than European countries to recognize surgeons as a distinct group of clinicians separate from internists and general practitioners, would spearhead the move toward surgical specialization with great alacrity. The course of surgical fragmentation into specialties and subspecialties continues apace today, particularly in the United States.

Bibliography Bankoff G. The Story of Surgery. London: Arthur Barker; 1947. Bishop WJ. The Early History of Surgery. London: Robert Hale; 1960. Cartwright FF. The Development of Modem Surgery. London: Arthur Barker; 1967. Dally AD. Women Under the Knife: A History of Surgery. London: Hutchinson Radius; 1991. Glaser H. The Road to Modem Surgery. London: Butterworth; 1960. Graham H. The Story of Surgery. New York: Doubleday & Doran, 1939. Haeger K. The Illustrated History of Surgery. New York: Bell; 1988. Hurwitz A, Degenshein GA. Milestones in Modem Surgery. New York: Hoeber-Harper; 1958. Leonardo RA. History of Surgery. New York: Proben, 1943. Meade RH. An Introduction to the History of General Surgery. Philadelphia: Saunders; 1968. Power D. A Short History of Surgery. London: John Hale; 1933. Richardson RG. Surgery: Old and New Frontiers. New York: Scribner's; 1968. Rutkow 1M. Surgery: An Illustrated History. St. Louis: Mosby; 1993. Rutkow 1M. American Surgery: An Illustrated History. Philadelphia: Lippincott; 1998. Thorwald J. The Century of the Surgeon. New York: Pantheon; 1957. Thorwald J. The Triumph of Surgery. New York: Pantheon; 1960. Wangensteen OH, Wangensteen SD. The Rise of Surgery From Empiric Craft to Scientific Discipline. Minneapolis: University of Minnesota; 1978. Zimmerman LM, Veith I. Great Ideas in the History of Surgery. Baltimore: Williams & Wilkins, 1961.

Evidence-Based Surgery Robin S. McLeod

Are We Practicing Evidence-Based Medicine? Requirements for Practicing Evidence-Based Surgery

T

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he term evidence-based medicine was coined by Sackett and colleagues in the 1980s. They defined it as "the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients."! The practice of evidence-based medi cine means integrating individual clinical expertise with the best-available clinical evidence from systematic research. In short, evidence-based medicine means systematically search ing for the best evidence rather than relying on expert opinion or anecdotal experience. In addition, Sackett and colleagues recognized the importance of the clinical expertise that most physicians possess and were explicit in stating that the evidence must be integrated with clinical acumen. Finally, the preferences and values of the patient must be considered in the decision making. Critics of evidence-based medicine have argued that most clinicians already base their decisions on evidence even though, as discussed in this chapter, there is evidence that indicates that may not be true . Others feel that evidence based medicine does not place a value on the experience of the individual clinician. However , there is a recognition that patients vary in their disease manifestations and response to therapy, so even the best evidence may not be completely generalizable to the individual patient; therefore, the judgment of the clinician is crucial. Similarly, individual patients differ in their expectations and preferences, and management decisions must be guided by them. There are five linked ideas central to the practice of evidence-based medicine. First, clinical decisions should be based on the best -available scientific evidence; second, the clinical problem, rather than the habits of protocols, should determine the type of evidence to be sought; third, identifying the best evidence means using epidemiological and biostatistical ways of th inking; fourth, conclusions derived from identifying and critically appraising evidence are useful only if put into action in managing patients or making health care decisions; and finally , performance should be constantly evaluated.' Why the necessity for evidence-based medicine? The basis for the trad itional practice of surgery has been the under-

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 33

standing of the pathophysiology of a disease, introduction of procedures or maneuvers to alter the process, and close observation of the results of treatment reported through case series.' This practice has led to many advances and accepted therapies, including appendectomy for appendicitis, cholecystectomy and common bile duct exploration for cholangitis, and antireflux surgery for gastroesophageal reflux . On the other hand, there are striking examples for which the translation of basic physiological principles has not led to improved clinical outcomes. For example, gastric cooling was found to reduce acid secretion sharply, but when gastric cooling was used clinically to treat bleeding duodenal ulcers, it failed.' There has been evidence that inflammatory mediators are elevated in septic shock, but interventions with antagonists have failed to change outcome in these patients.v" No one would argue that modem medicine is different from that practiced earlier in this or previous centuries. For example, the discovery of penicillin led to a dramatic improvement in outcome in patients with pneumococcal pneumonia. It was obvious that penicillin was effective. Today, rarely do new interventions or technologies lead to such dramatic changes in outcome. More commonly, they lead to a small improvement in survival or possibly no improvement in sur vival but a change in function or quality of life. Whereas large differences can be readily detected by observation alone , certainty that the small change in outcome is due to the treatment itself and not inherent differences in patients requires more rigorous evaluation. This need for higher-quality evidence has also led to a need for physicians to be able to interpret the evidence . Since the introduction of the term evidence-based medi cine, it has been adopted by a wide range of specialties, including surgery . Many fear that evidence-based medicine is simply an excuse by policymakers to cut costs and curb clinical freedom . It is certainly true that rationing of health care dollars has increased, and with that there is increasing pressure to do more with less. Physicians may be unhappy with th at prospect, but it is likely the reality. In the United States, $1.1 trillion were spent on health care in 1997 compared with $700 billion in 1990. Since 1970, the proportion of gross 21

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CHAPTER 2

domestic product spent on health care has nearly doubled to 13.6% compared with 7.10/0. 7 Thus, with health care costs increasing exponentially, it is understandable that providers have concerns. Clinicians should also be concerned because without judicious use of available funds, there may be inadequate resources for interventions that are effective and thus for the ability to deliver high-quality care. There are, however, other reasons to practice evidencebased medicine. First, most physicians want to do the best for their patients on an individual basis. To do so, one must be abreast of the current knowledge in the area. Second, patients are better educated and informed and are challenging physicians' views. Patients have access to the medical literature and can often cite it. Not only are individual patients questioning what doctors are doing but also patient advocacy groups are playing a major role in medical care. Finally, if physicians wish to play a role in policy decision making and allocation of resources, they must have the evidence to justify the introduction and maintenance of these programs. Thus, physicians can no longer rely on their anecdotal experience.

Are We Practicing Evidence-Based Medicine? It has been shown that even high-quality information published in the literature is often not applied by practicing physicians. Antman and colleagues looked at interventions used in the management of acute myocardial infarction. 8 They determined the date when the first randomized controlled trial (RCT) indicated that a treatment was effective or ineffective and the dates of subsequent trials and performed meta-analyses of the individual trials. As a measure of when the treatment became standard practice or conversely was no longer standard practice, they looked at standard medical texts to determine whether the treatment was recommended as standard practice, might be useful, or was experimental. There were discrepancies between the results of meta-analyses and the recommendations of experts. In some cases, over 20 years elapsed between the time a medication was first shown to be effective in an RCT until it was recommended as routine therapy. No similar studies have been performed studying surgical procedures and their adoption or abandonment. However, the marked variations in the rates of some operations observed across small and large areas are likely an indication of the same phenomenon." Anderson and colleagues'? reviewed discharge data from 16 hospitals in Massachusetts during an 18-month period between 1985 and 1986. They found that 170/0 of patients were at high risk for developing a venous thromboembolism. Of these, 50% were surgical patients. Despite evidence from multiple RCTs dating to the 1970s, prophylaxis for venous thromboembolism was administered to only 32 % of these high-risk patients. The proportion of patients receiving prophylaxis ranged from 9% to 56% at the study hospitals. Overall, patients at teaching hospitals were more likely to receive prophylaxis. On the other hand, there is some evidence from two small studies performed at institutions in the United Kingdom suggesting that many of the decisions made by both internists and surgeons are based on high-quality evidence.!':" Ellis and colleagues examined the treatments given to 109 patients

with a known diagnosis admitted through the emergency room to a general internal medicine ward." They reported that treatment was based on evidence from RCTs in 53% and on convincing nonexperimental evidence in 29%; interventions without substantial evidence were employed in 18%. Those interventions based on RCT evidence included aspirin for transient ischemic attacks, omeprazole for esophagitis, and 100% oxygen for carbon monoxide poisoning. The interventions with convincing nonexperimental evidence included cardiopulmonary resuscitation for cardiac arrest and surgery for complete small bowel obstruction due to a cecal cancer. Treatment of various poisonings, noncardiac chest pain, and presumed food poisoning were classified as having unsubstantial evidence. A similar study was performed by Howes et al. of 100 patients on a general surgical ward." It is noteworthy that only 24% received treatment based on evidence from RCTs compared with 53 % of decisions in the internal medicine study. Treatment based on other convincing evidence was received by 71%. The latter group included the conservative management of adhesive small bowel obstruction, conservative management of splenic hematoma and blunt liver trauma, and endoscopic retrograde cholangiopancreatography and endoscopic management of gallstones and jaundice. The authors concluded that, for the most part, surgical therapy is evidence based. However, it is debatable whether nonsurgeons would be accepting that all of the treatments based on nonexperimental evidence would be based on "convincing" evidence as stated by these surgical authors.

Requirements for Practicing Evidence-Based Surgery Rosenberg and Donald outlined some of the steps involved in the application of evidence-based practice." First, the clinician must clearly identify and articulate a question that has arisen from clinical practice. External evidence is then sought, usually by performing a focused search of the literature. The information thus retrieved is subjected to critical appraisal; finally, the newly acquired knowledge is implemented in clinical practice. Thus, the necessary elements to practice evidence-based medicine are production and dissemination of high-quality evidence and retrieval and critical appraisal of the evidence. The remainder of this chapter discusses these two major issues.

Providing the Evidence Various hierarchies have been proposed for classifying study design.":" In simplest terms, studies can be classified as case series, case-control studies, cohort studies, and RCTs. The case series is the weakest and the RCT is the strongest for determining the effectiveness of treatment (Table 2.1). CASE SERIES

Case reports (arbitrarily defined as involving 10 or fewer subjects) and case series are the typical surgical studies performed. There is no concurrent control group, although there may be a historical control group. Patients may be followed from the same inception point and followed prospectively not

EVIDENCE-BASED SURGERY

TABLE 2.1. Hierarchy of Study Designs.

Case series Case-control study Cohort study Randomized controlled trial

COHORT STUDIES

Control group

Prospective follow-up

No

No No

Yes Yes Yes

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Yes Yes

Random

allocation of subjects

No No No Yes

for the purpose of the study but in the normal clinical course of the disease. Typically, data from patient charts or clinical databases are reviewed retrospectively. Thus, the outcome of interest is present when the study is initiated. Despite the limitations of this study design, the importance of results from case series should not be minimized. It is because of careful observation that innovations in surgical practice and techniques have been and continue to be made. However, results from case series should be likened to those observations made in the laboratory. Just as those observations should lead to generation of a hypothesis and performance of an experiment to test it, an RCT should be performed to confirm the observations reported in a case series. Case series are plagued with biases (e.g., selection and referral biases), and because data are not collected specifically for the study, they are often incomplete or even inaccurate. Therefore, incorrect conclusions about the efficacy of a treatment are common, and the mistake that surgeons make is relying solely on evidence from case series. CASE-CONTROL STUDIES

The case-control study is the design used most frequently by epidemiologists to study risk factors or causation. There are two groups of patients: the case group is composed of subjects in whom the outcome of interest is present, whereas it is not present in subjects in the control group. Controls are selected by the investigator rather than by random allocation, so the likelihood of bias introduction is real; thus, there is a risk of drawing an erroneous conclusion. Generally, the controls are matched to the cases with respect to important prognostic variables other than the factor under study. While it is important to match the subjects to avoid an incorrect conclusion about the significance of the factor studied, it is equally important not to overmatch the controls so that a true difference is not observed. In case-control studies, as in case series, data are collected retrospectively. Thus, the outcome is present at the start of the study. As an example, Selby and colleagues performed a case-control study to make inferences about the effectiveness of flexible sigmoidoscopy in preventing rectal cancer." The cases were patients who had been receiving regular yearly examinations at a health maintenance organization (HMO) who developed rectal cancer (the outcome of interest). The controls were individuals from the same cohort of patients who had not developed rectal cancer. They were matched to the cases with respect to age, sex, and date of entry into the health plan. Selby and colleagues found that cases were less likely to have had a flexible sigmoidoscopy than controls in the preceding 10 years (8.80/0 of cases vs. 24.2% of controls).

Cohort studies may be performed retrospectively or prospectively. There are two or more groups, but subjects are not randomly allocated to the groups. One group receives the treatment or exposure of interest; the other group of subjects receives another or no treatment or exposure. The inception point may not be defined by the study, and the intervention and follow-up may be ad hoc. However, the outcome is not present at the time that the inception cohort is assembled. There is less possibility of bias than for a case-control study because cases are not selected and the outcome is not present at the initiation of the study. However, the likelihood of bias is still high because subjects are not randomly allocated to groups. Instead, there is some selection process by either the subject or the clinician that allocates them to groups. For instance, subjects may be allocated to groups according to where they live (when the effect of an environmental toxin is under study), by choice (when a lifestyle factor such as dietary intake is under study), or by physician (when a nonrandomized study of a treatment intervention is performed). Retrospective cohort studies differ from prospective cohort studies in that data analysis and possibly data collection are performed retrospectively, but there is an identifiable time point that can be used to define the inception cohort. Such a date could be the date of birth, date of first attendance at a hospital, or other selection. Cohort studies typically are performed by epidemiologists studying risk factors for which randomization of patients is unethical. Although they are more powerful than case-control studies, subjects are not randomized, so the cohorts may potentially be biased. An example of a cohort study would be the use of a database to follow patients who had a mucosectomy versus no mucosectomy in restorative proctocolectomy to determine the long-term outcome. RANDOMIZED CONTROLLED TRIALS

The RCT is accepted as the best trial design for establishing treatment effectiveness. There are several essential components of the RCT. First, subjects are randomly allocated to two groups: usually a treatment group (in which the new treatment is tested) and a control group (in which the standard therapy or placebo is administered). Thus, the control group is concurrent, and subjects are randomly allocated to the two groups. Second, the interventions and follow-up are standardized and performed prospectively. Thus, it is hoped that both groups are similar in all respects except for the interventions studied. Not only does this guard against differences in factors known to be important, but also it ensures that there are no differences due to unknown or unidentified factors. This latter point is especially important. Statistical techniques such as multivariate analysis can be employed to adjust for known prognostic variables but obviously cannot adjust for unknown prognostic variables. There are multiple examples of studies showing differences between groups that cannot be accounted for by the known prognostic variables. I? When differences in treatment effect are small, the RCT may minimize the chance of reaching an incorrect conclusion about the effectiveness of treatment. There are, however, some limitations to RCTs. First, RCTs tend to take a long

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CHAPTER 2

time to complete because of the time required for planning, accruing and following patients, and finally analyzing results. As a consequence, results may not be available for many years. Second, clinical trials are expensive to perform, although their cost may be recuperated if ineffective treatments are abandoned and only effective treatments are implemerited." Third, the results may not be generalizable or applicable to all patients with the disease because of the strict inclusion and exclusion criteria and inherent differences in patients who volunteer for trials. As well, not all patients will respond similarly to treatment. Fourth, when the disease or outcome is rare or only occurs after a long period of follow-up, RCTs are generally not feasible. Finally, the ethics of performing RCTs is controversial, and some clinicians may feel uncomfortable with randomizing their patients when they believe 1 treatment to be superior even if that is based only on anecdotal evidence. There are elements common to all RCTs as outlined in Table 2.2. The first and perhaps the most important issue in designing an RCT is to enunciate clearly the research question. Most RCTs are based on observations or experimental evidence from the laboratory. Always, RCTs should make biological sense, have clinical relevancy, and be feasible to perform. The research question will determine who will be included, what the intervention will be, and what will be measured. Frequently, a sequence of RCTs will be performed to evaluate a particular intervention. Initially, a small trial that is highly controlled using a physiological or surrogate endpoint may be performed. This trial would provide evidence that the intervention is effective in the optimal situation (efficacy trial). However, it might lack clinical relevance, especially if the endpoint were a physiological measure. However, if it were positive, then it would lead to another trial, with more patients and a more clinically relevant outcome measure. If this were positive, a large trial might be indicated to assess the effectiveness of the intervention in normal practice (effectiveness trial). Such an example would be studying the effect of a chemoprevention agent in colon cancer. Initially, the agent might be prescribed to a group of individuals at high risk for polyp formation (e.g., patients with familial polyposis coli) for a short time with the outcome measure a rectal biopsy looking for proliferative changes. A

TABLE 2.2. Elements of a Randomized Controlled Trial. 1. 2. 3. 4.

Stating the research question Selecting the subjects Allocating the subjects Describing the maneuver a. The interventions b. Minimizing potential biases c. Baseline and follow-up maneuvers 5. Measuring outcome a. Assessing treatment effectiveness b. Assessing side effects and toxicity 6. Analyzing the data 7. Estimating the sample size 8. Ethical considerations 9. Administrative issues a. Feasibility of the trial b. Administration of the trial c. Data management d. Funding issues

subsequent trial might look at polyp regression in this same cohort of patients, with subsequent trials aimed at the prevention of significant polyps in average-risk individuals followed for several years. As one can see, the selection of subjects, the intervention, the duration of the trial, and the choice of outcome measure may vary depending on the research question. Ultimately, however, investigators wish to generalize the results to clinical practice, so the outcome measures should be clinically relevant. For this reason, quality-of-life measures are often included. While there are elements common to all RCTs, there are issues of special concern in surgical trials." The issue of standardization of the procedure is of major importance in surgical trials. Standardization is difficult because surgeons may vary in their experience with and ability to perform a surgical technique; there may be individual preferences in performing the procedure, and technical modifications may occur as the procedure evolves. Moreover, differences in perioperative and postoperative care may also have an impact on the outcome. There are two issues related to standardization of the procedure. First, there is the issue of who should perform the procedure: experts only or surgeons of varying ability. Second, there is the issue of standardization of the procedure so it is performed similarly by all surgical participants and can be duplicated by others following publication of the trial results. The implications of these two issues are different, and strategies to address them differ. The first issue is analogous to assessing compliance in a medical trial. Thus, if the procedure is performed by experts only in a controlled fashion, this is analogous to an efficacy trial. The advantage of such a trial is that if the procedure is truly superior to the other intervention, then this design has the greatest likelihood of detecting a difference. The disadvantage, obviously, is that the results are less generalizable. Like most issues in clinical trials, there is no right or wrong answer. If the procedure is usually performed by experts, then it probably is desirable to have only experts involved in the trial. On the other hand, if a wide spectrum of surgeons performs the procedure usually, then it would be appropriate not to limit surgical participation. No matter how many surgeons are involved in the trial and that investigators want to mimic routine practice, there must be at least a certain amount of standardization so that readers of the trial results can understand what was done and can duplicate the procedure in their own practice. There are several strategies to ensure a minimum standard. First, all surgeons should agree on the performance of the critical aspects of the procedure. It may not be necessary that there is agreement with all of the technical aspects, but there should be consensus on those that are deemed to be important. Furthermore, if there are aspects of the perioperative and postoperative care that have an impact on outcome (e.g., postoperative adjuvant therapy), then they should be standardized. Teaching sessions may be held preoperatively and feedback given to surgeons on their performance during the trial. As well, obtaining documentation that the procedure has been performed satisfactorily (e.g., through postoperative angiograms to document vessel patency or pathology specimens to document resection margins and lymph node excision) may contribute to ensuring that the surgery is performed adequately. Finally, patients are usually stratified


according to surgeon or center to ensure balance in case there are differences in surgical technique between centers or surgeons. Blinding is often a difficult issue in surgical trials. It may not be an issue if two surgical procedures are compared but is a major issue if a surgical procedure is compared with a medical therapy. There is often a placebo effect of surgery. The classic example was observed in a series of 18 patients in which 13 patients underwent ligation of the internal mammary artery for coronary artery disease, and 5 patients underwent a sham operation." All of the patients in the latter group reported subjective improvement in their symptoms. Currently, it would be difficult ethically to perform a sham operation, so it might be impossible to conceal which treatment the patient received. The lack of blinding is especially worrisome if the primary outcome is a change in symptoms or quality of life rather than a "hard" outcome measure such as mortality or morbidity. In these situations, if a hard outcome measure is also measured and it correlates with the patient's assessment, then there is less concern about the possibility of bias. Assessments may be performed by an independent assessor who is unaware of the patient's treatment group. Finally, if criteria used to define an outcome (e.g., criteria to diagnose an intraabdominal abscess) are explicitly specified a priori, then it may minimize or eliminate bias. Investigators may also choose in this situation to have a blinded panel review the results of tests to ensure that the tests meet the criteria. The issue of timing of trials is difficult. Chalmers argued that the first patient who receives a procedure should be randomized." Most surgeons would argue, however, that a learning curve exists in any procedure, and modifications to the technique are made frequently at its inception. By including these early patients, one would almost certainly bias the results against the new procedure. The introduction of laparoscopic cholecystectomy and the initially high rate of common bile duct injuries is a good example of this problem. On the other hand, it may be difficult to initiate a trial when the procedure is widely accepted by both the patient and the surgical community. The paucity of RCTs testing surgical therapies supports this latter contention. This dilemma arises because, unlike the release of medical therapies, there is no regulating body in surgery that restricts performance of a procedure or requires proof of its efficacy. Probably, RCTs should be performed early, before they become accepted into practice, recognizing that future trials may be necessary as the procedure evolves and surgical experience increases. This is analogous to medical oncological trials, in which trials are planned as one is completed. On the other hand, the procedure must be established adequately for one certainly would not want to invest a large amount of money and time into a trial and have the results be of no value at its completion. Finally, patient issues may be of greater concern in surgical trials. In a medical trial, patients may be randomized to either treatment arm with the possibility that at the conclusion of the trial they can receive the more efficacious treatment if the disease is not progressive and the treatment is reversible. Surgical procedures, however, are almost always permanent. This may be of particular concern if a medical therapy is compared to a surgical procedure or the two surgical procedures differ in their magnitude or invasiveness.

25

Patients may have a preference for one or the other treatments and therefore refuse to participate in the trial. There also tends to be more emotion involved with surgery} and patients may be less willing to leave the decision regarding which procedure will be performed to chance. Surgeons themselves may feel uncomfortable in discussing the uncertainty of randomization with patients requiring surgery." Thus} accruing patients for surgical trials may be more difficult than for medical trials. In a survey of subjects who had already participated in a trial of maintenance therapy for Crohn's disease} Kennedy et al. found that 91 % would agree to participate in a trial again if it involved comparison of two medical treatments, but only 440/0 would agree to participate if it included a surgical arm." While accrual may be more difficult} there are notable examples of important surgical trials that have been performed.r':" Thus, they can be performed, though they may require a larger pool of eligible patients for sampling. OUTCOME STUDIES

The outcomes movement probably began in the 1980s in the United States when the Joint Commission on Accreditation of Healthcare Organizations launched a restructuring of its survey and accreditation procedures." Rather than simply measuring processes of care (e.g., number of surgical procedures performed), there was a shift to measuring patient outcomes. The outcomes and health services research movement has continued to gain momentum, and now many countries are employing these techniques to assess health care delivery in their jurisdiction. Health services research, which includes outcomes research} has been defined by the Institute of Medicine as "a multidisciplinary field of inquiry, both basic and applied, that examines the use} costs, quality and accessibility} delivery} organization, financing and outcomes of health care services to increase knowledge and understanding of the structures, processes and effects of health services for individuals and populations. ,,28 Health services research includes all types of evaluations} including studies using the RCT design. Outcomes research has been used to describe many different types of research. Outcomes studies are usually used to describe those studies for which outcomes are assessed in large cohorts of patients, often using data from administrative databases. These cohorts may include patients registered in an HMO or living in a geographical area or some other defined group. Thus, outcomes studies} using the previously discussed hierarchy of study designs, are cohort studies. The strength and rationale for outcome studies are provided with their focus on populations or large groups of patients to minimize selection and referral biases found in small institutional series. In addition} outcomes studies often use patient-based or patient-derived evaluations of care. The hope for the outcomes movement was that the information derived would inform decision making by clinicians} health care administrators, and patients and thereby lead to a cycle of improved care. The number of outcomes studies evaluating surgical procedures in all disciplines has increased exponentially in recent years. While they have an important role, they should be viewed as complementary to RCTs. Generally, an RCT is needed to establish the effectiveness of a treatment. The strength of the RCT is that conditions are tightly controlled

26

CHAPTER 2

to minimize bias and the risk of coming to an incorrect conclusion. However, because of this, they also may lack generalizability. Whereas variations in structure and process variables are minimized in RCTs, outcomes studies try to determine what role these factors play in routine care because there is no control over the selection of patients and the practice of physicians." Optimally, outcome studies can be used to determine whether services work as well in routine practice as they did in trials. For example, NASCET (North American Symptomatic Carotid Endarterectomy Trial) showed that carotid endarterectomy is superior to medical therapy in preventing strokes and reducing mortality in patients with significant carotid stenosis." However, this study was done under controlled conditions by expert surgeons who had to provide evidence, prior to participating in the study, that they could do the operation adequately. Following the trial, experts recommended that carotid endarterectomy should be performed only if perioperative stroke and mortality rates of less than 6% could be achieved. Kucey et al. examined data from the University of Toronto to determine whether the benefits of carotid endarterectomy could be achieved in an academic setting that included surgeons with a range of expertise and potentially including some with resultant higher-than-recommended stroke rates." Overall, the combined stroke and death rate was 6.3 % among 27 surgeons at the 8 hospitals, suggesting indeed that the benefit of carotid endarterectomy was realized. Unfortunately, not all surgeons achieved this threshold rate, with hospital complication rates ranging from 4.0% to 30.00/0. Information such as this may be useful in determining whether results from RCTs can be generalized to the nontrial situation." While RCTs are the standard for determining treatment effectiveness, another potential role for outcome studies occurs when RCTs are not feasible (e.g., involving a rare condition) or are not ethical. The availability of large administrative databases and ready access to this information with modem computers and statistical software packages has allowed outcome studies to be performed. These databases have several important limitations. First, the data within a database may be inaccurate or incomplete. Second, the databases have usually been set up for administrative purposes; therefore, clinically relevant data such as comorbid illness may be limited. Occasionally, it may be possible to link the administrative database to a clinical database that contains clinically relevant data. Alternately, additional information can be garnered by abstracting medical records or individual patient records. Finally, like clinical trials, outcome studies tend to be as good as the rigorousness of the methodology of the study. Thus, prior to embarking on the study, a hypothesis should be formulated, outcomes should be specified (e.g., length of stay, reoperative rate, readmission rate, etc.), plus comorbidities or risk factors (e.g., gender, age, hospital or surgeon, etc.) should be explicitly defined. Testing of the database to ensure accuracy is also an important step. Finally, multivariate statistical tests and logistic regression analyses are performed to adjust for possible known confounders (i.e., to control for the case mix). There are several limitations of outcomes studies. Outcome studies are essentially observational studies, lacking the rigorous control of variables as in an ReT. Thus, there is the risk of bias. If recognized, then adjustments can be made

in the analysis. However, there may be unidentifiable factors that bias the results. Thus, inferences must be made cautiously because there may be unmeasured variations in the patients, practitioners, and processes, and these may be the real explanation for differences in outcome. Second, often the available databases used have been set up for another purpose (i.e., to administer health care delivery). Thus, clinically relevant data may be limited. Optimally, patient relevant outcomes such as quality of life should be measured. However, endpoints may be limited to length of hospital stay, operative mortality, reoperation rates, and readmission rates. In addition to the limited number of endpoints, there may be inadequate or inaccurately recorded data on comorbidities. Furthermore, it may be impossible to know whether a com orbidity was present preoperatively or occurred following surgery. This may limit the ability to adjust the data adequately for varying levels of risk or disease severity. Third, outcomes studies can only assess the impact of patient variables and practice patterns on the process of health care delivery. Because patient preferences are not recorded, their impact cannot be assessed. However, certainly these playa major role in both decision making and outcome. Finally, there may be large fluctuations in outcome just due to chance for low-frequency procedures, and rates may not be stable statistically. The confusion surrounding outcome research includes not only the different design characteristics of outcomes research as described in this section but also because the term has been applied to at least two other kinds of studies: to assess small-area variation and to assess the relationship between volume and outcome. SMALL-AREA VARIATION

The term area variations describes the phenomenon of differences in the rates of medical and surgical services observed among geographic regions (so-called large areas). These variations have been recorded among countries, states, and provinces and among counties or health services areas (so-called small areas). These findings elicit concern because those in areas of high volume may be receiving too much or inappropriate care (and thereby potentially be exposed to iatrogenic illness and postoperative death), while those in low volume areas may be receiving too little care (and thereby not benefiting from modem medical care]." In the Province of Ontario, the rate of breast-conserving operations in females with newly diagnosed breast cancer ranged, by county, from 11% to 840/0. Iscoe and colleagues raised concerns that whether a woman had a breast-preserving procedure seemed to be related to factors at the local hospital level and not to patient factors or geography. Indeed, this large variation (15%-760/0) was observed even within metropolitan Toronto." While the 2 main reasons cited for the variations have been differences in physician practice style and access to medical care, Eddy warned that the variations may be due to a multitude of other causes, including difficulties defining or diagnosing the disease, differences in the prevalence and severity of disease, and regional differences in patient preferences in seeking and accepting medical care." Variation in surgical rates is related to variation in physician opinion. For many procedures, there is little variation (including such operations as inguinal hernia, acute myocardial infarction,


and hip fractures) when there is general consensus among the medical profession regarding the diagnosis and treatmerit." However, Wright and colleagues showed that the rates of knee replacement surgery in individual counties was directly related to the opinions of orthopedic surgeons." Where differences in physician opinion do exist, there tends to be large geographic variations. For example, when a panel of experts from the United States and the United Kingdom were asked to review the indications for coronary artery bypass surgery, only 130/0 of US physicians considered the indications to be inappropriate compared with 35 % of British physicians." The results of such studies are only of value if the causes and consequences of variation can be ascertained so strategies to minimize these variations can be implemented." The conduct of RCTs to improve the quality of evidence available and develop evidence-based practice guidelines may be useful in this regard. An additional problem with the interpretation of area variation studies is knowing what the rate should be." For some procedures, there may be no correct rate if patient preferences are considered/" VOLUME OUTCOME DIFFERENCES

Increasingly, studies have shown that for complex operations (e.g., esophagectomy, Whipple procedure, low anterior resection and abdominoperineal resection, liver resection and sarcoma surgery), surgical volume may have an impact on outcome.v" For instance, Porter and colleagues reported a 2.5-fold increase in local recurrence for patients having curative surgery for rectal cancer when surgery was performed by surgeons who performed at a low volume (defined as fewer than 21 procedures over a 7-year period]." Similarly, reports from Canada and the United States have shown a significantly lower postoperative mortality rate in centers performing a high volume of Whipple procedures compared with low-volume centers.":" Birkmeyer et a1. reported that the outcomes of low-volume surgeons were equivalent to those of high-volume surgeons if the low-volume surgeon worked at a high-volume hospital," suggesting that the health care team and facilities may be as important or even more important than the individual expertise of the surgeon. This trend has not been consistently observed, particularly in procedures of low or intermediate complexity. Khuri and colleagues studied 3D-day outcome information on seven of the most commonly performed operations (e.g., colectomy, total hip arthroplasty, cholecystectomy) at Veterans Affairs hospitals in the United States and found no correlation between mortality and hospital volume." Halm and colleagues performed a systematic review of the literature pertaining to volume outcome studies." There were 135 studies that covered 27 procedures and clinical conditions. The methodologic rigor of the studies varied, with few using clinical data for risk adjustment. However, 71 % of studies of hospital volume and 690/0 of studies of physician volume reported statistically significant associations between higher volume and better outcomes. The magnitude of the association was variable. Interestingly, studies that performed risk adjustment using clinical data were less likely to report significant associations. Halm et a1. concluded that differences in case mix and processes of care might explain part of the observed relationship between volume and outcome.

27

The implications of such studies are enormous and must be reviewed by policy- and decision makers. There has been a suggestion that there should be regionalization of more complex procedures. Before doing so, however, one must be certain that the results of current studies are not biased, and that observed differences are not due to factors other than volume. Thus, rigorous volume outcome studies with prospective collection of data with risk adjustment and studies addressing patient preferences may be required for each procedure before such decisions can be made. As well, implementation of educational measures may be another strategy to improve outcome. LEVELS OF EVIDENCE

There are several grading systems for assessing the level of evidence. 14,47-50 The first was developed by the Canadian Task Force on Periodic Health Examination in the 1970s and has been adopted by the US Task Force (Table 2.3). While differing in some respects, most systems consider the a priori design of the study and the actual quality of the study. Studies in which there has been blinded random allocation of subjects are given highest weighting because the risk of bias is minimized. Thus, an RCT will provide level I evidence if it is well executed with respect to the issues discussed in this chapter. This system is of value because of its simplicity, but difficulties may arise when pooling results from several studies, either informally during reading or when performing systematic reviews or developing guidelines. Decisions must be made on whether studies should be included or excluded depending on the quality of the study. As well, the systems are not sensitive to the relevance of the findings of studies. For instance, the clinical relevance of the outcome measures, the baseline risk of the effect, and the actual results of the studies (e.g., study results that are not consistent with results from other RCTs) are not considered in any system. In this volume, the quality of the evidence is generally classified according to the system listed in Table 2.3. The Center for Evidence-Based Medicine (Oxford, UK) has developed" the system shown in Table 2.4. It is used for the levels of evidence about prevention, diagnosis, prognosis, therapy, and harm. It differs from that initially proposed by

TABLE 2.3. Levels of Evidence.

II-I

11-2 II-3

Evidence obtained from at least one properly randomized controlled trial Evidence obtained from well-designed controlled trials without randomization Evidence obtained from well-designed cohort or casecontrol analytic studies, preferably from more than one center or research group Evidence obtained from comparisons between times or places with or without the intervention; could also include dramatic results in uncontrolled experiments (e.g., the results of treatment with penicillin in the 1940s)

III

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

Source: From Canadian Task Force on Periodic Health Examination." Used by permission of Canadian Medical Association Journal.

28

CHAPTER 2

TABLE 2.4. Oxford Centre for Evidence Based Medicine Levels of Evidence. Level

Therapy/prevention, etiology/harm

Prognosis

Diagnosis

la

Systematic review

Systematic review

lb

Individual RCT

Ie

All-or-none case series

Individual inception cohort studies All-or-none case series

Systematic review of Levell diagnosis studies Cohort study with reference standard

2a

Systematic review of cohort studies

2b

Individual cohort studies

2c

3b

Outcomes research Systematic review of case-control studies Individual case-control study

4

Case series

5

Expert opinion

3a

Systematic review of either retrospective cohort studies or untreated control groups in RCTs Retrospective cohort study or follow-up of untreated control patients in an RCT Outcomes research

Case series (and poor-quality prognostic cohort studies) Expert opinion

Differential diagnosis/ symptom prevalence study

Systematic review of prospective studies Prospective cohort study All-or-none case series

Systematic review of level

Control of Cellular Activity There are about 200 distinct cell types in an adult human being. All these several hundred different cell types share a core of "housekeeping" proteins necessary for metabolism and replication; these include some abundant proteins, such as those of the cytoskeleton, the major histone and nonhistone chromosomal proteins, proteins essential to the ER and Golgi membranes, the proteins of the nuclear lamina, RNApackaging proteins, ribosomal proteins, and so on. Many of the different enzymes involved in metabolism are also similar in different cell types. Different cell types, however, also express different subsets of the total protein-coding capacity of the genome. For example, hemoglobin is only expressed in red blood cells, although the DNA sequences that code for this protein are present in all mammalian cells. Each of these 200 different cell types contains exactly the same DNA, yet each cell type expresses distinct structural, chemical, and functional characteristics. How then do cells become specialized? This generation of cellular diversity is known as differentiation, a highly programmed, temporal pattern of gene activation and gene repression. A process involving the covert commitment of cells to a particular fate or set of fates precedes this overt change in cellular biochemistry and function. Here, the cell does not appear phenotypically different from its uncommitted state, but somehow its developmental state has been restricted. This control is accomplished by the regulation of gene expression.

Regulation of Gene Expression Extracellular Space

Cytosol

FIGURE 3.17. Hydrolysis of ATP can be used by membrane proteins to establish ion gradients. The Na+-K+ ATPase pumps Na" out of the cell in exchange for K+ in a 3 :2 ratio for every molecule of ATP that is hydrolyzed. The ion gradient that is established can then be used to drive other membrane-bound transport pumps, such as those that transport glucose and amino acids into the cell in exchange for sodium.

As noted, there are many steps in the pathway leading from DNA transcription to polypeptide synthesis. Thus, control of protein synthesis can be achieved at a number of checkpoints (Fig. 3.18). For the vast majority of cells, the primary control of gene expression is at the level of transcription. However, there are a number of posttranscriptional steps at which eukaryotic gene expression can be controlled. For example, variations in RNA processing can modulate RNA splicing (alternative splicing), thus allowing the generation of two closely related mRNAs and, in tum, types of proteins from the same primary RNA transcript. Alternatively, RNA stability can be regulated via proteins that bind to the 5'· and 3'untranslated regions (UTRs) of the mRNA. Cases in which RNA stability is regulated are often those for which rapid and transient availability of the protein is required. Similarly, RNA translational control can select specific mRNAs for transport to the cytoplasm or, once in the cytoplasm, for translation by the ribosomal complex. In general, translational control mechanisms supplement the regulation of gene expression by transcription.v"

,"

,, , ,I, DN ,, , I

"

.. --- .... .... ,

Nucle us

", ',

I

\

\ ,

Cytoplasm

\

,

".. _--_ " ....

55

CELL STRUCTURE , FUNCTION, AND GENETICS

....

FIGURE 3.18. Eukaryotic gene expression can be controlled at multiple sites . A cell can control the proteins that it makes through a variety of mechanisms. It can control (1) when and how often a gene is transcribed, (2) how the primary RNA transcript is processed, (3) the transport of the mRNA transcripts out of the nucleus, (41 the selection of transcripts for translation, (5) the stability of the mRNA transcript, and (6)the activation of the protein. Transfer tim e through the cells is quite short, lasting perhaps 20h.

Transcriptional Regulation of Gene Expression The regulation of gene activity at the transcriptional level has been generally thought to take place through the interaction of gene regulatory proteins called transcription factors with specific DNA sequences adjacent to the gene. Eukaryotic RNA polymerase II, for example, requires general transcription factors that must be assembled at the promoter before transcription can occur. These transcription factors must be assembled in a particular order and require binding to a short DNA regulatory sequence, the TATA box, found upstream of almost all RNA polymerase-binding sites. Additional regulatory sequences for the binding of gene regulatory proteins can be found thousands of base pairs away from the start site. Binding sites that activate transcription are termed enhancer sequences. Proteins that bind to these sites contain domains that interact with both the enhancer DNA sequence and one of the general transcription factors in the promoter region or with the RNA polymerase itself. Thus, DNA binding, although necessary for transcriptional activation, is not sufficient. A protein that negatively regulates transcription is termed a transcriptional repressor. These factors can act either by binding to DNA, thus displacing or preventing th e binding of a positive factor, or by directly blocking th e transcription machinery. Alternatively, a repres sor can bind an activator so that it can no longer enhance transcription.Y" Transcription factors are regulated by distinct mechanisms. For example, factors may be regulated by tissuespecific expression. MyoD is one example of an essential transcriptional activator of muscle-specific genes that is required throughout myogenesis and is found only in muscle

tissue. Gene regulatory proteins may also exist in a tissue but be nonfunctioning until a tissue-specific stimulus modifies the protein through conformational change, either through ligand binding or by covalent modification. For example, steroid binding to the glucocorticoid receptor displaces the receptor from heat-shock protein 90, facilitating its movement from the cytosol to the nucleus to activate transcription. The mammalian CREB (cyclic adenosine 5'·monophosphate [cAMPI-responsive element binding) factor is activated once it is phosphorylated by protein kinase A (PKAl, which in tum is activated by binding of cAMP to its regulatory subunit. Phosphorylation also regulates the activation of nuclear factor kappa beta INF-KE) in response to a variety of stimuli. However, it is the phosphorylation of an associated protein, I-KE (inhibitor of NF-KEl, that leads to transcriptional activation. The NF-KE is bound in the cytoplasm to I-KE in an inactive complex. Phosphorylation of I-KE leads to the release of NF-KE from this complex so that NF-KB can translocate to the nucleus to activate gene expression.P:" Evidence has indicated that controlling the balance of nuclear import and export of transcription factors may be a common mechanism for regulating transcriptional activation. Examples of transcription factors that may be regulated by nucleocytoplasmic shuttling include signal transducer and activator of transcription 1 (STATl), adenomatous polyposis coli (APCj protein, and the sry box (SOX) family of developmental transcription factors. " Interactions between DNA and transcription factors are very specific. Typically, DNA-binding proteins contain one of a small set of DNA-binding structural motifs that use either ~-sheets or a-helices. The helix-tum-helix motif is one of the most common DNA-binding motifs and is characterized by the homeobox proteins in Drosophila. It is composed of two a-helices linked by a short amino acid sequence in which the carboxy-terminal a-helix serves as the DNAbinding domain. Other motifs include the zinc finger motif, which also uses an a-helix to recognize the major groove of DNA but requires a zinc molecule as a structural element. The DNA-binding proteins that contain the zinc finger motif include TFIIIA, Egr I, and SpI. In addition, the steroid thyroid hormone receptor gene family also encodes proteins with a DNA-binding region that contains a zinc finger motif (Table 3.3). Most gene regulatory proteins recognize DNA as dimers. The ability of selected transcription factors to dimerize provides an additional mechanism of gene regulation by these proteins (see Table 3.3). For example, two identical proteins with identical recognition sequences can form homodimers, but proteins with different DNA-binding specificities can also form dimers (heterodimers) . Often, the homodimers and heterodimers recognize distinct sequences or have different gene

TABLE 3.3. Transcription Factor Domains. Domain

Role

Factors containing domain

Cysteine-histidine zinc finger Cysteine-c ysteine zinc finger Leucine zippers Helix-loop-helix

DNA binding DNA binding Protein dimerization Protein dimerization

TFIIIA, SPl , Egrl , MKl , MK2, Evil Nuclear hormone receptor famil y C/EBP, Iun B, [un, Pos, Fra I, c-myc, n-myc c-myc, Myo D

Source: Data from Latchman."

56

CHAPTER 3

activation properties. For example, c-fos and c-iuti are transcription factors that form dimers. A e-iun homodimer binds to the AP-l transcription site but not a c-fos homodimer, whereas a c-iun-c-ios heterodimer binds to AP-l with 30-fold greater affinity when compared to the c-iun homodimer. Gene regulatory proteins that form dimers contain distinct structural motifs, such as the leucine zipper motif, so-called because of the way the a-helices from each monomer interdigitate via leucine-rich regions on the respective helices. The DNA-binding proteins that contain the leucine zipper motif include c/EBP, jun B, e-iun, Gcn 4, c-fos, Fra I, c-myc, and n-myc. The basic helix-loop-helix (HLH)motif plays a similar role to the leucine zipper in mediating protein dimerization. These transcription factors are composed of two a-helices connected by a flexible loop. One helix mediates DNA binding, the other interacts with the HLH motif of another protein. The HLH proteins are prevalent in muscle development and include members of the transcription activator family, MyoD. Homodimerization of MyoD leads to musclespecific gene transcription. However, MyoD can also dimerize with a helix-tum-helix protein, Id, which lacks the a-helical extension required for DNA binding. The MyoD-Id heterodimer is unable to bind DNA (Id acts as a transcriptional repressor in this instance). This example illustrates how heterodimerization can be used to both positively and negatively regulate transcription activation.v" The direct regulation of transcription factor expression or activity is not the sole method of transcriptional regulation. Rather, biological control of transcription may also occur via the modulation of transcriptional coactivators, proteins that dock on transcription factors to allow transcription to take place. Transcriptional coactivators have been shown in some settings to be the primary targets of developmental or biological signals. Coactivators function in a variety of ways but can generally be segregated into three classes. One class of proteins modifies histones to improve the access of other proteins to the DNA. These include p300 and CBP, powerful HATs. A second class of proteins binds to transcription factors and recruits RNA polymerase II to facilitate transcription. Examples of these include members of the TRAP/DRIP/ Mediator/ARC complex. The final class of proteins contain DNA unwinding activities that, by improving access of transcription factors to the DNA, create more efficient gene transcription. Transcriptional corepressors have the opposite activity, making the DNA less accessible to transcription factors. These proteins are often associated with HDAC activity." Silencing of gene transcription can occur through DNA methylation, which is a covalent chemical modification of DNA that results in the addition of a methyl (CH3 ) group at the carbon 5 position of the cytosine ring. Most DNA methylation occurs in the sequence context of 5/CG3/, also called the CpG dinucleotide. The DNA methylation is brought about by a group of enzymes known as the DNA methyltrans[erases, of which there are currently eight isoforms identified. Methylation can occur both de novo (when CpG dinucleotides on both DNA strands are unmethylated) and as maintenance (when the CpG dinucleotide on one strand is already methylated). Mice deficient in these enzymes die early in development or shortly after birth. In addition to DNA methyltransferases, the other mechanisms for the regulation of methylation include demethylases, methylation centers that

trigger DNA methylation, and methylation protection centers. In the promoter region of target genes, DNA methylation can effectively silence transcription, both by interfering with the binding of transcription factors to the DNA and by the specific binding of transcriptional repressors to methylated regions of the DNA. For example, the transcription factors, AP-l, CREB, and NF-KB recognize sequences that contain CpG sequences, and the binding of each has been shown to be inhibited by methylation. In addition, the methyl-CpGbinding domain (MBD) proteins are transcriptional repressors. Hypermethylation of a number of genes has been associated with oncogenic transformation."

Translational Regulation of Gene Expression The final step in protein synthesis, the translation of mRNA into protein, is regulated by a variety of biological signals. Two general mechanisms of translational control of protein expression have been described. The first involves the global regulation of translation and usually requires the modification of translation-initiation factors that serve as the ratelimiting step in the translation process. The second method involves the specific regulation of individual mRNAs. This commonly occurs via an interaction between regulatory elements in either the 5/- or 3'-UTRs of the mRNA and specific protein or RNA complexes that target these elements. Plus, there are a variety of structural features of the mRNA that contribute to its translational fate.

Regulation of Translation Initiation Translation initiation is a complicated event that requires the formation of a large, multiprotein complex. The first step in the process is the binding of a small (40S) ribosomal subunit to the 5' end of the mRNA, which then scans the mRNA until the initiation codon is identified. This small rRNA is joined by the eIFs to form a 43S preinitiation complex. This complex includes the initiator tRNA attached to methionine. The eIFs that are important to this process include (1) the eIF4E that associates with the 5' cap structure, (2) the eIF4A that contains RNA helicase activity, and (3) the eIF4G that binds to eIF4E and functions as a scaffold for the recruitment of other eIFs. Together, they form part of the eIF4F translation initiation complex that regulates cap-dependent protein translation. Other eIFs serve important roles by providing the energy source to catalyze the addition of the 60S subunit. For example, eIF2 joins the complex bound to GTP, which is then hydrolyzed to enable the formation of an "elongation-competent" 80S ribosome at the site of the initiation codon." Global control of mRNA translation usually occurs by changes in the phosphorylation status of the eIFs or their regulators. For example, phosphorylation of the a-subunit of the GTP-donor, eIF2 (eIF2a), blocks GTP-GDP exchange, resulting in the inhibition of translation. Similarly, phosphorylation can modulate the binding of regulatory proteins called 4E-binding proteins (4E-BPs j also called PHAS-l) to the cap complex. These proteins, when hypophosphorylated, disrupt the association between eIF4E and eIF4G, halting translation. The phosphorylation of 4E-BPs frees them from eIF4E, allowing the eIF4E-eIF4G interaction to occur and translation to proceed."

CELL STRUCTURE, FUNCTION, AND GENETICS

Mammalian Target of Rapamycin and Surgical Disease One of the key regulators of cell growth and proliferation is the mammalian target of rapamycin (mTOR) pathway. Much of the information regarding mTOR is derived from use of the drug rapamycin (also referred to as sirolimus), a specific inhibitor of mTOR that has significant immunosuppressive properties. Rapamycin inhibits cell growth through its interaction with a cellular receptor called FKBP12. Screens performed in yeast to identify mutants resistant to rapamycin identified two genes, TORl and TOR2, which have a single mammalian homologue, mTOR (also known as RAFT, FRAP, and RAPT).32/33 The mTOR belongs to a family of phosphoinositide kinase-related kinases that contain a lipid kinase-like domain. However, mTOR functions only as a serine-threonine kinase and does not contain lipid kinase activity. The rapamycin/ FKBP12 complex binds to the amino-terminus of mTOR at a site that flanks the mTOR kinase domain and that has been identified as an FKBP12-rapamycin-binding (FRB) domain. As a consequence, mTOR signaling is inhibited. One affected downstream target of mTOR includes 4E-BP1, an important regulator of translation initiation. For example, in times of nutrient sufficiency, mTOR-mediated signaling results in 4E-BP1 becoming highly phosphorylated and dissociating from eIF4E. An additional target of mTOR is the elongation factor eEF2, a GTP-binding protein that mediates the translocation step of peptide-chain elongation. The mTOR signaling regulates a kinase that phosphorylates eEF2 and inhibits the translocation step. In these capacities, mTOR may function as a sensor for nutrient and energy levels in the cell. Dysregulation of mTOR signaling has been implicated in oncogenic transformation, intimal hyperplasia, and cardiac hypertrophy.32/33

Control of Translation by RNA Interference In 1998, initial studies performed in Caenorhabditis elegans demonstrated that double-stranded RNA (dsRNA) that was homologous to a specific gene could induce effective posttranscriptional gene-specific silencing. Preliminary attempts to use dsRNA in mammalian systems were initially unsuccessful, primarily because the use of long dsRNA triggered activation of the interferon system. As a consequence, protein translation was inhibited, leading to cellular apoptosis. However, elucidation of the mechanism of action of dsRNA soon revealed the extraordinary potential of small interfering RNA (siRNA). It is now known that gene silencing occurs via two main steps. The first step in the RNA interference (RNAi) pathway involves the processing of large dsRNA molecules into short (21-23bp) siRNA molecules. An RNAase III enzyme that recognizes and cleaves the dsRNA is Dicer, a highly conserved enzyme found in diverse species, including yeast, Drosophila, mice, and humans. Following the cleavage of dsRNA into siRNAs, the second important stage of mRNA degradation occurs. Hammond et al." demonstrated that RNAi ablates target mRNAs through the generation of a sequencespecific nuclease activity. They termed the enzyme responsible for this activity RISC (RNA-induced silencing complex);

57

RISC is guided to its mRNA target by siRNAs containing homologous sequence. Subsequently, the mechanism of action of RISC has been determined, and it exists in both an active and an inactive form. Although RISC requires doublestranded siRNA, unwinding of the siRNA is required for RISC activation. Then, active RISC associates with the antisense form of the siRNA. These data suggest that the RISC-siRNA complex has ATP-dependent helicase activity or that a helicase enzyme is associated with RISC.35/36 To apply RNAi methodology to mammalian cells, gene silencing had to be induced without long dsRNA. Once it was determined that siRNAs targeted mRNA degradation via RISC, small synthetic siRNAs (21-22bp) were used to bypass the Dicer enzyme. Synthetic siRNAs have now been used successfully to elicit strong suppression of gene expression in mammalian cells both in vitro and in vivo. The short half-life of siRNAs led to the development of short hairpin RNAs (shRNAs). Briefly, shRNAs are generated from expression cassettes composed of the eukaryotic polymerase III promoter followed by the sense strand of the siRNA followed by a spacer and then the antisense strand, which ended in a series of 5 U residues. The spacer sequence permitted the sense and antisense strands to anneal, forming a hairpin RNA molecule that has a longer half-life and can be continuously synthesized. This system has demonstrated potent gene suppression in mammalian cells. The availability of libraries of shRNA expression cassettes has created a powerful tool for the genetic manipulation of mammalian cells." Small endogenously produced regulatory RNAs have been implicated in the control of translation. Termed microRNAs (miRNAs), these sequences derive from original transcripts. Their features are very close in structure to siRNA but are believed to act by translational repression rather than by inducing RNA degradation. They bind to sequences in the 3' UTR of the target mRNA. However, the mechanism of translational repression is not known."

The Cell Cycle The eukaryotic cell cycle is divided into four stages or phases: G I , S, G 2, and M. The most dramatic of these phases is the M or mitotic phase. It is during the M phase that the nucleus divides and cytokinesis occurs. The period between successive M phases is known as interphase. A nondividing or interphase cell is not a resting cell, as it is sometimes described, because during this period the cell carries out all the normal activities (growth, respiration, protein synthesis, etc.) of the cell with the exception of division. It is thus only "resting" from the actual process of division. The interphase period may be subdivided into three recognizable stages as follows. In actively dividing cells, the actual division process (M phase) may take 1 or 2h, the G I phase approximately 8h, the S phase about 6h, and the G 2 phase about 4 to 5 h. Thus, the total cell cycle (period from one division to the next) in actively dividing cells is quite short, lasting perhaps 20 h. The significant events that occur within the G I , S, and G 2 phases are as follows. In the G 1 phase, the chromosomes decondense. At this point, the cells become biochemically active, synthesizing proteins needed for the replication and subsequent segregation of DNA. Here, normal cells must

58

CHAPTER 3

decide whether to remain quiescent or to proliferate. Cellular proliferation requires activation of various biomolecular signals, such as the cyclin-dependent kinases (Cdks), transcription factors, and phosphorylation of the retinoblastoma protein. Once a cell becomes committed to proliferation, this biochemical programming becomes irreversible, and the cell progresses into the S phase. Within dividing cells, the S phase is critical because this is the period during which the DNA is replicated in-preparation for the next division. Histones and nonhistone proteins are deposited on the daughter DNA molecules to reproduce the chromatin structures. Replication of DNA in eukaryotes is semiconservative. Each DNA strand acts as a template for the synthesis of a new DNA molecule by the sequential addition of complementary base pairs, thereby generating a new DNA strand that is the complementary sequence to the parental DNA. Each daughter DNA molecule ends up with one of the original strands and one newly synthesized strand.1,2/4/10 Eukaryotic DNA replication begins with the denaturation of the DNA double helix followed by the assembly of short RNA primer molecules by the action of an enzyme, DNA primase, and the semiconservative replication of the DNA. Initiation of DNA replication occurs at specific sites or origins (mouse chromosomes may contain as many as 25,000 origins) on the chromosome where the double helix denatures into single strands. The precise nature of eukaryotic origins is still somewhat obscure, although sequences have been identified that appear to be essential for replication of plasmid sequences in yeast. They are called autonomously replicating sequences {ARSs).1/2/4/1O Topoisomerases and helicases facilitate the unwinding of DNA during replication, the activity of these enzymes increasing as cells enter the S phase of the cell cycle. The DNA helicases move rapidly along single-stranded DNA. When they encounter a region of double helix, they continue to move along their strand, thereby prying apart the helix. Single-stranded DNA-binding (SSB) proteins aid helicases by stabilizing the unwound, single-stranded DNA. The SSB proteins also coat single-stranded regions on the lagging strand, thereby preventing formation of hairpin helices that would otherwise impede synthesis by DNA polymerase. Replication proceeds bidirectionally, and the DNA double helix opens to expose single strands that act as templates for new DNA synthesis. A Y-shaped structure forms when a double-stranded DNA molecule unwinds to expose the two single-stranded templates. This structure is called a replication fork. Replication of DNA is catalyzed by DNA polymerase. Four different polymerases, designated o; ~, "I, and 0, have been identified, although only DNA polymerases (l and 0 are responsible for nuclear DNA replication. Both can use RNA primers for the initiation of DNA replication. The fidelity of "copying" is such that only about 1 error is made in 109 basepair replications. This high fidelity of DNA replication depends on "proofreading" mechanisms that act to remove errors. The exact nature of proofreading proteins in eukaryotes is as yet unclear; however, several eukaryotic proteins have been discovered that are homologous in their amino acid sequence to several bacterial mismatch proofreading enzymes.1/2,4,10 Cells that complete the S phase almost always enter the G2 phase and proceed into cell division. Cells not destined to

divide again (e.g., certain epithelial cells, nerve cells, differentiated muscle cells) stop in the G 1 phase and never enter the S phase. It is in the G 1 phase that the cell carries out the normal metabolic processes for that particular cell type. Cells that complete the G2 phase enter the M (mitotic) phase of the cell cycle. 1/2/4,l0 Mitosis is nuclear division plus cytokinesis and produces two identical daughter cells. Mitosis consists of four stages: prophase, metaphase, anaphase, and telophase. During prophase, chromatin in the nucleus begins to condense and becomes visible in the light microscope as chromosomes. In metaphase, spindle fibers of the developing spindle apparatus penetrate into the region originally occupied by the nucleus and align the chromosomes along the equator of the spindle. During anaphase, the paired chromosomes separate at the centromeres, thereby generating two individual chromosomes. The beginning of telophase is marked by the arrival of the two sets of chromosomes at opposite poles of the spindle. Cytokinesis, or division of the cytoplasm, also begins during this stage.

Cell-Cycle Regulation Most molecular mechanisms that control a cell's progress through the cell cycle regulate initiation of the S phase or of mitosis. These regulatory mechanisms operate by using molecular brakes that can stop the cell cycle at one of several checkpoints, effectively keeping the cell cycle from progressing until a stage has been completed. These checkpoints are also points where the control system becomes regulated by signals from other cells. The G 1 checkpoint regulates passage into the S phase and checks for cell size, environment, and DNA damage. Only cells that are competent to progress through the rest of the cell cycle are allowed to proceed. The G2 checkpoint is the gate for passage into mitosis. Cells here must be of a certain size and must have stockpiled all the necessary components to undergo DNA replication. Both these transitions are regulated by heterodimeric protein kinases composed of a catalytic subunit and a regulatory subunit that contributes to substrate specificity. The regulatory subunits are called cyclins because the concentrations of most of them cycle in phase with the cell cycle. The protein kinase activity of the catalytic subunits depends on their association with cyclin, leading to the name cyclin-dependent kinases, or Cdks. When activated, these Cdk-cyclin heterodimers phosphorylate multiple different proteins, activating some and inhibiting others, to control the many molecular events associated with DNA replication and mitosis. Mitosis-promoting factor (MPF) is the cyclin-Cdk complex that controls entry into M phase; it regulates the activity of a large number of other proteins by phosphorylating them. For example, MPF causes chromosomes to condense and the nuclear envelope to break down by phosphorylating lamins. Phosphorylation of MAPs causes reorganization of microtubules to form the mitotic spindle. Two independent processes control Cdk-cyclin activity: (1) phosphorylation of Cdk and (2) proteolysis of cyclins. 1,2,4,l0

How does this system get shut off? Initiation of mitosis results in the activation of a number of genes with protein products that are enzymes that add the ubiquitin peptide to cyclin. This "tags" the cyclin for degradation via the

59


proteosome pathway. The rapid drop in cyclin concentration results in a corresponding drop in Cdk-eyclin enzyme activity. 1,2,4,10

Cell Death Programmed cell death, or apoptosis, is a process that is important to all multicellular organisms. It regulates cell number and tissue size by balancing cell proliferation with cell death. Cells undergoing apoptosis shrink and condense. Their cytoskeleton collapses, their nuclear envelope disassembles, the nuclear DNA fragments, and the cell surface becomes altered. Apoptotic cells are then rapidly recognized and phagocytosed by neighboring cells, with little residual debris. By contrast, cell death from accidental causes leads to cell swelling and lysis, triggering an inflammatory response in the surrounding tissue. Defects in the apoptotic mechanism have been implicated in a wide variety of disease processes, from the systemic inflammatory response syndrome (SIRS) to cancer, and thus the study of the regulation of this pathway has received enormous attention. The apoptotic machinery of a cell is produced constitutively. However, survival signals from the cell keep activation of the death program in check. In the event that the cell detaches from its environment or suffers irreversible damage, apoptosis is initiated. For example, DNA damage often leads to the accumulation and activation of the tumor suppressor protein p53. Activation of p53 either leads to growth arrest or directs cells to the apoptotic pathway. Although the mechanisms by which p53 promotes apoptosis are not completely understood, they involve the transcriptional activation or repression of specific target genes that lead to the activation of the apoptotic pathway. For example, p53 controls transcription of proapoptotic members of the Bcl-2 family such as Bax and Bid; p53 may exert transcriptional control on regulatory proteins in the intrinsic apoptotic pathway, including Apaf-1 and caspase-6. Finally, p53 also targets survival signaling by positively regulating the expression of protein tyrosine phosphatase (PTEN), a lipid phosphatase that antagonizes prosurvival signals generated by phosphatidyl inositol 3-kinase (PI 3-kinase).38 The morphological appearance of apoptotic cells relies on the activation of a family of proteases. First identified in the nematode C. elegatis, members of the cell death abnormal

TABLE 3.4. Caspases and Their Regulators. Group

Caenorbabditis elegans proteins

Initiator caspase Effector caspase

Ced-3

Caspase activator Antiapoptotic Bcl-2 homologue

Ced-4 Ced-9

Mammalian proteins

Caspase (2), -8, -9, -10 Caspase (2), -3, -4, -5, -6, -7, -II, -12, -13 Apaf-l, FADD, RAIDD Bcl-2, Bel-XL, Bcl-w, Mcl-l

Source: Data from Latchman."

(CED) gene family have been found to encode a family of ubiquitously expressed cysteine proteases that cleave their protein target at specific aspartic acid residues and are called caspasesP/" To date, 14 mammalian caspase family members have been described, of which at least 7 have been implicated in apoptosis (Table 3.4). Typically, a caspase molecule is transcribed as a single polypeptide chain that exists as a large inactive precursor in the cytosol and is composed of a large, variable-length, aminoterminal prodomain; a large subunit; and a small subunit. Proapoptotic signals lead to the activation of the procaspase by enzymatic cleavage, often through the action of an associated, initiator caspase. Proteolytic processing separates the three domains, removing the predomain and allowing the two subunits to form a heterodimer. The active caspase is a tetramer composed of two heterodimers. The prodomains are important because they contain regions that regulate the interaction of the caspase with other proteins, targeting them either to the activating death receptor at the cell membrane or to an assembled caspase-activating apparatus in the cytoplasm. Once activated, caspases cleave other specific proteins in the cell, which serve both to initiate and to directly cause the destruction of the cell (Table 3.5). These so-called death substrates include proteins involved in RNA splicing, DNA repair, and scaffolding of the cytosol and nucleus. Caspases are also known to cleave proteins involved in the maintenance of cell-ECM and cell-cell attachment and to inactivate proteins that function to protect the cell from apoptosis, such as Bcl-2.

TABLE 3.5. Selected Caspase Substrates. Death substrate

Function

Structural proteins Gelsolin Gas-2 Nuclear lamins DNA degradation CAD (caspase-activated deoxyribonuclease) Antiapoptotic proteins Bcl-2 Bel-XL Kinases PAK2 PKC-o PKC-v MEKK-l

Caspase cleavage of the cytoskeletal protein gelsolin and the microfilament protein; Gas-2 induces actin filament disruption

Source: Data from Cryns and Yuan.39

Lamin cleavage induces disassembly of the nucleus Caspases cleave the inhibitor of CAD, ICAD Caspase cleavage of Bcl-2 proteins transforms them into proapoptotic molecules Caspase cleavage generates a constitutively active kinase resulting in nuclear/ cytoplasmic condensation, cellular detachment, and phosphatidyl serine extemalization (?? mechanism)

60

CHAPTER 3

The inhibition of caspase function, while preventing the appearance of apoptosis, does not always rescue the cell from the apoptotic pathway and cell death. These data suggest that caspases can be divided into two groups: upstream or "initiator" caspases, which include caspases 2, 8, 9, and 10, and downstream or "effector" caspases, which include caspases 3, 6, and 7 (Fig. 3.19). Initiator caspases contain regions in their prodomains that target them to the plasma membrane, where they are activated as a result of cell-surface-receptor signaling events such as those mediated by the" death receptors" of the tumor necrosis factor-a (TNF-a) superfamily.t'r" Interestingly, the substrate cleavage preferences for these initiator caspases correspond to the sites of proteolytic activation in several downstream caspases. The activation of effector caspases is carried out by an initiator caspase and is responsible for the cleavage of proteins that leads to cell destruction. The substrate cleavage preferences for these effector caspases correspond to the sites of proteolytic activation in the majority of known apoptotic substrates. The activation of the apoptotic response occurs through two distinct pathways, designated intrinsic or extrinsic Damage pathways

Signal transduction pathways

Activation of "initiator" caspases

@+~+ Changes in mitochondrial membrane permeability

ATP

+ ICaspase-9!

!

Activationof "effector" caspases

B p

,,,,\'

!

Cleavage of death substrates APOPTOSIS

FIGURE 3.19. Mechanisms of programmed cell death. Proapoptotic signals act via the activationof initiator caspases or the disruption of mitochondrial membrane integrity. Mitochondrial membrane collapse leads to the release of cytochrome c into the cytoplasm. Once there, cytochrome c binds to Apaf-l [apoptotic protease-activating factor-I], caspase-9, and ATP to form a complex, referred to as the vertebrate apoptosome, that activates pro-caspase-3; this results in the activationofdownstream caspases, leading to substratecleavage. In contrast, the activationof initiator caspases by "death receptors" leadsdirectly to the activation of effector caspases.

depending on the ongm of the death stimulus. With the intrinsic pathway, the proapoptotic signal causes the release of proapoptotic proteins from the mitochondria, leading to mitochondrial membrane collapse, membrane depolarization, and the release of proapoptotic proteins from the mitochondria into the cytoplasm. These proteins include cytochrome C, SMAC (second mitochondria-derived activator of caspases)j DIABLO (direct inhibitor of apoptosis [IAPI binding protein with low pI), and AIF [apoptosis-inducing factor), to name a few. In the cytoplasm, cytochrome c binds to APAF-l [apoptotic protease-activating factor-I , a homologue of the worm CED-4), to facilitate the binding of APAF-l to ATPjdATP, thus forming the vertebrate apoptosome that mediates the activation of caspase-9.44,45 In fact, caspase-9 is capable of selfprocessing when bound to APAF-9. This complex results in the activation of procaspase-3 (a downstream caspase) and the processing and activation of other caspases, leading to substrate cleavage. In contrast, SMACjDIABLO acts by binding to the lAPs in the cytoplasm, relieving the lAP-mediated inhibition of caspase-3 and -9. In this model of the apoptotic pathway, the inhibition of caspases will delay but not prevent cell death. Other caspases, such as caspase-I and the related caspase-4 and -5, may be able to act as both initiators and effectors.tv" The disruption of mitochondrial membrane integrity leading to mitochondrial membrane permeability (MMP) is often observed before caspase activation is regulated at mul tiple levels. Induction of MMP can occur by proapoptotic second messengers, including calcium, reactive oxygen species (ROS), cerqamide, and other lipid messengers. In addition, it may involve the activation of the mitochondrial permeability transition pore complex (PTPCj, which includes the voltage -dependent anion channels in the outer membrane and the adenine-nucleotide translocase in the inner membrane. This multisubunit complex participates in the regulation of a variety of important mitochondrial membrane functions, and its opening has effects on energy metabolism, the generation of ROS, and the release of cytochrome c from the mitochondrial intermembrane space into the cytoplasm. Further, activation of the PTPC has been implicated in the physical disruption of the mitochondrial outer membrane. Although it is not clear which events [i.e., caspase activation or mitochondrial membrane disruption) constitute the "point of no return" in the apoptotic pathway, it is apparent that both are critically interrelated. A second mechanism exists that enables certain cells to induce other cells to self-destruct. This process is particularly important in the immune system. The receptors that mediate this response are members of the TNF superfamily that contain a conserved cytoplasmic protein-protein interaction module termed the death domain (DD). This cytoplasmic domain, first identified in studies involving the TNF receptor-I (TNFR-l), is responsible for the generation of cytotoxic death signals and the activation of acid sphingomyelinase." Mammalian death receptors include FasjAPO-ljCD95, TNFR-l, Apo-3jTRAMP, and the TRAIL receptors. The best described of these are CD95 or Fas and TNFR-l (Fig. 3.20). Clustering of the Fas receptor in response to ligand binding leads to the recruitment of DD-containing adaptor proteins such as FADD [Pas-associated death domain) to the receptor complex. This can occur either directly via FADD DD in the case of the Fas receptor or indirectly via the protein TRADD

61


Fas-R

TNF-RI

FIGURE 3.20. A schematic of the proposed signaling mechanisms of two members of the tumor necrosis factor receptor ITNFR) superfamily . Ligand binding to TNFR-l or to Fas-R leads to receptor oligomerization. Adaptor proteins such as FADD [Pas-associated death domain I and TRADD (TNFR-l-associated death domain) are recruited to the receptors via their death domains (DD). This phase is followed by an interaction between FADD and initiator procaspases (e.g., caspase-8 or -10) via their death effector domains (DEDI. This interaction results in caspase activation, which in tum leads both to activation of downstream caspases and to alterations in mitochondrial membrane permeability. Alternately, ligation of TNFR-l can recruit RIP (receptor interaction protein) to the receptor via an interaction between the DD of TRADD and a DD motif in RIP. The RIP is a serine-threonine kinase with activation that may regulate TNF-mediated activation of NF-lCB and c-Iun NH 2-terminal kinase lJNKl, possibly resulting in survival signals . An additional mechanism for TNFR-l signaling is via the recruitment of TRAF-2 (TNF-receptor-associated protein) and ASK-l [apoptosis signal-regulating kinase-I], ASK-l is an upstream kinase that leads to the activation of JNK [ASK-l lJNKK kinase) > JNK kinase lJNKKI > JNKI·

RIP

Pro-initiator Caspases CASPASE-8 CASPASE-lO

/1

INK Activation

-:

NF-KB Activation

(TNFR-I-associated death domain) in the case of TNFR-l. The FADD contains a death effector domain (DEDI that interacts with a DED module in procaspase-8 or procaspase-lO, leading to their activation. Caspase-2 and -9 also contain DED domains. Caspase-8 then activates, either directly or indirectly, downstream effector caspases (caspase-3 and -7) that cleave key death substrates. The extrinsic pathway can crosstalk to the intrinsic pathway through the caspase-8-mediated cleavage of Bid, a widespread proapoptotic protein of the Bcl2 pathway.v" Once Bid is cleaved by caspase-B, the Cvterminus of Bid moves to the mitochondria, where it induces the dimerization of Bax and Bak to promote the release of cytochrome c from the mitochondria. Mammalian inhibitors of the death receptor pathway include FLIP, which may act by displacing caspase-8 or -lO from their interaction with FADD. The formation of an adaptor protein complex via the DD also initiates important cellular signaling events that are required for the stress response." The TNFR-I-mediated induction of these signals may involve a second receptorassociated protein called RIP (receptor-interacting protein] that is also recruited to the signaling complex via a DD. The

Active caspase

/

MITOCHONDRIAL DISRUPTION

-:

EFFECTOR CASPASES

APOPTOSIS

RIP is a serine-threonine kinase with activation that may regulate the function of NF-KB and JNK (also called stressactivated protein kinase or SAPK). This action may occur via its association with other receptor-associated signaling molecules such as TRAD-2 (TNF receptor-associated factor-2) and ASK-I [apoptosis-signal regulating kinase-I], The TNFR engagement also leads to the activation of acid sphingomyelinase. Sphingomyelinase acts on membrane-associated sphingomyelin to generate the lipid second messenger ceramide, which may play an important role in the initiation of apoptosis. Ceramide-induced apoptosis may occur via two separate mechanisms, one involving the transcriptional regulation of the JNK pathway and the other via an alteration in mitochondrial membrane function." A major class of proteins that are intracellular regulators of apoptosis are the Bcl-2 family members, of which 18 have been identified in mammals thus far (see Table 3.4 for examples). These proteins are characterized by the presence of Bcl-2 homology (BH) domains, designated BHI , BH2, BH3, and BH4, and can be anti- or proapoptotic. In general, the antiapoptotic proteins Bcl-2, BclXL, Mel-I, and Bcl-w are thought to regulate apoptosis by interacting with the

62

CHAPTER 3

mitochondrial PTPC either to modulate its opening or to preserve mitochondrial ATP synthesis. The proapoptotic Bel1 family members Bax, Bak, and Bok exist as monomers in viable cells but oligomerize to form multimers on receipt of a death signal. Also, Bax and Bak are capable of forming heterodimers with the antiapoptotic family members." Studies have shown that the presence of the BH3 domain among proapoptotic family members is key to their function. Further, the identification of the importance of this domain has led to the discovery of a class of proteins known as the BH3-only proteins. These include Bid, Bad, Bik, and Bim, to list a few. The BH3-only proteins are thought to link cell death signals to the core apoptotic pathway. Their expression is regulated by a variety of mechanisms, including transcriptional regulation, phosphorylation, sequestration by cytoskeletal proteins, and proteolytic cleavage. Increasingly, these small molecules have been implicated in the pathogenesis of human disease processes, including oncogenic transformation and ischemic cell injury, making them important targets for future drug discovery."

Cell Communication Membrane Transport The ability of cells to respond appropriately to their environment is dependent on the function of membrane proteins that mediate intercellular signaling. A protein that is embedded in the membrane is referred to as an integral or intrinsic membrane protein. Virtually all these are transmembrane proteins that span both leaflets of the lipid bilayer. However, some can be anchored only in one leaflet, usually through the presence of a covalently bound hydrocarbon side chain. Classes of these proteins include glycosyl phosphatidylinositol-linked (GPI-linked) proteins, myristosylated proteins, and farnesylated proteins. In contrast, peripheral membrane proteins are not integrated into the membrane but rather are bound to the membrane indirectly by an association with an integral membrane protein or with a phospholipid; these include cytoskeletal and signaling molecules such as protein kinase C. In addition, phospholipases such as phospholipase A (PLA) can bind to the fatty acyl groups of phospholipids in the membrane.v'? Integral membrane proteins have common structural motifs. The transmembrane portion of the protein is usually an a-helix composed primarily of hydrophobic amino acids. This portion of the molecule makes a single pass through the membrane. Alternately, proteins may be composed of multiple a-helical regions that pass through the membrane multiple times. It is these multipass proteins that typically serve as transport molecules or as signal transducers. As lipid bilayers are essentially impermeable to even the smallest charged molecules, specialized transport proteins are required to move molecules such as amino acids or ions into and out of the cell. While membrane proteins can diffuse in the plane of the membrane, some cells can confine specific membrane components to particular regions of the membrane compartmentalizing their function. These cells are termed polar cells. The best example of this type of cell is the intestinal epithelial cell, which has an apical surface that is highly specialized for

absorption, whereas its basolateral surface mediates the transport of absorbed nutrients out of the cell. Epithelial cell polarity is maintained by tight junctions. Tight junctions are essential structures that segregate specialized regions of the plasma membrane (i.e., fence function) and provide an apical barrier to the paracellular movement of water and solutes. Their structural and functional integrity is based on an intact actin cytoskeleton and requires functional Rho GTPases. Protein components that have been identified in tight junctions include the transmembrane protein occludin and cytosolic plaque proteins ZO-l and ZO-2. 49 Membrane proteins that regulate intercellular communication are called receptors. When bound to a ligand, receptors serve to transduce signals into the cell through a conformational change, dimerization, enzymatic activation, or association with other molecules; this results in the activation of effector pathways that are specific to individual ligands. Cellsurface receptors have a wide variety of functions. However, they can be divided into two broad categories, transport receptors or signaling receptors; the former ferry required substrates into the cell, whereas the latter link ligand binding to the activation of intracellular signaling pathways.v'" There are two main classes of multipass membrane transport proteins. Carrier proteins bind solutes and undergo conformational change to transfer the solute across the membrane. Channel proteins consist of hydrophilic pores that, when open, allow solutes such as ions to pass through the membrane. All channel proteins and many carrier proteins function by passive transport. In this instance, solutes move according to their concentration gradient or to the membrane potential of the cell. Other carrier proteins have the capacity to move solutes against their concentration gradient by using active transport, a process that couples transport to an energy source. One well-described ion pump that is dependent on active transport is the Na+-K+ ATPase. The Na+-K+ ATPases are found in the plasma membranes of most animal cells and function to transport Na" out of the cell in exchange for K+, thus maintaining low intracellular Na" concentration. This process requires the hydrolysis of ATP to ADP. Although the pump is electrogenic, its main function is to regulate cell osmolarity. Cells contain a large concentration of organic solutes in the cytosol, including a high number of negatively charged molecules, thus requiring the retention of positively charged ions for charge balance. This large number of solutes draws water into the cell and must be countered by the extrusion of cations by Na+-K+ ATPase, thus contributing to a high extracellular ion concentration [Na" and CI+). Another membrane-bound ATPase that is homologous to the Na+-K+ ATPase is the calcium pump. The plasma membrane of most eukaryotic cells contains Ca 2+ pumps that pump Ca 2+ out of the cell against its gradient, thus maintaining an extremely low cytosolic Ca 2+ concentration relative to the outside of the cell. As a result, a small influx of Ca 2+ can lead to a substantial response within the cell by Ca2+-dependent signaling molecules. Muscle cells also contain a special pump in the sarcoplasmic reticulum. The rapid removal of Ca 2+ from the cytoplasm following muscle contraction is necessary for muscle relaxation to occur.v" A separate class of transport proteins that require ATP to function are the ATP-binding cassette (ABC) family of proteins. These include the cystic fibrosis transmembrane

63

CELL STRUCTURE , FUNCTION , AND GENETICS

regulator (CFTRJ, P-glycoprotein, the multidrug resistance transporter, and the sulfonylurea receptors. The CFTR receptor is localized predominantly in the apical membrane of epithelial cells, where it functions as an ATP-stimulated Cl channel. Evidence has suggested, however, that CFTR may also regulate other Cl" conductance channels and Na" channels, perhaps by facilitating cellular ATP release. Energy stored in the cell's ion concentration gradients drive active transport. For example, Nat-driven carrier proteins that are present in the plasma membrane can regulate cytosolic pH by exchanging Na' (in) for H+(out). The energy stored in the Na' gradient is used to drive this transport, which becomes active to decrease acidity when H+ leaks into or is made in the cell. Alternately, Na" can be brought in with bicarbonate (HCOa-). The Na" concentration gradient can also be used to drive a chloride-bicarbonate exchange, which is also very effective in pH regulation. In addition to ion exchange, the sodium gradient can be coupled to cellular import of glucose and amino acids . Channel proteins form holes or pores in the plasma membrane, allowing the passage of millions of ions per second when effectively triggered. There are two classes of membrane channel proteins, gap junctions, which bridge the cytoplasm between two cells, and ion channels. Ion channels, rather than functioning simply as pores, are selective for the ions that pass through (Fig. 3.21). Moreover, they have"gates" that open and close in response to specific stimuli, including (1) a change in voltage across the membrane (voltage-gated channels), (2) a mechanical stimulus, or (3) the binding of a ligand such as a neurotransmitter. The most common ion channels are those that are permeable to potassium. These channels are important because the potassium gradient across the cell membrane is the primary determinant of the resting membrane potential. Voltage-gated channels are responsible for the generation of action potentials in electrically excitable cells such as neurons and muscle cells and for the recovery of the resting membrane potential once the signal has passed . Ligand-gated channels, such as those activated by neurotransmitters, transfer a chemical signal to an electrical signal. The best-described members of

this family are the fast-acting nicotinic acetylcholine receptors of skeletal muscles. These are multisubunit proteins (typically composed of five subunits) that span the plasma membrane multiple times. The subunit architecture forms an array around a central channel that opens in response to acetylcholine binding to the extracellular domain of the receptor, allowing rapid sodium influx and membrane depolarization. In nerve cells, the end result is the initiation of an action potential. In other cells, however, membrane depolarization is linked to voltage-gated calcium channels, leading to increased intracellular Ca2+ concentration and triggering of Ca 2+-linked signaling events.':"

Cell Signaling Eukaryotic cells have the capacity to respond to a tremendously diverse array of biological stimuli. How is this information processed in an efficient and effective manner? The ability of cells to respond appropriately to their environment is dependent both on extracellular signaling molecules and on the presence of receptor proteins that bind to signaling molecules and transduce their specific responses. The chemical signaling molecules can be generally categorized by their membrane permeability. Small hydrophilic molecules such as peptide signaling molecules and growth factors require cell-surface receptors to transduce an appropriate signal. Many of these molecules act in a paracrine fashion to signal cells in the immediate environment. The availability of these signaling molecules is tightly controlled through a variety of mechanisms, including rapid uptake of the molecule and enzymatic degradation. Other molecules are either small enough or lipophilic enough to pass directly across the cell membrane to interact with intracellular targets. One example of this is the gas nitric oxide (NOI. It diffuses readily out of the cells where it is produced and passes directly into nearby cells. Its half-life is so short, however, that its effects are kept local. In contrast, lipophilic signaling molecules such as hormones can affect the entire organism and signal in an endocrine fashion. These small hydrophobic molecules are released into the bloodstream and

'i?i?n' gM

+++ .

! FIGURE 3.21. Ion channels open and close in response to specific stimuli, including (1' a change in the voltage across the membrane, (21 the binding of a ligand, or (31 a mechanical stimulus.

mechanically gated

Iigandgated

voltagegated

,.

. .

~l?

'"

gM

!

+ gM ~t l~~ gM

!

64

CHAPTER 3

can travel to distant sites, where they permeate target cells and are recognized by specific intracellular receptors that directly regulate gene transcription. The receptors for these molecules, which include steroid and thyroid hormones, retinoic acid, and vitamin D, are members of the nuclear hormone receptor gene superfamily. These proteins are single polypeptide chains with a modular structure that consists of a DNA-binding domain (containing two zinc finger motifs), nuclear localization signals, and a conserved ligand-binding domain (LBD). Unligated steroid receptors are found bound in the cytoplasm to a complex of heat-shock proteins, including hsp 90 and hsp 70. Hormone binding dissociates the receptors from the complex, and the ligand-bound receptors form homodimers via the LBD. The homodimers translocate to the nucleus, where they bind to DNA sequences called hormone response elements in the promoter region of target genes, leading to the activation or repression of gene transcription. In contrast, the nonsteroid family members, which include the vitamin D and retinoic acid receptors, are found bound to their response elements in the nucleus, even in the absence of ligand. In this instance, ligand binding alters the conformation of the receptor protein, increasing the affinity of the receptor for the DNA sequence (Fig. 3.22).

inhibitory protein complex

Ligandbinding domain

steroid

Cells have streamlined the transmission of messages by cell-surface receptors by linking them to a limited number of intracellular signaling pathways. It is apparent that the major currency of signal transduction is through the phosphorylation and dephosphorylation of pivotal regulatory proteins. The membrane receptors involved in signal transduction are grouped on the basis of the mechanism by which they activate downstream effectors. The largest family of signaling receptors is those associated with heterotrimeric GTP-binding proteins (G proteins). These proteins regulate the formation of intracellular second messengers such as calcium and cyclic adenosine 3',S'-monophosphate (cAMP). A second major family possessing intrinsic or associated enzymatic activity includes receptors with tyrosine kinase, serine-threonine kinase, tyrosine phosphatase, or guanyl cyclase activity. A third class of receptors, already discussed, are those ligandgated ion channels that initiate cell signaling by allowing rapid flux of ions across the plasma membrane.P The G-protein-coupled or serpentine receptors are seven transmembrane-spanning, integral membrane proteins that respond to a variety of stimuli and are linked via one or more G proteins to the activation of specific effector pathways (Fig. 3.23). These stimuli include a diverse variety of factors, including mitogens, vasoactive polypeptides,

DNA-binding site exposed

hormone

I

I

iiiiili!'" ··'rtB ·n ,·· . . [=~

_

, ,, ,,,,, ,

Inactive Receptor

"'--:,-11,' 'p..."':..,.' :

Nuclear translocation

+

":: :" ':;J)~P'::> :::[=.= Activated Receptor

Transcriptional Regulation

,' ..!Ii Ligandbinding domain

transcriptional enhancer vitamin D

~ ( PREGNENOLONE)

n

0:> 11·DEOXYCORTICOSTERONE

n n

CORTICOSTERONE

FIGURE 4.6. Steroid synthesis from cholesterol. ACTH is a principal regulator of steroid synthesis. The end products are mineralocorticoids, glucocorticoids, and sex steroids.

Cortisol is the major glucocorticoid in humans and is essential for survival following significant physiological stress. The cortisol response is altered in injury and may remain persistently elevated depending on the type of systemic stress. Bum patients have demonstrated elevated circulating cortisol levels up to 4 weeks; soft tissue injury and hemorrhage may sustain elevated cortisol levels for as long as a week." Circulating cortisol rapidly returns to normal levels on restoration of blood volume following hemorrhage. Coexisting systemic stress such as infections can also prolong the elevated cortisol levels following injury. Cortisol is a major effector of host metabolism. It potentiates the actions of glucagon and epinephrine (EPI), leading to hyperglycemia in the host." In the liver, cortisol stimulates the enzymatic activities favoring gluconeogenesis. IS Peripherally, it decreases insulin binding to insulin receptors in muscles and adipose tissue. In skeletal muscle, cortisol induces proteolysis as well as the release of lactate. The release of available lactate and amino acids has the net effect of shifting substrates for hepatic gluconeogenesis. Cortisol also stimulates lipolysis and inhibits glucose uptake by adipose tissues. It potentiates the lipolytic activities of ACTH, growth hormones (GHs), glucagon, and EPI. The resulting increased plasma free fatty acids, triglycerides, and glycerol

~ROGESTERO~

n

DEHYDROEPIANDROSTERONE

17-a-QH-PROGESTERONE

ANDROSTENEDIONE

n n

CORTISOL

MINERALOCORTICOID

CORTISOL/GLUCOCORTICOIDS

17-a-CH-PREGNENOLONE

11·DEOXYCORTISOL

ALDOSTERONE

in CRH and ACTH that are proportional to the severity of injury. Although pain and anxiety are prominent mediators of ACTH release in the conscious injured patient, other ACTH-promoting mediators may become relatively more active in the injured patient; these include vasopressin, AT-II, cholecystokinin, vasoactive intestinal peptide (VIP), catecholamines, oxytocin, and proinflammatory cytokines. Within the zona fasiculata of the adrenal gland, ACTH signaling activates intracellular adenylate cyclase, the cAMP-dependent protein kinase pathway, and the mitochondrial cytochrome P-450 system. This chain of activities leads to increased glucocorticoid production via desmolasecatalyzed side-chain cleavage of cholesterol (Fig. 4.6). Conditions of excess ACTH stimulation result in adrenal cortical hypertrophy.

~ r----------------,

GLUCOCORTICOID

n

n n

TESTOSTERONE

ESTRADIOL

SEX STEROIDS

from adipose tissue mobilization serve as available energy sources. In plasma, only 100/0 of cortisol is present in the free, biologically active form. The remaining 900/0 is bound to corticosteroid-binding globulin (CBG) and albumin. On injury, total plasma cortisol concentrations increase, but CBG and albumin levels decrease by as much as 500/0. 16 This alteration can lead to an increase of free cortisol by as much as 10-fold over normal. 17 Glucocorticoids exert immunosuppressive influences. Administration of glucocorticoids can induce rapid lymphopenia, monocytopenia, eosinopenia, and neutrophilia. IS Immunological changes include thymic involution, depressed cell-mediated immune responses reflected by decreases in T-killer and natural killer (NK) cell functions, T-Iymphocyte blastogenesis, mixed-lymphocyte responsiveness, graftversus-host reactions, and delayed hypersensitivity responses. With glucocorticoid administration, monocytes lose the capacity for intracellular killing but appear to maintain normal chemotactic and phagocytic properties. Neutrophil function is affected by glucocorticoid treatment in terms of intracellular superoxide reactivity and depressed chemotaxis. 19 However, neutrophil phagocytosis remains unchanged. Finally, glucocorticoids are inhibitors of immunocyte proinflammatory cytokine synthesis and secretion.P:" Indeed, glucocorticoid infusion in human endotoxemia downregulates tumor necrosis factor-alpha (TNF-a) production and increases the production of IL-IO, the antiinflammatory mediator.F This glucocorticoid-induced downregulation of cytokine stimulation serves an important negative regulatory function in the inflammatory response to injury. MACROPHAGE INHIBITORY FACTOR

Initially identified as a Tvlymphocyte-derived inhibitor of macrophage migration, macrophage inhibitory factor (MIF) is a glucocorticoid antagonist produced by the anterior pituitary." This hormone can potentially reverse the immunosuppressive effects of glucocorticoids both systemically via anterior pituitary secretion and at local sites of inflammation where MIF is produced by T lymphocytes. In experiments in which anti-MIF antibodies were administered to endotoxemic mice, survival increased, presumably because glucocor-

80

CHAPTER 4

ticoid antiinflammatory effects were not counterregulated by MIF. THYROTROPIN-RELEASING HORMONE AND THYROID-STIMULATING HORMONE

Thyrotropin-releasing hormone (TRH) serves as the primary stimulant for the synthesis, storage, and release of thyroidstimulating hormone (TSH) in the anterior pituitary." The TSH in tum stimulates thyroxine (T4 ) production from the thyroid gland, which is converted to triiodothyroxine (Ta) by peripheral tissues. The Ts is more potent than T 4, but both are transported intracellularly by cytosolic receptors, which then bind DNA to mediate the transcription of multiple protein products. Free forms of both T 4 and T a in the circulation can inhibit the hypothalamic release of TRH and pituitary release of TSH via negative-feedback loops. Both TRH and estrogen stimulate TSH release by the pituitary, whereas T a, T 4, corticosteroids, GHs, somatostatin, and fasting inhibit TSH release. Thyroid hormones [thyronines], when elevated above normal levels, exert diverse influences on cellular metabolism and function. Thyronines enhance membrane transport of glucose and increase glucose oxidation. These hormones increase the formation and storage of fat when carbohydrate intake is excessive, but this process decreases during starvation. The increase in cellular metabolism from excess thyroid hormone production leads to proportional elevations in overall oxygen consumption as well as heat production. Although T, levels are frequently decreased after injury, there is no compensatory rise in TSH release." In fact, following major injury, reduced circulating TSH levels are observed, and peripheral conversion of T 4 to T, is impaired concomitant with a reduction in available T a• This impaired conversion may be explained in part by the inhibitory effects of cortisol and an increased conversion of T 4 to the biologically inactive molecule known as reverse T, (rTa). Elevated rT a, but reduced T 4 and Ta, is an observation characteristic of acute injury or trauma, referred to as euthyroid sick syndrome or nonthyroidal illness. Experimentally, mild endotoxemia in otherwise healthy humans has shown that thyroid hormone alteration in systemic inflammation is not mediated by endogenous IL-1. Although total T 4 (protein bound and free) levels may be reduced following injury, free T 4 concentrations remain relatively constant. In severely injured or critically ill patients, a reduced free T 4 concentration has been predictive of high mortality. Lymphoid cells have high-affinity nuclear and cytoplasmic binding sites for thyronines, and one consequence of exposure to thyronines is an increase in the uptake of amino acids and glucose into the cell. Whether this is a direct effect of thyroid hormones or a secondary effect of increased cellular metabolism is unknown. As with other somatic cells, leukocyte metabolism measured by oxygen consumption is increased in hyperthyroid individuals and subjects receiving thyroid hormones. Functionally, animal studies have demonstrated that surgically or chemically induced thyroid hormone depletion significantly decreases cellular and humoral immunity. By contrast, thyroid hormone repletion is associated with enhancement of both types of immunity. Human monocytes, NK cells, and activated B lymphocytes express receptors for TSH. Exposure of B cells to TSH in vitro induces a moderate increase in immunoglobulin secretion.

GROWTH HORMONES AND INSULIN-LIKE GROWTH FACTORS

Hypothalamic growth hormone-releasing hormone (GHRH) traverses through the hypothalamo-hypophyseal-portal circulation to the anterior pituitary and stimulates the release of GHs in a pulsatile fashion during the sleeping hours. In addition to GHRH, GH release is influenced by autonomic stimulation, thyroxine, vasopressin, ACTH, ~-MSH, glucagon, and sex hormones. Other stimuli for GH release are physical exercise, sleep, stress, hypovolemia, fasting hypoglycemia, decreased circulating fatty acids, and increased amino acid levels. Conditions that inhibit GH release include hyperglycemia, hypertriglyceridemia, somatostatin, a-adrenergic stimulation, and cortisol. During times of stress, GH promotes protein synthesis as well as enhances the mobilization of fat stores. Fat mobilization occurs by direct stimulation in conjunction with potentiation of adrenergic lipolytic effects on adipose stores. In the liver, hepatic ketogenesis is also promoted by GH. Insulin release is inhibited and glucose oxidation is decreased by GH, leading to elevated glucose levels. The protein synthesis properties of GH following injury are mediated in part by the secondary release of insulin-like growth factor-1 (IGF-1).26 This hormone, which circulates predominantly in bound form with several binding proteins, promotes amino acid incorporation and cellular proliferation and attenuates proteolysis in skeletal muscle as well as in the liver. The IGFs (formerly referred to as somatomedins) are mediators of hepatic protein synthesis and glycogenesis." In the adipose tissue, IGF increases glucose uptake and lipid synthesis. In skeletal muscles, it increases glucose uptake and protein synthesis. Also, IGF has a role in skeletal growth by promoting the incorporation of sulfate and proteoglycans into cartilage. In vitro studies utilizing proteoglycan synthesis as a marker for IGF-1 activity demonstrated that IL-1a, TNF-a, and IL-6 can inhibit the effects of IGF-1. There is a rise in circulating GH levels following injury, major surgery, and anesthesia. However, the associated decrease in protein synthesis and observed negative nitrogen balance is attributed to a reduction in IGF-1 levels following injury." Administration of GH has been shown to improve the clinical course of pediatric bum patients, but its use in injured adult patients remains unproven. The liver is the predominant source of IGF-1, and preexisting hepatic dysfunction may further contribute to the negative nitrogen balance following injury. The IGF-binding proteins are also produced within the liver and are necessary for effective binding of IGF to the cell. In sum, IGF has the potential for attenuating the catabolic effects following surgical insults." Leukocytes express high-affinity surface receptors for GH. In general, GH and IGF-1are immunostimulatory and promote tissue proliferation. In vitro, GH augments the proliferation of T lymphocytes to mitogens and the cytotoxicity of T killer cells to allogenic stimuli. Macrophages also respond to GH with a modest respiratory burst. Mice deficient in GH manifest immunodeficiencies that can be partially reversed by the administration of GH. However, GH-deficient humans do not display any clinically significant immunological abnormalities. Normal humans given intravenous GH demonstrate no significant immunological changes except for neutrophilia. It is evident that GH has immunomodulating effects, but the clinical relevance of this influence remains to be determined.

81

MEDIATORS OF INFLAMMATION AND INJURY

SOMATOSTATIN

Somatostatin is a 14-amino-acid polypeptide produced by diverse cell types that include the gastric antrum and pancreatic islet D cells. It is a potent inhibitor of CH, TSH, renin, insulin, and glucagon release." The role of somatostatin during injury is yet unclear, but it may serve to regulate excessive nutrient absorption and the activities of CH and IGF during the convalescence period.

OPIOID PRECURSOR

CLEAVAGE PRODUCTS ACTH

Pre-POMC

c::::=:::=:::>

(Jl receptor)

p-Endorphin a-Melanocyte-stimulating hormone y-Endorphin

Pre-Proenkephalin-A (8 receptor)

c::::=:::=:::>

met-Enkephalin leu-Enkephalin

GONADOTROPHINS AND SEX HORMONES

Luteinizing hormone-releasing hormone (LHRH) or gonadotropin-releasing hormone (CnRH or gonadotrophins) is released from the hypothalamus and stimulates follicle-stimulating hormone (FSH) and luteinizing hormone (LH) release from the anterior pituitary. The release of these hormones can be effectively blocked by CRH, prolactin, estrogen, progestins, and androgens. The most relevant clinical correlation is seen following injury, stress, or severe illness when release of LH and FSH is suppressed. The reduction in LH and FSH consequently reduces estrogen and androgen secretion. This change is attributed to the inhibitory activities of CRH on LH and FSH release and accounts for the menstrual irregularity and decreased libido reported following surgical stress and other injuries. Estrogens inhibit cell-mediated immunity, NK cell activity, and neutrophil function but stimulate antibody-mediated immunity. Androgens appear to be predominantly immunosuppressive. In fact, in animal experiments castration is associated with enhanced immune function that can be reversed by exogenous androgens. Conversely, ovariectomy in the same type of animals results in immunodepression following trauma." Experimental data have shown greater survival rates in female animals following trauma than in male animals.P Although a strong experimental basis supports the concept that female animals have improved survival following inflammatory stresses, the documentation of this sexual dimorphism survival bias is far less evident clinically. Studies documented modest differences between young, healthy male and female subjects regarding systemic phenotype responses (temperature, blood pressure) but no differences in cytokine responses after an endotoxin challenge." PROLACTIN

The role of the hypothalamus is to suppress prolactin secretion from the anterior pituitary; this is achieved by the activities of LHRH/GnRH and dopamine. Stimulants for its release are CRH, TRH, GHRH, serotonin, and VIP. Elevated prolactin levels following injury have been described in adults; reduced levels are noted in children. The hyperprolactinemia may also account for the amenorrhea frequently seen in women following injury or major surgeries. Like GH, prolactin has immunostimulatory properties. Chemically induced inhibition of prolactin in animals has demonstrated increased susceptibility to infection, decreased lymphocyte proliferation, decreased IL-2 production and receptor expression, decreased interferon-alpha (IFN-a) production, and macrophage dysfunction. Exogenous administration of prolactin reversed these effects. There is increasing evidence that prolactin is also synthesized and secreted by T lymphocytes and may function in an autocrine or paracrine fashion.

Pre-Prodynorphin (lC receptor)

FIGURE 4.7. Precursors of endogenous opioids.

ENDOGENOUS QPIOIDS

Elevated endogenous opioids are measurable after major surgeries or insults to the patient." In addition to their role in attenuating pain perception, ~-endorphins are capable of inducing hypotension through a serotonin-mediated pathway. On the other hand, the enkephalins produce hypertension. In the gastrointestinal tract, the occupation of opioid receptors reduces peristaltic activity as well as suppresses fluid secretion. The role of endogenous opioids in glucose metabolism is probably complex." Although endorphins and morphine induce hyperglycemia, they also increase both insulin and glucagon release by the pancreas. In animal models, endogenous opioids such as dynorphins have demonstrated a paracrine role in modulation of vasopressin and oxytocin secretion. Studies demonstrating the presence of opioid receptors in the adrenal medulla also suggest their role in regulating catecholamine release. Certain immune cells release endorphins that also share an antinociceptive role in modulating the response of local sensory neurons to noxious stimuli. Endorphins also influence the immune system by increasing NK cell cytotoxicity and T-cell blastogenesis." There is evidence that IL-1 stimulates the release of endorphins from the pituitary gland. Both endogenous opioids (endorphin and enkephalin) and exogenous opiates mediate their effects through mammalian delta, kappa, and mu receptors (Fig. 4.7). Opioids appear to compromise both the natural (innate) and specific (adaptive) immune system through dose-dependent inhibition of proliferation and differentiation in lymphocytes and monocytes/ macrophages.

Posterior Pituitary Function VASOPRESSIN

Vasopressin (antidiuretic hormone, ADH) is synthesized in the anterior hypothalamus and transported by axoplasmic flow to the posterior pituitary for storage. The major stimulus for vasopressin release is elevated plasma osmolality as detected by sodium-sensitive hypothalamic osmoreceptors. There is evidence of extracerebral osmoreceptors for vasopressin release in the liver and the portal circulation. Vasopressin release is enhanced by a-adrenergic agonists, AT-II stimulation, opioids, anesthetic agents, pain, and elevated glucose

82

CHAPTER 4

concentrations. Changes in effective circulating volume by as little as 100/0 can be sensed by baroreceptors, left atrial stretch receptors, and chemoreceptors, leading to vasopressin release. Release of vasopressin is inhibited by ~-adrenergic agonists and ANP. There is now substantial evidence documenting a "vasopressin-resistant" condition in many patients suffering from severe injury and sepsis. While efforts to overcome this resistance state have included the exogenous administration of arginine vasoporessin (AVP), the potentially limiting toxicity of the agent requires other support measures. Data confirm that glucocorticoids may improve the vasopressin-resistant condition, although the mechanisms for this interaction remain unclear." In the kidney, vasopressin promotes reabsorption of water from the distal tubules and collecting ducts. Peripherally, vasopressin mediates vasoconstriction. This effect in the splanchnic circulation may cause the trauma-induced ischemia/reperfusion phenomenon antecedent of gut barrier impairment. Vasopressin, on a molar basis, is more potent than glucagon in stimulating hepatic glycogenolysis and gluconeogenesis. The resulting hyperglycemia increases the osmotic effect, which contributes to the restoration of effective circulating volume. Elevated vasopressin secretion is another characteristic of trauma, hemorrhage, open heart surgery, and other major operations. This elevated level typically persists for 1 week after the insult. The syndrome of inappropriate antidiuretic hormone release (SIADH) describes the excessive vasopressin release that is manifested by low urine output, highly concentrated urine, and dilutional hyponatremia. Clinically, this diagnosis can only be made if the patient is euvolemic. Once normal volume is established, a plasma osmolality less than 275mOsm/kg H 20 and a urine osmolality greater than 100mOsm/kg H 20 are indicative of this diagnosis. SIADH is commonly seen in patients with head trauma and bums. In the absence of vasopressin, a situation of central diabetes insipidus occurs in which there is voluminous output of dilute urine. Frequently seen in comatose patients, the polyuria in untreated diabetes insipidus can precipitate a state of hypernatremia and hypovolemic shock. Attempts at reversal should include free water and exogenous vasopressin (desmopressin, DDAVP). OXYTOCIN

Oxytocin and vasopressin are the only known hormones to be secreted by the posterior pituitary. Although both hormones share structural similarities, the role of oxytocin in the injury response is unknown. In humans, the only consistent stimulus for oxytocin secretion is suckling or other nipple stimulation in lactating women, which stimulates contraction of lactating mammary glands and induces uterine contractions in parturition. There is no recognized stimulus for oxytocin release or any known functions in men.

Autonomic Regulation A balance of autonomic function is increasingly recognized as important for regulating inflammation at the local and systemic levels." Studies have identified dysfunction of autonomic signaling either via classic neurohumoral mediators such as catecholamines," or through neurally transmitted signals, such as those elicited by vagus nerve traffic,4o,41 as

consequential to the regulation of pro- and antiinflammatory responses. The latter pathway, now termed the cholinergic a?tiin{lammatory pathway, appears to regulate the producnon of TNF-a within tissue macrophages." CATECHOLAMINES

Catecholamines exert significant influence in the physiological response to stress and injury. Indeed, the hypermetabolic state observed following severe injury has been attributed to activation of the adrenergic system. Both norepinephrine (NE) a~d EPI are increased in plasma immediately following injury, WIth average elevations of three- to fourfold above baseline. Catecholamines increase immediately after injury and reach their peak in 24 to 48 h before returning to baseline levels. The patterns of both NE and EPI appearance parallel each other following injury. Most of the NE in plasma results from synaptic l~akage during sympathetic nervous system activity, whereas VIrtually all plasma EPI is secreted by adrenal chromaffin cells. ~at.echolamines exert metabolic, hormonal, and hemodynamI~ Influences on cells. In the liver, EPI promotes glycogenolysis, gluconeogenesis, lipolysis, and ketogenesis. It also causes decreased insulin secretion but increases glucagon secretion. Peripherally, EPI increases lipolysis in adipose tissues and inhibits insulin-facilitated glucose uptake by skeletal muscle. These effects collectively promote the oftenevident stress-induced hyperglycemia, not unlike the effects of cortisol on blood sugar. Catecholamines also increase the secretion of thyroid and parathyroid hormones, T 4 and T 3, and renin but inhibit the release of aldosterone. Catecholamines elicit discernible influences on immune function. As an example, catecholamine occupation of ~ receptors present on leukocytes increases intracellular cAMP which may decrease immune responsiveness in lymphocytes. Like cortisol, EPI enhances leukocyte demargination with resultant neutrophilia and lymphocytosis. Also, EPI lowers the ratio of CD4+ to CD8+ T lymphocytes. Immunological tissues such as the spleen, thymus, and lymph nodes possess extensive adrenergic innervation. Chemical sympathectomy of peripheral nerves has been demonstrated to augment antibody response following immunization with a specific antigen. It also reverses the depressed mitogenic response of splenocytes preincubated with endotoxin. Normal volunteers infused with EPI exhibited depressed mitogen-induced Tlymphocyte proliferation. ALDOSTERONE

The mineralocorticoid aldosterone is synthesized, stored, and released in the adrenal zona glomerulosa. Aldosterone release during injury is stimulated by AT-IT, hyperkalemia, pituitary aldosterone-stimulating factor, and most potently, ACTH. The major function of aldosterone is to maintain intravascular volume by conserving sodium and eliminating potassium and hydrogen ions in the early distal convoluted tubules of the nephrons. Although the major effect is exerted in the kidneys, this hormone is also active in the intestines, salivary glands, sweat glands, vascular endothelium, and brain. In the late distal convoluted tubule, further sodium reabsorption takes place while potassium ions are excreted. Vasopressin also acts in concert with aldosterone to increase osmotic water flux into the tubules.

83

MEDIATOR S OF INFLAMMATION AND INJURY

Patients with aldosterone deficiency develop hypotension and hyperkalemia, whereas patients with aldosterone excess develop edema, hypertension, hypokalemia, and metabolic alkalosis. Following injury, ACTH stimulates a brief burst of aldosterone release. Angiotensin II induces a protracted aldosterone release that persists well after ACTH returns to baseline . Like cortisol, normal aldosterone release is also influenced by the circadian cycle, but this effect is lost in the injured patient. RENIN-ANGIOTENSIN

Renin is synthesized and stored primarily within the renal juxtaglomerular UG) apparatus near the afferent arteriole. The JG apparatus is comprised of the JG neurogenic receptor, JG cell, and macula densa. Renin initially exists in an inactive form as prorenin. The activation of renin and its release are mediated by ACTH, vasopressin, glucagon, PGs, potassium, magnesium, and calcium. The JG cells are baroreceptors that respond to a decrease in blood pressure by increasing renin secretion. The macula densa detects changes in chloride concentration within the renal tubules. Angiotensinogen is a protein primarily synthesized by the liver but also identified in the kidney. Renin catalyzes the conversion of angiotensinogen to angiotensin I (AT-I) within the kidney. Angiotensin I remains physiologically inactive until it is converted in the pulmonary circulation to AT-II by angiotensin-converting enzyme (ACE) present on endothelial surfaces (Fig. 4.8). The potent vasoconstrictor AT-II also stimulates aldosterone and vasopressin synthesis. It is capable of regulating thirst; AT-II stimulates heart rate and myocardial contractility. It also potentiates the release of EPI by the adrenal medulla, increases CRH release, and activates the sympathetic nervous system . It can induce glycogenolysis and gluconeogenesis . Expectedly, the renin-angiotensin system participates in the response to injury by acting to maintain volume homeostasis.

t. ACE~;1I"'~

INSULIN

Insulin is derived from pancreatic beta islet cells and released on stimulation by specific substrates, autonomic neural input, and other hormones. In normal metabolism, glucose is the major stimulant of insulin secretion. Other stimulants are amino acids, free fatty acids, and ketone bodies. Hormonal and neural influences during stress alter this response. Insulin release is inhibited by EPI and sympathetic stimulation. Other factors that further diminish insulin release include glucagon, somatostatin, gastrointestinal hormones, endorphins, and IL-I. Peripherally, cortisol, estrogen, and progesterone interfere with glucose uptake. The net result of impaired insulin production and function following injury is stress-induced hyperglycemia. These mechanisms are in keeping with the general catabolic state immediately following major injury . Insulin exerts a global anabolic effect in which it promotes hepatic glycogenesis and glycolysis, glucose transport into cells, adipose tissue lipogenesis, and protein synthesis. In the injured patient, there are two phases to the pattern of insulin release. The first phase occurs within a few hours after injury and manifests as relative suppression of insulin release, reflecting the influence of catecholamines and sympathetic stimulation. The later phase is characterized by a return to normal or excessive insulin production but with persistent hyperglycemia, demonstrating a peripheral resistance to insulin. Activated lymphocytes express receptors for insulin. Furthermore, insulin has been shown to enhance T-Iymphocyte proliferation and cytotoxicity. In fact, mouse spleen cells transiently exposed to a mitogen can continue to proliferate and maintain cytotoxicity if insulin is added to the medium. Clinically, institution of insulin therapy to newly diagnosed diabetics is associated with increased B- and T-Iymphocyte populations. The utilization of intensive insulin therapy for control of hyperglycemia has received much attention as this therapy is presumed to exert, at least partial, antiinflammatory influences ." Although appealing as an explanation for

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,

FIGURE 4.8. Endocrine activity of endothelium-derived mediators nitric oxide INO' and endothelin lEn ANP, atrial natriuretic peptide ; NE, norepinephrine; ACTH, adrenocorticotropin; EPI, epinephrine; ACE, angiotensin-converting enzyme ; A-I and A-II, angiotensin I and

ARTERY

o

II, respectively; PGI 2, prostacyclin, PGH 2, prostaglandin H 2• Arrows, stimulatory signal; lines with diamond sym bols, inhibitory signal. (Adapted from Luscher.l" with permission.]

84

CHAPTER 4

the presumed benefit of this therapeutic approach , few, if any, of the several inflammation regulatory mechanisms attributable to insulin have been clearly established.

that excessive antiinflammatory cytokine production activity may promote a condition of immunocompromise and enhance susceptibility to infectious morbidity.

GLUCAGON

Cytokine Response to Injury

Glucagon is a product of pancreatic alpha islet cells. Similar to insulin, the release of glucagon is also mediated by its substrates, autonomic neural input, and other hormones. However, whereas insulin is an anabolic hormone, glucagon has catabolic properties. Glucagon has a half-life of approximately 5 min and operates by adenylate cyclase secondmessenger activity. The primary stimulants of glucagon secretion are low plasma glucose concentrations and exercise. Glucagon stimulates hepatic glycogenolysis and gluconeogenesis, which under basal conditions account for approximately 75% of the glucose produced by the liver. In contrast to insulin, glucagon promotes hepatic ketogenesis and lipolysis in adipose tissue. The release of glucagon following injury is initially decreased, but returns to normal IZh later. By 24h, glucagon levels are supranormal and can persist for as long as 3 days.

Immune and Cellular Response to Injury Endogenous mediators of inflammation orchestrate the hemodynamic, metabolic, and immune responses following acute injury and severe infections. Unlike classic hormonal mediators, which are produced by specialized tissues and exert their influence predominantly by endocrine routes, cytokines are polypeptides or glycoproteins produced by diverse cell types at the site of injury as well as by systemic immune cells. Moreover, cytokines are not stored as preformed molecules but rather are produced on demand by active gene transcription and translation by the injured or stimulated cell. Once released into the circulation, cytokines function predominantly via paracrine and autocrine mechanisms. Cytokines bind to specific cellular receptors that result in activation of intracellular signaling pathways and gene transcription." By this mechanism, cytokines influence immune cell activity, differentiation, proliferation, and survival. These mediators also regulate the production and activity of other cytokines, which may either augment [proinflammatory] or attenuate (antiinflammatory) the inflammatory response. The capacity of cytokines to activate diverse cell types and to incite equally diverse responses underscores the pleiotropism of these inflammatory mediators. There is also significant overlap in bioactivity among different cytokines. Cytokines are necessary mediators that direct the inflammatory response to sites of infection and injury and are essential promoters of proper wound healing. However, exaggerated production of proinflammatory cytokines from the local site of injury can manifest systemically as hemodynamic instability [e.g., septic shock) or metabolic derangements (e.g., muscle wasting] ." Following severe injuries or infections, persistently exaggerated proinflammatory cytokine response can contribute to end-organ injury, leading to multiple-organ failure (MOF) and late mortality." The presence of antiinflammatory cytokines may serve to attenuate some of these exaggerated responses. However, it is presently assumed

The cytokine cascade activated in response to injury is complex. Hence, a proper perspective of the immunobiological functions of cytokines can have important applications in the comprehensive care of the surgical patient (Fig. 4.9).47The list of cytokines is rapidly expanding, and the ones described here represent only a partial list of mediators pertinent to injury and the inflammatory response [Table 4.2). TUMOR NECROSIS FACTOR-a

Following acute injury or during infections, TNF -a is among the earliest and most potent mediators of subsequent host responses. The primary sources of TNF-a synthesis include monocytes/rnacrophages and T cells, which are abundant in the peritoneum and splanchnic tissues." Furthermore, Kupffer cells represent the single largest concentrated population of macrophages in the human body. Therefore, surgical or traumatic injuries to the abdominal viscera undoubtedly have profound influences on the generation of inflammatory mediators and homeostatic responses such as acute-phase protein production.v-" Although the half-life of TNF-a is less than 20 min, this brief appearance is sufficient to evoke marked metabolic and hemodynamic changes and activate mediators distally in the cytokine cascade . Also, TNF -a is a major inducer of muscle catabolism and cachexia during stress by shunting available amino acids to the hepatic circulation as fuel substrates. Other functions of TNF -a include coagulation activation, promoting the expression or release of adhesion molecules, PGEz, platelet-activating factor (PAF), glucocorticoids, and eicosanoids." Soluble [i.e., circulating] TNF receptors (sTNFRs) are proteolytically cleaved extracellular domains of membrane1600 /-,

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4cm) receiving multimodality treatment: report of a feasibility study. Br J Cancer 1994;69:918-921. 27. Brittenden J, Heys SD, Ross J, Park KGM, Eremin O. Nutritional pharmacology: effects of L-arginine on host defenses, response to trauma and tumour growth. Clin Sci 1994;86:123-132. 28. Kirk SJ, Barbul A. Role of arginine in trauma, sepsis, and immunity. J Parenter Enteral Nutr 1990;24:S226-S229. 29. Beaumier L, Castillo L, Ajami AM, Young VR. Urea cycle intermediate kinetics and nitrate excretion at normal and therapeutic intakes of arginine in humans. Endocrinol Metab 1995;32: E884-E896.

Nutrition Kenneth A. Kudsk and Danny

History of Nutrition Support Implications of Nutrition Support for Clinical Outcome Determination of Nutritional Status. . . . . . . . . . . . . . . . Implications of Specialized Nutrition Support in Malnourished Versus Well-Nourished Patients . . . . Enteral Versus Parenteral Versus No Speciali zed Nutrition Support

S

III 112 112 113 113

ince the earliest recorded evidence of nutrition support using nutrient enemas some 3500 years ago in Egypt,' progressive malnutrition with it s negative impact on strength, resistance to infection, and ability to heal hav e challenged clinicians. With today's highly sophisticated, highly technical procedures to deliver nutrients intravenously or enterally, the field of nutrition support still struggles with the identification and reversal of malnutrition-induced vulnerability in patients. The implications of nutritional intervention-or lack of it-are still being defined despite tremendous growth in nutrition research since the late 1960s, when Dudrick and colleagues supported normal growth and development of beagles by intravenous nutrition alone. " The impact of specialized nutrition support on malnourished or well-nourished patients sustaining, or about to sustain, infectious, operative, or traumatic stress has generated debate concerning the ability to identify nutrition-related risks, the importance of route of nutrition, the effectiv eness of administered nutrients, and the appropriate amount and composition of diets for specific clinical conditions. Technological successes generate new complications that warrant consideration as therapy is instituted. Despite clear evidence in randomized, prospective studies of positive effects of nutrition support in defined patient populations , many clini cal practices are controversial and highl y debat ed among nutrition support professionals. The institution of any therapy as invasive as nutrition support carries potential costs and ben efits defined from studies of a heterogeneous population that may or may not be applicable to an individual pati ent's condition.

o. Jacobs

Type of Nutrient Diet . . . . . . . . . . . . . . . . . . . . . . . . . . .. Potential Mechanism for Reduced Infectious Complications with Enteral Feeding. . . . . . . . . . . .. Determining Dietary Requirements . . . . . . . . . . . . . . . . . Enteral Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Parenteral Nutrition References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

117 121 122 123 128 134

History of Nutrition Support The modem era dates to the late 1700s, when Hunter used oral gastric feeding with an eel-skin-covered whalebone to adm inister solutions of eggs, milk, wine, sugar, and jelly," In the late 1800s, rectal feedings were administered, with the most notable case that of u.S. President Garfield's " enteral" support for 79 days using whiskey and beef broth." Small-bore feeding tubes gradually became common practice, as did dilute nutrient solutions, which were soon replaced with "blenderized" foods. Intravenous feeding using feather quills with a pig's bladd er as a reservoir dates to the 1600s, when nutrient solutions consisted of milk, sugar, and egg white. In the 20th century, attempts at infusion of fat, carbohydrate, protein, and alcohol produced thrombosis with hypertonic solutions or pulmonary edem a with dilute solutions even if diuretics were given ." The subclavian catheter with central access allowed Dudrick, Rhoads, and Wilmore to administer low-volume, hypertonic solutions containing quantities of nutrients necessary to support metabolic needs.v' In th e late 1970s, research regenerated interest in the gastrointestinal (GIl tract as a primary route for nutrient administration when Kudsk and Sheldon identified that enteral feeding improved survival of animals after septic peritonitis.' Since th en, the bias has swung toward provision of nutrients enterally whenever feasible , particularly in malnourished or severely in jured trauma patients. The avoidance of immunological and metabolic complications and the preservation of mucosal integrity with enteral feeding has expanded the field of nutrition support and increased insight into malnutritionrelated defects. 111

112

CHAPTER 6

Im'plications of Nutrition Support for Clinical Outcome To critically evaluate a specific therapeutic intervention, three criteria should be satisfied." First, evidence should show that treatment is better than no treatment. Second, beneficial effects should outweigh harmful effects. Third, compared with other alternatives, the treatment should represent wise use of resources. These issues are paramount in nutrition support because comprehensive studies of intravenous nutrition documented a 290/0 incidence of complications related to catheter placement (5.7%), sepsis (6.50/0), metabolic (7.70/0) and mechanical (9%) complications, and death (0.20/0)9 caused by fluid and electrolyte problems (e.g., refeeding syndrome with sometimes-lethal drops in potassium, phosphate, and magnesium levels), metabolic complications such as hyperglycemia, and other technical issues. Enteral complications include aspiration, tube dislodgement, and abdominal complications such as diarrhea, nausea, vomiting, and intestinal necrosis.'? Potential serious and life-threatening complications dictate close inspection of existing clinical data obtained from heterogeneous and homogeneous populations. An evaluation of existing data of nutrition support in medical and surgical patients was published." This review is limited by the failure of the document to judge the quality of individual research studies," but it serves as a guideline for the review of the literature.

Determination of Nutritional Status The ability to quantify malnutrition, measure metabolic stress, and measure the effectiveness of nutrition is limited. Benefits are clear in some circumstances. Patients with shortgut syndrome from vascular disasters or chronic disease that leave no colon and less than 100cm of jejunum or less than 50 em of jejunum or ileum with an intact colon die without parenteral nutrition. 12 Parenteral nutrition restores body composition, allowing a meaningful, productive existence. Without such dramatic GI loss or severely impaired nutritional status, improved clinical outcome with specialized support is less clear. There is a strong inverse correlation between protein status and complications after patients undergo major GI surgery." Measurement of protein status is inexact because of difficulties quantitating degree of malnutrition and because diseases influence markers of malnutrition and clinical outcome. The continuum of nutritional status ranges from the well-nourished to the cachectic individual. Weight loss, albumin, prealbumin (PA), and immune competence (measured by delayed cutaneous hypersensitivity or total lymphocyte count) have been used to classify clinical states of malnutrition.l':" but individual markers may not accurately represent the status of a patient. Important information is the amount of weight loss or percentage of usual body weight calculated by the following equations: 0/0 Body weight loss = [(Usual body weight - Current body weightl/ Usual body weight] x 100 or

% Usual body weight = (Current body weight/ Usual body weight) x 100 In general, a weight loss of 5% to 100/0 over a month or of 10% to 20% over 6 months is associated with increased complications." Although considered the single best marker of status in stable patients, serum albumin levels are influenced by synthesis rates, degradation rates, and vascular losses into the interstitium or through the gut and kidney. Protein energy malnutrition decreases albumin synthesis, but reduced rates can maintain normal serum levels; for example, marasmus, a severe deficiency of protein and energy, is associated with a normal albumin level, which usually drops precipitously once nutrition is provided. Albumin (T1/2 = 21 days), and other transport proteins such as transferrin (T1/2 = 8 days) and PA (TI /2 = 2-3 days), also drops in inflammatory conditions such as sepsis, peritonitis, trauma, and bums, for which high interleukin (IL) 6 levels stimulate acute-phase protein production, such as C-reactive protein (CRP) and cxI-acidglycoprotein (AAG), and inhibit transport protein production." Delayed cutaneous hypersensitivity is influenced by injury; hepatic and renal failure; infections; edema; anesthesia; medications such as corticosteroids, coumarin, and cimetidine, and immunosuppressants. As a predictive tool, combinations of these measurements have been used to quantify the risk of complications. The Prognostic Nutritional Index correlates with poor outcome in the following equation: PNI (%) = 158 - 16.6 (ALB) - 0.78 (TSF) - 0.20 (TFN) - 5.8 (DH) where PNI is the risk of complication occurring in an individual patient, ALBis serum albumin [g/dl], TSF is the triceps skinfold thickness (mm), TFN is serum transferrin [rng/dl], and DH is delayed hypersensitivity reaction to one of three recall antigens (0, nonreactive; I, 5mm induration]." Because DH is rarely used in clinical practice, the equation can substitute the lymphocyte score, using a scale of a to 2, where a is less than 1000 total lymphocytes/ mrrr', 1 is 1000 to 2000 total lymphocytes/mm", and 2 is more than 2000 total lymphocytes/mm"." The higher the score using either of these equations, the greater the risk of postoperative complications will be. In acute disease, elevations in acute-phase proteins occur with simultaneous reductions in constitutive proteins. The Prognostic Inflammatory Nutrition Index (PINI) appears to correlate with recovery from injury as the acutephase protein response abates in the following equation: PINI

= (CRP)(AAG)/(PA)(ALB)

where CRP, AAG, and PA are measured in milligrams per deciliter and albumin in grams per deciliter." The subjective global assessment clinically evaluates nutritional status by determining restriction of nutrient intake, changes in organ function and body composition, and the disease process." There is close interobserver agreement and good prediction of complications in general surgical patients, liver transplant patients," and dialysis patients.f Anthropometry, creatine-height index, and muscle function have been used to assess nutritional status. Anthropometry using TSF and midarm muscle circumference provides an indirect measure of muscle mass and, in general

NUTRITION

populations, correlates with the degree of malnutrition. Its use is limited by high interobserver variability, influences of hydration and age, and overall response to nutrition therapy. Use of the creatine-height index, requiring complete urinary collection and meat-free diets, has fallen out of favor because of variability in metabolic status. Muscle function assessed by grip strength, respiratory status, and response to electrical stimulation does correlate with postoperative complications and response to nutrition therapy, but correlation with improvement in clinical outcome is unknown. In summary, there is no "gold standard" for determining nutritional status because of the influence of illness and injury on parameters and difficulty in isolating the individual influences of malnutrition and disease on clinical outcome. This conclusion was supported by nonrandomized prospective, retrospective, or case cohort-controlled studies. 10 Malnutrition is a continuum influenced by the duration of altered nutritional intake, the degree of insult and metabolic stress, and the ability to control or reverse the disease and metabolic perturbations induced by that disease.

Implications of Specialized Nutrition Sup-port in Malnourished Versus Well-Nourished Patients The effect of nutrition on outcome in patients with midrange degrees of malnutrition is unclear, but significant class I data (class of evidence) describe its impact in nontrauma/ noncritically ill general surgical patients at both ends of the nutritional scale, that is, well-nourished and severely malnourished patients (Table 6.1). The six articles on perioperative nutrition that reflect the effect of nutrition supportenteral or parenteral-on well-nourished general surgery patients'2.51 within 72h. With successful early enteral feeding, supplemented diet significantly reduced ventilator days, length of stay, ICU stay, and systemic inflammatory response syndrome. No effect on mortality. 221 patients undergoing pancreatectomy randomized to a standard diet versus an arginine/ omega-3 fatty acid/RNA supplemented diet or parenteral nutrition. Postoperative complications lower in the supplemented (33.8%) than standard diet (43.8%) or parenteral group (58.8%, P = .005 vs. supplemented diet). Length of stay shorter in the supplemented group (15.1 days] versus standard (17.0 days, P < .05) or parenterally fed groups (18.8 days, P< .05).

2000

Caparros!"

2001

deLuis

2002

Conejero!"

2002

Braga"

2002

Zhou l46

2003

Hall 14 7

2003

Carrel!"

2003

176 patients randomized to diet enriched with arginine, RNA, and omega-3 fatty acids or high-protein control diet . Mortality significantly lower (17/89 vs. 28/87, P < .05) and bacteremia significantly reduced in the supplemented group (7/89 vs. 19/87, P = .01). Significantly reduced nosocomial infections with supplementation (5/89 vs. 17/87, P = .01). Reduced mortality rate in supplemented patients with Apache 2 scores between 10 and 15 (1/26 vs. 8/29, P = .02). ICU patients randomized to high-protein diet with arginine, fiber, and antioxidants versus a high-protein formula . Infectious complication rates, ICU mortality, and in-hospital mortality similar. Patients receiving the enriched diet had a better survival at 6-month follow-up (76% vs. 67%, P = .061 and medical patients had a better survival with the enriched diet (76% vs. 59%, P < .051. 47 patients with oral laryngeal carcinoma randomized to standard diet or isonitrogenous isocaloric diet with arginine and fiber. Total complications similar, but fistula development lower in the enriched nutrient group (0% vs. 20.8%, P < .05). Postoperative stay shorter with the enriched diet (22.8 ± 11.8 days vs. 31.2 ± 19.1 days, P = .On 84 patients with systemic inflammatory response syndrome randomized to glutamineenriched or standard enteral diet . Infections significantly lower in the enriched group (11 vs. 17, P < .05) due primarily to reduced nosocomial pneumonia (6 vs. 11). 196 malnourished patients undergoing elective surgery for GI malignancy randomized to standard postoperative enteral feeding (N = 50), preoperative feeding of a diet enriched with arginine, omega-3 fatty acids and RNA and standard enteral formula postoperatively (N = 50), or enriched diet pre- and postoperatively (N = 501. Baseline demographics, surgical variables, and morbidity factors similar. Complications significantly highest in the group with standard diet alone and lowest in those with the enriched diet pre- and postoperatively. Postoperative length of stay significantly shorter in both groups receiving enriched diet than control group (P = .01 for both). 40 injured patients with body surface burns of 50%-80% and third-degree burns of 20%-40% randomized to groups given glutamine-enriched or a standard enteral formula for 12 days. Hospital stay significantly shorter with glutamine (67 ± 4 days vs. 73 ± 6 days, P = .026), and by 30 days wound healing significantly greater (86% ± 2% healed vs. 72% ± 3%, P = .0411. Cost of hospitalization significantly lower with glutamine (P = .031), but cost of nutrition greater. 363 general ICU patients requiring mechanical ventilation randomized to glutaminesupplemented diet or an isonitrogenous isocaloric control. No significant difference in death within 6 months, incidence of severe sepsis or secondary outcomes of infections, duration of febrile episodes, antimicrobial therapy, or use of isotropes . No benefit from enteral glutamine supplementation was noted . 45 burn patients randomized to either a standard diet or a glutamine-supplemented diet. The length of stay not significantly different (0.9 vs. 1.0 days per % total body surface area burn for glutamine vs. control), but positive blood cultures three times more frequent in control patients (4.3 vs. 1.2 days per patient, P < .05). Pseudomonas aeruginosa in 6 control versus a with glutamine diet (P < .051. Mortality rate significantly lower with glutamine (2 deaths vs. 12, P < .051.

limits 0.64-1.00); and a shorter hospitalization (risk ratio of -2.6 days, 95 % confidence limits -4.5 to -0.7 days). Other subgroup analyses were not statistically different; however, the data suggested that improvements in mortality tended to occur when glutamine was provided parenterally and at high doses compared with enteral or low-dose supplementation.

Furthermore, the reduction in length of stay appeared to occur in operated patients relative to those who were critically ill. Considering the data that are currently available, it would be premature to recommend glutamine supplementation as standard therapy outside its use in new or ongoing clinical trials."

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.tJn

121

TABLE 6.5. Carbohydrate Versus Lipid as Primary Nonprotein Calorie Source.

Author

Year

Reference

Smith"

1992

The effect on protein and amino acid metabolism of an intravenous nutrition regimen providing seventy percent of nonprotein calories as lipid. Surgery (St. Louis) 111:12-20.

de Chalain"

1992

The effect of fuel source on amino acid metabolism in critically ill patients. J Surg Res 52:167-176.

Chassard'?

1994

Kohlhardt"

1994

Effects of intravenous medium-chain triglycerides on pulmonary gas exchanges in mechanically ventilated patients. Crit Care Med 22:248-251. Metabolic response to a highlipid, high-nitrogen peripheral intravenous nutrition solution after major upper -GI surgery. Nutrition 10:317-326.

Roulet'?

1997

Tappy '"

1998

Class of evidence

Effects of intravenously infused fish oil on platelet fatty acid phospholipid composition and on platelet function in post-operative trauma. J Parenter Enteral Nutr 21:296-301. Effects of isoenergetic glucosebased or lipid-based parenteral nutrition on glucose metabolism, de novo lipogenesis, and respiratory gas exchanges in critically ill patients. Crit Care Med 26:813-814.

Potential Mechanism for Reduced Infectious Complications with Enteral Feeding Intravenous nutrition or lack of enteral feeding is associated with bacterial translocation in animal models of stress." Clinically, bacterial translocation occurs in a few clinical settings, such as bowel obstruction or hemorrhagic shock, but does not appear to correlate with extraintestinal infections." Within the GI tract, parenteral feeding alters mucosal architecture" and increases in permeability." A component of the mucosal barrier defenses is the gut-associated lymphoid tissue (GALT), which composes approximately 50 % of the

Conclusions

20 patients requiring IV nutrition randomized to receive 36kcal/ kg/day with glucose -based solution or 37kcal/kg/day as a lipidbased solution (70% nonprotein calories as lipid), glucose -based solution increased plasma transferrin and suppressed alanine efflux from peripheral tissues significantly greater than lipidbased formula . Glucose was more effective at suppressing gluconeogenesis. 18 evaluable of 50 patients randomized to either glucose or glucose plus lipid-based solution providing 125% of the basal energy expenditure. Whole-body protein synthesis and metabolism correlated with the development of sepsis. The glucose-based solution led to more hyperglycemia, requiring withdrawal of four patients. Both formulas improved whole body protein kinetics. Mechanically ventilated patients prospectively randomized in crossover trial to two 8-h infusion periods of either 50% MCTs (50% LCT solution) or 100% LCTs. The MCTs increased oxygen consumption by 28% and minute ventilation by 14%, but CO 2 production, Pao-, and Paco , were not different , suggesting slower infusion rate for intravenously administered MCTs. Of 18 patients status post-upper Gl surgery randomized to either peripheral nutrition (75% nonprotein calories as lipid) or central intravenous nutrition with both groups receiving 0.56gNkg/day and 100: 1 calorie:nitrogen ratio, with the central nutrition group receiving only glucose; the metabolic response to major surgery was similar in both groups . In 19 postoperative patients randomized to 20% soybean fat emulsion with 10% marine fish oil emulsion or 20% soybean fat emulsion alone, large increases in omega-3 fatty acids in platelet membranes and increase in omega -3/omega-6 ratios and platelets without toxicity or evidence of increased postoperative bleeding were produced. In 16 surgical ICU patients randomized to receive isocaloric isonitrogenous parenteral nutrition with 75% (TPN glucose) or 15% (TPN lipid) glucose over a 5-day period with a metabolic procedure using tracers, TPN glucose increased plasma glucose, plasma insulin, and total CO 2 compared with lipid glucose solution. Both formulas failed to inhibit endogenous glucose production and net protein oxidation, suggesting absence of suppression of gluconeogenesis. Fractional de novo lipogenesis markedly increased by TPN glucose . There was no measured metabolic negative consequence of lipid-based formula.

body's total immunity. The GALT is sensitive to route and type of nutrition in the animal model. lOo,lOl Naive T cells and Bcells produced within the peritoneal cavity and bone marrow circulate through the Peyer's patches. If sensitized by antigens processed by cells within the Peyer's patches, then the cells migrate through mesenteric lymph nodes and into the thoracic duct. The blood carries them to the lamina propria and intraepithelial spaces of the small intestine and to the upper and lower respiratory tract. In these sites, the sensitized B cells become plasma cells that produce immunoglobulin (Ig) A i the sensitized T cells produce cytokines that upregulate or downregulate IgA production.F' In addition to IgA, defensins, lactoferrin, and other innate defenses as well as mucin provide

122

CHAPTER 6

barriers to prevent attachment of bacteria to the mucosal surfaces. Parenteral nutrition reduces the size and effectiveness of the GALT. lOl Significant decreases in absolute numbers of T cells and B cells within the small intestine occur in association with decreasing intestinal and respiratory tract IgA levels. These decreases in IgA levels impair resistance against many types of viruses and bacteria. 103 Supplementation of the parenteral nutrition with glutamine partially preserves IgA levels and defenses against IgA-mediated antiviral defenses.'?' Route of nutrient administration also affects peritoneal defenses. With intravenous feeding, the immunological response within the peritoneal cavity is blunted with reduced peritoneal immunological cell numbers and decreased tumor necrosis factor (TNF) response with impaired bacterial killing.l'" Similar cytokine responses to endotoxin have been shown to occur in humans.l'"

Determining Dietary Requirements Standard equations, such as the Harris-Benedict equation, multiplied by correction factors are used to determine nutrient goals. The use of indirect calorimetry has shown that stress and activity correction factors frequently lead to overestimates of nutrient needs. 107,108 Increased oxygen consumption, increased CO 2 production, hepatic lipogenesis, immunosuppression, and other negative effects occur with overfeeding, and it is important to provide appropriate amounts of each nutrient.

Energy Calculations Estimated energy requirements must consider organ function, body weight, and the clinical condition. Guidelines are noted in Table 6.6. For calculations using body weight, actual body weight is appropriate for malnourished, euvolemic, or wellnourished patients. Overfeeding results when actual body weight is used in obese patients, and an adjusted form should be used to avoid overfeeding'?": Adjusted body weight = Ideal body weight + 0.25 (Actual - Ideal body weight) In cases of significant fluid overload, an estimated dry body weight should be obtained by history. The Harris-Benedict equation is based on gender, height, weight, and age to generate estimated body energy expenditure (BEE)l1O (Table 6.7, calculation A). Indirect calorimetry has shown these correction factors overestimate energy

TABLE 6.6. Energy and Protein Needs for Surgical Patients. Condition

kcal/kg/day

Protein/kg/day

Non-protein calories/gN: N

Normal-tomoderate malnutrition Moderate stress Hypennetabolic, stressed Bums

25-30 (low stress)

1.0

150: 1

25-30 30-35

1.5 1.5-2.0

120: 1 90-120:1

35-40

2.0-2.5

90-120: 1

TABLE 6.7. Calculations Used to Determine Metabolic and Nutritional Parameters. A. Male: BEE = 66 + (13.8 x W) + (5 x H) - (6.8 x A) Female: BEE = 655 + (9.6 x W) + (1.85 x H) - (4.7 x A) where W is the weight in kilograms, H is the height in centimeters, and A is the age in years. B. Protein oxidation (gjd) = 6.25 x UUN Carbohydrate oxidation (gjd) = (4.12 x Vco-] - (2.91 x Vo 2 ) (2.56 xUUN) Fat oxidation (gjd) = (1.69 x Vo 2 ) - (1.69 x Vco-] - (1.94 x UUN) If UUN is not available, then MEE is calculated by MEE (kcaljd) = (3.9 x Vo 2 ) + (1.1 x Vco-] If UUN is available, then the MEE is adjusted for protein metabolism in the equation: Adjusted MEE (kcaljd) = MEE - (2.17 x UNN) C. Nitrogen balance = Protein intakej6.25 - [(UUN x 0.8) + 1] MEE, metabolic energy expenditure

expenditure,107,108,11 1 with a more appropriate correction factor approximately 15% greater than the BEE. Indirect calorimetry by portable metabolic carts uses expired gas analysis to determine overall resting energy expenditure (REE). By measuring carbon dioxide production (VC02) and oxygen consumption (Vo2), these values are applied to the Weir equation to determine REE. The metabolic rate in kilocalories as well as protein, carbohydrate, and fat oxidation can be calculated when the V0 2 and VC02 are combined with the urine urea nitrogen (UUN)112 (Table 6.7, calculation B). Although variations occur in the V02 and VC02 during a 24h period, intermittent measurements can confirm that the prescription is within a reasonable range of the administered nutrient dose to avoid significant underfeeding or overfeeding. The respiratory quotient (RQ) is the ratio of VC02 to Vo 2, and a characteristic RQ exists for each fuel metabolized: fat RQ = 0.7, glucose RQ = 1.0, and protein RQ = 0.8; lipogenesis has an RQ of approximately 8. If the RQ of a patient is greater than I, then it is a strong indicator of overfeeding. There are limitations to indirect calorimetry. Accuracy is lost in mechanically ventilated patients as the FI02 (fraction of inspired oxygen) increases because of measurement errors between inspired and expired oxygen levels. A 1% measurement error in the inspired or expired V0 2 in a patient receiving an F102 of 0.8 produces a 100% error in V0 2 calculation. Air leaks around tracheostomies or through chest tubes must be recognized in measurements. Indirect calorimetry is labor intensive and requires dedicated personnel with defined protocols to provide reliable data.!" Because postsurgical patients usually have increases of 100/0 to 15% over the BEE calculated by the Harris-Benedict equation, the current guidelines in Table 6.6 are adequate for most patients. If 30kcal/kg is provided to most hypermetabolic patients, then approximately 900/0 of them will attain their energy requirement, with minimal overfeeding in only 150/0 to 20%.106

Protein Requirements The recommended daily allowance for protein intake in wellnourished, healthy individuals is approximately 0.8g/kg/ day.'!" Each gram provides 4.0kcal/g. The recommended dose of amino acids (or protein with enteral feeding) for stressed or septic patients without renal dysfunction is 1.5 to 2g/kg/

NUTRITION

day.!" Although blood urea nitrogen (BUN) may increase to 40mg/dl in some patients, this is without adverse consequences. In nonhypermetabolic patients who have existing malnutrition or who are at risk of developing starvation-induced malnutrition, 1.0 to 1.5g/kg/day of protein meets nutrient needs. In bum patients, excessive urinary and wound losses generally dictate administration of 2 to 2.5g/kg/day. These administered doses, however, may need to be reduced in patients with chronic or acute renal failure. Under these conditions, it is prudent to provide 0.6 to 0.8 g of amino acids or protein per kilogram per day before dialysis and increase the dose to 1 to 1.5g protein/kg/day once dialysis is instituted. Adequacy of protein administration may be assessed by a determination of nitrogen balance (Table 6.7, calculation C) in a 24h urine collection. The UUN generally represents approximately 800/0 of excreted nitrogen, and additional nitrogen losses are estimated at 1g/day. Accurate urine collection and accurate records of protein intake determine the accuracy of this calculated value.

Glucose The maximal rate of glucose oxidation is 4 to 5 rug/kg/min or approximately 7.2g/kg/day. Total glucose administration in intravenous fluids, parenteral nutrition, or enteral nutrition should not exceed these Ievels.!" In a 70kg man, these needs are met by 21 of 25 % dextrose solution, providing 500 g of glucose. Blood sugar should ideally be maintained well below 200 mg%. It is suggested that complications are increased with high blood sugars.!" Administration of the glucose in these doses provides approximately 500/0 to 600/0 of total caloric requirements. Hydrated glucose in parenteral nutrition provides 3.4kcal/g, and oral carbohydrates provide 4.0kcal/g. Work demonstrated reduced mortality with rigid control of glucose in an ICU setting, although almost all benefit occurred in cardiac patients. 1l8

Fat Requirement Remaining nonprotein caloric needs are met by lipid infusion of approximately 1gjkgjday. The maximum adult dose of intravenous lipid is 2.5 g/kg/day.1l9 Rarely is this higher limit administered except, for example, in the brittle diabetic with uncontrolled hyperglycemia. Enterally, fat provides 9.1 kcal/ g. Intravenous lipid provides 10kcaljg obtained due to emulsifiers and glycerol. If overfeeding is suspected, then total calories should be reduced. In patients with diabetes or receiving corticosteroids, high rates of fat administration may control glucose but induce hyperlipidemia, cholestasis, and perhaps immunosuppression.Pv'" Lipid emulsions available in the United States contain omega-6 PUFAs derived from vegetable oils. There is concern about their immunosuppressive effects. Intravenous lipid emulsion in the critically ill patient should be limited to 1g/kg/day if triglyceride levels are less than 300mg% and withheld in patients with hypertriglyceridemia, particularly if values are greater than 500mg/dl. There is no evidence that intravenous lipid emulsions aggravate acute pancreatitis if hyperlipidemia is not the cause of the pancreatitis.

123

Organ System Complications of Overfeeding PULMONARY FAILURE

Lipogenesis from overfeeding increases CO 2 production but rarely causes ventilator dependence in patients sustaining multiple trauma or sepsis. Failure to wean is usually the result of the increased metabolic rate, pneumonia, multiple rib fractures, pulmonary contusions, or sepsis. In selected surgical patients-particularly those with chronic pulmonary disease or after prolonged intubation-increasing fat as a percentage of nonprotein calories may assist in reducing CO 2 production and decreasing ventilator demands. These patients usually have GI function, and a high-fat enteral formula may be used with a calorie-to-nitrogen ratio of approximately 120-150: 1 with 400/0 to 500/0 of the calories as fat. The routine use of these solutions in intubated patients is usually unnecessary. HEPATIC FAILURE

Hepatic failure generally carries a dismal prognosis, and excessive protein restriction should be avoided. Intravenous amino acid solutions are better tolerated than enteral protein. Typically, these patients should receive 0.5 to 0.8 g of protein and approximately 30kcal/kg/day. These formulas appear to be of little value in desperate situations of severe hepatic failure in a setting of multiple organ dysfunction secondary to uncontrolled sepsis and metabolic collapse.

Enteral Nutrition Both clinical and economic considerations support the use of the enteral route for feeding whenever possible. Currently, more than 200 enteral products varying in composition, complexity, and physical characteristics are available to meet restrictions and requirements of most clinical conditions. "Ileus" is often limited to the stomach and colon, whereas the small intestine remains a site capable of absorption of nutrients. Because of the wide array of enteral products and the potential for expensive duplication in a hospital formulary, understanding basic concepts of enteral formulation and techniques of access can produce both clinical and economic benefits.

Enteral Access Most preoperative and postoperative patients tolerate intragastric feeding. A small-bore NG tube is better tolerated than a large tube. Small-bore tubes reduce the risk of complications such as esophageal stricture, reflux, or necrosis of the nasal alae. Styletted tubes help placement, and their location can be confirmed with aspiration of gastric juice or confirmation via fluoroscopy or x-ray. Simple air insufflation is inadequate to confirm placement because sounds transmitted from the left lung or distal esophagus may be auscultated in the left upper quadrant. In patients at increased risk of aspiration due to reflux, advancement of the tube beyond the ligament of Treitz via endoscopic techniques or fluoroscopy may provide additional protection. A double-lumen tube allows gastric decompression and feeding beyond the pylorus and, ideally, beyond the ligament of Treitz.

124

CHAPTER 6

Unfortunately, nasojejunal or NG tubes are frequently dislodged, increasing the cost and complexity in providing enteral nutrition. In these situations, if laparotomy is not necessary, an endoscopic gastrostomy with direct intragastric feeding may be preferable because it can be performed with minimal mortality and morbidity (Fig. 6.1). This technique is useful in patients requiring long-term intragastric feeding because of dysphagia or chronic neurological dysfunction. It should be used with caution in patients with a history of esophageal reflux and aspiration. Direct gastric feeding is not recommended in neurologically impaired pediatric patients with recurrent pneumonia secondary to reflux. Access distal in the GI tract or surgical, correction of the reflux is advisable. 122 Laparotomy allows access beyond the ligament of Treitz for direct small-bowel feeding. Jejunostomies with a largebore (14-, 16-, or 18F) tube or needle catheter jejunostomies

(5- and 7F) allow direct administration of tube feedings in patients expected to have prolonged gastroparesis. In critically injured patients with severe intraabdominal or chest, head, bony, or soft tissue injuries, there is a significant reduction in pneumonia and intraabdominal abscess with early small-bowel feeding.33-3 5 Needle catheter jejunostomies are useful for 3 to 4 weeks following injury. Jejunostomies should be located at a site with a long mesentery so that abdominal distension does not tear the jejunostomy off the anterior abdominal wall as a result of the tethering effect at the ligament of Treitz. A Witzel tunnel should be constructed for a distance of about 4 em and the jejunostomy sutured lateral to the rectus sheath with four to five sutures to eliminate volvulus. Fiber-containing diets can be administered through both small- and large-bore needle catheter jeiunostomies.l" but

Stomach wall

A

c

D Caudad

Tapered end of gastrostomy tube attached to guidewire

Cephalad

Needle with

inner stylet

B

FIGURE 6.1. A. The procedure for percutaneous endoscopic gastrostomy includes transillumination of the stomach and identification of the needle insertion site. B. A needle is inserted into the stomach across the abdominal wall under direct vision. C. A guidewire passed through the lumen of the needle is grasped with a snare. D. The

E

ensnared guidewire is removed via the mouth. E. The tapered end of the gastrostomy tube is attached to the guidewire and pulled out through the stomach and abdominal wall to seal the button end. The external portion of the gastrostomy tube is then trimmed to fit the patient's body habitus as desired.

NUTRITION

protein supplements and immune-enhancing diets clog SF tubes. Tubes should be flushed at least four times a day. Elixirs in medications coagulate the enteral products and clog the tubes rapidly. Needle catheter jejunostomies usually cannot be replaced once lost. Larger-bore catheters can be replaced after 1 week and are more useful for long-term requirements. Transgastric tubes allow simultaneous decompression of the stomach and feeding into the duodenum (Moss tube) or beyond the ligament of Treitz (transgastric jejunostomy). Location of the distal port in the duodenum stimulates both pancreatic and gastric secretions and may cause fluid and electrolyte problems, but infusion beyond the ligament of Treitz produces little stimulation. Transgastric jejunostomies rarely dislodge back into the stomach, but the size of the jejunal channel dictates product choice similar to SF needle catheter jejunostomies. Anastomosis above the site of enteral access or in the mid- or distal small bowel and colon provides no contraindication to direct small-bowel feeding. There is no evidence of increased intraabdominal infection with small-bowel access in patients with no other hollow viscus violation.I" Enteral feeding is not contraindicated in acute pancreatitis if nutrients are delivered beyond the ligament of Treitz. 51- 54 Short-gut syndrome, uncontrollable diarrhea, distal bowel obstruction, or upper GI hemorrhage are relative contraindications.

Initiation of Tube Feeding Direct intragastric feeding should be attempted in most patients. In bum patients, intragastric feeding soon after admission prevents subsequent gastroparesis with a 950/0 success rate. The highest success rate occurs when feedings are instituted within 6 to 8h 55; success drops to less than 500/0 when feeding is instituted after 18h. Even when pressors are used, intragastric feedings are safe because small-bowel intolerance prompts high gastric residuals, protecting the small intestine from potential necrosis.l" With direct small-bowel feeding, the low but real rate of intestinal necrosis preempts institution of feeding until resuscitation is complete, tissues are perfused, patients are not receiving pressors, and splanchnic blood flow can increase in response to enteral feeding. Hypertonic or isotonic formulas can be infused into the stomach, but it is preferable to use isotonic solutions with intrajejunal feedings, although more concentrated solutions have been used with success if started as a more dilute solution and then increased in concentration as the volume increases. 33,126 Gastric feedings can be administered as either bolus or continuous infusions. Jejunostomy feedings should be continuously infused, although some patients adapt to bolus intrajejunal feeding over time. Intragastric and intrajejunal f~edings are started at 25 to 30 ml/h and advanced over varying times to a goal that meets caloric and nutrient needs. With intragastric feeding, residuals are measured every 4 h, and tube feeding is advanced by 25 ml/h if residuals remain below 200ml/h. With intrajejunal feedings, signs of intolerance include abdominal distension, diarrhea, and cramping. Most commonly, intrajejunal feedings are increased by 25 ml/h over 12 or 24h increments to the goal rate. Direct small-bowel feedings should be discontinued if feedings reflux into the NG tube.

125

Enteral Formulas Choice of formula is determined by functional status of the GI tract, patient nutrient requirements, or restrictions imposed by organ failure. A summary of some enteral feeding formulas is presented in Table 6.8. With an intact GI tract and mucosa, formulas with complex proteins, carbohydrates, and fats are well tolerated. Formulas that contain lactose should be avoided in patients who have not been fed via the GI tract for some time because of rapid decreases in disaccharidase production (lactase is the most rapid) in the GI tract. Critically ill patients have increased protein requirements and may be less tolerant of glucose or lipid. In these conditions' a lower nonprotein calorie-to-nitrogen ratio (range 80-120: 1) may better meet these macronutrient needs. In patients with mucosal disease, such as Crohn's disease chemically defined formulas containing amino acids with dior tripeptides may improve digestion and absorption. Fibercontaining formulas provide soluble fiber, which can be metabolized by intraluminal bacteria to produce short-chain fatty acids (butyrate, propionate, and acetoacetate), and provide substrate for the colonocyte to maintain water absorption and reduce or prevent diarrhea.!" The MCTs may be better tolerated than long-chain triglycerides (LCTs) since they are more easily digested and absorbed. The MCTs do not contain essential fatty acids, and some LCTs must be provided.

Categories of Enteral Feeding Formulations STANDARD ISOTONIC FORMULAS

Standard isotonic formulas contain an appropriate balance of carbohydrate, protein, and fat (usually with a nonprotein calorie-to-nitrogen ratio of approximately 150: 1).The macronutrients require digestion but provide adequate nutrition in a low volume with low osmolality (approximately 300mOsm/ I) and a caloric density of l Dkcal/ml, These diets are considered low residue because they do not contain fiber. In general, these formulas are used in stable patients at risk of starvation-induced malnutrition or those with existing states of malnutrition who are neither stressed nor septic. STANDARD FIBER-CONTAINING FORMULAS

Standard fiber-containing formulas are similar to the standard isotonic products but contain a combination of soluble and insoluble fiber, most often as soy polysaccharide. Fiber prolongs intestinal transit time, stimulates intestinal lipase activity, and provides the substrate for short-chain fatty acid metabolism by intraluminal bacteria.!" These formulas are tolerated even in critically ill patients fed via needle catheter jejunostomies and appear to reduce the incidence of diarrhea compared with chemically defined diets. They do not occlude small-bore feeding catheters when catheters are properly flushed and often have a high protein content appropriate for critically ill patients. SPECIALTY, "IMMUNE-ENHANCING" FORMULAS

Several products enriched in nutrients such as BCAAs, glutamine, arginine, omega-3 fatty acids, nucleotides, or beta-

126

CHAPTER 6

TABLE 6.8. Some Enteral Feeding Formulas.

PRODUCT, Supplier

PRECISION LR, Sandoz TRAVASORB STD, Baxter REABILAN, O'Brien TRAVASORB, Baxter ENSURE, Ross RESOURCE CRYSTALS, Sandoz RESOURCE POWER, Sandoz ENRICH, Ross COMPLEAT, REG, Sandoz ENSURE HN, Ross PRECISION HN, Sandoz REABILIAN HN, O'Brien MERITENE, Doyle SUSTACAL, Mead Johnson MERITENE POWDER, Doyle SUSTACAL POWDER, M.J.

kcal/ml

1.1 1

1.3

1.3

Total calorie/ nitrogen

Liters to provide 100% RDA vitamins tllJdminerals

mOsm

Protein

Carbohydrate

Fat

Na

K

Features a

239 184

1.7 2

530 560

26 30

248 190

1.6 14

30 40

2.3 30

P,F P,U,MCT

175 154 153 154

3 1.9 1.9 1.9

350 450 450 450

32 35 37 37

131 136 145 145

39 35 37 37

30 30 37 37

32 31 40 40

L,U,MCT L,F,MCT L,F F

178

1.9

450

37

145

37

37

40

P,F

148 131

1.4 1.5

480 405

40 43

162 128

37 43

37 57

40 36

L,F, high residue L,U

125 125

1.3 2.8

470 525

44 44

141 216

35 1.3

40 43

40 23

L,F P,F

125

2.9

490

58

158

52

43

43

L,U,MCT

104 79

1.2 1

550 625

58 61

110 140

32 23

38 41

41 53

L,F L,F

104

1.2

690

66

113

32

44

68

P,F

80

0.8

899

77

180

34

54

87

Mixed w/whole

183

1.6

300

29

144

30

20

25

P,F

167 154 153 131

1.9 2 1.9 1.5

300 300 300 300

34 35 37 4.3

133 136 145 141

44 35 39 37

23 31 24 29

34 31 26 36

L,U,MCT L,U L,U,MCT L,U

131

2

260

40

127

39

22

16

L,U,MCT

125 86

1.3 1.8

310 300

44 68

141 156

37 34

40 27

40 27

L,U,MCT P,F,MCT

milk

Isotonic

PRECISION ISOTONIC, Sandoz ISOCAL, Mead Johnson ENTRITION, Biosearch OSMOLITE, Ross COMPLEAT MODIFIED, Sandoz PEPTAMEN, C1intec Nutrition OSMOLITE HN, Ross ISOTEIN HN, Sandoz

1 1.2

For impaired GI tract and other special situations

TOLEREX, Eaton VIVONEX T.E.N., Eaton SURGICAL LIQUID, Diet Ross CRITICARE HN, Mead Johnson VITAL HN, Ross TRAUMA-AID HBC, McGaw STRESSTEIN, Sandoz TRAVASORB MCT, Baxter IMPACT, Novartis PERATIVE, Ross ALITRAQ, Ross SUBDUE, Mead Johnson

1 1

284 149

1.8 2

550 630

21 38

226 206

1.5 2.8

20 20

30 20

P,U P,U,BCAA

0.7

117

1.2

545

38

136

0

36

21

P,F

148

2

650

38

222

3.4

28

34

L,U

125 132

1.5 3

460 640

42 56

185 166

11 7

20 23

34 30

P,F,MCT P,F,MCT,BCAA

97 100

2 1.3

910 450

70 74

173 185

27 49

29 23

29 26

P,U,MCT,BCAA L,F,MCT

91

1.5

375

56

130

28

48

36

122

1.2

425

67

177

37

45

44

120 120

1.5 1.2

480 330

53 50

165 127

16 34

44 48

31 41

L,U,MCT, fish oil L,U,MCT, arginine F,F, glutamine L,F,MCT

1.2 1.5

1.3

127

NUTRITION

TABLE 6.8. (continued)

kcallml

PRODUCT, Supplier

Total calorie/ nitrogen

Liters to provide 100% RnA vitamins and minerals

mOsm

Protein

Carbohydrate

1.95

23

384

25

1.0

44

158

490

Fat

Na

K

14

5

For renal failure

34

5

6

For liver failure

63

106

92

57

Features"

For specific pathological entities

AMINIAID, McGaw

1.9

362

TRAVASORB RENAL, Baxter

Packets of 112g, 467 cal, 470rnOsrn/1 1.1

For renal failure

Packets of 96 g, 378 cal, 480rnOsrn/1 1.5

For liver failure 150

ENSURE PLUS, Ross

1.5

146

1.6

600

55

200

53

SUSTACAL HC, Mead Johnson ENSURE PLUS HN, Ross

1.5

134

1.2

650

61

190

57

1.5

125

0.9

650

62

200

50

MAGNACAL, Sherwood ISOCAL HCN, Mead Johnson TWOCAL HN, Ross

2

154

590

70

250

2

145

1.5

690

75

2

126

0.9

700

84

HEPATIC AID IL, McGaw TRAVASORB HEPATIC, Baxter PULMOCARE, Ross

174

49

To decrease CO2 production

50

54

L,F

37

38

L,F

51

47

L,F

80

44

32

L,F

224

91

35

36

L,F,MCT

217

90

46

59

L,F,MCT

High calorie density

Protein, carbohydrate, and fat are expressed as gram per liter (gil) standard dilution, Na and K are expressed as milliequivalents per liter (mEq) standard dilution. a P, powder; L, liquid; F, flavored; U, unflavored; BCAA, branched-chain amino acids; MCT, medium-chain triglycerides.

carotene have been studied in clinical populations. These specialty immune-enhancing formulas are nitrogen rich given the supplementation with arginine or glutamine. The proposed clinical functions of individual nutrients have been previously described. HIGH-DENSITY FORMULAS

High-density formulas provide 1.5 to 2kcal/ml for patients requiring food restriction or very high calorie and protein requirements, but osmolality is higher than that of isotonic formulas. They are most often used as intragastric feedings in patients requiring fluid restriction or those intolerant of large volumes. Potential for diarrhea is greater. HIGH-PROTEIN FORMULAS

To meet the high protein needs of severely stressed and injured patients, formulas containing nonprotein calorie-tonitrogen ratios of less than 125: 1 are well suited for critically ill patients. Both isotonic and nonisotonic formulas are available. ELEMENTAL/PEPTIDE-BASED FORMULAS

The products in the elemental/peptide-based formulas have been predigested compared with formulas with intact micro-

nutrients. Protein is provided as mono-, di-, or tripeptides, fat is provided as MCTs and LCTs, and complex carbohydrates are limited. The fat content in some formulas is extremely low (less than 100/0 of total calories), which limits their longterm usefulness. However, these products are more readily absorbed in patients with maldigestion or malabsorption. In critically ill patients, these formulas should be started at a lower rate (15-20ml/h) and advanced more slowly or initially diluted with water to produce a more isotonic formula; as the rate increases, the concentration of these formulas can be increased. RENAL FAILURE FORMULAS

Renal failure formula products contain only essential amino acids or a high ratio of essential to nonessential amino acids, and they are designed with a high calorie-to-nitrogen ratio to allow endogenous synthesis of nonessential amino acids from urea nitrogen. These formulas also contain moderate to low concentrations of the intracellular electrolytes potassium, phosphorus, and magnesium to control serum levels. They are more expensive, and it is unclear whether there is significant clinical benefit over standard mixes of crystalline amino acids, but the restriction of electrolytes is often beneficial and cannot be achieved with other enteral formulas.

128

CHAPTER 6

Applications of Enteral Feeding Complications of tube feeding include diarrhea, aspiration, vomiting, distension, metabolic abnormalities, and tube dislodgment. 128 Avoid intragastric feeding in patients with severe reflux and prior evidence of aspiration. Elevation of the head of the bed by 30°, administration of prokinetic agents, or feedings beyond the ligament of Treitz may minimize aspiration. Diarrhea is frequent in tube-fed patients. Fiber-containing diets may reduce diarrhea by providing substrate for the colonocytes. Administration of medications via the tube or use of antibiotics is often the cause of diarrhea in enterally fed patients.!" Elixirs in medications are rich in sorbitol, causing diarrhea through osmotic effects. Magnesium-containing antacids, bacterial overgrowth from antibiotics, or the overuse of prokinetic agents also produce diarrhea, which is reversed with discontinuation of these medications. Stools should be cultured for Clostridium diijicile and medications reviewed for those noted earlier.l" Diarrhea usually is not caused by the tube feedings but by other therapies. Metabolic complications include hyperglycemia, hypophosphatemia, hyper- or hypokalemia, and hypomagnesemia in postoperative patients with preexisting nutritional deficiencies, renal failure, or diabetes mellitus. The sodium content in most enteral formulas is 30 to 35 mEq/I, which can lead to hyponatremia, especially when multiple medications are administered in dextrose and water or if the patient has inappropriate antidiuretic hormone secretion. Hypernatremia occurs when medications or intravenous fluids are provided in normal saline or when diabetes insipidus complicates head injuries or neurosurgical procedures. Refeeding syndrome with intracellular mobilization of potassium, phosphate, and magnesium can occur with enteral nutrition, particularly in patients with significant preexisting nutrient deficiencies. 130 Small-bowel necrosis and pneumatosis intestinalis can occur with direct small-bowel feedings. The cause is unknown, but speculation that inability to increase blood flow to the splanchnic bed may be one etiological factor. It is prudent to delay jejunal feedings until hemodynamic stability is achieved and there is adequate splanchnic perfusion (adequate urine output). Intragastric feedings are safe because high gastric residuals will reflect the small-bowel intolerance.

External jugular vein Right subclavian vein

Internal jugUlar vein

Suprasternal ....:....;;,,;;--- notch Left subclavian vein

FIGURE 6.2. Anatomic sites and landmarks for central venous access procedures.

therapy, or have distorted anatomy. The right side is preferred as this avoids the possibility of injury to the thoracic duct, and the guidewire may be somewhat easier to thread because of a typically more gentle angulation present between the right innominate vein and the superior vena cava as compared to the left side. Access to the superior vena cava can also be obtained by transcutaneous puncture of the external or internal jugular veins, but catheters that exit in the neck are more difficult to care for, more uncomfortable for many patients, and probably more likely to become infected. Multiple-lumen central venous catheters are usually inserted. Catheter infection rates are the lowest when catheters to be used for parenteral nutrition support are inserted under the strictest sterile conditions, including use of a hat, mask, gown, and gloves. 13 1,132 Currently, safe practice dictates that a chest x-ray should be obtained to verify that the catheter tip is centrally located before concentrated dextrose solutions are administered. Rarely, a lateral chest film will be required to verify that the

Parenteral Nutrition Parenteral Access Parenteral nutrient solutions with dextrose concentrations greater than 100/0 are hypertonic and must be administered into a large, centrally located vein to avoid thrombophlebitis and venous sclerosis associated with administration of these hyperosmolar formulas. The superior vena cava is an ideal site in which to administer concentrated parenteral nutrition formulas. Infraclavicular transcutaneous puncture and cannulation of the right subclavian vein usually accomplish access to the superior vena cava (Figs. 6.2 and 6.3). A supraclavicular approach may occasionally be preferred if the infraclavicular approach is contraindicated or inaccessible, as occurs in patients who have suffered chest trauma or bums or have tumor involving this region, have had extensive radio-

Suprasternal notch

Cannucation . needle FIGURE 6.3. Cannulation of the subclavian vein by an infraclavicular approach.

NUTRITION

catheter tip is located in the superior vena cava rather than in an internal mammary vein. Once the line is inserted, at least one lumen should be reserved solely for the administration of the parenteral formulation because multiuse catheters appear to have higher infection rates.P? This precaution makes intuitive sense because of the likely correlation between the number of line breaks and the likelihood of contamination of the nutrient solution. Similarly, although it would be theoretically advantageous to have a single-lumen catheter inserted for the administration of parenteral nutrition, this approach is impractical for most hospitalized patients who require the therapy. Thus, while one lumen of a multiple-lumen catheter should be devoted to the administration of parenteral nutrition, the other lumens may be used for monitoring, for blood drawing, or to administer medications. Regardless of the type of catheter that is inserted, it is critically important that the multilumen catheters be handled carefully and dressing changes be made regularly, typically at least every third day, by a knowledgeable, certified, and trained individual. Access to the superior vena cava can also be obtained using catheters that are inserted peripherally in the upper extremity and threaded to the appropriate location. Such peripherally inserted central venous catheters, known by the acronym PICC lines, offer the ability to obtain central venous access without the risks associated with subclavian or jugular puncture. As discussed for catheters inserted via other approaches, it is important to dedicate a single lumen for the administration of parenteral nutrition and to manage the catheter carefully. These lines can be used for several months and are often used for hydration or other parenteral therapy for home-bound patients. Dedicated central venous access via the subclavian or jugular veins may rarely be impossible to obtain, for example, because of preexisting thrombosis or occlusion of the subclavian or innominate veins or superior vena cava or anatomical problems preventing safe puncture, or may be too risky, especially in patients with refractory coagulopathies and pulmonary insufficiency. In these circumstances, most institutions favor a policy by which the dextrose concentration of parenteral nutrition solutions is limited to 150/0 or less. This

129

measure is recommended in an effort to limit the risk of lower extremity venous thrombosis. It would also appear to be prudent to change these lines every 3 days or more often to minimize the risk of infection associated with the higher number of skin bacteria in the femoral region. Safe parenteral nutritional therapy would also mandate that the dextrose concentration of nondedicated lines, that is, lines that have been used for any purpose other than the administration of nutritional formulas, be limited to 10% or less. This restriction is advised because the risk of infection is probably higher when more concentrated solutions are used.

Composition of Central and Peripheral Venous Solutions The common macronutrients and their caloric densities and functions are presented in Table 6.9. As mentioned, with central venous nutrition, hypertonic nutrient solutions (>100/0 dextrose) are infused via a catheter inserted into a large central vein. Access to a large central vein is needed because these formulas usually have osmolarities greater than or equal to 1900mOsmjkg, and administration of the solutions into peripheral veins causes thrombophlebitis and venous sclerosis (Table 6.10). When infused into the central venous system, the nutrients are rapidly diluted to near isotonicity and then metabolized. These solutions usually contain about 1kcal/ ml. Typically, 2 to 31 are administered over a 24h period, thereby providing about 2000 to 3000kcaljday. Occasionally, as for patients who will require home parenteral nutrition support, it may be advisable and feasible to administer the feeding solution over less than 24h (a procedure known as cycling), if only to provide some time free from intravenous infusion. Peripheral nutritional alimentation solutions typically have dextrose concentrations of 50/0. Between 1000 and 1500 calories can be administered using this method, and the volume of fluid required to administer these calories is usually greater than 2ljday. In contrast to the case for central venous alimentation solutions, in which the substrate mixture is predominantly composed of carbohydrate, most of the calories from peripheral parenteral nutrition solutions are

TABLE 6.9. Caloric Densities, Sources, and Functions of the Major Macronutrients. Macronutrient (caloric density)

Common sources

Functions

Carbohydrates (3.4kcaljg)

Dextrose

Lipids [l Okcal/g]

Polyunsaturated

Proteins (4kcal/gm)

Crystalline amino

Essential fuels used by glycolytic tissues; normally the major or sole energy source for the central nervous system, peripheral nerves, red blood cells, and some phagocytes. During prolonged starvation, the glucose requirement of the brain decreases as adaptation to ketone oxidation occurs. Are used by tissues that oxidize fat (e.g., muscle) when carbohydrates are administered as the major fuel source. Maintain hepatic glycogen stores, which may protect hepatocytes during hypoxia or exposure to toxins. The most concentrated forms of energy. Long-chain lipids protect vital structures. Complex with fat-soluble molecules like some vitamins are used as structural components in biological triglycerides from soybean oil or a safflower-soybean oil mixture membranes. Major structural component of the body. Some are essential acids (histidine, isoleucine, leucine, valine, methionine, cysteine, phenylalanine, tyrosine, threonine, tryptophan, and lysine) because they cannot be synthesized by the body. Others are nonessential because they can be made from carbon and nitrogen precursors. Act as peptide hormones, enzymes, and antibodies. May join with carbohydrates to form glycoproteins, to serve as plasma proteins and immune globulins, and components of connective tissue cell membranes and mucous secretions.

130

CHAPTER 6

TABLE 6.10. Central Parenteral Nutrition. Daily calories Protein Volume of fluid required Duration of therapy Route of administration Substrate profile

Osmolarity

TABLE 6.12. Fatty Acid Content of Intravenous Lipid Preparations.

Central

Peripheral

2000-3000 Variable 1000-3000ml

1000-1500 56-87g 2000-3500ml

4-7 days

5-7 days

Dedicated central venous catheter

Peripheral vein or multiuse central catheter 30% carbohydrate

55%-60% carbohydrate 15%-200/0 protein 25% fat 2000mOsm/1

20% protein 500/0 fat Approx. 600900mOsm/1

Manufacturer Concentration (%)

TABLE 6.11. Some Parenteral Amino Acid Solutions. Novamine 15%

Protein equivalent 15 (g/100ml) Total nitrogen 2.3 (g/100ml) 1300 Osmolarity (mOsm/l) pH 5.6 Essential amino acids (mg/100ml) Isoleucine 749 1040 Leucine 1180 Lysine 749 Methionine Phenylalanine 1040 Threonine 349 Tryptophan 250 Valine 960 Nonessential amino acids (mg/100ml) Cysteine 1470 Arginine 2170 Alanine 894 Proline 1040 Glycine 592 Serine Tyrosine

Travasol 10%

TrophAmine

10

6

1.6

6%

0.93

998 6.0

525 5.5

600 730 580 400 560 420 180 580

490 840 490 200 290 260 120 470

1150 2070 680 1030 500

14 730 320 410 220 230 15

Liposyn H

Liposyn IH

Clintec Nutrition 10 20

Abbott

Abbott

10 20

10 20

10 20

5 10 5 10

10 20

50 50 26 26 10 10 9 9 3.5 3.5 260 260

65.8 65.8 17.7 17.7 8.8 8.8 4.2 4.2 3.4 3.4 276 258

54.5 54.5 22.4 22.4 10.5 10.5 8.3 8.3 4.2 4.2 284 292

Oil (%) Safflower Soybean Fatty acid content (%) Linoleic Oleic Palmitic Linoleic

derived from fat. Peripheral nutritional prescriptions typically provide approximately 300/0 of calories as carbohydrate, 20% as protein, and at least 50% of calories as fat. Peripheral parenteral nutrition is usually undesirable for several reasons. First, there is no evidence that this improves outcomes or significantly decreases nitrogen losses when it does not closely approximate a patient's energy needs. Second, the high-fat content typically administered as part of peripheral parenteral nutrition regimens may impair reticuloendothelial cell function and therefore immune responsiveness. 133 Parenteral alimentation solutions are prepared by a pharmacist and typically combine 500ml of 50% dextrose with 500ml of a 10% to 150/0 amino acid mixture. Examples of amino acid and intravenous lipid preparations are shown in Tables 6.11 and 6.12, respectively. Vitamins, electrolytes, and

Intralipid

Stearic Osmolarity (mOsm/l)

trace elements are added to the formulation as needed. Central parenteral nutrition solutions usually provide about 55% to 60% of calories as carbohydrate and 15% to 20% of calories as protein. Lipids should contribute no more than 30% of the total calories administered in nearly all circumstances. A typical prescription would administer 21 of this standard solution each day. Administration of 500ml of 20% fat emulsion for 1 day each week is sufficient to prevent essential fatty acid deficiency. This method of administration is satisfactory if lipids are needed only as a source of essential fatty acids and are not needed as an additional source of calories, for example, by patients whose caloric requirements would require dextrose infusions at rates greater than 5 rug/kg/min. If additional calories from lipids are needed on a daily basis, then they can be administered as a separate infusion or most commonly as part of a mixture of dextrose and amino acids. These three major nutrients are added together in a 3-1bag in a technique known as triple mix or three-in-one. In this instance, the entire contents of a single bag are infused during a 24h period. With a mixed-fuel system, the rate of infusion of lipid is constant over the infusion period. This method increases the efficiency of fat utilization and may minimize the risk of reticuloendothelial system dysfunction associated with infusion of lipids during the 10 to 12h period used for intermittent infusion protocols. However, the inclusion of intravenous fat emulsion into a parenteral nutrition admixture changes the conventional nutritional solution into an emulsion. For example, various micronutrients can adversely influence emulsion stability. The higher the cation valence, the greater the destabilizing influence to the emulsifier. Therefore, trivalent cations such as the ferric ion (iron dextran) are more disruptive than divalent cations such as calcium or magnesium ions, which are more disruptive than monovalent cations such as sodium or potassium. Evidence demonstrated that there is no concentration of iron dextran that is safe in

131

NUTRITION

triple-mix formulations.!" In-line filtration is necessary for all parenteral nutrition solutions, including triple-mix solutions, as it is impossible to detect precipitates visually until they are grossly incompatible and unsafe for infusion. Once the basic solution is created, electrolytes are added as needed (Table 6.13). Sodium or potassium salts are given as chloride or acetate according to the requirements of the individual patient. Normally, equal amounts of chloride and acetate are provided. However, if chloride losses from the body are increased, such as may occur in patients who have NG tubes, then most of the salts should be given as chloride. Similarly, more acetate should be given to patients when additional base is required because acetate generates bicarbonate when it is metabolized. Sodium bicarbonate is incompatible with parenteral nutrition solutions and so cannot be added to the mixture. Phosphate may be given as the sodium or potassium salt. Lipid emulsions contain an additional 15mmol/1 of phosphate. Commercially available preparations of vitamins, minerals, and trace elements are added to the nutrient mix unless they are contraindicated. Both fat- and water-soluble vitamins should be given. Until recently, a standard 10-ml vial of a multivitamin preparation that contained the recommended doses of vitamins was routinely added to the parenteral nutrition solutiorr'" (Table 6.14). However, due to a national shortage of this standard preparation, various new vitamin preparations are being introduced into the market. As alluded to, the provision of adequate thiamin is essential for patients receiving parenteral nutrition and can be provided separately. Vitamin K is not a component of any of the vitamin mixtures formulated for adults. Adding vitamin K in the parenteral nutrient solution can satisfy maintenance requirements; 10mg of vitamin K are given weekly to patients who are not receiving anticoagulants such as warfarin (coumadin). Trace element preparations that include zinc, copper, manganese, and chromium are added to the parenteral nutrition solution in amounts consistent with the American Medical Association (AMA) guidelines; 60pg of selenium are also given daily. Because copper and manganese are excreted in the biliary tract, the dosages of these micronutrients should be modified or eliminated in patients with significant liver disease or biliary obstruction. In the absence of clear data in the literature, safe practice would withhold copper and manganese when the patient's serum bilirubin level exceeds 5mg/ dl. Also, 10 to 15 mg/day of zinc are provided to patients TABLE 6.13. Electrolyte Concentrations in Parenteral Nutrition.

Electrolyte

Recommended central PN doses

Recommended peripheral PN doses

Usual range of doses

Potassium (mEq/l)

30

30

Sodium (mEq/l) Phosphate [mmol/l] Magnesium (mEq/l) Calcium (mEq/l) (as gluconate) Chloride (mEq/l) Acetate (mEq/l)

30 15 5 4.7

30 5 5 4.7

0-120 (CVL) 0-80 (PV) 0-150 0-20 0-16 0-10

50 40

50 40

0-150 0-100

CVL, central venous line; PN, parenteral nutrition; PV, peripheral vein.

TABLE 6.14. Vitamin and Trace Element Recommendations for Adults. Recommended daily allowance

Parenteral requirements

Vitamin A Vitamin D Vitamin E Ascorbic acid (C) Folic acid Niacin Riboflavin (B2 ) Thiamine (Br) Pyridoxine (B6 ) Cyanocobalamin (B12 ) Pantothenic acid Biotin Zinc Copper Chromium Manganese Selenium

4000-5000IU 4DOIU 12-15IU 60mg 400Jlg 12-20mg 1.1-1.8mg 1.0-1.5mg 1.6-2.0mg Sug S-10mg 150-300Jlg lSmg 2-3mg 0.OS-Q.2mg 2.2S-5mg 0.OS-Q.2mg

3300.0IU 2DD.OIU 10.0IU 100.0mg 400.0Jlg 40.0mg 3.6mg 3.0mg 4.0mg 5.0Jlg 15.0mg 60.0Jlg 2.5-4mg O.S-l.Smg 10-15 ug 0.lS-1.8mg

Iron

10-lSmg

Iodine

lS0Jlg 1.5-4mg

Vitamin/trace element

Fluoride Molybdenum

O.lS-4mg

Cobalt

As part of B12 requirements

whose GI losses are likely to be excessive. Iron is not a part of commercial additive preparations because it is incompatible with triple-mix solutions and may cause anaphylactic reactions when it is given intravenously. Patients who need this trace element should receive it orally or by injection. Iron is not given to the critically ill because hyperferremia can increase bacterial virulence, alter polymorphonuclear cell function, and increase host susceptibility to infection.!"

Initiation and Maintenance of Infusion: Patient Monitoring All patients should be metabolically and hemodynamically stable before parenteral nutrition support is begun. Little is known about how vitamin and mineral requirements are changed by disease. In 1979, guidelines for parenteral vitamin and trace element administration were established by the Nutrition Advisory Group of the AMA. 135 The AMA recommendations for daily intravenous intake, as well as the recommended daily allowances, are shown in Table 6.14. It is imperative that patients are provided with adequate vitamins and trace elements while receiving parenteral nutrition. Patients receiving a carbohydrate load are particularly susceptible to thiamine deficiency. In 1988, several deaths resulted from cardiac failure caused by thiamine deficiency when long-term parenteral nutrition patients did not receive vitamins for a few weeks. Megaloblastic anemia secondary to folate deficiency can occur in parenteral nutrition patients who do not receive folate for several weeks. Selenium is a trace element for which requirements have not been well

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established, but it nonetheless should be added to solutions for patients receiving prolonged parenteral nutrition. There have been several cases of parenteral nutrition-associated selenium deficiency manifested as cardiomyopathy. Parenteral nutrition-associated deficiencies of copper, zinc, chromium, selenium, and molybdenum have also been reported. There is some evidence to indicate that, in certain disease states, vitamin and mineral requirements are altered because of increased losses, greater utilization, or both.!" In most instances, vitamin supplementation is accomplished by using single vitamin preparations. For example, higher doses of vitamins A and Care indicated for wound healing, and additional thiamin and folic acid are necessary in patients with alcoholism. As alluded to previously, zinc is required in higher amounts when there are excessive GI losses, as in massive diarrhea from short-bowel syndrome, inflammatory bowel disease, and malabsorption syndromes. Typically, one initiates parenteral nutrition with up to 21 of the nutrient solution and 500kcal as lipid. However, it may be advisable to start with 11 of parenteral nutrition and then to increase the volume as indicated. Blood glucose concentrations should be less than 200mg/dl, and abnormal electrolyte levels should be corrected, especially for potassium, phosphate, and magnesium, before starting or advancing to the goal nutritional prescription. Obviously, patients with diabetes mellitus may need to be advanced more slowly to prevent severe glucose intolerance. Lipid can be infused as an alternative fuel source to fulfill energy requirements without increasing the glucose infusion rate. The solutions should be administered using a volumetric pump set at a constant rate up to the levels previously specified. It is important not to modify the infusion rate during any given day to try to compensate for excess or inadequate administration of the parenteral nutritional solution. A cyclic schedule (8-16h/day) for patients requiring long-term parenteral nutrition can be initiated once the patient is metabolically stable. Cycling should be done gradually, and the last hour of infusion should be tapered to one-half the maintenance infusion rate to prevent rebound hypoglycemia. Before central parenteral alimentation is discontinued, the volume of infusion should be decreased by at least half to avoid adverse effects that may occur secondary to relative hyperinsulinemia if the body is not allowed sufficient time to equilibrate. In emergency situations when the central parenteral nutrition solution must be suddenly discontinued, 10% dextrose should be given at the same infusion rate as was used for the parenteral nutrition unless there is severe hyperglycemia. When patients who are receiving parenteral nutrition require a surgical operation, one can continue to administer the solution through the procedure, but decreasing the infusion rate may make circulating glucose and electrolyte levels easier to control, especially in patients with glucose intolerance or other severe organ dysfunction. During the initiation of central parenteral nutrition, serum chemistries must be monitored frequently. Once the patient has stabilized on his or her individual nutritional prescription, blood samples should be obtained at least twice weekly to measure chloride, CO 2, potassium, sodium, BUN, creatinine, calcium, and phosphate levels and once weekly for liver function tests and albumin, total protein, uric acid, magnesium, and triglyceride levels. Patients should be weighed each day on the same scale. Urine or blood should

be tested for sugar and acetone every 6h initially and until blood glucose concentrations .are stable. Electrolytes and other medications should be added only by the pharmacist when the parenteral nutrition solution is prepared. Numerous common metabolic abnormalities may arise during the course of parenteral (or enteral) nutrition. Several of these are outlined in Table 6.15.

Parenteral Nutrition for Patients with Abnormal Organ Function DIABETES MELLITUS

Control of blood glucose levels is important for all patients who receive parenteral nutrition. However, regulation may be especially difficult in patients who are known to have diabetes or in patients who develop insulin resistance in response to severe stress or infection. If blood glucose levels are not maintained at less than 200mg/dl, then immune function is likely to be impaired, and patients may be at increased risk for infection.137-139 In the insulin-dependent patient, the same amount of insulin that would normally be taken is added to the parenteral nutrition solution on the first day. Because as much as one-half of the insulin given binds to the container and intravenous tubing, the insulin given in this manner is almost always an underestimate of actual requirements. For example, if a patient's normal dose of regular insulin is 40U/day for a 2000-kcal diet, then 20U should be added to a parenteral nutrition solution of 1000kcal. Thereafter, blood glucose concentrations obtained by finger-stick or blood sampling are determined every 6h, and a sliding scale for subcutaneous regular insulin is used to provide supplementary insulin doses as needed. For the next day, one-half or all the insulin given on the previous day according to the sliding scale is added to the parenteral nutrition solution, depending on the level of control that is required. For nondiabetic patients who develop hyperglycemia, a similar procedure is used by which a sliding scale estimates the amount of insulin that is needed to maintain blood glucose levels below 200mg/dl, and one-half this amount is then added to the next day's parenteral nutrition orders. ACUTE RENAL FAILURE

In general, most patients with acute renal failure are catabolic

with elevated energy requirements. Calories should be provided in sufficient quantities to minimize protein degradation. Energy requirements can generally be met with the provision of 35 to 40 kcal/kg dry weight. Protein should be provided in the range of 1.2 to 1.5g/kg/day with a standard solution containing both essential and nonessential amino acids. Traditionally, formulas designed for renal failure contained predominantly essential amino acids. However, there is no conclusive data to show that special formulas containing essential amino acids only are superior to the less-expensive standard formulations containing both nonessential and essential amino acids. Moreover, the provision of nonessential amino acids may enhance protein synthesis and nitrogen retention. A balance of fat and carbohydrate should be provided. Lipid emulsions can be used as a source of concentrated energy in the patients who are fluid restricted. The contribution of fat to the total caloric intake should be no more than

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TABLE 6.15. Possible Etiologies and Treatment of Common Complications of Central Parenteral Nutrition. Problem

Glucose Hyperglycemia, glycosuria, hyperosmolar nonketotic dehydration or coma Diabetic ketoacidosis Rebound hypoglycemia Hypercarbia

Possible etiology

Treatment

Excessive dose or rate of infusion; inadequate insulin production; steroid administration; infection Inadequate endogenous insulin production and/or inadequate insulin therapy Persistent endogenous insulin production by islet cells after long-term high carbohydrate infusion Carbohydrate load exceeds the ability to increase minute ventilation and excrete excess

Decrease the amount of glucose given; increase insulin; administer a portion of calories as fat Give insulin; decrease glucose intake

Rapid infusion; decreased clearance

Decrease rate of infusion; allow clearance (approximately l2h) before testing blood Administer essential fatty acids in doses of 4%-7% of total calories

CO 2

Fat Hypertriglyceridemia Essential fatty acid Amino acids Hyperchloremia metabolic acidosis Prerenal azotemia Miscellaneous Hypophosphatemia Hypomagnesemia Hypermagnesemia Hypokalemia Hyperkalemia Hypocalcemia Hypercalcemia Elevated liver transaminases or serum alkaline phosphatase and bilirubin

Inadequate essential fatty acid administration efficiency

Give 50/0-100/0 glucose before total parenteral infusion is discontinued Limit glucose dose to 5mg/kg/min, Give greater percentage of total caloric needs as fat (up to 300/0-40%)

Excessive chloride content of amino acid solutions Excessive amino acids with inadequate caloric supplementation calories

Administer Na" and K+ as acetate salts

Inadequate phosphorus administration with redistribution into tissues Inadequate administration relative to increased losses (diarrhea, diuresis, medications) Excessive administration; renal failure Inadequate intake relative to increased needs for anabolism; diuresis Excessive administration, especially in metabolic acidosis; renal decompensation

Give l5mm phosphate/lOOO i.v. evaluate antacid and Ca2+; administration Administer Mt+ (15-20mEq/lOOOkcal)

Inadequate administration; reciprocal response to phosphorus repletion without simultaneous calcium infusion Excessive administration; excess vitamin D administration Enzyme induction secondary to amino acid imbalances or overfeeding

30%, while the remainder of the caloric requirements is provided by glucose. Fluid and electrolyte balances are often impaired in patients with acute renal failure. Potassium, phosphate, and magnesium levels must be monitored carefully, and these should be added to parenteral nutrition if blood levels fall. Acetate salts of potassium or sodium can be administered to help correct a metabolic acidosis. Standard doses of the watersoluble vitamins and additional folic acid (1 rug/day total) should be added to the solution of patients who are undergoing dialysis because these substances are lost from the body in the dialysate bath. The supplementation of fat-soluble vitamins is usually not required, especially in patients who are also eating, because excretion is reduced in renal failure. In anuric patients, trace elements are not added to the nutrient solutions. However, for patients who require prolonged parenteral nutrition support and are dialyzed, trace elements and fat-soluble vitamins should be replaced. The various ultrafiltration techniques are also associated with highly variable but increased amino acid losses in the dialysate. In these instances, additional protein may be required to meet the patient's esti-

Reduce amino acids; increase the amount of glucose

Decrease Mt+ supplementation Increase K+ supplementation Reduce or stop exogenous K1; if EKG changes are present, treat with Ca gluconate, insulin, diuretics Increase Ca2+ dose Decrease Ca2+ and/or vitamin D administration Reevaluate nutritional prescription

mated needs. However, a portion of the patient's nonprotein calorie needs may be met by the dextrose contained in replacement solutions. HEPATIC DYSFUNCTION AND LIVER FAILURE

Protein intake for patients with stable chronic liver disease depends on the patient's nutritional status and protein tolerance. Nutritionally depleted patients may require as much as 1.5 g of protein per kilogram estimated dry weight. However, protein intake may need to be decreased in patients with liver failure and encephalopathy. Protein-sensitive encephalopathic patients should be given 0.5 to 0.7 g protein per kilogram per day and increased gradually to 1.0 to 1.5g/kg/day if possible. These patients have altered plasma amino acid profiles with increased concentrations of aromatic amino acids (phenylalanine, tyrosine, and tryptophan) and methionine and decreased BCAAs (valine, leucine, and isoleucine). Fluid restriction may be necessary in some patients with ascites and edema. In this instance, the concentration of dextrose can be increased to maintain the number of calories

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administered as carbohydrate. The amount of sodium given is reduced because these patients excrete nearly sodium-free urine. As mentioned, administration of trace elements is often contraindicated because a major route of excretion for these substances, such as copper and manganese, is via the biliary system. Zinc deficiency is common in cirrhotic patients, and supplementation of this mineral may be necessary, especially if there are excessive GI losses. OTHER CONDITIONS AND NUTRITIONAL TREATMENTS

The catabolism of major surgery, trauma, bums, and sepsis is characterized by a net breakdown of body protein stores to provide substrates for gluconeogenesis and acute-phase protein synthesis. The provision of adequate nutrition can attenuate whole-body catabolism but rarely if ever prevents or reverses loss of lean body mass using conventional management principles during the acute phase of injury. Several new strategies to accomplish this are under investigation; these include the administration of hormones or growth factors and the provision of conditionally essential amino acids, such as glutamine. Growth hormone administration to patients increases the rate of wound healing and decreases wound infection rates, hospital stays, and perhaps the catabolism and muscle wasting associated with critical illness as well. However, growth hormone is a very expensive therapy. Furthermore, preliminary data suggest that it may be harmful to some critically ill patients.!" For these reasons, other agents, such as oxandrolone (Oxandrin) are being pursued to induce positive nitrogen balance and enhance wound healing in critically ill patients. The use of growth factors currently remains investigational in acute care settings. The use of adjuvant anabolic agents should be reserved for patients who have not responded to aggressive nutrition support but whose underlying disease processes are controlled.

Common Complications and Their Management CATHETER SEPSIS

Catheter sepsis is a very serious complication associated with central venous alimentation. Primary catheter sepsis occurs when there are signs and symptoms of infection, and the indwelling catheter is the only anatomical focus of infection. Secondary catheter infections are associated with another focus or multiple infectious foci that cause bacteremia and seed the catheter. Management of the patients with catheter infection depends on their clinical condition. If extremely ill patients with high fevers are hypotensive or have local signs of infection around the catheter site, then the catheter should be removed, its tip cultured, and peripheral and central venous blood cultures obtained. In primary catheter sepsis, signs and symptoms should return to normal quickly. The organisms that grow from the catheter tip are the same as the ones that are identified in peripheral blood culture. Usually, more than 1 x 103 organisms are grown from cultures of the catheter tip. Specific therapy should be initiated against the primary source in patients in whom a source of infection other than the catheter tip is present. Peripheral blood cultures are

obtained. One should avoid taking blood cultures from the central venous catheter port dedicated for parenteral nutrition because this increases the risk of contaminating the line. If the infection resolves, then central venous feedings can be continued. If a secondary source is not identified and the symptoms persist, then the catheter should be removed, and its tip should be cultured. If the catheter tip culture returns positive or if the index of suspicion is high, then appropriate antibiotic therapy is initiated. Central venous feeding can be resumed, maintaining blood glucose levels below 200mg/dl. Occasionally, the situation arises in which a site of infection other than the catheter is identified, but signs and symptoms persist despite what is assumed to be adequate therapy. As before, if blood cultures are positive, the safest course of action may be to remove the catheter. If peripheral blood cultures are negative, then the catheter may be changed over a guidewire and the catheter tip cultured to determine if it was contaminated. Central venous feedings can be continued during this interval if the patient is stable. If the catheter tip returns a positive culture, then a new catheter should be inserted ata different site. Changing the central venous catheter over a guidewire can also facilitate the diagnosis of primary catheter infections. OTHER COMPLICATIONS

Complications of central venous alimentation are usually related to excess administration or underadministration of the energy sources, electrolytes, or trace metals. The etiologies of some common complications and treatment options are outlined in Table 6.15. Prolonged administration of parenteral nutrition may result in altered hepatic function tests and changes in liver pathological conditions that can lead to liver failure. Initially (1-2 weeks after initiation of parenteral nutrition), serum transaminases may be elevated. These abnormalities frequently resolve without any change in the composition or rate of parenteral nutrition administration. However, in patients receiving long-term (>20 days) parenteral nutrition, serum transaminase levels may remain elevated, even after parenteral nutrition support is discontinued. Serum levels of alkaline phosphatase and bilirubin may also increase in some patients who receive long-term parenteral nutrition. Patients who do not receive some lipid as part of their parenteral nutrition may have more frequent and severe hepatic abnormalities. The provision of excess glucose increases insulin secretion, which stimulates hepatic lipogenesis and results in hepatic fat accumulation. Fatty infiltration is the initial histopathological change; it is readily reversible and may not be accompanied by altered liver function. Longer parenteral nutrition therapy may be associated with cholestasis and nonspecific triaditis and may progress to active chronic hepatitis, fibrosis, and eventual cirrhosis. The management of parenteral nutrition-related liver dysfunction is summarized in Table 6.15.

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NUTRITION

87. van der Hulst RRWJ, von Meyenfeldt MF, van Kreel BK, et al. Glutamine and the preservation of gut integrity. Lancet 1993; 334: 1363-1365. 88. Smith RC, Mackie W, Kohlhardt SR, Kee AJ. The effect on protein and amino acid metabolism of an intravenous nutrition regimen providing 70 % of nonprotein calories as lipid. Surgery (St. Louis) 1992; Ill: 12-20. 89. de Chalain TM, Mitchell WL, O'Keefe SJ, et al. The effect of fuel source on amino acid metabolism in critically ill patients. J Surg Res 1992;52:167-176. 90. Chassard D, Guiraud M, Gauthier J, et al. Effects of intravenous medium-chain triglycerides on pulmonary gas exchanges in mechanically ventilated patients. Crit Care Med 1994;22:248251. 91. Kohlhardt SR, Smith RC, Kee AJ. Metabolic response to a high-lipid, high-nitrogen peripheral intravenous nutrition solution after major upper-gastrointestinal surgery. Nutrition 1994; 10:317-326. 92. Roulet M, Frascarolo P, Pilet M, et al. Effects of intravenously infused fish oil on platelet fatty acid phospholipid composition and on platelet function in postoperative trauma. J Parenter Enteral Nutr 1997;21:296-301. 93. Tappy L, Schwarz JM, Schneiter P, et al. Effects of isoenergetic glucose-based or lipid-based parenteral nutrition on glucose metabolism, de novo lipogenesis, and respiratory gas exchanges in critically ill patients. Crit Care Med 1998;26:813-814. 94. Novak F, Heyland DK, Avenell A, et al. Glutamine supplementation in serious illness: a systematic review of the evidence. Crit Care Med 2003;30:2022-2029. 95. Miskovitz P. Glutamine supplementation in critically ill and elective surgery patients: does the evidence warrant its use? Crit Care Med 2003;30:2152-2153. 96. Deitch EA. Does the gut protect or injure patients in the ICU? Perspect Crit Care 1988;1:1-31. 97. Moore FA, Moore EE, Poggetti R, et al. Gut bacterial translocation via the portal vein: a clinical perspective with major torso trauma. Trauma 1991;31:629-638. 98. Johnson LR, Copeland EM, Dudrick SJ, et al. Structural and hormonal alterations in the gastrointestinal tract of parenteral fed rats. Gastroenterology 1975;68:1177-1183. 99. Purandare S, Offenbartl K, Westrom B, et al. Increased gut permeability to fluorescein isothiocyanate-dextran after total parenteral nutrition in rat. Scand J Gastroenterol 1989;24:678682. 100. McGhee JR, Mestecky J, Dertzbaugh MT, et al. The mucosal immune system: from fundamental concepts to vaccine development. Vaccine 1992;10:75-88. 101. Li J, Kudsk KA, Gocinski B, et al. Effects of parenteral nutrition on gut-associated lymphoid tissue. J Trauma 1995;39:44. 102. Tomasi TB Jr. Mechanisms of immune regulation at mucosal surfaces. Rev Infect Dis 1983;5:S784. 103. Kudsk KA, Li J, Renegar KB. Loss of upper respiratory tract immunity with parenteral feeding. Ann Surg 1996;223:629638. 104. Li J, Kudsk KA, Ianu P, Renegar KB. Effect of glutamine-enriched TPN on small intestine gut-associated lymphoid tissue (GALT) and upper respiratory tract immunity. Surgery (St. Louis) 1997; 121:542-549. 105. Lin M-T, Saito H, Fukushima R, et al. Route of nutritional supply influences local, systemic, and remote organ responses to intraperitoneal bacterial challenge. Ann Surg 1996;223:8493. 106. Fong Y, Marano MA, Barber E, et al. Total parenteral nutrition and bowel rest modify the metabolic response to endotoxin in humans. Ann Surg 1989;210:449-457. 107. Hunter DC, Iaksik T, Lewis D, et al. Resting energy expenditure in the critically ill: estimations versus measurement. Br J Surg 1988;75:875-878.

137

108. Hwang T-L, Hwang S-L, Chen M-F. The use of indirect colorimetry in critically ill patients-relationship with measured energy expenditure to injury severity score, a septic severity score, and Apache II score. J Trauma 1993;34:247-251. 109. Choban PS, Burge JC, Flancbaum L. Nutrition support of obese hospitalized patients. Nutr Clin Prac 1997;12:149-154. 110. Harris JA, Benedict FG. A Biometric Study of Basal Metabolism in Man. Publication 279. Washington, DC: Carnegie Institution, 1919. Ill. Garrel DR, Jobin N, delonge LHM. Should we still use the Harris and Benedict equations? Nutr Clin Pract 1996;11:99103. 112. Weir JB de V. New methods for calculating metabolic rate with special reference to protein metabolism. J Physiol (Camb) 1949; 109:1-9. 113. Campbell SM, Kudsk KA. "High tech" metabolic measurements: useful in daily clinical practice? J Parenter Enteral Nutr 1988;12:610-612. 114. Food and Nutrition Board, National Research Council. Recommended Dietary Allowances, 10th ed. Washington, DC: National Academy of Sciences, 1989. 115. Kudsk KA, Teasley-Strausburg KM. Enteral and parenteral nutrition. In: Irwin RS, Cerra FB, Rippe JM, eds. Intensive Care Medicine, 4th ed. New York: Lippincott-Raven, 1998. 116. Wolfe RR, Shaw JHF. Glucose and FFA in kinetics in sepsis: role of glucagon and sympathetic nervous system activity. Am J PhysioI1985;248:E236-E243. 117. Pomposelli H, Baxter JK, Babineau TJ, et al. Early postoperative glucose control predicts nosocomial infection rate in diabetic patients. J Parenter Enteral Nutr 1998;22:77-81. 118. van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. NEngIJMed2001;8;345: 13591367. 119. Pelham LD. Rational use of intravenous fat emulsions. Am J Hosp Pharm 1981;38:198-208. 120. Kinsella JE, Lokesh B, Broughton S. Dietary polyunsaturated fatty acids and eicosanoids: potential effect on the modulation of inflammatory and immune cells: an overview. Nutrition 1990;6:24-44. 121. Allardyce DB. Cholestasis caused by lipid emulsions. Surg Gynecol Obstet 1982;154:641-647. 122. Fonkalsrud E. Surgical treatment of gastroesophageal reflux (GER)syndrome in infants and children. Am J Surg 1987;154:1118. 123. Collier P, Kudsk KA, Glezer J, et al. Fiber-containing formula and needle catheter jejunostomies: a clinical evaluation. Nutr C1in Pract 1994;9:101-103. 124. Dent D, Kudsk K, Minard G, et al. Risk of abdominal septic complications following feeding jejunostomy placement in patients undergoing splenectomy for trauma. Am J Surg 1993; 166:686-689. 125. Smith-Choban T, Max MH. Feeding jejunostomy: a small bowel stress test. Am J Surg 1988;155:112-117. 126. Adams S, Dellinger EP, Wertz MJ, et al. Enteral versus parenteral nutritional support following laparotomy for trauma: a randomized prospective trial. J Trauma 1986;26:882-891. 127. Smith CD, Sarr MG. Clinically significant pneumatosis intestinalis with postoperative enteral feeding by needle catheter jejunostomy: an unusual complication. J Parenter Enteral Nutr 1991;15:328-331. 128. Guenter PA, Settle RG, Perlmutter S, et al. Tube feeding-related diarrhea in acutely ill patients. J Parenter Enteral Nutr 1991; 15:277-280. 129. Edes TE, Walk BE, Austin JL. Diarrhea in tube-fed patients: feeding formula not necessarily the cause. Am J Med 1990;88:9193. 130. Solomon SM, Kirby DF. The refeeding syndrome: a review. J Parenter Enteral Nutr 1990;14:90-97.

138

CHAPTER 6

131. Pemberton LB, Lyman B, Lander V, et al. Sepsis from tripleversus single-lumen catheters during total parenteral nutrition in surgical or critically ill patients. Arch Surg 1986;121:591. 132. Miller JJ, Venus B, Mathru M. Comparison of the sterility of long-term central venous catheterization using single lumen, triple lumen, and pulmonary artery catheters. Crit Care Med 1984;12:634. 133. Pomposelli JJ, Bistrian BR. Is total parenteral nutrition immunosuppressive? New Horiz (US) 1994;2:224-229. 134. Kumpf VJ. Parenteral iron supplementation. Nutr Clin Pract 1996;11:139-146. 135. American Medical Association Department of Foods and Nutrition, 1975. Multivitamin preparations for parenteral use: a statement by the Nutrition Advisory Group. J Parenter Enteral Nutr 1979;3:258-262. 136. De Biasse MA, Wilmore DW. What is optimal nutritional support? New Horiz 1994;2:122-130. 137. Kwoun MO, Ling PR, Lydon E, et al. Immunologic effects of acute hyperglycemia in nondiabetic rats. J Parenter Enteral Nutr 1997;21:91-95. 138. Delamaire M, Maugendre D, Moreno M, et ala Impaired leucocyte functions in diabetic patients. Diabetes Med 1997;14:2934. 139. Alexiewicz JM, Kumar D, Smogorzewski M, et al. Polymorphonuclear leukocytes in non-insulin dependent diabetes mellitus: abnormalities in metabolism and function. Ann Intern Med 1995;123:919-924. 140. Pharmacia and Upjohn. Safety Statement From Pharmacia and Upjohn Regarding the Use of Recombinant Somatropin (Genotropin/Genotonorm) for Treatment of Acute Catabolism in Critically III Patients. Pharmacia/Upjohn: Kalamazoo, MI, 1997.

141. Brown RO, Hunt H, Mowatt-Larssen CA, et al. Comparison of specialized and standard enteral formulas in trauma patients. Pharmacotherapy 1994;14:314--320. 142. Gianotti L, Gentilini 0, Braga M. Nutrition in oncological surgery. Nestle Nutr Workshop Ser Clin Perform Programme 2000;4:239-21; discussion 251-254. 143. Galban C, Montejo JC, Mesejo A, et al. An immune-enhancing enteral diet reduces mortality rate and episodes of bacteremia in septic intensive care unit patients. Crit Care Med 2000;28:884885. 144. Caparr6s T, Lopez J, Grau T. Early enteral nutrition in critically ill patients with a high-protein diet enriched with arginine, fiber, and antioxidants compared with a standard high-protein diet. The effect on nosocomial infections and outcome. JPEN J Parenter Enteral Nutr 2001;25:299-309. 145. Conejero R, Bonet A, Grau T, et al. Effect of a glutamine-enriched enteral diet on intestinal permeability and infectious morbidity at 28 days in critically ill patients with systemic inflammatory response syndrome: a randomized, single-blind, prospective, multicenter study. Nutrition 2002;18:716-721. 146. Zhou YP, Jiang ZM, Sun YH, Wang XR, Ma EI, Wilmore D. The effect of supplemental enteral glutamine on plasma levels, gut function, and outcome in severe bums: a randomized, doubleblind, controlled clinical trial. JPEN J Parenter Enteral Nutr 2003;27:241-245. 147. Hall JC, Dobb G, Hall J, de Sousa R, Brennan L, McCauley R. A prospective randomized trial of enteral glutamine in critical illness. Intensive Care Med 2003;29:1710-1716. 148. Garrel D, Patenaude J, Nedelec B, et al. Decreased mortality and infectious morbidity in adult bum patients given enteral glutamine supplements: a prospective, controlled, randomized clinical trial. Crit Care Med 2003;31:2444-2449.

Perioperative Fluids and Electrolytes

Avery B. Nathens and Ronald V. Maier Physiology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139 Disorders of Sodium Homeostasis. . . . . . . . . . . . . . . . .. 141 Disorders of Potassium Homeostasis 143

S

urgical patients undergo acute alterations in the volume and composition of fluids in the intracellular and extracellular spaces. To a great extent, these changes occur as a result of the patient's underlying disease. For example , hemorrhage or bowel obstruction may acutely change the volume of fluid in the intravascular or extracellular compartments. However, these alterations are not limited to patients requiring urgent operative intervention as even elective surgery may result in dramatic fluid shifts in the absence of significant blood loss. In addition to changes in fluid volume, surgical patients may develop potentially dangerous fluctuations in concentrations and total body content of important electrolytes. Precise perioperative management of fluids and electrolytes is thus required to minimize perioperative morbidity and mortality.

Physiology Body Fluid Compartments Accurate replacement of fluid requires an understanding of the distribution of water, electrolytes, and colloid across the various body fluid compartments. Total body water (TBW) approximates 60% of total body weight, or 421 in a 70-kg person ; TBW is composed of the intracellular and extracellular compartments. The intracellular compartment or intracellular volume (ICV) constitutes 40% of total body weight (281 in a 70-kg patient), whereas the extracellular volume (ECV) makes up the remaining 20% . The ECV is composed of interstitial fluid (IF) and the intravascular or plasma volume (PV). The PV const itutes 25% of ECV (5% of total body weight or approximately 3.51), while the remainder is IF. Red cell volume, approximately 2% to 3 % of TBW, is part of th e ICV. Thus, total blood volume is approximately 7% to 8% of total body weight, or approximately 51 in a 70-kg patient (Fig. 7.1). Body water composition differs in obese subjects, with less TBW per unit of weight and a relatively expanded ECV compared to ICV due to the relatively low water content of adipose tissue. This low water content is a reflection of the

Disorders of Mineral Homeostasis. . . . . . . . . . . . . . . . .. 145 Acid-Base Abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . 146 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148 relative low water content of adipocytes. ' (Body water composition is also altered in the elderly such that by 80 years of age, TBW contributes only 50% of total body weight. i] The solute and colloid compositions of the intracellular and extracellular fluid compartments differ markedly. The ECV contains most of the sodium in the body, with equal sodium concentrations in the PV and IF (140mEqjl), while the intracellular [Na+] is only 10 to 12mEqfl. By contrast, the predominant intracellular cation is potassium, with the intracellular concentration [K+] approximating 150mEqjl in contrast to an ECV [K+] of 4.0mEqjl. Albumin represents the most important osmotically active constituent of the ECV and is virtually excluded from the ICV. Albumin is unequally distributed within the ECV; the serum concentration of albumin approximates 4.0gjdl, whil e the IF concentration averages 1.0gjdl. The distribution volume of various crystalloid or colloid solutions is that volume in which the administered solution will equilibrate over the short term. For example, TBW is the distribution volume for sodium-free water; ECV is the distribution volume for crystalloid solution in which [Na"] approximates 140mEqjl, whereas PV represents th e distribution volume for most colloid solutions. To clarify this concept, assume a 70-kg patient has suffered an acute blood loss of 1000ml, approximately 20% of the predicted 5-1 blood volume. Anyone of 5% dextrose in water (D5W), lactated Ringer's solution, or 5% albumin may be chosen to replace the lost blood volume. The formula describing the effects of fluid infusion on PV expansion is as follows: . Volume infused x Normal PV Expected PV mcrement = - - - - - , - - - - - - - - Distribution volume Rearranging the equation would yield the following : Volume _ Expected PV increment x Distribution volume infused Normal plasma volume In this example, the expected PV increment is 11 (to replace shed blood), and the normal PV is approximately 3.51. To restore blood volume using D5W, which distributes throughout TBW (421), it would be necessary to administer 121. By 139

140

CHAPTER 7

Total Body Water

[600/0 Body Wt. (421)]

INTRACELLULAR

EXTRACELLULAR

[400/0 Body Wt. (281)]

CATIONS Na- 12.0 mEqll k+ 150 mEqll

[200/0 Body Wt. (141)]

CATIONS Nat 142 mEq/1 Ca 2+ 2.5 mEq/1 k+ 4.3 mEq/1 Mg2+ 1.1 mEq/1

Ca2+ 4.0 mEq/1 Mg2+ 34.0 mEq/1

ANIONS

ANIONS

CI4.0 mEqll Proteins 54 mEq/1 HC03- 12.0 mEqll Other 90 mEq/1 HP042- , H2 P0 4- 40 mEqll

•

CI104 mEq/1 Proteins 14 mEq/l HC03- 24 mEq/l Other 5.9 mEq/1 HP042- , H2P04- 2.0 mEq/l

INTERSTITIAL (10.51)

contrast, if lactated Ringer's solution (which distributes throughout ECV) were chosen, a 1-1 PV increment would require approximately 41 of crystalloid. Colloid solutions with similar oncotic pressures to plasma (e.g., 50/0 albumin) distribute within the intravascular space and thus have a distribution volume equal to the PV. In this example, 11 of 5 % albumin would be required to replace the shed blood.

Maintenance Body Fluid and Electrolyte Requirements Healthy adults require a minimal amount of fluid and electrolyte intake to maintain systemic homeostasis. Sufficient water is required to replace obligatory urinary losses of approximately 1000ml/day and gastrointestinal (GI) losses of 100 to 200ml/day. Insensible water losses must also be considered in estimating maintenance fluid requirements. Insensible losses amount to 8 to 12ml/kg/day and are equally divided into respiratory and cutaneous water loss. Cutaneous insensitive losses increase by approximately 100/0 for each degree of temperature greater than 37°C; thus, these losses may become significant in the febrile patient. Respiratory insensitive water losses tend to be greater with inspiration of unhumidified air, as may occur with a tracheostomy. Overall maintenance fluid requirements are dependent on weight and are approximated using either of the approaches in Table 7.1. For example, a 60-kg patient would require approximately 100ml/h of water (4ml/kg x 10kg plus 2ml/kg x 10kg plus 1ml/kg x 40 kg) to keep up with obligatory water losses. Daily sodium intake in normal individuals approaches 100 to 250mEq/day. This intake is balanced by sodium losses in sweat, stool, and urine. However, renal conservation of sodium is extraordinary, and in cases of profound volume depletion, urinary losses of sodium may be less than 1mEq/ day. In the perioperative period, adequate maintenance of sodium may be achieved with an intake of 1 to 2mEq/kg/day. Normal potassium intake is approximately 40 to 120mEq/ day, approximately 10% to 150/0 of which is excreted as TABLE 7.1. Maintenance Water Requirements. Weight

First 10kg Second 10kg Each kilogram above 20 kg

ml/kg!h

ml/kg/day

4

100 50 20

2 1

PLASMA (3.51)

FIGURE 7.1. Distribution of body water and electrolytes in a healthy 70-kg male. (Adapted from Narins and Krishna," with permission.)

normal urinary losses. In individuals with normal renal function, body potassium stores can be maintained with an intake of approximately 0.5 to 1.0mEq/kg/day. In the past, glucosecontaining fluids have been administered in an effort to prevent hypoglycemia and limit protein catabolism. However, because of the hyperglycemic response associated with surgical stress, only infants and patients receiving insulin or drugs that interfere with glucose synthesis are at high risk for hypoglycemia. The supplementation of other electrolytes (e.g., calcium, magnesium, and phosphate) is usually unnecessary in patients with normal nutritional status. Based on estimated maintenance requirements of Na" and K+, there are several options for maintenance fluid replacement (Table 7.2). A 60-kg patient should receive approximately 60 to 120mEq/day of sodium and 30 to 60mEq/day of potassium. The most commonly used maintenance solutions are D5W 1/2 normal saline (NS) or 2/3 D5W 1/3 NS, which are relatively isotonic and provide the required amount of sodium over a 24h period. Potassium is often added to these solutions at concentrations approximating 20mEq/1 to ensure that maintenance requirements are met. Although 0.9% saline is used frequently, the relatively high concentration of chloride results in a hyperchloremic metabolic acidosis because of the inability of the renal tubule to excrete the excess Cl.

Perioperative Fluid Requirements Appropriate management of fluids and electrolytes in the perioperative period requires a flexible yet systematic approach to ensure that fluid administration is appropriately tailored to the patient's changing requirements. The amount of fluids administered in the immediate postoperative period (within the first 12-24h) must take into account the existing deficit, maintenance requirements, and any ongoing losses. Estimation of the existing deficit must incorporate an approximation of intraoperative blood loss as well as fluid losses from evaporative and third-space (Le., extravascular) fluid sequestration. It is important to realize that the surgeon's estimated intraoperative blood loss is often 500/0 less than when calculated using more rigorous methods.v' This discrepancy should be taken into account when estimating postoperative fluid requirements. Due to the shift of crystalloid from the intravascular space to the interstitium, crystalloid should replace blood loss in a ratio of 3-4: 1.

141

PERI OPERATIVE FLUIDS AND ELECTROLYTES

TABLE 7.2. Options for Maintenance Fluid Replacement. Na+ (mEqll)

K+ (mEqfl)

Cl: (mEqll)

Ca" (mEqll)

Lactate" (mEqll)

Glucose (gIl)

154 0 77 50 130

0 0 0 0 4

154 0 77 50 109

0 0 0 0 3

0 0 0 0 28

0 50 50 33 0

Normal (0.90/0) saline (NS) Dextrose 5% in water (D5W) D5W 1/2 NS 2/3 D5W, 1/3 NS Lactated Ringer's

'Lactate is used instead of Cl- to maintain electroneutrality. It is converted to HCO a- by hepatic metabolism.

solutions compared to dextrose-containing solutions ensures that adequate intravascular volume is maintained despite ongoing extravascular fluid sequestration. On the first postoperative morning, these solutions are switched to dextrosecontaining solutions (2/3 D5W 1/3 NS or D5W 1/2 NS) supplemented with KCl, providing that urine output has been adequate.

Extravascular fluid sequestration represents another important source of intraoperative fluid loss. Extensive dissection at the operative site induces a localized capillary leak, the result of which is extravasation of intravascular fluid into the interstitium with edema formation. The loss of intravascular volume via this route depends on the extent of exposure and degree of dissection. For example, estimated intravascular fluid losses associated with inguinal herniorrhaphy are approximately 4 ml/kg/h, while losses during aortic aneurysmectomy may be as high as 8 ml/kg/h, This capillary leak may persist as long as 24h into the postoperative period and should be considered as part of ongoing losses in the immediate postoperative period. Ongoing fluid requirements usually represent GI losses from stomas, tubes, drains, or fistulae. These losses may be accurately estimated by closely following recorded hourly outputs from any tube or drain. The electrolyte composition of the output depends on the source of effluent' (Table 7.3). The replacement fluid should be chosen to best approximate the composition of the ongoing losses. For example, nasogastric losses are typically replaced with NS supplemented with 10mEq KCl/l, whereas losses from a duodenal fistula may best be replaced using lactated Ringer's solution. Postoperative fluid orders should take into account the overall fluid balance in the operating room as an estimate of the existing deficit along with maintenance fluid requirements and any ongoing losses. The preferred approach is to reassess the patient frequently to determine intravascular volume status. In this regard, evaluation of heart rate, blood pressure, and most importantly, hourly urine output provides an excellent measure of intravascular volume status. Orders for intravenous fluids should be rewritten frequently to maintain a normal heart rate, a urine output of approximately 1 rnl/kg/h, and adequate blood pressure. It has become common practice to avoid potassium supplementation within the first 24 h. The rationale behind this approach is to prevent life-threatening hyperkalemia should oliguria become a significant problem in the early postoperative period. The preferred practice is to administer NS or lactated Ringer's in the first 24h. The smaller volume of distribution of these

Disorders of Sodium Homeostasis Maintenance of a normal serum sodium concentration (135145mEq/l) is intimately associated with control of plasma osmolarity (Pos m)' Plasma osmolarity is determined by the sum of the individual osmotically active substances as described in the following equation: Posm = 2 x Plasma [Na"] + [Glucose]/20 + [BUN]/3

From this equation, it is evident that plasma [Na"] is the major determinant of Posm in normal individuals. Further, it is important to realize that plasma [Na"] alone provides no information about the total content of sodium in the body but simply provides an estimate of the relative amounts of free water and sodium. Maintenance of the plasma osmolarity within normal limits depends on the ability of the kidneys to excrete water, thus preventing hypoosmolarity, and on a normal thirst mechanism with access to water to prevent hypernatremia. The ability to excrete maximally dilute urine «100mOsm/ kg) allows the kidneys to excrete in excess of 181 of water per day. In the presence of normal renal perfusion and intact renal function, antidiuretic hormone (ADH) is the principal regulator of serum osmolarity. A 1% to 2 % reduction in Pos m maximally inhibits ADH release, leading to a urine osmolarity that is maximally dilute. By contrast, a 1 % to 2 % increase in Posm above normal or a 50/0 to 100/0 decrease in blood volume or blood pressure stimulates ADH release. Importantly, when both a low plasma osmolarity and low blood volume or pressure are present, the latter effect will dominate, resulting in

TABLE 7.3. Volume and Composition of Gastrointestinal Fluid Losses. Source

Volume (ml)

Stomach Duodenum Ileum Colon (diarrhea) Bile Pancreas

1000-4200 100-2000 1000-3000 500-1700 500-1000 500-1000

Na+ (mEqll)

20-120 110 80-150 120 140 140

cr (mEqfl) 130 115 60-100 90 100 30

K+ (mEqfl)

10-15 15 10 25 5 5

HC03- (mEqfl)

H+ (mEqll)

30-100 10 30-50 45 25 115

142

CHAPTER 7

ADH release

, -----....-L..:.:.:::= = :........::!I Thirst (a) Osmotic changes in the extracellular fluid provide the normal stimulus for water contro l.

h~~~=::::::dfM Supraoptic and

•

ADH release

' - - - - - t r ,"l Thirst center

A

c 'Vi

(b) Severe depletion of biood volume constitutes an overriding stimulus, Restoration of blood volume takes precedence over osmotic requirements,

FIGURE 7.2. A. Graphic depiction of the law of circulating volume. In the setting of volume depletion, this stimulus takes precedence over osmotic requirements. ADH, antidiuretic hormone. (From Goldberg."] B. Effect of intravascular volume on the regulation of osmol ality by ADH. Each line represents the relationship of plasma

an increase in ADH release (Fig. 7.2). This is one of the principal mechanisms leading to the development of hyponatremia in patients with low intravascular volume. In addition, changes in blood pressure or volume status will alter the osmolar set point and, to a lesser extent, the sensitivity of the osmotic response. " The elderly are particularly prone to alterations in sodium homeostasis.' The reduction in glomerular filtration rate that occurs with aging limits the ability of the aged to excrete a sodium load, making them more prone to overexpansion of the extracellular fluid compartment. In addition, a combination of impaired thirst mechanism and decreased ability to concentrate the urine predispose them to hypematremia.

Hyponatremia The approach to hyponatremia begins with an assessment of the serum osmolarity" (Table 7.41. If serum osmolarity is high, then it is important to consider the possibility of other effective plasma osmoles , the most common of which is glucose. Hyperglycemia shifts H 20 from cells, leading to dilutional hyponatremia. As a result, for every IOOmgjdl rise in glucose the [Na+J falls by 1.3mEqfl. The treatment requires definitive management of the osmotically active agent, which in the case of glucose, would be insulin. In rare cases, the serum osmolarity may be normal. This phenomenon is referred to as pseudohyponatremia and is caused by hyperlipidemia or hyperproteinemia, it is an artifact of the laboratory assay. No treatment is required. More frequently, a low [Na+J will be associated with reduced plasma osmolarity. The etiology and treatment of hypoosmolar hyponatremia may be classified into three groups depending on the ECV status of the patient. A reduction in ECV leads to an increase in ADH secretion, impairing the kidney's ability to excrete free water. Either administration of Nat-free solutions or the ingestion of free water induced by thirst aggravates the resulting hyponatremia. The most common causes of hypovolemic hyponatremia are Na' loss. Typically, perioperative isotonic losses (plasma, gastric

10

8

l/l

6

l/l

4

a. o

HYPOTHALAMUS

~~~:'i§~~~ paraventricu lar ~i1" nuclei

E

en a.

CIl

>

CIl

E l/l

CIl

n:

Hypovolemia or hypotension

I

Hypervolemia or hypertension

2

o 260 270 280 290 300 310 320 330 340

Plasma osmolality mOsm/kg B vasopressin to plasma osmolarity in the presence of varying levels of volume status or blood pressure. The hemodynamic influences raise or lower the set point and, to a lesser extent, alter the slope or sensitivity of the osmotic response. (From Robertson," Science and Medicine Publishing.)

losses) are replaced with hypotonic solutions in the face of mild hypovolemia. Treatment involves replenishing the extravascular volume with isotonic fluids in concert with restriction of free water. Hyponatremia in the presence of an increased extravascular volume probably represents the next most common scenario in the perioperative period . Typically, these represent edematous states in which there is a reduction in the effective circulating volume. Low cardiac output states, cirrhosis, and other hypoalbuminemic states are the more common etiologies. Both water restriction and Na" restriction are necessary. Depending on the severity of the hyponatremia, a loop diuretic may be required to increase both Na" and water loss, in most cases, this induces an excess of urinary water loss over Na" loss and should correct the hyponatremia. Patients with a normal ECV status and hypoosmolar hyponatremia may have the syndrome of inappropriate ADH secretion (SIADH). In the surgical patient, SIADH is not often TABLE 7.4. Causes of Hyponatremia. Pseudohyponatremia (normal plasma osmolality) Hyperlipidemia, hyperproteinemia Dilutional hyponatremia (increased plasma osmolality) Hyperglycemia, mannitol True hyponatremia (reduced plasma osmolality) Reduction in ECF volume Plasma, GI, skin , or renal losses (diuretics I Expanded ECF volume Congestive heart failure Hypoproteinemic states (cirrhosis, nephrotic syndrome, malnutrition) Normal ECF volume SIADH (syndrome of inappropriate antidiuretic hormone release) Pulmonary or CNS lesions Endocrine disorders (hypothyroidism, hypoadrenalism) Drugs [e.g., morphine, tricycl ic antidepressants, clofibrate , antineoplastic agents, chlorpropamide, aminophylline, indomethacin) Miscellaneous (pain, nausea)

PERIOPERATIVE FLUIDS AND ELECTROLYTES

considered as a possible cause of hyponatremia, but nausea, pain, and narcotics, all of which are common in the postoperative period, may result in SIADH and contribute to postoperative hyponatremia. Diagnosis is confirmed by demonstrating a low plasma osmolarity, a less than maximally dilute urine (Uos m. > 100mOsm/I), and renal salt wasting (UNa. > 20mEqjl).7 Treatment includes management of the underlying cause and water restriction. Isotonic (0.90/0) saline should not be administered to patients with SIADH as it may cause the plasma [Na+] to fall. The presence of symptoms in hyponatremia depends on the rate at which hyponatremia occurred. Symptoms of increased intracranial pressure from cerebral edema are the most prominent features and may be present at plasma [Na'] less than 125mEqjl if the development of hyponatremia was rapid in onset. If the reduction in [Na"] occurs slowly, then symptoms may not be evident until plasma [Na'] drops to as low as 110mEqjl. Too rapid correction of plasma [Na"] may result in central pontine myelinosis, a process of demyelination caused by cell shrinkage that may result in irreversible brainstem injury. If the patient is asymptomatic or mildly symptomatic, then the goal should be to raise the [Na'] by approximately 0.5 mEqjh; if the patient is symptomatic with coma or convulsions, then more rapid correction is necessary. The aim is to give sufficient Na" as 30/0 NaCI until either the symptoms have improved or the plasma [Na"] has increased by 5 mEqjl, whichever comes first. The following formula may be used to estimate the amount of Na" required to raise the [Na'] to a safe level (approximately 120mEqjl): Na" deficit = 0.60 x Lean body weight (kg) x (120 - Measured plasma Na']

Hypernatremia Hypernatremia (plasma [Na'], > 150mEqjl) is far less common than is hyponatremia. Cellular shrinkage caused by fluid shifts from the intracellular space to the extracellular compartment may cause confusion, coma, and intracranial hemorrhage. Symptoms are usually not evident below a plasma [Na+] of 160mEqjl. Elevated plasma [Na"] occurs as a result of excessive free water loss and is thus frequently associated with hypovolemia. Excessive insensible losses caused by fever, hyperventilation, and bums or hypotonic fluid losses due to perspiration or severe diarrhea are the principal causes. If hypovolemia is sufficiently severe that tissue perfusion is compromised, then initial therapy should be isotonic saline until tissue perfusion is restored. If perfusion is adequate, then 0.5 NS or DSW is sufficient to return plasma [Na'] to normal. Polyuria associated with excessive renal free water losses represents another frequent cause of hypernatremia. For example, osmotic diuresis induced by hyperglycemia or mannitol may cause profound hypernatremia if left unchecked. An inability to concentrate urine because of high-output renal failure commonly associated with the recovery phase of acute tubular necrosis may also cause severe hypernatremia. In the context of the clinical scenario, the diagnosis is usually straightforward. Treatment simply involves measuring urinary electrolyte losses and providing adequate free water replacement. Central diabetes insipidus is not uncommon following neurosurgical operations or head injury and may cause profound hypernatremia. Administration of exogenous

143

vasopressin in the form of dDAVP (1-desamino-8d-arginine vasopressin) is both diagnostic and therapeutic. Rapid correction of severe hypernatremia may cause irreversible neurological deficits. Plasma [Na"] should not be corrected at a rate faster than 0.5 to 1.0mEqjl per hour. In the presence of convulsions, sufficient free water should be administered either to return the plasma [Na'] to the concentration documented before the convulsion or to reduce the [Na"] by about 6mmoljl. The following formula may help to guide therapy: Water deficit = Total body water x {(Plasma [Na'] -:- Desired plasma [Na'[] - 1}

Disorders of Potassium Homeostasis Potassium is the major intracellular cation. Total intracellular K+ is approximately 40 to 50mmoljkg body weight, with only 2 % of total body potassium located in the extracellular fluid. Despite the small quantity of K+ in the extracellular space, slight alterations in plasma [K+] may have dramatic effects on muscle contraction and nerve conduction as the concentration gradient across the plasma membrane is the main determinant of membrane excitability. For this reason, abnormalities in plasma [K+] should be treated expeditiously.

Hypokalemia Hypokalemia in the surgical patient is usually due to losses from the GI tract, kidneys, or skin (Table 7.5). Rarely, transcellular flux of K+ may cause significant alterations in plasma [K+], and these causes should be considered in the appropriate context. In the case of diarrhea, stool potassium losses represent the principal reason for hypokalemia. By contrast, the mechanism for hypokalemia in vomiting is more complex. The content of K+ in gastric secretion is only about 10mEqjl. As a result, massive vomiting would be necessary to cause hypokalemia. Typically, renal K+ losses account for potassium depletion associated with vomiting. The ECV contraction leads to elevated levels of aldosterone, which results in enhanced renal Na' reabsorption and increased K+ secretion. Massive bums may also cause hypokalemia because of a combination of tissue breakdown and fluid loss. TABLE 7.5. Causes of Hypokalemia. Extrarenal losses Gastrointestinal (vomiting, nasogastric suction) Diarrhea Massive bums Profuse sweating Renal losses Diuretic therapy Vomiting Tubular disorders (e.g., type I renal tubular acidosis) Drugs (cisplatin, amphotericin B) Transcellular flux of K+ into the cell Metabolic alkalosis Insulin administration ~2-Adrenergic stimulation Other Primary hyperaldosteronism Renal artery stenosis Cushing syndrome

144

CHAPTER 7

tion in the absence of intractable arrhythmias should be no greater than 20 to 40mEq/h. At this rate of administration, continuous ECG monitoring is indicated.

5.0

••

i

~ ~ Q)

{/)

Hyperkalemia

4.0

3.0

2.0

o

100

200

300

400

500

600

700

800

K+ Deficit (mEq/70 kg BodyWt) FIGURE 7.3. Effect of potassium depletion on serum potassium. Results are summarized from studies of experimental potassium depletion in normal subjects and in potassium-depleted patients. The relationship between serum potassium and total body potassium appears to be linear when moderate deficits exists. (From Stems et al.," with permission.)

The major danger associated with hypokalemia is cardiac arrhythmias. The potential for arrhythmias is exacerbated in the presence of a metabolic alkalosis, digoxin, or hypercalcemia. Electrocardiographic (ECG) changes associated with hypokalemia correlate poorly with the plasma [K+] but typically are not manifest until the plasma [K+] drops below 3mmol/1. Early changes include T-wave flattening or inversion and depressed ST segments, followed by the development of U waves and a prolonged QT interval. Hypokalemia may also manifest with weakness once plasma [K+] drops below 2.5mmol/l, Potassium replacement therapy should be geared toward rapid correction of plasma [K+], followed by slower repletion of the total body K+ deficit. The potassium deficit may be large. For example, a fall in plasma [K+] from 4 to 3 reflects a total deficit of 100 to 400mmol3 (Fig. 7.3). Too rapid correction may result in inadvertent hyperkalemia because it takes time for the administered K+ to be transferred into cells. When possible, K+ supplementation should be administered orally. However, if the plasma [K+] is less than 3.0 or enteral supplementation is not possible, then parenteral administration is indicated. Potassium can be administered intravenously into peripheral veins in concentrations as high as 40mmol/1. Higher concentrations may cause phlebitis and thus should be administered into a central vein. The rate of administra-

Sudden increases in- plasma [K+] are almost always caused by rapid administration or transcellular flux of K+. By contrast, sustained hyperkalemia implies that there is impairment of renal K+ excretion. It is important to be aware of pseudohyperkalemia, observed when the serum potassium (as measured by the laboratory) is spuriously elevated by potassium release from red blood cells or platelets after the blood specimen has been obtained. The diagnosis of pseudohyperkalemia can be made by demonstrating that the plasma [K+] is normal in a nonhemolyzed plasma sample in which clotting is prevented by drawing the blood into a heparinized tube. Transcellular flux of K+ from the cell into the extracellular fluid may occur in patients with severe metabolic acidosis, insulin deficiency (e.g., diabetes mellitus), or rhabdomyolysis as the intracellular potassium stores are released. Administration of succinylcholine may also cause a transient rise in plasma [K+] because of en masse muscle depolarization, particularly following paralysis or prolonged bed rest, such as is seen in severe bum injury. In the surgical patient, hyperkalemia occurs most frequently as a result of impaired renal excretion of K+ caused by oliguric renal dysfunction. It is for this reason that K+ should not be added to maintenance intravenous fluid therapy within the first 24h of surgery. Rarely, hypoaldosterone states may induce hyperkalemia. The main risks associated with hyperkalemia are similar to those of hypokalemia: weakness and myocardial irritability. Electrocardiographic signs of hyperkalemia proceed from an increase in T-wave amplitude, leading to a narrow, peaked symmetrical T wave, followed by reduced P-wave amplitude and widening of the QRS complexes. If untreated, severe hyperkalemia may eventually cause a sinusoidal ECG complex and ultimately ventricular fibrillation. Signs or symptoms are rare at plasma [K+] below 6.0mmol/l; beyond this, there is poor correlation with the serum potassium level and arrhythmias. The rate of rise of plasma [K+] appears to be extremely important; many patients with chronic renal failure tolerate plasma [K+] levels in excess of 6 or 6.5 without symptoms. Treatment is dependent on the presence or absence of EeG changes and the plasma [K+]. Individuals with mild hyperkalemia «6.0mmol/l) can usually be treated conservatively by reducing daily intake. Active treatment to lower the plasma [K+] or to antagonize its effects on the cell membrane should be started if the [K+] has risen acutely to greater than 6.0mmol/1 or if any ECG manifestations of hyperkalemia are present. These therapeutic modalities should be used in conjunction with other methods to reduce total body potassium stores (Table 7.6).

TABLE 7.6. Treatment of Hyperkalemia. Treatment

Mechanism of action

Time frame

Intravenous calcium gluconate Glucose, insulin, sodium bicarbonate Rectally or orally administered potassium-binding resins Dialysis

Antagonizes effects of hyperkalemia on the cell membrane Translocation of potassium into cells Binds and hastens excretion of K+ secreted into colon

Seconds to minutes 3Q-60min 1-4h (rectal); >6h (oral)

Movement across a concentration gradient and excreted

Immediate


Disorders of Mineral Homeostasis In most surgical patients, abnormalities in the body fluid composition of calcium (Ca), magnesium (Mg), and phosphate (P04 ) are seldom extreme enough to cause concern. However, in the critically ill patient, these alterations may exacerbate potentially life-threatening situations.

Calcium Abnormalities Total body calcium stores are approximately 1000g, with almost 990/0 apportioned in bone. The remainder is located within the extracellular fluid and is either free (400/0) or bound to albumin (500/0) or other anions such as citrate, lactate, and sulfate. Only the free or ionized component is biologically active. Acid-base alterations affect the binding of calcium to albumin and account for the symptoms of hypocalcemia associated with hyperventilation. The resultant respiratory alkalosis increases the binding affinity of calcium for albumin, leading to a reduction in the serum ionized calcium levels. Similarly, changes in serum protein levels affect total serum calcium. The ionized calcium level (normal range 4.5-5.5mgj dl) can be estimated using the following formula: Ionized calcium (mgjdl) = Total serum calcium (mgjdl) - 0.83 x Serum albumin (mgjdl) Normal daily intake of calcium is between 500 and 1500mg per day. The GI tract excretes most of this, with the efficiency of intestinal absorption inversely related to the amount ingested. Routine supplementation or assessment in postoperative patients is usually not indicated. However, in patients with major fluid shifts, prolonged immobilization, alterations in GI absorption, or operative procedures on the thyroid or parathyroid, significant alterations in calcium homeostasis may arise.

Hypocalcemia The most frequent cause of hypocalcemia is low serum albumin. In this case, the ionized fraction remains normal, and no treatment is indicated. Frequent alternate causes to consider include acute pancreatitis, massive soft tissue infection, small-bowel fistulae, and hypoparathyroidism. Massive blood transfusion induces hypocalcemia caused by chelation of calcium with citrate. Each unit of blood contains approximately 3 g of citrate. The normal adult liver metabolizes 3 g of citrate every 5 min, so hypocalcemia may result at blood transfusion rates exceeding 1 unit every 5 min. 7 If the rate of transfusion is less than this, then calcium should only be given if there is biochemical, clinical, or ECG evidence of hypocalcemia. Manifestations of hypocalcemia may become evident at serum levels less than 8 mgjdl. The earliest symptoms include numbness or tingling in the circumoral region or at the tips of the fingers. Tetany or seizure may arise at more profound levels of hypocalcemia. A positive Trousseau's sign or Chvostek's sign may be suggestive of hypocalcemia. Hypocalcemia alters myocardial repolarization and results in a prolonged QT interval on the ECG. ECG monitoring may be useful to guide calcium supplementation in massive transfusion when rapid assays are unavailable.

145

The treatment of hypocalcemia depends on its severity. In symptomatic patients with an ionized calcium level less than 3gjdl, intravenous replacement therapy should be administered: a 10-ml ampule of either 100/0 calcium gluconate (93mg elemental calcium) or calcium chloride (232mg elemental calcium) should be administered in 50 to 100ml D5Wover 10 to 15min. In less-severe cases, oral supplementation may suffice, and any oral preparation providing 1 to 3 g of elemental calcium per day will be adequate.

Hypercalcemia There is an extensive differential diagnosis for hypercalcemia (see chapter 55, "Parathyroid"). Primary hyperparathyroidism and malignant disease account for 900/0 of cases, with the former more common in outpatients and the latter most common among hospitalized patients." Hypercalcemia has protean manifestations, including confusion, lethargy, coma, muscle weakness, anorexia, nausea, vomiting, pancreatitis, and constipation. Renal stones may develop in cases of prolonged hypercalcemia. Hypercalcemia may also induce nephrogenic diabetes insipidus and result in polyuria. Finally, ECG changes include a shortened QT interval. This alteration in cardiac repolarization predisposes the patient to fatal arrhythmias, particularly in the presence of digitalis. A serum calcium concentration in excess of 15mgjdl or in association with ECG changes requires urgent treatment. Most patients will respond to vigorous hydration with NS. Dehydration is not uncommon as the result of polyuria, and thus rehydration both dilutes the serum calcium and improves renal calcium excretion. Once the patient is rehydrated, furosemide may be administered to further increase calcium excretion. Rarely, adjunctive measures, including administration of diphosphonates, calcitonin, or mithramycin, may be necessary. These agents may inhibit osteoclast resorption (diphosphonates, calcitonin) or reduce serum calcium levels by forming calcium-phosphate complexes (diphosphonates) .9

Magnesium Abnormalities Magnesium is the principal intracellular divalent cation. Approximately 50% of total body magnesium is found in bone and is not readily exchangeable. Serum magnesium concentrations typically range between 1.5 and 2.5 mEqjl. Magnesium absorption occurs throughout the small intestine and is reabsorbed effectively in the renal tubules, with renal excretion as low as 1mEqjday. Hypomagnesemia may occur because of poor nutritional intake, malabsorption, or increased renal excretion due to diuretics. Hypomagnesemia is common in patients abusing alcohol. In this population, the effect is caused by both dietary deficiency and the diuretic effect of alcohol. The signs and symptoms of hypomagnesemia are characterized by neuromuscular and central nervous system (CNS) irritability and in this respect are similar to those seen with hypocalcemia. Low serum magnesium levels appear to impair parathyroid hormone excretion and may induce hypocalcemia refractory to calcium supplementation unless the hypomagnesemia is corrected. 10 Hypomagnesemia may be treated with either oral or parenteral magnesium preparations. If the serum magnesium level is less than 1mEqjl or the patient is symptomatic, then

146

CHAPTER 7

parenteral treatment is indicated. In the presence of normal renal function, up to 2 mEq magnesium per kilogram of body weight may be administered daily. This dosage may be administered as magnesium sulfate diluted in intravenous fluid and administered over 3 to 6h. If administered in large doses, then vital signs and cardiac rhythm should be monitored as excessively rapid administration may induce hypotension, respiratory or cardiac arrest, or coma. Ongoing oral or parenteral replacement over several days to weeks may be required to correct the total body magnesium deficit. Hypermagnesemia is extraordinarily rare in the absence of renal failure. Flaccid paralysis, hypotension, confusion, and coma may become evident at serum levels exceeding 6mEqj 1. Electrocardiographic features are similar to those seen in hyperkalemia. Emergency treatment of severe symptomatic hypermagnesemia involves administration of calcium as either calcium gluconate or calcium chloride. Calcium effectively antagonizes the effect of magnesium on neuromuscular function. Definitive treatment requires increasing renal magnesium excretion with a combination of hydration and diuresis. If renal function is impaired, then dialysis will be necessary.

Phosphate Abnormalities Phosphate is the most abundant intracellular anion, and only D.1 % of total body phosphorus is in the extracellular fluid compartment. As a result, circulating plasma levels do not reflect total body stores. Hypophosphatemia may occur as the result of impaired intestinal absorption or increased renal excretion. Hyperparathyroidism may induce a drop in serum phosphate levels through an increase in renal excretion. Significant hypophosphatemia is common following major liver resection, an effect caused by rapid phosphate utilization in the regenerating hepatocytes." In this clinical setting, serum phosphate should be measured frequently and treated appropriately. Careful monitoring of phosphate should also occur with the administration of parenteral nutrition after prolonged starvation because profound hypophosphatemia may result." The potential adverse effects associated with severe hypophosphatemia include impaired tissue oxygen delivery due to decreased 2,3-diphosphoglycerate levels, muscle weakness, and rhabdomyolysis. Severe hypophosphatemia may be treated parenterally using potassium phosphate. Phosphate (D.DS-D.16mmoljkg body weight) may be diluted in intravenous fluid and administered over 4 to 6h. Phosphate levels should be reassessed and additional supplementation provided as required. Hyperphosphatemia is most commonly seen in the setting of impaired renal phosphate excretion and in this scenario is frequently associated with hypocalcemia. Similarly, hypoparathyroidism reduces renal phosphate excretion, leading to an increase in serum phosphate levels. In these cases, treatment should be directed toward the underlying cause.

Acid-Base Abnormalities The concentration of hydrogen ions in body fluids is maintained within an optimal pH range (7.35-7.45) to ensure adequate function of structural and enzymatic proteins. This narrow range is ensured by the availability of several buffer

systems, including intracellular proteins and phosphates and the bicarbonate-carbonic acid system. The former functions primarily as an intracellular buffer and the latter as a buffer in the extracellular fluid. Further, alterations in excretion or retention of CO 2 or HC03- through changes in minute ventilation or renal tubular handling of HC03- provide an additional homeostatic mechanism for maintaining normal pH. By combining information on the various buffering systems, a nomogram can be constructed to describe the normal compensatory responses to acute and chronic acid-base disturbances (Fig. 7.4).

Metabolic Acidosis Metabolic acidosis arises as a result of retention (or administration) of fixed acids or the loss of bicarbonate. In this way, disorders associated with a metabolic acidosis are categorized by the presence or absence of an anion gap (AG), in that addition of fixed acids results in an AG metabolic acidosis, and bicarbonate loss results in a nonAG metabolic acidosis (Table 7.7). The AG refers to the difference between measured cations [Na"] and measured anions (Cl- and HC03- ): AG5Na+ - (CI- + HC03- ) The normal anion gap ranges from 3 to 11mM/I. These unmeasured anions consist of proteins (primarily albumin), sulfates, phosphates, and organic acids. A reduction in the plasma albumin concentration will reduce the baseline AG approximately 2.5mEq for every fall of l g/dl in the serum albumin. Thus, a severely hypoalbuminemic patient may have an AG metabolic acidosis with an apparently II normal" AG if this is not considered. Lactic acidosis represents the most frequent cause of acidosis in hospitalized patients. Most commonly, it arises as a result of impaired tissue oxygenation caused by a reduction in tissue perfusion or hypoxia. Infrequently, it may occur in the presence of severe anemia or carbon monoxide poisoning, both of which impair tissue oxygen delivery, or uncoupling of oxidative phosphorylation as occurs with cyanide poisoning. Finally, hepatic dysfunction may also be associated with the presence of lactic acidosis because of impaired lactate clearance. An AG acidosis is also a feature of renal failure. In uncomplicated renal failure, typically the AG does not exceed 23, and the serum bicarbonate does not drop below 12. If the acidosis extends beyond these parameters, then another cause of acidosis should be considered. The principal early manifestation of metabolic acidosis is an increase in minute ventilation primarily resulting from an increased tidal volume. The increase in minute ventilation serves to compensate for the metabolic acidosis by eliminating more CO 2 • The appropriate ventilatory response should reduce Pace, by 1mmHg (from 4DmmHg) for every 1mmolj 1 drop in HC03- . If the reduction in CO 2 is less than expected, then ventilatory support should be strongly considered because any further aggravation of the acidosis may lead to rapid decompensation. As the pH drops below 7.2, loss of vasomotor tone and a reduction in myocardial contracility may lead to cardiovascular collapse. Treatment of metabolic acidosis is dependent on the underlying etiology. In the case of lactic acidosis, efforts should be directed toward optimizing tissue perfusion through administration of crystalloid solutions or blood products.

147


Acute metab. alkalosis

60 __ 50

+ 7.8 7.7

pHa

7.6

7.5

7.4

-------,-r----.,.....r--~---r--__,.--___,

~[BB+]ECF +30 / +25

/

+20

/

7.3

7.2 pHa

40 7.1 [HCO"3]a 30 (mEq/l)

FIGURE 7.4. Compensatory responses to acute and chronic acid base alterations. [BB 1lECF represents the base deficit. The black diagonal box in the center represents the normal range. As an example, if a metabolic acidosis develops such that a base deficit of 215 mEqjl occurs, then the resulting acidosis would lower the pH to 7.1. However, normal respiratory compensation would reduce the Paco; to 27mmHg and raise the pH to about 7.25. (From Johnson and Ramanathan," with permission. )

Acute resp. alkalosis

100 = 0; 1.0g/l = 0;

iii Co c: 0

U Q>

E

a "'en" a:

1:10000

1:100 000

1:1000000

1:10 000 ooo .l..-.- .,....---.------r- ..---,-----r- ..---,----,-- r ---.-----,-1985 1987 1983 1989 1991 1993

,--..,..---.--

,--..,..--- , 2001

Year

FIGURE 9.5. Risks associated with blood transfusion.

(From Busch et a1. 921

175

TR AN S FU SI ON THERAPY

REFERENCE

ODDS RATIO (95% C.I.)

P-value

9. Surgery 1986; 100-796-801 10. Br J Surg 1988; 75:789 -792 11. Eur J Cancer Clin Onco11988; 24:741-747 12. Surg Gyn Obst 1990; 171:59-62 13. Transfusion 1991; 31:212-217 14. Transfus ion 1992; 32:517-524 15. Transfusion 1992; 32:318-322 16. Eur J Surg 1992 ; 158:419-425 17. Otolaryngol Head Neck Surg 1992 ; 106:60-67 18. Br J S urg 1992; 79:51 3-516 19. J Tra uma 1992; 33:659 -661 20 . Surg ery 1993; 113:603-607 21. Arch Surg 1993; 128:171-177 22. La ncet 1993 ; 342:1328-1333 23 . Lancet 1994 ; 344:573-578 24 . Eur J Surg 1995; 161 :487-492 25. J Orthop Trauma 1997; 11:260-265 26. Transfusion 1997; 37:126-134 27. Am J Surg 1998 ; 176:462-466 28. Vox Sanguinis 2000 ; 78:13-18 Common

•

0.005

11-1 5.03 (1.75- 17.86) 3.39 (1.85-6.33)

0.00 01 0.24* 0.008 0.01 0.011 0.42* 0.15* 0.03 0.011 0.0001 0.0002 0.0001 0.03 0.05 0.002 0.00 1 0.0001 0.0001 0.0001 *n.s .

1.68 (0.72-4.22)

(I

I I ~ I I I I I I (I I I(

I I I I I I I I( I ~

I I I I I I I I I I

1.62 (1.13-2.31) 11--111 15.15 (2.5-333.3)

•

1/----1 6.99 (1.49-38.46) 1.47 (0.59-4.15) 1.85 (0.81- 5.13) 2.46 (1.08-5.71 ) I~

•

7.04 (1.75-47.62) 5.43 (2.90-10.42) 4.55 (2.16-10.87)

•

5.21 (4.46-6.09)

(--+--l

•

2.97 (1.13-8.33) 1.43 (1.00-2 .05)

IH

•

4.78 (1.81-13.70)

t---l

1.93 (1.32-2.86)

•

2.03 (1.44- 2.89)

(

•

•

IH

•

6.25 (3.07-12.82) 4.55 (3.18-6.49) 3.45

----.1.-.....I.--.1.-..J.--.1.--.1.--.1.--L--L--L---L 1 10-l1~ 5

0.0

5.0

1.0

Odds Ratio (95% confiden ce inte rvals ) FIGURE 9.6. Blood transfusion association with perioperative bacterial infection. Odds ratios (-I of postoperative bacterial infection (95 % confidence intervals) occurring after allogeneic blood transfu sion .

Broken vertical lin e represents an odds ratio of 1.0 (no increased risk}, Values of P ::; .05 were considered significant l*n.s., not significant). (From Hill et al .." by permission of [oumal of Trauma .)

Transfusion-Related Acute Lung Injury

the etiologic factors and pathophysiology of TRALI remain poorly understood." Now, TRALI is the leading cause of transfusion-related mortality, even though it is probably still underdiagnosed and underreported." Two different etiologies have been proposed: a single antibody-medicated event, involving anti-HLA class I and class II, or antigranulocyte antibodies; and a two-event model, which includes the clinical condition of the patient resulting in pulmonary endothelial activation and neutrophil sequestration. The second event is the transfusion of a biologic response modifier (lipids or antibodies) in the blood component that activates primed neutrophils. Based on the fact that TRALI is now the leading cause of transfusion-associated mortality, the National Hear t, Lung, and Blood Institute convened a working group to identify

Transfusion-related acute lung injury (TRALI) is a potentially life-threatening complication of allogeneic blood transfusion manifested typically by dyspnea, tachypnea, fever, and hypotension and may result in severe hypoxemia, requirement for mechanical ventilation, and eventual progression to the acute respiratory distress syndrome." It has been estimated to occur in 0.04% to 0.16% of patients transfused, and some studies estimate an incidence as high as 1 in 5000 blood product transfusions. This complication has been identified as the third leading cause of transfusion-related mortality. Despite the increasing recognition that TRALI represents an important clinical syndrome, it remains underreported, and accu rate estimates of its incidence are not available .P Furthermore,

176

CHAPTER 9

TABLE 9.7. Mild and Moderate Blood Transfusion Reactions. Signs

Symptoms

Possible cause

Category 1: mild reactions

Immediate management

1. Slow the transfusion. 2. Administer antihistamine intramuscularly (e.g., 0.1 mg/kg chlorpeniramine or equivalent). 3. If no clinical improvement within 30min or if signs and symptoms worsen, then treat as category 2.

Localized cutaneous reactions Category 2: moderately severe reactions

Pruritus (itching)

Flushing

Anxiety

Urticaria

Pruritus

Rigors

Palpitations

Fever Restlessness Tachycardia

Mild dyspnea Headache

Hypersensitivity (mild) 1. Stop the transfusion. Replace the infusion set and keep intravenous line open with normal saline. 2. Notify the blood bank and the doctor responsible for the patient immediately. 3. Send blood unit with infusion set, freshly collected urine, and new blood samples (one clotted and one anticoagulated) from vein opposite infusion site with appropriate request form to blood bank for laboratory investigations. 4. Administer antihistamine intramuscularly (e.g., 0.1 mg/kg chlorpheniramine or equivalent) and oral or rectal antipyretic (e.g., 10 mg/kg paracetamol, 500 mg to 1 g in adults). Avoid aspirin in thrombocytopenic patients. 5. Give intravenous corticosteroids and bronchodilators if there are anaphylactoid features (e.g., bronchospasm, stridor). 6. Collect urine for the next 24 h for evidence of hemolysis and send to laboratory. 7. If clinical improvement, then restart transfusion slowly with new blood unit and observe carefully. 8. If no clinical improvement within 15min or if signs and symptoms worsen, then treat as category 3. Hypersensitivity (moderate-severe) Febrile nonhemolytic transfusion reactions: antibodies to white blood cells; platelets; proteins, including immunoglobulin A Possible contamination with pyrogens or bacteria

Source: From WHO,91 with the permission of the World Health Organization.

areas of research needed in TRALI.25 The working group identified the immediate need for a common definition and thus developed the clinical definition of TRALI. The major concept is that TRALI is defined as new acute lung injury occurring during or within 6h after a transfusion, with a clear temporal relationship to the transfusion. Also, another important concept is that acute lung injury temporally associated with multiple transfusions can be TRALI because each unit of blood or blood component can carry one or more of

the possible causative agents: antileukocyte antibody, biologically active substances, and other yet-unidentified agents. This group recommended that all future studies utilize the new TRALI definition and proposed that clinicians can diagnose and report TRALI cases to the blood bank. Importantly, researchers can use this TRALI definition to determine accurate incidence, pathophysiology, and strategies to prevent this leading cause of transfusion-associated mortality.

177

TRANSFUSION THERAPY

TABLE 9.8. Category 3: Life-Threatening Reactions. Signs

Symptoms

Possible causes

Rigors Fever Restlessness Hypotension (fall of 200/0 or more in systolic blood pressure) Tachycardia (rise of 200/0 or more in heart rate)

Anxiety Chest pain Pain near infusion site Respiratory distress/shortness of breath Loin/back pain

Acute intravascular hemolysis Bacterial contamination and septic shock Fluid overload Anaphylaxis

Hemoglobinuria (red urine) Unexplained bleeding (DIC) Immediate management 1. Stop the transfusion. Replace the infusion set and keep intravenous line open with normal saline. 2. Infuse normal saline (initially 20-30 mlJkg) to maintain systolic pressure. If hypotensive, then give over 5 min and elevate patient's legs. 3. Maintain airway and give high-flow oxygen by mask. 4. Give adrenaline (as 1: 1000 solution) 0.01 mg/kg body weight by slow intramuscular injection. 5. Give intravenous corticosteroids and bronchodilators if there are anaphylactoid features (e.g., bronchospasm, stridor). 6. Give diuretic (e.g., 1 mg/kg i.v, frusemide or equivalent). 7. Notify the blood bank and the doctor responsible for patient immediately. 8. Send blood unit with infusion set, fresh urine sample, and new blood samples (one clotted and one anticoagulated) from vein opposite infusion site with appropriate request form to blood bank for investigations. 9. Check a fresh urine specimen visually for signs of hemoglobinuria. 10. Start a 24-h urine collection and fluid balance chart and record all intake and output. Maintain fluid balance. 11. Assess for bleeding from puncture sites or wounds. If there is clinical or laboratory evidence of DIC, give platelets (adult: 5-6 units) and either cryoprecipitate (adult: 12 units) or fresh frozen plasma (adult: 3 units). 12. Reassess. If hypotensive: Give further saline 20-30 ml/kg over 5 min. Give inotrope, if available. 13. If urine output falling or laboratory evidence of acute renal failure (rising K+, urea, creatinine): Maintain fluid balance accurately. Give further frusemide. Consider dopamine infusion, if available. Seek expert help: The patient may need renal dialysis. 14. If bacteremia is suspected (rigors, fever, collapse, no evidence of a hemolytic reaction), then start broad-spectrum antibiotics intravenously.

Headache Dyspnea

Transfusion-associated acute lung injury (TRALI)

Note: 1. If an acute transfusion reaction occurs, first check the blood pack labels and the patient's identity. If there is any discrepancy, then stop the transfusion immediately and consult the blood bank. 2. In an unconscious or anesthetized patient, hypotension and uncontrolled bleeding may be the only signs of an incompatible transfusion. 3. In a conscious patient undergoing a severe hemolytic transfusion reaction, signs and symptoms may appear quickly-within minutes of infusing only 5-10ml of blood. Close observation at the start of the infusion of each unit is essential. Source: From WHO/ 1 with permission of the World Health Organization.

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CHAPTER 9

TABLE 9.9. Investigation of Acute Transfusion Reactions. 1. Immediately report all acute transfusion reactions, with the exception of mild hypersensitivity (category 1), to the doctor responsible for the patient and to the blood bank that supplied the blood. If you suspect a severe life-threatening reaction, seek help immediately from the duty anesthetist, emergency team, or whoever is available and skilled to assist. 2. Record the following information on the patient's notes: Type of transfusion reaction. Length of time after the start of transfusion that the reaction occurred. Volume, type, and pack numbers of the blood products transfused. 3. Take the following samples and send them to the blood bank for laboratory investigations: Immediate posttransfusion blood samples (one clotted and one anticoagulated: EDTA/Sequestrene) from the vein opposite the infusion site for Repeat ABO and RhO group. Repeat antibody screen and crossmatch.

Full blood count. Coagulation screen. Direct antiglobulin test. Urea and creatinine. Electrolytes. Blood culture in a special blood culture bottle. Blood unit and infusion set containing red cell and plasma residues from the transfused donor blood. First specimen of the patient's urine following the reaction. 4. Complete a transfusion reaction report form. 5. After the initial investigation of the reaction, send the following to the blood bank for laboratory investigations: Blood samples (one clotted and one anticoagulated: EDTAI Sequestrene) taken from the vein opposite the infusion site 12h and 24 h after the start of the reaction. Patient's 24h urine sample. 6. Record the results of the investigations in the patient's records for future follow-up, if required.

Source: From WHO,91 with permission of the World Health Organization.

Red Blood Cell Transfusion and Outcome in Surgery The impact of perioperative RBC transfusion on outcome in surgical patients has come under increased scrutiny. The effect of perioperative RBC transfusion on 30-day and I-year mortality following coronary artery bypass grafting (CABG) was examined in a retrospective analysis of 3024 consecutive patients (January 1999 to December 2001) in the United Kingdom." Confounding variables were controlled for by constructing a propensity score from core patient characteristics, including the lowest recorded laboratory hemoglobin, for the probability of receiving a transfusion. Of the patients, 940 (31.10/0) patients received RBC transfusion during or within 72h of surgery. Predictors of the need for transfusion were low hemoglobin, lower body mass index, use of cardiopulmonary bypass, female sex, number of grafts, renal dysfunction, increased age, extent of disease, and prior CABG. These factors were all included in the propensity score. After 1 year of follow-up, 122 (4.03%) deaths occurred. After adjusting for the propensity score, reoperation for bleeding, perioperative blood loss, and postoperative complications, the adjusted 30day mortality was 1.9% in transfused patients compared to 1.1% in patients not transfused (P < .05). The adjusted HR for I-year mortality in patients transfused was 1.88 (P < .01). The authors concluded that perioperative RBC transfusion after CABG is associated with an increased risk of mortality during a I-year follow-up period, with a large proportion of deaths occurring within 30 days.

Red Blood Cell Transfusion and Outcome in Critical Care New evidence has emerged documenting the associated risks and lack of efficacy or improvement in clinical outcome with blood transfusion for the treatment of anemia in critically ill patients who are hemodynamically stable. Emerging data have documented that the use of blood transfusions for the

treatment of anemia in hemodynamically stable critically ill patients is not associated with improved outcome. The TRICC (Transfusion Requirements in Critical Care) trial conducted by the Canadian Critical Care Trials group was the only prospective study that randomized patients (n = 838) to a restrictive transfusion strategy (red cells transfused if the hemoglobin concentration dropped below 7g/dl and maintained at 7-9 gjdl) or a liberal strategy (red cells transfused if the hemoglobin concentration fell below 10gjdl and maintained at 10-12gjdl).27 Overall, 30-day mortality was similar in the two groups (18.7% vs. 23.30/0, P = .11). However, mortality rates were significantly lower with the restrictive transfusion strategy among patients who were less acutely ill-those with an Acute Physiology and Chronic Health Evaluation II score below 20 (8.70/0 in the restrictive-strategy group and 16.1 % in the liberal-strategy group, P = .03)-and among patients who were less than 55 years of age (5.7% and 13.00/0, respectively; P = .02). The mortality rate during hospitalization was significantly lower in the restrictive-strategy group (22.2% vs. 28.1%, respectively; P = .05). The authors concluded that a restrictive strategy of red cell transfusion is at least as effective as and possibly superior to a liberal transfusion strategy in critically ill patients, with the possible exception of patients with acute myocardial infarction and unstable angina. Interestingly, in the CRIT study the mean pretransfusion hemoglobin was 8.6 ± 1.7gjdl. This study documented that since the publication in 1999 of the TRICC trial," little has changed in the practice of anemia and blood transfusion in critical care. Critical care practitioners had not yet adopted the restrictive transfusion strategy (transfuse if hemoglobin is 108 ) via recombination and somatic mutation of genes that encode for the constant, variable, and hypervariable regions of each heavy and light chain; each B cell is capable of secreting Ig that binds to a specific antigen. The B-cell-bound IgD is capable of binding antigen directly, which triggers proliferation of a clone of B cells that secretes antibody; some of these cells circulate for long periods of time (memory cells). It has become clear, however, that T-helper lymphocytes and macrophages interact with B cells, acting as accessory cells that facilitate the antibody response. Some antigens are capable of directly stimulating Bcells to produce antibody absent accessory cell interactions, although in general this type of response is less vigorous. The humoral immune response serves to target multiantigenic pathogens for complement-mediated lysis and augmented phagocytosis that occurs via the Fe portion of the Ig molecule. Eventually, antigens are cleared from the body sites or the systemic circulation if they are present in the circulation. Most types of antigens engender production of antibody of the pentameric IgM class initially, but within about 2 to 3 weeks antibody of similar binding specificity but of the IgG class is secreted. Thereafter, if antigen persists or reexposure occurs after initial clearance, IgG of greater binding affinity is produced in ever-larger amounts. Two subclasses of dimeric IgA (IgAl' IgA2) are secreted at mucosal surfaces by submucosal resident B lymphocytes, which act to prevent the ingress of antigens, including pathogenic microbes, while IgE is present in small amounts in the circulation and is secreted into the respiratory tract. Although natural antibodies exist in low levels to many pathogens, initial contact followed by subsequent exposure to a particular pathogen triggers a more intense response because of the presence of memory cells. This phenomenon is the basis for vaccination against specific pathogens or toxins. Complement consists of a large number of inactive proteins that circulate within the bloodstream; these proteins are activated and thereby modified in a specific sequence, several steps of which serve to trigger the production of large amounts of bioactive compounds. Activation of this cascade of proteins

occurs by means of the binding of certain types of Ig to microbial antigens (lgMis extremely efficient) and via direct activation by specific components of the microbial cell wall, such as gram-negative bacterial lipopolysaccharide (endotoxin, LPS) or yeast saccharides such as Candida mannan. Two different complement activation pathways (classical, alternate [Properdin]) lead to a single common pathway in which complement protein fragments play key roles in the host defense response. For example, C3b and C4b enhance Ig adherence, while C3bi and Clq serve as opsonins, leading to enhanced phagocytosis of microbes by leukocytes. The fragments CSa, C3a, and C4a are anaphylatoxins (listed in order of potency) acting to increase vascular permeability and concurrent influx of additional proteins; CSa also is a chemoattractant that causes phagocytic cell chemotaxis. Finally, CSb6-9 form what is termed a membrane attack complex that creates a hole in microbes, leading to osmotic cell disruption and death. Monocytes and polymorphonuclear leukocytes (PMNs) are capable of engulfing microbes via the process of phagocytosis. Once internalized, the portion of the leukocyte membrane that has enveloped the pathogen (phagocytic vacuole) fuses with an intracellular structure termed the lysosome, which contains a variety of enzymes (e.g., lysozyme, cathepsin) and reactive oxygen metabolites (02- , OH) that serve to kill and degrade the invading microorganism. The body contains large numbers of resident macrophages within various tissues that serve as one of the first lines of host defense against microbial invasion. For example, pulmonary alveolar macrophages within the lung, Kupffer cells within the liver, and peritoneal macrophages act in this capacity. Microbial invasion also triggers the recruitment of PMNs to the site of infection via the aforementioned activity of the complement cascade and because of the presence of peptide sequences in which N-formyl methionine is present. The latter compounds are found in microbes and mammalian mitochondria and are potent chemoattractants for PMNs. This characteristic leads to an influx of large numbers of these highly active phagocytic cells within 2 to 4h of invasion, with the magnitude and duration of this response proportional to the size of the inoculum and ability of the microbes to proliferate and remain at the site of infection or spread. Both macrophages and PMNs secrete a number of highly bioactive substances into the internal milieu during cellular activation. Unfortunately, many of these compounds also exert deleterious effects on the host. For example, the contents of lysosomes and reactive oxygen metabolites are extremely toxic to mammalian cells, and release of copious amounts of cytokines secreted by macrophages in response to bacterial cell wall products is thought to be responsible in large part for sepsis syndrome. Cytokines function as regulatory molecules that play an important role during infection as follows: (1) coordination of cellular immunity with other aspects of host defense and (2) regulation of host defense via augmentation and suppression of specific defense components, including their own activity. Bacteria and fungal cell wall compounds trigger macrophages to synthesize and secrete large amounts of what are termed proinflammatory cytokines: tumor necrosis factor-a (TNF-a), interleukin-Iji (IL-l~), interleukin-6 (IL-6), and interferon-y (IFN-y). Presumably because cytokines exert such potent effects within the local tissue environment and systemati-

DIAGNOSIS AND TREATMENT OF INFECTION

cally, counterregulatory compounds are secreted in response to the release of proinflammatory cytokines. This process has been precisely delineated in response to endotoxin challenge in animals and humans as this gram-negative microbial cell wall component represents an extremely potent macrophage activator provoking cytokine secretion. Similar effects occur in response to challenge with intact gram-negative bacteria, as well as gram-positive bacteria and yeast. It should be noted, however, that the sequence of events that occurs during clin ical infection has been difficult to elucidate, probably because the magnitude, temporal onset, and duration of the infectious insult as well as the ensuing host response varies from patient to patient. Subsequent to endotoxin challenge, it is well established that peak serum levels of TNF-a occur within 1.5 to 2h and rapidly decline thereafter in animals and humans." Maximal secretion of IL-1~ occurs slightly later, although it has been more difficult to measure, and elevated levels are observed inconsistently, particularly during clinical infection. The IL-6 levels rise even later (-4h) after endotoxin injection in animals and humans, as do IL-8 levels in humans." Peak TNF-a levels can occur much later (IO-16hl after bacterial challenge in experimental models of infection, in contrast to the early peak evidenced after endotoxin injection.' This difference is most probably related to the fact that host defense initially may be able to contain infection, after which such containment fails and unchecked microbial proliferation occurs. Cytokines, acting in concert with the cellular and humoral branches of the immune system, are an important host defense mechanism against infection, acting to activate oth er cells within the local tissue milieu in the presence of invading microbes. However, widespread activation of tissue macro phages at many sites can lead to the presence of high systemic levels of cytokines such as TNF-a that provoke deleterious effects on the host . This process may represent one of the inciting events that lead to sepsis syndrome, septic shock, and multiple system organ failure (MSOF), although many other mediators may play significant roles in these processes . Effects of TNF-a and IL-1 ~ are mediated by binding to and interacting with their specific cellular receptors; TNF-a has

FIGURE 11.1. Complex regulatory events occur in

relation to the humoral, cellular , and cytokine com ponents of host defense in the surgical wound.

215

two receptors, TNF RI (p55) and TNF RII (p75). The effects of TNF-a appear to be manifested primarily by signal transduction through TNF RI, while TNF RII plays an integral role in T-cell proliferation." There are two IL-1 receptors, IL-1 RI (p80) and IL-1 RII (p68). However, only IL-RI appears to be functional because no cellular signaling has yet been identified for IL-1 RII.9 These cytokine receptors exist in both membrane-associated and soluble forrns, which appear to serve regulatory functions as well. COORDINATION OF HOST DEFENSES

Complex regulatory events occur in relation to the humoral, cellular, and cytokine components of host defense (Fig. 11.1). As noted, repeated antigenic stimulation leads to refinement of the antibody response such that high levels of increasingly high-affinity IgG are produced. Intriguingly, it is not solely Ig clearance of antigen that serves to regulate this response as antiidiotypic Ig directed against the antigen-binding site of the initial Ig is produced in small amounts as well. In addition, it has become clear that the host cellular response to infection is not confined to phagocytic cells. The T lymphocytes have been thought to be an important defense mainly against intracellular pathogens such as M. tuberculosis, but their role in defense against common bacterial infections has been elucidated as well. A paradigm in which a subset of Thelper lymphocytes [Th .] is associated with proinflammatory cytokines including IL-2, IFN-y, and TNF-a has emerged, and this system is regulated by a separate subset of similar cells (Th 2 ) that are associated with antiinflammatory cytokines such as IL-4 and IL-IO. Concurrent with the secretion of IL-1~ and TNF-a during gram-negative bacterial infection and endotoxemia, a complex network of endogenous cytokine antagonists for these cytokines functions to damp the host cytokine response. Interleukin-l receptor antagonist [Il-Lra] is secreted, tumor necrosis factor-binding protein (TNF-BP) is shed from the cell surface (representing TNF RI), and other agents tightly regulate cytokine elaboration under normal circumstances, although during severe infection an exaggerated, dysregulated

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CHAPTER 11

cytokine response can occur.P:" In addition, there is increasing evidence that those cytokine receptors that bind a particular cytokine but do not transduce an intracellular signal serve to damp the initial response as well. Recent data indicate that elevated levels of both a specific cytokine and its cellular receptor may not lead to adverse effects early in sepsis, while exaggerated cytokine secretion concurrent with secretion of the endogenous antagonist for several days may most closely correlate with deleterious consequences." Most likely, this response represents a surrogate marker for uncontrolled infection at the primary site of disease. Finally, certain parts of the body possess unique host defense mechanisms. For example, specialized areas on the peritoneal mesothelial surface of the diaphragm form stomata that lead into lymphatic channels, which in tum coalesce into large channels within the thoracic cavity that eventually drain into the thoracic duct." Via this pathway, large volumes of fluid containing phagocytic cells, erythrocytes, or microbes can be pumped from the peritoneal cavity. However, if a large inoculum of microbes enters the bloodstream via this mechanism, sepsis syndrome can occur.

Antimicrobial Agents Subsequent to the discovery and successful clinical use of penicillin and sulfonamides, a profuse number of antibiotics have been developed. New agents appear each year; many are suitable for use in surgical patients. The precepts of antimicrobial agent usage entail familiarity with the following: (1) microbes commonly encountered during the prevention or treatment of specific types of infections; (2) antibiotic class, mechanism of action, and spectrum of activity of index agents; (3) spectrum of activity of specific agents within a class; (4) prophylactic, empiric (preemptive), or therapeutic use coupled with duration of administration; (5) global, institutional, and unique patient care unit microbial antibiotic resistance patterns; (6) culture and antibiotic sensitivity patterns of organisms cultured from a specific site; and (7) clinical course of the patient. Types of antimicrobial agents are discussed first, then specific types of infection and the manner in which they are diagnosed and treated are described. A representative, but by no means exhaustive, list of antimicrobial agents and their spectrum of activity is provided in Table 11.3.

~-Lactam

Agents

Four subclasses of ~-lactam drugs have been developed; all are bactericidal: penicillins, cephalosporins, monobactams, and carbapenems. These drugs act to inhibit bacterial cell wall synthesis, with the ~-lactam ring competitively inhibiting transpeptidation of the n-alanyl group of N-acteylmuramic acid residues. This step in microbial cell wall peptidoglycan synthesis and cross-linking is critical to microbial cell wall integrity. Numerous agents have been developed within each class, and although general rules regarding their spectrum of activity can be stated, numerous exceptions exist that must be considered carefully when the surgeon selects a particular agent.

Penicillin G is the index drug for this class; it possesses activity against many common gram-positive organisms, such as most streptococci, including anaerobic species, and against less commonly encountered microbes such as Clostridium perfringens and Treponema pallidum. However, today it exhibits activity to only a limited number of strains of S. aureus and enterococci, and resistant isolates of S. pneumoniae now are common. Depot forms of the drug (procaine and benzathine penicillin) remain extremely useful agents, and penicillin V is available as an oral formulation. Ampicillin and amoxicillin exhibit activity against some enterococci and streptococci and a limited number of strains of gramnegative aerobes, such as E. coli. So-called semisynthetic penicillins such as methicillin exhibit substantial grampositive activity, similar to penicillin G for streptococci, plus activity against S. aureus, although the prevalence of methicillin-resistant S. aureus (MRSA) strains has increased substantially. Carboxypenicillins (carbenicillin, ticarcillin) and ureidopenicillins (acylampicillins [piperacillin, azlocillin]) exhibit substantial activity against gram-negative aerobes, including many strains of P. aeruginosa, and the latter agents also are active against some strains of enterococci based on their derivation from ampicillin. Many microbes secrete enzymes that cleave the ~-lactam ring of these agents, and several inhibitors of these virulence factors have been developed (clavulanate, sulbactam, tazobactam). These compounds have been combined with ~-lactam antibiotics, and the combined drugs (ticarcillin-clavulanate, amoxicillin-clavulanate, ampicillin-sulbactam, piperacillintazobactam) possess an extended spectrum of activity that generally includes more strains of gram-positive and gramnegative aerobes than the parent antibiotic alone plus potent anaerobic activity. A large number of cephalosporins have been developed as well, and these agents are grouped into first-, second-, third-, and more recently, fourth- (cefipime) and fifthgeneration (ceptobiprole) drugs. A simple way to remember the spectrum of activity of the agents in each generation is that first-generation drugs exhibit considerable gram-positive aerobic activity, including activity against methicillinsensitive S. aureus (MSSA), but little gram-negative aerobic activity. Gram-positive activity decreases progressively with second- and third-generation agents, whereas the gramnegative activity increases; selected second- and thirdgeneration agents (ceftriaxone, cefoxitin, cefotetan) possess considerable activity against anaerobes. This activity occurs because bacterial enzymes located at the cell wall division plate to which different types of ~-lactam antibiotics bind are distinct among gram-positive and gram-negative bacteria. Finally, most cephalosporin agents do not possess any degree of enterococcal activity, with the exception of recently developed novel agents currently under investigation. A single monobactam agent has been developed (aztreonam), and this drug has activity against only gram-negative aerobes such as E. coli and some strains of P. aeruginosa. Finally, an increasing number of carbapenem agents derived from a parent thienamycin compound are available for use; all exhibit potent activity against many gram-negative aerobes, including P. aeruginosa and most anaerobes, and varying degrees of activity against gram-positive aerobes. Imipenem-cilastatin is a combination drug in which cilastatin prevents degradation of the ~-lactam component by renal

+ + + 6

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-

Anaerobes

++ ++ ++++

+++

+++

++

Pseudomonas aeruginosa

+++

+

++

Escherichia coli

+++

+

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Enterococcus faecium

-

++ +++

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Enterococcus faecalis

-

-

-

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-

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Staphylococcus epidermidis

-

6 6

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+ ++ +++ + +++ ++ ++ ++ 6

+ ++ ++ +

+++++ +++++ +++ ++

Staphylococcus aureus

»v indicates variability within the group, as denoted by the difference in activity among specific agents for certain types of organisms.

a-+++++ indicates maximal activity; - indicates none.

Penicillins Penicillin G Methicillin Ticarcillin Ampicillin Penicillin agent Ib-Iactamase inhibitors Piperacillin Ampicillin-sulbactam Ticarcillin-clavulanate Piperacillin-tazobactam First-generation cephalosporins Second-generation cephalosporins'' Cefoxitin Cefaperazone Third-generation cephalosporins" Cefotaxime Cefotetan Ceftazadime Ceftriaxone Fourth-generation cephalosporins Cefapime Aztreonam Carbapenems Vancomycin Quinupristine-dal£opristine Erythromycin Aminoglycosides Quinolones" Naladixic acid Norfloxacin Ciprofloxacin Moxifloxacin Trimethoprim-sulfamethoxazole Clindamycin Metronidazole

~-Lactam agents

Streptococcus pyrogenes

TABLE 11.3. Activity of Selected Antimocrobial Agents. a

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218

CHAPTER 11

tubular epithelial brush border dihydropeptidases. Meropenem, ertapenem, and doripenem are not degraded in this fashion.

Glycopeptides Vancomycin and teicoplanin are glycopeptides that act to kill bacteria by inhibiting bacterial cell wall synthesis in a fashion distinct from that of ~-lactam drugs. These agents demonstrate potent activity against most strains of grampositive pathogens, including streptococci, many enterococci, MSSA, and MRSA. Bacteria resistant to one agent are generally resistant to the other. Vancomycin exhibits nephrotoxicity, and drug-level and serum creatinine monitoring generally is required. Potential advantages of teicoplanin include reduced nephrotoxicity and less-frequent dosing, although it is not available for use in the United States. Vancomycin-resistant enterococci increasingly are encountered, and strains of S. aureus with intermediate or high levels of resistance to vancomycin have been isolated, albeit infrequently.

Aminoglycosides The aminoglycosides are available only in parenteral formulation and are bactericidal, acting to inhibit microbial ribosomal protein synthesis plus a second poorly defined microbicidal mechanism, both of which lead to bacterial killing. Their spectrum of activity is primarily gram-negative aerobes, including Enterobacteriaceae and pseudomonads, and they exhibit some degree of activity against some strains of gram-positive microbes, such as E. faecalis and E. faecium as well, although they rarely are used alone for treatment of the latter organisms. Their use is associated with nephrotoxicity, and for that reason many clinicians believe that drug levels and serum creatinine values should be monitored to avoid high peaks and troughs of drug levels if more than 3 days of therapy are needed or if the patient exhibits renal dysfunction before initial administration.

Quinolones The quinolones act to inhibit bacterial replication by binding to one of several DNA topoisomerases. Naladixic acid is the index agent, and this drug possesses activity primarily against gram-negative aerobic microbes, such as E. coli. Derivatives of this drug have been developed (e.g., norfloxacin) that demonstrated superior activity to a broader array of these types of bacteria. More recently, a number of fluoroquinolones have become available; all possess greater activity against gram-negative aerobes and some degree of grampositive activity compared to the aforementioned agents in this class. For example, ciprofloxacin demonstrates suitable activity against gram-negative aerobes, including P. aeruginosa, while levofloxacin, ofloxacin, gatifloxacin, and moxifloxacin exhibit activity against select gram-positive bacteria as well.

Sulfonamides Sulfonamide agents act by inhibition of microbial folic acid production, blocking the synthesis of tetrahydropteroid acid.

A number of agents are available, and one of the most useful is sulfamethoxazole. When combined with trimethoprim, which inhibits the enzyme dihydrofolate reductase that catalyzes a later step in the same biosynthetic pathway, these drugs are extremely active against a wide spectrum of pathogens, including gram-negative aerobes such as E. coli, as well as organisms such as N. asteroides, Listeria monocytogenes, Pneumocystis catinii, and L. pneumophila. This agent commonly is used to treat urinary tract infections (UTIs) and to prevent and treat infection caused by these last pathogens in immunosuppressed patients.

Other Antibacterial Agents Erythromycin is a macrolide antibiotic that acts to inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit. It possesses activity against a number of grampositive organisms and some degree of anaerobic activity. Azithromycin and clarithromycin also are macrolides and possess greater anaerobic activity. None of these drugs should be considered "first-line" agents for either staphylococci or streptococci, although they often are administered to patients who are allergic to ~-lactam drugs. Streptogramins are a class of agents that act to prevent bacterial growth by inhibition of ribosomal synthesis. Streptogramins A and B act via two separate mechanisms, both of which are distinct from that of other protein synthesis inhibitors. Quinupristine-dalfopristine combines these two types of streptogramins and is active against many gram-positive pathogens, including streptococci, S. aureus (including many MRSA strains) and S. epidermidis, and E. faecium but not E. faecalis. At present, only an intravenous formulation is available. Linezolid, an oxazolidinone antibiotic, also inhibits ribosomal synthesis by binding to the 23S subunit. It possesses activity against many gram-positive aerobes, including many vancomycin-sensitive and resistant E. [aecium and E. faecalis. Clindamycin, chloramphenicol, and various tetracyclines are structurally unrelated but act to inhibit various steps in bacterial protein synthesis; they possess considerable activity against anaerobes as well as many gram-positive pathogens. Metronidazole is a drug that is available in oral and intravenous formulations; it possesses potent activity against virtually all anaerobic bacteria as well as gut parasites such as Giardia lamblia and Entamoeba histolytica. It is often used to treat the anaerobic component of a polymicrobial infection; it is also effective against Clostridium difficile, and its oral formulation is used to treat colonic infection caused by this pathogen.

Antifungal Agents A more limited number of agents are available to treat fungal pathogens; these consist of amphotericin B azole drugs and echinocandins. Amphotericin B acts to prevent fungal growth and kills fungi by binding to fungal cell wall sterols and causing cell death via lysis. However, this agent causes nephrotoxicity, the occurrence of which is related to the cumulative dose of drug administered. Several different liposomal preparations of this agent have been developed that allow


administration of much higher (three- to fivefold) doses with less associated nephrotoxicity and equivalent or perhaps superior efficacy, albeit at higher cost, compared to the routine preparation. Azole agents inhibit fungal sterol synthesis that is critical to cell wall growth and therefore division. Agents such as ketaconazole are active against many commonly encountered fungi, such as Candida, as well as specific agents such as Blastomyces derma tiditis. Triazole drugs (fluconazole, itraconazole, voriconazole) are active against a wider array of fungi. For example, fluconazole possesses greater activity than ketaconazole against C. albicatis, although C. knisei, C. tropicalis, and C. glabrata are routinely resistant. Itraconazole demonstrates efficacy against some strains of Aspergillus, although it is not as active as amphotericin Band is available only as a parenteral formulation. A single echinocandin (caspofungin) has been developed, and it possesses activity against Candida spp., including azole-resistant strains as well as many Aspergillus spp., it acts by inhibiting fungal cell wall synthesis.

Antiviral Agents Only a limited number of viral agents are available, although the number has increased. Acyclovir, ganciclovir, and their derivatives valacyclovir and valganciclovir exhibit activity primarily directed against herpesviruses. Acyclovir and valacyclovir possess activity against HSV, herpes zoster, EpsteinBarr viruses (EBVs), and, to a lesser extent, CMV. Ganciclovir and foscamet possess activity against CMV, although the latter agent is nephrotoxic, which represents a concern in renal transplant patients or patients with renal dysfunction. Amantadine is effective against influenza virus A (but not B), a pathogen that causes disease rarely even in immunosuppressed patients. Ribavarin is used to treat respiratory syncytial virus, and although it has been used to treat infection caused by adenovirus, its efficacy for this and other pathogens is limited. The hepatitides are diseases caused by a diverse group of pathogens considered together because of their propensity to cause hepatocellular cytotoxicity, eventual cirrhosis and hepatic failure, and hepatocellular carcinoma. The most common pathogens among surgical patients are HBV and HCV, both of which can be transmitted via blood or body fluid exposure. Disease caused by HBV can be prevented by vaccination, and individuals at high risk for exposure (hemodialysis patients and all surgeons and health care workers who participate in invasive procedures) should receive three doses of the recombinant vaccine. IS Disease caused by HBV can range from asymptomatic infection identified solely by serological studies to fulminant hepatic failure. Postexposure prophylaxis of nonimmunized individuals consists of administration of hepatitis B immune globulin (0.06mljkg i.m. immediately and at 1 month), following which standard vaccination should take place. There is some evidence that progression of hepatitis can be ameliorated by use of lamivudine, and patients undergoing liver transplantation whose underlying disease is caused by this virus can receive this agent plus HBIg to attempt to reduce the high incidence of recurrent disease in the allograft. Transmission of HCV occurs in a fashion similar to HBV and also is identified via serological studies as well as RNA-

219

based assays. Interferon-o-, is used to treat chronic hepatitis caused by HCV (3 X 106 U s.c. 3 x a week x 12 months), and a vaccine is under development." Various other hepatitis viruses (D and E) have been identified; most appear to be associated and to require HBV coinfection to cause disease. Five classes of drugs have been developed against HIV, including three types of agents that act to prevent viral growth by inhibiting retroviral reverse transcriptase (nucleoside, nucleotide, and nonnucleoside reverse transciptase inhibitors), as well as protease inhibitors and a fusion inhibitor. Current recommendations for postexposure prophylaxis in health care workers consist of administration of zidovidine plus lamivudine for 1 month or in combination with other retroviral agents for serious or massive exposure, including deep percutaneous injury. I?

Appropriate Use of Antimicrobial Agents Antibiotic usage in surgical patients can be categorized as prophylaxis, empiric (referred to as preemptive by some authors), and treatment. For surgical patients, antibiotics generally are used to prevent infection (prophylaxis) when the risk of wound infection is high, that is, the likelihood of presence of microbes is substantial. In this situation, one or more agents that possess activity against the most likely pathogens should be administered. For example, if only skin microbes are likely to be present and prosthetic material is to be implanted, then a single dose of a parenteral first-generation cephalosporin agent (or vancomycin if MRSA commonly is encountered) should be administered 5 to 10min before creating the incision to allow ample time for the antibiotic to be present in the wound tissue fluid. Similarly, patients undergoing procedures in which substantial numbers of aerobic and anaerobic microbes may be present, such as elective colonic resection, should receive mechanical bowel preparation using a polyethylene glycol-based agent, oral antibiotics such as erythromycin and neomycin, and a single dose of an agent that exhibits activity against skin and colonic microflora. In general, second-generation cephalosporin agents such as cefoxitin, cefotetan, or penicillin drugs with a ~-lactamase inhibitor [e.g., ampicillin-sulbactam) are chosen for this purpose. So-called preemptive therapy entails the use of preoperative prophylaxis, following which postoperative doses are administered as well in a situation in which a large inoculum is likely to be present such as penetrating gastrointestinal tract trauma. Although antibiotics routinely are used to treat infection, it should be noted that for many disease processes the precise duration of therapy has not been established. Basic tenets regarding antibiotic therapy in surgical patients are as follows: (1) define the disease process treated and its severity and set duration of antibiotic therapy from the outset; (2) reevaluate the patient's clinical course on an ongoing basis in relation to the need for antibiotic administration; (3) use antibiotics in conjunction with other treatment modalities such as drainage and debridement; (4) use stains, cultures, and sensitivity studies and other laboratory tests to guide therapy but do not change agents or extend the antibiotic treatment course in a patient who is faring well solely on the basis of this information; (5) review the patient's drug allergy history carefully; (6) choose the least toxic drug appro-

220

CHAPTER 11

priate for the infection; and (7) consider cost and, if equivalent agents are available, select the least expensive. IS

Antibiotic Allergy It is important to ascertain whether a patient has had any type of allergic reaction in association with administration of a particular antibiotic. However, one should take care to ensure that the purported reaction consists of true allergic symptoms and signs such as urticaria, bronchospasm, or other similar manifestations rather than indigestion or nausea. Penicillin allergy is common, occurring in 7 to 40 of 1000 treatment courses. The incidence of cross-reactivity to other ~-lactam drugs is difficult to ascertain because some initial cephalosporin preparations contained penicillin drugs as well. Although avoiding the use of any ~-lactam drug is appropriate in patients who manifest significant allergic reactions to penicillins, the incidence of cross-reactivity appears highest for carbapenems, much lower for cephalosporins (---50/0-70/0), and extremely small for monobactams. Severe allergic manifestations to a specific class of agents, such as anaphylaxis, generally preclude the use of any agents in that class except when use of an agent represents a lifesaving measure. In some centers, patients also can undergo intradermal testing of a dilute solution of a particular antibiotic to determine whether a severe allergic reaction would be elicited after parenteral administration, although this type of testing is rarely employed because it is simpler to select alternative classes of agents.

Endocarditis Prophylaxis Patients with valvular heart disease, prosthetic heart valves, or other cardiac defects should receive prophylactic antibiotics before undergoing dental, upper respiratory, and gastrointestinal or genitourinary procedures to prevent the occurrence of microbial endocarditis. Suggested regimens are listed in Table 11.4. TABLE 11.4. Recommendations for Endocarditis Prophylaxis in Adult Surgical Patients. Procedure

Routine oral

Routine parenteral

p-Lactam allergy

Oropharyngeal/ dental Clean Gastrointestinalj genitourinary" Centamicin'

Amoxicillin"

Ampicillinb

Clindamycin"

Amoxicillin Amoxicillin

Cetazolin" Ampicillin"

Clindamycin Vancomycin"

Gentamicin"

a2g p.o. 1h before procedure. b2g i.m. or i.v, 30 min before procedure. C600 mg 1h before procedure; cephalosporins such as cephalexin or cefradroxil or macrolides such as azithromycin or clarithromycin also are suitable alternatives. "l g i.m, or i.v. 1h before procedure. "Consideration should be given to use of amoxicillin-clavulanate as an oral agent instead of amoxicillin or the addition of clindamycin or use of an agent such as ampicillin-sulbactam in place of gentamicin to provide wound infection prophylaxis in selected patients, particularly those undergoing colonic procedures. 'Lfirng/kg (120mg maximum dose) i.m. or i.v. 30 min before procedure. &1 g i.v. administered slowly 1h before procedure.

Antibiotic Resistance The widespread use of antibiotics for the treatment of infectious diseases has led to significant improvements in morbidity and mortality rates but has concomitantly heralded the appearance of microbes resistant to many different agents. Resistance patterns parallel the duration and extent of usage both of classes of agents and of a particular agent, particularly within an institution. Currently, MRSA continues to plague patients in many hospitals, yet this has been superseded by the appearance of multidrug-resistant gram-negative aerobes belonging to the genera Pseudomonas, Serratia, Aeromonas, Acinetobacter, and Citrobacter. Moreover, both vancomycinresistant Enterococcus faecalis and E. faecium (VRE or VREF) exhibiting either low- or high-level resistance to this drug have become prevalent, with their appearance temporally associated with third-generation cephalosporin and vancomycin use. A small number of strains of vancomycin-resistant S. aureus have been identified, which has caused great consternation for practitioners because there are few, if any, alternative agents that are capable of treating infection caused by such organisms. Resistance of fungal and viral pathogens to fluconazole and to acyclovir and ganciclovir, respectively, has been reported as well. It is imperative that the practitioner become familiar with global, institutional, and patient care unit resistance patterns, which are of particular importance in surgical patients, for whom prophylactic and preemptive therapy frequently is employed, the latter before culture and sensitivity results are available. A number of maneuvers serve to decrease resistance rates, most of which have not been subjected to rigorous examination in the clinical setting. These include (I) precluding patient-to-patient spread by routine procedures such as handwashing by health care personnel after each patient contact; (2) limiting extent of use of antimicrobial agents such that patients receive then under highly constrained circumstances and for a defined course of therapy; (3) using appropriate bactericidal doses and only sufficient duration of therapy because a prolonged course of suboptimal doses of any agent foments resistance; and (4) switching global usage within a unit to a distinct class of antibiotics after a defined period of usage of a particular antibiotic class. It is by no means clear that antibiotic restriction programs do anything more than serve as a surrogate for attempting to employ these principles, and such programs should never be coupled with a mandated consultative process by infectious disease experts.

Surgical Infectious Diseases Surgical infectious disease states encompass both infections occurring in surgical patients and infections that require surgical intervention as part of the treatment regimen. Ancient physicians diagnosed and treated many infections that occurred after traumatic wounding in battle, and it is intriguing to note that many advances in surgery were principally related to human conflict. Early physician-surgeons described a series of symptoms and signs that occur during infection and that remain useful today, and it is intriguing that they speculated about the existence of the microbial world. These signs are calor (warmth), rubor (redness), tumor (swelling),


dolor (pain), and functio laessa (loss of function). The hallmark of infection is the development of purulent material, part of the body's attempt to limit infection to a local site. From a teleological standpoint, this makes sense because local infections generally are less morbid, may resolve, and may not be associated with mortality compared to systemic infection. However, in many surgical patients these external manifestations do not occur, and for that reason the importance of clinical acumen regarding epidemiology and causative pathogens in the diagnosis of surgical infections cannot be overemphasized.

Nosocomial Infections in Surgical Patients Evaluation of postoperative fever in surgical patients represents an important diagnostic undertaking in which the onus is on the surgeon to exclude the presence of a serious infection that may have profound detrimental effects on the patient." Potential sites of such nosocomial infections in surgical patients include UTIs, pneumonia, surgical site (wound) infections (SSIs), and bloodstream infection bacteremia; the last may occur with or without infection identified at a specific site, including that of an intravascular device. Extensive survey data have been collected regarding the epidemiology of nosocomial infections, including (1' site-specific rates, (2) causative pathogens, and (3) associated morbidity and mortality (Table 11.5).20 This information is useful in identifying and monitoring high-risk patients, implementing preventive strategies, and diagnosing and treating those infections that occur. URINARY TRACT INFECTION AND PNEUMONIA

The most common type of nosocomial infection, UTls can occur in surgical patients as the result of underlying genitourinary disease or prolonged indwelling catheter drainage." For that reason, every attempt should be made to remove this type of device after the initial operation. In general, this can be accomplished within 1 to 3 days even for major procedures. However, many patients in surgical intensive care units (SICUs) require prolonged urinary and tracheal intubation. Although urinary catheters do become colonized and elicit diapedesis of PMNs into the urine, significant infection can TABLE 11.5. Epidemiology of Nosocomial Infections in Patients in Surgical Intensive Care Units. Nosocomial infection

Urinary tract Surgical site Pneumonia Central line-associated bacteremia Other

Rate

5.3b 0.14-5.28 14.5d

Distribution a (%) C

4.g e

20.7 13.2 31.4 15.1

19.6

"Percentage that each type of infection contributes to 100% of infections among surgical patients. "Number of urinary catheter days/number of patient days.

'Number of infections per 100 cases. "Number of ventilator days/number of patient days. "Number of central line days/number of patient days. Source: From National Nosocomial Infections Surveillance (NNISl System report."

221

be diagnosed based on the presence of more than 100,000 CFU/ ml. Initial therapy should be directed against common gramnegative aerobic organisms such as E. coli, although UTIs caused by gram-positive bacteria such as E. faecalis and E. faecium are common as well. Meticulous aseptic technique during catheter insertion and tubing changes and daily meatal care diminish the risk of such infections. If a UTI occurs during the postoperative period, then it should be treated for 10 to 14 days with an antibiotic demonstrated to have efficacy based on sensitivity testing, and a urine sample should be obtained for culture 3 to 5 days after completion of therapy. Identification of recurrent infection mandates a search for an underlying anatomical abnormality. The occurrence of postoperative pneumonia in a surgical patient is a grave, potentially highly morbid event. In some patients, the diagnosis is readily established based on the presence of a discrete area of pulmonary consolidation on chest roentgenogram and a single organism identified on Gram stain and culture from a sample of sputum. In most hospitals, initial empiric therapy should be directed against gram-negative aerobic pathogens, although gram-positive microbes such as S. aureus also cause such infections. In some SICUs, highly antibiotic-resistant gram-negative bacteria such as P. aeruginosa, Acinetobacter calcoaceticus, and Citrobacter freundii are common, and in those settings initial single- or dual-drug therapy should be instituted on the basis of the institutional and unit sensitivity patterns for these microbes. Patients who undergo prolonged tracheal intubation who develop fever and infiltrates on chest roentgenogram should undergo diagnostic bronchoscopy if routine sputum sampling does not reveal the presence of more than 25 PMNs per low-power field (100x) via microscopic examination and a single causative organism using the former technique or routine culture. Use of the so-called covered-brush technique to obtain satisfactory specimens has not been unequivocably demonstrated as beneficial in establishing the diagnosis. Postoperative pneumonia should be treated with a 14- to 21-day course of an appropriate parenteral antibiotic; it is associated with a mortality rate of more than 500/0 among patients requiring mechanical ventilation.F:" SURGICAL SITE INFECTIONS

The SSls are categorized according to whether they involve the superficial wound that constitutes the skin and subcutaneous tissue above the fascia, the deep wound that is the body cavity in which the procedure is performed, or both regions concurrently. Rigorous definitions of wound infection have been established (Table 11.6), and wound infection surveillance is mandated in the United States at all major inpatient facilities. Because of the importance of administering prophylactic antibiotics in reducing wound infection rates for certain types of procedures, surgical wounds are classified into three strata according to the potential risk of microbial contamination. Class I or clean wounds are those in which only skin microflora are likely to contaminate the operative field; because no hollow viscus that possesses endogenous microflora is entered, the risk of infection is low (---I %-4 0/0). A subset of class I wounds (ID) are those in which prosthetic material such as mesh, a vascular graft, a cardiac valve, or a medical device is implanted; although the risk of infection is similar to other

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CHAPTER 11

TABLE 11.6. Criteria for Diagnosis of Superficial and Deep (Organ Space) Surgical Site Infections Within 30 Days of All Procedures (1 Year If Prosthetic Material Is Implanted). Purulent drainage from superficial wound is seen Surgeon declares the presence of a wound infection (cellulitis, fever, and suspected infection) and opens superficial wound Superficial or deep wound exudes fluid that demonstrates bacteria on Gram stain or culture from specimens obtained under aseptic conditions Presence of an abscess in the deep wound Deep wound (organ space) reexplored because of dehiscence in the presence of infection

class I wounds, the consequences of wound infection can be dire, often defeating the purpose of the procedure. Class II clean contaminated wounds are those in which a hollow viscus likely to harbor microbes is entered (gut, biliary tract), such that both skin microflora plus resident microbes may be present in the wound, producing a slightly higher risk of infection (....3%-6%). Class III wounds are those in which substantial microbial contamination (e.g., fecal soilage; traumatic heavily contaminated wound) maybe present, and the overall wound infection risk is substantial (.... 40/0-200/0), particularly if the skin edges of the superficial wound are apposed. Note that some degree of overlapping risk occurs among the various wound classes. For this reason, survey data using a separate wound infection risk index have been accumulated using additional variables, including patient American Society of Anesthesiology score and duration of procedure. Examples of operative procedures and ranges of wound infection rates are provided in Table 11.7. Wound classification systems are used by the surgeon to decide whether to administer prophylactic antibiotics, whether to select agents with activity against pathogens that are likely to contaminate the wound and cause infection, and whether to close the skin edges of the wound per primurn.

A series of maneuvers appear, in composite, to reduce the rate of infection of either the superficial or deep portions of the wound or both sites. These include (1) preoperative patient skin preparation in the form of scrubbing the prospective wound area and showering using a topical microbicide; (2) clipping of hair, but avoidance of shaving the skin of the prospective wound site, particularly in advance of the procedure because microbial proliferation can occur in areas of epidermal damage; (3) surgeon hand scrubbing and patient skin preparation using a topical microbicide immediately before the procedure; (4) instrument sterilization and avoidance of breaks in aseptic technique; (5) use of mechanical preparation, intraluminal antibiotics, or antiseptics for selected procedures to reduce the microbial inoculum within a hollow viscus that will be entered as part of the procedure; and (6) administration of prophylactic antibiotics that possess activity against numerically common, albeit not all, potential pathogens that may contaminate the wound during the operation. It should be noted that not all these modalities have been examined in rigorous fashion as independent variables in randomized, prospective clinical trials, although they represent the standard of care for most patients. The effect of prophylactic antibiotics, however, has been carefully examined experimentally and in the clinical setting. Although they are in routine use today, less than three decades ago the importance of prophylactic antibiotics in reducing the incidence of wound infections had not been determined. Using an experimental animal model, Burke demonstrated that there was a "golden period" 2 to 4h after inoculation of microbes into a wound during which prophylactic antibiotics were effective." Subsequent clinical trials demonstrated the efficacy of antibiotics in reducing wound infection rates that in some institutions were as high as 500/0 to 70%.25,26 In current clinical practice, prophylactic usage of antibiotics consists of administration of an agent with activity against pathogens that could be present in substantial numbers and in which the statistical likelihood of these microbes causing infection is low but measurable. For practi-

TABLE 11.7. Surgical Site Infection Risk Stratification and Rates of Infection. Rate (%)

Class

Definition

Examples

I: Clean

Atraumatic wound' No inflammation No break in aseptic technique No entry of biliary, respiratory, GI, or GU tracts Same as I, clean

Hemiorraphy Excision of skin lesion Thyroidectomy

1-4

Vascular surgery with graft material implanted

1-4

Appendectomy without perforation

3-6

ID: Clean; prosthetic II: Clean contaminated

III: Contaminated

Cardiac valve replacement Atraumatic wound No inflammation Minor break in aseptic technique Biliary, respiratory, GI, or GU tracts entered with either minimal spillage or prior preparation Traumatic wound with delay in therapy or exogenous contamination Inflammation or purulence Major break in aseptic technique Entry of biliary, respiratory, GI, or GU tract with gross spillage of contents

GI, gastrointestinal; GU, genitourinary.

Elective colectomy after bowel preparation Cholecystectomy Colectomy for colonic perforation Open drainage of intraabdominal abscess

4-20

223


cal purposes, this amounts to a risk of infection of more than 2 % to 4 0/0. Thus, standard practice entails administration of a prophylactic antibiotic 5 to 10min before creating the skin incision for class ID, II, and selected class IIIprocedures (Table 11.8).27-30 In addition, the agent should be readministered during those procedures in which the duration of the operation exceeds the serum iin of the agent to ensure that microbial levels are continually present. For many commonly administered prophylactic antibiotics, this occurs between 4 and 5h. 31 In general, the risk-benefit analysis demonstrates that administering antibiotics to 100 patients to prevent as few as 2 to 4 wound infections is reasonable, and that few adverse events occur. Because the risk of infection for many, if not most, types of clean surgery falls below this value, whether systemic antibiotics should be administered to patients undergoing clean surgery continues to be debated. Several clinical trials have attempted to resolve this issue, but none has provided definitive evidence of the value of prophylactic antibiotics in reducing wound infection rates. 32,33 The subset of patients undergoing clean surgery in whom a prosthetic device is implanted into a tissue space (e.g., pacemaker, vascular graft) should receive an agent directed against skin microflora because in most cases wound infection is associated with considerable morbidity and occasional mortality. Frequently, the device must be removed to cure the infection, obviating the purpose of the initial procedure. The effect of prophylactic antibiotics has been most carefully examined in patients undergoing elective colonic resection. Initial studies provided evidence of the efficacy of mechanical preparation of the bowel using cathartics and enemas plus oral antibiotics administered on three occasions before the operation. Poorly absorbed agents directed against gram-negative aerobes (neomycin) and absorbable agents with activity against anaerobes (erythromycin, tetracycline, metronidazole) were examined, and clear benefits in reducing both superficial and deep wound infection rates were observed." Statistical analysis demonstrated that entry of about 1500 patients is required to determine the added benefits of a single dose of a parenteral agent over and above that of mechanical preparation of the large bowel and administra-

tion of neomycin and erythromycin in reducing the rate of superficial and deep wound infection." Current standard of care based on survey results conducted during the past decade is the use of mechanical bowel preparation, two separate oral agents, plus a single dose of a parenteral agent with a spectrum of activity against aerobes and anaerobes." Primary closure of class III wounds remains controversial because of the high rate of infection. However, the controversy revolves around the attendant morbidity and cost associated with the occurrence of wound infection. Few studies have demonstrated the efficacy of use of topical antimicrobial powder, wicks, or open or closed wound irrigation systems to achieve primary closure without infection. Rarely, closure of a contaminated wound is associated with the occurrence of necrotizing fasciitis, sepsis syndrome, or death. Many clinicians employ delayed primary closure techniques in this setting, although this approach does not entirely obviate the occurrence of wound infection. Superficial surgical wound infection must be treated by opening the wound, draining purulent material, debriding devitalized tissue, and instituting dressing changes that include packing the wound with gauze. Obtaining cultures and using an antimicrobial agent should be reserved for patients who exhibit extensive cellulitis (>2cm from incision margin) and immunosuppressed patients in whom unusual pathogens may be causative, although the added benefit of antibiotics has not been rigorously studied. Cultures may serve to direct therapy for the rare serious soft tissue infection that ensues and may provide important epidemiological and microbiological data, but routinely obtaining cultures is hard to justify in relation to cost-containment measures. Deep wound infections require percutaneous drainage if no ongoing source of infection, such as a leaking anastomosis, is present, although in some patients reexploration is required. Finally, although wound infection surveillance is required in the United States for a minimum of 30 days in all patients undergoing major operative procedures (1 year for any ID procedures), it has not been established that this process itself serves to alter wound infection rates. However, it seems clear that surveillance retrospectively serves to carefully monitor adherence to standards of clinical practice and to direct atten-

TABLE 11.8. Indications for Use of Prophylactic Antibiotics in Surgical Patients. Procedure

Class I and ID Cardiac Vascular Orthopedic Class II Upper gastrointestinal Biliary Lower gastrointestinal Thoracic Genitourinary Gynecological Head and neck Class ITI Perforated viscus Traumatic wound

Standard

Alternatives

{j-Lactam allergy

Cefazolin Cefazolin Cefazolin

Cefuroxime Cefuroxime Cefuroxime

Vancomycin Vancomycin Vancomycin

Cefazolin Cefazolin Oral neomycin + erythromycin plus intravenous cefoxitin Cefazolin Ciprofloxacin Cefoxitin Gentamicin + clindamycin Cefoxitin Cefazolin

Same oral plus intravenous cefotetan or ampicillin-sulbactam or cefazolin + metronidazole Cefuroxime

Vancomycin Vancomycin Clindamycin + gentamicin Vancomycin

Cefotetan

Gentamicin + clindamycin

Cefotetan or ampicillin-sulbactam or cefazolin + metronidazole

Gentamicin + clindamycin

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CHAPTER 11

tion to any deviations that could be subsequently avoided. In addition, variance in intensity of surveillance among institutions may confound direct comparisons of outcome measures. BLOODSTREAM INFECTIONS AND SEPSIS SYNDROME

Bloodstream infections occur frequently in the nosocomial environment; currently, the incidence of nosocomial bloodstream infection is about 250,000 to 300,000 per annum in the United States.F:" Gram-positive microbes account for about 50% to 60% of events and gram-negative bacteria about 300/0; fungemia, mainly caused by Candida spp., accounts for the remainder. Sepsis syndrome occurs in a subset of patients who manifest the systemic inflammatory response syndrome (SIRS) on the basis of infection. Currently, SIRS describes patients with two or more of the following: temperature above 38°C, heart rate greater than 90 beats/min, respiratory rate above 20 breaths/min, white blood cell count above 12,000 cells/mrrr', and the presence of more than 10% immature band forms of neutrophils on the peripheral blood smear." It is highly likely, however, that most episodes of bacteremia and fungemia are both intermittent and transient, precluding isolation of the offending pathogens during every clinical event. The term severe sepsis syndrome refers to the added presence of organ dysfunction. Septic shock is defined as the sepsis syndrome in association with hypotension that persists despite adequate fluid resuscitation. Clinical studies indicated that about 45% of patients who develop SIRS harbor infection such that they are classified as having sepsis syndrome." Bacteremic episodes are causally most closely linked to sepsis syndrome, although the latter process can occur without identification of bloodstream infection. Clinical trials have provided evidence that fewer than 50% of patients who develop sepsis syndrome have a microbial pathogen cultured from their bloodstream. Sepsis syndrome can progress to MSOF and is the 13th most common cause of death among patients in the United States, with as many as 400,000 cases occurring annually, and surgical patients account for about 30% of these cases. 40,41 Despite improvements in antimicrobial therapy and intensive care (e.g., aggressive fluid resuscitation, hemodynamic monitoring, and metabolic support), mortality associated with sepsis syndrome remains at about 40%, a statistic that has changed but little over the past several decades. Even more distressing, bacteremia and sepsis syndrome caused by antibiotic-resistant gram-positive or gram-negative microbes are associated with higher mortality rates. Staphylococcus epidermidis has become a major causative pathogen of bacteremic episodes and intravascular catheter infections; it is now the most common gram-positive organism isolated from blood (-30% of isolates) and accounts for the majority of infections that are associated with an intravascular catheter. Formerly thought to possess minimal virulence, this organism increasingly has become recognized as a significant pathogen. Staphylococcus aureus and Enterococcus spp. also have become prevalent as etiological agents. Of particular concern is the increasing identification of bacterial strains that are resistant to multiple antimicrobial agents (MRSA, VRE) as pathogens causing bacteremic episodes. Because staphylococci are responsible for the majority of gram-positive bacteremic events, initial antibiotic therapy

should target these organisms. Because of the appearance and rapid spread of VRE that has been associated with widespread vancomycin use, consideration should be given to the use of semisynthetic penicillins such as nafcillin or methicillin or a first-generation cephalosporin as initial empiric therapy. For the patient allergic to ~-lactams or a patient who has developed a life-threatening infection, a short course (at most 3 days) .of vancomycin should be administered, after which empiric therapy with this drug should be halted if no grampositive organism is isolated either from blood or from a specific site of infection. In critically ill surgical patients such as those with extensive bums or traumatic injuries, antimicrobial coverage should also be directed against E. faecalis and E. faecium (ampicillin or an acylampicillin aminoglycoside, or vancomycin alone for patients allergic to ~-lactam drugs or those who develop infection associated with sepsis syndrome or aggressive local infection with bacteremia). Empiric therapy subsequently can be tailored based on culture and sensitivity data. The VRE isolates that cause infection require use of agents such as quinupristine-dal£opristine, tetracycline, rifampin, chloramphenicol, or other drugs alone or in combination according to the sensitivity pattern of the particular organism. In VRE isolates that demonstrate low-level vancomycin resistance, teicoplanin can be considered an alternative agent. Bacteremia caused by gram-negative bacterial infections remains common, accounting for about 30% to 35 % of cases. The mortality associated with gram-negative bacteremia in normal individuals is 10% and may exceed 50% in immunocompromised patients. A wide variety of gram-negative bacteria are capable of causing infection in the clinical setting. Commonly isolated microbes include E. coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Enterobacter aerogenes and Enterobacter cloacae. Although infections caused by Pseudomonas and Klebsiella species appear to be more virulent, these infections occur more commonly in patients with serious underlying diseases (e.g., extensive trauma, bums, or malignancy), such that it has not been possible to ascertain the relative contributions of bacterial virulence and the underlying disease process to overall outcome. Antibiotic therapy should be initiated if evidence of sepsis syndrome and a potential source of gram-negative bacterial infection are identified; therapy should not be delayed for culture documentation of bacteremia. The initial choice of antimicrobial agent should be based on the institutional or care unit antibiotic resistance patterns. Aminoglycosides remain potent agents but have fallen into disfavor because of their associated nephro- and ototoxicity and the perceived need for drug-level monitoring. In general, many ~-lactam drugs such as third-generation cephalosporins, acylampicillins, monobactams, and carbapenems exhibit satisfactory activity against gram-negative bacteria. Quinolones and trimethoprim-sulfamethoxazole may be useful for specific organisms. After a specific organism has been identified and antibiotic sensitivity testing performed, refinements in antimicrobial agent therapy can be made. Clinical trials in which febrile neutropenic patients were treated with either single agents or two agents in combination, usually a ~-lactam drug plus an aminoglycoside, have provided evidence that the dual-agent therapy is more effective than single-agent therapy in this particular heavily immunosuppressed patient population. Currently, a single


broad-spectrum ~-lactam agent is used with or without vancomycin.P:" Although use of dual-agent therapy frequently is extended to other patient groups, no clinical trials have been performed to provide evidence of similar efficacy in the general patient population. Thus, the added benefit of two agents has not been demonstrated in patients who are not neutropenic, and single-agent therapy targeting the infecting organism should be utilized in most circumstances. When a microbe is identified that is typically highly resistant to many agents (e.g., Pseudomonas or Xanthomonas species), dualagent therapy should be considered." Prolonged treatment of high-risk patient populations such as immunosuppressed diabetics with broad-spectrum antibacterial agents coupled with the widespread use of intravascular devices represent some of the factors that have led to an increase in the incidence of fungemia. Candida species are the most common isolates, and C. albicans accounts for more than half the fungi cultured from clinical infections. Isolation of Candida from the bloodstream should prompt immediate initiation of antifungal treatment and a search for the source of infection. In nonneutropenic patients, either intravenous fluconazole or amphotericin B can be used initially unless the isolate is known to be resistant to triazole drugs." Fluconazole is efficacious against many strains of Candida, particularly the commonly encountered C. albicans, although some isolates of C. krusei, C. tropicalis, C. glabrata, and Candida guilliermondii are resistant and may emerge during fluconazole prophylaxis in immunosuppressed patients." If the infection is unresponsive to such therapy based on clinical parameters or if an organism resistant to fluconazole is identified, then amphotericin B therapy should be instituted. Fungemic patients who exhibit hemodynamic instability or neutropenia should receive amphotericin B as the initial therapeutic agent. Therapy for bacteremia or fungemia should be continued for 10 to 21 days, although the precise duration of therapy is unknown and has not been examined in clinical trials. Endotoxin and a number of different endogenous mediators (TNF-a, IL-1, platelet-activating factor [PAF]) have been implicated in the development of sepsis syndrome, and for that reason clinical trials have been performed in an attempt to diminish lethality from this disease process. Two different antiendotoxin monoclonal antibodies were developed (£5, HA-IA), and their efficacy was examined in several randomized, placebo-controlled trials. Unfortunately, the target patient population with sepsis syndrome caused by gramnegative microbes represented only about one-third of the patients, and in composite these trials did not demonstrate a decrease in mortality in either the overall group of patients or the subgroup of patients with presumed endotoxemia.V" Clinical trials in which large numbers of patients who had developed sepsis syndrome received either one of a number of anti-TNF-a agents (TNF-BP, TNFR:Fc, anti-TNF-a monoclonal antibodies), IL-Ira, anti-IFN-y, or a PAF receptor antagonist (PAFra BN 52021) were subsequently conducted.v" However, data obtained from these trials did not provide evidence of efficacy in any of these agents in decreasing mortality during sepsis syndrome. Currently, clinical trials using more potent antiendotoxin agents such as bactericidal permeability-increasing protein (BPI) and cytokines that appear to exert antiinflammatory effects on the host defense response (e.g., IL-10) are under way or in consideration.

225

INTRAVASCULAR CATHETER INFECTIONS

Within the nosocomial environment, many bacteremic episodes are associated with intravascular catheters and other devices. These devices serve a variety of functions: drug administration, parenteral nutrition, hemodynamic monitoring, hemodialysis, or plasmapheresis. Many patients undergo intravascular catheter placement at some time during their hospitalization, and epidemiological data indicate that among about 3 million central venous catheters inserted per annum in the United States, approximately 25 % will become colonized, and about 50/0 (150,000) will become colonized and be associated with bacteremia. Similar events are 10-fold less common when peripheral catheters are considered, probably because of their short duration of use." Prevention of catheter infections requires adherence to strict aseptic technique and subsequent meticulous insertion site care. The risk of catheter infection is increased if inserted through infected or contaminated skin (e.g., bums), so these areas should be avoided if at all possible. Femoral vein catheters are more likely to become infected than subclavian or internal jugular vein catheters, probably related to both degree of skin contamination and catheter movement in and out of the exit site. Multilumen catheters may also have a higher rate of infection than single-lumen catheters, but this may not be clinically significant because multilumen catheters are typically used for short periods of time. Although tunneled or cuffed catheters initially were thought to decrease infection, several prospective studies have shown that these devices offer no advantage over noncuffed catheters. 57 In composite, the risk of infection increases significantly with the length of time a catheter is in place, although this is most probably a surrogate marker for catheter use and manipulation. The use of routine catheter changes either via guidewire exchange or insertion at a separate site has been rigorously examined. The former increased infection rates; the latter increased the incidence of mechanical complications. 58 Administration of prophylactic antibiotics before catheter insertion or during the period of time that the catheter is in place in the patient is not indicated as only data from small-scale clinical trials among patients with hematological malignancies have provided evidence supporting their use, and this form of prophylaxis is expensive and assuredly promotes antibiotic resistance. 59 Clinical trials have examined the capacity of intravascular catheters in which antibiotic is bonded to the prosthetic material to reduce the incidence of colonization and infection. Two types of catheters have been studied: (1) chlorhexidine-silver sulfadiazine bonded on the extraluminal surface and (2) minocycline-rifampin bonded on both the intra- and extraluminal surfaces. 60- 62 On balance, it would appear that colonization and infection rates indeed are reduced, but it remains to be determined whether the cost of these devices is justified. In particular, it may be that many catheter infections can be prevented by applying sound surgical judgment such that no catheter is inserted or, if one is inserted, it is left in place for only a short period of time. Identification of infection of intravascular catheters can prove vexing; this process can involve solely the exit site, the intravascular portion of the catheter itself, or both regions. If the intravascular portion of the catheter is involved, then

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bacteremia can occur. Several key principles should be considered when attempting to diagnose intravascular catheter infections: (1) infections extending along the track of a tunneled catheter or subcutaneous port pocket are potentially serious and do not invariably manifest either locally or systemically, and (2) catheter infection should be suspected in any patient with an intravascular catheter who exhibits bacteremia and no other obvious source of infection. Superficial, limited intravascular catheter-related infections are diagnosed by the presence of redness, swelling, pain, and occasionally purulent exudate in proximity to the peripheral or central venous catheter exit or subcutaneous port site. Infection of a peripheral intravenous line site in general can be cured by removal of the catheter, and culture of the catheter tip or insertion site is unnecessary. Antibiotics directed against gram-positive microbes should be used to treat accompanying cellulitis or ascending lymphangitis, and the appearance of a doughy vein proximal to a peripheral catheter site is cause for concern because suppurative thrombophlebitis may be present. Under these circumstances, the catheter should be removed and the site examined; if more than 1 ml of purulent material is encountered, then the patient should be taken to the operating room and this area explored. The presence of purulent material and infected clot extending proximally in the vein mandates removal of the infected vein and treatment with a 14- to 21-day course of a parenteral antibiotic selected on the basis of initial Gram stain and subsequent culture and sensitivity data. Purulent material at the catheter exit site should be cultured, and ultrasonography can be used to identify and percutaneously sample fluid within a subcutaneous port pocket. Demonstrably infected wounds should be locally explored and drained, and in most cases catheter removal is required. In the absence of obvious infection, however, blood cultures should be obtained peripherally and through the catheter, but the diagnosis is established unequivocally only by removing the device, demonstrating large numbers of microbes on the device itself, and observing resolution of the patient's signs and symptoms. Increasingly, however, potentially infected catheters are allowed to remain in situ; identification, via blood culture obtained through the catheter itself and from peripheral blood samples, of the same microbe with the identical antibiotic sensitivity pattern at the exit site establishes the diagnosis. Rarely, however, can the same organism be isolated from all three sites. More commonly, the same organism is isolated from peripheral blood cultures and from blood withdrawn via the catheter or from the catheter tip after guidewire exchange, either of which supports but does not establish the diagnosis. Therefore, additional microbiological techniques have been employed. In the most commonly used semiquantitative method, the distal 2 em of the catheter is rolled across an agar plate and growth of more than 15 colonies per plate is considered diagnostic of catheter infection. However, a number of studies have shown that as few as 5 colonies may be associated with bacteremia." Because the most serious event with catheter infection is bacteremia, a positive blood culture is probably of the most practical importance. Blood cultures drawn through the catheter growing 5- to 10-fold more colonies than peripheral cultures obtained simultaneously verify the catheter as the source of bacteremia. In general, patients with signs of infection and a positive blood culture drawn through

the catheter or a positive catheter tip culture (>15 colonies per plate) should be treated for catheter infection. Patients should undergo catheter removal if catheter infection is suspected and the device can be readily removed without altering the patient's treatment course. However, if the catheter is required for ongoing treatment, then the potentially infected line can be removed, the tip cultured, and a new catheter inserted over a guidewire. If the catheter tip culture shows that the original catheter was infected, then a new catheter can be placed at a fresh site. Neither the need for delaying catheter reinsertion to prevent catheter seeding nor the need for antimicrobial therapy or specific duration of therapy to treat vascular catheter infections, particularly after catheter removal or exchange, has been determined in clinical trials. Antibiotic therapy should be adjusted on the basis of culture data, including halting therapy among patients in whom neither bacteremia nor catheter colonization is identified, particularly in those individuals in whom systemic manifestations resolve rapidly. Approximately 800/0 of catheter infections are caused by increasingly common gram-positive microbes, and about 750/0 to 85% can be successfully treated with a 14- to 21-day course of a parenteral antibiotic without catheter removal.r':" A small number of trials also have provided data indicating that instilling an antibiotic such as teicoplanin and allowing it to dwell for 12h before removal may eradicate some catheter infections." Because of the high incidence of S. epidermidis that is resistant to most ~-lactam drugs as well as MRSA, vancomycin usually is selected for initial therapy among patients who exhibit systemic manifestations such as fever or an elevated serum white blood cell count. Initial empiric antibiotic therapy should not be extended more than 3 to 5 days without confirming the presence of a gram-positive microbe in blood or catheter exchange cultures. If a grampositive microbe sensitive to ~-lactam agents is isolated, then therapy can be refined to obviate the use of vancomycin. In addition, serious enterococcal infections often are treated by combining ampicillin with an aminoglycoside because this combination appears to be synergistic. Antibiotic therapy should not be continued if the patient's clinical course fails to improve after 24 to 48h. Under those conditions, the catheter should be removed. Patients who exhibit sepsis syndrome initially; those who harbor catheters infected with gram-negative bacterial pathogens or fungi, whether or not sepsis syndrome is manifest; and those who exhibit recrudescence soon after completion of an initial treatment for gram-positive catheter infections do not respond solely to antibiotic therapy. Under any of these conditions, the catheter should be removed without a trial of antimicrobial agent administration in the presence of an infected device. In immunocompromised patients, gramnegative infections are likely, and antibiotic coverage should be broadened to cover these microbes (usually by adding a second- or third-generation cephalosporin or, less commonly, an aminoglycoside) before establishing the diagnosis. VASCULAR AND CARDIOVASCULAR INFECTIONS

Infections involving the vascular system are rare and probably occur subsequent to hematogenous seeding of either a pathological abnormality or one created by operative intervention. Salmonella and staphylococcal infection can involve the

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great vessels on rare occasions, leading to "mycotic" aneurysm formation. This type of aneurysm can rapidly expand, and the risk of rupture is high. Acute and chronic infection of prosthetic vascular grafts are more common, occurring after about 2 % to 6 % of vascular procedures in which such material is implanted." Complications associated with these infections include rupture, thrombosis, distal embolization, bacteremia, and sepsis syndrome. Standard care consists of removal of the infected portion of the graft and any surrounding infected tissue, concurrent vascular bypass to avoid recontamination (often extraanatomical), and administration of a 6- to 12-week course of an antimicrobial agent. The microbiology of these infections is similar to that of intravascular catheter infections in that gram-positive microbes (i.e., S. aureus and S. epidermidis) predominate. Anecdotal clinical studies have examined the effect of antibiotic impregnation of prosthetic grafts in reducing the incidence of these types of infection, but added benefit has not been clearly demonstrated. It remains controversial regarding whether extraanatomical bypass invariably needs to be performed if removal of the entire graft is required; some surgeons advocate the use of in situ reconstruction, favoring the use of autogenous graft over prosthetic material. The results of several retrospective series have demonstrated satisfactory results using this technique, although no prospective clinical trials have been performed. 68,69 In general, more prolonged antibiotic treatment courses are selected when in situ reconstruction is performed or highly virulent microbes are present. If multidrug antibioticresistant, virulent organisms are encountered, then a second antimicrobial agent with a separate mechanism of action often is added to the regimen. Treatment of recurrent infection generally requires graft removal. Native or prosthetic cardiac valvular infection initially is treated with a 6- to 12-week course of one or more antibiotics, but significant cardiac dysfunction, recurrent infection, particularly that associated with sepsis syndrome unresponsive to initial antimicrobial agent therapy, or fungal infection warrants valvular removal and replacement." Every attempt should be made to reduce the inoculum size via administration of perioperative antibiotics, and the resected valve tissue should be examined microscopically for the presence of microbes and cultured. Generally, implantation of autogenous valves is preferred over use of prosthetic valves in this situation, and parenteral antibiotics should be continued for about 6 to 12 weeks after replacement of an infected cardiac valve in an attempt to reduce the likelihood of recurrent infection.

Skin and Soft Tissue Infections Many eponyms have been used historically that often describe the same disease process (e.g., Fomier's gangrene, scrotum; Meleney's synergistic gangrene, abdominal wall). Currently, these infections are classified according to (1) tissue plane affected and extent of invasion, (2) anatomical site, and (3) causative pathogen(s) (Table 11.9).71 Parameters such as rapidity of progression and clinical manifestations (e.g., septic shock) are important to consider as well. The most common of these diseases are superficial infections (cellulitis, erysipelas, lymphangitis, and furunculosis) caused by gram-positive aerobic skin microflora, although gram-negative bacteria and

TABLE 11.9. Classification of Soft Tissue Infections. Superficial soft tissue infections

Deep soft tissue infections

Cellulitis Erysipelas Furuncles Lymphangitis

Necrotizing fasciitis Necrotizing myosi tis Parasitic muscle infections Pyomyositis

yeast also are capable of causing these infections, particularly in immunocompromised patients. Most commonly, erythema and mild cellulitis are associated with mild abrasive or penetrating trauma to the surrounding skin, the presence of dermatological disease, or a superficial surgical wound infection. These infections rarely progress to more serious infection and can be treated by a 3- to 5-day course of an oral firstgeneration cephalosporin or a semisynthetic penicillin. Superficial surgical wound infection must be treated by opening the wound, as mentioned. More extensive cellulitis in which spread of erythema occurs is referred to as erysipelas. A life-threatening form of this disease occurs as the result of ~-hemolytic streptococci; rapid progression of disease from a single site occurs, and systemic toxicity is severe because of bacterial exotoxin secretion." Treatment consists of administration of 16 to 20MU/day of penicillin G i.v. and debridement of necrotic tissue. Spread of infection via lymphatic drainage channels manifests as "streaks" and is termed lymphangitis. Either of these types of infection should be treated with a parenteral antibiotic with gram-positive activity until resolution occurs. An involved extremity should be elevated and mobility restricted until the infection is effectively treated. Furuncuolosis represents more extensive disease in which superficial subcutaneous abscesses form; treatment generally requires antimicrobial agent therapy and surgical incision and drainage if spontaneous drainage does not occur. In all patients with what appears to be superficial infection, a careful search for the presence of a more aggressive underlying soft tissue infection should be undertaken. Aggressive infections involving the deep soft tissues can occur with or without the presence of a superficial infection, and the most difficult to diagnose and treat are those that involve only the deep tissue because few external manifestations occur. Deep soft tissue infections are classified as follows: (1) necrotizing fasciitis, (2) necrotizing myositis, (3) pyomyositis, and (4) parasitic muscle infections.P:" These infections are rare and difficult to diagnose, and it remains difficult to predict their occurrence. For that reason, few if any rigorous clinical trials have been performed examining the impact of various therapeutic modalities on outcome. The body of literature in this area provides evidence that several factors must coincide in the same patient to facilitate the occurrence of these infections: (1) impairment of some aspect of the immune system and host defenses, (2) compromise of fascial blood supply, and (3) presence of microbes capable of proliferating in this area. The most common types of deep soft tissue infections are necrotizing fasciitis and necrotizing myositis. The former is a necrotizing infection of the fascia deep to the panniculus adiposus. Invariably, there is rapid, extensive spread in the deep soft tissues that may secondarily involve the surround-

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ing muscles. Necrotizing myositis primarily involves the muscles and will rapidly involve and impair muscle bed and spread to adjacent soft tissues. Either of these types of infection can be caused by a single organism, most commonly S. pyogenes or C. perfringens, and rarely gram-negative aerobes such as P. aeruginosa or Vibrio vulnificans. More commonly, however, polymicrobial infections occur. These infections involve gram-positive aerobes such as S. pyogeties, S. aureus, or E. faecalis plus gram-negative aerobes (E. coli, P. aeruginosa) as well as anaerobes, including C. peiitingens, B. fragilis, and Peptostreptococcus, and occasionally fungi. The clinical presentation of such infections often is indolent. Fever and confusion may be the first signs, and there may be pain out of proportion to any findings on physical examination, particularly if an extremity is involved. Drainage of watery, grayish fluid from the wound or an open sore, an odd coppery hue of the skin, brawny induration, and skin blebs or crepitus are pathognomonic of these infections, and rapid extension to adjacent sites can occur. Patients often exhibit high fever, tachycardia, hypotension, shock, incipient MSOF with disseminated intravascular coagulation (most probably related to bacterial exotoxin secretion and bacterial synergistic interactions that occur during polymicrobial infections), and occasionally renal failure secondary to rhabdomyolysis. Ascertaining the presence of a deep soft tissue infection can be difficult. Initially, the patient's history should be reviewed for the presence of any risk factors, and the patient should be thoroughly examined to determine whether possible entry sites, skin changes, or crepitus are present. Plain roentgenograms looking for gas in the soft tissue should be performed, and computerized tomography or magnetic resonance imaging can occasionally be helpful in establishing the diagnosis. However, radiological studies, particularly timeconsuming scans, should not be performed if it seems highly likely that a deep soft tissue infection is present, particularly if the patient exhibits hemodynamic instability. Under those circumstances, rapid fluid resuscitation should take place, and an incisional biopsy should be performed in the operating room, obtaining direct visualization of both the soft tissue and muscle. Fluid can be obtained for performance of Gram stain and cultures. The presence of a deep soft tissue infection mandates radical debridement of all infected tissue, and the surgeon must be prepared to proceed with such intervention at the time of initial diagnostic exploration. For the most part, the surgeon must use personal judgment to debride tissue to the point at which all devitalized tissue has been removed. Some clinicians have advocated frozen section analysis, but it remains unclear whether this definitively provides information to assist with determining the extent of resection." This type of surgery often is cosmetically disfiguring and may involve amputation of an extremity to save the patient's life. Planned reexploration and debridement must occur in almost all cases until the infection has been eradicated. Antibiotic therapy initially should be directed against gram-positive aerobes, gram-negative aerobes, anaerobes, and C. perfringens until Gram stain and culture results are available. Antifungal therapy is often administered as well to immunosuppressed patients. Initial antimicrobial agent therapy consists of aqueous penicillin G (approximately 1620 x 106U every 24h) plus vancomycin plus an aminoglyco-

side or a third-generation cephalosporin plus clindamycin or metronidazole. Alternative regimens include vancomycin plus a single broad-spectrum agent such as imipenemcilastatin, ampicillin-sulbactam, ticarcillin-clavulanate, or piperacillin-tazobactam. Amphotericin B therapy should be instituted if fungi are identified. Alterations and refinements in antibiotic therapy can be made within 1 to 2 days based on microbiological data. Deep soft tissue infections are associated with a mortality rate of about 500/0, even with rapid diagnosis, radical debridement, and administration of appropriate antibiotics. Minimal debridement, incision and drainage plus antibiotics, or use of antibiotics alone is associated with approximately 800/0 to 100% mortality." Higher rates of morbidity and mortality are associated with delay of diagnosis, less than radical debridement, initial selection of antibiotics that in retrospect prove to be ineffective against the pathogens encountered, and the occurrence of these infections in elderly, diabetic, or immunosuppressed patients. Several studies have been performed in an attempt to determine whether added benefit is achieved by use of hyperbaric oxygen (HBO) therapy in addition to the aforementioned treatment regimen.F:" Although there is some experimental evidence to support the use of HBO, no prospective clinical trials have been performed that unequivocally demonstrated efficacy, and several trials have used historical controls or have not carefully stratified patients regarding each aspect of multimodality therapy. The HBO therapy is expensive and seems to be used at centers that possess such equipment. At best, it most likely represents adjunctive therapy that provides a modicum of benefit in selected patients. The referral of patients who develop deep soft tissue infection solely to centers that possess HBO equipment is not invariably indicated for use of that modality alone, although many such institutions possess considerable expertise in the management of these patients. Pyomyositis consists of abscesses deep within the muscle compartment. Patients develop fever and localized swelling. The surrounding muscle initially is not involved but may become infected subsequently. Causative organisms include S. aureus and E. coli. 80 Treatment consists of open drainage and debridement and antibiotics. Parasitic myositis is similar, but occurs as the result of Trichinella or Toxocara among patients in tropical environments or those infected with HIV. The presentation is more indolent, and treatment also consists of open-drainage administration of an antiparasitic agent.

Intraabdominal Infections Infection within the abdominal cavity is termed microbial peritonitis and is classified according to etiology into primary, secondary, and tertiary forms. During any type of microbial challenge, resident (peritoneal macrophages, translymphatic clearance) and recruited (PMNs) host defenses act efficiently, and sequestration mechanisms become active. However, effective treatment of this type of closed-space infection requires use of antimicrobial agents, operative intervention particularly if a potential ongoing source of peritoneal soilage (perforated viscus, abscess) is present, or both modalities. Primary microbial peritonitis occurs without the presence of perforation of a hollow viscus and probably is caused by seeding of microorganisms, directly or perhaps via bacterial


translocation from the gut or via hematogenous dissemination, into the peritoneal cavity. This process is caused by a single type of organism (monomicrobial), and common causative pathogens include E. coli or other aerobic gram-negative bacilli, S. aureus, E. [aecalis, E. faecium, and less frequently C. albicans. This disease process is associated with the presence of abnormal amounts of fluid within the peritoneal cavity, which normally contains only 50ml or less. Thus, patients who develop hepatic cirrhosis and ascites and individuals undergoing peritoneal dialysis are prone to this type of infection. Patients who harbor these conditions and subsequently develop primary microbial peritonitis generally present complaining of diffuse abdominal pain without localization. The presence of any of the disease processes just mentioned should lead the surgeon to suspect this diagnosis and perform abdominal paracentesis. Confirmatory evidence includes the presence of numerous PMNs and a single type of microbe on Gram stain. If polymicrobial flora are observed on Gram stain, then the diagnosis of primary microbial peritonitis is incorrect, and secondary microbial peritonitis most likely is present. Treatment of primary microbial peritonitis consists of administration of parenteral antimicrobial agents directed against the causative pathogen for 14 to 21 days. Removal of prosthetic material such as a peritoneal dialysis catheter generally is necessary, although it may be possible to treat some patients solely with antibiotics. Resolution of symptoms is the best indicator of successful therapy, although posttreatment paracentesis can be considered for severe or recurrent cases. Secondary microbial peritonitis occurs subsequent to perforation of a hollow viscus in which endogenous microbes spill out into the peritoneal cavity, forming the initial inoculum. Intriguingly, despite the huge number of microbes that form the initial inoculum during gastrointestinal tract perforation, only a limited number are capable of causing infection. Clinical observations and experimental studies have made clear that microbial simplification occurs among the hundreds of microbes initially present by means of a variety of mechanisms such that only a limited number of species (""'312) survive the initial stages of infection during the first 2 to 7 days after contamination." These mechanisms include (1) microbial numerical contribution to the initial inoculum; (2) additive, inhibitory, and synergistic effects of one microbe on the growth of others; and (3) inhibition of specific host defenses. Not surprisingly, perforation of the colon is associated with higher infection rates compared to other types of perforation because of the large inoculum size, consisting of both aerobes and anaerobes. After such contamination, the clinical manifestations of infection include severe abdominal pain associated with distension, ileus, and fever and evidence of free intraperitoneal air or leakage from the gut on routine radiographic studies or those using contrast material, respectively. At the time of abdominal exploration, fibrinopurulent peritonitis is encountered that may be localized or diffuse. Aerobic microbes (e.g., E. coli and other gram-negative bacilli such as Enterobacter, gram-positive microbes including E. faecalis and E. faecium), and anaerobic isolates (B. [ragilis and other species; Peptidostreptococcus, Peptostreptococcus, and Clostridium species) are encountered in about 800/0 to 900/0 of specimens; rarely are only aerobes or anaerobes

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isolated. Candida albicans is isolated in about 100/0 to 200/0 of cases. Subsequent to expeditious fluid resuscitation, patients who develop secondary microbial peritonitis should undergo surgery to alleviate the source of ongoing peritoneal soilage. The optimal duration of therapy has proved difficult to ascertain among all patients who develop intraabdominal infection, although it has been determined for certain types of patients. For example, those patients who suffer penetrating gastrointestinal tract trauma clearly benefit from a short course (12-24h) of an antibiotic that exhibits both aerobic and anaerobic activity, whereas massive blood loss and colon perforation and performance of a colostomy are associated with higher rates such that 3 to 5 days of therapy have been demonstrated to be more effective.f-" Several major trauma centers have developed algorithms based on these data to use during the operative procedure that allow selection of high-risk patients for more prolonged treatment courses. Also, gangrenous or perforated appendicitis without diffuse fibrinopurulent peritonitis can be treated with 3 to 5 days of therapy after operative intervention. In general, after appropriate surgical intervention, patients with any type of localized peritoneal contamination can be treated with a 3- to 5-day course of an antimicrobial agent, whereas longer courses are indicated for immunosuppressed patients and patients with more extensive contamination. Severe fibrinopurulent peritonitis in immunosuppressed patients generally is treated for longer periods (10-14 days), although the efficacy of such prolonged therapy has not been rigorously compared to shorter treatment course. Formerly, the mortality rate attributed to secondary microbial peritonitis was greater than 300/0 to 500/0. 84 Currently, 100/0 or fewer patients die if the initial therapy cures the disease; however, the mortality rate remains about 300/0 to 500/0 among those individuals with unsuccessful initial therapy that is not successful. Even after timely surgical intervention and preemptive antibiotic therapy, about 150/0 to 300/0 of patients demonstrate ongoing infection consisting of recurrent secondary microbial peritonitis, intraabdominal abscess, or tertiary microbial peritonitis. This problem has been studied in a large number of both retrospective and prospective randomized clinical trials. Concurrently, because aerobes and anaerobes are present in most cases, antimicrobial agent therapy directed against both these types of pathogens should be administered. Initially, it was demonstrated in a series of trials that the efficacy of two agents in combination was superior to that of single agents that demonstrated efficacy against either type of pathogen. It also was demonstrated that anaerobic coverage could be achieved with similar results using either clindamycin or metronidazole, and the specific aminoglycoside selected was of little consequence.v'" Such therapy can be achieved by using two agents, one directed against gram-negative aerobes (e.g., third-generation cephalosporin, aminoglycoside) plus an antianaerobic agent (e.g., clindamycin, metranidazole) or by use of a single broadspectrum agent that encompasses a similar spectrum of activity. The latter type of therapy is simple and increasingly common, and a large number of suitable agents are available. Commonly selected antibiotics include cefoxitin, cefotetan, ampicillin-sulbactam, ticarcillin-clavulanate, imipenem-

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cilastatin, and piperacillin-tazobactam. The last two agents are extremely potent and often are used for patients who develop more severe infections, such as hospitalized individuals who develop peritonitis after an initial surgical procedure, immunosuppressed patients, or patients with severe disease. An extensive review of clinical trials performed in this patient population determined that a success rate of 70% to 85% can be expected, but only when initial surgical intervention is appropriate and suitable agents with concurrent aerobic and anaerobic activity are selected.P?? In addition, it has been rigorously demonstrated that it is possible to switch from a parenteral to an oral drug regimen without detrimental effects at the juncture in the postoperative period at which the patient regains gut function." Parameters that should alert the surgeon to the presence of ongoing intraabdominal infection, particularly at the conclusion of antibiotic therapy, include fever (temperature above 37.6°C), more than 10,000 peripheral white blood cells/ml, and band forms on peripheral smear. 92,93 Note, however, that the presence of these indicators does not necessarily warrant continuance of antibiotics or alteration of agents to cure recrudescent infection; rather, it mandates an intensive search for a problem (e.g., intraabdominal abscess, leaking anastomosis, UTI, catheter infection) that may be rectified by further intervention. Although, historically, culture data have provided the basis of our understanding of the microbiology of intraabdominal infection, currently their associated cost precludes their extensive use for all patients. Increasingly, it has become apparent that initial culture information serves to direct subsequent therapy only in a small subgroup of patients. This issue has been examined retrospectively in about 450 patients; the conclusion reached was that antibiotic changes were not helpful and were in some cases detrimental." Unfortunately, some patients underwent alterations in therapy that were discordant with culture and sensitivity data. Thus, selection of a highly efficacious agent with activity against aerobes and anaerobes from the outset is appropriate, and alterations in antibiotic therapy should not be made for patients who exhibit resolution of infection. A subset of patients who develop secondary microbial peritonitis and who are unable to either eradicate or sequester intraabdominal infection develop what has been termed persistent or tertiary microbial peritonitis." Many of these patients are immunosuppressed and require reexploration to ensure that a source of ongoing contamination is not present. Generally, cloudy infected peritoneal fluid is encountered, and cultures reveal the presence of microbes that frequently are resistant to the antibiotics used to treat the initial episode of secondary microbial peritonitis. These microbes include low-virulence pathogens such as S. epidermidis, E. faecalis, and E. faecium as well as more virulent organisms such as C. albicans and P. aeniginosa. It seems highly likely that the combination of diminished peritoneal host defenses plus initial use of potent antibiotics directed against gramnegative aerobes and anaerobes facilitates the selection of such organisms. Treatment is directed against pathogens isolated at the time of reexploration, and frequent abdominal reexploration to perform lavage and debridement may be required. The mortality of this disease process remains above 50% despite use of potent antibacterial and antifungal agents and reexploration.

The subgroup of patients who develop intraabdominal infection due to appendicitis bears mention. Many studies have been performed examining the effect of antimicrobial agents on the incidence of superficial and deep (intraabdominal abscess) wound infection. A series of studies demonstrated that (1) either dual-agent or single-agent therapy was effective as long as the spectrum of activity encompassed gram-negative aerobes and anaerobes, and (2) under such circumstances the wound edges could be closed with an infection rate of about 2% to 3 % .96-98 Other studies have examined the effect of antimicrobial agents in reducing the wound infection rate with severity of inflammatory disease of the appendix at the time of surgery, with a clear correlation demonstrated. In particular, only minimal impact of preemptive antibiotics could be demonstrated in patients who exhibited minimal disease, whereas a substantial decrease in wound infection rate was evidenced among patients who suffered more serious disease such as perforation or gangrene with surrounding fibrinopurulent peritonitis." The efficacy of routine use of antifungal or antienterococcal agents for the treatment of intraabdominal infection has not been subjected to rigorous scrutiny in the clinical setting, and any additive beneficial effects of such agents have not been substantiated. The number of patients in whom enterococcus is encountered has not been carefully studied in relation to outcome. Similarly, only retrospective data support the use of antifungal agent therapy when Candida is cultured during intraabdominal infection.l'" Patients who suffer gastroduodenal perforation and in whom Candida is isolated probably do not require antifungal therapy if surgical intervention is prompt. However, based on retrospective analysis of patients in whom yeast was isolated from established intraabdominal infection, seriously ill immunocompromised patients probably benefit from such therapy with either amphotericin B (300-500mg total dose) or a triazole drug. In selected patients who suffer less-severe disease, amphotericin B can be used initially and then switched to an oral triazole to allow earlier discharge. Both these organisms are less virulent, present in smaller numbers than more commonly encountered pathogens, and therefore probably contribute to a lesser extent to serious intraabdominal infection in a subset of patients. Because large numbers of patients were required to establish the efficacy of the combination of antiaerobic and antianerobic agents, it is doubtful that controlled trials will be conducted to determine whether coverage of additional antienterococcal or antifungal agents will provide added benefit.

Other Bacterial Infections Mediastinal infection after cardiothoracic surgery requires exploration, drainage, and debridement. Watery gray purulent material with lack of culture of microbes may be indicative of the presence of Mycoplasma hominis infection, a rare cause of mediastinal infection after cardiac surgery. This infection should be treated by administration of a tetracycline antibiotic. Gram-positive microbes cause most of these types of infection. Extensive infection may require open packing and eventual coverage using vascularized muscle flaps. Large (>3-5cm) hepatic, splenic, and pulmonary abscesses can be percutaneously drained. Concurrent antibiotic therapy against aerobes and anaerobes should be administered. Abscess


drainage catheters should be left in place until such time as the output falls below about 30 to 50ml/day, although some surgeons have noted that removal within 5 days is associated with recurrence, probably because collapse of the cavity has not occurred. However, the appropriate duration of catheter drainage treatment has not been rigorously examined. Clostridium diiiicile colonization and infection can occur in hospitalized patients, and colonic and intestinal inflammatory disease caused by this pathogen is closely linked to antimicrobial agent usage, immunosuppression, and spread within the hospital environment. Treatment consists of oral metronidazole for 10 to 14 days. Recrudescence occurs in 10 % to 15% of patients and should be treated with a 10- to 14-day course of oral vancomycin. Rarely, severe disease leads to severe colitis with sepsis syndrome, colonic necrosis, or perforation, any of which require subtotal or total colectomy.

Fungal Infections The incidence of fungal infections has increased markedly over the past decade, in large part because of the increase in HIV infection as well as the ability to treat cancer and perform bone marrow and solid organ transplantation. Fungi are identified as a component of a polymicrobial infection or as sole pathogens. These types of infections can be classified according to (1) site of infection and (2) pathogenic and invasive potential of the causative microbe. Candida represent fungi that generally possess low pathogenic potential when present in superficial sites such as the intertrigonous folds of the skin, although they are capable of invasive behavior, as is C. neoformans. More highly pathogenic fungi include Aspergillus, Histoplasma, and Blastomyces, while those organisms belonging to the order Mucorales (Mucor, Rhizopus, and Absidia) are highly invasive and resistant to antifungal agents. Common fungal infections encountered by surgeons include those caused by Candida and Aspergillus, and although other organisms bear mention they are less commonly cultured. Urinary tract infections, esophagitis, and fungemic events caused by C. albicans can be treated with a 14- to 21-day course of fluconazole or amphotericin B. Azoleresistant Candida should be treated with amphotericin B. Cryptococcus neoformans can cause cerebromeningitis in immunosuppressed patients and can be treated with either amphotericin B or fluconazole, although there is some indication that the latter form of therapy is associated with slightly higher recurrence rates in HIV-infected patients. 101 More aggressive fungal infections caused by Aspergillus may manifest as pulmonary nodules or infiltrates in immunosuppressed individuals, although diffuse bronchoalveolarinfection caused by this organism is common in this patient population. Although infections limited to a single site have been treated with itraconazole, most such infections require prolonged "amphotericin B therapy (1.5-2.0 g total dose) concurrent with a reduction in immunosuppressive drug therapy in transplant patients. Lack of complete resolution within 3 to 4 weeks mandates consideration of surgical extirpative therapy. Fungi belonging to the Mucor-Rhizopus group are highly invasive and can cause aggressive rhinocerebral or wound infection in immunosuppressed patients and diabetics who suffer poor glucose control. Aggressive surgical intervention is required

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from the outset, plus high-dose amphotericin B therapy (2.03.0g). On occasion, dual therapy using amphotericin Band either fluconazole or itraconazole has been employed with success for the treatment of highly drug-resistant fungi, although whether additive or synergistic effects of two drugs together occur remains to be established. Also, some patients who develop invasive infection from minimally pathogenic organisms probably can receive initial amphotericin B followed by oral triazole therapy, the latter in the outpatient setting. Pulmonary infection caused by P. catinii occurs in immunosuppressed patients and produces cough, tachypnea, mild fever, and bilateral diffuse alveolar infiltrates or interstitial pneumonia on the chest roentgenogram. Bronchoscopy should be performed in patients who develop these manifestations; treatment consists of parenteral trimethoprim-sulfamethoxazole, trimethoprim-dapsone, or pentamidine even if the diagnosis is presumptive.

Viral Infections Viral infections that come to the attention of surgeons include herpesviruses, HBV, HCV, HIV, and many other pathogens. Many of these types of infections occur in immunosuppressed solid organ and bone marrow transplant patients or in patients who have developed AIDS due to HIV. Generally, HSV and varicella zoster virus (VZV) cause mucocutaneous lesions that are self-limited, while VZV can present as shingles. Either can be effectively treated with a 14- to 21-day course of acyclovir. Therapy often is initiated using a parenteral formulation, following which oral drug is administered. On occasion, either virus can cause severe disease (encephalitis, pneumonitis, and endophthalmitis) in immunocompromised patients. Such manifestations should be treated with highdose parenteral acyclovir (,...10-12.5 mg/kg every 6 h in patients with normal renal function) and a concurrent reduction in exogenous immunosuppression in solid organ transplant patients. Infrequently, EBV causes a primary mononucleosis syndrome that should be treated with high-dose acyclovir, but more commonly it is closely associated with posttransplant lymphoproliferative disorders (PTLDs) in immunosuppressed patients. The incidence among solid organ transplant patients ranges from about 1% to 50/0 and appears to be correlated with the extent of exogenous immunosuppression. The optimal treatment of PTLD remains controversial; reduction in immunosuppression, surgical extirpation, acyclovir, ganciclovir, IFN-a2b, and multidrug cancer chemotherapy regimens all have been employed alone or in combination with anecdotal success. Mortality rates in limited series remain at about 400/0 to 70 % .102 In solid organ transplant patients, CMV remains a common problem, with 500/0 to 750/0 reported rates of infection; clinical disease is somewhat less frequent (,...150/0-25 % ).103 Infection with CMV occurs in temporal association with maximal host immunosuppression and thus is frequent during the first several months after transplantation; after antirejection therapy, particularly with potent agents such as antilymphocyte antibody (polyclonal or monoclonal); after repeated courses of antirejection therapy; and after cadaver transplantation because of the higher doses of immunosuppressive agents generally administered to this last group of patients. In addition, several experimental and clinical studies have

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indicated that CMV exerts a direct immunosuppressive effect on the host, acting to diminish T-helper lymphocyte function. Infection with CMV can occur via several distinct mechanisms. Primary CMV infection occurs when an individual who has not been previously infected with CMV becomes infected by viral transmission from an organ or a blood donor who harbors latent CMV infection. Secondary infection occurs as the result of reactivation of a strain of virus that caused an initial infection in the recipient and entered the latent state, only to again become active during suppression of host defenses. Superinfection with a second strain of CMV also can occur after a patient has experienced CMV infection from one strain of virus and is inoculated with a second strain. If this second strain is sufficiently different from the first or host defenses are diminished to the point that the second strain can produce an infection, then CMV disease may occur because of reactivation, superinfection, or both. Any of these types of infection can lead to clinical manifestations of CMV disease. Several studies have provided information indicating that CMV disease caused by primary infections is the most severe, that caused by superinfection is less severe, and reactivation disease is most frequently mild. Infection with CMV often presents as a mild disease syndrome consisting of fever, myalgias, malaise, lethargy, leukopenia, and mild dyspnea. More serious illness may present initially as severe retinitis, interstitial pneumonia, gastrointestinal hemorrhage, hepatitis, or pancreatitis and may evolve into a lethal CMV syndrome consisting of severe hypoxia and respiratory failure caused by progressive pneumonitis, as well as hypotension, disseminated intravascular coagulation, massive gastrointestinal hemorrhage, MSOF, and death. Superinfections due to other Viral, bacterial, and fungal agents are often present as well, and it is often difficult to determine whether CMV is a primary infecting pathogen. With the advent of new immunosuppressive drugs that can be used in combination with reduced toxicity plus potent agents that exhibit efficacy against CMV, the impact of this pathogen has diminished such that mortality is rare, and morbidity in terms of allograft loss and intercurrent superinfections has diminished.Fv'?' A series of randomized, prospective clinical trials has demonstrated that prophylactic administration of acyclovir, anti-CMV Ig, ganciclovir, and valacyclovir during the first 3 months after solid organ transplantation can reduce the incidence of CMV disease. 104-107 Many centers use initial parenteral ganciclovir, following which oral drug is administered. Patients who develop CMV disease should receive 14 to 21 days of parenteral ganciclovir, following which an additional 9 to 10 weeks of oral therapy is administered to prevent recurrent disease, which occurs in 100/0 to 250/0 of patients. Foscarnet is rarely used because of its nephrotoxicity, and few ganciclovir-resistant strains of CMV have been identified among patients receiving this drug for initial prophylaxis. Reduced efficacy of prophylaxis and recurrent disease occur more commonly among patients who suffer primary CMV infection and disease.

Parasitic Infections Entamoeba histolytica, Echinococcus multilocularis, and Echinococcus granulosus can cause hepatic abscesses.!" Gen-

erally, such abscesses are large and can become secondarily infected with bacterial pathogens. The diagnosis of infection caused by these pathogens should be established by examination of the stool, serological studies, and abdominal computerized tomography for amoebic disease; only the last two approaches are helpful in identifying echinococcal infection as humans are not definitive hosts. Treatment of amoebic abscesses consists of antiparasitic drugs such as metronidazole or tinidazole, although a number of alternative agents are available. Percutaneous drainage is not undertaken unless rupture seems imminent or there is no response to therapy within 72h. Echinococcalliver disease generally requires cyst excision via pericystectomy and placement of omentum within the liver defect; hepatectomy is associated with higher rates of morbidity and mortality.l'" Initial sterilization of the cyst(s) can occur either preoperatively or intraoperatively using a scolicidal agent such as 3N saline or formalin, and antiparasitic agent therapy should be administered thereafter. Care must be taken to avoid cyst rupture and spillage, which can lead to widespread intraabdominal dissemination of daughter cysts containing viable scolices capable of peritoneal implantation and growth. Occasionally, surgeons encounter biliary tract disease caused by the liver fluke Chlotiotchis senesis or patients who develop acute abdominal pain from visceral larval migrans or bowel obstruction caused by helminths. Operative intervention invariably is required under these circumstances to treat the underlying disease in addition to therapy with antiparasitic agents. Toxoplasma gondii can cause necrotizing encephalitis, myocarditis, pneumonitis, and death in immunosuppressed patients, and a higher incidence of infection occurs among cardiac transplant patients. Treatment consists of administration of pyrimethamine and sulfadiazine.

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Infections of Skin and Soft Tissue Philip

s. Barie and Soumitra R. Eachempati

Unc omplicat ed Skin and Soft Ti ssue Complicated Skin and Soft Tissue. . . . . . . . . . . . . . . . . . Operating Room Environment . . . . . . . . . . . . . . . . . . . . . Man agem ent of the Incision . . . . . . . . . . . . . . . . . . . . . . .

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nfections of skin and soft tissue (SSTIs ) encompass a diverse set of conditions, but th ere are comm onalities th at jus tify th eir cons ideration as a group. Som e SSTIs are not dangerous to th e patient, wh ereas others are life threat ening and require radical surgi cal debridement as well as broadspectru m antibiotic th erapy. The U.S. Food and Drug Admin istration (FDA) classified SSTIs as un complicated or complicat ed infections for th e purp oses of clinical trial design and enro llme nt. This framework is also useful for clinical description .1 Uncomplicat ed SSTIs are th ose th at are superficial or selflim ited. They ma y requ ire only incision and draina ge (without antibiotics )or oral antibiotic s (without drain age). Hospitalization is rarely necessary. Examples of un complicated infections include cellulitis, impetigo, erys ipelas , furuncul osis, carbunc ulosis, and small abscesses . Cellulitis ma y coexist with th e last three entities . Uncomplicat ed infections are excluded from trials of antibiotic th erapy for complicat ed SSTI (cSSTI) and vice versa. Complicat ed SSTIs involve deeper tissues or requ ire major surgical intervention. An infection is also considered complicated if th e patient has me dical comor bidities, specifically renal insufficiency, diabetes mellitus, or peripheral arte rial disease. Examples of cSSTIs include major abscesses, deepspace infections, diabet ic foot infections (DFIsl, some postoperative surgical site infectio ns (SSIs; th ose with system ic signs of infect ion], infect ed decubitus ulc ers, and necrot izing soft tissue infections (NSTIs). Clinical trials of drug th erapy for cSSTI exclude NSTIs becaus e th e m ortality rat e is high, and th e timeliness and extent of surgical debridem ent are crucial in determin ing th e outco me.

Uncomplicated Skin and Soft Tissue Cellulitis Cellulitis is an acute, pyogenic infecti on of the dermis and subcutaneous tissues, usually complicat ing a breach of skin

Postop erative Period Diagn osis and Tr eatment of Surgical Site Infection . . .. Necrotizing Soft Ti ssue Infection . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

250 251 252 254

integrity.' The infected tis sue is warm, erythe ma to us, edemat ous, and tender; th e lower extremity is th e most common site of infect ion . The differential diagno sis of cellulitis includes both infectious and noninfectious entities. Early manifestations of NSTIs may be modest and can be confused initially for cellulitis. Inflammatory conditions that can mimic cellulitis include insect bites, acute gout, deep venous th romb osis, drug reactions , pyoderma gangrenosum (characteristi c of inflam ma tory bowel disease or colla gen vascular disease), and met astatic carcin om a. Identificati on of th e source of cellulitis can provide im portant clu es to help define th erapy. The most com mo n cau se of cellulitis is trauma to th e skin. Edema predisposes to cellulitis (e.g., ipsilateral arm edema after ma st ect omy] ." Other imp ortant clu es include physical activity, water contact, and human or animal bit es. Cellulitis ma y also manifest a deeper infection, (e.g., spread of subjac ent osteomyelitis, cellulitis of th e thigh following colon perforation into th e retroperitoneum) . Bloodstream infecti on is a rare cause of SSTI, but cases have been report ed after meningococcal, pneumococcal, or staphyloco ccal bact erem ia. Pseud om onas bact eremia can caus e skin lesions in neutropenic pati ents. Bacteremic SSTI (usually an NSTI) cause d by Vibrio vulnificus has been associate d with ingestion of raw shellfish, and NSTI cause d by Bacillus cereus has been associa ted with ingesti on of a wide variety of foodstuffs. Th e diagnosis of cellulitis is made clinically based on th e circumstances and the appearance of the lesion; neither imaging studies nor cultures of th e lesion have a high diagnostic yield. Needle aspiration yields an organism onl y about 30% of th e time. Pun ch biopsies of skin have a higher yield, but the invasiveness is seldom just ified as em piric thera py is usually successful in un complicated cases. Bloodstream infection is un common in cellulitis ; th e incidence of positive blood cultures is less than 5%, and th erefore th ey are not cost-effective except perhaps for cellulitis complica ting lymphedem a, for which th e incidence of bloodstream infect ion may be higher . Radiol ogic studies are unnecessary in most patients un less a complicated, 23 7

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TABLE 12.1. Summary of Recommendations from Practice Guideline for Diagnosis and Treatment of Skin and Soft Tissue Infections (SSTIs), Infectious Diseases Society of America. Level I Impetigo

Erysipelas Cellulitis Cutaneous abscess Furunculosis MRSA NSTI Type I NSTI Type IT NSTI Level IT Furunculosis Type I NSTI Type IT NSTI Animal bites Level ITI Cutaneous abscess Furuncle Animal bites Human bites

Mupirocin is the best topical agent, and is equivalent to oral systemic antimicrobials when lesions are limited in number. Patients with numerous lesions or who do not respond to topical therapy should receive an oral antimicrobial agent. PCN or penicillinase-resistant PCN are TOCs for nonbullous lesions. PCN or I-G cephalosporin is recommended for bullous lesions. PCN is TOC for streptococcal infection. Penicillinase-resistant PCN or I-G cephalosporin is recommended if staphylococci are suspected. Penicillinase-resistant PCN or I-G cephalosporin are the TOCs unless resistant organisms are common in the community. Use clindamycin or vancomycin for PCN-allergic patients. Incision and drainage is the TOC. Recurrent furunculosis may be treated with mupirocin to the anterior nares (for chronic staphylococcal carriers) or clindamycin lS0mg/day for 3 months. Linezolid, daptomycin, and vancomycin have excellent efficacy in SSTI in general and in particular those caused by MRSA. Surgical intervention is the major therapeutic intervention. Ampicillin-sulbactam plus ciprofloxacin plus clindamycin is TOC for community-acquired infection. Clindamycin/PCN combination therapy is TOC. Attempt to eradicate the staphylococcal carrier state among colonized persons. A variety of antimicrobials directed against aerobic gram-positive and -negative bacteria and anaerobes may be used in mixed necrotizing infection. Consider intravenous gamma globulin (MG) therapy. PCN/clindamycin combination therapy is the TOC for infections caused by Clostridium perfringens. Oral amoxicillin-clavulanic acid or intravenous ampicillin-sulbactam or ertapenem should be administered to nonPCN-allergic patients because of suitable activity against Pasturella multocida. Acceptable alternative regimens include piperacillin-tazobactam, imipenem-cilastatin, and meropenem. Gram stain, culture, and systemic antibiotics are rarely necessary. Systemic antibiotics are usually unnecessary, absent fever or extensive surrounding cellulitis. I-G cephalosporins, penicillinase-resistant PCN, macrolides, and clindamycin should be avoided as therapy because of poor activity against P. multocida. Intravenous ampicillin-sulbactam or cefoxitin are the TOCs for non-PCN-allergic patients. A hand surgeon should evaluate clenched-fist injuries for penetration into synovium, joint capsule, or bone.

I-G, First-generation cephalosporin; MRSA; methicillin-resistant Staphylococcus auteus, NSTI, necrotizing soft tissue infection; PCN, penicillin; SSI: surgical site infection; TOC, treatment of choice. Suspicion of possible SSI does not justify use of antibiotics without a definitive diagnosis and the initiation of other therapies, such as opening the incision. All infected surgical incisions should be opened. Source: From Stevens,' by permission of Clinical Infectious Diseases.

deep-seated SSTI or NSTI cannot be excluded by examination of the patient. Most cases of cellulitis are caused by gram-positive cocci, either streptococci or Staphylococcus auteus" Diffuse or poorly circumscribed lesions are more likely to be caused by streptococci. The ~-lactam antibiotics with activity against penicillinase-producing S. aureus (methicillin-sensitive S. aureus, MSSA) are the treatment of choice for most cases of cellulitis. Oral therapy is appropriate unless the patient has systemic signs (e.g., fever, chills); medical comorbidity, or a rapidly spreading lesion, any of which indicate initial intravenous therapy. Choices for initial parenteral therapy include penicillin G (for erysipelas; see below); cefazolin, nafcillin (or oxacillin or methicillin); or ceftriaxone (Table 12.1). If methicillin-resistant S. aureus (MRSA) is suspected or the patient is highly allergic to penicillin (i.e., anaphylactoid reaction), then vancomycin or linezolid may be chosen. Appropriate oral agents include dicloxacillin, cephalexin, cephradine, or cefadroxil. Minocycline or linezolid may be appropriate for oral therapy of MRSA. METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS IN SURGICAL SITE INFECTION

Methicillin-resistant S. aureus in SSTI requires particular mention. Approximately 600/0 of hospital isolates of S. aureus

are MRSA;shospitalized or recently hospitalized patients who develop an SSTI must be considered for empiric therapy against MRSA. Increasingly, MRSA SSTIs are observed among patients who have had no contact with the health care system. Community-onset or community-acquired MRSA (CAMRSA) has emerged since 2001 as a major pathogen." Molecular epidemiologic studies show clearly that CA-MRSA is not a feral, escaped clone of the hospital-associated MRSA, but is a unique pathogen that has a unique antibiotic susceptibility pattern. The CA-MRSA clone probably arose from antibiotic selection pressure on a commensal, saprophytic Staphylococcus sp. that is part of normal skin flora. Communityassociated MRSA may cause pneumonia as well as SSTI; either manifestation may be associated with tissue necrosis; a handful of cases of NSTI have been reported as well.' However, about 75% of infections caused by CA-MRSA are SSTIs. In many areas of the United States, CA-MRSA is now the predominant cause of SSTIs that present to emergency departments. 8 The antimicrobial susceptibilities of CA-MRSA differ from the hospital clones. Although CA-MRSA is similarly susceptible to vancomycin and linezolid, CA-MRSA may be susceptible in vitro to macrolides, clindamycin, and cotrimoxazole, the last drug is most reliable for oral therapy. Clindamycin resistance that is inducible by macrolides has been associated with treatment failures; therefore, caution is

INFECTIONS O F S K I N AND S O F T TISSUE

239

advised if using clindamycin for therapy," especially if the organism is macrolide resistant. Outbreaks of CA-MRSA have been associated with groups of people who are in close contact, including prison inmates, amateur and professional sports teams, military recruits, and clients of day care centers." Direct contact with skin is a definite risk factor, as are shared personal hygiene items such as towels or bars of soap . Other patient groups at risk are young children and people of lower socioeconomic status. Infections (SSTIs) caused by CA-MRSA have a characteristic appearance that may raise suspicion of the diagnosis . The lesions are usually superficial and well demarcated, often with a necrotic center (Fig. 12.1). If the lesions are uncomplicated, then incision and drainage alone or topical mupirocin ointment or chlorhexidine solution may be sufficient therapy. If antibiotic therapy is required, then co-trimoxazole should be considered.

Erysipelas Erysipelas, a form of cellulitis, is distinguished from other uncomplicated SSTIs by two factors. P'" Lesions of erysipelas are raised above the level of surrounding skin, and there is sharp demarcation between infected and normal skin. Most infections remain superficial, but deep extension is reported. Erysipelas is most common among young children and older adults. The etiologic agent is almost always group A streptococci, sometimes group C or G streptococci, or rarely group B streptococci or S. aureus. Because of the streptococcal predominance, penicillin is the treatment of choice unless staphylococci are suspected' (Table 12.1).

Impetigo Impetigo is a common SSTI that consists of discrete purulent lesions that are nearly always caused by ~-hemolytic streptococci or S. auteus'? (Fig. 12.2). Impetigo is most common among economically disadvantaged children in warm climates (during the summer in temperate climates). Organisms probably initially colonize unbroken skin as a prelude to impetigo, emphasizing personal hygiene in the pathogenesis. Inoculation into skin by minor trauma occurs subsequently.

FIGURE 12.1. Necrotizing skin lesion characteristic of communityassociated methicillin-resistant S. aureus infection.

FIGURE 12.2. Staphylococcal impetigo.

Nasal carriage of staphylococci is a risk factor for impetigo caused by those organisms. Impetigo usually invades exposed skin, primarily of the face and extremities. The lesions are usually multiple and may be bullous (S. aureu s) or nonbullous. A deeply ulcerated form of impetigo is known as ecthyma. A penicillinase-resistant penicillin or first-generation cephalosporin is preferred for therapy, but cases caused by MRSA are on the increase. Topical therapy with mupirocin is equivalent to therapy with oral antibiotics' (Table 12.1).

Cutaneous Abscess Cutaneous abscesses may infect the dermis and subcutaneous tissue. These lesions are usually painful, tender, and fluctuant, with a central pustule and surrounding erythema and edema. These infections are typically polymicrobial, with pure culture of S. aureus isolated in only one-quarter of cases . Epidermoid cysts (erroneously called sebaceous cysts) may contain skin flora in the soft, keratinous, "cheesy" center, even when not inflamed. Inflammation usually results from cyst rupture with extrusion of cyst contents into surrounding tissue rather than infection per se. Organisms, when identified, are usually skin flora. Treatment of cutaneous abscesses is incision and drainage, with mechanical destruction of intracavitary loculations (Table 12.1).1 Gram stain, culture, or systemic antibiotics are rarely necessary unless a patient has systemic signs or severe immunocompromise. Furuncles ("boils") are infected hair follicles, usually caused by S. aureu s,' Suppuration extends through the dermis to subcutaneous tissue, forming a small abscess. This contrasts with folliculitis, which is also an infection arising in hair follicles, but the inflammation is more superficial, and pus is present in the epidermis. Furuncles can appear anywhere on hair-bearing skin. Infection of several adjacent follicles can cause coalescence, with multiple draining sites, which is called a carbuncle (Fig. 12.3). Carbuncles have a strong predilection to form on the dorsum of the neck in patients with diabetes mellitus. Small furuncles may be treated with moist heat, which promotes spontaneous drainage. Systemic antibiotics again are rarely necessary. Outbreaks of staphylococcal furunculosis (either MSSA or MRSA)

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FIGURE 12.3. Several fumncles have coalesced to form a spontaneously draining carbuncle on the nape of the neck . Formal incision and drainage is necessary.

among persons in close personal contact [e.g., prisoners, families, team sports participants) may require institution of infection control measures, such as bathing with antibacterial soaps, careful laundering, no sharing of personal hygiene it ems, and eradication of the staphylococcal carrier state if present. Some patients are also subject to recurrent episodes of furunculosis, for which nasal carriage of staphylococci is a strong predisposing factor. Intranasal 2 % mupirocin ointment twice daily for 5 days each month can reduce the incidence of recurrence by one-half." Oral clindamycin 150mg/day for 3 months is even more successful, reducing recurrences by 80%.14

Hidradenitis Suppurativa Hidradenitis suppurativa is a chronic acneiform infection of the cutaneous apocrine glands that also can involve adjacent subcutaneous tissue and fascia of the axillae, groin, or wherever apocrine glands are concentrated.P:" In addition to common manifestations in the axilla or groin, the areola, the intramammary cleft, gluteal folds, perineum, circumanal area, or infraumbilical skin may be affected. Ingrown hairs are a predisposing factor; thus, the incidence is increased in patients with curly hair. The incidence of hidradenitis suppurativa is greater in females . Hidradenitis suppurativa does not present in prepubescent patients because apocrine secretion is hormone sensitive. The condition may be observed in patients of any age after puberty, and symptoms may be affected by the menstrual cycle. Hot weather, excessive perspiration, and obesity may be aggravating factors. A genetic predisposition to hidradenitis suppurativa exists , including Down syndrome. Disease activity may be related to stress or in association with other chronic conditions such as inflammatory bowel disease, irritable bowel syndrome, or autoimmune disorders such as arthritis, Hashimoto thyroiditis, or Sjogren syndrome. Hidradenitis suppurativa occurs when apocrine gland secretion becomes obstructed by perspiration or glands are unable to drain normally because of structural abnormality. Trapped secretions and bacteria extravasate bacteria into surrounding tissue, causing subcutaneous inflammation and

infection. As suppuration progresses, surrounding cellulitis may be present. The condition presents most commonly as painful, tender, firm, nodular lesions in one or both axillae . When infection is active , hidradenitis suppurativa may resemble bacterial folliculitis or furunculosis. The differential diagnosis also includes granuloma inguinale, lymphogranuloma venereum, pilonidal cyst, and tuberculosis of the skin. The nodules may open and drain pus spontaneously, then heal slowly, with or without drainage, over a 2- to 4-week period. Remissions may last months or years, but recurrences are frequent, and some patients are afflicted continuously. Patients with chronic affliction may present with multiple nodules that have coalesced and are associated with a fibrotic reaction that results in scarring and an unsightly appearance. Most nodules will resolve without surgical drainage. Incision and drainage may be helpful for fluctuant nodules that have not opened spontaneously. Antibiotics are indicated if cellulitis or fever is present, and hospitalization should be considered if the patient has systemic toxicity. In severe or intractable cases, excision of the pathologic tissue with splitthickness skin grafting offers the best chance for cure. Radiation and laser treatments are investigational but have shown some promise for patients with severe hidradenitis suppurativa. Complications or intractable disease include lymphedema due to inflammation and scarring of lymphatic channels, restricted limb mobility from scarring and contracture, or arthritis secondary to inflammatory injury of synoval tissue or cartilage. Disseminated infection is rare. Squamous cell carcinoma may develop in indolent sinus tracts. Prevention includes minimized heat exposure and consequent perspiration. Patients should lose weight if overweight. Constrictive clothing and frictional trauma to affected skin should be avoided, as should underarm antiperspirants and deodorants. Affected hair-bearing areas should be kept shaved to prevent re-ingrowth of hair.

Complicated Skin and Soft Tissue Complicated SSTIs involve deeper tissues or require major surgical intervention. Infection in the presence of medical comorbidities, particularly renal insufficiency, diabetes mellitus, or peripheral arterial disease, also defines a cSSTI. Examples of cSSTIs include major abscesses, deep-space infections, DFIs, some postoperative SSIs (those with systemic signs of infection), infected decubitus ulcers, and NSTIs . Clinical trials of drug therapy for cSSTIexclude NSTIs because the mortality rate is high, and the timeliness and extent of surgical debridement are crucial in determining the outcome. Table 12.2 presents an evidence-based summary of recent clinical trials of antibiotic therapy.19-27 Most trials are designed to demonstrate "noninferiority" of the tested regimen against the comparator regimen, so numerous regimens appear comparable despite widely divergent spectra of activity. Notably, comparable outcomes are achieved by agents that treat only gram-positive cocci [e.g., vancomycin, linezolid, daptornycin, dalbavancin), but the many options available to investigators (e.g., choice of comparator in "standard therapy" regimens, addition of aztreonam] makes the literature a challenge to interpret.

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_u

TABLE 12.2. Recent Prospective Trials of Antibiotic Therapy for Complicated Skin and Skin Structure Infections.

Study

Drug

Comparator

Result

Notes

Stevens"

Linezolid 600mg i.v, daily

Vancomycin 1g i.v. every 12h

Seltze r'?

Dalbavancin I g i.v. day I and 500 mg day 8

Standard therapy

MRSA only; open label; 7 days of therapy; underpowered Open-label, dose-ranging, phase 2 trial

Arbeir"

Daptomycin 4mgfkg i.v. daily

Wilcox"

Linezolid 600mg i .v.] p.o. every 12h

Giordano"

Moxifloxacin 400 mg Lv.fp.o. every 12h

Ellis-Crosse"

Tigecycline 100mg load, then 50mg i.v. every 12h Dalbavancin I g day 1, 500mg day 8

Standard therapy or vancomycin 1g i.v , every 12h , oral switch to synthetic penicillin OK if MSSA Teicoplanin dose determined by inv estigator Piperacillin-tazobactam 3.375 g i.v, every 6h; arnoxicillin-clavulanate 800mg p.o. every 12h Vancomycin l g every 12h plus aztreonam 2g i.v. every 12h Linezoli d 600mg Lv.fp.o. every 12 h

73% vs. 73% cure , E population 95% CI 1-16.6 to 16.8) 94% vs. 76%, E population; only result for 2 doses of dalbavancin shown 83% vs. 84% cure, E population; 95% CI (-4 .0 to 5.61

[auregui"

Weigelt"

Linezolid 600mg every 12h i.v.fp.o., aztreonam permitted

Fabian"

Meropenem 500mg i.v.

Vancomycin Ig i.v . every 12h; switch to semisynthetic penicillin if MSSA, aztreonam permitted Imipenem-cliastatin 500mg i.v. every 8h

Combined report of two pha se 3 trials; noninferior treatment for 7-14 days

96% vs. 88% cure, ITT population; 95 % CI (2.5 to 13.2) 79% vs. 82% cure, E population; 95% CI (-12 .04 to 3.29)

Linezolid superior to teicoplanin, but dose of teicoplanin questionable Noninferior treatment for 7- 14 days

80% vs. 82% cure, mITT population; 95% CI I-7.1 to 2.8) 89% vs. 91% cure, E population; 97.5% CI calculated, only lower limit of -7.28 reported 92% vs. 89% cure, ITT population; 95% CI (-0 .11 to 7.47)

Combined report of two phas e 3 trials; noninferior treatment Randomized; 0 : L 2: I; treatment for 14 days

73% vs. 75% cure, mITT group; 95% CI (-2 .8 to 9.31

Open-label, phase 4; treatment up to 14 days; linezolid superior in MRSA subset; 95% CI (6.08 to 25.70) mitt population: eligible, randomized, and received at least one dose of drug

E, evaluable patient group; lIT, intention-to-treat patient group; i.v., intravenous; mlIT, modified int ention-to-treat patient group; p.o., oral administr ation . Standard therapy means that selection of the comparator agent was at the discretion of the investigator. Noninferiority is defined statistically when the lower limit of the 95% confidence interval is greater than - 15, and the confidence interval contains zero. A tria l with a relatively narrow confidence int erval is likely to have greater statistical power lor more homogeneo us result s) than one with a wider interval.

Diabetic Foot Infection Foot infections in patients with diabetes mellitus cause considerable morbidity, including limb loss. 28,29 Diabetic foot infections usually begin in skin ulcerated from either abra sions or ischemia. One-third of patients presenting with a DFI have had a foot lesion for more than 1 month prior to presentation. Skin ulcers are common in diabetic patients not only because of vascular insufficiency, but also because of peripheral sensory neuropathy, which ma y render the foot insensate. Two-thirds of patients with DFI will pre sent with peripheral arterial disease, and the prevalence of sensory neuropathy is about 80%. Although most DFIs remain superficial, as many as 25% of such infections will spread contiguously to involve subcutaneous tissue or bone (osteomyelitis). The compartmentalized anatomy of the foot, with its various spaces , tendon sheaths, and neurovascular bundles, may create conditions that favor ischemic necrosis of tissues within a compartment or spread along anatomic tissue planes.

Recurrent infections are common as 10%-30 % of affected patients ma y come to amputation eventually." Diabetic patients are predisposed to foot infections not onl y because of the portal of entry, but also because of defects in humoral immunity, including impaired neutrophil chemotaxis, phagocyto sis, and intracellular killin g." and impaired monocyte/macrophage function , which appear to correlate with the adequacy of glycemic control." Cell-mediated immunity and complement function may be impaired as well. Diabetic patients ha ve a higher prevalence of nasal carriage of S. auteus, which also predisposes to SSTls . Acute infections in untreated patients are usually caused by gram-positive cocci, most commonly S. auteus, often as monomicrobial infections' v" (T able 12.3 ). Staphylococcus aureus is the most important pathogen in DFI j even when it is not the onl y isolate, it is usually part of the flora of mixed infections. Chronic wounds or recurrent infections may harbor complex flora. Serious infections in hospitalized patients are more likely to be mixed infections, including

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TABLE 12.3. Pathogens Isolated in a Clinical Trial of Antibiotic Therapy of Diabetic Foot Infection. Organisms

Staphylococci Staphylococcus auieus (total) Methicillin-sensitive S. auteus Methicillin-resistant S. auteus Coagulase-negative staphylococci Streptococci Streptococcus agalactiae ~-hemolytic streptococci Streptococcus species Enterococci Pseudomonas species Enterobacteriaceae

Isolates

158 127 31 65 52 6 14 60 27 88

Of cases, 50% had only gram-positive cocci isolated. Source: Data from Lipsky et a1. 34

both aerobic and anaerobic flora." Among gram-negative bacilli, bacteria of the family Enterobacteriaceae are common, and Pseudomonas aeruginosa may be isolated from wounds that have been treated with hydrotherapy or wet dressings. Enterococci may be recovered from patients treated previously with a cephalosporin. Anaerobic bacteria seldom cause DFIs as the sole pathogen, but they may be isolated from deep infections or necrotic tissue. Antibiotic-resistant bacteria, especially MRSA, may be isolated from patients who have received antibiotics previously or who have been hospitalized or reside in long-term care facilities. Infections affect the forefoot most commonly, especially the toes and the metatarsal heads on the plantar surface. Infection must be diagnosed clinically because all skin wounds contain microorganisms, many of which are commensal. The presence of systemic signs (e.g., fever, chills, leukocytosis); purulent drainage; or at least two local signs of inflammation (e.g., calor [warmth], rubor [redness], dolor [pain or tenderness], and tumor [induration]) are suggestive. Deep-space infections may have few surface signs. Chronic wounds may manifest discoloration, friability, delayed healing, or malodor. Signs of systemic toxicity are uncommon in DFI, even with limb-threatening infection, but metabolic abnormalities (e.g., poorly controlled blood sugar, ketoacidosis, hyperosmolar state) may provide a clue. Many patients do not complain of pain on presentation, and more than one-half of patients do not have fever, leukocytosis, or an elevated erythrocyte sedimentation rate (ESR). Whenever the diagnosis of DFI is considered, aggressive management is indicated because these infections sometimes progress rapidly. Several severity scores have been proposed for DFI,36 but none has achieved universal acceptance. Severity may be assessed clinically by determining the depth of the wound and whether tissue ischemia is present. Local wound exploration with a sterile surgical instrument is important to identify necrotic tissue or the presence of a foreign body (e.g., a needle that the patient stepped on but did not feel at the time) and the possibility of osteomyelitis.":" An assessment of severity is essential to select an antibiotic regimen (including route of administration) and determine the need for hospitalization and the potential necessity and timing of surgical debridement or level of amputation. Systemic signs, when present, should raise suspicion of a deep-space infection. Indications

for hospitalization include fluid resuscitation, correction of metabolic abnormalities, parenteral antibiotic therapy, or the need for surgical intervention. Other reasons to hospitalize a patient with a DFI include an inability or unwillingness of the patient to provide local wound care or to maintain non-weight-bearing status or likely noncompliance with an outpatient antibiotic regimen. Antibiotic therapy alone will not overcome suboptimal wound care and glycemic control. ANTIBIOTIC THERAPY

Of diabetic patients who are treated for a foot ulcer, 40 % to 60% receive antibiotics, but antibiotic therapy does not

improve the outcome of uninfected foot lesions in diabetic patients.P-" Successful antibiotic therapy requires achievement of a therapeutic drug concentration at the site of infection. Intravenous antibiotics are indicated for patients with systemic illness, severe infection, intolerance of oral antibiotics, or pathogens that are not susceptible to oral agents. After the patient is stabilized and shows signs of improvement, a switch to oral antibiotic therapy may be appropriate. The slower delivery of antibiotic with an initial oral dose is inconsequential for noncritically ill patients, so the main issue with oral antibiotic therapy is the bioavailability of the chosen agent. Among the potential choices of oral antibiotics for DFIs, clindamycin and fluoroquinolones have good oral bioavailability. Even parenteral antibiotics may not penetrate tissue adequately in the presence of peripheral arterial disease, even when serum concentrations are adequate." Most initial therapy is empiric, directed at common pathogens. 34,39,41,42 Severity of infection may influence antibiotic choice in that mild infections may be treated more narrowly because disease progression is unlikely to interfere with the opportunity to modify the regimen when microbiology data become available. Regimens for severe infections should utilize broad-spectrum intravenous antibiotics. Any regimen must also account for allergy, renal function, recent antibiotic therapy and the possibility of antibiotic-resistant pathogens, and local susceptibility patterns. Empiric coverage for gram-positive bacteria (staphylococci and streptococci) is almost always required, so the usual question is whether to broaden the regimen to cover gram-negative bacteria (Table 12.4).34,41,42 Anaerobic coverage should be considered for necrotic or foul-smelling wounds. If the patient responds to the empiric therapy, then the regimen may be narrowed when microbiology data become available. If the patient does not respond, then the possibility of fastidious organisms missed by culture should be reconsidered, or surgery may be needed. Agents that have been effective for therapy of DFIs in clinical trials include cephalosporins, ~-lactamase inhibitor combination antibiotics, fluoroquinolones, clindamycin, carbapenems, vancomycin, and linezolid. Select results from clinical trials are shown in Table 12.4. The optimal duration of therapy for DFI has not been determined. A I-week course of therapy is sufficient for most mild infections, whereas up to 2 weeks may be necessary for serious infections. Adequate debridement, resection, or amputation can shorten the necessary duration of therapy. Bloodstream infection is a rare complication for which many experts recommend 2 weeks of therapy. Therapy may be discontinued when

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INFECTION S O F S K I N AN D S O F T TI S SUE

TABLE 12.4. Recent Prospective Trials of Antibiotic Therapy for Complicated Skin and Skin Structure Infections of the Foot in Patients with Diabetes Mellitus. Study

Drug

Com parator

Result

N otes

Lipsky"

Linezolid 600mg i.v.] p.o.

Ampicillin-sulh actam 3g i.v. every 6 h, then amoxicillinclavulanate 875mg every 12h

IP = n.s.], linezolid superior

Clinical cure 81% vs. 71%

Ope n label; randomized; L:A-S 2: I; treatment for 7-28 days

Harkless"

Piperacillin-tazobactam 4.5g every 8 h i.v,

Amp icillin-sul bactam 3g i.v, every 6 h

Lipsky' !

Ertapenem 1g daily

Piperacillin- tazobactarn 3.375g every 6h for 5 days, arnoxicillin-clavulanate 1g p.o. every 12h for up to 23 days

all signs and symptoms of infection have resolved; incomplete wound healing is not an indication to prolong antibiotic therapy. ADJUNCTS TO ANTIBIOTIC THERAPY

Hyperbaric oxygen may improve wound healing and decrease the rate of amputation of DFI according to one double-blind randomized trial." However, most evidence of hyperbaric oxygen effect in DFI is anecdotal." The hyperbaric oxygen literature is difficult to interpret because of poor controlling for multiple patient comorbidities, small sample sizes, and poor documentation of wound size and severity. Potential candidates for hyperbaric oxygen therapy include those patients with deep infections who are unresponsive to therapy, making amputation a definite possibility. Objectively, hyperbaric oxygen may be most beneficial when the transcutaneous oxygen tension is less than 40mmHg before therapy and increases to above 200mmHg after therapy." Surgical revascularization may also be considered." Improving blood flow to the ischemic, infected foot may be a crucial determinant of outcome. Initial debridement is undertaken in the presence of infection; revascularization is generally postponed until sepsis is controlled, but should not be postponed more than a few days lest there be additional tissue loss. Successful revascularization of an ischemic, infected foot can result in 3-year limb salvage rates of up to 98%,,6 A good outcome may be expected in 80%-90% of mild cases treated appropriately and 50%-60 % for more advanced DFIs. Aggressive surgical debridement is often needed for infections of deep tissue or bone . Partial amputations (e.g., toe amputation, "ray" amputation of a metatarsal) may be foot sparing and lead to effective control of infection in more than 80% of cases. Healing is facilitated when there is no exposed bone, absent tissue edema, a palpable popliteal pulse , ankle systolic blood pressure above 80mmHg, and a white blood cell(WBC) count below 12,OOO/mm3. Infection recurs in 20%-30% of cases and should increase the suspicion of underlying osteomyelitis. O STEOMYELITIS

Osteomyelitis is a feared complication of DFI (incidence, 50%-60% in serious DFIs and 10%-20% in mild infectionsl," but diabetic patients may have destructive bone lesions that are caused by peripheral neuropathy [e.g., Charcot joint]. Dis-

in post hoc foot ulc er an d no nosteomyelitis groups Clinical cure 81% vs. 83%; confidence interval not report ed 94% vs. 92 % cure, E popul at ion; 95 % CI (-2 .9 to 6.91

Open label ; vancomycin I g i.v. every 12h optional for both groups No ni nferior; treatment for up to 28 days

tinguishing between neuropathic and infectious destruction of bone can be difficult. The likelihood of osteomyelitis is increased with foot ulcers that are chronic (>4 weeks), large (>2cm diameter I, deep (>3mml, or associated with a marked elevation of ESR (>70mmfh).38 Wound exploration that "probes to bone " has a positive predictive value of more than 90% for the diagnosis of osteomyelitis. The initial diagnostic test should be plain radiographs of the foot. It may take 2 weeks for radiographic changes to become manifest, so repeating an initially negative study in a stable patient may be a better strategy than proceeding immediately to more sophisticated imaging. If clinical and plain radiographic findings are nondiagnostic, then various types of scans may be useful. Technetium 99 m bone scans are 85% sensitive but only 45% specific . Leukocyte scans (e.g., 111In ) are comparably sensitive but more specific (-75 %). However, magnetic resonance imaging (MRI) is usually the diagnostic test of choice despite its expense because of high sensitivity (>90%) and specificity (>80%1. A definitive diagnosis of osteomyelitis requires a bone biopsy for culture and histology, obtained without traversing an open wound to avoid contamination by colonizing organisms. Surgical biopsy is indicated if the diagnosis remains in doubt after imaging studies are obtained or if the etiologic agent(s) cannot be ascertained because of previous antibiotic therapy or confusing culture results. Most cases of osteomyelitis are polymicrobial; S. aureus is isolated most commonly (-40 %), but S. epiderm idis, streptococci, and Enterobacteriaceae are also isolated commonly. Antibiotic therapy of osteomyelitis should be based on results of bone culture because soft tissue culture results do not predict bone pathogens accurately." Empiric therapy should always cover S. aureus; broader coverage should be administered based on history or results of soft tissue cultures. Most antibiotics penetrate bone poorly, and leukocyte function is impaired, so long-term (at least 6 weeks) parenteral (at least initially)therapy is required. Osteomyelitis complicating DFI can be arrested by antibiotic therapy alone in about twothirds of cases, so resection of infected bone is not always necessary. Oral antibiotics with good bioavailability [e.g., fluoroquinolones, clindamycin) may be useful for most of the therapeutic course. If all infected bone is removed, then a shorter course of therapy (e.g., 2 weeks) may be appropriate. Clinical resolution may be documented by a decrease to normal of the ESR or loss of increased uptake on a leukocyte scan .

244

CHAPTER 12

Skin

Superficiallncisional SSI

Subcutaneous Tissue ":>I---~-----4-----------

DeepSoftTissue (fasciaand muscle)

.,.

Deep Incisional SSI

>1----------1---------------

Organ/Space

Organ/Space SSI

".

""-----"""---'----_..&._----------------------_.. Surgical Site Infection Infections of surgical incisions are now referred to as surgical site infections (SSls),47 a common surgical complication that occurs after about 3 % of all surgical procedures." Potential complications of SSls include tissue destruction, failure or prolongation of wound healing, incisional hernias, and occasionally bloodstream infection. Recurrent pain and disfiguring scars may also result. The SSls result in substantial morbidity, prolonged hospital stays, and increased direct patient costs, creating a huge economic burden on health care systems." Infection may occur within the surgical site at any depth, from the skin to the intracavitary operative field. Superficial TABLE 12.5. Risk Factors for the Development of Surgical Site Infections. Patient factors Ascites Chronic inflammation Corticosteroid therapy (controversial) Obesity Diabetes Extremes of age Hypocholsterolemia Hypoxemia Peripheral vascular disease (especially for lower extremity surgery) Postoperative anemia Prior site irradiation Recent operation Remote infection Skin carriage of staphylococci Skin disease in the area of infection (e.g., psoriasis) Undernutrition Environmental factors Contaminated medications Inadequate disinfection/sterilization Inadequate skin antisepsis Inadequate ventilation Treatment factors Drains Emergency procedure Hypothermia Inadequate antibiotic prophylaxis Oxygenation (controversial) Prolonged preoperative hospitalization Prolonged operative time Source: Adapted from National Nosocomial Infections Surveillance System (NNIS I System Report," by permission of the American Journal of Infection Control.

FIGURE 12.4. Cross section of the abdominal wall depicting U.S. Centers for Disease Control and Prevention (CDC) classifications of surgical site infection. (Source: Adapted from Mangram et al.," by permission of Infection Control Hospital Epidemiology. )

incisional SSI involves tissues down to the fascia (Fig. 12.4', whereas deep incisional SSI extends beneath the fascia but not intracavitary. Organ/space infections are intracavitary, but if related directly to an operation, are considered to be SSls. EPIDEMIOLOGY

Numerous factors determine whether a patient will develop an SSI, including factors contributed by the patient, the environment, and the treatment (Table 12.5).sO As described by the National Nosocomial Infections Surveillance System (NNIS)sQ-s2 of the U.S. Centers for Disease Control and Prevention (Table 12.6), the most recognized factors are the wound classification (contaminated or dirty; see below and Table 12.7),American Society of Anesthesiologists (ASA) designation above class 3 (chronic active medical illness; Table 12.8), and prolonged operative time, with time longer than the 75th percentile for each such procedure. Clean surgical procedures (class I) (Table 12.7) involve only integumentary and musculoskeletal soft tissues (e.g., groin hernia, breast, thyroid). Clean-contaminated procedures (class II) open a hollow viscus (e.g., alimentary, biliary, genitourinary, respiratory tract) under controlled circumstances (e.g., elective colon surgery). Contaminated procedures (class III) involve extensive introduction of bacteria into a normally sterile body cavity but too briefly to allow infection to become established (e.g., penetrating abdominal trauma, enterotomy during adhesiolysis for mechanical bowel obstruction). Dirty procedures (class IV) are those when the surgery is performed to control TABLE 12.6. National Nosocomial Infections Surveillance System (NNIS) Risk Index for Surgical Site Infections, Traditional class

Clean Clean/contaminated Contaminated Dirty All

0

1

2

3

All

1.0% 2.10/0 NA NA 1.5%

2.30/0 4.9% 3.40/0 3.10/0 2.9%

5.40/0 9.50/0 6.60/0 8.1% 6.8%

NA NA 13.20/0 12.80/0 13.0%

2.1 0/0 3.30/0 6.40/0 7.10/0 2.80/0

NA, not applicable. Source: Adapted from National Nosocomial Infections Surveillance System (NNISI System Report," by permission of the American Journal of Infection Control.

INFECTIONS OF SKIN AND SOFT TISSUE

245

TABLE 12.7. Surgical Site Infection Wound Classification and Approximate Rates of Infection. Class

Definition

Examples

I: Clean

Atraumatic wound No inflammation No break in aseptic technique No entry of biliary, respiratory, GI, or GU tracts If drained, by closed drainage Same as I, clean

Hemiorraphy Excision of skin lesion Thyroidectomy

1-5

Vascular surgery with graft

1-5

Appendectomy without perforation Elective colectomy after bowel preparation Cholecystectomy

2-9

Penetrating abdominal with hollow viscus injury Inadvertent enterotomy during adhesiolysis for mechanical small intestinal obstruction

3-13

ID : Clean; prosthetic material implanted IT: Clean-contaminated

Cardiac valve replacement Atraumatic wound No inflammation

lIT: Contaminated

Minor break in aseptic technique Biliary, respiratory, GI, or GU tract entered under controlled conditions with minimal contamination Traumatic wound with delay in therapy or exogenous contamination Acute nonpurulent inflammation Major break in aseptic technique Entry of biliary, respiratory, GI, or GU tract with gross spillage of contents

Rate (%)

GI, gastrointestinal; GU, genitourinary.

established infection (e.g., colon resection for complicated diverticulitis). According to the NNIS classification, the risk of SSI increases with an increasing number of risk factors present, irrespective of the wound class and almost without regard for the type of operation. Laparoscopic abdominal surgery is associated with a decreased incidence of SSIunder certain circumstances, which has required a modification of the NNIS risk classification." For laparoscopic biliary, gastric, and colon surgery, one risk factor is subtracted if the operation is performed via the laparoscope-a new category has been created specifically for the circumstance, representing essentially minus one risk factor. Laparoscopy decreases the risk of SSI

TABLE 12.8. American Society of Anesthesiologists (ASA) Physical Status Score. ASA 1 ASA2

ASA3

ASA4

ASA5

ASA6

A normal healthy patient. A patient with mild-to-moderate systemic disturbance that results in no functional limitations. Examples: hypertension, diabetes mellitus, chronic bronchitis, morbid obesity, extremes of age. A patient with severe systemic disturbance that results in functional limitations. Examples: poorly controlled hypertension, diabetes mellitus with vascular complications, angina pectoris, prior myocardial infarction, pulmonary disease that limits activity. A patient with a severe systemic disturbance that is life threatening with or without the planned procedure. Examples: congestive heart failure; unstable angina pectoris; advanced pulmonary, renal, or hepatic dysfunction. A morbid patient not expected to survive with or without the operative procedure. Examples: ruptured abdominal aortic aneurysm, pulmonary embolism, traumatic brain injury with increased intracranial pressure. Any patient for whom the procedure is an emergency.

Source: From Cohen and Duncan. 130

for several reasons, including decreased wound size, limited use of cautery, and a diminished stress response to tissue injury. Laparoscopic appendectomy, on the other hand, is a unique circumstance in that the risk of SSI is reduced by laparoscopy only if no risk factors are present (i.e., the patient is otherwise healthy, the appendix is not perforated, and the operation does not take more than 1h). Outpatient surgery poses problems for surveillance of SSI. 53 Although many SSls will develop in the first 5-10 days after surgery, an SSI may develop up to 30 days after surgery. Estimates of the incidence of SSI after ambulatory surgery thus depend on inherently unreliable voluntary self-reporting by surgeons. Therefore, the incidence of SSIin NNIS is almost certainly an underestimate. Organ/space SSls also are not identifiable separately in the data reported by NNIS. Host-derived factors are important contributors to the risk of SSI,which the ASA score may not capture. Increased age,54 obesity, malnutrition, diabetes mellitus.v" hypo cholesterolemia," and other factors are not accounted for specifically by NNIS. In a study of 2345 patients undergoing cardiac surgery, the incidence of SSI was 8.5% (199/2345).58 The relative risk (RR) of SSI among diabetic patients was 2.29 (95% confidence interval [CI] 1.15-4.54), and the RR among obese patients (body mass index >30) was 1.78 (95% CI, 1.24-2.55). Malone et al. found an incidence of SSI of 3.20/0 among 5031 noncardiac surgery patients at a Veterans Affairs hospital. Independent risk factors for the development of SSI included ascites, diabetes mellitus, postoperative anemia, and recent weight loss but not chronic obstructive pulmonary disease, tobacco use, or corticosteroid use." Other studies have linked low serum albumin concentration and increased serum creatinine concentration to an increased risk of SSI.59 MICROBIOLOGY

Inoculation of the surgical site occurs during surgery, either inward from the skin or outward from the tissues operated on. The microbiology of SSIdepends on the type of operation,

246

CHAPTER 12

Escherichia coli) and anaerobic (e.g., Bacteroides fragilis) bacteria.

TABLE 12.9. Incidence of Pathogen Isolation in Surgical Site Infection (Collected Series). Organism

Staphylococcus aureus Coagulase-negative staphylococci Enterococci Pseudomonas aeruginosa Escherichia coli Enterobacter spp. Proteus mirabilis Streptococcus spp. Klebsiella pneumoniae Candida albicans

Percentage

20 14 12

8 8

7 3 3 3 2

with an increased likelihood of gram-negative bacilli after gastrointestinal surgery or infrainguinal vascular surgery. However, most SSIs are caused by gram-positive cocci that are commensal skin flora (Table 12.9),60 including S. aureus, coagulase-negative staphylococci .(usually S. epidermidis), and Enterococcus spp. Head and neck surgery (if pharyngoesophageal structures are entered) and intestinal surgery may be associated with SSI caused by enteric facultative (e.g.,

PREOPERATIVE PREPARATION

The patient should be assessed before elective surgery for correctable risk factors. Open skin lesions should heal beforehand if possible. The patient should be free of bacterial infections of any kind and should quit smoking if possible, preferably 1 month before surgery. The patient should shower with an antibacterial soap the night before the operation. The patient must not be shaved the night before, considering that the risk of SSI is increased by bacteria that colonize the inevitable small cuts and abrasions." Particular attention should be paid to the patient's nutritional status. Obese patients should lose as much weight as is safely possible. Malnourished patients can reduce the risk of SSIsignificantly with as few as 5 days of enteral nutritional supplementation. 61,62 ANTIBIOTIC PROPHYLAXIS AND THE RISK OF

SSI

Preoperative administration of prophylactic antibiotics to reduce the risk of postoperative SSI is of proven benefit in many circumstances (Table 12.10). However, only the

TABLE 12.10. Appropriate Cephalosporin Prophylaxis for Selected Operations.' Operation

First-generation cephalosporin (i.e., cefazolin,cefuroxime) Cardiovascular and thoracic Median sternotomy Pacemaker insertion Vascular reconstruction involving the abdominal aorta, insertion of a prosthesis, or a groin incision (except carotid endarterectomy, which requires no prophylaxis) Implantable defibrillator Pulmonary resection Lower limb amputation General Cholecystectomy (high risk only: age >60, jaundice, acute, prior biliary procedure) Gastrectomy (high risk only: not uncomplicated chronic duodenal ulcer) Hepatobiliary Major debridement of traumatic wound Genitourinary (ampicillin plus gentamicin is a reasonable alternative) Gynecological Cesarean section (STAT) Hysterectomy (cefoxitin is a reasonable alternative) Head and neck/oral cavity Major procedures entering oral cavity or pharynx Neurosurgery Craniotomy Orthopedics Major joint arthroplasty Open reduction of closed fracture Second-generation [i.e., cefoxitin]' Appendectomy Colon surgery" Surgery for penetrating abdominal trauma

Alternative prophylaxis in serious penicillin allergy

Clindamycin (for all cases herein except amputation]" Vancomycin

Gentamicin and metronidazole Gentamicin Gentamicin and metronidazole Gentamicin and metronidazole Gentamicin Ciprofloxacin Metronidazole (after cord clamping) Doxycycline Gentamicin and clindamycin or metronidazole Clindamycin, vancomycin Vancomycin" Vancomycin" Metronidazole with or without gentamicin (for all cases herein)

"Should be given as a single intravenous dose just before the operation. Consider an additional dose if the operation is longer than 3-4 h. "Primary prophylaxis with vancomycin (i.e., for the non-penicillin-allergic patient) may be appropriate for cardiac valve replacement, placement of a nontissue peripheral vascular prosthesis, or total joint replacement in institutions where a high rate of infections with methicillin-resistant Staphylococcus auteus or Staphylococcus epidermidis has occurred. The precise definition of high rate is debated. A single dose administered immediately before surgery is sufficient unless operation lasts for more than 6h, in which case the dose should be repeated. Prophylaxis should be discontinued after a maximum of two doses but may be continued for up to 48 h. cAn intraoperative dose should be given if cefoxitin is used and the duration of surgery exceeds 3-4h because of the short half-life of the drug. A postoperative dose is not necessary but is permissible for up to 24 h. "Benefit beyond that provided by bowel preparation with mechanical cleansing and oral neomycin and erythromycin base is debatable.

247

INFE CTI ON S OF SKIN AND SOFT TISSUE

-lI'";_ _

TABLE 12.11. Systemic An timicrobial Prophylaxis in Colorectal Surgery: Systematic Review of Ran domized Controlled Trials.

Analysis

Cefuroxime + metronidazole vs. m etronidazole alone vs. m ezlocillin vs. all comparators overall First "-generation cephalosporins vs. later-generat ion cephalosporins Single-dose prophylaxis vs. multiple-dose prophylaxis Parenteral antibiotics vs. parenteral plu s oral antibiotics

No. of trials

OR

4 3 16

0.32 0.55 No difference [not reported)

0.15...Q.68 0.32...Q.93

6

1.07

0.54-2.12

17

1.17

0.90-1.53

4

1.13

0.60-2.14

95 % CI

·With or without metronidazole. Source: Data from Song and Glenny."

incision itself is protected, and antibiotics are not a panacea . If not administered properly, then antibiotic prophylaxis will not be effective and may be harmful. Antibiotic prophylaxis is indicated for most clean-contaminated and contaminated lor potentially contaminated) operations. An example of a clean-contaminated operation for which antibiotic prophylaxis is not always indicated is elective cholecystectomy." Antibiotic prophylaxis is indicated only for high-risk biliary surgery; patients at high risk include those over age 70 or who have diabetes mellitus and patients whose biliary tract has been instrumented recently (e.g., biliary stenn." The vast majority of patients who undergo laparoscopic cholecystectomy do not require antibiotic prophylaxis." An example of a potentially contaminated operation is adhesiolysis for mechanical small bowel obstruction; intestinal ischemia cannot be predicted accurately before surgery, and an enterotomy during adhesiolysis increases the risk of SSI twofold . Antibiotics for dirty operations represent treatment for an infection, not prophylaxis. Elective colon surgery is a clean-contaminated procedure for which preparatory practices are in evolution." Historically, mechanical bowel preparation to reduce bulk feces made colon surgery safe, but trauma surgeons have demonstrated that the injured, unprepared colon can be operated on safely. Antibiotic bowel preparation, standardized in the 1970s by the oral administration of nonabsorbable neomycin and erythromycin base, reduced the risk of SSI further to its present rate of approximately 4%-8%, depending on the number of risk factors . However, preoperative oral antibiotics are omitted increasingly because there may be no additive benefit beyond parenteral antibiotic prophylaxis with cefoxitin or ampicillin-sulbactam (or a quinolone or monobactam plus metronidazole for the penicillin-allergic patient) given within 1h prior to the skin incision." Parenteral antibiotic prophylaxis is undeniably effective (Table 12.11).66 Compliance with the performance standards of the Surgical Care Improvement Program (SCIP)/ ? which is mandatory for U.S. health care facilities , will be achieved by oral or parenteral prophylaxis or both (Table 12.12). Antibiotic prophylaxis of clean surgery has been controversial. If bone is incised (e.g., craniotomy, sternotomy) or a prosthesis is inserted, then antibiotic prophylaxis is generally

indicated. Some controversy persists with clean surgery of soft tissues (e.g., breast, hernia) . Meta -analysis of randomized controlled trials shows some benefit of antibiotic prophylaxis of breast cancer surgery without immediate reconstrucnon'f-" (Table 12.13), but no decrease of SSI rate for groin hernia surgery .P'" even when a nonabsorbable mesh prosthesis is implanted (Table 12.13). Arterial reconstruction with prosthetic graft material of vein is an example of clean surgery for which the susceptibility to infection is high owing to the presence of ischemic tissue and the infrainguinallocation of many such operations. Several aforementioned strategies have been studied in an attempt to reduce the risk of SSI.A meta-analysis" identified 35 randomized, controlled trials for prevention of infection after peripheral arterial reconstruction, with 23 of these pro-

TABLE 12.12. Surgical Care Improvement Program: Approved Antibiotic Prophylactic Regimens for Elective Surgery. Type of operation

Antibiotic(s)

Cardiac (including coronary artery bypass grafting [CABG]),' VascularHip/knee arthroplasty" Colon".•

Cefazolin or cefuroxime or vancomycin?

Hysterectomy'

Cefazolin or cefuroxime or vancomycin" Oral: neomycin sulfate plus either erythromycin base or metronidazole administered for 18 h before surgery Parenteral: cefoxitin or cefotetan or cefazolin plus metronidazole or ampicillin-sulbactam Cefazolin or cefoxitin or cefotetan or cefuroxime or ampicillin-sulbactam

' Prophylaxis may be administeredfor up to 48h for cardiacsurgery; for all other cases, the limit is 24h. bFor ~-lactam allergy, clindamycin or vancomycin are acceptable substitutes for cardiac, vascular, and orthopedic surgery. 'Vancomycin is acceptable with a physician-documented justification for use in the patient's medical record. dFor ~-lactam allergy, clindamycin plus gentamicin, a fluoroquinolone, or aztreonam, or metronidazole plus gentamicin or a fluoroquinolone are acceptable choices. 'For colon surgery, either oral or parenteralprophylaxisalone or both combined are acceptable.

248

C H A P T E R 12

TABLE 12.13. Antibiotic Prophylaxis for Reduction of Surgical Site Infection Following Clean Surgery: Two Meta -Analyses.

Analysis

Breast surgery" Overall Breast cancer surgery'" No immediate reconstruction Immediate reconstruction Abdominal wall hernia surgery Overall results" Inguinal herniorraphy (no prosthetic material) Inguinal hernioplasty (prosthetic material used) Overall results' (groin, mesh repairs only) Deep incisional SSI (groin, mesh) Other abdominal wall hernias, mesh

No. of trials

OR

5/1307

0.60

0.45-0.81

5/1254 Insufficient data for analysis

0.66

0.48-0 .89

8/2907

0.65 0.84 0.28 0.54 0.50

0.35-1.21 0.53-1.34 0.02-3.14 0.24-1.21 0.12-2.09

6/2507 5/1987 Insufficient data for analysis

95% CI

'Data from Tejirian et al.68 bData from Cunningham et al." 'Analysis of the same five trials. dData from Sanchez-Manuel and SeeD-GiL" ' Data from Aufenacker et al.70

phylactic systemic antibiotics trials (Table 12.14). Prophylactic systemic antibiotics reduced the risk of SSI by approximately 75% and earl y graft infection by about 69 % . There was no benefit to prophylaxi s for more than 24h, of antibiotic bonding to the graft material it self, or preoperative bathing with an antiseptic agent compared with unmedicated bathing. Four principles should guide selection of the appropriate antimicrobial agent for prophylaxis: The agent should be safe, the agent should have an appropriately narrow spectrum of coverage of relevant pathogens; the agent should not be one that is relied on for therapy of infection (owing to the possible induction of resistance with heavy usage], and the agent must be administered for a defined, brief period of time (ideally, a single dose, certainly for no more than 24 h ). According to TABLE 12.14. Meta -Analysis of Measures to Prevent Infection Following Arterial Reconstruction.

Intervention

Systemic antibiotic prophylaxis Surgical site infection >24 h prophylaxis Early graft infection Rifampicin bonding of polyester grafts Graft infection, 1 month Graft infection, 2 years Suction wound drainage, groin Surgical site infection Preoperative antiseptic bath Surgical site infection In situ surgical technique Surgical site infection Source: Data from Stewartet al."

No. of trials

Odds ratio

95% CI

10

3 5

0.25 1.28 0.31

0.17-0 .38 0.82-1.98 0.11-0 .85

3 2

0.63 1.05

0.27-1.49 0.46-2.40

2

0.96

0.50-1.86

3

0.97

0.70-1.36

2

0.48

0.3 1-0 .74

these principles, third-generation cephalosporins or quinolones should never be used for surgical prophylaxis. Given that most SSIs are caused by gram-positive cocci, the antibiotic chosen should be directed primarily against staphylococci for clean case s and high-risk, clean-contaminated elective biliary and gastric surgery. A first-generation cephalosporin is preferred (Table 12.101, with clindamycin used for penicillin-allergic patients." Vancomycin prophylaxis is appropriate only in in stitutions where the incidence of MRSA infection is high (>20% of all SSIs caused by MRSA). The optimal time to give parenteral antibiotic prophylaxis is within I h prior to the time of incision." Antibiotics given sooner are ineffective, as are agents that are given after the incision is closed. Antibiotics with short half -lives «2 h, e.g., cefazolin or cefoxitin) should be redosed every 3-4h during surgery if the operation is prolonged or bloody." Choice, timing, and duration of prophylactic antibiotic administration have been standardized as part of SCIp 67 (Tables 12.12 and 12.151, and institutional compliance (eventually, possibly compliance by individual surgeons) will be required. Preoperative topical antiseptics or antibiotics may also he lp prevent SSI. A preoperative shower with an antiseptic soap (e.g., ch lorhexidine] should be a standard part of preoperative preparation but is omitted often. Topical 2% mupirocin ointment applied to the nares of patients who are chronic carriers of S. aureus may reduce the increased incidence of SSI that is cha racteristic of chronic staphylococcal carriage." :" Unfortunately, excessively prolonged antibiotic prophylaxis is both pervasive and potentially harmful. Recent U.S. data showed that only 40 % of patients who receive antibiotic prophylaxis do so for less than 24 h.78 Antibiotic penetration into the incision immediately after surgery is questionable as a result of ischemia caused by surgical hemostasis. Singledose preoperative prop hylaxis is often su fficien t, with intraoperative dosing as noted above, but 24- to 48-h regimens (the latter for cardiac surgery) have become standardized . Antibi-


TABLE 12.15. Surgical Care Improvement Project: Performance Measures Relevant to Prevention of Surgical Site Infection. Antibiotic prophylaxis

• Proportion of patients who have their antibiotic dose initiated within 1h before surgical incision (2h for vancomycin or fluoroquinolones) • Proportion of patients who receive prophylactic antibiotics consistent with current recommendations (published guidelines) • Proportion of patients whose prophylactic antibiotics were discontinued within 24h of surgery end time (48h for cardiac surgery) Clindamycin use is preferred for patients allergic to ~-lactam antibiotics. Vancomycin is allowed for prophylaxis of cardiac, vascular, and orthopedic surgery if there is a physician-documented reason in the medical record or documented ~-lactam allergy. Glucose control (cardiac surgery patients)

• Blood glucose concentration must be maintained 14 days of storagel.l'" A recent meta-analysis estimated that transfusion of any volume of red blood cell (RBC) concentrates more than triples the risk of nosocomial infection compared with no transfusion.l'" Observational

studies suggested that transfusion of critically ill patients not only increases the risk of infection'?' but also may worsen organ dysfunction and increase mortality.105

Hyperglycemia, Nutrition, and Control of Blood Sugar Hyperglycemia is deleterious to host immune function, most notably impairing function of neutrophils and mononuclear phagocytes. Hyperglycemia may also be a marker of the catabolism and insulin resistance associated with the surgical stress response. Poor control of blood glucose during surgery and in the perioperative period increases the risk of infection and worsens outcome from sepsis. Diabetic patients undergoing cardiopulmonary bypass surgery have a higher risk of infection of both the sternal incision and the vein harvest incisions on the lower extremities.l'" Tight control of blood glucose by the anesthesiologist during surgery and during the early postoperative period decreases the risk. Control of blood glucose for cardiac surgery patients is mandatory under SCIP (Table 12.15). Moderate hyperglycemia (>200mgjdl) at any time on the first postoperative day increases the risk of SSI fourfold after noncardiac surgery." In a large randomized trial of critically ill postoperative patients, exogenous insulin administration to keep blood glucose concentrations below 110mgjdl was associated with a 40% decrease of mortality, fewer nosocomial infections, and less organ dysfunction.'!" Metaanalysis of the approximately 35 existing trials indicates that the risk of mortality is decreased significantly (relative risk [RR] 0.85, 950/0 CI 0.75-0.97] by tight glucose control, especially so for critically ill surgical patients (RR 0.58, 95 % CI 0.22-0.62), regardless of whether the patients had diabetes mellitus (RR 0.71, 950/0 CI 0.54-0.93) or stress-induced hyperglycemia (RR 0.73,950/0 CIO.58-0.90).108 The need to manage carbohydrate metabolism carefully has important implications for the nutritional management of surgical patients. Gastrointestinal surgery may render the gastrointestinal tract unusable for feeding, sometimes for prolonged periods. Ileus is common in surgical intensive care units (ICUs), whether from traumatic brain injury, narcotic analgesia, prolonged bed rest, inflammation in proximity to the peritoneal envelope (e.g., lower lobe pneumonia, retroperitoneal hematoma, fractures of the thoraco-lumbar spine, pelvis, or hip), or other causes. Parenteral nutrition is used frequently for feeding, despite evidence of a lack of efficacy'?" and the possibility of hepatic dysfunction; hyperglycemia may be an important complication as well. Every effort should be made to provide enteral feedings, including the use of promotility agents such as erythromycin to improve tolerance."? Early enteral feeding (within 36 h) reduces the risk of nosocomial infection by more than one-half among critically ill and injured patients. III

Oxygenation It is somewhat intuitive that the administration of oxygen in the postoperative period would be beneficial for wound healing and the prevention of infection.l" The fresh surgical incision is ischemic; maintenance of normothermia may promote vasodilation of local tissue beds to improve nutrient blood flow to the incision. Moreover, oxygen has been postu-


lated to have a direct antibacterial effect. However, clinical trials have had conflicting results. 1l3,114 In a study of 500 patients undergoing elective colorectal surgery, administration of 80% oxygen (vs. 300/0 oxygen) during surgery and for 2 h thereafter decreased the incidence of SSI by more than 500/0 (5.20/0 vs. 11.2%),113 whereas another prospective trial of the utility of 800/0 versus 350/0 oxygen administered to 165 patients undergoing major intraabdominal procedures showed that the infection rate was twice as high (25.00/0 vs. 11.3%) after 80% oxygen.!" Although the latter trial can be criticized for the high overall rate of SSI (18.1%) and possible underpowering, supplemental oxygenation administration specifically to reduce the incidence of SSI is now controversial.

Diagnosis and Treatment of Surgical Site Infection Specific criteria have been established by the Centers for Disease Control and Prevention for the diagnosis of SSI(Table 12.16). Adherence to these diagnostic guidelines is important

TABLE 12.16. Criteria for Diagnosis of Superficial and Deep (Organ Space) Surgical Site Infections (SSIs) Within 30 Days of All Procedures (1 Year If Prosthetic Material Is Implanted). Incisional SSI

Superficial: Infection involves skin or subcutaneous tissue of the incision and at least one of the following: 1. Purulent drainage from the superficial incision. 2. Organisms isolated from an aseptically obtained culture from the superficial incision. 3. One or more of the following: pain, localized swelling, erythema, or heat, and incision is opened deliberately by surgeon unless incision is culture negative. 4. Diagnosis of superficial incisional SSI by surgeon. Deep: Infection involves fascial or muscle layer of the incision and at least one of the following: 1. Purulent drainage from the deep incision, excluding organ/space.' 2. Incision that dehisces spontaneously or is opened deliberately by a surgeon in the presence of fever (>38°C) or pain, unless site is culture negative. 3. Evidence of infection is found on direct examination, during repeat surgery, or by histopathologic or radiologic examination. b 4. Diagnosis of deep incisional SSI by surgeon. Organ/space SSI

Infection of any part of the anatomy (e.g., organs or surgically created spaces) opened or manipulated during an operation and at least one of the following: 1. Purulent drainage from a drain that is placed into the organ/ space. 2. Organisms isolated from an aseptically obtained culture from the organ/space. 3. Evidence of infection is found on direct examination, during repeat surgery, or by histopathologic or radiologic examination." 4. Diagnosis of an organ/space SSI by surgeon. For all classifications, infection is defined as occurring within 30 days after the operation if no implant is placed or within 1 year if an implant is in place and the infection is related to the incision. "Report infection that involves both superficial and deep incision sites as a deep incisional SSI. "Report an organ/space SSI that drains spontaneously through the incision as a deep incisional SSI.

Source: Adapted from Mangram et a1.,6O by permission of Infection Control Hospital Epidemiology.

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because SSI can be misdiagnosed otherwise. Not all draining or erythematous incisions are infected. A superficial swab culture will likely become contaminated during specimen collection and be overinterpreted. Proper surveillance requires the prospective involvement of specifically trained personnel, adhering to the aforementioned criteria, who inspect incisions directly. Retrospective studies are nearly certain to be plagued by diagnostic inaccuracy and therefore are inherently dubious. Likewise, voluntary self-reporting by surgeons produces notorious underestimates of incidence because reporting does not occur and because the plethora of ambulatory surgical procedures escape hospi tal-based surveillance programs. Therefore, published data from the NNIS (Table 12.6) probably are at or near the lower end of the confidence interval. There is only one constant in the management of established SSI: incise and drain the incision. Often, opening the incision and applying basic wound care (e.g., topical saline-soaked wet-to-dry cotton gauze dressings) is sufficient, provided that the incision is opened wide enough to facilitate wound care and the diagnosis of associated conditions. Making an incision that is too small may fail to bring the infection under control. Most nostrums other than physiologic saline applied to gauze dressings (e.g., modified Dakin's solution, 0.25% acetic acid solution) actually suppress fibroblast proliferation and may delay secondary wound healing. Opening the incision adequately is essential not only to gain control of the infection but also to diagnose and treat any associated conditions, such as skin, subcutaneous tissue, or fascial necrosis that requires debridement; fascial dehiscence or evisceration that requires formal abdominal wall reconstruction; or drainage from beneath the fascia that could signal an organ/space infection or an enteric fistula. Without control of complicating factors, a SSI will be difficult to control, if not impossible. Antibiotic therapy is not required for uncomplicated SSIs that are opened and drained adequately and that receive appropriate local care. Likewise, if antibiotic therapy is unwarranted, then culture and susceptibility testing of wound drainage are of no value and can be omitted. Even if cultures are taken, routine swabs of drainage are not recommended because the risk of contamination by commensal skin flora is high. Rather, tissue specimens or an aliquot of pus collected aseptically and anaerobically into a syringe are recommended for analysis. Antibiotics may be indicated if there is systemic evidence of toxicity (e.g., fever, leukocytosis) or cellulitis that extends more than 2 em beyond the incision. Antibiotics are also indicated as adjunctive management of several of the complications mentioned. The choice of antibiotic is defined by the operation performed through the incision and the likely infecting organism, as discussed. Coverage against grampositive cocci is indicated in most circumstances. Wound closure by secondary intention can be protracted and disfiguring. Reports of vacuum-assisted wound closure (VAC) are proliferating. Putative benefits of VAC dressings include reduced inflammation, increased fibroblast activity, improved wound hygiene as fluid is aspirated continuously from the field, and more rapid wound contraction and closure.!" However, these benefits remain conjectural in the absence of definitive class I data.

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CHAPTER 12

Necrotizing Soft Tissue Infection Necrotizing soft tissue infections (NSTIs) are dangerous but fortunately also uncommon.!" There is danger because of rapid progression and much systemic toxicity. Bacterial proteases cleave tissue planes, facilitating the rapid spread of infection. Host defenses are rapidly overwhelmed, leading to hemodynamic instability and hypoperfusion. Ischemic tissue in tum is susceptible to progression of the infection, and organ dysfunction may also result. Necrotizing STIs are also dangerous because they are uncommon, and their initial manifestations can be subtle, increasing the possibility of a delay in diagnosis. Although most presentations are obvious, an NSTI must always be considered whenever a patient presents with severe pain, particularly of the perineum or an extremity, that is out of proportion to any physical findings. There may be no obvious portal. The presence of gas in the soft tissues on examination (crepitus) or by imaging study is helpful but unreliable if absent. Delayed definitive therapy (Le., surgical debridement) is the major risk factor for mortality in cases of NSTI; therefore, familiarity is crucial for anyone (e.g., surgeon, emergency physician, primary care physician) who might encounter an early presentation. True NSTIs cannot be treated successfully with antibiotics alone (although broad-spectrum antibiotics are an essential adjunct to surgery), so timely surgical consultation is mandatory. Even with optimal therapy, mortality is approximately 25%-300/0, and the hospitalization will be protracted, complicated, and expensive regardless of the outcome. Although many names have been applied to these serious infections, such as synergistic gangrene and the eponymous Fournier gangrene (of the scrotum), it is most useful to characterize NSTIs based on the deepest tissue layer involved by necrosis. Involvement of the skin and subcutaneous tissue only is necrotizing cellulitis, whereas involvement of the fascia (most common) is referred to as necrotizing [asciitis, and involvement of underlying muscle is referred to as necrotizing myositis or sometimes myonecrosis. Some experts classify NSTIs further by the causative pathogen (e.g., clostridial myositis) or whether the infection is polymicrobial (type I) or caused by a single organism (type IT). It is important to distinguish NSTIs from their nonnecrotizing SSTIsbecause the latter may be treated effectively with intravenous antibiotics alone. However, only operative debridement can classify accurately the anatomic extent of NSTI; therefore, attempts to classify NSTIs preoperatively can only engender dangerous, even life-threatening, delay.

Etiology Necrotizing STIs can be primary or secondary events. Primary, or idiopathic, infections are less common and lack a portal of entry. Whether the source of bacteria in primary NSTIs is the bloodstream or epithelial disruptions too small to be apparent is debated; either mechanism is possible. One well-known example, the halophilic marine bacteria of the genus Vibrio (especially V. vulni{icUS),117 can cause NSTIs after ingestion of raw seafood or skin trauma while wading in seawater. Another example is an NSTI caused by Clostridium septicum, which is specifically associated with occult carcinoma

of the colon (and likely arises after a bacteremia). Much more common are the secondary infections, which may arise after burns or trauma, in recent surgical incisions, or as a consequence of unrecognized, neglected, or inadequately treated SSTIs.Other potential portals of entry include human, animal, or insect bites and parenteral drug abuse.!" Secondary NSTls often have associated conditions that can predispose to tissue necrosis or impede containment by local host defenses. Inadequate treatment of SSTls, such as decubitus ulcers, 119 ischemic leg ulcers, Bartholin cyst abscess, or perirectal or ischiorectal abscess pose a high risk of progression to NSTI. However, for reasons unclear, SSTls of the face, neck, or chest I2D-123 progress less often to NSTI than infections of the perineum and lower extremity.

Microbiology Approximately 80% of NSTIs are polymicrobial (type I NSTI), with bacteria acting synergistically to promote dissemination and increase toxicity. Monomicrobial NSTIs are most commonly caused by Streptococcus pyogenes, with Clostridium perfringens also a relatively common pathogen. Rare causes of monomicrobial NSTI include V. vulnificus, communityassociated MRSA,7 and B. cereus. 124 Pseudomonas aetuginosa rarely is a pathogen of NSTI; rarer still are the infections caused by C. septicum and V. vulniiicus. Phycomycotic NSTI (mucormycosis) caused by Rhizopus, Mucor, or Absidia spp. may occur in profoundly immunosuppressed patients or after accidental burial by a landslide. In contrast, polymicrobial NSTI is the norm, with aerobic gram-positive and -negative bacteria and anaerobes usually all present in tissue. Escherichia coli and B. [ragilis are the most common anaerobic and aerobic isolates, respectively. The most likely gram-positive coccus to be isolated depends on the clinical context. For example, enterococci are more likely to be isolated when the NSTI complicates a recent abdominal incision.

Pathogenesis After inoculation of susceptible tissue, several factors determine the extent of infection, including the size of the inoculum, the invasiveness of the organism,125,126 the presence of a foreign body or ischemic tissue, and impaired host responses. Inoculation can occur from delayed or inadequate treatment of an initially localized process, inappropriate closure of a contaminated surgical incision that should have been left open, or in the presence of an enterostomy or retention sutures. Inoculation may also be occult; for example, NSTI of the thigh can be the initial manifestation of a colon perforation into the retroperitoneum. The hallmark of NSTI is rapid progression and a fulminant clinical course, especially for monomicrobial infections, but polymicrobial NSTIs are also bona fide emergencies that require rapid diagnosis and definitive treatment. Several bacterial enzymes cause tissue damage and promote bacterial invasiveness, including hemolysin, fibrinolysin, hyaluronidase, and streptokinase elaborated by S. pyogenes, collagenase elaborated by P. aeniginosa, and lecithinase elaborated by C. peihingens. Polymicrobial NSTIs are characterized by synergistic activity of facultative aerobes and anaerobes. Tissue hypoxia and impaired neutrophil function create conditions favorable for the proliferation of facultative bacteria, which


TABLE 12.17. Objective Criteria to Distinguish Necrotizing Soft Tissue Infections from Nonnecrotizing Infections. A. Diagnostic Accuracy Sensitivity

Specificity (%)

Positive predictive value (%)

Negative predictive value (%)

38 39 24 81 75 30 70

100 95 100 76 100 100 88

100 88 100 77 100 100 88

62 62 57 80 77 55 71

(%)

Tense edema Gas on x-ray Bullae WBC > 14 x 109 /1 Sodium < 135mg/dl Chloride < 95 mg/dl BUN> ISrng/dl

B. Incidence of Positive Laboratory Parameters (Univariate Analysis) Necrotizing fasciitis

WBC > 14 x 10 /1 Sodium < 135 mEq/l Chloride < 95 mEq/l Serum urea nitrogen> 15 mg/dl 9

17/21 15/20 6/20 14/20

(810/0) (750/0) (300/0) (700/0)

Other infection

5/21 0/17 0/17 2/17

(240/0) (00/0) (00/0) (120/0)

P value

.0002 .0001 .02 .0007

Source: Data from Hohlweg-Majert et al. 12 1 and Toran et al. 122

consume oxygen in the microenvironment and lower the tissue redox state, thereby creating conditions favorable for the growth of anaerobes. Extensive tissue necrosis develops from direct tissue injury caused by bacterial toxins, inflammation and tissue edema, and vascular thrombosis. The subcutaneous fat and fascia are more likely than the overlying skin to develop necrosis. Thus, there may be little or no early cutaneous evidence of underlying infection. However, as the infection progresses, thrombosis of the cutaneous microcirculation leads to the characteristic erythema, edema, bullae, and overt gangrene of advanced NSTI. Soft tissue gas mayor may not be present, depending on the pathogens involved, but develops as a result of anaerobic wound conditions that allow proliferation of gas-forming organisms, including C. perfringens, B. [tagilis, E. coli, Klebsiella ptieumoniae, P. aetuginosa, and Proteus spp. These bacteria produce insoluble gases such as hydrogen, nitrogen, and methane, which remain in the tissue to a variable degree. Gas in the tissue tends to be a late finding in nonclostridial polymicrobial infections and to be absent in NSTI caused by S. pyogenes.

Diagnosis The diagnosis of NSTI is based primarily on the history and physical examination. One notable early characteristic is a complaint of severe pain that is disproportionate to local physical findings. Inspection of the overlying skin may yield few early clues. Characteristic features to elicit include edema and tenderness that extend beyond the margin of erythema, skin vesicles or bullae, crepitus, and the absence of lymphangitis and lymphadenitis. As infection progresses, cutaneous anesthesia and necrosis develop along with clinical manifestations of sepsis (fever, tachycardia, hypotension, encepha-

253

lopathy). Occasionally, patients with clostridial sepsis will present with anemia and jaundice secondary to hemolysis, and patients with myonecrosis will present with myoglobinuria, rhabdomyolysis, and acute renal failure. Some common laboratory tests may point the clinician toward the diagnosis of NSTI in the appropriate clinical context. Wall et al. showed that hyponatremia ([Na]serum < 135mEq/dl) and leukocytosis (WBC count> 14 x 109 /1) have good diagnostic accuracy'F'!" (Table 12.17). Wong et al. described the Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score (Table 12.18)/29 which may be even more accurate" Although these observation have not been subjected to independent validation, they may be valuable to the extent that it heightens the suspicion of a clinician confronted with a possible NSTI who has seen one previously only rarely, if at all. If the diagnosis is not obvious by physical examination and laboratory testing, then radiographic studies may be obtained provided surgical exploration, which is the definitive diagnostic test as well as therapeutic intervention, is not unduly delayed. Plain radiographs can demonstrate gas in the soft tissues in the absence of crepitus, but the absence of gas does not exclude the presence of NSTI as it is usually a late finding when it does develop. Computed tomography (CT) is sensitive for the presence of soft tissue gas, and it may also demonstrate asymmetric edema of tissue planes (a nonspecific finding). A CT scan may be helpful in the evaluation of the obese patient with a deep-seated infection, for whom the physical examination can be unreliable. However, to the extent that obtaining any imaging study will delay the operative management of the patient, they should be avoided. The use of imaging studies as "confirmatory" tests cannot be

TABLE 12.18. Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) Score. Parameter

C-Reactive protein, mg/l 15 colonies by semiquantitative roll plate or > 103 colonies by sonication), then the catheter should be removed. In this setting, a course of antibiotics is not recommended. If a catheter and blood are positive (CR-BSI) and the catheter is a short-term catheter, then it should be removed. While some authors advocate that catheters can be treated through the catheter with an antibiotic lock, this cannot be generally recommended except in patients for whom venous access is a significant concern.'!" For patients with a longterm catheter and CR-BSI, the risks and benefits of keeping the catheter in situ should be balanced. For many pathogens, success can be obtained by treating through the catheter. However, some authors would argue that for catheter-related infection and certain microorganisms such as S. aureus and Candida species, the time until microbial clearance is shortened, the possibility of metastatic infection decreased, and perhaps survival is improved by earlier catheter removal. Antibiotics should be directed toward the likely pathogens. 103 / 104 Since more than two-thirds of all patients will have a gram-positive CR-BSI, antibiotics should be selected with this in mind. Risk factors considering the likelihood of MRSA should be carefully examined, including duration of hospital

279

stay, known colonization with MRSA or location near a patient who is colonized with MRSA, antibiotic therapy, and an open wound. If risk factors are present, then therapy with an agent that covers MRSA (vancomycin or linezolid) should be considered. If not, then therapy with a staphylococcus direct penicillin such as oxacillin or nafcillin would be appropriate. Duration of therapy depends on the pathogen isolated. If the patient has S. aureus bacteremia, then therapy should be at least 10-14 days due to the high rate of relapse if duration is 7 days or less, and an echocardiogram may be required to determine which patients should have prolonged therapy. If the patient has relapse, continuous fever, or bacteremia despite catheter removal, then a search for complications such as endocarditis or metastatic infection should be undertaken.

PREVENTION

The majority of infections associated with the use of intravascular devices in critically ill patients requiring short-term catheterization are preventable." Prevention relies first on strict observation of the basic rules of hygiene, of which hand hygiene represents the first and most important. More specific measures, including the use of maximal sterile barriers during insertion,'!" optimal insertion site preparation, III detailed guidelines for catheter replacement, and defining particular situations in which the use of antiseptic- or antibioticcoated devices may be used have been examined in detail in hundreds of clinical studies.l'
Urinary Tract Infections Urinary tract infections are the most common NIs, accounting for up to 40% of all Nls, most are associated with the use of a urinary catheter. l20,12l Approximately 24 million urinary catheters are used annually in the United States, and nearly 25% of hospitalized patients have a urinary catheter during their hospitalization.F" Some studies have indicated that attending and resident physicians are unaware that patients have a urinary catheter in place in as many as 38 % of patients, and that the catheter is frequently not indicated.l" Catheter use can be divided into short- and long-term use by time, with fewer than 30 days defining short-term use and the difference between common and universal colonization with bacteria or fungi.!" For short-term use, the risk of developing bacteriuria in catheterized patients has been reported to be between 3 % and 5% per day of catheterization, with an estimated probability of bacteriuria in patients not receiving antibiotics and having a catheter in place for 2-10 days is at 260/0 (950/0 CI 230/0-29%).125 After the development of bacteriuria the development of symptomatic UTI without bacteremia has been estimated at 25% (160/0-32%) and for the development of bacteremia at 3.60/0 (950/0 CI3.40/0-3.8%).126 In the United States, it is estimated that 9 million episodes of nosocomial UTI occur annually, increasing the cost of health care by more than $500 million annually (estimated minimum of $676 per episode without bacteremia, $2836 for those with UTI and bacteremial.!" In addition to the direct effect of treating complicated UTIs, many catheter cultures represent colonization and do not require antibiotic therapy. Although the costs of catheter-associated UTIs are not as high as, for example, those for a deep surgical site infection or a nosocomial pneumonia, UTIs are a major reservoir of resistant pathogens.Fr'" PATHOGENESIS

Much like other NIs, a UTI is caused by the combination of an invasion of local defenses and the easy transmission of pathogens through the uretheal meatusinto the bladder. 120,121,129 In addition, the presence of a foreign body allows for the formation of a biofilm and the development of a protected site for the growth of bacteria and accounts for the difficulty in penetration of antibiotics into the biofilm. Extraluminal contamination of the urinary tract can occur via breaks in sterile technique during insertion of the catheter or from colonization of the meatus and ascent of pathogens along the catheter into the bladder.!" Intraluminal contamination occurs from breaks in the drainage system during irrigation of the bladder or because of improper technique and lack of hand hygiene when draining the closed drainage system. Pathogens can then ascend from the collection bag into the bladder, where they can easily multiply. In a large study of more than 1000 patients, more than two-thirds of infections were attributed to extraluminal contamination, and one-third were intraluminal.r" Interestingly, there was a difference in the type of organism by mode of acquisition. Candida, enterococci, and staphylococci more commonly ascended along the catheter from the perineum.

On the other hand, the water-borne gram negatives such as Pseudomonas, Enterobacter, and Acinetobacter were more commonly associated with the intraluminal route from the collection bag. RISK FACTORS

Several studies131-133 have examined the risk factors for the development of a UTI in hospitalized patients. The two most important risk factors are the duration of catheterization and female gender. Other risk factors that have been identified include having the catheter placed in an environment outside the operating room, having the patient on a urology service (which may be a proxy for structural abnormalities of the urinary tract), other infections, malnutrition, diabetes, and renal failure. In improvement efforts, only efforts to keep the drainage bag below the patient have consistently been helpful in decreasing the infection rate. 124 DIAGNOSIS

While the diagnosis of a UTI may seem straightforward, in fact there is controversy and lack of consistency about the exact classification, diagnosis, and management of a UTI. 134,135 General classification and considerations include site of infection (bladder vs. kidney), the presence or absence of symptoms (asymptomatic vs. symptomatic), origin of infection (community vs. hospital), and the severity of infection (uncomplicated vs. complicated). While these broad aspects of classification may help determine pathogens and need for treatment, they are not clearly defined or universally accepted. For instance, a complicated UTI can be found in at-risk patient populations or those with specific conditions, such as the elderly, pregnant, critically ill, those with structural abnormalities of the urinary tract, or catheterized patients.P" The presence of pyuria is used as a general criterion for a UTI in noncatheterized patients. However, a study of more than 750 patients demonstrated that pyuria was a better predictor of the presence of gram-negative infection; the presence of large numbers of yeast, staphylococci, and enterococci was not as frequently associated with pyuria.':" This difference is postulated to be due to the lower levels of inflammation elicited by these pathogens. Thus, pyuria should not be used as the sole criterion in determining the need for a urine culture or treatment. Unfortunately, symptoms cannot be used to determine who should have therapy. In a large prospective study, no differences were seen in the presence or absence of fever or symptoms such as dysuria or suprapubic pain in patients with and without catheter-associated UTI. This is likely secondary to the fact that the catheter itself may cause symptoms, and that the catheter prevents bladder distention and thereby bladder symptoms. However, when the catheter becomes obstructed, symptoms develop, and infection is also much more likely.!" PATHOGENS

In contrast to uncomplicated UTIs, for which E. coli is the predominant pathogen, catheter-associated UTIs have additional pathogens, including the enterococci (including VRE) and C. albicans. 124,129,137 In complicated UTIs, polymicrobial infections are not uncommon.

NOSOCOMIAL INFECTIONS

TREATMENT

As is true in any infection, knowledge of the likely pathogens is essential in selecting the appropriate antimicrobial agent. A urinary culture must be obtained in suspected cases of UTI, and antibiotic therapy should be molded to isolated pathogens. There are many available oral and intravenous agents that are appropriate for UTIs (Table 14.6), and no state-of-the art guidelines exist to suggest preferred agents. In seriously ill or critically ill patients with a suspected UTI, empirical coverage with an antipseudomonal agent is recommended until cultures have returned (Table 14.7).124)29,131 Empiric coverage of the gram-positive agents is usually reserved for proven serious infection based on cultures, known colonizers, or a Gram stain with gram-positive agents alone. These gram-positive infections can be treated with vancomycin, quinpristin/dalfopristin, or linezolid following identification.13S-140 Uncomplicated UTIs can be treated for 3 days, while complicated UTIs should be treated for 7-14 days. While E. coli remains the most common pathogen if the UTI is an initial infection, resistance to the sulfa (trimethoprim/sulfamethoxazole) agents commonly suggested as first-line therapy may be seen in as many as 100/0-22 % of isolates. Recurrent E. coli and the remaining gram-negative isolates tend to be more resistant. These resistant E. coli strains are often susceptible to the fluroquinolones, nitrofurantoin, carbapenems, and the aminoglycosides. Agents that were effective for Klebsiella include the third- and fourthgeneration cephalosporins, pipercillin-tazobactam, the carbapenems, aminoglycosides, and fluroquinolones. The most active fluroquinolones against Pseudomonas in vitro studies was ciprofloxacin (750/0 susceptible), followed by levofloxacin (710/0) and gatifloxacin (660/0 ).136 A randomized controlled trial demonstrated that a single dose of ciprofloxacin (1000mg) was as effective as ciprofloxacin given twice daily for the treatment of complicated UTIs for 7-14 days.'?"

TABLE 14.6. Distribution of Infecting Urinary Pathogens in Two Large Study Populations. Pathogen

Escherichia coli Enterococcus spp. Klebsiella spp. Pseudomonas. aeruginosa Staphylococcus aureus Proteus tnirabilis

Coagulase-negative staphylococci Streptococcus spp. Miscellaneous Other gram negatives Other gram positives Yeast "Data from Merle et a1.161 "Data from Jones et a1.162

Percentage of isolates:

Percentage of isolatesb

13 21 Other gram negatives 25 11

46.9 12.8 11.0

Other gram negatives 5.0

5.0

8 See below 13 1 3

7.5

3.4

3.4 Listed above Not listed Not listed

281

TABLE 14.7. Empiric Antibiotic Selection for Catheter-Associated Urinary Tract Infection. Empirical agents for UTI, Pseudomonas not suspected Fluroquinolones: Ciprofloxacin, gatifloxacin, levofloxacin Cephalosporins: Second generation (cefuroxime, cefotiam), third generation (cefotaxime, ceftriaxone) Penicillins: Amoxicillin/clavulanic acid; ampicillin/sulbactam Aminoglycosides: Gentamicin, tobramycin, amikacin Carbapenem: Ertapenam Severe infections or Pseudomonas suspected Fluroquinolone: Ciprofloxacin Penicillin: Pipercillin/tazobactam Cephalosporin: Cetazadome, cefipime ± aminoglycoside Carbapenem: Imipenem, meropenem

The goals of antimicrobial therapy are to rapidly resolve symptoms, eradicate pathogens, minimize recurrence and resistance, and reduce morbidity and mortality. Correction of underlying risk factors such as catheter removal or correction of an underlying abnormality should be performed as able. PREVENTION

One of the primary areas for prevention of UTIs involves the decision whether to use a urinary catheter.P''!" In men, an alternative to the indwelling catheter is the condom catheter. 142While there have not been any properly designed studies directly comparing these two modes, repeat studies from the same institutions suggest a substantially lower incidence of bacteriuria. However, it should be noted that urine inside the condom catheters may contain a large number of bacteria, skin breakdown may occur, the meatus may become colonized, and bacteriuria may develop. Intermittent catheterization is a reasonable alternative to indwelling catheters, with an incidence of bacteriuria of about 1%-3 % per catheterization. No well-designed studies have compared long-term indwelling catheters with intermittent catheterization for overall or specific outcomes. Catheters should not be placed indiscriminately, for convenience, or as "routine" postoperative care if a patient can urinate spontaneously. Use of indwelling catheters should be limited to patients with anatomic or physiologic urinary obstruction; patients undergoing surgery of the genitourinary tract; patients requiring accurate monitoring of urine output (i.e., critically ill or postoperative patients); and debilitated, comatose, or paralyzed patients. If a catheter has been placed, then two clear practices should be used to decrease infection risk. First, the catheter should be removed as soon as possible. In our ICUs, we use a daily goals sheet that specifically ask if any lines or catheters can be discontinued." This tool has helped eliminate unnecessary devices. Second, the drainage system must remain closed except at the bag-tube drain, and care should be made to avoid the emptying port from touching contaminated containers.143-145 While logical to decrease urethral colonization, topical application of microbial agents has not effectively decreased infection. In fact, in some series the incidence of bacteriuria increased. Similarly, bladder irrigation had not been effective. 125 Antiinfective agents applied to catheters have been a subject of significant interest, especially with silver as an antimicrobial.l'v'P' Thirteen trials of silver-coated catheters

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CHAPTER 14

generally supported the use of these devices, but few had patients in an ICU setting or demonstrated a homogeneous benefit of prevention, and there is no consensus about whether these catheters should be widely used.

Miscellaneous With the exception of surgical site infections, this chapter has covered the most common Nls. Postoperative fever is not always indicative of infection, and risk factors such as operation performed, time from operation, patient risk factors, and signs and symptoms should be defined. A thorough search for localizing signs and symptoms should thus be undertaken. While not all infectious causes can be discussed, two additional diseases should be considered, infections with C. difficile and sinusitis. Clostridium difficile-associated disease (CDAD) is the major hospital-acquired gastrointestinal infection, with an estimated 3 million cases annually in the United States. ISS The annual estimated cost of CDAD has been estimated at $1.1 billion, with an increase in length of stay of 3.6 days and hospital costs of $3669 per case, 54% more than for patients without CDAD. Several reports have suggested an increase in the incidence of this disease, which has been confirmed by NNIS ICU data in hospitals with more than 500 beds.l" For a hospitalized patient with diarrhea, C. difficile will be responsible for 30% of cases; for patients with colitis and antibiotics, the number is 50%-700/0, and if pseudomembranes are present, nearly 1000/0 are due to C. difficile. l s7 Risk factors associated with hospital-acquired CDAD include antimicrobial use, advanced age, laxative use, antineoplastic chemotherapeutic agent use, bowel colonization with C. diiiicile, production of toxin A, renal insufficiency, or gastrointestinal surgery or procedures. The three antibiotics most closely linked to CDAD include ampicillin (amoxicillin), clindamycin, and the cephalosporins, especially the third-generation agents. Clostridium difficile produces two toxins: toxin A, which is both enteropathic and cytotoxic, and toxin B, which is only cytotoxic. The enteropathic toxin A effects induce fluid flux into the bowel, as potent as cholera toxin. However, the range of presentation of disease is wide and varies from asymptomatic, culture positive in 20% to an overwhelming life-threatening toxic presentation. Diarrhea is not always present; leukocytosis is often present and can be marked. Diagnosis is established based on immunoassay on fructose agar as the most sensitive test; culture has a 20%-25% false-positive rate. The immunoassay is rapid but a bit less sensitive (700/0750/0) for a single stool specimen; additional specimens may increase sensitivity by 100/0. Serial studies should not be performed to assess treatment effectiveness or test of cure since the stool may be positive for 3 to 6 weeks after successful treatment and does not predict relapse."? Endoscopy should not be performed routinely but may be indicated when a rapid diagnosis is needed, where immunoassay is not available, when the assay is negative but CDAD is strongly suspected, or when alternative colon diseases may be present. 157 Treatment of CDAD depends somewhat on symptoms. Antibiotics should be stopped or changed to those with a lower propensity for causing disease. Asymptomatic patients should not be treated as well as some patients with mild disease because spontaneous resolution is not associated with

relapse. Metronidazole (either 250mg every 6h or 500mg every 8h) should be the first-line agent of choice and can be administered orally in those who can tolerate it or intravenously in those who cannot. Cure rates are in the range of 95%, with relapse rates of 5%-15%. If patients are not improving after 3-5 days, then 125mg vancomycin p.o. every 6h is recommended, as well as in those patients pregnant or lactating. A vancomycin retention enema can be used as an adjunct to intravenous metronidazole in patients with an ileus. Additional agents with some efficacy against CDAD include bacitracin, rafixamine, and an agent not available in the United States, tecoplanin. In their recent Cochrane review, authors concluded that vancomycin is the only agent compared to and better than placebo, but this was a small trial. They did not support a clear choice of the available agents based on current information. 158 Acute purulent sinusitis is a well-known cause of fever of unknown origin in the ICU. The disease has a wide spectrum of presentation and can be a life-threatening problem requiring urgent diagnosis. The problem with diagnosis of this disease in postoperative patients is that radiographic findings in patients with nasogastric tubes are almost uniformly found after 48h, and microbiologic cultures may indicate contamination or colonization. Moreover, purulent secretions may be sterile. A study of antral puncture versus rhinoscopy demonstrated that 25 of 53 patients had mucopurulent effusions, most commonly polymicrobial (40%). Staphylococcus aureus and gram negatives were the most common isolates. While antral puncture was safe and effective, with anterior rhinoscopy showing a normal examination, only 8% of cultures would be positive.!" In a study specifically designed to examine anaerobic cultures, 18/30 patients with nosocomial sinusitis had anaerobes isolated.'?" Thus, anaerobic coverage should be strongly considered. As stated earlier, while sinusitis and VAP are linked, there is no clear evidence that a systematic search for sinusitis should be undertaken in all patients.

Conclusion This chapter has covered the common Nls, risk factors, methods of diagnosis, treatment, and effective methods for prevention. Nosocomial infections are among the most important causes of postoperative morbidity, prolonged hospital and ICU stay, increased costs, and mortality. Every effort should be made to employ the proven preventive strategies.

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Severe Sepsis and Septic Shock Steven M. Opal Sepsis: Definitions and Epidemiology 287 Sepsis Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288 Diagnostic Methods for Severe Sepsis/Septic Shock . . . . . . . . . . . . . . . . . . . . . . . . . .. 296

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his chapter reviews the remarkable recent advances in the understanding of the molecular basis that underlies the pathophysiology of sepsis . This knowledge has improved diagnostic techniques and introduced new therapeutic agents into the standard management of patients with severe sepsis/septic shock. The current treatment regimens for sepsis are discussed, and the evidence to support each ma jor treatment strategy is outlined in detail. Research priorities to further the optimal management of septic shock in the future are highlighted.

Sepsis: Definitions and Epidemiology Definitions The terminology used to describe the septic process is, by necessity, imprecise and lacking in analytical clarity since there is no single, universally accepted, diagnostic or confirmatory test for sepsis. This has plagued the field of sepsis research as the majority of intensive care specialists in a recent survey' felt that the current definitions are inadequate and frequently miss the correct diagnosis. The loosely applied term sepsis is used to connote a syndrome when a patient develops a deleterious systemic host response to an infectious process. In its early stages, sepsis can be difficult to distinguish from an appropriate and localized inflammatory reaction to an uncomplicated infection . The innate im mune response and coagulation networks evolved to defend the host from blood loss and generalized infection following minor injury. These same inflammatory and clotting systems can be detrimental when they become excessive or dysfunctional , as they often become following ma jor injury or systemic infection. The clinical syndrome of sepsis becomes more readily recognizable and distinguishable for controlled inflammation when overt signs of systemic inflammatory responses, tissue hypoperfusion, and organ dysfunction develop. According to current consensus definitions/ sepsis accompanied by objective signs of organ dysfunction is classified as severe sepsis.

Organ Dysfunction in Sepsis . . . . . . . . . . . . . . . . . . . . . .. 297 Management of Septic Shock . . . . . . . . . . . . . . . . . . . . .. 298 References 301

It is often apparent only in retrospect that the patient was

"becoming septic," and that subtle, telltale signs were progressing to a potentially devastating pathologic state such as severe sepsis . Septic shock is defined as sepsis complicated by organ dysfunction and systemic hypotension refractory to an adequate fluid challenge. These definitions are independent of the nature of the infecting microorganism, and th ey correctly acknowledge the central role of the host inflammatory and coagulation response rather than microbial factors in the pathogenesis of sepsis. A brief summary of the recommended terminology of sepsis definitions is listed in Table 15.1. While these consensus definitions are imperfect and have limitations,' they have stood the test of time, and the sepsis definitions in common parlance today are still useful as working definitions for clinical use and for comparative clinical trials.'

Epidemiology and Secular Trends Sepsis, and the associated multiorgan failure that often accompanies this systemic inflammatory process, remains a leading cause of mortality in the intensive care units (IeUs) worldwide.' It is currently estimated that as many as 700,000 patients develop severe sepsis each year in the United States.v" with similar incidence rates in several European countries.Y The incidence of severe sepsis/septic shock has continuously increased over the past three decades, and the occurrence of sepsis likely will further increase over the next several decades as the population of elderly and vulnerable patients continues to expand. The mortality rate for fully developed septic shock rema ins between 35 % and 45 % despite recent improvements in treatment options and outcome.V" The outcome in sepsis is highly variable and dependent on a large number of preexisting and physiological elements, nonetheless, it is clear that this process alone accounts for hundreds of thousands of deaths per year.4,5 The incidence of sepsis is increasing for several reasons, but primary among them is the fact that sepsis largely has become a disease of medical progress. While sepsis certainly

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TABLE 15.1. Classification and Working Definitions of Sepsis. Term

Definition

Comments

Bacteremia (or fungemia)

Presence of viable bacteria (or fungi) in the bloodstream

Sepsis

A clinical syndrome manifested as a deleterious host response to an infectious process

Severe sepsis

Sepsis complicated by one or more major organ dysfunction(s)

Septic shock

Severe sepsis with systemic hypotension refractory to early fluid therapy

Bacteremia or fungemia is not necessary or sufficient for the diagnosis of sepsis. Microorganisms may transit the bloodstream briefly and without clinical consequences; fatal septic shock may occur in the absence of documented bacteremia or fungemia. Infection (local or systemic) accompanied by a systemic inflammatory response (e.g., fever, leukocytosis, tachycardia, tachypnea). It may be difficult to distinguish a physiologic host response to infection from a deleterious (septic) response. Sepsis-induced organ dysfunction (central nervous system dysfunction, acute lung injury, renal failure, hepatic dysfunction, coagulopathy, metabolic acidosis, cardiovascular dysfunction) remote from the site of active infection; this should be distinguished from preexisting organ dysfunction. This is clinically defined as failure to maintain a systolic blood pressure above 90mmHg (or mean arterial pressure >65mmHg) following an adequate fluid challenge (>40ml/kg over 6h).

Source: From Levy et al.,? by permission of Critical Care Medicine.

occurs in previously healthy persons (e.g., meningococcal sepsis, toxic shock syndrome, and severe community-acquired pneumonia), the majority of septic patients have significant underlying diseases that place them at risk for sepsis.'? Successful management of a variety of severe trauma situations and medical illnesses and advances in surgical interventions are salvaging patients who only a few generations ago would have rapidly succumbed. This has produced a large susceptible population of patients with prolonged critical illness and impaired host defenses." These patients have a greatly increased risk of developing sepsis. Innovations in organ transplantation, implanted prosthetic devices, and long-term vascular access devices continue to expand in this patient population. The gradual aging of the population in many developed countries and the increasing prevalence of antibiotic-resistant microbial pathogens also conspire to increase the incidence of severe sepsis/septic shock. In a study by Martin et al., over 10 million cases of sepsis from the National Hospital Discharge Survey were reviewed over a 21-year time period throughout the United States." They found that the incidence of sepsis increased by an average of 8.70/0 per year from 1979 to 2000, from 82.7 to 240/100,000 population. Sepsis was consistently and significantly more common in men than women and more common in nonwhite populations compared to white populations. The mean age of patients with severe sepsis was 60 years," but the incidence of sepsis by age was heavily splayed to the extremes of age, with a small peak in the neonatal period and a marked and progressive rise in sepsis in the elderly after age 65. 4 Gram-positive bacterial pathogens now outnumber gramnegative pathogens as a cause of sepsis, and the incidence of fungal sepsis has increased by over 200% in the past two decades. While the incidence has progressively increased, the overall crude mortality rate has steadily decreased to less than 18% from 27.9% average 20 years earlier." Similar findings have been reported in a large French study, with significant improvements in management outcomes from sepsis noted over the past decade."

The human resource losses attributable to sepsis for affected patients, family members, and society in terms of years of life lost, long-term disability, and diminished qualityof-life indices are enormous and incalculable. Recent evidence indicates that the long-term disability suffered by survivors of sepsis and other critical illnesses is considerable." The financial implications in health care expenditures for the management of sepsis are daunting as well. Each episode of severe sepsis extends the average hospital length of stay by 11 additional days and costs approximately $40,000/ episode. The added costs accrued from sepsis that develops in patients while hospitalized for other medical or surgical indications may be even higher. 13 Angus and colleagues estimated that expenditures in the United States for sepsis alone account for an incremental annual cost of nearly $17 billion."

Sepsis Pathogenesis Predisposing Factors Severe sepsis and septic shock usually arise in an unexpected fashion in patients who have another primary illness," and the severity of the underlying illness is a principal determinant of the mortality rate attributable to sepsis. This relationship was first noted by Jackson and McCabe several decades ago," and it remains true today despite numerous advances and innovations in supportive care and in medical and surgical management. IS The source of the septic focus has repeatedly been shown to have a major impact on the risk of adverse outcome from sepsis. Catheter-related sepsis and urinary tract infections have the most favorable prognosis, while intraabdominal sites of sepsis and pulmonary sources of sepsis are associated with the worst outcome.P-" The risk of disseminated infection and sepsis following the onset of tissue invasion by pathogens from an initial site of injury varies markedly depending on the type of infection, location and degree of tissue invasion, and the intrinsic vim-

SEVERE SEPSIS AND SEPTIC SHOCK

lence of the causative pathogen. The likelihood of developing multiorgan dysfunction, hemodynamic compromise, and lethal septic shock after infection begins is heavily dependent on the antimicrobial defense capacity and fundamental nature of the individual host response to the microbial challenge. Many hereditary and acquired factors contribute to the risk of severe sepsis following similar types of microbial challenge. While it is widely appreciated that the elderly patient," the neutropenic patient," and the asplenic patient" all have readily measurable differences in outcome when compared with the same type of systemic infection in an otherwise healthy young adult, it is increasingly apparent that much of the mortality risk from sepsis is actually determined by our genomic background." An expanding array of polymorphisms in immune response and regulatory genes are known to potentially affect the risk of sepsis and its outcome.P:" A major research priority in clinical research at present is the development of an information system that can rapidly and correctly identify and balance the influence of all the relevant genes and gene products that ultimately determine the fate of patients with systemic inflammatory states. The magnitude, dynamics, and complexity of interacting networks that contribute to acute inflammatory states such as sepsis indicate that deciphering this process in real-time patient care settings will be a challenge indeed. An entirely different conceptual framework on which to formulate a greater understanding of sepsis pathophysiology may be required to adequately integrate this information. An initial attempt at accomplishing the goal of reanalyzing sepsis in the genomic era has been proposed as the PIRO system," which stands for predisposing factors, infection, response, and organ dysfunction. This classification system is depicted in Table 15.2 and is fashioned after the TNM (tumor, nodes, metastases) system in codifying malignant diseases. It is predicated on the hypothesis that breaking down sepsis into its component parts (the reductionist

289

approach to complexity) will lead to an improved understanding of the mechanisms that underlie sepsis itself. Intuitively, a classification scheme that adequately separates a number of important and easily recognizable subgroups of patients with very different risk factors for the development of sepsis, and risk of death from sepsis, is an appealing strategy in better understanding sepsis in general.

Microbial Factors MICROBIAL MEDIATORS

The microbiology of sepsis (or the I in the PIRO system) has changed over the past 50 years from what was once a primarily gram-negative bacterial infection in the 1950s through the 1980s (previously termed gram-negative sepsis or endotoxic shock) to what is now principally a gram-positive bacterial process.' The ubiquitous use of vascular catheters, other implantable devices, progressive antibiotic resistance among gram-positive bacteria, and improved antimicrobial agents against gram-negative bacterial pathogens have all contributed to the progressive emergence of gram-positive bacterial pathogens as the major causative microorganisms of sepsis by the beginning of the 21st century." Fungal organisms are increasingly recognized as important pathogens as a cause of sepsis in leu patients, and these infections are associated with a markedly increased mortality rate compared to bacterial sepsis.v" Polymicrobial infections account for up to 300/0 of severe sepsis and are primarily related to complex infections such as a contaminated wound, perforated viscus, or intraabdominal abscess." No clear microbial agent is recognized in approximately 150/0 of septic patients, and this is most often attributable to the widespread use of empiric antibiotic therapy that obscures culture documentation of infection. Translocation and circulation of microbial mediators in the absence of viable and cultivatable

TABLE 15.2. The PIRO Conceptual Framework for the Study of Sepsis. Category

Specific element

Comments

P: Predisposing factors

Recognition of preexisting conditions in sepsis pathogenesis (immunodeficiency, diabetes, cancer, chronic disease states, medications); genetic factors; nutritional, age, and gender differences Accounts for differences in the site of infection, quantity, and intrinsic virulence of each type of infecting microorganism; different causative organisms induce different signaling networks within the innate immune and coagulation systems Mortality risk primarily determined by the patient's response to sepsis; optimal host mediator-targeted therapy predicated on ability to rapidly assess individual host responses

The use of genomics and proteomics may define genetic polymorphisms of the immune response to systemic infection; need to recognize important patient subgroups based on baseline predisposing factors. Outcomes differ in sepsis depending on the site of infection and number and type of pathogen. Rapid microbial detection systems (LPS, lipopeptides, fungal elements, bacterial DNA or RNA) may direct sepsis therapies according to the nature of the pathogen. Markers of inflammation (peT or IL-6); status of host responsiveness (e.g., HLA-DR, TNF receptor, or TLR density); or gene transcript profiles by genomics and proteomics may guide individualized therapy in the future. Dynamic measures of organ-specific cellular and microcirculatory responses to infection or insult (apoptosis, cytopathic hypoxia, cell stress, and energy depletion) may provide a system to guide therapy for individual patient needs.

I: Infection

R: Response

0: Organ dysfunction

Preexisting organ damage and variations in the pattern of organ dysfunction affect outcome in sepsis; organ damage caused by microbial pathogen or its toxins requires different approach than remote organ injury from host immune response

HLA, human leukocyte antigen; IL, interleukin, LPS, lipopolysaccharide; peT, procalcitonin; TLR, Toll-like receptor; TNF, tumor necrosis factor. Source: Adapted from Levy et al..' by permission of Critical Care Medicine.

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microorganisms may also account for some cases of "culturenegative" sepsis." ROLE OF ENDOTOXIN

Bacterial endotoxin, which is composed of lipopolysaccharide (LPS), is an intrinsic component of the outer membrane of gram-negative bacteria and is essential for the viability of enteric bacteria." An endotoxin-deficient strain of Neisseria meningitidis has been isolated that is viable and is 10- to 100fold less potent an inducer of cytokine production than wildtype bacteria." Lipopolysaccharide is a phosphorylated, polar macromolecule that contains hydrophobic elements in the fatty acids of its lipid A core structure and hydrophilic elements in its repeating polysaccharide surface components. Humans are one of the most susceptible species to the profound immunostimulant properties of endotoxin, which may be lethal following intravenous challenge in minute doses. Whether endotoxin is released into the human circulatory system in its free form (released from dead organisms or shed from the membrane sf viable organisms as microparticles) or bound to the cell wall of intact bacteria, an intense systemic inflammatory response results. Endotoxin in the prototypic pathogen-associated molecular pattern (PAMP) that functions to alert the host's innate immune defenses to the presence of invading gram-negative bacteria." It is the host response to the systemic release of endotoxin (or other PAMPs), rather than the endotoxin itself, that accounts for its potentially lethal consequences.'

In human plasma, endotoxin immediately comes in contact with endotoxin-binding proteins, the most important of which is LPS-binding protein (LBP).39 This protein facilitates the transfer of LPS to the surface of immune effector cells expressing the anchoring receptor molecule CDI4. 40 Another endogenous LBPin plasma is bactericidal permeability-increasing protein (BPI),41 which is principally expressed on neutrophil membranes and primary granules. Bactericidal permeability-increasing protein binds with high affinity to LPS and is a potent inhibitor of endotoxin activity. The concentration of LBP in the plasma is two to three orders of magnitude higher than that of BPI, and therefore, most of the LPS released in the plasma binds to LBP and is efficiently carried to myeloid cells in its active form. The BPI functions as an endogenous antiendotoxin molecule, and systemic infusions of high levels of BPI may become a treatment strategy for endotoxin-induced injury." The long-sought-after primary cellular receptor for endotoxin on immune cells has been identified.P" The Toll-like receptors (TLRs) are type 1 transmembrane receptors and are now known to be the receptors for multiple microbial structures such as endotoxin, peptidoglycan, bacteriallipopeptides, viral and bacterial nucleic acids, flagella, and lipoteichoic acid. The TLRs belong to a network of pattern recognition receptors of the innate immune system that alert effectors cells to the presence of a microbial pathogen." This system includes up to 11 TLRs, CD14, and components of the alternate complement system and mannose-binding lectin system (Table .15.3 ).46-50

TABLE 15.3. Human Toll-like Receptors, Their Ligands, and Other Pattern Recognition Receptors. Receptor

Major cell type

Known actions and recognized ligands

TLRI

Myeloid cells, T and B lymphocytes, NK cells

TLR2

Myeloid cells, T cells

TLR3

Dendritic cells, epithelial cells

TLR4

Myeloid cells

TLRS TLR6

Myeloid cells, epithelial cells Myeloid cells, dendritic cells

TLR7

B cells, plasmacytoid dendritic cells

TLR8

Myeloid cells, dendritic cells

TLR9 TLRIO TLRII

B cells, plasmacytoid dendritic cells, epithelial cells B cells, myeloid cells Macrophages, uroepithelial cells

Forms heterodimers with TLR2 for bacteriallipopeptide, outer surface proteins of Borrelia spp., and possibly other microbial ligands Bacterial and Mycoplasma lipopeptide, ? peptidoglycan; lipoarabinomannan from Mycobacteria, lipoteichoic acid, fungal cell wall components, LPS of spirochetes Double-stranded viral RNA probably signals from inside endosomal vacuoles LPS, respiratory syncytial virus proteins, HSP60, fibrinogen, heparan sulfate Flagellin from gram-positive or gram-negative bacteria Forms heterodimers with TLR2 in recognition of Mycoplasma lipopeptides and fungal elements (zymosan) Binds to single-strand (ss) RNA in mice (? humans); binds to antiviral compounds, imidazoquinolines" Recognizes ssRNA in humans inside intracellular endosomes, binds imidazoquinolines" Unmethylated CpG motifs in microbial DNA; signaling occurs inside endosomal vacuoles Unknown, may interact with TLR2 to form heterodimers Recognizes uropathogenic bacteria in the urogenital tract in mice (? humans )48

CD14

Myeloid cells

Alternate C pathway

Plasma proteins

MBL

Plasma protein

Recognizes LPS, peptidoglycan, lipoarabinomannan, fungal antigens; binds with TLRs for cell signaling Pathogen-associated molecular patterns that are exposed to the C3 thioester bond" Recognizes mannosides expressed on bacterial, fungal, viral surfaces and activates C4 and C2 s0

C', complement; HSP, heat-shock protein; LPS, lipopolysaccharide; MBL, mannose-binding lectin; TLR, Toll-like receptor.

Source: Adapted from Cristofaro and Opal,46 by permission of Expert Opinion on Therapeutic Targets.

291


The principal endotoxin transmembrane receptor is TLR4.43 It functions along with an extracellular adaptor protein known as MD2 and a critically important pattem recognition receptor CD14 that anchors microbial antigens to the surface of myeloid cells .39,5 l These surface receptor molecules aggregate on membrane regions known as lipid rafts where the intracellular signaling process begins . The precise mechanisms by which TLR4 activates gene transcription of cytokines, acute-phase proteins, coagulation, and nitric oxide synthase (NOS) are known in considerable detail (Fig, 15.1),46 although other regulatory and accessory pathways of gene induction and control have not yet been fully characterized." A well-characterized series of tyrosine and theoninefserine kinases is activated by TLR4 engagement with LPS, and this intracellular signaling leads to phosphorylation of IKB (inhibitor of nuclear factor kappa B [NF-KB]). This releases the transcriptional activator NFKB from the cytoplasm and allows it to translocate into the nucleus. The NFKB and a number of other of transcriptional activators are transferred to the nucleus, where hundreds of genes are activated or suppressed in response to the presence of endotoxin.P:" Details of these events and interactions are important as they form the molecular basis for novel therapeutic agents to treat sepsis . The receptor TLR2 recognizes a large number of bacterial, fungal, mycobacterial, and mycoplasma surface structures in heterodimeric combination with either TLRI or TLR6.54 Toll -

0': :~:~ ".

Extracellular space

like receptor 9 is the cellular receptor for unmethylated CpG motifs found in bacterial DNA, 55 while TLR3 recognizes double-strain viral RNA, 56 and TLR8 detects single-strand RNA. 47 Also, TLR5 recognizes bacterial flagellin found on motile gram-positive and gram-negative bacteria.57 The TLRs belong to the pattern recognition molecules' innate immune system and initiate this rather nonspecific, antimicrobial defense system. It lacks the precision of the highly specific and clonal acquired immune system (B cells and T cells I, yet its rapid reaction time in phagocytosis and clearance of pathogens in the early phases of microbial inva sion makes the innate immune response a critical host defense mechanism. Excessive activation and disordered regulation of the innate immune system and its cellular components (neutrophils, monocytes, macrophages, natural killer INK] cells) are primarily responsible for the pathogenesis of early septic shock. 23,38 Elements of the acquired immune system and defects in adaptive immunity may playa pivotal role in toxic shock syndromes" and in the later stages of sepsis (the late immune-suppressive phase of sepsis]." BACTERIAL SUPERANTIGENS

Another important microbial mediator in some forms of septic shock from gram-positive bacterial pathogens is bacterial superantigen. Superantigens are a unique group of microbially derived protein antigens found in some streptococci,

TLR4 Signaling

1J1trr~

LBP

OS-RNA TLR 3

Cell Membrane The "Fasf ' My088dependent pathway Intracellular space

IP-10 Proinflammatory Translocation cytokines, acute ...-_ _....."'-_ nucleus phase proteins, NOS ~ .".... cytokine genes

FIGURE 15.1. The signaling pathways of the TLR4 complex. LPS, lipopolysaccharide; DS-RNA, double-stranded ribonucleic acid; LBP, LPS-binding protein; TLR, Toll-like receptor; TIR, Toll interleukin receptor; MyD88, myeloid differentiation factor; TIRAP, Toll interleukin receptor adapter protein; Mal, MyD88 adapter like; Tollip , Toll interactive protein; TRIF, TIR domain adapter inducing interferon-j, IRAK, interleukin 1 receptor-associated kinase; TRAF6, tumor necrosis factor receptor associated factor 6; ECSIT, evolutionarily conserved signaling intermediate of Toll; TAK-I, transforming

t MHC Ii B 7 expression TH1 cell activation

growth factor-associated kinase-I, JNK, Janus N-terminal-linked kinase; MAPK, mitogen-activat ed protein kinase; IRF3, int erferon regulatory factor; IFN, interferon; IP-lO, interferon-inducible protein10; IKK, I1cB kinase; NEMO (another name for IKK-NFlCB essential modulator); IlCB, inh ibitory subunit lCB; NFlCB, nuclear factor 1CB; MHC, major histocompatibility complex; NOS, nitric oxide synthase; TH 1, type 1 thymic-derived CD4+ lymphocyte helper cells. ISource: Modified from Cristofaro and Opal,46 by permission of Expert Opinion on Therapeutic Targets .]

292

CHA P TER 15

staph ylococci, and perhaps other pathogens; each possesses an unusual immunologic property. These superantigens have the capacity to rapidly activate large numbers of CD4+T cells by circumventing the conventional antigen-processing and presentation system of adaptive immunity." Conventional protein antigens are internalized by antigen-presenting cells (APCs) and undergo limited proteolysis. They are then processed within the endosomal component of macrophages or dendritic cells . Appropriate size peptide sequences of these antigens [epitopes] are then processed and inserted into the central groove of major histocompatibility (MHC) class IT molecules on the membrane surface of APCs . Specific, clonotypic CD4+T cells that recognize each unique epitope are then activated. Clonal expansion of this small subset of T cells results in a physiologic immune response to the neoantigen/" Superantigens, by contrast, do not undergo processing by APCs and bind directly to class II molecules outside the epitope-specific peptide groove on APCs . Superantigens then bind to the V~ region of the T-cell receptor (TCR) on CD4+ T cells. This binding brings CD4+ T cells, and APC forms a bridge that then activates both the APC and T-cell populations expressing the appropriate V~ region of the TCR . Conventional peptide antigens specifically stimulate about I in 105 circulating lymphocytes that can recognize its unique epitope. Superantigens such as the toxic shock syndrome toxin-I from Staphylococcus aureus binds to the V~2 region of T cells that is found in up to 10%-20% of human lymphocyte populations." This activates large numbers of both lymphocytes and macrophages, and the synthesis and release of proinflammatory cytokines proceeds in an uncontrolled fashion. Staphylococcal and streptococcal strains can

produce a variety of different superantigenic exotoxins capable of widespread immune activation if introduced into the circulation. 58,6O,61 Superantigen-induced immune activation may terminate in a form of septic shock known as toxic shock syndrome if the source of the superantigen is not expeditiously removed. Polymicrobial infections that release both bacterial superantigens and endotoxin may be particularly injurious to the host. The systemic toxicity of bacterial endotoxin is magnified by immune activation by superantigens that prime the immune system to overreact to endotoxin signaling (Fig. 15.2).62 Peptidoglycan from the cell wall of bacteria, capsular antigens, lipoteichoic acid, lipopeptides, microbial DNA, viral RNA, fungal elements, microbial toxins, and pro coagulant substances produced by microbial pathogens may all contribute to the pat hogenesis of sepsis. Peptidoglycan and lipopeptides from gram -positive bacteria interact with CDI4 molecules and activate inflammatory cells via TLR2 in a manner comparable to that observed by bacterial endotoxin." Moreover, gram -positive bacterial and fungal pathogens may induce hypotension with redistribution of blood flow and splanchnic vasoconstriction. The ischemia and reperfusion of blood vessels that supply the mucosal surfaces of the gastrointestinal (GI) tract may disrupt the permeability barrier to bacterial products. Translocation of microbial antigens, including bacterial endotoxin, may occur during periods of hypoperfusion of the GI rnucosa.f This injurious process has prompted interest in efforts to boost the GI mucosal barrier through immunonutrition, epithelial growth factors, and selective decontamination of the GI tract in critical illness.

B t n

lL-2 L8P

+

71' ~ ""

0 1-1

,

,/

~ I

IL- II!

FIGURE 15.2. Interactions between bacterial endotoxin and bacterial superantigen. Interactions between bacterial endotoxin and bacterial superantigens, CD4, CD4+ T cell; TLR2/4, Toll-like receptor 2/4; ICE, interleukin-Iji converting enzyme (also known as caspase 1); IFN-y, mterferon-j; IL, interleukin, LBP, LPS-binding protein; TNF-a., tumor necrosis factor-a. (Source: Modified from Opal and Huber .f with permission from Scientific American Medicine.l


Host Response CYTOKINE NETWORKS

Proinflammatory cytokines playa pivotal role in the pathogenesis of sepsis. In animal studies, the administration of human tumor necrosis factor-a (TNF-a), an endogenous monocyte-macrophage-derived protein, is potentially lethal." and pronounced hemodynamic, metabolic, and hematologic changes occurred when TNF-a was administered to human volunteers." Hypotension induced by even minute amounts of interleukin-Iu (IL-la) when given as an infusion to humans is a graphic demonstration of the pathologic potential of proinflammatory cytokines." The major proinflammatory cytokines, TNF-a and IL-l~, function in concert with an expanding group of host-derived proinflammatory mediators and an equally impressive array of antiinflammatory mediators that work in a coordinated fashion to produce the systemic inflammatory response (see Table 15.4). Cytokines and chemokines function as a network of communication signals among neutrophils, monocytes, macrophages, lymphocytes, and endothelial cells. Autocrine and paracrine activation amplifies cytokine signaling of the inflammatory response within the microenvironment once it is activated by a systemic microbial challenge (e.g., endotoxemia). Much of the proinflammatory response is compartmentalized within the proximal region of initial injury (e.g., lung tissue or peritoneum). If local control is not achieved, then the inflammatory response spills over into the systemic circulation, resulting in a generalized reaction with endothelial injury, coagulation activation, and remote organ injury. The endocrine-like effects of the circulating cytokines and chemokines maintain the generalized inflammatory process that typifies the septic state. 67,68

293

The proinflammatory mediators are activated in the early phases of sepsis (the first 12 to 24h) and are rapidly countered by the endogenous antiinflammatory components of the systemic immune response. Cytokine antagonists, decoy receptors, soluble receptors, antiinflammatory cytokines, and downregulation of tissue receptors prevail in the later phases of sepsis." Mice deficient in T cells and B cells respond to endotoxin challenge in the same manner as normal mice." indicating that neutrophils and monocyte-macrophage generated cytokines are sufficient to induce the early septic process. Lymphocyte activity and their cytokines and interferons become important in the regulation of later phases of sepsis and may ultimately determine the outcome in septic shock. IMMUNE-REFRACTORY STATE OF SEPSIS

Important functional differences exist within CD4+ T cells. Activated, yet uncommitted, CD4+ T cells (THo cells) have two major pathways of functional differentiation. The T cells exposed to IL-12 in the presence of IL-2 are driven toward a TH1-type functional development. These cells produce large quantities of interferon-y(IFN-y),TNF-a, and IL-2and promote a proinflammatory, cell-mediated immune response. Uncommitted CD4+T cells exposed to IL-4will preferentially develop into a THrtype phenotype; TH 2 cells secrete IL-4, IL-lO, and IL-13. These cytokines promote humoral immune responses and attenuate macrophage and neutrophil activity." The TH1-type cytokines suppress the expression of TH 2 type cytokines. Interferon-y inhibits the synthesis of IL-lO; conversely, the TH 2-cell-derived cytokine IL-lO is a potent inhibitor of TNF-a and IFN-y synthesis by TH 1 cells. The nature of the initial lymphocyte response is critical because the system tends to polarize over time into either a TH 2 - or

TABLE 15.4. Host-Derived Inflammatory Mediators in Septic Shock. Proinpammatory mediators

Antiinpammatory mediators

Proinflammatory cytokines: TNF-a, interleukins-I, -2, -12, -18, Iymphotoxin-o Fas ligand Proinflammatory chemokines: IL-8, MCP-I Interferon-v Complement activators and components: C3a, CSa, MBL, C reactive protein Lipid mediators: Leukotriene B4, platelet-activating factor, oxidized phospholipids, phospholipase A2 Bradykinin, histamine Prooxidants Reactive oxygen and nitrogen species Granulocyte-macrophage colony-stimulating factor Macrophage migration inhibitory factor Upregulation of receptors: TLR4, TLR2, CDI4 Coagulation factors: Thrombin, factor Xa, tissue factor: FVIIa, fibrinogen, heparan sulfate, uPAR High-mobility group box-I

Antiinflammatory cytokines: Interleukins-4, -6, -10, -II, -13 Interleukin-I receptor antagonist Soluble cytokine receptors: sTNF receptor, sIL-I receptor, sIL-6R Type I interferons (IFN-a~) Complement inhibitors: C I inhibitor, factor H Stress hormones: Glucocorticoids, epinephrine, norepinephrine Prostaglandin E2, prostacyclin Antioxidants Glutathione, selenium, uric acid Granulocyte colony-stimulating factor Decoy cytokine receptors (IL-I type 2 R) Downregulation of receptors: TLR4, MHC IT, TNF R, glucocorticoid receptors Anticoagulants: Antithrombin, tissue factor pathway inhibitor, activated protein C Transforming growth factor-B Vagal cholinergic antiinflammatory reflex

MBL, mannose-binding lectin; MCP, monocyte chemoattractant protein; R, receptor; TLR, Toll-like receptor; uPAR, urokinase plasminogen activator receptor.

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Tl-L-type response." Functional differentiation of CDS cells has also been detected (CDS+ type 1 and type 2 cells]." Cytotoxic T cells can induce apoptosis by surface expression of Fas ligand, which fixes to cell membrane Fas on target cells and via the release of perforins and granzymes. Regulation of T-cell activity in sepsis is clinically relevant. A generalized TH2-type response characteristically occurs after an initial septic insult. The stress hormone response in septic shock, with expression of adrenocorticotropic hormone, corticosteroids, prostaglandins, and catecholamines, promotes a TH2 response after systemic injury. Hotchkiss et a1. 59,72 have provided another potential explanation for the relative immune suppression (or immune paralysis) that often accompanies sepsis. Selective apoptosis of CD4+ T cells and B cells along with follicular dendritic cells is highly characteristic of severe sepsis. This selective loss of immune effector cells may contribute to the increased risk for secondary bacterial or fungal infection in the later phases of sepsis. Neutrophils are naturally apoptotic cells, and inflammatory cytokines and growth factors actually cause delayed apoptosis of neutrophils in sepsis." Accelerated caspase function and excess apoptosis also occur in intestinal epithelial cells, compromising mucosal permeability barrier function of the gut. 59 This pathophysiologic state is further aggravated by sepsis-induced endotoxin tolerance (or reprogramming]" and deactivation of monocytes, macrophages, and neutrophils by cytokine inhibitors such as IL-l receptor antagonist and antiinflammatory cytokines such as IL-I0. 75 Depressed expression of MHC class II antigens (HLA-DR), TNF receptors, TLRs, and perhaps other cell surface activation signals may contribute to this functionally immunosuppressed state." ROLE OF NITRIC OXIDE

Nitric oxide (NO) is a freely diffusible gas and highly reactive free radical with a short half-life (1-3s).76 It has an essential role in the pathophysiology of septic shock. Nitric oxide is generated by one of three isoforms of NOS (endothelial, neuronal, and inducible NOS).77 Regulation of the human NOSs is complex. Full expression of the inducible form of NOS requires TNF-a, IL-l, LPS, and probably other regulatory elements. Nitric oxide is the major endothelial-derived relaxing factor that initiates the systemic hypotension observed in septic shock. Nitric oxide activates guanylate cyclase, which increases cyclic guanosine monophosphate levels inside vascular smooth muscle cells. The resultant smooth muscle relaxation in precapillary arterioles lowers peripheral vascular resistance.76 The other major physiologic effects of NO in septic shock are increased intracellular killing and regulation of platelet and neutrophil adherence. In the presence of reactive oxygen intermediates such as superoxide anion, NO leads to the formation of peroxynitrite. Peroxynitrite decays intracellularly into highly cytotoxic molecules, including hydroxyl radicals and nitrosyl chloride. These reactive nitrogen intermediates (RNI) activate an intracellular enzyme known as PARP (poly ADP-ribose polymerase). This enzyme rapidly depletes the cellular contents of adenosine triphosphate (ATP), resulting in cellular energy starvation." These RNIs also induce lipid peroxidation and cause loss of cell viability." Nitric oxide also inhibits a variety of metalloenzymes and

essential enzymes in the tricarboxylic acid cycle, the glycolytic pathway, DNA repair systems, and electron transport pathways. As with many other elements of the host inflammatory response, NO may have both advantageous and disadvantageous properties in sepsis. Nitric oxide regulates microcirculation to vital organs and contributes to intracellular killing of microbial pathogens. Excess and prolonged release of NO, however, results in systemic hypotension and contributes to septic shock. Regulation of NO synthesis remains an experimental target in the treatment of sepsis, but preservation of the favorable attributes of NO in the microcirculation while limiting its toxic effects remains a major therapeutic challenge.77 ROLE OF THE COAGULATION SYSTEM

Activation of the coagulation system, generation of a consumptive coagulopathy, systemic fibrinolysis, and diffuse microthrombi are potentially life-threatening complications of severe sepsis." The innate immune system and the coagulation system coevolved as early defense systems against microbial invasion and tissue injury and remain highly integrated and coregulated. The tissue factor pathway (formerly known as the extrinsic pathway) is the principal mechanism by which the coagulation system is activated in human sepsis." The contact factors (also known as the intrinsic pathway) play an accessory role as amplifiers of clotting once thrombin is generated (Fig. 15.3). Intravascular fibrin deposition impairs blood flow, promotes neutrophil and platelet adherence, and may contribute to at least some forms of multiorgan failure in sepsis." Depletion of coagulation factors and activation of plasmin, antithrombin, and activated protein C may result in a hemorrhagic diathesis in some septic patients. Depletion of endogenous anticoagulants and impaired fibrinolysis may generate a procoagulant state and portend a poor prognosis." Inflammatory signals generated by intravascular thrombin generation and fibrin deposition contribute to microvascular injury as neutrophils and monocytes are drawn into areas of clot formation. Specialized receptors known as the protease-activated receptors (PAR 1-4) recognize thrombin, tissue factor:factor VII complex, factor X, and activated protein C. 83 These receptors are present on endothelial surfaces, neutrophils, and platelets and initiate the release of inflammatory cytokines, chemokines, platelet-activating factor, and P-selectin, among other mediators. The clotting system works in concert with the inflammatory networks in an attempt to localize the site of injury or infection from the rest of the host tissues. Extensive injury or failure of the early local control mechanism leads to generalized coagulation activation, inflammation, and the pathologic process of severe sepsis and septic shock." Clinical trials with recombinant tissue factor pathway inhibitor," activated protein C,86 and plasma-derived antithrombin" for treatment of sepsis resulted in disappointing results except for recombinant human activated protein C (drotrecogin alfa activated). This treatment strategy yielded a statistically significant survival benefit in a multicenter clinical trial with 1690 patients. The 2S-day all-cause mortality in the recombinant human activated protein C group was 24.7%, while the mortality rate in the placebo group was

295

S E V E R E S E PS IS AND S E P TIC S H O C K

1. Neutrophil Activation (Cytokines, Complement)

FIGURE 15.3. The interactions between coagulation and inflammation in sepsis. Solid bold arrows, ma jor coagulation pathways; thin solid arrows, accessory and amplification clotting pathways; open arrows, inflammation and clotting interactions; dashed open arrows, inhibitory pathways; TF, tissue factor; uPA, urokinase plasminogen activator; tPA, tissue plasminogen activator; PAI-I, plasminogen activator inhibitor-I, Fbg, fibrinogen; PAR, protease-activated receptor; IL, interleukin, TNF, tumor necrosis factor; MIF, macrophage migration inhibitory factor; MCP-I , monocyte chemoattractant protein-L

3. Neutrophil p Integrins Adherence (Cb11lCD18) (P2Integrins)

-:-/ , ,.r: , , "w

•

Sialylated , Fucosylated , Sulfated Glycoproteins or Glycolipids

TNF-a.IL-lp.IL-8.

PAF MCP-l -'----~---'

Interstitium Macrophage

30.9% IP < .005, with a 6.1 % absolute reduction in mortality]." This drug received regulatory approval in 2002 for the use of drotrecogin alfa activated in severe sepsis/septic shock at high risk of mortality [e.g., multisystem failure or an APACHE [Acute Physiology and Chronic Health Evaluation] II score of 25 or greater). The precise mechanism of action of recombinant human activated protein C that accounts for its beneficial effects is not entirely clear, but it is not likely to be its direct anticoagulant activity." Heparin alone and other anticoagulants such as hirudin have not been shown to improve outcome in clinical settings or experimental models of sepsis,89,90and all of these endogenous anticoagulants have antiinflammatory properties." Activated protein C also has profibrinolytic activity and antiapoptotic activities on endothelial cells in experimental systems." which may spare the endothelial surface for the injurious effects of systemic inflammation and disordered coagulation.i' :" Clinical investigations with antithrombin, tissue factor pathway inhibitor, and other coagulation inhibitors continue as possible treatment regimens for specific subgroups of septic patients.

4. Transmigration

where invasive microorganisms are found, are depicted in Figure 15.4.62 Activated neutrophils degranulate and expose endothelial surfaces and surrounding structures to reactive oxygen and nitrogen intermediates, and a number of lytic proteases, including elastase. This process involves ongoing communication between endothelial surfaces and inflammatory cells. The process is initiated by the selectins and culminated by engagement of neutrophil /3-2 integrins (CD11/ CDI8) and adhesion molecules on endothelial cells such as ! Inflammatory and Coagulatio n Networks in Sepsis Amp lificati on pathway

F Xla

MONOCYTE, PLATELET, NEUTROPHIL, AND ENDOTHELIAL CELL INTERACTIONS IN SEPSIS

The recruitment of neutrophils, platelets, and other inflammatory cells to an area of localized infection or clot formation is an essential component of the host innate immune response . Localization and eradication of invasive microorganisms at the initial site of injury is the primary defense strategy against microbial pathogens. Th is physiologic process may become deleterious if diffuse neutrophil-endothelial cell interactions occur throughout the circulation in response to systemic inflammation.w" :" The mechanisms responsible for the migration of neutrophils from the intravascular space into the interstitium,

FIGURE 15.4. Neutrophil-endothelial cell interactions in sepsis. Ls, Lselectin, PSGL-I, P-selectin glycoprotein ligand-I , Ps, Pvselectin, Es, Evselectin, sl.e", sialylated-Lewis' , ICAM-I, intercellul ar adhesion molecule-I, PAF, platelet-activating factor; TNF-a, tumor necrosis factor-a; IL-I~, interleukin-Hl, MCP-I, monocyte chemo attractant protein-I, C, complement; PECAM, platelet endothelial cell adhesion molecule. (Source: From Opal and Huber," with permission from Scientific American Medicine.)

296

CHAPTER 15

intercellular adhesion molecule-l and -2. Neutrophil egress commences and chemotactic factors direct phagocytic cells to the site of microbial infection. Platelet and monocyte infiltration follow and provide additional inflammatory signals, adherence molecules, and procoagulant surfaces for clot formation and cell migration. This process may lead to diffuse endothelial injury in the face of generalized systemic inflammatory responses. Regulation of events at the neutrophilendothelial interface is an important area for therapeutic intervention in the management of sepsis. 79,81,84,88,91 OTHER MEDIATORS OF SEPSIS

It has been discovered that several host-derived mediators may contribute to the pathogenesis of septic shock. Macrophage migration inhibitory factor (MIF) is a late mediator induced by glucocorticoid excess; it has many proinflammatory actions on effector cells, including the capacity to upregulate TLR4 expression," impair myocardial function," delay neutrophil apoptosis," and contribute to lethal septic shock." Inhibitors of MIF may have a potential therapeutic role in human sepsis. 93,96

High-mobility group box-l (HMGB-l) protein is a lateacting cytokine-like DNA-binding protein that appears to contribute to late-onset inflammatory activities in septic shock.":" Inhibitors of HMGB-l demonstrate some therapeutic benefit in experimental sepsis." Complement components, particularly the chemoattractant factor C5a,l00 and loss of the regulatory element Cl esterase inhibitor" can produce vasodilatation and may participate in the pathogenesis of septic shock. The triggering receptor expressed on myeloid cells TREM-I 101and NODI/NOD2 (nucleotide-binding oligomerization domain proteinl'?' are additional, recently identified, signaling systems that mediate inflammatory signals independent of the TLRs and may play a pathogenic role in the initiation of the septic process. The cholinergic antiinflammatory system is a well-characterized vagally transmitted mechanism by which the nervous system is able to directly modulate host macrophage inflammatory signals via a nicotinic receptor-mediated process.l'" This neuronal-immune communication system may also prove to be amenable to therapeutic modulation in the care of septic patients.

Diagnostic Methods for Severe Sepsis/Septic Shock Fully developed septic shock is obvious to the clinician, yet the early phases of severe sepsis and even septic shock may be quite subtle even to experienced clinicians. Early symptoms include confusion, apprehension, or decreased sensorium. Sudden and unexplained dyspnea (respiratory alkalosis) is a frequent early event, and it is often missed or attributed to other causes (congestive heart failure, anemia, pulmonary embolus, bronchial plugging, etc.). Fever is usually, but not invariably, present. Hypothermia in fact is a more specific and reliable finding; its presence portends an unfavorable prognosis. An unexplained decrease in urinary output, sudden onset of cholestatic jaundice, unexplained metabolic acidosis, excessive bleeding at venipuncture sites, or even sudden unexplained hypotension may be the presenting finding in septic shock. Clinicians need to recognize these

early signs and symptoms since successful outcomes from severe sepsis/septic shock depend on early recognition and rapid intervention.' Myriad clinical, laboratory, and hemodynamic abnormalities are recognized in septic shock (Table 15.5). There is no single clinical or laboratory test that is pathognomonic of septic shock; therefore, the clinical diagnosis of sepsis remains a challenging problem. 1 Blood cultures need not be positive (and reveal no pathogen in about two-thirds of septic patients); leukocytosis or neutropenia may occur; hyperglycemia, euglycemia, or hypoglycemia may be observed; and a variety of acid-base abnormalities may occur. It is the progressive evolution of a constellation of signs and symptoms that leads to a clinical diagnosis of septic shock. The most common hemodynamic findings in early septic shock are a high cardiac output and a low systemic vascular resistance state. Vasodilatation within the peripheral vascular system is principally related to increased NO synthesis; however, downregulation of adrenergic receptors with progressive loss of catecholamine sensitivity; excess production of the vasoactive mediators histamine, adrenomedullin, platelet-activating factor, and bradykinin; and deficiency of vasopressin all contribute to reduced vascular tone in sepsis. 84,100,104-106 The heart attempts to compensate for the loss of systemic vascular tone despite diminished myocardial performance even in the early phases of septic shock.'?' Without adequate intervention, circulating blood volume is continually lost into the interstitial spaces and intracellular locations. The heart cannot compensate indefinitely as myocardial depressant factors (NO, MIF, IL-6, TNF, other factors) are released, and cardiac performance deteriorates. Late septic shock is marked by systolic hypotension despite intense peripheral vasoconstriction and reduced cardiac index. 91,94,100 Septic shock may be associated with a loss of normal autoregulation within the microcirculation, with an imbalance between oxygen delivery and oxygen consumption.l'" A supply-dependent dysoxia may occur, and cytopathic hypoxia'" from diminished oxygen utilization may develop as well. Attempts to enhance oxygen delivery in sepsis to supranormal levels have not improved outcomes.v'?" but a controlled clinical trial of early goal-directed resuscitation found rapid restoration of tissue perfusion and oxygen delivery remains a critically important target in sepsis therapy. 110

Experimental Diagnostic Methods and Biomarkers for Sepsis f Since timely intervention is essential for successful outcomes in severe sepsis/septic shock, a concerted effort has been undertaken to improve the early diagnostic tools available to detect sepsis. Improved blood culture methods or measurement of plasma endotoxin levels may have diagnostic utility.'!' Circulating levels of bacterial superantigens can be detected in selected patients with toxic shock syndrome.l" Interleukin-6 has been considered an indicator of cytokine activation as its synthesis is induced by TNF-a and IL-l (3. Patients with elevated IL-6 levels appear to respond favorably to anticytokine therapies.!" In several studies,113-115 elevations of IL-6 or failure of IL-6 levels to decline over time have been associated with poor outcome. Unfortunately, the variability and lack of specificity or IL-6 measurement limits its reliability as a diagnostic method for septic shock.

297


TABLE 15.5.

Charac~eristic

Hemodynamic and Laboratory Findings in Severe Sepsis.

Parameter

Common findings

Clinical interpretation and implications

Mixed venous O2 saturation

4l/min/m2

Systemic vascular resistance (SVR)

2000 >40% >140

120

Normal or increased Normal or increased

Decreased Decreased

Decreased Decreased

Decreased Decreased

14--20 >30

20-30 20-30

30-40 5-15

>35

Slightly anxious Crystalloid

Mildly anxious Crystalloid

Auudous, co~sed Crystalloid and blood

Negligible Confused, lethargic Crystalloid and blood

*For a 70-kg man. The guidelines are based on the 3-for-l rule. This rule derives from the empiric observation that most patients in hemorrhagic shock require as much as 300mL of electrolyte solution for each 100mL of blood loss. Applied blindly, these guidelines can result in excessive or inadequate fluid administration. For example, a patient with a crush injury to the extremity may have hypotension out of proportion to his or her blood loss and require fluids in excess of the 3: 1 guidelines. In contrast, a patient whose ongoing blood loss is being replaced by blood transfusion requires less than 3:1. The use of bolus therapy with careful monitoring of the patient's response can moderate these extremes. Source: Reprinted with permission from Advanced Trauma Life Support for Doctors, Committee on Trauma, American College of Surgeons. Chicago: 2004.

307

SHOCK AND RESUSCITATION

tion is to ensure that one is not treating cardiogenic shock as the appropriate therapy differs dramatically. The findings of jugular venous distension, rales, and the presence of an S3 gallop in cardiogenic shock may assist in their differentiation. Both forms of shock, however, are associated with a reduction in cardiac output and a compensatory sympathetic-mediated response. Further, both types of shock may be treated with, and respond to, volume resuscitation. If the diagnosis is in doubt or the clinical situation suggests both as a possibility, then invasive monitoring using a pulmonary artery catheter (PAC) might be helpful. Treatment of hypovolemic shock involves achieving two primary goals concurrently: reexpanding the circulating blood volume and proceeding with any necessary interventions to control ongoing volume loss. The rate at which volume expansion is achieved should take into account the clinical status of the patient. In patients with hemorrhagic shock, there is increasing evidence to suggest that limiting volume until bleeding is controlled is not harmful and might in fact be beneficial." However, in patients with clear evidence of shock in whom ongoing blood loss is not a concern, vigorous volume resuscitation is paramount. Adequate repletion of the circulating volume reexpands capacitance vessels, restores venous return, and reestablishes ventricular filling. As a result of improved left ventricular end-diastolic volume, contractile function, stroke volume, and cardiac output respond positively; as cardiac output improves, the systemic vascular resistance returns to normal, and tissue perfusion is restored. Even after adequate resuscitation, diastolic compliance may remain abnormal for some time because of increased myocardial interstitial fluid. This reduced compliance may necessitate higher left ventricular end-diastolic pressures to optimize ventricular performance.

inability to maintain systolic blood pressure above 90mmHg after trauma-induced hypovolemia are associated with a mortality of more than 50%.5 However, rapid and adequate restoration of circulating blood volume simultaneous with control of bleeding can reverse even severe hemorrhagic shock. If shock is prolonged, then hypoperfusion of the various microvascular beds may lead to cellular injury and the elaboration of inflammatory mediators, setting up the vicious self-propagation of ongoing tissue injury and organ dysfunction. 6,7 Hypovolemic shock is easily diagnosed when there is an obvious source of volume loss and when overt signs of hemodynamic instability and increased adrenergic output are present. However, assessment is more difficult with lesser degrees of hypovolemia. Table 16.3 demonstrates the diagnostic utility of changes in heart rate and systolic blood pressure." Most evident is the lack of sensitivity of these measures in patients with moderate acute blood loss. The most helpful physical findings are severe postural dizziness (preventing measurement of upright vital signs) or a postural pulse increment of 30 beats/min or more. Supine hypotension and tachycardia are frequently absent, even with more than 1000ml blood loss. In addition, capillary refill time, once considered a valuable physical sign of hypovolemia, has a sensitivity for moderate blood loss of only 11% and specificity of 890/0 8 The diagnosis is even more challenging when there is an occult source or a slower rate of volume loss, such as might occur with excessive gastrointestinal, urinary, or insensible loss. Laboratory evaluation may provide some diagnostic information. Nonhemorrhagic forms of hypovolemic shock tend to cause hemoconcentration. If the principal abnormality is caused by loss of free water, then hemoconcentration will be accompanied by hyponatremia. Acutely following hemorrhage, there may be no alteration in the hemoglobin or hematocrit values until compensatory fluid shifts have occurred or exogenous red cell-free resuscitation fluid is administered. In the absence of exogenous resuscitation, these values decrease secondary to transcapillary refill or osmotic-induced shifts, a process that may take several hours to achieve. The diagnosis of hypovolemic shock is usually made on the basis of the complete clinical picture. However, when the underlying shock state is not clear, the most critical distinc-

Intravenous Access Resuscitation of hemorrhagic shock or severe hypovolemia irrespective of the cause requires two large-bore (16-gauge or larger) intravenous lines for rapid volume restoration. Access may be achieved by peripheral vein catheterization; cutdowns on the basilic, greater saphenous, or cephalic veins; or percutaneous central venous access via subclavian, internal jugular,

TABLE 16.3. Systematic Review of the Diagnostic Utility of Changes in Heart and Blood Pressure in the Assessment of Hemorrhagic Shock. Specificity

(95%

Sensitivity (95% confidence interval)

Postural" pulse increment ~30/min or severe postural dizziness Postural hypotension (~20mmHg decrease in systolic blood pressure) Age ~65 Age ~65 Supine tachycardia (pulse >100/min) Supine hypotension (systolic blood pressure ~95mmHg)

Moderate blood loss (450-630ml) 22 (60/0-48%)

confidence interval)

Specificity

Large blood loss (630--1150ml) 97 (91%-1000/0)

98 (97-99)

9 (6-12) 27 (14-40)

NA NA

94 (84-99) 86 (76-97)

0(0-42) 13 (0-50)

12 (5-24) 33 (21-47)

96 (88-99) 97 (90--100)

NA, not applicable in this setting. "Supine to standing position.

Source: From McGee et al.," by permission of the Journal of the American Medical Association.

308

CHAPTER 16

or femoral venous puncture. In a large, randomized controlled trial, femoral venous catheterization was associated with a 4-fold increase in rates of catheter-related infection and over a lO-fold increased risk of thrombotic complications.'? suggesting that this approach should be used only when other sites are inaccessible. If absolutely required, then the catheter should be removed at the earliest possible time . For the purposes of resuscitation, the most important consideration for vascular access is the choice of catheter and tubing. The rate of flow is proportional to the fourth power of the radius of the cannula and is inversely related to its length (Poiseuille's law]. Thus, a short, large-bore catheter connected to the widest administration tubing possible or direct insertion of beveled tubing via a cutdown venotomy provides the most rapid flow rates. There is a lO-fold increase in flow rates when a large-boreintroducer catheter /8.5 French) is used in conjunction with trauma administration tubing (0.22 inch internal diameter] compared to a typical l8-gauge catheter with regular intravenous tubing (0.10 inch internal diameter]." Flow rates are also dependent on the viscosity of the administered fluid. Finally, accurate placement with avoidance of catheter kinking is critical to maximize flow rates (Fig. 16.2).

Choice of Fluid for Volume Resuscitation The optimal fluid for volume resuscitation has been a subject of controversy for decades. The most efficacious and costeffective approach is to restore intravascular volume with rapid infusion of isotonic saline or a balanced salt solution. Infusion of 2 to 31 of crystalloid over 10 to 30min should restore adequate intravascular volume in most cases as the result of its large volume of distribution. In patients with hemorrhagic shock, final restoration of blood volume with A

600

HYPERTONIC SALINE

Hypertonic (7.5%) saline has been considered an alternative to isotonic solutions for several reasons. First, it achieves a similar increase in intravascular volume with the administration of smaller infusion volumes by drawing water out of the intracellular space and thus replenishes the depleted extracellular space; in effect, it is a form of autotransfusion from the relatively large intracellular compartment to the smaller interstitial and intravascular compartments. The relative cellular dehydration induced by HS might also play a role in reducing cerebral edema (and thus lower intracranial pressure) in patients with head injury. In addition, there are experimental data suggesting that hypertonic solutions might lessen the inflammatory response following shock and resuscitation.P:" To increase the intravascular oncotic pressure, hyperonic saline is often administered in 6% dextran . The colloid component transiently partitions the recruited fluid to the intravascular space and thus, in theory, should prolong B

800 700

crystalloid usually requires at least three times the estimated blood loss. However, if blood pressure does not improve after rapid administration of 21 of crystalloid, this suggests that blood loss is in excess of l500ml, there is ongoing active bleeding, or another cause of shock must be considered. Further volume resuscitation should therefore include simultaneous blood transfusion, either as fully cross-matched blood, type-specific blood, or in dire circumstances, O-positive or O-negative packed cells. Although administration of isotonic crystalloid and blood products remains the conventional approach to patients with hemorrhagic or hypovolemic shock, several other products have been considered and promoted as possible alternatives. These options include hypertonic saline (HS), a variety of colloids, and blood substitutes.

TRAUMA TUBING with Diluted Packed Cells

TRAUMA TUBING with Who le Blood

500

400 300 BLOOD TUBING with Diluted Packed Cells BLOOD TUBING with Who le Blood

100 BLOOD TUBING with Piggybacked Cold W hole Blood (7°C)

10°

20° 30° 40° 50° 60° 70° 80° Degrees of catheter angulation

FIGURE 16.2. A. Flow studies using different blood products administered through an 8.S-French catheter. B. Kinking is a frequent problem and significantly reduces maximal flow rates, particularly in

the subclavian position . jSource: Adapted from Dutkey et al.," with permission.)


the beneficial hemodynamic effects of the solutions. In addition, HS induces a poorly defined pressor response following its administration. In most clinical trials, outcomes of patients receiving HS with or without dextran (HSD) are compared to those receiving standard crystalloid solutions of either lactated Ringer's or 0.9% saline. The solution is administered as a 250-ml bolus either in the prehospital setting or as the first resuscitation fluid in the emergency department. When dextran is administered with HS, it persists in the circulation with a half-life of 7 to 10h; thus, some effect should persist beyond the acute resuscitation phase. IS In a large American multicenter study trial consisting of 359 evaluable patients with hypotension caused by trauma, patients were randomized to receive either HSD (250ml) or standard isotonic resuscitation during prehospital transport. 16 Mortality was 83% in patients receiving HSD compared to 80% in those receiving standard crystalloid solutions, an insignificant difference. Post hoc subset analysis demonstrated a significant survival benefit in those patients requiring operation for penetrating trauma. However, when this group of patients was studied prospectively, there was only a trend toward improved survival in the patients receiving HSD. 17 Unfortunately, the small sample size (48 patients) precludes any definitive interpretation of the effect of HS as a resuscitation fluid in this subset of patients. In the highest-quality randomized controlled trial to date, 229 patients in coma with shock following injury were randomized to receive either a single 250-ml bolus of 7.5% saline or Ringer's lactate in the field. In-hospital survival and longterm (6-month) neurological outcomes were equivalent across groups. IS To specifically evaluate the importance of dextran, a large multicenter trial was performed to evaluate the effects of isotonic saline and HS with or without dextran during the prehospital resuscitation of trauma patients with hemorrhagic shock." This study suggested only a trend toward improved survival in the entire cohort of patients receiving HS solutions. There was no significant benefit with the addition of dextran. However, post hoc subset analysis demonstrated a significantly improved survival in patients with severe head injury in combination with hemorrhagic shock. Unfortunately, this effect did not persist in a subsequent trial in which this subset of patients was specifically evaluated prospectively." Most, but not all, of the studies to date do not have sufficient statistical power to detect a difference in outcome between patients treated with HSD and isotonic crystalloid solutions. To circumvent this problem, two meta-analyses have been published.i'r" In one evaluation, individual patient data were collated from all randomized controlled trials of HSD or HS in patients with hemorrhagic shock due to trauma." The overall study population consisted of more than 600 patients. When the entire population of patients was considered, there was a definite suggestion of an improvement in survival associated with HSD, with the greatest effect demonstrable in patients requiring surgery for penetrating injuries. In a separate publication, these data were analyzed specifically to determine the effectiveness of HS resuscitation in patients with severe head injury." In an analysis of 233 patients with combined shock and severe head injury from six different trials, patients receiving HSD were

309

twice as likely to survive until discharge. However, these results do not include data from the more recent, negative, large randomized controlled trial." In a second meta-analysis, the effects of HS, HSD, and isotonic crystalloid in patients with traumatic hemorrhagic shock were evaluated.f This study differs because of the use of intent-to-treat analysis; that is, patients were evaluated according to treatment assignment rather than actual treatment received. After an analysis of more than 1200 patients in a total of 14 studies, there was no difference in survival. Patients treated with HS generally exhibited larger blood pressure increases and had reduced early and 24-h total fluid and blood requirements than observed in patients treated with isotonic solutions. Based on published data, HS with or without dextran probably offers little benefit to standard resuscitation regimens. Hypertonic saline as a method of small-volume resuscitation may also offer certain advantages in less-controlled medical environments where prolonged transport or evacuation times require longer periods of resuscitation with limited supplies. In addition, the low weights and small volumes of HS required for resuscitation may prove advantageous in the battlefield. FLUID RESUSCITATION USING COLLOID

Much of the controversy regarding the optimal fluid for shock resuscitation has centered on the use of crystalloid solutions versus colloid solutions. In addition, there is controversy regarding which colloid offers the greatest benefit. In a metaanalysis of 31 randomized controlled trials in which albumin was compared to crystalloid solutions, mortality was 50% higher in patients receiving albumin." For every 20 patients treated with albumin, it is estimated that there is 1 additional death. Another meta-analysis suggested neither harm nor benefit with albumin infusion." Taken together, the absence of benefit and potential for harm coupled with the certain increase in costs, albumin cannot be recommended for shock resuscitation. The putative mechanisms by which administration of albumin may exert any adverse effects are unclear. Potentially, increased transcapillary flux of albumin from increased microvascular permeability might reduce the oncotic pressure difference across the capillary wall, making edema more likely and more resistant to subsequent mobilization. An increase in interstitial edema may globally worsen tissue oxygenation while impairing alveolar gas exchange in the lungs." There is also some evidence to suggest that albumin may impair sodium and water excretion and worsen renal failure. 27 There are several forms of synthetic colloid in use. Most are derived from a 60/0 hydroxyethyl starch solution and differ in the molecular weights of the hydroxyethyl moiety. These large molecules provide superb oncotic properties while maintaining the agent in the intravascular space. As a result of these properties, these agents have a volume-expanding effect that lasts as long as 24h (Fig. 16.3). Potential disadvantages with the use of hydroxyethyl starch solutions include rare anaphylactic reactions and a coagulopathy when given in large volumes. The development of coagulopathy depends on the specific colloid and is frequent in some with larger molecular weights (e.g.,hetastarch)

310

CHAPTER 16

9000 8000 7000 ~ 6000 15000 ~ 4000 u::: 3000

0.9% Saline

Hetastarch 5% Albumin

2000 n..._--~

1000 O +----r------.,----~---__,

o

6

12

18

24

Hours following admission

FIGURE 16.3. Total fluid requirements in patients with hypovole mic shock receiving a synthetic colloid (hetastarch), 5% albumin, or 0.9% saline. Synthetic colloids have a far greater volume-expanding effect than crystalloid solutions, roughly equal to that of 5 % albumin. (Source: Adapted from Rackow et al. 112 )

compared to others with relatively small molecular weights [e.g., pentastarchl.Vr" Randomized controlled trials in a variety of clinical settings suggested that these solutions do provide volume expansion superior to crystalloid solutions 29,3o and, along with this, some improvement in microcirculatory blood flow." There is a suggestion that these synthetic colloids might increase the risk of acute renal failure, an effect dependent on the in vitro molecular weight of the compound, the degree of substitution (the proportion of hydroxyethylated glucose molecules), and the volume administered as these characteristics affect the time to elimination from the intravascular space and the degree of macromolecule accumulation." ALTERNATIVES TO BLOOD TRANSFUSION

Although the current blood supply is safer than ever owing to improved donor screening and testing, it is likely, because of the inevitable appearance of new viruses and the potential for false-negative screening tests, that disease transmission will never be completely eradicated. In addition, there is some evidence to suggest that blood transfusion is an independent risk factor for posttraumatic organ dysfunction, an effect putatively mediated by priming of recipient neutrophils by inflammatory mediators within stored blood. 33,34 In this regard, a randomized controlled trial of a restrictive (maintaining hemoglobin between 7 and 9 g/dl) versus a liberal (maintaining hemoglobin between 10 and 12g/dl) transfusion policy demonstrated a reduced risk of death and organ dysfunction in the restrictive group . This effect was significant in patients less than 55 years of age and in those with scores below 20 on the APACHE (Acute Physiology and Chronic Health Evaluation) II. 35 Finally, blood transfusion involves the need for compatibility testing, which increases the time required for its availability. To circumvent the problems asso ciated with the transfusion of allogeneic blood, two alternatives exist to standard blood transfusion: autotransfusion and red blood cell substitutes. A UTOTRANSFUSION

Autotransfusion of shed blood is a valuable adjunct to elective cardiothoracic, abdominal, orthopedic, and vascular surgery, although its use in the resuscitation of trauma patients was

first reported more than 50 years ago." Transfusion of shed blood has several advantages over homologous blood. In the acutely injured patient in need of immediate blood, autotransfusion is readily available. Autotransfusion is safe without risk of hemolytic, febrile , or allergic reactions or transmissible disease . Further, salvaged blood is already warm and has better oxygen-transport properties because of preservation of normal levels of 2,3-diphosphoglycerol. Despite reductions in platelet count and function, labile clotting factors are present in greater concentration than in banked blood , although fibrinogen levels drop significantly in salvaged blood ." Although enteric contamination was at one point considered a contraindication to the use of autotransfusion devices, there is evidence to suggest that even moderate amounts of contamination pose little risk if perioperative antimicrobial therapy is used. 38,39 Despite the potential advantages of autotransfusion, its contribution to blood replacement in the patient with hemorrhagic shock is variable. In several studies, autologous blood met from II % to 45% of the total blood requirement.Vr'r? In the exsanguinating patient, two limitations preclude its greater use . First, there is usually insufficient time available to organize the necessary personnel and equipment. In addition, by design the suction apparatus is less efficient at aspirating blood to minimize hemolysis, and this feature makes it less useful in patients with massive hemoperitoneum. Regardless , the use of autotransfusion devices is cost-effective and reduces the use of banked blood." Its use should be considered in any operative pat ient with hemorrhagic shock who does not im mediately respond to crystalloid resuscitation in the emergency room. '? RED BLOOD CELL SUBSTITUTES

There are several potential benefits to using a red blood cell substitute, including immediate availability, no need for compatibility testing, freedom from disease transmission, and long-term storage. Diaspirin cross-linked hemoglobin (DCLHI is the most well studied of the currently available blood substitutes. It has been evaluated in two clinical trials in patients with hemorrhagic shock following injury. In the first study, there was a significantly increased risk of organ failure and death in patients receiving DCLH. 43 Another study in a sim ilar group of patients in whom the DCLH was administered in the prehospital phase of care demonstrated no benefit in the treatment group." In other studies in patients undergo ing major surgery, DCLH spared the transfusion of allogeneic red blood cells but frequently resulted in decreases in cardiac index and jaundice, hemoglobinuria, pancreatitis, and abnormalities in liver function tests.":" Preliminary data on other blood substitutes do not suggest an increase in adverse events. For example, an open-label prospective trial of human polymerized hemoglobin (Polyheme) in 39 patients with acute blood loss due to either trauma or emergency surgery demonstrated a relatively good safety profile .48,49 In a subsequent randomized, prospective evaluation of polymerized human hemoglobin versus alloge neic blood in a series of trauma patients, there were no significant adverse effects except for a small rise in bilirubin evident by day 3, representing the clearance and metabolism of acellular hemoglobin." Large randomized controlled trials are under way with both Polyheme and Hemopure, a form of bovine polymerized hemoglobin.

311


Traumatic Shock The major contributor to shock following trauma is hypovolemia, and acute hemorrhage is a frequent cause of death after injury." Once hemorrhage ceases or is controlled, patients can continue to suffer loss of plasma volume into the interstitium of injured tissues and develop progressive hypovolemic shock. In addition, hypovolemia coupled with tissue injury evokes a greater systemic inflammatory response and a potentially more devastating degree of shock than hypovolemia alone. Specific injuries can also produce superimposed cardiogenic or neurogenic shock. Pericardial tamponade or tension pneumothorax can produce hemodynamically significant compression of the heart, and myocardial contusion can cause cardiogenic shock. Neurogenic shock can accompany spinal cord injury. The degree to which direct tissue injury and an inflammatory response participate in the development and progression of traumatic shock distinguishes it from hypovolemic shock. Cellular injury, devitalized tissues, ischemia-reperfusion injury, bacterial contamination, and accumulations of blood or other body fluids contribute to the development of SIRS. It is the inflammatory response to these various stimuli that evokes the functional and metabolic disturbances that follow and place the trauma patient at high risk for postinjury organ dysfunction and death. The management of traumatic shock is similar to that of hypovolemic shock. Apart from prompt reversal of perfusion defects, efforts must be focused on limiting the inflammatory response to other stimuli. For example, maneuvers directed toward aggressive early reestablishment of the circulation to ischemic tissues, prompt debridement of devitalized or necrotic tissues, and early fracture fixation 51,52 might all play a role in limiting the inflammatory response.

Cardiogenic Shock The syndrome of cardiogenic shock has been defined as the inability of the heart-as a result of impairment of its pumping function-to deliver sufficient blood flow to the tissues to meet resting metabolic demands." Thus, the purest clinical definition of cardiogenic shock requires a low cardiac output and evidence of tissue hypoxia in the presence of an adequate intravascular volume. If hemodynamic monitoring is available, then the diagnosis is confirmed by the combination of a low systolic blood pressure and a depressed cardiac index «2.21/min/m2 ) in the presence of an elevated pulmonary capillary wedge pressure (>15mmHg). Intrinsic causes of cardiogenic shock include myocardial infarction, contusion from direct chest trauma, cardiomyopathy, valvular heart disease, and rhythm disturbances. In the context of myocardial infarction, autopsy studies show that cardiogenic shock is generally associated with loss of more than 400/0 of left ventricular myocardium. 54 The cumulative nature of myocardial damage should be taken into account. In a patient in whom compensation for previous myocardial damage is marginal, even a small additional amount of infarction or direct contusion from blunt trauma can result in cardiogenic shock. In addition, the loss of a functional component of the heart, including a valve or valvular support, free

wall, or ventricular septum, because of acute ischemic necrosis or direct trauma can result in shock either in isolation or in conjunction with loss of left ventricular function. Finally, a variety of other causes may result in acute deterioration leading to cardiogenic shock; these include acute myocarditis, sustained arrhythmias, acute primary valvular catastrophes, and decompensation in patients with previous end-stage cardiomyopathies. In a large prospective cohort study assessing outcomes of cardiogenic shock following acute myocardial infarction, left ventricular failure was the most frequent etiology leading to shock (780/0); isolated right ventricular failure was causal in only 2.80/0. Only 1.40/0 of patients in cardiogenic shock had evidence of tamponade due to rupture of the ventricular wall, 6% had severe mitral regurgitation as a result of papillary muscle dysfunction or rupture, and 4 % had ventricular septal rupture." Although these mechanical complications leading to cardiogenic shock following myocardial infarction account for the etiology in only 12 % of patients, they require prompt recognition and treatment to ensure survival. The mechanisms leading to the development of cardiogenic shock reflect a complex interplay between the heart, the peripheral circulation, and maladaptive compensatory responses. The progressive deterioration that occurs in the absence of intervention can be seen as a vicious cycle in which normal physiological compensatory mechanisms in response to reduced cardiac output tend to propagate in a downward spiral, ultimately leading to death (Fig. 16.4). A reduction in blood pressure activates the sympathetic nervous system through the stimulation of baroreceptors. The adrenergic response leads to an increase in heart rate, myocardial contractility, and arterial and venous vasoconstriction. The renin-angiotensin system is activated by inadequate renal perfusion and sympathetic stimulation, leading to additional vasoconstriction and salt and water retention. Finally, hypotension potentiates the secretion of antidiuretic hormone, which further increases water retention. The reduction in

ILeft ventricular dysfunction I Reduction In myocardial oxygen delivery

-,

t

Reduction in coronary perfusion pressure

f

IIncrease In LVEOP r-------o

1

1

t Sympathetic tone t Renin-anglot8nsln-aldosterone ,/ t Antl-dluretic hormone

,-------... I Salt and water retention

FIGURE 16.4. The reduction in cardiac output associated with left ventricular dysfunction results in a series of compensatory responses that function to maintain blood pressure at the expense of aggravating any disparity in myocardial oxygen demand and supply. This imbalance increases left ventricular dysfunction and sets up a vicious cycle.

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blood pressure in conjunction with an elevated left ventricular end-diastolic pressure resulting from fluid retention and impaired left ventricular function reduces coronary perfusion pressure and thus myocardial oxygen delivery. Meanwhile, the increase in heart rate, systemic vascular resistance, and contractility all increase myocardial oxygen consumption and demand. The discrepancy between myocardial oxygen demand and oxygen delivery further impairs left ventricular function and will lead to circulatory collapse unless appropriate and timely intervention interrupts the cycle. The manifestations of cardiogenic shock develop as a consequence of a reduction in peripheral perfusion, the associated adrenergic response, and the inability of the heart to accommodate pulmonary venous return. Except for the last, the clinical features of cardiogenic shock are remarkably similar to those of hypovolemic shock. If right-sided failure predominates, then the predominant clinical features are those of accumulation of blood in the systemic veins and capacitance vessels. If this is severe or chronic, then peripheral edema, hepatomegaly, and hepatojugular reflux may develop. By contrast, the principal features of left-sided failure are related to an increase in extravascular lung water. The large capacitance pulmonary vasculature initially accommodates the increase in pulmonary venous pressures and blood volume. With normal pulmonary capillary permeability, pulmonary interstitial fluid flow overwhelms the capacity of pulmonary lymphatics, and edema develops at capillary pressures higher than 20mmHg. Overt pulmonary edema develops at pressures of more than 24 mmHg. In making the diagnosis of cardiogenic shock, any history of cardiac disease may be of diagnostic value. Physical exam may demonstrate evidence of inadequate tissue perfusion in conjunction with an elevated jugular venous pressure, an S3 gallop, and pulmonary edema. An electrocardiogram should be obtained immediately because evidence of serious abnormalities should direct the investigation toward the myocardium. A chest radiograph provides valuable diagnostic information regarding the presence of pulmonary edema, pleural effusion, or cardiac chamber enlargement. Laboratory data are supportive and may offer critical information for optimal management. Cardiac enzymes may provide evidence of acute myocardial infarction, and arterial blood gas analysis provides information regarding the adequacy of gas exchange. Severe hypoxia in the presence of a normal chest radiograph may support the diagnosis of massive pulmonary embolus rather than a primary cardiac cause of shock. Urinary indices may demonstrate decreased urinary sodium and elevated urine osmolarity, a function of renal conservation of sodium and water in response to a drop in renal perfusion. Transthoracic and transesophageal echo cardiography are excellent noninvasive aids in sorting through the differential diagnosis of cardiogenic shock; they may provide information on regional and global ventricular wall function, valvular integrity, and the presence or absence of pericardial fluid. In selected cases, it is difficult to ascertain the role of cardiac dysfunction in the shock state. Pulmonary edema associated with an increase in pulmonary capillary permeability may arise from noncardiac causes. Mechanical ventilation or underlying pulmonary disease may obscure the role of cardiogenic failure. Occasionally, a sudden cardiac event may lead to a fall or motor vehicle crash, making the differential diagnosis of shock particularly difficult. In these

situations, use of a PAC may provide additional diagnostic information. Management of cardiogenic shock is geared toward therapeutic interventions that interrupt the vicious cycle leading to progressive myocardial dysfunction. General supportive measures should be initiated immediately concurrent with the diagnostic evaluation. Critical elements include ensuring adequate oxygenation and ventilation, correction of electrolyte and acid-base abnormalities, and restoration of sinus rhythm. In the case of supraventricular tachycardia associated with hypotension, synchronized cardioversion will rapidly establish a normal sinus rhythm. Administration of crystalloid may improve perfusion if inadequate intravascular volume is contributing to the shock state. In patients with inadequate tissue perfusion and adequate intravascular volume, infusion of inotropic or vasopressor drugs should be begun immediately. However, it is important to be cognizant that pharmacological therapy, through an increase in heart rate, contractility, or systemic vascular resistance, tends to increase myocardial oxygen requirements. Dobutamine, because of its beneficial effect on afterload reduction, is preferable to other sympathomimetics unless substantial hypotension is present. Through its vasodilatory and inotropic effects, it increases left ventricular emptying while augmenting diastolic coronary blood flow. In the presence of moderate hypotension, dopamine is the preferred agent, whereas norepinephrine is reserved for cases of profound hypotension while other resuscitative measures are undertaken. 56 Inotropic support should be considered only a temporizing measure; it has never been demonstrated to improve survival in patients with cardiogenic shock." Afterload reduction through the use of vasodilators may be beneficial for patients in cardiogenic shock, but caution must be exercised because of the risk of exacerbating hypotension. Either intravenous nitroglycerin or sodium nitroprusside may be used. Although nitroprusside is a more potent arterial vasodilator, nitroglycerin is preferred as it has the advantage of not producing coronary steal (preferential coronary blood flow to nonischemic vascular beds]." Patients with right ventricular infarction leading to cardiogenic shock deserve special mention. The marked reduction in right ventricular compliance causes these patients to be extremely sensitive to volume depletion. The focus of therapy in such patients should be the immediate restoration of adequate left ventricular filling pressure while accepting significantly elevated central venous pressures. If volume resuscitation fails to resolve hypotension, then dobutamine should be used in an attempt to improve the contractility of the dysfunctional right ventricle." One adjunctive approach to patients with severe cardiac dysfunction is the use of intraaortic balloon counterpulsation (IABC), which is achieved by placing a counterpulsation balloon catheter in the descending thoracic aorta via the femoral artery. 59 Inflation of the balloon during diastole augments diastolic pressure at the aortic root and thus improves coronary blood flow; deflation during systole then provides some degree of afterload reduction. The reduction in afterload in concert with improved coronary perfusion is reflected by favorable changes in myocardial oxygen metabolism, with a decrease in oxygen extraction and a shift from lactate production to lactate extraction." Thus, unlike inotropic support, use of the intraaortic balloon pump reduces rather than


increases myocardial oxygen requirements. Objective findings include immediate and significant increases in cardiac index, stroke volume, and stroke work index, while reduction in pulmonary capillary wedge pressure and systemic vascular resistance are noted within hours." Generally, IABC is used as a means of temporary support for patients in cardiogenic shock, either with the hope of recovering myocardial function or while preparations are made for other interventions, whether they are percutaneous or operative attempts at myocardial revascularization, correction of other anatomical defects, or cardiac transplantation. There is some evidence that use of the IABC in patients subsequently undergoing revascularization may offer a significant survival benefit.f However, a randomized controlled trial comparing early revascularization (within 6 h) to initial medical stabilization (thrombolysis or IABC) in patients with cardiogenic shock following acute myocardial infarction showed a significant benefit in functional status and mortality at 1 year, suggesting that prolonged attempts at medical stabilization are unwarranted if facilities for revascularization are available. 63 Compressive (or obstructive) cardiogenic shock is a discrete entity that occurs as a result of extrinsic compression of the heart. The extrinsic compression limits diastolic filling, effectively reducing preload, which adversely affects stroke volume and cardiac output. Blood or fluid within the poorly distensible pericardial sac may cause pericardial tamponade, which is the most frequently cited cause of extrinsic cardiogenic shock. However, any cause of increased intrathoracic pressure-such as tension pneumothorax, herniation of abdominal viscera through a diaphragmatic hernia, mediastinal hematomas (rarely pneumomediastinum), and in some instances excessive positive pressure ventilation or intraabdominal compartment pressure-can cause cardiogenic shock. The classic clinical findings of pericardial tamponade include jugular venous distension, muffled heart sounds, and hypotension (Beck's triad). A drop in blood pressure of more than 10mmHg with inspiration, known as pulsus paradoxus, may be demonstrated. Placement of a central venous catheter confirms the elevation in right-sided filling pressures despite persistent hypotension. In the patient at risk, echocardiography is the most sensitive and specific modality to demonstrate pericardial fluid and need for operation. Pericardiocentesis as a diagnostic maneuver is not ideal because of the likelihood of inadvertent ventricular puncture causing a false-positive diagnosis, risk of significant iatrogenic injury, and the inability to withdraw clotted blood that has not yet lysed. These pitfalls limit the technique to only acute lifesaving situations.

Septic Shock Septic shock is the second most frequent cause of shock in the surgical patient. Invasive bacterial infection represents the most common cause of septic shock, with the most likely sites of infection the lungs, abdomen, and urinary tract. Bacteremia occurs in 400/0 to 600/0 of such patients. In the remainder, causative organisms may not be isolated because of previous exposure to antibiotics, episodic patterns of seeding, or fastidiousness of the organisms. In the past, gram-negative

313

aerobic organisms were thought to be the primary organisms responsible for septic shock. It is now clear that the same clinical features may be evident in patients with gram-positive, fungal, viral, and protozoal infections. The pathophysiological alterations in septic shock are a resul t of the local and systemic response to bacteria and their products. Although endotoxin from gram-negative bacilli is the best studied of these bacterial toxins, other bacterial products may initiate a similar response. These agents derived from infectious organisms include formyl peptides, exotoxins, and proteases from gram-negative organisms as well as exotoxins, enterotoxins, peptidoglycans, and lipoteichoic acid from gram-positive organisms. Bacterial products stimulate the release of endothelial and macrophage-derived proinflammatory cytokines, the most potent of which are tumor necrosis factor-a (TNF-a) and interleukin-l (IL-l). The TNF-a and IL-l may stimulate the release of IL-6, IL-8, and other mediators, including thromboxanes, leukotrienes, plateletactivating factor, prostaglandins, complement, and nitric oxide (NO). The inflammatory milieu induces several circulatory changes that impair tissue perfusion. First, myocardial depression is often evident despite an increase in cardiac index. Several factors contribute to cardiac dysfunction, including biventricular dilation.f myocardial hyporesponsiveness to catecholamines," and diastolic dysfunction." Together, these phenomena result in a significant reduction in ejection fraction and a suboptimal response to volume infusion that persists for as long as 10 days. Possibly in conjunction with NO, TNF-a and IL-l are thought to be responsible for these alterations." The increase in cardiac index despite a reduction in myocardial contractility occurs as a result of a profound reduction in vasomotor tone, the principal cause of hypotension in septic shock. Decreases in vascular tone affect both arterial and venous circuits. The reduction in venous tone leads to pooling in large capacitance vessels, effectively reducing circulating blood volume. Dilation of the small arterioles in skeletal muscle beds contributes to the decreased systemic vascular resistance and hypotension on the basis of the large microvascular surface area and volume, respectively, of skeletal muscle/" Based on several clinical and experimental studies, NO appears to be the principal mediator responsible for the changes.Y" Pharmacologic blockade of nitric oxide synthase reverses the septic shock state more readily than conventional catecholamine-based inotropes and vasopressors in phase II studies." However, a phase III study was discontinued at interim analysis due to higher mortality in patients receiving the nitric oxide synthase inhibitor. Presumably, the vasopressor effects of NO blockade increased systemic vascular resistance (to achieve an increase in blood pressure) and thus reduced cardiac output, leading to greater impairment of tissue oxygenation." Several microcirculatory changes distinct from changes in vasomotor tone also playa role in the manifestations of septic shock. The mediator environment of sepsis results in activation of the coagulation cascade, leading to microthrombus formation and marked decreases in deformability of neutrophils and erythrocytes, leading to capillary plugging." This microvascular occlusive phenomenon induces the opening of arteriovenous shunts, effectively depriving tissues of adequate perfusion. Several proinflammatory mediators also increase

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neutrophil-endothelial adherence and subsequent extravasation of activated inflammatory cells into the interstitium, where they induce tissue injury. This same process also significantly increases endothelial permeability. The combination of increased capillary pressure secondary to capillary plugs in concert with an increase in vascular permeability results in loss of intravascular volume into the interstitium, further exacerbating hypotension and edema. Edema effectively increases the diffusion distance required for cellular oxygen delivery and may, in concert with opening of arteriovenous shunts, induce cellular hypoxia. In addition to shunting, there also appears to be a direct or indirect toxic effect on mitochondrial utilization of oxygen. Thus, even in the face of normally adequate delivery of oxygen, the ability to utilize O 2 leads to a relative intracellular hypoxia and anaerobic metabolic shift. Early manifestations of severe sepsis include tachypnea, tachycardia, oliguria, and changes in mental status. These clinical features may precede the onset of fever and leukocytosis, particularly in immunocompromised patients. Thus, these simple clinical features should be considered evidence of impending shock in those at risk. Early, aggressive management is critical for minimizing the morbidity and mortality of septic shock. Patients often require intubation and ventilatory support, particularly if there is evidence of acute respiratory distress syndrome (ARDS). Because of the systemic vasodilation and increase in microvascular permeability, it is not unusual for patients to require large amounts of intravenous fluid to restore a normal blood pressure. Vasopressor support with dopamine, epinephrine, or norepinephrine may be necessary if there is an inadequate blood pressure response to fluid resuscitation. As a result of the increase in microvascular permeability within the pulmonary capillary network, administration of large amounts of intravenous fluid may reduce lung compliance and impair alveolar gas exchange. Although early use of vasopressors may minimize the possibility of pulmonary edema, it is not often possible or wise to limit volume resuscitation to prevent this clinical scenario; thus, close monitoring in an intensive care unit setting is essential to optimize resuscitation. In patients not responding to fluid infusion or those with underlying cardiac or renal disease, the use of a PAC might guide therapy. Relative adrenal insufficiency might contribute to the manifestations of septic shock and should be considered and treated (see below). During the resuscitation process, it is imperative that all measures be taken to reverse the infectious process as expediently as possible. If the organism or site is unknown, then treatment may require empiric broad-spectrum antimicrobial agents, based in part on known bacterial patterns in the institution, until further information is available. The correct choice of antibiotic or antibiotic combination is critical as there is a significantly higher case-fatality rate if inappropriate antimicrobials are administered (see Chapter 11 ).74 If the infection source is an abscess or there is ongoing soiling of the pleural or peritoneal cavities, then either drainage or control of contamination is mandatory. Similarly, necrotic, infected tissue requires aggressive debridement. In patients with sepsis, tissue injury occurs as a result of the host inflammatory response rather than the organism per seeAs a result, a variety of therapies directed toward modulating the inflammatory response have been attempted with

discouraging results. These approaches and their limitations are more fully discussed in Chapters 4 and 15.

Neurogenic Shock Hypotension and bradycardia may occur following acute cervical or high thoracic spinal cord injury as a result of disruption of sympathetic outflow in conjunction with unopposed vagal tone. This constellation of clinical features is referred to as neurogenic shock, a syndrome that must be considered separately from the inappropriate term spinal shock, which refers to loss of spinal cord reflexes below the level of spinal cord injury. Following acute spinal cord transection, there is a marked systemic pressor response from acute activation of the sympathetic nervous system and adrenal medulla. This response, manifested as hypertension and tachycardia, lasts for several minutes and because of its short duration is usually not appreelated." As the pressor response abates, the interruption of descending supraspinal fibers in the intermediolateral cell column that activate the preganglionic sympathetic nervous system results in the loss of sympathetic activity. As the sympathetic nerves generally exit from the first thoracic to the first lumbar segment, any patient with a spinal cord injury above the level of Ll is potentially at risk. The loss of sympathetic tone results in hypotension secondary to arterial vasodilation and venodilation. Hypotension is frequently accompanied by marked bradycardia due to loss of the sympathetic cardioaccelator fibers and persistent, unopposed vagal tone. Neurogenic shock typically manifests in patients with cervical spinal cord injuries, particularly when there is complete loss of motor function below the level of injury. In this group of patients, bradycardia is a universal feature with hypotension an accompaniment in approximately two-thirds of patients." Partial cervical spinal cord injuries may cause bradycardia but only rarely is hypotension problematic. Finally, patients with injuries to thoracolumbar segments rarely demonstrate features of neurogenic shock. The cardiovascular abnormalities are only transient and tend to resolve spontaneously in 2 to 6 weeks. The diagnosis should be suspected in any patient with hypotension and bradycardia following injury. In some cases, these findings may represent the first suggestion of a spinal cord injury in a comatose patient. The patient with neurogenic shock is typically warm and well perfused. If a PAC is in situ, the cardiac index may be elevated while the systemic vascular resistance is markedly reduced." It is critical to remember that hemorrhage remains the most common cause of shock in patients with spinal cord injury. Thus, occult hemorrhage should be ruled out before attributing spinal cord injury as the exclusive cause of hypotension.

Hypoadrenal Shock Shock secondary to adrenal insufficiency occurs infrequently and usually within the context of a concomitant critical illness. As a result, the diagnosis of adrenal insufficiency as a cause of the shock state is rarely suspected until late in the disease process. Unfortunately, if the diagnosis is missed, the

315


patient will likely succumb to refractory shock. In North America, adrenal insufficiency most commonly arises as a consequence of the chronic therapeutic administration of high-dose exogenous corticosteroids with resultant suppression of the hypothalamic-pituitary-adrenal axis. If adrenal insufficiency is slow in onset, then there may be adequate cortisol production to maintain homeostasis in the unstressed state. By contrast, once the patient is severely stressed, typically following major infection, operation, or trauma, adrenocortical function may be insufficient to support the necessary physiological response, and the clinical picture of shock due to adrenal insufficiency will become manifest. In a small proportion of patients, adrenal insufficiency onset is abrupt and occurs directly as a result of the acute underlying illness. For example, overwhelming sepsis may cause adrenal insufficiency because of adrenal infarction secondary to hypotension or adrenal hemorrhage caused by coagulopathy. Diagnosis of shock secondary to hypocortisolism requires a high level of suspicion. Findings associated with adrenal insufficiency include weakness, fatigue, anorexia, abdominal pain, fever, nausea, vomiting, and weight loss. If longstanding (i.e., Addison's disease), then there may be hyperpigmentation of the skin and mucous membranes. Hyponatremia, hypochloremia, and hyperkalemia are consistent with decreased mineralocorticoid activity. Adrenal insufficiency may also present acutely with fever, shock, and an acute abdomen. More typically, surgical patients with adrenal insufficiency present with refractory shock in the course of injury or illness. There may be no findings other than the failure to respond to standard shock therapy. Hypotension may be marked despite massive fluid resuscitation and inotropic support. The hemodynamic changes associated with acute adrenal insufficiency tend to occur in two predictable patterns. In the relatively hypovolemic patient, the appearance is one of cardiogenic shock with decreased preload, depressed myocardial contractility, and high systemic vascular resistance. By contrast, if the patient had been adequately volume resuscitated, the cardiac output is usually high with a low systemic vascular resistance, suggesting that there are no classic hemodynamic features of hypoadrenalism. In this regard, evidence suggests that adrenal insufficiency has been underrecognized, and there is a large proportion of critically ill patients who have relative adrenal insufficiency. These patients do not present in fulminant shock but typically have persistent inotropic requirements or prolonged ventilator dependence. It is important to identify these patients as corticosteroid replacement leads to significantly improved outcomes (see below). In patients in whom the diagnosis is suspected, a blood sample for measurement of plasma cortisol and corticotrophin should be obtained and a cosyntropin (synthetic corticotrophin) stimulation test performed. Although several methods for cosyntropin stimulation testing have been suggested, a standard test involves an intravenous bolus of 250 ug of cosyntropin and repeat cortisol levels 30 and 60min later. Relative adrenal insufficiency is defined as an increase in serum cortisol of 91lgfdl or less. 78,79 In a large, double-blind, randomized controlled trial, approximately 75% of patients presenting with septic shock met the criteria for relative adrenal insufficiency." In this study, there was a significant reduction in mortality among nonresponders receiving 50mg hydrocortisone every 6 h in concert with 50 ug fludricortisone

daily for 7 days. Several other randomized controlled trials have confirmed the benefits of corticosteroid replacement (i.e., stress dose) in patients with septic shock. A metaanalysis of these and other trials using higher doses of corticosteroids suggests a 20% reduction in mortality in patients with septic shock receiving steroids at low dose «300mgfday) for at least 5 days." By contrast, patients receiving high dose (>300mgfday) for shorter periods of time demonstrated no benefit. Together, these data suggest that low-dose corticosteroid replacement should be administered to all patients with septic shock while waiting for the results of a cosyntropin stimulation test. If the test is negative (i.e., an increase in serum cortisol of >9Ilgfdl), then the corticosteroids can be discontinued. The number needed to treat (irrespective of responder status) to prevent a single death is only 8, indicating that this intervention might have tremendous benefit to critically ill patients with shock due to sepsis.

Diagnostic and Therapeutic Adjuncts in the Management of ShOCk Pulmonary Artery Catheter The differential diagnosis of the shock state is usually relatively straightforward. The clinical setting in conjunction with physical examination is often sufficient to guide diagnosis and therapy. However, occasionally the cause of the shock state is unclear. Typically, this occurs when the cause of the shock state may be multifactorial. For example, a trauma patient with persistent hypotension may have a combination of spinal shock and hemorrhagic shock. Alternatively, an elderly patient with septic shock may have significant myocardial dysfunction that often will confuse the clinical picture. In these scenarios, hemodynamic parameters derived from a PAC may provide valuable insight into the principal mechanism underlying the shock state (Table 16.4).

Despite its conceptual appeal, there are no data supporting an improvement in outcome among patients whose resuscitation is guided by a PAC. In one randomized controlled trial of 201 patients with shock or acute respiratory failure, patients with a PAC had more fluid administration, a higher incidence of renal failure, and a greater incidence of thrombocytopenia." In another such study involving almost 700 patients with shock or ARDS, patients receiving a PAC had equivalent outcomes to those without." TABLE 16.4. Differential Diagnosis of Shock States Based on Hemodynamic Parameters.

Type of shock

CVPor

PCWP

Cardiac output

Systemic vascular resistance

Venous O2 saturation

Hypovolemic Cardiogenic Septic Traumatic Neurogenic Hypoadrenal CVP, central venous pressure; PCWP, pulmonary capillary wedge pressure.

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Resuscitative Thoracotomy Resuscitative thoracotomy (also referred to as emergency room thoracotomy) represents an adjunctive measure to manage patients in extremis or profound shock following trauma. This approach involves performing a left anterolateral thoracotomy in the emergency room while the rest of the resuscitation team continues with managing the airway, intravenous access, and fluid resuscitation. After entry into the left chest, the pericardium is inspected for evidence of tamponade, and a pericardiotomy is performed to decompress the pericardial space or allow for open cardiac massage. Major pulmonary hemorrhage or hilar injury can be managed by cross-clamping the pulmonary hilum. The descending thoracic aorta can be occluded, thus optimizing perfusion to the coronary and cerebral circulation while limiting intraabdominal hemorrhage. The results of resuscitative thoracotomy have been reported in the form of retrospective studies from individual institutions. Despite the heterogeneity of patients, the effectiveness of this approach appears to depend on both the site and mechanism of injury and the physiological status of the patient. Although the survival in unselected patients ranges from 1.8% to 13%,83-85 survival in patients with penetrating cardiac injury may be as high as 22 0/0. 85,86 By contrast, patients undergoing resuscitative thoracotomy following hypovolemic arrest caused by blunt trauma have 00/0 to 2 % chance of surviva1.84-86 The principal reason for this differential survival benefit is that a resuscitative thoracotomy with pericardiotomy may prove to be the definitive management for patients in cardiogenic shock due to tamponade, while an easily remediable problem is rarely evident in blunt trauma patients. Several reports have attempted to prognosticate survival based on the presence or absence of respiratory attempts, brainstem reflexes, movement, or vital signs (blood pressure, pulse, or viable cardiac rhythms). It is clear that survival is negligible in patients without signs of life in the prehospital phase of care." Based on these data, the American College of Surgeons Committee on Trauma and the National Association of EMS Physicians have come out with a joint position statement indicating that a resuscitative thoracotomy in blunt trauma patients found apneic, pulseless, and without organized electrocardiogram (ECG) activity on the arrival of emergency medical services (EMS) at the scene is unwarranted." Similarly, a resuscitative thoractomy is not warranted in victims of penetrating trauma found by EMS to be apneic and pulseless and who have no signs of life (pupillary reflexes, spontaneous movement, or organized ECG activity) at the scene.

Inotropes and Vasopressors Management of shock requires manipulation of intravascular volume (preload), systemic vascular resistance (afterload), and myocardial contractility. Optimal volume resuscitation should precede pharmacological intervention. The use of inotropic agents should be considered when tissue perfusion remains inadequate despite adequate fluid administration. Both catecholamine and noncatecholamine agents are used clinically, and the agents differ in their degree of a- and ~ activity, chronotropic effects, and influence on myocardial oxygen consumption.

DOPAMINE

Dopamine is an endogenous sympathetic amine that is a biosynthetic precursor of epinephrine and also functions as a central and peripheral neurotransmitter. At low doses (13 mg/kg/min], dopamine may increase renal blood flow and maintain diuresis via effects mediated through DAI and DA2 receptors in the renal vasculature.P'" At moderate doses (5mg/kg/min], stimulation of cardiac ~-receptors produces increases in contractility and cardiac output with little effect on heart rate or blood pressure. With increasing doses (5IOmg/kg/min], ~-adrenergic effects still predominate, but further increases in cardiac output are accompanied by increases in heart rate and blood pressure. At higher doses (more than LOrng/kg/min], peripheral vasoconstriction from increasing a-activity becomes more prominent, resulting in elevation of systemic vascular resistance, blood pressure, and myocardial oxygen consumption. DOBUTAMINE

Dobutamine is a synthetic catecholamine that has been used for its ~-adrenergic effects and the absence of significant aactivity. The predominant effect is an increase in cardiac contractility with little increase in heart rate. Dobutamine also has a peripheral vasodilating effect resulting from ~r receptor activation that is independent of any increase in cardiac output. The combination of increased contractility and reduction in afterload contribute to improved left ventricular emptying and a reduction in pulmonary capillary wedge pressure. Blood pressure may drop slightly. As a result of these properties, dobutamine is an ideal agent when the therapeutic goal is to improve cardiac output rather than to improve blood pressure. This improvement in cardiac output frequently occurs without a significant increase in myocardial oxygen requirement due to the reduction in afterload and little, if any, chronotropic effect. NOREPINEPHRINE

The sympathetic neurotransmitter norepinephrine exerts both a- and ~-adrenergic effects. The ~-adrenergic effects are most prominent at lower infusion rates, leading to increases in heart rate and contractility. With increasing doses, the a-mediated effects become evident and are responsible for increases in systemic vascular resistance and blood pressure. Due to favorable effects on the splanchnic circulation, either norepinephrine or dopamine are the recommended vasopressors in patients with septic shock." EPINEPHRINE

Epinephrine has a broad spectrum of systemic actions. At lower rates of infusion, ~-adrenergic responses predominate, leading to an increase in heart rate and contractility (~l-effect) in conjunction with peripheral vasodilation (~2-effect). These effects result in an increase in stroke volume and cardiac output with a variable effect on blood pressure. At a higher rate of infusion, a-effects predominate, leading to an increase in systemic vascular resistance and blood pressure. Limitations in the use of epinephrine arise from its renal vasoconstrictive activity, its arrhythmogenic potential, and its substantial contribution to increasing myocardial oxygen demand. However, epinephrine remains the drug of choice for


317

anaphylactic reactions, primarily because of extensive experience with this agent for this indication. In septic shock, it is considered a second-line agent for patients not responding to dopamine or norepinephrine.

tory response associated with tissue injury.Sl,S2,93 Novel approaches to modulating the aberrant host response are currently under evaluation to determine their effectiveness in minimizing reperfusion injury.

AMRINONE

Hypothermia

Amrinone (or milrinone) is a synthetic bipyridine with inotropic and vasodilator effects. Its principal mechanism of action involves phosphodiesterase inhibition, through which it raises the intracellular concentration of cyclic adenosine monophosphate (AMP). It appears to be a useful agent in cardiogenic shock complicating myocardial infarction as it may significantly increase cardiac contractility and cardiac output without increasing myocardial oxygen requirement due to concomitant vasodilation and afterload reduction. Drawbacks to the use of amrinone are the variability of the individual response, its relatively long half-life (3.6h), and the potential for acute significant hypotension if intravascular volume is inadequate. In addition, its use is not infrequently accompanied by the development of thrombocytopenia. VASOPRESSIN

Vasopressin is a peptide hormone synthesized in the hypothalamus and then transported to and stored in the pituitary gland, where it is released in response to decreases in intravascular volume and increased plasma osmolarity. There is evidence to suggest that vasopressin secretion might be impaired in patients with shock, and several case series have demonstrated the effectiveness of exogenous vasopressin administration in patients with catecholamine-resistant septic shock. It is typically administered at a rate of 0.04 u/ min (ranging from 0.01 u/min to as high as 0.08u/min). Vasopressin acts as a vasopressor and might reduce cardiac index and tissue oxygen delivery. Relatively small randomized controlled trials suggest that it spares the use of norepinephrine and improves creatinine clearance.P-" There are no studies comparing outcomes in patients treated with vasopressin compared to conventional catecholamine-based vasopressors. Currently, it is recommended for use as second-line therapy after norepinephrine or dopamine."

Complications of Shock and Resuscitation Multiple Organ Dysfunction Syndrome The syndrome associated with multiple organ dysfunction (MODS) has evolved only recently as a result of advances in our ability to salvage patients who would have otherwise died as a result of their shock state. Shock in all its forms represents the most common predisposing factor leading to the development of MODS. Although the mechanisms leading to the development of organ dysfunction following shock are unclear, it appears that an unbridled systemic inflammatory response is in part responsible. There is no specific treatment for MODS. Efforts should be directed toward minimizing the duration of shock and rapidly ensuring adequate organ perfusion. Infection should either be prevented if possible or treated early and aggressively. Fracture fixation and debridement of necrotic tissue should be performed early to reduce the systemic inflamma-

A potential adverse consequence of massive volume resuscitation to reverse shock is hypothermia. Prolonged extrication or examination in a cold environment following trauma and evaporative heat losses in the operating room also may contribute to this condition. Iatrogenic paralysis may prevent endogenous heat production through shivering. Nearly onehalf of patients develop incidental hypothermia between the time of injury and completion of surgery." Hypothermia invokes a variety of systemic responses, including a reduction in heart rate and cardiac output, while temperatures below 32°C may induce supraventricular or ventricular arrhythmias." Most importantly, at temperatures less than 35°C, hypothermia induces coagulopathy due to effects on both coagulation factors and platelet function. Because coagulation assays are routinely performed after warming blood samples to 37°C, the clinical impact of the patient's hypothermia is often underestimated. In fact, coagulation assays that appear normal at 37°C are significantly prolonged and clinically important when performed at the core body temperature of the hypothermic patient." The combination of coagulopathy and hypothermia produces a vicious cycle; the coagulopathy leads to more blood loss, requiring more replacement with cool fluids or blood products, leading to further hypothermia and aggravation of the coagulopathy. Prevention of hypothermia should be considered in all patients with shock. Fluid warmers utilizing a countercurrent heating technique allow for rapid administration of warm fluids or blood products. Warming blankets and warmed ventilator circuits should be used routinely. Rewarming techniques, including pleural or peritoneal lavage with warm crystalloid solutions may be useful. Continuous arteriovenous rewarming may be the most efficacious method because it allows for rapid rewarming using an extracorporeal countercurrent mechanism through percutaneously placed catheters in the femoral artery and vein" (Fig. 16.5). This process does not require a pump and rapidly rewarms from 30°C to 36°C in less than 30min. In a randomized prospective study of this rapid rewarming technique, patients undergoing rapid rewarming required less fluid resuscitation, were more likely to rewarm, and demonstrated improved survival compared to those receiving standard rewarming techniques."

Abdominal Compartment Syndrome The abdominal compartment syndrome (ACS) is a sequela of massive resuscitation following shock or visceral ischemia. The most common clinical scenarios giving rise to ACS are emergent repair of an abdominal aortic aneurysm, abdominal trauma, pancreatitis, severe intraabdominal infection, and bums. Aggressive fluid resuscitation in concert with alterations in microvascular permeability result in marked visceral edema. Similarly, increasing soft tissue edema results in a reduction in abdominal wall compliance. The combination of an increase in the volume of intraabdominal contents in

318

CHAPTER 16

Warm blood

outflow

t

Water inlet

(40°C)

FIGURE 16.5. Continuous arteriovenous rewarming is achieved by cannulating the femoral artery and vein using an 8.5- or 10-French catheter and creating a circulatory fistula through a countercurrent heating mechanism. (Source: Adapted from Gentillelo et al.," with permission.

concert with a stiff abdominal wall significantly increases the pressure in the abdominal cavity, a phenomenon that may be exacerbated by intraabdominal packing to control bleeding or hematoma. A progressive increase in intraabdominal pressure (lAP) produces a graded decrease in cardiac output, an effect mediated by a reduction in venous return and an increase in systemic vascular resistance due to caval compression and mechanical compression of capillary beds, respectively." Left and right atrial filling pressures obtained using a pulmonary artery catheter may be spuriously elevated because of the increase in intrathoracic pressure.100 Passive elevation of the diaphragm allows the transmission of high lAP into the pleural cavity, reducing both static and dynamic lung compliance.P'r'" This reduction in compliance results in the need for high inspiratory airway pressures to maintain effective ventilation. Intraabdominal hypertension may also result in significant increases in intracranial pressure due to impaired cerebral venous outflow secondary to an increase in intrathoracic pressure.P':'?' Oliguria is the most overt clinical manifestation of sustained intraabdominal hypertension. The etiology of renal dysfunction in ACS is multifactorial. A reduction in cardiac output and hence renal blood flow is in part responsible; however, the most plausible explanation for the renal effects of elevated lAP is renal vein compression, leading to increased venous pressure within the renal parenchyma. The combined effect of increased renal parenchymal pressure and a reduction in renal blood flow decrease the pressure gradient across the glomerular membrane and thus the glomerular filtration rate.'?' The local effects of intraabdominal hypertension are not limited to the kidney as even moderate increases in lAP may result in visceral mucosal ischemia and acidosis.lOs,106 Diagnosis of the ACS requires recognizing the clinical syndrome and, ultimately, some objective measurement of

lAP. The classic clinical clues to the presence of ACS are (1) a tense or distended abdomen, (2) massive intravenous fluid requirements, (3) elevated central venous and pulmonary capillary wedge pressures, (4) decreased cardiac output, (5) elevated peak airway pressures, and (6) oliguria. In a prospective study, Rapanos et al. compared physical exam to objective evaluation of lAP in a series of critically ill blunt trauma patients. Physical exam was notoriously unreliable in detecting clinically significant elevations in lAP (>I5mmHg), suggesting that an objective evaluation of lAP may be necessary for the patient with a clinical presentation suggestive of ACS.107 The most widely used method of measuring lAP involves transurethral measurement of urinary bladder pressure using a Foley catheter. 106,108 In the supine position, the normal lAP is less than IOmmHg. Following abdominal surgery, pressures are typically in the range of 3 to 15mmHg. 106Treatment should be considered if lAPs exceed 25 to 30mmHg. 109,110 Optimally, management involves either reopening a prior laparotomy incision or, in patients without a recent laparotomy, opening the" peritoneal cavity via a midline incision. Some form of temporary abdominal closure is then necessary to bridge the fascial defect and prevent evisceration. The morbidity associated with an "open abdomen" is significant, with fluid, electrolyte, and nutritional implications, and should not be undertaken unless clear benefit is expected. There are no studies demonstrating a survival benefit with decompressive celiotomy.

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filtration rate, and renal plasma flow. J Clin Invest 1973;45:733742. 90. Hollenberg SM, Ahrens TS, Annane D, et al. Practice parameters for hemodynamic support of sepsis in adult patients: 2004 update. Crit Care Med. 2004;32:1928-1948. 91. Dunser MW, Mayr AJ, Ulmer H, et al. Arginine vasopressin in advanced vasodilatory shock: a prospective, randomized, controlled study. Circulation 2003;107:2313-2319. 92. Patel BM, Chittock DR, Russell JA,Walley KR. Beneficial effects of short-term vasopressin infusion during severe septic shock. Anesthesiology 2002;96:576-582. 93. Goris RJA. Prevention of ARDS and MOF by prophylactic mechanical ventilation and early fracture stabilization. Prog Clin BioI Res 1987;236B:163. 94. Gregory JS, Flancbaum L, Townsend MC, Cloutier CT, Ionasson O. Incidence and timing of hypothermia in trauma patients undergoing operations. J Trauma 1991;31:795-798. 95. Paton BC. Cardiac function during accidental hypothermia. In: Pozos RE, Wittmer LE,eds. The Nature and Treatment of Hypothermia. Minneapolis: University of Minnesota Press, 1983:133142. 96. Gubler KD, Gentilello LM, Hassantash SA, Maier RV. The impact of hypothermia on dilutional coagulopathy. J Trauma 1994;36:847-851. 97. Gentilello LM, Cobean RA, Offner PJ, Soderberg RW, Jurkovich GJ. Continuous arteriovenous rewarming: rapid reversal of hypothermia in critically ill trauma patients. J Trauma 1992;32:316327. 98. Gentilello LM, Jurkovich GJ, Stark MS, Hassantash SA, O'Keefe GE. Is hypothermia in the victim of major trauma protective or harmful? A randomized, prospective study. Ann Surg 1997; 226:439-447. 99. Ivatury RR, Diebel L, Porter JM, Simon RJ. Intra-abdominal hypertension and the abdominal compartment syndrome. Surg Clin North Am 1997;77:783-800. 100. Cullen DJ, Coyle JP, Teplick R, Long MC. Cardiovascular, pulmonary, and renal effects of massively increased intraabdominal pressure in critically ill patients. Crit Care Med 1989;17:118-121. 101. Meldrum DR, Moore FA, Moore EE, Haenel JB, Cosgriff N, Burch JM. Cardiopulmonary hazards of perihepatic packing for major liver injuries. Am J Surg 1995;170:537-542.

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102. Bloomfield GL, Ridings PC, Blocher CR, Marmarou A, Sugerman HJ. A proposed relationship between increased intraabdominal, intrathoracic and intracranial pressure. Crit Care Med 1997;25:496-503. 103. Bloomfield GL, Ridings PC, Blocher CR, Marmarou A, Sugerman H. Effects of increased intra-abdominal pressure upon intracranial and cerebral perfusion pressure before and after volume expansion. J Trauma 1996;40:936-943. 104. Caldwell CB, Ricotta JJ. Evaluation of intra-abdominal pressure and renal hemodynamics. Curr Surg 1986;43:495-498. 105. Bongard F, Pianim N, Dubecz S, Klein SR. Adverse consequences of increased intraabdominal pressure on bowel tissue oxygen. J Trauma 1995;39:519-525. 106. Kron IL, Harman PK, Nolan SP. The measurement of intraabdominal pressure as a criterion for abdominal re-exploration. Ann Surg 1984;199:28-30. 107. Kirkpatrick AW, Brenneman FD, McLean RF, Rapanos T, Boulanger BR.Is clinical examination an accurate indicator of raised intra-abdominal pressure in critically injured patients? Can J Surg 2000;43:207-211. 108. Iberti TJ, Kelly KM, Gentili DR, Hirsch S, Benjamin E. A simple technique to accurately determine intra-abdominal pressure. Crit Care Med 1987;15:1140-1142. 109. Burch JM, Moore EE, Moore FA, Franciose R. The abdominal compartment syndrome. Surg Clin North Am 1996;76:833842. 110. Meldrum DR, Moore FA, Moore EE,Franciose RJ,Sauia A, Burch JM. Prospective characterization and selective management of the abdominal compartment syndrome. Am J Surg 1997;174: 667-672. Ill. Schwaitzberg SD, Bergman KS, Harris BH. A pediatric trauma model of continuous hemorrhage. J Pediatr Surg 1988;23:605609. 112. Rackow EC, Falk JL, Fein lA, et al. Fluid resuscitation in circulatory shock: a comparison of albumin, hetastarch and saline solutions in patients with hypovolemic and septic shock. Crit Care Med 1983;11:839-850. 113. American College of Surgeons. Shock. In: Advanced Trauma Life Support Manual. Chicago: American College of Surgeons, 1997:87-107.

Perioperative Management Philip Defin ing the Perioperative Period. . . . . . . . . . . . . . . . . .. Who Should Provide Perioperative Care?. . . . . . . . . . . . . What Sort of Evidence Should Be Accepted?. . . . . . . . .. What Constitutes Quality of Care ? Preoperative Cardiovascular Assessm ent . . . . . . . . . . . . . Adjustment of Cardiovascular Medications. . . . . . . . . . . Preoperative Preparation in the Intensive Care Unit , Preoperative Pulmonary Evaluation ,

323 324 324 325 326 330 33 1 33 1

P

erioperative care, put simply, is the medical care provided to prepare a patient for surgery and to hasten recovery thereafter. Perioperative patient care is as integral to the outcome of th e patient as th e operation itself. In many cases, quality care may be more important to the achievement of a good outcome than the operation [e.g., when a ma jor complication occurs after minor surgery or when a patient with complex medical problems must be managed for a straightforward operation). Th e simplicity of these statements belies the complexity of the issues because numerous fundamental questions must be addressed before considering th e specifics involved. What is the duration of the perioperative period, and what marks its beginning and end? What constitutes a good outcome, and from the perspective of whom-the physician, th e patient, or some external agency? What constitutes quality care, how can quality be measured, and are there characteristics of high-quality providers or units that are worthy of emulation? What standards of evidence should be applied for the evaluation of efficacy and effectiveness, and what are their flaws ? Even the question of who should provide perioperative care is debated, especially for the hospitalized and seriously ill patient. By addressing these questions, it is intended that the reader create a framework for independent analysis rather than an expectation of "right" or "wrong" answers that som etimes do not exist.

Defining the Perioperative Period The concept that the perioperative period can be defined temporally is arbitrary but necessary despite obvious flaws . The necessity has derived from th e impetus to describe the incidence of "postoperative complications"; the flaws include the compartmentalization that results when an event occurs

s. Barie

Prophylaxis of Venous Thromboembolism Evaluation of the Risk of Bleeding . . . . . . . . . . . . . . . . . . Management of the Therapeutically Anticoagulated Patient. . . . . . . . . . . . . . . . . . . . . . . . . Steroid Prophylaxis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Resuscitation: The Interface Between Preoperative and Postoperative Care . . . . . . . . . . . . . . . . . . . . . . . . Approach to the Febrile Surgical Patient . . . . . . . . . . . .. References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

332 334 335 335 336 342 349

subsequent to a defined point in time or from speculation that a complication is "unrelated" to a procedure. Surgical literature relating to the preoperative period is scant compared to that relating to intraoperative management and postoperative care, perhaps because the definition of the preoperative period is nebulous, or perhaps because so much of the care in the prehospital setting is provided by nonsurgeons. Regardless, it is crucial for surgeons to be involved in all phases of perioperative care because many stand ready to provide care if surgeons are not involved. The preoperative period begins when it is decided that a patient needs surgery. This period may extend for the few minutes that it takes to get a trauma patient to the operating room or for several weeks if comorbid factors must be addressed in preparation. The postoperative period is more defined, albeit arbitrarily, as 30 days after surgery; operative mortality and complication rates are generally reported using that criterion. Other models use the length of hospital stay to define the period, but that is increasingly irrelevant in modem practice considering that many surgical patients are never hospitalized. A model that has financial underpinnings is the use of the Center for Medicare and Medicaid Services (CMS)concept of the "aftercare" period, which varies depending on the magnitude of the procedure and constitutes the postoperative care portion of the global surgical fee. Set at 90 days for most procedures, even minor operations, it is 10 days for some procedures (e.g., tube gastrostomy), 0 days for others (e.g., central venous catheter insertion, tube thoracostomy), and is therefore unusable for clinical results reporting. It is increasingly apparent that long-term outcome data (extending well past the 90-day period) are important. To continue to justify the expensive, high-complexity treatments that are offered to increasingly older, high-risk patients, long-term benefit must be demonstrable. 323

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Who Should Provide Perioperative Care? Fundamental questions are being asked about the evidence of efficacy for even"standard" interventions. Millions of patients undergo ambulatory surgery annually without the "benefit" of hospitalization. Minimal-access surgery is reducing the metabolic stress response to surgery and challenging conventional widsom regarding wound care, pain management, recovery of gut function, and whether hospitalization is necessary in the immediate postoperative period. Traditionally, perioperative care was provided by the surgeon with consultative assistance by the primary care physician. In that reversal of roles (consultant as primary caregiver, primary physician as consultant), the primacy of the surgeon in directing perioperative care was perpetuated. Now, there is nothing simple about perioperative care, and traditions are becoming anachronisms. The diagnosis of surgical illness is often made before the patient sees a surgeon; patients now often present to the surgeon for management of acute appendicitis after a diagnostic computed tomographic (CT) scan.' Even as postoperative care is provided increasingly in the outpatient setting, conceptions are changing regarding who should be providing perioperative care. Nonphysicians (e.g., advanced practice nurses) increasingly practice without direct medical supervision, can be primary care providers, or may provide care in acute inpatient settings such as the intensive care unit (lCU). Physician assistants require supervision but can be credentialed to provide sophisticated, invasive care such as placement of catheters for hemodynamic monitoring.? Even primary care physicians sometimes limit their practices to the outpatient setting, just as some surgeons now do. The medical care of hospital inpatients is increasingly transferred to hospital-based physicians, known as hospitalists. Hospitalist physicians are willing and increasingly able to provide perioperative care and have the time to devote to the patient that the surgeon, performing more operations for less reimbursement, decides to spend in the operating room. That decision is also a factor in the rising phenomenon of closed ICUs/ where care is provided to patients by dedicated multiprofessional critical care teams, while the operating surgeon is a consultant. Traditionally, the operating surgeon has had primary responsibility for perioperative care for reasons that are several and substantial." Critical care is defined as one of the core components of general surgery by the American Board of Surgery, and sufficient experience with the management of critically ill patients must be gained for the surgeon to be proficient in providing critical care in practice. Primary responsibility for the care of critically ill surgical patients may rest with a surgeon, pulmonary-critical care physician, or anesthesiologist. The individual who provides perioperative critical care must have an intimate knowledge of surgical physiology. In a true open ICU model, all patient care decisions are made by the primary team. Continuity of care is ensured, and surgical residents receive the experience requisite to their training. In a true closed ICU model, decisions regarding triage and therapy become the responsibility of the ICU service. In academic centers, the ICU team is most often led by surgeons and sometimes anesthesiologists, but in other circumstances a nonsurgical team is in charge. In effect, the operating surgeon becomes a consultant on his or her own

patient, but other involved subspecialty consultants are fewer. This model is effective for cost containment'" and highly concentrated educational activities. Communication is often facilitated, which is a positive attribute of high-quality units. 7,8 Data indicate that the closed ICU model may provide superior and cost-effective patient care. 3,9,l0 Several comparisons between open and closed ICU care models are available.Y'" One study examined a before-after cohort comparison in which the cohorts were well matched for age and admission severity of illness (Acute Physiology and Chronic Health Evaluation [APACHE] ill).3 There were no differences in the duration of invasive hemodynamic monitoring, antibiotic use, the route of feeding, or the administration of vasopressors. Length of stay in the ICU was not decreased, but the overall rate of morbidity was significantly reduced by 20%, and mortality was reduced by 57% (14.4% vs. 6.0%; P < .05). The status of perioperative care is in flux, as is the eventhornier issue of whether complex or rarely performed operations should be undertaken outside specialized centers.!':" For surgeons to maintain a central role in perioperative care, they are well advised to exert leadership rather than to assert ownership.

What Sort of Evidence Should Be Accepted? Much of perioperative care is empirical, meaning that interventions have more of a basis than simply a hypothesis. However, empirical evidence may derive from observation, experience, or experiment, and much patient care is not based firmly on the last. Evidence-based medicine emphasizes consideration of the quantity and quality of the evidence as part of the evaluation process. There is a paucity of top-quality studies on which to base day-to-day decisions. In one prospective evaluation," each of 281 pediatric surgical patients was allotted a primary diagnosis and intervention, and each intervention was recorded and over a l-month period categorized according to its level of scientific support. Only 31 interventions (110/0) were based on randomized controlled trials; 66% of the interventions could be traced to "convincing nonexperimental evidence," such that the conduct of a randomized controlled trial might be considered unethical or unjustified. However, 23 % of interventions were not supported by evidence. This result has many implications, not all of them negative. Literature searches may be flawed, and all evidence may not be identified. Targets for focused research projects can be identified for which expense is high, alternative therapies carry morbidity, and complexity can be reduced. On the other hand, beliefs can be held strongly, and the literature is replete with examples of clinical trials that failed because of low patient accrual and a lack of cooperation from practitioners. 14 Although surgical procedures and devices should be evaluated by randomized clinical trials in the same manner as medical therapy, IS such an inherently desirable outcome has many obstacles. Despite the desire and even the wherewithal to conduct more trials, many aspects of surgical care may not be amenable to a rigorous prospective evaluation. Considering that randomized prospective clinical trials (class I data) are few, what other types of evidence can be relied on? Prospective nonrandomized trials or case-control studies with a

PERIOPERATIVE MANAGEMENT

clearly defined comparison cohort constitute class II data, whereas class III evidence is composed of retrospective studies, small case series, or case reports. Within classes, the quality of the study can be defined by blinding, the methods of treatment allocation, protocol violations, whether the data set was clinical (patient derived) or administrative (e.g., statewide trauma database]," and whether the data analysis was on an intention-to-treat basis. After the evidence has been compiled and classified, recommendations are made by a panel of experts. Classification systems abound, but they share the characteristic of providing recommendations based on the strength of the evidence. I have taken some license here to convert these to standardized terminology so that a level I recommendation is one that is based on sufficient class I data. Level II recommendations represent strong recommendations but indicate the data are not quite as solid scientifically, are equivocal, or depend to a degree on expert opinion. Level III recommendations are by definition weakest, depending on retrospective data, scant prospective but nonrandomized studies, or expert opinion in large part. In every case, the reader is encouraged to consult the original document for answers to questions or the resolution of detail. It would be virtually impossible to assemble evidentiary tables for an independent review of the evidence for the many aspects of perioperative care in a chapter of this scope, and therefore I chose to rely on published analyses, if available. Many such publications exist, and they also are of uneven quality. Hundreds of clinical practice guidelines have been published on a multitude of topics. Many of those are evidence based, which ideally have been accompanied by publication of evidentiary tables. Evidence-based guidelines (EBGs) generally are thoughtful documents of high quality. These must be distinguished from consensus-based guidelines (CBGs), which although often produced by a panel of experts and crafted with great care, do not disclose the quality of the evidence on which they are based and therefore are of lesser value. Meta-analysis is a statistical method by which the results of several trials may be pooled for an aggregate analysis." There is disagreement regarding the strength of evidence represented by meta-analysis. Is it class I data or class III? Meta-analysis is unique in that underpowered trials (with possible type II errors); negative trials (to the extent they can be identified, as many are not published); data in abstract form only (and therefore not peer reviewed); and non-English publications are all eligible for review and inclusion, making the assessment of methodological quality a crucial issue. The inclusion of poor-quality studies, small studies, or other flawed data sets can lead a meta-analysis to an erroneous conclusion" or two analyses to disparate conclusions from a largely similar primary data set." Sometimes, a pivotal clinical trial reaches a conclusion opposite to that of a previous meta-analysis. In such a circumstance, was the metaanalysis flawed by a lack of quality data, the exclusion of important studies, or some other methodological error? Would the conclusion hold up if the analysis were redone to incorporate the additional data? Considering that this chapter incorporates the results of .meta-analysis in several important areas, the reader must be aware of the limitations of the technique.P'" Because of the limitations and potential error, some consider meta-analysis to be class III data, with less-

325

persuasive force than recommendations made in the context of an EBG.

What Constitutes Quality of Care? Quality patient care has been defined variously as maximized patient welfare, consistent contributions to the improvement or maintenance of quality and duration of life, or the degree to which health services increase the likelihood of desired health outcomes consistent with current health knowledge." The complexity and variability of terminology can be confusing, especially when the endpoints are vague or the ideal means to achieve a defined outcome are unknown. From the perspective of the caregiver, quality consists of appropriate care provided with skill. In other words, both the decision making and the performance must be of high quality. Intangibles that help define quality include communication (between providers and with patient and family), proper distribution of workload (so that the right person is performing the correct task), trust, and compassion. Quality of care can also be evaluated in terms of structure or outcome in addition to process. Quality-of-care criteria based on structure or process data must demonstrate that variations lead to differences in outcome. Conversely, it must be demonstrated that different outcomes can be attributed to changes in structure or process. For individual encounters, the implicit criteria are three: Was the process adequate? Could better care have improved the outcome? Considering the process and outcome, was the overall quality acceptable'"! Two other methods examine explicit process criteria: Was a cholesterol concentration checked in the past 12 months in this patient with heart disease? What percentage of the population was checked (against some benchmark value) in the past 12 months? Increasingly, the latter, more strict, processtype criteria are examined, which has important implications. In a given population, the percentage of patients who receive adequate care will be lower than if implicit criteria are used. However, not every patient needs every possible intervention to improve, and costs may escalate to achieve explicit process targets with only a marginal benefit in outcome.

Error in Medicine The need to describe and evaluate quality through the use of systematic evidence reviews, EBGs, analysis of resource utilization, and outcomes assessments has been heightened by developing evidence that serious errors are commonplace in medical care. There has been much recent emphasis on errors in health care, which are prevalent and for the most part preventable. The proportion of hospitalizations in which some sort of adverse event occurs exceeds 3 0/0, and more than 500/0 are associated with errors that are preventable.P'" Adverse events are associated with mortality in 90/0 to 140/0 of episodes, resulting in as many as 98,000 deaths annually in the United States that are attributable to preventable medical errors. 25,26 Deaths from medication errors alone exceed the number of workplace deaths each year. In ICUs, where patients are seriously ill and treated with invasive procedures, the chance of an adverse event has been reported to be 46 0/0, with 18 % producing either disability or death. The likelihood of an adverse event increases about 6 % for each day of

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hospitalization." Medication-related complications tend to be most common, followed by surgical site infections (SSIs; but many are not errors) and technical complications." Errors can also be described as "active" or "latent" errors." Active medical errors are usually made by direct caregivers, and their effects are recognizable almost immediately. Latent errors, sometimes called system errors, tend to be out of the direct control of individuals (e.g., poor design, inadequate installation, faulty maintenance, and poor organizational structure). Latent errors have more potential to cause harm in complex systems because they often go unrecognized and may result in many types of active errors. Administrative responses to errors tend to focus on punitive measures directed at the individual causing the active error. However, such a focus is an ineffective way to prevent recurrence because the latent failures remain in the system. Elimination of latent failures is more likely to increase safety than minimizing active errors.

Outcomes Assessment Increasingly, a good surgical outcome is defined by the quality of life enjoyed by the patient after surgery." Surgical results reporting must extend beyond the hospital portal. These types of quality endpoints will be incorporated increasingly into clinical research and quality audits, and therefore clinicians must be familiar with the administration and interpretation of these types of studies. Quality-of-life assessment tools have five essential characteristics": reliability, validity, responsiveness (sensitivity to change), appropriateness, and practicality. Many published tools have not been evaluated carefully for all these characteristics." so the researcher must be careful in the choice of an instrument. Validated instruments can be divided into three types." Generic instruments are applicable across a wide variety of diseases and breadth of illness severity, making them especially valuable for long-term follow-up of ICU care. Disease-specific instruments are especially sensitive for the measurement of changes of clinical importance over time for a discrete entity. Symptom-severity instruments focus solely on symptoms without measuring the impact of the symptoms on other aspects of the quality of life. No one instrument can fit all situations, but general guidance for the choice is available."

Preoperative Cardiovascular Assessntent More than 3 million patients with coronary artery disease (CAD) undergo surgery each year in the United States. Among them, 50,000 patients sustain a perioperative myocardial infarction (MI). The incidence may be increasing because of an aging population. Overall mortality for perioperative MI remains nearly 400/0. Aortic and peripheral vascular surgery, orthopedic surgery, and major intrathoracic and intraperitoneal procedures are more frequently associated with perioperative cardiac mortality than are other types of surgery. Absent a history of heart disease, men are at increased risk above 35 years of age, whereas women are at increased risk after age 40. Cardiac mortality risk increases markedly in patients over age 70. Cigarette smoking also confers increased risk.

Crucial to the task of risk-benefit analysis is the prospective identification of the patient at risk for a perioperative cardiac complication. Unfortunately, although the presence of CAD is not difficult to demonstrate by screening techniques, there is little evidence that prophylactic coronary revascularization, whether by open surgery or angioplasty, can reduce risk before noncardiac surgery. Routine noninvasive testing is expensive, and clinical criteria may be nearly as good for the identification of patients at high risk. Until recently, it has been unclear whether medical management in preparation for surgery accomplishes much unless the patient has decompensated disease (e.g., congestive heart failure, recent MI),34 but new evidence indicates that perioperative ~-blockade can reduce cardiovascular mortality even when started immediately preoperatively.v-" In addition to the presence of CAD, the perioperative history and physical examination must ascertain the presence of valvular heart disease (particularly asymptomatic aortic stenosis [AS]), congestive heart failure (CHF), or arrhythmias. Congestive heart failure is strongly predictive of perioperative pulmonary edema and other complications. A prospective study of 254 predominantly hypertensive diabetic patients who underwent elective general surgery operations revealed a 17% incidence of perioperative CHF among patients with cardiac disease (previous MI, valvular disease, or CHF).37 Patients with both diabetes and heart disease were at especially high risk. In contrast, CHF developed in fewer than 10/0 of patients without prior cardiac disease. Severe AS (defined as a pressure gradient >50mmHg) must be detected preoperatively because the risk of perioperative mortality has been estimated at 130/0. The increased mortality results from a limited capacity to increase cardiac output in response to stress, vasodilation, or hypovolemia. Patients with AS tolerate poorly the development of hypovolemia, tachycardia, or new-onset atrial fibrillation. Moreover, left ventricular hypertrophy decreases ventricular compliance and leads to decreased diastolic filling. Elective aortic valve replacement before noncardiac surgery may be indicated in severe AS, even in the absence of symptoms. Patients with less-critical AS require invasive hemodynamic monitoring in the perioperative period and caution with the use of afterloadreducing agents. Aortic and mitral insufficiency subject the left ventricle to high-volume loads that may impair contractility, but the risk is comparatively small compared to that conferred by AS. Occult ventricular dysfunction may be present in the asymptomatic patient, and therefore close monitoring is required, but patients can be expected to tolerate surgery well if they are not in CHF. Patients with mitral stenosis or hypertrophic cardiomyopathy are at intermediate risk of perioperative pulmonary edema, especially with tachycardia and decreased left atrial emptying. Perioperative fluid shifts of little consequence to the healthy patient may wreak havoc in the setting of mitral stenosis. Hypovolemia and a resultant low-flow state may occur despite relatively high pulmonary vascular pressures, but overzealous volume or blood administration may cause pulmonary edema rapidly. Atypical or unstable chest pain requires careful evaluation. Stable chest pain does not increase perioperative risk, but unstable disease (e.g., new-onset or crescendo angina, a recent MI, or recent or current CHF) certainly warrants both evaluation and stabilization. The preoperative evaluation of

327


TABLE 17.1. Risk Stratification Parameters and Criteria for Cardiac Events Following Noncardiac Surgery. Parameter

Low risk

Intermediate risk

High. risk

Clinical characteristic

Advanced age

Mild angina

Abnormal ECG (LVH, LBBB, ST-T abnormalities) Atrial fibrillation or other nonsinus rhythm Low functional capacity (climb 130) ST depression >0.1mV Typical angina One or two abnormal leads

a patient with angina should determine whether the patient's disease and symptoms are truly stable. If so, surgery may proceed with the maintenance of an effective antianginal regimen during and after operation. Similarly, asymptomatic or only minimally symptomatic patients who have previously undergone coronary bypass grafting tolerate surgery well. A recent MI is the single most important risk factor for perioperative infarction (Table 17.1). The risk is greatest within the early aftermath following an infarction, probably the first 30 days. Estimates of the risk of anesthesia following an MI range as high as a 27% reinfarction rate within 3 months, 11 % between 3 and 6 months, and 50/0 after a 6month interval. Patients who suffer nontransmural (non-Qwave) infarctions appear to be at identical risk. However, cardiac risk management strategies may be succeeding. With intraoperative hemodynamic monitoring, the risk may be reduced to as low as 6% within 3 months of the first MI and only 2 % incidence within 3 to 6 months. Elective surgery should be postponed for 6 months following an acute MI. When major emergency surgery is necessary, it should be performed with intraoperative hemodynamic monitoring. When operation is urgent, as for a potentially resectable malignant tumor, it can be undertaken from 4 to 6 weeks after infarction if the patient has had an uncomplicated recent course and the results of noninvasive stress testing are favorable. The Cardiac Risk Index System (CRIS) is an accepted system that was developed from a cohort of patients aged 40 years or more who underwent noncardiac surgery." Risk classes (I-IV) are assigned on the basis of accumulated points (Table 17.2). According to CRIS, any elective operation is

Previous or compensated congestive heart failure Diabetes mellitus

Carotid endarterectomy Head and neck procedure Intraabdominal procedures Intrathoracic procedures Orthopedic surgery Prostate surgery Ischemia at moderate-level exercise (heart rate 100-130) ST depression >0.1mV Typical angina Three or four abnormal leads Persistent ischemia 1-3 min after exercise

Emergent major surgery Aortic and other major vascular procedures, including peripheral procedures Long procedures/major fluid shifts or blood loss

Ischemia at low-level exercise (heart rate O.lmV Typical angina Five or more abnormal leads Persistent ischemia >0.3min after exercise

TABLE 17.2. Cardiac Risk Index System (CRIS). Factors

Points

History Age >70 years Myocardial infarction ~6 months ago Aortic stenosis Physical examination S3 gallop, jugular venous distension or congestive heart failure Bedridden Laboratory P02 50mmHg Potassium 50mg/dl Creatinine >3mg/dl Operation Emergency Intrathoracic Intraabdominal Aortic

5 10 3 11 3 3 3 3 3 3 4

3 3 3

Approximate cardiac risk (percentage incidence of major complications) Class: baseline

I

Minor surgery Major noncardiac surgery, age >40 years Abdominal aortic surgery or age >40 with other characteristics

1 4 10

H

ill

IV

0.3 1

1 4

3 12

19 48

10

30

75

3

aCRIS class I, 0-5 points; class II, 6-12 points; class ill, 13-25 points; class IV, points.

~26

Source: Adapted from Goldman et al.," by permission of New England [oumal of Medicine.

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contraindicated if the patient falls within class IV. One benefit of CRIS is that more than one-half of the total points are potentially controllable (e.g., treating CHF reduces the score by 11 points, delaying surgery for a recent MI decreases it by 10 points), thereby reducing risk. Further study of CAD serves primarily to quantify risk in patients with identified risk factors. Whether patients with no cardiac risk factors should undergo additional preoperative testing is still debated. Algorithms from the American College of Cardiology/American Heart Association (ACC/AHA) Task Force on Practice Guidelines can be used to guide the evaluation (Table 17.3; Figs. 17.1-17.3).39 The routine resting electrocardiogram (ECG) remains the primary screening modality for virtually all patients over age 40 who are to undergo general anesthesia. It is undeniably cost-effective but may be normal in many patients with CAD. However, evidence of a prior MI (Q-wave 0.04s or wider and at least one-third the height of the R-wave) is nearly indisputable evidence of CAD. A wide array of other tests have been employed for the preoperative assessment of cardiac risk, including ambulatory ECG, exercise ECG, stress echocardiography, radionuclide imaging, and coronary angiography. Noninvasive tests are sufficiently sensitive to identify most patients at increased risk. Exercise ECG (exercise stress testing) is the historical standard to unmask myocardial ischemia. The sensitivity for detection of CAD ranges up to 810/0, whereas specificity varies up to 96 %, depending on the testing protocoL Testing has important prognostic value when ST segment depression of 1.5mm or greater occurs early during testing, is sustained into the recovery period, is associated with a submaximal increase in heart rate or blood pressure, or is accompanied by angina or an arrhythmia. However, false-negative studies are problematic. Moreover, the test has limited value as a screening procedure for healthy, asymptomatic individuals. Radionuclide cardiac imaging is popular for preoperative evaluation of cardiac disease, most commonly with thallium perfusion scanning, which can be performed at rest, during

TABLE 17.3. Evaluation Steps Corresponding to ACC/AHA Guideline Algorithms for Perioperative Cardiovascular Evaluation of Noncardiac Surgery," Step 1. Step 2. Step 3. Step 4.

Step 5.

Step 6.

Step 7.

Step 8.

What is the urgency of the proposed surgery? If emergent, detailed risk assessment must be deferred to the postoperative period. Has the patient had myocardial revascularization within the past 5 years? If so, further testing is generally unnecessary if the patient is stable/asymptomatic. Has the patient had a cardiologic evaluation within the past 2 years? If so, further testing is generally unnecessary if the patient is stable/asymptomatic. Does the patient have unstable symptoms or a major predictor of risk? Unstable chest pain, decompensated congestive heart failure, symptomatic arrhythmias, and severe valvular heart disease require evaluation and treatment before elective surgery. Does the patient have intermediate clinical predictors of risk, such as prior myocardial infarction, angina pectoris, prior or compensated heart failure, or diabetes? Consideration of the patient's capacity to function and the level of risk inherent in the proposed surgery can help identify patients who will benefit most from perioperative noninvasive testing. Patients with intermediate risk and good-to-excellent functional capacity can undergo intermediate-risk surgery with very little risk. Consider additional testing for patients with multiple predictors about to undergo higher-risk surgery. Further testing can be performed on patients with poor functional capacity in the absence of clinical predictors of risk, especially if vascular surgery is planned. For high-risk patients about to go to high-risk surgery, coronary angiography or even cardiac surgery may be less risky than the noncardiac operation. Clinical, surgery-specific, and functional parameters are taken into account to make the decision. Indications for coronary revascularization are identical whether or not considered in preparation for noncardiac surgery.

'See Figs. 17.1-17.3. Source: Adapted from Eagle et al.," by permission of the Ioumal of the American College of Cardiology.

Postoperative risk

stratification and

risk factor management

F~P symptoms

I -------Consider coronary

Major cIiniclII

predidors •• ,

--~~----

angiography

"10peraq! room

Intermediateclinical

Major Clinical Predictors ••

predidorst

+

~ ~

FIGURE 17.1. American College of Cardiology/American Heart Association guideline algorithm for evaluation of cardiac risk before noncardiac surgery. Patients with major clinical predictors of risk

~ ~

• Unstable coronary syndromes • DecompensatedCHF • Significant arrhythmias • Severe valwlar disease

may have to have surgery postponed or cancelled or undergo an invasive evaluation. See Table 17.5 for additional information. (Reprinted from Eagle et a1.,39 with permission.)

329


Clinical predictors

Functional capacity

Surgical risk

@

Noninvasive testing

Postoperative risk stratification and risk factor reduction

Intermediate CllnlC81 Predlctora t • Mild angina pectoris

Invasive testing

• Prior MI

• Compensated or priorCHF

• Diabetesmellitus

FIGURE 17.2. American College of Cardiology/American Heart Association guideline algorithm for evaluation of cardiac risk before noncardiac surgery. Patients with intermediate clinical predictors of risk or who are about to undergo high-risk surgery may have to have

noninvasive testing before surgery. See Tables 17.3 and 17.5 for additional information. Four metabolic equivalents (METs) are equivalent to climbing one flight of stairs with a bag of groceries. (Reprinted from Eagle et al.," with permission.)

exercise, or during a pharmacological exercise equivalent [e.g., dipyridamole) for patients who cannot exercise (e.g., those with peripheral vascular disease, lower-extremity orthopedic problems). Myocardial perfusion imaging using intravenous 201Th analyzes the extent and localization of CAD, the reversibility of the lesions, and the stress response of 201Th in the coronary circulation. The isotope is taken up by myocytes in a manner analogous to potassium. Rapid uptake allows visualization of ischemic or unperfused myocardium. Normal coronary blood flow is relatively homogeneous, such that perfusion deficits cannot be detected in the resting state unless severe (900/0 or greater) coronary artery stenosis is present. Heterogeneity can therefore be enhanced by superimposed myocardial stress, which reflects ischemia. Because myocardial clearance of 201Th is rapid, redistribution during reperfusion of ischemic myocardium can also be observed. The accuracy of 201Th perfusion scans is limited by lower sensitivity with lesser degrees of coronary stenosis. Single-vessel disease involving the circumflex or right coro-

nary circulations may not be detected, and disease in the left anterior descending artery may go unrecognized if redistribution occurs in other segmental circulations. Although the negative predictive value is high (900/0), the presence of redistribution during reperfusion is identified so often, particularly in vascular surgical patients, that its positive predictive value is low (300/0). It is also possible to estimate the left ventricular ejection fraction (LVEF), which portends increased risk when below 350/0 however it is measured (e.g., echocardiography). Stress echocardiography (usually with infusion of dobutamine) may be even more accurate than 201Th scanning according to a meta-analysis of the recent literature." Dobutamine echocardiography is less expensive than a 201Th perfusion scan and has the advantage of additional imaging possibilities. Valvular function can be assessed, wall motion and wall thickening can be quantified, and an estimate of LVEF can be made from measurements of end-systolic and end-diastolic areas. Dobutamine echocardiography should probably be

Clinicalpredictors

Functionalcapacity

Surgical risk

~

Minor Clinical Predieto ... Noninvasive testing

Invasive testing

Operating room

*

• Advanced age • Abnormal ECG • Rhythm other than sinus • Low functional capacity • History of stroke • Uncontrolled systemic hypertension

FIGURE 17.3. American College of Cardiology/American Heart Association guideline algorithm for evaluation of cardiac risk before noncardiac surgery. Patients with minor or no clinical predictors who are about to undergo high-risk surgery may have to have noninvasive

testing before surgery. See Tables 17.3 and 17.5 for additional information. Four metabolic equivalents (METs) are equivalent to climbing one flight of stairs with a bag of groceries. (Reprinted from Eagle et al.," with permission.)

330

CHAPTER 17

considered the provocative test of choice for moderate- to high-risk patients. Echocardiographic estimates of ventricular function correlate well with angiographic and radionuclide data. Such information can be of great value as reduced LVEF (

Control group (157 events) ------- Cardiac-index group (156 events) Oxygen-saturation group (164 events)

0.8

.~

:::l

en

0.6

'0

~

:c CO

0.4

0~

0.2

~

.c

a..

0.0

0

90

45

135

180

Days after Randomization PATIENTSAT RISK (NO.OF EVENTS)

FIGURE 17.4. Kaplan-Meier plot of lBO-day survival for three resuscitation strategy groups. There was no significant difference among the groups. (Reprinted from Gattinoni et al.," with permission.)

Control group Cardiac-index group Oxygen-saturation group

5051 patients estimated the odds ratio (OR) for death associated with the use of the PA catheter. Overall, the OR for death was 1.04 (950/0 confidence interval [Cll 0.90-1.20, P = .59). Use of a PA catheter was associated with greater use of inotropic agents (OR 1.58; 95% CI 1.19-2.12, P = .02) and intravenous vasodilators (OR 2.35; 950/0 CI 1.75-3.15, P < .001). However, use of a PA catheter in selected patients (e.g., for shock, CHF, acute renal failure) may still be justified (see Chapter 16)54. Oxygen delivery (002) and consumption (\702) may also be calculated if actual O2 context is measured separately. In contrast to directly measured \702 (e.g., by indirect calorimetry), calculated \702 data can be misinterpreted because of a bias called shared measurement error that is introduced because calculated 002 and \702 are not independent variables. This bias misinformed the resuscitation of critically ill patients for many years, based on a strategy of enforced supraphysiological 002 rather than mere restoration to physiological levels (see chapter 16). Gattinoni et al. tested this hypothesis directly in a multicenter trial performed in 56 ICUs. 55A total of 10,726 patients were screened to identity 762 patients in predefined diagnostic categories (Simplified Acute Physiology Score above 11

108 (13) 102 (8) 106 (16)

90 (3) 86 (3)

94 (4) 90 (4) 89(4)

85(1)

87

83

84

and one of the following: high surgical risk, massive blood loss, severe sepsis or septic shock, acute respiratory failure, or multiple trauma). The patients were randomized to therapy consisting of resuscitation via increasing the cardiac index to a predetermined level (>4.51/min/m2 ), increasing the mixed venous oxygen saturation to normal (700/0), or a control group. Mortality was not different among the groups (Fig. 17.4) and ranged from 48 % to 52 % at the time of ICU discharge to 620/0 to 640/0 at 6-month follow-up. Among survivors, there were no differences among groups in terms of organ dysfunction or the length of ICU stay. There were no differences in mortality when stratified by diagnostic subgroup (Fig. 17.5) or among the subsets of patients in which the resuscitation goal was met. Velmahos et al.56 found in a randomized prospective trial of normal versus supranormal oxygenation that those who achieved supranormal oxygen transport had better outcomes, but they did so spontaneously; therapy had no effect on whether the endpoint was achieved. Younger patients were much more likely to achieve supranormal oxygenation; elderly patients rarely did so. These studies may be considered definitive, and the enforced oxygen transport hypothesis to be therefore disproved.

40

1 Control group 2 Cardiac-index group 3 Oxygen-saturation group

2

20

252 (129) 253 (133) 257 (133)

3 2 3

2

Living

3

o ...-

2

1 23

3

c:

Q)

~

Q.

o

0

~

o z 20

FIGURE 17.5. Overall survival for three resuscitation strategy groups, stratified by study inclusion criteria. There was no significant difference within or among the groups. (Reprinted from Gattinoni et al.," with permission. )

40

Dead

Postoperative Risk

P

= 0.3n

Massive Blood Loss

P

= 0.896

Septic Shock P = 0.335

Sepsis Syndrome P = 0.150

Acute Respiratory Failure P = 0.395

P

COPO 0.325

=

Multiple Trauma

P = 0.276

338

CHAPTER 17

TABLE 17.12. Indications for Blood and Blood Component Therapies. Leukocyte-reduced red blood cell units Congenital hemolytic anemias Hypoproliferative anemias likely to need multiple transfusions Recurrent severe febrile hemolytic transfusion reactions Known HLA alloimmunization Irradiated cellular blood components Bone marrowjstem cell transplants Intrauterinejpostuterine transfusions Directed donations (HLA-matched or blood-relative donors) Hodgkin disease Acute lymphocytic leukemia Solid-organ transplant recipients Antineoplastic chemo- or radiotherapy Exchange transfusionjextracorporeal membrane oxygenation HIV opportunistic infections

Transfusion of Blood and Blood Products The issue of blood transfusion is of great concern to patients and physicians because of real and perceived risks of infectious disease transmission, increased risk of nosocomial infections, and other consequential complications (also see chapter 9). The decision to transfuse a patient with blood or blood products must be predicated on several factors, such as the underlying diagnosis (Tables 17.11-17.15),57,58 the availability of blood, the "optimal" hematocrit for oxygen transport, and alternatives to transfusion itself. Options for blood transfusion therapy currently include no transfusions whatsoever (which may be dictated for religious reasons), a lowering of the transfusion "trigger" such that a lower hematocrit is tolerated, or possibly therapy with recombinant human erythropoietin (rHuEPO). Alternatives to allogeneic (anonymous volunteer donor) transfusion include blood from a designated donor, autologous transfusion of blood predonated by the patient, and intraoperative isovolemic hemodilution with auto transfusion of reserved blood at the end of the case. Several studies indicated that higher transfusion targets (hemoglobin 8-lOg/dl) may lead to higher mortality than the more parsimonious strategy of transfusion for a hemoglobin concentration of about 7g/dl. 59,60 Spiess et al. observed 2202 patients prospectively who underwent coronary artery bypass ~U__•

TABLE 17.13. Summary of Evidence-Based Guidelines for Red Blood Cell Tra nsfusions for Acute Blood Loss..

Evaluate for risk of ischemia Estimatejanticipate degree of blood loss .50%, V02,5 0% of baselin e: Transfusion usually needed

PV 0 2,

' Practice Paramete r of the College of American Path ologists, 1997.

flJ. . .

TABLE 17.14. Summary of Evidence-Based Guidelines for Red Blood Cell and Plasma Transfusions"

Red blood cell transfusions

Level I: Level II:

No recommendations. Transfusions should be given to alleviate symptoms or mortality. No single transfusion trigger is appropri ate for all pat ients or situations. Red blood cell concentrates should not be used to expand intravascular volum e when oxygen carryin g capacity is adequate. Red blood cell concentrates should not be us ed to treat anemia if less-risk y alternatives are availabl e.

Fresh-frozen plasma tran sfusion s

Level I:

Level II:

FFP is indicated for adult thrombotic thrombocytopenic purpura, followe d by plasm aph eresis. FFP is ind icated for bleedin g in patients with abnormal PT, aPTT, or INR. FFP is not indicated prophylactically for INR 1000mg/dl), depressed sensorium, marked dehydration, and prerenal azotemia. By definition, acidosis, ketonemia, and ketonuria are absent unless

there is coexistent DKA. Precipitants include many stresses typical of the surgical patient, including bums, severe infections, pancreatitis, and major surgery. Mortality appears to be higher in cases associated with sepsis or pancreatitis. Therapy with ~-blockers, diazoxide, furosemide, glucocorticoids, TPN, or thiazides may precipitate HHNC, as may renal replacement therapy. Diabetic ketoacidosis and HHNC share two similarities: relative insulin deficiency and marked volume depletion. The diagnosis of HHNC should be suspected in the setting of marked hyperglycemia (>700mg/dl) and azotemia without ketonemia. The serum sodium concentration may be factitiously normal in the setting of elevated blood glucose (decreased 3mEq/dl per 100mg glucose elevation). Ketosis is absent because sufficient insulin is present to suppress lipolysis. Hyperglycemia itself suppresses lipolysis, and the stress hormone response in HHNC is modest compared to that in DKA. Changes in mental status can be related directly to the degree of hyperosmolarity. Neurological abnormalities include lethargy, focal or generalized seizures, or coma. As with DKA, therapy consists of rehydration, intravenous insulin, electrolyte replacement, and correction of the precipitant. Isotonic saline is the fluid of choice except for the hypernatremic patient. As much as 101 may be required in the first 24h. Potassium supplementation up to 20mEq/h may be necessary. Fluid administration is then adjusted based on the response to resuscitation. Intravenous insulin is given as an infusion of 6-10U/h until blood glucose is below 250mg/dl, when a change is also made to dextrosecontaining fluid to prevent hypoglycemia and cerebral edema.

Approach to the Febrile Surgical Patient Fever is common in surgical patients. The list of potential causes of fever is long and includes many noninfectious etiologies (Table 17.16). Any fever in a surgical patient is a potential cause for concern. A tendency to equate fever with infection is understandable, but approximately one-half of febrile episodes in surgical patients are noninfectious in origin. Unfortunately, there are few comprehensive epidemiological studies of fever in surgical patients. The workup and therapy for the individual patient will vary depending on the patient's underlying diagnosis, clinical appearance, and the clinician's suspicion of infection. Current guidelines for the evaluation of fever in critically ill adults suggest that fever mandates a history and physical examination (Table 17.17).85 Subsequent testing should be based on the findings of the clinical evaluation; in some instances, no further evaluation will be necessary.

What Constitutes a Fever? The magnitude of temperature elevation necessary to constitute a fever may simply be the particular temperature at which the clinician believes that investigation is necessary, most commonly in the range of 38.0°C to 38.5°C. Elevated body temperature increases basal metabolic rate 7%-150/0/oC, but aside from increased insensible fluid losses and some


343

TABLE 17.16. Noninfectious Causes of Fever of Importance in Surgical Patients. Cardiovascular Myocardial infarction Aortic dissection Pericarditis Central nervous system disease Cavernous sinus thrombosis Hypothalamic dysfunction N onhemorrhagic infarction/stroke Seizures Subarachnoid hemorrhage Traumatic brain injury Gastroenterological Acalculous cholecystitis Gastrointestinal hemorrhage Hepatitis (toxic/ischemic) Inflammatory bowel disease Ischemic colitis Pancreatitis (early) Hematological Venous thrombosis (superficial or deep) Retroperitoneal/pelvic hemorrhage/hematoma Transfusion reaction

Inflammatory Gout/pseudogout Intramuscular injections Transplant rejection Vasculitis Endocrine/metabolic Adrenal insufficiency Alcohol/drug withdrawal Hyperthyroidism Miscellaneous Allergic drug reaction Drug fever Tissue ischemia/infarction Neoplastic Febrile neutropenia Metastatic disease Primary tumors Pulmonary/airway Acute respiratory distress syndrome (fibroproliferative phase) Atelectasis Aspiration pneumonitis Pulmonary embolism/infarction

discomfort, fever is usually not the primary source of morbidity. Tachycardia or increased oxygen demand may make it desirable to suppress fever in select patients with coronary ischemia or critical acute respiratory failure. However, most adults without a neurologic diagnosis do not specifically require antipyresis unless temperature exceeds 4DoC; in fact, to do so may be harmful because of the salutory effects of fever on host defenses (e.g., enhanced neutrophil function, suppressed bacterial growth). If antipyretic therapy is chosen, then cyclooxygenase (COX) inhibition is most effective, bearing in mind that deleterious effects on renal function and the gastric mucosa are possible with COX inhibitors. Topical cooling is generally ineffective (cutaneous vascoconstriction causes core retention of heat), although core cooling (e.g., iced fluid lavage of the stomach) can be effective. The site where the temperature is determined may also influence the observed temperature value. The accepted standard for measuring an accurate core body temperature is the thermistor reading of a PA catheter, now seldom increasingly used. Rectal temperatures may be several tenths of a degree higher than the core temperature, and axillary values generally are lower and poorly reproducible. Infrared tympanic membrane devices have been popularized and do represent the core temperature, but there may be problems with reproducibility.

The most common cause of early postoperative fever is atelectasis. If atelectasis is present, then pulmonary physiotherapy and early ambulation (if possible) should be undertaken immediately; cultures are generally not useful in the immediate postoperative period. It is unusual for a fresh postoperative patient to have been admitted with a communityacquired pneumonia, but the clinician must remain alert to the possibility. After the third postoperative day, nosocomial pneumonia is possible. In addition to atelectasis, aspiration pneumonitis (which is usually noninfectious), tissue ischemia or infarction, acute vasculitis, gout or pseudogout, intracerebral hemorrhage, retroperitoneal hematoma, pericarditis, and transfusion reactions can cause fever. There are several miscellaneous causes of fever that are not caused by infection. Withdrawal from alcohol, benzodiazepines, or opioids can all cause fever. Endocrine emergencies, including acute adrenal insufficiency or thyroid storm, can be challenging to diagnose because they can be precipitated by infection. Adrenal insufficiency and thyrotoxicosis can create high fevers with a constellation of systemic signs. Two types of patients are at high risk for adrenal insufficiency: those with a history of corticosteroid use and those with an acute condition that ablates adrenal function. It is debatable whether stress can otherwise unmask latent adrenal insufficiency in previously asymptomatic patients. Both conditions are rare (thyrotoxicosis, especially) and therefore treacherous because the diagnosis can be overlooked. Patients with adrenal insufficiency present with variable degrees of temperature elevation, hypotension, hyponatremia, hyperkalemia, or hypoglycemia. Severe thyrotoxicosis or thyroid storm can cause fevers above 39.DoC with a variety of other systemic signs, including tachyarrhythmias, atrial fibrillation; diaphoresis; palpitations; CHF; gastrointestinal symptoms (abdominal pain, nausea, vomiting, and diarrhea); neurological symptoms (tremors, seizures, anxiety); and heat intolerance. Treatment is supportive and includes propranolol, fluids, iodine, and possibly antithyroidal agents such as methimazole or propylthiouracil.

Noninfectious Causes of Fever A nosocomial infection is a less likely cause of postoperative fever than a noninfectious cause in the first 72h after surgery. The problem of postoperative fever is a useful paradigm for consideration of the priorities in the workup. Perhaps more money is wasted in evaluation of early postoperative fever than in any other aspect of postoperative care. Although common, fever in the early postoperative period can be the result of a few things, provided pulmonary aspiration and gross breaks in surgical technique or for insertion of intravascular catheters are avoided.

$.~_

TABLE 17.17. Evidence-Based Practice Management Guideline for the Evaluation of Fever in Critically III Adult Patients!

Temperature measurement

Level I:

Level II:

Blood cultures

Level I:

Level II:

Record the temperature and the site of measurement in the patient's medical record . The nosocomial spread of pathogens must be avoided when using temperature measurement devices. Temperature is measured most accurately by indwelling vascular or bladder thermistors, but most other sites are acceptable. Axillary measurements should not be used. Laboratory testing for the evaluation of fever should be individualized for each patient. For skin preparation, povidone-iodine should be allowed to dry for 2min or tincture of iodine for 30s. Alcohol skin preparation, an acceptable alternative for iodine-allergic patients, need not be allowed to dry. Obtain a single pair of blood cultures after appropriate skin disinfection after the initial temperature elevation and another pair within 24h thereafter from a second peripheral site. Additional cultures should be based on high clinical suspicion of bacteremia or fungemia and not instituted automatically for each temperature elevation. If two peripheral sites are not available, then one pair of cultures may be drawn through the most recently inserted catheter, but the diagnostic accuracy is reduced . Draw at least 10-15ml blood/culture.

Suspected intravascular catheter infection

Level II:

Examine the catheter insertion site for purulence and distally on the extremity for signs of vascular compromise or embolization. Any expressed purulence from an insertion site should be collected for culture and Gram stain. The catheter should be removed and cultured for evidence of a tunnel infection, embolic phenomena, vascular compromise, or sepsis . Two blood cultures should be drawn peripherally, or one may be drawn from the most proximal port [if a multilumen catheter). Both the introducer and the catheter itself should be cultured for suspected pulmonary artery catheter infection. It is not routinely necessary to culture the intravenous fluid infusate.

Suspected leU-acquired pneumonia

Level I:

Level II:

A chest x-ray should be obtained to evaluate for suspected pneumonia. Posteroanterior and lateral films or computed tomography of the chest can offer more information. Lower respiratory tract secretions should be sampled for direct examination and culture. Bronchoscopy may be considered. Respiratory secretions should be transported to the laboratory within 2h of collection. Pleural fluid should be obtained for culture and Gram stain if there is an adjacent infiltrate or another reason to suspect infection.

Evaluation of the febrile patient with diarrhea

Level II:

If more than two diarrheal stools occur, then a single stool sample should be sent for Clostridium difficile evaluation. A second sample should be sent if the first is negative and suspicion remains high. If illness is severe and rapid testing is unavailable or nondiagnostic, then consider flexible sigmoidoscopy. If illness is severe, then consider empiric therapy with metronidazole until the results of studies are available. Empiric therapy (especially with vancomycin I is not recommended if two stool evaluations have been negative for C. difficile and is discouraged because of the risk of producing resistant pathogens. Stool cultures are rarely indicated for other enteric pathogens if the patient is HIV negative or did not present to the hospital with diarrhea .

Suspected urinary tract infection

Level II:

Suspected sinusitis

Level I: Level II:

Postoperative fever

Level II:

Obtain urine for culture and to evaluate for pyuria. If the patient has an indwelling Foley catheter, urine should be collected from the urine port and not the drainage bag. The specimen should be transported rapidly to the laboratory or refrigerated if transport will exceed 1h. Aspirate should be Gram stained and cultured. Computed tomography of the facial sinuses is the imaging modality of choice for the diagnosis of sinusitis. Puncture and aspiration of the sinuses should be performed using sterile technique if mucosal thickening or an airfluid level is present in the sinus. Examine the surgical wound for erythema, fluctuance, tenderness, or purulent drainage. Open the wound for suspicion of infection. Culture and Gram stain should be obtained from purulent material if from deep within the wound.

Suspected central nervous system infection

Level II:

Gram stain and culture of cerebrospinal fluid should be performed in cases of suspected infection. Other tests should be predicated on the clinical situation. A computed tomographic study is usually required before lumbar puncture, which may need to be deferred if a mass lesion is present. Consider lumbar puncture for new fever with unexplained alteration of consciousness or focal neurological signs . In febrile patients with an intracranial device, cerebrospinal fluid should be sent for culture and Gram stain.

Noninfectious causes of fever

Level II

Reevaluate all recent medications and blood products the patient has received . Stop all nonessential medications or substitute medications for treatments that cannot be stopped.

'Summary of clinical recommendations, Society of Critical Care Medicine, 1998; levellII guidelines excluded. Source: Adapted from O'Grady et a1."


DRUG FEVER

Fever coincident with administration of a drug that disappears after discontinuance, when no other cau~e of ~ev~r is apparent, characterizes the disorder. The diagnosis IS therefore one of exclusion, and skepticism is always in order lest another treatable cause of fever is overlooked. True drugrelated fever probably accounts for no more than 2 % to 30/0 of episodes of fever in hospitalized patients. Most are ~yper sensitivity reactions; therefore, malignant hyperthermia and the neuroleptic malignant syndrome (NMS; see following) are generally not classified as drug fever. Other potential me~ha nisms associated with drug administration include chemical phlebitis or sterile abscesses, pyrogenic contaminants, or generation of endogenous pyrogens. Some drugs, notably thyroxine, atropine, and epinephrine, may affect thermore~l~tion directly. Most classes of drugs require long latent administration periods, but antibiotics, phenytoin, and antineoplastic agents are capable of producing fever within a few days. As a group, antimicrobial agents are the most common cause of fever. Penicillins, cephalosporins, tetracyclines, and vancomycin are commonly prescribed culprits. Fever usually abates within 72h of discontinuance of the offending drug unless its half-life is prolonged (e.g., phenytoin), so additional therapy is usually unwarranted. Hyperthermia occurs when heat production exceeds h~at loss in the presence of a normal set point. Work or exercise in hot environments may precipitate hyperthermia (heat stroke), as mayan inability to dissipate heat (such as in a high-humidity environment where evaporation cannot occur). In some patients, set-point temperature is increased by trauma, hemorrhage, or tumors of the hypothalamus. However, such "central" or "hypothalamic" fevers are unusual, except in neurosurgical patients. . Malignant hyperthermia syndrome can occur when certain anesthetics and adjuncts (e.g.,succinylcholine, volatile hydrocarbons) produce in susceptible patients a rapid uncoupling of oxidative phosphorylation, which is often fatal (300/0-70% mortality). Rare causes of malignant hyperthermia include anoxia, lymphoma, and viral infections. Most cases occur in the operating room but may develop up to 24 h after the offending agent has been given. Patients are predisposed genetically to this disorder, which can be suspected by a family history of anesthesia complications and confirmed by genetic testing. Medication for both prophylaxis and the overt syndrome includes the administration of freshly prepared dantrolene (1-2mg/kg every 10min) along with supportive care. Malignant hyperthermia usually does not respond to antipyretic therapy. Another form of hyperthermia, NMS, occurs in patients taking neuroleptic drugs, typically phenothiazines or butyrophenones, although metoclopramide therapy has been implicated. All such drugs decrease hypothalamic dopaminergic tone. Despite the different etiology, both malignant hyperthermia and NMS present with similar symptoms and have similar therapies, except that the magnitude of the core temperature response is somewhat lower, and signs of muscle damage (e.g., tenderness, immobility, and elevated serum creatinine phosphokinase) are absent in NMS. HEMATOLOGIC CAUSES OF FEVER

Several hematologic causes of fever exist (see Table 17.16). One of the most common causes of fever in the inpatient

345

setting is a transfusion reaction. Passenger leukocyt~s are th.e chief cause of alloimmunization to leukocyte-specific antigens in transfusion recipients. Alloimmunization m.ay result in febrile transfusion reactions, platelet refractoriness, or acute lung injury." Leukocytes are also the vector for tr~ns fusion-associated cytomegalovirus infection. Technological advances have made it possible to reduce the number of leukocytes to fewer than 107 per transfusion. The us~ ~f ~euko cyte-reduced cellular blood components ~ay m~n1l1~.1Ze or prevent recurrent febrile reactions and alloImmunIzatIon~ to leukocyte antigens and minimize the risk of cytomegalovirus transmission (see Table 17.12), but the data are mixed. The presence of a coexisting hematologic dyscrasia may also increase the likelihood of a transfusion reaction. Almost any neoplasm itself may manifest fever. The postchemoth.era~eu tic state may lead to the tumor lysis syndrome, which IS a common source of fever in hospitalized cancer patients. Febrile neutropenia is common on oncology wards and bone marrow transplant units, and the initiation of therapy with any of the colony-stimulating factors or cytokines (e.g., interleukin-2 therapy) may also cause fever. Almost any intracranial pathology can lead to centrally mediated fevers. Any traumatic or infectious condition of the brain can stimulate a hyperpyrexic response, but most common is subarachnoid hemorrhage. In actuality, a blood clot anywhere in the body can cause fever. Hematomas can occur in the soft tissue from trauma or in the retroperitoneum or abdominal wall spontaneously in the anticoagulated patient. A clot in the vasculature may be either an arterial or a venous thrombosis. Suspicion of deep venous thrombosis and pulmonary embolism must be high because these problems are often occult. High fever can certainly be caused by uncomplicated superficial phlebitis of a subcutaneous vein of an extremity. Fine-needle aspiration with Gram stain and culture may be necessary to exclude suppuration. Uncomplicated superficial phlebitis responds promptly to warm soaks, elevation, and ibuprofen (if not contraindicated), but the vein must be explored and excised to bleeding tissue for suppu~ative p~le bitis. For lower-extremity deep venous thrombosis, the diagnostic approach includes lower extremity duplex ultrasound studies or in some institutions, magnetic resonance imaging of the pelvic veins." Although ICU patients are at high risk for venous thromboembolism, routine screening does not appear to be cost-effective. Many authorities believe that helical CT has now supplanted venography/pulmonary angiography for the diagnosis of venous thromboembolism." If a central catheter-related venous thrombosis occurs, then the therapy includes the removal of the catheter and the possible institution of anticoagulant or thrombolytic the.rapy. If thrombolysis is chosen, then it must be accomplished before the catheter is removed to avoid the possibility of hemorrhage. With arterial thrombosis, it is often the resulting tissue ischemia that causes fever.

Infectious Causes of Fever: Nosocomial Infection Many emergency operations are performed for control of an infection. Even under optimal circumstances (definitive surgical source control, timely administration of appropriate broad-spectrum antibiotics), it may take 72h or more for the patient to defervesce. New or persistent fever more than 3 days after surgery should raise a strong suspicion of persistent illness or a new complication.

346

CHAPTER 1 7

DEVICE-RELATED INFECTIONS, CATHETER-RELATED INFECTIONS, AND VENTILATOR-ASSOCIATED PNEUMONIA

Health care-associated (nosocomial) infections are potentially devastating complications. Therefore, every effort must be made to prevent them (Table 17.18).89,90 Nosocomial infections often arise in association with indwelling devices, such as intravascular catheters, endotracheal or tracheostomy tubes, or other devices that breach or degrade a natural epithelial barrier to infection." The patients most at risk for pneumonia are those who require prolonged mechanical ventilation (ventilator-associated pneumonia, VAP). Pneumonia is a particular prob lem for surgical patients, with cardiothoracic, neurosurgical, and trauma patients and those who have undergone major head

TABLE 17.19. Device-Related Nosocom ial Infection Rates 19921998.' Type of infection

Type of ICU

Bum Cardiothoracic Medical Neurosurgical Surgical Trauma

Urinary catheter

Central lin e bacteremia

Ventilatorassociated pneumonia

10.0 (N/A) 3.3 (2.1) 7.8 (7.0) 8.5 (7.8) 5.7 (4.9) 7.9 (N/A)

12.8 (N/A) 2.8 (1.8) 6.1 (5.3) 5.4 (4.4) 5.7 (4.9) 7.0 (N/A)

21.1 (N/A) 11.7 (11.3) 8.5 (7.6) 17.3 (13.8) 14.9 (12.71 17.0 (N/A)

N / A, not available. Data are expres sed as mean [median], and as Number of occurrences/Number of patient-days with device indwelling x 1000. ' N ational Nosocomial Infection Surveillance System, Centers for Disease Control and Prevention. Data are available in the public domain at www.cdc . gov/ ncidod/h ip/ nni s/sar98net.pdf.

~"rJ". TABLE 17.18. Summary of Evidence-Based Clinical Guidelines for the Prevention of Nosocom ial Bacterial Pneum onia.' Surveillance

Level I:

Conduc t surveill ance of bacterial pneumonia among ICU patients at high risk . Routine surveillance cultures of patients, equipment, or devices is unnecessary.

Int errupting person-to-person transmission of bacteria

Level I:

Level II:

Regardless of whether gloves are worn, wash hands after contact with mucous membranes, respiratory secretio ns, or objects contaminated with respiratory secretions. Regardless of whether gloves are worn, wash han ds both before and after contact with a patient who has an endotracheal or tracheostomy tube in place, or for handling respiratory secretions. Chan ge gloves and wash hands after handling respiratory secretions or objects before contact wit h another patient, object, or environmental surface. Change gloves and wash hands between contacts with a contaminated body site and the respiratory tract or device on the same patient. Use aseptic techniques when changing a tracheostomy tube .

Modifying host risk for infection

Level I:

Level II:

Do not routinely administer systemic antimicrobial agents to prevent nosocomial pneumonia. Discontinue enteral tube feeding and remove devices as soon as the clinical indications are resolved. If not contraindicated, elevate the head at an angle of 30°-45° of the bed of a patient at high risk for aspiration. Routinely assess the patient's intestinal motility and adjust the rate and volume of enteral feeding to avoid regurgitation. Before deflating the cuff of an endotracheal tube, ensure that secretions are cleared from above the tube cuff. Instruct preoperative patients, especially those at high risk for contracting pneumonia, regarding frequent coughing, taking deep breaths, and ambulating. Encourage postoperative patients to cough frequently, take deep breaths, move about the bed, and ambulate unless medica lly contraindicated. Control pain that int erferes with coughing and deep breathing during the immediate postope rative period.

Source: Adapt ed from Centers for Disease Control and Prevention?"

and neck or gastrointestinal operations at hig h risk (Table 17.19). Although the presence of (1) purulent sputum, (2) fever, (3) leukocytosis, and (4) a new or changed radiographic infiltrate (i.e., the definition of the U.S. Centers for Disease Control and Prevention) may suggest pneumonia, only about 40 % of patients with these four typical findings are found to have pneumonia when evaluated with a consistent and systematic protocol that includes noncon tam inated sputum collection" and microbiology. Bronchoalveolar lavage or protected specimen-brush sampling increases the specificity and therefore the accuracy of the diagnosis of pneumonia." Any oropharyngeal or nasopharyngeal apparatus can promote the development of sinusitis." Patients with maxillofacial or skull fractures, traumatic brain injury, or nasotracheal intubation are at high risk. The optimal diagnostic test for sinusitis is a CT scan with thin cuts of the facial bones, followed by sinus aspiration and lavage for culture of any patient with mucosal thickening or an air-fluid level. Although the diagnostic yield is low and the evaluation is laborious, the incidence of sinusitis is increasing. For prevention and treatment, early removal of transpharyngeal devices is important, especially nasotracheal tubes, which are associated with sinusitis approximately one-th ird of the time after nasotracheal intubation." Peripheral or central venous catheters may become infected and then cause a bloodstream infection. The complication is serious but largely preventable with rigid adherence to infection control practice and meticulous technique for catheter insertion and maintenance. Central venous catheters impregnated with antimicrobial agents ma y decrease the risk of infection in high-incidence units." Urinary tract infection is commonplace because of the ubiquitous use of urinary catheters but is seldom destabilizing. Nosocomial upper urinary tract infections are rare in nonneurological patients. Most of these infections are caused by instrumentation of the urinary bladder. The duration of catheterization is the most important risk factor for the development of nosocomial bacterial cystitis. Most episodes of bacteriuria are asymptomatic, but symptoms, including fever and leukocytosis, can develop in 10% to 30 % of patients. The indications for cat heterization should be reviewed daily. The


best prevention and therapy is removal of the catheter at the earliest opportunity. The closed -drainage system should be handled as little as possible and only with meticulous attention to good infection control practice. NOSOCOMIAL INFECTIONS NOT RELATED TO DEVICES

Surgical site infection (SSI) or infection of a traumatic wound is rare in the first few days after operation because effective methods of prevention are recognized. The only important exceptions to this rule are the development of erysipelas, a necrotizing soft tissue infection caused by pyogenic streptococci, and clostridial fasciitis or myonecrosis. Thus, it is important to take down the surgical dressing to inspect the incision for a fever in the early postoperative period, but the diagnosis of these serious infections can be made by inspection alone, and such patients are usually "toxic" appearing. Crush injury syndrome and tetanus are two rare complications of traumatic wounds that may cause fever. Other SSIs, either of the incision or intracavitary for surgery of the torso, generally manifest themselves after the fourth postoperative day in the absence of a gross break in technique.

Antibiotic-Associated Colitis One complication to which every surgical patient who receives antibiotics is potentially subject is AAC. The most distinguishable of these syndromes, Clostridium difficileassociated disease (CDAD), results from overgrowth and toxin production after antibiotic use, even a single dose of a cephalosporin used appropriately for surgical incision prophylaxis. Practically every antibiotic has been implicated in the pathogenesis. The symptoms are nonspecific because the spectrum of disease is broad, ranging from asymptomatic disease to fulminant colonic ischemia. The proportion of severe cases is increasing because of a mutation of a suppressor gene for toxin production."?" The diagnosis of AAC usually depends on isolation of exotoxin A or B from a fresh stool sample. Sigmoidoscopic visualization of colonic pseudomembranes may assist in the diagnosis when the exotoxins are not detected, but the pseudomembranes are present less than 500/0 of the time, and endoscopy is therefore seldom performed. Treatment for AAC includes supportive care, the exclusion of peritonitis or an indication for laparotomy, and metronidazole (intravenous or oral), which is comparable to oral vancomycin at about 800/0 effectiveness, even for clinically severe cases. Oral vancomycin can be used for patients who are intolerant of metronidazole or who fail therapy with metronidazole, but vancomycin use is discouraged for infection control reasons. Vancomycin can be administered by gavage or enema if necessary because intravenous vancomycin is ineffective. Increasingly, severe cases require a total abdominal colectomy for cure, with attendant operative mortality of up to 500/0. 97

Acute Acalculous Cholecystitis Acute acalculous cholecystitis (AAC)may complicate surgery or critical illness or injury." Diabetes mellitus, abdominal vasculitis, CHF, cholesterol embolization, and resuscitation from major trauma or bums, hemorrhagic shock, or cardiac

347

arrest have been associated with AAC. The unifying theme is that the pathogenesis of AAC is ischemia-reperfusion injury of the gallbadder. The diagnosis of AAC can be difficult to make. These patients almost invariably are jaundiced and often unable to communicate. The differential diagnosis of jaundice in the critically ill patient is complex, including intrahepatic cholestasis from sepsis or drug toxicity and "fatty liver" induced by TPN, in addition to cholecystitis. The diagnosis of ACC should be considered in every critically ill or injured patient with a clinical picture of sepsis and no other obvious source. Fever is generally present, but other physical findings are less reliable. Leukocytosis and hyperbilirubinemia are nonspecific, and biochemical assays of hepatic enzymes are of little help. The diagnosis of ACC thus often rests on radiologic studies. Ultrasound of the gallbladder is the preferred modality to diagnose ACC because of low cost and the ability to image the patient at the bedside. Thickening of the gallbladder wall of 3.5mm or more is the most accurate criterion. Radionuclide hepatobiliary imaging is unreliable in critically ill or injured patients because of false-positive scans due to fasting, alcoholism or other forms of liver disease, or TPN feeding. Computed tomography is as accurate as ultrasound in the diagnosis of ACC, and the diagnostic criteria for ACC are similar. The mainstay of therapy for ACC is percutaneous cholecystectomy." The advantages of percutaneous cholecystostomy are bedside applicability, local anesthesia, and avoidance of an open procedure. The technique controls the acute syndrome in about 85 % of patients.

Diagnostic Approach to Fever The likelihood of infection as a cause and the potential for destabilization of a tenuous patient create a sense of urgency surrounding the workup of many febrile episodes. However, some fevers are not destabilizing and do not require either workup or treatment. An individual approach is essential, both for evaluation and for therapy. Unlikely diagnoses should not be pursued initially until more common problems have been considered and excluded. However, it is costly as well as nonbeneficial to make diagnoses that are unlikely to have an important effect on the patient's overall diagnosis or treatment. Two major problems to resolve are distinguishing sterile systemic inflammation from systemic infection and distinguishing bacterial colonization from tissue invasion. Many patients with sterile inflammation (e.g., early pancreatitis, major trauma, bums) develop an inflammatory host response characterized by elaboration of the very cytokines implicated in the febrile response. The picture may be indistinguishable from clinical infection. The distinction is crucial because these patients are at high risk to develop antibiotic-resistant infections if unnecessary antibiotics are administered." A careful history and physical examination should direct further diagnostic tests, recognizing that individual tests may yield equivocal or even misleading results. Severe sepsis can occur with a normal or even low white blood cell (WBC) count. A very low WBC count from transient bone marrow suppression in a nonimmunocompromised patient may be highly suggestive of sepsis. Also, any stressed state such as the postoperative or posttraumatic state can cause

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leukocytosis via epinephrine- and cortisol-mediated demargination, as can administration of either as a drug in the absence of infection. Other diagnostic tests may be helpful in certain patients. The most commonly ordered initial tests are cultures of blood, sputum, and urine, although the yield of blood cultures is low in the early postoperative period «72h) and in patients already on broad-spectrum antibiotics." Other possible culture sites include stool (the yield is extremely low in surgical patients), cerebrospinal fluid (central nervous system infection is rare except in neurosurgical patients), sinus fluid, or vascular catheters and depends on the individual patient's circumstances. Importantly, after positive cultures are reported, the astute clinician must determine whether the culture represents infection that may require treatment or colonization that does not require specific therapy. The most commonly performed imaging study to evaluate fever is chest radiography. However, a CT scan can often be helpful, especially after abdominal surgery. Because of the earlier presence of various nonspecific changes, the best yield for CT scan for suspected intraabdominal abscess is for scans obtained at least 7 days after operation. Chest CT scans may be useful in some patients to help rule out an empyema or to rule out pneumonia in a patient with ARDS (itself an increasingly recognized noninfectious cause of fever) or to exclude venous thromboembolic disease.

Empiric Antibiotic Therapy The decision to administer empiric antibiotic therapy is not considered with sufficient care in many circumstances. The result is that many courses of antibiotic therapy are inappropriate because infection is not present, therapy is delayed, the chosen drug is not effective against the likely pathogens, or the duration of treatment is too long. Several questions are worth asking each time empiric antibiotic therapy is considered. First, are antibiotics indicated at all? The answer is ultimately often no, but the decision to start treatment must often be made before definitive information becomes available if the patient is unstable. In the absence of definitive data, the decision to start antibiotics is based on the likelihood of infection, its likely source and the likely pathogens, and whether the patient's condition is sufficiently precarious that a delay will be detrimental. Outcome is improved if antibiotics are started promptly, but on the other hand, only about 50% of fever episodes in hospitalized patients are caused by infection. Many causes of the systemic inflammatory response syndrome (SIRS) (e.g., aspiration pneumonitis, bums, trauma, pancreatitis) are not due to infection, although they may be complicated later by infection. Multiple-organ dysfunction syndrome may progress as the result of a dysregulated host response even after an infectious precipitant has been controlled. Must antibiotics be started immediately? If the patient is stable hemodynamically, then the decision also depends on the overall status of the patient, considering such host factors as age, debility, renal and hepatic function, and immunosuppression. Culture yields are highest when collected before antibiotics are administered. However, for many infections (e.g., bacteremia, intraabdominal infection, pneumonia), data indicate that early therapy with an appropriate antibiotic in adequate dosage improves outcome.

Which organisms are the likely pathogens, and are they likely to be antibiotic resistant? This assessment requires rapid formulation of the differential diagnosis, for which there may not be time to perform diagnostic testing other than blood testing and obtaining specimens for culture. The clinical setting must be considered (e.g., nosocomial vs. community-acquired infection, recent antimicrobial therapy), as must the patient's environment (e.g., proximity to other infected patients, the presence of resistant organisms in the unit) and any recent microbiology obtained from the patient. Will a single antimicrobial agent suffice? This answer depends on the answers to the questions regarding the likely diagnosis and the nature of the probable pathogens. Under certain circumstances, it is desirable to use more than one antibiotic to treat an infection. This approach is most common with empiric therapy, for which the pathogen (or even the source of the infection) is assumed (or guessed at) and the potentialities are so broad and the consequences of inaccurate initial therapy so deleterious that more than one drug must be chosen. Two-drug empiric therapy is commonplace for presumed polymicrobial infections such as nosocomial pneumonia or recurrent or persistent intraabdominal infection or for sepsis of unknown origin. If there is reason to suspect a nosocomial gram-positive pathogen (e.g., SSI, catheter-related infection, infection of an implanted prosthetic device, pneumonia) and methicillin-resistant staphylococci are endemic, then empiric vancomycin is appropriate. Serious Pseudomonas infections may require dual-agent therapy with agents that act in a dissimilar manner (e.g., an antipseudomonal ~ lactam drug to disrupt the bacterial cell wall along with an aminoglycoside to disrupt protein synthesis). Infections that involve anaerobic pathogens are usually mixed anaerobicaerobic infections, the only common exceptions being community-acquired aspiration pneumonia and clostridial soft tissue infections. Nosocomial mixed anaerobic infections can be treated effectively by a single agent if a ~-lactam/~ lactamase inhibitor combination drug or a carbapenem is chosen; for community-acquired infections, a second-generation cephalosporin may be appropriate, whereas carbapenem therapy is not. If the aerobic component is treated with a fluoroquinolone, monobactam, or a late-generation cephalosporin, then metronidazole is the preferred antianaerobic agent. Whatever is chosen, it is recommended strongly that triple-antibiotic regimens (e.g., ampicillin or vancomycin plus gram-negative coverage plus metronidazole) should be avoided because administration costs are high, and there is no added benefit.

Duration of Therapy The endpoint of antibiotic therapy is difficult to define. Unfortunately, duration of therapy is not well established in the literature, and new studies are seldom designed with duration of therapy as a primary endpoint. Much depends on expertise and clinical judgment, which is accumulating in favor of shorter courses of therapy. If bona fide evidence of infection is evident, then treatment is continued as indicated clinically. Careful culture techniques and specimen handling, combined with modem microbiology laboratory support, make it unlikely that substantive pathogens will be missed. Therefore, continuing empiric antibiotic therapy beyond 48 h


becomes difficult to justify. There are two possible exceptions. One occurs when fungal infection is suspected because the organisms can be difficult to culture, and the other occurs when deep cultures are needed from areas that are inaccessible until a drainage procedure is performed. There is a clear trend toward shorter courses of antibiotics for established infections. Many infections can be treated with therapy lasting 5 days or less. Infections that require 24 h of therapy or less (sometimes just a single dose) include uncomplicated acute appendicitis or cholecystitis, uncomplicated bacterial cystitis (with some agents), and intestinal infarction without perforation. Most cases of intraabdominal infection require no more than 5 days of treatment. Every decision to start antibiotics must be accompanied by a decision regarding the duration of therapy. A reason to continue therapy beyond the predetermined endpoint must be compelling. Bacterial killing is rapid in response to effective agents, but the host response may not subside immediately. Therefore, the clinical response of the patient should not be the sole determinant for continuation of therapy. If a patient still has sepsis syndrome at the end of a defined course of therapy, then it is more useful to stop therapy and obtain a new set of cultures to look for new sites of infection, resistant pathogens, and noninfectious causes of inflammation. There is seldom justification to continue antibacterial therapy for more than 10 days. Examples of bacterial infections that require more than 14 days of therapy include tuberculosis of any site, endocarditis, osteomyelitis, brain abscess, liver abscess, lung abscess, postoperative meningitis, and endophthalmitis. Among the many reasons to limit therapy is that antibiotic therapy has adverse consequences. Adverse consequences of antibiotics include allergic reactions; development of nosocomial superinfections, including fungal infections, enterococcal infections, and CDAD; organ toxicity; promotion of antibiotic resistance; reduced yield from subsequent cultures; and vitamin K deficiency. The worldwide emergence of multidrug-resistant bacteria, superinfections in immunosuppressed patients, and the increased mortality associated with nosocomial infections in general make it important that adequate therapy is provided rapidly and for the shortest possible duration.

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70. Thorell A, Efendic S, Gutmak M, et al. Insulin resistance after abdominal surgery. Br J Surg 1994;81:59-63. 71. Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. N Engl JMed 2001;345:13591367. 72. Van den Berghe G, Wouters PJ, Bouillon R, et al. Outcome benefit of intensive insulin therapy in the critically ill: insulin dose versus glycemic control. Crit Care Med 2003;31:359-366. 73. Pittas AG, Siegel RD, Lau J. Insulin therapy for critically ill hospitalized patients: a meta-analysis of randomized controlled trials. Arch Intern Med 2004;164:2005-2011. 74. Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med 2006;354:449-461. 75. Mackenzie CR, Charlson ME. Assessment of perioperative risk in the patient with diabetes mellitus. Surg Gynecol Obstet 1988; 167:293-299. 76. Clement R, Ronson JA, Engelman RU, Breyer RH. Perioperative morbidity in diabetics requiring coronary artery bypass surgery. Ann Thorac Surg 1988;46:321-323. 77. Pomposelli JJ, Baxter JK III, Bakineau TJ, et al. Early postoperative glucose control predicts nosocomial infection rate in diabetic patients. JPEN J Parenter Enteral Nutr 1998;22:77-81. 78. Iwasaka H, Itoh K, Myakawa H, et al. Glucose intolerance during prolonged sevoflurane anaesthesia. Can J Anaesth 1996;43: 1059-1061. 79. Uchida I, Asoh T, Shirasaka C, Tsuji H. Effect of epidural analgesia on postoperative insulin resistance as evaluated by insulin clamp technique. Br J Surg 1988;75:557-562. 80. Svedjeholu R, Hakanson E, Vanhaneu I. Rationale for metabolic support with amino acids and glucose-insulin-potassium (GIP) in cardiac surgery. Ann Thorac Surg 1995;59(suppl 2):515-522. 81. Svedjeholu R, Ekroth R, Joachinersson PO, Tyden H. High-dose insulin improves the efficacy of dopamine early after cardiac surgery. A study of myocardial performance and oxygen consumption. Scand J Thorac Cardovasc Surg 1991;25:215-221. 82. Svensson S, Ekroth R, Nilsson F, et al. Insulin as a vasodilating agent in the first hour after cardiopulmonary bypass. Scand J Thorac Cardiovasc Surg 1989;23:139-143. 83. Svensson S, Ekroth R, Milocco I, et al. Glucose and lactate balances in heart and leg after coronary surgery: influence of insulin infusion. Scand J Thorac Cardiovasc Surg 1989;23:145-150. 84. Brandi LS, Fredian M, Oleggini M, et al. Insulin resistance after surgery: normalization by insulin treatment. Clin Sci 1990;79: 443-450. 85. O'Grady NP, Barie PS, Bartlett JG, et al. Practice guidelines for evaluating new fever in critically ill adult patients. Task Force of the Society of Critical Care Medicine and the Infectious Diseases Society of America. Clin Infect Dis 1998;26:1042-1059.

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86. Muylle L, Ioos M, Wouters E, et al. Increased tumor necrosis factor alpha (TNF-a), interleukin-1, amid interleukin-6 (IL-6) levels in the plasma of stored platelet concentrates: relationship between TNF-a and IL-6 levels and febrile transfusion reaction. Transfusion 1993;33:195-199. 87. Montgomery KD, Potter HG, Helfet DL. Magnetic resonance venography to evaluate the deep venous system of the pelvis in patients who have an acetabular fracture. J Bone Joint Surg [Am] 1995;77:1639-1649. 88. Ferretti GR, Bosson JL,Buffaz PD, et al. Acute pulmonary embolism: role of helical CT in 164 patients with intermediate probability at ventilation-perfusion scintigraphy and normal results at duplex US of the legs. Radiology 1997;205:453-458. 89. Pearson ML. Guideline for prevention of intravascular devicerelated infections. Hospital Infection Control Practices Advisory Committee. Infect Control Hosp Epidemiol 1996;17:438473. 90. Centers for Disease Control and Prevention. Guidelines for prevention of nosocomial pneumonia. MMWR Morb Mortal Wkly Rep 1997;46(RR-1):1-79. 91. Talmor M, Li P, Barie PS. Acute paranasal sinusitis in critically ill patients: guidelines for prevention, diagnosis and treatment. Clin Infect Dis 1997;25:1441-1446. 92. Meduri GU, Mauldin GL, Wunderink RG, et al. Causes of fever and pulmonary densities in patients with clinical manifestations of ventilator-associated pneumonia. Chest 1994;106:221-235. 93. Croce MA, Fabian TC, Waddle-Smith L, et al. Utility of Gram's stain and efficacy of quantitative cultures for posttraumatic pneumonia: a prospective study. Ann Surg 1998;227:743-751. 94. Veenstra DL, Saint S, Saha S, et al. Efficacy of antiseptic-impregnated central venous catheters in preventing catheter-related bloodstream infection: a meta-analysis. JAMA 1999;281:261267. 95. Bartlett JG, Perl TM. The new Clostridium difficile-what does it mean? N Engl J Med 2005;353:2503-2505. 96. McDonald LC, Killgore GE, Thompson A, et al. An epidemic, toxin gene-variant strain of Clostridium diiiicile. N Engl J Med 2005;353:2433-2441. 97. Loo VG, Poirier L, Miller MA, et al. A predominantly clonal multiinstitutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality. N Engl J Med 2005; 353:2442-2449. 98. Kollef MH. Antibiotic use and antibiotic resistance in the intensive care unit: are we curing or creating disease? Heart Lung 1994;23:363-367. 99. Darby JM, Linden P, Pasculle W, Saul M. Utilization and diagnostic yield of blood cultures in a surgical intensive care unit. Crit Care Med 1997;25:989-994.

Anesthesia Joseph D. Tobias and Russell Wall

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Intraoperative Anesthetic Care 370 Specific Perioperative Issues . . . . . . . . . . . . . . . . . . . . . . . 371 References 375

here are five basic methods for th e administration of anesthesia: local; monitored anesthesia care; peripheral nerve blockade ; and neuraxial anesthesia, including spinal or epidural anesthesia; and general anesthesia. Peripheral nerve blockade and neuraxial anesthesia are frequently considered together under the title of regional anesthesia. Local anesthesia involves th e infilt ration of a surgical site with a local anesthetic agent to render the site insensitive to pain. Monitored anesthesia care involves monitoring a patient with standard noninvasive mon itors (see below for a description of standard American Society of Anesthesiologists [ASA] monitors), administering a sedative or analgesic agent intravenously to make the patient comfortable, and frequently infiltrating the surgical site with a local anesthetic agent. It frequently is provided using a combination of a drug with amnestic properties [midazolam or propofol) with a drug that provides analgesia (an opioid such as fentanyl). With monitored anesthesia care, th e goal is to have the patient maintain spontaneous ventilation during the procedure . The depth of sedation may range from minimal, in wh ich the patient is in an awake, relaxed state and able to respond to verbal stimuli, to deep, in which a painful stimulus is required to elicit a response. A peripheral nerve block involves th e in jection of a local anesthetic agent around a nerve or group of nerves (plexus) to render a specific dermatome or dermatomes insensitive to pain . Examples of plexus blockade include cervical plexus blockade for carotid endarterectomy, brachial plexu s blockade for upper-extremity or shoulder procedures , or lumbar plexus blockade for hip or leg surgery. Alternatively, a single nerve or select number of nerves can be blocked if the surgical procedure is confin ed to thc distribution of that nerve or those nerves, for exampl e, median nerve and ulnar nerve blockade for carpal tunnel surgery or femoral and sciat ic nerve blockade for procedures on th e lower extremity distal to the knee . Intravenous regional anesthesia (Bierblock), may be considered another exampl e of a peripheral nerve block. A

Bier block is produc ed by in jecting a specific volume of a dilute local anesthetic intravenously into an extremity after that extremity has been exsangu inated by wrapping it with a bandage and then occluded with a tourniquet. Neuraxial anesthesia involves injecting a local anesthetic into the subarachnoid or epidural space to block an area of the spinal cord and its accompanying nerve roots to render an entire region of th e body (lower abdomen, pelvis, perineum, or lower extremities) insensitive to pain . Examples of neuraxial anesthesia include spin al, epidural, and caudal anesthesia . During regional anesthesia (peripheral nerve block, Bier block , or neuraxial anesthesia), patients are monitored and generally receive intravenous sedatives or analgesics for comfort. A regional anesthetic technique such as a peripheral nerve block or epidural anesthesia is frequently combined with a general anesthetic (see below) as part of a balanced anesthetic technique. In many cases, the regional anesthetic technique can be continued into th e postoperative period by use of a continuous infusion via catheter and thereby provide ongoing postop erative analgesia. General anesthesia includes four requis ites: amnesia, analgesia, muscle relaxation, and the attenuation of th e sympathetic nervous system's response to surgical trauma. Gen eral anesthesia can be broken down into induction, maintenance, and emergence phases . Th e induction of anesthesia can be provided by the administration of an intravenous anes thetic agent (a barbiturate such as thiopental, propofol, or etomidate) or by the inhalation of an inhalational anesthetic agent such as halothane or sevoflurane. The advantages of intravenous induction include rapid onset of anesthesia and avoidance of the pun gent odor of th e inhalational anesthetic agents. In pediatric pati ents , the inhalation induction of anesthesia is frequently chosen to avoid the need for obtaining intravenous access on an awake child. The downside of such a technique is the lack of intravenous access during a time when airway and cardiovascular problems may occur with the

Preoperative Evaluation. . . . . . . . . . . . . . . . . . . . . . . . . .. Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. PUrwayManagement Pharmacology of Anesthetic Practice . . . . . . . . . . . . . . ..

T

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administration of an inhalational anesthetic agent. Hemodynamic compromise was more common with the use of halothane given its negative inotropic and chronotropic properties. Such issues are less of a concern with the introduction of the newer inhalational anesthetic agent sevoflurane, which is now widely used in the practice of pediatric anesthesia for inhalation induction. However, laryngospasm and glottic closure may still occur, resulting in an inability to ventilate the patient. In such instances, the intramuscular administration of succinylcholine may be used to break laryngospasm and prevent hypoxia if intravenous access is immediately attainable. The inhalation induction of anesthesia also allows the maintenance of spontaneous ventilation even during deep planes of anesthesia (deep enough to allow for direct laryngoscopy and endotracheal intubation). Such a technique may be used if there is any question regarding the ability to bagvalve-mask ventilate the patient, such as patients with airways compromised by infection, tumor, or anatomic abnormalities. Maintenance of general anesthesia can be accomplished by balanced, inhalation, or combination techniques. The balanced technique includes nitrous oxide or a continuous infusion of an intravenous anesthetic, a nondepolarizing muscle relaxant, and an opioid. The inhalation technique includes a potent inhalation anesthetic such as halothane, enflurane, isoflurane, desflurane, or sevoflurane in nitrous oxide and oxygen or air and oxygen. The combination technique is the balanced technique plus the addition of a small concentration of a potent inhalation agent. In most circumstances, the choice of maintenance anesthesia is based on the presence of comorbid features and the preferences of the attending anesthesiologists.

Preoperative Evaluation Regardless of the type of procedure, a preoperative evaluation is recommended. In many hospitals, the preoperative evaluation is performed in a specialized clinic and frequently accomplished the same day that the patient sees the surgeon. Alternatively, in low-risk patients without accompanying comorbid diseases, the preoperative evaluation can be performed the day of surgery. The preoperative evaluation of the patient for anesthesia and surgery includes obtaining a history of present illness, past medical problems, past surgical and anesthetic history, and reviewing the patient's current and possibly prior medical record and medication list. Current medical problems should receive optimal therapy before surgery. The physical examination is directed primarily at the central nervous, cardiovascular, and respiratory systems, including an examination of the airway. An ASA physical status classification is assigned to the patient based on their comorbid features and associated medical conditions (Table 18.1 ).1 The physical classification is based on the physical condition of the patient and does not include the planned surgical procedure. In addition to the history and physical examination, a review of current drug therapy, a history of allergies, and an interpretation of laboratory data are essential. Laboratory tests should be ordered on the basis of positive findings obtained during the history and

TABLE 18.1. American Society of Anesthesiologists (ASA) Physical Status Classification. Classification

Description

1

Normal healthy patient Mild systemic disease with no functional limitation Severe systemic disease with functional limitation Severe systemic disease that is a constant threat to life Moribund patient not expected to survive without operation Brain-dead patient; organs are being removed for donor purposes Emergency operation

2

3 4 5 6

E

Source: From American Society of Anesthesiologists, 1 with permission of Anesthesiology.

physical examination and on the complexity of the surgical procedure.' Preoperative testing of all patients for elective surgery is unjustified and expensive. However, state, local, and accrediting body regulations may necessitate policies requiring certain tests. In general, in males who are 40 years of age or younger without identified comorbid conditions, no laboratory or radiologic evaluation is necessary; a hemoglobin is all that is generally recommended for women who are 40 years of age or younger. A 12-lead electrocardiogram (ECG) is generally recommended in patients who are 40 years of age or older; a chest radiograph may be obtained in patients who are 50 years of age or above. In addition, an ECG or chest radiograph should be obtained in patients with a history or symptoms suggestive of respiratory or cardiovascular disease. Although commonly performed, routine testing of coagulation function has been shown to be of limited value without an antecedent history of bleeding problems.' Another area of ongoing controversy is the role of routine preoperative pregnancy testing. Given the theoretical potential for anesthetic agents to be teratogenic and the risks of spontaneous abortion, the history should include specific questioning about the potential for pregnancy, including information about the patient's last menstrual cycle. In addition, some centers routinely obtain urinary pregnancy tests. The planned management of anesthesia is discussed with each patient, and risks and possible complications are reviewed. Options and plans for postoperative pain management are discussed. Answering questions and obtaining an informed consent completes the preoperative evaluation. Patients with preexisting heart disease who are to have noncardiac surgery may present a significant perioperative challenge.v' The goals of the preoperative evaluation in the patient with the potential for underlying cardiac disease are to identify patients with ischemic heart disease who may require specific perioperative monitoring for ischemia detection; evaluate the patient's cardiac function (generally by means of echocardiography or occasionally cardiac catheterization); identify patients with ischemic heart disease that requires intervention (stenting or coronary artery bypass grafting) prior to elective surgical procedures; ensure that maximal pharmacologic therapy has been obtained to optimize the patient's cardiovascular performance; and identify

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those patients who may benefit from perioperative therapy, including the use of ~-adrenergic blockade to decrease the risk of perioperative cardiac events (see belowl.v" The evaluation of patients for the presence of ischemic heart disease starts with a thorough history and physical examination with an evaluation of the patient's symptomatology and exercise tolerance. This is supplemented by a standard 12-lead ECG. As the ECG may be a relatively insensitive marker of ischemic heart disease in the absence of a pervious myocardial infarction or some type of ongoing acute ischemic event, additional evaluation may include exercise testing ("stress test") or a pharmacologic stress test using dobutamine in patients who cannot actively exercise; this increases their heart rate to the specific threshold necessary to provide diagnostic information. The last group includes patients with various conditions, including orthopedic issues which limit activity. Clinical markers may be major, intermediate, or minor predictors of increased perioperative cardiovascular risk. Major predictors include unstable coronary syndromes (myocardial infarction within the past 6 months, unstable or severe angina), decompensated congestive heart failure (CHF), significant dysrhythmias, and severe valvular disease. Intermediate predictors include minor angina, prior myocardial infarction, compensated CHF, and diabetes mellitus. Minor predictors include advanced age, an abnormal ECG, rhythms other than sinus, low functional capacity, history of stroke, and uncontrolled hypertension. Although a preoperative cardiology evaluation is frequently performed to assess such patients, the use of the cardiologist or internist to "clear patients for surgery" should no longer be practiced. Consultant physicians are asked to assess the patient's cardiovascular status, perform diagnostic evaluations such as echo cardiography or stress testing, and determine if additional preoperative evaluations (cardiac catheterization to evaluate for coronary artery disease) or changes in the patient's pharmacologic regimens are needed. In addition to continuing the patient's current pharmacologic regimen, perioperative morbidity and mortality may be reduced by preoperative preparation with ~-adrenergicantagonists or a-adrenergic agonists [clonidinel.t" In addition to patient-specific issues, there may also be surgery-related factors that have an impact on perioperative outcome. Surgery-specific risks are determined by the type of surgery and the degree of hemodynamic stress created by the surgery. High-risk surgeries include major emergency surgery, especially for the elderly, major vascular (aortic) and peripheral vascular surgery, and prolonged procedures with large fluid shifts or blood loss. Intermediate-risk surgeries include carotid endarterectomy, head and neck surgery, intraperitoneal and intrathoracic procedures, orthopedic surgery, and prostatic surgery. Low-risk procedures include endoscopic procedures, superficial procedures, cataract extractions, and surgeries on the breast. Is regional anesthesia safer than general anesthesia? Although some studies suggest that regional anesthesia and regional anesthesia in combination with general anesthesia result in less cardiac morbidity than general anesthesia alone, studies examining this question in patients undergoing peripheral vascular surgery have reported no significant difference in cardiac morbidity and mortality among general, spinal, and epidural anesthesia.tP

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Guidelines for Patients Receiving Nothing by Mouth Although the pulmonary aspiration of gastric contents is an uncommon event, the consequences may be severe (pneumonitis, respiratory failure, death), and other than supportive therapy, there is no specific therapy. Classical teaching relates that the severity of the aspiration injury relates to the volume aspirated as well as its pH, with severe complications occurring with the aspiration of greater than O.4ml/kg or with aspirates with a pH less than 2.5. Although aspiration may occur in any setting, patients at risk include parturients, obese patients; diabetics; patients who have received opioids, patients with gastrointestinal (GI) disease (reflux, obstruction); patients with altered mental status; patients with intraabdominal pathology (acute abdominal emergencies, including appendicitis); and patients in whom difficult airway management is anticipated. These factors may predispose to aspiration by limiting the patient's ability to protect his or her airway, decreasing the normal barrier to aspiration (lower esophageal sphincter tone), increasing gastric volume, or delaying gastric emptying.P:" Patients at greatest risk are those with high ASA physical status classifications and those having emergency surgery. The majority of aspirations occur during the induction of anesthesia or following tracheal extubation when the patient has blunted or lost protective airway reflexes. Classically, keeping patients nil per as (NPO) has been the mainstay of therapy to prevent acid aspiration. In the past, adult patients were fasted 8 to 12h before surgery to reduce the volume of gastric contents at the time of induction of anesthesia and to decrease the risk of aspiration pneumonitis. This preoperative fast does not take into account differences in gastric emptying of clear liquids and solids. Clear liquids have a gastric emptying time of 1 to 2 h. Solids have an unpredictable gastric emptying time greater than 6h. There is no scientific evidence confirming the benefit of a fluid fast.":" The ingestion of clear liquids up to 2 h before surgery does not increase gastric fluid volume or acidity. As a result, the liberalization of guidelines for ingestion of clear liquids for elective surgery of otherwise healthy patients has been recommended.V-" A national survey of anesthesiologists in the United States has shown that 690/0 have either changed their NPO policy or are flexible in their practice in allowing clear liquids before elective operations in children and in 41 % of adults." Suggested guidelines for patients with no known risk factors include no solid food for at least 8 h before surgery and unrestricted clear liquids until 2h before surgery. Oral medications may be given 1 to 2h before surgery with as much as 150ml of water. Some centers even allow the ingestion of one cup of coffee prior to elective outpatient surgical procedures as a common complaint of outpatients is a postoperative headache related to caffeine withdrawal. What should be done with patients with risk factors for acid aspiration? Although no definitive studies have demonstrated its efficacy, many centers routinely use preoperative medications to decrease the acidity of the gastric fluid (H2 antagonists or proton pump inhibitors) and speed gastric emptying (metoclopramide). However, to be effective, it is recommended that these medications be administered 60-90min prior to anesthetic induction. Alternatively, a

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nonparticulate antacid (sodium bicitrate) can be given immediately prior to anesthetic induction, which is a common practice in obstetrical anesthesia. In addition, in patients at risk for acid aspiration, rapid sequence induction is practiced. This involves the use of a rapidly acting neuromuscular blocking agent (NMBA; see below) with an anesthetic induction agent and the application of cricoid pressure. As the cricoid is the only complete ring of the trachea, it can be gently pushed posteriorly to effectively occlude the esophagus and prevent passive regurgitation of gastric contents.

Preoperative Medication There are several categories and uses of preoperative medications (Table 18.2). The most common use of a preoperative medication is to provide sedation and anxiolysis prior to transport to the operating room. Preparing the patient for surgery includes psychological preparation and frequently pharmacological premedication. Psychological preparation includes the preoperative visit and an interview by the anesthesiologist. Pharmacological premedication may be given orally or rarely intramuscularly 1 to 2h before the induction of anesthesia or intravenously in the immediate preoperative period. Popular choices include benzodiazepines such as midazolam or occasionally o,2-adrenergic agonists such as clonidine. Analgesia for placement of invasive lines such as arterial cannulae or central venous lines can be provided by incremental intravenous doses of fentanyl while the patient is in the preoperative holding area, where appropriate monitoring of hemodynamic and respiratory status can be provided. Additional preoperative medications may be used in patients with certain comorbid features. This includes the use of Hj-antagonista or proton pump inhibitors or motility agents to increase gastric pH and decrease gastric volume in patients at risk for acid aspiration, while inhaled ~-adrenergic agonists (albuterol) or anticholinergic agents (ipratropium) may be administered to patients with reactive airway diseases (asthma, recent upper respiratory infection, or chronic obstructive pulmonary diseases). Anticholinergic agents may be used to dry airway secretions in patients requiring fiber-optic intubation.

TABLE 18.2. Types and Uses of Premedications. Type of medication

Purpose

Benzodiazepines Opioids

Sedation, anxiolysis, amnesia Analgesia during invasive procedures Prevent bradycardia, blunt airway reflexes, dry secretions Prevention or relief of bronchospasm

Anticholinergic agents (atropine, glycopyrrolate) Inhaled ~-adrenergic agonists (albuterol), inhaled anticholinergic agents (ipratroprium) Hj-antagonists, proton pump inhibitors Promotility agents

Decrease pH of stomach contents Decrease volume of gastric secretions

Monitoring The standards for basic anesthetic monitoring have been developed by the ASA and apply to all general anesthetics, regional anesthetics, peripheral nerve blocks, and monitored anesthesia care. Similar monitoring guidelines have also been suggested for nonanesthesiologists who are providing procedural sedation. The standards for intraoperative monitoring include the presence of qualified anesthesia personnel throughout all anesthetics and the ongoing evaluation of a patient's oxygenation, ventilation, circulation, and temperature. To fulfill these criteria, the following monitors are used: oxygen analyzer, blood pressure cuff, continuous ECG, pulse oximeter, end-tidal carbon dioxide analyzer, precordial or esophageal stethoscope, temperature probe, and a ventilator disconnect alarm. Based on the medical condition of the patient and the surgical procedure, more elaborate, invasive monitoring may be added. These additional monitors may include a urinary catheter; catheters for measuring intraarterial, central venous, and pulmonary artery (PA) pressures; and transesophageal echocardiography (TEE). Few studies have compared outcomes in patients managed perioperatively with or without PA catheters.f-" The ASA recommends considering three variables when assessing benefit versus risk of PA catheters: disease severity, magnitude of the surgical procedure, and practice setting." The American College of Cardiology/American Heart Association (ACC/AHA) guidelines indicate that the patients most likely to benefit from PA catheters in the perioperative period are those with recent myocardial infarctions complicated by CHF, those with significant coronary artery disease undergoing surgery associated with significant hemodynamic stress, and those with systolic or diastolic left ventricular dysfunction, cardiomyopathy, or valvular disease undergoing highrisk operations." Additional information regarding structural and functional issues of the myocardium may be obtained by the use of TEE. The strongest indications for perioperative TEE that are supported by evidence-based medicine include cardiac surgery procedures such as repair of valvular lesions (insufficiency or stenosis) or congenital lesions, assessments and repairs of thoracic aortic aneurysms and dissections, pericardial window procedures, and the repair of hypertrophic obstructive cardiomyopathy." For noncardiac surgery, intraoperative TEE is indicated to evaluate acute, persistent, and life-threatening hemodynamic disturbances in which ventricular function and its determinants are uncertain and have not responded to treatment, especially when placement of a PA catheter is not feasible. In addition to routine ASA monitors and invasive hemodynamic monitoring, there is continued interest in the development and potential use of "consciousness" or "awareness" monitors. The importance of such monitors is highlighted by the results of several different studies, which demonstrated that intraoperative awareness may occur in anywhere from 0.1 % to 0.2% of all patients, with even higher incidences in specific procedures, including trauma, cardiac, obstetrical, and emergency surgery. Of even more concern is the fact that as many as one-third of patients who have intraoperative awareness will have long-term consequences, such as a posttraumatic stress disorder.P" To avoid such issues, several manufacturers have marketed or are developing monitors that

ANESTHESIA

provide the anesthesia provider with a numerical value against which anesthetic agents are titrated. There are currently five such monitors: the Bispectral Index (BIS monitor, Aspect Medical, Newton, MA); the Narcotrend (MonitorTechnik, Bad Bramstedt, Germany), which is currently available only in Europe; Patient State Analyzer (PSA 4000, Baxter Healthcare, Deerfield, IL); SNAP (Everest Medical, Minneapolis, MN); and Auditory Evoked Potential Monitor (AEP Monitor, Danmetter Medical). To date, the one that has received the most clinical use is the BIS monitor. The BIS is a modified electroencephalographic (EEG) monitor that uses a preset algorithm based on intraoperative data obtained from adults to evaluate the EEG. The BIS number is determined from three primary factors: the frequency of the EEG waves, the synchronization of low- and high-frequency information, and the percentage of time in burst suppression. Part of the simplicity and attraction of the BIS monitor is that the depth of sedation/anesthesia is displayed numerically, ranging from 0 to 100, with 40-60 a suitable level of anesthesia to ensure amnesia and lack of recall. With the use of BIS monitoring, a decreased incidence of awareness has been demonstrated as well as a decrease in the total amount of anesthetic agent used."':" Additional studies have suggested faster recovery times and faster discharge times from the postanesthesia care unit, all of which may translate into reduced perioperative costS.31/32 Although not yet considered the standard of care for intraoperative anesthesia care, the ASA does recommend the availability of such monitors whenever general anesthesia is provided. Given the success of such monitors in the perioperative arena, there is ongoing interest in the application of such technology in the ICU and the procedural sedation arena. 33/34

Airway Management Tracheal intubation is performed on many patients receiving general anesthesia for surgery. The ASA Closed Claims Project has demonstrated that airway misadventures such as inadequate ventilation, difficult intubation, and esophageal intubation are the leading causes of complications involving the respiratory system and are responsible for the most serious injuries (death, brain injury, airway trauma). Guidelines have been developed by the ASA to facilitate management of the difficult airway and decrease the likelihood of adverse outcomes." A difficult airway is defined as a clinical situation in which a conventionally trained anesthesiologist experiences difficulty with mask ventilation, difficulty with tracheal intubation (more than three attempts or more than 10min required for completion), or both. The preoperative evaluation can identify many patients with a difficult airway. An airway history should be obtained seeking medical, surgical, and anesthetic factors that may indicate a difficult airway. Examination of previous anesthesia records is helpful, although a patient's airway may change with changes in weight or the development of comorbid conditions. A physical examination of the airway is performed to detect physical characteristics associated with a difficult airway such as a large tongue, small mouth, short neck (shortened thyromental distance), recessed mandible, limited extension or flexion of the neck, limited

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mouth opening, and difficulty visualizing the uvula and tonsillar pillars when the patient opens his or her mouth. The last is assessed with the Mallampati grading system so that visualization of the entire uvula and tonsillar pillars (Mallampati grade) suggests that endotracheal intubation will be uncomplicated, while failure to visualize the tonsillar pillars and the soft palate (Mallampati class IV) is suggestive that endotracheal intubation will be difficult. When a difficult intubation is suspected, preparation to manage the airway includes having the following readily available: laryngoscope blades of various sizes and designs; endotracheal tubes of different sizes; stylets/guides/wands; fiber-optic intubation equipment; retrograde intubation equipment; equipment for emergency nonsurgical ventilation (transtracheal jet ventilator, hollow jet ventilation stylet, laryngeal mask airway [LMA], esophageal-tracheal Combitube); equipment for emergency surgical airway; and an endtidal carbon dioxide detector. This equipment should be available on a separate cart (difficult airway cart) so that it can be immediately moved into the operating room when needed for dealing with the unsuspected difficult airway. In addition to the appropriate equipment, every anesthesiologist should have a preformulated strategy for managing the difficult airway.35/36 When securing the airway in any setting, there are three basic management options: (1) awake endotracheal intubation versus endotracheal intubation after the induction of general anesthesia, (2) nonsurgical versus surgical approaches (cricothyrotomy or tracheostomy), and (3) maintenance of spontaneous ventilation versus ablation of spontaneous ventilation. In most anesthetic scenarios, the assessment of the airway is such that the decision is made to proceed with the intravenous induction of anesthesia and routine oral endotracheal intubation with a standard laryngoscopic approach. In this scenario, the patient is brought into the operating room and routine ASA monitors are placed. The patient is then allowed to breathe 100% oxygen via the anesthesia circuit and a tightfitting anesthesia mask. This "denitrogenates" the patient's lungs so that there is little nitrogen left (less than 5 0/0), and the lungs are filled with 100% oxygen. When anesthesia is induced and an NMBA administered, the lung volume will fall to its functional residual capacity (FRC). In an otherwise healthy patient without alveolar space disease (pneumonia or adult respiratory distress syndrome), the FRC is approximately 25-30ml/kg or 21 in a 70-kg adult. Given that the normal oxygen consumption is approximately 200-250ml/minute, this will provide the patient with an oxygen reserve to maintain an acceptable oxygen saturation during up to 6-8 minutes of apnea. This provides a significant margin of safety if there are problems with bag-valve-mask ventilation or endotracheal intubation. After preoxygenation, anesthesia is induced with a rapid-acting intravenous anesthetic agent (see below) such as thiopental, propofol, or etomidate, and once apnea occurs, effective bag-valve-mask ventilation is demonstrated. Once this has been accomplished, endotracheal intubation is facilitated by the use of an NMBA (see below). Techniques for managing an unconscious patient who is difficult to ventilate include the insertion of oral or nasopharyngeal airways; two-person bag-valve-mask ventilation; and use of an LMA (Fig. 18.1), an esophageal-tracheal Combitube (Fig. 18.2), an intratracheal jet stylet, a rigid ventilating

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bronchoscope; transtracheal jet ventilation; and surgical airway access.36,37 Techniques for managing the unconscious patient who can be ventilated but is difficult to intubate include using altemative laryngoscope blades, a light wand, an intubation stylet/tube changer, blind intubation (oral or nasal), fiber-optic intubation, retrograde intubation, and surgical airway access. Multiple attempts at endotracheal intubation should be avoided since this may result in progressive airway trauma, thereby turning the "cannot intubate/can ventilate" scenario into the "cannot intubate/cannot ventilate " scenario (see below). In elective or urgent cases, the most prudent measure may be to continue bag-valve-mask ventilation and allow the effects of the intravenous induction agent and NMBA to dissipate. In a small percentage of patients, an airway emergency occurs in that the patient cannot be bag-valve-mask ventilated and endotracheal intubation cannot be accomplished. This is known as the cannot intubate/cannot ventilate scenario. When this occurs, there are four appropriate choices after a second attempt has been made at endotracheal intubation : (1) insertion of an LMA, (21 insertion of a Combitube, (3) institution of transtracheal jet ventilation, or (4) establishing a surgical airway ." Given the emergency nature of this scenario, an organized, prerehearsed approach to such problems is mandatory. In many instances, the patient can be rescued with the placement of an LMA and ventilation provided. When placing the LMA, cricoid pressure (see below) should be released as it has been shown to be more difficult to obtain correct LMA placement with the application of cricoid pressure . Although the LMA does not protect against acid aspiration, it may provide effective ventilation and oxygenation when bag-valve-mask ventilation fails. The LMA can also be used as a conduit for blind endotracheal intubation or fiber-optic assisted intubation. The same preformulated strategy is also necessary to extubate a patient with a difficult airway. Follow-up care includes documenting and informing the patient of the difficult airway management and observing for potential complications such as airway edema or bleeding, tracheal or esophageal perfora-

FIGURE 18.1. Photograph of a laryngeal mask airway (LMA). The LMA is used routinely for airway management for many types of surgical procedures and is a key element in the American Society of Anesthesiologists' difficult airway algorithm.

FIGURE 18.2. Photograph of a Combitube. The Combitube is a modification of the esophageal obturator airway that is a suggested means of managing the airway in the American Society of Anesthesiologists' difficult airway algorithm.

tion, a pneumothorax, and aspiration. The development of the ASA difficult airway algorithm has resulted in a dramatic decrease in the number of respiratory-related anesthetic adverse outcomes.

Pharmacology of Anesthetic Practice Local Anesthetic Agents There are two chemically distinct classes of local anesthetics: amino esters and amino amides. Amino esters used in anesthetic practice include procaine, chloroprocaine, and tetracaine . Amino ami des used clinically include lidocaine, mepivacaine, prilocaine, bupivacaine, levobupivacaine, and ropivacaine. These two classes of local anesthetic agents differ in their site of metabolism, plasma half-lives, adverse effect profile, and allergic potential. Amino esters are metabolized in the plasma by cholinesterases, while amino amides are metabolized in the liver. Para-aminobenzoic acid (PABA) is a metabolite of amino ester breakdown and rarely may result in allergic reactions, whereas amino amides rarely cause allergic reactions. Regardless of their chemical structure (ester vs. amide), the mechanism of action for the majority of local anesthetic agents involves blockade of sodium channels in the nerve membrane, thereby preventing depolarization. The nonionized portion of the local anesthetic agent penetrates the lipid membrane, while the ionized portion reversibly blocks the inner aspect of the sodium channel. Local anesthetic agents differ in intrinsic potency, onset of action, duration of action, and their ability to produce differential sensory and motor blockade (Table 18.3). Potency is determined primarily by lipid solubility. The higher the lipid

359

ANESTHESIA

TABLE 18.3. Local Anesthetic Agents. Agent

Esters Procaine Chloroprocaine Tetracaine Amides Mepivacaine Prilocaine Lidocaine Bupivacaine Ropivacaine Etidocaine

% Protein binding

Onset

Relative potency

pKa

Duration

Slow Fast Slow

1 1

8

8.9 9.1 8.S

Short Short Long

76

Fast Fast Fast Moderate Moderate Fast

2 2 2 8 6 6

7.6 7.7 8.1 8.1 8.2 8.1

Moderate Moderate Moderate Long Long Long

78 55 64 96 94 94

6

Maximum dose range (mg/kgf

7-10 7-10 5-7 8-10 5-7 2-3 2-4 3-4

"Upper dose range is for drug combined with epinephrine.

solubility partition coefficient, the more potent the local anesthetic agent is." Bupivacaine and tetracaine are examples of potent local anesthetic agents. The onset of action of a local anesthetic agent is determined primarily by the pKa •39,40 The pKa of local anesthetic agents ranges from 7.6 to 9.1. The closer the pKa is to the physiological pH of 7.4, the more rapid the onset of action because the percentage of local anesthetic in the nonionized form is greater, promoting penetration of the nerve membrane. Lidocaine has a pKa of 7.7, and at a pH of 7.4, 350/0 exists in the nonionized base form, yielding a relatively rapid onset of blockade. In contrast, tetracaine has a pKa of 8.6, with only 50/0 in the nonionized form at a tissue pH of 7.4, resulting in a slower onset of blockade than lidocaine. Duration of action is determined primarily by the degree of protein binding." Local anesthetic agents bind to protein receptors in the sodium channels. A greater degree of protein binding produces a longer-lasting blockade of sodium channels and a longer duration of action. Bupivacaine, levobupivacaine, tetracaine, and ropivacaine are long-acting local anesthetic agents. Duration of action is also influenced by the degree of vasodilation produced by the local anesthetic.f Lidocaine and mepivacaine have similar degrees of protein binding, but mepivacaine creates less vasodilation and therefore remains at the site of action longer. A desirable feature of several local anesthetic agents is their ability to produce significant sensory anesthesia while creating minimal inhibition of motor activity." Bupivacaine and ropivacaine demonstrate this property, which is beneficial for postoperative analgesia administered through an epidural catheter so that patients are able to ambulate with minimal discomfort. When performing regional anesthesia, the practitioner's experience, knowledge of anatomy, and manual dexterity are important. Knowledge about the appropriate dose of the local anesthetic, the use of a vasoconstrictor, and the impact of the site of administration are necessary to increase the rate of success and limit potential complications. Increasing the dose of a local anesthetic yields a faster onset of effect, a longer duration of action, and a greater depth of blockade.f-" Dosage can be increased by increasing the concentration or the volume of the local anesthetic. However, higher plasma concentrations of the local anesthetic agent will also be achieved, thereby increasing the risks of toxicity (see below). Epinephrine (0.5Ilg/ml or a concentration of 1: 200,000) may be added to the local anesthetic solution during performance of a regional anesthetic technique (epidural or periph-

eral nerve blockade) to decrease the vascular absorption of the drug, thereby increasing the number of anesthetic molecules available to diffuse to the nerve membrane." This results in an increase in duration of action and an increase in the density of the blockade. However, the ability of epinephrine to prolong duration of action depends on the local anesthetic used and the site of administration. For peripheral nerve blocks and skin infiltration, epinephrine prolongs the duration of action of all local anesthetics." For epidural anesthesia, epinephrine added to lidocaine increases the duration of action, but epinephrine added to bupivacaine does not. 4 7,48 This relates to the fact that lidocaine causes more vasodilation than bupivaine. Therefore, the addition of epinephrine to lidocaine counteracts its vasodilatory effects, which would normally hasten the resolution of the block. Since less vasodilation occurs with bupivacaine, the effect of epinephrine is less pronounced. For spinal anesthesia, epinephrine added to a local anesthetic will prolong duration of action through decreased vascular absorption and possibly through a direct antinociceptive effect on the spinal cord." Epinephrine is also used as a marker for inadvertent intravascular injection. This is especially important when large doses of local anesthetic agents (epidural or plexus blockade) are administered. For such procedures, gentle aspiration is recommended prior to injection and intermittently while the dose of local anesthetic agent is administered. However, even with negative aspiration for blood, there is the potential for inadvertent intravascular administration. In attempt to identify such a problem, a "test dose" is frequently used. This test dose entails the administration of 3 ml of the 5llg/ml epinephrine solution or a total epinephrine dose of 151lg. If this amount of epinephrine is injected intravascularly, then it generally can be detected by changes in heart rate, blood pressure, or the ST-T wave segments of the EeG and thereby alert the practitioner that inadvertent intravascular injection is occurring. so The site of injection of the local anesthetic agent also has a significant impact on its clinical effects. The shortest durations of action are seen with intrathecal (i.e., spinal anesthesia) and subcutaneous administration, whereas the longest durations of action (and slowest onsets) are seen with major peripheral nerve blocks (i.e., brachial plexus blockade). Spinal anesthesia with bupivacaine has an onset of 5 min and a duration of 3 to 4 h, while a brachial plexus block with bupivacaine will take effect in 20 to 30 min and last 6 to 8h. s 1,52 The site of administration also determines the vascular absorption

360

CHAPTER 18

of the drug and hence the plasma concentration. The highest venous plasma concentration of local anesthetic agents occurs following an intercostal nerve block or interpleural analgesia, followed by a paracervical block, caudal epidural, lumbar/thoracic epidural, brachial plexus, peripheral nerve blockade, subarachnoid anesthesia, and last, subcutaneous infiltration. 53 For example, 400mg of lidocaine for a brachial plexus block yields a peak venous plasma concentration of 3 mg/ml, whereas 400mg of lidocaine for an intercostal nerve block yields a plasma concentration of 7mg/ml, With the use of local anesthetic agents, the greatest risk of morbidity is the potential for the achievement of toxic plasma concentrations of the drug. Local anesthetic-induced systemic toxicity affects the central nervous system (CNS) and the cardiovascular system. With most local anesthetic agents, CNS toxicity occurs at doses and blood levels below those that produce cardiovascular toxicity. This provides some degree of safety as the CNS symptoms (seizures) are generally more amenable to treatment than the cardiovascular effects (arrhythmias and conduction blockade). Toxicity with lidocaine occurs in the CNS at 8 to IOrng/ml, whereas cardiovascular toxicity occurs at 20mg/ml. 54 The signs and symptoms of CNS toxicity include lightheadedness, dizziness, circumoral numbness, tinnitus, twitching, tremors, and ultimately tonic-clonic seizures. With higher doses, CNS excitation, including seizure activity, is followed by CNS depression, unconsciousness, and respiratory arrest. Seizures result from the blockade of inhibitory pathways in the cerebral cortex yielding unopposed activity of facilitatory neurons." Depression of the CNS and unconsciousness result from inhibition of inhibitory and facilitatory pathways. Hypercarbia and acidosis decrease the convulsive threshold of local anesthetic agents as well as potentiating their cardiotoxicity." Death from local anesthetic toxicity is most commonly the result of the cardiovascular effects of these agents. Local anesthetic toxicity can adversely affect cardiac electrical and mechanical activity. 57 Bupivacaine may produce severe cardiac dysrhythmias by inhibiting the fast sodium channels and the slow calcium channels in the cardiac membrane. Local anesthetic agents depress myocardial contractility, with the most potent drugs (bupivacaine, tetracaine) causing the greatest dose-dependent myocardial depression." At toxic plasma concentrations, bupivacaine can cause profound myocardial depression and intractable cardiac arrest. These effects are so profound that resuscitative measures for ventricular tachycardia/fibrillation, including standard advanced candiac life support (ACLS) protocols, may be ineffective. Anecdotal case reports have suggested the potential role of various agents such as amiodarone for refractory ventricular arrhythmias or lipid emulsions, which bind the local anesthetic agent and decrease its free fraction. It is only the free fraction and not the local anesthetic that is bound to plasma proteins that has the potential to cause toxicity. In some cases, resuscitation has included the use of extracorporeal circulation. The toxic effects of bupivacaine on the CNS and cardiovascular system occur at the same plasma level of 3 to 5 flg/ml. Ropivacaine and levobupivacaine have pharmacological properties similar to bupivacaine but demonstrate fewer cardiodepressant and arrhythmogenic effects." The signs of local anesthetic cardiovascular toxicity include hypertension and tachycardia during the CNS excitation phase, followed by myocardial depression and mild-to-

moderate hypotension, then sinus bradycardia, profound hypotension, ventricular dysrhythmias, and finally circulatory collapse. Hypercarbia, acidosis, and hypoxia potentiate the negative chronotropic and inotropic effects of high plasma concentrations of local anesthetic agents. On vascular smooth muscle, most local anesthetics have a biphasic effect, producing vasoconstriction at low concentrations and vasodilation at high concentrations. When considering the subject of local anesthetic toxicity, the primary method of treating the toxicity should be avoidance by careful calculation of the dose, use of the lowest necessary dose (concentration and volume), use of a test dose with epinephrine to identify inadvertent intravascular injection, intermittent aspiration to identify vascular penetration, and slow incremental injection of the dose. Local anesthetic agents in recommended concentrations and doses are relatively free of localized tissue effects or irritation. However, additives can cause tissue damage. Prolonged sensorimotor blockade with the epidural and subarachnoid administration of large doses of chloroprocaine was attributed to the low pH of the solution and sodium bisulfite, the antioxidant.P?' As a result, the pH was raised, and sodium bisulfate was replaced with EDTA, thereby eliminating the potential neurotoxic effects. However, EDTA may result in back pain from spasms by chelating calcium in paraspinous muscles following epidural anesthesia.F Although the addition of epinephrine is recommended to aid in the identification of inadvertent intravascular administration, it should not be added when the local anesthetic will be injected into the area around end arteries (digits, nose, ear, penis) as intense vasoconstriction and tissue necrosis may occur.

Intravenous Anesthetic Agents Anesthetic agents are administered intravenously to induce general anesthesia or in lower doses to provide sedation. The ideal intravenous anesthetic would have a rapid, smooth onset of action following a nonirritating and painless injection. The drug would demonstrate a steep dose-response relationship, allowing a rapid change in anesthetic depth, and would be rapidly metabolized to inactive metabolites. It would cause minimal cardiovascular and respiratory depression and reduce cerebral blood flow (CBF), cerebral metabolism, and intracranial pressure (ICP). It would allow a rapid and smooth return of consciousness even after prolonged administration and a rapid recovery without postoperative side effects. It would have a low potential to cause histamine release or precipitate hypersensitivity reactions. Commonly used intravenous anesthetic agents include the barbiturates thiopental and thiamylal, propofol, an alkylphenol, etomidate, an imidazole; ketamine, an arylcyclohexylamine, and midazolam, a benzodiazepine. Sodium thiopental, although far from ideal, remains the most commonly used intravenous induction agent (along with propofol) and is the gold standard against which all other intravenous anesthetics are compared. Although any of these agents can be used to induce anesthesia and begin the anesthetic process, the specific choice of the agent and its dose are based on the clinical scenario, the anticipated duration of the surgical procedure, and the patient's underlyng hemodynamic status. The intravenous induction agents produce their effects by enhancing inhibitory or inhibiting excitatory neurotransmission. Thiopental, midazolam, propofol, and etomidate inter-

ANESTHESIA

act with different components of the GABAA receptor complex to enhance the function of the inhibitory neurotransmitter system, y-aminobutyric acid (GABA).63-66 When the GABAA receptors are activated, transmembrane chloride conductance increases to create a hyperpolarization of the postsynaptic cell membranes and a functional inhibition of postsynaptic neurons. Ketamine acts differently by blocking open channels of N-methyl-D-aspartate (NMDA) receptors that have been activated by glutamate, an excitatory transmitter, and interacting with brain acetylcholine to create a dissociation between the thalamocortical and limbic systems.Fr" The intravenous anesthetic agents demonstrate different pharmacodynamic effects in the CNS and respiratory and cardiovascular systems. The barbiturates propofol and etomidate reduce cerebral metabolism cerebral metabolic rate O2 (CMR0 2 ), CBF, and ICP and therefore are valuable induction agents for neuroanesthesia or in critically ill patients with increased ICP. Etomidate may be preferred in the latter setting because it provides greater hemodynamic stability, and as a result, cerebral perfusion pressure (CPP = MAP - ICP) is maintained, whereas propofol and thiopental may decrease mean arterial pressure (MAP) through effects on systemic vascular resistance (vasodilation) and negative inotropic effects. Thiopental and perhaps etomidate and propofol may also possess "neuroprotective" properties secondary to reducing CMR02, which improves the ability of the brain to tolerate incomplete ischemia during procedures such as carotid endarterectomy or the temporary occlusion of cerebral arteries during an aneurysm repair.P'" Ketamine's direct effects on ICP remain somewhat controversial, with the older literature suggesting that ketamine may directly increase CBF and ICP. However, it is apparent from recent studies that ketamine has limited effects on CBF and ICP when given in combination with other anesthetic agents, including midazolam.P:" Propofol, midazolam, and the barbiturates have similar EEG effects, causing a transient period of high-frequency activity at low brain concentrations, followed by lower-frequency, higher-amplitude waveforms at high brain concentrations, and finally by burst suppression. Most intravenous anesthetics are anticonvulsants, with both the barbiturates and propofol used in algorithms for the treatment of refractory status epilepticus.Y" Etomidate can produce involuntary myoclonic movements from an imbalance of inhibitory and excitatory influences in the thalamocortical tract and can stimulate the EEG pattern, increasing amplitude and frequency." Myoclonic movements and opisthotonic posturing have also been reported following the administration of propofol. These movements are attributed to propofol's antagonism at glycine receptors in subcortical structures. Thiopental, propofol, etomidate, and midazolam cause dose-dependent respiratory depression with a decrease in tidal volume and minute ventilation and a rightward shift in the CO 2 response curve. The potential for respiratory depression is increased in patients with specific comorbid conditions, including chronic respiratory or cardiovascular disease, and in patients receiving opioids. Following an induction dose of any of these agents, a transient period of apnea occurs. In contrast, ketamine causes minimal respiratory depression in clinically relevant doses and may preserve protective airway reflexes, although aspiration has been reported.":" Ketamine is the only intravenous anesthetic with bronchodilating properties from the release of endogenous cate-

361

cholamines." Although it lacks inherent bronchodilating properties, propofol has been shown to be an effective induction agent for patients with reactive airway disease, resulting in limited risk of a wheezing postintubation. In a prospective trial, 77 patients were randomized to receive propofol (2.5mg/kg), etomidate (O.4mg/kg), or thiopental (5mg/kg) for anesthetic induction and tracheal intubation." Following placement of the endotracheal tube, respiratory resistance was significantly lower with propofol when compared to either etomidate or thiopental. In a second study, asthmatic or nonasthmatic patients were randomized to anesthetic induction with thiopental/thiamylal (5 mg/kg], methohexital (1.5mg/kg), or propofol (2.5mg).81 In asthmatic patients, the incidence of wheezing was 45% with thiopental/thiamylal, 260/0 with methohexital, and 0% with propofol. In nonasthmatic patients, the incidence of wheezing was 160/0 with thiopental/thiamylal and 30/0 with propofol. The potential beneficial effects of propofol on airway reactivity are further supported by animal studies. Propofol attenuates carbachol-induced airway constriction in canine tracheal smooth muscle.F The reported mechanism involves a decrease of intracellular inositol phosphate, resulting in a decrease of intracellular calcium availability.. Propofol has also been shown to be more effective in preventing bronchoconstriction following provocative agents in an isolated guinea pig tracheal smooth muscle model. 83 Intravenous anesthetic agents can depress the cardiovascular system by various mechanisms, including a reduction of central or peripheral autonomic nervous system activity, blunting compensatory baroreceptor reflexes, decreasing preload or afterload, or directly depressing myocardial contractility. Hemodynamic function during the induction of anesthesia may also be affected by preexisting cardiovascular disease, volume status, resting sympathetic nervous system tone, residual effects of chronically administered drugs (angiotensin-converting enzyme inhibitors, B-adrenergic antagonists), and the administration of preinduction drugs, including opioids and benzodiazepines. An induction dose of thiopental causes a variable decrease in cardiac output, systemic vascular resistance, and MAP. 84 The decrease in cardiac output is the result of venodilation and direct myocardial depression. This effect is generally well tolerated in patients with adequate cardiovascular function but is exaggerated with preexisting cardiovascular disease, necessitating the use of a lower dose of thiopental or preferably the use of alternative agents in patients with compromised cardiovascular function. Likewise, propofol demonstrates cardiovascular depressant effects similar to or greater than those of thiopental. Propofol is a direct myocardial depressant and reduces systemic vascular resistance. Significant cardiovascular responses following propofol administration are more common with high doses, in hypovolemic patients, in elderly patients, and in patients with significant cardiovascular disease. 85,86 The administration of calcium chloride [l Orng/kg] has been shown to prevent the deleterious cardiovascular effects of propofol." In addition to its effects on systemic vascular resistance and myocardial function, propofol may augment central vagal tone, leading to bradycardia, conduction disturbances, and asystole.P:" Bradycardia may be more likely when propofol is combined with other medications known to alter cardiac chronotropic function (fentanyl or succinylcholine). Although the relative bradycardia is generally considered a beneficial

362

CHAPTER 18

effect in patients at risk for myocardial ischemia, it may be detrimental in patients with a fixed stroke volume in whom cardiac output is heart rate dependent. In contrast, etomidate causes minimal cardiovascular depression and is frequently the induction agent of choice in patients with significant cardiovascular disease.Y" Ketamine stimulates the cardiovascular system by central and peripheral activation of the sympathetic nervous system and release of endogenous catecholamines." Induction doses of ketamine (1-2mgjkg) generally increase heart rate and MAP. Therefore, ketamine is not recommended in patients with significant coronary artery disease in whom the balance of myocardial oxygen supply and demand is critical. Aside from its indirect effects with the release of endogenous catecholamines and stimulation of the sympathetic nervous system, ketamine is a direct myocardial depressant, but this effect is seen only when catecholamine reserves are depleted. Midazolam demonstrates relative hemodynamic stability, causing a mild decrease in MAP secondary to a decrease in systemic vascular resistance. A number of other significant pharmacodynamic and physiologic effects may occur with each of the specific intravenous anesthetic agents. Etomidate inhibits the activity of 17-u-hydroxylase and l l-Bdiydroxylase, which are necessary for the production of adrenal corticosteroids.P-" This effect occurs even after the use of a single dose for anesthetic induction, with adrenal suppression lasting 5 to 8 h. There is no evidence to suggest that the adrenal suppression from a single induction dose of etomidate has clinical sequelae, although increased mortality has been reported in critically ill patients in the intensive care unit (ICU) when receiving continuous infusions of etomidate for days." Etomidate and ketamine can also cause significant postoperative nausea and vomiting (PONY). In contrast, propofol is the only intravenous anesthetic with antiemetic properties.P'" Ketamine is unique in producing profound analgesia, while the other anesthetic induction agents do not have analgesic properties. Thiopental, midazolam, and etomidate can precipitate acute intermittent porphyria and are therefore contraindicated in patients with this comorbidity." Although all intravenous anesthetics except etomidate cause some histamine release, the incidence of severe anaphylactic reactions is low. Additional problems with propofol relate to its delivery in a lipid emulsion (the same lipid preparation used in parenteral hyperalimentation solutions, otherwise known as intralipid). These problems include rare reports of anaphylactoid reactions (more likely in patients with a history of egg allergy?"], pain on injection, and elevated triglyceride levels with prolonged infusions. Variable success in decreasing the incidence of pain has been reported with various maneuvers, including the preadministration of lidocaine, mixing the lidocaine and propofol in a single solution, mixing the propofol with thiopental.l'" diluting the concentration of the propofol, or cooling the propofol prior to bolus administration. Another alternative is the administration of a small dose of ketamine (0.5mgjkg) prior to the administration of propofol.'?' Since propofol has limited analgesic properties, ketamine and propofol can be administered together to take advantage of the analgesia provided by ketamine and the rapid recovery with propofol.

Additional problems related to the lipid content of propofol may occur when propofol is used for continuous sedation in the ICU setting. High doses and prolonged infusions may result in hypertriglyceridemia and its associated effects. A propofol infusion of 2 mgjkgjh provides approximately 0.5 gmj kg/day of fat. In an attempt to eliminate or lessen such problems, a 2 % solution of propofol (twice the amount of propofol with the same amount of lipid per milliliter as the 1% solution) is undergoing clinical evaluations.l' > o

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References 1. National Academy of Sciences/National Research Council. Accidental Death and Disability: The Neglected Disease of Modem Society. Washington, DC: National Academy of Sciences, 1966. 2. National Research Council and the Institute of Medicine. Injury in America. Washington, DC: National Academy Press, 1985. 3. Mann NC, Mullins RJ, MacKenzie EJ,et al. A systematic review of published evidence regarding trauma system effectiveness. J Trauma 1999;47:S15-S21. 4. Mullins RJ. A historical perspective of trauma system development in the United States. J Trauma 1999;47(suppl):S8S14. 5. Freeark RJ. Accident hospitals. Bull Am Coll Surg 1986;71:2430. 6. West JG, Trunkey DD, Lim RC. Systems of trauma care: a study of two counties. Arch Surg 1979;114:455-460. 7. Leppaniemi A. Trauma systems in Europe. Curr Opin Crit Care 2005;11:576-579. 8. Liberman M, Mulder DS, Lavoie A, Sampalis J. Implementation of a trauma care system: evolution through evaluation. J Trauma 2004;56:1330-1335. 9. http://www.ahrq.gov/data/his96/clinclas.htm. 10. Cayten CG, Stahl W, Agarwal N, Murphy J. Analyses of preventable deaths by mechanism of injury among 13,500 trauma admissions. Ann Surg 1992;21:510-520. 11. Trunkey DD. History and development of trauma care in the United States. Clin Orthop Relat Res 2000;374:36-46. 12. Mann NC. Assessing the effectiveness and optimal structure of trauma systems: a consensus among experts. J Trauma 1999; 47(suppl):S69-S73. 13. Eastman B. Blood in our streets: status and evolution of trauma care systems. Arch Surg 1992;127:677-681. 14. Mann NC, Mullins R, MacKenzie EJ, et al. Systematic review of published evidence regarding trauma system effectiveness. J Trauma 1999;47(suppl):S25-S33. 15. Morrison W, Wright JL, Paidas CN. Pediatric trauma systems. Crit Care Med 2002; 30 (suppl): S448-S456. 16. Hulka F. Pediatric trauma systems: critical distinctions. J Trauma 1999;47(suppl):S85-S89. 17. Keller MS, Vane D. Management of pediatric blunt splenic injury: comparison of pediatric and adult trauma surgeons. J Pediatr Surg 1995;30:221-224. 18. Nathens AB, Brunet F, Maier RV. Development of trauma systems and effect on outcomes after injury. Lancet 2004;363: 1794-1801. 19. Esposito TT, Danddal T, Reynolds S, Sandall N. Effect of a voluntary trauma system on preventable death and inappropriate care in a rural state. J Trauma 2003;54:663-670. 20. Olson CJ, Arthur M, Mullins RJ, et al. Influence of trauma system implementation on process of care delivered to seriously injured patients in rural trauma centers. Surgery (St. Louis) 2001;130:273-279. 21. West JG, Williams M, Trunkey DD, Wolferth CC. Trauma systems: current status-futurechallenges. JAMA1988;259:35973600. 22. Mitchell FL, Thal ER, Wolferth CC. Analysis of American College of Surgeons trauma consultation program. Arch Surg 1995;130:578-584. 23. DiRusso S, Holly C, Kamath R, et al. Preparation and achievement of American College of Surgeons Levell trauma verification raises hospital performance and improves patient outcome. J Trauma 2001;51:294-300.

24. Piontek FA, Coscia R, Marselle CS, et al. Impact of American College of Surgeons verification on trauma outcomes. J Trauma 2003;54:1041-1047. 25. Hammond JS, Gomez G, Eckes J. Trauma systems: economic and political considerations. J Fla Med Assoc 1990;77:603605. 26. Cowley RA, Hudson R, Scanlon E, et al. An economical and proved helicopter program for transporting the emergency critically ill and injured patient in Maryland. JTrauma 1973;13:10291038. 27. Waters J, Wells C. The effects of a modem emergency medical care system in reducing automobile crash deaths. J Trauma 1973;13:645-647. 28. Boyd DR, Dunea MM, Flasher BA. The Illinois plan for a statewide system of trauma centers. J Trauma 1973;13:24-31. 29. Boyd DR, Lowe R, Baker R, Nyhus L. Trauma registry: new computer method for multifactorial evaluation of a major health problem. JAMA 1973;223:422-428. 30. Eastman AB, Lewis F, Champion H, Mattox K. Regional trauma system design: critical concepts. Am J Surg 1987;154:79-87. 31. Bazzoli GJ. Community based trauma system development: key barriers and facilitating factors. J Trauma 1999;47(suppl):S22S29. 32. Hammond JS, Breckinridge MB. Longitudinal analysis of the impact of a level 1 trauma center designation at a university hospital. J Am ColI Surg 1999;188:217-224. 33. Mann NC, MacKenzie E, Teitelbaum SD, et al. Trauma system structure and viability in the current healthcare environment: a state-by-state assessment. J Trauma 2005;58:136-147. 34. MacKenzie EJ, Hoyt D, Sacra J, et al. National inventory of hospital trauma centers. JAMA 2003;289:1515-1522. 35. American College of Surgeons Committee on Trauma. Resources for the Optimal Care of the Injured Patient. Chicago: American College of Surgeons, 2003. 36. Nathens AB, Jurkovich GJ, MacKenzie EJ, Rivara F. A resourcebased assessment of trauma care in the United States. J Trauma 2004;56:173-178. 37. Norcross E, Ford D, Cooper M, et al. Application of American College of Surgeons field triage guidelines by pre-hospital personnel. J Am ColI Surg 1995;181:539-544. 38. Baez AA, Lane P, Sorondo B. System compliance with out-ofhospital trauma triage criteria. J Trauma 2003; 54:344-351. 39. Liberman M, Mulder DS, Jurkovich GJ, Sampalis JS. The association between trauma system and trauma center components and outcome in a mature regionalized trauma system. Surgery (St. Louis) 2005;137:647-658. 40. Kaplan L, Santora T, Blank-Reid C, Trooskin SZ. Improved emergency department efficiency with a three tier trauma triage system. Injury 1997;28:449-453. 41. Gutierrez de Ceballos JP, Turegano Fuentes F, Perez Diaz D, et al. Casualties treated at the closest hospital in the Madrid, March 11, terrorist bombings. Crit Care Med 2005;33(1 suppl): S107-8112. 42. Jacobs L, Bums K, Gross R. Terrorism: a public health threat with a trauma system response. J Trauma 2003;55:1014-1021. 43. American Medical Association. Advanced Disaster Life Support, provider manual, version 2.0. Chicago: AMA, 2004. 44. Avitzour M, Libergal M, Assaf J, et al. A multicasualty event: out-of-hospital and in-hospital organizational aspects. Acad Emerg Med 2004;11:1102-1104. 45. Klein J, Weigelt JA. Disaster management: lessons learned. Surg Clin N Am 1991;71:257-266. 46. Norcross ED, Elliott BE, Adams D, Crawford F. Impact of a major hurricane on surgical services in a university hospital. Am Surg 1993;59:28-33.

Monitoring of Cardiovascular and Respiratory Function Philip S. Barie and Soumitra R. Eachempati Blood Testing Electrocardiography Pulse Oximetry Temperature Capnography Invasive Hemodynamic Monitoring

" 409 410 410 411 411 412

P

atient acuity is increasing in the intensive care unit (ICU),requiring more sophisticated methods to monitor, support, and evaluate critically ill patients.v" Mechanical ventilation is a mainstay of modem ICU care. Monitoring of blood flow, acid-base status, oxygen transport, coagulation, pulmonary and other visceral organ function, and the development of nosocomial infection are a few of several aspects of patient surveillance.

Blood Testing Blood testing is essential for patient monitoring, but such testing can be excessive . Cost and quality are linked; expenditure of additional resources decreases quality if there is no benefit to the patient. Blood removed for testing can average more than 70mL/day4; an indwelling arterial catheter may increase blood testing by one-third." Waste of blood occurs each time a catheter is aspirated and flushed," and the risk of nosocomial infection is increased by catheter manipulation? and transfusion of red blood cell concentrates." Strategies to reduce blood testing while preserving optimal patient care include noninvasive hemodynamic monitoring, adoption of practice parameters for diagnostic evaluation, and point-ofcare testing.

Point -of-Care Testing Point-of-care (PaC) testing of blood occurs at or near the bedside and is recognized to be accurate and to confer numerous advantages. Turnaround time is reduced, enhancing clinical care and reducing repetitive testing. Very small [i.e.,

Noninvasive Cardiac Output Intracranial Pressure Monitoring Gastric Tonometry Near-Infrared Spectroscopy References

418 419 419 419 419

microliter) blood samples are required, and in some cases samples are not even removed from the patient if indwelling sensors or a closed-circuit extracorporeal sampling device is employed. Perhaps the most prevalent example of pac testing is glucose monitoring," which is performed frequently now that the benefits of "tight" glucose control [i.e., serum glucose concentration 80-110mg/dL) by use of a continuous infusion of insulin are recognized to reduce the risk of nosocomial infection, duration of mechanical ventilation, organ dysfunction, and death among critically ill surgical patients." Expected error tolerances for bedside glucose monitoring are ± 15%. Blood gases and electrolyte concentrations can also be analyzed accurately at the bedside with good precision across a range of concentrations for each analyte. In a recent comparison trial, " precision studies performed at three different concentrations for each analyte demonstrated an intraassay coefficient of variation of 2.5% or less and interassay precision of 4% or less in all tests.

Blood Gas Monitoring Blood gas analyzers report several results, but the parameters measured directly are the partial pressures of oxygen (p02) and carbon dioxide (pC0 2l and blood pH. Hemoglobin saturation (Sa02) is calculated from the p02 using the oxyhemoglobin dissociation curve, assuming a normal Pso (the p02 at which Sa02 is 50%, normally 26.6mmHg), and normal hemoglobin structure. Blood gas analyzers with a co-oximeter measure the various forms of hemoglobin directly, including oxyhemoglobin, total hemoglobin, carboxyhemoglobin, and

409

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CHAPTER 22

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Continuous ECG monitoring is invaluable in assuring ongoing control of heart rate in patients at risk for myocardial ischemia" Perioperative mortality is decreased among patients who receive beta-adrenergic blockade preoperatively, and continued for 1 week after surgery." Even if beta-blockade cannot be started before an emergency operation (e.g., uncorrected hypovolemia), it should be started as soon as possible thereafter. 18

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800

700

900

1,000

Wavelength (nm)

FIGURE 22.1. Modem pulse oximetry uses two wavelengths of light, red (660nm) and infrared (940nm), to differentiate oxyhemoglobin (Hb02 ) from deoxyhemoglobin (Hb). (Adapted with permission from JCrit Illness 1989;4:23-31.)

methemoglobin. The actual bicarbonate, standard bicarbonate, and base excess are calculated from the pH and pC0 2. A fresh, heparinized, bubble-free arterial blood sample is required. Heparin is acidic; if present to excess, pC02and HC03 are reduced spuriously. Delay in measurement allows continued metabolism by erythrocytes, reducing pH and p02 and increasing pC02. An iced specimen can be assayed accurately for up to 1 h. Air bubbles decrease pC02 and increase p02. The solubility of all gases in blood increases with a decrease in temperature; thus, hypothermia causes p02 and pC02 to decrease and pH to increase. Analysis at 37°C of a sample taken from a hypothermic patient will cause a spurious increase in p02 and pC0 2, but the error is usually too small to be meaningful.

Electrocardiography Electrocardiographic (ECG) monitoring is standard in many clinical settings." Four or five limb and chest leads are used for routine monitoring, which provides instantaneous information regarding cardiac rhythm and rate. Tachycardia is underappreciated as a source of serious morbidity, especially in older patients, and may be a manifestation of hypovolemia, hemorrhage, inadequate analgesia, or other causes. Because tachycardia may precipitate myocardial ischemia, it is inherently dangerous. However, routine ECG monitoring is insensitive for detection of acute ST-T wave changes," which may portend ischemia" detectable by 12-lead ECG. 1S Continuous 12-lead ECG monitoring is a sensitive indicator of myocardial ischemia, but it is prone to lead displacement and is not used widely.

Pulse oximetry has revolutionized perioperative monitoring in that even slight decreases in Sa02 are detectable with only about a 60-s delay." So successful has been pulse oximetry that deaths attributable to general anesthesia have decreased dramatically. The device calculates Sa02 by estimating the difference in signal intensity between oxygenated and deoxygenated blood from red (660nm) and near-infrared (940nm) light. Pulse oximetry must detect pulsatile blood flow to be accurate (Figure 22.1; Table 22.1), but all things being equal, data can be obtained from a detector on the finger, the earlobe, or the forehead." Pulse oximetry is generally accurate ( ± 2 % ) over the range of 5a02 700/0 to 100%, but it is less accurate below 700/0. Interestingly, a recent Cochrane systematic review was unable to identify any demonstrable benefit of pulse oximetry." Several aspects of the technology and patient physiology limit the accuracy of pulse oximetry." If the device cannot detect pulsatile flow, the waveform will be damped. Consequently, patients with hypothermia, hypotension, hypovolemia, or peripheral vascular disease, or who are treated with vasoconstrictor medications (e.g., norepinephrine), may have inaccurate pulse oximetry readings. Additionally, an elevated carboxyhemoglobin concentration will lead to falsely elevated 5a02 because reflected light from these entities is absorbed at the same wavelength as oxyhemoglobin (Figure 22.2). Other

Table 22.1. Sources of Error in Pulse Oximetry. False depression of Sa02 Methemoglobinemia (reads at 85 %) Methylene blue dye Indocyanine green dye Nonpulsatile blood flow (no reading may be appreciable at all) Vasoconstriction Hypotension Hypothermia Hypovolemia Venous congestion with exaggerated venous pulsation Peripheral edema Nail polish Fluorescent lighting Use of electrocautery (electrical interference) Severe anemia (hemoglobin concentration 3-4gjdL) Shivering (may cause mechanical loss of signal) False elevation of Sa02 Carboxyhemoglobin No effect Fetal hemoglobin Hyperbilirubinemia

411

MONITORING OF C A R D I O V A SC U L A R AND RESPIRATORY FUNCTION

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FIGURE 22.2. Different forms of dyshemoglobinemia, in particular methermoglobinemia and carboxyhemoglobin, mimic the light absorbance characteristics of oxyhemoglobin, resulting in false pulse oximetry reading of the true oxyhemoglobin saturation. (Adapted with permission from J Crit Illness 1988;3:103-107.1

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640

causes of inaccurate pulse oximetry include ambient light and motion artifact.

Temperature Measurement of core body temperature is an essential part of routine monitoring. Hypothermia may contribute to metabolic acidosis, vasoconstriction, myocardial dysfunction, arrhythmias, electrolyte imbalances, altered pharmacokinetics and metabolism, platelet dysfunction, and an increased risk of surgical site infection. Hypothermia may develop under anesthesia for many reasons, including exposure, evaporative water loss, and rapid infusion of ambient temperature fluid or cold blood, and must be avoided by the use of fluid warmers and warming blankets. On the other hand, hyperthermia results in an increased metabolic rate that will increase a patient's heart rate, oxygen consumption, insensible fluid losses, and maintenance fluid requirement.P The most reliable method of temperature monitoring is to obtain a core temperature, whether by transoral esophageal probe, bladder catheter thermistor, or the thermistor tip of a pulmonary artery catheter (PAC).

680

720

800

840

880

920

960

1000

Light wavelength (nm)

The peak CO 2 concentration occurs at end-exhalation and is regarded as the patient's "end-tidal CO 2 '' (ETC02 ), at which time ETC02 is in close approximation to the alveolar gas concentration (Figure 22.3). Capnography is useful in the assessment of successful tracheostomy or endotracheal tube placement, to monitor weaning from mechanical ventilation, and as a monitor of resuscitation (Table 22.21.24 The ability to detect hypercarbia during ventilator weaning of intubated patients can diminish the need for serial determinations of blood gases. In conjunction with pulse oximetry, many patients can be weaned successfully from mechanical ventilation altogether, without reliance upon arterial blood gases or invasive hemodynamic monitoring. Other information is acquired from capnography as well. Prognostically, an ETC0 2-PaC02 gradient of 13mmHg or more after resuscitation has been associated with increased mortality in trauma patients. A sudden decrease or even dis-

Capnogram

Capnography Capnography measures changes in the concentration of CO 2 in expired gas during the ventilatory cycle . This technique is most reliable in ventilated patients and employs either mass spectroscopy or infrared light absorption to detect the presence of CO 2 • The gas sample may be collected by either sidestream or mainstream sampling; the former is more common and has the advantage that the analyzer is light in weight. However, sidestream sampling is susceptible to accumulation of water vapor in the sampling line. In the ICU, where respiratory gases are humidified, mainstream sampling may be preferable.

760

4 Q)

"0

'x o

3

'5 c

..8 Co o

Inspired carbon dioxide

End-tida l carbon dioxide

2

•Inspiration• •

Expiration

FIGURE 22.3. A normal capnograph tracing.

412

CHAPTER 22

TABLE 22.2. Changes in End-Tidal CO 2 (ETC02) . Increased ETC02 Decreased alveolar ventilation Reduced respiratory rate Reduced tidal volume Increased equipment dead space Increased CO 2 production Fever Hypercatabolic state Excess feeding with carbohydrate Increased inspired CO 2 concentration CO 2 absorber exhausted Increased CO 2 in inspired gas Rebreathing of expired gas Decreased ETC02 Increased alveolar ventilation Increased respiratory rate Increased tidal volume Decreased CO 2 production Hypothermia Hypocatabolic state Increased alveolar dead space Decreased cardiac output Pulmonary embolism (clot, air, fat) High positive end-expiratory pressure (PEEP) Sampling error Air in sample line (no or diminished signal) Water in sample line (no or diminished signal) Inadequate tidal volume (no or diminished signal) Disconnection of monitor from tubing (no signal) Artificial airway not in trachea (e.g., esophageal intubation) (no signal)

appearance of ETC02 can be correlated with potentially serious pathology or events, such as a low cardiac output state, disconnection from the ventilator, or pulmonary thromboembolism (see Table 22.2).25 A gradual increase of ETC02 can be seen with hypoventilation; the converse is also true. Another cause of gradually decreasing ETC0 2 is hypovolemia. The characteristics of the waveform can indicate information about the patient's pulmonary status and in particular whether obstructive disease or inadequate ventilation is present." Recently, some investigators have studied sublingual capnography and its utility as a marker of tissue perfusion, but this technology is still awaiting clinical substantiation as a useful technique. 27

Invasive Hemodynamic Monitoring Arterial Catheterization Measurement of a patient's arterial blood pressure is one of the simplest and most reproducible methods of evaluating hemodynamic status. For most operations, automated noninvasive blood pressure cuff devices, in conjunction with continuous ECG monitoring, can assess the anesthetized patient's volume status adequately (error, ± 2%). These automated blood pressure devices can be set to measure the patient's blood pressure as often as every 5 min. In some patients in whom blood pressure fluctuations occur more frequently than these intermittent measurements can capture, continuous monitoring is needed via an indwelling arterial catheter." These catheters may be placed either preoperatively or intra-

operatively in patients undergoing major operations such as cardiac bypass procedures, surgery for multiple trauma, or major chest or abdominal surgery. Blood pressure will be overestimated if the cuff is too small and if actual systolic blood pressure is less than 60mmHg. Arrhythmias such as atrial fibrillation affect accuracy adversely. Alternatively, an arterial monitoring catheter may be placed for monitoring of potentially or actually unstable patients in the ICU. Candidates for intraoperative invasive arterial monitoring include patients whose operations are anticipated to be longer than 4h in duration, those who are already unstable hemodynamically (e.g., intraabdominal infection complicated by septic shock) or who may lose substantial amounts of blood, those who need frequent monitoring of blood samples, or those who may need precise blood pressure control (e.g., neurosurgical patients, patients on cardiopulmonary bypass). Patients with an anticipated postoperativeneed for continuous blood pressure monitoring, ventilator support, or inotropic support often benefit from intraoperative arterial catheterization. Arterial monitoring catheters are often placed in the ICU for monitoring of hemodynamic instability or mechanical ventilation, among other indications. Although there is morbidity from insertion and from indwelling catheters, there is also morbidity from repetitive arterial punctures; the risk:benefit analysis is a matter of clinical judgment for "less unstable" patients. Arterial catheters may be placed in any of several locations. The catheter should be a special-purpose thin-walled catheter to maintain fidelity of the waveform and also to obstruct minimally the lumen of the vessel. A standard intravenous cannula should not be used for arterial catheterization. The radial artery at the wrist is the most commonly used site; although the ulnar artery is usually of larger diameter, it is relatively inaccessible to percutaneous access compared with the radial artery. Careful assessment to ensure patency of the collateral circulation to the hand is mandatory before cannulation of an artery at the wrist, to minimize the possibility of tissue loss from arterial occlusion or embolization of debris or clot from the catheter tip. Alternative sites are many. In neonates, the umbilical artery may be catheterized; intestinal ischemia is a rare complication. The axillary artery is relatively spared by atheromatous plaque, supported by good collaterals at the shoulder, and easy to cannulate percutaneously, making it a suitable choice. The superficial femoral artery may also be used, but this is not a location of choice because the burden of plaque (and therefore the risk of distal embolization) is higher, as is the infection rate because skin bacterial counts in the inguinal crease are among the highest anywhere on the body. The superficial temporal artery is difficult to cannulate because of small caliber and tortuosity. The dorsalis pedis artery is accessible but should be avoided in patients with peripheral vascular disease. The brachial artery should be strictly avoided because the collateral circulation around the elbow is poor and the risk of ischemia of the hand or forearm is high. The waveform may be damped by severe peripheral vasoconstriction in patients who are being treated with vasopressors, and it may be necessary to use a longer catheter at a more central location (e.g., axillary, femoral) to get the catheter tip into an artery in the torso that would be less affected. Nosocomial infection of arterial monitoring is unusual provided basic tenets of infection control are honored and femoral artery catheterization is avoided."

M ONITORING OF C A R D I O V ASC U L A R AND RESPIRATORY FUNCTION

because of ease of accessibility, a high technical success rate of cannulation, and a low rate of complications. However, it is difficult to keep an adherent dressing in place, and the infection rate is higher than for subclavian vein catheters.

R

p

T

ECG trac ing

Q

Ol

S

I

E E

a

413

c

Jugula r traci ng

FIGURE 22.4. The central venous pressure waveform . See text for explanation.

Other complications from arterial catheterization include bleeding, hematoma, and pseudoaneurysm.

Central Venous Pressure Monitoring The central venous pressure (CVP) is an interplay of the circulating blood volume, venous tone, and right ventricular function. The CVP measures the filling pressure of the right ventricle, providing an estimate of intravascular volume status. The normal CVP waveform (Figure 22.4) consists of three upward deflections (a, c, and v waves) and two downward deflections (x and y descents). These waves are produced as follows: The "a" wave is produced by right atrial contraction and occurs just after the P wave on the ECG. The "c" wave occurs as a consequence of isovolumic ventricular contraction, forcing the tricuspid valve to bulge upward into the right atrium. The pressure within the right atrium then decreases as the tricuspid valve is pulled away from the atrium during right ventricular ejection, forming the "x" descent. The right atrium continues to fill during late ventricular systole, forming the "v" wave. The "y" descent occurs when the tricuspid valve opens and blood from the right atrium empties rapidly into the right ventricle during early diastole. The indications for cannulation of a central vein are numerous and the contraindications are relatively few (Table 22.3). Strict adherence to asepsis, full barrier precautions, and the principles of infection control are crucial if the serious, potentially life-threatening complication of catheter-related bacteremia is to be avoided." Central venous access can be obtained at several body sites , including the basilic vein, femoral vein , external jugular vein, internal jugular vein, or subclavian vein. The basilic vein is used only for placement of a peripherally inserted central catheter (PICC), which is generally used only for long-term venous access (e.g., antibiotics, chemotherapy, parenteral nutrition). The external jugular vein is used rarely outside the operating room . In the ICU, the internal jugular, subclavian, and femoral veins are used, listed in decreasing frequency . Each has advantages and disadvantages. The internal jugular vein site is most popular

TABLE 22.3. Indications and Contraindications for Central Venous Pressure Monitoring and Pulmonary Artery Catheterization. Central venous catheter placement Indications Major operative procedures involving large fluid shifts or blood loss Hypovolemia or shock Intravascular volume assessment when urine output is not reliable or unavailable (e.g.: renal failure) Major trauma Surgical procedures with a high risk of air embolism, such as sitting-position craniotomy or major liver resection Frequent venous blood sampling Venous access for vasoactive or irritating drugs Chronic drug administration Inadequate peripheral IV access Rapid infusion of IV fluids (using large cannulae) Parenteral nutrition Insertion of other devices PA catheters Transvenous pacing wires Access for renal replacement therapy Absolute contraindications Infection at the site of insertion Large tricuspid valve vegetations Superior vena cava syndrome Tumor or thrombus in the right atrium Relative contraindications Anticoagulant therapy Coagulopathy Contralateral diaphragm dysfunction (risk of recurrent nerve injury with internal jugular cannulation) Newly inserted pacemaker wires Presence of carotid disease Recent cannulation of the internal jugular vein Thyromegaly or prior neck surgery (especially ipsilateral carotid endarterectomy) Pulmonary artery catheterization: Indications Cardiac surgery: Poor left ventricular function (ejection fraction 18 mmHg) Recent myocardial infarction Compli cations of myocardial infarction [e.g., mitral insufficiency, ventricular septal defect, ventricular aneurysm) Combined lesions, e.g., coronary artery disease with mitral insufficiency or aortic stenosis Asymmetrical septal hypertrophy Intraaortic balloon pump Noncardiac indications Shock of any cause Severe pulmonary disease Complicated surgical procedures Multiple trauma Hepatic tran splantation Aortic surgery Contraindications The same contraindications for central venous catheterization apply here. Additionally: Absolute Tricuspid or pulmonary valvular stenosis Right ventricular masses (tumor or thrombus) Tetralogy of Fallot Relative Ventricular arrhythmia

414

CHAPTER 22

FIGURE 22.5. The subdivision of the anterior triangle of the neck. (Bypermission of JE Skandalakis, SW Gray, and JR Rowe, Am Surg 45(9):590-596, 1979.)

The subclavian site is the most technically demanding for placement and has the highest rate of pneumothorax (1.5%3 % ),30 but the infection rate is the lowest of the three because catheter care is facilitated by the relatively flat surface of the upper chest. The femoral vein site is least preferred, despite the relative ease of catheter placement. It is accessible during cardiopulmonary resuscitation or emergency intubation, so procedures can occur concurrently. However, the site is particularly prone to infection, and the risks of arterial puncture (9%-15%) and venous thromboembolic complications are

FIGURE 22.6. Internal jugular vein cannulation. When using the middle approach, the apex of a triangle formed by the medial and lateral heads of the sternocleidomastoid muscle (SCM) with the clavicle is localized. The vein runs parallel to and below the lateral head of the SCM. Applying gentle pressure (to avoid collapsing the vein that lies in the same sheath), the operator locates the carotid artery pulse with the index finger of the nondominant hand . The needle is inserted at the apex of the triangle and directed toward the ipsIlateral nipple.

much higher than for jugular or subclavian venipuncture. Overall complications are comparable for internal jugular and subclavian vein cannulation (6%-12%) and much higher for femoral vein cannulation (13%-19%).30 The internal jugular vein begins just medial to the mastoid process at the base of the skull and runs directly inferior from the mastoid process, passing under the sternal end of the clavicle where it joins the subclavian vein. In terms of surface landmarks, the internal jugular vein courses straight down from the mastoid process to the medial side of the insertion point of the clavicular head of the sternocleidomastoid muscle. For purposes of internal jugular vein access, an important anatomic triangle is formed by the two heads of the sternocleidomastoid muscle and the medial one-third of the clavicle (Figure 22.5). Within the triangle, the internal jugular vein is most safely and readily cannulated (Figures 22.6, 22.7) (on the left, the thoracic duct may be punctured inadvertently; Figure 22.8) . Within the triangle, the carotid artery lies medial and slightly posterior to the internal jugular vein; the incidence of carotid artery puncture during internal jugular vein cannulation (6%-9%) is somewhat higher than that of puncture of the subclavian artery during subclavian vein catheterization (3%-5 %) (Figure 22.9).30

Pulmonary Artery Catheterization A pulmonary artery catheter (PAC) is a balloon -tipped, flowdirected catheter that is usually inserted percutaneously via a central vein and transits the right side of the heart into the pulmonary artery. This catheter can provide a variety of clinical information and typically contains several ports that can monitor pressure or be used for administration of fluids . Some PACs also include a sensor to measure central (mixed) venous oxygen saturation (Smv02) or right ventricular volume. Data from PACs are used mainly to determine cardiac output (Ql and preload, which is most commonly estimated in the clinical setting by the pulmonary artery occlusion pressure (PAOP).

FIGURE 22.7. Internal jugular vein cannulation. When using the posterior approach, the operator locates the posterior aspect of the lateral belly of the sternocleidomastoid muscle. The needle is inserted above the point where the external jugular vein traverses the lateral belly of the sternocleidomastoid muscle and is directed (underneath the muscle] toward the suprasternal notch.

415

MONITORING OF CARDIOVASCULAR AND RESPIRATORY FUNCTION

L. int. jugul ar v. -

- Int. jug ular t. Transverse _ _/ ., ce rvic al t.

.-~

Ant. med iasti nal t. L. brachiocephalic v.

FIGURE 22.8. The thoracic duct and main left lymphatic trunks. Trunks are variable and may enter the veins with the thoracic duct or separately. (By permission of JE Skandalakis, SW Gray, and JR Rowe, Anatomical Complication s in General Surgery, New York: McGraw -Hill, 1983.1

INSERTION AND MONITORING

The insertion of the PAC (as well as a central venous catheter) is performed in the following manner. The operator dons cap, mask, eye protection, and a sterile gown and gloves before preparing the patient's skin (2% chlorhexidine gluconate is associated with a lower incidence of catheter-related infec tion than 10% povidine-iodine solution) and draping the patient completely with a full-bed drape. After infiltration of a local anesthetic, an introducer sheath is placed into the subclavian or internal jugular vein, and the catheter is inserted through the introducer with the balloon deflated . Once the catheter tip reaches the superior vena cava (after approximately 20cm) , partial inflation of the balloon (generally O.5mL)permits blood flow to advance the catheter. The position of the catheter tip is usually determined by pressure monitoring or occasionally by fluoroscopy . Entry into the right ventricle is indicated by a sudden increase in systolic pressure to at least 30mmHg (Figure 22.10), while the diastolic pressure remains unchanged from right atrial or vena

FIGURE 22.9. Subclavian vein cannulation. The operator locates the junction of the middle and medial thirds of the clavicle. The needle is inserted 1cm below this point and directed toward the suprasternal notch, which is marked by the operator 's nondominant hand's index finger. The needle is maintained as parallel to the skin as possible.

caval pressure. When the catheter enters the pulmonary artery, the systolic pressure does not change, but diastolic pressure increases above right ventricular end-diastolic pressure or central venous pressure (CVP), and consequently, the pulse pressure narrows. Advancement of the catheter with periodic inflation of the catheter wedges the balloon, usually in a lobar pulmonary artery. A chest X-ray confirms proper placement and rules out complications such as hemothorax or pneumothorax. As a general rule, if the tip of the catheter extends beyond the hilum, it has advanced too far and must be withdrawn partially and repositioned. The pulmonary artery systolic pressure (normal, 1530mmHgl and diastolic pressure (normal, 5-13mmHg) are recorded with the catheter balloon deflated . The diastolic pressure corresponds well to the PAOP. Diastolic pressure can exceed the PAOP when pulmonary vascular resistance is high secondary to primary pulmonary disease [e.g., pulmonary fibrosis, pulmonary hypertension). The PAOP is measured in the following manner." With the balloon inflated, the tip of the catheter records the static

40

30

RA

01-

OJ

0-8 (mean)

I

E 20 E

10

FIGURE 22.10. Waveform for insertion of a pulmonary artery catheter. See text for explanation.

-

-

RV

15- 3010

-

PA

15- 3010 -....

PAOP -4-

5- 15 -

(mean)

416

CHAPTER 22

back-pressure of the pulmonary veins . The balloon must not remain inflated for longer than 30 s to prevent pulmonary art ery rupture or pulmonary infarction. Normally, PAOP approximates left atrial pressure, which in tum approximates left ventricular end-diastolic pressure (LVEDP), itself a reflection of left ventricular end-diastolic volume (LVEDV). The LVEDV represents preload, which is the actual target parameter. Many factors cause PAOP to reflect LVEDV inaccurately: these factors include mitral stenosis, high levels of positive end-expiratory pressure (PEEP> lOcm H20), and changes in left ventricular compliance (e.g., because of myocardial infarction, pericardial effusion, or increased afterload). Inaccurate readings may result from balloon overinflation, improper catheter position, alveolar pressure exceeding pulmonary venous pressure (as with ventilation with PEEP), or severe pulmonary hypertension (which may make PAOP measurement difficult or, indeed, hazardous], Elevated PAOP occurs in left-sided heart failure. Decreased PAOP occurs with hypovolemia or decreased preload. A desirable feature of PA catheterization is the ability to measure Smv02' although controversially, sampling from the superior vena cava via a central venous catheter may provide data of comparable utility. True mixed venous blood is composed of blood from both the superior and inferior vena cava that has admixed in the right atrium. The blood may be sampled for blood gas analysis from the distal port of the PAC, but some catheters have embedded fiberoptic sensors that measure Smv02 saturation directly. Causes of low Smv02 include anemia, pulmonary disease, carboxyhemoglobinemia, low Q, and increased tissue oxygen demand. The Sa02:(Sa02 - Smv02) ratio determines the adequacy of O2 delivery (00 2), Ideally the Pmv02 should be 35-40mmHg, with a Smv02 of about 70%. Values of Pmv02less than 30mmHg are critically low . Another monitoring feature of the PAC includes the ability to measure Q. With these catheters, Q is measured either by intermittent bolus injection of ice water or, in new cath eters, continuous warm thermodilution.f Other parameters can be calculated from th e Q, including systemic and pulmonary vascular resistance (SVR, PVR) and right and left ventricular stroke work (RVSW, LVSW) (Table 22.4). TABLE 22.4. Derived Hemodynamic Parameters from Pulmonary Artery Catheter Data. Formula

CI = CO (L/ min)/BSA SV = (L/m in l CO · IOOO/HR SI = SV/BSA LVSWI = I.36· (MAP - PAOP)·SVI/IOO RVSWI = I.36· (PAP - CVP)·SVI/lOO SVR = (MAP - CVP)·SO/CO SVRI = (MAP - CVPI·SO/CI PVR = (PAP - PAOP)·SO/CO PVRI = (PAP - PAOP)·80jCI

Normal value

2.8-4.2 L/min/m 2 5D-IIOmLfbeat 30-65 ml.jbeat/m'' 45-60 g.mfbeat/m2 5- IOg.mfbeat/m 2 90D-1400dyne.s.cm -5 150D-2400 dyne .s.cm ? 15D-250dyne.s.cm-5 250-400 dyne .s.cm"

BSA, body surface area; cr, cardiac index; CO, cardia c output; CVP, central venous pressure; g.m, gram .meter, HR, heart rat e; LVSWI, left ventricular stroke work index; MAP, mean art erial blood pressur e; PAOP, pulmonary artery occlusion pressure; PAP, pulmonary artery pressure ; PVR, pulmonary vascul ar resistance; PVRI, pulmonary vascular resistance index ; RVSWI, right vent ricul ar stroke work index; Sl, stro ke volume index; SV, stroke volume; SVR, system ic vascular resistan ce; SVRI, systemic vascular resistance index .

Positive inotropic effect

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FIGURE 22.11. A stylized Frank-Starling curve. A wide range of cardiac output values is possible for a given filling pressure. CLINICAL USE OF THE PULMONARY ARTERY CATHETER

Many indications have been championed for the PAC,24 despite a lack of convincing evidence. One suggested indication is perioperative monitoring of patients with coronary artery disease or congestive heart failure undergoing noncardiac surgery (see Table 22.3).33-,35 A specific population that has been studied frequently is perioperative vascular surgery patients.36--38 A purported benefit to the preoperative placement of a PAC is that it allows the "optimization" of cardiac function. By this technique, the incremental manipulation of fluids, blood products, inotropes, and possibly diuretics is undertaken to define the Frank-Starling curve for the individual patient before surgical stress (Figure 22.111.39-4 1 Additionally, the patient would be prepositioned to undergo aggressive resuscitation intraoperatively if it were necessary," theoretically reducing the risk of organ dysfunction in the perioperative period . Despite this rationale, no studies have demonstrated unequivocally that PAC use decreases morbidity or mortality (Table 22.5). However attractive the concept may be of perioperative cardiac optimization to decrease morbidity (the lack of data notwithstanding), certain features of the practice make it undesirable for routine use in surgical patients." First, monitoring by a less invasive method such as central venous monitoring or even by physical examination and clinical judgment may be equally useful in determining volume status in many patients.tv" Second, PAC-derived data can be difficult to interpret, and inexperienced practitioners misinterpret frequently the data derived, oftentimes with deleterious consequences, Cardiac pathology that may confound even experienced clinicians includes valvular disease, pulmonary hypertension, cardiomyopathy, or fluctuations in core temperature. Imprecise "optimization" of a patient's cardiac function may augment myocardial work excessively and contribute to myocardial ischemia. The lack of demonstrable benefit, coupled with the trend to same-day admission for elective surgery, have decreased PAC placement in substantially in the perioperative period ." :" Pulmonary artery catheters may still be useful in selected circumstances, such as cardiomyopathy, shock of various eti ologies, or an unpredicted or poor response to conventional fluid therapy. The PAC may be useful during aortic surgery; proximal aortic cross-clampingfdeclamping may cause

MONITORIN G OF C A R D I O V A S C U L A R AND RESPIRATORY FUNCTION

.JIO

417

TABLE 22.5. Evidence for Utility of Pulmonary Artery Catheter in Perioperative Patients.

Author

Class of data

Numbers of patients: protocol/control

Population

Bonazzi et al.40

Elective infrarenal abdominal aortic an eury sm optimized to CI > 3.0 L/ min/m", 00 2 > 600mL/min/m 2

SO/SO

Bender et al."

Mandatory PA catheter monitoring vs. conventional treatment in elective vascular surgery PA catheter VS. CVP monitoring in elective abdominal aortic aneurysm surgery High-risk elective surgery patients randomized to PA catheter optimization to 00 2 > 600mL/ min/m ' Elect ive vascular surgery patients randomized to CI > 2.8 Elect ive vascular pati ent s receiving aortic surgery rand omized to CI > 2.8, SVR < 1100 Elective vascular surgery patients randomized to PCWP > 12, SV0 2 > 65%

51/53

Isaacson et al." Boyd et al."

Berlauk et a1,36 Valent ine et al." Ziegler et a1,37

Findings

No differences in in-hospital m ort ality, cardiovascular morbidity, renal failure, hospital length of stay No mortality, morbidity difference, or change in leU or hospital length

51/51

No morbidity or mortality difference

54/53

Decreased mortality and morbidity in protocol group

68/21

Decreased mortality in PA cathe ter group No differences in mortality or adverse postoperative events

60/60 32/40

No differences in mortality or complications between groups

CI, cardiac index ; CVP, central venous pressure; DO" oxygen deliv ery; ICU, intensive care unit; PA, pulmonary artery ; PAOP, pul m onary artery occlus ion pressure; SVO" veno us oxygen satura tion; SVR, systemic vascul ar resistance.

marked, instantaneous hemodynamic changes . Intraoperative transesophageal echocardiography has its advocates for intraoperative monitoring, but it is not widely available outside cardiac surgery operating rooms, and requires considerable expertise for data interpretation. Critically ill patients receiving one or more inotropic agents despite resuscitation with large volumes of fluid may also benefit from monitoring by PAC, both in the operating room and in the ICU .48 A summary of the data regarding the use of pulmonary artery catheters for monitoring of critically ill patients is provided in Table 22.6.41,42,48 Shoemaker et al. achieved superior outcomes in a small number of critically ill patients who were resuscitated to "supranormal" [i.e., oxygenation in excess of metabolic need) oxygen transport endpoints, but the hypothesis that more rapid "repayment" of the "oxygen debt" incurred in shock/ hypoperfusion is beneficial has been disproved by multiple recent studies.50 Another study suggested that use of a PAC may be associated with decreased mortality after acute renal failure." However, the preponderance of data has failed to demonstrate benefit, as shown in Table 22.6.52-54 Some retrospective data even suggest that PAC use is associated with excess mortality.P:" Several theories may explain why PAC use has not improved outcomes. In observational studies, mortality may be higher with PAC use because they are more likely to be placed in sicker patients," leading to a higher incidence of complications as well as misinterpretation of the data." Other clinicians have noted that goal-directed therapy guided by a PAC may lead to increased fluid administration and resultant abdominal compartment syndrome.59 Nevertheless, clini-

cians continue to believe that PACs do aid in the management of certain critically ill patients when combined with other objective and clinical data/" As with many physiological measurements, a changing trend in measurable parameters may be more informative than a single abnormal value. In the past 15 years, innovative new PACs have become available, including catheters that allow continuous monitoring of Q and continuous oximetric monitoring of Smv02. Continuous availability of data may be useful in certain circumstances where oxygen transport is marginal, such as patients with acute respiratory distress syndrome (ARDS) on high levels of positive end-expiratory pressure (PEEP). The application of PEEPcan decrease venous return markedly, and therefore Q, in a short time period; maintenance of Q is important to maintain ventilation-perfusion matching. Pulmonary artery catheters that measure right heart function by estimating right ventricular volume have also been championed in recent years. Proponents of this technology claim that a more accurate assessment of right ventricular preload can be obtained." This contention is arguable; there is a paucity of Class I data from patients managed by these "right ventricular" catheters. Complications specific or common to PACs include difficulty with insertion, infection (2%-5 %), hemopneumothorax (2%-5%), migration (5%-10%), patient discomfort, arrhythmia (10%-15%), and hemorrhage (0.2%). Other more rare complications have been reported, including catheter knotting resulting from redundancy of the catheter within the right ventricle (especially in patients with heart failure, cardiomyopathy, or increased pulmonary pressure); pulmonary

418

CHAPTER 22

~~. TABLE 22.6. Evidence for Utility of Pulmonary Artery Catheter in Monitoring Critica lly III Patients.

A uth or

Class of data

Richard et al.49

Numbers of patients: protoco l/control

Population

ICU patients with shock, sepsis, ARDS randomized with or without PA catheter High-risk surgical patients randomized with or without PA catheter

335/341

Rhodes et al."

ICU patients randomized with or without a PA catheter

90/105

Yu et al.48

ICU patient s with shock, sepsis, ARDS randomi zed to D0 2 > 600 or 450 mL/min/ m 2 Severely ill trauma patients resuscitated to 600mL/min/m 2 [supranorrnal] vs. 500mL/min/ rrr' [norma l] before and after ICU protocol change ICU patien ts with septic shock rando mized to CI > 6.0 or C1 3.0 Severely ill trauma patients randomized to CI > 4.5 L/ min/ m 2 or D0 2 > 670 m L/min/m 2 ICU patient randomized to supranormal goals of CI > 4.5 L/m in/m 2 , D0 2 > 600mL/min/m 2, CO 2 > 170mL/min/m 2

27/2 1 189 origina lly enrolled patients)

Sandham et al."

Balogh et al.59

II

Tuchschmidt et al. 53 Fleming et aU 2

Hayes et al. 54

78/77

Findings

No significant differences in mortality with or without catheter at day 14 No survival difference for in-hospital stay, 6 months or 12 months; PA catheter group with more pulmonary embolism No survival difference ; PA group had more fluids and more renal failure by ICU day 3 No mortality or myocardial infarction difference

85/71

Supranormal group with more organ failure, mortality, abdominal compartment syndrome

26/25

No significant mortality difference

33/34

Decreased mortality in protocol patients compared to control patients

50/50

Decreased mortality in control group compared to protoc ol group

ARDS, acute respiratory distress syndrome; CI, cardiac index; DO" oxygen delivery; ICU, intensive care unit; PA, pulmonary artery; VO" oxygen consumption.

infarction secondary to an overinflated or "permanently wedged" balloon; pulmonary artery perforation; intracardiac perforation; valvular injury; and endocarditis. A devastating complication is pulmonary artery rupture, which occurs in less than 0.1 % of cases of PAC usage. This catastrophic complication is generally fatal and occurs upon wedging the catheter during insertion or during routine determination of PAOP. Distal migration of the PAC within the pulmonary artery increases the risk dramatically of pulmonary artery rupture and argues for routine daily bedside chest radiography for all patients with an indwelling PAC.62

Noninvasive Cardiac Output Thoracic bioimpedance systems to monitor Q are being developed for clinical use. Thoracic bioimpedance derives information from topical electrodes placed onto the anterior chest and neck to estimate Q by incorporating a modified form of the Kubicek equation and by estimating the left ventricular systolic time interval from time 1/~ derivative bioimpedance signals . The lag time for the system to provide data is approximately 2 to 5 min from initial lead placement and activation. The main drawback of thoracic bioimpedance is that the

technique is very sensitive to any alteration of the electrode contact or positioning on the patient. The esophageal Doppler monitor (EDM) device is a soft, 6-mm catheter that is placed noninvasively into the esophagus. A Doppler flow probe at its tip allows continuous monitoring of Q and stroke volume. A 4-MHz continuous wave ultrasound frequency is reflected to produce a waveform , representing the change in blood flow in the descending aorta (about 80% of Q) with each pulsation. In contrast to the invasive PA catheter, the EDM does not require percutaneous insertion.f The EDM also avoids the risk of infection. An EDM may yield more accurate hemodynamic data than a PA catheter in patients with cardiac valvular lesions, septal defects, arrhythmias, or pulmonary hypertension. The primary disadvantage of the EDM is that the device may sometimes lose its waveform with only a slight positional change and render damped, inaccurate readings." Consequently, although both thoracic bioimpedance and esophageal Doppler monitoring represent potentially useful techniques for monitoring of Q, neither device has proved to be as consistently reliable as the invasive method of Q mea surement via PAC. Currently, no data exist to demonstrate superior outcomes between invasive and noninvasive hemodynamic monitoring techniques. However, a prospective


study comparing patients monitored simultaneously with PAC and bioimpedance techniques concluded that the methods gave comparable estimates of Q.65 Similarly, a trial comparing measurements between esophageal echo-Doppler and pulmonary artery catheters did demonstrate comparable values." The noninvasive modalities may still supplant the use of the PAC if equivalent results can be obtained with greater safety.

Intracranial Pressure Monitoring Monitoring of intracranial pressure (ICP) has become a standard method of evaluating patients with severe traumatic brain injury (TBI).67 Several different types of ICP monitors have been described. In TBI, these devices can be used to "optimize" the cerebral perfusion pressure (CPP) (mean arterial pressure minus ICP). Typically, the CPP should be kept above 60mmHg in these cases. Importantly, although ICP monitoring and calculation of CPP have become standard, no Class I data in human beings show an outcome benefit for ICP monitoring in patients with traumatic encephalopathy.68 Perhaps the most useful method of ICP monitoring involves the use of the intraventricular or "ventriculostomy" catheter. This device is the preferred method of ICP monitoring because the catheter can also drain cerebrospinal fluid and consequently decrease elevated ICP. In this way, the ventriculostomy can be both diagnostic and therapeutic. However, ventriculostomy is also the most invasive method of ICP monitoring and poses the highest infection risk (.. . 8 0/0). Occasionally, the ventriculostomy may be impossible to place or may become occluded because of severe brain edema or extruding brain matter. Other types of intracranial devices include an intraparenchymal monitor or the epidural bolt; no consensus has developed as to how to choose among these devices. Despite the high risk of infection with ventriculostomy, neither prolonged antibiotic prophylaxis nor, controversially, regular replacement of the catheter at 5- to 7-day intervals serves to reduce the risk.

Gastric Tonometry Tonometry is used to determine the gut intramucosal pH (pHd of the patient. Tonometer catheters are available for placement via the stomach or sigmoid colon. The tonometry catheter contains a port that leads to a chamber with a semipermeable membrane into which saline is instilled and allowed to equilibrate with the intragastric (or intracolonic) milieu. Investigators have focused on both the absolute pl-I, and the tissue CO 2 to arterial CO 2gradient as being surrogates of splanchnic perfusion and consequently markers of resuscitation. Proponents of the device believe it to be a valuable tool because gastric mucosal ischemia is an early sign of impaired splanchnic perfusion, which in tum is believed to be more sensitive as an indicator of hypoperfusion than global indicators such as Q or acidosis." Optimal splanchnic perfusion during surgery has been suggested to decrease complications postoperatively after abdominal surgery, cardiac surgery, and aortic aneurysm repair. 7o,71 A recent multicenter, observational study in elective general surgery patients revealed

419

that patients monitored with semicontinuous gastric tonometry could be predicted accurately to have postoperative complications based on the gastric: ETC0 2 ratio." Questions persist as to the utility of gastric tonometry. Prospective trials demonstrating superior outcomes with the device have yet to be published, despite more than a decade of use. Tonometry has fallen into disfavor as well because the device is expensive, difficult to use, and prone to dislodgment and errors of calibration. Consequently, most clinicians currently use acidosis, base deficit, hyperlactatemia, creatinine clearance, or Smv02 to guide resuscitation. Newer tonometers that utilize air rather than saline, or which use fiberoptic infrared technology to measure mucosal blood flow directly, may revitalize this approach to monitoring.

N ear-Infrared Spectroscopy Near-infrared (NIR) technology relies on the principle that mitochondrial cytochrome a, a redox shifts can be determined by near-infrared wavelength reflection, which can penetrate skin and bone. In animal studies, significant correlations were detected between certain NIR waveform attributes and oxygen delivery during shock, with NIR probes placed directly on the stomach, small bowel, and other viscera. Consequently, NIR technology appears to be useful for assessing tissue perfusion." Also, NIR monitoring of small bowel pH may be used to gauge the adequacy of resuscitation. However, the technique is still being adapted, especially for indications other than hemorrhagic shock. Near-infrared spectroscopy may also develop a variety of other clinical uses including detection of compartment syndrome, neonatal perfusion, vascular graft patency, and microvascular flap perfusion." This technology is useful for the early detection of ischemia by external placement of the probe after free tissue transfer. The technology may prove useful for postoperative monitoring of the patency of lower extremity vascular bypass grafts, onset of extremity compartment syndrome, or the risk of wound failure or surgical site infection after surgery.

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31. O'Quin R, Marini H. Pulmonary artery occlusion pressure; clinical physiology, measurement and interpretation. Am Rev Respir Dis 1983;128:319-326. 32. Stetz CW, Miller RG, Kelly GE, et al. Reliability of the thermodilution method in the determination of cardiac output in clinical practice. Am Rev Respir Dis 1982;126:1001-1010. 33. Barie PS. Perioperative management. In: Norton JA, Lowry SF, Pass H, et al., eds. Surgery: Scientific Basis and Current Practice. New York: Springer-Verlag, 2000:363-395. 34. Bender JS,Smith-Meek MA, Jones CEo Routine pulmonary artery catheterization does not reduce morbidity and mortality of elective vascular surgery: results of a prospective, randomized trial. Ann Surg 1997;226:229-236. 35. Isaacson IJ, Lowdon JD, Berry AT, et al. The value of pulmonary artery and central venous monitoring in patients undergoing abdominal aortic reconstructive surgery: a comparative study of two selected, randomized groups. J Vase Surg 1990;12:754760. 36. Berlauk JF, Abrams JH, Gilmour IT, et al. Perioperative optimization of cardiovascular hemodynamics improves outcome in peripheral vascular surgery. Ann Surg 1991;214:290-299. 37. Ziegler DW, Wright JG, Choban PS, et al. A prospective randomized trial of preoperative optimization of cardiac function in patients undergoing elective peripheral vascular surgery. Surgery (St. Louis) 1997;22:584-592. 38. Valentine RF, Duke ML, Inman MH, et al. Effectiveness of pulmonary artery catheters in aortic surgery. A randomized trial. J Vase Surg 1998;27:203-212. 39. Fischer SP. Cost-effective preoperative evaluation and testing. Chest 1997;115(suppl):96S-100S. 40. Bonazzi M, Gentile F, Biasi GM, et al. Impact of perioperative haemodynamic monitoring on cardiac morbidity after major vascular surgery in low risk patients. A randomised pilot trial. Eur J Vase Endovasc Surg 2002;23:445-451. 41. Rhodes A, Cusack RJ, Newman PJ, et al. A randomised, controlled trial of the pulmonary artery catheter in critically ill patients. Intensive Care Med 2002;28:256-264. 42. Sandham JD, Hull RD, Brant RF, et al. A randomized, controlled trial of the use of pulmonary-artery catheters in high-risk surgical patients. N Engl J Med 2003;348:5-14. 43. Morris AH, Chapman RH, Gardner RM. Frequency of technical problems encountered in the measurement of pulmonary artery wedge pressure. Crit Care Med 1984;12:164-170. 44. Trottier S1, Taylor RW. Physicians attitudes toward and knowledge of the pulmonary artery catheter: Society of Critical Care Medicine membership survey. New Horiz 1997;5:201-206. 45. Shippy CR, Appel PL, Shoemaker WC. Reliability of clinical monitoring to assess blood volume in critically ill patients. Crit Care Med 1984;12:107-112. 46. Connors AF, Speroff T, Dawson NV, et al. The effectiveness of right heart catheterization in the initial care of critically ill patients. JAMA 1996;276:889-897. 47. Boyd 0, Grounds RM, Bennett ED. A randomized clinical trial of the effect of deliberate perioperative increase of oxygen delivery on mortality in high-risk surgical patients. JAMA 1993;270:2699-2707. 48. Yu M, Takanishi D, Myers SA, et al. Frequency of mortality and myocardial infarction during maximizing oxygen delivery: a prospective, randomized trial. Crit Care Med 1995;23:10251032. 49. Richard C, Warzawski J, Anguel N, et al. French Pulmonary Artery Catheter Study Group. Early use of the pulmonary artery catheter and outcome in patients with shock and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2003;290:2713-2720. 50. Shoemaker WC, Appel PL, Kram HB, et al. Prospective trial of supranormal values of oxygenation as therapeutic goals in highrisk surgical patients. Chest 1988;94:1176-1186.


51. Uchino S, Doidg GS, Beloomo R, et al. Diuretics and mortality in acute renal failure. Crit Care Med 2004;32:1669-1677. 52. Fleming A, Shop M, Shoemaker W, et al. Prospective trial of supranormal values as goals of resuscitation in severe trauma. Arch Surg 1992;7:1175-1179. 53. Tuchschmidt J, Fried J, Astiz M, et al. Elevation of cardiac output and oxygen delivery improves outcome in septic shock. Chest 1992;102:216-220. 54. Hayes MA, Timmins AC, Yau EH, et al. Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Engl J Med 1994;330:1717-1 722. 55. Marik PE. Pulmonary artery catheterization and esophageal Doppler monitoring in the ICU. Chest 1999;116:1085-1091. 56. Connors AFT, Speroff T, Dawson NV, et al. The effectiveness of right heart catheterization in the initial care of critically ill patients. SUPPORT Investigators. JAMA 1996;276:889-897. 57. Zion MM, Balkin J, Rosenmann D, et al. Use of pulmonary artery catheters in patients with acute myocardial infarction. Analysis of experience with 5,841 patients in the SPRINT registry. Chest 1990;98:1331-1335. 58. Iberti TJ, Fischer EP, Leibowitz AB, et al. A multicenter study of physician's knowledge of the pulmonary artery catheter: Pulmonary Artery Catheter Study Group. JAMA 1990;264:29282932. 59. Balogh Z, McKinley BA, Cocanour CS, et al. Supranormal trauma resuscitation causes more cases of abdominal compartment syndrome. Arch Surg 2003;138:637-643. 60. Shoemaker WC. Use and abuse of the balloon tipped pulmonary artery (Swan-Ganz) catheter: are patients getting their money's worth? Crit Care Med 1990;18:1294-1296. 61. Diebel L, Wilson R, Tagett MG, et al. End diastolic volume: a better indicator of preload in the critically ill. Arch Surg 1992;127:817-822. 62. Fang Y, Whalen GF, Hariri RH, Barie PS. Utility of daily chest radiographs in the surgical intensive care unit: a prospective study. Arch Surg 1995;130:764-768. 63. Eachempati SR, Young C, Alexander J, et al. The clinical use of an esophageal Doppler monitor for hemodynamic monitoring in sepsis. J Clin Manit Comput 1999;15:223-225.

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64. Lefrant JY, Bruelle P, Aya AG, et al. Training is required to improve the reliability of esophageal Doppler to measure cardiac output in critically ill patients. Intensive Care Med 1998;24:347352. 65. 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 1998;114:1643-1652. 66. Su NY, Huang CJ, Tsai P, et al. Cardiac output measurement during cardiac surgery: esophageal Doppler versus pulmonary artery catheter. Acta Anaesthiol Sin 2002;40:127-133. 67. Rincon F, Mayer SA. Novel therapies for intracerebral hemorrhage. Curr Opin Crit Care 2004;10:94-100. 68. Forsyth R, Baxter P, Elliott T. Routine intracranial pressure monitoring in acute coma. Cochrane Database Syst Rev 2001;3: CD002043. 69. Hameed SM, Cohn SM. Gastric tonometry: the role of mucosal pH measurement in the management of trauma. Chest 2003;123(5 suppl):475S-481S. 70. Gardeback M, Settergren G, Brodin LA, et al. Splanchnic blood flow and oxygen uptake during cardiopulmonary bypass. J Cardiothorac Vase Anesth 2002;16:308-315. 71. Frumento RJ, Mongero L, Naka Y, Bennett-Guerrero E. Preserved gastric tonometric variables in cardiac surgical patients administered intravenous perflubron emulsion. Anesth Analg 2002;94:809-814. 72. Lebuffe G, Vallet B, Takala J, et al. A European, multicenter, observational study to assess the value of gastric-to-end tidal PC02 difference in predicting postoperative complications. Anesth Analg 2004;99:166-172. 73. Cohn SM, Crookes BA, Proctor KG. Near-infrared spectroscopy in resuscitation. J Trauma 2003;54(5 suppl):S199-S202. 74. Gentilello LM, Sanzone A, Wang L, et al. Near-infrared spectroscopy versus compartment pressure for the diagnosis of lower extremity compartmental syndrome using electromyographydetermined measurements of neuromuscular function. J Trauma 2001;51:1-9.

Imaging of the Critically III Patient Amy D. Wyrzykowski and Grace S. Rozycki Chest Radiographs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423 Ultrasound 423 Developing Portable Technologies . . . . . . . . . . . . . . . . . . 431

F

or reasons of cost -effectiveness, time savings, and, most importantly, patient safety, diagnostic and therapeutic procedures are being performed more frequently in the intensive care unit (ICU) at the patient's bedside . This development is not surprising, because the transport of patients to other areas of the hospital, the "road trip," may be associated with risks that should not be undertaken without a judicious assessment of the risk :benefit ratio of the test. Some of the adverse events that have occurred during the se transports include delays in th e administration of medication, equipment malfunction, malposition of the patient's endotracheal tube, and cardiopulmonary arrest .V Although th e implementation of a specially trained ICU transport team has been shown to reduce th ese complications, there is a trend to avoid the risks altogether by doing as much imaging in the ICU as possible .v'" To that end, the following includes a discussion of the most commonly performed imaging procedures in the intensive care environment.

Chest Radiographs The portable chest radiograph (pCXR) is one of the most common radiologic tests performed on the critically ill patient. In a recent study, it was estimated that about 12,000 pCXRs were performed annually in one academic medical center." Table 23.1 lists the common indications for the performance of a portable CXR in the ICU. Frequently, the film is both ordered and interpreted by the surgeon who knows the patient's history, performs the physical examination or invasive procedure , and understands the patient's clinical picture. With this comprehensive knowledge of the pat ient and a systematic method for reading the film (Table 23.2), the surgeon can make rapid and accurate decisions about the patient's management. The clinical utility and the cost-effectiveness of performing routine daily pCXRs on patients in the ICU have been questioned and, therefore , the frequency with which they should be performed has yet to be clearly established.

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 431 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431

Although some authors suggest that daily pCXRs should be performed on almost all patients in the ICU, others recommend that the decision to perform a pCXR be based on the patient's clinical picture.v" The latter practice is supported by a study that showed no decrease in either length of stay or mortality of critically ill patients who had daily pCXRs.s In contrast, however, there are data to support that the routine performance of these films is beneficial when unanticipated pathology or the malposition of a life support device is detected and addressed before a complication ensues.' Figures 23.1, 23.2, and 23.3 provide examples of unanticipated findings from daily pCXRs that required intervention. Although both sides of the argument are reasonable, clinical judgment and patient acuity should be taken into consideration when deciding if a daily, routine pCXR is needed . Furthermore, as the patient's clinical condition changes, this issue should be reassessed frequently. In addition to cost, another concern raised regarding the use of a daily pCXR is the cumulative radiation exposure to which th e patient is subjected. In reality, the amount of radiation exposure with a CXR is minimal compared with other radiographic studies. Even in the most critically ill patients with prolonged ICU stays, the cumulative radiation exposure from daily pCXRs is only two to three times that of th e background radiation in the United States and well within safe Iimits.v" Regardless, it is recommended that appropriate lead shields be utilized, part icularly for children and gravid patients, to protect the neck and pelvis as appropriate. Of note , so long as standard radiation precaution protocols are adhered to, it has also been documented that these studies do not pose a radiation hazard to the healthcare provider in the intensive care unit. 10

Ultrasound The surgeon 's use of ultrasound is particularly applicable to th e evaluation of critically ill patients for several reasons : (11 many patients have a depressed mental status, making it dif423

424

CHAPTER 23

TABLE 23.1. Common Indications for pCXR in the ICU. Indication for peXR

Change in clinical status Hypoxia

Fever Purulent sputum Postprocedure monitoring Intubation Central line placement

What to look for

• Atelectasis • Poor placement of endotracheal tube • Lobar collapse • Effusion • Hemothorax • Pneumothorax • Infiltrate • Contusion • ARDS • Infiltrate • Loculated effusion • Infiltrate

Pulmonary artery catheter (PAC)

• • • •

Thoracentesis

• •

Chest tube placement

• • • •

Appropriate tube position Ensure tip is in SVC Evaluate for pneumothorax Ensure PAC tip is in appropriate position Evaluate for pneumothorax Evaluate adequacy of procedure Evaluate for pneumothorax Evaluate position of tip of tube Evaluate position of sentinel hole Assess resolution of pneumothorax, hemothorax, or effusion

pCXR, portable chest X-ray; PAC, pulmonary artery catheter; SVC, superior vena cava; ARDS, acute respiratory distress syndrome.

ficult to elicit pertinent signs by physical examination; (2) physical examination is further hampered by tubes, drains, and monitoring devices; (3) the clinical picture often changes, necessitating frequent reassessments; (4) transportation to other regions of the hospital is not without risk; and (5) these patients frequently develop complications, which if diagnosed and treated expediently may lessen their morbidity, length of stay in the ICU, and mortality.'! Both diagnostic and therapeutic ultrasound examinations can be performed by the surgeon while on rounds in the ICU. These focused examinations should be done with a specific purpose and as an extension of the physical examination, not as its replacement. Several retrospective studies have documented the utility of portable ultrasound examinations performed in diverse groups of critically ill patients.P:" In these studies, evaluation for sepsis of unknown origin, suspected gallbladder pathology, and renal dysfunction were the most common indications for the examinations. Slasky et al. reported their findings on the ultrasound evaluations of 107 patients in the ICU. 14 The sonographic results of their examinations supported the suspected diagnosis in 29 (270/0) patients and excluded the initial diagnosis in 78 (73%) patients. There were no false-negative studies in this series. Additionally, 22 of the ultrasound examinations showed unsuspected abnormalities, but the management of only 5 patients was altered on the basis of these findings. Lichtenstein and Axler performed ultrasound examinations prospectively on 150 consecutive patients admitted to

the medical ICU. 13 The purpose of their study was to determine which patients had their clinical management altered as a result of routine ultrasound examinations performed within 48h of admission. Examinations of both pleural cavities, the abdomen, and the femoral veins were performed and interpreted by members of the ICU team. They found that information derived from their sonographic examinations contributed directly to a change in the management of 33 (22%) patients. There was one missed diagnosis in this series in which the ultrasound examination was initially believed to be consistent with peptic ulcer disease; however, the patient was diagnosed subsequently with and treated for renal pathology. They concluded that ultrasound examinations of critically ill patients should be performed frequently because of their diagnostic accuracy and positive effect on patient care. Lerch et al. performed and interpreted 690 ultrasound examinations on patients admitted to a medical ICU. 12 A total of 71 patients during the study required emergency abdominal surgery. The bedside sonographic examination provided the definitive diagnosis in 18 (25%) of the 71 patients, thereby TABLE 23.2. A Suggested Systematic Method for Reading a Chest X-Ray. Area or part visualized

What to look for

Label

• Correct patient • Correct day • CXR should not be under- or overpenetrated • The symmetrical view of the clavicles is a good indicator of the patient's position. • Examine all the bone fractures, including the clavicles and scapula • Examine the soft tissue for signs of subcutaneous emphysema • Note the position of the endotracheal tube, central lines, and foreign bodies • Nonvisualization of the hemidiaphragm should prompt consideration of the following: 1. Diaphragm rupture 2. Pulmonary contusion 3. Infiltrate 4. Effusion 5. Atelectasis • An abnormally high diaphragm may be indicative of: 1. A paralyzed diaphragm 2. An intraabdominal process (especially with pneumoperitoneum without recent «7 days) abdominal surgery) • An abnormally low costophrenic angle may be indicative of a pneumothorax (deep sulcus sign) • Examine for: 1. Pneumothorax 2. Hemothorax/effusion 3. Infiltrate 4. Contusion 5. Atelectasis • Subtle changes, new lesions

Penetration and position

Bones and soft tissues

Tubes and lines Hemidiaphragm

Lung parenchyma

Comparison with previous film

IMAGING OF THE C R I TI C A L L Y ILL PATIENT

FIGURE 23.1. Pulmonary artery catheter (PAC) advanced too far. Note the position of the tip of the PAC. Attempting to wedge the PAC in this position by inflating the balloon could result in the lethal complication of pulmonary artery rupture.

obviating the need for further diagnostic studies. Operative findings at exploration confirmed the initial clinical diagnosis in all 18 cases. The authors suggested that the patients most likely to benefit from a bedside ultrasound examination are those with occult hemorrhage and sepsis of unknown origin. In the surgical intensive care unit (SleU) at Grady Memorial Hospital, surgeons routinely perform bedside ultrasound on patients to examine for intraabdominal fluid collections hemoperitoneum, pleural effusions, and femoral vein thrombosis, and as a guide for the cannulation of central veins in patients with difficult access.

FIGURE 23.2. Inappropriately placed right thoracostomy [chest] tube.

425

FIGURE 23.3. Film taken approximately 12h following the initiation of tube [enteral] feeding. The feeding tube labeled Dobhoff was placed at the bedside the previous day, and position was confirmed by auscultation. As it was believed the feeding tube was placed appropriately in the stomach, feedings were initiated. This portable chest X-ray (pCXRI taken the following morning clearly shows that the feeding tube is actually in the right lower lobe (RLLI bronchus. The "effusion " is actually feeding solution.

Intraperitoneal Fluid/Blood Developed for the evaluation of injured patients, the focused Assessment for the Sonography of Irauma (FASTl is a rapid diagnostic examination to assess patients with potential truncal injuries. IS-I ? The test surveys sequentially for the presence or absence of blood in the pericardial sac and depen dent abdominal regions, including the right upper quadrant, left upper quadrant, and pelvis. Ultrasound transmission gel is applied on four areas of the thoracoabdomen, and the examination is conducted in the following sequence: the pericardial area, right upper quadrant, left upper quadrant, and the pelvis (Figure 23.4) The pericardial area is visualized first so that blood within the heart can be used as a standard to set the gain and ensure that hemoperitoneum will appear anechoic. A 3.5-MHz convex transducer is oriented for sagittal sections and positioned in the subxiphoid region to identify the heart and to examine for blood in the pericardial sac. Normal and abnormal views of the heart are shown in Figure 23.5. Occasionally, this view is unobtainable in a patient who has a narrow subxiphoid area, and a parasternal or apical view is needed . The transducer is then placed in the right midaxillary line between the l lth and 12th ribs to identify the liver, kidney, and diaphragm. The presence or absence of fluid is sought in Morison's pouch and in the subphrenic space (Figure 23.6) Next, with the transducer positioned in the left posterior axillary line between the 10th and l l th ribs, the spleen and kidney are visualized. The presence or absence of blood is sought in between the two organs and in the subphrenic space (Figure 23.7j. Finally, the transducer is directed for a transverse view and placed about 4 cm superior to the symphysis pubis. It is swept inferiorly to obtain a coronal view of the

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FIGURE 23.4. Transducer positions for the focused Assessm ent for the ~onography of Trauma (FAST) examination of the abdomen : pericardial, right upper quadrant, left upper quadrant, and pelvis.

A

FIGURE 23.5. Pericardial view of the FAST. A. Normal pericardial window . Note that the heart and liver appear contiguous, separated only by the pericardium. B. Abnormal pericardial view with fluid

A

FIGURE 23.6. Right upper quadrant FAST. A. Normal ultrasound examination of the right upper quadrant or Morison's pouch. Note the diaphragm abuts the liver, which rests directly on the right

B appearing as an anechoic band between the heart and the pericardium.

B kidney . B. A copious amount of fluid appears between the diaphragm and the liver as well as between the liver and the right kidney.

IMA GING OF THE CRITICALLY ILL PATIENT

A

427

B

FIGURE 23.7. Left upper quadrant FAST. A. Normal left upper quadrant FAST or splenorenal window. Note that the spleen appears to be in direct contact with the kidney. B. Fluid is clearly

present between the spleen and kidney, making this an abnormal examination.

full bladder and the pelvis, examining for the presence or absence of blood (Figure 23.8a,b). In our experience, an indirect sign of a pelvic hematoma is elongation of the bladder, as shown in Figure 23.8c. A sudden decrease in a patient's blood pressure or persistent metabolic acidosis despite continued resuscitation are common indications to reassess the peritoneal cavity as the source of hemorrhage. The FAST examination can be performed as needed at the patient's bedside to exclude hemoperitoneum as a potential source of hypotension. This examination may be applied to the patient with multisystem in juries or the patient receiving anticoagulant therapy. In these cases, ultrasound can detect hemoperitoneum rapidly, or, occasionally, retroperitoneal hemorrhage. Ultrasound can also be used to evaluate a patient who has ascites and to perform an ultrasound-guided aspiration of the fluid without injury to the bowel.

strated that surgeons can perform ultrasound examinations successfully for patients with acute abdominal pain and use the information to assist with management.

TECHNIQUE

The ultrasound study used to detect or exclude hemoperitoneum is the FAST examination that was described earlier. Examination of the peritoneal cavity with ultrasound should be performed in a systematic fashion to ensure that abnormal findings are not missed. As described by Miner and Sly, the patient is placed in the supine position, and the right upper quadrant is imaged with the transducer oriented for longitudinal sections. " The gallbladder, liver, and kidney are identified with special attention focused on the subhepatic space. The mobility of the diaphragm is also confirmed as the patient breathes, and the right subdiaphragmatic region and right pleural cavity are inspected for fluid collections. The left upper quadrant is imaged in a similar fashion with the transducer oriented in the longitudinal direction. The diaphragm, spleen, and left kidney are identified, and the pleural cavity, subphrenic space, and splenorenal recess are examined for fluid. Parys et al. conducted their own study of surgeonperformed ultrasound examinations for the evaluation of patients with acute abdominal pain ." These studies demon-

Pleural Effusions One of the earliest reports on the use of ultrasound for the evaluation of fluid collections in the pleural space was written by Joyner et al. in 1967.20 Gryminski et al.ll were the first to document the superiority of ultrasound over standard radiography for the detection of pleural fluid . Using A-mode ultrasonography, they found that ultrasonography detected pleural fluid in 74 (93%) of 80 patients, whereas plain radiography detected pleural fluid in only 66 (83%) of these patients. In addition, ultrasonography established the absence of fluid in 32 (89%) of 36 patients compared to only 26 (61 %) for standard X-rays. Adams and Galati used M-mode ultrasound to identify fluid in 34 of 50 patients whose physical and radiographic examinations were nondiagnostic for pleural cavity disease." In this series, 30 of 34(88%) patients had a successful ultrasound-guided thoracentesis with the aspirates ranging from 10mL to 1 L. Using a slight modification of the FAST and applying basic ultrasound physics principles, a focused thoracic ultrasound examination was developed that can be used for the detection of a traumatic or nontraumatic pleural effusion ." The ultrasound examination of the thorax is performed using a 3.5-MHz convex transducer while the patient is supine. Ultrasound transmission gel is applied to the right and left lower thoracic areas in the mid- to posterior axillary lines (Figure 23.9). The transducer is slowly advanced cephalad to interrogate the supradiaphragmatic space for the presence or absence of an effusion (Figure 23.10). In our institution, we recently examined the utility of ultrasound in the SIeu and its value in teaching physical examination to a medical student. Serial focused thoracic ultrasound examinations were performed by a surgeon-sonographer and medical student for the early detection of pleural effusions in critically ill patients." Ultrasound images were

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critically ill patients and that the results can be used successfully in the decision matrix for patient care. TECHNIQUE

In the SICU at Grady Memorial Hospital, ultrasound-directed

thoracentesis procedures are performed at the bedside by the Surgery/ICU Team. The head of the bed is elevated to a 45°-60° angle if the patient's spine is not injured, if spine precautions are needed, the patient is kept flat but the bed is placed in the reverse Trendelenburg position. A 3.5- or 5.0MHz transducer is oriented for sagittal sections and placed on the chest wall in the region of the midaxillary line at the sixth or seventh intercostal region. The liver (or spleen) and diaphragm are identified. Normally, the lung is seen poorly as a result of the presence of air within the alveoli, which produces weak transmission of the ultrasound waves. In contrast, in the presence of pleural fluid, the lung can be seen moving freely with respirations during real-time imaging. After the fluid is localized, the area adjacent to the transducer is marked using a felt-tipped pen, and the chest is prepared and draped for this procedure using sterile technique. Local anesthesia is injected into the skin near the mark and extended to the underlying subcutaneous tissue and parietal pleura with a 22- or 25-gauge needle . The pleural space is entered with an 18-gauge needle obtained from a commercial central line kit and then the pleural fluid is aspirated in its entirety. For large effusions, a guidewire is passed through the needle into the pleural cavity using the Seldinger technique. A small skin incision is made around the guidewire and, if necessary, a dilator is passed just through the dermis, but not into the pleural cavity, to facilitate passage of the catheter. A standard central venous catheter is placed into the pleural space, and a three-way stopcock is connected to one of the ports so that the fluid can be aspirated entirely and collected for analysis. The catheter is removed from the pleural space while applying constant suction with a syringe, and then an occlusive

A

B

i

c FIGURE 23.8. A. Normal ultrasound view of the pelvis. B. Fluid is seen to surround the bladder. C. Deformation of the normal contour of the bladder suggests the presence of a pelvic hematoma that compresses the bladder extrinsically.

recorded on hard copy and videotape and then compared with the chest X-ray readings, yielding an 83.6% sensitivity, 100% specificity, and 94% accuracy for the detection of pleural effusion with ultrasound. Based on these findings, some patients underwent an early thoracentesis or insertion of a thoracostomy tube . We concluded that a focused thoracic ultrasound examination detects pleural effusions reliably in

FIGURE 23.9. FAST plus 2. The original FAST examination with two additional views to assess for the presence of fluid in the pleural cavity.

IM A GIN G O F T HE C R IT I CAL L Y I LL PATIENT

429

B

A FIGURE 23.10. Ultrasound examination of the pleural cavity. A. Normal view of the pleural cavity on ultrasound examination.

air, whichis not a good mediumforultrasoundtransmission. B. Lung is clearly seen "floating" in fluid within the pleural cavity.

dressing is placed over the small inci sion . Real-time ultrasound imaging can also be used for the detection and aspiration of small or loculated fluid collections because the needle is observed as it enters the collection and collapse of the space confirms that the fluid is removed entirely.

an ultrasound machine that has color flow duplex and Doppler capabilities. We have found that ultrasound-guided central venous catheter insertions are especially useful in patients with anasarca or morbid obesity and for the immobilized patient with a potential cervical spine injury. The internal jugular vein is easily visualized with ultrasound. With a 7.5-MHz transducer, the internal jugular vein and common carotid artery are identified using B-mode imaging. Although color flow duplex and Doppler imaging can be used to localize the vein, such technology is generally not necessary. The skin insertion site may be marked before creating a sterile field, or the cannulation can be performed with real-time imaging. Cannulation of th e subclavian vein is slightly more difficult because of its location beneath the clavicl e and, therefore, color flow duplex and Doppler ultrasound may be beneficial in identifying the vein before cannulation. We suggest a technique similar to that described by Gualtieri et al. 29 The axillary vein and artery are identified caudal to the lateral aspect of the clavicle. Patency of the vein is determined by its ability to be compressed easily with the ultrasound transducer. The vein is then imaged about 2 to 3 em medially to the point of the planned insertion sit e. The transducer should be held in the nondominant hand, and the cannulating needle is followed during real-time imaging as it trav erses the soft tissue toward the vein . Once the vein is cannulated, the remainder of th e procedure is completed using the standard Seldinger technique.

The normal lung is difficult to discern as the alveoli are filled with

Central Venous Catheter Insertion Placement of a central venous catheter is a commonly performed procedure for critically ill patients. Complication rates range from 0.3% to 12% and include failure to cannulate the vessel, hemothorax, pneumothorax, dysrhythmia, venous thrombosis, and misplacement of the catheter.25,26 As expected, adverse events occur more frequently when cannulation is performed by inexperienced phys icians . In the past decade, several studies have evaluated the use of ultrasound as an aid for central venous catheter placement to reduce the incidence of complications.v'" Fry et al. used ultrasound guidance to obtain central venous access successfully in 52 pati ents who had relative contraindications to the procedure. With the exception of a single pneumothorax, no other complications were not ed." These studies suggest that th e use of real-time audio Doppler or duplex ultrasound results in a decreased number of cannulation attempts and complications for subclavian and internal jugular venous catheter procedures. This result was especially notable when the procedures were performed by junior housestaff. " On the other hand, Mansfield et al. reported a large experience of 821 cannulations of the subclavian vein in a prospective, randomized trial using duplex imaging ." The authors found no difference in the rate of successful cannulations or complications using this localization technique. Although surgical residents are generally adept at th e insertion of central venous catheters, ultrasoundguided procedures may be helpful when th e resident is learning the technique initially, or when th e patency of a vessel is unc erta in. TECHNIQUE

The central veins in the cervical and upper thoracic region can be imaged easily with a 7.S-MHz linear transducer and

Common Femoral Vein Thrombosis Important risk factors associated with deep vein thrombosis (DVTj after major trauma include head and spinal cord injuries, prolonged immobilization, pelvic fractures, major venous in jury, and advanced age.32-3 5 Depending on the methods of detection and the index of suspicion, the incidence of DVT varies from 4.7% to 60% in these patients.34,36--38 Many thromboses, however, remain silent clin ically or present as sudden death from a pulmonary embolism, making th e actual inci dence of DVT higher. Despite DVT prophylaxis with lowdose unfractionated heparin, low molecular weight heparin,

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and sequential pneumatic compression devices to the lower extremities, DVT still occurs in high-risk injured patients, emphasizing the inadequacy of prophylaxis alone.33,37,39 In our SICU, select high-risk patients receive DVT prophylaxis and a weekly screening formal duplex study. The characteristics of venous thrombosis as seen on the duplex imaging study include the following: dilation, incompressibility, echogenic material within the lumen, absent or decreased spontaneous flow, loss of phasic flow with respiration, and absent or decreased augmentation of flow with com pression of the veins.40,4 1 In the diagnosis of acute DVT, incompressibility and visualization of the thrombus are the major diagnostic criteria.40,42,43 The other ultrasound characteristics of DVT, such as absent or decreased spontaneous flow, loss of phasic flow with respiration, and absent or decreased augmentation of flow with compression, are evident with the use of duplex scanning, which combines Band Doppler flow modes. Although each ultrasound characteristic of a thrombosed vein is important in making the diagnosis of DVT, loss of compressibility of a thrombus-filled vein is the most useful with the other criteria considered supportive of the diagnosis.41,43-I5 In an effort to detect DVT as early as possible and to define further those patients who develop DVT despite prophylaxis, we developed a focused ultrasound examination of the femoral veins for the detection of intraluminal thrombus." Our focused ultrasound examination is based on the following principles: (1) most lethal pulmonary emboli originate from the iliofemoral veins; (2) the common femoral artery is identified as a pulsatile vessel lateral to the common femoral vein on B-mode ultrasound, therefore providing a consistent anatomic landmark; (3) B-mode ultrasound can be used to evaluate for vein incompressibility, echogenic material (thrombus) within the lumen of the vein, and dilation of the vein; and (4) surgeons are familiar with B-mode ultrasound because it is used frequently by them to detect hemopericardium, hemoperitoneum, and pleural effusion/traumatic hemothorax in critically ill patients, hence enhancing its practical applicability in this setting. 17,23,47- 50 In addition to its role as a diagnostic modality for DVT, ultrasound is increasingly being utilized in the prevention of pulmonary embolism. Using real-time intravascular ultrasound to assess the diameter of the inferior vena cava and location of the renal veins, inferior vena cava filters can be placed at the bedside in the critically ill patient safely and accurately.t':" In addition to avoiding the need for transportation of the critically ill patient to the radiology suite or operating room for filter placement, the bedside ultrasound-guided procedure also eliminates the need for potentially nephrotoxic intravenous contrast. TECHNIQUE

The focused ultrasound examination of the common femoral veins is performed with the patient in the supine position as an extension of the physical examination. A 7.5-MHz transducer is used to examine the common femoral veins according to the following protocol, as described by Lensing et a1. 4 1 1. The transducer is oriented for transverse imaging and the right common femoral vein and artery are visualized (Figure 23.11a).

B FIGURE 23.11. Ultrasound exami nation of the femoral vasculature. A. Normal transverse view of the comm on femoral artery (CFA) and common femoral vein (CFV). B. Attempt to compress the common femoral vein unmasks the presenc e of thrombus within the lumen of the CFV.

2. The vein is examined for the presence or absence of intraluminal echogenicity (consistent with thrombus) (Figure 23.l1b) and for ease of compressibility. 3. The transducer is positioned for sagittal images and a view of the common femoral vein is identified. The vein is inspected for intraluminal thrombus and adequate compressibility. The diameter of the vein is measured just distal to the saphenofemoral junction. 4. The same examination (steps 1 through 3) is then conducted on the left lower extremity.t' :"

A positive study is defined as dilation of the common femoral vein (more than 10% increase) when compared to the opposite extremity, incompressibility of the vein, or the pres ence of echogenic foci consistent with an thrombus.53 A negative study is the presence of a normal caliber vein with good

IMAGING OF THE CRITICALLY ILL PATIENT

compressibility and the absence of an echo genic intraluminal thrombus. Although this focused examination is not equivalent to the duplex imaging study, it can provide valuable clinical information as a routine screening tool or for the rapid assessment of a patient in acute distress in whom pulmonary embolism is in the differential diagnosis. For example, a 68year-old man with a history of prostate cancer and a recent subtotal colectomy for lower gastrointestinal bleeding underwent a focused routine ultrasound screening of the common femoral veins while in the SICU. He was asymptomatic with adequate DVT prophylaxis, but a thrombus was noted in the right femoral vein on focused examination, later confirmed by duplex imaging; the patient underwent placement of an inferior vena cava filter. Another example is that of a 74-yearold man who underwent a colectomy for cancer and in the postanesthesia care unit suddenly developed cardiopulmonary collapse. The pCXR and electrocardiogram were unremarkable, but the arterial blood gas showed a markedly abnormal D[A-a]02' Ultrasound of the right femoral vein demonstrated a thrombus. In contrast, evaluation of the left femoral vein was normal. Such findings supported the diagnosis of a pulmonary embolism and facilitated early treatment.

Developing Portable Technologies Portable Computed Tomography Computed axial tomography (CT) scans have become integral in the management of the critically ill patient. CT scans are used to follow up on known injuries such as traumatic brain injury and blunt solid organ injuries that are being managed nonoperatively. These scans provide valuable diagnostic information for a wide range of maladies from sinusitis to intraabdominal abscesses to tumors. Interventions such as the drainage of abscesses, bilomas, loculated pleural effusions, and empyemas performed with CT guidance have also become invaluable. Unfortunately, it is often the most critically ill patients, patients with decompensated septic shock or worsening neurological examinations, who need CT scans, and physicians are often reticent to transport these tenuous patients even with appropriate resources. To address these issues, portable CT scanners have been developed and are in use in a handful of centers worldwide. Although the data on portable CT scans are limited, initial reviews have been favorable, with portable CT offering a potentially safer alternative to conventional CT scan. 54-56

Conclusion Theoretically, any imaging modality that exists within the hospital is available to the critically ill patient in the ICU. However, the risks of road trips required to accomplish this imaging should not be underestimated in these often tenuous patients. To minimize these risks, we recommend that as much imaging as possible be conducted within the ICU, which is arguably the safest environment for the patient. To that end, the use of pCXR and ultrasound should be optimized.

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References 1. Stearley HE. Patients' outcomes: intrahospital transportation and monitoring of critically ill patients by a specially trained ICU nursing staff. Am J Crit Care 1998;7(4):282-287. 2. Lovell MA, Mudaliar MY, Klienberg PL. Intrahospital transport of critically ill patients: complications and difficulties. Anaesth Intensive Care 2001;29(4):400-405. 3. Waydhas C. Intrahospital transport of critically ill patients. Crit Care 1999;3:R83-R89. 4. Warren J, Fromm R, Orr R, et al. Guidelines for the inter- and intrahospital transport of critically ill patients. Crit Care Med 2004;32:256-262. 5. Krivopal M, Shoblin 0, Schwartzstein R. Utility of daily routine portable chest radiographs in mechanically ventilated patients in the medical ICU. Chest 2003;123(5):1607-1614. 6. Hall J, White S, Karrison T. Efficacy of daily routine chest radiographs in intubated, mechanically ventilated patients. Crit Care Med 1991;19:689-693. 7. Brainsky A, Fletcher R, Glick H, et al. Routine portable chest radiographs in the medical intensive care unit: effects and costs. Crit Care Med 1997;25(5):801-805. 8. Pandit-Bhalla M, Diethelm L, Espenan G. Portable chest radiographs in the intensive care units: referral patterns and estimated cumulative radiation exposures. J Thorac Imaging 2002; 17:211-213. 9. Kim P, Gracias V, Maidment A, et al. Cumulative radiation dose caused by radiologic studies in critically ill trauma patients. J Trauma 2004;57:510-514. 10. Mostafa G, Sing R, McKeown R, et al. The hazard of scattered radiation in a trauma intensive care unit. Crit Care Med 2002;30(3):574-576. 11. Braxton C, Reilly P, Schwab C. The traveling intensive care unit patient: road trips. In: Schwab C, Reilly P, eds. Critical Care of the Trauma Patients. Philadelphia: Saunders, 2000:949-956. 12. Lerch M, Riehl J, Buechsel R, et al. Bedside ultrasound in decision making for emergency surgery: its role in medical intensive care patients. Am J Emerg Med 1992;10:35-38. 13. Lichtenstein D, Axler O. Intensive use of general ultrasound in the intensive care unit: prospective study of 150 consecutive patients. Intensive Care Med 1993;19:353-355. 14. Slasky B, Auerbach D, Skolnick M. Value of portable real-time ultrasound in the ICU. Crit Care Med 1983;11:160-164. 15. Rozycki G, Ochsner M, Iaffin J, et al. Prospective evaluation of surgeons' use of ultrasound in the evaluation of trauma patients. J Trauma 1993;34:516-527. 16. Rozycki G, Ochsner M, Schmidt J, et al. A prospective study of surgeon-performed ultrasound as the primary adjuvant modality for injured patient assessment. J Trauma 1995;39:492-500. 17. Rozycki G, Ballard R, Feliciano D, et al. Surgeon-performed ultrasound for the assessment of truncal injuries: lessons learned from 1,540 patients. Ann Surg 1998;228:557-567. 18. Miner N, Sly F. Fever of unknown origin. In: Sanders RC, ed. Clinical Sonography: A Practical Guide. Boston: Little, Brown, 1991:255-264. 19. Parys B, Barr H, Chantarasak N, et al. Use of ultrasound scan as a bedside diagnostic aid. Br J Surg 1987;74:611-612. 20. Joyner C Ir, Herman R, Reid J. Reflected ultrasound in the detection and localization of pleural effusion. JAMA 1967;200:399402. 21. Gryminski 1, Krakowka P, Lypacewicz G. The diagnosis of pleural effusion by ultrasonic and radiologic techniques. Chest 1976;70:33-37. 22. Adams F, Galati V. M-mode ultrasonic localization of pleural effusion. JAMA 1978;239:1761-1764. 23. Sisley A, Rozycki G, Ballard R, et al. Rapid detection of traumatic effusion using surgeon-performed ultrasound. J Trauma 1998;44:291-297.

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24. Rozycki G, Pennington S. Surgeon-performed ultrasound in the critical care setting: its use as an extension of the physical examination to detect pleural effusion. J Trauma 2001,50:636642. 25. Mansfield P, Hohn D, Fornage B, et al. Complications and failures of subclavian-vein catheterization. N Engl J Med 1994:331:1735-1738. 26. Mallory D, McGee W, Shawker T, et al. Ultrasound guidance improves the success rate of internal jugular vein cannulation: a prospective, randomized trial. Chest 1990;98:157-160. 27. Gilbert T, Seneff M, Becker R. Facilitation of internal jugular venous cannulation using an audio-guided Doppler ultrasound vascular access device: results from a prospective, dual-center, randomized, crossover clinical study. Crit Care Med 1995;23:6065. 28. Gratz I, Ashfar M, Kidwell P, et al. Doppler guided cannulation of the internal jugular vein: a prospective, randomized trial. J Clin Monit 1994;10:185-188. 29. Gualtieri E, Deppe S, Sipperly M, et al. Subclavian venous catheterization: greater success rate for less experienced operators using ultrasound guidance. Crit Care Med 1995;23:692-697. 30. Leger D, Nugent M. Doppler localization of the internal jugular vein facilitates central venous cannulation. Anesthesiology 1984;60:481-482. 31. Fry W, Clagett G, O'Rourke P, et al. Ultrasound-guided central venous access. Arch Surg 1999;134:738-741. 32. Knudson M, Collins J, Goodman S, et al. Thromboembolism following multiple trauma. J Trauma 1992;32:2-11. 33. Knudson M, Lewis F, Clinton A, et al. Prevention of venous thromboembolism in trauma patients. J Trauma 1994;37:480487. 34. Geerts W, Code K, Jay R, et al. A prospective study of venous thromboembolism after major trauma. N Engl J Med 1994;331:1601-1606. 35. Shackford S, Davis J, Hollingsworth-Fridlund P. Venous thromboembolism in patients with major trauma. Am J Surg 1990;159:365-369. 36. Kudsk K, Fabian T, Baum S, et al. Silent deep vein thrombosis in immobilized multiple trauma patients. Am J Surg 1989;158:515-9. 37. Bums G, Cohn S, Frumento B, et al. Prospective ultrasound evaluation of venous thrombosis in high-risk trauma patients. J Trauma 1993;35:405-408. 38. Flinn W, Sandager G, Cerullo L, et al. Duplex venous scanning for the prospective surveillance of perioperative venous thrombosis. Arch Surg 1989;124:901-905. 39. Knudson M, Morabito D, Paiement G, et al. Use of low molecular weight heparin in preventing thromboembolism in trauma patients. J Trauma 1996;41:446-459. 40. Langsfeld M, Hershey F, Thorpe L, et al. Duplex B-mode imaging for the diagnosis of deep venous thrombosis. Arch Surg 1987;122:587-591.

41. Lensing A, Prandoni P, Brandjes D, et al. Detection of deep-vein thrombosis by real-time B-mode ultrasonography. N Eng J Med 1989;320:342-345. 42. Sullivan E, Peter D, Cranley J. Real-time B-mode venous ultrasound. J Vasc Surg 1984;1:546-571. 43. Appleton P, De long T, Lampmann L. Deep venous thrombosis of the leg: US findings. Radiology 1987;163:743-746. 44. Polak J, Culter S, O'Leary D. Deep veins of the calf: assessment with color Doppler flow imaging. Radiology 1989;171:481485. 45. Vogel P, Laing F, Jeffrey R [r, et al. Deep venous thrombosis of the lower extremity: US evaluation. Radiology 1987;163:747751. 46. Rozycki G, Tchorz K, Riehle K, et al. A prospective study of a focused surgeon-performed ultrasound examination for the detection of occult common femoral vein thrombosis in critically ill patients. Arch Surg 2004;139:275-280. 47. Wheeler H, Anderson F Jr. Can noninvasive tests be used as the basis for treatment of deep vein thrombosis? In: Bernstein E, ed. Noninvasive Diagnostic Techniques in Vascular Disease. St. Louis: Mosby, 1985:805-818. 48. Rozycki G, Feliciano D, Schmidt J, et al. The role of surgeonperformed ultrasound in patients with possible cardiac wounds. Ann Surg 1996;223:737-746. 49. Rozycki G, Feliciano D, Ochsner M, et al. The role of ultrasound in patients with possible penetrating cardiac wounds: a prospective multicenter study. J Trauma 1999;46:543-552. 50. Boulanger B, Brenneman F, McClellan B, et al. A prospective study of emergent abdominal sonography after blunt trauma. J Trauma 1995;39:325-330. 51. Ashley D, Gamblin T, McCampbell B, et al. Bedside use of vena cava filters in the intensive care unit using intravascular ultrasound to locate renal veins. J Trauma 2004;57:26-31. 52. Wellons E, Rosenthal D, Shuler F, et al. Real-time intravascular ultrasound-guided placement of a removable inferior vena cava filter. J Trauma 2004;57:20-25. 53. Effeney D, Friedman M, Goading G. Iliofemoral venous thrombosis: real-time ultrasound diagnosis, normal criteria, and clinical application. Radiology 1984;150:787-792. 54. Teichgraber U, Pinkemell J, Iurgensen J, et al. Portable computed tomography performed on the intensive care unit. Intensive Care Med 2003;29:491-495. 55. McCunn M, Mirvis S, Reynolds M, et al. Physician utilization of a portable computed tomography scanner in the intensive care unit. Crit Care Med 2000;28(12):3808-3812. 56. Maher M, Hahn P, Gervais D, et al. Portable abdominal CT: analysis of quality and clinical impact in more than 100 consecutive cases. AJR 2004;183:663-670.

Risk Prediction, Disease Stratification, and Outcome Description in Critical Surgical Illness John C. Marshall Historical Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433 Defining Risk in the Intensive Care Unit . . . . . . . . . . .. 434 Risk Prediction: Prognostic Scores. . . . . . . . . . . . . . . . . . 435

T

he first half of the 20th century saw a number of important advances in the ability of the surgeon to care for the critically ill or multiply injured patient. An understanding of fluid resuscitation, the development of blood transfusion, and the development of positive-pressure mechanical ventilation and hemodialysis all served to reduce the mortality for wartime trauma from close to 100% at the tum of the century to less than 5% by the time of the Vietnam War. l Rapid death from acute physiological insufficiency gave way to uncomplicated recovery for some; for others, it opened the door to an unprecedented series of clinical challengesthe sequelae of life-threatening physiological instability and of the deleterious consequences of the interventions employed to sustain life during a period of otherwise lethal organ system insufficiency. Known as the multiple organ dysfunction syndrome (MODS)/ this complex disorder has emerged as the leading unsolved problem in the management of the critically ill patient. Acute physiological instability is the antecedent of MODS, a disorder of chronic physiological instability. It is self-evident that the patients who are most likely to die during their intensive care unit (ICU) stay are those who are the sickest. A corollary of this concept is that the risk of death in critical illness can be quantified through accurate evaluation of how sick the patient is.3 This awareness has given rise to a number of scoring systems that use measures of acute physiological severity determined early during the course of illness to estimate the probability of survival and so to provide an objective estimate of illness severity at the onset of care.r" or that use measures of chronic physiological instability to describe the outcome of such care, using the construct of the MODS.?-IO

Organ Dysfunction Scores as Outcome Measures . .. .. 439 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 443

Historical Background Remote organ dysfunction as a consequence of, but not pathologically related to, an acute life-threatening disorder was first recognized in the first half of the 19th century, when Curling published his classic description of gastrointestinal hemorrhage in bum patients.'! During the Second World War, syndromes of hepatic" and renal" dysfunction were recognized in the survivors of battlefield injuries. However, in the absence of technologies to support patients with life-threatening organ system insufficiency, these syndromes were uncommon and generally lethal. Techniques for endotracheal intubation and mechanical ventilation, central venous access and monitoring, and renal dialysis were all developed in the decade following the Second World War and provided the impetus for the first dedicated ICU, established in Baltimore in 1958.14 During the next decade, ICUs became a standard fixture in tertiary care hospitals. The evolution of the MODS parallels the development of the ICU. Acute respiratory insufficiency in association with severe peritonitis was described by Burke et al. in 1963,15 and 4 years later, Ashbaugh and Petty defined the phenomenon as the adult (now acute) respiratory distress syndrome (ARDS).16 Descriptive studies of gram-negative bacteremia" and the characteristic hemodynamic profile of septic shock" appeared during this period, and their association with a number of syndromes of acute organ insufficiency, including disseminated intravascular coagulation (DICl, acute renal failure, and stress ulceration, was recognized. The first suggestion that the failure of several organ systems might comprise a syndrome was published in 1969,19 followed 4 years later by a comprehensive review of 433

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CHAPTER 24

sequential organ failure following repair of ruptured aneurysms." Baue, in an editorial published in 1975, commented on the remarkable similarities in autopsy findings of patients dying of diverse diseases in the ICU, and suggested that multiple organ failure, rather than the isolated failure of a single system, was the most important unsolved problem in critical care." His ideas opened the door to a number of investigators who proceeded to characterize the clinical course of organ failure 22,23 and to emphasize the important role played by uncontrolled infection in the pathogenesis of the syndrome. 23-25 The MODS has gone by various names, including multiple organ failuref and multiple system organ failure." The terminology multiple organ dysfunction syndrome was proposed by a consensus conference in 1991, in recognition of the fact that the syndrome is characterized by graded degrees of potentially reversible dysfunction, rather than by the absolute failure of vital organ function.' It is generally accepted that MODS develops in approximately 80% of all patients dying in a surgical ICU 7,26,27 and that the syndrome is the leading cause of ICU morbidity. Indeed, critically ill patients in a contemporary ICU rarely die as a direct consequence of the disease process that led to admission, but rather of a complex pattern of physiological derangements that arise from the host response to the underlying disease and its treatment in the ICU.

Defining Risk in the Intensive Care Unit ICUs provide supportive physiological care for a heterogeneous group of patients with organ system dysfunction, rather than curative therapy for a group of patients with a particular disease. As a consequence, physiological derangements alone, rather than the distinctive manifestations of a unique disease process, provide the best measure of illness severity. Acute, preresuscitation physiological derangements are crucial early determinants of the probability of survival and the focus of scales that have been developed to predict outcome. Chronic, stable, and postresuscitation physiological abnormalities comprise the syndrome of MODS and so are the focus of organ dysfunction scales whose purpose is to measure outcome. The distinction between scores designed as predictive tools and those designed as measurement tools is subtle but important (Table 24.1). Clinical intervention in a disease serves to increase the probability of survival (to reduce mortality) or to reduce pain and suffering and to improve the quality of life (to reduce

morbidity). Measurement tools, therefore, are developed on the basis of their ability to predict mortality or to measure morbidity. Death is a relatively common outcome for patients who are ill enough to be admitted to an ICU; thus, the prediction of survival is the basis for the most widely used prognostic scoring systems, and parameters are selected and calibrated on the basis of their ability to maximize the prediction of death. Hospital mortality is generally used as the criterion against which such scales are developed, because hospital survival usually implies a return to an independent existence. However, the role of the contemporary ICU is not simply to sustain life at any cost. Indeed, as surgeons increasingly care for sicker patients with significant underlying comorbid conditions, the therapeutic focus is shifting from mere survival to improved quality of life. And as the limitations of ICU supportive care become better understood, it is apparent that the majority of patients who die in an ICU do so not because of unsupportable organ failure, but because a conscious decision is made by the patient's family and the clinical caregivers that continued support is inappropriate and that supportive measures should be discontinued." The need for objective measures of ICU quality of life, therefore, is increasing. Organ dysfunction scales represent a response to this need. They emanate from the assumption that improved quality of life within the ICU is reflected in reduced dependence on ICU technology. Although predictive scores are calibrated to hospital mortality, organ dysfunction scores are generally calibrated with reference to ICU mortality, because survival outside the ICU can be equated to survival without the need for technological intervention, even if the consequence is imminent death. Similarly, in an environment where the majority of deaths follow the withdrawal of support, death in the ICU reflects the ongoing need for physiological supportive measures. ICUs generate volumes of data that, taken in isolation, often provide contradictory impressions of patient status. Is the patient with an elevated white blood cell count and vasopressor dependence, but relatively intact neurological function, sicker than another patient who is hemodynamically stable but unresponsive to all but painful stimuli? The calculation of a severity score allows the intensivist to evaluate the potential impact of these divergent parameters by transforming them into a single numeric result that itself is known to correlate with outcome. In essence, a score permits the physician to compare apples and oranges by converting them to fruit. However, the score does not provide the clinician with new information: it simply integrates existing information.

TABLE 24.1. Scoring Systems in the ICU: Methodological Considerations. Prognostic scales: severity of illness scores

Outcome measures: organ dysfunction scales

Uses

Prognostication; risk stratification

Timing of ascertainment Selection of variables

Early during ICU stay Physiological measures Worst values Selected to maximize predictive capability Maximize prediction

Outcome measurement; evaluation of clinical course over time Following resuscitation; at any time during ICU stay Measures of physiology or therapeutic response Stable, representative values Selected to reflect clinical construct Maximize description

Calibration leUI intensive care unit.

RISK PREDICTION, DISEASE STRATIFICATION, AND O U T C O M E DESCRIPTION IN CRITICAL SURGICAL ILLNESS

Scoring Systems: Methodological Principles A scoring system relates two or more predictor variables (the independent variables) to a single outcome variable (the dependent variable). That outcome is commonly, although not necessarily, death.

Three models for the early evaluation of illness severity in the ICU have found widespread use: the APACHE (Acute Physiology, Age, and Chronic Health Evaluation) score," the SAPS (Simplified Acute Physiology Scorel." and the MPM (Mortality Prediction Model]." Each of these models has undergone several revisions since its initial iteration. Prognostic scores are developed so that their predictive capacity is optimized, which is accomplished by evaluating the ability of a panel of candidate parameters to predict mortality (or any other outcome of interest) independently using logistic regression analysis, a statistical technique that relates continuous or binary independent (predictor) parameters to a binary (yes or no) dependent (outcome) variable. Analyses are performed in a stepwise fashion to produce a model that maximizes predictive capacity; during this process, parameters that do not contribute independently to the predictive capability of the model are eliminated. The weight that each parameter contributes to the predictive model can be determined by its coefficient in the logistic regression equation; parameters are then weighted to reflect their differing predictive influence. The performance of a predictive model is evaluated in two ways. Discrimination is the ability of the score to predict survival and nonsurvival correctly at differing levels of the score; it can be determined by calculating the area under a receiver operating characteristic (ROC) curve that plots sensitivity against I-specificity (Figure 24.1). In general, values greater than 0.80 indicate good discrimination." Calibration is the agreement between the observed and expected numbers of deaths at differing levels of the score; it is evaluated using the Hosmer-Lemeshow goodness of fit chi-square statistic. Probability values greater than 0.10 [i.e., the absence of a 1.0

0.8 ~ ...-

;:

.0··

0.6

"(j)

e

CD

en

0.4 .0·

- . - Score Random chance

0.2 0.0

6.:-_ _-----....--_ _~ - - - ~_ _-...._--____.

0.2

0.4

0.6

1 - Specificity

0.8

A number of scales have been developed to measure the severity of organ dysfunction, including the Multiple Organ Failure score." the Multiple Organ Dysfunction (MOD) score," the Sequential Organ Failure Assessment (SOFA) score," the Brussels score," and the Logistic Organ Dysfunction (LaD) score." Pediatric versions have also appeared.P-" The intent of these measures is not to predict an outcome but rather to describe it. Thus, although it is generally accepted that the MODS is the leading cause of death in critical illness, an organ dysfunction scale is not developed primarily on the basis of its ability to predict death, but rather on its ability to reflect organ dysfunction as the clinician sees it. Such a scale should give a low score to a patient who dies of a process other than MODS (for example, an acute myocardial infarction or an exsanguinating hemorrhage) and a high score to a patient who survives with the syndrome. An outcome measure must be reliable, reproducible, and valid." Validity, in tum, entails a variety of domains. Construct validity reflects the ability of the score to measure the outcome of interest as the clinician views it. Content validity reflects the ability of the score to embody the entire spectrum of the outcome of interest, whereas criterion validity refers to the ability of the score to measure an outcome when evaluated against an independent gold standard. For the MOD score," construct validity of the variables was maximized through the use of a systematic review of previously published systems for quantifying organ dysfunction; the SOFA score" used a process of expert consensus. Because there is no independent biochemical measure of MODS, both scores use ICU mortality for the establishment of criterion validity. There are, therefore, two classes of measurement tools available to the intensivist. Predictive scores integrate data available early during the course of care to provide an objective estimate of the probability that a patient will survive. They maximize predictive capacity at the cost of construct validity (the ability to mirror a process as the clinician sees it). Organ dysfunction scales combine stable physiological data to provide an objective measure of the extent of morbidity at a single point in time, or over a defined time interval: they emphasize construct validity over predictive power. The uses and limitations of these are explored next in greater detail.

Risk Prediction: Prognostic Scores

····0····

0.0

significant difference between groups) indicate good calibration." The validity and reproducibility of the score are determined by evaluating the performance of the score in different groups of patients from the original one in which it was developed. OUTCOME SCORES

PROGNOSTIC SCORES

oS;

435

1.0

FIGURE 24.1. A receiver operating characteristic (ROC) curve plots sensitivity against l-s-speciflcity, discrimination is evaluated as the area under the curve. (From Hanley J, McNeil B/2 by permission of Radiology. )

Generic Prognostic Scores APACHE (ACUTE PHYSIOLOGY, AGE, AND CHRONIC HEALTH EVALUATION)

The first scale that measured acute severity of illness in the ICU by predicting the risk of nonsurvival using data available at the time of ICU admission was the APACHE system,

436

CHAPTER 24

developed by Knaus et al. at George Washington University" (Table 24.2). The APACHE score incorporates a panel of common physiological variables measured within the first 24h following ICU admission to provide a numeric estimate of illness severity that predicts the likelihood of survival to hospital discharge. The initial variables of APACHE were selected through a process of expert consensus. The 34 variables of APACHE were subsequently reduced to 12 physiological variables by eliminating those that were measured infrequently or which provided less predictive power, giving rise to the widely used APACHE II score." The score yields a number between 0 and 71 that correlates in a graded fashion with the predicted risk of hospital mortality (Figure 24.2). Estimates of the risk of death are further refined using an equation that integrates the physiological data with the patient's underlying diagnosis: for a given APACHE II score, for example, the risk of death is higher for patients with a diagnosis of sepsis than for those with a diagnosis of diabetes

mellitus, reflecting in part the fact that diabetes mellitus can be readily controlled with insulin. More recently, additional variables have been incorporated into the APACHE III score." The APACHE III score incorporates revised diagnostic codes and parameters that correct for potential lead time bias through consideration of the patient's location before ICU admission. However, its use is less intuitive than the APACHE II system, and the extent to which it represents an improvement in predictive power is uncertain. Moreover, unlike its predecessors, APACHE III is a proprietary system, and its additional costs and complexity have limited its acceptance outside the United States. SIMPLIFIED ACUTE PHYSIOLOGY SCORE

The Simplified Acute Physiology Score (SAPS) was developed in Europe and first published in 1984.30 A revised version, SAPS II, was published in 1993.5 The score incorporates 17

TABLE 24.2. The APACHE II Score Sheet: Use Worst Physiological Values Within First 24h of ICU Care. High abnormal range

Low abnormal range

1 34-35.9

0 36-38.4

1 38.5-38.9

4 40.9

70-109

Hemoglobin (g/L)

Chronic Health Score = 1'--

3 39-40.9

50-69

40mmHg APACHE, Acute physiology and chronic health evaluation; TX, transplantation; POSTOP, postoperative; PTS, patients; COPD, chronic obstructive pulmonary disease; ICU, intensive care unit; SOB, shortness of breath; CVS, cardiovascular system; ESRD, end-stage renal disease; AIDS, acquired immune deficiency syndrome.

RI SK P R E D IC T ION, DI SE A SE ST R A TI F I CA TION , A N D O U T COM E D ESC R I PTIO N I N C R I TIC AL S U R G I C A L ILLNE S S

100 90 80

~

~0

:!:

19

70 60

40

0

30

:I:

Non-operative Pos t-operative

50

'0. Ul

_

""*'"

20 10 0

0-4

5-9

10-14 15-19 20-24 25-29 30-34

35+

APACHE II Score FIGURE 24.2. Mortality as a function of increasing APACHE (Acut e Physiology, Age, and Chronic Health Evaluati on) II score. Although mortality is slightly lower for postoperative patient s at compar able score levels, for both, an APACHE II score of 25-29 is associat ed with approximately 50% mortalit y. (From Knaus et al.," with permission.]

parameters: 12 physiologi cal parameters, age, type of admission, and 3 parameters reflecting concomitant disease, specifically acquired immunodeficiency syndrome (AIDS), metastatic cancer, and hematological malignancy. Risk of mortality can be calculated independent of the patient's diagnosis, although customization for particular pathological processes such as sepsis has been reported ." MORTALITY PREDICTI ON M ODEL

The Mortality Prediction Model (MPM), and its updated version, MPM II,31employ a somewhat different approach to prognostication. Its parameters are less physiology-ba sed than are those of APACHE and SAPS, and they are recorded as binary (yes or no) states. In contrast to APACHE and SAPS, which were developed and validated based on abnormalities present during the first 24 h of ICU admission, MPM permits recalculati on of th e risk of mortality at 24 and 48h and so incorporates an evaluation of the response to th erapy.

Sources of Error in Prognostic Scores There are multiple potential sources of random or systematic error (bias) that may render inaccurate th e estimates derived from a prognostic scale. First, the indiv idual calculating the score must be fully versed in the basics of score calculation. Common errors in the calculation of APACHE II, for example, include assignment of maximal neurological points for the patient who returns from the operating room still anesthetized and paralyzed," or the inappropriate assignment of chronic health points. Similarly, because th e score records th e worst value for a given parameter, a higher score is more likely to be recorded when parameters are measured more frequently. Thus, th e use of an automated data collecti on system that records data continuously results in higher mortality predictions, with th e result that th e performance of an ICU with such a system appears to be better than one in which data are measured less frequently. " Similarly, because

437

most scores assign a value of a to missing data, a score is likely to be recorded as higher when more comprehensive data collection occurs . The impact of these sources of error can be considerable." Although prognostic scores generally consid er the worst values for a param eter during th e first 24h of care, there is consid erable variability in how this time is measured." Param eters may be recorded from the flowsheets for the first ICU day and thus reflect a time interval ranging from several hours to an entire day. Data collected at the tim e the patient present ed initially may not be available . In addition, scores may be artifactually low for patients who have received their initial resuscitation and treatment in another ward or hospital,44,45 a phenome non termed lead-tim e bias. Scores developed in large heterogeneous datab ases may not reflect adequately th e clinical prognosis of more homogeneous pati ent populations; th e incorporation of diagnosis to generate a probability of mortality does not eliminate this problem entirely.":" Similarly, regional variability in clinical approaches to care or changing practices over time may render prognostic estimates inaccurate. Mortality predictions with a given model are most reliable wh en the population under study reflects th e population from which the model was derived. In contrast, in a specialized ICU, a prepond erance of pati ent s with a particular diagnosis ma y affect model performance adversely."

Keeping Score: A Comparison of Prognostic Scales Although subtle differences in performance can be demonstrated when differing scales are compared in distinct patient populations, th ere is no convincing evidence that anyone is superior to another, and considerations of familiarity, ease of use, and specific needs generally guide the choic e of a given score." Th e performance of APACHE II and III, SAPS I and II, and MPM I and II was studied in a cohort of nearly 15,000 pati ent s adm itted to 1371CU s in Europe and North America." Th e performance of the newer versions of the scores was considered superior, based on larger areas und er the ROC curv e, and better fit; all showed good discrimination and calibration . Th e APACHE II and APACHE III scores were compared in a British study." Th e APACHE III score did not show superior performance characteristics; in fact, for surgical admis sions, the risk estimations of APACHE II were superior. Th e APACHE III score has also been evaluated in a cohort of more than 37,000 patients from 285 American ICUs; discrimination was good (area und er the ROC curve, 0.891; howev er the goodness of fit of th e model was suboptimal, particularly for trauma patients. 53 Similarly, a European comparison of SAPS I and SAPS II showed better discrimination for SAPS II, but less than ideal calibration ." Prognostic scores have also been compared to clinical judgme nt, with param eter results. Marks et a1. found that the sub jectiv e prediction of an experienced ICU doctor and nurse was superior to APACHE II in identifying patients who were likely to die." In reality, small but statistically significant differences in discrimination or calibration th at are reported when scores are compared head to head in large dat abases are probably not meaningful clinically. A prognostic score is not a diagnostic test and cannot be used reliably to make clinical decisions regarding the management of individual patients." Indeed, if a score could predict th e outcome for an individual

438

CHAPTER 24

patient reliably, one would be forced to conclude that care provided following ICU admission is irrelevant to the final outcome.

Uses of Prognostic Scores Severity scores have found a number of uses in the management of complex critically ill patients. However, it is important to emphasize two key points. First, a score does not provide new information but simply provides a method of integrating information that is already available. Second, despite the increasing sophistication of the methodologies used to develop prognostic scores, their power derives from their application across groups of patients, and they cannot, therefore, be expected to provide definitive prognostic information for an individual patient." OPTIMIZING THE PROCESS OF ICU CARE

Scoring systems can provide insight into the impact of administrative measures on ICU performance. For example, analysis of the reasons that survival varied for similar predicted outcomes among different ICUs in the APACHE II database revealed that better than expected survival rates could be attributed to processes of care such as the presence of dedicated full-time intensivists and a team approach to patient care that involved both nurses and physicians." Using the MPM to stratify patients, Multz et al. found that the transition of an ICU from an "open" to a "closed" unit was associated with a significant reduction in length of ICU stay, days on mechanical ventilation, and mortality. 59 An Israeli study found that hospital mortality was significantly lower for patients admitted to the ICU than for those to whom admission was denied, particularly for patients with APACHE II scores between 11 and 20, the population for which intensive care has the most to offer.60 Scoring systems have also been used to evaluate the acuity of illness in a unit so that appropriate staffing and resources can be provided. Similarly, variability in illness acuity has been used by regional health administrators to rationalize the distribution of critical care resources among healthcare institutions, or to provide "report cards" on quality of care in differing units. AUDIT AND QUALITY ASSURANCE ACTIVITIES

Severity scales can play an important role in quality assurance activities. Clinical outcomes that differ strikingly from predicted outcomes-either death when survival was predicted, or survival when death was predicted-can be audited for quality assurance purposes. Such an approach has proved to be superior to the performance of a random audit of cases in identifying potentially correctable problems with the delivery of care." Severity scores also provide an objective basis for comparing the performance of similar types of ICUs in a given region'" and, perhaps, for stratifying ICUs on the basis of performance characteristics. 63 EVALUATION OF REGIONAL, NATIONAL, AND INTERNATIONAL DIFFERENCES IN ICU CARE

Prognostic scoring systems have been used to compare patient demographics and outcome of care between ICUs in different

regions or countries. Because of the many unrecognized sources of error already discussed, the comparison of different ICUs can be misleading.r'e" especially if data collection is not standardized and lead-time bias is not recognized.f Moreover, differences in case mix between ICUs can exert a significant, but unmeasured, effect on mortality prediction." Nonetheless, as qualitative measures of variability in the process of providing critical care services, such comparisons can be enlightening. It has been observed that when prognostic scores derived in one population are applied to a new and unrelated patient group, the models show good discrimination but poor calibration." This discordance is least evident when the two populations are most similar. The APACHE system, developed in a cohort of American ICUs, performs well when applied in Canada" but less well when used in Britain." Iapan," Brazil," or Tunisia." These differences may reflect differences in available resources, personnel training, or quality of care; however, the complex interplay of these factors makes it risky to attempt to draw simplistic inferences regarding ICU performance. A comparison of Canadian and American ICUs, for example, found ICU use to be more frequent in the United States and clinical acuity of illness to be lower. There was no evidence that increased ICU utilization resulted in a more favorable clinical outcome." SEVERITY STRATIFICATION FOR CLINICAL RESEARCH

One of the most important applications of severity scores has been as an instrument in clinical research, to provide an objective measure of the severity of illness in a particular study population and to ensure that mortality risk is equally distributed among study arms at baseline. Scores can be used as an inclusion criterion to define a minimum severity of illness or as an exclusion criterion to define a maximum severity of illness. Moreover, severity scores can be used to stratify patients into differing risk groups; it is a common finding that the benefit or harm resulting from a particular study intervention is not homogeneous but may vary in subgroups with low or high severity scores. In a randomized trial comparing a liberal with a restrictive transfusion strategy in critically ill patients, the greatest benefit associated with limiting blood exposure was seen in the stratum of patients with a lower APACHE II score." CLINICAL DECISION MAKING

Although severity scores are not sufficiently reliable to be used in isolation for decision making in individual patients, they can provide the clinician with objective data to support discussions of prognosis and limiting of support." For a predicted mortality of 900/0, the therapeutic decision reached in the management of a 24-year-old trauma victim may well differ from that made for a 78-year-old patient with disseminated malignant disease. Moreover, awareness that survival is improbable when the patient first presents for care provides some consolation to the family and caregivers when a decision is made to terminate support in the face of a failure to respond. Quantification of risk early in the course of a disease process also allows the surgeon to implement measures that might reduce that risk. An elevated SAPS or APACHE score in a patient with acute pancreatitis identifies a patient who

RISK PREDICTION, DISEASE STRATIFICATION, AND OUTCOME DESCRIPTION IN CRITICAL SURGICAL ILLNESS

is likely to benefit from admission to an leu for more intensive management," whereas the risk of developing nosocomial infection in the leu increases with increasing admission SAP scores." Implicit in the ability to prognosticate outcome for a population of patients is the recognition that the ultimate outcome is determined to an important degree by events that have occurred before the patient received medical attention and that are, therefore, not amenable to any therapeutic intervention. The magnitude of the contribution of severity of illness is unknown but may be as high as 750/0.

Organ Dysfunction Scores as Outcome Measures The severity of acute physiological derangement, independent of its cause, is the predominant determinant of survival for patients admitted to an leu. However, the mortality of critical illness does not occur precipitously because of an inability to reverse the acute physiological abnormalities. Rather, their correction sets the stage for the development of a more chronic form of physiological derangement whose evolution mirrors both the initial injury and the consequences of resuscitation and ongoing supportive care. This processthe leading unsolved problem in acute care-has been termed MODS. 2 A disorder characterized by the development of acute but potentially reversible physiological dysfunction involving two or more organ systems, MODS arises in the wake of a potent threat to normal homeostasis. There is considerable clinical variability in the particular systems that are involved in a given patient, in the temporal sequence in which organ dysfunction occurs, and in the severity of the syndrome. Moreover, it is uncertain whether the particular patterns of organ dysfunction that develop in an individual patient represent a single pathophysiological process with variable expression, or multiple discrete disorders with a common phenotypic presentation; that is, whether MODS denotes a disease, or a single syndrome, or simply the limited repertoire of manifestations of a common final pathway to death. Nonetheless, it is apparent that prognosis is a function of both the number of failing systems and of the degree of dysfunction within a given system. Description of MODS as a clinically relevant process denotes more than the self-evident truism that the sickest patients are those who are most likely to die. First, the concept of MODS emphasizes the fact that morbidity and mortality in the leu are multifactorial and that the clinician can rarely point to a single disease or event as being responsible for the patient's demise. Second, because organ dysfunction is generally supportable, and often reversible (at lesser degrees), death from the syndrome sometimes reflects a conscious decision by the leu staff and the family of the patient to discontinue active supportive care in the face of a lack of response to therapy (or a relapse]." Finally, MODS almost invariably arises following the activation of a systemic inflammatory response. Just as functio laesa, or loss of function, is a cardinal manifestation of local inflammation, MODS is a manifestation of systemic inflammation. A number of descriptive systems have been developed to quantify the severity of MODS. 7-10,34,78,79

439

The Multiple Organ Failure Score The initial reports establishing the concept of multiple organ failure quantified its severity as the number of failing organ systems. Goris et al. were the first to extend the quantification of organ failure to consider not only the number of failing systems but also the degree of failure within each system." The MOF score evaluates the dysfunction of each of seven organ systems on a scale from 0 (normal function) to 2 (failure); the maximum number of organ failure points, therefore, is 14.

The Multiple Organ Dysfunction Score The Multiple Organ Dysfunction Score' evaluates organ dysfunction in six organ systems, using physiological parameters that are measured without reference to therapy (Tables 24.3, 24.4). Parameters were selected to maximize construct, content, and criterion validity. Intervals for each of the variables were established so that a score of 0 in a given system reflects normal function and an leu mortality rate of less than 50/0, whereas a score of 4 reflects markedly deranged function and an leu mortality rate in excess of 500/0; intervening values are established to reflect equal increments, with sensible cutoffs. The MOD score employs a novel variable to quantify cardiovascular dysfunction: the pressure-adjusted heart rate (PAR). Developed by analogy to the Pa02:FI02 ratio, the PAR is calculated as the product of the heart rate (HR) and the central venous pressure (eVP) divided by the mean arterial pressure (MAP): Pressure-adjusted rate (PAR) = HR x evp/MAP In the absence of a central line, the evp is assumed to be normal and is assigned a value of 8. An increase in the heart rate or a decrease in blood pressure increases the value of the PAR, as does fluid administration resulting in increased right atrial pressure. The value, therefore, increases with increasing cardiovascular dysfunction, and high values reflect hemodynamic instability that is refractory to volume challenge.

Sequential Organ Failure Assessment Score The sequential organ failure assessment (SOFA) score was developed in Europe as an alternate method of quantifying organ dysfunction." It also evaluates organ dysfunction in six systems, but uses as its cardiovascular component the amcount of inotropic support provided. It differs from the MOD score in that it employs the worst daily values for its variables.

Other Organ Failure Scores Hebert et al. reported an organ failure score that counts the number of failing organs using seven readily measured clinical variables." Bernard developed a scale that is similar to the MOD and SOFA scores, differing in the parameter used to quantify cardiovascular dysfunction." The originators of the SAPS score have developed a score called the Logistic Organ Dysfunction (LOD) score.'? Differing from other organ

TABLE 24.3. Multiple Organ Dysfunction (MOD) and Sequential Organ Failure Assessment (SOFA) Scores. Number of Points

o

System

Respiratory Pa02/FI02 Pa02/FI02 Renal Creatinine [mmol/L] Creatinine or Urine output Cardiovascular Pressure-adjusted rate" Use of vasoactive agents" Hematological Platelets (/mL x 10-3 ) Platelets (/mL x 10-3) Hepatic Bilirubin [umol/L] Bilirubin (flmol/L) Neurological Glasgow Coma Score Glasgow Coma Score

1

3

2

4

>300 >400

226-300 301-400

151-225 201-300

76-150 101-200 (with support)

~100

101-200 110-170

201-350 171-299

351-500 300-440; or urine output 500 >440; or urine output 15 or norepinephrine >0.1

>120,000 >150,000

80-120,000 101-150,000

50-80,000 51-100,000

20-50,000 21-50,000

204

15 15

13-14 13-14

10-12 10-12

7-9 6-9

1 drug) Central intravenous parenteral nutrition Pacemaker on standby Chest tubes Intermittent mandatory ventilation or pressure support ventilation Continuous positive airways pressure (CPAP) Concentrated K+ infusion via central catheter N asotracheal or orotracheal intubation Blind intratracheal suctioning Complex metabolic balance (frequent intake and output) Multiple blood gas, bleeding, and/or stat studies (>4 per shift) Frequent infusions of blood products (>5 units/24 h)

Source: From Keene AR, Cullen DJ.,80 by permission of Critical Care Medicine.

(1) (m)

(n)

(0) (p) (q)

(r)

(s) (t) (u) (v) (w) (x) (y) (z)

(aa) (bb) Two points (a) (b) (c) (d) (e)

(f)

(g) (h) (i) (j) (k)

One point

(a) (b) (c) (d) (e)

(f)

(g) (h)

(i)

(j) (k)

Bolus intravenous medication (nonscheduled) Vasoactive drug infusion (1 drug) Continuous infusion of antiarrhythmic agents Cardioversion for arrhythmia (not defibrillation) Hypothermia blanket Arterial line Acute digoxin administration (within 48 h) Measurement of cardiac output Active diuresis for fluid overload or cerebral edema Active therapy for metabolic alkalosis Active therapy for metabolic acidosis Emergency thora-, para-, and pericardiocentesis Acute anticoagulation (initial 48h) Phlebotomy for volume overload Administration of more than 2 intravenous antibiotics Therapy of seizures or metabolic encephalopathy (within 48 h of onset) Complicated orthopedic traction Central venous pressure monitoring Two peripheral intravenous catheters Hemodialysis (stable patient) Fresh tracheostomy (less than 48h) Spontaneous respiration via endotracheal tube or tracheostomy Enteral feedings Replacement of excess fluid loss Parenteral chemotherapy Hourly neurological vital signs Multiple dressing changes Pitressin infusion ECG monitoring Hourly vital signs One peripheral intravenous catheter Chronic anticoagulation Standard intake and output (every 24h) Stat blood tests Intermittent scheduled intravenous medications Routine dressing changes Standard orthopedic traction Tracheostomy care Decubitus ulcer (preventive therapy)

442

CHAPTER 24

DAILY QUANTIFICATION OF ILLNESS SEVERITY

Organ dysfunction scores calculated on a daily basis provide a composite picture of clinical course over time." Barie and Hydo demonstrated that although surviving and nonsurviving patients admitted to a surgical ICU have comparable degrees of organ dysfunction at baseline, they can be differentiated by the second day on the basis of the resolution of organ dysfunction in survivors and its persistence in nonsurvivors'" (Figure 24.3). Moreover, resolution of organ dysfunction, reflected in serial reduction in score values in patients with postoperative peritonitis, suggests satisfactory control, whereas prolonged elevation suggests persistence of infection." Because physiological derangement implies the need for therapeutic intervention, daily scores also provide a point measure of the intensity of resource utilization, analogous to the TISS score (see following). Serial scores can be compared between two or more populations in a randomized controlled clinical trial to measure treatment effect over time: Staubach et al., for example, showed that pentoxifylline can attenuate organ dysfunction in severe sepsis." QUANTIFICATION OF GLOBAL PHYSIOLOGICAL DERANGEMENT: AGGREGATE SCORES

Summing the worst daily scores for each of the component variables of an organ dysfunction score provides a composite picture of the severity of organ dysfunction over a defined time period. This time period may be the ICU stay but can also be any arbitrarily defined interval (for example, over 28 days following an experimental intervention) (Figure 24.4). DELTA MOD SCORES

The difference between the aggregate score and the score recorded at the time of ICU admission provides a measure of organ dysfunction arising following ICU admission and therefore attributable to events occurring within the ICU (and potentially amenable to therapeutic intervention). Jacobs et al., for example, found that although survivors and nonsurvi10 9

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1 2 3 4 567 89101112131415161718192021222324

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FIGURE 24.3. Daily multiple organ dysfunction (MOD) scores for 115 patients remaining in a surgical intensive care unit (ICU) for more than 3 weeks. Daily scores of nonsurvivors (open circles) are significantly higher than those of survivors (closed circles) after the first ICU day. (From Barie et al.," with permission.)

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Aggregate MOD Score FIGURE 24.4. ICU survival as a function of the aggregate MOD score in a cohort of 851 critically ill surgical patients. (From Marshall et al.," with permission.)

vors of septic shock had similar admission MOD scores, nonsurvivors had significantly higher delta scores." Delta scores can be calculated over any defined time interval, such as during the administration of an experimental therapy, over the ICU stay, or over any defined time period. In addition, analysis of changes in individual organ system function has shown that mortality risk varies by system over time with the result, for example, that respiratory or hepatic dysfunction are associated only with increased mortality when they arise later during the ICU stay." MORTALITy-ADJUSTED MOD SCORES

A single combined measure of morbidity and mortality can be derived through the calculation of mortality-adjusted MOD scores: The aggregate score is recorded for patients who survive, whereas those who die are assigned a maximal number of points plus one. In a randomized multicenter controlled trial evaluating transfusion needs in critical illness, Hebert et al. showed significant benefit for patients who were not transfused until the hemoglobin level dropped below 7, in comparison to patients who were transfused at a threshold of 10 g/dl., Measured as mortality or organ dysfunction alone, evidence of benefit just failed to attain statistical significance; mortality-adjusted MOD scores, however, were significantly different between the two groups. 74

From Scores to Staging Systems Scores such as those described here provide prognostic information but are of relatively limited use in making therapeutic decisions because they stratify patients by risk of adverse outcome but not by their potential to respond to a particular therapy. Although some interventions appear to be more efficacious in certain populations stratified on the basis of acute physiological derangements or degree of organ dysfunction, 74,92 staging based on potential to respond to treatment is a relatively new concept in the ICU setting. On the other hand, staging has been a fixture of cancer therapy for a full century," and it would be unthinkable for


a surgeon treating a patient with carcinoma of the colon to make a definitive decision in the absence of information regarding the clinical and pathologic stage of the tumor. Staging in oncology stratifies patients on their risk of developing recurrent disease, but even more importantly, on their potential to benefit from specific treatments. A localized colon cancer without nodal spread may be cured by surgical resection alone, whereas nodal spread identifies a population that is more likely to benefit from chemotherapy, and the presence of distant metastases shifts the treatment program toward palliation and symptom control. By analogy to the TNM (tumor, nodes, metastasis) staging system used in oncology, a template for a staging system for critical illness has recently been proposed.P:" The PIRO model proposes the stratification of patients with sepsis on the basis of their £redisposition, the nature of the Insult, the Response of the patient, and the degree of Qrgan dysfunction present. Ample evidence exists to support the concept that each factor can individually influence both prognosis and the potential to respond to treatment. Genetic factors are potent determinants of outcome for patients with infection," and genetic variability or polymorphisms in key innate immune response genes are strongly associated with the risk of mortality in sepsis.":" whereas the response to therapies that target the inflammatory response (for example, corticosteroids or activated protein C) is affected by the nature of that response, whether measured as a response to corticotropin (ACTH) stimulation" or the degree of organ dysfunction at the time of intervention." However, development of the PIRO model awaits more extensive epidemiological study.

Conclusion Scoring systems have become a standard fixture of ICU practice because they facilitate the integration of large amounts of disparate and often contradictory clinical data into a single number that correlates with a recognizable outcome. Just as an experienced clinician relies on a clinical gestalt ("she is getting better" or "I am worried about him") to provide a context for the results of investigations, the intensivist can use the data provided by a score to interpret the status or prognosis of an individual patient, and the investigator can use these data as reliable population descriptors. But neither a gestalt nor a score can predict what will happen to the individual patient: they simply suggest a probable trajectory. So long as clinical intervention retains the capacity to alter clinical outcome, mathematically derived scores will remain a decision tool, rather than a divining rod.

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443

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a specialty intensive care unit. Crit Care Med 1996;24:19681973. 50. Lemeshow S, Le Gall JR. Modeling the severity of illness of ICU patients. A systems update. JAMA 1994;272:10491055. 51. Castella X, Artigas A, Bion J, Kari A. A comparison of severity of illness scoring systems for intensive care unit patients: results of a multicenter, multinational study. The European/North American Severity Study Group. Crit Care Med 1995;23:13271335. 52. Beck DH, Taylor BL,Millar B, Smith GB. Prediction of outcome from intensive care: a prospective cohort study comparing Acute Physiology and Chronic Health Evaluation II and III prognostic systems in a United Kingdom intensive care unit. Crit Care Med 1997;25:9-15. 53. Zimmerman JE, Wagner DP, Draper EA, Wright L, Alzola C, Knaus WA. Evaluation of acute physiology and chronic health evaluation III predictions of hospital mortality in an independent database. Crit Care Med 1998;26:1317-1326. 54. Bertolini G, D'Amico R, Apolone G, et al. Predicting outcome in the intensive care unit using scoring systems: is new better? A comparison of SAPS and SAPS II in a cohort of 1393 patients. Med Care 1998;36:1371-1382. 55. Marks RJ, Simons RS, Blizzard RA, Browne DR. Predicting outcome in intensive therapy units: a comparison of APACHE II with subjective assessments. Intensive Care Med 1991;17: 159-163. 56. Teres D, Lemeshow S. Why severity models should be used with caution. Crit Care Clin 1994;19:93-110. 57. Lemeshow S, Klar J, Teres D. Outcome prediction for individual intensive care patients: useful, misused, or abused? Intensive Care Med 1995;21:770-776. 58. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. An evaluation of outcome from intensive care in major medical centers. Ann Intern Med 1986;104:410-418. 59. Multz AS, Chalfin DB, Samson 1M, et al. A "closed" medical intensive care unit (MICU) improves resource utilization when compared with an "open" MICU. Am J Respir Crit Care Med 1998;157(5 pt 1):1468-1473. 60. Sprung CL, Geber D, Eidelman LA, et al. Evaluation of triage decisions for intensive care admission. Crit Care Med 1999;27:1073-1079. 61. Mackenzie TA, Greenaway-Coates A, Djurfeldt MS, Hopman WM. Use of severity of illness to evaluate quality of care. Int J Qual Health Care 1996;8:125-130. 62. Teres D, Lemeshow S. Using severity measures to describe high performance intensive care units. Crit Care Clin 1993;9:543554. 63. Teres D, Higgins T, Steingrub J. Defining a high-performance ICU system for the 21st century: a position paper. J Intensive Care Med 1998;13:195-205. 64. Randolph AG, Guyatt GH, Carlet J, for the Evidence Based Medicine in Critical Care Group. Understanding articles comparing outcomes among intensive care units to rate quality of care. Crit Care Med 1998;26:773-781. 65. Boyd 0, Grounds RM. Physiological scoring systems and audit. Lancet 1993;341:1573-1574. 66. Rowan KM, Kerr JH, Major E, McPherson K, Short A, Vessey MP. Intensive Care Society's APACHE II study in Britain and Ireland. I: Variations in case mix of adult admissions to general intensive care units and impact on outcome. BMJ 1993;307:972977. 67. Teres D, Pekow P. A night in Tunisia. Crit Care Med 1998;26: 812-813. 68. Wong DT, Crofts SL, Gomez M, McGuire GP, Byrick RJ. Evaluation of predictive ability of APACHE II system and hospital outcome in Canadian intensive care unit patients. Crit Care Med 1995;23:1177-1183.


69. Rowan KM, Kerr JH, Major E, McPherson K, Short A, Vessey MP. Intensive Care Society's APACHE II study in Britain and Ireland. IT: Outcome comparisons of intensive care units after adjustment for case mix by the American APACHE IT method. BMJ 1993;307:977-981. 70. Sirio CA, Tajimi DT, Tase C. An initial comparison of intensive care in Japan and the United States. Crit Care Med 1992;20:12071215. 71. Bastos PG, Sun X, Wagner DP, Knaus WA, Zimmerman JE. Application of the APACHE ITI prognostic system in Brazilian intensive care units: a prospective multicenter study. Intensive Care Med 1996;22:564-570. 72. Nouira S, Belghith M, Elatrous S, et al. Predictive value of severity scoring systems: comparison of four models in Tunisian adult intensive care units. Crit Care Med 1998;26:852-859. 73. Rapoport J, Teres D, Barnett R, et al. A comparison of intensive care unit utilization in Alberta and western Massachusetts. Crit Care Med 1995;23:1336-1346. 74. Hebert PC, Wells G, Blajchman MA, et al. A multicenter randomized controlled clinical trial of transfusion requirements in critical care. N Engl J Med 1999;340:409-417. 75. Halevy A. Severity of illness scales and medical futility. Curr Opin Crit Care 1999;5:173-175. 76. Nathens AB, Curtis JR, Beale RI, et al. Management of the critically ill patient with severe acute pancreatitis. Crit Care Med 2004;32:2524-2536. 77. Girou E, Pinsard M, Auriant I, Canone M. Influence of severity of illness measured by the amplified Acute Physiology Score (SAPS) on occurrence of nosocomial infections in ICU patients. J Hosp Infect 1996;34:131-137. 78. Hebert PC, Drummond AI, Singer J, Bernard GR, Russell JA. A simple multiple system organ failure scoring system predicts mortality of patients who have sepsis syndrome. Chest 1993;104:230-235. 79. Moore FA, Moore EE, Poggetti R, et al. Gut bacterial translocation via the portal vein: a clinical perspective with major torso trauma. J Trauma 1991;31:629-638. 80. Keene AR, Cullen DJ. Therapeutic intervention scoring system: update 1983. Crit Care Med 1983;11:1-3. 81. Cullen D1, Ferrara LC, Briggs BA, Walker PF, Gilbert J. Survival, hospitalization charges and follow-up results in critically ill patients. N Engl J Med 1976;294:982-987. 82. Dickie H, Vedio A, Dundas R, Treacher DF, Leach RM. Relationship between TISS and ICU costs. Intensive Care Med 1998;24:1009-1017. 83. Marshall JC, Vincent JL, Guyatt G, et al. Outcome measures for clinical research in sepsis: a report of the 2nd Cambridge Colloquium of the International Sepsis Forum. Crit Care Med 2005;33:1708-1716. 84. Pettila V, Ppetilla M, Sarna S, Voutilainen P, Takkunen O. Comparison of multiple organ dysfunction scores in the prediction of hospital mortality in the critically ill. Crit Care Med 2002;30:1705-1711.

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85. Peres Bota D, Melot C, Lopes Ferreira F, Nguyen Ba V, Vincent J-L. The Multiple Organ Dysfunction Score (MODS) versus the Sequential Organ Failure Assessment (SOFA) score in outcome prediction. Intensive Care Med 2002;28:1619-1624. 86. Ferreira FL, Bota DP, Bross A, Vincent J-L. Serial evaluation of the SOFA score to predict outcome in critically ill patients. JAMA 2001;286:1754-1758. 87. Barie PS, Hydo LJ. Influence of multiple organ dysfunction syndrome on duration of critical illness and hospitalization. Arch Surg 1996;131:1318-1323. 88. Paugam-Burtz C, Dupont H, Marmuse JP, et al. Daily organsystem failure for diagnosis of persistent intra-abdominal sepsis after postoperative peritonitis. Intensive Care Med 2002;28: 594-598. 89. Staubach KH, Schroder J, Stuber F, Gehrke K, Traumann E, Zabel P. Effect of pentoxifylline in severe sepsis. Results of a randomized, double-blind, placebo-controlled study. Arch Surg 1998;133:94-100. 90. Jacobs S, Zuleika M, Mphansa T. The multiple organ dysfunction score as a descriptor of patient outcome in septic shock compared with two other scoring systems. Crit Care Med 1999; 27:741-744. 91. Cook R1, Cook DJ, Tilley 1,Lee KA, Marshall JC. Multiple organ dysfunction: baseline and serial component scores. Crit Care Med 2001;29:2046-2050. 92. Bernard GR, Vincent J-L, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699-709. 93. Marshall JC, Vincent J-L, Fink MP, et al. Measures, markers, and mediators: towards a staging system for clinical sepsis. Crit Care Med 2003;31:1560-1567. 94. Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ ACCP /ATS/SIS International Sepsis Definitions Conference. Intensive Care Med 2003;29:530-538. 95. Sorenson TI, Nielsen GG, Andersen PK, Teasdale PW. Genetic and environmental influences on premature death in adult adoptees. N Engl J Med 1988;318:727-732. 96. Mira l-P, Cariou A, Grall F, et al. Association of TNF2, a TNF-a promoter polymorphism, with septic shock susceptibility and mortality. JAMA 1999;282:561-568. 97. Gibot S, Cariou A, Drouet L, Rossignol M, Ripoll L. Association between a genomic polymorphism within the CD14 locus and septic shock susceptibility and mortality rate. Crit Care Med 2002;30:969-973. 98. 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 2002;288:862871. 99. Marshall J, Foster D, McKenna C, et al. Quantification of the multiple organ dysfunction syndrome (MODS) as a risk factor, outcome descriptor, and surrogate measure of morbidity in the ICU. Crit Care Med 1996;24:A53.

Burns and Inhalation Injury Roger W. Yurt Evaluation of the Patient Resuscitation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Wound Care Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

447 450 451 453

T

he disruption of homeostasis caused by a major bum injury provides one of the greatest challenges in clinical patient care. The loss of integrity of the skin destroys the barrier between the balanced inner environment and that of the external world, leading to loss of body temperature, fluids, proteins, and electrolytes, and at the same time allowing ingress of foreign material and invasion by microbes. However, the local tissue damage and the response to it is only the external sign of what quickly becomes a massive systemic respons e leading to fluid loss in uninjured tissues and dysfunction of distant tissues and organs. From a teleological perspective, the injured human being has not evolved to survive such a massive insult, and therefore it is only in recent years that advances in resuscitation, infection control, and wound care have allowed survival to the point that the full expression of the body to such an injury can be recognized. Success in caring for these patients has come in a stepwise fashion and provides demonstrable support for the value of continuing investigation and the advantages of integrated multidisciplinary care of seriously ill patients.

Evaluation of the Patient The initial evaluation of the patient with bum injury is the same as with all victims of trauma. Initially, attention is turned to maintenance of the airway, breathing, and circulation. Although some aspects of the evaluation are specific with regard to bums, for example, inhalation injury, it should always be remembered that a bum-injured patient may have multiple system injuries. Only the aspects of evaluation that are peculiar to the bum-injured patient are emphasized in this chapter.

Extent of Bum Injury The extent of injury sustained from tissue damage by burning is more easily quantified than in most other types of trauma. A knowledge of the surface area involved and the depth of

Hypermetabolism and Nutrition. . . . . . . . . . . . . . . . . . . . Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rehabilitation References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

455 456 457 457

injury assists in determining a prognosis for the patient and is used to guide fluid resuscitation and to develop a plan of care. The area of the total body surface that has been injured can be estimated in adults by using the rule of nines, which divides the surface area into sections or multiples of 9% (Figure 25 .11. Although the use of this estimate is helpful in initial assessment and triage of patients, a more exact measurement should be made using a Lund & Browder chart or Berkow's formula.' A section taken from the patient chart used at the Bum Center of NewYork-Presbyterian Hospital (Figure 25 .1) shows the distribution of surface area at several different ages. It is essential that such a chart be used when children are evaluated because the distribution of body surface area varies with age. The determination of the depth of injury presents a greater challenge because the clinical findings are not exact except in the extremes and the wound is dynamic. A partialthickness bum involves the outer layer of the skin and may extend into the dermis. This wound, commonly termed a second-degree bum, is characterized by blistering of the skin and is red, moist, and painful; sensation is intact. This depth of injury is further subdivided into superficial and deep partialthickness injury. The clinical differentiation of these different depths of injury is challenging, as evidenced by the fact that even experienced bum surgeons are able to accurately determine depth of injury only 64% of the time.' Although some believe that the depth of injury can be assessed by identifying the fact that a pinprick is appreciated as sharp in superficial injury and as a pressure sensation in deeper injury, the only absolute way to confirm the depth of injury is by the length of time it takes these injuries to heal. A superficial partialthickness bum should heal within 2 weeks, whereas a deep partial-thickness wound takes 3 weeks to reepithelialize. Figure 25.2 depicts a cross section of skin with indication of the various depths of injury. As shown, the superficial bum wound involves the epidermis but spares islands of epidermis that provide the source of epidermal regeneration. The deep partial-thickness injury can only resurface from residual epidermis from the organelles of the skin.

447

448

CHAPTER 2.5

AREA Head Neck

Ant. Trunk Post. Trunk R. Buttock L. Buttock Genitalia

0-1 YEAR 19 2 13 13

4

4

2Y. 2Y.

SY. SY. S S

L. Thigh R.Leg L. Leg R. Foot L. Foot

3Y.

3 \I.

The clinical importance of differentiating the depth of injury lies in the recognition that a superficial wound heals with minimal cosmetic or functional consequence. The deep partial-thickness wound, although it will heal given enough time, results 'in both cosmetic deformity and disturbance of function. Skin grafting of deep partial-thickness bums will improve the outcome and is the preferred approach . Because wound care is directed by the depth of injury, numerous attempts have been made to improve diagnostic accuracy in assessing the depth of partial-thickness wounds. More recent studies have applied laser Doppler-based techniques to evaluate wounds. Schiller et a1. 3 were able to differentiate between hand bums that would heal within 15 days and those that required a mean of 42 days to heal; however, they were unable to correlate these findings with cosmetic or functional results. Other studies" have shown that this technique works well when low blood flow is detected but is less helpful when high flow is observed in partial-thickness bums. That this approach may be of assistance in evaluating the depth of injury is supported by studies in which measurements with a heated laser Doppler flowmeter could predict whether bum wounds would heal within 3 weeks of injury." An additional complicating factor in evaluating depth of injury is the fact that the wound evolves over a 3-day period and that external influences such as adequacy of resuscitation, exposure of the wound to noxious agents, and infection

.

-:'=-~uperf+:l I + Deel)

13 13

2Y. 2Y.

4 3 3

R.Hand L.Hand R. Thigh

2

2Y. 2Y. 1

R.U.Arm L.U.Arm R.L.Arm L.L. Arm

S-9YEARS 11

Partial

Thickness

I

~

Thickness

I

FIGURE 25.2. Cross section of skin showing tissue levels and depth of injury.

1

4

3 3

2Y. 2Y.

8 8 S \I. SY.

3Y. 3Y.

ADULT 7 2 13 13

2Y. 2Y.

1 4 4 3

3

2Y. 2Y. 9Y. 9Y. 7

7

3Y. 3Y.

FIGURE 25.1. Distribution of body surface area at different ages .

modify the progression of the wound. Thus, complications or even inexpert care may deepen the depth of injury or convert a partial-thickness bum to a full-thickness injury. Furthermore, wounds often are of mixed depth such that evaluation of discrete areas may not reflect the depth of the overall wound. Full-thickness wounds are leathery, white or charred, dry, and insensate. Because all the epidermis is destroyed (see Figure 25.21, these wounds can heal only by migration of epidermis from the margins of the wound. During the process of healing, contraction occurs; this decreases the area that must be epithelialized but leads to a poor cosmetic result and a wound that is less resistant to trauma. Further, if the wound is adjacent to or involves a joint, the function of the joint will be impaired. Except for small surface area wounds, fullthickness wounds should be either excised and closed primarily or grafted with the patient's skin.

Types of Injury The pathophysiology involved in the wounds of a patient with a bum injury is basically the same regardless of the cause. In the superficial area of injury, coagulative necrosis occurs . In this zone protein is denatured irreversibly and cellular integrity is 10st.6 Adjacent to this zone is the zone of stasis in which tissue is viable but subject to further necrosis as the wound evolves. A third zone has been recognized below the zone of stasis and is characterized as a zone of hyperemia. The zones of stasis and hyperemia are the areas where the inflammatory response of the patient is initiated. The depth of the coagulative necrosis that occurs in bums that are caused by scalding, flame, or contact with a hot object is related directly to the temperature, duration of exposure, thickness of the tissue, and state of the blood supply in the tissue. For example, with the same temperature and duration of exposure, wounds on the inner aspect of the arm or thigh will be deeper than wounds on the lateral aspect. Injury of the back or sole of the foot is less likely to be deep because the epidermis is thicker in those areas. The skin of the face is more protected than other areas because the rich blood supply dissipates heat and provides for rapid recovery of injured tissues.

BURNS AND INHALATION INJURY

TABLE 25.1. Common Agents that Cause Burn Injury to the Skin by Category.

Agent

Site of injury

Treatment

Acids Hydrochloric nitric, sulfuric Hydrofluoric

Superficial

Irrigate with water

Deep

Phenol

Deep

Initial irrigation with water, then calcium gluconate Irrigate with 50: 50 water and polyethylene glycol

Alkali Ammonia, sodium hydroxide Cement Tar

Deep

Irrigate with water

Superficial Superficialjdeep

Irrigate with water Cool, then Vaseline

Chemical bums cause denaturation of protein and disruption of cellular integrity. The degree of injury is dependent on the time of exposure, the strength of the agent, and the solubility of the agent in tissue. Alkali tends to penetrate deeper into tissues than does an acid. One exception to this is hydrofluoric acid, which penetrates lipid membranes readily. Table 25.1 provides a list of common agents that cause bum injury.' The major concern in evaluating patients who sustain electrical injuries is that the surface injury, which may appear similar to other bum injuries, is often not indicative of the extent of injury. In the local area of injury subcutaneous tissue, muscle, and bone may be injured. Electrical current follows the path of least resistance and therefore will pass through nerves and blood vessels preferentially" and cause injury to these tissues. If the current passes through the torso of the patient, organ injury may result. Injury of the heart is primarily associated with arrhythmia." Injury of other viscera including the pancreas and gastrointestinal tract has been reported." Late sequelae of electrical injury include the development of cataracts and transverse myelitis of the spinal cord. These sequelae have been reported to occur months or even years after electrical injury. 11 Injury caused by exposure to ionizing radiation may be limited to the skin but often is deeper. Because these wounds do not heal well, care must be taken to avoid additional damage of the tissue. The vasculitis that is associated with these injuries is usually a lifelong problem. 12

Inhalation Injury Inhalation injury is often attributed inappropriately to heatrelated damage to the airway or lung. Thermal injury to the airway is rare because the upper airway can dissipate heat effectively, but upper airway injury may occasionally be associated with a direct inhalation of superheated steam." The majority of injuries to the lung are caused by inhalation of toxic chemical products of combustion. The deleterious components of smoke are primarily aldehydes." In addition, carbon monoxide and cyanide may be inhaled. Similar to a chemical bum of the skin, these agents cause erythema and edema of the airway and can lead to blistering, ulceration, erosions, and sloughing of airway mucosa, possibly resulting in airway obstruction. The local edema, infiltration of the tissue with polymorphonuclear leukocytes, and sloughing of

449

bronchial mucosa lead to the formation of an endobronchial cast and obstruction of terminal bronchioles. Pulmonary edema occurs from damage to the alveolar-capillary membrane, microvascular injury, and increased pulmonary lymph flow and microvascular permeability." The debris in the airway cannot be cleared because injury to the mucosa disrupts airway host defenses, including mucociliary transport. Small airway obstruction and accumulation of carbonaceous material and necrotic debris, and impaired local host defenses provide a fertile ground for the development of infection. Some authors have reported that the incidence of pneumonia in these patients is as high as 700/0 16 within a week of injury. Because the diagnosis of inhalation injury is difficult to make, a presumptive diagnosis is made based on a history that is consistent and signs and symptoms that are associated with injury to the airway. Any patient who sustains injury in a closed space and has bums above the clavicle, singeing of nasal vibrissae, hoarseness, or carbonaceous sputum should be assumed to have sustained an inhalation injury. Elevated carboxyhemoglobin concentrations confirm exposure to carbon monoxide but are not diagnostic for lung injury. Because the primary concern early after inhalation injury is airway obstruction, the upper airway should be evaluated immediately, usually in the emergency department. Flexible bronchoscopy provides the opportunity to confirm the diagnosis and initiate therapy. An endotracheal tube is passed over the bronchoscope before the endoscopy, and if injury is identified in the airway the tube is passed over the scope into the trachea. Injury to the parenchyma of the lung is subtle in presentation in the early period after injury except in the most severe injuries such as those found in patients who sustained cardiac or respiratory arrest in the field. Findings on chest X-ray, arterial blood gases, and physical examination are frequently not helpful in the first 48 to 72h post injury." Xenon ventilation/perfusion scans are of value in detecting parenchymal injury to the lung; however, the extent of injury cannot be determined with this test. The results of multiple evaluations with pulmonary function testing and xenon scanning improve diagnostic accuracy." Nevertheless, because the therapy for lung injury is not specific and the injury is not quantified by testing, most patients are treated presumptively. Therapy consists of aggressive pulmonary toilet, use of mucolytics, and early identification and treatment of infection. Prophylaxis with antibiotics is not used, and glucocorticoids are of no benefit and are potentially harmful." Table 25.2 provides evidence for management of inhalation injury. The practice guidelines for bum care, developed by the American Bum Association, indicate that there are insufficient data to support a standard treatment guideline."

Decision to Transfer to Specialized Care The resources required to care for patients with major bum injury are not available at many medical centers. For this reason, a regionalized system for care of the burn-injured patient has been developed. Although travel time and distance to a bum center are of concern, transfer of burn-injured patients after initial evaluation has been shown to be safe especially if initiated early after injury." Patients with bums over more than 30% of their body surface area, those at the

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CHAPTER 25

_"fJ"'_ TABLE 25.2.

Management of Inhalation Injury.

Trial

Year

Class of evidence

19 20 21

1978 1982 1991

III

± Steroids

III

22

1995

III

Volumetric Diffusive Respiration Permissive Hypercarbia

n

Groups

Intervention/design

Comments

Steroids/gentamicin

Prospective Two cohorts Prospective

No benefit with either No difference in outcome Outcome improved

Prospective (histo rical control)

Decreased mortality

extremes of age, with injury of crucial body parts such as genitalia, and those with substantial preexisting disease should be cared for in a bum center. Specific guidelines have been published by the Am erican Bum Association.P

Resuscitation General Principles Because intravascular fluid loss begins to occur immediately after bum injury, initial resuscitative efforts are oriented toward volume replacement. If transport of the patient to an emergency care facility can be accomplished within 30min of injury, intravenous access can be delayed until arrival at th e receiv ing institution. Peripheral venous cannulation is preferred over central venous access and may be performed through bum-injured tissue if access through noninjured sites is not available. Patients with greater than 20 % total body surface area (TBSA) injury (15% in children) require intravenous fluid resuscitation and should have a urinary bladder catheter placed. In addition, patients who have sustained a major injury should have a nasogastric tube placed to decompress the dilated stomach. During transport and resuscitation, every effort sho uld be made to maintain body temperature. Patients are wrapped in clean sheets or blankets and the room is warmed in the initial phase in the emergency care area. Recirculating forced-air warming blankets are also of use . Resuscitation fluids should be warmed when fluids are given at rates of greater than 200mL/h. Bum-injured extremities should be elevated above the level of the heart.

Fluid Resuscitation During the first 24h after injury, there is fluid loss into and through the bum injury. In addition, there is a shift of intravascular fluid into noninjured tissues. There is general agreement that during this period crystalloid solutions should be used .23- 25 As the fluid losses are large, formulae have been developed to provide an estimate of the fluid requirements. Every guideline that has been developed carries with it the mandate that the patient's response to resuscitation be used as the actual determinant of fluid administration, not the formula! The goal of resuscitation is to maintain adequate tissue perfusion and therefore preserve organ function. The traditional assessment of adequacy of resuscitation in bum injury has been based on observation of blood pressure, heart rate, and urine output." In this approach the patient is "titrated" with fluid to maintain a normal blood pressure and heart rate and a urine output of 1mL/kg/h or 30 to 50mL/h in an adult patient. That this is the best method to resuscitate these patients has been challenged by reports suggesting that hyperdynamic resuscitation" yields improved outcome. Furthermore, controversy has arisen regarding the best endpoint to use in assessing adequacy of resuscitation from shock in general (reviewed by Elliott"], Elliot reports that a variety of studies of resuscitation from shock suggests that mean arterial pressure should be maintained at 60mmHg and that mea surement of blood lactate concentrations may be a useful adjunct in assessing response to resuscitation. The Parkland formula" is the crystalloid-based formula that provided the foundation for current methods of resuscitation. This formula calls for th e initiation of resuscitation with Ringer 's lactate solution at a rate based on the TBSA of bum

TABLE 25.3. Fluid Resuscitation in Patients with Thermal Injury. Fluid required Regimen

Hypertonic Hyp ert onic + colloid

% of Parkland

Weigbtgain" (%)

Reference

7.3 7.3

36 36

4.8 3.16

13.9 11.99

2.68 5.3 3.9

4.37

37 37 37

mL/kg/% burn

75 57

Ringer's lactate Hyp ert oni c Fresh -frozen pla sma Ringer' s lactate Hypertonic 'At 48h compar ed to initial. bMean valu e, first 24h. ' At 3 days after injury.

Serum Sodium

141.6

b

143.8

35 35

451

BURNS AND INHALATI ON INJURY

TABLE 25.4. Bum Shock Resuscitation.

Trial

Year

37 38 39 40

1981 1981 1985 2003

41 36

2000 2001

Closs of Evidence

II

III III II III III

Intervention/Design

Minor

Major

Comments

Inhalation injury Fluid required

Resuscitati on Resuscit ation Resuscit ati on Base deficit

4mL/k g/ % bum 2 m L/ kg/ % bum 3.9mL/kg/% bum S.7 m L/kg/ % bum Greater deficit = 8.SmL/kg/% bum Lesser deficit = 6.3 mL/k g/ % bum 58% required >4.3 mL/kg/% bum No standard, most 2-4 mL/kg/% bum

Ret rospectiv e Retrospective Prospective Retrospective Review

injury and the patient's body mass . The calculated resuscitation volume for the first 24h is 4mL times mass in kilograms times the percent of the TBSA that is burned. One-half of this volume is given in the first 8 h after injury and the other half is given in the following 16h. Resuscitation of children is based on this volume plus a volume equal to the estimated daily maintenance fluid requirements. Graves et al.,3° at the U.S. Army Institute of Surgical Research, suggested that the same success can be obtained by using a formula that estimates requirements as 3 mL/kg per percent of the TBSA that is burned. To minimize the volume of fluid used during resus citation, Monafo et al." recommended the use of higher concentrations of sodium in the resuscitation fluid. Others have not had success with hypertonic saline resuscitation regimens and in fact have reported higher complication and mortality rates compared to historical controls who were resuscitated with Ringer's lactate solution." A comparison of various regimens of fluid resuscitation (Table 25.3) indicates that various regimens lead to differences in weight gain and serum sodium concentration. Evidence is not sufficient to develop a guideline at this time. " The current evidence, summarized in Table 25.4, supports a crystalloid-based regimen in the range of 2-4mL/kg/% burn in the first 24h. However, it should be noted that more recent data indicate that patients who have sustained inhalation injury and all patients in general are receiving more than estimated needs. Delay in the initiation of resuscitation may result in higher than anticipated fluid requirements. Most authors continue to suggest that administration of colloid-containing solutions be reserved for the second 24 h after injury when the capillary leak is assumed to have resolved. Thereafter, daily maintenance fluids are given with a recognition of ongoing evaporative losses and the knowledge that total body sodium content is high . Evaporative fluid loss from the burn-injured tissue has been estimated to occur at an hourly rate equal to the sum of 25 and the percent of the TBSA that is injured multiplied by the TBSA.

Wound Care General Principles Small (2-cm diameter or less) blisters are often left intact whereas larger blisters and full -thickness wou nds should be

Fluid required Fluid requ ired

debrided and covered with a topical agent . Inpatient wound care is provided in a warm environment at the bedside or more often in an area reserved for wound care in a burn center. The objective of wound care is to avoid infection and protect the wound from further injury. Agents that may cause additional tissue damage are avoided, and the perfusion of the wound is protected by avoiding hypotension and excluding the use of alpha-adrenergic agents [e.g., norepinephrine, phenylephrine) , which will lead to additional tissue ischemia. Sterile gloves should be worn at all times when a wound is manipulated. Chemical injury of tissue is treated with irrigation with copious amounts of either normal saline or tap water for as long as 6h. Neutralizing agents are not used because they can lead to additional tissue damage caused by heat generated in an exothermic reaction between the chemicals. Hydrofluoric acid injuries can lead to systemic hypocalcemia, and therefore brief irrigation should be followed by topical application of calcium gluconate gel. If pain persists, clysis [subeschar infusion I of the wound with calcium gluconate is used, except in digits. For injury to distal extremities, intraarterial infusion of calcium gluconate has been recommended."

Prophylaxis Against Wound Infection Because there is concern for inducing microbial resistance to antibiotics, systemic antimicrobial prophylaxis is not used in burned patients admitted to the hospital. The wounds are observed closely for infection, and treatment is initiated if this occurs. There are differences in how antibiotics are used in the outpatient setting." Some have advocated the use of systemic antibiotics in outpatients whereas others have not." If it is anticipated that compliance with a topical therapy regimen will be poor, systemic prophylaxis should be provided. The advent of effective topical antimicrobial agents has substantially reduced the mortality associated with burn wound infection." The commonly used agents and their advantages and disadvantages are listed in Table 25.5. The ideal topical regimen includes the use of an agent with good antimicrobial activity that also provides an opportunity to evaluate the wound easily and to perform regular physical therapy. According to a recent international survey," 1% silver sulfadiazine is the topical agent used most commonly for partial-thickness (32% use), mixed partial- and full -

452

CHAPTER 25

TABLE 25.5. Commonly Used Topical Antimicrobial Agents. Agent

Wound dressing

Advantages

Disadvantages

Silver sulfadiazine (1%)

Open or light gauze

Does not penetrate eschar possible neutropenia

Mafenide acetate cream (5%)

Open or light gauze

Mafenide acetate (5% solution)

Continuous moist bulky dressing Continuous moist bulky dressing

Soothing, optimal physical therapy, good antimicrobial activity Penerates eschar, optimal physical therapy, good antimicrobial activity Good antimicrobial, use over skin grafts Good antimicrobial

Aqueous silver nitrate (0.50/0)

thickness (34% use), and full-thickness (300/0 use) bum wounds. Because this agent and most others do not penetrate bum wounds well, they are indicated for prophylaxis against infection but not for therapy. An aqueous solution of 0.50/0 silver nitrate has been used for years for its topical antimicrobial activity, however, only 4 % of centers employ this agent currently for primary topical use. Mafenide acetate does penetrate the wound and is the first-line agent used for therapy of bum wound infection, either as a cream or topical solution. More recent approaches include the use of silver as an antimicrobial, preliminary reports" suggest that Acticoat (Smith &. Nephew, Hull, UK), a silver-coated polyethylene mesh dressing, provides antimicrobial activity in a dressing that may be left on a partial-thickness wound for 2 to 3 days.

Surgical Care Excision and closure of wounds has the advantage of reducing the extent of injury and eliminating the risk of wound infection. Tangential excision, which is the sequential removal of layers of necrotic tissue until viable tissue is identified, is the most commonly used method of excision of bum-injured tissue. The advantage of this method is that it yields the best cosmetic and functional result, however, it also is associated with considerable blood loss. Tourniquets have been shown to minimize blood loss when they are applied during excision of extremities." This approach presents a challenge to even the experienced bum surgeon because the identification of the depth to excise to viable tissue is difficult to ascertain in the absence of capillary bleeding. Excision of the wound to the level of the fascia is associated with minimal blood loss and is used when wounds are deep full thickness, are infected, or when large areas are excised. The cosmetic results are poor, and lymphatic drainage is impaired after this type of excision. Early excision of bum wounds has led to a decrease in length of hospital stay and a decrease in complications.t':" but there are no randomized prospective data to indicate that outcome is affected. Excision has been initiated by some within the first 24h after injury43 j however, many authors suggest that excision is best done when the patient with a large bum has been stabilized and within 3 to 4 days after injury.44,45 In addition to the stability of the patient, coexistent factors such as inhalation injury affect the timing of operative intervention. When a patient has wounds that will require grafting, that is, deep partial- and full-thickness wounds over more than 40% of the TBSA, the strategy for surgical intervention must take into account the skin donor

Painful, metabolic acidosis caused by inhibition of carbonic anhydrase Restricts physical therapy, stains wound Hyponatremia, does not penetrate

sites available and a goal of reducing the amount of open wound as soon as possible. In such cases, closure of the wound takes precedence over cosmetic and functional considerations. At the present time, the ultimate closure of the excised wound requires the use of autograft. If sufficient donor sites are available, the preferred skin graft is a split-thickness autograft (0.008-0.01 inch in thickness). A thicker, fullthickness graft is preferred for cosmetic reconstruction and in areas where scarring would lead to functional compromise. However, this thickness of donor skin requires grafting in tum of the donor site. When donor sites are limited, autograft can be expanded by passing it through a mechanical meshing device to enlarge the skin graft up to six times the surface area of the intact donor skin, but not usually more than threefold for practical purposes. Closure of the excised wound may be staged by temporary coverage with biological or manufactured dressings. Allograft (skin harvested from a human cadaver) provides for closure of the wound and also may be used as a test graft in areas where there is a concern for infection or when the adequacy of the excised wound bed is suspect. If an allograft is left in place for longer than 10 to 14 days, it becomes incorporated into the wound to the extent that the wound must be excised to remove it. In recent years, a number of skin substitutes have been developed that replace the function of some or all layers of the skin. Integra provides a temporary epidermis as an outer layer of silastic and an inner layer matrix for the growth of a neodermis. Success with use of this product has been reported by a number of authors,46A7 all of whom noted improved cosmetic and functional results. However, there is concern regarding increased rates of infection when the wound bed is subject to contamination. A thin layer of epidermis must ultimately be grafted onto the neodermis. Alloderm is human dermis that has been processed to provide an acellular nonantigenic matrix that provides a scaffold upon which a thin epidermal graft may be placed, which may improve cosmesis." The advantage of these products for patients with large bums is that donor sites are available sooner for reharvesting of epidermis for further grafting. Immediate application of other products such as pigskin or Biobrane (a synthetic membrane composed of silastic and a chondroitin sulfate-coated surface) on partial-thickness wounds moderates pain and eliminates the need to change dressings, but these products will slough off from deep partialthickness wounds. A new dressing called TransCyte (Smith &. Nephew) derived from human fibroblasts is reported to increase the rate of epidermal healing in partial-thickness


wounds." These substitutes.

products

are

only

temporary

skin

Circumferential Bums A full-thickness circumferential bum injury carries with it the risk of compression of structures underneath the wound. In the extremities, the combination of increased extravascular fluid in the wound and underlying tissues and the lack of elasticity of the bum wound can lead to subeschar pressures that compromise blood flow to viable tissue. All extremities with circumferential full-thickness bums should be elevated to minimize edema formation and should be evaluated hourly for signs of vascular compromise. The classic signs of ischemia-pallor' pain, parasthesia, paralysis, and poikilothermia-should be assessed. Because these signs are often difficult to evaluate in a bum-injured extremity, blood flow, measured by Doppler, should be assessed. However, loss of Doppler signals may not occur until after tissue becomes damaged" and therefore one should have a low threshold for performing an escharotomy to release subeschar pressure. An escharotomy is performed by making an incision through the eschar on the lateral surface of the extremity. An additional escharotomy may need to be performed on the medial surface as well. The preferred sites for escharotomy are indicated in Figure 25.3. A multicenter study has suggested that delay in decompression of extremities may be associated with occult intracompartmental infection." Decompression of the hand should be performed when full-thickness burn injury of the hand leads to ischemia and dysfunction. Escharotomies are performed on fingers in the midaxial line on the ulnar side and on the radial side of the thumb so as to preserve tactile sensation of the surfaces of opposition of the fingers and thumb. A recent review'? emphasizes the importance of timely escharotomy of the fingers and the dorsum of the hand that has sustained full-thickness bum injury. A circumferential full-thickness burn of the chest can compromise chest wall motion and cause a decrease in total pulmonary compliance. When this occurs, escharotomy of the chest in the anterior axillary line will often decrease the inspiratory pressures required to maintain tidal volume. If in addition there are circumferential full-thickness burns of the abdomen and back, an escharotomy following the costal margin may be necessary. Incision of the eschar may be performed with a scalpel but is often done with electrocautery so that minor bleeding can be controlled. Because fullthickness wounds are insensate and avascular, anesthesia is not necessary, and these procedures may be performed under

FIGURE 25.3. Preferred sites for escharotomy incisions. The patient should be in the anatomical position as depicted. The incisions are made in the lateral or medial aspect of the extremities.

453

sterile conditions at the bedside. Circumferential fullthickness bums on the abdominal wall can contribute to the development of increased intraabdominal pressure during resuscitation. If abdominal compartment syndrome develops, it may be relieved by escharotomy, drainage of intraabdominal fluid, or decompressive laparotomy.53

Infection General Aspects in Burn Injury The systemic inflammatory response that is associated with a major bum ignites a cascade of events that presents a clinical syndrome that is difficult to distinguish from infection. These patients often have core body temperatures of 39° to 39.5°C, often develop an intestinal ileus, become disoriented, develop hyperglycemia, and develop positive fluid balance. The bum wound has been seen as a "black box" in which a local inflammatory process occurs that leads to leakage of mediators of inflammation into the systemic circulation and causes activation of cells as they pass through the milieu of the wound. 54 These events compound the responses to injury and are described here only to the extent that they distinguish the bum-injured patient from patients with other injuries. Arturson has summarized the pathophysiology that occurs in the bum wound. 55 Locally produced prostanoids may not only cause local injury" but may lead to effects elsewhere. An increased susceptibility to infection related to the extent of bum injury that has been noted clinically has been confirmed in animal models." Those studies indicated that polymorphonuclear leukocytes (PMNs, neutrophils, granulocytes) were activated. Others have confirmed that granulocytes from bum patients have a baseline increase in cytosolic oxidase activity," suggesting that in vivo activation has occurred. In addition, PMN surface receptors are altered following thermal injury59,60; this may lead to increased adhesion of PMNs, causing neutrophil aggregation and sequestration. 59,61 The decrease in bactericidal activity that has been noted may also be the result of in vivo stimulation of the PMN, which leads to a decrease in oxidase activity.58,62 Decreases in oxidase activity were shown to decrease production of superoxide anion and decrease oxygen consumption'" by PMNs from bum-injured patients. That there are other mechanisms that modulate the overall activity of PMN is supported by the report that apoptosis in PMNs is inhibited after a bum, possibly by exposure of the cells to granulocytemacrophage colony-stimulating factor (GM-CSF) or by other mediators in plasma/" A randomized prospective study has shown that a monoclonal antibody to intercellular adhesion molecule-l diminishes progression of tissue injury in partialthickness burns." These data suggest that leukocyte adherence is involved in the pathogenesis of bum injury. Cytokines are elevated following a bum injury, and plasma levels of interleukin-l-beta (IL-l~), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-a) have been found to be elevated in severely burned patients. 66-69 IL-6 and TNF concentrations were reported to be higher in patients with severe infection," and TNF concentrations have been noted to be elevated early after bum injury in as many as 80% of patients. It has been suggested that IL-I0 production by CD41 T-helper

454

CHAPTER 25

cells is increased following severe bum injury" and that this cytokine may increase susceptibility to infection. The net result of activation of cells and mediator pathways appears to be indiscriminant recruitment of the normal pathways that maintain homeostasis, which leads to increased susceptibility of infection and distant organ and further local tissue injury.

Burn Wound Infection In an attempt to standardize the evaluation and classification of infection in the wounds of the bum-injured patient, a subcommittee of the American Bum Association has provided a proposal for categorization of these infections," providing a foundation for describing the four categories of wound-related infection that occur in the patient with bum injury.

Impetigo Impetigo "involves the loss of epithelium from a previously reepitheialized surface such as a grafted bum, a partial thickness bum allowed to heal by secondary intention, or a healed donor site."?' This definition assumes that no other cause for epithelial loss is present such as mechanical damage, hematoma formation, or ischemia. This infection, which has also been termed melting graft syndrome;" is not necessarily associated with systemic signs of fever or elevated white blood cell count. Although it is often caused by streptococcal or staphylococcal species, it may be caused by other organisms as well. In distinction to burn wound surface cultures, which give no insight into what is occurring in the wound, surface cultures are helpful in determining the organism that is the agent of these infections. Treatment consists of local care of the wound and systemic antibiotics.

Open Surgical Site Infection These infections occur in wounds associated with surgical intervention that are not healed. As defined by the committee, they may occur in an ungrafted excised bum or donor sites that have not healed and are associated with culturepositive purulent exudate. In addition, at least one of the following conditions is present: 1. Loss of synthetic or biological covering of the wound

2. Changes in wound appearance, such as hyperemia 3. Erythema in the uninjured skin surrounding the wound 4. Systemic signs, such as fever or leukocytosis

These infections require a change in local wound care, usually the addition of a topical antimicrobial agent, more frequent dressing changes, and the administration of systemic antibiotics.

Cellulitis The local inflammatory response to a bum injury is manifest at the wound margin as erythema. This finding is differentiated from cellulitis by its localized nature, usually less than 1 to 2 em from the margin of the wound, and by its lack of extension beyond that zone. The guidelines suggest that in addition to a requirement for antibiotic treatment the definition of cellulitis requires at least one of the following:

1. Localized pain, tenderness, swelling, or heat at the affected site 2. Systemic signs of infection, such as hyperemia, leukocytosis, or sepsis 3. Progression of erythema and swelling 4. Signs of lymphangitis, lymphadenitis, or both

Invasive Infection The diagnosis of invasive burn wound infection rests on the recognition of changes in the wound, which include discoloration, maceration, or early separation of eschar and systemic manifestations of infection. In addition to the clinical assessment of the wound, biopsy may be performed for quantitative culture or histological evaluation. When more than 105 organisms per gram are cultured, it has been held that invasive wound infection is present." However, considerable variability in results with the use of this technique" and its lack of correlation with histological findings" have limited its application to use for identification of organisms in wounds. Histological evaluation, although not readily available at most institutions, is diagnostic for invasive infection when organisms are identified in viable tissue." Invasive wound infection requires surgical excision of the wound to the level of viable tissue and administration of systemic antibiotics. Topical antimicrobials are not used for therapy for invasive bum wound infection because they do not penetrate eschar, with the exception of mafenide acetate, which may be used in preparation for excision. The criteria for definition of invasive infection as outlined in the guidelines may be associated with these conditions: 1. Inflammation of the surrounding uninjured skin 2. Histological examination that shows invasion of the organism into adjacent viable tissue 3. Bacteremia in the absence of other infection 4. Systemic signs of infection such as hyperthermia, hypothermia, leukocytosis, tachypnea, hypotension, oliguria, hyperglycemia at a previously tolerated level of dietary carbohydrate, or mental confusion

Pneumonia Effective topical antimicrobial agents for prevention and therapy of wound infection along with earlier surgical intervention in wound care has decreased the incidence of wound infection. Respiratory failure is now the leading cause of death in the patient with thermal injury." Although inhalation injury is a prominent cause of respiratory complications in these patients, there is a high incidence of pneumonia and acute respiratory distress syndrome even when direct lung injury is not present." Up to 400/0 of deaths have been attributed to respiratory failure," and even a higher number of children succumb to their injuries as the result of pulmonary complications." Early detection of pulmonary infection by Gram's stain of sputum and culture of secretions, with respiratory support with volume-cycled ventilators when pulmonary failure develops, are standard care." More recent studies suggest that barotrauma can be minimized by the use of highfrequency ventilation in these patients, particularly those with inhalation injury." The presence of white blood cells and bacteria in the sputum associated with other signs of


455

infection should prompt the initiation of systemic antimicrobials that will address the organisms which predominate in the flora of the unit at the time. Specific antimicrobials are then selected when culture reports are available.

sites such as cardiac valves or the brain," making perioperative administration of antibiotics of likely benefit.

Suppurative Thrombophlebitis

Just as in any seriously injured patient, host immunosuppression may set the stage for infection at any site. These patients have a high incidence of urinary tract infections and pneumonia." They also develop other infections such as appendicitis and diverticulitis but often do not present with classic features because of the lack of the normal inflammatory response. A high index of suspicion is necessary to detect these infections. Additional infections of concern in the bum-injured patient are listed next.

Bacterial colonization of venous catheters in patients in intensive care units'" and in particular of central catheters in the bum-injured patient has been reported to be as high as 250/0. 84 Many centers have a policy, such as that at the Hearst Bum Center at NewYork-Presbyterian Hospital, that requires that all peripheral, central venous, and arterial lines are changed over a wire on day 3 and a new site is used on day 6. Others have suggested that a once-a-week catheter change is sufficient to maintain a rate of catheter-related sepsis at 3.20/0. 85 The reason for concern, especially in burn-injured individuals, is that suppurative thrombophlebitis can be an insidious and life-threatening infection." The only findings may be persistent fever and bacteremia that continues despite appropriate antibiotic treatment. Peripheral veins are affected. The classic findings that are associated with phlebitis of edema-erythema, pain, and a palpable cord at an intravenous site-may not be identifiable. Diagnosis is confirmed by aspiration of purulent material from the affected vein, and treatment consists of excision of the involved vein to the point that the vessel is normal where bleeding is encountered."

Suppurative Chondritis Infection of the external ear that has sustained a partial- or full-thickness injury can lead to loss of integrity of the entire ear." The cartilage of the ear has minimal protection and blood supply and is highly susceptible to infection when the overlying tissue is damaged. Dressings should not be applied to the ear, and pillows should not be used. Auricular bums should be treated with twice-daily open wound care and debrided gently. The topical agent of choice is mafenide acetate because it penetrates eschar and avascular cartilage. When suppurative chondritis occurs, systemic antibiotics are of little value because cartilage is avascular," and the ear must be surgically drained under anesthesia by bivalving of the cartilage with excision of devitalized tissue.

Bacteremia Associated with Wound Manipulation It may be anticipated that debridement and surgical excision of the burn wound will cause bacteremia; however, the data are not consistent. Bacteremia has been observed transiently in 21 % of procedures related to bum care." and 460/0 91 of burn patients have bacteremia following bum excision. That the incidence of bacteremia in wound manipulation is related to the extent of injury is supported by the finding of an 80/0 incidence of bacteremia in patients with 31 % to 600/0 TBSA bums compared to an incidence of 750/0 in those with more than 600/0 TBSA bums. More recent studies have suggested that the incidence of bacteremia is low in the early period after injury, and the authors have questioned the need for perioperative antibiotics." Nevertheless, bacteremia related to bum care, especially in patients with a large burn injury who have colonized or infected wounds, may seed distant

Other Infections

SINUSITIS

One source of sepsis that is frequently overlooked in the bum patient is nosocomial sinusitis." Factors that predispose to sinusitis are indwelling catheters for nasogastric or nasoduodenal feeding and nasotracheal intubation, especially in patients with inhalation injury. The clinical diagnosis of nosocomial sinusitis is difficult because purulent nasal discharge is present in only 270/0 of cases." The diagnosis is made by computerized tomography of the sinuses, followed by maxillary sinus aspiration and culture. If diagnosed, treatment of sinusitis consists of removal of all tubes and catheters and appropriate antibiotic therapy. If a nasotracheal tube is responsible, it may be necessary to perform a tracheostomy. Persistent or recurrent infection may require formal surgical drainage of the sinuses. BACTERIAL ENDOCARDIDITIS

Immunocompromise, recurrent bacteremia, and the frequent presence of central venous catheters in the patient with bum injury provide a basis for the development of endocarditis." That central venous and pulmonary artery catheters are associated with the development of bacterial endocarditis in these patients is well documented.P'" Similar to suppurative thrombophlebitis, this infection is insidious and should be suspected after any bacteremia without an obvious source, especially because the incidence of bacterial endocarditis is 14 to 70 times higher than in other intensive care unit patients. The presence of a new cardiac murmur supports the diagnosis, which should be confirmed by echocardiography. Bacterial endocarditis was associated previously with nearly 1000/0 mortality with burn injury," but early diagnosis and valve replacement have led to improved survival in recent years.

Hypermetabolism and Nutrition The classic description of the metabolic response to injury includes an early ebb phase that is characterized by low cardiac output and a decreased metabolic rate followed by a hypermetabolic phase that starts at 24 to 36h after injury. After bum injury, the increase in metabolic rate may often exceed the resting energy expenditure (REE) by twofold.'?" but this is variable among patients. Various prior estimates of the caloric needs of these patients often overestimated the needs of current patients; this has been attributed to improved care

456

CHAPTER 2S

TABLE 25.6. Comparison of Metabolic Rate in Thermally Injured Patients: Estimates by Various Formulae Compared to Rate Based on Measurement of Resting Energy Expenditure (REE). Formula

Calculation

HBEE Actual'P' Curreri et al. 112 Wilm ore et al. 100 Long1l 6 Molnar et al. 117 Xie and Wang 1l 8

66.5113 .75 (kg) + 15.0 (em) + 26.76 (years) Based on measured REE 25 (kg) + 40 (%TBSA bum) 2000 (BSA) 2.1 (HBEE) (1.2 or 1.3)' 2 (HBEEl 1000 (BSA) + 125 (% TBSA bum)

103

kcal/day

% ofHBEE

1837 3260 4097 3928 4629 3674 3240

178 223 214 252 200 176

HBEE, Harris-Benedict energy expenditure; TBSA, total body surface area. 'Dependent on level of activity. Source: Data from Kohrram-Sefat et a1. 103

of the thermally injured patient.101,102That the metabolic rate of these patients is substantially increased has recently been reconfirmed by measurement of the REE of patients during the first 20 days after injury.l'" These data confirm those of others'?' and that of the summary of the 28 studies that had been performed before 1990.105A comparison of the calculated caloric requirements of various formulae is shown in Table 25.6. These data, taken from the report of Khorram -Sefat et al./ oo are listed by year of publication from the 1974 study of Curreri et al. to the 1993 report by Xie and Wang and support the suggestion that the metabolic requirements of patients cared for in the modern era are not as high as those of the past . Nevertheless, even the more recent studies indicate that there is a wide variation in metabolic rate among patients and that the hypermetabolism associated with thermal injury may persist well beyond wound closure . Patients with large burns often do not return to a normal metabolic rate until weeks or months after the burn wound is closed.l'" Most clinicians advocate the use of a formula such as that of Curreri or the Harris-Benedict equation adjusted with a stress factor, but in patients with a large injury or those who sustain complications, the metabolic rate should be measured by indirect calorimetry. Because of losses in the wound, muscle breakdown, and increased demands for healing of the wound, the patient with thermal injury has a requirement for protein replacement that is proportionately greater than that for calories. Protein administration should be two to three times greater than the normal requirement of 0.8gjkgjday or 2.0 to 2.5gjkgjday. This amount can be provided in relationship to the estimated """",..-

or measured calorie needs by providing a nonprotein calorie to nitrogen ratio of 100 to 150: 1.107

Prognosis Survival after burn injury has improved significantly during the past 20 years'?" and appears to have reached a plateau over the past 10 years in some studies.!" Because mortality rates have changed, the suggestion of two decades ago" ? that mortality could be estimated as the addition of age and percent of the body surface area that sustained thermal injury no longer holds true. However, multiple studies have confirmed that patient age and extent of injury are the two most powerful predictors of outcome.108,111,112 Studies from the past 10 years (summarized in Table 25.7) suggest that the overall mortality rate in burn centers is approximately 4%. 113 These data also confirm the significant contribution of inhalation injury in that the mortality rate was 25% to 35% in the presence of this injury and only 0.5% to 4% in its absence. The high mortality rate when thermal injury is associated with inhalation injuryll4,115 is well recognized in other reports of an increase in mortality as high as 20% with inhalation injury." A comparative study of patie nts ma tched for burn size and age" reported an observed mortality rate of 9.6% in patients wit hout inhalation injury compa red to 46.6% in those with inhalation injury. The report of outcome in multiple centers11 6 indicates that 50% of young adults survive a burn injury that involves 81% of their TBSA.To specifically prognosticate the outcome

TABLE 25.7. Reports on Mortality in Patients with Thermal Injury in the Past Decade.

Mortality (%) Trial

Year

126 127 128 122 11,234 (total patients)

1990 1994 1995 1998

Class of Evidence

Design

%TBSA

Incidence of inhalation (%)

III

Retrospective Retrospective Retrospective Retrospective

15.1 18.0 14.1 15.0 14.9

7.3 19.6 10.9 14 11.9

III TIl III

Overall

Inhalation (with/without)

4.1 9.5 4.1 4.0 4.8

34.7/1.7 31.0/4.3 29.4/2.2 24.6/0.49 29.4/2.0


of the thermally injured patient, most authors have suggested that multivariate statistical techniques, such as probielO/117 or regressiont':'!' analysis, be applied. A recent report'I" suggests that mortality can be predicted by a risk scoring system in which one point is given for each of bum size greater than 400/0 of the TBSA, age greater than 60 years, and presence of inhalation injury. This analysis suggests that mortality rates are 0.3% with no risk factors, 30/0 with one factor, and 330/0 and 90% for two or three risk factors, respectively. Although this approach provides a quick estimate, it does not include other variables such as preexisting medical conditions and also does not allow for a continuous stratification of patients by age and extent of injury.':"

Rehabilitation Advances in medical care leading to increased survival from thermal injury have led to a renewed emphasis on quality of life after these injuries. Rehabilitation of the patient with a bum injury begins from the time of initial medical care, requires intense care in the first year after injury, and often is lifelong. Splinting of injured extremities begins as soon as the patient is stabilized, and range-of-motion exercises begin within the first day. The team approach is important to coordinate therapy, surgical intervention, and medical care. As soon as wounds have a stable epidermal closure, usually within 2 weeks after grafting or primary healing has occurred, attention is turned to wound and scar management. Garments that apply pressure to the wounds are tailor made for the patient and worn 24h per day. The opportunity to modulate the development of cicatrix is restricted to the time when the wound is immature and actively remodeling. This period may extend up to a 'year postinjury, but mechanical intervention is of little benefit beyond that time. Surgical intervention for cosmetic deformity is usually delayed until the wound is mature, as is intervention for functional restriction, unless a surgical procedure is necessary to allow for physical therapy.

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Traumatic Brain Injury Kyle Chapple and Roger Hartl

Epidemiology 461 Pathophysiology: Secondary Brain Injury 461 Management of Patients with Severe Traumatic Brain Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 462

T

raumatic brain injury (TBI) is graded as mild, moderate, or severe based on the level of consciousness or the Glasgow Coma Scale (GCSI score after resuscitation (Table 26.1). Mild TEl is defined with a GCS score between 13 and 15. In most cases it represents a concussion, and there is full neurological recovery, although many patients reveal short-term memory and concentration deficits . Patients with moderate TBI are typically stuporous and lethargic with a GCS score between 9 and 13. A comatose patient who is unable to open his or her eyes or follow commands has a GCS score of less than 9 and by definition has a severe TBI. During the past two decades, it has become increasingly clear that patients with TEl are susceptible to posttraumatic arterial hypotension, hypoxia, and brain swelling, or so-called secondary brain injury. All major advances in the care of these patients have been achieved by reducing the occurrence and severity of these secondary insults on the already injured central nervous system. Initial resuscitation and rapid transport of trauma patients in the field and direct transport to a major trauma center, and improved critical care management with intracranial pressure monitoring, have decreased the rate of mortality from as much as 50% in the 1970s and 1980s to between 15% and 25% in most recent series.'> The development of scientifically based management protocols for the treatment of patients with TEl holds considerable promise for further improvement in outcome. The goal of this chapter is to familiarize the reader with the basic principles of TEl management. Herein, reference is made to recently published evidence-based guidelines for the pre-hospital and in -hospital surgical and medical management of patients with severe TBI.3- s These guidelines have been endorsed by the American Association of Neurological Surgeons (AANSI and the Con gress of Neurological Surgeons and can be accessed via the Internet at http://www.braintrauma.org.

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 469

Epidemiology About 1.6 million people sustain a TEl each year in the United States, and 270,000 require hospitalization. With about 52,000 deaths per year, TBI is the most common cause of death and disability in young people and accounts for about one-third of all trauma deaths ." The costs of TEl to society are enormous; neurotrauma is a serious public health problem requiring continuing improvement in the care of injured patients. Motor vehicle crashes are the major cause of TEl, particularly for young people. Falls are the leading cause of death and disability from TBI for people older than 65 years of age.

Pathophysiology: Secondary Brain Injury Neurological injury not only occurs during the impact (primary injury) but also evolves over the following hours and days (secondary brain injury). Within the first days and weeks after TEl, the brain is extremely vulnerable to decreases in blood pressure and oxygenation that are well tolerated by the noninjured central nervous system (Figure 26.1).7 Secondary brain damage is the most dominant cause of TEl in-hospital death. The most important insults that may lead to secondary brain damage and poor outcome are listed in Table 26.2. Many of these insults are preventable. In the pre-hospital phase, hypoxia and arterial hypotension have been shown to be the most important secondary insults. Studies have reported that 27% to 55% of TEl patients are hypoxemic (Sa02 38.3°C or • Ibuprofen 400mg NG/PR q 8h pm if T > 38.3°C Sedation • Propofol drip, titrate dose to level of sedation and to maintain SBP (preferred) or • Lorazepam drip, titrate dose to level of sedation GI prophylaxis • Famotidine (Pepcid) 20mg PO/IV bid or proton pump inhibitor IV/PO Seizure prophylaxis • Phenytoin 1g IV loading dose over 1h • Phenytoin 300mg IV qd Arterial hypertension • Call for SBP > 180mmHg Others • Lidocaine 2% IV infusion 5 mL down endotracheal tube before suctioning or bronchoscopy Laboratory studies • Complete blood count, platelet count, prothrombin time, activated partial thromboplastin time, type and crossmatch for possible blood transfusion, biochemical profile, blood and urine for toxicology screening, blood alcohol concentration Ventilator settings to maintain Sa02 above 900/0 and PaC02 approximately 35 mmHg

465

TRAUMATIC BRAIN INJURY

INTRACRANIAL PRESSURE MONITORING AND TREATMENT OF INCREASED INTRACRANIAL PRESSURE

Comatose head injury patients (GCS score, 3 to 8) with abnormal CT scans should undergo ICP monitoring. ICP monitoring helps in the earlier detection of intracranial mass lesions, can limit the indiscriminate use of therapies to control ICP, which themselves can be potentially harmful, can reduce ICP by cerebrospinal fluid drainage and thus improve cerebral perfusion, helps in determining prognosis, and may improve outcome. 11 Elevated ICP is present in the majority of TBI patients. Cerebral perfusion pressure is defined as the mean arterial blood pressure minus ICP. This physiological variable defines the pressure gradient driving cerebral blood flow and metabolite delivery and is therefore closely related to cerebral ischemia. A threshold for cerebral perfusion pressure of approximately 60mmHg for adults is recommended currently. 12 The CNS/AANS Guidelines recommend that ICP monitoring is appropriate in severe head injury patients (GCS score,3 to 8) with an abnormal CT scan, or a normal CT scan if two or more of the following are noted upon admission: systolic blood pressure less than 90mmHg, age greater than 40 years, and unilateral or bilateral motor posturing." Treatment of increased intracranial pressure should be initiated at an upper threshold of 20 or 25 mmHg. Cerebral perfusion pressure (mean arterial pressure minus ICP) should be maintained at approximately 60mmHg. In the absence of cerebral ischemia, aggressive attempts to maintain cerebral perfusion pressure (CPP) about 70mmHg with fluids and pressors should be avoided because of the risk of acute

respiratory distress syndrome." Increased ICP should be treated vigorously. The management of the typical severe TBI patient with ICP monitoring at our institution is outlined in Table 26.5. MANNITOL

Mannitol is effective for control of raised ICP after severe TBI. Limited data suggest that intermittent bolus doses may be more effective than continuous infusion. Effective doses range from 0.25 to 1 g/kg body weight. Hypovolemia should be avoided by fluid replacement. Serum osmolarity should be kept below 320mOsm to avoid renal failure. Euvolemia should be maintained by adequate fluid replacement. A Foley catheter must be placed to monitor urine output whenever mannitol is administered. Reduction of ICP reaches a maximum approximately 30 to 60min after bolus infusion and persists between 90min and 6h or longer. Mannitol together with furosemide may cause rapid diuresis and depletion of intravascular volume and electrolytes and is therefore not recommended. Effective doses range from 0.25 to 1 g/kg body weight. HYPERVENTILATION

Hyperventilation should not be used routinely in patients with TBI because of the risk of further compromising cerebral perfusion." Hyperventilation should be used only for brief periods when there is acute neurological deterioration or if intracranial hypertension is refractory to other treatment interventions. Under these circumstances, we use intraparenchymal brain tissue oxygen monitoring to titrate the degree of hyperventilation and to avoid cerebral ischemia (see Table 26.5). The use of prophylactic hyperventilation (PaC0 2

TABLE 26.5. Management of Elevated Intracranial Pressure (ICP) in the Patient with Severe TBI. In all patients with GCS score below 9

Add if ICP >20mmHg

Add if ICP >25mmHg

ICP monitoring Elevate head of bed 30°

Ventricular CSF drainage

Neuromuscular blockade: vecuronium, atracurium

Maintain euvolemia and hemodynamic stability, keep CVP S-10 mmHg

Sedation: midazolam or lorazepam

Mannitol 0.2S-1 g/kg IV over S-10min q 4-6h PRN; serum osmolarity 300-320mOsm/L, serum sodium 1S0-1SSmEq/L

Pa02 > 90 mmHg

Analgesia: fentanyl or morphine

PaC023S-40mmHg Systolic blood pressure >90mmHg

CPP approximately 70mmHg

Add for persistent ICP >25mmHg

Moderate hypothermia, core temperature 34°-36°C Hyperventilation to PaC02 30-3S mmHg

"CPP management": inotropic and pressor support to maintain CPP (dopamine, S-20 Jlg/kg/ min, norepinephrine, O.OS-o.S Jlg/kg/min Repeat head CT to exclude operable mass lesion

CSF, cerebrospinal fluid; CVP, central venous pressure; CPP, cerebral perfusion pressure; CT, computed tomography.

Add for persistent ICP >25mmHg or pupillary abnormalities

High-dose propofol infusion Hyperventilation to PaC022S-30mmHg

Consider hypertonic saline bolus infusion; consider decompressive craniectomy

466

CHAPTER 26

1500 m L or >200mL/h over 4hl, cardiac tamponade, evidence of ma jor vascular or cardiac injury, massive air leak, or evidence of esophageal or tracheal injury. Nonacute, or delayed, thoracotomy may be performed days to years following the injury in th e setting of retained hemothorax, persistent air leaks, empyema, missed esophageal or tracheal injuries, diaphragmatic hernias, or posttraumatic major vessel injury such as arteriovenous fistula. Thoracoscopy is also useful in the nonemergent set ting for evacuati on of retained hemothorax, repair of diaphragmatic in juries, control of ch est wall bleeding, and repair of minor lung in juries.67,177- 179 Transmediastinal gunshot wounds have hi storically been con sidered an ind ication for intervention. Recent work has demonstrated that patients can safely undergo diagno st ic workup, and up to 50 % of patients can be managed nonop-

eratively." " Some authors believe the indications for thoracotomy should be different for blunt and penetrating trauma secondary to th e higher likelihood of nontherapeutic thoracotomy after blunt trauma. 18 l ,182 The incision chosen for operative intervention for of tho racic trauma must be individualized. Median sternotomy, anterolateral thoracotomy with or without extension into the contralateral chest (the " clam-shell" thoracotomy), and posterolateral thoracotomy each provide access to certain intrath oracic and mediastinal structures. A median st ernotomy generally provides the best access to the heart and proximal great vessels . It can be easily extended superiorly or laterally to obtain control of the more distal great vessels. Likewise, it can be extended inferiorly to th e abdomen if laparotomy is necessary . It is the incision of choice in the setting of cardiac tamponade or penetrating cardiac trauma. Anterolateral thoracotomy provides th e quickest access to the lung and hilum and can be performed without special positioning of the patient. 1£ a concomitant laparotomy is necessary, supine or 30° partial decub itus positioning of the patient allows access to th e abdomen. Extending an anterolateral thoracotomy across th e sternum to th e contralateral che st provides excellent access to th e heart and proximal great vessels . Posterolat eral th oracotomy is usually reserved for isolated injury to one hemithorax (e.g., the descending aortal and provides excellent exposure to the entire hemithorax, but unstable patients may not tol erate lateral positioning.

480

CHAPTER 27

TABLE 27.3. Representative Clinical Experience with CT Scan for the Diagnosis of Blunt Abdominal Trauma.

Number of patients

Trial

Year

Level of evidence

132

1986

11

128

143

1994

1lI

26

147

1996

1lI

256

139

2001

1lI

133

2002

123

140

Median follow-up

Minor endpoint

Prospective evaluation of the use of abdominal CT scan in stable blunt trauma patients with an equivocal abdominal exam, closed head injury, spinal cord injury, hematuria, or pelvic fracture Retrospective review of blunt trauma patients with sma ll bowel injuries who underwent abdominal CT scan

N/A

Major endpoin t

Int erpretationslcomm ents

N/A

Detection of abdominal injuries in stable blunt trauma patients

Accuracy for the detecti on of intraabdominal injuries with CT scan was 98.3%. Solid organ in jurie s we re reliably detect ed as were m inor injuries requiring no specific th erapy.

N/A

N/A

Identification of blunt small bowel injuries by abdominal CT scan

Retrospective review of blunt tra uma patients who underwent CT of the abdomen

N/A

N/A

Identification of in traabdominal in jury by CT scan in hemodynamically stable blunt trauma patients

74

Retrospective review of patients with blunt bowel and mesenteric injuries who underwent laparotomy and helical CT scan

N/A

N/A

Detection of small bowel injuries by CT scan in blunt trauma patients

1lI

87

Retrospective review of hollow viscus injuries identified by abdominal CT scan in blunt trauma patients

9 days

N/A

Accurate detection of small bow el in juries by CT scan in blunt trauma patients

2003

1lI

457

Retrospective chart review of patients who underwent CT of the torso in conjunction with cranial CT scan

6.6 days

N/A

2004

11

500

Prospective evaluation of the use of abdominal CT without oral contrast administration

N/A

N/A

Identification of tor so injury in patients with su spected brain in jury who underwent routine body CT when cranial CT was performed Accurate identification of blunt intestinal and mesenteric injuries

Overall accuracy of CT scan for th e detect ion of sma ll bowel injury was 94%. Sensi tivity was 92% and specificity was 94% . Subtly abn orm al findings on CT scan warr ant further evaluation or observat ion . Abdominal CT dete ct ed 83.7% of injuries. It is safe and noninvasive . Sensitivit y of pancreatic and intestinal injuries was low in thi s study. The use of CT in this setting can avoid non therapeutic laparotomies. Helical CT scan had an overall sensitivity of 94 % for bowel injury and 96% for mesenteric injury. Th e need for operative intervention was correc tly established in 86 % of patients with bowel injuries but onl y 75% of mesenteric injuries. CT was 97.7% sensitive, 98.5 % specific, and 99.4 % accurate for th e diagn osis of blunt small bowel inju ry. CT is useful in patients with an unreliable phy sical exam secondary to depres sed level of consciousness. Torso CT scan when performed routinely in patients und ergoin g head CT is ben eficial. Thirt y-eight percent of patients had an une xpected finding of th e tor so. Mana gem ent was alte red in 10%.

Intervention/design

The sen sitivity and specificity of abdominal CT witho ut oral contrast for th e det ect ion of blunt bow el and mesenteric injuries was 95% and 99.6% respectively. Oral contrast is not necessary for th e detecti on of th ese injuries.

TRAUMA TO THE TORSO

Emergency Department Thoracotomy Emergency department (ED) or resuscitative thoracotomy should be performed only in a limited set of circumstances for patients in extremis. Patients with penetrating thoracic trauma who have lost vital signs or with severe hypotension may benefit from ED thoracotomy, although the survival rates vary widely in the literature. Survival was 460/0 in one series in patients with no vital signs and 750/0 when ED thoracotomy was performed in patients with penetrating injury in shock. 183,184 In patients without "signs of life," defined as absence of blood pressure, cardiac activity, respiratory effort, or pupillary response, survival is 00/0 to 40/0 in the setting of penetrating injury, although one series reported a survival of 24 % in patients with cardiac injuries.185-188 Patients with cardiac injuries from stab wounds are the most likely to benefit from resuscitative thoracotomy. 184,189,190 In blunt trauma, the reported success rates in the larger series are typically less than 2 % .186,187,189,191-193 ED thoracotomy is generally not recommended in the setting of cardiac arrest or profound shock secondary to blunt trauma except in extraordinary circumstances.193,194 Emergency department thoracotomy begins with a rapid left anterolateral thoracotomy at the fourth or fifth interspace. The incision can be extended across the sternum for wider access and better exposure of the heart. If the sternum is transected, the internal mammary arteries must be identified and ligated if resuscitation is successful. Once the thorax is entered, the pericardium is elevated and entered. Care should be exercised to avoid injury to the phrenic nerves. Opening the pericardium releases tamponade and provides the best access for open cardiac massage and internal defibrillation. To improve coronary perfusion or if there is suspicion of infradiaphragmatic hemorrhage, aortic cross-clamping can be performed inferior to the hilum of the lung. Clamping the pulmonary hilum can control bleeding from the lung parenchyma. Cardiac injuries can be temporized with clamping, manual occlusion, a skin stapler, or a Foley catheter with the balloon inflated. If vital signs are regained, the patient should be transported rapidly to the operating room for definitive management.

Indications for Laparotomy The most clear-cut indication for laparotomy in the setting of torso trauma is hemodynamic instability with evidence of intraabdominal injury. Whether secondary to blunt or penetrating abdominal trauma, hemorrhagic shock is an absolute indication for surgical exploration. Regardless of the diagostic modality used, other clear indications include peritonitis, evidence of hollow organ or pancreatic injury, intraperitoneal bladder rupture, evisceration, diaphragmatic injury, and impalement of objects in the abdominal wall. 195,196 In the absence of these clear indications, laparotomy may also be used as a diagnostic modality when clinical suspicion warrants further evaluation unobtainable by radiographic studies or DPL. Laparoscopy may provide an alternative to diagnostic laparotomy in the hemodynamically stable patient. 63,67,75,175 Gunshot wounds with a possibility of transperitoneal trajectory have been considered an indication for mandatory

481

laparotomy. Work done in several centers has demonstrated that a subset of these patients (i.e., tangential injury) may be safely managed nonoperatively with careful serial physical examinations and additional diagnostic studies such as CT or DPL. 13,36,42-49,197-199 Stab wounds to the abdomen with evidence of fascial penetration were also previously considered an indication for laparotomy. Recently, it has been demonstrated that a subset of these patients can similarly be managed safely with observation and serial physical examinations" or with further diagnostic workup to determine whether intra- or retroperitoneal injury has occurred.r':" Diagnostic laparoscopy may also be helpful in identifying intraabdominal injury in some patients with penetrating abdominal injury.36,78,198 Other more controversial indications for operative intervention for blunt abdominal trauma include the presence of free intraperitoneal fluid without evidence of solid organ in jury.200-203 Laparotomy for trauma is performed via a midline incision from xiphoid to pubis. The skin should be prepared from neck to midthigh in case entry into the thorax or vein harvest for revascularization is needed. The room should be warm and, ideally, rapid infusion and reinfusion systems should be available. Upon entry into the abdomen, depending on the degree of hemoperitoneum, the abdomen should be packed sequentially with laparotomy pads and evaluated systematically. Priorities include control of bleeding, identification of injuries, control of contamination, and prioritization and performance of definitive repair. The surgeon must be cognizant of the development of hypothermia, coagulopathy, and acidosis in assigning priorities.

Damage Control The abbreviated laparotomy was first described by Stone et al. in 1983.204 The concept emerged with recognition that the development of coagulopathy, acidosis, and hypothermia (the "lethal triad") secondary to hemorrhagic shock was an almost uniformly lethal event.205-21O Rotondo et al. then coined the term "damage control" for use in the setting of profound shock secondary to penetrating trauma."! The technique of "damage control" includes three steps: rapid control of bleeding and contamination followed by abdominal packing and temporary closure, active warming and resuscitation in an intensive care unit (ICU), and return to the operating room for definitive repair of injuries once the patient is stabilized and the acidosis and coagulopathy have been reversed. In their original report, Rotondo et al.noted that survival was greater when damage control was used in the subset of patients with major vascular injury and two or more visceral injuries. Subsequent work has demonstrated a discrete survival advantage in patients with penetrating abdominal trauma. 212,213 Damage control has now become standard for patients with severe hemorrhagic shock from both penetrating and blunt trauma. The techniques for damage control in the abdomen include hepatic packing, balloon tamponade of bleeding, temporary enteric closures, placement of vascular shunts, rapid splenectomy, nephrectomy or distal pancreatectomy, use of topical hemostatic agents, the use of systemic hemostatic agents (Factor VIla), and intraperitoneal packing. Major morbidity of damage control, if successful in preventing early death, includes abdominal compartment syndrome,

482

CH APTER 27

TABLE 27.4. Representative Clinical Experience with Ultrasoun d for th e Diagnosis of Torso Trauma.

Number of patients

Trial

Year

Level of evidence

50

1995

II

245

163

1995

II

51

1995

164

Median follow-up

Minor endpoint

Prospective evaluation of US for the detection of free intrathoracic and intraperitoneal fluid by eme rgency department physicians in patients with blunt tra uma

N/A

206

Prospective evaluation of US compared to CT or DPL in patients with blunt trauma

II

371

1996

ill

153

1996

168

Major endpoint

Interpretations/comments

N/A

Accurate detection of pleural, pericardial, retroperitoneal, and intraperitoneal fluid

us was accurate in

N/A

N/A

Evaluation of US to detect intraperitoneal fluid

Prospective study of surgeon-performed ultrasound in patients with both blunt and penetrating trauma

N/A

N/A

Identification of hemoperitoneum or pericardial effusion

1,000

Evaluation of an institutional algorithm to evaluate patients wit h BAT utilizing US as the preliminary diagnostic modality

N/A

N/A

Accurate identification of intraabdominal injuries necessitating further diagnostics or intervention

II

800

Prospective evaluation of the diagnostic accuracy of US in selected patients with BAT

N/A

N/A

Identification of intraabdominal injuries using US

1996

II

69

Blinded prospective evaluation of the accuracy of US in detecting the need for urgent laparotomy in hypotensive BAT patients

N/A

N/A

Accuracy of detection of hemoperitoneum in hypotensive patients

54

1998

II

360

Prospective evaluation of the ability of US to detect traumatic effusions in inju red patients

6.4 days

N/A

Accuracy of detection of traumatic pleural effusions by US

165

1998

III

Retrospective evaluation of the use of US to detect intraabdominal injuries

N/A

N/A

Identification of intraabdominal injuries following trauma with US

1,239

Intervention/design

detecting fluid in blunt trauma patients. Sensitivity was 90%, specificity was 99%, and accuracy was 99%. Emergency department physicians can perform and interpret this diagnostic test. US is an effective method of determining the presence of intraabdominal fluid in patients with blunt abdominal trauma. Accuracy was 96% and could be performed rapidly. US can be used reliably as a primary diagnostic modality in patients with traumatic injuries. Sensitivity was 81.5 % and specificity was 99.7 %. Initial evaluation of injured 15 patients with ultrasound may be costeffective . US accurately detected injuries in 97% of patients. Sensitivity and specificity were 88% and 99%, respectively. US is an effective primary modality to evaluate patients with BAT. US can be performed rapidly and in conjunction with resuscitation to evaluate patients with BAT. Overall accuracy for the detection of abdominal injury was 97%. US is a rapid method of detecting hemoperitoneum in unstable patients after BAT. Sensitivity of 100%, specificity of 94%, and accuracy of 96 % were reported for predicting the need for laparotomy. Surgeon-performed US can accurately detect traumatic pleural effusions. Accuracy is equivalent to radiographs and can be performed faster. Sensitivity of US was 94.6% with a specificity of 95.1%. Overall accuracy was 94.9%.

483

TR AUM A T O TH E TOR SO

TABLE 27.4. (continued) Number of patients

Trial

Year

Level of evidence

Median follow-up

Minor endpo int

52

1998

II

1,540

Prospective study of the accuracy of FAST by trauma team members

N/A

58

2001

II

75

Prospective study of the use of FAST in hemodynamically stab le patients with penetrating abdominal injury

55

2001

II

72

II

177

Prospective evaluation of clinical protocols to determine the efficacy of the FAST exam in the setting of penetrating trauma Prospective study of the use of US in the setting of penetrating abdominal trauma

57

2004

Intervention/design

Major endpoint

Interpretationslcommeats

N/A

Determination of the accuracy of FAST in detection of injuries following precordia l or thoracic penetrating tra uma or blunt abdominal trauma

N/A

N/A

Identification of in traab dominal injury in hemodynamically stable patients with penetrating abdominal trauma with ultrasound

5.2 days

N/A

N/A

N/A

Detection of intraabdominal or intrapericardial fluid in patients with penetrating torso trauma Correlation of US results with patient outcome and the need for therapeutic laparotomy and thoracotomy

US is rapid and accurate. Sensitivity of 83.3% and specificity of 99.7% are reported. Sensitivity of 100% is reported for hypotensive patients with BAT and precordial penetrating injuries. US should be the initial test of choice in hemodynamically unstable patients or in the setting of penetrating precordial trauma. A positive FAST in this setting warrants immediate surgical intervention. In patients with penetrating abdominal injury, a positive FAST is predictive of the need for laparotomy. Negative studies should be followed by additional testing due to the low negative predictive value (60%). The use of FAST in the set ting of penetrating torso trauma is beneficial. Negative exams, however, do not exclude abdominal injury. Routine use of FAST does not change the management in a significant number of patients with penetrating torso injury. Sensitivity of 48 %, specificity of 98%, and accuracy of 85% were reported.

us, ultrasound; FAST, focused assessment for sonography in trauma ; DPL, diagnostic periton eal lavage; BAT, blunt

multiple orga n dysfunction syndrome, and complications associated with an open abdomen, such as enteric fistulas .213 - 2 18 One of the tenets of damage control is that patients who manifest clinical signs of ongoing bleeding or abdominal compartment syndrome following damage control laparotomy should be reexplored or undergo adjunctive pro cedures, such as an giography.PY " There are many unresolved is sues surrounding damage control for trauma. There are no defined selection criteria th at are clearly predictive of who would benefit from damage control or who should have a definitive procedure on presentation, although several authors have suggested such algorithms. 2 1O,2 14,2 15,22D-224 Generally, patients with multisystem trauma, multiple abdominal injuries, or a large transfusion requirement, coagulopathy, acidosis, or hypothermia ben efit from damage control. Clearly, the earlier damage control is

abdominal trauma.

instituted, the better the outcome.l" Issu es concerning the timing of reoperation have also been discussed extensively in the literature. 2 14,2 15,219,225-228 In general, the patient shou ld be returned to the operating room once coagulopathy and acidosis have been corrected and the patient has been stabilized, usually within 24 to 48 h . Caution must be taken as excessive time to reoperation increases the risk of infection, and tissue inflammation and friability makes definitive repair technicall y difficult. Also unresolved are the optimal temporary abdominal closure and how to provide definitive abdominal wall reconstruction.t" The principles of damage control have also been extended to areas of the body other than the abdomen . Damage con trol thoracotomy has been well described.215 ,229- 233 The gen eral principles are the same as for damage control laparotom y. Seve ral techniques have been described for rapid operative

484

CHAPTER 27

management in unstable patients with thoracic injury. These include thoracic packing, pulmonary tractotomy, nonanatomic pulmonary resection, intravascular shunting, esophageal diversion and drainage, placement of double-lumen endotracheal tubes for tracheal or bronchial injuries, and temporary chest closure. 215,229-231,233-235

Cardiac Injury Cardiac injuries can occur from either penetrating or blunt mechanisms. Penetrating injuries are frequently fatal, with widely varying survival rates from 25 % to 89 0/0. 232-239 Survival from stab wounds is markedly better than from gunshot wounds. 232-239 Stab wounds to the heart tend to present with evidence of pericardial tamponade. Gunshot wounds often cause profound hemorrhage and shock from hypovolemia secondary to the large cardiac defects caused by bullets. The right ventricle is most frequently injured secondary to its anterior location. 232,239,240 Multichamber injuries are most likely to be fatal. 237,238 In the setting of hemodynamic instability, immediate operation is indicated. With cardiac arrest or profound hypotension, ED thoracotomy may be performed. In centers in which there is not a surgeon immediately available, pericardiocentesis may be used as a temporizing measure. In the hemodynamically stable patient, diagnosis is typically made by ultrasound. Sensitivity has been reported to be as high as 1000/0 in this setting. 52,62 Echocardiography can also be useful, as can the performance of a diagnostic subxiphoid window. All penetrating injuries to the heart require operative intervention. Median sternotomy or left anterolateral thoracotomy can be used. Simple lacerations are typically repaired with pledgeted sutures, avoiding injury to the coronary arteries, valves, and septum. If a distal coronary artery is lacerated as a result of the primary injury, it may be ligated. Injuries to proximal or midcoronary arteries will likely require repair or bypass. Typically, patients are followed with echocardiography to identify delayed complications. 239,241-243 Recent data suggest that only symptomatic patients require echocardiography and that asymptomatic patients can be followed with physical examination, chest radiography, and electrocardiography.24o,244 Blunt trauma can result in a spectrum of injury from mild "contusion" to free cardiac rupture. The reported incidence of blunt myocardial injury varies widely in the literature secondary to discrepancies in diagnostic criteria.245-248 Typically, these patients have sustained major chest trauma and are usually injured in motor vehicle collisions or falls from a great height. 249,250 The cardiac injury is secondary to a direct force to the precordium, which compresses the heart between the sternum and vertebral bodies.r" Blunt cardiac injury (BCI) may be associated with sternal or rib fractures. The incidence of associated traumatic brain, abdominal, and aortic injuries in these patients is high.i" The principles of treatment are the same for blunt cardiac injury with rupture as for penetrating injuries. The less dramatic forms of BCI , previously named cardiac "contusion," are seen much more frequently. Presentation of BCI varies widely from minor electrocardiogram (ECG) changes and hemodynamically insignificant arrhythmias to

cardiogenic shock and cardiac arrest.?" The diagnosis can be difficult and requires a high index of suspicion. There is good evidence that in the hemodynamically stable patient with clinical suspicion of BCI, a normal ECG effectively excludes a BCL If these patients have no other comorbidities, they may be discharged home safely from the emergency department.252-260 If abnormalities are found, or if the patient is symptomatic, admission to a telemetry unit for 24 to 48 h is indicated for observation. 252,253,258,261 The role of cardiac isoenzymes and serum troponin concentrations in the diagnosis of BCI is controversial, with some studies supporting their use,245,248,262-265 whereas others demonstrate no clinical benefit. 252,254,255,257,261,266-270 Additional testing such as echo cardiography should be reserved for patients with symptoms, dysrhythmias, or underlying cardiac disease 253,259,260,269,271; transesophageal echo cardiography may be more useful than transthoracic echocardiography in this setting?72,273 Arrhythmias and cardiac dysfunction resulting from BCI are usually self-limited and treated with supportive care. Even if BCI is diagnosed, the risk of cardiac complications requiring emergency surgery is not increased if the patient is stable hemodynamically, and necessary interventions need not be delayed. Although rare, long-term complications of BCI can occur, including wall motion abnormalities, pericardial effusions, valvular dysfunction, ventricular aneurysms, and ventricular thrombi.274,275

Injury to the Chest Wall, Lung, and Trachea Injuries to the chest account for 25 % of all trauma deaths in the United States.?" Chest wall injuries are most commonly caused by blunt mechanisms, but occasionally high-velocity penetrating injuries can cause extensive destruction of the bony thorax. Fractures of the ribs, sternum, clavicles, or scapula are often associated with underlying pulmonary injury with resultant pulmonary complications. 276-280 The identification of chest wall injuries should prompt a search for other injuries as these injuries rarely occur in isolation.i" Injuries of the chest wall caused by major mechanisms include traumatic asphyxia (which usually affects children), open chest wall defects, flail chest, and scapulothoracic dissociation. These injuries carry high mortality and severe long-term morbidity in survivors. 282,283 Treatment is primarily supportive, but major chest wall disruption may require operative stabilization or closure. 284-286 The morbidity of more minor injuries, including rib, sternal, or clavicle fractures, is commonly the result of associated injuries. Elderly patients are particularly at risk for morbidity from these types of injuries. 276,287-289 Pain control and early mobilization are the mainstays of therapy.278-280 Injuries to the lung and pleura occur after both blunt and penetrating trauma. Penetrating injuries tend to manifest early, whereas blunt injuries may not become apparent for hours or days. Some of these injuries can be immediately life threatening, such as tension pneumothorax or massive hemothorax, whereas others, such as simple pneumothorax, may progress if left untreated. One very common disorder of the lung secondary to trauma is pulmonary contusion, which can range from minor and clinically insignificant to profound acute respiratory failure. The diagnosis of pulmonary injury is typically made by physical examination and chest radiography, but CT scans can also be useful in detecting small

TRAUMA TO THE TORSO

contusions, hemothorax, or occult pneumothorax and for differentiating between pleural and parenchymal disease. Most lung trauma can be treated appropriately with supportive care. Pneumothorax and hemothorax are treated with tube thoracostomy. Chest tubes placed for trauma indications should have a large bore (at least 32-36 Fr.) and be placed in a superior and posterior position. Once the acute process has resolved, chest tubes should be removed expeditiously. Management of chest tubes according to an institutional protocol improves efficiency and possibly decreases complication rates. 290,291 Although tube thoracostomy is usually a relatively straightforward bedside procedure, complication rates approach 20% to 250/0. 292,293 Prophylactic antibiotics to decrease infectious complications of bedside tube thoracostomy are controversial.P"?" There is also controversy as to whether patients with "occult" pneumothorax, seen on CT scan but not chest X-ray, require chest tubes. 298-302 This decision is particularly an issue for patients on mechanical ventilation, as there is concern of progression of these pneumothoraces with positive-pressure ventilation.i'" Pulmonary contusions are treated with supportive care, sometimes requiring mechanical ventilation. Judicious fluid administration is advised, but this must be weighed against the need to provide adequate resuscitation of these often multiply injured patients. Emergency thoracotomy for lung injury is reserved for patients with hemodynamic instability, massive hemothorax, or massive air leaks. Operative techniques for lung trauma include anatomic and nonanatomic resections, tractotomy, stapling of peripheral injuries, and repair of major pulmonary vasculature. The morbidity and mortality in these patients is quite high, with survival rates of less than 500/0 following pneumonectomy and less than 700/0 after lobectomy.303-308 Thoracotomy for injury to the lung in patients with blunt injury carries a higher mortality than in penetrating trauma victims.r" Delayed thoracotomy or thoracoscopy may be necessary for retained hemothorax, empyema, or persistent air leak. Intrathoracic tracheal and major bronchial injuries are relatively rare and require a high index of suspicion for diagnosis. When secondary to penetrating trauma, these injuries often coexist with major lung, great vessel, or cardiac trauma; consequently, the morbidity and mortality are high. When secondary to blunt trauma, these injuries typically occur within 2 em of the carina. The clinical presentation varies widely; approximately 60% of the more minor injuries in the thorax will not be diagnosed for more than 24h. 309,31O The diagnosis is typically made with the discovery of pneumomediastinum or persistent pneumothorax following tube thoracostomy, usually with a large air leak. Bronchoscopy is the test of choice for diagnosis."! Most of these injuries will require operative repair. Operative management consists of debridement of devitalized tissue and primary repair in most instances. Studies have demonstrated that outcome is improved when the repair is done early after injury.312-314

Injury to the Esophagus Injuries to the thoracic esophagus are fortunately quite rare, as they are difficult to diagnose and morbidity and mortality are high. Most esophageal injuries are secondary to

485

penetrating injury, but the incidence is still relatively low, even with gunshot wounds.':" There is a high rate of injuries to surrounding structures secondary to the anatomic position of the thoracic esophagus in the posterior mediastinum.l" Most patients demonstrate some abnormality on chest radiograph, although these are likely to be nonspecific.Wr'" Esophagoscopy can be used for diagnosis, but there may be a small risk of worsening the injury with cndoscopy.t" Esophagography is also used for diagnosis. The treatment of thoracic esophageal injuries is always surgical. Early intervention is paramount. Operative strategies for the treatment of thoracic esophageal injuries include debridement of devitalized tissue, primary repair, muscle flap coverage, and wide drainage. Injuries less than 24h old can usually be repaired primarily.317,32o If operation is delayed more than 24 h, or if there is substantial inflammation or contamination, esophageal diversion and wide drainage are prudent. Complications, such as leaks and subsequent mediastinitis, are common, extremely morbid, and often fatal.

Injury to the Diaphragm Diaphragm injuries are common, particularly in centers with a large proportion of penetrating injuries. Penetrating injuries tend to cause smaller, more discrete injuries, whereas blunt trauma often causes larger avulsion-type injuries. Diaphragm injuries secondary to both blunt and penetrating causes are often associated with injuries to the lungs and abdominal viscera. The diagnosis of a diaphragm injury can be difficult. 321-323 In any penetrating injury in the thoracoabdominal region, a diaphragm injury should be suspected." In blunt injuries, physical examination is notoriously unreliable. If thoracotomy or laparotomy is performed secondary to associated injuries, the diaphragm should be inspected thoroughly for evidence of injury and repaired at that time. In patients in whom operative intervention is not needed, the diagnosis can easily be missed by plain radiographs, as the findings are often misinterpreted as pulmonary pathology.322-324 CT scans have low sensitivity for esophageal injury.323,325,326 Other possible diagnostic modalities include magnetic resonance imaging (MRI), contrast studies, and ultrasonography.Wr''" Diagnostic laparoscopy or thoracoscopy can be extremely valuable, but requires a high index of suspicion to select patients in whom to perform the procedure.":" Some authors suggest that all thoracoabdominal penetrating injuries should be evaluated with laparoscopy or thoracoscopy to determine diaphragm injury in the absence of other indications for surgical in tervention. 78 Once identified, all diaphragm injuries should be repaired secondary to the risk of visceral herniation days to years after injury. This morbid complication of untreated diaphragmatic injuries is associated with substantial morbidity and mortality.323,331 Most diaphragm injuries are repaired via laparotomy. The edges of the injury should be debrided and closed primarily if possible. Large defects may require prosthetic mesh placement, and a thoracoabdominal approach may be needed. Concomitant bowel injuries with local contamination by enteric contents necessitate irrigation or drainage of the thorax secondary to the high risk of empyema. Chronic diaphragmatic hernias secondary to missed injuries have tradi-

486

CHAPTER 27

tionally been approached via thoracotomy secondary to abdominal adhesion formation. However, there are numerous reports of successful laparoscopic repair of diaphragm. injuries, which may prove to be the optimal approach to a relatively isolated injury. 75,77

Injury to the Liver The liver is the most frequently injured organ in blunt abdominal trauma and, because of its size and location, is often injured in penetrating trauma as well. The Organ Injury Scaling Committee of the American Association for the Surgery of Trauma (AAST) has outlined a classification scheme that can be used to describe the degree of injury.'? Injuries range from minor lacerations and capsular hematomas, which have little clinical importance, to hepatic avulsion, which is a uniformly fatal injury. The mortality rises substantially with each grade, as the incidence decreases.r" The first step in operative treatment of hepatic injuries is the division of the ligamentous attachments to facilitate inspection. Thoracotomy or a thoracoabdominal incision may be needed to fully access the injury. Many techniques for control of hepatic hemorrhage have been described. The Pringle maneuver controls vascular inflow at the porta hepatis.P" Failure to control major bleeding with the Pringle maneuver should call attention to the possibility of a retrohepatic vena cava or other major venous injury. Retrohepatic vena cava injuries are often fatal, and these patients are typically profoundly unstable.r" Several techniques must often be used in concert for severe injuries (Grades III-V). These patients are frequently acidotic and coagulopathic and often require a damage control approach. Hepatic packing is the most effective temporizing measure for massive hemorrhage. Damage control measures may include atriocaval shunting, venovenous bypass, or hepatic vascular isolation. 335-3 40 If a damage control approach is used for hemorrhage not attributable to major venous injury, packing and deep liver sutures can be used as a temporizing measure. Other damage control techniques for massive hepatic trauma include balloon tamponade and hepatic resection. These patients may benefit from angiographic embolization as an adjunctive measure.341-3 43 If the patient stabilizes, definitive repair is attempted, which can be accomplished with a finger fracture technique. 344-3 46 This technique allows direct visualization and ligation of blood vessels and bile ducts. Devascularized tissue is then debrided, and omental packs can be used to tamponade minor bleeding.r" Other techniques such as topical hemostatic agent or argon beam coagulation may be helpful as well. Closed-suction drains are routinely placed to prevent abscess or biloma formation.PY" Some patients may benefit from hepatic resection in the case of major hepatic vascular injury or tissue destruction. Hepatorrhaphy with absorbable mesh has also been described. 349,35o Minor hepatic injuries, when discovered at laparotomy, rarely require treatment beyond simple electrocautery coagulation, argon beam coagulation, or topical hemostatic agents. Indications for operative management in the setting of hemodynamic stability include treatment of associated injuries and management of complications such as abscesses, bilomas, biliary injury, or failure of

nonoperative therapy."! Postoperative complications include biliary and infectious complications.F' As many as 50% to 80% of patients with liver injuries may be managed nonoperatively.P'r'" Selection of patients is determined by the degree of hemodynamic stability, as opposed to injury grade or CT findings. 355,356 The failure rate of nonoperative management is generally attributable to associated injuries,"? but a few failures are secondary to hemorrhage from the liver itself. 353,358 Nonoperative management may result in fewer abdominal complications, and there is good evidence that patients treated nonoperatively have lower transfusion requirements than with operative intervention. 353,355 Length of stay for these patients may also be lower. 353,354,359 High-grade injuries can often be safely managed nonoperatively, but need to be observed closely secondary to the higher rate of failure. 353 Table 27.5 presents representative clinical experiences with nonoperative management of hepatic injuries. Findings on CT scan may identify patients who will benefit from angiographic embolization.Pv''" Patients with a "blush" on CT or active extravasation of contrast, regardless of the grade of injury, should undergo hepatic artery angiography and embolization.P'r'" Angiography and embolization may also be a useful adjunctive therapy in patients with highgrade lesions even in the absence of pseudoaneurysm or extravasation.r" Follow-up CT scans are useful in identifying patients at risk for infectious and biliary complications.r" The timing of routine follow-up CT scan is controversial, with some advocating early imaging (48-72h) and others advocating for later routine follow-up, or sequential examinations.P'r'" Nonoperative management of hepatic injuries is usually successful, but potential complications are numerous. In the largest reported series, bleeding was the most common complication of nonoperative management.i" Biliary complications also occur, bilomas can often be treated successfully with percutaneous drainage, although occasionally operative intervention is required. 351-3 53 Endoscopic retrograde cholangiopancreatography (ERCP) can be a valuable adjunct in the identification and treatment of biliary complications, and allows therapy with sphincterotomy and biliary stenting. 356,362 Infectious complications, such as hepatic and intraabdominal abscesses, have also been reported.i" One of the most morbid complications of nonoperative management of hepatic injuries is the development of the abdominal compartment syndrome. 48,351,357,362,363 Routine intraabdominal pressure monitoring in these patients has been advocated by some centers.t'" There are also numerous reports of missed abdominal injuries when nonoperative management of hepatic trauma is undertaken. 353,355,364 Fortunately, the incidence of missed associated injuries is small, but clinicians must be vigilant about careful observation of all these patients.

Injury to the Spleen The spleen is also commonly injured following blunt trauma, albeit not as often as the liver. Penetrating injury to the left thoracoabdominal region also can injure the spleen. The AAST has outlined a classification scheme that describes the degree of splenic iniury.r" As with the liver, Grade I spleen injuries are the most minor, often simple lacerations or

48 7

TRAUMA TO THE T ORS O

TABLE 27.5. Representative Clinical Experience with Nonoperative Management of Blunt Hepatic Injuries.

Number of patients

Trial

Year

Level of evid ence

354

1994

III

72

Retrospective review of all patients with blunt hepatic injuries admitted to a single institution

359

1994

II

30

355

1995

II

353

1996

358

357

Median followup

Minor endpoint

Ma;or endpoin t

In terpretations/commen ts

N/A

Transfusion requirements

Successful nonoperative managem ent of blunt hepat ic injuries

Prospective study of nonoperative vs. operative management of blunt hepatic injuries

N/A

Complications of nonoperative manag ement

Successful non operative management of blunt hepatic injuries

112

Prospective stu dy of nonoperative management of blunt hepatic injuries of all severities compared to operative management in a matched cohort

N/A

Transfusion requirements, length of stay, abdominal complications

Successful nonoperative man agem ent of blunt hepatic injuri es

III

404

Retrospective multicenter study of nonoperative management of blunt hepatic injuries

N/A

Transfusion requirements, length of stay, complications

Mortality from nonop erativ e management of blunt hepatic in juries

2003

II

63

Prospective evaluation of a protocol for the nonoperative management of blunt hepatic in jury in hemodynamically stable patients

N/A

Complications of non operativ e management

Failur e of nonoperative management in patients with blunt hepatic trauma

2003

II

55

Prospective evaluation of a prot ocol for the nonoperative management of blunt hepatic injury in hemodynamically stable patients

N/A

Factors associated with nonoperative failure

Failur e of nonoperative management in patients with blunt hepat ic trauma

Ni nety-seven percent of pati ent s in wh om nonoperative managem ent was attemp ted were safely managed without surgery. The nonopera tive groups had lower transf usio n requireme nts and shorter length of stay. Nonoperativ e managem ent of blunt hepatic injuries is safe and efficacious in hem odynamically sta ble pati ent s. Tr ansfusion requirem ents were lower in the nonoperative group. Nonoperative managem ent of blunt hepati c inju ries is safe even for high-grade injuri es. Transfusion requirem ent , were less in th e nonoperative groups as were abdominal complications, although th ere was no differenc e in length of stay . Nonoperative manageme nt of blunt hepatic in juries is safe and efficacious. Th ere were 27 deaths (7%1, but only 2 were attributable to th e liver injury. Hemorrh age occurred in 3.5 % with 0.7% requirin g operative intervent ion . High er-grade injuri es were mor e likel y to fail. Failure of non operati ve management occurred in 17.5% of pati ent s. ICU length of stay and transfu sion requi rements were high er in th e group who failed. Complicati on rates of nonoperat ive managem ent was 9.5 %. Failure of nonop erati ve managem ent was 15%. None of th ese failures was attributable to th e liver itself. Nonoperative man agem ent is safe regardless of th e grade of liver in jury. Failur e may be predict ed by fluid and blood requir ements and th e presence of associated intraabdominal injurie s.

Intervention/design

leU, int ensi ve care unit; N /A , not available.

488

CHAPTER 27

subcapsular hematomas. Grade V injuries are splenic avulsion or complete devascularization. In the early 1980s, operative exploration and splenectomy was believed to be necessary for every splenic injury. However, concerns about the incidence of overwhelming postsplenectomy infection (OPSI) led pediatric surgeons to begin to observe selected splenic injuries. Their success prompted use of the same strategy in adults. However, early results were not as good. Simple observation failed approximately 15% to 20% of the time. 36s Few objective data are available to guide nonoperative therapy. Observation generally involves keeping the patient at bed rest for several days, maintaining the patient on nothing by mouth and utilizing serial abdominal examinations and hematocrits to gauge the efficacy of nonoperative management. Triggers to abandon nonoperative treatment are not clearly defined and vary among institutions and individual clinicians. The evolution of CT scanning has allowed clinicians to reliably exclude associated injuries, estimate the severity of splenic injury, and plan nonoperative management. However, CT grading does not correlate with operative findings. Early on, observation was restricted to those under the age of 55 years secondary to evidence that failure rates were higher in older patients.r" Early recommendations were that observation should only be attempted with splenic injury grades of less than 3.367 However, it became clear that some highergrade injuries could also be treated nonoperatively as well. 368,369 Additionally, studies have demonstrated that older patients may also be safely managed with observation of splenic injuries. 37o,371 Hemodynamic instability mandates operative management of blunt splenic injuries; this may occur at the time of patient presentation or if patients bleed while being observed. Any patient who presents with hemodynamic stability and does not have another indication for laparotomy is a candidate for nonoperative management. There would be great utility in knowing which patients are more likely to fail observation. In the Eastern Association for the Surgery of Trauma (EAST) multi-institutional retrospective trial, Peitzman et al. demonstrated that splenic injury grade, degree of hemoperitoneum, and hemodynamic stability at the time of patient presentation most accurately predicted who would fail. 367 Approximately 400/0 of these nearly 1500 patients over 15 years of age were managed primarily with laparotomy. Seventy percent of patients who failed observation did so within 24h of admission. In addition, the presence of a contrast "blush" on CT scan predicts failure of simple observation, as does the presence of pseudoaneurysm on helical CT scan. 372,373 Pseudoaneurysms are often not visible at the time of initial CT but may appear on repeat CT scan several days later. Complications of simple observation of splenic injuries include hemorrhage, development of pseudoaneurysms, and splenic abscesses. 367,372,374

Angiographic embolization may improve splenic salvage during nonoperative management. First described in 1995 by Sclafani et al., the splenic artery is embolized proximal to the pancreatic branches.F" Splenic viability is maintained via collateral blood flow. The first series demonstrated a 98.50/0 splenic salvage rate, the highest reported in the literature. Several recent series have demonstrated statistically significantly better results in higher-grade splenic injuries when

compared against the EAST trial. 369,371,372,376,377 Selective use of angiography also reduces hospital charges and length of stay.378 Complications following embolization, other than failure of hemostasis, are relatively uncommon but include technical errors, splenic infarctions, and splenic abscess. 376,378 Table 27.6 presents representative clinical experiences with nonoperative management of splenic injuries. Operative management of splenic injury includes either splenorrhaphy or splenectomy. As 900/0 of patients with blunt splenic injury are now treated nonoperatively, the need for splenectomy is higher in those undergoing operative management. Splenic salvage is a reasonable option in stable patients without other life-threatening injuries who have injury architecture amenable to splenorrhaphy. Unstable patients or those with other priorities should undergo splenectomy. Patients who have a splenectomy should be vaccinated against pneumococcus to prevent OPSI. Whether vaccination is necessary against meningococci or Hemophilus influenzae is debatable. Those who will be exposed to large groups of people (i.e., students or those in the military) should be considered for immunization against Hemophilus and meningococcus. Autotransplantation of pieces of the spleen into the omentum after splenectomy may offer some immunological benefit. Options for operative splenic salvage include simple topical hemostasis, fibrin sealants, or use of the argon beam coagulator. Deeper lacerations can be treated by suture repair with Teflon or absorbable pledgets. Multiple lacerations or capsular avulsions may be treated by utilizing a wrap of polyglycolic acid mesh. Proximal splenic artery ligation works similarly to proximal coil embolization.

Injury to the Pancreas and Duodenum Injuries to the duodenum and pancreas can occur as result of either blunt or penetrating trauma. The mortality of duodenal injuries ranges from 12% to 250/0 for penetrating injuries and from 100/0 to 350/0 for blunt injuries. 379-384 Similarly, for pancreatic injuries the mortality ranges from 3 % to 36 % in the setting of penetrating injury and is about 200/0 for blunt injuries. 38S-388 Fatalities in these patients are often secondary to associated injuries to the surrounding major vasculature.r" Isolated injuries to the pancreas or duodenum are rare. 390,391 The retroperitoneal location of these structures protects the duodenum and pancreas from frequent injury, but also makes their diagnosis and treatment extremely challenging. Delay in the diagnosis and treatment of these injuries results in significantly increased morbidity and mortality.38o,38s,386 In the setting of penetrating trauma, the diagnosis typically is made by laparotomy. With blunt trauma, in the absence of indications for exploration, the diagnosis is often made by CT. A high index of suspicion must be maintained for these patients, as findings on physical examination or CT scan may be equivocal or delayed. Once recognized, the degree of hemodynamic stability, associated injuries, and the grade of the injuries determine the treatment. Organ injury scales exist for both duodenal and pancreatic injury and can be helpful in guiding treatment.l" As a general rule, all these injuries require formal operative evaluation. Full mobilization of the overlying viscera is essential for proper identification and management of these injuries.

TRAUMA TO THE TORSO

Minor duodenal injuries, such as mural hematomas or serosal tears, can be managed with careful inspection and close observation. Intermediate-grade injuries can often be treated with primary repair and drainage.l" In a large multicenter review of duodenal injuries, primary repair was performed in 71 % of cases.l" The most severe injuries may require resection and diversion or enteric bypass. These repairs and anastomoses should generally be protected with omental or serosal patches, pyloric exclusion, or retrograde duodenostomy tubes.379-381 Placement of enteral feeding access distal to the duodenum is advisable. Care must always be exercised in evaluating the ampulla of Vater and common bile duct in the setting of a proximal duodenal injury. Concomitant injuries to these structures require alternative techniques, such as choledochojejunostomy or pancreaticoduodentomy. Complications from duodenal injuries include dehiscence and duodenal fistula. The incidence is higher in the setting of a concomitant pancreatic iniury.v" Mortality from these complications alone may be as high as 20 % .380-382 Pancreatic injuries are similarly treated based on organ injury scaling and often occur in concert with duodenal injuries secondary to their close anatomic relationship. The principles of treatment of pancreatic injuries are to control exocrine secretion while preserving endocrine function. Pancreatic injuries must be evaluated in two ways: whether the injury is to the head or tail, and whether the main pancreatic duct is involved. Determination of the duct's integrity is essential in the management of these injuries. Minor injuries without duct disruption require no more than closed-suction drainage.P" If the duct is involved, and the injury is to the tail of the pancreas, distal pancreatectomy is prudent. The most morbid injuries are with major duct disruption in the head of the pancreas. If relatively isolated, these injuries may be managed with wide drainage and postoperative ERCP and stenting.i" Often these pancreatic head injuries are associated with severe duodenal and major vascular injuries. Damage control may be needed with a staged reconstruction once the patient is stabilized. Very rarely (e.g., combined pancreatic/duodenal injury) is a pancreaticoduodenectomy indicated in the acute setting."? All pancreatic injuries should be drained widely, and distal enteral access should be achieved for postoperative nutrition.I" Complications of pancreatic injuries include fistula, abscess, pseudocyst, late hemorrhage, pancreatitis, pancreatic enzyme deficiency, and diabetes mellitus. 388,395,396 Complications may be seen in more than one-third of patients with pancreatic injuries who survive at least 48 h. 395

Injury to the Gastrointestinal Tract Injuries to the stomach and small intestine occur infrequently from blunt injury, but are quite common in the setting of penetrating trauma,399,400 particularly gunshot wounds. Diagnosis is typically made at laparotomy in the setting of penetrating injury, as these injuries frequently cause peritonitis on physical examination. Pneumoperitoneum, seen on plain radiograph or CT scan, always necessitates laparotomy. The treatment is relatively straightforward and consists of debridement of devitalized tissue and primary repair or resection with anastomosis. If damage control is being utilized, both

489

stomach and small bowel can be readily stapled closed, with definitive repair or resection performed later. In the setting of blunt trauma, small bowel and stomach injuries can be more difficult to identify.i'" If secondary to motor vehicle collisions, a "seat-belt sign" may be present. 80,81,400,401 CT may be helpful in diagnosis, as is DPL. Findings on CT may include only free peritoneal fluid or bowel wall edema.i'" Delayed presentations can occur with blunt injuries. Often these injuries are associated with other major injuries as substantial force is needed to cause blunt perforation. Mesenteric tears or hematomas can also be seen that may cause small bowel devascularization, which must be addressed operatively. The principles of treatment are the same as in penetrating trauma, with resection of devitalized tissue and repair or resection and anastomosis. Colon injuries are also common after penetrating trauma. Blunt injuries are relatively rare, but occur secondary to the same mechanisms that cause small bowel injury.402-404 Blunt injuries may be frank perforations, serosal tears, or devascularizations from mesenteric injury. Diagnosis is often made by physical examination, but DPL and CT scan may be useful as well. At laparotomy these injuries can be subtle, especially when caused by stab wounds or small-caliber bullets. All colonic hematomas should be inspected carefully and opened to confirm the integrity of the bowel wall. The management of these injuries has been extensively debated in the literature. Three basic options exist: primary repair, resection and reanastomosis, or resection with diversion. Historically, all colonic injuries were treated with diversion. In 1979, Stone and Fabian challenged the notion of diversion for all colonic injuries and demonstrated that primary repair or anastomosis was safe in a select group of patients.t'" Work by others reached similar conclusions and demonstrated that more than 500/0 of patients may be treated safely with primary repair or anastomosis.P"?" One study demonstrated an increased failure rate in left-sided anastomoses when compared to ileo-colostomies.'!" Certain conditions must be met to perform primary repair and anastomosis safely,405,407,408,419 including hemodynamic stability, modest blood loss, no associated abdominal injuries, minimal degree of fecal contamination, and short time interval from injury to laparotomy. These factors may be predictive of anastomotic failure and abscess formation. The risk of these complications must be weighed against the morbidity of colostomy and additional surgery. Several studies have demonstrated increased morbidity in patients treated with diversion, but this may be secondary to the clinical scenario that led the surgeon to choose diversion, rather than the morbidity of colostomy per se.412,414,415,417,418 All these patients should be given perioperative antibiotics directed against bowel flora 416,418 for 24 h, but longer antibiotic prophylaxis is not beneficial. Rectal injuries usually occur secondary to penetrating injuries, usually from transpelvic gunshot wounds. Other injuries may occur through transanal insertion of objects or from pelvic fractures with bony penetration. In any patient with a suspected rectal injury, digital rectal examination should be performed, which may demonstrate gross blood. Rigid proctoscopy or sigmoidoscopy should be performed as well if the patient is hemodynamically stable. However, these exams may be nondiagnostic, with nonspecific findings such as intraluminal blood.f" Attempts to identify rectal injuries

490

CHAPTER 27

TABLE 27.6. Representative Clinical Experience with Nonoperative Management of Blunt Splenic Injuries

Number of patients

Trial

Year

Level of eviden ce

365

1989

III

112

373

1995

III

99

375

1995

III

374

1998

372

1998

Median follow-up

Minor endpoint

Ma;or endpoin t

Interpretationslcomm ents

N/A

Out come following observatio n of blunt splenic injuries

N/A

N/A

Identification of factor s predictive of failure of nonoperative management of blunt splenic injuries

Review of an algori thm for management of blun t splenic injury to determine the efficacy of angiography and embolization

N/A

Det ermination of th e efficacy of coil embolization in nonop erat ive management

Det ermination of th e angiographic findin gs that predict successful non operative management of blunt splenic injuries

87

Retrospective review of patients with blunt splenic injury ma naged nonoperatively

N/A

Number of units transfused, ICULOS, LOS, and outcome

Identification of delayed complications following nonoperative management of blunt splenic injuries

344

Retrospective review of pati ents with blunt splenic injury managed nonoperatively

N/A

N/A

Identification of factors predicti ve of failure of non operative management of blunt splenic injur ies

Failure rat es of 11.6%. Of th e pati ent s wh o failed observation, 58% had splenic salvage at laparot omy. No deaths were attributable to splenic inju ry. Recommends that lowgrade (I- III) splenic in juries can safely be observed in hemodynamic ally stable pati ent s. Failure rate of 13% is report ed. Contrast blu sh on CT scan predicted failur e with nonop erative management and was present in 67% of failures vs. only 6% of pat ients successfully managed with observation alone. Overall success rat e was 88% . Splenic salvage rate was 97%. Hemodynamically stable pati ents with splenic in juries can be safely managed nonop eratively regardless of grade. Th e absence of contrast extravasation on angiography is predictive of succe ss of nonop erative management. Proxim al coil embolization is effect ive and increases th e number of patie nts who can be m anaged non operatively. Failur e rate for patients managed nonoperatively was 6%. Complications occurred in 8% of thos e observed. Complications included bleedin g, pseudoaneurysm formation, and splenic abscess. Nonoperative man agem ent was successful in 94% of pati ent s in whom it was attempted. Presence of a pseudo aneurysm on CT scan is strongly predictive of failure of observation alone. Splenic artery pseud oan eurysms may not be apparent on th e initial CT scan .

Int ervention/design

Review of blunt splenic injuries ma naged nonoperatively

N/A

Review of CT findings in patients with blunt splenic injuri es

150

III

III

491

TRAUMA T O T HE TORSO

TABLE 27.6. (continued) Number of patients

Trial

Year

Level of evidence

367

2000

III

913

369

2001

III

371

2004

376

2005

Median follow-up

Minor endpoint

Mu lti institutional retrospective review of patients managed with observation following blunt splenic trauma

N/A

126

Retrospective review of patients with blunt splenic injury who underwent angiograp hy as an adjunct to nonoperative management

III

140

III

368

Intervention/design

Ma;or endpoint

Interpretations/comments

N /A

Identification of factors predictive of failure of nonoperative management of blunt splenic injuries

N/A

N/A

Nonoperative salvage rates for patients with blunt splenic injuries managed with angiography and embolization as ind icated

Multiinstitutional retrospective review of patients managed with splenic emboliza tion following blunt splenic trauma

N/A

Complications of splenic embolization, factors predictive of failure

Failure of nonoperative management of splenic trauma with splenic artery embolization

Retrospective review of patients treated non operatively for blunt splenic in juries

N/A

N/A

Splenic salvage rates for patients treated nonoperatively for blunt splenic injuries

Failure rate was 10.8% in those patients in whom nonoperative management was attempted. Sixty -one percent of failures occurred in the first 24 h following injury. Failure rates increased significantly with increased grade and an increased degree of hemoperitoneum on CT. Vascular injury is more frequent with highergrade in juries. Nonoperative salvage rates of 92 % are reported with the addition of angiography. Ten percent of patients who initially had negative angiograms required laparotomy or a second angiogram. Failure rate following embolization was 10% . This rate was not different whether proximal coil embolization or selec tive techniques were applied. Failure was not predicted by degree of hemoperitoneum. Higher-grade injuries demonstrated better results when compared with other studies using simple observation. Complications occurred in 32%. Failure of nonoperative management occurred in 0% of patients observed, 6% with a negative angiogram, and 10% who were treated with splenic embolization. Salvage rates decreased with increasing grade of injury. Nonoperative salvage rate was 80% in grade IV and V injuries. Arteriovenous fistulas predict failure of nonoperative therapy.

CT, computed tomagraphy, ICULOS, intensive care unit length of stay; N/A, not available.

492

CHAPTER 27

at laparotomy can be difficult secondary to the deep extraperitoneal pelvic location of most of the rectum. The safest course of action is to treat the patient as if a rectal injury is present rather than risk the high morbidity of a missed injury. The treatment of rectal injuries consists of diversion, repair, and drainage. The Hartmann procedure (coletomy, end colostomy, and closure of the distal rectal stump) is performed for extensive injuries, rather than attempting a primary repair. Repair with a proximal loop colostomy is advocated for more minor injuries. 42D-423 The necessity of drainage for all extraperitoneal injuries has recently been challenged. 42o,422-424 There is conflicting literature on whether distal irrigation of the rectum is needed as well. 422,425-427 There is some evidence that small distal injuries may be treated safely with drainage and antibiotics alone, or transanal repair without diversion.f" In the setting of associated open pelvic fractures, drainage and diversion are essential to prevent pelvic sepsis.?"

Injuries to the Kidney, Ureter, and Bladder Hematuria is the hallmark of renal injury, although it is not invariably present. Although the diagnosis is made at laparotomy when performed to treat other injuries, CT scan and contrast studies are the diagnostic modalities that often identify these injuries. Minor injuries rarely require specific treatment, whereas a Grade V renal injury (shattered or avulsed kidney) typically necessitates nephrectomy. Documentation of contralateral renal function is important before nephrectomy. The moderate-grade injuries can be treated by a variety of algorithms. Intraoperative options include nephrectomy, partial nephrectomy, or nephrorrhaphy. Nonoperative management of the stable patient can be accomplished safely for both penetrating and blunt injuries. 341,429-432 Kidney salvage rates are typically greater than 95 % .429,431 Angiographic embolization plays an important role in the management of these injuries. Urine leaks can typically be managed with external drainage with or without ureteral stenting.t" Ureter injuries are almost entirely secondary to penetrating trauma. Associated injuries are common. Hematuria in these patients is typically microscopic or may be absent. 433,434 Contrast studies or CT scan may help to identify injuries. 43o,433 Missed injuries are not uncommon, especially when major associated injuries are present, and may cause substantial morbidity.435,436 The management of ureteral injuries includes debridement and primary repair, typically over a stent. Psoas hitch and the Boari flaps are techniques that can be used if blast injury resection results in loss of a segment more than 2 to 3 em in length.r'" Bladder injuries are quite common in the setting of blunt trauma, especially in association with pelvic fractures.?" Hematuria in the presence of a pelvic fracture should prompt evaluation of the bladder with cystography.t" Often, these injuries are extraperitoneal and require only simple transurethral catheter drainage.i" Repeat cystography after 7 to 10 days usually demonstrates healing of the injury, but occasionally direct repair may be needed. Intraperitoneal bladder injury from either blunt or penetrating trauma requires operative repair. Direct two-layer closure is recommended. Transurethral bladder drainage is advisable when possible, as suprapubic tubes may lead to higher complication rates."?

Complications Complications of torso trauma are quite frequent and are the leading cause of death among patients who survive the initial insult.' Most commonly, death is secondary to the development of multiple organ dysfunction syndrome. Infectious complications and missed injuries contribute dramatically to postinjury morbidity and mortality.441-443 Strategies to reduce the incidence of missed injuries include the tertiary survey of the patient, "24-h" observation, routine reimaging, and maintenance of a high level of suspicion in the event of clinical deterioration.r' 18], delaying fixation markedly increased the incidence of ARDS, fat embolism syndrome, and pneumonia, and the length of hospital stay." Many retrospective series subsequently corroborated these findings, and early definitive fixation became the gold standard in trauma patients, shifting the paradigm from "too sick to operate" to "too sick not to operate.,,59-64,66-69,n

Damage Control Orthopedics During the past decade, several authors noted poor outcomes with early definitive fracture fixation in patients with severe injuries and challenged the dogma that immediate intramedullary nailing of femoral shaft fractures was ideal for all trauma patients.70,73-77 Several reports of an increased incidence of ARDS and MODS following reamed nailing of femoral fractures in the most severely injured patients caused investigators to reexamine the pathophysiology of this situation. 70,78,79 Inflammatory mediators came under scrutiny both for their possible role in the pathogenesis of systemic complications and for their potential use in monitoring and prognostication." Concomitantly, several centers defined new high-risk patient groups" and proposed modified treatment algorithms to minimize inflammatory response in these patients.76,77,82

Basic Science of Long Bone Fractures Long bone fractures are associated with a variety of local and systemic cellular events and microvascular changes, the pathogenesis of which are complex and have not been elucidated fully. Fat-laden bone marrow contents extravasate into the venous circulation and embolize the lung, directly stimulating an inflammatory response and lung microvascular injury.83,84 However, although fat emboli to the lungs following long bone fracture almost always occur, clinically apparent respiratory changes occur rarely." Additionally, "fat embolism syndrome," which classically involves the triad of refractory hypoxia, neurological changes, and petechiae, may in fact not be a unique syndrome at all but rather one of several precipitants of ARDS. Therefore, actual mechanical

lodging of fat globules in the pulmonary microcirculation may be irrelevant to the pathogenesis of respiratory failure after long bone fracture. 85 A local inflammatory response is elicited at the fracture site as well.86 Cytokine concentrations, both locally and systemically, correlate with the severity of soft tissue injury. Persistently increased cytokine concentrations in the circulation following local trauma, particularly interleukin (IL)-6 and IL-8, have been demonstrated to be an "overspill" of local immune mediators from the fracture site." This upregulated systemic inflammatory response results in neutrophil activation and adhesion to endothelial cells, with subsequent extravasation." Proteases and reactive oxygen species are released, increasing capillary permeability and causing interstitial edema, ultimately leading to organ dysfunction."

Basic Science of Long Bone Fracture Treatment Intramedullary nailing of femoral shaft fractures is a reliable procedure that facilitates early mobilization and predictable bony union. Compared to traditional plate fixation, intramedullary fixation leads to less soft tissue disruption and a decreased rate of infection.Y'" However, instrumentation of the femoral canal causes local pressure in the marrow cavity to increase up to 600 mmHg, 91 leading to further embolization of marrow contents and an inflammatory burst, both of which may be deleterious to the trauma patient (Figure 28.3).92-94 En route to the lung, the fat globules aggregate with platelets and other mediators and increase in size." Once in the lung, these particles may induce the coagulation and fibrinolytic systems. 93,96-98 Barie et al." reported a dose-related increase in endothelial permeability when bone marrow was injected experimentally into the pulmonary circulation. Mechanical occlusion may be responsible for transitory pulmonary hypertension as well, although this appears to playa lesser role.93,100 Overall, a complex proinflammatory response occurs, involving both local mechanisms (e.g., vasoactive mediators) and systemic factors such as shock and coagulopathy.94,101,102 PATIENT CONDITION

EFFECT OF TRAUMA AND TREATMENT

damage control orthop-surgery

y

,,• ,

in extremis

unstable borderline

shock,thoracictrauma rescueconditions generaltrauma preinjury morbidity

stable

FIGURE 28.3. Schematic of the cumulative physiological effects of the preinjury morbidity, traumatic incident, and subsequent treatment. (Reprinted from Pape HC, Giannoudis P, Krettek C,77 by permission of American Journal of Surgery, Excerpta Medica.)

511

TRAUMA TO THE PELVIS AND EXTREMITIES

Although many physical and biochemical effects of femoral reaming and nailing have been investigated in animal and human studies, their clinical significance is still being determined. Kropfl et al. 103 evaluated 39 patients with femur fractures prospectively who underwent intramedullary nailing and, despite a correlation between the pressure generated and the amount of fat extravasated into the circulation, neither could be related to the development of FES or ARDS, even in patients with thoracic injury. 103 Robinson et a1. 93found several changes in cardiopulmonary parameters between patients who underwent reamed versus unreamed nailing, but there was no clinical difference in the traumatic femur fracture group. Other studies have also indicated that the inflow of fat into the pulmonary vasculature may be a necessary prerequisite for development of ARDS following nailing, but insufficient to cause ARDS alone, and that other pathophysiological events must also OCCUr. 98/104-109 The numerous combinations of possible injuries, as well as the various biological responses to trauma in individual patients, makes quantifying the systemic physiological burden of the trauma and surgery difficult by clinical parameters. Advances in molecular medicine have allowed the analysis of systemic inflammatory mediators to quantify the trauma-induced burden and the subsequent effects of treatment.""!" Initial reports of the responses of interleukin-If (IL-IP) and tumor necrosis factor-alpha (TNF-a) showed promise in this role, but their clinical utility was subsequently found to be limited.76/ll2-114 More recently, IL-6 and IL-8 concentrations have been shown to correlate well with the ISS after trauma. 73/ll5 Changes in IL-6 are also reliable in quantifying the immunological burden following femoral nailing." as well as other physiological secondary insults, 116 and predict which patients are at a higher risk for postoperative complications.W'!"

Clinical Aspects of Damage Control It has been suggested in several series that a subgroup of patients exists, the so-called "borderline patients" (Table 28.3),81 whose clinical status is neither stable nor hemodynamically unstable, and in whom a greater risk of deterioration exists following invasive procedures.Y'?" These patients have a limited biological reserve following the initial insult of the trauma and are particularly susceptible to a "second hit" superimposed by a physiologically demanding surgical TABLE 28.3. Clinical Parameters in "Borderline" Patients, Which May Indicate a Patient May Not Tolerate the Physiological Stress of Primary Intramedullary Nailing. Polytrauma + ISS >20 and additional thoracic trauma (AIS > 2) Polytrauma with abdominal/pelvic trauma (>Moore 3) and hemodynamic shock (initial BP 24mmHg Pulmonary artery pressure increase during intramedullary nailing >6mmHg ISS, Injury Severity Scale score; AIS, abbreviated injury scale; BP, blood pressure. Source: Reprinted from Pape HC, Giannoudis P, Krettek C,81 by permission of American Journal of Surgery, Excerpta Medica.

~ clinica~ondition ............... Stable

1

OR

1

ETC

Borderline .ij

Unstable

In extremis

OR

ICU Ex. Fix. (distractor)

hemorrhage control decompression (thorax) ~

Reevaluation ABG, ultrasound, urine output RR, inflammatory response (IL-6) ~ stable ""OR ETC

~

1

uncertain ~OR

DCO

DCO

OR =operating room; ICU =intensive care unit; ETC early total care; DCO damage control orthopedic; Ex.Fix. =external fixation; ABG =arterial blood gas; RR = respiratory rate.

=

=

FIGURE 28.4. Suggested flow diagram for managing femur fractures in multitrauma patients, incorporating damage control orthopedics, and focusing on borderline patients. (Reprinted from Pape He, Giannoudis P, Krettek C,81 by permission of American Journal of Surgery, Excerpta Medica.)

procedure.!" Subclinical inflammatory responses and subsequent surgical procedures are compounded and may lead to MODS. 102 Several authors have stressed the importance of taking a "damage control" approach to patients who fall into this category.76/81/82/121 Principles of damage control include immediate debridement of open fractures, control of hemorrhage, decompression of fascial compartments and intracranial lesions, and stabilization of femoral fractures in an attempt to minimize soft tissue injury, fat embolism, and the inflammatory response. In unstable or borderline patients, external fixation of the femur is an expedient and minimally invasive technique that stabilizes the fracture effectively but avoids a prolonged procedure. 121 In the next phase of treatment, resuscitation in the ICU continues until any coagulopathy, hypothermia, acidosis, or hemodynamic instability is reversed (Figure 28.4). This procedure is akin to the management of the multitrauma patient with an unstable pelvic fracture, which has been the standard of practice for many years. Fakhry et a1. 75 conducted a large database review of 2805 femoral shaft fractures and found the highest mortality in patients treated nonoperatively. Among those treated surgically, patients with an ISS of 15 or more who underwent nailing within 24h had a higher mortality. Reynolds et a1. 74 identified 105 consecutive patients with an ISS of 18 or more who underwent intramedullary nailing of a long bone at different time points following injury. In their series, outcomes were related to severity of injury, not time to fixation, and they hypothesized that fluid shifts associated with surgery may compound the first hit of the trauma." Scalea et al.,76 who first coined the term "damage control orthopedics," also reported on the usefulness of external fixation of femoral shaft fractures in the severely injured patient to allow ongoing resuscitation and to avoid the physiological insult of intramedullary nailing. To evaluate prospectively the effect of a damage control approach versus early intramedullary nailing, a randomized multicenter study was conducted in Europe." These investigators found greater increases in inflammatory mediators,

Retrospective coh ort Retrospective cohort

3 In = 35, 13, 57) 8 In = 665, 965, 387, 256, 200, 2 12,55, 651 4 In = 24, 26, 33, 231

II-2

II-2

II-2

1995

1994

1993

Fakhry et aU 5

Pape et al. 70

Retrospective coh ort

Pneumonia Hospitalization

Hospitalization Hospitalization

Blood loss , OR time

Demographics

Inflammatory markers

Minor endpoints

Fracture healing ICU stay, ventilator days Length of stay

12 months

Hospitalization

3 weeks

Hospitalization

Median follow-up

ARDS, mortality

Mortality

Mortality, complications Pulmonary complications

Mortality, ARDS

Mortality, complications

Complications, mortality

Major endpoints

24h, 24-48h, >48 h 24 h, 24 days, >4 days 24 h

N/A

24h

24h

24h

Time cutoff for early fixation

IMN, intramedullary nailing; DCO, damage control orthopedics; ARDS, acute respiratory distress syndrome; Ex-fix, extenal fixation; lCU, intensive care unit; IL, interleukin; OR, operating room.

= 54) Case series

1 In

II-3

1997

= 43, 284)

Nowotarksi et al. 77 Reynolds et al."

2 In

II-2

2000

Scalea et aU6

Retrospective cohort over different time periods Retrospective cohort

3 (n = 235,88, 191)

II-3

2002

Prosp ective, randomized, multicenter

Pape et a1.102

Pape et al.

I

= 17, 18)

2 (n

Groups (0)

Intervention/ design

2003

Year

Level of evidence

TABLE 28.4. Prospective Evaluation of the Effect of a Damage Control Approach Versus Early Intramedullary Nailing.

73

Trial

...1 '

Ex-fix took avg 35min [vs. 130) and blood loss was 90mL (vs. 4001 with 1M nails, good alternative Safe treatment, no comparison group Outcome related to severity of injuries, not timing of femoral nailing Higher mortality in pat ients with femoral nailing within 24h of injury Higher incidence of mortality, ARDS, and pneumonia following early nailing with che st trauma

Immediate IMN has higher inflammatory response (IL-6 &. IL-8) than ex-fix, but no clinical differences DCO era had fewer complications, compared to earlier time group

Comments

co

''"'""

..,

o 0:: >-'"d

tv

-'

U1


513

most notably IL-6 and IL-8, in patients treated with initial nailing compared to those who underwent external fixation. Additionally, this substantial increase in cytokine concentration did not occur when patients underwent conversion from external fixation to a femoral nail at an average of 2.9 days. Most notably, there were no differences in complications, including ARDS or mortality, between the groups (Table 28.4).73 To address the most appropriate timing for secondary definitive skeletal fixation, a large retrospective study concluded that procedures requiring more than 3 h should be undertaken after postinjury day 4 to minimize the risk of developing MODS. 122 A prospective study confirmed these recommendations, reporting greater concentrations of IL-6 and a threefold greater incidence of postoperative organ dysfunction in patients who underwent definitive surgery between days 2 and 4. 115 In this time period following severe trauma, fluid balance and immunological disturbances are often still normalizing, and it may not be an ideal time for definitive procedures."

tal effects of early intramedullary nailing on the outcomes of patients with pulmonary injury. Likewise, van der Made et al. could demonstrate no ill effect of reamed intramedullay nailing on coexistent pulmony injury.':" The majority of data refutes the notion that lung injury is exacerbated by reamed intramedullary nailing, despite the biochemical and animal studies. However, it is important to keep in mind that these data largely compare early to delayed nailing. Early external fixation has few drawbacks; the infection rate has been reported to be only 2 % and 3 % following intramedullary fixation,":" it is less likely to cause intraoperative hypotension (which itself may exacerbate lung injury]," and it allows immediate stabilization of the fracture. Because of minimal disadvantages and theoretical benefits, it may be the preferable technique when any doubt exists about the patient's pulmonary status, although no prospective data are available.

Femoral Fractures and Concomitant Chest Trauma

Traumatic brain injuries (TBls) occur in up to 20% of multitrauma patients and are the most common cause of death. 132 Similarly, femur fractures occur in up to 22 % of severely traumatized patients.':" The timing of skeletal stabilization after TBI, particularly of the femur, has been much debated. Despite the many apparent advantages associated with early skeletal stabilization in multiply injured patients in general,6o,65 other associated risks may outweigh these benefits, in the subset of patients with TBI, as protection of the central nervous system is the first priority. Several mechanisms of secondary brain injury have been postulated following trauma, with hypotension and resulting cerebral hypoxia being key components.P"!" A hypoxic episode, even as brief as 5 min, can have profound negative effects on patient outcome.P'r"" and early hypotension doubles the mortality. 141 It has been suggested that early, prolonged operations may cause intraoperative hypotension, hypoxia, coagulopathy, and blood loss that compromise cerebral perfusion, exacerbating the traumatic event.!" Specifically, reaming of the femoral canal carries the risk of extravasation of marrow contents with fat microembolization to the brain, with a subsequent increase in edema and intracranial pressure. 83,142,143 Jaicks et al.!" reviewed 33 patients with TBI and long bone fractures over a 4-year period and reported that the 19 patients who underwent fracture fixation within 24h required greater intraoperative fluid and blood administration, had a higher incidence of hypoxic episodes (16% vs. 7%), and had slightly worse neurological outcomes. The authors suggested that secondary brain injury from the procedures contributed to the neurological complications. However, their groups were small and heterogeneous with respect to orthopedic injuries, which were treated with unspecified techniques.!" Martens and Ectors!" reported on 77 patients, 22 of whom had fractures. Early fracture stabilization led to worse neurological outcomes, and these authors recommended delayed fixation (Table 28.6). Several more recent series have reported that early fixation of fractures may not be deleterious in the brain-injured patient. 142,143,146-152 Kotwica et al. 148 evaluated 100 patients retrospectively, and those patients who received fracture care within 12h of presentation, simultaneously with

A multitude of animal and echo cardiographic studies demonstrating embolization of fat and debris to the lung following intramedullary nailing have raised concern about the effects of femoral nailing in patients with chest injury.94-101, 103-105,107-109,123 Patients with trauma to the pulmonary parenchyma may be particularly susceptible to the deleterious effects of early intramedullary fixation as a consequence of the priming of the immune system and the subclinical effects of the initial pulmonary injury.124,125 Pape et al.70 reported retrospectively on 106 patients treated from 1982 to 1991 with a femoral shaft fracture and an ISS greater than 18 points. Patients with chest trauma who underwent femoral nailing within 24h had a higher incidence of ARDS (33 % vs. 7.70/0) and mortality (210/0 vs. 40/0).70 This report spurned controversy and led to much research into the harmful effects of early femoral nailing following chest trauma. Several multicenter retrospective studies subsequently contradicted these data (Table 28.5). Bosse et al. 126 compared plate fixation to reamed intramedullary nailing in femur fractures in more than 200 patients with lung injury, finding no differences in the development of ARDS or mortality. They concluded that postoperative complications in patients with multiple trauma and lung injury were unrelated to reamed nailing. Further investigations into the pulmonary dysfunction caused by intramedullary nailing concluded that a preoperative increase in alveolar dead space was predictive of pulmonary dysfunction but that increased dead space was not the consequence of femoral nailing.'?" Similarly, Weresh et al. 127 concluded that intramedullary nailing did not produce enough embolization of the pulmonary microcirculation to affect the physiological dead space or alveolar-arterial oxygen gradient.!" Bone et al. 128 reported that the lowest rates of ARDS occurred with early femoral fixation in patients with pulmonary injury. Several other authors have reported that early reamed femoral nailing in patients with a coexistent thoracic injury causes no harmful effect. 67,129,130 Of note, Charash et al.68 duplicated the study by Pape et al.70 at their institution and were unable to demonstrate similar detrimen-

Femoral Fractures in Patients with Traumatic Brain Injury

1998

1997

1997

1996

1995

1994

1994

1993

Carlson et al. 13O

Bosse et al. 126

Boulanger et al. 129

van der Made et al. IJ I

Bone et al. 128

Charash et al. 68

van Os et aU 7

Pape et aI.7°

Groups (0)

4 (n = 24, 26, 33, 23)

2 (n = 30,271

JI-2

JI-2

4

In = 49, 8, 56, 25)

3 In = 24, 18, 55)

3 (n = 21, 17, 22)

Retrospective cohort






In = 68, 57, 15, 9)

4



Intervention/design

3 In = 221, 232, 254)

4 In = 532, 43, 18, 64)

JI-2

JI-2

JI·2

JI·3

JI·2

JI·2

Level of evidence

ICU stay, intubation time

Hospitalization

Mortality, ARDS

Pulmonary function

Mortality Hospitalization

Mortality, ARDS

Mortality

Mortality

Mortality, ARDS

ICU Stay

ARDS, MODS

ICU stay, ventilation time

Mortality

Complications

Major endpoints

Mortality

Minor endpoints

ARDS, pneumonia

ICU stay, intubation time

Hospitalization

Hospitalization

Hospitalization

Hospitalization

Hosp italization

Hospitalization

Median follow- up

ARDS. acute respiratory distress syndrome; fx, fracture; ICU. intensive care unit; ISS. injury severity score; MODS, multiple organ dysfunction syndrome.

Year

Trial

TABLE 28.5. Plate Fixation to Reamed Intramedullary Nailing in Chest Injury.

Comments

No detrimental effect of reamed nailing in patients with chest injury No difference in outcomes in patients with both thoracaic and femur fx vs. patients with one or the other No effect on mortality or complications with reamed nailing with coexistent che st injury No effect on mortality or ARDS with reamed nailing with coexistent chest injury Only severity of chest injury was predictive of pulmonary dysfunction, not reamed nailing Duplicated Pape et al. study, only surgical delay was predictive of pulmonary compromise, particularly in high ISS patients Concluded thoracic injury not a contraindication for early surgical stabilization of femur fractures Group with chest trauma treated early had higher ARDS and mortality

ce

t~

"

-I rn

'":l

r.

:t: ;..

.:::.

VI

5 15

TR AUM A T O TH E PELVIS A N D E XTREM ITIE S

TABLE 28.6. Early Fracture Stabilization and Worse Neurological Outcomes.

Trial

Year

Level of evidence

Townsend et al.l53

1998

11-2

4 (n = 22, Retrospective Hospitalization Hypotensive episodes 24, 3, 12) cohort

Iaicks et al.!"

1997

11-2

2 (n = 19, Retrospective Hospitalization Intraoperative 14) cohort hypotension/ hypoxia; fluid administration

Martens and

1988

II-3

2 (n = 55, Retrospective Hospitalization Neurological 22) cohort outcomes

Ectors !"

Groups (n)

Intervention / design

Median follow-up

neurosurgical treatment, had decreased incidences of fat embolism and mortality. In another review of 58 patients, the 15 patients treated wi th early fixation had a lower mortality and better neurological outcomes despite more severe injuries ."" Poole et al. 142 evaluated 114 patients retrospectively with early, delayed, or no fixatio n, and demonstrated that earl y fixation had no negative effec ts on cerebral events, which were related onl y to the severity of the TBL Poole et al. stressed that earl y stabilization faci litated nursing care .!? In a retrospective review of 171 patients with TEl and lower extremity frac tures, Scalea et al. 146 found that surgical fixation within 24h, which included intramedullary nailing, plating, and external fixation, did not lead to more neurological events or an increased risk of mortality. Kalb et aLISO reported that early fixation required vigilant intraoperative monitoring and administration of larger amounts of blood and fluids but was not associated with more hypotensive episodes or neurological events. In a large trauma registry review, Brundage et al. 72 reported no increase in mortality or adverse neurological outcomes associated with earl y femoral fracture fixation in patients with TBI (Table 28.7). No prospective studies with Class 1 evidence exist to evaluate the timing of fracture fixation in patients with TBL Severa l retrospective reviews suggest that the risk of secondary brain injury from intraoperative hypotension and hypoxemia may not justify early fixation .144,145,15.J Most series, however, have reported no increased risk of neurological events with earl y fracture stabilization in patients with TEl, provided vigilant monitoring is maintained. 142,148,149,154 In general, these retrospective cohort studies rarely describe the criteria used to determine which patients underwent early fixation. Although injury severity is often compared, some studies are skewed toward sicker patients, who tended to have their fixation delayed,143,l44 whereas in other studies there is a strong bias toward early fixation .!"

Minor endpoints

Major endpoints

Time cutoff for early fixation

Comm ents

Neurological outcomes

24h stabilized 0-2 h, twofold increase if 2-24h Neurological 24h Early fixation complications led to greater fluid administration and more hypoxic episodes (16% vs. 7%1 Mortality 24h Patients with early fixation had worse neurological outcomes

These conflicting data have precluded the generation of stringent guidelines, rather suggesting that the surgeon individualize management when treating T El patients with long bone fractures . Important to consider is the mobilization allowed by early stabilization; and a valuable option ma y be immediate external fixation, which avoids reaming and instrumentation of the intramedullary canal while still allowing fracture splinting and hematoma consolidation.!" Retrospective data are available, and although studies are often conflicting and poorly controlled, there does not appear to be a significant disadvantage with early fracture fixation after TEl, provided necessary precautions and monitoring are utilized.!" Neurological prognosis is likely most closely related to the severity of the brain injury,133,142 and an y surgical procedure must be undertaken with in vasive monitoring of both hem odynam ics and intracranial pressure, with aggressive resuscitation to avoid hypoxic episodes.!34,140,146,153

Conclusion Patients who sustain high-energy pelvic fractures are often difficult to treat, and the associated soft tissue injuries and hemorrhage continue to be a substantial source of morbidity and mortality. Evidence exists that in the setting of hemodynamic instability and unstable pelvic fracture patterns, mechanical stabilization is crucial. In the case of refractory hemodynamic instability when other sources have been excluded, emergent angiography is often successful in treating arterial bleeding, although this applies only to a small group of patients. Several large series have demonstrated improved outcomes with formal clinical trauma pathways and pelvic fracture management algorithms, and adherence to a multidisciplinary approach is essential.

1998

1998

1998

1997

1994

1992

1991

1990

1986

Kalb et al. ISO

Velmah os et al. 15 1

Starr et al. l43

McK ee et al. 14 7

Mali san o et al. 152

Poole et al. 142

Hofm an and Gori s!"

Kotwica et al. 14S

Lozman et al. 71

Ret rospective cohort Ret rospective cohort

21n = 238,95) In = 147, 24)

Ret rospect ive cohort Ret rospect ive coh ort Ret rospect ive case- contro l

In = 22,25) = 14, 18)

In In = 46,99)

-

I 2ln = 9)

Prospective, random ized

Ret rospective coho rt

-

2

Disch arge

Ret rospecti ve coh ort

58 In = IS, 43 )

11-2

11-2

Neu rol ogical outco me

Discha rge

Retrospecti ve cohort

3 In = 46, 26, 42)

Discha rge

Cardiac index, pulmonary in dice s

Neu rological outcome

Un ion , sepsis

11-2

18 m onths

to 4 yea rs

Ret rospect ive coho rt

2ln = 88,20 )

Hospi tal/ICU stay

N eu rological comp lica tio ns, ven tilat ion day, LOS CNS complication

Hospita l/ ICU stay, ne uro logica l outcomes Hospital/ ICU stay, neurologica l outcomes ICU/hospital stay, flui d/ blood requireme nts Fluid /bl ood adm in istration

11-2

Di sch arge

Disch arge

Discharge

8-34 months

Discharge

Di scha rge

Di sch arge

Minor endp oints

2

2

2

Ret rospect ive cohort

2ln = 84,39)

2

Retrospective case-control

2 In = 28, 120 )

Int ervention/design

11-2

11-2

11-2

11-2

11-2

11-2

11-2

Groups (n)

Median follow-up

Mortali ty, ARDS

Mortality

Mort ality

Mort ality, pulmon ary com pli cation, neu rological comp lication Pulmon ary outco mes

Mortality, neurological outcomes

Mortality, pulmon ary com plicat ion

Int raoperative hypoxia, m ortality

Mortality, disc harge GCS, neu rol ogical complication s Hypoperfus ion, mortality, cardial hypot en sion

Mortality, pu lmonary complica tions

Mortality

Maior endpoin ts

ARDS, acute respiratory distress syndrome ; CNS , central nervous system; ICU , intensive care unit; LOS, leng th of stay; NIS, not stated.

1999

Scalea et al. 146

2003

Year

2002

154

Brundage et al. 72

N au et al.

Trial

Level of evidence

TABLE 28.7. Early Fixation of Fractures in the Brain-Injured Patient with Good Outcomes.

N /S

12h

24 h

24 h

N /S

24 h

24 h

24 h

24 h

24h

24h

24 h

Tim e cutoff for early fixation Commen ts

Ce rebra l events related only to severity of head injury , not tim in g of fixatio n; no delet eriou s effects Earl y fixat ion group had higher ISS but lower m ort ali ty an d better neu rol ogical ou tco mes Early fixation had less fat em bolism and lower mortali ty th an delayed Mi no r differe nces in indices, no differe nce clinica lly, recommend early fixa tio n

Fracture stabilization delay in creased pul m onary risk, ea rly sta biliza tio n had no inc reased C NS eve nts Earl y intramedullary of fem ur fractures in headinjured patients had no delet eriou s effects Aggressive ope rative intervention produced no additio na l at tributable neurological seq ue lae

Early fixatio n group had m ore blood and fluid req uirements, bu t no in crease in h ypoperfu sion or adve rse ou tcomes Early fixat ion had no impact on neu rol ogical com pli cat ion s

No ev idence that early fixation led to neurological compromise

Early femora l fixation was associated wi th lowest mortality and morbidi ty

Early fixation had no impact on m ortality or ne urological complications

o

cc '"

?:l

'"

'>-I""

»

:J:

0\

~

VI


The issue of technique and timing in the treatment of multiply injured patients with femoral fractures has not been resolved fully. The benefits of early fixation in the less severely injured patient are clear. Patients with a multitude of severe injuries (ISS> 18) are likely to benefit from a damage control approach to fixation, which centers on initial external fixation of long bone fractures to minimize the overall physiological insult, followed by continued aggressive resuscitation. Direct measurement of inflammatory mediators has recently become available in some centers and may become commonplace in quantifying the physiological insult of trauma and the risk of subsequent interventions. Prospective evidence exists that early definitive fixation leads to an increased inflammatory response, but this response has not coincided with poorer outcomes. In patients with concurrent chest or brain injury, there is no clinical evidence that early reamed nailing exacerbates either injury. A plethora of in vitro and animal data have demonstrated the pulmonary fat microembolization following reaming, as well as the potentially detrimental consequences of fat microembolization in pulmonary or cerebral tissue. No prospective data are available to address this question, but the available retrospective clinical data, which include several large multicenter studies, have failed to show any harmful effects in these circumstances.

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138. Chesnut RM, Marshall LF, Klauber MR, et al. The role of secondary brain injury in determining outcome from severe head injury. J Trauma 1993;34:216-222. 139. Pietropaoli JA, Rogers FB, Shackford SR, et al. The deleterious effects of intraoperative hypotension on outcome in patients with severe head injuries. J Trauma 1992;33:403-407. 140. Wald SL, Shackford SR, Fenwick J. The effect of secondary insults on mortality and long-term disability after severe head injury in a rural region without a trauma system. J Trauma 1993;34:377-381; discussion 381-382. 141. Chesnut RM. Secondary brain insults after head injury: clinical perspectives. New Horiz 1995;3:366-375. 142. Poole GV, Miller JD, Agnew SG, Griswold JA. Lower extremity fracture fixation in head-injured patients. J Trauma 1992;32:654659. 143. Starr AJ, Hunt JL, Chason DP, et al. Treatment of femur fracture with associated head injury. J Orthop Trauma 1998; 12:38-45. 144. Iaicks RR, Cohn SM, Moller BA. Early fracture fixation may be deleterious after head injury. J Trauma 1997;42:1-5; discussion 5-6. 145. Martens F, Ectors P. Priorities in the management of polytraumatised patients with head injury: partially resolved problems. Acta Neurochir (Wien) 1988;94:70-73. 146. Scalea TM, Scott JD, Brumback RJ, et al. Early fracture fixation may be "just fine" after head injury: no difference in central nervous system outcomes. J Trauma 1999;46:839-846. 147. McKee MD, Schemitsch EH, Vincent LO, et al. The effect of a femoral fracture on concomitant closed head injury in patients with multiple injuries. J Trauma 1997;42:1041-1045. 148. Kotwica Z, Balcewicz L, Jagodzinski Z. Head injuries coexistent with pelvic or lower extremity fractures early or delayed osteosynthesis. Acta Neurochir (Wien) 1990;102:19-21. 149. Hofman PA, Goris RJ. Timing of osteosynthesis of major fractures in patients with severe brain injury. J Trauma 1991;31:261263. 150. Kalb DC, Ney AL, Rodriguez JL, et al. Assessment of the relationship between timing of fixation of the fracture and secondary brain injury in patients with multiple trauma. Surgery (St. Louis) 1998;124:739-744; discussion 744-745. 151. Velmahos GC, Arroyo H, Ramicone E, et al. Timing of fracture fixation in blunt trauma patients with severe head injuries. Am J Surg 1998;176:324-329. 152. Malisano LP, Stevens D, Hunter GA. The management of long bone fractures in the head-injured polytrauma patient. J Orthop Trauma 1994;8:1-5. 153. Townsend RN, Lheureau T, Protech J, et al. Timing fracture repair in patients with severe brain injury (Glasgow Coma Scale score
esis and direct anterior odontoid screw fixation. Anterior screw fixation preserves atlanto-axial joint mobility, has a published fusion rate of 90 % to 100%, and is also indicated for elderly patientsy w-l23 However, contraindications to anterior screw fixation include an established nonunion, irreducible fracture, osteoporosis or osteopenia preventing solid screw purchase, and known unstable injury to the transverse ligament.t-!" More research is necessary to elucidate the absolute indications and contraindications for different methods of surgical fixation in odontoid fractures, but it is clear that a precise diagnosis is necessary so that appropriate treatment modalities may be planned.

Traumatic Spondylolisthesis of the Axis: The Hangman's Fracture Traumatic spondylolisthesis of the axis is aptly named "the Hangman's Fracture," as it represents a hyperextension injury

TRAUMATIC INJURY OF THE SPINE

in which the isthmus of C2 is broken bilaterally as the occipital base provides shear forces on the posterior structures of C2. 125,126 Additional injury may occur in the soft tissue structures (ligaments and disks) of C2 and C3. 126 In addition to being hanged, motor vehicle crashes, falls, and cranial angled impact injuries such as diving may cause a hangman's fracture. 117,127 A number of classification systems have been used to define traumatic spondylolisthesis injuries to C2, but the most recognized is that published by Levine and Edwards, which represents a modification of the Effendi classification. 128,129 Type I injuries typically result from a hyperextension-axialloading force and represent a fracture of the C2 pars interarticularis with less than 3 mm of displacement and no angulation. Type II injuries typically result from the same mechanism, but are followed by severe flexion; they represent fractures of the pars interarticularis with more than 3 mm of displacement and with substantial angulation. Type Ila injuries result from flexion-distraction and involve a fracture of the pars interarticularis with minimal or no displacement but substantial angulation, and with C2-C3 unilateral or bilateral facet dislocation. Type III injuries result from flexioncompression with rebound extension and involve a displacement of an anterior fragment with angulation, C2-C3 facet dislocation, and C2-C3 disk space disruption.Fv!" According to Levine and Edwards, type I injuries are stable and require only hard collar immobilization, whereas type II injuries require more rigid halo immobilization (type II injuries benefit from initial traction, whereas type Ila injuries worsen with traction but reduce with mild extension); type III injuries are unstable and require surgical fixation.!" Vaccaro et al. also found halo immobilization to be effective in treating type II and IIa fractures, especially in patients with angulation less than 12°.130 Few data exist to support one treatment over another, but it is generally recognized that type I fractures, the most common type (approximately 650/0), can be treated with immobilization via halo or hard collar. 114,117,128 Absent any Class I evidence to support surgical management of hangman's fractures, the AANS/CNS guidelines support surgical stabilization and fixation in cases of severe angulation (some type II and type Ila fractures) and in cases of disk space disruption (type 111).117 Additionally, for patients with combination fractures of Cl and C2, the prevailing standard is to treat according to the type of C2 injury.131,132

Lower Cervical Spine Fractures Fractures from C3 to C7 are classified using several different systems, but the most recognized is based upon the mechanism of injury. This system, developed by Allen et al., divides lower cervical injuries into mechanistic categories: compression flexion (resulting in anterior vertebral body fractures with kyphosis and teardrop fractures), distraction flexion (resulting in locked facets and ligamentous injury; Fig. 30.5), vertical compression (burst fracture with or without retropulsion), compression extension (facet fracture), distraction extension (anterior longitudinal ligament disruption with superior retrolisthesis), flexion alone (facet dislocation), and extension alone (spinous process fractures with or without lamina fracturesl.!" Such a system provides distinct diagnostic categories for each fracture, but the management of lower cervical injuries requires an assessment of spinal stability. White and Panjabi categorized clinical criteria for stability

555

assessment; some important elements include spinal cord or nerve root damage, change in radiographic or clinical examination with traction, abnormal disk anatomy, congenital canal stenosis, anterior-posterior displacement greater than 3.5 mm, sagittal plane angulation greater than 110, a~d sagittal plane rotation.!" The presence of such factors should prompt further radiographic investigation with CT and MRI. Particular fracture types that are recognized easily on plain cervical films are the teardrop fracture (a compression flexion injury) and locked facets (a distraction flexion injury). A teardrop fracture is an oblique fracture through the vertebral body with resulting posterior displacement of the inferior fracture margin into the spinal canal.!" Radiographic findings can include a "teardrop" shape of bone displaced anteriorly from the vertebral body (may be confused with an avulsion fracture), a large triangular portion of the vertebral body representing the inferior fracture margin, disrupted facet joints, soft tissue swelling (soft tissue shadow greater than 5-7mm from C2-C4 and 22mm from C5-C7 in adults).92,136 If a teardrop fracture is suspected, it should be evaluated fully and ruled out definitively, as teardrop fractures are generally considered unstable and require fusion in most cases because of retropulsion of the inferior fragment into the central canal. Locked facets occur from distraction flexion injury and involve unilateral or bilateral dislocation of the facets with reversal of the normal relationship. Typical radiographic signs of unilateral locked facets include ipsilateral rotation of the spinous processes superior to the locked facet on AP plain films and a "bow-tie" sign on lateral plain film (visualization of the left and right facets at the level of the injury that are normally superimposed). Treatment choices for locked facets include traction and surgical reduction/stabilization; the employment of one over the other depends upon factors affecting stability in each patient.

Thoracic and Lumbar Spine Fractures: A Three-Column Injury Model In assessing injury to the thoracolumbar spine, the biomechanical relationships inherent in the anatomy must be understood. Denis developed a biomechanically based system for classifying thoracolumbar injuries known as the threecolumn model (Fig. 30.6).137 The anterior column is defined

as the anterior half of the vertebral body and intervertebral disk and includes the anterior longitudinal ligament and the anterior annulus fibrosus. The middle column is defined as the posterior half of the vertebral body and disk and includes the posterior longitudinal ligament. The posterior column is defined as the posterior spinal bony complex, including the facet joints, the ligamentum flavum, the spinous processes, and supraspinous and interspinous ligaments. Injuries to just one part of one column are generally considered stable and include isolated transverse process fractures (posterior column), isolated pars interarticularis fractures, and spinous process fractures." Similarly, evidence of injury to multiple columns should prompt the consideration of instability until further diagnostic studies can elucidate clearly the extent of injury. Current classification of thoracolumbar fracture injuries is based upon the column model, the classification system developed by McAfee, and more recent systems that account for mechanism of injury as well as factors affecting instability.138-141 Major thoracolumbar injuries are divided

556

CHAPTER 3 0

A

B

FIGURE 30.5. A 26-year-old woman was pushed down a flight of

went an angiogram that found a right vertebral dissection (D); the vessel was occluded intentionally after collateral cross-filling was noted.

into four categories : compression fractures, burst fractures, flexion-distraction fractures (also called Chance or seat-belttype fractures), and fracture-dislocations. A compression fracture reflects a failure of the anterior column, with an intact middle column, possibly resulting in a wedge kyphotic deformity. These fractures involve no significant loss of height of the vertebral body, no subluxation, and no neurological deficit, but do disrupt the vertebral body anterior endplate. Most occur from TIl to L2 and are the result of a motor vehicle crash or fall. 142 In assessing the resulting kyphos is for these and other types of fractures, th e Cobb angle (angle mea sured between the superior endplate of the next cephalad vertebral body and the inferior endplate of the next caudal vertebral body) may be helpful both to monitor preoperative kyphotic progression and to assess postoperative reduction and fixation. Although generally considered stable, worsening kyphosis by measurement may result in refractory pain and instability, necessitating more aggressive therapy. As such, patients with compression fractures should be followed clinically and radiographically.

Burst fractures result from an axial load on the spine and cause failure of the anterior and middle columns (see Figure 30.6). These fractures result from falls from height and motor vehicle crashes. Typical radiographic findings include loss of vertebral body height both anteriorly and posteriorly, retropulsion of bone fragments from the endplates into the spinal canal, and widening interpedicular distance (on AP radiograph). Once diagnosed, stability must be assessed, there are no strict criteria, but th e categorical standards of White and Panjabi apply.!" Of note, loss of vertebral body height greater than 50% of normal is associated with progressive kyphosis and spinal stenosis and represents one factor favoring surgical intervention.P' 2.5, Ppa, we < 16, MV < 7d Coronary ins ufficiency, prior lung disease, barot rauma, uncontrolled acidosis, intracranial hypertension terminal disease

LIS > 2.5, MV < 3 d Left heart failure, acute or chronic organ failure , chest wall abnormality, intracran ial hypertension, head injury, term inal disease

Pa02/Fr0 2 < 200, MV < l d Ave < 18, left hear t failure, acute neurologic disease, chronic lung disease, th oracic surgery

Pa02/FI02 < 250, MV< l d Age < 18, left heart failure, myocardial ischemia, acute or chronic neurologi c disease, PIP > 30 for 2 h, termi nal disease

Pa02/Fr0 2< 300, MV < 36 h Age < 18, left heart failure, acute neurologic disease, life expectancy 50 cm H2O

2 above pflex

0-15, tit rat ed to best P:F ratio Same

5-20 ti trate d to best P:F ratio Same

5-2 0 titrated to best P:F ratio Same

Ti trated to gas excha nge Titra ted to gas exchange

30 versus 37 16 versus 7 350 versus 770mL

26 versus 32 11 versu s 11 7 versus IOmL/ kg

55 versus 32

60 versus 41

25 versus 32 10 versus 9 7 versus IOmL/kg 50 versus 40

22 versus 28 9 versus 7 7 versus 11m L/kg 54 versus 46

25 versus 32- 34 8- 9, both groups 6.2 versus 11.8 mL/k g

Titrated to P:F ratio

123 versus 145

31% versus 39 % 13/26 (50%) 30/60 (50%) versus 12/26 versus 28/60 (47%) (46%1 1 (4%) versus 6 (10%) versus Barotrauma 2 (7%) versus 10 8 (14%1 versus 7 No difference (12%) 4 (7%) (42%) 2 (8%1 Definitions of abbreviations: CPAP = continuous airway pressure; IBW = ideal body weight (note : the formu las used for calculation of IBW were not uniform across studies; Brochard and coworkers used "dry weight " to determine tidal volume) ; LIS = lung inj ury score; MV = mechanical ventilation; Pdriving = driving pressure; Pflex = pressure at lower inflection point of pressure-column curve; P:F = Pa02: F/0 2 ratio; PIP = peak in spiratory pressure; Ppa.we = pulmonary artery wedge pressure; Pplateau = plateau pressure; VT = tidal volume. 13/29 (45%1 versus 17/24 (71%1

47% versus 38%

Source: From International consensus conferences in inte nsive care medicine: ventilat or-associated lung injury in ARDS. Am J Respir Crit Care Med 1999;160: 2118-2124.

ferential burns) . Although sus tained inflation wi th high pressure has been used trad itionally, it is less well tolerat ed hem odynamically th an recru itme nt by pev, which achieve s lower average airway pressure but sim ilar peak airway pressure during inspirat ion .Pv?" If oxygenatio n and lung m echanics do not improve thus, th e patient is considered to have low recruitment potential. Man agement goals in the recrui table

group em phasize maintenance of high-level PEEP to maintain inflation of opened gas-exchange units. In poorly recruitable patients, PEEP may be maintained as low as feasible, gene rally in th e range of 5- 10cmH 20 . In both groups, endexpiratory plat eau pressur e is kept below 30 cmH2,O except when ches t wa ll compliance is low. Patients with recruitable lu ng units should respond to incre ased PEEP in recruiting

591

ME CHANI CAL V ENTIL A T IO N

TABLE 32.8. ARDSNet Ventilator Management. • Assist control mode-volume ventilat ion • Reduce VT to 6mL/kg lean body weight • Keep Pplat 35

616

CHAPTER 34

After a number of case reports of fatal secondary ACS in bum patients, a small prospective evaluation was conducted of bums greater than 20% total body surface area (TBSA). In 7 of 10 patients, IAH developed; 2 patients progressed to ACS that required decompression." In a retrospective review of bum patients with ACS, an overall 1% incidence was found. The patients developing ACS had an average 70% TBSA bum and survival of 400/0. 33

Physiological Effects of Increased Abdominal Pressure CARDIOVASCULAR

The cardiovascular effects of lAP were first described by Cullen et al. in a small clinical series." Hypotension is the most obvious finding and is recognized as part of the ACS clinical triad. It is, however, a late finding of the disease process. Other studies are listed in Table 34.3. 15,34-4 5 Becau.se of compression of vascular beds, peripheral vascular reSIStance is increased. Venous return via the inferior vena cava is decreased by high abdominal and thoracic pressures. Cardiac compression, whether from intrathoracic pressure or abdominal compression, results additionally in decreased production of atrial natiuretic peptide and increased fluid sequestration, resulting in increasing lung water and potentially worsened visceral edema. Despite ongoing volume resuscitation, cardiac index is typically not improved. This lack of response to volume loading may be the first sign of impending ACS. Additionally, futile attempts to improve cardiac performance with additional fluid result in increasing interstitial and visceral edema and worsening of lAP. Patients with ACS have artificially elevated high pulmonary artery occlusion pressures (PAOP) and high central venous pressures (CVP) from high intrathoracic pressures that correlate poorly with actual volume status. Several studies have demonstrated that right ventricular end-diastolic volume index is the best measure of volume status in patients with IAH. All series demonstrate that release of abdominal compartment results in prompt restoration of blood pressure and may reveal a relative hypovolemia as PWP and CVP decrease precipitously. Hence, in ACS, patients have decreased intravascularvolume, despite high CVP and severe edema. Third-space fluid losses are the result of cytokine release and decreased transmural atrial pressure, which induces fluid retention. All the foregoing conditions result in a vicious cycle of hypotension, treated with volume resuscitation, resulting in fluid sequestration and worsening ACS. Additionally, there is extensive evidence to support ACS as part of a "second-hit" phenomenon, as all the physiological sequelae are worsened when ACS occurs in conjunction with hypovolemia, shock/ reperfusion, or inhalational anesthesia. PULMONARY

The second component of the ACS triad is high peak airway pressures. Clinically, this presents as difficulty with oxygenation and ventilation. Initially, this was believed to be caused by cephalad movement of the diaphragm from lAP, which alone results in a 400/0 to 50% decrease in pulmonary compliance. Although clearly part of the pathophysiology,

several other factors are important (Table 34.4).46-49 The decreased excursion of the diaphragm results in less negative pressure within the chest, particularly in the lower lung, with ventilation in these areas becoming mismatched with blood flow, leading to increased physiological dead space and shunt. Patients with ACS have undergone aggressive fluid resuscitation for hypotension and are typically quite edematous. Resulting decreased chest wall compliance increases the work of breathing. Also, several studies have shown increased lung water, even in the face of normal PAOP and cardiac output, because of third-space losses, both from cytokine release and increased intrathoracic vascular pressures. Decreased lung compliance results, exacerbating the inspiratory pressures needed for lung expansion. Positive end-expiratory pressure (PEEP) must be considered carefully in patients who are developing IAH. lAP and PEEP both result in increased intrathoracic pressures and decreased venous return. Hence, lAP and PEEP act in concert to decrease cardiac return and cause hypotension. Additionally, compression of the heart may contribute to decreased cardiac output and worsening of visceral blood flow. Hence, PEEP should be decreased as much as possible in patients with IAH, and a high PEEP requirement must be considered as a factor when deciding on the appropriate treatment of any specific level of lAP. Last, cytokine release caused by either the initial injury or ACS places this patient population at high risk for the development of acute respiratory distress syndrome (ARDS), further complicating the pulmonary management. RENAL

The third component of the triad of ACS is impaired renal function, seen clinically as oliguria. In 1876, Wendt reported decreased urine flow in association with increased IAP.50 . More recent data are presented in Ta bl e 34.5. 1751 ' -58 01·iguna is typically seen at an lAP of 15 to 20mmHg, and anuria occurs at 30mmHg. The renal impairment is independent of volume expansion and the maintenance of normal cardiac output. Additionally, the incidence of renal insufficiency increases with increasing abdominal pressure. Neither is ureteral compression the Gause of oliguria, as ureteral stenting fails to correct oliguria. Compression of the renal parenchyma has been studied in several ways with conflicting results. Compression of the renal veins clearly results in oliguri~ in ACS, presumptively the result of renal venous hypertension and consequent decreased renal blood flow. Endocrine changes such as increased production of vasopressin and aldosterone may contribute variably to oliguria and may also account for the hypertension and nephrotic syndrome seen in patients with chronically elevated abdominal pressure. No study has been definitive, but it is likely that the oliguria of IAH is a result of decreased cardiac output ~nd renal venous compression with renovascular hypertension. Renal parenchymal compression and vasoactive hormone secretion likely cause only minor effects in acute IAH. SPLANCHNIC CIRCULATION

All factors of the triad of ACS become apparent clinically, but the changes that are not readily apparent may be even more

~U__•

TABLE 34.3. Intraabdominal Pressure (lAP) Effects on th e Cardiovascular System.

Study characteristics (Grade of Evidence, for Clinical Studies)

Author, year

Study population

Cheatham 199935

ICU patients with ACS before and after decompression

Conc urr ent observation (III

Balogh 200336

"High-risk" trauma patients

Retrospective review of therapy with a standardized protocol (III)

Schachtrupp 200337

Pigs with ACS, evaluated intravascular volumes

Controlled, compared to baseline

Simon 199738

Pigs with ACS with or without prior hem orrh age and resuscitation ICU pati ents with ACS before and after decompression


Chang 199839

Concurrent observation (Ill

Shelly 198740

Orthotopic liver transplant patients

Case series (III)

Robotham 198542

Dogs with exte rnal abdominal comp ression and open ches t on right heart bypass Pat ients with ACS


Ivankovich 197541

Dogs with induced lAP


Diamant 197843



Kelman 197244

Laparoscopy patients


Cullen

198~4

Case series (III)

(Ill Kashtan 198145



Ridin gs 1995 15

Pigs with lAP to 25mmHg

Con trolled, compared to baseline

Findings

PAOP and CVP do not correlate well with CO an d are poor predictors of volu me sta tus . Right ventricular end-diastolic volume ind ex is th e best indicator of volume sta tus. In pati ents who developed ACS, volume loading increased PAOP but not CO. Lack of respon se to volume loading can be used to predict likely onset of ACS. ACS group required mor e crystalloid and blood infusion. Despite fourfold increase in CVP, total circu lating blood volume decreased by 67%, inc rease d hemato crit , 27% decreased CO , increased extravascular lung water volume . Prior hemorrhage resulted in more severe decline in cardiac and pulmonary fun ction despite resusci tationACS acts as a "second hit ." Abdom inal decompression resul ts in decreased lAP, increased filling pressur es best monitored by RVEDVI. PAOP is a poor predictor of volume status in ACS due to decreased cardiac compliance. Decompression reduced pulmonary shunt fract ion, improved dynam ic compliance, urine output, and gastric m ucosal pH . Report of immediate hem odynamic changes at release of ACS: hypotension, decreased SVR and PAOP, increased CO . With th e bypass removing changes from veno us return, increased abdominal pressur e resulted in increased aortic and left atrial pressur es and decreased flow in th e aorta. Pati ents before decompression had small to norrnalleft ventricular end-di astolic volume, norm al ejection fraction, and high right and left atri al fillin g pressures, but clin ically appeared hyp ovolemic. They requi red high ventilato ry pressur es and oxygen and were oliguric. With abdominal decom pression, fillin g pressures, cardiac output, and stroke volume increased signific antly with improved oxygenati on, ventilat ion, and urine output. Increased abdomi nal pressure resulted in incr eased mean arterial, right atrial, pleur al and femoral vein pressur es with 60 % reduction in cardia c outp ut an d vena caval flow. Calculated transmural right atrial pressure decreased, resulting in volume retention . lAP to 40 torr during normovolemia results in 35% reduction in cardiac output correla ted with decreased inferior vena caval blood flow . Hypovolem ia and or inhalational anesthesia resulted in a furth er 26%-43 % decrease. Femoral venous pressure and centr al venous pressure inc reased with lAP. A small increase in cardiac outp ut and intrathoracic pressure was also seen. With higher lAP to 40cm H 20 , CVP, cardiac output, and MAP decreased with increased heart rate . lAP to 40 mmHg resulted in 53 % decreased cardiac output in hypovolemic dogs, 17% decrease in normovolem ia and 50% increase in hypervolem ia. Bladder pressures correlated with lAP. CI decreased, and PAOP, PA, and pleural pressures increased. Worsened Pa02 and PaC0 2. CI improved with volume resu scitation, despite elevat ed PAOP.

ICU, int ensive care unit; ACS, abdom inal compartment syndrome; PAOP, pulmonary arte ry occlu sion pressur e; CVP, central venous pressure; CI, cardiac index ; CO, cardiac output; lAP, intraa bdominal pressure; PA, pulm onary artery; MAP, mean art erial pressur e; IAH, intraabdom inal hypertension; SVR, systemic vascular resistanc e; torr, rnml-lg, RVEDVI, right ventricular end-diastolic volume index .

618

C HA PT E R 34

_"I"l"'_ TABLE 34.4.

Intraabdominal Pressure Effects on the Pulmonary System.

Study population

Study characteristics

Findings

Murtoh 1991

Pigs with induced lAP


Kotzampassi 2000 47

Pigs with IAH at various levels of PEEP


Oda 200248

Pigs with shock , ACS, and both

Control group, five pigs per group

lAP results in elevation of th e diaphragm with 40% reduction in functional residual capacity but also results in decreased tidal compliance, resulting in both decreased expansion and a shift to less negative pleural pressures in the lower lung fields, resulting in less uniformity of ventilation. PEEP and IAH have additive effects with decreased £low in the SMA by 35%, mucosal microcirculation by 31 %, mucosal pH to 7.1, hepatic artery £low reduced 33% and portal £low 24%. Measurements of cytokines, mye loperoxi dase, and lung white cells indicate that the combination of shock and ACS results in more severe lung injury, likely due to cyto kines, than either alone.

Buchard 198549

Dogs with induced lAP at various levels of PEEP


Author, year 46

Combination of PEEP and lAP results in significant decrease in CO, increase in PAOP and CVP and lactate. ?Changed hepatic metabolism of lactate.

ACS, abdominal compartment syndrome; IAH, intraabdominal hypertension; lAP, intraabdominal pressure, PEEP, positive end -expiratory pressure; SMA, supe rior mes ent eric artery, CO, cardiac output; CVP, central venous pressure; PAOP, pulmonary artery occlusion pressure.

important. As first described by Caldwell and Ricotta" in an early animal model, lAP results in visceral ischemia. Further studies (Table 34 .6)' 7,58-75 demonstrate that flow to all abdominal viscera, except the adrenal glands, is decreased by 50 % or more. This decrease in flow is independent of cardiac output. Additional clinical evidence demonstrates decreased gastric and intestinal mucosal pH. These decreases in flow and int estinal ischemia result in cytokine release, ischemiajreperfusion injury, and possibly

AJ,.._

bacterial translocation. Hence, ACS is likely a cau se of multiple organ dysfunction syndrome. Additionally, intestinal anastomotic failure is associated with ACS, likely because of bowel ischemia." INTRACRANIAL PRESSURE

Several case reports, a small series," and some animal data indicate that the increased intrathoracic venous pressure

TABLE 34.5. Intraabdominal Pressure Effects on the Renal System.

Author, year

Study population


Findings

Sugrue 1995, 199917•51

ICU patients

Concurrent observation

Doty 199952

Pigs with renal vein constriction Renal transplant patient with IAH due to very large kidney Pigs with direct renal parenchymal compression Rhesus monkeys with aortic cross-clampinduced renal ischemia Dogs with induced lAP

Controlled, compared to baseline Case report Controlled, compared to baseline

40% of 263 patients developed IAH (>18mmHg). Renal impairment was more common with IAH (32% vs. 14%). Factors related to development of renal dysfunction were hypotension, age greater than 60 years, sepsis, and IAH in order of clinical significance. Decreased renal artery blood £low and glomerular filtration independent of cardiac index . Increased aldosterone and renin. Reversal of diastolic arterial £low was an early sign of increased abdominal press ure on the kidney and resolved with release of pressu re. No change in GFR, renal blood £low, renin, or aldosterone production.

Controlled against the contralateral kidney

Removing the renal capsule decreased the loss of function as measured by creatinine clearance.


Bradley 194757

Human experimental subjects with external abdominal compression


Biancofiore 2002 58

Liver transplant patients


Increased lAP results in decreased rena l blood £low and glomerular filtrat ion to 25% of baseline at 20mmHg lAP and to aneuria at 40mmHg lAP. Restoration of cardiac output does not prevent renal dysfunction. Increased lAP to 20mmHg results in increased renal venous pressure (decreased £low gradient across the parenchymal, decrease d rena l plasma £low, GFR, and filtration fraction, increased water reabsorpt ion, and urinary concentration. Patients wit h lAP greater than 25mmHg had a significantly higher rate of renal failure .

Weibe 2004 53 Doty 2000 54 Stone 197755 Harman 198256

ICU, intensivecare unit; IAH, intraabdominal hypertension; lAP, intraabdominal pressure; GFR , glomerularfiltration rate.

-~,..- TABLE 34.6.

lAP Effects on the Splanchnic Circulation.

Author, year

Study popu lation

Study characteristics (Grade of Eviden ce if a Clinical Study)

Caldwell 198759

Dogs with ind uced IAP

Contro lled, comp ared to baseli ne

Diebe l 199261


Con trolled, compa red to baseli ne

Diebel 199262


Controlled, compare d to baseli ne

Eleftheriadis 199663

Rats wit h lAP at 15mmHg pneumoperitoneum

Randomi zed con trol group

Diebel 199764

Rats with induced IAP Human abdomi nal surgery patients

Con trolled, compared to baseli ne Concurrent observa tion (III

Pigs with induce d IAH with an d withou t hemorrhage and resuscitation Rabbits with induced IAH

Con trolled, comp ared to baselin e

Andrei 199868

Laparoscopy patie nts

Retrospect ive (III)

Andrei 199969

Laparoscopy patients

Case reports (III)

Doty 2002 70

Pigs with hypotens ion and IAH Trauma patients

Controlled, compare d to baseline Retrospec tive (III)

Sugrue 1995 17

Abdominal surgery patients

Con current observation (II)

Hsu 2004 72

Rat s with induced IAP to 30 mmHg Pigs with pneumoperitoneum Pigs with lAP from helium

Control group

Surgical ICU pat ients

Concurrent observa tion (II)

Sugrue 199665

Freidlander 199866 Nakatani 199867

lvatury 199871

Rasmussen 1995 73 Bongard 199574

Pusajo 199475

Con trolled, comp ared to baseline

Control group Controlled, compa red to baseline

Findings

HR, R atria l pressure, PAOP, MAP SVR, and hematocrit increased and CO decreased wit h lAP and returned to baseline with release . Organ flow by mi crospheres decreased to all intraabdominal organs by greater than 50% (omen tum, esophagus, stomach, duodenum, jejunu m, ileum, colon, pancreas, gallbladder, liver, spleen, renal cortex) except the adrenal gland, which had increased flow . Organ blood flow index calculation sho ws decline in flow independent of the decrease in CO . Mesenteric blood flow decreased to 73%, intestinal blood flow decreased to 61% at 20 mmHg, 31% an d 28%, respectively, at 40 mmHg wi th severe mucosal ischemia by in testinal mucosal pH. Hepatic arterial blood flow decreased to 45%, portal blood flow to 65%, and hepatic m icrocirculatory flow decreased to 71% of normal at 20 mm Hg. Further decreases to 30%,48%, and 48 %, respectively, were seen at 40 m mHg, despite maint ained MAP and CO. No change in MAP, decreased jejun al microcirculation, and gut me tabo lic activi ty . Increased ma lon dialdehyde concentrations in gut mucosa, live r, spleen, and lung indicating free radical forma tion. Bacterial translocation to mesenteric lymp h node s, liver, and spleen. Decreased mesenteric flow and prese nce of bacterial translocation with lAP of 20-25 mmHg. Half th e patie nts had abnormally low gastric mucosal pH . Those patients were 11 times m ore likely to have elevated lAP. Both findings predicted increased risk for hypotension, intraabdominal sepsis, renal imp airme nt , need for repeat laparo tomy, and death. SMA flow decreases with increasing levels of lAP. Th is decrease is greater with prior hemorrhage an d greater than explai ned by the decrease in CO. Hepatic flow decrease at 20mmHg abdominal pressure did decrease sinusoi dal blood flow but did no t change energy expenditure. At 30mmHg, reduced mito chondrial energy expenditure was seen, lik ely from cellular hypoxia, and was not ameliorated by increased oxygen admi nistration. Liver-assoc iated enzymes in creased statis tica lly more after laparoscopic cholecyst ect omy th an open cholecystecomy, although wi tho ut clini cal significance. Int est inal ischemic necrosis after laparoscopic surgery attributed to increased lAP. No increase in bacterial translocation. lAP resulted in decreased gastr ic mu cosal pH. Closure of the abdomen resu lts in decreased rate of IAH (22% vs. 52%). MODS and death were decreased with mesh closure. Elevated lAP present in 33 % of patie nts , rena l failure developed in 33% of patients, and 69% of pat ients wi th elevated lAP developed renal failure and incr eased risk for death. After induction of IAH, isolated hepatocytes had depleted glutathione, indicating ische mia -reperfusion injury. 66% port al venous flow, and increased portal an d hepatic vascu lar resistance (360% and 650% increase), wit h lAP 25 mmHg. Bowel tiss ue oxygen decreased by 25% at 15mmHg and by 50% at 25 mmHg. Although th ere was also a change in cardiac output and mixed venous oxygen, there was no change in subcutaneous oxygen levels. Patients with IAP less tha n lOmmHg had significantly higher gastric pH and urine output than those with lAP great er than lOm mH g. Addit ionally, the re was a highe r rate of reopera tio n (30% vs. 0%), MODS (80% vs. 20%), sepsis (50% vs. 9%), and m ortali ty (50% vs. 9%) in pat ient s with elevated IAP.

ICU, intensive care unit; IAH, intraabdominal hypertens ion; lAP, intraabdominal pressure; HR, heart rate; PAOP, pulmonary artery occlusion pressure; MAP, mean arterial pressure; SVR, systemic vascular resistance; CO, cardiac output ; SMA, superior mesenteric artery; MODS, multiple organ dysfunction syndrome .

620

C HA P TE R 3 4

~u. . . TABLE 34.7.

Effect of lAP on Int racranial Pressure (ICP).

A uthor, year

Citerio 2001

78

Bloomfield 199579; Ertel 200025 Bloomfield 1996, 199780,81

Josephs 199482

Study population

Stu dy characteristics

Findings

Head in jury patients wit h external abdominal compression ICU pati ent s


Pigs wit h induced lAP


Pigs with induced elevated ICP and lAP

Controlled, compared to baselin e

Increased lAP result ed in increases in CVP, jugular pressure, and ICP and MAP. The re was no chan ge in CPP. Intractable ICP responded to decompression of elevate d lAP. ICP increased with increasing lAP, sternotomy reduced ICP independent of lAP, indicatin g tran smitt ed tho racic venous pressure. ICP increase d with increased lAP caused by pneum operitoneum . Laparoscopy in patient s with head injury is potenti ally hazardous.

Case reports

ICU. intensive care unit; IAH, intraabdominal hypertension; lAP, intraabdominal pressure; ICP, intracranial pressure; CYP, central venous pressure; MAP, mean arterial pressure; CPP, cerebral perfusion pressure.

induced by IAH is transmitted to the cranium, and resulting in elevated intracranial pressure (ICP) (Table 34.7).25,78--82 Dec ompression of even low levels of lAP (mean, 27 mmHg) in head -injured patients result ed in prompt decreases in ICP. All pat ients with elevated ICP that persisted after decompression died, whereas the rem aining patients survived to be disch arged to a rehabilitation facility. Early decompression of th e abdomen sho uld thus be considered in patients with intractable elevations in ICP, possibly at levels lower than with isolated abdominal in jury. Indeed, there is speculation that the effect of lAP on ICP ma y result in a hormonal cascad e that induces many of the phy siological findings of ACS, rather than just a mechanical effect of th e IAP.77 ABDOMINAL WALL

The abdominal wall is very important in the development of lAB , as its capability for expansion is not linear. With greater distension, th e degree of elasticity reduces rapidly, such that large increases in pressure will result in onl y slight increases in volume. Clinically, thi s means th at whe n using intermittent measurement of lAP, more frequent measurements should be taken to avoid mi ssing a rapid and dangerous pressure increase (Table 34.81.84,85 In addition to affecting lAP, th e abdominal wall is affect ed as an organ by th e pressure. Increasing lAP results in decreased .JO. . . .

epigastric blood flow, with resultant ischemia of th e abdominal wall. Diebel et al. 83 found that rectus sheath blood flow in swine decreased by 42 % at lOmmHg lAP and by 80% at 40 m rnHg j thi s results in the potential of necrosis or fascial dehiscence. Hence, attem pts to close the abdomen under tens ion results in two insults to th e abdomi nal wall, one from the tension at the sutures and another from the relative isch emia from inc reased lAP. The result may be necrosis and even mo re difficulty in closing th e abdominal wall in th e future. OTHER

Specific effects of ACS on neuroendo crine function remain to be determined. There are some conflicting clinical and basic science data that reflect changes in hormone con centrations, specifically vasopressin, renin, and aldoste rone." It is likely that all end ocrine systems are affected in some way. On a molecular level, changes in gene expression have also been studied, although th e clinical conse quences of th ese are unknown (Table 34.9).88-90 Another effect attributed to ACS, but not yet shown in clinical or laboratory studies, is deep venous thrombosis caused by vena cava compression and pooling of blood in th e lower extremities. Release of ACS ma y place these pati ents at inc reased risk of pulmonary embolism as normal venous flow resumes." Additionally, there is a case report attributing lower extremity art erial graft failur e to ACS.87

TABLE 34.8. lAP Effect on Abdominal Wall.

Author, year

Study population


Findings

Barnes 198584


Cont rolled, compared to baseline

Obied 199585

Laparoscopic cholecystectomy patient s


Abdominal compli ance decreased to minimal at 40mmHg pressure and is nonlinearly decreased. Cardiac output and stroke volume reduced 36% and flow to the celiac, superior mesenteric, renal, and femora l arteries decreased by 42%, 61%, 70%, and 65%, respectively. Oxygen consumption, pH, and P02 decreased. Abdominal insufflation resulted in 50% decreased compliance at 16mmHg. Rectal and gastric pressures were found to be position-dependent and less reliable than bladder pressures.

621

OPEN ABD OME N

~~--

TABLE 34.9. lAP Effect on Endocrine and Cytokine Function.

Au thor, year

Stud y population

Study characteristic s

Findings

Edil 2003 88

Rat s with induced IAH


Rezende-Ne to 2002 89

Rat s with IAH and hypotension


Le Roith 198290

Dogs with ind uc ed lAP


Overall decr eased gene expression, decrease in upregulated gene s, and in crease in downregulated genes. Induction of proinflammat ory cyt okines, lik ely cause for MODS, alt hough also had hypotension as potential cause. lAP to 80mmHg resu lt ed in doubl e baseline production of vasop ressin ; this was prevented with infu sion of dext ran to no rmalize cardiac ou tput .

IAH. intraabdomin al hype rtension; lAP. intraabdominal pressure; MODS, multiple organ dysfunction syndrome.

Clinical Outcomes of Increased Intraabdominal Pressure and Abdominal Compartment Syndrome As ACS has become increasingly recognized, the natural history is no longer described because treatment occurs after recognition of the syndrome. However, past experience has shown clearly that multiple organ dysfunction syndrome and death are the inevitable result of delayed treatment. Despite our increased understanding of ACS, it is not clear at exactly what level of abdominal pressure dangerou s clinical changes occur. Indeed, the crucial number probably varies from patient to patient, depending on th e clinical scenario and individual respon se. The hemodynamic effects and clinical organ dysfunction are worsened with increasing pressures, and at some point become critical. Utilizing the grading scale described earlier, Table 34.10 displays the degree of concurrent organ dysfunction." Given the mortality of organ failure in the ICU, it is hardly surprising that untreated ACS carries such high mortality. A large ICU study demonstrated dramatically increased mortality with IAH (65% vs. 8%), and that th e mortality risk was increased for the ICU stay as well as the hospital stay . In multivariate analysis, IAH was also a risk factor for prolonged mechanical ventilation, renal failure, renal replacement therapy, and prolonged ICU and hospital stay. lAP as low as 12mmHg was found to cause significant risk of mortality and organ dysfunction."

Prevention of IAH and ACS Prevention of IAH and ACS is by far the best method of preventing further injury to th ese precarious patients. In a retrospective study of 52 damage control pati ent s, ACS occurred in 80% of those whose fascia was closed, with an associated 90% rat e of ARDS or multiple organ dysfunction syndrome (MODS). In tho se patient s in whom skin only was closed, th e incidence of ACS was 24%, with ARDS or MODS in 36 %.

Closure with a temporary prosthesis or transitional dressing, in this case the "Bogota bag" (a sheet of polyvinyl chloride cut from an intravenous fluid bag), reduced the incidence of ACS to 18%, but with 47% ARDS/MODS. The development of ACS increa sed the incidence of ARDS/MODS to 42% versus 12% in the non-ACS group; the development of ARDS/ MODS increased mortality from 12% to 42%.93 Similar studies show low rates of IAH or ACS (0%-22 %)and decrea sed rate s of MODS and death by not closing the fascia in high-risk cases. " :" It is not possible to predict with complete certainty which patients are going to progress to IAH or ACS, so leavin g the abdomen open should be considered for all patients undergoing emergency laparotomy and all pati ents with shock or hemodynamic instability during laparotomy." :" Any patients with extensive visceral or retroperitoneal edema and any in which approximation of the fascia is difficult should be considered for a temporary closure method. The risk of maintaining the abdom en open after the first operation is relatively low, The pat ient will require deep sedation, and henc e ICU care and mechanical ventilation, and at least one further operative procedure. The risk of closure and development of IAH and/or ACS is potential organ failure and death. Thus, when in doubt, it is safer to maintain an open abdomen in unstable and critically ill laparotomy patients. The risk of peritonitis is low, and antibiotic prophylaxis is not requ ired for th e open abdom en regardless of whether a temp orary prosthesis is placed . Additionally, temporary closure allow s rapid termination of operative procedures and transfer to the ICU for further resuscitation if the patient is unstable or has developed the "lethal triad" of hypothermia, coagulopathy, and acidosis. Speculation regarding the use of colloid resuscitation to prevent development of IAH or to prevent worsening of IAH to ACS is completely unsupported, not even by preliminary data; therefore, current resuscitation regimens that emphasize administration of crystalloid solutions should not be modified for possible or actual IAH.

TABLE 34.10. Organ Dysfunction Associated with ACS by Grade. Grade of ACS

I

n

III IV

Bladder pressure (mmHg)

Renal dysfunction

Pulmonary dysfunction

Cardiovascular dysfunction

10-15 15- 25 25-35

0% 0% 65% 100 %

0% 40 % 78% 100%

0% 20% 65 % 100%

>35

622

CHAPTER 34

Treatment of IAH and ACS Treatment is necessary for IAH, but the absolute level of pressure requiring therapy and the optimal therapy for each level of pressure remain a matter of debate. The patient's overall physiological status is more important than the numerical value of the pressure, although it must be remembered that even at low levels of IAH, ischemia is occurring that is not clinically apparent. All patients with elevation of lAP must be observed closely. Serial urinary bladder pressures should be checked and optimal fluid balance maintained. It must be remembered that fluid balance is difficult to assess in this patient population because PAOP and CVP begin to increase despite inadequate intravascular volume. In addition, excessive volume resuscitation will result in worsened visceral edema, creating a difficult clinical balance. Hence, the endpoints of resuscitation must be monitored as well, such as clearance of acidosis, restoration of cardiac output, or normalized right ventricular end-diastolic index. Patients should be monitored for the development of clinical sequelae of ACS, particularly the triad of hypotension, oliguria, and elevated peak airway pressures. Abdominal perfusion pressure has been studied as a determinant of survival in IAH, the hypothesis being that abdominal pressure alone is not sufficient to determine effects on the patient's physiology. Abdominal perfusion pressure is defined as mean arterial blood pressure minus the lAP. In a hypotensive patient, lower levels of IAH may therefore be threatening, mirroring the concept of cerebral perfusion pressure, which is widely measured in brain-injured patients. This is likely also the reason that patients with chronically elevated abdominal pressure do not suffer clinical consequences-mean arterial pressure increases to compensate. Maintenance of abdominal perfusion pressure resulted in an 85 % prediction of survival in one series of patients with IAH. 97 Neuromuscular blockade should be considered for all patients with elevated lAP, certainly grade II and above. Induced paralysis provides maximal abdominal wall compliance and also removes confounding variables such as asynchronous ventilation, which may lead to overestimation of the actual abdominal pressure. However, pharmacotherapy should not delay surgical decompression if the patient's lAP or clinical circumstances warrant." Medical management of IAH (not ACS) has been described utilizing vasopressor support and diuresis. Although successful in lowering bladder pressures and correcting hypotension, this intervention likely results in increased visceral ischemia consequent to vasoconstriction and hence is not recommended. Limited success of nonsurgical management of IAH in patients who are not considered to be candidates for open abdomen management, because of either a "frozen abdomen" or end-of-life decision making, have been reported. As such, there are no data outside of isolated anecdotal experience. In patients with secondary ACS, hence without abdominal pathology, the use of peritoneal catheters or paracentesis to remove fluid has been sufficient to reduce IAH and prevent the development of ACS in selected patients. Particularly, this has been described in burned patients." This therapy seems to be effective in about one-half of patients with IAH,

preventing progression to ACS. 99 Escharotomy has also been shown to reduce lAP when the bum eschar is believed to contribute to decreased abdominal wall compliance and should be considered as a first-line treatment modality for selected patients.P:'?" Several recent small studies have examined other less invasive methods to reduce lAP. External negative abdominal pressure shows some promise in animal studies; however, IAH was artificially created in an otherwise healthy animal. Use in ICU patients remains to be investigated.'?' In patients with primary abdominal pathology, the development of IAH or ACS must be considered a harbinger of hemorrhage, missed injury, or worsening of the inciting disease process. Additionally, ACS in the surgical patient has been associated with the finding of necrotic bowel at decompression. This finding may result from ACS causing decreased visceral perfusion, or the converse may be true; high volume requirements induced by intestinal ischemia, leading to development of ACS. 102,103 It is agreed by most intensive care physicians that treatment of ACS (i.e., IAH with clinical deterioration) and IAH with pressures greater than 35 mmHg regardless of symptomatology mandate abdominal decompression. Many centers have the capability to perform bedside surgery in the ICU when the patient is deemed too unstable to transport. However, if bleeding or bowel resection is likely, the operating room is a safer place to perform decompression. Despite isolated case reports of lateral releasing incisions, only a formal midline laparotomy can reliably provide decompression of the abdominal compartment. Abdominal decompression is clearly the method of choice for relieving lAP, but it is not without risks. Immediately upon decompression, a "reperfusion syndrome" occurs with washout of by-products of anaerobic metabolism or unquenched reactive oxygen species (ROS) resulting from reintroduction of oxygen to ischemic tissue; this may result in worsening hemodynamic instability and even asystole that is refractory to resuscitation.l'" Even if hemodynamics remain stable, ischemia-reperfusion injury to viscera (e.g., liver, lung, stomach) caused by ROS may cause severe MODS. Predecompression resuscitation with volume and consideration for bicarbonate or mannitol loading should be undertaken, similar to unclamping during aortic surgery. The search has begun for the "magic bullet" to prevent the injury induced by reperfusion. In rats, utilizing induced IAH, octreotide and melatonin mitigated against oxidant injury, but survival was not measured and the data must be considered preliminary. 105,106 IAH and ACS are more likely to develop in patients with closed abdominal fascia, but it is also possible to develop increased pressure with a temporary abdominal closure, especially if the abdomen is packed for hemostasis. Despite an initially loose temporary closure, ongoing monitoring for IAH is necessary as development of "recurrent" ACS has been described within a temporary abdominal containment dressing. In a retrospective analysis of these patients, the mortality was 60%, compared with a rate of 7% among patients who had an open abdomen but did not develop recurrent ACS. 107 Based on ACS grades, one management schema is described in Table 34.11. It is crucial to provide aggressive resuscitation, but to temper it with reasonable targeted endpoints so as to reduce abdominal and retroperitoneal edema

OPEN ABDOMEN

TABLE 34.11. Management of ACS Based on Grade.

Grade

Bladder pressure (mmHg)

10-15 II

15-25

1II

25-35

IV

>35

Treatment recommendations

Normovolemic resuscitation, consider neuromuscular blockade. Hypervolemic resuscitation with neuromuscular blockade. Release of abdominal fascia in intensive care unit. Release of abdominal fascia in operating room .

Source: From Burch 1M, Moore EE, Morre FA, Fancoise R. Th e abdominal compartment syndrome. Surg Clin North Am 1996;76: 833-842.22

formation . Additionally, frequent monitoring and prompt treatment of IAH are required to prevent the development of the ischemic sequelae of ACS. Opening the abdomen is not without risk, but development of full-blown ACS is essentially always fatal.

Managing the Open Abdomen The foregoing discussion has concentrated on ACS, but there are other reasons for maintaining an open abdomen, which include severe peritonitis requiring serial abdominal wash outs, ischemic viscera requiring a second -look laparotomy, removal of packs used for hemostasis, or serial debridements for pancreatic necrosis. Avoiding multiple closures of the fascia results in decreased fascial injury and loss and preserves the ability to close the abdomen with native tissue in the future . With the decision to keep an abdomen open, several additional concerns develop, including how to keep the viscera within the abdomen and when and how to close the abdomen. As most of the data from the literature consist of case series with essentially no prospective trials, the following discus sion consists mainly of the options available and the experience of individual surgeons and centers with these options.

623

Interposition methods of closure provide coverage for any amount of intestinal protuberance. By preventing development of, or treating ACS, they have been shown to decrease the incidence of MODS, ACS, abscess, necrotizing fasciitis, and fistula, and to improve outcome in retrospective reviews of a diverse group of patients.93, 108, 109 A variety of materials can be used that may be attached to fascia or skin. Enough laxity must be provided to prevent later development of recurrent IAH. The most common"? and least expensive!" option is the "Bogota bag." An opened sterilized intravenous solution bag, usually a 3-Liter irrigation bag, is sewn into the abdominal defect; this has the advantage of transparency, which allows the abdominal contents to be inspected, but it does not provide a watertight seal and requires time to sew it in place. At repeat laparotomy, as it can be opened down the middle and then reclosed with a continuous suture. Mesh of all types has been described; however, none is watertight. Vicryl (polyglactic acid; Ethicon, Somerville, NJ) or Dexon [polyglycolic acid; Davis &. Geck, Danbury, CT) meshes may tear unless multiple layers are placed, resulting in evisceration. Polypropylene mesh [Marlex, Bard, Billerica, MA; Prolene, Ethicon, Somerville, NT; Surgipro, US Surgical, Norwalk, CT ) is abrasive and will adhere to bowel , resulting in fistulae in 12% to 50% of patients.!" GoreTex (polytetrafluoroethylene, Gore, Flagstaff, AZ) is quite expensive and may become infected if left uncovered. Additional drawbacks to all types of interposition dressings are increased time for implantation and fascial injury. Added time needed in the operating room to sew the material in place may be life threatening to a critically ill, damage control patient. The material must be sewn to either skin or fascia, and these sutures may result in damage to already ischemic abdominal wall structures. Loss of fascia or skin makes later definitive closure more difficult. Our preferred method for temporary abdominal containment is an adhesive vacuum dressing (/lVac-Pac/l). This

Temporary Abdominal Containment Temporary abdominal containment methods are used until the abdomen can be closed, either by delayed primary closure or by a transitional closure . Many methods have been described but, optimally, containment will keep the abdomi nal viscera inside, prevent further contamination of the peritoneal cavity, and be large enough to cover protruding viscera without increasing lAP (Fig. 34.1). Rapid application and reopening and inexpensive materials are best . A dressing that provides for egress of peritoneal fluid but prevents leakage allows for accurate measurement of fluid balance and facilitates skin care. Most important is that the material in contact with the intestines is nonadherent to prevent injury. Skin closure only results in a watertight seal and may be used occasionally as a permanent closure with eventual repair of the ventral hernia. Closure is rapid and does not use prosthetic material, but provides little increase in abdominal volume, and hence is typically not used for a patient with or at risk for ACS.

FIGURE 34.1. Protuberance of abdominal contents in early damage control abdomen .

624

CHAPTER 34

FIGURE 34.2. "Vac-Pac" application with insertion of plasticized

towel and drains.

dressing consists of a nonadhesive, soft, clear plastic layer tucked under the abdominal wall against the bowels and covered by roll gauze containing closed-suction drains that allows fluid out of the abdomen and maintains negative pressure within the dressing and abdomen. A large adhesive drape is then placed over this and the anterior abdominal wall, with the drains placed to low continuous suction. The dressing can be applied rapidly, will cover abdominal contents of any size, costs about $40 (U.S.), is watertight, and can be reopened rapidly if lAB or the need for reexploration develop (Fig. 34.2, 34.3).

Resuscitation With ongoing resuscitation in the ICU, patients often receive large volumes of fluid or blood products, which may result in edema of the intraabdominal contents. Thus, frequent measurement of bladder pressures should continue until the patient is physiologically stable. The majority of patients will stabilize quickly and normalize their physiological and laboratory parameters. These patients can usually return to the operating room in 24 to 36 h for unpacking, definitive operative repair, and primary closure if possible without tension. If there is evidence of ongoing visceral edema, or if a subsequent operation is planned, another temporary dressing is applied. A small group of patients will not have normalization of their hemodynamics despite appropriate resuscitation. The potential reasons for this include bleeding, missed injury, and missed ACS. These patients will require early reexploration, either at the bedside or in the operating room with another temporary dressing thereafter.

these procedures. Serial washouts or maintenance dressings while waiting for visceral edema to subside can be done in a sterile manner in the rcu. The more frequently these dressings are changed, the greater the risk of bowel injury from manipulation, but not changing the dressings may result in increased risk of infection, particularly with packing in place. Generally, every other or every third day is adequate. With each dressing change, a decision should be made as to timing of closure . Patients who have a rapid decrease in their edema may be considered for delayed primary closure, which is the optimal method of closure. The longer the abdomen is left open, however, the less likely this can be accomplished as there is progressive loss of abdominal domain, increasing the likelihood that a transitional closure will be necessary. In total, 50% to 70% of open abdomen patients will be able to undergo delayed primary closure, with the remainder requiring a transitional closure.!"

Transitional Closure Closure should be accomplished as soon as possible to decrease the metabolic demand of serial abdominal explorations and a large open wound. In patients who remain too edematous to close the abdomen without causing lAB, several methods of transitional closure exist . The placement of an absorbable interposition mesh to the skin or fascia is safe and simple. Closure should not be tight, or tearing of the mesh with evisceration or lAB may result. This method does little to maintain abdominal domain as the mesh has low distensibility. It is safe for use in the presence of infection, and the risk of fistulation is low (5%)yO,112,1l3 Wet dressings over the mesh encourage formation of granulation tissue that will accept a split-thickness skin graft (Fig. 34.4). Although the patient is left with a large ventral hernia that will eventually require complex closure, it is the most rapid and safest method to facilitate rehabilitation and restoration of positive nitrogen balance. Although strong enough to maintain containment, polypropylene mesh is less likely to be incorporated in an infected field and has a high rate of intestinal fistula development.

Managing and Changing Temporary Closure Temporary abdominal containment dressings cannot be left in place indefinitely. However, the optimal duration between changes has not been determined. Patients with packs for hemostasis, a need for serial debridement or washout, and patients requiring reestablishment of intestinal continuity should return to the operating room as soon as possible for

FIGURE 34.3.

"Vac-Pac" coverdressing over fluffed gauze.

OPEN ABDOMEN

625

position. Drains should have slack tubing, and all transabdominal tubes and stomas should be brought out as lateral as possible to prevent scarring to the rectus muscle, which can make later definitive closure more difficult .

Fistulae

FIGURE 34.4. Mesh transitional closure polyglactin 910 after

granulation.

Polytetrafluoroethylene mesh is strong and nonadherent, with a very low fistula rate; however, the risk of infection is high if not covered immediately with tissue." Methods of closure with soft tissue advancement flaps (abdominal com ponent separation) with or without mesh have been described but have a high failure rate in critically ill and malnourished patients because of the metabolic strain of such an extensive procedure; thus, the technique is best reserved for delayed definitive closure of recovered patients. Attempts to draw the fascia together for delayed primary closure have been described, varying from silo creation, retention sutures, serial mesh tightening, and hook-and-loop fabrics.'!"!" Modest success has been described with all these series, although the advantage of avoiding a mandatory second procedure is outweighed by several substantial drawbacks. Any attempt to bring the fascia together under tension may result in abdominal wall complications, such as fascial ischemia, tearing, necrosis, or hernia formation, if indeed lAH/ ACS is avoided. Any attempt to close fascia under tension in the critically ill patient population may result in increased lAP, and the physiological consequences may be dire or even lethal. The rate of successful primary closure in these diverse populations is about 52%,117 not significantly different from regular delayed primary closure .

Tubes and Stomas Development and resolution of visceral and abdominal wall edema results in ongoing changes in the topography of the abdomen, which causes particular difficulty as drains and feeding tubes may pull out and stomata may withdraw into the abdomen or become ischemic because of tension on the mesentery. For these reasons , avoidance of artificial openings in the abdominal wall is optimal. Despite the risk of anastomotic dehiscence, many surgeons choose to perform a primary bowel anastomosis rather than bring out a stoma. 96,104 Nasoduodenal feeding is preferred to feeding tubes placed operatively. Nasogastric feeding may be just as safe and effective with the adjunctive use of promobility agents (e.g., erythromycin) and positioning of the patient in the head -up

Enterocutaneous fistulae develop in 1% to 15% of patients with open abdomen management, depending on the initial pathology and the method of abdominal containment." These fistulae are a major cause of morbidity. Because there is no intervening tissue, they usually form to the mesh and have been called entero-atmospheric fistula. Because there is usually no overlying tissue to collapse on the tract as drainage decreases, they have only about a 25% rate of closure without surgery,"? and, as these occur in a granulating bed, fitting a collection appliance is difficult . Prevention of fistulization is usually possible with gentle bowel handling and interposition of the omentum over the intestines whenever possible . Anastomoses should not be left exposed in the wound. Transitional or definitive closure as soon as possible reduces the number of dressing changes . Dressings over the mesh must be kept moist; petrolatum gauze can also be used to prevent adhesion to intestinal serosa. Skin grafting is also protective and should be placed as soon as sufficient tissue granulation has occurred." When a fistula develops, standard management is bowel rest and parenteral nutrition. Fistula output control may require placement of a suction drain at the site. Early skin grafting around the fistula is beneficial as, even though some loss of engrafted skin can be expected, a mature skin graft around the fistula will allow placement of an appliance to manage secretions. Although small or initially low-output (300-500mL/day) or even high-volume fistulae may close with nonoperative management, larger fistulae will usually not close without surgery, usually resection and anastomosis of the involved segment of intestine. The patient should be allowed to recover completely from the initial disease process, regain positive nitrogen balance, and be ready for definitive abdominal closure, at which time fistula resection, anastomosis, and abdominal wall closure can be completed in a single operation with an optimal chance for success.

Definitive Abdominal Wall Repair Definitive abdominal wall reconstruction should be attempted when the patient has recovered from the initial disease process, is repleted nutritionally, and intraabdominal adhesions have softened; this usually requires 6 to 12 months from the last operation. An abdominal binder helps provide comfort and maintains abdominal domain in the interim. Additionally, physical therapy, cessation of substance abuse and smoking, and psychological counseling may be helpful. When it is apparent that the underlying bowel has separated from the mesh and skin graft, based on physical ability to "pinch" the skin (Figure 34.5), and sufficient weight gain for subcutaneous flaps has developed, the patient is considered for closure . Patients with a stoma may be evaluated for restoration of intestine as a separate initial operation or at the same time as abdominal closure . The majority of patients are closed by rectus component separation with occasional mesh

626

CHAPTER 3 4

FIGURE 34.5. "Pinch" test for readiness for reconstruction.

n

FIGURE 34.7. Case shown in Figures 34.5 and 34.6 after reconstruction with separation of components.

reinforcement (Figures 34.6, 34. In patients with substantial loss of abdominal domain, seen most often in patients waiting for more than a year for reconstruction.I" plastic surgical techniques such as tissue expanders may be needed (Figure 34.8). Management with an open abdomen is lifesaving in a group of patients in extremis, although it leads to a prolonged hospital course and potential for many severe complications. Patients with a skin-grafted ventral hernia perceive a decreased level of physical, social, and emotional health; these percep-

tions return to the baseline of the healthy general population after definitive abdominal closure . Seventy-eight percent of previously employed patients return to work. The morbidity is substantial, but the majority of patients can eventually be expected to return to near-normal lifestyles after open abdomen management. ns

FIGURE 34.6. Case shown in Figure 34.5 before reconstruction.

FIGURE 34.8. Loss of abdominal domain.

OPEN ABDOMEN

Conclusion Intraabdominal hypertension may progress to ACS with the clinical triad of hypotension, oliguria, and high peak airway pressure. This syndrome causes a predictable and preventable cycle of ischemia and reperfusion injury. Risk factors remain poorly understood but include damage control surgery and large volumes of resuscitation fluid. Observed hemodynamics overestimate the quality of resuscitation, with the most accurate measure of volume status being right ventricular enddiastolic volume index. Definitive treatment is by surgical decompression of the abdomen. The exact level of abdominal pressure at which this is necessary is unclear, but pressures greater than 35 mmHg mandate decompression. Methods for earlier"subclinical" detection are needed as multiple effects of ischemia occur before the overt presentation of the clinical triad. Managing the open abdomen is a challenge. Careful bowel handling, prevention of injury to the fascia, prevention of recurrent IAH, and early transitional closure are necessary to minimize complications. Time for physical and nutritional recovery is paramount for successful definitive closure.

References 1. Ivatury RR, Sugerman HJ. Abdominal compartment syndrome: a century later, isn't it time to pay attention? Crit Care Med 2000;28:2137-2138. 2. Kron IL, Harman PK, Nolan SP. The measurement of intraabdominal pressure as a criterion for abdominal re-exploration. Ann Surg 1984;199:28-30. 3. Sanchez NC, Tenofsky PL, Dort JM, Shen LY, Helmer SD, Smith RS. What is normal intra-abdominal pressure? Am Surg 2001;67: 243-47. 4. Pelosi P, Croci M, Ravagnan I, et al. Respiratory system mechanics in sedated, paralyzed morbidly obese patients. Appl Physiol 1997;82:811-818. 5. Luca A, Cirera I, Garcia-Pagan CJ, et al. Hemodynamic effects of acute changes in intra-abdominal pressure in patients with cirrhosis. Gastroenterology 1994;104:222-227. 6. Sugerman HJ, DeMaria EJ, Felton III WL, Nakatsuka M, Sismanis A. Increased intra-abdominal pressure and cardiac filling pressures in obesity-associated pseudotumor cerebri. Neurology 1997;49:507-511. 7. Sugarman HJ. Effects of increased intra-abdominal pressure in severe obesity. Obesity surgery. Surg Clin N Am 2001;81:10631076. 8. Bloomfield GL, Sugerman HJ, Blocher CT, Gehr TWB, Sica DA. Chronically increased intra-abdominal pressure produces systemic hypertension in dogs. Int JObes 2000;24:819-824. 9. Nguyen NT, Wolfe BM. The physiologic effects of pneumoperitoneum in the morbidly obese. Ann Surg 2005;241:219-226. 10. Pierri A, Munegato G, Carraro L, Zaccaria F, Tiso I, Zotti EF. Hemodynamic alterations during massive incisional hernioplasy. JACS 1995;181:299-302. 11. Wesley JR, Drongowski R, Coran, AG. Intragastric pressure measurement: a guide for reduction and closure of the silas tic chimney in omphalocele and gastroschisis. J Pediatr Surg 1981;16:264-270. 12. Lacey SR, Carris LA, Beyer JIll, Azizkhan RG. Bladder pressure monitoring significantly enhances care of infants with abdominal wall defects: a prospective clinical study. J Pediatr Surg 1993;28:1370-1375. 13. Kirkpatrick AW, Brenneman FD, McLean RF, Rapanos T, Boulanger BR. Is clinical examination an accurate indicator of raised

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intra-abdominal pressure in critically injured patients? Can J Surg 2000;43:207-211. 14. Engum SA, Kogon B, Jensen E, Isch J, Balanoff C, Grosfeld JL. Gastric tonometry and direct intraabdominal pressure monitoring in abdominal compartment syndrome. J Pediatr Surg 2002;37: 214-218. 15. Ridings PC, Bloomfield GL, Blocher CR, Sugerman HJ. Cardiopulmonary effects of raised intra-abdominal pressure before and after intravascular volume expansion. J Trauma 1995;39:10711074. 16. Malbrain MLNG. Different techniques to measure intra-abdominal pressure (lAP): time for a critical re-appraisal. Intensive Care Med 2004;30:357-371. 17. Sugrue M, Buist MD, Hourihan F, et al. Prospective study of intra-abdominal hypertension and renal function after laparotomy. Br J Surg 1995;82:235-238. 18. Richardson JD, Trinkle JK. Hemodynamic and respiratory alterations with increased intra-abdominal pressure. J Surg Res 1976; 20:401-404. 19. Pickhardt PJ, Shimony JS, Heiken JP, Buchman TG, Fischer AJ. The abdominal compartment syndrome: CT findings. AJR 1999; 173:575-579. 20. Epelman M, Soudack M, Engel M, Beck R. Abdominal compartment syndrome in children: CT findings. Pediatr Radiol 2002; 32:319-322. 21. Wachsberg RH, Sebastiano LLS, Levine CD. Narrowing of the upper abdominal inferior vena cava in patients with elevated intraabdominal pressure. Abdom Imaging 1998;23:99-102. 22. Burch JM, Moore EE, Morre FA, Fancoise R. The abdominal compartment syndrome. Surg Clin N Am 1996;76:833-842. 23. McNelis J, Marini CP, Jurkiewecz A, et al. Predictive factors associated with the development of abdominal compartment syndrome in the surgical intensive care unit. Arch Surg 2002; 137:133-136. 24. Balogh Z, McKinley BA, Cocanour CS, et al. Supranormal trauma resuscitation causes more cases of abdominal compartment syndrome. Arch Surg 2003;138:637-643. 25. Ertel W, Oberholzer A, Platz A, Stocker R, Trentz O. Incidence and clinical pattern of the abdominal compartment syndrome after "damage-control" laparotomy in 311 patients with severe abdominal and/or pelvic trauma. Crit Care Med 2000;28:174753. 26. Hong H, Cohn SM, Perez JM, Colich MO, Brown M, McKenney MG. Prospective study of the incidence and outcome of intraabdominal hypertension and the abdominal compartment syndrome. Br J Surg 2002;89:591-596. 27. Malbrain MLNG, Chiumello D, Pelosi P, et al. Prevalence of intra-abdominal hypertension in critically ill patients: a multicentre epidemiological study. Intensive Care Med 2004;30:822829. 28. Biancofiore G, Bindi ML, Romanelli AM, et al. Intra-abdominal pressure monitoring in liver transplant recipients: a prospective study. Intensive Care Med 2003;29:30-36. 29. Kopelman T, Harris C, Miller R, Arrillaga A. Abdominal compartment syndrome in patients with isolated extraperitoneal injuries. J Trauma 2000;49:744-749. 30. Maxwell RA, Fabian TC, Croce MA, Davis KA. Secondary abdominal compartment syndrome: an under-appreciated manifestation of severe hemorrhagic shock. J Trauma 1999;47:995999. 31. Biffl WL, Moore EE, Burch JM, Offner PJ, Franciose RJ, Johnson JL. Secondary abdominal compartment syndrome is a highly lethal event. Am J Surg 2001;182:645-648. 32. Ivy ME, Atweh NA, Palmer J, Posseti PP, Pineau M, D' Aiuto M. Intra-abdominal hypertension and abdominal compartment syndrome in bum patients. J Trauma 2000;49:387-391. 33. Hobson KG, Young KM, Ciraulo A, Palmieri TL, Greenhalgh DG. Release of abdominal compartment syndrome improves

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survival in patients with bum injury. J Trauma 2000;53:11291134. 34. Cullen DJ, Coyle JP, Teplick R, Long MC. Cardiovascular, pulmonary, and renal effects of massively increased intraabdominal pressure in critically ill patients. Crit Care Med 1989;17:118-121. 35. Cheatham ML, Safesak K, Block EFJ, Nelson LD. Preload assessment in patients with an open abdomen. J Trauma 1999;46:1622. 36. Balogh Z, McKinley BA, Cacanour CS, Kozar RA, Cox CS, Moore FA. Patients with impending abdominal compartment syndrome do not respond to early volume loading. Am J Surg 2003;186:602-608. 37. Schachtrupp A, Graf J, Tons C, Hoer J, Fackeldey V, Schumpelick V. Intravascular volume depletion in a 24-hour porcine model of intra-abdominal hypertension. J Trauma 2003;55:734-740. 38. Simon RJ, Friedlander MH, Ivatury RR, DiRaimo R, Machiedo GW. Hemorrhage lowers the threshold for intra-abdominal hypertension-induced pulmonary dysfunction. JTrauma 1997;42: 398-405. 39. Chang MC, Miller PR, D'Agostino R, Meredith JW. Effects of abdominal decompression on cardiopulmonary function and visceral perfusion in patients with intra-abdominal hypertension. J Trauma 1998;44:440-445. 40. Shelly MP, Robinson AA, Hesford JW' Park GR. Haemodynamic effects following surgical release of increased intra-abdominal pressure. Br J Anaesth 1987;59:800-805. 41. Ivankovich AD, Miletich DJ, Albrecht RF, Heyman HJ, Bonnet RF. Cardiovascular effects of intraperitoneal insufflation with carbon dioxide and nitrous oxide in the dog. Anesthesiology 1975;42:281-287. 42. Robotham JL,Wise RA. Bromberger-Bamea B. Effects of changes in abdominal pressure on left ventricular performance and regional blood flow. Crit Care Med 1985;13:803-809. 43. Diamant M, Benumof JL, Saidman LJ. Hemodynamics of increased intra-abdominal pressure. Anesthesiology 1978;48:2327. 44. Kelman GR, Swapp GH, Smith I, Benzie RJ, Gordon NLM. Cardiac output and arterial blood-gas tension during laparoscopy. Br J Anesth 1972;44:1155-1161. 45. Kashtan J, Green JF, Parsons EQ, Holcroft JW. Hemodynamic effects of increased abdominal pressure J Surg Res 1981;30:249222. 46. Murtoh T, Lamm WJE, Embree LJ, Hilebrandt J, Albert RK. Abdominal distension alters regional pleural pressure and chest wall mechanics in pigs in vivo. J Appl Physiol 1991;70:26112618. 47. Kotzampassi K, Paramythiotis D, Eleftheriadis E. Deterioration of visceral perfusion caused by intra-abdominal hypertension in pigs ventilated with positive end-expiratory pressure. Surg Today 2000;30:987-992. 48. Oda J, Ivatury RR, Blocher CR, Malhotra AJ, Sugerman HJ. Amplified cytokine response and lung injury by sequential hemorrhagic shock and abdominal compartment syndrome in a laboratory model of ischemia-reperfusion. JTrauma 2002;52:625632. 49. Buchard KW, Ciombor DM, McLeod MK, Slotman GJ, Gann DS. Positive end expiratory pressure with increased intra-abdominal pressure. Surg Gynecol Obstet 1985;161:313-318. 50. Wendt EC. Uber den Einflus des intra-abdominellen Druckes auf dies Absonderungsgeschwingigkeit des Hames. Arch Heilkd 1876;17:527. 51. Sugrue M, Jones F, Deane SA, Bishop G, Bauman A, Hillman K. Intra-abdominal hypertension is an independent cause of postoperative renal impairment. Arch Surg 1999;134:1082-1085. 52. Doty JM, Saggi BH, Sugerman HJ, et al. Effect of increased renal venous pressure on renal function. J Trauma 1999;47:10001003.

53. Wiebe S, Kellenberger CJ, Khoury A, Miller SF. Early Doppler changes in a renal transplant patient secondary to abdominal compartment syndrome. Pediatr Radiol 2004;34:432-434. 54. Doty JM, Saggi GH, Blocher CR, et al. Effects of increased renal parenchymal pressure on renal function. J Trauma 2000;48:874877. 55. Stone HH, Fulenwider JT. Renal decapsulation (decaps) in the prevention of post-ischemic oliguria. Ann Surg 1977;186:343355. 56. Harman PK, Kron IL, McLachlan HD, Freedlender AE, Nolan SP. Elevated intra-abdominal pressure and renal function. Ann Surg 1982;196:594-597. 57. Bradley SE, Bradley GP. The effect of increased intra-abdominal pressure on renal function in man. J Clin Invest 1947;26:101022. 58. Biancofiore G, Bindi L, Romanelli AM, et al. Renal failure and abdominal hypertension after liver transplantation: determination of critical intra-abdominal pressure. Liver Transplant 2002; 8:1175-1178. 59. Caldwell CB, Ricotta JR. Changes in visceral blood flow with elevated intraabdominal pressure. J Surg Res 1987;43: 14-20. 60. Behrman SW, Bertken KA, Stefanacci HA, Parks SN. Breakdown of intestinal repair after laparotomy for trauma: incidence, risk factors, and strategies for prevention. J Trauma 1998;45:227233. 61. Diebel LN, Dulchavsky SA, Wilson RF. Effect of increased intraabdominal pressure on mesenteric arterial and intestinal mucosal blood flow. J Trauma 1992;33:45-49. 62. Diebel LN, Wilson RF, Dulchavsky SA, Saxe J. Effect of increased intra-abdominal pressure on hepatic arterial, portal venous, and hepatic microcirculatory blood flow. J Trauma 1992;33:279283. 63. Eleftheriadis E, Kotzampassi K, Papanotas K, Heliadis N, Sarris K. Gut ischemia, oxidative stress and bacterial translocation in elevated abdominal pressure in rats. World J Surg 1996;20:1116. 64. Diebel LN, Culchavsky SA, Brown WJ. Splanchnic ischemia and bacterial translocation in the abdominal compartment syndrome. J Trauma 1997;43:852-855. 65. Sugrue M, Jones F, Lee A, et al. Intraabdominal pressure and gastric intramucosal pH: is there an association? World J Surg 1996;20:988-991. 66. Friedlander MH, Simon RJ, Ivatury R, DiRaimo R, Machiedo GW. Effect of hemorrhage on superior mesenteric artery flow during increased intra-abdominal pressures. J Trauma 1998; 45;433-439. 67. Nakatani T, Sakamoto Y, Kaneko I, Ando H, Kobayashi K. Effects of intra-abdominal hypertension on hepatic energy metabolism in a rabbit model. J Trauma 1998;44:446-453. 68. Andrei VE, Shein M, Margolis M, Rucinski JC, Wise L. Liver enzymes are commonly elevated following laparoscopic cholecystectomy: is elevated intra-abdominal pressure the cause? Dig Surg 1998;15:256-259. 69. Andrei VE, Schein M, Wise L. Small bowel ischemia following laparoscopic cholecystectomy. Dig Surg 1999;16:522-524. 70. Doty JM, Oda J, Ivatury RR, Blocher CR, Christie GE, Yelon JA, Sugerman HJ. The effects of hemodynamic shock and increased intra-abdominal pressure on bacterial translocation. J Trauma 2002;52:13-17. 71. Ivatury RR, Porter JM, Simon RJ, Islam S, John R, Stahl WM. Intra-abdominal hypertension after life-threatening penetrating abdominal trauma: prophylaxis, incidence, and clinical relevance to gastric mucosal pH and abdominal compartment syndrome. J Trauma 1998;44:1016-1023. 72. Hsu YP, Chen RJ, Fang JF, et al. Increased susceptibility to oxidant injury in hepatocytes from rats with intra-abdominal hypertension. J Trauma 2004;57:569-575.

OPEN ABDOMEN

73. Rasmussen I, Berggren U, Aevidsson D, Ljungdahl M, Haglund U. Effects of pneumoperitoneum on splanchnic hemodynamics: an experimental study in pigs. Eur J Surg 1995;161:819-826. 74. Bongard F, Pianim N, Cubecz S, Klein SR. Adverse consequences of increased intra-abdominal pressure on bowel tissue oxygen. J Trauma 1995;39:519-525. 75. Pusajo JF, Bumaschny E, Agurrola A, et al. Postoperative intraabdominal pressure: its relation to splanchnic perfusion, sepsis, multiple organ failure and surgical reintervention. Intensive Surg Crit Care Dig 1994;13:2-4. 76. Joseph DK, Dutton RP, Aarabi B, Scalea TM. Decompressive laparotomy to treat intractable intracranial hypertension after traumatic brain injury. J Trauma 2004;57:687-695~ 77. Rosin D, Rosenthal RJ. Adverse hemodynamic effects of intraagdominal pressure-is it all in the head? J Surg Invest 2000;2:335-345. 78. Citerio G, Vascotto E, Villa F, Celotti S, Pesenti A. Induced abdominal compartment syndrome increases intracranial pressure in neurotrauma patients: a prospective study. Crit Care Med 2001;29:1466-1471. 79. 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 1995;39:1168-1170. 80. Bloomfield GL, Ridings PC, Blocher CR, Marmarou A, Sugerman HJ. Effects of increased intra-abdominal pressure upon intracranial and cerebral perfusion pressure before and after volume expansion. J Trauma 1996;40:936-943. 81. Bloomfield GL, Ridings PC, Blocher CL, et al. A proposed relationship between increased intra-abdominal, intrathoracic, and intracranial pressure. Crit Care Med 1997;25:496-503. 82. Josephs LG, Este-McDonald JR, Birkett DH, Hirsch EF. Diagnostic laparoscopy increases intracranial pressure. J Trauma 1994;36:815-819. 83. Diebel L, Saxe J, Dulchavsky S. Effect of intra-abdominal pressure on the abdominal wall blood flow. Am Surg 1992; 58:573. 84. Barnes GE, Laine GA, Giam PY, Smith EE, Granger HJ. Cardiovascular responses to elevation of intra-abdominal hydrostatic pressure. Am J Physiol 1985;248:R208-R213. 85. Obeid F, Saba A, Fath J, et al. Increases in intra-abdominal pressure affect pulmonary compliance. Arch Surg 1995;130:544548. 86. MacDonnell SPJ, Lalude OA, Davidson AC. Letter to the editor. JACS 1996;183:19-20. 87. Biffl WL, Moore EE, Burch J. Femoral arterial graft failure caused by the secondary abdominal compartment syndrome. J Trauma 2001;50:740-742. 88. Edil GH, Tuggle DW, Puffinbarger NK, Mantor PC, Palmer GW, Knutson ZA. The impact of intra-abdominal hypertension on gene expression in the kidney. J Trauma 2003;55:857-859. 89. Rezende-Neto JB, Moore EE, De Andrade MVM, et al. Systemic inflammatory response secondary to abdominal compartment syndrome: stage for multiple organ failure. J Trauma 2002;53: 1121-1128. 90. Le Roith D, Bark H, Nyska M, Glick SM. The effect of abdominal pressure on plasma antidiuretic hormone levels in the dog. J Surg Res 1982;32:65-69. 91. Meldrum DR, Moore FA, Moore EE, Francoise RJ, Sauala A, Burch JM. Prospective characterization and selective management of the abdominal compartment syndrome. Am J Surg 1997;174:667-673. 92. Malbrain M. Abdominal pressure in the critically ill: measurement and clinical relevance. Intensive Care Med 1999;25:14531458. 93. Offner PJ, de Souza AL, Moore EE, et al. Avoidance of abdominal compartment syndrome in damage-control laparotomy after trauma. Arch Surg 2001;136:676-681.

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94. Mayberry JC, Mullins RJ, Crass RA, Trunkey DD. Prevention of abdominal compartment syndrome by absorbable mesh prosthesis closure. Arch Surg 1997;132:957-962. 95. Rotondo MF, Schwab CW, McGonigal MD, et al. "Damage control": an approach for improved survival in exsanguinating penetrating abdominal injury. J Trauma 1993;35:375-383. 96. Johnson JW, Gracias VH, Schwab CW, et al. Evolution in damage control for exsanguinating penetrating abdominal injury. J Trauma 2001;51:261-269. 97. Cheatham ML, Whiet MW, Sagraves SG, Johnson JL, Block EFJ. Abdominal perfusion pressure: a superior parameter in the assessment of intra-abdominal hypertension. J Trauma 2000;49: 621-627. 98. Macalino JU, Goldman RK, Mayberry JC. Medical management of abdominal compartment syndrome: case report and a caution. Asian J Surg 2002;25:244-246. 99. Latenser BA, Kowal-Vern A, Kimball K, Chakrin A, Dujovny N. A pilot study comparing percutaneous decompression with decompressive laparotomy for acute abdominal compartment syndrome in thermal injury. J Bum Care Rehabil 2002;23:190195. 100. Tsoutsos D, Rodopoulou S, Kermidas E, Lagios M, Stamatopoulos K, Ioannovich J. Early escharotomy as a measure to reduce intraabdominal hypertension in full-thickness bums of the thoracic and abdominal area. World J Surg 2003;27:13231328. 101. Bloomfield G, Saggi B, Blocher C, Sugerman H. Physiologic effects of externally applied continuous negative abdominal pressure for intra-abdominal hypertension. J Trauma 1999;46: 1009-1014. 102. McNelis J, Soffer S, Marini CP, et al. Abdominal compartment syndrome in the surgical intensive care unit. Am Surg 2002;68:18-23. 103. Williams M, Simms HH. Abdominal compartment syndrome: case reports and implication for management in critically ill patients. Am Surg 1997;63:555-558. 104. Morris JA Jr, Eddy VA, Blinnman TA, Rutherford EJ, Sharp KW. The staged celiotomy for trauma: issues in packing and reconstruction. Ann Surg 1993;217:576-586. 105. Sener G, Kacmaz A, User Y, Ozkan S, Tilki M, Yegen BC. Melatonin ameliorates oxidative organ damage induced by acute intra-abdominal compartment syndrome in rats. J Pineal Res 2003;35:163-168. 106. Kacmaz A, Polat A, User Y, Tilki M, Ozkan S, Sener G. Octreotide improves reperfusion-induced oxidative injury in acute abdominal hypertension in rats. JGastrointest Surg 2004;8: 113119. 107. Gracias VH, Braslow B, Johnson J, et al. Abdominal compartment syndrome in the open abdomen. Arch Surg 2002; 137:11981300. 108. Oelschlager BK, Boyle EM, Johansen K, Meissner MH. Delayed abdominal closure in the management of ruptured abdominal aortic aneurysms. Am J Surg 1997;173:411-415. 109. Rasmussen TE, Hallett JW, Noel AA, et al. Early abdominal closure with mesh reduces multiple organ failure after ruptured abdominal aortic aneurysm repair: guidelines from a 10-year case-control study. JVasc Surg 2002;35:246-253. 110. Mayberry JC. Bedside open abdominal surgery. Critical Care Clin 2000;16:151-172. Ill. Ghimenton F, Thomson SR, Muckart DJJ, Burrows R. Abdominal content containment: practicalities and outcome. Br J Surg 2000;87:106-109. 112. Jernigan TW, Fabian TC, Croce MA, et al. Staged management of giant abdominal wall defects. Ann Surg 2003;238:349-357. 113. Barker DE, Kaufman H], Smith LA, Ciraulo DL, Richart CL, Bums RP. Vacuum pack technique of temporary abdominal closure: a 7-year experience with 112 patients. J Trauma 2000;48:201-206.

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114. Wittmann DH, Aprahamian C Bergstein JM. Etappenlavage. Advanced diffuse peritonitis managed by planned multiple laparotomies utilizing zippers, slide fastener, and Velcro analogue for temporary abdominal closure. World J Surg 1990;14:218226. 115. Kafie FE,Tessier DJ, Williams RA, et al. Serial abdominal closure technique (the "SAC" procedure): a novel method for delayed closure of the abdominal wall. Am Surg 2003;69:102-105. 116. Koniaris LG, Hendrickson RJ, Drugas G, Abt P, Shoeniger LO. Dynamic retention. A technique for closure of the complex

abdomen in critically ill patients. Arch Surg 2001;136:13591362. 117. Tremblay LN, Feliciano DV, Schmidt J, et al. Skin only or silo closure in the critically ill patient with an open abdomen. Am JSurg 2002; 182:670-675. 118. Cheatham ML, Safcsak K, Llerena LE, Morrow CE Jr, Block EFJ. Long-term physical, mental and functional consequences of abdominal decompression. J Trauma 2003;56:237-242.

Principles of Surgical Rehabilitation Michael W. O'Dell and Tammy Noren Definition and Philosophy of Rehabilitation Medicine Rehabilitation Team Members . . . . . . . . . . . . . . . . . . . . . Progression of Mobility Following Surgery . . . . . . . . . . . Surgical Rehabilitation Principles: Specific Diagnoses . . . . . . . . . . . . . . . . . . . . . . . . . . . .

631 631 633

Cardiac and Pulmonary Rehabilitation in Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641 Amputation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642

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Definition and Philosophy of Rehabilitation Medicine Rehabilitation is the branch of medicine that addresses the maximization of human performance. Because rehabilitation interventions differ widely among various clinical settings, the definition of "perform ance" might be as sophisticated as the speed of an elite athlete following a musculoskeletal injury or as basic as bed mobility in a patient with catastrophic brain or spinal cord injury. However, interventions in both settings focus on improving performance at some level. Performance activities required to move more effectively in the environment or to care for one's self are termed "functional activities," or function. Maximization of func tion is the primary endpoint in nearly all rehabilitation in a surgical setting. Advances in surgical and medical care during the past decades have substantially decreased mortality from many types of illness and injury. These achievements magnify the importance of rehabilitation professionals in the initial mobilization of surgical patients in the hosp ital and management of residual functional deficits after discharge. The 1980 World Health Organization (WHO) International Classification of Impairment, Disability, and Handicaps' serves as a helpful philosophical framework to discuss the relationships between (1) illness and performance and (2) rehabilitation medicine and surgery. Table 35.1 outlines the WHO terminology and interventions within the context of a person with a C7 traumatic spinal cord injury. Ultimately, all branches of medicine strive to improve quality of life by maximizing performance, that is, minimizing disability. Surgery improves performance by the direct treatment of disease, such as the removal, repair, replacement, or reconstruction of abnormal or injured tissues. Internal medicine does the same with the use of medications and various procedures. However, interventions in rehabilitation medicine

often occur directly at the level of functional performance and may have no appreciable impact on the underlying disease process or injury (see Table 35.1 for examples of rehabilitation interventions for disability and handicap). Treatment of functional performance uses several basic strategies.' including techniques to enhance recovery of affected or diseased systems/ to use compensatory techniques to utilize fully the nonaffected systems that remain intact," to prevent further disability during treatment." to use adaptive equipment to facilitate function of an extremity," to modify or match th e environment with a person's capabilities , and to understand the importance of patient motivation, cognitive deficits, depression, and anxiety in the rehabilitation process? (see Table 35.2; adapted from Delisa et al.']. Implementing one or several of these strategies results in greater independence in mobility or self-care, even if the disease process itself is likely unaffected.

Rehabilitation Team Members Rehabilitation professionals work as a team to maximize independence. Patient, family, and team should realize that, in some cases of severe disease or injury, "maximizing," rather than "norm alizing," performance may be the only realistic endpoint of treatment.' Physical therapy (PT) focuses on locomotion in the form of bed mobility, transfers, ambulation with or without an assistive device, and manual or motorized wheelchair mobility. Occupational therapy (OT) is concerned with activities of daily living (ADL, such as bathing, dressing, feeding, and grooming) and instrumental-ADL (higher -level skills such as cooking, home maintenance, use of public transportation). OT professionals also have special training in functional cognition, visual rehabilitation, and swallowing evaluation. Some PT and OT have expertise in the evaluation 631

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TABLE 35.1. World Health Organization Classification of Human Disablement (1980).a Case description: Consider a 26-year-old construction worker with complete C7 spinal cord injury from a fall. He has a wife, was planning on having children, and lives in a three-story walk-up apartment.

Term

Level of dysfunction

Example

Interventions

Disease

Cellular

Spinal cord edema, petechial hemorrhages, secondary injury from calcium influx into parenchymal cells

Surgery: methylprednisolone, adequate oxygenation and supportive care Rehabilitation: none

Impairment

Organ system (i.e., signs and symptoms)

Acute: unstable cervical spine fracture, paraplegia, complete sensory loss Chronic: spastic hypertonia, flexion contractures of hips and knees, depression

Disability

Person (i.e., performance)

Unable to move in bed, unable to stand or ambulate, unable to transfer into a wheelchair, unable to feed self or perform lower extremity bathing and dressing

Handicap

Society, roles

Unable to support family as a construction worker, cannot return to non-elevator-accessible home, sexual dysfunction impacting family planning

Surgery: acute: surgical fixation of spine, traction; chronic: functional tendon transfers, surgical management of decubiti, placement of intrathecal baclofen pump Rehabilitation: acute: stretching, range of motion, positioning, cushions to prevent skin breakdown, splints, strengthen arms; chronic: home stretching and exercise program, functional splints, spasticity medications or injections, mood counseling or treatment Rehabilitation: wheelchair mobility, transfer training with sliding board, adaptive equipment for dressing and bathing, education in self bowel and bladder management, monitor skin status Surgery: routine follow-up for interventions outlined above Rehabilitation: social service support for housing and job retraining, electroejaculation for pregnancy, explore wheelchair-level activities to interact with children Surgery: none

"Source: World Health Organization. International Classification of Impairments, Disability, and Handicaps. Geneva: WHO, 1980. 1

and treatment of vestibular disorders with dizziness. The speech-language pathologist assesses and treats communication (aphasia, dysarthria, and dysphonia), cognitive disorders, and in many cases, swallowing. Rehabilitation medicine physicians (physiatrists) are trained to assess the relationships

between impairment and disability and how a patient's medical status will impact the treatment of those deficits by the rehabilitation team. In the inpatient rehabilitation setting, the physiatrist directs the team in a coordinated and goaldirected plan of care. Rehabilitation services are often pro-

TABLE 35.2. Categories of Rehabilitation Intervention for Disability. Intervention category

Example

Result

Prevent further disability

Serial casting Early bladder training Nighttime hand splint Constraint-induced therapy Neuromuscular stimulation Discontinue detrimental drugs Strengthen arms Left-handed writing/dressing Below-knee prostheses Walker, cane Sliding board Install grab bars in home bathroom Install ramp into home Initiation of antidepressant Using written instructions

Improved ROM Fewer UTI Improved ROM, less pain Improved strength, movement Improved strength, movement Improved rate of recovery Compensate for paraparesis Compensate for right hemiplegia Facilitate ambulation in BKA Improved safety and endurance Improved safety and independence of transfers Improved safety and independence Decreased burden of care, increase independence Improved participation in and benefit from therapy Facilitate carryover with poor auditory comprehension/memory

Enhance affected systems Enhance unaffected systems Adaptive equipment and prostheses Environmental modification Psychological techniques

ROM, range of motion; UTI, urinary tract infections; BKA,below-knee amputation. Source: Adapted from DeLisa TA, Currie DM, Martin GM. Rehabilitation medicine: past, present and future. In: DeLisa TA, ed. Physical Medicine and Rehabilitation: Principles and Practice, 3rd ed. Philadelphia: Lippincott, 1998:3-32. 2

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vided without the direct involvement of a rehabilitation medicine physician. However, in certain circumstances, direct consultation is particularly useful. For example, a patient with a moderate traumatic brain injury may have bilateral lower extremity spastic hypertonia, ankle contractures, pain from a concomitant fracture, and hemiparesis with resultant severe ambulation deficits. A physiatrist may be helpful in delineating the extent to which each impairment contributes to the ambulation deficit. Management suggestions can then be made to both the surgical team and therapy staff. It is common for the physiatrist to recommend discharge venues for further rehabilitation such as acute or subacute rehabilitation, outpatient therapy, or home care. Consultation may also be helpful in surgical planning, for example, how a patient's cardiovascular limitations might impact prosthetic training in an amputee or the functional choice of a tendon for transfer. When providing orders for either inpatient or outpatient PT and OT, the surgeon or surgeon-in-training should clearly provide the diagnosis for treatment, the frequency and duration of treatment, and delineate any precautions or special monitoring required of the therapist (e.g., weight-bearing restrictions, range-of-motion limitations, parameters for vital signs with activity).

Progression of Mobility Following Surgery The role of rehabilitation evolves dramatically following surgery (Table 35.3), serving both a preventive and therapeutic role. There may be little or no rehabilitation involvement

for the critically ill patient who will not tolerate additional activity physiologically. Activities progress from passive prevention of complications to active bed mobility in the intensive care unit (ICU), through short-distance ambulation and home independence on the general hospital floor to community reentry in the outpatient setting. For a subset of substantially impaired patients, acute or subacute inpatient rehabilitation may be appropriate. In these settings, mobilization and self-care skills are the primary focus of hospitalization. Treatment interventions include manual techniques, therapeutic exercise, functional mobility activities, adaptive equipment, bracing, gait training, and patient/family education.

Consequences of Immobility In the mid-20th century, bed rest and prolonged immobilization were prescribed commonly as treatment. Although warranted in certain conditions (e.g., fractures, back pain), immobilization is now understood to have detrimental consequences (Fig. 35.1).8 Even after only 72h, the deleterious effects of bed rest have already commenced in several systems." Muscle strength can decline by as much as 1.50/0 per day after strict bed rest, with the greatest loss after the first week (as much as 400/0.)1° Type I muscle fibers used for transfers and ambulation appear to be affected disproportionately." Even when strength is decreased only mildly, poor endurance can still be a primary functional limitation. Both the central and peripheral cardiovascular systems are altered, with increased heart rate and decreased stroke volume and cardiac size. Close communication with the surgical team

TABLE 35.3. Evolution of Surgical Rehabilitation Interventions. Time period

Typical surgical activities

Typical rehabilitation activities

ICU: medically unstable

Stabilization of vital signs and hemorrhage, mechanical ventilation, surgical stabilization of injury Ventilation weaning, treatment of infections, further surgical interventions as needed, nutritional supplementation

None (if medically unstable), passive ROM by nursing staff

ICU: medically stable

Medical-surgical floor

Adjustment of oral medications, further nonemergent diagnostic or therapeutic testing, observation of surgical wounds for healing

Acute inpatient rehabilitation

Occasional follow-up on IRU to monitor wound healing, medication adjustment, late surgical complications

Subacute inpatient rehabilitation

Surgical FlU for late complications of surgery and medication adjustments, transport from skilled nursing facility to clinic

Outpatient rehabilitation

Routine outpatient FlU as needed, may have been discharged from surgical care

Active ROM, positioning and splinting of limbs to prevent contracture, bed mobility to facilitate pressure relief, bedside sitting, standing, steps Short-distance ambulation training, strengthening, endurance, education on precautions or restrictions, ADL training, assess safety for home discharge or need for further rehabilitation Primary focus (3h/day) on home-level mobilization, self-care training: householdlevel ambulation with assistive device, transfer training, wheelchair use, use of prosthetic device, bathing, dressing; expect 1- to 3-week length of stay and need for daily medical care Substantial focus (1-2h/day) on householdlevel mobilization along with general convalescence, does not require daily medical care Focus on community-level ambulation and home maintenance skills, high-level endurance, balance, and strengthening; transportation sometimes limited

ICU, intensive care unit; IRU, inpatient rehabilitation unit; ADL, activities of daily living; ROM, range of motion; FlU, follow-up.

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I

/

\

Inactivity

~__ Disease Condition

Total Body Deconditioning

Reduced Muscular Activity

t

)

Reduced Functional Capacityof Cardiovascular & Other Systems

'20

100mL/kg 1000 mL + 50 mL for each 1kg over 10 kg 1500 mL + 20 mL for each 1kg over 20 kg

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is safe for the patient's status. This initial volume is essentially a "best guess" volume. The effects of this volume on the patient's physiology are then monitored and appropriate changes are made. CALCULATION OF ADDITIONAL LOSSES

External losses from intestinal drainage, fistulas, and drainage tubes are directly measured and replaced volume for volume with an appropriate electrolyte solution. In neonates it is wise to measure the electrolytes in the fluid to more accurately guide replacement. Protein-rich losses (e.g., pleural fluid from chest tubes) are replaced with albumin solutions or freshfrozen plasma. Internal losses into body cavities or tissues (third space losses) cannot be measured, and adequate replacement of these losses depends on careful monitoring of the patient's response to fluid therapy. CONSIDERING PREEXISTING FLUID DEFICITS OR EXCESSES

In addition to addressing maintenance requirements and additional losses, the fluid management of the neonate should include an assessment of any preexisting fluid deficits or excesses. Preexisting deficits may be caused by in utero or intrapartum hemorrhage as well as third space losses. Preexisting excesses may be secondary to prematurity leading to a high total body water content. In all these cases, the preexisting condition should be considered when determining a fluid management plan. MONITORING THE FLUID AND ELECTROLYTE PROGRAM

Once a fluid and electrolyte management program has been initiated, proper monitoring must occur to identify the newborn's response. In this manner, therapy may be adjusted dynamically to meet the specific needs of each neonate. The newborn's response to a fluid and electrolyte program may be monitored by clinical examination, body weight measurements, and urine volume and composition measurements.

Clinical Features Severe isotonic and hypovolemic dehydration results in poor capillary filling and collapse of peripheral veins. The skin is cool and mottled, with reduced turgor; the mucous membranes are dry, and the anterior fontanelle is sunken. These findings occur with 100/0 body fluid losses in an infant of more than 28 days of age and with 150/0 losses in a neonate. Hypertonic dehydration is more difficult to detect clinically because the decrease in circulating blood volume is considerably less than the total loss of body fluids. Signs of shock occur late, and eNS signs such as lethargy, stupor, and seizures predominate. Body Weight

Serial measurements of body weight are a useful guide to total body water in the neonate. Fluctuations over a 24-h period are primarily related to loss or gain of fluid; 1g body weight being approximately equal to 1mL water. Errors occur if changes in clothing, dressings, tubes, and standard intravenous arm/leg boards are not accounted for and if weighing scales are not regularly calibrated. Urine Volume and Composition If the volume of fluid administered is inadequate, urine volume falls and its concentration increases. If excess fluid is administered, the opposite occurs. One should aim to achieve a urine output that will maintain a urine osmolality of approximately 280 mOsm/ dL. In neonates, this usually results in a urine output of

2 mL/kg/h. For infants and older children, hydration is adequate if the urine output is 1-2 mL/kg/h with an osmolality of 280-300 mOsm/kg. Serial hematocrit determinations, in the absence of hemolysis or bleeding, also suggest a loss or gain of plasma water. When the osmolar load is large, for example, with extensive tissue destruction or with infusion of high osmolar solutions, urine flow may have to be increased to provide adequate renal clearance. Accurate measurements of urine flow and concentration are fundamental to the management of critically ill infants and children. In this situation, the insertion of an indwelling urinary catheter is recommended. The specific gravity of the urine is a reliable indicator . of hypertonicity (>1.012 specific gravity) and hypotonicity «1.008 specific gravity) but is unreliable if urine is in the isotonic range (1.009-1.011 specific gravity). When fluid monitoring is critical, urine osmolality estimations provide more precise information than specific gravity. An increase in osmolality suggests that too little water or too much electrolyte has been given. A fall in osmolality suggests that sodium replacement is inadequate or that too much water has been administered. An unexpected change in osmolality, particularly an increase, requires immediate determination of serum levels of electrolytes, blood urea nitrogen, and glucose values and a calculation of the osmolality. Serum osmolality can be measured directly or calculated by the formula: Osmalility = serum sodium x 1.86 + (blood urea nitrogen/2.8) + (glucose/18) + 5 From this equation, it is possible to determine whether the rise in osmolality is caused by an increase in serum sodium, the development of hyperglycemia, or high blood urea nitrogen. Occasionally the measured serum osmolality is higher than the calculated osmolality, suggesting that the increase in serum osmolality is caused by some unidentified osmolar active substance such as a metabolic byproduct resulting from sepsis, shock, or radiopaque contrast material. A rising blood urea nitrogen level and falling urine output may be caused by acute renal failure or prerenal oliguria with azotemia resulting from hypovolemia. The distinction between these two states is important for appropriate treatment. Initially, the response to a fluid challenge of 20 mL/kg 5 % dextrose and sodium chloride over 1h is monitored. If oliguria persists, the sodium, creatinine, and osmolality levels in both blood and urine are determined. The fractional excretion of sodium (FeNa) is calculated using the formula: FeNa = (urine Na/serum Na)/ (urine creatinine/xerum creatinine) x 100 A normal FeNa is 2 % to 3 %. A value below 2 % implies prerenal azotemia and a value above 3 % implies renal failure.

Calcium and Magnesium Homeostasis In addition to fluid and sodium management, calcium and magnesium homeostasis are clinically significant challenges in the newborn surgical patient. The fetus receives calcium by active transport across the placenta, 750/0 of the total requirement being transferred after the 18th week of gestation. Hypocalcemia, defined as a serum level of ionized

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calcium below 1.0mg/100mL, is most likely to occur 24 to 48h after birth. Causes include decreased calcium stores, decreased renal phosphate excretion, and relative hypoparathyroidism secondary to suppression by high fetal calcium levels. Low birth weight infants are at a great risk (particularly if they are preterm), as are those born of a complicated pregnancy or delivery (e.g., diabetic mother) or those receiving bicarbonate infusions. Exchange transfusions or the rapid administration of citrated blood may also lead to hypocalcemia. The symptoms of hypocalcemia are nonspecific and include jitteriness, high-pitched crying, cyanosis, vomiting, twitching, and seizures. Diagnosis is confirmed by determining the serum calcium level. However, the ionized fraction of the serum calcium may be low, resulting in clinical hypocalcemia without a great reduction in total serum calcium. Therefore, evaluation of the serum ionized calcium level is often useful.

Practical Considerations Hypocalcemia is prevented by adding calcium gluconate to daily maintenance therapy, 1-2g/24h intravenously or 2g/24h by mouth." Symptomatic hypocalcemia is treated by intravenous administration of 100/0 calcium gluconate in a dose of 1-2mL/kg over IOmin, the rate should not exceed 1mL/min. Infants at high risk for hypocalcemia are also at risk for hypomagnesemia. In fact, the two conditions may coexist. If there is no response to attempted correction of a documented calcium deficiency, hypomagnesemia should be suspected and serum magnesium levels measured. Hypomagnesemia is corrected by administering 500/0 magnesium sulfate, 0.2mEq/ kg every 6 h intravenously, followed by oral magnesium sulfate 30mEq/day. Although most seizures that occur in the neonatal period have a cerebral cause and are not secondary to hypoglycemia or hypocalcemia, hypocalcemia should be suspected in highrisk infants, particularly after surgery. Immediate blood glucose determination and serum glucose and calcium measurements should therefore be performed in a "jittery" neonate. Treatment should be prompt, with intravenous glucose when hypoglycemia is suspected, followed by intravenous calcium if symptoms persist.

General Considerations in the Perioperative Care of the Neonate INVASIVE MONITORING

Because of the dynamic physiology of the neonatal period, newborn surgical patients should be monitored continuously in the neonatal unit. As already described, transcutaneous pulse oximetry is useful for monitoring episodes of apnea and bradycardia, which can be common in the preterm infant. In addition, accurate monitoring of fluid status often requires an indwelling urinary catheter and frequent laboratory evaluations. Invasive monitoring and access in the newborn can be achieved through the umbilical vessels as they are relatively accessible in this population. Specifically, umbilical venous catheters provide central venous access. A 3.5 Fr. catheter is required for infants less than 1500g; those 1500 to 3500g can accommodate a 5 Fr. catheter. Umbilical artery catheters may be indicated in infants with significant respiratory distress or

any infant who may require frequent blood sampling. These catheters usually enter the aorta through the internal iliac arteries: 3.5 Fr. catheters are used in infants weighing less than 1200g and 5 Fr. catheters are used in infants weighing more than 1200g. NUTRITION

In the neonatal surgical patient, proper nutrition must be delivered to meet their relatively large energy requirements. Specifically, neonates require a large energy intake because of their high basal metabolic rate, requirements for growth and development, energy needs to maintain body heat, and their limited energy reserves. These requirements vary according to age and environmental factors and are significantly increased by cold stress, surgical procedures, infections, and injuries. Energy requirements are increased 100/0 to 25% by surgery, more than 500/0 by infections, and 1500/0 by burns." Energy reserves are limited in the neonate, whose liver glycogen stores are usually consumed in the first 3 h of life. These limited reserves are even more restricted in the preterm and SGA infant. The energy needs of individual newborns can be calculated according to the requirements for basal metabolism plus growth. Table 36.8 lists the energy requirements of children by age group. Consideration must also be given to the adequacy of energy reserves in the presence of stress factors such as cold, infection and trauma, and surgery. Protein should be administered at a rate of 2-3g/kg/24h to achieve a normal weigh gain of 10-15 g/kg/24h; 300/0 to 400/0 of the total nonprotein calories should be provided as fat. ENTERAL NUTRITION

The best means of providing calories is via the GI tract either by mouth, or nasogastric or nasojejunal feeding tube, or through a surgically placed gastrostomy or jejunostomy tube. Gastric feeding is preferable because it allows for normal digestive processes and hormonal responses, a greater tolerance for larger osmotic loads, and a low incidence of dumping. Breast or bottle feeding is preferable for infants, usually more than 32 to 34 weeks gestation, who have a coordinated suck TABLE 36.8. Energy Requirements of Various Age Groups. Age at delivery

Basal metabolism: full-term infant: Birth 2 weeks 1 year Teen Growth calories: Birth 3 months 6 months 1 year Teen Total calories (maintenance and growth): Neonatal term (0-4 days) Low birth weight infant 3-4 months 5-12 months 1-7 years 7-12 years 12-18 years

Energy required per 24h (J)

134 202 168 97 139 76 50 50 76 462-504 504-546 420-445 420 378-315 315-252 252-126

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and swallow mechanism. Gavage feeding is indicated for infants with an impaired coordinated suck and swallow mechanism, or for supplementation for those infants with a high metabolic rate who cannot gain weight with oral feeding alone and is performed by passing a 5 Fr. silastic or polyethylene feeding tube into the stomach. The use of nasoduodenal or nasojejunal tubes is reserved for infants who cannot tolerate intragastric feeding (e.g., delayed gastric emptying, gastroesophageal reflux, depressed gag reflex). A silastic mercury-tipped feeding tube (length: tip of nose to knee) is passed through the nose into the stomach. Transpyloric tube placement can be accomplished by one of two methods: placement of a mercury-weighted tube into the stomach, positioning the patient right side down, and administering a prokinetic agent if gastric peristalsis does not propel the tube into the duodenum; or fluoroscopic placement. It is mandatory to confirm proper tube placement by aspirating and obtaining a chest radiograph. A prolonged delay or inability to initiate oral feeding mandates placement of a gastrostomy or a jejunostomy tube placed during open surgery, or laparoscopic surgery, or by a percutaneous approach aided by either gastroscopy or fluoroscopy. PARENTERAL NUTRITION

The indications for parenteral feeding include the following: extremely low birth weight infant, surgical GI tract abnormalities with prolonged postoperative ileus (gastroschisis, necrotizing enterocolitis), short gut syndrome following extensive bowel resection, chronic diarrhea (malabsorption syndrome), inflammatory bowel disease, severe acute alimentary disorders (pancreatitis, necrotizing enterocolitis), chylothorax, intestinal fistulae, and persistent vomiting associated with cancer chemotherapy." Short-term or supplemental, relatively low calorie, parenteral nutrition may be administered via a peripheral vein. However, concentrated glucose solutions greater than 15% will thrombose a peripheral vein, so peripheral parenteral nutrition is limited to 12.5% dextrose solution. In contrast, central venous administration allows the large blood flow to immediately dilute the solution. Central venous access can be obtained either percutaneously or via cutdown. The tip of the catheter should be at the superior vena cava/right atrial junction as judged by fluoroscopy. A postprocedure chest radiograph is mandatory to rule out pneumothorax. The daily component requirements for total parenteral nutrition (TPN) are detailed in Table 36.9. Initiating TPN

CARBOHYDRATES. Begin neonates at 4-6mg/kg/min dextrose, infants and children at 7-8 mg/kg/min, Increase by 2mgfkgfmin every day until the goal of 10-12mgfkgfmin is reached. Do not exceed 12.50/0 dextrose in peripheral veins. Central veins can tolerate up to 300/0 dextrose. PROTEIN. Begin neonates and infants at 0.5g/kg/day and advance by 0.5-1.0g/kg/day until 3g/kg/day. Do not exceed 10% to 12% of total daily caloric intake. Start children at 1g/kg/day and advance 1g/kg/day until 3 g/kg/day is reached. Protein intake should be restricted in patients who cannot tolerate a large nitrogen load (e.g., patients with renal insufficiency).

TABLE 36.9. Total Parenteral Nutrition Requirements. Component

Neonate

6 months10 years

Calories (kcal/kg/day) Fluid (mL/kg/day) Dextrose [mg/kg/min] Protein (g/kg/day) Fat (g/kg/day) Sodium (mEq/kg/day) Potassium (mEq/kg/day) Calcium (mg/kg/day) Phosphate [mg/kg/day] Magnesium (mEq/kg/day) Zinc (Jlg/kg/day) Copper (Jlg/kg/day) Chromium (Jlg/kg/day) Manganese (Jlg/kg/day) Selenium (Jlg/kg/d)

90-120 120-180 4-6 2-3 0.5-3.0 3-4 2-3 80-120 25-40 0.25-1.0 300 20 0.2 6 2

60-105 120-150 7-8 1.5-2.5 1.0-4.0 3-4 2-3 40-80 25-40 0.5 100 20 0.2 6 2

More than 10 years

40-75 50-75 7-8 0.8-2.0 1.0-4.0 3-4 1-2 40-60 25-40 0.5 3mg/day 1.2mg/day 12mg/day 0.3mg/day 10-20/day

FAT. Begin neonates at 0.5 g/kg/day, infants and children at 1.0g/kg/day, and advance 0.5-1.0g/kg/day as a continuous infusion until the goal of 3.0g/kgfday. Contraindications to lipid infusion include allergy to egg yolk phospholipids and fat metabolism abnormalities (e.g., hyperlipidemia, lipoid nephrosis). Thrombocytopenia is a relative contraindication to lipids (intralipid may interfere with platelet function). Do not exceed 1g/kg/day in premature infants with hyperbilirubinemia (free fatty acids can displace bilirubin from albumin). Intralipids must account for at least 2 % of the caloric requirements to prevent essential fatty acid deficiency.

Pain Management Postoperative pain management in the newborn surgical patient may be challenging. In particular, the use of opioid analgesics in the neonate must be monitored carefully. As a group, neonates have a narrower therapeutic window for postoperative morphine analgesia than older age groups. In addition, neonates treated with opioids exhibit variable pharmacokinetics and are at a high risk for respiratory depression." Despite these challenges, postoperative opiate analgesia can be effectively used to control pain in neonates. However, this requires close monitoring and may necessitate consultation with a pain management service. In addition to opiate analgesics, acetaminophen and nonsteroidal antiinflammatory agents may be used to for pain control. In particular, acetaminophen has had a long safety record in newborn patients.

Gastrointestinal Decompression The importance of gastric decompression in the neonate undergoing surgery cannot be overemphasized. The distended stomach carries the risk of aspiration and pneumonia, and may impair diaphragmatic excursions, resulting in respiratory distress. With congenital diaphragmatic hernia, ventilation is progressively impaired as the herniated intestine becomes distended with air and fluid. With gastroschisis, omphalocele,

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and diaphragmatic hernia, the ability to reduce the herniated intestine into the abdominal cavity is impaired by intestinal distension, which may be alleviated by adequate orogastric or nasogastric decompression. A double-lumen sump tube, such as a Replogle tube, is preferred, utilizing low continuous suction. If a single-lumen tube is used, intermittent aspiration is required. The correct position of the tube in the stomach is confirmed by carefully measuring the tube before insertion, by noting the nature of the aspirate, and by radiography. The tube should be carefully taped to avoid displacement. The use of gastrostomy tubes for postoperative gastric decompression is decreasing in popularity, but should be considered when prolonged postoperative gastric or intestinal stasis is anticipated.

Diagnostic Studies Most laboratory tests pose an additional burden to the already stressed neonate. Therefore, diagnostic studies should be restricted to those essential for diagnosis and proper management. The volume of blood drawn for laboratory tests should be documented as these small volumes cumulatively represent significant loss in a small infant. When the patient is transferred to other departments for investigational procedures, monitoring and resuscitation equipment should be available with a surgeon in attendance. All studies should be performed with minimal disturbance, taking steps to prevent heat loss. Before using hyperosmolar radiopaque contrast materials, intravenous fluids must be administered and fluid deficits corrected, regardless of the route of administration. To counteract the osmotic effect of the contrast medium, an intravenous infusion of sodium chloride 34mEqjL at twice the maintenance rate should be given during the radiographic study and for 2 to 4 h afterward. During this period the patient should be carefully monitored as already described.

Antimicrobial Therapy Deficiencies in the immune system of the newborn infant render it vulnerable to major bacterial insults. Prophylactic antimicrobial therapy is advised for infants undergoing major surgery, particularly of the GI tract or genitourinary (GU) system. Adequate coverage is provided by combining a penicillin (e.g., ampicillin) or first-generation cephalosporin (e.g., cefazolin)withanaminoglycoside(e.g.,gentamicin).Clindamicin or metronidazole is added when anaerobic coverage is deemed necessary. Alternatively, single-drug therapy using a broad-spectrum cephalosporin (e.g., cefoxitin) may be appropriate. Antibiotics are commenced before the operation and may be discontinued postoperatively at the surgeon's discretion.

Preoperative NPO Guidelines PATIENTS YOUNGER THAN 6 MONTHS. No food or formula 4h before the procedure. Children may continue to have breast milk and clear liquids (water, Pedialyte, glucose water, or apple juice) until 2h before the procedure. PATIENTS FROM 6 MONTHS TO 18 YEARS. Nothing to eat or drink after midnight except clear liquids (water, apple

TABLE 36.10. Bowel Preparation Before Elective Pediatric Surgery. Inpatient preparation

• Begin prep at noon or sooner, the day before surgery • Place a small nasogastric (NG) feeding tube if unable to take Golytely orally • Administer Reglan (unless contraindicated) • Dose: O.l-O.2mg/kg/dose (maximum of O.8mg/ kg over 24h); may give per NG q 4h • Begin Golytely 25mL/kg/h by NG tube for 4h or until effluent is clear • Clears or Pedialyte by mouth ad lib until n.p.o.

Outpatient preparation

Patients over 1 year of age: • Clear liquids only the day before surgery. Examples: Pedialyte, glucose water, juice without pulp, clear broths, Gatorade, tea, boullion, water, popsicles, Iell-o Alternative for children over 1 year of age with history of moderate to severe constipation: • Magnesium citrate (I oz./year of age, maximum l Ooz.] by mouth, once in the evening for 2 days before surgery • Start clear liquids 24 h before surgery Patients 12-16 years of age add: Dulcolax 5mg PO daily x 2 days Patients over 16 years of age add: Dulcolax IOrng PO daily x 2 days

JUIce, Pedialyte, plain Jell-o, popsicles, white grape juice), which can be continued until 2 h before the procedure. PATIENTS OLDER THAN 18 YEARS. Nothing to eat or drink after midnight except clear liquids (water, apple juice, plain Jell-o, popsicles) until 4h before the procedure.

Bowel Preparation Instructions The bowel is mechanically cleansed for elective bowel resection. There is varied opinion as to whether a bowel preparation is needed for certain procedures, as well as what to use to accomplish it, and whether to do it at home or in the hospital. Examples of inpatient and outpatient regimens are detailed in Table 36.10.

Lateral Neck Masses The differential diagnosis of a laterally presenting neck mass is extensive and includes branchial cleft remnants, lymphangioma, dermoid cyst, epidermoid cyst, hemangioma, lymphadenitis, leukemia, torticollis, neurofibroma, lipoma, metastatic tumor to the cervical lymph nodes, parotid tumor, and tumors of dentigerous origin. Of these, branchial cleft remnants, lymphangioma (cystic hygroma), lymphadenitis, and torticollis are discussed.

Branchial Cleft Cysts, Sinuses, and Remnants The branchial arches develop and partially regress all during the first 6 weeks of life." They are composed of endodermal pouches on the pharyngeal wall and are noted externally by the presence of ectodermal clefts. The dorsal portion of the first cleft becomes the external auditory canal; the other clefts are obliterated. The first, third, and fourth pharyngeal pouches persist as adult organs. The first pouch becomes the eusta-

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chian tube, the middle ear cavity, and the mastoid air cells. The second pouch incompletely regresses and becomes the palatine tonsil and the supratonsillar fossa. The third pouch forms the superior parathyroid; the fourth forms the inferior parathyroid and the thymus glands. Cysts developing from branchial structures usually appear later in childhood as opposed to sinuses, fistulae, and cartilaginous remnants. Incomplete sinus tracts are mere dimples in the skin, which are often associated with a small segment of ectopic cartilage. Approximately 15% are bilateral, and one frequently observes similar lesions in siblings. ANOMALIES OF THE FIRST BRANCHIAL CLEFT

These anomalies are rare and often present in adulthood as a small cyst lying close to the parotid gland. During infancy, this anomaly is usually noted as a draining sinus located anterior to the ear. Excision should be undertaken cautiously because the tract extends to the external auditory canal, placing the branches of the facial nerve at risk for injury. ANOMALIES OF THE SECOND BRANCHIAL CLEFT

These are the most common lesions, arising in the mid - or lower neck, along the anterior border of the sternocleidomastoid muscle. A cyst, sinus, or fistula may be present. The fistula tract classically extends from the skin opening, deep to the platysma, superiorly beneath the stylohyoid and digastric muscles at the level of the hyoid bone, passes over the hypoglossal and glossopharyngeal nerves and between the bifurcation of the carotid artery, and passes medially to enter the lateral pharyngeal wall . ANOMALIES OF THE THIRD BRANCHIAL CLEFT

These are extremely rare and, similar to the second branchial cleft remnant, are located along the anterior border of the sternocleidomastoid muscle. However, these are usually lower on the neck and the fistula tract, when present, passes lateral to the carotid artery bifurcation rather than through it and enters the piriform sinus. TREATMENT

Rarely are branchial cleft anomalies cosmetically unappealing. Rather, they should be excised early in life, shortly after diagnosis, because repeated infection is quite common, making resection more difficult. When infection occurs, antibiotic therapy and often incision and drainage are indicated. The definitive excision is staged, approximately 6 weeks later, giving the inflammation adequate time to resolve, thus assuring a complete resection. Every effort should be made to excise the entire cyst wall or fistula tract (including the skin punctum, if present] as recurrence and infection are common with incomplete removal.

Lymphangioma (Cystic Hygroma) These hygromas are benign multilobular, multinodular cystic masses lined by endothelial cells. They result from maldevelopment of the lymphaticovenous sacs." Eventually, sequestrations of lymphatic tissue develop that do not communicate with the normal lymphatic system. Fifty percent to 65% appear at birth, 90% by the second year of life. They are

FIGURE 36.1. Typical neonatal lymphangioma arising from the posterior cervical triangle. (Reproduced with permission from Seminars in Pediatric Surgery 1994;(3):147-159.)

located most commonly in the posterior triangle of the neck (75%) (Fig. 36.1); axilla (20%); and mediastinum, retroperitoneum, pelvis, and groin (5%). Neck hygromas may communicate beneath the clavicle with an axillary hygroma, mediastinal hygroma, or rarely both. The majority are asymptomatic, although large lesions invading the floor of the mouth may cause symptoms referable to pharyngeal and/or upper airway obstruction. The skin is never involved; these lesions grow along fascial planes and around neurovascular structures. There are two modes of treatment that are chosen based on imaging [computed tomography (CT) or magnetic resonance imaging (MRI)) studies; sclerotherapy and excision. Intralesional injection of a sclerosing agent is most effective for unilocular cysts. Examples of agents that have been used are OK-432 (a lyophilized mixture of Streptococcus pyogenes and penicillin G potassium) and bleomvcin.P:" Excision is carried out with bipolar cautery to ensure a hemostatic dissection and decrease the incidence of lymph leak and nerve injury. Intraoperative cyst rupture increases the difficulty of the dissection because the thin-walled empty cyst is difficult to identify and the margins are obscured. The recurrence rate is low (10%) if all microscopic disease is resected. When gross disease is left, recurrence occurs in up to 100%.

Cervical Lymphadenitis Cervical adenitis is an inflammatory enlargement of one or more lymph nodes of the head and neck ." There is tenderness, erythema, fever, and leukocytosis. It is often secondary to an acute staphylococcal or streptococcal infection originating in the upper respiratory tract, scalp, ear, or neck. Treat-

PEDIATRIC SURGERY

ment is with antibiotics, warm compresses, and surgical drainage when the lymph node(s) become fluctuant. A more indolent form of cervical adenitis is caused by nontuberculous (atypical) mycobacteria and cat scratch disease. Nontuberculous adenitis is a local process without systemic involvement. There is unilateral nontender enlargement of submandibular/submaxillary lymph nodes, often with a draining sinus, that is refractory to antibiotic therapy. Excisional biopsy is indicated. Cat scratch disease is benign and self-limited. After 3 to 5 days, a characteristic papule appears at the site of inoculation. Adenopathy and mild constitutional symptoms evolve over 1 to 2 weeks. Suppuration is rare, and resolution occurs without treatment. More obscure causes of cervical adenitis include tuberculous adenitis, Actinomyces israelii, toxoplasmosis, Francisella tularensis, Epstein-Barr virus, Yersinia enterocolitica, Nocardia sp., and fungi.

Torticollis Torticollis occurs in newborns and results from fibrosis and shortening of the sternocleidomastoid muscle, producing a "tumor" in the muscle that causes the face to turn toward the contralateral side and the head to tilt toward the ipsilateral shoulder. 22 Increasing facial and cranial asymmetry results from this abnormal positioning. Facial hemihypoplasia and plagiocephaly (flattening of the ipsilateral posterior skull) occurs in untreated cases, usually within 6 months. The etiology is unclear and most likely results from birth trauma. Passive range-of-motion exercises, coupled with a change in the infant's feeding position, will cure most. Often the "tumor" disappears well before full range of motion is acquired. The only indication for operation (division of the muscle) is facial hemihypoplasia.

Midline Neck Masses These masses usually present in children more than 6 months old and are often thyroglossal duct cysts/sinuses, dermoid/ epidermoid inclusion cysts, or goiter. Less common differential diagnoses are ectopic midline thyroid, pyramidal lobe of the thyroid, thyroid adenoma of the isthmus, carcinoma of the thyroid with a pretracheal nodal metastasis, dermoid or seabaceous cyst, lipoma, and submental lymphadenitis. In contrast, cervical teratoma and lymphangioma are the most common midline neck masses in the newborn. They are often quite large and may threaten the airway.

Thyroglossal Duct Cysts and Sinuses Thyroglossal duct remnants are three times more common than branchial cleft remnants. The majority are noted before the age of 5 years and 75 % are cysts, 25 % draining sinuses. These develop as the thyroid diverticulum descends from the foramen cecum of the tongue, often through the midline of the developing hyoid bone." The thyroid diverticulum remains connected to the foramen cecum by the thyroglossal duct. Normally the duct disappears by the time the thyroid reaches its final position. When the thyroid descends fully but elements of the duct persist, a thyroglossal duct cyst may develop. Thyroid tissue (often dysgenetic) may be present in

661

the cyst or the along the sinus tract. Because the mass is located within the strap muscles and may be attached to the base of the tongue, it moves with deglutition or when the tongue is protruded. Complete excision is indicated because of the risk of acute or chronic infection and the possibility of papillary carcinoma arising from dysgenetic ectopic thyroid tissue later in adulthood. The procedure should include excision of the cyst and the entire tract upward to the base of the tongue. The central portion of the hyoid bone should be removed because the duct often passes through this structure. Recurrences occur when the hyoid is not removed or when the cyst was previously infected and/or drained. If thyroid tissue is noted in the resected specimen, thyroid scanning is indicated to identify those children in whom there is no other thyroid tissue remaining as they require lifelong thyroid hormone replacement therapy.

Inclusion Cysts Inclusion cysts occur when ectodermal elements become trapped beneath the skin at sites of embryonic fusion lines. 23,24 These often contain sebum, hair follicles, connective tissue, and papillae. They are commonly noted in the supraorbital region or just above the sternal notch. Removal is justified to confirm the diagnosis and to avoid infection.

Congenital Anomalies of the Lung Congenital Cystic Adenomatoid Malformation Congenital cystic adenomatoid malformations (CCAM) are cystic, solid, or mixed intrapulmonary hamartomas that communicate with the normal tracheobronchial tree and do not have an anomalous blood supply." Embryologically, they arise from excessive proliferation of cartilage and mucous gland-deficient bronchial structures without alveoli. They are most often lobar and are classified radiologically based on cyst size 26,27; type I are large (>2ern] cysts, type II are smaller cysts «2cm), and type III have cysts that are so small as to impart a solid appearance. Histologically, a CCAM may be found in conjunction with a pulmonary sequestration. The majority of these lesions are lobar and can be identified prenatally by ultrasound. The prenatal natural history can be quite variable." Some may grow so large and produce such severe mediastinal shift that heart failure and hydrops results. If the mass is not resected (either via in utero surgery or after emergency cesarean delivery), death ensues in virtually 100 % . Others may remain the same size or regress considerably. Those children in whom hydrops did not occur before birth may be born asymptomatic (small lesions) or have variable degrees of respiratory distress caused by compression of the ipsilateral normal lung. Asymptomatic children may be observed, but resection (pulmonary lobectomy) is recommended because these lesions often become infected and there are case reports of malignant transformation occurring in untreated, long-standing cysts."

Pulmonary Sequestration This cystic lung lesion is most commonly noted in the lower left hemithorax. It has an aberrant arterial supply, usually

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from the infradiaphragmatic aorta and venous drainage, that is either pulmonary or systemic." There is an extralobar variant that has its own investing pleura but no communication with the tracheobronchial tree. In contrast to prenatally diagnosed CCAMs, sequestrations rarely grow large enough to produce hydrops and in utero demise. Children with extralobar sequestrations are usually asymptomatic at birth and have been diagnosed either prenatally or by chest radiograph demonstrating a radiopaque mass in the lower hemithorax. These are often associated with congenital diaphragmatic hernia and are noted incidentally during repair of the diaphragmatic defect. The intralobar variant is enveloped within the visceral pleura of the adjacent normal lung and has common alveolar communications, predisposing it to infection and lung abscess formation. Treatment is by excision of the sequestration; this mayor may not require lower lobectomy, depending on the degree of inflammation.

Congenital Lobar Emphysema Congenital lobar emphysema (CLE) consists of hyperinflation of a single lobe, usually the upper or middle lobes." There are a variety of causes such as bronchial obstruction (deficient bronchial cartilage support, redundant mucosa, bronchial stenosis, bronchial compression by anomalous vessels or mediastinal mass, mucous plug), a polyalveolar lobe (large number of abnormal alveoli that are prone to expansion), or hypoplastic emphysema (reduced number of bronchi and alveoli with increased air space size). Infants with CLE usually do not present with respiratory distress for several days or weeks. Many infants, however, present with mild tachypnea at birth. In only 5 % of cases do symptoms develop after 6 months of life. Most of the babies require excision of the affected lobe because of progressive hyperinflation. At thoracotomy, the large, overdistended lobe characteristically "pops out" when the ribs are separated. Anesthesia should not be started until all surgical personnel are present and prepared for emergency thoracotomy because positive pressure ventilation may acutely enlarge the emphysematous lobe, thereby compressing the normal lung tissue and heart.

Mediastinal Masses Mediastinal masses are relatively common in infants and children and can be classified according to the compartment of the mediastinum from which they arise." The most common mediastinal mass is a posterior mediastinal neurogenic tumor. ANTERIOR MEDIASTINAL MASSES

1. Thymic cysts and thymomas are rare and account for 50/0 of cases. 2. Lymphoma accounts for approximately 100/0 and is either Hodgkin's or non-Hodgkin's variety. About 40% to 60% of children with Hodgkin's disease present with an anterior mediastinal mass. 3. Teratoma (150/0) may be cystic, solid, and may also be found within the pericardium; approximately 200/0 are malignant.

4. Lymphangioma occur in 7% and most commonly extend caudally from the neck into the mediastinum; these rarely arise primarily in the mediastinum. MIDDLE MEDIASTINAL MASSES

1. Bronchogenic cysts (150/0): these extrapulmonary cysts are located in either the paratracheal or juxtahilar regions. The intrapulmonary variant has airway connections and is thus prone to infection. They are three times more common on the right side than on the left. 2. Pericardial cysts are rare, are almost always asymptomatic, and are usually an incidental chest radiograph finding. POSTERIOR MEDIASTINAL MASSES

1. Neurogenic tumors (see Childhood Tumors section) account for 33% and include neuroblastoma, ganglioneuroblastoma, ganglioneuroma, neurofibroma, and neurofibrosarcoma. Common symptoms include respiratory distress (via tracheal or lung compression), Homer's syndrome, and pain. 2. Enterogenous cysts (28 %) are esophageal duplica-tions that often contain ectopic gastric tissue (see GI duplications below). They are termed neurenteric cysts when there is an associated cervical or thoracic vertebral anomaly. They can end blindly (above or below the diaphragm) or may communicate with the jejunum. Ten percent to 15% are associated with a separate intraabdominal GI duplication.

Congenital Diaphragmatic Hernia Congenital diaphragmatic hernia (CDH) is a highly lethal and morbid disease that affects 1 in 2000 live births." Anatomically, CDH results from an embryological fusion defect, allowing herniation of intraabdominal contents into the chest. Failure of posterolateral fusion of the various components comprising the diaphragm leads to a persistent pleuroperitoneal canal, the foramen of Bochdalek. Diaphragmatic fusion occurs just before the return of the intestinal tract into the abdomen following its physiological herniation (10-12 weeks gestation). The hernia is most common on the left side (90%), with a rate of associated anomalies of 200/0 (chromosomal abnormalities, neural tube defects, and congenital heart disease). Pulmonary hypoplasia is believed to occur when the developing fetal lungs are compressed by the herniated abdominal viscera, limiting the number of bronchopulmonary generations.r':" An alternate theory based on experimental studies with nitrofen-induced CDH in rodents suggests that pulmonary hypoplasia may be a separate developmental defect not related to the mass effect of viscera on the developing lungs." Herniation of gut through the diaphragmatic defect prevents normal intestinal rotation and fixation, accounting for the almost universal presence of intestinal rotational anomalies in infants with CDH. The size of the defect ranges from a small slit to complete diaphragmatic agenesis. Commonly, the posterolateral diaphragmatic rim is represented by a thin ridge of muscle under the peritoneum, or it may be completely absent. The anteromedial diaphragmatic rim is usually intact. A hernia sac can be found

PEDIATRIC SURGERY

in up to 20% of patients and may be associated with an improved survival. Physiologically, children born with CDH frequently develop respiratory distress from pulmonary hypoplasia and/ or persistent fetal circulation with pulmonary hypertension. The development of symptoms in CDH correlates with the degree of pulmonary hypoplasia and pulmonary hypertension. The abdomen is classically scaphoid. Breath sounds may be absent on the ipsilateral side, and cardiac sounds may be distant. The babies are usually symptomatic in the delivery room with tachypnea, grunting respirations, retractions, and cyanosis and may require urgent intubation. The radiographic findings include air-filled loops of bowel in the hemithorax, a paucity of gas within the abdomen, radiopaque hemithorax if the bowel does not contain a significant amount of gas or if the liver occupies the majority of the hemithorax, contralateral mediastinal shift with compression of the contralateral lung, loss of normal ipsilateral diaphragmatic contour, and the nasogastric tube may coil in the hemithorax. The radiographic differential diagnosis includes congenital cystic lung diseases (e.g., cystic adenomatoid malformation), congenital lobar emphysema, pulmonary sequestration, diaphragmatic eventration, and unilateral pulmonary agenesis. Prenatal diagnosis is occurring more and more frequently and allows the mother and fetus to be referred to an institution where sophisticated perinatal and pediatric surgical units are available. Treatment before birth has been studied in two randomized trials and was found to be no more efficacious than treatment after birth.":" Treatment includes prompt orotracheal intubation after sedation and paralysis. Avoid bag-mask ventilation, even for brief periods, as the gut may distend with air. Administer 1000/0 oxygen; peak inspiratory pressures >35mmHg should be avoided, if possible. Insert a sump gastric tube and place it on low continuous suction. Monitor pre- and postductal oxygen saturations and treat right-to-left shunting (pulmonary hypertension) (Table 36.11). Persistent pulmonary hypertension may respond only to extracorporeal membrane oxygenation (ECMO) support. Repair of the diaphragmatic defect is not a surgical emergency and should be performed once the infant has stabilized and has demonstrated minimal to no pulmonary hypertension (usually more than 48 h postnatally). Early reduction and

TABLE 36.11. Treatment of Pulmonary Hypertension. Goal

Treatment

Oxygenate Correct acidosis

Mechanical ventilation, F102 1.0 Hyperventilate Sodium bicarbonate (or THAM if retaining CO 2 ) Adequate volume replacement as needed Inotropic agents: dopamine, dobutamine Fentanyl infusion, neuromuscular blockade (vecuronium) Nitric oxide? Intravenous calcium supplements (CaCb, Ca gluconate)

Correct malperfusion

Sedation/paralysis Pulmonary vasodilation Correct hypocalcemia THAM, tromethamine.

663

repair has been shown to transiently worsen pulmonary function by decreasing the pulmonary compliance and increasing airway reactivity" A subcostal incision on the affected side should be performed, although some surgeons prefer a transthoracic approach, particularly for right-sided defects. The herniated abdominal contents should be carefully reduced from the chest. There may be a negative pressure "seal" that can be relieved by placement of a right-angled retractor below the anterior edge of the diaphragm, into the chest, and gently pulling upward. Reduction of the liver in right-sided defects can be very challenging and may require evisceration of all the abdominal contents as well as complete incision of the falciform and triangular ligaments. A hernia sac may be present and must be excised before closure to avoid a postoperative cystic collection that may enlarge, producing a mass effect. Primary diaphragmatic closure using interrupted nonabsorbable sutures can be performed if the defect is small. If the defect is too large for a primary closure, then a prosthetic patch (e.g., Gore-Tex) should be inserted and sutured around the ribs of the posterolateral body wall. The majority of children with CDH who survive the neonatal period and are successfully extubated enjoy relatively normal lives. In the long term, there are a number of probably clinically insignificant physiological abnormalities such as a reduction in total lung volume, restrictive or obstructive lung disease, and abnormal lung compliance. A small subset of patients survive as "pulmonary cripples" and remain oxygenor ventilator dependent, often requiring tracheostomies. Recurrent diaphragmatic hernia occurs in 100/0 to 200/0 of infants and should be considered in any child with a history of CDH who presents with new GI or pulmonary symptoms. Standard anteroposterior and lateral chest radiographs are diagnostic. Recurrence is most common when a prosthetic patch is used for the repair. As there may be deficient periesophageal muscular tissue or an abnormal orientation of the gastroesophageal junction, gastroesophageal reflux is common. It is most commonly treated nonoperatively, but refractory cases may require an antireflux procedure.

Foramen of Morgagni Hernia The foramen of Morgagni (or space of Larrey) represents the junction of the septum transversum, the lateral portion of the diaphragm, and the anterior thoracic wall and allows the passage of the superior epigastric vessels. This anterior diaphragmatic defect accounts for only 2 % of diaphragmatic hernias. They are most commonly right parasternal but may be left parasternal, retrosternal, or bilateral. 40 This defect, when noted in newborns, can be associated with the pentalogy of Cantrell", this is a disorder with considerable morbidity and mortality that consists of the diaphragmatic defect, distal sternal cleft, epigastric omphalocele, apical pericardial defect, and congenital heart disease (usually a septal defect). Typically, however, children are asymptomatic and the defect is discovered later in life on a chest radiograph taken for reasons unrelated to the hernia. The lateral chest radiograph demonstrating an air-filled mass extending into the anterior mediastinum is pathognomonic. Repair is indicated in the asymptomatic patient for reasons of the risk of bowel incarceration or strangulation. The viscera are reduced and any associated hernia sac excised. The defect is closed by suturing

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the posterior rim of the diaphragm to the posterior rectus sheath (as there is no anterior diaphragm). Large defects require a prosthetic patch. There is no associated pulmonary hypoplasia or hypertension. Thus, excluding patients with the pentalogy of Cantrell, survival is 100%.

Eventration of the Diaphragm Diaphragmatic eventration is an abnormally elevated portion of the diaphragm or, most commonly, hemidiaphragm. It may be congenital (usually idiopathic, but can be associated with congenital myopathies or intrauterine infections) or acquired (as a result of phrenic nerve injury during forceps delivery or thoracotomyl.f There is a variable absence of diaphragmatic muscle, at which point its distinction from a CDH with a persistent hernia sac is obscure . The elevated hemidiaphragm produces abnormalities of chest wall mechanics with impaired pulmonary function. Respiratory distress and pneumonia are frequent presenting symptoms, although GI symptoms such as vomiting or gastric volvulus may occur. The diagnosis is made by chest radiograph and confirmed by fluoroscopy or ultrasound, which demonstrates paradoxical movement of the diaphragm during spontaneous respiration. Incidentally discovered small, localized eventrations do not need to be repaired. Eventrations that are large or which are associated with respiratory symptoms should be repaired by plicating the diaphragm using interrupted nonabsorbable sutures. In cases of complete eventration, a prosthetic patch may be required.

CLEFT STERNUM WITH THORACOABDOMINAL ECTOPIA CORDIS (PENTALOGY OF CANTRELL)

There are five components to this disorder, cleft sternum with thoracoabdominal ectopia cordis; minimal distal sternal cleft, ventral diaphragmatic defect (central tendon defect), epigastric abdominal wall defect [omphalocele], CHD, and apical pericardial defect . Because the heart is not completely outside the mediastinum and retains most of its investing pericardium, this is not considered true ectopia cordis. The CHD is typically not severe (usually a septal defect). The mortality is appreciable and is related to the huge upper abdominal wall defect and the cardiorespiratory compromise that results from attempted closure.

Pectus Excavatum Pectus excavatum is a depression deformity and is the most common congenital chest wall abnormality, occurring in 1 in 300 live births, with a 3:1 male predominance. It is associated with other musculoskeletal disorders (Marfan's syndrome, Poland's anomaly, scoliosis, clubfoot, syndactylism), and 2% have CHD. There is a familial form . It results from unbalanced posterior growth of costal cartilages that are often fused, bizarrely deformed, or rotated." The body of the sternum secondarily exhibits a prominent posterior curvature, usually involving its lower half (Fig. 36.2). Asymmetrical deformities are common, particularly with sternal rotation to the right. It is identified during infancy in 90%. The depression progresses during childhood, becoming most pronounced during the growth spurt of puberty. The physio-

Congenital Chest Wall Deformities Congenital chest wall deformities are a heterogeneous group of disorders noted in infants and adults that commonly consist of bony and cartilaginous absence or deformity, often associated with musculoskeletal abnormalities.

Sternal Defects SIMPLE CLEFT STERNUM

Simple cleft sternum results from a failure of the embryonic sternal bars to unite and fuse, typically involving the manubrium and varying lengths of the body. Rarely is the entire st ernum bifid. Patients are usually asymptomatic. Operative correction is performed in the neonatal period as the chest wall is so pliable and consists of simple suture approximation of the sternal halves . CLEFT STERNUM WITH TRUE ECTOPIA CORDIS

Cleft sternum with true ectopia cordis consists of varying degrees of upper sternal cleft associated with ectopia cordis or a "bare" heart (no investing pericardium) that is located outside the chest wall, via the cleft. Intrinsic congenital heart disease (CHD) is common, as are extracardiac anomalies including cleft lip, cleft palate, hydrocephalus, and other CNS disorders. This defect is generally incompatible with life because of the severe congenital heart Iesionls] .

FIGURE 36.2. Adolescent with a pectus excavatum deformity. Note that the most pronounced posterior sternal curvature is in the lower one-half. (Reproduced with permission from Shamberger R. Congenital chest deformities. In: O'Neill JA, Rowe MI, Grosfeld JL, eds. Pediatric Surgery, 5th ed. © 1988 CV Mosby, Co.]

PEDIATRIC SURGERY

FIGURE 36.3.

Severe pectus carinatum deformity.

logical data implicating adverse cardiopulmonary effects as a result of deformity are controversial and contradictory." In general, there is no cardiopulmonary benefit after chest wall repair except in rare instances when the deformity is extensive. Otherwise, the repair is performed solely to improve appearance. However, the psychosocial benefits of repair of this often embarrassing deformity cannot be minimized. There is no standard age for repair . Traditionally, an open repair is performed in which the abnormal cartilages are resected and the sternum is often fractured and fixed in a corrected position (often with a Kirschner wire or steel strut]." Recently, a minimal access technique has been proposed by Nuss et al." in which a preformed sternal strut is passed, either blindly or with thoracoscopic assistance, under the chest wall muscles, into each hemithorax, and across the mediastinum under the sternum via two small incisions in the midaxillary line. The curve bar is passed upside down and "flipped" into position under the sternum, effectively lifting the sternum and chest wall into a corrected position. The bar is left in place for 2 years, and the children can resume activity in 3 months. The recurrence rate for the open procedure is less than 3%; there are not enough long-term follow-up data to assess the Nuss technique presently.

Pectus Carinatum Pectus carinatum is a protrusion deformity, also referred to as pigeon or chicken breast" (Fig. 36.3). It is approximately 10 times less frequent than depression deformities. It results from overgrowth of costal cartilages, with forward buckling

665

and secondary deformation of the sternum. Atypical and asymmetrical forms with rotation are common. There is a familial form . It is associated with Marfan's disease, neurofibromatosis, Poland 's disease, and Morquio's disease. The defect does not affect cardiopulmonary function. In contrast to pectus excavatum, the deformity is typically mild or nearly imperceptible in early childhood and becomes increasingly prominent during the rapid growth in early puberty. There is no cardiorespiratory compromise with this deformity, and repair is performed solely for an improved cosmetic appearance . The deformed cartilages are resected, leaving the costochondral membranes (perichondrium) intact." Sternal fracture usually is not necessary. To ensure that the costal cartilages grow back on a straighter line, reefing sutures are placed in the costochondral membranes. The costal cartilages regenerate within 6 weeks. A thorough procedure will produce an excellent cosmetic result in nearly 100% of cases. Recurrences are rare.

Congenital Anomalies of the Esophagus Anomalies of the esophagus, namely esophageal atresia, tracheoesophageal fistula, and their variants, are potentially life threatening in the newborn period." Shortly after birth, the infant with esophageal atresia is noted to have excessive salivation and repeated episodes of coughing, choking, and cyanosis, and attempts at feeding are unsuccessful. Those with an associated tracheoesophageal fistula are prone to gastric reflux into the tracheobronchial tree with resulting chemical tracheobronchitis and pneumonia, especially if they are on mechanical ventilatory support. The diagnosis is confirmed by demonstrating that a small feeding tube coils in the upper esophageal pouch on a plain radiograph . A contrast study is almost never indicated. Bronchoscopy is the most sensitive means of identifying a tracheoesophageal fistula. The rare esophageal atresia variant, in which there is no tracheoesophageal fistula ("pure" atresia), can be confirmed by the absence of gas in the GI tract on plain radiograph . There is a 50% to 70% incidence of associated anomalies, namely, cardiac [patent ductus arteriosus (PDA), septal defects], GI (imperforate anus, duodenal atresia), GU, and skeletal. The VACTERL association (vertebral, anorectal, cardiac, tracheoesophageal, renal, and limb anomalies) is present in 25% of cases. The classification is based on the presence or absence of an esophageal atresia and the presence and location of a fistula(e). These are listed below in descending order of their frequency (Fig. 36.4). Historically, they have been classified as types A through E: E

FIGURE 36.4. A. Pure(long gap] esophageal atresia. B. Esophageal atresia with proximal tracheoesophageal fistula. C. Esophageal atresia with distal tracheoesophageal fistula. D. Esophageal atresia with proximal and distal fistulae. E. Tracheoesophageal

fistula without esophageal atresia. (From Grosfeld JL. Pediatric surgery. In: Sabiston DJ, ed. Textbook of Surgery, 1991, by permission of WE Saunders.)

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1. Esophageal atresia with distal tracheoesophageal fistula (type C, 850/0 of cases). The distal tracheoesophageal fistula ends in the distal one-third of the trachea or in the carina. 2. Pure esophageal atresia (type A, 8%-100/0). This is referred to as "long gap atresia" as the distal esophageal pouch is remote from the upper pouch, usually just above the diaphragm. 3. Tracheoesophageal fistula without esophageal atresia (type E, 4%-5%). The fistula, unlike the type C variant, is usually located in the cervical region. It is often termed an "H"-type fistula, although in reality the anatomic configuration resembles an "N," with the entrance into the esophagus as the most cephalad point. 4. Esophageal atresia with proximal and distal fistulae (type D, 20/0). In contrast to the H-type fistula, the proximal fistula is usually from the distal portion of the upper esophagus. 5. Esophageal atresia with proximal tracheoesophageal fistula (type B, 1%). There mayor may not be a long gap between the esophageal segments. Treatment begins with stabilization of the child and assessment for associated anomalies. A Replogle sump suction catheter should be placed in the upper esophageal pouch and the head of the bed elevated. An echocardiogram is required to determine the position of the aortic arch because a rightsided arch makes the standard right thoracotomy repair difficult. The goal of operative therapy is to divide and ligate the fistula and repair the atresia in one stage. This procedure is usually performed using a right posterolateral thoracotomy with an extrapleural dissection, although the thoracoscopic approach is gaining favor.t" Staged operations are reserved for extremely premature babies and those with severe anomalies or long gaps between the esophageal pouches. A staged procedure involves either division of the fistula alone, or creation of a cervical esophagostomy and insertion of a feeding gastrostomy tube for those with long gap atresia (type A). A feeding gastrostomy tube is no longer routinely inserted except when the esophageal repair is under extreme tension, when there is long gap atresia not amenable to single-stage repair, and when there are severe associated anomalies (e.g., congenital heart disease). A transanastomotic feeding tube is placed for postoperative feeding, pending the demonstration of a leak-free anastomosis by esophagram obtained 7 days after surgery. There are several strategies for repairing long gap esophageal atresia without fistula: these include cervical esophagostomy and gastrostomy tube, followed several months later by esophageal replacement (colon or stomach interposition); gastrostomy tube alone with intermittent bougienage and stretching of the upper esophageal pouch, followed by primary esophageal anastomosis; and immediate interposition graft." , Immediate postoperative complications include anastomotic leak, stricture, and recurrent fistula. Long-term complications include gastroesophageal reflux (GER), dysphagia caused by the intrinsically poor esophageal motility in these children, and tracheomalacia from in utero tracheal compression by the large proximal esophageal pouch and/or from the repair of the fistula.

Gastrointestinal Tract Abnormalities Gastroesophageal Reflux Gastroesophageal reflux is physiological at birth because the lower esophageal sphincter does not mature for approximately 2 months; this accounts for the commonly noted regurgitation (chalazia, or "wet" burps) during and after feeds in a normal newborn. Although most GER is idiopathic, GER is found in association with neurological disorders, esophageal atresia, CDH, delayed gastric emptying, and abdominal wall defects. The symptoms of GER in infants and children are protean. 52,53 The most common is vomiting, which can cause failure to thrive, aspiration pneumonia, apnea, bronchospasm that is confused with asthma, and laryngospasm which may lead to sudden infant death. Reflux may produce esophagitis, which can lead to heartburn, dysphagia, and odynophagia. Long-standing GER can cause occult esophageal bleeding, esophageal stricture, and Barrett's metaplasia. The gold standard diagnostic test is lower esophageal 24-hpH monitoring. 53 An upper GI series is less sensitive but is used to rule out other disorders (e.g., intestinal malrotation) and to assess for esophageal stricture. Upper endoscopy is useful to diagnose and monitor the inflammatory changes in the distal esophagus. Gastric emptying may be assessed by technetium pertechnetate scan. There is little role for esophageal manometric studies in children, except for those in whom one suspects achalasia or diffuse esophageal spasm. Nonoperative treatment is successful in most cases. For infants, thickening the feeds with rice cereal and upright positioning during and shortly after feeding is effective. Persistent symptoms mandate drug therapy with an antacid (e.g., H 2 blocker or proton pump inhibitor) with or without a prokinetic agent (e.g., Reglan). The indications for operation are failure of medical therapy, complications while on medical treatment (e.g., recurrent pneumonia), severe esophagitis, Barrett's esophagitis, esophageal stricture, or significant bleeding. 54 The gold standard antireflux surgical procedure is the Nissen fundoplication," although some advocate the Thal partial fundoplication." Controversy exists as to whether to assess for delayed gastric emptying. There are growing data that suggest that the "funneling" effect of the fundoplication promotes gastric emptying, even in the face of known delayed emptying. Gastric emptying is most often delayed in neurologically impaired children. In recent years, the traditional open approach to antireflux operations has been gradually replaced by the more cosmetic and better visualized laparoscopic procedure." At this time, most data from the pediatric population regarding laparoscopic antireflux procedures consist of retrospective case series. Evaluating the efficacy of the laparoscopic approach is not straightforward in children as parameters such as symptom control and satisfaction rates are difficult to obtain and may be confounded by a number of variables (patient age, neurological impairment, and other congenital abnormalities). Because of this, many studies have evaluated the effectiveness of laparoscopic antireflux procedures in relationship to the development of recurrent GER as well as wrap failure.

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Based on review of the large (more than 100 patients) retrospective case series published to date, recurrent GER has been reported to occur in 2% to 6 % of pediatric patients after laparoscopic antireflux operations.tv" Differences vary from series to series, with variables including the type of operation performed (e.g., Nissen versus Thal fundoplication) . In contrast, failure rates reported for open Nissen fundoplication have been reported to range from 20% to 47% .~4 Wrap failure most commonly occurs as a result of crural breakdown and migration of the wrap into the chest through the resulting hiatal hernia. In the adult population, wrap migration has been report ed to occur in 20 % of patients whereas the pediatric literature displays failure rates from 2% to 5 %.65.66 Furthermore, wrap migration appears to occur more commonly in neurolog ically impaired children, presumably as a result of increased abdominal pressure from retching and concomitant seizure disorders. Symptomatic dysphagia, which is the most common postoperative complaint in th e adult population, appears to be significantly less prevalent in children, likely because infants tend to consume a primarily liquid diet, transitioning to solid foods well after postoperative edema in the distal esophagus is no longer a concern. Tabl e 36.12 summarizes the published series to date reviewing large experiences (more than 100 patients) with laparoscopic antireflux procedures. At this time all report s consist of retrospective case series with relatively shortterm follow-up. Multiple operations are utilized including Niss en, Nissen-Rosetti, Thal, and Toupet fundoplications. Overall, recurrence of GER, complication rates , and conversion rates appear favorable. In total (more than 1500 patients), only 4 death s have been reported: 1 operative, 3 postoperative. Although the se studies are retrospective and do not directly compare the laparoscopic to open approach, they indicate that th e laparoscopic operat ions represent at least as safe and an equivalent alternative to the traditional open approach .

Pyloric Stenosis Pyloric stenosis is the most common surgical disorder producing emesis in infancy. The symptoms are of gastric outlet obstruction and are caused by concentric hypertrophy of the pyloric muscle with progressive narrowing of the pyloric canal. The disease evolves postnatally because it is rare in preterm infants, and symptoms are usually absent in the first week of life. It is usually diagnosed in the first 3 to 6 weeks after birth. It is most common in Caucasians, least common in Asians, and there is a male-to-female ratio of 4 : 1. There is a familial predilection, particularly if the mother has been afflicted. Clinically, there is progressive, forceful nonbilious emesis. The vomiting occurs immediately or within 30 to 45 min of the last feeding and consists of undigested formula with thick curds . Brownish or coffee-ground material may be present, suggesting gastritis. Affected infants are voraciously hungry after vomiting and will eagerly take to the bottle or nurse. The differential diagnosis is overfeeding (most common), formula intolerance, GER, pyloric duplication, antral web, CNS lesion with increased intracranial pressure, and salt wasting andrenogenital syndrome. Infants are often dehydrated with sunken fontanelles, dry mucous membranes, and poor skin turgor . Jaundice (elevated indirect bilirubin) may be present as a result of decreased glucuronyl transferase activity. A firm, mobile hypertrophic pylorus, or "olive," is palpated by an experienced examiner in 90 % of cases, provided the child is relaxed and the stomach is decompressed. Diagnostic imaging is required only if the olive cannot be palpated. Ultrasonography is the most sensitive test, although a negative study is non diagnostic for other entities. An upper GI contrast study can provide anatomic and functional details . Plain abdominal radiographs are never indicated. Prolonged vomiting of gastric fluid can result in a hypochloremic, hypokalemic metabolic alkalosis. Hydrogen and chloride ion-rich

TABLE 36.12. Large (More Than 100 patients) Published Series of Pediatric Laparoscopic Fundoplication for Gastroesoph ageal Reflux Disease (GERD). Antireflux procedure

Recurrence ofGER

Complication rates

6.1% Toupet 3.5% Ni ssen 2.10 %

2 deaths (1 operat ive) Intraoperati ve, 5.1% Postop erative, 3.4%

284

201 Toupe t 188 Nissen 148 NissenRossetti 141 Toupet Thai

2.10 %

220

Nissen

3.40 %

142

56 Toupet 83 Nisse n

4.20%

104

Nissen

2.90%

154

Nisse n

2%

Intraop erative, 0 % Postoperative, 1% Int raoperative, 2.6% Postoperative, 7.3% Intraoperative, 0.5% Postop erative, 2%; 1 death Major, 12.7%; 1 death Intraoperative, 0 % Postoperative, 2%

Author/year

Study design

Georgeson 199857 Esposito 2000 137

Retros pective case series Retrospective case series

389

Montupet 2001138 Rothe nberg 199866 Allal 2001 139

Retrospecti ve case series Retrosp ect ive case series Retrospective case series

Iglesias 2001 140 Ostlie 2003 141

Retrospective case series Retrospective case series

N

289

N/A, not available; LOS, length of stay; TIF, time to feed.

LOS

ITF

Operation time

3.3 %

-3 days

N /A

- 60 m in

1.3 %

N/A

N/A

70 mi n

N /A

N /A

- 3 days

1.0%

1.6 days

N/A

82 m in

2.1%

3 days

N/ A

105 min

1.0 %

More than 10 days 2.8 days

-3 days

60 m in

- I day

90min

Conve rsion rat es

0%

- 60 m in

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gastric fluid is lost by prolonged vomitmg. The kidney attempts to maintain a normal serum pH by excreting alkaline urine. Hypokalemia results from K+ loss in the urine as the cations are excreted with bicarbonate and cellular uptake of K+ in exchange for hydrogen ions in the face of an alkaline serum. With continued vomiting, the kidney attempts to maintain volume by reabsorbing sodium in exchange for hydrogen ions, producing a paradoxical aciduria. The fluid and electrolyte abnormalities are corrected using D5 0.45 % normal saline at lSD-I 75mL/kg/day. Potassium (20mEqJL) is added after the child voids. The volume of resuscitation fluid is adjusted based on the child's urine output, urine specific gravity, and vital signs. The timing of operation is dictated solely by the fluid and electrolyte status. Surgery may be undertaken when an adequate amount (1-2mL/kg/h) of nonconcentrated (specific gravity ::;;1.012) urine is established and the serum chloride and potassium are corrected. The surgical repair consists of an extramucosal myotomy beginning l-2mm proximal to the pyloroduodenal junction and extending onto the antrum. There are three approaches to the pylorus: a right upper quadrant transverse skin incision, a circumumbilical or intraumbilical skin incision, or a laparoscopic approach with the camera in the umbilicus and the two working instruments placed directly through the abdominal wall .67,68 Regardless of technique, a complete myotomy will allow independent movement of the upper and lower muscular edges. If the mucosa is entered (usually on the duodenal side), it can be closed with fine nonabsorbable suture and an omental patch. Large perforations are managed by closing the pyloromyotomy, rotating the pylorus 90°, and repeating the myotomy. Multiple postoperative feeding schedules have been described, ranging from immediate full feeds to delayed feeds with incremental advances in volume, stemming from the observation that nearly all patients with pyloric stenosis vomit after surgery, presumably as a consequence of gastric ileus, gastritis, GER, or all of these. An incomplete pyloromyotomy (usually on the antral side) is suspected when vomiting persists after 2 weeks postoperatively. Pyloric stenosis never recurs, and there is a uniformly excellent outcome.

tion should be performed to assess if an anus is present, patent, and in the normal location. Meconium, the first newborn stool, is passed in the first 24 h of life in 94 % of normal full-term infants and by 48h in 98'7'0 .J2 Failure to pass meconium may be indicative of lower GI tract obstruction. Nonbilious emesis is caused by esophageal atresia, proximal duodenal obstruction (see below), antral web, pyloric atresia, or gastric duplication. Depending on the plain abdominal radiograph, an upper GI series mayor may not be needed before operative intervention. Bilious emesis may be caused by distal duodenal obstruction, jejunal or ileal atresia, intestinal malrotation (with either obstructing peritoneal bands or volvulus), meconium plug syndrome, meconium ileus syndrome , small left colon syndrome, Hirschsprung's disease, rectal atresia, or imperforate anus. Because the plain abdominal radiograph in a newborn cannot differentiate small bowel from large bowel in an infant with multiple distended bowel loops, the most common test in the workup of bilious emesis is the contrast enema. It can be both diagnostic and therapeutic (e.g., wash out a meconium plug).

Duodenal Obstruction Duodenal obstruction can be complete (e.g., atresia) or partial (e.g., stenosis]." The various causes are idiopathic atresia (failure of canalization), annular pancreas, preduodenal portal vein, or peritoneal bands (Ladd's bands) from malrotation. There may also be a mucosal web or diaphragm that can partially (perforated web) or completely obstruct the duodenum. Approximately one-third of babies with duodenal atresia or stenosis have trisomy 21 (Down's syndrome). Patients present with bilious emesis and the presence of a "double bubble" on plain abdominal radiographs (Fig. 36.5). Rarely are contrast studies needed preoperatively. Treatment is by duodenoduodenostomy with tapering of the proximal, hugely dilated duodenum (tapering duodenoplasty) because this overstretched bowel segment has impaired aboral progression of ingested feedings. In contrast, an obstructing duodenal web is simply excised. Obstruction from Ladd's bands requires division of the bands and correction of the malrotation (see fol-

Intestinal Obstruction in the Newborn As fetuses continually swallow amniotic fluid into their GI tracts and excrete it via the urine, intestinal obstruction may be noted on prenatal ultrasound by the presence of polyhydramnios (increased amniotic fluid level). The presence of polyhydramnios correlates with the level of the obstruction; it is most common with proximal GI tract obstruction [e.g., esophageal and duodenal atresia), is rarely noted with ileal atresia, and is never noted in association with anorectal obstruction [e.g., rectal atresia). After birth, vomiting is the principal symptom, and it is bile stained if the obstruction is distal to the ampulla of Vater. It is important to note that newbom bilious vomiting is pathological until proven otherwise. On physical examination, the presence and degree of abdominal distension depend on the level of the obstruction and should be noted. For example, there is no significant distention with duodenal obstruction versus massive distension with colonic obstruction [e.g., Hirschsprung's disease). A careful perineal examina-

FIGURE 36.5. Plain abdominal radiographs demonstrating a gasfilled stomach and proximal duodenum ("double bubble "), indicative of proximal duodenal obstruction. The radiograph on the left was taken with the baby supine ; in the one on the right, the child is upright .

PEDIATRI C SUR GERY

lowing). The distal bowel must be irrigated and assessed for intrinsic obstruction (1%-3% incidence).

Disorders of Intestinal Rotation Disorders of intestinal rotation are classified in four ways: incomplete rotation (the most common-also termed malroration], nonrotation, reversed rotation (the least common I, and anomalous mesenteric fixation.P'" To understand the four types of abnormal anatomy, one must acknowledge the series of fetal events that lead to normal intestinal rotation and fixation. The fetal intestine begins as a somewhat straight tube that grows faster than the abdominal cavity and thus herniates into the body stalk (future umbilicus I at about week 4 to 6 weeks gestation. At 10 to 12 weeks gestation, the bowel returns to the abdominal cavity where it will rotate and fixate. The duodenojejunal portion undergoes a counterclockwise 270° rotation posterior to the superior mesenteric artery (SMAl and fixes to the posterior body wall as the ligament of Treitz at the level of th e 12th thoracic vertebra, to the left of the midline above the level of the pylorus . The cecocolic portion also rotates 270°, but anterior to the SMA and becomes fixed in the right lower quadrant at the level ~f the 5th lumbar vertebra. Incomplete rotation may affect the duodenojejunal port ion, the cecocolic portion, or both. Because only partial rotation occurs, the bowel is fixed posteriorly by a relatively narrow mesenteric base that is prone to twisting (volvulus). Volvulus occurs around the SMA in a clockwise direction and can lead to gangrene of the entire midgut, heralded by abdominal distension, bloody stools, and often hematemesis. It presents either acutely in infancy or as a chronic intermittent obstruction (intermittent volvulus] in older children. The partial rotation of the cecum may result in duodenal obstruction by Ladd's bands, which are peritoneal folds that serve to fix the cecum to the posterior body wall; if rotation halts in the right upper quadrant, these bands will stretch out over and obstruct the third portion of the duodenum. Using an upper abdominal transverse incision, the volvulus should be untwisted in a counterclockwise direction. Incomplete intestinal rotation is managed by division of Ladd's bands, division of any intermesenteric adhesions, straightening the duodenum as much as possible, and placing the cecum on the left side of the abdomen. In essence, one is creating nonrotated ~ntestinal anatomy, much as in early fetal life. Appendectomy IS advocated based on the abnormal final position of the appendix. With nonrotation of the intestine, the midgut is "suspended " from the superior mesenteric vessels; the majority of the small intestine lies on the right side of the abdomen, the large bowel on the left. It is often noted in patients with CDH, gastroschisis, and omphalocele. This anatomy is less prone to volvulus compared to the incomplete rotation variant. In reversed rotation, the duodenojejunal bowel rotates varying degrees in a clockwise direction about the SMA. The cecocolic portion may rotate clockwise or counterclockwise . or posterior to the SMA. Anomalous mesenteric' antenor fixation accounts for internal mesenteric and paraduodenal hernias. The bowel may rotate normally but fixes to the abdominal wall abnormally. Excessive cephalad rotation of the duodenojejunal portion results in obstruction of the third portion of the duodenum in thin patients (SMA syndrome).

669

Atresia of the Jejunum, Ileum, and Colon In contrast to duodenal atresia, more distal intestinal atresias are caused not by a failure of canalization but by a mesenteric vascular accident with resultant aseptic resorption of the bowel, usually later in gestation. The spectrum of anomalies (Fig. 36.6) ranges from a stenosis or mucosal web (type I), a fibrous cord between two bowel ends (type II), blind-ending proximal and distal bowel loops with a V-shaped mesenteric defect (type IlIa), and multiple atresias of any kind (type IVl.72 Type IIIb is the rarest and is associated with short bowel syndrome. It is termed the apple peel deformity or Christmas tree deformity, in which there is a blind-ending proximal jejunum, absence of a large portion of the midgut, and a ter minal ileum that is coiled around its ileocolic blood supply. The most common site of atresia is the ileum, followed by the jejunum and the colon . Bilious emesis is uniform. Because the atresia is believed to be a late gestational event, these babies often pass a normal meconium stool after birth. Plain radiographs demonstrating only a few dilated bowel loops are indicative of a proximal obstruction, and a contrast study is not required. If many loops are dilated, a contrast enema will help differentiate a distal small bowel atresia from a potentially nonoperative cause of obstruction such as meconium plug syndrome (see below). At operation, the distal portion of the proximal blindending bowel segment is disproportionately dilated and should be resected because it is functionally abnormal and

FIGURE 36.6. The anatomical spectrumof intestinal atresia. Type I is a stenosis or mucosal web; type II, a fibrous cord between two b~wel ends; type IIIa , blind-ending proximal and distal bowel loops WIth a .v-shaped mesenter ~c defect. Type IIIb (apple peel deformity ?~ Chnstmas tree deformity] consists of a blind-ending proximal ~eJunum , ab~ence . of a large portion of the midgut, and a terminal Ileu~ that IS . COIled around its ileocolic blood supply; type IV, multlp~e atresias of any kind. (From Grosfeld JL. Pediatric surgery. In: Sabiston OJ, ed. Textbook of Surgery, 1991, by permission of WB Saunders.]

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CHAPTER 36

atonic. If this is a long segment of proximal jejunum, the antimesenteric portion of the bowel should be tapered over a large tube using a stapler or a running suture. There is always a discrepancy in bowel diameter between the proximal and distal ends, so an end-to-side or end-to-oblique anastomosis is necessary.

Duplications of the Gastrointestinal Tract Duplications are rare congenital cystic abnormalities of the GI tract that have been reported to occur anywhere from the mouth to the anus. They originate on the mesenteric side of the associated alimentary tract and shared a common blood supply with the native bowel. 73 Based upon embryology, duplications have been categorized into foregut, midgut, and hindgut. Foregut duplications include the pharynx, respiratory tract, esophagus, stomach, and the first portion and proximal half of the second portion of the duodenum. Midgut duplications include the distal half of the second part of the duodenum, the jejunum, ileum, cecum, appendix, the ascending colon, and the proximal twothirds of the transverse colon. The hindgut is composed of duplications of the distal third of the transverse colon, the descending and sigmoid colon, the rectum, anus, and components of the urological system. In one series, 390/0 of duplications involved the foregut while 61 % represented duplications of both mid- and hindgut." Duplication cysts are spherical or tubular in shape and share a common seromuscular coat and similar mucosal lining as the normal adjacent GI tract. Further, they are typically located on the dorsal or mesenteric side of the native bowel." Heterotopic gastric mucosa is seen in up to one-third of these lesions and may result in severe ulceration, bleeding, and eventual perforation. Communication with the lumen of the gut is more common with tubular duplications. Eightyfive percent of duplications are diagnosed before age 2 and 600/0 by 6 months of age. Vertebral anomalies are seen in 21 0/0 of patients, whereas other congenital anomalies are encountered in 48 % of patients with alimentary tract duplications. The signs and symptoms of alimentary tract duplications are not unique and therefore may be confused with other GI tract pathology. Although many duplications remain "silent" and are incidentally discovered during an operative procedure, others present with severe GI distress. Abdominal pain and melena are the most common symptoms, and a mobile abdominal mass may be palpated in approximately half of patients. Accumulation of secretions within the duplication can cause intense pain and potential obstruction from compression of the adjacent bowel lumen. Heterotopic gastric mucosa is present in up to one-third of duplications; as such, patients may develop occult or obvious blood loss or frank perforation secondary to peptic ulceration within the duplication. Specific complaints and findings may also be attributable to the location of the duplication. Foregut duplications may present with vomiting, respiratory distress, failure to thrive, dysphagia, and hematemesis. Gastric and duodenal lesions typically present with a palpable abdominal mass and may cause vomiting, abdominal distension, melena, and peritonitis following perforation. Gastric outlet obstruction mimicking hypertrophic pyloric stenosis is also a common presentation of these duplications.

Midgut duplications are frequently associated with abdominal distension, vomiting, and melena. Other less common symptoms include pain, peritonitis, and diarrhea. These duplications are often difficult to identify preoperatively as they can easily mimic acute appendicitis. Additionally, they can cause an intussusception and thereby obscure the diagnosis. Duplications of the hindgut may present with vomiting, constipation, diarrhea, or abdominal distension. The treatment for the majority of intraabdominal duplications is excision. Before operative intervention, plans for intraoperative radiography, which may include scintigraphy, ultrasonography, and cholangiography should be made. The location and association of the lesion to its native structures will help determine the appropriate surgical procedure. Extreme care must be taken to recognize the common blood supply between the duplication cyst and the adjacent native bowel. Additionally, the presence of heterotopic gastric mucosa will negate the ability to perform an internal drainage procedure because of the risk of secondary ulceration and possible hemorrhage."

Meckel's Diverticulum A Meckel's diverticulum is present in 1 % to 3% of the population and is the most common remnant of the omphalomesenteric duct." It is located 10 to 90cm from the ileocecal valve and may contain ectopic gastric (most common) or ectopic pancreatic tissue. The lifelong risk of complications is 40/0, and 40 % of these cases occur in children under 10 years of age. Complications include bleeding (400/0), intussusception (200/0), diverticulitis or peptic perforation (150/0), umbilical fistula (150/0), intestinal obstruction (70/0), and abscess (30/0). Bleeding is the most serious complication and most often occurs in children younger than 5 years. It is often massive, seldom occult. Contrast studies rarely outline the diverticulum. The diagnosis is often made by a technetium99m pertechnetate scan, which demonstrates uptake of the tracer by ectopic gastric parietal cells. The sensitivity of the scan is increased with pretreatment by either cimetidine or pentagastrin. Resection can be accomplished by laparotomy or laparoscopically. The diverticulum is easily excised using a surgical stapler or Endoloop if the base is narrow.

Anorectal Anomalies: Imperforate Anus Anomalies of the rectum develop as a result of the faulty division of the cloaca into the urogenital sinus. The sphincters and levator muscle complex as well as the sacral nerves are affected to varying degrees. Therefore, a "perfect" surgical repair may not result in perfect continence." There is a wide range of anomalies, many of which can be simply classified as either "low" or "high" based on physical examination and imaging studies (Figs. 36.7-36.10). Low defects are defined by an orifice that is visible at the perineum but is not in the normal location or is partially covered in the normal location. In males, the orifice is anywhere on the perineum, including the median raphe of the scrotum, or it may simply be a covered anus in which there is an incomplete epithelial membrane over the anus. In females, the orifice is either at the perineal body, fourchette, vestibule, or distal vagina. These babies often have well-developed perineal/gluteal musculature and rarely have sacral vertebral anomalies. High defects

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671

FIGURE 36.7. A. Low female anomaly. Perineal fistula . B. Low female anomaly. Fourchette/vestibule fistula. (Reproduced with permission from Pena A. Surgical Management of Anorectal Malformations. New York: Springer-Verlag, 1992.)

FIGURE 36.8. A. High female anomaly. Low vaginal fistula . B. High female anomaly. High vaginal fistula. (Reproduced with permission from Pena A. Surgical Management of Anorectal Malformations. New York: Springer-Verlag, 1992 .)

A

FIGURE 36.9. A. Low male anomaly. Perineal fistula . B. Rectobulbar urethra fistula . (Reproduced with permission from Pena A. Surgical Management of Anorectal Malformations. New York: Springer-Verlag, 1992 .)

A

B

A

B

FIGURE 36.10. A. High male anomaly. Rectoprostatic urethra fistula . B. High male anomaly. Rectobladder neck fistula . (Reproduced with permission from Pena A. Surgical Management of Anorectal Malformations. New York: SpringerVerlag, 1992 .)

B

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most often have a fistulous connection to the urethra or bladder neck (males) or the upper vagina (females).The rectum may end blindly in 10% of cases. The most severe of the high deformities is the cloacal anomaly, also termed a persistent urogenital sinus. There is only one visible orifice on the perineum; within it there is a common channel between the vagina and urethra with the rectum opening into the vagina. Patients with high imperforate anus often have deficient pelvic and gluteal musculature, a high incidence of sacral anomalies, and a poor prognosis for continence after surgical repair. Imperforate anus is associated with the V ACTERL syndrome. The most common isolated association is genitourinary (e.g., unilateral renal agenesis, vesicoureteral reflux). Sacral anomalies by plain radiographs warrant a further evaluation by MRI to assess for spinal cord abnormalities such as a tethered filum terminale or lipomeningocele. All infants with imperforate anus should be prophylactically treated against a urinary tract infection until a voiding cystourethrogram is obtained that rules out vesicoureteral reflux. Low deformities are treated by perineal anoplasty using a muscle stimulator to precisely determine the location of the sphincter complex. Traditionally, a high deformity was treated by a three-stage repair, which consisted of a divided loop colostomy, a posterior sagittal anorectoplasty 4 to 6 weeks later, and closure of the colostomy several months later.t' Fistulae to the bladder neck usually require division via laparotomy. Recently, the staged approach has been challenged and a one-stage repair has been performed by both the posterior sagittal" and a laparoscopic approach." In all cases, the neoanus must be dilated for several months to prevent circumferential cicatrix formation.

Meconium Plug and Meconium Ileus Meconium plug syndrome, or neonatal small left colon syndrome, is believed to result from transient colonic immaturity-related dysmotility. More than 50% of these babies were born to diabetic mothers. In some, hypermagnesemia is noted in response to maternal magnesium sulfate administration to treat preeclampsia. Infants present with abdominal distension, bilious emesis, and failure to pass meconium. The obstructing plug of meconium is most often located in and around the splenic flexure. The contrast enema, using a water-soluble agent, is both diagnostic and therapeutic. It demonstrates a small left colon and dilated bowel proximal to the meconium filling defects. Persistent symptoms after evacuation of the meconium mandate a suction rectal biopsy to rule out Hirschsprung's disease. It is important to differentiate meconium plug syndrome from meconium ileus. Meconium ileus results from obstruction of the terminal ileum by abnormal meconium. Ten percent to 33 % of patients with meconium ileus have a family history of cystic fibrosis. 56 The presentation is no different from that of meconium plug syndrome, Hirschsprung's disease, or distal intestinal atresia. Characteristically, the proximal ileum is greatly dilated and contains thick, viscous meconium, while the terminal ileum is collapsed and obstructed by thickly packed round mucous pus that resembles rabbit stool pellets. In some cases, the weight of the meconium-filled ileum may cause a localized volvulus (not midgut volvulus); this may result in intestinal obstruction, ileal atresia, or perforation with pseudocyst formation. Plain

abdominal radiographs show dilated bowel loops, and air mixed with the viscous meconium conveys a ground-glass or soap-bubble appearance. There are no air-fluid levels because the thick meconium fails to layer rapidly. There may be calcifications on the plain film if an antenatal perforation has occurred. A contrast enema is both diagnostic and potentially therapeutic. It shows a microcolon, and reflux into the ileum demonstrates a small-caliber terminal ileum with multiple filling defects. Further reflux demonstrates a large-caliber ileum packed with meconium. Initial treatment is with a hypertonic contrast enema mixed with a mucolytic agent (e.g.,N-acetylcysteine). This treatment draws hypotonic fluid into the intestinal lumen, so the infant must be kept well hydrated. If this fails to relieve the obstruction, laparotomy is indicated. The ileum is opened and, if possible, flushed clear. The bowel can be reanatomosed or brought out as a double-barrel stoma. Alternatively, a T-tube may be placed in the bowel and brought out the anterior abdominal wall for postoperative irrigations. All patients should be evaluated for cystic fibrosis.

Hirschsprung's Disease Congenital intestinal aganglionosis (Hirschsprung's disease) results from a failure of craniocaudal migration of neuroblasts that are destined to become the parasympathetic ganglion cells of the intestine. The absence of ganglion cells always begins just proximal to the dentate line, never skips intestinal segments, and extends proximally for varying lengths. In approximately 750/0 of cases, the disease is limited to the rectosigmoid colon. Five percent of cases involve the entire colon (total colonic aganglionosis), and 5% can involve varying lengths of small intestine. The absence of ganglion cells results in a functional obstruction because the affected area fails to relax as a consequence of unopposed sympathetic tone. The disease may run in families and is associated with trisomy 21 and congenital heart disease. Males are affected four times more frequently than females when the disease is limited to the rectosigmoid. Longer lengths of disease and the familial forms favor females. The typical neonate with Hirschsprung's disease has bilious emesis, abdominal distension, and passes little or no meconium. Rectal examination of the infant may produce an expulsion of stool and air. Short segments of disease may allow a baby to escape diagnosis for weeks, months, or even years. The older patients present with chronic constipation alternating with diarrhea and failure to thrive. Children with constipation from Hirschsprung's disease do not exhibit soiling of their diapers or undergarments, distinguishing this form of constipation from idiopathic constipation (encopresis). The differential diagnosis includes all the aforementioned causes of neonatal mechanical obstruction along with a variety of functional causes such as hypermagnesemia, hypocalcemia, hypokalemia, and hypothyroidism. Untreated Hirschsprung's disease may lead to enterocolitis, characterized by fever, abdominal distension, and foul-smelling watery stools. Enterocolitis is the principal cause of neonatal mortality associated with Hirschsprung's disease. Plain abdominal radiographs demonstrate dilated loops of bowel. A contrast enema is the imaging test of choice. Typically, it demonstrates a transition zone in which there is proximal colonic dilation and distal narrowing, most evident

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673

torically, the operations have been performed via a low transverse abdominal incision. However, a laparoscopic-assisted operation is quickly becoming the method of choice." A solely transanal mucosectomy has been used for those babies with short segment disease ."

Necrotizing Enterocolitis

FIGURE 36.11. Lateral view of a contrast enema from a baby with

Hirschsprung's disease shows distal rectosigmoid narrowing with proximal dilation of the colon.

in the lateral projection (Fig. 36.11), in contrast to a normal neonate's rectum, which is the widest portion of the colon. The transition zone may be difficult to identify in the first weeks of life because the newborn's normally liquid stool may pass through the aganglionic bowel. Contrast (e.g., barium) is usually retained for prolonged periods (>24h) after the initial study. Th e definitive diagnosis is made by rectal biopsy, a painless bedside procedure in which the mucosa and submucosa are sampled beginning I em above the dentate line . Serial sections demonstrate an absence of ganglion cells, hypertrophied nerve trunks, and increased acetylcholinesterase staining. If sampling error occurs , it can be repeated or a full-thickness biopsy performed under general anesthesia in the operating room . Although not indicated in neonates, manometric studies will show a failure of relaxation of the internal sphincter following balloon distension of the rectum. Traditionally, the surgical treatment was staged and consisted of a leveling colostomy followed several months later by resection of the aganglionic bowel and one of three pullthrough procedures. " Recently, there has been a trend toward performing a single-stage procedure (no colostomy] in the newborn period." This paradigm is as follows : bowel obstruction and mild enterocolitis (if present) may be relieved by placement of a large (30Fr.) rectal tube and repeated warmed saline irrigations in lOmL/kg aliquots preoperatively. Infants with moderate to severe enterocolitis should be treated with a diverting colostomy. At the time of surgery, frozen section analysis of the colonic muscle is required to establish the correct (ganglionic) level for the stoma. Those infants who are not ill may undergo anyone of three effective operat ive procedures : Swenson operation, Duhamel operation, and Soave operation. The main operative principles for these procedures are removal of most or all of the aganglionic bowel while preserving the surrounding nerves to the pelvic organs, and anastomosing ganglionic bowel (confirmed by frozen section analysis) to the rectum 0.5 to 1.0 cm above the dentate line. In contrast to the Swenson and Soave procedures, the Duhamel operation leaves a cuff of aganglionic rectum along which the ganglionic bowel is stapled, creating a mini-reservoir. His-

Necrotizing enterocolitis (NECj is the most serious and frequent GI disorder of predominantly premature infants, with a median onset of 10 days after birth. Although the true incidence of NEC is unknown, it appears to be increasing given the recent therapeutic advancements in neonatal intensive care that have allowed smaller and smaller babies to survive. In the United States, NEC accounts for 1% to 7% of all neonatal intensive care admissions or 1 to 3 cases per 1000 births. 84•85 Despite years of investigation, the pathogenesis of NEC remains unclear. Prematurity continues to be the most consistent and important risk factor ." Strong evidence exists that infection in a vulnerable host plays the key role in the pathogenesis of NEC. 87 In addition, the initiation of enteral feedings has been accepted as an important risk factor for the development of NEC as approximately 90% of infants develop the disease after being fed whereas only 10% develop the disease before feedings.86,88 Overall, the development of NEC appears to be multifactorial, involving some aspects of mucosal compromise, pathogenic bacteria, and feedings combined in a susceptible host leading to bowel injury and an inflammatory cascade. In children who develop NEC, the most common site of involvement is the terminal ileum, followed by the colon. Together, the large and small bowel are involved in 44% of cases. Pan-necrosis is the most fulminating form of the disease and is characterized by involvement of greater than 75% of the length of the intestine. Mucosal cellular injury causes necrosis and ulceration, followed by edema and hemorrhage of the submucosa, muscularis, and then serosa. Full-thickness necrosis often leads to perforation. Gas-producing bacteria in the in testinal wall may lead to pneumatosis, a finding that may be noted on gross examination as well as on plain abdominal radiographs . Clinical findings include abdominal distension; feeding intolerance; palpable abdominal mass; and abdominal wall edema, erythema, and crepitus. Rectal bleeding is frequent but seldom massive." A variety of nonspecific clinical findings suggest physiological instability, such as apnea , bradycardia, hypoglycemia, temperature instability, and lethargy. Plain abdominal radiographs (supine and either left lateral decubitus or cross-table lateral views) may demonstrate pneumatosis, portal vein air, or pneumoperitoneum. There is virtually no role for contrast studies to evaluate the acute disease . Initial treatment consists of cessation of feeds, broadspectrum antibiotics, gastric suction, and correction of hypovolemia, acidosis, and electrolyte abnormalities. The only absolute indication for operation is pneumoperitoneum. Relative indications are portal vein air, clinical deterioration, a fixed intestinal loop on serial radiographs, erythema of the abdominal wall, an abdominal mass, and a paracentesis demonstrating bacteria on Gram stain. At laparotomy, all necrotic bowel is resected and the proximal bowel is made into a stoma. Rarely is primary anastomosis safe. Late complications

674 _'r...._

C HA PTE R 36

TABLE 36.13. Published Data Comparing Laparotomy (LAP) to Primary Peritoneal Drainage (PPD) for the Treatment of Perforated Necrotizing Enterocolitis (NEe). LAP

Study

Cheu et a1. Takamatsu et al. l43 Morgan et al.1 44 Azarow et al. 145 Snyder et al. 146 142

Lessin et al. 147 Ahmed et al. 148 Ravin et al. 149 Downard et al. 150 Dimmitt et a1. 151

PPD

No.

GA (weeks )"

BW (g)"

Survival rate (%)

No .

GA (weeks)"

BW(g)*

Survival rate (%)

41 3 20 42 91 3 22 10 9 9

32 3 32 31 31 3 35 29 30 26

1875 3 1854 1700 1628 3 2271 1274 1510 807

31 (76)

51 4 29 44 12 9 23 18 24 17

29 27 27 28 29 25 27 28 26 25

1158 808 994 1100 1134 615 910 1118 794 677

18 (35) 4 (100) 23 (79) 27(61) 3 (25) 6 (67) 10 (43) 16 (89)

3 18 1901 241571 52 1571 3 19 (86) 9 (90) 7 (78) 5 (561

19 1791 71411

No., number of patients; GA, gestational age; BW, birth weight. "Mean (SEMI. Source: Moss R, Dimmit R, Henry C, Geraghty N, Efron B.9l A me ta-analys is of peritoneal drainage versus laparot omy for perforated necrotizing enterocoliti s. Journal of Pediatric Surgery 2001;36(81:1210-12 13.

of NEe include short bowel syndrome and stricture formation in the distal, defunctionalized bowel (usually the left colon). For this reason, a contrast enema is used to evaluate the defunctionalized distal bowel before closing the stoma. Another strategy that is gaining acceptance for those with documented intestinal perforation is bedside peritoneal drainage using a penrose drain inserted under general anesthesia." In a recent review, Moss et al. performed a meta-analysis of 10 published studies from 1978 to 1999 comparing laparotomy to primary peritoneal drainage for the treatment of perforated necrotizing enterocolitis." The authors of the studies were contacted and all available raw patient data were obtained and included in the analysis. In all, the ana lysis included the results of 475 different patients, 2.44 undergoing laparotomy and 2.31 undergoing primary peritoneal drainage. However, the mean birth weight and gestational ages were far lower and younger in the patients undergoing laparotomy. The authors used logistic regression to control to determine the relative survival rate after laparotomy or primary peritoneal drainage, controlling for the effects of institution and gestational age. Overall, they found that the combined probability of survival did not show an advantage for either laparotomy or primary peritoneal drainage. No significant differences were found even after ana lysis of the obtained raw patient data as well as correction for birth weight. The authors concluded that, based on the availab le data , it was not possible to determine if laparotomy or primary peritoneal drainage led to better survival. In response to these questions, a randomized multicenter clinical tria l is currently underway to determine the best treatment for these children. Table 36.13 details the 10 published studies comparing laparotomy versus primary peritoneal drainage for the treatment of infants with perforated NEe.

Intussusception Intussusception (Fig. 36.12) is the most common cause of intestinal obstruction in children under 2. years of age. The

peak incidence is 6 to 12. months, and there is a 3 : 1 male predominance. It is defined by the telescoping of a segment of proximal bowe l (intussusceptum) into the adjacent distal bowel (intussuscipiens). It is typically idiopathic and involves the terminal ileum and right colon (ileocolic intussusceptio n). In most cases, hypertrophied Peyer's patches are noted to be a leading point. Ileoileal, ileoileocolic, jejunojejunal, and colocolic intussusception have been described. Organic causes that act as lead points are most common in the older (>2. years) patients and include Meckel's diverticulum, hemangioma, polyp, intramural hematoma [Henoch-Schonlein purpura), lymphoma, inspissated stool (cystic fibrosis

FIGURE 36.12. Ileocolic intussusception. (Reproduced with permission from de Lorimier AA. Pediatric surgery. In: Way LW, ed. Current Surgical Diagnosis and Treatment, 1994, Appleton &. Lange.)

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ated with a rise in the direct bilirubin fraction, and mandates prompt evaluation. The most frequent causes of prolonged jaundice in infancy are biliary atresia, a variety of hepatitides, and choledochal cyst. The differential diagnosis of neonatal jaundice is summarized in Table 36.14. The workup of neonatal jaundice consists of an analysis of liver function tests, complete blood count, metabolic and serological screening, and ultrasound. Depending On these results, hepatobiliary nuclear scanning and/or liver biopsy may be indicated. In those cases where a firm diagnosis has not been established using the aforementioned tests, intraoperative cholangiography is indicated.

Biliary Atresia

FIGURE 36.13. Contrast enema demonstrating obstruction to retrograde flow of barium by a filling defect (intussusceptum) in the midtransverse colon. patients), and enteric duplication. Rarely, intussusception may result from differential return of bowel function, typi cally after retroperitoneal surgery. The characteristic clinical presentation is one of crying and drawing the legs upward, alt ernating with periods of apparent well-being or even lethargy. Reflex vomiting may occur, but vomiting from bowel obstruction is a late finding . Bloodand mucus in the stool are noted in one-third of patients and have a characteristic "currant jelly" appearance. A mass may be palpable where the intussusceptum ends . For example, a typical ileocolic intussusception ends at the level of the hepatic flexure so there would be a right upper quadrant mass. Contrast enema is both diagnostic and therapeutic in more than 90% of cases (Fig. 36.13). The contrast agent may be either barium or air." If barium is used, the column of COntrast should not exceed 3.5 feet above the sedated patient to minimize the risk of perforation. When air is used as the COntrast agent, it is pumped into the colon at a pressure of 60 to 80mmHg (maximum, 120mmHg). A successful study reduces the intussusceptum and demonstrates reflux of barium or air into the terminal ileum. Several attempts should be made before taking the child to surgery . The indications for operation are peritonitis, bowel perforation, and inability to completely reduce the intussusceptum using COntrast. The procedure may be performed either by laparotomy or laparoscopy. The intussusceptum is reduced manually and appendectomy performed. Occasionally, bowel resection with primary anastomosis is requ ired for gangrene because of longstanding obstruction.

Biliary Tract Anomalies Neonatal Jaundice Neonatal jaundice is common and physiological for the first 7 to 10 days of life. It is principally caused by immaturity of the hepatic enzyme glucuronyl transferase and results in a predominantly indirect hyperbilirubinemia. Jaundice persisting after 2 weeks following birth is pathological, often associ-

Biliary atresia is the absence of patent bile ducts draining the liver." The atretic ducts COnsist of solid fibrous cords that may contain islands of biliary epithelium. The disease is progressive postnatally because infants are rarely born with remarkable jaundice . The extent of ductal involvement may vary greatly. There are three anatomic patterns of obstruction: (1) the proximal extrahepatic bile ducts are patent and the ducts distal to the cystic duct are obliterated; (2) the gallbladder, cystic duct, and common bile duct are patent and the proximal hepatic ducts are occluded; and (3) the entire ductal system is obstructed, noted in 83% of infants. Liver biopsy demonstrates proliferation of the bile canaliculi containing inspissated bile. Over time, the failure to excrete bile from the liver results in progressive periportal fibrosis and obstruction of the intrahepatic portal veins , resulting in biliary cirrhosis. Neonates with biliary atresia are usually healthy appear ing and active , in COntrast to those with neonatal hepatitis. Jaundice is progressive and is a result of a predominantly direct hyperbilirubinemia. The urine is dark from bilirubin and the stools are light (acholic). Firm hepatomegaly appears by 4 weeks . Ascites and portal hypertension do not become manifest for several months. Ultrasonography may demonTABLE 36.14. Differential Diagnosis of Neonatal Jaundice. ABO, Rh, and rare blood group incompatibilities: Breast-feeding Sepsis Metabolic disorders Alpha-I-antitrypsin deficiency Gaucher's disease Galactosemia Tyrosinemia Hypothyroidism Cystic fibrosis Criglar-Najjar syndrome Gilbert's disease Hepatitis Biliary atresia Choledochal cyst Inspissated bile syndrome Parenteral alimentation cholestasis Alagille's syndrome Byler's disease Pyloric stenosis

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strate absence or inability to visualize a contracted gallbladder. There is no intrahepatic biliary dilation with biliary atresia. A technetium 99m-labeled iminodiacetate compound scintiscan (e.g., HIDA, DISIDA) will demonstrate uptake but no intestinal excretion. Percutaneous liver biopsy may be necessary to distinguish biliary atresia from neonatal hepatitis, although there is considerable histological overlap in advanced cases. Unless the workup has conclusively diagnosed another entity, all children suspected of having biliary atresia should undergo operative cholangiography with the intention of proceeding to exploration of the porta hepatis. Confirmed biliary atresia requires hepatic portoenterostomy (Kasai procedure.]" The scarred bile ducts and gallbladder are removed, and a Roux-en-Y limb of jejunum is sutured to an area of the hilum bounded laterally by the hepatic artery branches. It is important to dissect any scar off the portal,nd its branches so the Roux limb can be sutured to as large a hilar surface as possible. A liver biopsy should also be performed. Other biliary conduits have been used such as the appendix and jejunal limbs with surgically created antirefluxing valves. A good long-term outcome is related to a meticulously performed procedure, age at operation less than 2 months, absence of cirrhosis at the time of operation, the presence of microscopic ductules in the hepatoduodenalligament, and whether adequate bile flow was established." In general, 33 % will have excellent bile flow and do not develop liver failure, 33 % never have bile flow and require early liver transplantation, and 33% have initially good bile flow, but months to years later develop progressive biliary cirrhosis requiring liver transplantation. Patients in whom bile flow was established are at lifelong risk of cholangitis, which is a source of major morbidity and rehospitalization and is often treated prophylactically after operation with a once-daily oral antibiotic (e.g., trimethoprim-sulfamethoxazole).

Choledochal Cyst Choledochal cysts are dilations or diverticuli of all or a portion of the common bile duct. The incidence is estimated from 1 in 13,000 to 1 in 2,000,000. 96 There is a female predominance (3: 1) and they are more common in Asians, with a large majority of the reported cases originating from Japan. Choledochal cysts are classified into one of five subtypes." Type I is a fusiform dilation of the extrahepatic bile duct. Type II is a saccular outpouching of the common bile duct. Type III is referred to as a choledochocele and is a widemouth dilation of the common duct at its confluence with the duodenum. Type IV is a cystic dilation of both the intraand extrahepatic bile ducts. Type V consists of lakes of multiple intrahepatic cysts with no extrahepatic component, and when type V is associated with hepatic fibrosis, it is termed Caroli's disease. Type I and type IV are the most common. Caroli's disease is associated with type V, appears to be a congenital syndrome, and often follows an autosomal recessive pattern of inheritance in association with various other anomalies, such as polycystic kidney disease and renal tubular ectasia." There are several theories to explain the development of the common forms of choledochal cysts The increased incidence in girls and in Asians suggests a genetic etiology causing a primary congenital ductal ectasia. Nevertheless, familial

cases have not been described, and an alternative explanation for geographic increases in incidence indicates that an infectious agent may be involved." Alternatively, cystic dilation may be a result of embryological obstruction of the bile duct." Another popular theory postulates that an anomalous entry of the pancreatic duct into the common bile duct results in a long common channel and reflux of potentially injurious activated pancreatic enzymes into the bile duct.'?" The long common channel theory is attractive, but the abnormal long common channel anatomy has been demonstrated by cholangiography in only 65 % to 800/0 of patients. If left untreated, choledochal cysts may cause cholangitis and cholangiocarcinoma in the long term. The risk of cholangiocarcinoma in the first decade of life is only 0.70/0; however, this increases to about 140/0 at 20 years and is postulated to increase even further throughout life. WI It has been suggested that type III cysts, or choledochoceles, represent a form of duodenal duplication and therefore do not share the malignant potential of the other bile duct cysts. The classic presentation of a choledochal cyst is the triad of abdominal pain, jaundice, and an abdominal mass. However, in children, the complete triad proves to be the exception rather than the rule. Ultrasonography is increasingly responsible for detecting choledochal cysts in the fetus. Neonates more commonly present with asymptomatic jaundice (predominantly direct hyperbilirubinemia) or an abdominal mass. As children grow older, the cyst may become painful or infected. In adults, an abdominal mass is rarely appreciated, and patients present more commonly with symptoms of cholangitis and/or pancreatitis. On rare occasions, children have been described with bile peritonitis secondary to perforation of a choledochal cyst. An ultrasound usually confirms the diagnosis, although radionuclide scanning, MRI, and endoscopic retrograde cholangiopancreatography (ERCP)have also been used. Historically, choledochal cysts were treated with internal drainage by anastomosis of the cyst wall to the stomach, duodenum, or small bowel. Internal drainage procedures have an unacceptably high morbidity, including persistent biliary stasis with the development of sludge, stones, cholangitis, chronic inflammatory fibrosis, and anastomotic stricture. Furthermore, the unresected cyst is capable of malignant degeneration. Presently, the gold standard operation consists of complete cyst excision with Roux-en-Y hepaticojejunostomy. Distally, the common bile duct is transected just above the pancreatic duct, limiting the amount of residual biliary tissue at risk for malignancy. The results of choledochal cyst excision with hepaticojejunostomy reconstruction are consistently excellent, but these children do require lifelong follow-up because of the risk of anastomotic stricture and intrahepatic stone formation.

Abdominal Wall Defects Ornphalocele Omphalocele is a midline abdominal wall defect noted in 1 in 5000 live births. The abdominal viscera (commonly liver and bowel) are contained within a sac composed of peritoneum and amnion, from which the umbilical cord arises at

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defect is primarily closed . The outcome is excellent when there are no serious associated anomalies.

Gastroschisis

""

FIGURE 36.14. Neonate with an omphalocele. The liver and bowel herniatedthrougha midlineabdominal wall defect andare contained within a sac of amnion and chorion from which the umbilical cord emanates. the apex and center!" (Fig. 36.14). When the defect is less than 4 em it is termed a hernia of the umbilical cord and when greater than IOcm it is termed a giant omphalocele. Associated abnormalities occur in 30% to 70% and include, in descending order of frequency, chromosomal abnormalities (trisomy 13, 18, 21), congenital heart disease, BeckwithWiedemann syndrome (hyperinsulinism, gigantism, macroglossia), cloacal exstrophy (hypogastric omphalocele, open hemibladders separated by a vesicointestinal fissure, ambiguous genitalia], pentalogy of Cantrell (see chest wall deformities, above], and prune belly syndrome (absent abdominal wall muscles, genitourinary abnormalities, cryptorchidism). After delivery, the omphalocele is covered by placing the baby's lower extremities and torso within a sterile bag (bowel bag) or placing Saran wrap around the defect to minimize heat and water loss. Intravenous fluids are administered and nasogastric suction commenced. Emergency operation is not necessary, so a thorough physical examination and workup for associated anomalies are performed. The primary goal of surgery is to return the viscera to the abdominal cavity and close the defect. The success of primary closure is predicated on the size of the defect and the size of the abdominal and thoracic cavities. It is wise to leave the sac in situ because primary closure may not be possible and thus one has maintained the best biological dressing for the viscera. If the viscera reduce but abdominal wall closure is not possible, there are two options: staged repair and prosthetic patch repair. A staged repair aims to create a protective extraabdominal extension of the peritoneal cavity (termed a silo), allowing gradual reduction of the viscera and gradual abdominal wall expansion using two parallel sheets of reinforced silastic sheeting sutured to the fascial edges or a preformed, springloaded silo. A prosthetic patch repair can be used to bridge a wide fascial gap and the skin is closed over the patch. In rare cases, nonoperative treatment is indicated because of the presence of a giant omphalocele or severe associated anomalies [e.g., pentalogy of Cantrell). The aim is to allow the sac to dry and form an eschar, allowing epithelialization to occur over the ensuing 16 to 20 weeks. The result is a ventral hernia that is repaired electively when the patient is stable. A silo repair is managed by daily manual reduction at the bedside . Complete reduction usually takes 5 to 7 days, and then the

Compared to an omphalocele, a gastroschisis is a much smaller, right paramedian defect without an investing sac lO2 (Fig. 36.15). It is twice as common as omphalocele, and the hernia contains gut and pelvic organs but not the liver . Forty percent of affected infants are born prematurely or are small for gestational age. The bowel may be edematous, matted, foreshortened, and have extensive fibrin coating or "peel" because of amniotic peritonitis. In both omphalocele and gastroschisis, nonrotation of the gut is common. In contrast to omphalocele, associated anomalies are rare; the most common is intestinal atresia (10%-15%) . At delivery, the bowel should be assessed for ischemia from obstructed mesenteric vessels herniating out a small defect or for a volvulus. The infant should be placed on his or her side to prevent "kinking" of the mesentery as it drapes over the abdominal wall. The bowel is covered with a sterile bag, as already described, and the GI tract is decompressed with a gastric tube. In contrast to omphalocele, urgent repair is necessary. Primary closure is often possible except when the abdominal cavity is small or there is significant edema and thickening of the bowel and mesentery. It is important to irrigate the colon free of meconium before attempting reduction and repair . If an intestinal atresia is noted, there are three options: (I) no immediate treatment, reduce the bowel, and reoperate in 2 to 4 weeks and either repair or create a stoma; (2) immediate stoma (beware of possible contamination of the silo, if present); and (3) resection and primary anastomosis (least likely). A staged silo repair and/or prosthetic patch closure of the fascia may be necessary, as described above for an omphalocele. In contrast to infants with omphalocele, those with repaired gastroschisis have a predictably prolonged ileus (2-6 weeks I and require central parenteral nutrition. If bowel function does not return in 4 to 6 weeks, obtain a contrast study to rule out an obstruction from inspissated meconium or an intestinal atresia not noted during the initial surgery because of the extensive inflammation and matting of the bowel loops.

FIGURE 36.15. Neonate with a gastroschisis. The defect is to the right of the umbilical cordand the bowelhas no investingsac. Note the edemaof the bowel wall and the dilatedstomach adjacent to the umbilical cord.

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Umbilical Hernia An umbilical fascial defect is very common in newborns. The highest incidence is in preterm infants and those of AfricanAmerican descent. In most children (95%), a defect less than 1.5 em will progressively diminish in size and eventually close 103; this may take months or years . Unlike inguinal hernias, complications (incarceration, strangulation) from umbilical hernias are extremely rare . Repair of the defect is indicated when the defect is larger than 1.5 em or the child is 4 years or older because defects in these children are not likely to close spontaneously.

Inguinal and Scrotal Disorders FIGURE 36.17. Bilateral inguinalhernias in a neonate.This babyalso has an undescended testicle on the left as characterized by a flat left

Inguinal Hernia and Hydrocele Inguinal hernia is a common condition in infancy and childhood.'?' Differing from hernias in adulthood, these hernias nearly exclusively result from a patent processus vaginalis (indirect hernia) and not a weakness in the floor of the inguinal canal (direct hernia) . The processus vaginalis follows the descent of the testis into the inguinal canal. Failure of obliteration of the processus may lead to a variety of anomalies including scrotal hernia, inguinal hernia, communicating hydrocele, noncommunicating hydrocele, hydrocele of the spermatic cord, and hydrocele of the tunica vaginalis (Fig. 36.16). The incidence of a clinically detectable inguinal hernia varies with gestational age: 9% to 11% in preterm infants and

c

A

F

D

E FIGURE 36.16. Spectrum of inguinoscrotal disorders. A. Normal

anatomy. The processus vaginalis is obliterated and there is a small remnant, the tunica vaginalis, adjacentto the posteriorsurface of the testis. B. Scrotalhydrocele. C. Communicating hydrocele. Note the proximal patency of the processus vaginalis. D. Hydrocele of the spermatic cord. E. Inguinal hernia. B Inguinoscrotal hernia. (Reproducedwith permission from Rowe MI. Inguinaland serotal disorder. In : Essentials of Pediatric Surgery, 1995, by permissionof CV Mosby Co.)

hemiscrotum without rugae.

3% to 5% for full-term infants. They occur on the right side 60% (because of later descent of the right testis), left 30%, and bilaterally 10%, and are more common in males. Conditions associated with an increased risk of inguinal hernia include prematurity, family history, abdominal wall defects, cryptorchidism, intersex anomalies, connective tissue disorders, and ascites from any cause [e.g., ventriculoperitoneal shunt, peritoneal dialysis, liver disease). The usual presentation is a nontender mass in the inguinal region (Fig. 36.17). The hernia is often appreciated only when the child strains or cries . One must always locate the position of the testis during an examination for a hernia because an inguinal bulge caused by an undescended or retractile testis may be mistaken for a hernia. Commonly, testicular hydroceles are mistaken for hernias. The hallmark of the hydrocele is that one can palpate the normal spermatic cord above the level of the hydrocele. Transillumination is not reliable in the newborn because intestine and fluid transilluminate equally well. It may be difficult to distinguish between a large inguinoscrota1 hydrocele and an incarcerated hernia. In the first 2 months of life, one can palpate the area of the internal ring by digital rectal examination and potentially feel the bowel entering the internal ring. In general, hydroceles that do not communicate with the peritoneal cavity are physiological, and most resolve within 1 year . Those that persist after 1 year or those which demonstrate changes in size (communicating hydrocele) should be repaired. All inguinal hernias in children should be repaired shortly after diagnosis to prevent incarceration (nonreducible viscera in the hernia sac), strangulation (vascular compromise to the incarcerated bowel), or injury to the ipsilateral testis from compression of the spermatic cord by the incarcerated bowel. An incarcerated hernia can usually be reduced before surgery. If the initial manual reduction is unsuccessful, the child should be sedated and reduction reattempted. After reduction, repair is delayed 48 to 72 h to allow the edema to subside. At operation, a small inguinal crease incision is made, the external oblique opened, and the anteromedially positioned hernia sac is dissected free from the cord structures and ligated flush with the internal ring (high ligation). Distally, as much sac is removed as possible and any remnant is left open to drain. Historically, it was recommended that all boys

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under 2 years of age and all girls under 5 years undergo operative exploration of the contralateral inguinal canal in search of a clinically silent patent processus vaginalis. l'" This approach has been replaced, in large part, by laparoscopic exploration'P''!" , this is performed either through the ipsilateral hernia sac, through th e umbilicus, or in line with the internal ring (at the lateral border of the hemirectus muscle) using a needlescope. If a patent processus vaginalis is demonstrated laparoscopically, then a second inguinal incision is made and the procedure repeated as described earlier. The incidence of complications from inguinal hernia repair (recurrence, wound infection, and damage to the spermatic cord ) should be 2% or less .

Disorders of the Testes Cryptorchidism By the eighth month of gestation, testicular descent should be complete. The incidence of undescended or partially descended testis is 1% to 2% in full-term infants and up to 30% in premature babies . The cryptorchid testis ma y be located in the inguinal canal, in the peritoneal cavity, or anywhere on the lower abdomen, thigh, and perineum (ectopic testis). The cryptorchid testis may continue to descend into the scrotum up to 1 year after birth. Operation is indicated after 1 year because degenerative changes begin to take place in these testes that may impair spermatogenesis and lead to malignant transformation. Additionally, cryptorchid testes are more prone to trauma and torsion, often have an associated inguinal hernia, and may cause adverse psychosocial effects The incidence of testicular canc er in a cryptorchid testis (30 times higher than the normal population) is not lessened by repair, but a scrotal testicle can be more reliably examined for a testicular mass later in life. The differential diagnosis includes retractile testis (a normal testis that has a hyperreactive cremasteric reflex and can be manually pulled into the mid-hemiscrotum), ectopic testis, and absent testis (usually because of in utero torsion). Between 6 and 12 months of age, orchiopexy using th e dartos pouch technique is performed. lOB If the testis is not palpable when the child is anesthetized, laparoscopy should be performed before making an inguinal inc ision to allow for identification of an abdominal testis or the diagnosi s of an absent testis. A two-stage repair (clip or laser the spermatic art ery and vein , followed by positioning in the scrotum 6-8 weeks later) is indicated for a high intraabdominal testis. If spermatic cord structures are seen entering the inguinal ring, an inguinal incision is then made .

Testicular Torsion Testicular torsion is most frequent in late childhood and early adolescence, although th e range is from fetus to newborn.109 Anatomically, there are two forms of testicular torsion: intravaginal torsion (bell-clapper deformity), the most common form, and extravaginal torsion, which occurs principally in neonates and in children with an undescended testis (Fig. 36.18). Rarely, the testis may twist on a long epididymal mesentery. In children, testicular torsion is either idiopathic or occurs after activity or trauma. There is acute scrotal or

Testicular Torsion

FIGURE 36.18. Three anatomical variants of testicular torsion . A. Intra vaginal. B. Extravaginal. C. Torsion around a long epididymal mesentery.

testicular pain that may radiate to the lower abdomen. Progressive swelling, edema, and erythema of the hemiscrotum occur. The testicle is exquisitely tender on palpation. The testicle may be foreshortened, the epididymis may lie anteriorly, and the cremasteric reflex may be absent, although these signs can be difficult to elicit. Fetal or neonatal torsion is probably responsible for the "abs ent" testis noted during the workup of cryptorchidism. Testicular salvage after neonatal torsion is rare . Tor sion of the testicular appendices I 10 (vestigial Mullerian duct structures) and epididymitis may mimic testicular torsion. With epididymitis, there is often pyuria, voiding symptoms, and fever. Torsion of a testicular appendix often has a gradual onset, and careful palpation may reveal point, rather than diffuse, tenderness. There may be a visible necrotic lesion on scrotal transillumination (blue dot sign). The diagnosis of testicular torsion is made principally on clinical grounds. Although one ma y utilize Doppler ultrasonography and radio nuclide scanning to aid in the diagnosis, these tests are time consuming and, in the case of ultrasound, not very specific. If the diagnosis is strongly suspected, the best "test" is operative scrotal exploration. The testicular salva ge rate if detorsion is performed within 6 h of symptoms is up to 97 % versus less than 10% if more than 24h have elapsed. At operation, the testicle is detorsed and, if viable, it is fixed to the hemiscrotum in three places. The contralateral testicle is at risk for torsion because the test icular anatomy tends to mirror itself, so a contralateral orchiopexy should be performed in all cases. Tor sion of th e testicular appendices tends to be self-limiting because necrosis and autoamputation usually occur. Treatment is with warm baths, limited activity, and an antiinflammatory agent. If significant pain persists after 2 to 3 days, the appendix has not autoamputated and excision is indicated.

Cutaneous Vascular Anomalies Cutaneous vascular anomalies constitute a group of congenital and acquired vascular malformations of the skin. They are present in 2.6% of all newborns. These anomalies are broadly divid ed into two categories: hemangiomas and vascular malformations. I II They are most precisely classified by the biological activity of the endothelium.

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Hemangiomas Hemangiomas demonstrate endothelial hyperplasia and are seen in children and adults but behave differently at different ages. Hemangiomas are much more common than vascular malformations. In the neonatal period, hemangiomas can be subclassified according to their growth phase. A rapid proliferating phase is usually seen during the first few years of life, followed by the involuting phase that may last several years. Their clinical appearance depends on depth of the lesion; superficial dermis lesions (capillary hemangiomas, strawberry hemangiomas) appear raised and profoundly erythematous with an irregular texture, whereas deep lesions (cavernous hemangiomas) appear smooth, slightly raised, with a bluish hue or a faint telangiectatic pattern on the overlying skin. Mixed lesions are often noted (capillary-cavernous hemangiomas). Twenty percent of patients have multiple lesions. Complications from hemangiomas consist of ulceration (during proliferative phase), bleeding, thrombocytopenia (Kasabach-Merritt syndrome), consumptive coagulopathy, high output heart failure, visual field encroachment, airway obstruction, and minor skeletal distortions. Fifty percent will involute without treatment by age 5 years, 700/0 by 7 years. The remainder will slowly resolve by age 10 to 12 years. Steroid therapy hastens the rate of proliferation of hemangiomas by 300/0 to 900/0 and is indicated for complicated lesions (i.e., those causing severe physiological or anatomical abnormalities).

Cutaneous Vascular Malformations Vascular malformations have normal endothelial cell turnover and tend to grow with the child. These lesions are structural anomalies that are considered errors in vascular morphogenesis. They are usually visible at birth but may take years or even decades to manifest. They are separated into low- and high-flow variants, and further classified according to the type of vascular channel abnormality: capillary, venous, arterial, and mixed malformations. Capillary and venous malformations are low-flow variants; arterial and mixed arterial/ venous are high-flow variants. Capillary malformations consist of port-wine stain (nevus flammeus), nevus flammeus neonatorum (angel's kiss), nevus flammeus nuchae (stork bite, salmon patch), angiokeratomas, telangiectasias [spider, hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome)]. They are prone to infection and are treated aggressively with intravenous antibiotics. A compression garment should be used if anatomically feasible. Some lesions can be excised or injected with a sclerosing solution. Venous malformations have a wide spectrum of appearances ranging from simple varicosities to complex deep lesions that may be located in deeper tissues (e.g., bone, muscle, salivary gland). Pain is often related to thrombosis within the lesion. Radiographic imaging delineates the nature and extent of the lesion (angiogram, CT, MRI). Photocoagulation or YAG laser may be effective for superficial lesions. Resection is the definitive treatment because it can reduce bulk, improve contour and function, and control pain. It is limited by anatomic boundaries, and multiple staged procedures may be required.

Arterial and arteriovenous malformations have multiple small fistulae surrounded by abnormal tissues and can cause high-output cardiac failure. They are most common in the head and neck region (especially intracerebral). There is pain and overlying cutaneous necrosis. Adjacent osseous structures are often destroyed. Selective embolization is used either as palliation or presurgically to limit hemorrhage. Excision, when possible, is the procedure of choice. Combined vascular malformations and hypertrophy syndromes consist of Klippel-Trenaunay-Weber syndrome (combined capillary-lymphatic venous malformation associated with lower limb hypertrophy), Parkes-Weber syndrome (upper limb arteriovenous shunting), Marffucci's syndrome (lowflow vascular malformations and multiple extremity enchondromas with hypoplastic long bones), and Sturge-Weber syndrome (upper facial port-wine stain and vascular anomalies of the choroid plexus and leptomeninges).

Childhood Tumors Neuroblastoma Neuroblastoma is the most common tumor in infants less than 1 year of age and the second most common solid tumor of childhood (after brain tumorsl.!" Approximately 600/0 of all cases occur in children less than 2 years of age and 970/0 before age 10. The most common site for primary disease is in the abdomen (adrenal), followed by the thorax, pelvis, and, occasionally, head and neck. They may reach massive size and violate tissue planes such that they envelop major blood vessels, their branches, and other important structures (e.g., ureter), making primary resection potentially hazardous. Large tumors may have calcifications because of hemorrhage and necrosis. They contain small blue round cell tumors and thus must be differentiated from peripheral neurectodermal tumors, Ewing's sarcoma, rhabdomyosarcoma, and lymphoma. They may show the full range of maturation from neuroblastoma to ganglioneuroblastoma to ganglioneuroma. Several molecular and cellular characteristics of neuroblastic tumors are prognostically important. The most important is the high incidence of amplification of the protooncogene n-myc, seen in approximately 30% of tumors. Amplification of n-myc (more than 10 copies) adversely correlates with prognosis, independent of clinical stage. Other genetic abnormalities include a deletion of the short arm of chromosome 1 and the tendency for hyperdiploid tumors to have an improved prognosis over diploid tumors. Using the Shimada index, well-differentiated, stroma-rich tumors have a favorable prognosis. Eighty-five percent to 900/0 secrete high levels of the catecholamine metabolites vanillymandelic acid (VMA) and homovanillic acid (HVA); an elevated ratio of VMA to HVA correlates with an improved outcome in patients with advanced disease. Other biochemical indicators of advanced disease include neuron-specific enolase, serum ferritin, serum ganglioside Gd2, and serum lactate dehydrogenase. Symptoms are site specific. The most common is pain (from the primary or metastatic disease). Other symptoms include failure to thrive, malaise, fever, weight loss, and anorexia. Children frequently appear "ill" at the time of diagnosis. Constipation and urinary retention are signs of pelvic

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disease. Orbital metastases commonly present with periorbital ecchymoses and proptosis ("raccoon eyes"). Spinal canal involvement may present with acute paralysis because of compression. The opsomyoclonus syndrome is an acute cerebellar encephalopathy characterized by ataxia, opsoclonus ("dancing eyes"), myoclonus, and dementia. It occurs in association with approximately 3 % of all neuroblastomas, and is usually associated with a good prognosis, although the neurological abnormalities tend to persist after successful treatment of the primary tumor. Infants with stage 4-S disease (Table 36.15) may display cutaneous metastases ("blueberry muffin" lesions) or respiratory embarrassment secondary to massive hepatomegaly from tumor infiltration. Imaging includes a chest radiograph, skeletal survey, and bone scan. Neuroblastoma is the most common abdominal tumor to demonstrate calcifications (500/0) before chemotherapy. The CT scan is instrumental in making the diagnosis and in determining resectability. CT myeleography is useful in assessing tumor within the spinal canal and spinal cord compression. MRI is as sensitive as CT scanning in terms of assessing tumor size and resectability, but has the added advantage of being superior to CT in assessing vessel encasement, vessel patency, and spinal cord compression. MRI can also demonstrate bone marrow involvement in selected cases. I-Meta-iodobenzylguanidine nuclear scanning is very sensitive in detecting tumors that concentrate catecholamines and has been useful in the diagnosis of primary, residual, and metastatic disease in patients with neuroblastoma. The staging systems are surgical and anatomically based, and all have prognostic value. The most recent is the International Neuroblastoma Staging System (see Table 36.15). TABLE 36.15. International Neuroblastoma Staging System and Estimated Survival Rates. Stage

Characteristics

Stage 1

Localized tumor confined to the area of origin; complete gross excision, with or without microscopic residual disease; identifiable ipsilateral and contralateral lymph nodes negative microscopically. Unilateral tumor with incomplete gross excision; identifiable ipsilateral nonadherent lymph nodes negative microscopically. Unilateral tumor with complete or incomplete gross excision; with positive ipsilateral nonadherent lymph nodes; identifiable contralateral lymph nodes negative microscopically. Tumor infiltrating across the midline (vertebral column) with or without regional lymph node involvement; or unilateral tumor with contralateral regional lymph node involvement; or midline tumor with bilateral regional lymph node involvement or extension by infiltration. Dissemination of tumor to distant lymph nodes, bone, bone marrow, liver, or other organs (except as defined in stage 4-S). Localized primary tumor as defined for stage 1 or 2 with dissemination limited to liver, skin, and/or bone marrow « 10 % tumor) in infants younger than 1 year.

Stage 2A

Stage 2B

Stage 3

Stage 4 Stage 4-S

Survival

100%

681

The diagnosis rests upon the demonstration of immature neuroblastic tissue obtained by tissue or bone marrow aspirate and biopsy. Tissue is obtained by biopsy (either by laparotomy or laparoscopically), which allows accurate determination of resectability and assures that adequate tissue (1g or 1crrr'] is available for determination of tumor markers, cytological studies, and the special stains required for accurate diagnosis and staging. Needle biopsy is used when open biopsy is hazardous. Primary excision is attempted whenever possible; sacrifice of major structures, such as intraabdominal organs or vessels, is not warranted at the first operation. Gross total excision is attempted, but negative microscopic tumor margins are not necessary. Tumors that are not safely resectable at diagnosis should be biopsied, along with any visible lymph nodes. Cyclic chemotherapy with or without radiation therapy frequently results in shrinkage and maturation of the tumor, allowing for later attempts at more aggressive resection. Removal of all residual disease is the goal, and a more radical approach is warranted. Abdominal midline tumors frequently encase the aorta, vena cava, and visceral vessels, making resection hazardous. The cavitron ultrasonic dissector (CUSA) has been useful in these cases. Basic tenets of tumor surgery need to be violated to remove tumors that encase major vessels: the tumor is often "split" to uncover and dissect major vessels and their branches. Lymph node sampling is a required component of most staging protocols; gross appearance alone is not adequate (false-negative and positive rates up to 25 0/0). The use of intraoperative radiation therapy is controversial. Liver biopsy is a part of the staging evaluation in all patients with an abdominal primary. Bone marrow transplantation is used for patients with stage 3 and 4 disease who are at high risk by virtue of their age, stage, or biological characteristics of their tumor.!" Patients receive sublethal doses of chemotherapeutic agents and total body irradiation, then are "rescued" with either allogeneic bone marrow or, more commonly, with purged autologous bone marrow.

Wilms Tumor 800/0

70%

40%

150/0 85%

Wilms tumor is the most common childhood intraabdominal tumor.l'" Seventy-five percent of children are less than 5 years old, the peak incidence is 2 to 3 years of age. It is associated with aniridia, hemihypertrophy, and the BeckwithWiedemann syndrome. The constellation of Wilms tumor, aniridia, genitourinary anomalies, and mental retardation (WAGR syndrome) and the Denys-Drash syndrome (mental retardation, pseudohermaphroditism, renal disease, and Wilms tumor) are associated with a deletion of 11p13. 11s Children are healthy appearing and present with an asymptomatic abdominal mass. It is not uncommonly detected during the workup of seemingly trivial traumainduced hematuria. The physical findings are generally limited to a large, nontender mass. Ascites may be present in advanced cases. There are no specific tumor markers. Imaging is required to determine the extent of the mass, to assess for bilateral disease, venous invasion, and metastases, and to confirm contralateral renal function; this is accomplished with an abdominal ultrasound and a CT scan of the chest and abdomen. The most important determinants of outcome for children are

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TABLE 36.16. Wilms Tumor Staging System. Stage

Characteristics

Stage I

Tumor limited to kidney and completely excised. The surface of the renal capsule is intact and the tumor was not ruptured before removal. There is no residual tumor. Tumor extends through the perirenal capsule but is completely excised. There may be local spillage of tumor confined to the flank or the tumor may have been biopsied. Extrarenal vessels may contain tumor thrombus or be infiltrated by tumor. Residual nonhematogenous tumor confined to the abdomen: lymph node involvement, diffuse peritoneal spillage, peritoneal implants, tumor beyond surgical margin either grossly or microscopically, or tumor not completely removed. Hematogenous metastases to lung, liver, bone, brain, etc. Bilateral renal involvement at diagnosis; each kidney should be staged separately.

Stage II

Stage III

Stage IV Stage V

histopathology and tumor stage. Histopathologically, there are two prognostic groups: favorable and unfavorable. Unfavorable types display varying degrees of anaplasia. Staging is based on surgical and pathological aspects of the tumor (Table 36.16). Surgical excision can often be accomplished without any preoperative treatment. The aim of surgery is to completely remove the tumor (nephrectomy) without spill and determine the stage by virtue of its size, extent, and lymph node involvement. Tumor rupture with gross spillage portends a sixfold increase in risk of local recurrence and requires the use of postoperative external-beam radiation. Palpation of the renal veins and inferior vena cava is performed to detect tumor thrombus. The contralateral kidney must be examined and palpated. Bilateral involvement (60/0) is a contraindication to primary nephrectomy. Suspicious lesions in the opposite kidney are biopsied. Bilateral disease mandates "nephronsparing" surgery (see following). If the tumor is too large for safe resection, it is biopsied, along with regional lymph nodes. Chemotherapy with or without radiation therapy usually results in a significant reduction in tumor size and allows subsequent resection. Preoperative chemotherapy is administered to patients with intracaval tumor thrombus; complete dissolution is the rule with one or two cycles.'!" The treatment of bilateral disease is individualized, with the goal of eradicating tumor while preserving the maximal amount of functional renal mass. After bilateral biopsy, the child is treated according to the most advanced stage. Delayed reexploration determines the response to treatment, and renal- preserving resection is performed. The overall survival is 850/0, and most patients are cured. Survival correlates with stage. The 4-year survival with respect to age and histology is presented in Table 36.17.

Rhabdomyosarcoma Rhabdomyosarcoma is a childhood malignancy that arises from embryonic mesenchyme with the potential to differentiate into skeletal muscle.l" It is the most common pediatric soft tissue sarcoma and is the third most common solid

malignancy. It accounts for 4 % to 8 % of all malignancies and 5% to 15% of all solid malignancies of childhood. The age distribution is bimodal: the first peak is between 2 to 5 years and the secondary peak between 15 and 19 years. Fifty percent present before 5 years, and 60/0 in infancy. There is an increased incidence in patients with neurofibromatosis, the Beckwith-Wiedemann syndrome, and Li-Fraumani cancer-family syndrome. Most studies divide rhabdomyosarcoma into distinct histological groups: favorable, intermediate, and unfavorable. Favorable types (50/0) include the sarcoma botryoides and spindle-cell variants. Botryoid tumors typically present in young children from within visceral cavities (e.g., vagina), whereas spindle-cell types have a predilection for paratesticular sites. Intermediate prognosis tumors (500/0) are of the embryonal type. Unfavorable prognosis tumors (200/0) include alveolar and undifferentiated tumors. Alveolar tumors arise from the extremities, trunk, and perineum. Undifferentiated tumors arise from the extremity and head and neck sites. Thirteen percent cannot be adequately characterized and are labeled "small, round cell sarcoma, type indeterminant." The clinical presentation varies with the site of origin of the primary tumor, age, and the presence or absence of metastatic disease. The majority of symptoms are secondary to the effects of tumor compression or by the presence of a mass. The most common site is the head and neck region (350/0); these are subdivided into orbital (100/0), parameningeal (150/0), and nonparameningeal (100/0) sites. They are usually embryonal and present as asymptomatic masses or functional deficits. Genitourinary rhabdomyosarcoma (260/0) are divided into two groups: bladder/prostate (10%) and nonbladder/prostate, including paratesticular sites, perineum, vulva, vagina, and uterus (160/0). The most common histological type is embryonal, although botryoid tumors and spindle-cell tumors are seen more frequently here than in any other site. These tumors may be so massive as to make determination of the primary tumor site impossible. There is a propensity for early lymphatic spread in GU primary tumors. Bladder/prostate tumors frequently present with urinary retention or hematuria, whereas vaginal and uterine tumors present with vaginal bleeding or discharge or with a mass exiting the vagina. Extremity rhabdomyosarcomas (10/0) are more common in the lower than upper extremity. These tumors are usually of the alveolar variety, with a high incidence of regional nodal involvement and distal metastases. "Other" sites account for 200/0; the most common are the thorax, diaphragm, abdominal and pelvic walls, and intraabdominal or intrapelvic organs. Staging is determined by the histological variant and the primary site; the extent of disease is mandatory as each has TABLE 36.17. Four-Year Survival for Wilms Tumor. Stage

Stage I/FH Stage I-ill/DH Stage II/FH Stage III/FH Stage IV/FH Stage IV/UH FH, favorable histology; UH, unfavorable histology.

Four-year survival

980/0 680/0 900/0-950/0 850/0-900/0 78%-860/0 520/0-58%

683

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TABLE 36.18. Intergroup Rhabdomyosarcoma Study Clinical Group Staging System. Group

Characteristics

Group I

Localized disease, completely removed a. Confined to muscle or organ of origin b. In~ltration outside organ or muscle of origin; regional nodes not involved Total gross resection with evidence of regional spread a. Grossly resected tumor with microscopic residual b. Regional disease with nodes, completely involved resected with no microscopic residual c. Regional disease with involved nodes, grossly resected, but with evidence of microscopic residual and/or histological involvement of the most distal regional node in the dissection Incomplete resection, or biopsy with presence of gross disease Distant metastases

Group II

Group III Group IV

an important influence on the choice of treatment and on prognosis CT or MRI scanning is essential to evaluate the primary tumor and its relationship to surrounding structures. A clinical grouping system was designed by the Intergroup Rhabdomyosarcoma Study Group (IRS) to stratify different extents of disease to compare treatment and outcome results (Table 36.18). It is based on pretreatment and operative outcome and does not account for the biological differences o~ the natural history of tumors arising from different primary sites. The surgical management is site specific and includes complete wide excision of the primary tumor and surrounding uninvolved tissue while preserving cosmesis and function. Incomplete excision (beyond biopsy) or tumor debulking is not beneficial, and severely mutilating or debilitating procedures should not be performed. Tumors not amenable to primary excision should be amply biopsied and then treated with neoadjuvant therapies; secondary excision is then perfor~ed and is associated with a better outcome than partial or Incomplete excisions. Clinically suspicious lymph nodes should be excised or biopsied, excision of clinically uninvolved nodes is site specific. Primary reexcision has been shown to improve outcome in patients where microscopic margins are positive, where the initial procedure was not a formal "cancer" resection, or where malignancy was not suspected preoperativcly.l'"

Liver Neoplasms Tumors of the liver are uncommon in childhood (2% of all pediatric malignancies). More than 70% of pediatric liver masses are malignant. The majority of hepatic malignancies are of epithelial orgin, most benign lesions are vascular in nature.I"

alcohol syndrome, and parenteral nutrition administration in infancy all increase the risk of hepatoblastoma. The most common finding is an asymptomatic abdominal mass or diffuse abdominal swelling in a healthy-appearing child. There may be obstructive GI symptoms secondary to compression of the stomach or duodenum, or acute pain secondary to hemorrhage into the tumor. Physical examination reveals a nontender, firm mass in the right upper quadrant or midline that moves with respiration. Advanced tumors present with weight loss, ascites, and failure to thrive. Approximately 100/0 of males present with isosexual precocity secondary to tumor secretion of beta-human chorionic gonadotropin (B-hCG). Laboratory studies reveal nonspecifically elevated liver function tests and a mild anemia. Thrombocytosis of unknown etiology is occasionally seen. Alpha-fetoprotein (AFP) is significantly elevated in 90% to 950/0. This marker is also associated with other malignant lesions such as germ cell tumors, but levels are lower. Serial serum AFP measurements are used to monitor patients for tumor recurrence. Levels fall to normal after curative resection. Abdominal ultrasound demonstrates a solid, usually unilobar (right lobe most common) lesion of the liver but lacks sufficient detail to determine resectability. An abdominal CT scan using intravenous contrast is currently the i~aging procedure of choice, both for diagnosis and for planmng therapy. The CT scan demonstrates the tumor's proximity to major vascular and hilar structures. The typical CT appearance is a solid, solitary mass with lower attenuation levels than the surrounding liver. MRI has proven to be very useful in defining the patency of vascular structures but is not used routinely. The definitive diagnosis requires a tissue biopsy. Although this can be performed percutaneously, there are reports of "seeding" of the biopsy tract. It is preferable to perform an open biopsy of the lesion with assessment of resectability. If the lesion is not primarily resectable, then vascular access is obtained during the same anesthesia for subsequent chemotherapy. A surgical staging system for childhood hepatic malignancies is noted in Table 36.19. Complete surgical resection is the major objective of therapy and is the only chance for cure.l " Approximately 600/0 of patients have primarily resectable lesions. A lobectomy or extended lobectomy (trisegmentectomy) is usual, but segmental (nonanatomic) resection of small, isolated tumors may be possible. Careful preoperative evaluation and planni~g has made liver resection in children a safe procedure, WIth a low mortality rate «50/0) in the hands of an experienced surgeon. Adequate exposure can be obtained via an extended subcostal or bilateral subcostal incision, although large, bulky lesions may require an extension into the right hemithorax to gain adequate vascular control during the dissection. Ascitic fluid is obtained for cytology. If the lesion is deemed unresectable, the tumor is biopsied. If the lesion is

TABLE 36.19. Hepatic Tumor Staging. HEPATOBLASTOMA

Hepatoblastomas account for almost 50% of all liver masses in children and approximately two-thirds of malignant tumors. The majority are seen in children less than 4 years of age, and two-thirds are noted before 2 years of age. The Beckwith-Wiedemann syndrome, hemihypertrophy, the fetal

Stage

Characteristics

Stage I Stage II Stage III Stage IV

Tumor localized and completely resected Tumor resected with microscopic residual disease Unresectable tumor or gross residual disease Metastatic disease

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CHAPTER 36

made resectable following chemotherapy, a lobectomy or trisegmentectomy is performed. Intraoperative cholangiography is helpful to verify the integrity of the remaining biliary tree. Postoperative complications include bleeding, biliary fistula, subphrenic fluid collections or abscess, and inadvertent injury to the biliary tree. Hepatic regeneration occurs quickly, and hepatic insufficiency is rare if 25% or more of the liver parenchyma remains. Hepatic transplantation is used for unresectable disease where chemotherapy has failed to allow complete resection but no demonstrable metastases exist.'?" Long-term follow-up is required before this becomes an accepted alternative treatment. The overall survival for all children with hepatoblastoma is approximately 500/0. The best survival (900/0) is seen in patients with stage I tumors who receive adjunctive chemotherapy after complete excision. Survival decreases as the surgical stage increases, although long-term survival approaches 60% to 700/0 in patients with unresectable disease who receive chemotherapy. HEPATOCELLULAR CARCINOMA

Hepatocellular carcinoma is less common than hepatoblastoma and typically presents in older children and adolescents (median age, 10 years). It is associated with preexisting chronic hepatitis, cirrhosis because of hepatitis B virus, and other causes of childhood cirrhosis (tyrosinemia, biliary cirrhosis, alpha-l-antitrypsin deficiency, type 1 glycogen storage disease), and cirrhosis caused by long-term parenteral nutrition. Signs and symptoms consist of an abdominal mass or diffuse swelling, abdominal pain, weight loss, anorexia, and jaundice. The serum AFP level is elevated in 500/0, although the absolute levels are lower than in patients with hepatoblastoma. The diagnostic studies, staging, and treatment are similar to hepatoblastoma.!" Only 15% and 20% of hepatocellular carcinomas are resectable because of multicentricity, bilobar involvement, portal vein invasion, and lymphatic metastases. Fibrolamellar hepatocellular carcinoma is a variant in younger patients with a high rate of resectability and a better prognosis. The overall long-term survival is poor (150/0), even for resectable disease. The role of liver transplantation remains unclear. HEMANGIOMA

Hemangioma is the most common benign pediatric hepatic lesion.'?' These are solitary {cavernous hemangioma) or multiple (infantile hemangioendothelioma), involving the bulk of the liver. Isolated cavernous hemangiomas are not often associated with cutaneous hemangiomas, whereas infantile hemangioendotheliomas commonly have hemangiomata in other parts of the body or integument. Patients with a solitary hemangioma frequently have no symptoms or present with a mass. Infrequently there is intratumor hemorrhage or rupture resulting in abdominal pain. Infants with hemangioendothelioma commonly present with massive hepatomegaly and high-output cardiac failure from arteriovenous shunting. Approximately 400/0 develop the Kasabach-Merritt syndrome. The diagnosis is made by red blood cell-labeled radionuelide or dynamic abdominal CT scanning. The CT scan demonstrates increased filling and rapid venous phase from

arteriovenous shunting. Angiography is unnecessary, and percutaneous biopsy is contraindicated. Treatment is not necessary in an asymptomatic child. Patients with congestive heart failure and/or thrombocytopenia are treated with corticosteroids, digoxin, and diuretics. Refractory patients benefit from hepatic artery embolization. External-beam radiation reduces hepatic size and controls symptoms. Their large size and diffuse involvement may preclude resection. Disease limited to one lobe can be surgically removed. Hemangioendotheliomas may undergo malignant degeneration into angiosarcoma. HEPATIC ADENOMA

Hepatic adenoma is a benign lesion that accounts for less than 50/0 of all pediatric liver tumors.!" The incidence is higher in adolescent females (associated with estrogen-containing oral contraceptives) and younger children with glycogen storage diseases. It presents as an asymptomatic mass; occasionally acute abdominal pain results from tumor rupture and bleeding. Abdominal CT scan demonstrates a well-circumscribed mass, usually confined to the right lobe. AFP levels and liver function tests are normal. The major management problem is the inability to differentiate adenomas from hepatocellular carcinoma. Thus, excision is recommended. FOCAL NODULAR HYPERPLASIA

Focal nodular hyperplasia is a well-circumscribed, nonencapsulated nodular liver mass. Its etiology is obscure, but there is an association with oral contraceptive use. 122 It presents as an asymptomatic hepatic mass or abdominal pain (from rupture or bleeding). Ultrasonography and CT scan demonstrate a solid mass, but one cannot differentiate it from an adenoma or malignancy without a biopsy. If the diagnosis can be made by biopsy (percutaneous or open), no further treatment is needed. MESENCHYMAL HAMARTOMA

Mesenchymal hamartoma is an uncommon benign lesion presenting in the first year of life as an asymptomatic large solitary mass usually confined to the right lobe of the liver. l 23 The CT scan demonstrates a well-defined tumor margin and minimal to no contrast enhancement. The treatment is surgical wedge resection; lobectomy is rarely required.

Teratomas Teratomas are embryonal neoplasms derived from totipotential cells containing tissue from at least two of three germ layers (ectoderm, endoderm, mesoderm). Approximately 80% are found in females. They are typically midline or para-axial tumors" and are distributed in the following regions: sacrococcygeal (570/0), gonadal (290/0), mediastinal (70/0), cervical (30/0), retroperitoneal (40/0), and intracranial (3%). Other sites are rare. Nongonadal teratomas present in infancy and gonadal in adolescence. Twenty-one percent are malignant. The serum AFP level is elevated in tumors containing malignant endodermal sinus (yolk sac) elements. Serial AFP levels are a marker for recurrence. ~-hCG is produced from those containing malignant choriocarcinoma tissue. Rarely, enough ~-hCG is produced to cause precocious puberty.

PEDIATRIC SURGERY

Elevated AFP and ~-hCG levels in histologically benign tumors indicate an increased risk of recurrence and malignant transformation, particularly with "immature" benign teratomas. SACROCOCCYGEAL TERATOMAS

The majority of sacrococcygeal teratomas present in the newborn period and can be detected by prenatal ultrasound. Females predominate, and a history of twins is common. Pregnancy may be complicated by high-output cardiac failure via arteriovenous shunting within the tumor, polyhydramnios, and hydrops fetalis leading to fetal demise. Fetal surgery has been utilized successfully in those with second-trimester hydrops. The tumors are classified according to location: type I, predominantly external (46 %); type II, external mass and presacral component (35%)j type III, visible externally, but predominantly presacral (90/0)j and type IV, entirely presacral, not visible externally (100/0). Treatment is excision of the tumor and coccyx'P, type I and II lesions are resected from the perineal approach, and type III and IV lesions require a combined intraabdominal and perineal resection. The majority (970/0) of newborn sacrococcygeal teratomas are benign and do not require adjuvant therapy. Follow-up requires serial AFP levels and physical examination, which include a digital rectal examination. Recurrent tumors are excised. The greatest risk factor for malignancy is age at diagnosis. The malignancy rate is approximately 50% to 600/0 after 2 months of age. Malignant tumors are often treated with surgery and chemotherapy. The 5-year survival for malignant germ cell tumors arising from a sacrococcygeal teratoma is approximately 500/0. MEDIASTINAL TERATOMAS

Mediastinal teratomas account for approximately 200/0 of all pediatric mediastinal tumors.!" They usually arise in the anterior mediastinum, although intrapericardial and cardiac lesions have been reported. Symptoms include respiratory distress, chronic cough, chest pain, and wheezing. Males with ~-hCG-producing tumors may display precocious puberty. Cardiac failure may develop from compression or pericardial effusion. The chest radiograph demonstrates a calcified (35%) anterior mediastinal mass. Ultrasonography delineates cystic and solid components. General anesthesia should not be induced until a CT scan evaluation of the airway has been obtained, because the supine position coupled with a loss of airway tone from the anesthetic agent(s) may allow the anterior mass to obstruct the distal trachea, making the rapid establishment of an airway nearly impossible. If significant airway compression is present, an awake needle biopsy under local anesthesia followed by radiation therapy and/or chemotherapy is indicated. The definitive treatment is complete resection. CERVICAL TERATOMAS

Cervical teratomas are rare neonatal neck masses which, by virtue of their large size, frequently result in respiratory distress. Calcifications may be seen on a plain radiograph and a mixed cystic/solid appearance on ultrasound. The rapid establishment of an endotracheal airway may be necessary. Tracheostomy is hazardous because of the distortion of landmarks by the large mass. Treatment is complete excision.

685

Pediatric Trauma Trauma is a significant cause of morbidity and mortality among children worldwide. In the United States, trauma was identified as the leading cause of mortality among children 30 years ago. Today, this statistic remains unchanged, with approximately 15,000 to 20,000 childhood deaths occurring each year because of trauma alone. 126- 128 Furthermore, more than 1.5 million childhood injuries occur each year, leading to approximately 500,000 hospitalizations.Pv'" With respect to trauma in general, more than 25% of all major injuries occur in patients under the age of 18.126- 128 Pediatric trauma is a multidisciplinary field requiring the collaboration of emergency room physicians, pediatricians, and multiple pediatric surgical specialists. However, the primary responsibility for the evaluation and care of the pediatric trauma patient falls to the pediatric general surgeon.

Evaluation and Resuscitation of the Pediatric Trauma Patient Compared to adults, children have distinct anatomic and physiological differences that impact their response to injury and influence their evaluation and treatment. Specifically, children have a smaller mass to body surface area ratio, a less-rigid skeleton, and more-elastic connective tissue.I" Overall, this leads to relatively vulnerable abdominal and thoracic structures because energy transmitted during trauma delivers a greater force per unit volume to less-developed protective structures. This vulnerability often leads to multisystem injuries in the pediatric patient. Examples include hepatic, splenic, and pulmonary injuries as a result of blunt trauma to the chest-the pliable ribs of the child are less protective. In addition, the higher surface area to body mass ratio of children make them more susceptible to heat loss and insensible fluid loss, this has significant implications with regard to resuscitation and may compound the physiological alterations associated with the traumatic injuries themselves. Taking these factors into consideration, the evaluation and resuscitation of the pediatric trauma patient follows wellestablished guidelines detailed in the Advanced Trauma Life Support (ATLS), The Pediatric Emergency Medicine Resource, and the Pediatric Advanced Life Support courses. These guidelines are part of the standard training of the pediatric surgeon and are beyond the scope of this chapter. However, several highlights are covered. Analogous to the care of adult trauma patients, the early evaluation of pediatric trauma patients follows the standard "ABCDE" (.~irway, breathing, circulation, disability, ~xpo sure) format detailed in the ATLS guidelines. With respect to airway, several critical aspects distinguish the care of the injured child.!" In very young children, there is a significant disproportion between the cranium and midface, this results in a tendency for the neck to flex when a child is in the supine position, often obstructing the posterior pharynx. In addition, the larynx of the young child is often more anterior compared to older children and adults. Similarly, the soft tissues of the head and neck of a child may be significantly different from those of the adult. In particular, the relatively large tongue of infants may contribute to decreased visibility during laryngoscopy and may lead to frank airway obstruction. The epi-

686

CHAPTER 36

glottis of children is more prominent and rigid than adults. The trachea of the child is short, and the cricoid ring represents the narrowest portion of the airway in children up to approximately 8 years of age. Overall, all these anatomic characteristics influence the airway management of the pediatric trauma patient. Specifically, traditional teaching dictates the use of uncuffed endotracheal tubes in children less than 8 years of age as the cricoid ring is thought to be a natural sealing point around the endotracheal tube. However, the use of cuffed tubes to decrease the risk of aspiration has recently gained popularity. In addition, the small anatomy of children under 11 years of age means the creation of a surgical airway, namely, emergent cricothyroidotomy, is rarely indicated because of the small target size of the cricothyroid membrane and the risk to nearby structures. Instead, needle cricothyroidotomy with jet insufflation is recommended when bagvalve and orotracheal ventilation are unsuccessful. With regard to breathing, the normal respiratory rate of children decreases with age, with infants breathing around 60 breaths per minute and older children down to 20 breaths per minute. Proper ventilation of the pediatric trauma patient is of utmost importance because hypoventilation can lead to profound respiratory acidosis and is the most common etiology of cardiac arrest in children. To achieve adequate ventilation, appropriate tidal volumes range from 7 to 10mL/kg. 129 The treatment of pneumothoraces may require needle thoracostomy at the second intercostal space at the midclavicular line or standard tube thoracostomy at the fifth intercostal space at the anterior axillary line. Assessment of circulation and shock in the pediatric trauma patient may be difficult. The accepted ranges for vital signs vary significantly with age and are readily available in any pediatric text. As a rule of thumb, ATLS guidelines state that the systolic blood pressure for a child should be approximately 8 mmHg plus twice the age in years.!" Compared to adults, children have a larger physiological reserve and often manifest the physical signs of hypovolemic shock much later. In addition, the relatively large head size of children leads to a higher incidence of head trauma, often decreasing the value of mental status changes in the assessment of shock. Finally, the lower overall blood volume of children can lead to significant physiological derangements with relatively small actual blood losses. The treatment of hypovolemic shock in the pediatric patient follows standard principles, with warmed crystalloid used as a first-line agent. Typical boluses are administered in 20-ml/kg increments. If the signs of shock do not resolve and/or significant blood loss is recognized, typespecific or a-negative blood is administered. The patient's urine output is an indicator of volume status, with normal urine output being more than 2mL/kg/h in children less than 1 year of age and 1 to 1.5mL/kg/h in older children and adolescents.l" Venous access is secured peripherally. If this is unsuccessful, and emergency access is necessary, intraosseus access in the proximal tibia below the tuberosity or in the distal femur can be used for children under 6 years of age. Saphenous vein cutdowns (ankle or groin) and central venous access are also options. As already stated, head injuries are particularly common among pediatric trauma patients, with more than 95,000 cases of pediatric traumatic brain injury in the United States each year.P" The appropriate assessment and treatment of neurological disability is of great importance in the injured

child. Historically, children with head injuries were often treated with a volume restrictive approach based on concerns that aggressive resuscitation may lead to increased intracranial pressures and worsen neurological injury. Today, these approaches are generally considered to be incorrect, as hypotension has been shown to be profoundly detrimental to the head-injured child. Specifically, it has been shown that pediatric trauma patients with a presenting Glasgow Coma Score (GCS).of 6 to 8 have a significantly higher mortality rate if they are also hypotensive.!" Therefore, aggressive resuscitation and treatment of hypotension are vital to the care of the head-injured child. The assessment of neurological injury is based on physical examination. CT scan of the head is often useful in patients suspected of intracranial injury because elevated intracranial pressure (ICP) may occur in children without any significant signs or symptoms. Patients with changes in mental status or affect may be at high risk for intracranial injury. Intubation is indicated in patients with a GCS of 8 or less or a GCS motor score of 2 or less. Antiepileptics (phenobarbitol, phenytoin, diazepam) may be administered to the brain-injured patient. Efforts to decrease ICP using diuretics (lasix, mannitol) may be performed but should be used with caution as they may exacerbate hypotension. Finally, exposure including a complete examination of the patient's front and back is important. This examination also includes the identification of any injurious environmental factors to which the child may have been exposed. Last, it is important to maintain an adequate thermal environment using heating devices or blankets throughout the trauma survey.

Pediatric Closed Head Injury Head injury accounts for nearly 7000 childhood deaths in the United States each year. 130 Common injuries in children include concussions, diffuse axonal injury, contusions, epidural hematomas, subdural hematomas, and skull fractures. CONCUSSIONS

A concussion may be defined as the mild end of a group of injuries resulting from angular acceleration-deceleration forces that result in a transient loss of consciousness, followed by a return of normal mental function. In children, concussions may occur after falls, collisions, or impacts with moving objects, and may present with a variety of symptoms including headaches, blurry vision, irritability, and decreased attention. No absolute guidelines exist for the workup and treatment of children suspected to have a concussion. In general, CT scan of the head is indicated in children with persistent symptoms. If this does not reveal any other injury but the patient's symptoms persist, admission and observation may be warranted. Children whose symptoms resolve and return to a baseline level of mental function can often be discharged with instructions to the parents to seek medical attention if symptoms return. DIFFUSE AxONAL INJURY

Diffuse axonal injury (DAI) occurs when shear strains applied to the brain cause axonal tears in a characteristic distribution. This injury commonly caused by severe angular or rotational

PEDIATRIC SURGERY

acceleration-deceleration forces. CT scan or MRI may display characteristic small hemorrhages within the brain. Typically, DAI is characterized by an immediate loss of consciousness associated with decerebrate or decorticate posturing. Hypertension, hyperhydrosis, and hyperthermia may also be seen. Similar to other closed head injuries, DAI is often managed nonsurgically with supportive care and management of intracranial pressures. CEREBRAL CONTUSION

Cerebral contusions are observed in up to 300/0 of patients with severe head injury. 130 They may be focal or diffuse and may occur with or without direct contact to the head. Contusions can occur underlying a point of external injury (coup contusions) such as under a skull fracture or may occur at a location remote from a point of contact (countercoup contusions) because of forces between the brain and the skull. Cerebral contusions may exhibit significant swelling of the injured tissue as well as adjacent tissues because of toxic metabolite release from the injured brain. This swelling typically peaks at 4 to 6 days postinjury. Medical management of cerebral contusions involves supportive care and management of intracranial pressure. Progressive mass effect may require surgical decompression. EPIDURAL HEMATOMA AND SUBDURAL HEMATOMA

Epidural hematomas (EDH) and subdural hematomas (SDH) in children under 3 years of age are caused by falls, motor vehicle accidents, bicycle accidents, and child abuse. As children reach adolescence, the incidence of head trauma from motor vehicle accidents and bicycle accidents increases while the incidence from falls decreases. In addition, assault becomes a more common cause of these injuries in the adolescent population. Epidural hematomas are usually caused by a tear in the middle meningeal artery. Once considered neurosurgical emergencies, EDHs have recently been managed nonsurgically in neurologically intact patients. In children, EDHs may show spontaneous regression and resorption in 4 to 6 weeks. Craniotomy and evacuation of the hematoma is indicated in patients with focal neurological deficits, increasing lethargy, and signs of brainstem compression. Similarly, small subdural hematomas in children with few to no neurological symptoms may be managed conservatively. Craniotomy and evacuation of the hematoma are indicated in patients with large SDHs who display neurological deficit. Compared to EDHs, SDHs are more commonly associated with underlying parenchymal injury to the brain. SKULL FRACTURES

Skull fractures are noted in 8 % to 41 % of head-injured children. Linear skull fractures account for 75 % 130; these are not often associated with underlying brain injury and commonly heal within 1 to 2 months. Depressed skull fractures occur in 70/0 to 100/0 and often require surgery; these are commonly caused by falls, motor vehicle and bicycle accidents, and birth injury. Operative intervention is indicated for grossly contaminated fractures, underlying symptomatic hematomas, intracerebral bone fragments, cerebrospinal fluid (CSF) leak, and associated neurological deficits.

687

MANAGEMENT OF SEVERE PEDIATRIC TRAUMATIC BRAIN INJURY

In a recent issue of seminars in pediatric surgery, guidelines for the management of severe traumatic brain injury in children were reviewed. 130 Highlights include the following:

• Airway management and resuscitation o Airway control should be obtained in children with a GCS of 8 or less. o Hypoxia and hypotension must be identified and treated immediately. • ICP monitoring and management o ICP monitors recommended in infants and children with a GCS of 8 or less. o ICP monitoring may be indicated in children in whom sedation, neuromuscular blockade, or anesthesia do not allow for serial neurological examination. o Treatment should be considered for ICP above 20 to 25mmHg. o Cerebral perfusion pressure (CPP) should be maintained above 40 mmHg. o Options for ICP management include drainage, neuromuscular blockade, sedation, administration of hypertonic saline, mannitol with serum osmolality maintained at less than 320 mOsm/L, and barbiturate-induced coma. o Chronic hyperventilation should be avoided because of hypocapnia-induced vasoconstriction and compromise of cerebral blood flow. • Anticonvulsant prophylaxis o The use of prophylactic anticonvulsants to prevent posttraumatic seizures has not been well studied. o The use of prophylactic anticonvulsants to prevent early (within 7 days of injury) posttraumatic seizures may be considered. o The use of prophylactic anticonvulsants to prevent late (after 7 days of injury) posttraumatic seizures is not recommended.

Thoracic Injury in Children Thoracic injuries represent a major source of morbidity and mortality among children, occurring in 40/0 to 6% of children hospitalized for trauma and accounting for 25% of pediatric trauma deaths.':" Penetrating thoracic trauma in children and adolescents is often severe and is most commonly caused by gunshot wounds, although knife wounds and impalement injuries occur.F" Chest radiographs and CT scans (in stable patients) are useful in determining the trajectory of injury and in identifying possible organ damage. Hemothorax and pneumothorax are the most common injury patterns seen. After airway management, needle decompression and/or tube thoracostomy is usually indicated. Thoracotomy is indicated in patients with immediate chest tube output of 200/0 of their estimated blood volume or 2mL/kg/h or more of persistent output. The indications for ER thoracotomy (ERT)in children are unclear. ERT may be useful in children with suspected cardiac tamponade from penetrating trauma. Such tamponade should be treated with a vertical incision above and parallel to the phrenic nerve. Myocardial lacerations may be repaired primarily using polypropylene suture.

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Blunt thoracic injury accounts for 800/0 to 850/0 of all pediatric thoracic injuries.':" These injuries commonly occur as a result of motor vehicle accidents, pedestrian accidents, and falls. In children, pulmonary contusions, rib fractures, and pneumothoraces are the most common chest injuries. Injuries to the heart, great vessels, tracheobronchial tree, diaphragm, and esophagus are rare. Overall, less than 10% of pediatric blunt chest injuries require surgical intervention. However, the presence of thoracic injuries in children with multiple injuries is associated with a 20-fold increase in mortality compared to children without chest trauma. Management of blunt thoracic trauma in children requires an understanding of the anatomic and physiological differences between children and adults.':" Compared to an adult, a child's chest wall is extremely compliant because of incomplete ossification of the ribs and a greater overall collagen content. This compliance means that significant amounts of energy may be transferred to the chest wall and intrathoracic contents without a resultant fracture. In fact, rib fractures occur in only half of children with pulmonary contusions. Similarly, the mediastinum of young children is very mobile compared to that of adults. This can lead to significant mediastinal shift with injuries such as hemothorax, pneumothorax, or diaphragmatic rupture. Eventually, this may result in decreased venous return to the heart and impaired cardiac output because of displacement of the heart and great vessels. From a metabolic standpoint, children consume more oxygen per kilogram of body weight compared to adults. This factor, combined with a relatively decreased pulmonary functional residual capacity, makes children particularly sensitive to the development of hypoxemia with chest injury. Evaluation of a child with a blunt chest injury follows standard ATLS principles. A high index of suspicion is critical for the early detection and management of blunt thoracic trauma as injuries are often not apparent on initial examination. Signs and symptoms associated with thoracic injuries include chest wall crepitus, subcutaneous emphysema, diminished breath sounds, and varying degrees of respiratory compromise evidenced by nasal flaring, retractions, tachypnea, dyspnea, and low oxygen saturation by transcutaneous pulse oximetry. Standard anteroposterior chest radiographs are a valuable tool in the evaluation of possible thoracic trauma and have been found to be abnormal in 60% to 900/0 of children with significant injuries.P' If a widened or abnormal mediastinum is demonstrated on chest radiograph, helical CT scan of the chest is warranted to rule out aortic injury. In addition, the chest CT scan is useful in identifying injuries not appreciated on plain films such as pulmonary contusion or rib fractures. Recent data suggest that the chest CT scan may identify additional thoracic injuries in up to 150/0 of patients with a normal chest X_ray.131 The management of thoracic trauma varies depending on the pattern of injury and organs affected. A complete discussion of thoracic trauma is beyond the scope of this chapter. However, the common blunt thoracic injuries are highlighted. RIB FRACTURES AND CHEST WALL INJURIES

Because of the compliance of their chest walls, rib fractures are relatively rare (1 0/0-2 0/0) in children. When present, they are often an indicator of significant trauma and have been

associated with a trauma mortality of 43% to 50%.131 Moreover, first rib fractures are uncommon and may be associated with significant vascular injuries. In patients under 3 years old, rib fractures are often because of child abuse, with a positive predictive value of 950/0 to 1000/0 in patients for whom motor vehicle collisions or predisposing medical conditions can be ruled out.':" Management of rib fractures is nonsurgical, consisting of pulmonary toilet and pain management. PULMONARY CONTUSIONS

Pulmonary contusions result in alveolar disruption, hemorrhage, and interstitial edema. The presentation of pulmonary contusions varies from radiographic abnormality alone to severe respiratory distress requiring mechanical ventilation. The process of inflammation and swelling associated with such injury often peaks at 24 to 48 h, with radiographic changes often becoming apparent 4 to 6 hours postinjury. Thus, significant pulmonary contusions cannot be ruled out by a normal chest radiograph, although such studies are abnormal in 67% to 900/0 of children with the injury. 131 Helical chest CT scan can be helpful in diagnosing and characterizing pulmonary contusions. Clinically, pulmonary contusions can lead to significant ventilation/perfusion mismatches, intrapulmonary shunting, atelectasis, and consolidation. Serious complications of these injuries include pneumonia (200/0), acute respiratory distress syndrome (50/0-20%), and death (15%-200/0).131 Management is usually supportive, consisting of pulmonary toilet, pain control, judicious fluid management to minimize alveolar edema, and sometimes assisted venitilation. Approximately 200/0 to 370/0 of children with pulmonary contusions require mechanical ventilation.F" With appropriate treatment, most pulmonary contusions resolve within 7 to 10 days. PNEUMOTHORAX AND HEMOTHORAX

As stated previously, the relatively mobile mediastinum of children makes them particularly sensitive to hemodynamic compromise as a result of pneumothorax. As in adults, pneumothoraces are most commonly treated with tube thoracostomy. Hemothorax is noted in 130/0 to 290/0 of children suffering from blunt chest trauma.!" Bleeding is most commonly from a pulmonary parenchymal laceration or a lacerated intercostal vessel. Tube thoracostomy is indicated in these cases to provide prompt evacuation of the intrapleural blood. Retained blood in the pleural space may lead to empyema or fibrothorax and should be evacuated within 1 week of injury. TRACHEOBRONCHIAL INJURIES

Tracheobronchial injuries in children are rare (0.7%-2.8%).131 The most common mechanisms for these injuries include motor vehicle accidents, pedestrian accidents, falls, and crush injuries. These injuries are generally severe, with an approximately 30% mortality, half of which occurs within the first hour after injury. Anatomically, tracheobronchial ruptures usually occur within 2.5 em of the carina because of anterior-posterior compressive forces. Tracheobronchial injuries may present with pneumothorax, hemothorax, hemoptysis,

PEDIATRIC SURGERY

or subcutaneous emphysema. Patients may initially display minimal symptoms or may be in acute respiratory distress. Chest radiograph and CT scan rarely demonstrate a clear disruption of the tracheobronchial tree, although pneumothorax or hemothorax may be easily visualized. A high index of suspicion is the key to prompt diagnosis, with suggestive clinical signs including failure of a pneumothorax to resolve with tube thoracostomy, persistent air leak, and persistent pneumomediastinum. Bronchoscopy is useful in diagnosing and determining the location of the injury so that an endotracheal tube may be passed beyond it for ventilation. Treatment of tracheobronchial injuries is based on the size of the injury and the respiratory stability of the patient. Injuries encompassing less than one-third the diameter of the bronchus in clinically stable patients may be managed nonsurgically. Larger injuries, or injuries in those clinically unstable (e.g., unable to adequately ventilate, increasing pneumothorax despite thoracostomy) may require operative intervention ranging from primary repair to pulmonary resection depending on the extent of the injury and potential concomitant injuries. Complications include pulmonary infections, bronchial stenosis, and bronchopleural fistulae. AORTIC INJURY

Blunt aortic injury (BAI) is rare (1 0/0) in children. Compared to adults, thoracic aortic injuries were found in only 2% to 50/0 of children dying of blunt trauma on autopsy versus 150/0 to 170/0. 13 1 These injuries are most commonly a result of motor vehicle accidents (usually improper use of restraint belts), pedestrian accidents, and falls. The majority die at the scene of the accident or during transport. However, children who remain alive until diagnosis have a survival of 670/0 to 91 0/0. 13 1 Injuries commonly occur at the aortic isthmus distal to the left subclavian artery (at the level of the ligamentum arteriosum). Chest radiograph findings that indicate the potential for BAI include a widened mediastinum, first rib fracture, and loss of the normal aortic contour. Aortic arch angiography is still the gold standard for the diagnosis of BAI, although helical CT scan with CT angiogram has become increasingly utilized. In addition, transthoracic echocardiography and intravascular ultrasound have been advocated as diagnostic adjuncts in patients in whom angiography is equivocal. At this time, operative repair of BAI remains the standard of care. Tight preoperative blood pressure control is important for decreasing the risk of injury extension or aortic rupture. Postoperative paraplegia is a complication of thoracic aortic repair; it can occur in 50/0 to 170/0 of patients and is associated with aortic cross-clamp times greater than 30min. 13 1 In children, primary repair is preferable to interposition graft, when possible, because of the possibility of aortic pseudocoarctation as a result of postoperative growth. If an interposition graft is necessary, the largest graft size possible should be used. In patients in whom concomitant injuries preclude operative aortic repair, delayed aortic repair or expectant management may be considered. In these cases, aggressive blood pressure control and serial imaging to monitor for changes in aortic hematoma are keys to successful management. Last, endovascular stent grafts to repair thoracic aortic injuries in adults and children have been used, although experience is extremely limited.

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Blunt cardiac injury (BCI) in children ranges from 0.3 % to 4.60/0. 131 By far the most common blunt injuries to the heart are cardiac contusions, accounting for 95% of all BCls. Cardiac rupture accounts for the other 5 % of injuries, with an extremely low survival rate. The clinical presentation of cardiac contusion is variable, ranging from isolated electrocardiographic (ECG) changes to dysrhythmias and hypotension. The diagnosis can be difficult. ECG, cardiac enzymes, and echo cardiography have been advocated as diagnostic methods. The management of cardiac contusion is supportive. Patients should be monitored (cardiac monitoring) until hemodynamic stability and cardiac rhythm abnormalities have been resolved. Dysrhythmias are treated pharmacologically. Most children do well with minimal long-term sequelae from the injury. Commotio cordis is a rare condition most commonly seen in 12- to 13-year-old children in whom sudden death occurs after blunt impact to the chest wall without evidence of significant injury. The injury commonly occurs during sports and is thought to be caused by ventricular fibrillation triggered by blunt impact to the chest during cardiac repolarization. The overall mortality rate for commotio cordis is approximately 160/0. The treatment is prompt cardiac defibrillation and supportive care.

Abdominal Injuries in Children Penetrating abdominal injuries in children are most commonly the result of gunshot wounds and stab wounds, although impalement injuries do occur.J" In general, these injuries require surgical intervention. The initial evaluation and treatment follow standard ATLS guidelines. Diagnostic tools include chest and abdominal radiographs to determine bullet trajectory and to identify retained foreign bodies. Concomitant chest injury should also be ruled in or out. CT scan and laparoscopy have been advocated in cases where it is unclear if the peritoneal cavity has been violated. The management of penetrating abdominal trauma depends on the particular organs injured. Solid organ injuries (e.g., liver, spleen) can typically be treated with packing and local hemostatic maneuvers, although resection may be required for severe injuries. In the pediatric population, the risk of postsplenectomy sepsis favors splenic salvage when possible. Similarly, the management of penetrating trauma to the GI tract is based on the location and extent of injury. Isolated injuries with minimal blast effect may be managed with debridement and primary repair, taking care to ensure normal bowel caliber. Larger injuries or multiple nearby injuries may require resection and reconstruction. Based on the adult literature, most colonic injuries are managed with primary repair or resection with primary reconstruction. A colostomy is created in unstable patients or in patients with complex injuries. However, data regarding these approaches are sparse in the pediatric population. Blunt abdominal trauma often is most commonly caused by motor vehicle accidents and falls. Overall, approximately 80/0 of all children suffering from blunt trauma sustain trauma to the abdomen.!" Most commonly, the solid organs (liver, spleen, kidney) are affected. Initial evaluation follows ATLS

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guidelines. The abdominal CT scan is the most commonly employed imaging study for the evaluation of pediatric blunt abdominal trauma. Such CT scans are performed with intravenous contrast. The use of oral contrast, although useful in diagnosing duodenal injuries, carries the risk of aspiration in the child with a head injury. Focused abdominal sonography (FAST) examination in the emergency department has gained wide acceptance for the evaluation of adult trauma patients. However, its use in children by pediatric trauma surgeons has been limited; this may be secondary to high rates of solid organ injury without hemoperitoneum (up to 40%). At this time, its role appears to be as a replacement for diagnostic peritoneal lavage in multiply injured patients too unstable to undergo CT scanning. The management of blunt abdominal trauma in children is based on the clinical stability of the patient. Physiological signs of ongoing hemorrhage such as refractory hemodynamic instability or progressive transfusion requirements require prompt operative exploration. In the adult population, radiographic predictors for the need for surgery versus nonoperative management such as the presence of a "contrast blush," the radiographic "injury grade," or the location and quantity of free peritoneal fluid have been studied. However, the utility of these findings to guide operative versus nonoperative management in the hemodynamically stable pediatric trauma patient is unclear. SPLENIC INJURY

Over the past few decades, the nonoperative management of blunt solid organ injuries in children has gained widespread acceptance. Of the solid abdominal organs, the spleen is the most frequently injured. Although numerous variations exist for the specific management of these injuries, a nonoperative approach is successful in more than 900/0 of patients with grade I to grade IV iniuries.F" Up to 40% of children with grade V injuries can be managed nonoperatively. The nonoperative approach decrease, morbidity, transfusion requirements, and long-term infectious complications. The specifics of management such as length of hospital stay, length of outpatient convalescence, and frequency of follow-up imaging are variable. For patients with low-grade injuries, there is a recent trend toward decreased hospital days (often only 3 days) and the use of nonmonitored, general ward beds instead of an intensive care setting. For the minority of patients who fail nonoperative management, splenectomy is the primary surgical treatment, although an attempt is made to repair the spleen, if possible. In addition, the use of endovascular embolization to control bleeding has been reported. Patients who require splenectomy need vaccination against the encapsulated organisms Streptococcus pneumonia, Haemophilus influenzae type b, and Nisseria meningitides. LIVER INJURY

Injuries to the liver are the most frequent cause of death in children sustaining blunt abdominal trauma. Similar to splenic injuries, the majority of blunt hepatic injuries are managed nonoperatively, and the decision to operate is predicated on the patient's hemodynamic status. Radiographic injury scoring systems do correlate with outcome in children. For patients who require operative intervention, packing and

damage control/hemostatic techniques are employed. Complications of nonoperative management include persistent bile leak, biloma formation, and hemobilia. RENAL INJURY

Children are particularly vulnerable to blunt renal trauma because of the relatively large size of the kidney and relatively less protective Gerota's fascia compared to adults. Nonoperative management of renal injuries has a high success rate in the pediatric population. In fact, renal salvage rates of nearly 900/0 have been reported in large series of children with blunt renal injuries treated nonoperatively.F" Similar series in adults have reported operative rates of approximately 85% across all injury grades. Furthermore, favorable results with nonoperative management have been reported in children with severe injuries including injuries associated with collecting system disruption, renovascular injury, and urinary extravasation. Delayed complications such as impaired renal function, urinomas, and renovascular hypertension are rare. When persistent, these complications may require nephrectomy. PANCREAS INJURY

Blunt pancreatic injury occurs in 30/0 to 12% of children sustaining blunt abdominal trauma and is the most common cause of pancreatitis in children.!" Common mechanisms of injury include child abuse and bicycle handlebar injuries. The diagnosis of pancreatic injury is often difficult, as initial serum enzyme evaluation and abdominal CT scanning may underestimate the extent of injury. In addition, elevated pancreatic enzyme levels poorly correlate with injury severity. Pancreatic injury is often managed nonoperatively. Nonoperative management includes bowel rest (with or without nasogastric decompression) and parenteral nutrition. Healing of the injury is documented with an imaging study (ultrasound or CT scan). Pancreatic pseudocyst formation is a complication that occurs in up to 100/0 of patients treated nonoperatively. These pseudocysts may be treated by percutaneous drainage, distal pancreatectomy, or an enteric drainage procedure. HOLLOW VISCUS INJURY

Intestinal injury has been reported to occur in 1% to 15% of children suffering from blunt trauma.P" Approximately 14% of all intraabdominal injuries in children are hollow organ injuries. These injuries are associated with a mortality rate of 150/0. This relatively high mortality rate is likely caused by the high frequency of associated nonintestinal injuries, namely, traumatic brain injuries. The most common mechanism of blunt hollow viscus injury in children is motor vehicle accidents, followed by bicycle accidents and abuse. In a review of a 12-year experience at one pediatric trauma center, Canty et a1. 135 reported 79 blunt injuries to the GI tract; 190/0 were from seatbelts, 130/0 from bicycle handlebars, and 19% from abuse. Intestinal injury rates are increasing as a consequence of mandatory use of vehicle restraints. When improperly positioned on a child, a lap belt transmits energy to the abdomen instead of the bony pelvis. During rapid deceleration, the lap belt compresses the intraabdominal organs against the spine, resulting in bowel

PEDIATRIC SURGERY

and/or mesenteric injuries. Lumbar spine fractures (Chance fracture) are common during deceleration/flexion injuries. The most common site of blunt hollow viscus injury is the small intestine. It often occurs near fixation points, such as the ligament of Treitz or the ileocecal valve. 134 In their reviews of large series at pediatric trauma centers, Canty et a1. 135 and Galifer et a1. 136 found the jejunum or ileum to be the most common site of damage, followed by the duodenum, colon, and finally, stomach. The diagnosis of hollow viscus injury caused by blunt trauma in children is often difficult. Delays in diagnosis are common, necessitating a high index of suspicion to facilitate early diagnosis and treatment. Overall, the diagnosis of these injuries is clinical, based on a conglomeration of factors (physical examination, imaging, observation). Physical examination mayor may not demonstrate peritoneal signs even in the presence of an intestinal leak. In children with blunt intestinal perforation, fewer than 50% were noted to have peritoneal signs on examination.J" In children involved in motor vehicle accidents, abdominal wall ecchymosis (seat belt sign) may be associated with a high incidence of significant injury to the intestine and/or lumbar spine. In addition to physical examination, vital sign abnormalities (temperature, heart rate, urine output, etc.) and adjunctive laboratory studies (complete blood count) may also be useful in evaluating the child with potential blunt intestinal trauma, although normal values do not preclude significant injury. Similarly, imaging studies are used in the evaluation of potential blunt intestinal trauma. Abdominal CT scan imaging is the preferred study, permitting accurate evaluation of the solid abdominal organs as well as the GI tract. The utility of oral contrast is still debated. Current evidence suggests that oral contrast does not increase the diagnostic accuracy of CT imaging and may only serve to delay the time required to complete the scan. CT findings suggestive of intestinal injuries have been described and include bowel wall thickening and enhancement, mesenteric stranding, and free fluid without associated solid visceral injury. Although these findings may increase the suspicion of injury, their presence alone is not an indication for laparotomy. Because of the limitations of noninvasive imaging, peritoneallavage has been advocated as a means of early diagnosis. However, this procedure is invasive and is associated with a significant nontherapeutic laparotomy rate (20%-400/0 ).134 Laparoscopy has been used as a tool for the evaluation of potential blunt intestinal injuries in patients with an abnormal physical examination and CT findings. The absence of all the aforementioned findings does not preclude significant GI tract injury. Therefore, all children with suspected blunt intestinal injuries should be observed for the development of physical findings (e.g., peritonitis). During the operation for blunt intestinal injury, hemorrhage is controlled as concomitant solid organ injury is common. The site of intestinal injury is repaired, debrided, or resected. Blunt injury to the small intestine in children requires inspection of the entire bowel and mesentery. The type of repair is dictated by the extent of injury. Injuries involving less than 500/0 of the bowel circumference are debrided and repaired primarily in a transverse fashion. Perforations involving greater than 500/0 of the bowel circumference require resection and primary anastomosis. Gastric wounds can often be debrided and repaired primarily.

691

A duodenal injury is most commonly a hematoma. In the absence of perforation, it is managed nonoperatively. Nonoperative management consists of supportive care, including nasogastric decompression and total parenteral nutrition, as the hematoma often causes partial or complete obstruction. Resolution of this obstruction often occurs within 10 days. Duodenal perforation requires repair and/or exclusion. The management of colonic injuries has been extensively studied in the adult literature. In the adult population, primary repair appears to be preferable to colostomy and is associated with fewer complications. This approach is likely applicable in the pediatric population but has not been extensively studied.

Maternal-Fetal Surgery Advanced fetal diagnostic techniques (e.g., chorionic villous sampling, amniocentesis) and serial imaging (e.g., ultrasound, magnetic resonance imaging) have led to an increased understanding of the natural history and outcome of many genetic and congenital anomalies. However, before the 1980s, obstetriciansand perinatologists could only observe helplessly as these disease processes took their toll, counseling parents on potentially grim prognoses. When such a fetus survived to birth, pediatricians were then left to care for an infant with devastating medical problems that were untreatable or only partly treatable at this later stage of development. This dilemma fostered basic science and clinical research aimed at understanding and treating congenital diseases during the fetal period. From this research, the field of fetal therapy, and more specifically, maternal-fetal surgery emerged. Although the majority of fetuses with anomalies amenable to surgery are best served by planned delivery and care after birth, there are highly select fetuses in whom an untreated anomaly will result in death in utero or shortly after birth. Prenatal intervention has, in large part, been predicated on those anomalies that result in either low- or highoutput cardiac failure resulting in hydrops, defined as skin and/or nuchal edema or fluid accumulation in two of three body cavities (pleura, pericardium, peritoneum). As the understanding of fetal disease improves, an increasing number of fetal anomalies, including nonlethal anomalies, are being considered amenable to fetal intervention. Currently, anomalies such as cystic adenomatoid malformation, sacrococcygeal teratoma, twin-twin transfusion syndrome, and twin reversed arterial perfusion (TRAP) sequence, obstructive uropathy, select heart anomalies, and congenital diaphragmatic hernia may be treated during the prenatal period. Table 36.20 lists the congenital anomalies that have been treated prenatally. Compared to other fields of surgery, maternal-fetal surgery is unique in that the risks and benefits of a potential intervention have to be considered for two patients, the mother and the fetus. The prerequisites for consideration of intervention include the absence of severe associated anomalies; a normal karyotype; and. the presence of a correctable lesion that if uncorrected will lead to fetal death or irreversible organ dysfunction before birth. Although the risk-benefit ratio may be clear for the fetus, the situation is less clear for the mother. Without antenatal treatment, the risks to the mother are little more than that of the pregnancy alone. With fetal intervention, the risks of preoperative evaluation including

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TABLE 36.20. Applications of Fetal Surgery. Defect

Effect on development

Lethal anomalies: Placental vascular anomalies Twin-twin transfusion syndrome (TTTS)

Vascular steal through placenta

Twin reversed arterial perfusion syndrome (TRAP)

Normal cotwin heart pumps for both twins

Obstructive uropathy

Hydronephrosis Lung hypoplasia Lung hypoplasia

Congenital diaphragmatic hernia Cystic adenomatoid malformation/ sequestration Sacrococcygeal teratoma Complete heart block Pulmonary/aortic stenosis Pericardial teratoma Ebstein's anomaly Congenital high airway obstruction syndrome Obstructive hydrocephalus Nonlethal abnormalities: Myleomeningocele

Lung hypoplasia or hydrops High-output heart failure Low-output failure Ventricular hypertrophy Heart failure Heart failure Pulmonary hypoplasia Overdistension by lung fluid Hydrocephalus

Chiari formation Exposed spinal cord Hydrocephalus

Tension hydrothorax

Lung hypoplasia

Cleft lip/palate Previable premature rupture of membranes

Facial defect Preterm labor

Gastroschisis

Bowel exteriorization

Amniotic bands

Limb/ digit/umbilical cord constriction

Open hysterotomy procedure

~

~

~

~

~

~

Fetal hydrops/demise Surviving twin with severe morbidity High output cardiac failure, hydrops Renal failure Pulmonary failure Pulmonary failure Respirator insufficiency Fetal hydrops/demise Fetal hydrops/demise

~

Fetal hydrops/demise Heart failure Single ventricle physiology Fetal hydrops/demise Fetal hydrops/demise Pulmonary failure Fetal hydrops/demise

~

Brain damage

~ ~

~

~

~

~

~ ~

~

~

Fetoscopic procedure

Fetectomy

Photocoagulation of chorangiopagus

Fetectomy

Selective reduction via umbilical cord ligation or radiofrequency needle Vesicoamniotic shunt Valve ablation Temporary tracheal occlusion (PLUG)

Vesicostomy Complete repair Temporary tracheal occlusion Pulmonary lobectomy Debulk Complete resection Pacemaker Valvuloplasty Resection Valve repair and atrial reduction Tracheostomy EXIT strategy Ventriculoamniotic shunt Ventriculoperitoneal shunt

Radiofrequency ablation Laser vascular occlusion Radiofrequency ablation Pacemaker Catheter valvuloplasty

Tracheostomy Ventriculoamniotic shunt

Paralysis Neurogenic bladder/ bowel Orthopedic anomalies Respiratory failure

Repair

Repair

Persistent deformity Fetal demise Fetal/maternal infection Bowel preivisceritis Prolonged ileus Limb/digit deformity or amputation Fetal demise (cord occlusion)

Repair

Serial thoracocenteses Thoracoamniotic shunt Repair Amniopatch Amniograft

amniocentesis, chorionic villous sampling, and percutaneous umbilical blood sampling, as well as the risks of an operation, must be considered. In addition, maternal comorbidities and psychosocial support structure must be taken into account. Although there have been no reported maternal deaths during or after fetal surgery, complications such as bleeding, wound infection, preterm labor, deep venous thrombosis, and pulmonary embolus have occurred.

Amnioexchange Laser separation of bands

At this time, several techniques have been utilized to perform fetal surgery. Overall, these techniques involve a method of accessing the fetus and represent an evolution of surgical technique toward a less invasive approach. The open hysterotomy technique involves a low transverse skin incision or vertical midline incision followed by a stapler-made hysterotomy. The ex utero intrapartum treatment (EXIT) procedure is another strategy that is used principally for late-

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_"fl"'_ TABLE 36.21.

Prospective Randomized Clinical Trials in Fetal Surgery for Severe Congenital Diaphragmatic Hernia.

Trial

Experimental group

Control group

Survival rate s

Harrison et al. 199737

4: Fetal open hysterotomy repair

Harrison et al. 200338

11: Fetoscopic balloon tracheal occlusion

7: Postnatal supportive therapy and repair 13: Postnatal supportive ther apy and repair

Experiment al: 75% Contro l: 86% Experimental: 77% Control: 73%

gestation fetuses with potential airway obstruction from a neck mass such as a teratoma or lymphangioma. It is similar to a cesarean delivery, except myometrial bleeding is controlled and the umbilical cord is not cut until an airway is obtained, either by orotracheal intubation, tracheostomy, or mass resection followed by intubation or tracheostomy. Once a definitive airway is obtained, the umbilical cord is cut and the patient is from placental support to mechanical support. Fetoscopy and endoscopic instrumentation are used for select procedures (e.g., laser coagulation for twin-twin transfusion syndrome], During the procedure, the turbid amniotic fluid is replaced with lactated Ringer's solution to enable videoscopic visualization. Two or three trocars are used. Although the clinical experience with fetal surgery is growing, it is still relatively limited because most anomalies amenable to fetal surgery are relatively rare, even at the busiest centers. Because of this, published clinical data regarding fetal surgery have primarily consisted of case series demonstrating the safety and feasibility of fetal surgical operations. To date, only two randomized prospective clinical trials have been completed investigating the efficacy of fetal surgical treatment of CDH. Published in 1997 by Harrison et a1.,37 the first trial compared fetal repair of a CDH via an open hysterotomy approach to standard postnatal care and surgery. The second trial, published in 2003,38compared fetoscopic balloon tracheal occlusion to induce lung growth for fetuses with severe CDH to postnatal care. In both trials, no statistically significant difference was found between the two treatment groups. Table 36.21 summarizes the results of these trials. In addition to these trials, ongoing prospective randomized trials exist for fetal surgical treatment of myelomeningocele and twin-twin transfusion syn dro m e. Overall, the clinical evidence regarding the efficacy of fetal surgery compared to conventional treatments is still sparse, and more data ar e needed. However, as scientific knowledge of fetal anomalies as well as clinical experience with fetal surgical techniques improves, the prenatal treatment of congenital diseases may become an increasingly utilized treatment option.

References 1. Grosfeld J1. Pediatric surgery. In: Sabiston DC, Lyerly HK, eds. Textbook of Surgery: The Biological Basis of Modem Surgical Practice, 15th ed. Philadelphia: Saunders, 1997:12341274. 2. Forster J. The Surgical Diseases of Children. London: John W. Parker & Son, 1860. 3. Guersant P. Notices sur la Chirurgie des Infants . Paris: Asselin : 1864.

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Surgery in the Immunocompromised Patient John Mihran Davis and Kathleen King Casey Drug Therapy Toxicities and Postexposure Prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Protection from Disease Transmission Centers for Disease Control Reclassification of HIV Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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t is currently estimated that more than 40 million people worldwide are infected with the human immunodeficiency virus (HIV). Although there is no end in sight to the epidemic, current therapeutics have significantly altered the course of the illness. HIV-infected people are much more likely to live longer, less likely to die of opportunistic infections, and more likely to present to the surgical community with relatively well-pre served immune function . Physicians must be not only armed with knowledg e on how to protect themselves from inadvertent infection but possess a basic und erstanding of the disease process and treatment. Patients present with malignancies, end-organ failures, and treatmentrelat ed toxicities as well as those illnesses expected in any adult population regardless of immune function . Surgical intervention is routine, and outcome will be influenced by how well we define preoperative risk and understand optimum perioperative management. The concept of evidence-based medicine is predicated on the availability of clinical evidence gleaned from systematic research coupled with individual clinical experience. More than two decades into the HIV/acquired immunodeficiency syndrome (AIDS) epidemic, there is still a paucity of systematic research and very few centers that have extensive clinical experience with performing surgery on HIV-infected individuals. A thorough review of the literature reveals that the bulk of the articles dealing with surgery and HIV concentrate on issues of risk of transmission in the workplace and not patient care. Even within the realm of antiretroviral management, evidence-based medicine has been slow to evolve. The urgency to develop antiretroviral agents resulted in an entirely new approach at the Food and Drug Administration (FDA) toward accelerating the approval process for therapeutic agents and allowing clinical use earlier in the approval process. The current standard of care involving a three-drug antiretroviral regimen only came into use in 1996. Until recently, a

Care of HIV-Infected Patients: Surgical Issues Pathogenesis of HIV Infection . . . . . . . . . . . . . . . . . . . . . . Specific Cancer Issues . . . . . . . . . . . . . . . . . . . . . . . . . . .. Miscellaneous Surgical Interventions. . . . . . . . . . . . . . . . References

702 702 703 704 70S

48-week protocol was perceived as a "long-term" study. It is only in the past 2 years that clinical trial data have provided conclusions that predict inferiority or toxicity with particular regimens. We now know that the use of stavudine and (d4T) didanosine [ddl ], simultaneously, increases the likelihood of lactic acidosis . Studies have also been able to document the clinical inferiority of triple nucleoside regimens in patients with high viral loads.

Drug Therapy Toxicities and Postexposure Prophylaxis All healthcare professionals who have occupational exposure to blood are at risk of acquiring HIV infection. Over the past two decades myriad innovations in safer needle devices, barrier protections, and safer practices have been introduced to minimize exposure to blood. Percutaneous injury is the most common mechanism of transmission. The pooled data from 21 prospective studies estimate the risk of percutaneous acquisition associated with needles and other contaminated devices to be 0.2%.1 Variable influences thought to favor the transmissibility of infect ion are hollow-bore needles and a high HIV viral load in the source patient, but undoubtedly there are other host variables, such as cytoxic T-lymphocyte response, and perhaps T-cell C3a/Csa receptors that may also influence the outcome. It is important to counsel the exposed healthcare worker as to his/her individual risk at the time of the incident. Mucocutaneous exposures accounted for about 12% of the HIV infections reported to the Centers for Disease Control (CDC) as occupationally related by 1992.2 The risk associated with such exposures is very difficult to quantify as many go unreported and those reported may differ substantially in characteristics of exposure . The estimated risk of mucocutaneous exposure is believed now to be approximately 0.09%. 697

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Proper management of occupational blood exposure focuses on a thorough assessment of the type of exposure, the source patient, and prompt counseling of the exposed healthcare worker. Is the source HIV infected? What type of exposure occurred? Is antiretroviral therapy appropriate in the exposed healthcare worker (HCW)? It is thought that to be efficacious such therapy should be administered within a 4-h window after exposure; consequently, time is of the essence. Establishing the source's HIV status should be done whenever possible. Fortunately rapid HIV testing is commercially available and should be employed if the source's status is unknown. The SUDS (Single Use Diagnostic System) HIV-1 test manufactured by Abbot-Murex Diagnostics is a rapid test requiring about 15min to perform. It is highly sensitive such that a negative test is reliable evidence against the presence of HIV infection. With the new enzyme-linked immunosorbent assay (ELISA) tests, the window between infection and a positive test is thought to be only a few days. Therefore, unless there was a clinical suspicion of acute retroviral syndrome in the source, a negative SUDS result should be taken to mean the HCW was not exposed and HIV postexposure prophylaxis (PEP) is unnecessary. If the source cannot be promptly tested, or the source is confirmed to be positive, further assessment of the injury is required. The likelihood of transmission is thought to be increased when a hollow-bore device caused a deep injury from a patient whose viral load is high. In the case control study done by the CDC,3 it was noted that death of the HIVpositive source within 2 months of exposure was associated with an increased likelihood of infection. We now presume this is a surrogate marker for a high viral load, but these data were collected before viral loads or highly active antiretroviral therapy (HAART) were part of the standard of care for HIV-infected patients. In accidents involving other devices such as suture needles and mucous membrane exposure, the risk of transmission is very low, but not zero. It is important to mention that transmission has been reported even when viral loads were nondetectable (Table 37.1). Each case warrants unique risk analysis as antiretroviral drugs used for prophylaxis are not without side effects; these can be merely nausea, diarrhea, or headache, but serious side effects such as rashes, nephrolithiasis, hepatitis, hyperglycemia, and pancytopenia have been reported (Table 37.2). When nevirapine was included as a prophylactic agent serious hepatotoxicity occurred and necessitated a liver transplant in one person. We now know that nevirapine poses a serious hepatic risk to anyone with immune competence, but when it is used therapeutically it can quickly drop the viral load in infected individuals. In fact, it is still a mainstay of perinatal vertical transmission intervention when no prenatal care has been available, for that very reason. In 1995, Julie Gerberding published a review article in the New England Journal of Medicine discussing management of occupation exposures to blood-borne viruses." This article stressed that there was a paucity of data regarding the utility of PEP with zidovudine. The argument to take zidovudine was mainly the biological plausibility that it might interfere with transmission by keeping the viral replication in check to allow the cellular immune system to respond to a relatively small inoculum and thereby avoid established infection. There were no controlled data, and Dr. Gerberding stated

TABLE 37.1. Possible Antiretroviral Regimens for Occupational Exposure to Human Immunodeficiency Virus (HIV).

Preferred regimens NNRTI based Protease inhibitor (PI) based

Alternative regimens NNRTI based PI based

Triple NRTI

Efavirenz" plus (lamivudine or emtricitabine) plus (zidovudine or tenofovir) Lopinavir/ritonavir (coformulated as Kaletra) plus (lamivudine or emtricitabine) plus zidovudine Efavirenz plus (lamivudine or emtricitabine) plus abacavir or didanosine or stavudine'' Atazanavir plus (lamivudine or emtricitabine) plus (zidovudine or stavudine or abacavir or didanosine) or (tenofovir plus ritonavir, lOOmg/day) Fosamprenavir plus (lamivudine or emtricitabine) or (abacavir or tenofovir or didanosine) Posamprenavir/ritonavir' plus (lamivudine or emtricitabine) plus zidovudine or stavudine or abacavir or tenofovir or didanosine) Indinavir/ritonavir-" plus (lamivudine or emtricitabine) plus (zidovudine or stavudine or abacavir or tenofovir or didanosine) Lopinavir/ritonavir (coformulated at Kaletra) plus (lamivudine or emtricitabine) plus (stavudine or abacavir or tenofovir or didanosine) N elfinavir plus (lamivudine or emtricitabine) plus (zidovudine or stavudine or abacavir or tenofovir or didanosine) Saquinavir (hgc or sgcl/ritonavir" plus (lamivudine or emtricitabine) plus (zidovudine or stavudine or abacavir or tenofovir or didanosine) Abacavir plus lamivudine plus zidovudine (only when an NNRTI- or PI-based regimen cannot or should not be used)

NNRTI, nonnucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; sgc, soft-gel saquinavir capsule [Portovase], hgc, hard-gel saquinavir capsule (Invirase). "Efavirenz should be avoided in pregnant women and women of childbearing potential. bHigher incidence of lipoatrophy, hyperlipidemia, and mitochondrial toxicities associated with stavudine than with other NRTIs. 'Low-dose (100400mg) ritonavir. dUse of ritonavir with indinavir might increase risk for renal adverse events. Source: u.s. Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HN-Infected Adults and Adolescents, October 29, 2004 revision. Available at http://www.aidsinfo.nih.gov/guidelines/ default_db2.asp?id=50. This document is updated periodically; refer to Web site for updated versions.

it should not be regarded as the standard of care given the uncertainties about the efficacy and safety of zidovudine in this setting. Despite this, its use became widespread, and by the time she wrote another review on the subject in 2003, antiretroviral therapy had become the standard of care." The 2001 U.S. Public Health guidelines recommend a 4week regimen of two drugs be started as soon as possible after HIV exposure by mucosal routes. If the injury includes damage by a hollow-bore needle, associated with a deep injury, or caused by a device that had directly entered an artery or vein,

699

S U R G E R Y IN THE IMMUNOC OMPROMISED PATIENT

TABLE 37.2. Adverse Effects of Antiretroviral Therapies. Reaction

Drug

Cutaneous: Hypersensitivity reaction Skin rash

ABC

Stevens-Johnson syndrome Toxic epidermal necrosis Hematological: Bone marrow suppression Increased bleeding episodes in hemophilia Gastrointestinal: GI intolerance Hepatic necrosis Hepatitis Hyperbilirubinemia Pancreatitis Metabolic: Fat maldistribution Hyperlipidemia Mitochondrial toxicity (with lactic acidosis/steatosis] Osteonecrosis Musculoskeletal: Myopathy Nephrotoxicity: Interstitial nephritis Renal stones Neurotoxicity: CNS effects Lactic acidosis with ascending neuromuscular weakness Peripheral neuropathy

NVP, EFV, DLV ABC, APV, f-APV, ATV TPV/RTV NVP, EFV, DLV APV, f-APV, ABC ZDV, delI, IDV, LPV/r ATV ZDV All PIs All PI's, ZDV, delI NVP All NRTIs, NNRTIs, and PIs IDV, ATV ddl, delI + d4T PIs, d4T All PIs except ATV, d4T,

±EFV

d4T most frequently implicated All NRTIs especially d4T, ddI, ZDV All PIs ZDV TDF IDV

EFV

d4T delI, d4T, ddc

For definitions of drug acronyms, see Table 37.3.

the addition of a third drug to the regimen was recommended. This change has come about primarily because of the success of perinatal intervention to prevent vertical transmission of HIV. Through the use of antepartum and postpartum antiretrovirals, the vertical transmission rate has been reduced by 90% . The true relevance of these data to occupational exposure is not known. It is clear, however, that with the relatively low risk of transmission from occupational injury it is unlikely that the numbers would ever be sufficient to power a placebo-controlled trial to prove or disprove efficacy. As it has now become the standard of care, it is unlikely that any controlled study will ever be performed. It remains now to refine treatment as to which drugs, for how long, and how many should be used. In 2004 a paper was published by Bassett et a1. regarding the statistical benefit of two-drug versus three-drug regimens. ! As the number of side effects in a three- versus two-drug regimen is greater, fewer people are likely to complete prophylaxis, perhaps negating any beneficial effect of the third drug . There is no evidence that a three-drug regimen is more efficacious in preventing transmission. Its recommendation is based upon the assumption that maximal viral suppression would be most likely to prevent infection. Furthermore, with antiretroviral resistance increasing, perhaps a more specific

FIGURE 37.1. A diagram showing the invasion and reproduction of human immunodeficiency virus (HlVI in a lymphocyte. 1, HIVenters the CD4 lymphocyte; 2, the virus reverse transcriptase converts its RNA to DNA; 3, HIV enters the nucleus and inserts its DNA into the host DNA; 4, new HIV leaves the cell. Sites of action of antiretroviral drugs are identified by the numbers: 1 is the site of the entry where fusion inhibitors work, 2 is the site where nonnucleoside reverse transcriptase and nucleoside reversetranscriptase drugs work; 4 is the site of action of protease inhibitors. selection of agents is warranted based on the knowledge of the source's antiretroviral history (shown schematically in Fig. 37.1 and in Table 37 .3). If available, consultation should be sought with the source's medical provider. As antiretroviral agents are not without harmful side effects, underlying conditions in the healthcare worker must be taken into consideration as well. Anemia, hepatitis, hyperglycemia, and nephrolithiasis are a few of the potential side effects. The only agent identified as not a candidate for use in a PEP regimen is Nevirapine. The 1998 CDC Guidelines had suggested zidovudine and 3TC for a two-agent therapy, now available as Combivir. They added indinavir or nelfinavir as the third drug. In 2001, the guidelines left the choice more open to expertise. Truvada (tenofovir/FTC) once a day with or without efavirenz is an attractive choice currently. However, the increasing prevalence of the 184 mutation among antiretroviral-experienced patients may make both FTC and 3TC ineffective. Local expertise should be sought. Ideally, prophylaxis should begin TABLE 37.3. Antiretroviral Therapies. Nucleoside reverse transcriptase inhibitors (NRTI): Abacavir Didanosine Emtricitabine Lamivudine Stavudine Zalcitabine Zidovudine Tenofovir Entry inhibitors: Enfuvirtide Nonnucleoside reverse transcriptase inhibitors (NNRTI): Delavirdine Efavirenz Nevirapine Protease inhibitors (PI): Amprenavir Atazanavir Fos-amprenavir

Indinavir Lopinavir/Rit Nelfinavir Saquinavir Tripanzvir/rit Darunavir/rit

ABC

delI

FIC

3TC d4T Ddc ZDV TDF T-20

DLV EFV NVP APV

ATZ

f-APV IDV LPV/r NLF SQV TRP/rit DRN/rit

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CHAPTER 37

within 4h of exposure and continue for 28 days. Testing for seroconversion with routine ELISA assays should be done at 6 weeks, 3 months, and 6 months. There is no defined role for polymerase chain reaction (PCR)-RNA assays in monitoring for seroconversion.

surfaces, such as endoscopes, should receive high-level disinfection, which can be achieved with solutions of glutaraldehyde (2%), hydrogen peroxide (3%-6%), or formaldehyde (1 %-80/0).

Transfusions

Protection from Disease Transmission An ongoing concern on the part of healthcare workers, in general, and surgeons in particular, is that of disease transmission. However, it is evident that the microorganisms infecting AIDS patients are not particularly contagious, providing proper precautions are taken (Table 37.4). One major concern for surgeons, operating room committees, infection control committees, and clinicians involved with endoscopy is how to effectively clean instruments, equipment, or other inanimate objects to be used with AIDS patients. Agents that are effective against mycobacteria, the most resistant group of organisms, are also the agents considered most effective against other bacterial and viral pathogens.Y (A complete list of agents and their efficacies can be obtained from the Disinfectants Branch, Office of Pesticides, United States Environmental Protection Agency, 401 M Street, S.W., Washington, DC 20460.) Agents are classified according to whether they are to be used for sterilization, disinfection, or antisepsis." Agents that sterilize inanimate objects kill all microbial organisms as well as bacterial endospores. Disinfectants are not quite as effective in that they are not capable of killing bacterial spores. In many cases, an agent may serve as a disinfectant when placed in contact for a short time with the object requiring cleansing. The same agent may be capable of sterilizing surgical instruments when exposed to them for longer periods. Disinfectants are subclassified as having high-level, intermediate-level, and low-level germicidal activity. High-level agents are effective against bacterial spores. Intermediatelevel disinfectants are less effective against spores but are mycobactericidal. Low-level disinfectants do not kill mycobacteria and some fungi. Antiseptic agents are used on tissue and therefore must be less toxic than sterilants or disinfectants. According to the current recommendations from the CDC, agents classified by the U.S. Environmental Protection Agency as sterilants can be used for sterilization or high-level disinfection, depending on contact time. All instruments entering the bloodstream or other sterile tissues should be sterilized before use. Instruments that contact mucosal

TABLE 37.4. Precautions Healthcare Workers Should Take When Handling Infectious Materials. 1. Wear gloves when handling body fluids. 2. Wear a gown to prevent contamination of clothing. 3. Wash hands after contact with body fluids. 4. Place fluid from a potentially contaminated host in two impervious containers. 5. Clean spills with either a 1:10 dilution of 5.25% sodium hypochlorite in water or with some other type of sterilant. 6. Wear masks and protective eyeglasses when there is a possibility of aerosolization of material.

Additional screening policies at the time of blood donation has reduced the risk of receiving a contaminated unit of blood. It is currently estimated that the risk of receiving a unit of blood that is contaminated with HIV is 1 in 1 million."

Transplantation Because it is known that HIV is present in semen, blood, urine, tears, breast milk, cerebrospinal fluid, and saliva, and because it is suspected that HIV can be present in all secretions and excretions as well as all body tissues,'? potential donors of tissue for transplantation must be tested for HIV to prevent inadvertent transfer of the virus. (The risk of transmitting the virus by artificial insemination has also been documented and should be considered whenever artificial insemination is planned. 11)

Healthcare Workers In 1989, the CDC recommended that universal precautions be adopted as a strategy for interacting with all patients to prevent accidental HIV transmission in the healthcare setting.":" Hospital personnel who come in contact with patients' tissues, blood, body fluids, or excreta must use barrier precautions. Even healthcare workers who do not have exfoliative dermatitis or an open wound should wear gloves during patient care. Evidence suggests that the affinity of HIV for Langerhans' cells may permit the virus to invade a host through apparently intact skin or mucous membranes." As part of any operative procedure on HIV-infected patients, all operating room, nursing, and anesthesia personnel, as well as employees of surgical pathology laboratories and any other laboratories, should use universal precautions for handling equipment and specimens. Employees in ancillary areas, such as housekeeping and dietary services, and the venipuncture team need to be trained in the use of universal precautions (see Table 37.4). Exposures to the virus in the workplace are preventable provided appropriate precautions are in place." Most injuries result from carelessness in handling sharp objects, such as needles and scalpels. Self-inflicted puncture incurred in the course of recapping used needles is the most common cause of inadvertent exposure to HIV and is the most dangerous because of the potential volume of blood in the needle and attached syringe that can serve as an inoculum. Newly designed syringes and needles with automatic self-capping tips have become recently available, as well as scalpels with blade covers. These newer technologies should reduce the accidental injuries. As of 2002 the Occupational Safety and Health Administration (OSHA)has mandated that each institution must maintain records of where and how injuries occur to prevent them in the future. The use of double gloves by the surgeon has been extensively studied in several prospective randomized trials. These

SURGERY IN THE IMMUNOCOMPROMISED PATIENT

studies have shown a surgeon who uses double gloves significantly reduces the chance of contact with patient blood.P:" However, none of the studies showed that the double gloves either reduced disease transmission from the patient to the surgeon or reduced the subsequent infection rate of the patient.

Transmission from Surgical Personnel The HIV-infected surgeon poses an immeasurable risk that he or she will transmit the virus to their patient. Although this concern has been well publicized." there is only one documented report of transmission from a surgeon to patient." Furthermore, the Centers for Disease Control and Prevention has not recommended restricting HIV-positive surgeons from operating." Suspected hepatitis C virus (HCV) transmission has occurred from a surgeon to a patient in which the transmission similarly occurred after the diagnosis in the surgeon. Because these transmissions occurred before the diagnosis of the involved individual, editorial review suggested, rather than promoting the restriction of the surgeon's practice, promoting better barriers to minimize exposure between the surgeon and the patient. In contrast to HIV surgeon-to-patient transmission, hepatitis B virus (HBV) transmission from surgeon to patient is a more significant concern. In a well-documented report involving a nonimmunized cardiac surgeon who acquired HBV infection in the workplace, transmission of the virus occurred in 19 (13%) of 122 patients on whom the surgeon operated over a 12-month period." The surgeon was positive for hepatitis Be antigen (HBeAg), and sweat from inside his glove was found to contain HBV antigen as well as HBV DNA. No deficiencies were found in the surgeon's infection control practice by the CDC, which suggested that the virus might have spread through microperforations in his gloves. This case did not receive the same publicity that cases of HIV transmission have received in the lay press. However, its significance is clear: contact between healthcare workers who are HBV (HBeAg) positive and patients should be restricted. The risk of transmission of HCV from the surgeon to the patient in the operating room is very small. A single well-documented case report is the best evidence that it can occur and supports the concept of improved intraoperative techniques to prevent intraoperative exposure of surgeon and patient blood.

Risks to Surgeons Since 1985 when HIV testing became available, 23,212 healthcare workers acquired HIV in the workplace. Fifty-seven healthcare workers had a negative HIV test at the time of the injury, followed by a documented conversion to HIV or AIDS without having another risk factor. These healthcare workers are listed as "possible" occupationally acquired HIV. No surgeon has had a documented conversion following a needlestick injury in the operating room. Six surgeons have suspected HIV transmission, having no other high-risk behavior than their surgical profession. The risk to a surgeon of acquiring an HIV infection while treating a patient who has undetected AIDS is quite 10w.17,23 The CDC initially evaluated nearly 1500 healthcare workers who cared for AIDS victims. Serum samples were taken from these workers when they first began to work with immunocompromised patients and were stored in anticipation of a

701

test for HIV. Of these workers, 666 were exposed to HIV through needle sticks or through cuts from sharp instruments. When tests were performed on these exposed individuals, none were found to have seroconverted after their exposure to HIV. However, two healthcare workers who had had no baseline blood sample drawn did show a positive antibody test after an injury. Because they did not belong to a known risk group for AIDS, they were believed to have generated antibody to HIV as a result of exposure in the workplace. On the basis of this study, the risk to a healthcare worker of acquiring HIV infection after an accidental needle-stick exposure was concluded to be 2 divided by 666, or 0.3%. A followup study found the rate of infection to be 0.5%.25 Subsequent surveillance of healthcare workers identified 151 individuals who acquired HIV infection in the workplace" had proven seroconversion and 102 were HIV positive, with no HIVnegative baseline serum sample. A serosurvey of 770 surgeons practicing in two inner-city areas where more than 3000 cases of AIDS have been reported was recently conducted by the CDC. 26 Accompanying the assay for HIV, HBV, and HCV was a questionnaire designed to elucidate the various practice patterns of the surgeons tested. One (0.130/0) of the 770 surgeons was HIV positive; he had practiced for more than 25 years and performed more than 300 operations in the past year. The study did not specify how the surgeon acquired HIV, except to note that he did not participate in high-risk behavior. To date, there has been no documented seroconversion in OR personnel after a solidbore needle injury in the operating room (http//www.cdc. gov/ncidod/hip/BLOOD/hivpersonell.htm). Transmission via skin contact with body fluids was documented in the case of a woman whose infant had received multiple transfusions, one of which was from an HIV-infected donor. The baby had received the contaminated transfusion at 3 months of age. The presence of HIV antibody in the mother was not determined until 1 year later, at which time an ELISAresult was positive. The mother was closely involved with the baby's care and took no precautions against contact with the child's blood and body fluids. Seventeen months after the child received the infected blood transfusion, the mother seroconverted. No other risk factors accounted for the change in the mother's HIV antibody titer."

Centers for Disease Control Reclassification of HIV Infection In 1993 the Centers for Disease Control and Prevention (CDC) revised the classification of the HIV-infected adult and adolescent. At that time a CD4 (T-helper lymphocyte) count of less than 200 cells/ul was recognized as an indicator of AIDS regardless of the symptoms. Once a patient has been classified into a given group, they will not be reclassified to a more favorable category, even if their symptoms resolve or the CD4 count rises. However, if the disease progresses or the CD4 count deteriorates, they will be reclassified into the next less favorable group. This system allows for uniformity in patient classification for research trials, scientific communication, and, most of all, facilitates formulation of healthcare policy and strategy. Unfortunately, the system does not take into account the immune reconstitution that occurs with highly active antiretroviral therapy (HAART). A number of studies

702

CHAPTER 37

have been done now to show that secondary prophylaxis for Pneumocystis pneumonia, cytomegalovirus (CMV) retinitis, toxoplasmosis encephalitis, and cryptococcal meningitis may be safely discontinued in patients whose CD4 counts have risen and remained above 200 cells/ul due to HAART. Therefore, patients originally classified as AIDS based on their CD4 count or level of immunocompromise may no longer be expected to behave, after successful treatment with antiretrovirals, as they would have based on their original CDC classification. Even more recent studies evaluating surgical infection rates in gynecological procedures have only been able to correlate increased infection rates with the current CD4 count showing that a CD4 level below 200 cells/ul at the time of the procedure is an independent risk factor for surgical complications. The previous nadir has not been shown to influence the outcome.

Diagnosis The enzyme-linked immunosorbent assay (ELISA) and the Western blot assay are designed to detect the presence of HIV antibody in serum. The ELISA test is considered very sensitive (i.e., its false-negative rate is low, 93 %-1000/0). The specificity of a repeatedly reactive ELISA approaches 99%. The weakness of the ELISA test is that some individuals have antibodies that react with HIV antigens but are not specific for HIV. The Western blot assay is a more specific test but is cumbersome and a less sensitive assay. It is therefore used most effectively in confirming ELISA results, but it is not a good screening test. Most blood banks will not use blood that has demonstrated a positive ELISA reaction even if HIV antibody was not detected by Western blotting." On August 8, 1995, the Food and Drug Administration recommended that all blood donated for transfusion be screened for the p24 antigen (the core structural protein of HIV).29 With the current test for HIV, there is a so-called window period of 25 days between infection and seroconversion. It has been estimated that since 1985, when all banked blood was tested for HIV, 35 patients have contracted HIV infection because the donor blood was collected from an HIVinfected individual during this window period. 3o,31 Additional laboratory tests that may help in the diagnosis of patients who are believed to have HIV infection but in whom HIV antibody screening yields negative results include DNA PCR, antigen testing after immune complex disruption, and RNA reverse transcriptase PCR. 31 The SUDS (single use diagnostic system by Murex Diagnostics) provides a rapid ELISA technology that can yield a reliable result in 15min. A positive SUDS must still be confirmed by Western blot. This assay is especially useful in occupational injury investigation.

Care of HIV-Infected Patients: Surgical Issues General The HIV-infected patient usually presents the surgeon with three clinical problems that relate to the general immunodeficiency of the individual. The surgeon first needs to be aware of the patient's level of immunosuppression because this has

the greatest bearing on the patient's outcome. For example, the risk of a complication after treating a patient with HIV and normal CD4 counts who has a perforated appendix is comparable to patients without an HIV infection. The infectious risks in a patient with AIDS «200 cells/mm"] are more related to an opportunistic organism associated with severe immunosuppression and not the common pathogens.Fr" Renal failure and cardiac dysfunction are also problems that arise as a complication of HIV infection. There is a specific HIV-related nephropathy that occurs in up to 100/0 of HIVinfected patients. The renal disease may also exist as a consequence of other underlying causes such as drug toxicity (pentamidine, foscarnet, and aminoglycosides cause acute tubular necrosis; acyclovir, indinavir, and sulfadiazine cause intratubular obstruction). Until recently the risk of cardiac disease in HIV-infected patients has not been as well documented as renal failure. As HIV-infected patients are living longer, the problems of acquired heart disease have been increasingly appreciated. The incidence of malignancy has also been increasingly recognized during the past two decades. Initially, AIDSdefining tumors, B-ceillymphoma and Kaposi's sarcoma, were associated with HIV and thought to relate to the immunosuppression of the host. Increasingly large numbers of tumors have been associated with HIV infection, including squamous cancer of the cervix, squamous cell cancer of the anus, and lung cancer. It is believed that at some point after HIV infestation, activation of oncogenes and loss of tumor suppressor genes give rise to microsatellite alterations, which are highly pleomorphic segments of DNA associated with tumor growth. The treatment options for these patients require the input of oncology and infectious disease, as well as surgery. Three principal concerns must be considered when evaluating patients who have both HIV and cancer: first, the HIV infection must be managed; second, the malignant disorder must be treated; and finally the underlying immunodeficiency must be considered in relation to the cancer and the HIV infection. The role of the surgeon in the management of these chronically, and sometimes critically, ill patients includes performing diagnostic biopsies, giving supportive care, and managing complications of malignant or infectious processes. These complications include a number of nonsurgical gastrointestinal problems, such as gonococcal proctitis and a fulminant watery diarrhea caused by CryptospotidiumPi"

Pathogenesis of HIV Infection Identified in 1985, HIV is an RNA virus, belonging to the retrovirus family, with the potential of causing neoplasia. This group of viruses was first identified in 1911 by the American pathologist Rous, who described their association with malignancies in animals." Human T-ceillymphotropic virus type I (HTLV-I), a retrovirus related to HIV, has been identified as causing leukemia in humans." The unique characteristic of retroviruses, such as HIV and HTLV, is the enzyme reverse transcriptase, which allows the virus to transcribe viral RNA to the host's DNA. The virus can synthesize double-stranded DNA from single-stranded DNA that has been liberated from the RNA-DNA hybrid. This double-stranded DNA inserts itself into the host's nucleus and serves as a template for viral replication. Thus,

703


whenever the infected host cell synthesizes proteins, new HIV particles are reproduced and disseminated in the host. During this process, the virus also kills the cell in which it resides. Because the CD4, or T-helper, cell is targeted by the HIV, loss of this important cell mediator results in the profound immune dysfunction.

Specific Cancer Issues The association of cancer with AIDS was established with the initial case descriptions in 1981 of immunodeficiency in gay men with Kaposi's sarcoma. Subsequently, intermediate- or high-grade B cell non-Hodgkin's lymphoma was seen with increasing frequency, as was cancer of the cervix uteri. These cancers have subsequently been referred to as AIDS-defining cancers (ADC). Although failing immune function and the development of malignancy appear to be directly related for the ADC, the actual relationship is not that simple.P'" For example, cervical cancer has been shown to occur in immunocompetent individuals who are HIV infected (Table 37.5). Other cancers have been seen with increasing frequency in HIV-infected patients, and the specific relationships with immune suppression in still being defined. As yet the data for individual cancers that are not AIDS-defining cancers (NADC) have been evaluated on a limited basis. It is clear that there is an increased risk in HIV patients to develop some form of cancer; however, this risk varies significantly depending on the part of the world where the study was done (see Table 37.6). One interesting trend is that breast cancer is decreased in incidence in HIV-infected patients.

Kaposi's Sarcoma The incidence of Kaposi's sarcoma has declined since the early 1980s and most dramatically after the introduction of highly active antiretroviral therapy (HAART). The pathogenesis of Kaposi's sarcoma (KS) in immunosuppressed patients became clearly defined in the early 1990s with the discovery of human herpesvirus (HHV-8), which is also known as KSassociated herpesvirus (KSHV). For more than two-thirds of the patients, HAART is sufficient for the treatment of KS. In those patients who do not respond, the clinical management of localized KS is radiation therapy. For the small number of

TABLE 37.5. AIDS Defining Cancers. Cancer

Immune related

Lymphomas NHL High grade Immunoblastic Burkitt Other high grade Intermediate grade Low grade Other unspec CNS Other cancers Cervical Kaposi's NHL, non-Hodgkin's lymphoma; CNS, central nervous system.

Yes Yes Yes No

No

Yes No Yes Yes No Yes

TABLE 37.6. Incidence of Non-AIDS Defining Cancer. Cancer

Study country Lung Hodgkin's Oral pharynx Lip Anus Prostate Melanoma Testis Breast CNS tumors

Grulich

SI~

Australia

Herida

1.4 8 2.5

2 31 1

ND

ND

37 1 1.3 1.7 1.3 1.8

SI~

France

1.1 0.5 1 ND ND ND

Frisch SIR8

United States

4.5 11.5 ND

3.1 33 .7 1.3 2 1.1 3.5

CNS, central nervous system; ND, not documented. aSIR, Standard Incidence Rates: calculated number of cases in HIV-positive patients compared to the incidence of the general population.

patients (about 50/0) with generalized KS who do not respond to HAART therapy with rapidly progressing, life-threatening KS, systemic chemotherapy is used. The combination of the chemotherapy agents bleomycin and vincristine, with or without doxorubicin, is the standard therapy. These patients need to be followed carefully for immunosuppression and maybe also treated with recombinant hematopoietic growth factors to prevent bacterial infections.

Non-Hodgkin's Lymphoma In contrast to KS, which has decreased in incidence, especially since the advent of HAART, non-Hodgkin's lymphoma (NHL) has increased. In 1986 the CDC recognized NHL as an AIDS-defining cancer (ADC).These tumors appear most commonly at the end stages of AIDS when patients are most immunosuppressed. NHL is clearly a more difficult entity to manage. Surgeons are involved for lymph node biopsy to obtain adequate tissue sampling for flow cytometry of the lymph node. While the relative risk for acquiring Kaposi's is increased up to 10-fold, the increase of NHL in the HIV population compared to age-matched controls is increased as much as 400-fold for intermediate- and high-grade NHL. It is suspected that the incidence of NHL is tremendously underestimated because a number of central nervous system (CNS) lymphomas are diagnosed only at the time of autopsy and a large number of patients who develop NHL do so at the end stage of their HIV infection and therefore are undocumented. It is suspected that the introduction of HAART, while having reduced the incidence of KS, has not significantly affected the development of NHL. In addition, the treatment for NHL has challenged oncologists because standard chemotherapy more adversely affects patients who are at the end stage of their immunosuppression.

Cancer of the Cervix Uteri The third type of AIDS-defining malignancy is cervical cancer, associated with chronic human papilloma virus (HPV) infection. Risk factors include multiple sex partners, cigarette smoking, and other sexually transmitted diseases. The highest

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CHAPTER 37

rates of cervical cancer are found in women who are professional sex workers rather than patients who acquired their HIV infection heterosexually. Clinical management requires heightened surveillance practices and, should a cancer occur, standard therapeutic recommendations for non-HIV-infected patients apply to patients with HIV-associated cervical cancer.

Non-AIDS-Defining Cancers in Patients with HIV Infections Many data have accrued during the past 8 to 10 years identifying HIV-positive patients to be at greater risk for developing cancers other than the three cancers identified as AIDSdefining malignancies. The data are based on a number called the Standardized Incidence Ratio (SIR), which is the calculated number of cases identified in HIV-positive patients compared to the incidence of the cancer in question based on age- and sex-specific data from the general population. The overall risk of developing a number of different cancers in the presence of HIV is approximately double that of the population at large. The cancers that have been most extensively studied include lung, prostate, Hodgkin's oropharyngeal, anal, melanoma, testis, and CNS cancer. In some cases the increased rate of cancer is not related to the declining immunity. For example, it is generally believed that the increase in the rate of lung cancer is associated with the 900/0 use of tobacco in HIV-affected patients. Nearly all lung cancers in the HIV population are adenocarcinoma. However, in the general population lung cancers are evenly divided between oat cell adenocarcinoma and squamous cell carcinoma. The data suggest that HIV disease alone is not the major factor causing the increase in this cancer. Another cancer with a very high incidence in HIV-infected males is anal cancer, which is caused by HPV, which is also associated with genital warts. Studies are now under way to evaluate the efficacy of anal Papanicolaou smears for early detection. The rates of ADC and NADC have been studied as a function of the patients' CD4 counts. The study was conducted by reviewing registries in the United States. As the CD4 counts fell from progression of HIV disease, the rates of eight cancers were analyzed (see Table 37.5). Falling immune function affected only oropharyngeal cancer rates. Anal cancer was not affected by lowered immune function, and similarly cancer of the cervix uteri was not affected. The relation-ship between failing immune system and development of Hodgkin's disease, however, has been directly documented. Specifically, when T-cell counts fall to less than 300, this is associated with a higher rate of development of Hodgkin's lymphoma. A prospective analysis of deaths from HIV disease in 2000 in France showed that 28 % of all the 964 HIV deaths were related to cancer. NHL was the most common cancer in the patients who died of ADC. A little more than half of the deaths (550/0) were caused by ADC, but a surprising 45 % were caused by NADC. The most common cause was respiratory cancer, 19% overall, followed by hepatocellular cancer (HCC), 7% overall. The relationship between HCC and HIV disease is understudied: for example, the National Cancer Institute (NCI) study did not even list HCC in its analysis. Because many of the HIV-infected patients are coinfected with HBV

and HCV, the risk of HCC in HIV-infected patients will probably be a developing issue to follow.

Miscellaneous Surgical Interventions Enlarged Spleen The role of splenectomy in patients with marked splenomegaly or with thrombocytopenia must be individualized. Some believe that coinfections such as HCV playa role in the development of HIV-related immune thrombocytopenia purpura (ITP). Thrombocytopenia occurs in AIDS patients as a result of the circulating immune complex deposition on platelets rather than as a result of a specific antiplatelet antibody.":" Splenectomy has been extremely successful in managing these patients, with a success rate greater than 900/0. Occasionally, patients with debilitating fevers associated with significantly enlarged spleens experience dramatic palliation after splenectomy. Some data indicate that splenectomy favors a slower progression of the HIV dissemination and progression to AIDS.43 In patients with massive splenomegaly and fever, simple splenomegaly is sometimes difficult to distinguish from abscess or parenchymal necrosis. In addition, splenectomy may be indicated in instances in which there is merely a likelihood of injury and in those in which a large spleen compresses the stomach, thereby contributing to the patient's malnutrition.

Implantable Venous Access Devices A request frequently directed to the general surgeon from the primary care physician, the infectious disease consultant, or the hematologist caring for an AIDS patient is for placement of an indwelling central catheter. Long-term venous access for treating fungal infections or, occasionally, for nutritional support in patients with debilitating diarrhea syndromes can significantly enhance the delivery of care to these patients. However, line placement often occurs when the patient is febrile, as a result of either the underlying infectious problem or treatment with amphotericin B. Therefore, the surgeon should keep a close watch postoperatively to ensure that fevers are not related to an infected catheter. Although the presence of a catheter-related infection is as high as 30%, mortality is not affected." The high rate of infection relates in part to the high incidence of staphylococcus colonization in these patients.

Lymphadenopathy Another group of HIV-infected patients defined by the CDC includes those with persistent generalized lymphadenopathy, that is, palpable lymphadenopathy measuring more than 1em in diameter in at least two extrainguinal sites and persisting for longer than 3 months. Before the availability of HIV antibody testing, the relation of this lymphadenopathy to systemic manifestations of immunosuppression (systemic symptoms, neurological symptoms, secondary infections, or cancers) was not known. It is now clear that lymphadenopathy is part of the general clinical spectrum associated with HIV infection, and that opportunistic infection, Kaposi's


sarcoma, or large cell lymphoma will develop in some, if not all, lymphadenopathy patients. The precise reason why lymphadenopathy occurs in some but not all patients who acquire HIV infection is not known. The role of lymph node biopsy in these patients is currently of academic interest only since the development of serological tests to diagnose HIV infection. 54 The histological appearance of a clinically enlarged lymph node has prognostic value (see following); however, when the decision whether to perform a lymph node biopsy is being made, the value of the biopsy findings must be weighed against the value of the information that can be obtained by means of clinical staging with lymphocyte helper: suppressor T-cell ratios and total lymphocyte counts. The total number of helper T cells in the circulation has been correlated with the risk of AIDS in patients with generalized Iymphadenopathyv'f the Walter Reed classification provides the most detailed clinical staging system.V:" Should the clinical condition warrant, a lymph node biopsy may help in the diagnosis of an opportunistic infection. Performing a gallium scan to locate the most suspicious nodes4,s9 can enhance the yield of the biopsy. Once a lymph node is removed from an HIV-infected patient and before the tissue is removed from the operative field, the surgeon should place representative specimens in sterile containers for routine bacterial culture, culture, and smear for tuberculosis, fungal culture, and viral culture. Tissue from the same lymph node should then be delivered to the pathologist as quickly as possible. It is important that culture material from the same lymph node be examined microscopically because granulomas or actual organisms may be detected before the culture results are available. Data from the pathologist may aid the microbiology laboratory staff in its handling of the cultures. The pathologist needs to receive the fresh, gently handled specimen, in saline, as soon after the biopsy as possible for two important reasons. First, because the tissue is not in formalin, it will rapidly autolyze if not processed immediately. Second, the pathologist must have the tissue when it is fresh to perform lymphocyte marker studies if the diagnosis is lymphoma. Because different lymphomas respond to different chemotherapeutic regimens, the cell type of the lymphoma is critical. Most surgical pathology laboratories are equipped to perform membrane marker studies on lymph

node tissue.

Gastrointestinal Diseases Cryptosporidiosis and cytomegalovirus infection of the biliary tree have been reported to cause both acute cholecystitis and acute cholangitis, necessitating emergency surgical interventions. It is suggested that choledochoenteric bypass provides the best palliation in these patients. It is not known, however, whether the biliary tree is ever cleared of the infectious pathogens. Candida infection and Kaposi's sarcoma have also caused cholangitis, necessitating bypass surgery." Because the gallbladder can be infected with a variety of unusual pathogens in more than 500/0 of HIV-infected patients, the gallbladder wall should be sent for culture and the pathologist should be alerted to process the tissue with special stains. 60 ,61 Acute perforations of the gastrointestinal tract from cytomegalovirus infection, cryptosporidiosis, and candidiasis, as

705

well as from necrotic lymphoma, have been reported.P:":" Obstruction of the gastrointestinal tract caused by Kaposi's sarcoma or lymphoma may also be an indication for resection, bypass, or colostomy. One study of AIDS patients requiring a laparotomy identified four distinct clinical syndromes that called for surgical intervention: (1) peritonitis secondary to cytomegalovirus enterocolitis and perforation, (2) nonHodgkin's lymphoma of the gastrointestinal tract (usually the terminal ileum), presenting as obstruction or bleeding, (3) Kaposi's sarcoma of the gastrointestinal tract, and (4) mycobacterial infection of the retroperitoneum or the spleen.? Another gastrointestinal lesion that has been increasingly associated with homosexual men who are HIV infected is squamous cell carcinoma of the anus (SCCA). It is estimated that the risk of developing SCCA is nearly 25 times greater in the HIV-infected homosexual male than in the population in general. The underlying relationship is not well understood because the development is not related to the time of the HIV infection. Some believe that human papilloma virus 16 and human papilloma 18 are important cofactors in the evolution of SCCA. 63 ,64

References 1. Ippolito G, Puro V, DeCarli G. The risk of occupational human immunodeficiency virus infection in healthcare workers. Italian Multicenter Study. The Italian Study Group on Occupational Risk of Human Immunodeficiency Virus. Arch Intern Med 1993;153:1451-1458. 2. Gerberding J. Management of occupational exposure to bloodborne virus. N Engl J Med 1995;332:444-45l. 3. Update: acquired immunodeficiency syndrome United States, 1981-1988. MMWR 1989;38:229. 4. Gerberding JL. Clinical practice. Occupational exposure to human immunodeficiency virus in healthcare settings. N Engl J Med 2003;348:826-833. 5. Bassett IV, Freedberg SA, Walensky DP. Two drugs or three? Balancing efficacy, toxicity, and resistance in post-exposure prophylaxis or occupational exposure to HIV. Clin Infect Dis 2004;39:395-401. 6. Sterilization, disinfection, and antisepsis in the hospital. In: Lenette EH, Balows A, Hausler W, et al, eds. Manual of Clinical Microbiology, 4th ed. Washington, DC: American Society for Microbiology, 1985:129. 7. http//www.gov/oppadOOl/pdf_files/workplan.2005.pdf. 8. Iawetz EMf, Adelberg EA. Antimicrobial chemotherapy. In: Review of Medical Microbiology, 15th ed. Los Altos: Lange Medical, 1982:117. 9. Dodd RY, Notari EP, Stammer SL. Current prevalence and incidence of infectious disease markers and estimated window period risk in the American Red Cross blood donor population. Transfusion 2002;42:975. 10. Ho DD, Byington RE, Schooley RT, et al. Frequency of isolation of HTLV-III virus from saliva in AIDS. N Engl J Med 1985; 313:1606. 11. Morgan 1, Nolan J. Risks of AIDS with artificial insemination. N Engl JMed 1986;314:386. 12. Recommendations for prevention of HIV transmission in healthcare settings. MMWR 1987;36(suppI2S):1. 13. Guidelines for prevention of transmission of human immunodeficiency virus and hepatitis B virus to health-care and publicsafety workers. MMWR 1989;38(suppl S-6):I. 14. Update: acquired immunodeficiency syndrome and human immunodeficiency virus infection among health-care workers. MMWR 1988;37:229.

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15. Recommendations for preventing transmission of FHV and HBV to patients during exposure-prone invasive procedures. MMWR 1991;40(suppl RR-8):1. 16. Braathen LR, Ramirez G, Kunze RO, et al. Langerhans cells as primary target cells for HIV infection (letter). Lancet 1987;2:1094. 17. McCray E. Occupational risk of the acquired immunodeficiency syndrome among health care workers. N Engl J Med 1986;314:1127. 18. Gerberding JL, Litten C, Tarkington A, et al. Risk of exposure of surgical personnel to patients' blood during surgery at San Francisco General Hospital. N Engl J Med 1990;322:1788. 19. Quebbeman EJ, Telford GL, Wadsworth K, et al. Double gloving: protecting surgeons from blood contamination in the operating room. Arch Surg 1992;127:213. 20. Tanner J, Parker H. Double-gloving to reduce surgical crossinfection. Cochrane Database Syst Rev 2005;1. 21. Gerbert B, Maguire BT, Hulley SB, Coates TJ. Physicians and acquired immunodeficiency syndrome: what patients think about human immunodeficiency virus in medical practice. JAMA 1989;262:1969. 22. Gerberding JL. Clinical practice. Occupational exposure to HIV in health care setting. N Engl J Med 2003;348:826-833. 23. Summary: recommendations for preventing transmission of infection with human T-lymphotropic virus type ill/lymphadenopathy-associated virus in the workplace. MMWR 1985; 34:681. 24. Harpaz R, Seidlein L von, Averhoff FM, et al. Transmission of hepatitis B virus to multiple patients from a surgeon without evidence of inadequate infection control. N Engl J Med 1996;334:549-554. 25. The CDC Cooperative Needlestick Surveillance Group. Surveillance of health care workers exposed to blood from patients infected with the human immunodeficiency virus. N Engl J Med 1988;319:1118. 26. Panlilio AL, Shapiro CN, Schable CA, et al. Serosurvey of HIV, HBV, HCV infection among hospital-based surgeons. J Am ColI Surg 1995;180:16. 27. Apparent transmission of human T-lymphotropic virus type ill/ lymphadenopathy-associated virus from a child to a mother providing health care. MMWR 1996;35:76-79. 28. Edlin BR, Irwin KL, Faruque S, et al. Intersecting epidemics: crack cocaine use and HIV infection among inner-city young adults. N Engl J Med 1994;331:1422-1427. 29. Public Health Service. Recommendations for Donor Screening with a Licensed Test for HIV-I Antigen. U.S. Department of Health and Human Services. Rockville, MD: Food and Drug Administration, 1995. 30. U.S. Public Health Service guidelines for testing and counseling blood and plasma donors for human immunodeficiency virus type I antigen. MMWR 1996;45(R-22):1. 31. Persistent lack of detectable HIV-I antibody in a person with HIV infections, Utah, 1995. MMWR 1996;45:182. 32. Sexually transmitted diseases. In: Rubenstein FD, ed. Scientific American Medicine, section 7, subsection XXll. New York: Scientific American, 1990. 33. Margulis SJ, Honig CL, Soave R, et al. Biliary tract obstruction in the acquired immunodeficiency syndrome. Ann Intern Med 1986;105:207. 34. Robinson G, Wilson SE, Williams RA. Surgery in patients with acquired immunodeficiency syndrome. Arch Surg 1987; 122:170. 35. Barone JE, Gingold BS, Nealon TF, Arvnatis ML. Abdominal pain in patients with acquired immune deficiency syndrome. Ann Surg 1986;204:619-623. 36. Davis JM, Mouradian J, Fernandez RJ, et al. Acquired immune deficiency syndromes surgical perspective. Arch Surg 1984;119:90.

37. Rubin R. Acquired immunodeficiency syndrome. In: Rubenstein FD, ed. Scientific American Medicine, section 7, subsection XXll. New York: Scientific American, 1990. 38. Rous P. Transmission of a malignant growth by means of cellfree filtrate. JAMA 1911;56:198. 39. Robert-Guroff M, Nakao Y, Notake K, et al. Natural antibodies to human retrovirus HTLV in a cluster of Japanese patients with adult T-cell leukemia. Science 1982;215:975. 40. Martin F, Grulich E, Johanseman AC. Cancer in the populationbased cohort of men and women registered homosexual partners. Am J Epidemiol2003;157:966-972. 41. Chiao E, Krown S. Update on non-acquired immunodeficiency syndrome defining malignancies. Curr Opin OncoI2003;15:389397. 42. Berretta M, Cinelli R, Martoletto F, Sbina M, Baccatr E, Tirelli U. Therapeutic approaches to AIDS-related malignancy. Oncogene 2003;22:6646-6659. 43. Tsoukas CM, Bernard NF, Abrahamowicz M. Effect of splenectomy on slowing human immunodeficiency virus disease progression. Arch Surg 1998;133:25-31. 44. Dega H, Eliaszewicz M, Gisselbrecht M, et al. Infections associated with totally implantable venous access devices (TIVAD) in human immunodeficiency virus-infected patients. J AIDS Hum Retrovirol1996;13:146-154. 45. Frisch M, Biggar R, Engles E, Goedert J. Association of cancer with AIDS-related immunosupression in adults, JAMA 2002;285:1736-1745. 46. Grulich AE, Li Y, McDonald A, Correll PKL, Law M, Kalgor JM. Rates of non-AIDS-defining cancers in people with HIV infection before and after AIDS diagnosis. AIDS 2002;16:11551161. 47. Hoffman C, Wolf E, Fatkenheuer G, et al. Response to highly active retroviral therapy strongly predicts outcome in patients with AIDS-related lymphoma. AIDS 2003;17:1521-1529. 48. Mbulaiteye S, Biggar R, Goedert J, Engel E. Immune deficiency and risk of malignancy among persons with AIDS. J AIDS 2003 j32:527-533. 49. Herida M, Mary-Kraus M, Kaphan R, et al. Incidence of nonAIDS defining cancers before and during the highly active retroviral therapy era in a cohort of human immunodeficiency virus-infected patients. J Clin Oncol 2003;21:3447-3453. 50. Sriplung H, Parkin D. Trends in the incidence of immunodeficiency syndrome-related malignancies in Thailand. Cancer (Phila) 2004;101:2660-2666. 51. Shahul E, Abdullah A, McKenna M, Hamers F. AIDS-defining cancers in Western Europe, 1994-2001. AIDS Patient Care 2004;18:501-508. 52. Bonnet F, Lewden C, May T, et al. Malignancy-related causes of death in human immunodeficiency virus-infected patients in the era of highly active retroviral therapy. Cancer (Phila) 2004;101:317-324. 53. Morton F, Biggar R, Engels E, Goedert J. Association of cancer with AIDS-related immunosuppression in adults. JAMA 2001;35:1736-1745. 54. Nugent P, O'Connell TX. The surgeon's role in treating acquired immunodeficiency syndrome. Arch Surg 1986;121:1117-1120. 55. Kaplan JE, Spira TJ, Fishbein DB, Pinsky PF, Schonberger LB. Lymphadenopathy syndrome in homosexual men: evidence for continuing risk of developing the acquired immunodeficiency syndrome. JAMA 1987;257:335. 56. Goedert JJ, Biggar RJ, Melbye M, et al. Effect of T4 count and cofactors on the incidence of AIDS in homosexual men infected with human immunodeficiency virus. JAMA 1987;257:331. 57. Redfield RR, Burke OS. HIV infection: the clinical picture. Sci Am 1988;259:70-78. 58. Redfield RR, Wright DC, Tramont EC. The Walter Reed staging classification for HTLV-Ill/LAV infection. N Engl J Med 1986;314: 131-132.


59. Fernandez R, Mouradian J. Metroka C, et al. The prognostic value of histopathology in persistent generalized lymphadenopathy in homosexual men. N Engl J Med 1983;309:185. 60. French AL, Beaudet LM, Benator DA, et al. Cholecystectomy in patients with AIDS: clinicopathologic correlations in 107 cases. Clin Infect Dis 1995;21:852-858. 61. Kavin H, Jonas RB, Chowdhury L, et al. Acalculous cholecystitis and cytomegalovirus infection in the acquired immunodeficiency syndrome. Ann Intern Med 1986;104:53-54.

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62. Wilson SE, Robinson G, Williams RA, et al. Acquired immune deficiency syndrome (AIDS): indications for abdominal surgery, pathology, and outcome. Ann Surg 1989;210:428. 63. Benator DA, French AL, Beaudet LM, et al. Isospora belli infection associated with acalculous cholecystitis in a patient with AIDS. Ann Intern Med 1994;121:663-664. 64. Lorenz HP, Wilson W, Leigh B, et al. Squamous cell carcinoma of the anus and HIV infection. Dis Colon Rectum 1991;34:336338.

Evidence-Based Bariatric Surgery John Morton Obesity as a Global Epidemic Obesity: Comorbidities and Mortality . . . . . . . . . . . . . . . Nonmedical Consequences of Obesity . . . . . . . . . . . . . .. Medical Tre atment of Obesity . . . . . . . . . . . . . . . . . . . .. Surgical Patient Selection . . . . . . . . . . . . . . . . . . . . . . . . . Medical Versus Surgical Treatment of Morbid Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Surgical Techniques : 1977-1989 . . . . . . . . . . . . . . . . . . . . Surgical Techniques : 1989-2006 Benefits of Weight Loss Surgery: Weight Loss Benefits of Weight Loss Surgery

709 709 710 710 711 711 714 714 714 715

Obesity as a Global Epidemic An obesity epidemic exists throughout the developed and

much of the developing world.':" Obesity, typically mea sured as body mas s index (BMI) of 30 kg/m? or higher, has three subclasses: obesity 1 (30-34.9); obesity 2 (35-39.9); and extreme obesity (>40). Extreme or morb id obesity is increasing particularly rapidly in the United States and may have the potential of decreasing life expectancy.t" From 1986 to 2000, the prevalence of BMI of 30 or more doubled, whereas that of BMI of 40 or more quadrupled, and even extreme obesity, BMI of SO or more, increased fivefold." Of particular concern is the alarming increasing prevalence of obesity among children, suggesting that the epidem ic will worsen before it improves.' In th e United States, 32% of adults and 17% of children and adolesc ents are classified as obese.v" When tracked over time, there has been a slow but steady rise in the percent of Americans classified as obese over the past several decades. Between 1980 and 2002, obesity prevalence doubled in adults aged 20 years or older, and obesity prevalence tripled in children and adolescents aged 6 to 19 years. However, over time there has also been a distinctively greater increase in the growth rates for the higher weight (BMI) categories. For instance, between the rnid-1980s and 2000, the prevalence of BMI of 40 or greater quadrupled from about 1 in 200 adult Americans to 1 in SO. At the same time, those individuals with BMI of SO or greater were five times more common in America , from about 1 in 2000 in the year 1985 to 1 in 400 in the year 2000.

Risks of Weight Loss Surgery Volume and Outcomes of Bariatric Surgery. . . . . . . . . .. Technique and Practice Patterns: Gastric Bypass Technique and Practice Patterns: Adjustable Gastric Banding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sleeve Gastrectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intragastric Balloon. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gast ric Pacing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Special Populations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

718 719 719 721 721 722 722 723 723 724

Other countries have also witnessed rising rates of obesity, including Canada. In the adult Canadian population, the prevalence of obesity was 6% in 1985, increasing to 15% by 1998.9 Indeed, worldwide, there are some 300 million obese people, a problem seen not only in industrialized countries but in developing nations also.' Importantly, the prevalence of morbid obesity (BMI of 40 or more) in 2003-2004 was estimated to be 2.8% in men and 6.9% in women, based on nationally representative sampling .' Based on the 2004 U.S. adult population of 103 million men and 109 million women (http://www.census.gov/popest/ national/asrh/NC-EST2004-sa.html; accessed December 2006), there were approximately 2.9 million men and 7.5 million women (totaling 10.4 million people ) with morb id obesity in America in 2004. Other est imates indicate that more than 1 million adolescents and young adults may be affected with extreme obesity." Because comorbidities and resulting healthcare expenditures are much higher among morbidly obese individuals, these trends warrant special attention and serious consideration of effective interventions, such as bariatric surgery .!':"

Obesity: Comorbidities and Mortality Epidemiological studies have demonstrated that increasing BMI is a causative factor in many life-threatening comorbidities, including type 2 diabetes , cardiovascular disease, and cancer . Body mass index has been established as an independent risk factor for premature mortality (Fig. 38.1 ).6,13 Obesity 709

710

CHAPTER 38

3.2

3.0

2.8 ~ 2.6 ~ 2.4 '0 2.2 ~ 2.0 CJ)

a:

Men .. •.. Cardiovascular disease - - Cancer - All other causes I ~

1.8

1.6 :; 1.4 ~ 1.2 1.0 0.8 0.6 ......- ...-....-.............r--....-.....~

.............-

..................

'b~ ~~ ,,~ r';)~ ~~ ro~ (\~ P!J~ ,~ bt.~ ~~ ~ H

RNYGB, Roux-en-Y gastrointestinal bypass; JIB, jejeunal-ileal bypass; VBG, vertical banded gastrop last y, HG, horizontal gastrop lasty, EWL, excess weight loss.

for surgery in the management of morbid obesity." In this study, morbidly obese patients in the province of Quebec were followed through all levels of care including clinic visits. Surgically treated morbidly obese patients were matched by age, gender, and comorbidity to medically managed patients. At 5 years, huge reductions in healthcare utilization, costs, and mortality were found. In this Quebec study, an 89% mortality risk reduction was demonstrated. A well-designed randomized clinical trial between laparoscopic adjustable gastric banding and traditional medical

...u . . . TABLE 38.2. Comparative Surgical Trials, 1989-2006.

Level of evidence

II II

Trial

Outcome

Hall (1990)50 Adelaide study HG vs. VG vs. RNYGB

3 years , % EWL > 50 HG ,17% VG,48% RNYGB,67% 2 years, % EWL 54 (R) vs. 42 (LB) 10 years, % weight change 25. 1%, RN YGB 16.5%, VBG 13.2%, LB 1 year, % EWL 78% (R) vs. 63 % (VI Weight loss , kg 43 (LB) vs. 35 (V)

Weber (2004)51 LRN YGB vs. LAP-BAND Sjostrom (20041 36 RNYGB vs. VBG vs. LB

Olbers 12006)55 LRNYGB vs. LAP VBG Nilsell(2001 )53 Lap-Band (LBI vs. LAP VBG(V) Morino (20031 54 Lap-Band (LB) vs. LAP VBG(V) II

Skro ub is (2006)52 RNYGB vs. BPD

LAP, laparoscopy, BPD, biliopancreatic diversion.

3 years , % EWL 39% (LB) vs. 59% (VI Late com pli cations 33% (LBI vs. 14% (V) 2 years, % EWL 72% (R) vs. 83% (BPD)

management for morbid obesity also found a similar decided advantage for bariatric surgery over medical ma nagement." In this study, 80 adu lts with mild to moderate obesity (BMI, 30-35 kg/m2 ) were randomized to nonsurgical intervention (VLCD [very low carbohydrate diet], orlistat, and lifestyle change) or to surgical intervention (gastric banding], surgical treatment was statistically significantly mor e effective than nonsurgical therapy in reducing weight, resolving the metabolic syndrome, and improving quality of life during a 24month treatment program. At 2-year follow-up, laparoscopic adjustable gastric banding achieved a remarkable 87% excess weight loss in contrast to a 22% excess weight loss for traditional medical management. The Swedish Obese Subjects (SOS) study also found very favorable results for bariatric surgery." With 12-year followup, percent weight change for surgically treated patients was a 23% decrease in contrast to 1.6% weight increase for med ically managed patients. Differe nces in surgical techniques, as detailed later, also resulted in differences in outcomes.

_u

TABLE 38.3. Medical Versus Surgical Treatment of Obesity.

Level of evidence

II II

Trial

Outcome

O'Brien (2006)39 Medical trea tment (MTI vs. laposcopic adjustable gastric ban ding (LBI Buchwald 12004)37 POSCH (diet vs. JIB)

% EWL, 2 years 21.8% IMTI vs . 87.2% (LBI

Christou (2004)41 Quebec study RNYGB vs. con trol Sjostrom (2004)36 Med ical IMT) vs. surgical treatmen t (STI

18-year follow-up 20% morta lity reduction with surgery 5-year follow-up 89% mortality reduction with surgery % EWL, 12 years 0.15% increase (MT ) vs. 23.4% decrease (STI

713

EV I DENCE - BASED B ARI A TRI C SURGERY

D D

Data based on nationwide inpatient sample Projection based on preliminary data from 12 states for 2003

120000 100000 (/)

~

80000

:J

"0 Ql

ea. U

60000

'0

ci

z

40000 20000 1998

1999

2000

2001

2002

2003

Year

FIGUR E 38.2. N ational tren ds in annual numbers of bariatric procedures from 1998 to 2003 . (From Santry HP, Gillen DL, Lauderdale DS,42 by permission of Journal of the American Medical Association. )

Error bars indicate 95% confidence intervals .

5

ok..__.-.-'......-~---.----.-c;;:;iroI' Control

-5

;g -10 ~

g;,-15

t=.---+---7Vi.t"e:;rt-;:ic::a~1b~a:::n::;;:d}d

t:

'" -20 B

astroplastYT

t-25

~

Gastric bypass

- 30

1

-35 -40 -45

FIGURE 38.3. Percent of weight change by proce dure. (From Sjostro m L, Lindr oos AK, Pelt on en M, et a1.,36 by permission of N ew Englan d Journal of Medicine.]

.

0.0 0.51.0

2.0

3.0

Control 627 585 594 Banding 156 150154 Vertical bandedgastroplasty 451 438438 Gastric bypass 34 34 34

587 153 438 34

577 149 429 33

No. of Subjects

4.0

6.0

8.0

10.0

563 150 417 32

542 147 412 32

535 144 401 29

627 156 451 34

Years of Follow-up

TABLE 38.4. Ty pes of Bariat ric Surgical Procedures Perform ed in the Unit ed States from 1998 to 2002 Based on Dat a from the Nat ionwide Inp atient Sam ple. No. (%) of procedures Procedure type

Gastric bypass Gastroplasty'' Malabsorptive" Gastrectomy" Other" T ot al no . of procedures

1998

1999

2000

2001

2002

P value for trend'

10,675 (79.9) 3,296(24.7) 990 (7.4) 258 (1.9) 43 (0.3) 13,365

20,42 1 (89.5) 2,097 (9.2) 1,277 (5.6) ~l l (3.2) 31 (0.1) 22,809

27,497 (88.5) 4,357 (14.0) 3,684 (11.9) 495 (1.6) 70 (0.2) 31,082

48,507 (85.4) 6,24 7 (11.0) 4,732 (8.3) 2,186 (3.8) 303 (0.5) 56,781

63,538 (88.0) 5,369(7.4) 7,495 (10.4) 3,082 (4.3) 1,446 (1.9) 72, 177

0.27 0.01 0.64 0.30 0.13

Z

-

I;::

Z

~

I;::

",

0

C/>

t"

'"t-

~

o

:>:J

12

7

8

1996

1997

1995

Ortega et aP5

Talamini et a1.172

Ho et apo

24

8

16

1998

1995

1996

Rademaker et a1.174

Davidson et a1.175

Access Horvath et al,I73

9

1995

Baseline Windenberger et a1.29

n

Year

Author

Pigs

Pigs

Pigs/ colectomy

Pigs

Pigs

Pigs

Pigs

Animal/procedure

CO 2

CO 2

CO 2

CO 2

Gas

15

12

40

15

30

30

15

60

NC

Gas less litter

NC NC

NC NC HePNP Gasless litter

r r

r r

NC NC

NC

NC NC NC NC

r

NC

PCWP

NC

NC

NC

NC NC NC NC

J.

i

r

SV

CO2 PNP

NC

NC

r r CO 2 PNP

NC

r NC r

NC

NC

NC

NC

r NC

J.

HR

r

CO

NC NC NC NC

r r r

NC

J.

SVR

NC

r

NC

r

15

60

NC

NC

NC

r

MAP

15

CVP

60

Open CO 2 PNP He PNP Gas less litter

Study groups

r

LAP (mmHg)

10-14

5

Length ofPNP (min)

TABLE 43.5 . Randomized Controlled Animal Studies (Level I Evidence) of Hemodynamic Responses to Laparoscopy Compared to Postinduction Control.

The effects of laparoscopic surgery an d open surgery on he modynamic responses are minimal, an d no one method is superior to another In contrast with CO 2 PNP, laparoscopy using abdominal wall retraction was not associated with adverse effects on hemodynamics or gas exchange Neither He PNP or the litter have significant deleterious pu lmonary or hemodynamic effects

Abdominal PNP was associated with increased CO , cardiac contractility, an d MAP The sharp in it ial rise of MAP could be the effect of a mechanical action, whereas sustained hemodynamic alterations would involve complex regulatory mechanisms like an increase of sympathetic activity, baroreceptor control, or a response to acidosis Complex interactions between the mechanical and systemic effects of the CO 2 PNP on venous return A significant reduction in CO occurs after surgical disrupt ion of the esophageal h iatus during LN F Accumulation of CO 2 is associated with an increase in MAP

A uthor's conclusions

10

1994

Luz et a1.177

Dogs/Laparos cop ic pelvic lymphaden ect om y

Pigs/s ubjecte d to PEEP

Pigs/s ubjected to hem orrhage

Pigs

Dogs

Piglets

Dogs

CO 2

CO2

CO 2

CO 2

CO 2

CO 2

CO 2

-

10

60

10

20

60

60

15

15

15

10cmH2O PEEP 20cm H 2 O PEEP lOmmHg lOmmHg, 8 PEEP 15mmHg 15mmHg, 8 PEEP

No hem orrh age lOcc/k g continuous bleeding for 1h 20cc/kg continuous bleeding for 1h 20 cc/ kg continuous bleeding for 1h and fluid resusc ita tion 5 cm H 20 PEEP

Int raperitoneal PN P Extraperito nea l PNP

lOm mHg 15mmHg 5 m m Hg 15 m mHg 25 m m Hg

8 m m Hg 12mmHg 16 mmHg

i

r i t

t

r t

i

r

NC

r

NC

NC NC

i

NC

NC

NC

NC

i

i

NC

NC NC

NC

NC

i

i

i

i

NC

r

NC

i

i

i

i

i

i

NC

i

i

NC

NC

r

NC

NC

NC

NC NC NC NC NC

NC NC NC

NC

i

NC NC

i

NC NC

NC

NC

t

NC NC

r

r

NC NC NC NC NC

r r r r r r

NC NC NC

NC NC NC

An increase in lAP up to 15mm Hg had no effect on th e cardiovascular system; however, the combin ati on of an inc reased lAP w ith PEEP m ark edl y depressed hem odyn am ic variables

CO 2 PN P increases afte rloa d and exacerbates th e adverse effects of PEEP

CVP, PCWP in creased faster in in traperi ton eal group; extraper ito nea l PN P might result in less cardiov ascu lar imp airm ent than intra peri to nea l PN P Fluid resusc ita tio n to baseline MAP did not maintain hem odyn am ics onc e CO 2 pn eumo was begun ; CO2 PNP for diagnost ic laparoscopy may be hazardou s in acutely hypovolem ic subjects

lAP from 8 to 12 mmHg is recom m en ded for laparoscopic sur gery to avoid complica tio ns cau sed by hem odynam ic derangem ent s CVP in creased in propo rtion of increase in lAP In th e dog, any hem odyn am ic alteratio ns induced by CO 2 PNP are secondary to altered LV preload

helium; HR, heart rate, lAP, in traabdominal pressure; MAP, mean arterial pressure; NC , no change; N0 21 nitrous ox ide; PCWP, pulm ona ry capill ary wedge pressure; PEEP, positive end ex piratory pressure; PN P, pneum operiton eum ; SV, stroke volume; SVR, sys temic vascu lar resista nce.

co, cardiac out put, COl,. carbon dioxid e; CVP, ce ntral venous pressure; He,

5

1993

Moffa et a1.176

32

16

1993

1997

10

Ho et a1.43

Specia l condition s Bannenb erg et a1. 42

Ma rathe et a1.

1996

4

1994

Liem et a1.4 1

22

21

1993

Press ures Ishi zak l et al Y

778

CHAPTER 43

central venous pressure (CVP) and pulmonary capillary wedge pressure (PCWP) but a concurrent decrease in stroke volume (SV). The rise in measured CVP is the result of an increase in lAP that directly compresses the low-pressure vasculature, such as the abdominal vena cava." The effects of PNP on cardiac parameters have been investigated via transesophageal echo cardiography (TEE) and pulmonary artery thermodilution catheters. In dogs, Marathe et al. used TEE and direct cannulation of the external jugular vein, left ventricle, and pericardial space to show that an lAP of 15mmHg or greater resulted in a significant decrease in left ventricular end-diastolic volume (preload) without a concomitant effect on left ventricular contractiliry.f In patients similarly insufflated and undergoing LC, Myre et al., using TEE with multiplane images, showed an increase in PCWP (1017mmHg, median 70%) with no change in the left ventricular diastolic area index." Therefore, perhaps paradoxically, the increase in CVP and PCWP actually results in decreased cardiac filling pressures or preload. AFTERLOAD

Most of the reported studies have shown an increase in both mean arterial pressure (MAP) and systemic vascular resistance (SVR) with moderate degrees of PNP. This increase in afterload, as reflected by an elevated MAP and a calculated increase in SVR, has been demonstrated in several humarr't" and animal studies. 29,3o Most authors believe that the increase in afterload in conjunction with PNP is the result of two factors: the release of humoral factors (catecholamines and vasopressin) soon after commencing insufflation and direct aortic compression due to increased IAP.31,32 There can also be a marginal'" increase in heart rate (HR) associated with PNP that is typically short-lived and most likely the result of early catecholamine release following induction. Finally, PNP has effects on co. Cardiac output is defined as the product of HR and SV. Several authors have reported a decrease in CO with PNP. 25,28 In these reports, patients undergoing LC at an insufflation pressure of 15mmHg had a reduction in cardiac index between 3% and 29%. However, in similar studies others reported no change in CO with moderate PNP. 24,27,34 In experimental animals similarly insufflated, several studies have shown not a decrease but actually an increase in CO .29,35 The difference in CO response to PNP among these various studies is most likely secondary to a difference in blood vessel distensibility among individuals and between species (i.e., atherosclerotic arteries are less-distensible vessels that result in an increase in afterload and a decrease in CO). Studies such as these have raised concern for the safety of PNP in patients with a known compromised cardiopulmonary system. However, the hemodynamic alterations seen in patients with known cardiopulmonary disease were similar to those reported in healthy adults. Therefore, although there was a mild36-38 or minimap9,4o decrease in CO, most agree that the effects of PNP on CO are clinically insignificant. It must be emphasized, however, that it is only with adequate hemodynamic monitoring and conscientious anesthetic management that untoward clinical outcomes can be reproducibly avoided in patients with cardiopulmonary disease. Patient positioning and duration of insufflation are additional factors influencing various hemodynamic parameters measured during PNP. Gannedahl et al. studied hemody-

namic variables in eight healthy patients undergoing PNP in various patient positions. Throughout the various position changes, minimal changes were seen in either MAP or CO. However, parameters directly reflecting changes in preload were significantly altered with patient repositioning. ReverseTrendelenberg (head-up) positioning combined with PNP, as in LC, counteracts the effects of PNP by causing a decrease in CVP and PCWP in comparison to the supine patient. Likewise, Trendelenberg (head-down) positioning combined with PNP, as in gynecological procedures, causes an increase in measured CVP and PCWP when compared to supine positioning." Although some warn that head-up positioning may compromise CO by decreasing preload." the incidence of documented clinically significant sequelae in such patients is low (see Table 43.5). Again, appropriate anesthetic management must be emphasized. In animal studies targeting various insufflation pressures, there appears to be a proportional increase in CVP with insufflation pressure.P:" Similarly, intraperitoneal insufflation seems to have a more dramatic physiological effect on CVP and PCWP than does extraperitoneal insufflation." Various special clinical circumstances have also been investigated by using laboratory animals. For example, there has been debate regarding whether it is safe to subject hypovolemic trauma patients to PNP. Ho et al. studied this issue in pigs subjected to controlled, varying levels of hemorrhagic shock and found that diagnostic laparoscopy may be hazardous in hypovolemic animals. During PNP, both SV and CO decreased with mild (10mL/kg) and moderate (20mL/kg) hemorrhage, and although these parameters initially responded to fluid resuscitation, they quickly fell to levels similar to unresuscitated animals." SPLANCHNIC/HEPATIC/RENAL

Just as PNP has been shown to decrease cardiac venous return, studies have also illustrated that an increase in lAP similarly affects the perfusion of many abdominal organs. These effects may occur locally before the recognition of the aforementioned systemic hemodynamic effects. The effects of PNP on specific mesenteric beds have been specifically illustrated through direct cannulation of these vessels in experimental animals. For instance, in pigs outfitted with gastric tonometry, Knolmayer et al.44 showed that a PNP in excess of 15mmHg significantly decreased gastric blood flow and subsequently lowered intramucosal gastric pH without affecting CO or arterial lactate levels." In dogs, Caldwell and Ricotta showed that during PNP there is a trend toward a decrease in absolute blood flow to all intraabdominal and extra-abdominal organs except the retroperitoneally located adrenal gland, and that this decrease was significant for the omentum, esophagus, stomach (and gastric mucosa), duodenum, and jejunum." Both hepatic and renal perfusion are decreased with increasing lAP (Fig. 43.2). Using an ultrasonic blood flowmeter in dogs, Ishizaki et al. reported an increase in portal venous pressure and a decrease in portal venous and hepatic artery flow in parallel with an increase in lAP. Total hepatic blood flow was significantly decreased after 30 min of insufflation." Other experimental models have confirmed these results." Similarly, laser Doppler flowmetry of the renal arteries of pigs showed there is a significant decrease in renal perfusion with an lAP of 15mmHg. 47 This was confirmed when renal hemo-

PRINCIPLES OF MINIMALLY INVASIVE SURGERY

160 140 0; 120 0 0

.5 100

E

I

80

~

60

~ 0

"C

0 0

iii

40 20 0

* --0-

HBF

- - RBF

pre

6mm Hg

12mm Hg

18mm 24mm Hg Hg

after

FIGURE 43.2. Changes in hepatic blood flow (HBF) and renal blood flow (RBF) with increasing intraperitoneal pressure. Hepatic blood flow was significantly reduced at pressures of 18 and 24 mmHg, and renal blood flow was significantly decreased at a pressure of 24 mmHg. Values are expressed as mean ± SE. pre, preinsufflation, after, after CO 2 evacuation; *, P < .05 versus each control value. (From Hashikura et al.," by permission.)

dynamics during intraperitoneal insufflation, extraperitoneal insufflation, and use of a lifting mechanism were directly compared. Significant renal hemodynamic changes were elicited in both the gaseous groups but not in the gasless laparoscopy group." However, the clinical implications of decreased renal perfusion are less apparent. Miki et al. compared the intraoperative renal function of patients undergoing LC (lAP, 12mmHg) to LC patients for whom the retraction method (lAP, 4mmHg) was used. Urine output, effective renal plasma flow (ERPF), and glomerular filtration rate (GFR) were each decreased in the former group as compared to the latter, suggesting that a retraction method may prevent transient renal dysfunction." In another study, when patients undergoing LC (lAP, 12mmHg) were compared to a minilaparotomy group, urine output, ERPF, and GFR were similarly decreased in the laparoscopy group" However, this transient decrease in intraoperative blood flow does not produce significant renal dysfunction postoperatively. Preoperative and postoperative serum urea nitrogen and creatinine concentrations were not different in a group of patients undergoing LC or pelvic lymph node dissection." Prospective studies involving patients with documented preoperative compromised renal function undergoing PNP are currently unavailable.

Coagulation Effects Virchow's triad of hypercoagulability, venous stasis, and trauma are the three main factors responsible for venous thromboembolism. Laparoscopic surgery entails the same risks of thromboembolism as the traditional approach; however, some have postulated that certain risk factors, namely venous stasis caused by PNP and hypercoagulability, pose a greater threat to the patient undergoing a laparoscopic procedure. The increase in lAP causes compression on the abdominal inferior vena cava, a subsequent rise in CVP, and a decrease in lower extremity venous return. As a result, venous stasis,

779

a known risk factor for deep vein thrombosis (DVT), occurs in the lower extremities. Venous stasis was confirmed by Jorgensen et al. by using an ultrasound flow probe in pigs to measure femoral venous flow. These authors found that venous outflow was markedly and significantly depressed as lAP was increased from 10 to 20mmHg. 52 Clinically, during LC and laparoscopic antireflux procedures, reverseTrendelenberg (head-up) positioning further predisposes the patient to venous stasis and the subsequent development of DVT. Millard et al. studied the femoral veins of 20 consecutive patients undergoing LC and found a significant reduction in common femoral venous flow." In general, surgical intervention induces a postoperative hypercoagulable state, and similar results of hypercoagulability have been noted following both LC and DC. 54 As a result, this hypercoagulable state following laparoscopy may be due in part to the body's response to general anesthesia and indirectly to venous stasis." Although there is an increased theoretical risk of DVT following laparoscopic procedures, clinically this complication is infrequently realized. The incidence of DVT following DC is between 50/0 and 100/0 depending on how it was detected and whether the patient received prophylaxis.v" In tum, of 1200 open cholecystectomies, there were 4 cases of pulmonary embolism (PE).57 The true incidence of DVT and subsequent PE following LC has yet to be established. 55 However, in one series of 77,604 patients undergoing LC, there were only 3 deaths attributable to PE.58 The incidence of DVT and PE seem to be lower than for comparable conventional procedures, but randomized data are not yet available. Regardless of the low reported risk of death from PE following LC, the provocative theoretical increased risk for DVT/PE have prompted the drafting of policies for DVT prophylaxis during laparoscopic procedures. In 1993, of 3500 fellows of the American College of Surgeons, 1018 responded to a survey querying their approach to DVT prophylaxis during LC. This survey showed that among those responding to the survey a similar approach (graduated compression stockings, sequential compression stockings [sequential compression devices, SCDs], or low molecular weight heparin) was employed for DC and LC patients." Shwenk et al., in a prospective, randomized trial involving 50 patients (25 patients with SCDs [+SCD] and 25 without [-SCDs]), studied the effectiveness of pneumatic SCDs in preventing venous stasis during LC. These authors found that peak flow velocity in the femoral vein decreased less from the baseline value in the +SCD group as compared to the -SCD group, supporting the routine use of SCDs. 60 Finally, in a study of eight consecutive patients undergoing laparoscopic herniorrhaphy, flow in the common femoral vein was reduced with intraperitoneal insufflation but not with preperitoneal insufflation." With the dramatic increase of laparoscopic bariatric procedures, the issue of DVT prophylaxis was reexamined" as these patients are at increased risk for thromboembolic complications. Most authors agree that pharmacologic prophylaxis is indicated.f frequently in increased doses, after appropriate adjustment for the patient's weight/" The theoretical risk of thromboembolism during laparoscopy, coupled with the measured decreased femoral venous flow without SCDs, make it prudent to recommend DVT prophylaxis for all patients who are approached laparoscopically. The low rate of documented DVT/PE in these

780

CHAPTER 43

patients is most likely the result of conscientious DVT prophylaxis. In patients at high risk for thrombosis, the benefits of laparoscopy must be weighed against the risks of thromboembolism.

Pulmonary Effects The pulmonary system is influenced by PNP both mechanically and chemically. In general, the intraoperative and postoperative respiratory embarrassment experienced by the patient undergoing a laparoscopic procedure is markedly less than for those undergoing the more traditional open approach. These pulmonary effects have been delineated using spirometryjpulmonary function tests and blood gas analysis. From a mechanical standpoint, as lAP is increased intraoperatively the diaphragm is shifted in the cephalad direction, which increases intrathoracic pressure. This reduced, paradoxical diaphragmatic movement in the face of increased intrathoracic pressure leads to an increase in peak airway pressure'" and the collapse of alveoli. As a result, forced residual capacity (FRC) is decreased." Concurrently, there is also a decrease in tidal volume'" as well as a decrease in compliance of both the lung and chest wall,64,67 leading to an overall increase in the work of breathing to maintain constant minute ventilation volume." The addition of positive end-expiratory pressure (PEEP) is a helpful ventilatory adjunct during conventional surgery to help recruit alveoli and to prevent further alveolar collapse. However, the hemodynamic implications of additional PEEP during PNP are complex. Increasing levels of PEEP coupled with abdominal insufflation have been shown to cause an increase in the MAP of pigs'" and a decrease in dogs." Although the direct implications of additional PEEP during PNP are controversial, there is clearly more hemodynamic instability with increasing levels of PEEP. Hypercapnia is another pulmonary concern requiring the attention of anesthesiologists during laparoscopic cases. Hypercapnia is defined as an increase in the plasma CO 2 concentration and may occur intraoperatively because CO 2 can easily diffuse across the peritoneal lining." In healthy patients, as CO 2 is absorbed (i.e., Paco, increases), the respiratory rate increases and CO 2 is expired through the lungs (i.e., Paco- increases). Wahba et al. showed that minute ventilation had to be increased by 12 % to 160/0 to maintain eucapnia." In unhealthy patients, or in patients unable to spontaneously increase their respiratory rate (i.e., anesthetized, intubated patients), the dissolved CO 2 in the blood is not effectively eliminated, and this can lead to systemic acidosis. Mild hypercapnia has few significant hemodynamic effects. However, severe hypercapnia (SO-70mmHg) can result in systemic hypotension by decreasing CO and SV, given that hypercarbia is both a myocardial depressant and a vasodilator." Because end-tidal CO 2 underestimates Pace, during PNP and is increasingly unreliable as Paco, increases.F invasive blood gas analysis is imperative in patients in whom minimal hypercarbia could be detrimental. There are several well-done studies of patients undergoing cholecystectomy that illustrate that LC causes less postoperative pulmonary embarrassment than OC. Pulmonary function tests administered to patients 1 to 2 days postoperatively show a smaller reduction in forced vital capacity (FVC), forced expiratory volume in 1 s (FEV!), and peak expiratory flow rate (PEFR) following LC as compared to OC. McMahon et al.

reported a smaller reduction of mean PEFR in LC compared to open (640/0 vs. 490/0; P < .001).74 In addition, spirometry values returned to preoperative values 4 to 10 days sooner in patients undergoing LC.75 Postoperative atelectasis and hypoxia are reduced after LC as compared to OC/5 although postoperative atelectasis or effusion can be shown on chest x-ray in 7 of 20 patients following LC.76 A decrease in oxygen saturation was one-third less after LC compared to OC on postoperative day 1/5 and Pa02 values, expressed as median change reduction from baseline, were significantly less for LC (-2) versus OC (-20) on postoperative day 2. 77 The majority of studies showed no difference in postoperative CO 2 retention for LC compared to OC. Clearly, the laparoscopic approach to cholecystectomy causes less pulmonary embarrassment than the traditional open approach. In patients with known chronic pulmonary disease, however, conscientious monitoring during anesthesia is necessary.

Effects on Intestinal Function Many studies have documented an earlier return of bowel function after laparoscopic procedures compared to open procedures.Y" Garcia-Caballero et al. found that flatus and bowel movement occurred significantly sooner after LC as compared to OC {10 and 36h vs. 60 and 96h, respectively]." However, there are conflicting animal studies reporting on the return of intestinal myoelectric activity following LC. Some evidence supports a faster return of intestinal myoelectric activity." while other does not." With the development of laparoscopic colon procedures, interest has surfaced regarding whether laparoscopic colon resection results in a faster return of bowel function compared to an open procedure. Although laparoscopic colon resection may afford the patient less postoperative pain" and shorter hospitalization.f there seems to be no improvement in myoelectric activity." In canine models for colon resection, transit studies favor laparoscopy," but measurements of intestinal myoelectric activity showed no difference."

Effects on Neurological Function Cerebral blood flow depends on cerebral perfusion pressure, which is calculated as MAP minus intracranial pressure (ICP). Mortality is increased with elevated, uncontrolled levels of ICP, and cerebral blood vessels constrict in response to hypocapnia." Animal studies directly measuring ICP showed a linear increase in ICP with rising levels of lAP. This trend also became worse following Trendelenberg (head-down) positioning.":" These physiological changes are the result of mechanical pressure forces as well as the transperitoneal diffusion of CO 2 • Abdominal insufflation results in decreased lumbar venous plexus drainage and increased MAP, both of which may contribute to the rise in ICP. In pigs outfitted for direct lumbar spinal pressure transducers, Halverson et al. showed an increase in lumbar spinal pressure with PNP. 88 Chemically, as Paco, levels rise during PNP, concomitant reflex cerebral vasodilation occurs that allows for an increase in cerebral blood flow and ICP. Fujii et al. studied 10 patients undergoing LC and showed an increase in cerebral blood flow velocity with increasing levels of PaC02 •89 There are limited reports of neurological deterioration with PNp90; however, laparoscopic intervention should be discouraged in patients

781

PRIN CIPLES OF MINIMALLY INVA SIVE SURGERY

-~,.-

TABLE 43.6. Level II Human Studies on the Metabolic and Immune Responses to Laparoscopic Versus Open Cholecystectomy.

Factor

Catecholamines '" Cortisol" ! Olucose"

IL_695,162,163 WBC

I64

CRp I6l- 163

TNFI64 DTH 165

OC

LC

r

it it ii it it it it

t

r r r r t

H

J,

CRP, C-reactive protein; DTH, delayed-type hypersensitivit y; LC, laparoscopic cholecystecto my; IL-6, inte rleuki n-o, OC, open cholecyst ectomy; WBC, whit e blood cell count.

in whom a marginal increase in ICP could be devastating [i.e., patients with head trauma).

Metabolic and Immune Effects Postoperative and posttraumatic immunosuppression have been extensively studied." It is well known that the extent of surgical intervention or trauma leads to a proportional acute-phase inflammatory response and postoperative immunosuppression. The acute-phase response is a biochemical defense that includes mobilized cytokines and cells of inflammation [i.e., white blood cells, macrophages) . This reaction may be accompanied by an elevated blood glucose, an increase in free fatty acids, and a liberation of catecholamines. In general, laparoscopy causes a blunted acute-phase and catabolic response compared to open surgery . In studies comparing LC to OC, LC caused a more modest increase in catecholamines (norepinephrine, epinephrine, dopamine), cortisol, and glucose (Table 43.6). Not only were levels of these stress indicators significantly less throughout the operative procedure, but also they returned to baseline faster following LC as compared to OC 92 (Fig. 43.3). Similarly, other markers of inflammation, including erythrocyte sedimentation rate, C-reactive protein," interleukin-6 (IL-6), white blood cell count, and tumor necrosis factor / 4,95 were each increased less following LC as compared to OC. 96 There is also less catabolism following laparoscopy as compared to

open surgery . Bouvy et a1. studied the level of catabolism in rats following open or laparoscopic bowel surgery by measuring serum insulin-like growth factor-l (IGF-I) levels and found a significantly lower IGF-I, less catabolism, in the laparoscopic group ." Both systemic and local immune responses have been studied during PNP . Systemically, delayed-type hypersensitivity (DTH), a marker for cell-mediated immunity, is less depressed following laparoscopic procedures." In a pig model, Bressler et a1. reported T-cell-related immune function as measured by DTH to be better preserved following laparo scopic as compared to open colon resection." Similarly, Brune et a1. compared LC and OC in a prospective study and showed that, although the antigen-presenting capacity of monocytes remained normal in both groups, T-cell stimulation was observed after OC but not after Lc. 99 Others have reported similar results. P'" ?' Trocar site tumor recurrences following laparoscopy have prompted research into the local effects of PNP on the peritoneal environment. Because CO 2 forms carbonic acid in an aqueous environment, the pH of the peritoneal milieu drops after the induction of CO 2 PNP. It has been speculated that this change in pH may affect the biochemical and cellular immune function inherent to the peritoneal cavity. In vitro functional assays have shown CO 2 to decrease the function of peritoneal macrophages of experimental animals as well as to decrease the spontaneous release of cytokines from human macrophages.F'{" Tung et a1., using open versus laparoscopic gut manipulation in mice, also showed less local infla mmatory response with laparoscopy by demonstrating that there was increased serum and gut mucosal IL-6 in the open group compared to laparoscopy.'?' Further experimental and clinical efforts are necessary to better understand the effects of PNP on intraperitoneal immunity and to help clarify a relevent clinical endpoint.

Special Circum stances Concerning Pneumoperitoneum Under certain physiological conditions, laparoscopy may be contraindicated. Initially, many believed that patient characteristics such as previous abdominal surgery, obesity, acute inflammation, and existing cardiopulmonary disease were absolute contraindications for a laparoscopic procedure. However, as experience has been gained and more advanced instrumentation has become available, several of these

2000 r-- -- - --

§' 1800

- - -- ----.,..----- -----, -

C, 1600

Openchole

- - Lap chole

a.

';;;' 1400 Ql .S 1200 ~o 1000 U 800 Ql 1ij 600 o

~

FIGURE 43.3. Changes in total plasma catecholamine concentration (mean ± SEM) after open and laparoscopic cholecystectomy. (From Schauer and Sirnek.!" by

permission.]

~

400 200 * 0L..;-";-.1--'---'---'---'---'---'--'--'--'--'--'--'--'--'---'---'--..L---J..----L---l 3 4 5 6 10

Before induct.

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t.!

1 Induct.

Time after skin incision (h)

782

CHAPTER 43

contraindications have been challenged. For example, mostly as a result of increased operator experience with the laparoscopic view, laparoscopic interventions for acute cholecystitis have become increasingly successful. However,laparoscopic interventions performed in septic laboratory animals have produced cloudy results and require further study.l'" Other special circumstances, which have been even more extensively studied in conjunction with laparoscopy, include cancer and pregnancy.

Pneumoperitoneum and Cancer Host immunity and cancer should be considered simultaneously. The systemic immune system seems to be better preserved following laparoscopy, however, some studies demonstrate that CO 2 PNP actually encourages tumor growth intraperitoneally. The initial reports documenting an increased risk of trocar site tumor recurrence following laparoscopic cancer procedures led some investigators to question the safety of CO 2 PNP in oncological patients. A discussion of PNP and cancer can be divided into systemic and local oncological effects of PNP. SYSTEMIC ONCOLOGICAL EFFECTS

Both laparotomy and laparoscopy encourage tumor growth. However, in several animal studies, it appears that full laparotomy encourages systemic postoperative tumor growth more than CO 2 PNP. In animal studies comparing the growth of injected intradermal tumor cells, the open intervention animals grew tumors that were significantly larger than CO 2PNP and control groups.l'" Likewise, several other studies that compared similar interventions showed a stepwise increase in postoperative tumor size or proliferation index from the anesthesia/control group through the CO 2 PNP group to the laparotomy groUp.107,108 PORT SITE METASTASIS

Several early reports claimed an increase in the incidence of

port site tumor recurrences following laparoscopic tumor resection as compared to incisional tumor recurrences following traditional surgery.109-112 In fact, these initial efforts of laparoscopic colon cancer resection reported an incidence of port site metastases as high as 21 0/0,113 as compared to a 0.69% to 3.30/0 incidence of abdominal wound recurrence following traditional resection for colorectal cancer.!" However, with an increase in experience with laparoscopic colon resection, more recent reports claim that these rates of trocar site recurrences were largely overestimated. Several large series have documented trocar site tumor recurrence as low as 20/0. 82,115-117 In one study of 208 cases of laparoscopic colon resections, there were 3 cases of port site recurrence after a minimum follow-up of 1 year.!" Similarly, in another prospective, randomized trial that included 109 patients and compared laparoscopic and conventional techniques of bowel resection for colorectal cancers or polyps, there were no instances of port site metastases in the laparoscopic group after a median follow-up of 1.5 years.!" Another prospective, comparative study of open versus laparoscopic colon resection (n = 224 vs. 191, respectively) also reported no cases of trocar implants in the laparoscopic group after 5 years of follow-up.!" It appears that the true incidence of port

site recurrences is close to that of incisional recurrences after open surgery.!" As the true incidence of port site tumor recurrence becomes increasingly defined, experimental studies have provided insight into the pathophysiology behind this phenomenon. In general, port site recurrences seem to be more of an issue in animal models than in most human studies. In animal studies comparing laparoscopy to open resection, the incidence of trocar site tumor recurrence is considerably higher following CO 2 PNP. In a hamster model of intraperitoneally injected human colon cancer cells, trocar site implantation tripled following laparotomy with the addition of CO 2 PNP as compared to laparotomy alone (26% vs. 750/0).112 Reports such as these have continued to raise skepticism regarding the safety of laparoscopy for oncological procedures, and several hypotheses have been developed to explain this increased occurrence. Most researchers agree that because systemic immunological and antioncological effects appear to be well preserved with laparoscopy, the increased port site tumor implantation demonstrated in these studies is most likely caused by a direct effect of PNP on the peritoneum, an effect that allows for the implantation of tumor. At the Second International Laparoscopic Physiology Conference, held in Frankfurt, Germany, efforts from several laparoscopic animal research laboratories were presented to address the possible origins of port site tumor recurrences'" (Fig. 43.4). The first two hypotheses highlight the biochemical effects of CO 2 PNP. As mentioned, there is well-designed experimental evidence demonstrating that the acidic environment created with CO 2 PNP is harmful to the peritoneal macrophage, and as a result there is ineffective tumor cell clearance.l'" Others believe that CO 2 actually has a stimulatory effect on tumor growth.'!' For instance, intradermally injected tumor cells were more easily established and grew more aggressively following laparotomy than after CO 2 insufflation.122 Clearly, tumor recurrence requires the presence of tumor cells at the trocar site, and direct contact between the solid

tumor and the port site enhances port site tumor growth'P, this contact could occur by removing the pathological speci-

FIGURE 43.4. Factors influencing trocar site tumor recurrence. IP, intraperitoneal immunity.

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PRIN CIPLES OF MINIMAL LY INVASIVE SUR GERY

men through an unprotected trocar site . Investigators who have treated trocar sites with various materials that deter cell adherence and prevent tumor implantation (i.e., heparin, taurolidin) have reported varying results.!" Evidence also exists showing that more trauma to the trocar site encourages tumor growth. In animals with trocar sites that were crushed with a surgical clamp before trocar insertion, there were greater numbers of port site metastases in the crushed sites as com pared to other, noncrushed sites .!" Further support for a mechanical cause as responsible for port site tumors was demonstrated in a human study in which CO 2 insufflation was found to contain very low levels of free-floating tumor cells even in the presence of mass ive contamination.126 Although some studies supported the chimney effect (gas leakage around trocarsl.! " the small clumps of cells found in the smoke during laparoscopy were not malignant.':" and aerosols of tumor cells are not likely to form .128,129 Further reports specifically implicating gas turbulence include studies in which gasless laparoscopy caused less abdom inal wall metastasis than CO 2 PNP . 123,130 A specimen containing or potentially containing cancer should be carefully manipulated and removed through a protected wound.

Pneumoperitoneum and Pregnancy If surgery during pregnancy is unavoidable, then the optimal time period for such intervention is during the second trimester. Second-trimester operative intervention avoids the potential disruption of organogenesis during the first trimester and possible labor induction during the third. For the safety of both mother and fetus , operative time should be kept to a minimum, and the fetus should be monitored intraoperatively. The typical indications for laparoscopic surgical intervention during pregnancy include acute appendicitis, acute cholecystitis, ectopic pregnancy, and ovarian torsion. When operating on the pregnant patient, three unique physiological factors must be considered: maternal physiological alterations with pregnancy, uteroplacental blood flow, and the overall well -being of the fetus'!' (Fig. 43.5). There are few studies presently available to delineate the effects of PNP on the developing fetus or the pregnant mother. The limited evidence that is available supports the safety of laparoscopy during pregnancy. In a retrospective study, Reedy et a1. reviewed a 20-year period of 2,015,000 delivery records

cO 2 - Pneumoperitoneum

t/

! TIAP

'--~

Vasopressin R-A - t P V R - - _

"cava cornp. Hypercarbia -

- t CO Acidosis-+

FIGURE 43.5. Maternal and fetal changes in pneumoperitoneum during pregnancy. (From Silva and Platt.':" by permission.)

_'r."'_ TABLE 43.7.

Vasc ular and Bowel Inj uries During 77,604 Laparoscopic Cholecyste ctomies (Level III Evidence). N o. of patients

(%)

In iury site

Vascula r Retroperitoneal vessels Aorta Inferior vena cava Iliac artery Iliac vein Total Portal vessels Hepatic artery Cys ti c artery Port al vein Total Other intraabdominal vessels T otal vasc ular Bowel Small intestine Colon Duo den um Stomach Total

13 5 11 7 36 (0.05 )

44 73 5

122 (0.16) 35 (0.051 193 (0.25 1

57

35 12 5 109 (0.14)

No . of patients requirin g laparotomy

12

3

10 6 31 36 63

4

103

24

158

42

26 12 5 85

Source: From Deziel et a1.,58 by perm ission.

in Sweden and found 2,181 laparoscopic interventions and 1,522 laparotomies during pregnancy. When these two groups were compared, these authors found no difference in fetal outcome in singleton pregnancies between 4 and 20 weeks of gestation.132 In one 6-year case-controlled study comparing 16 pregnant patients during the first or second trimester undergoing laparoscopic surgery (4 appendectomies and 12 cholecystectomies) to 18 similar patients undergoing laparotomy (7 appendectomy and 11 cholecystectomy], the authors found no difference in morbidity or mortality.!" Prospective data documenting the safety of laparoscopic general surgical interventions during pregnancy are presently not available. Experimental animal evidence supporting laparoscopy during pregnancy is also limited. COMPLICATIONS OF LAPAROSCOPY

Fortunately, major complications occur in well under 1 % of laparoscopic procedures, with an overall mortality of 4 to 8 deaths per 100,000 procedures.!" However, the minimally invasive nature of laparoscopy does not eliminate the potential for serious surgical complications. Several categories of complications unique to laparoscopy include complications related to needle and trocar site insertion.!" those specific to insufflation, and the establishment of PNP and those related to the use or misuse of specialized laparoscopic equipment. Most of the data illustrating the complications during laparoscopy have been accumulated during LC (Table 43.7). The overall morbidity rate for needle and trocar complications is between 0.2% and 0.5%, with mortality rates of 0.0033% to 0.1 %. 135- 137 The placement of the first trocar or Veress needle accounts for the majority of these iniuries.!" Because the Veress needle is placed blindly through a small skin incision, it can

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inadvertently puncture blood vessels or abdominal viscera. As a result, many operators opt for the open approach as originally described by H.M. Hasson.!" Using this technique, the fascia is directly visualized and incised. However, despite using the utmost care, the overall incidence of visceral injuries with the open approach is approximately 0.10/0. 58 The organ most likely injured is the small bowel (520/0), followed by colon, duodenum, and stomach (320/0, 110/0, and 4.50/0, respectively]." Bladder perforation can occur any time; however, this complication occurs most frequently during laparoscopic procedures in patients who have had previous surgery. Bladder perforation can be recognized by bubbling within the urine collection bag. Vascular injuries are reported less frequently"? but if unrecognized can be devastating. The placement of additional trocars can lead to bleeding from abdominal wall vessels, especially the epigastric vessels. The reported incidence of hemorrhage caused by injury of the epigastric vessels during trocar insertion ranges between 0.250/0 and 6.0%.141 These injuries can be controlled with electrocautery, by tamponade using a balloon-tipped catheter that is pulled against the abdominal wall, or by enlargement of the incision for suture ligation. Port site infection occurs in fewer than 1% of patients. The risk factors for port site infection are the same as for any incision, including poor nutrition, obesity, and diabetes mellitus. Port site infection can lead to hernia development. The overall incidence of port site herniation is relatively low, with larger trocar sites posing the highest risk. The umbilical trocar is the most common site of herniation, occurring in 0.1 % of patients undergoing LC.135 Inappropriate closure of a trocar site can lead to the development of a trocar site hernia. All trocar sites measuring 10mm or greater should be sutured closed, unless created with a dilating, noncutting trocar. Abdominal gas insufflation has been implicated as the cause of unusuallaparoscopic complications. The diffusion of CO 2 into the bloodstream or its direct introduction into the vascular system can lead to cardiac dysrythmias or embolization.142-145 Large volumes of intravascular CO2 can lead to sudden cardiac collapse by forming a gas lock in the right ventricular outflow tract. The signs of CO 2 embolization include hypotension, cyanosis, arrhythmia, and "millwheel" murmur that can be heard through an esophageal stethoscope. Fortunately, CO 2 embolization during laparoscopy is rare, with an incidence of 0.002% to 0.0160/0. 143 When it occurs, treatment entails release of the PNP and repositioning the patient in the left lateral decubitus position, head down, to float the gas bubble into the right atrium, thus avoiding obstruction of the pulmonary outflow tract. Inappropriate patient positioning and misuse of the specialized laparoscopic equipment can also lead to complications. The lithotomy position, often used during antireflux procedures or colon resections, can cause nerve stretching and ischemia that can lead to femoral neuropathy.146 As discussed, head-up and head-down positioning can each have cardiovascular implications. Proper functioning of all laparoscopic equipment should be ensured before beginning the operation. Unless on standby, the laparoscopic light source should be immediately attached to the laparoscope. If left unattached, then surgical drape combustion is possible. Instrumentation should be periodically inspected for proper functioning and intact insulation.

TABLE 43.8. Avoiding Complications During Laparoscopy. Training Patient selection Room setup Port placement (site/technique) Visualization (equipment/blood or debris) Familiarity with anatomical landmarks Early consultation

All operating personnel should be acquainted with the proper applications for the basic instrumentation. For instance, the laparoscopic grasper has many applications. As a result, the jaws are designed for secure fastening (with teeth) or for visceral manipulation (smooth). To avoid intestinal perforation, only smooth graspers should be used for intestinal manipulation. Bowel injuries have also been reported by careless application of the suction147 and irrigation stream. Because these devices are deployed with considerable force, the suction or irrigator should not be directed toward recently applied clips (i.e., cystic duct). Finally, thermal injuries from electrocautery can result from careless application, defective insulation, or improper grounding. The extent of such injury is directly related to the magnitude of current and the length of time that such current is applied. In 1993, a survey of 500 physician respondents at the American College of Surgeons meeting was conducted, and 18% of these physicians reported laparoscopic complications that they attributed to electrosurgery. It is safest to use properly insulated electrocautery instruments and short bursts of current to avoid thermal injuries. Attention to detail in laparoscopy, just as in all surgical procedures, avoids most complications (Table 43.8).

Training and Credentialing in Laparoscopic Surgery Surgical trammg is evolving. As laparoscopic techniques become more refined, they are increasingly important in general surgeons' practices. Indeed, general surgery is becoming more and more synonymous with laparoscopic surgery. Mostly because of the widespread acceptance of both LC and fundoplication, both basic and advanced laparoscopic techniques have been increasingly integrated into surgical residency programs. At the same time, private industry has propagated an explosion in the production of advanced laparoscopic instrumentation. These two developments, coupled with public pressure for minimally invasive techniques, spearheaded an evolution in surgical education. The hands, and in tum the working end of the instrument, of the trainer and trainee are now separated from each other by the patient's abdominal wall, and the surgical action is concurrently interpreted on the inanimate two-dimensional monitor. As a result, influence of the trainer over the trainee is more reliant on the verbal commands of the instructor than ever before. The trainer is less able to physically guide the trainee's hands through the preliminary stages of an operation, and as a result, there is increasing pressure to move the education of basic laparoscopic skills outside the clinical operating room. The student laparoscopist must now become


acquainted with the change in depth perception, the point of view of the laparoscope, as well as basic technical skills (laparoscopic suturing and knot tying) outside the clinical operating room. The paradigm for laparoscopic surgical education is evolving from the traditional surgical learning cliche of "see one, do one, teach one" to "see one, practice one, do one." The "practice one" step in laparoscopic skills education has been addressed through a variety of methods. Considerable effort has been expended to define the essentiallaparoscopic skills as well as the best method for educating students in these techniques. Since it was founded, the Society of American Gastrointestinal Endoscopic Surgeons (SAGES) has actively developed guidelines for the organized integration of laparoscopy into surgical residency programs. This group has divided laparoscopic procedures into two categories: basic (diagnostic laparoscopy, cholecystectomy, and appendectomy) and advanced (everything else).148 Presently, the majority of general surgery residents in the United States are being exposed to basic laparoscopic techniques by faculty with adequate and often exceptional experience. The importance of basic laparoscopy in undergraduate surgical education is emphasized by the American Board of Surgery (ABS), which now requires experience with LC during a surgical residency to qualify for certification. The plan to maintain laparoscopic training within the 5-year general surgery residency program has been emphasized by the ABS and echoed by SAGES.149 With regard to advanced laparoscopic techniques, training of both educators and residents remains a challenge. Advanced techniques such as antireflux procedures, solid organ surgery, and colon procedures require proficiency in both basic and advanced laparoscopic skills. In addition, the risk for significant operative complication is also increased. The faculty presently teaching advanced laparoscopic procedures have gained this experience in a variety of ways, including independent experience, weekend courses, visiting surgeon proctoring, and telementoring. These methods of education have had varying success.l'"!" To provide standards for these training methods as well as documentation for proficiency, SAGES has developed guidelines for granting privileges in laparoscopic surgery. According to SAGES, to sponsor an advanced laparoscopic training program, the educating surgeon "should demonstrate proficiency in laparoscopic procedures and clinical judgment equivalent to that obtained in a surgical residency program.t'"? It is only after educators well versed in advanced laparoscopic techniques become more available that advanced laparoscopic experience will become commonplace in surgical residency programs across the country. With a residency program, in-house skills labs and inanimate trainers are now staples in the education of basic laparoscopic skills, 153,154 the result of educational research that has documented the benefit of these media for laparoscopic skill acquisition. Rosser et al. described a method of training that includes specific drills (rope pass, cup drop, and triangle transfer), which translates to improved performance in more complex laparoscopic skills such as suturing. 1sS,ls6 In most institutions, these skill stations are located in-house with continuous availability. However, in conjunction with the development of more efficient microprocessors, these simulators are becoming increasingly compact and portable. In addi-

785

tion, more advanced learning materials such as CD-ROMs, the Internet, and virtual reality have also been shown to be effective in laparoscopic surgical education. 151, IS? Operating room experience in laparoscopy can also be targeted within a residency program toward residents with a particular interest in pursuing a career in general surgery. As advanced laparoscopic procedures become more commonplace, individual program directors should have the flexibility to direct these residents toward advanced laparoscopic cases.!" In the interim, training in advanced laparoscopy is offered in postresidency educational venues such as fellowship programs. Postresidency training experiences programs can be divided into two categories: private apprenticeships for those seeking practical experience and academic fellowships designed for physicians seeking more experience in advanced laparoscopic techniques combined with academic or research experience. Guidelines for laparoscopic fellowships have been delineated by SAGES,ls8 and just as in other fellowships, the training of advanced laparoscopists should not detract from the training of residents of that particular residency program. To prepare future educators, academic fellowships should not only include an emphasis on achieving appropriate clinical skills but also place particular emphasis on laparoscopic research (both basic science and clinical) and advanced education in information technology.

Future In the near future, advancement in minimally invasive surgery will occur in three areas: instrumentation, education, and basic science/outcomes research. As instruments and optics become smaller and more reliable, the place for this instrumentation will become better defined. Advancements in instrumentation will also lead to more sophisticated robotics that will not only assist surgery but also allow operators to perform surgery from remote locations or advance the ability to teleproctoring learning surgeons. Advancement in robotics coupled with information technology will further enhance surgical education. This arrangement allows expert technical consultation to be available both in and outside the operating room. Advancement in virtual reality has great potential to change the way we presently think of surgical education. More advanced simulators will allow surgeons the opportunity to practice a laparoscopic surgical case before attempting it in a patient. Finally, the creation of more sophisticated databases coupled with surgeons more acquainted with information technology will lead to a greater ease in collaboration and quicker, more effective clinical trials.

Acknowledgment. We would like to thank the previous edi-

tion's authors, Dr. Chekan and Dr. Pappas. We also thank Thomas J. Birdas, MD; Amjad Ali, MD; Erik Clary, DVM; Gray Hughes, MD; and Maureen Fina for their editing and clerical efforts. We also thank Robert Anderson, MD, for his ongoing support.

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47. Chiu AW, Chang LS, Birkett DH, Babayan RK. A porcine model for renal hemodynamic study during laparoscopy. J Surg Res 1996;60:61-68. 48. Chiu AW, Chang LS, Birkett DH, Babayan RK. The impact of pneumoperitoneum, pneumoretroperitoneum, and gasless laparoscopy on the systemic and renal hemodynamics. J Am Coll Surg 1995;181:397-406. 49. Miki Y, Iwase K, Kamiike W, et al. Laparoscopic cholecystectomy and time-course changes in renal function. The effect of the retraction method on renal function. Surg Endosc 1997; 11:838-841. 50. Iwase K, Takenaka H, Ishizaka T, Ohata T, Oshima S, Sakaguchi K. Serial changes in renal function during laparoscopic cholecystectomy. Eur Surg Res 1993;25:203-212. 51. Chang DT, Kirsch AJ, Sawczuk IS. Oliguria during laparoscopic surgery. J Endourol 1994;8:349-352. 52. Jorgensen JO, Gillies RB, Lalak NT, Hunt DR. Lower limb venous hemodynamics during laparoscopy: an animal study. Surg Laparose Endosc 1994;4:32-35. 53. Millard JA, Hill BB, Cook PS, Fenoglio ME, Stahlgren LH. Intermittent sequential pneumatic compression in prevention of venous stasis associated with pneumoperitoneum during laparoscopic cholecystectomy. Arch Surg 1993;128:914-918; discussion 918-919. 54. Vander Velpen G, Penninckx F, Kerremans R, Van Damme 1, Arnout J. Interleukin-6 and coagulation-fibrinolysis fluctuations after laparoscopic and conventional cholecystectomy. Surg Endosc 1994;8:1216-1220. 55. Caprini JA, Arcelus JI. Prevention of postoperative venous thromboembolism following laparoscopic cholecystectomy. Surg Endosc 1994;8:741-747. 56. Bergqvist D, Matzsch T, Jendteg S, Lindgren B, Persson U. The cost-effectiveness of prevention of post-operative thromboembolism. Acta Chir Scand SupplI990;556:36-41. 57. Morgenstern L, Wong L, Berci G. Twelve hundred open cholecystectomies before the laparoscopic era. A standard for comparison. Arch Surg 1992;127:400-403. 58. Deziel D1, Millikan KW, Economou SG, Doolas A, Ko ST, Airan MC. Complications of laparoscopic cholecystectomy: a national survey of 4,292 hospitals and an analysis of 77,604 cases. Am J Surg 1993;165:9-14. 59. Caprini JA, Arcelus JI, Hoffman K, et al. Prevention of venous thromboembolism in North America: results of a survey among general surgeons. J Vase Surg 1994;20:751-758. 60. Schwenk W, Bohm B, Fugener A, Muller JM. Intermittent pneumatic sequential compression (ISC) of the lower extremities prevents venous stasis during laparoscopic cholecystectomy. A prospective randomized study. Surg Endosc 1998;12:7-11. 61. Wu EC, Barba CA. Current practices in the prophylaxis of venous thromboembolism in bariatric surgery. Obes Surg 2000;10:7-13; discussion 14. 62. Nguyen NT, Owings JT, Gosselin R, et al. Systemic coagulation and fibrinolysis after laparoscopic and open gastric bypass. Arch Surg 2001;136:909-916. 63. Miller MT, Rovito PF. An approach to venous thromboembolism prophylaxis in laparoscopic Roux-en-Y gastric bypass surgery. Obes Surg 2004;14:731-737. 64. Volpino P, Cangemi V, D'Andrea N, Cangemi B, Piat G. Hemodynamic and pulmonary changes during and after laparoscopic cholecystectomy. A comparison with traditional surgery. Surg Endosc 1998;12:119-123. 65. Drummond GB, Martin LV. Pressure-volume relationships in the lung during laparoscopy. Br J Anaesth 1978;50:261-270. 66. Simonneau G, Vivien A, Sartene R, et al. Diaphragm dysfunction induced by upper abdominal surgery. Role of postoperative pain. Am Rev Respir Dis 1983;128:899-903. 67. Fahy BG, Barnas GM, Flowers JL, Nagle SE, Njoku MJ. The effects of increased abdominal pressure on lung and chest wall

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mechanics during laparoscopic surgery. Anesth Analg 1995;81:744-750. 68. Sharma KC, Brandstetter RD, Brensilver JM, lung LD. Cardiopulmonary physiology and pathophysiology as a consequence of laparoscopic surgery. Chest 1996;110:810-815. 69. Moffa SM, Quinn TV, Slotman GJ. Hemodynamic effects of carbon dioxide pneumoperitoneum during mechanical ventilation and positive end-expiratory pressure. JTrauma 1993;35:613617; discussion 617-618. 70. Luz CM, Polarz H, Bohrer H, Hundt G, Dorsam 1, Martin E. Hemodynamic and respiratory effects of pneumoperitoneum and PEEP during laparoscopic pelvic lymphadenectomy in dogs. Surg Endosc 1994;8:25-27. 71. Fitzgerald SD, Andrus CH, Baudendistel LJ, Dahms TE, Kaminski DL. Hypercarbia during carbon dioxide pneumoperitoneum. Am J Surg 1992;163:186-190. 72. Wahba RW, Mamazza J. Ventilatory requirements during laparoscopic cholecystectomy. Can J Anaesth 1993;40:206210. 73. Smith I, Benzie R1, Gordon NL, Kelman GR, Swapp GH. Cardiovascular effects of peritoneal insufflation of carbon dioxide for laparoscopy. Br Med J 1971;3:410-411. 74. McMahon A1, Russell IT, Ramsay G, et al. Laparoscopic and minilaparotomy cholecystectomy: a randomized trial comparing postoperative pain and pulmonary function. Surgery 1994; 115:533-539. 75. Schauer PR, Luna J, Ghiatas AA, Glen ME, Warren JM, Sirinek KR. Pulmonary function after laparoscopic cholecystectomy. Surgery 1993;114:389-397; discussion 397-399. 76. Torrington KG, Bilello JF, Hopkins TK, Hall EA Jr. Postoperative pulmonary changes after laparoscopic cholecystectomy. South Med J 1996;89:675-678. 77. Eden CG, Haigh AC, Carter PG, Coptcoat MJ. Laparoscopic nephrectomy results in better postoperative pulmonary function. J Endourol 1994;8:419-422; discussion 422-423. 78. Litwin DE, Girotti M1, Poulin EC, Mamazza J, Nagy AG. Laparoscopic cholecystectomy: trans-Canada experience with 2201 cases. Can J Surg 1992;35:291-296. 79. Garcia-Caballero M, Vara-Thorbeck C. The evolution of postoperative ileus after laparoscopic cholecystectomy. A comparative study with conventional cholecystectomy and sympathetic blockade treatment. Surg Endosc 1993;7:416-419. 80. Schippers E, Ottinger AP, Anurov M, Polivoda M, Schumpelick V. Laparoscopic cholecystectomy: a minor abdominal trauma? World J Surg 1993;17:539-542; discussion 543. 81. Ludwig KA, Frantzides CT, Carlson MA, Grade KL. Myoelectric motility patterns following open versus laparoscopic cholecystectomy. J Laparoendosc Surg 1993;3:461-466. 82. Ballantyne GH. Laparoscopic-assisted colorectal surgery: review of results in 752 patients. Gastroenterologist 1995;3: 75-89. 83. Liberman MA, Phillips EH, Carroll BJ, Fallas M, Rosenthal R. Laparoscopic colectomy versus traditional colectomy for diverticulitis. Outcome and costs. Surg Endosc 1996;10:15-18. 84. Davies W, Kollmorgen CF, Tu QM, et al. Laparoscopic colectomy shortens postoperative ileus in a canine model. Surgery 1997;121:550-555. 85. Carlson MA, Frantzides CT. Canine intestinal myoelectric activity after open versus laparoscopically assisted right hemicolectomy. Am J Surg 1997;174:79-82. 86. Pitts LH, Martin N. Head injuries. Surg Clin North Am 1982;62:47-60. 87. Rosenthal R1, Hiatt JR, Phillips EH, Hewitt W, Demetriou AA, Grode M. Intracranial pressure. Effects of pneumoperitoneum in a large-animal model. Surg Endosc 1997;11:376-380. 88. Halverson A, Buchanan R, Jacobs L, et al. Evaluation of mechanism of increased intracranial pressure with insufflation. Surg Endosc 1998;12:266-269.

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89. Fujii Y, Tanaka H, Tsuruoka S, Toyooka H, Amaha K. Middle cerebral arterial blood flow velocity increases during laparoscopic cholecystectomy. Anesth Analg 1994;78:80-83. 90. Paulson GW, DeVoe K Jr. Neurological complications of laparoscopy. Am J Obstet GynecoI1981;140:468-469. 91. Lennard TW, Shenton BK, Borzotta A, et al. The influence of surgical operations on components of the human immune system. Br J Surg 1985;72:771-776. 92. Schauer PR, Sirinek KR. The laparoscopic approach reduces the endocrine response to elective cholecystectomy. Am Surg 1995;61:106-111. 93. McMahonAJ, O'Dwyer PJ, Cruikshank AM, et al. Comparison of metabolic responses to laparoscopic and minilaparotomy cholecystectomy. Br J Surg 1993;80:1255-1258. 94. Bressler M, Whelan RL, Halverson A, Treat MR, Nowygrod R. Is immune function better preserved after laparoscopic versus open colon resection? Surg Endosc 1994;8:881-883. 95. Kloosterman T, von Blomberg BM, Borgstein P, Cuesta MA, Scheper RJ, Meijer S. Unimpaired immune functions after laparoscopic cholecystectomy. Surgery 1994;115:424-428. 96. Mealy K, Gallagher H, Barry M, Lennon F, Traynor 0, Hyland J. Physiological and metabolic responses to open and laparoscopic cholecystectomy. Br J Surg 1992;79:1061-1064. 97. Bouvy ND, Marquet RL, Tseng LN, et al. Laparoscopic versus conventional bowel resection in the rat. Earlier restoration of serum insulin-like growth factor 1 levels. Surg Endosc 1998;12:412-415. 98. Buunen M, Gholghesaei M, Veldkamp R, Meijer DW, Bonjer HJ, Bouvy ND. Stress response to laparoscopic surgery: a review. Surg Endosc 2004;18:1022-1028. 99. Brune IB,Wilke W, Hensler T, Feussner H, Holzmann B, Siewert JR. Normal T lymphocyte and monocyte function after minimally invasive surgery. Surg Endosc 1998;12:1020-1024. 100. Gutt CN, Kuntz C, Schmandra T, et al. Metabolism and immunology in laparoscopy. First Workshop on Experimental Laparoscopic Surgery, Frankfurt, 1997. Surg Endosc 1998;12: 1096-1098. 101. Berguer R, Dalton M, Ferrick D. Adrenocortical response and regional T-lymphocyte activation patterns following minimally invasive surgery in a rat model. Surg Endosc 1998;12:236240. 102. West MA, Hackam DJ, Baker J, Rodriguez JL, Bellingham J, Rotstein ODe Mechanism of decreased in vitro murine macrophage cytokine release after exposure to carbon dioxide: relevance to laparoscopic surgery. Ann Surg 1997;226:179-190. 103. Carozzi S, Caviglia PM, Nasini MG, Schelotto C, Santoni 0, Pietrucci A. Peritoneal dialysis solution pH and Ca2+ concentration regulate peritoneal macrophage and mesothelial cell activation. Asaio J 1994;40:20-23. 104. Tung PH, Wang Q, Ogle CK, Smith CD. Minimal increase in gut-mucosal interleukin-6 during laparoscopy. Surg Endosc 1998;12:409-411. 105. Jacobi CA, Krahenbuhl L, Blochle C, Bonjer HJ, Gutt CN. Peritonitis and adhesions in laparoscopic surgery. First Workshop on Experimental Laparoscopic Surgery, Frankfurt 1997. Surg Endosc 1998;12:1099-1101. 106. Whelan RL, Allendorf JD, Gutt CN, et al. General oncologic effects of the laparoscopic surgical approach. 1997 Frankfurt International Meeting of Animal Laparoscopic Researchers. Surg Endosc 1998;12:1092-1095. 107. Allendorf JD, Bessler M, Whelan RL, et al. Better preservation of immune function after laparoscopic-assisted versus open bowel resection in a murine model. Dis Colon Rectum 1996;39: S67-S72. 108. Bouvy ND, Marquet RL,Jeekel J,Bonjer HJ. Laparoscopic surgery is associated with less tumour growth stimulation than conventional surgery: an experimental study. Br J Surg 1997;84:358361.

109. Cirocco WC, Schwartzman A, Golub RW. Abdominal wall recurrence after laparoscopic colectomy for colon cancer. Surgery 1994;116:842-846. 110. Fodera M, Pello MJ,Atabek U, Spence RK,Alexander JB, Camishion RC. Trocar site tumor recurrence after laparoscopic-assisted colectomy. J Laparoendosc Surg 1995;5:259-262. Ill. Jacquet P, Averbach AM, Jacquet N. Abdominal wall metastasis and peritoneal carcinomatosis after laparoscopic-assisted colectomy for colon cancer. Eur J Surg OncoI1995;21:568-570. 112. Jones DB, Guo LW, Reinhard MK, et al. Impact of pneumoperitoneum on trocar site implantation of colon cancer in hamster model. Dis Colon Rectum 1995;38:1182-1188. 113. Wexner SD, Cohen SM. Port site metastases after laparoscopic colorectal surgery for cure of malignancy. Br J Surg 1995;82:295298. 114. Hughes ES, McDermott FT, Polglase AL, Johnson WR. Tumor recurrence in the abdominal wall scar tissue after large-bowel cancer surgery. Dis Colon Rectum 1983;26:571-572. 115. Lord SA, Larach SW, Ferrara A, Williamson PR, Lago CP, Lube MW. Laparoscopic resections for colorectal carcinoma. A 3-year experience. Dis Colon Rectum 1996;39:148-154. 116. Lacy AM, Delgado S, Garcia-Valdecasas JC, et al. Port site metastases and recurrence after laparoscopic colectomy. A randomized trial. Surg Endosc 1998;12:1039-1042. 117. Ramos JM, Gupta S, Anthone GJ, Ortega AE, Simons AJ, Beart RW Jr. Laparoscopy and colon cancer. Is the port site at risk? A preliminary report. Arch Surg 1994;129:897-899; discussion 900. 118. Milsom JW, Bohm B,Hammerhofer KA, Fazio V, Steiger E, Elson P. A prospective, randomized trial comparing laparoscopic versus conventional techniques in colorectal cancer surgery: a preliminary report. J Am Coll Surg 1998;187:46-54; discussion 54-55. 119. Franklin ME Jr., Rosenthal D, Abrego-Medina D, et al. Prospective comparison of open vs. laparoscopic colon surgery for carcinoma. Five-year results. Dis Colon Rectum 1996;39:S35-S46. 120. Curet MJ. Port site metastases. Am J Surg 2004;187:705-712. 121. Jacobi CA, Sabat R, Bohm B, Zieren HU, Volk HD, Muller JM. Pneumoperitoneum with carbon dioxide stimulates growth of malignant colonic cells. Surgery 1997;121:72-78. 122. Allendorf JD, Bessler M, Kayton ML, et al. Increased tumor establishment and growth after laparotomy versus laparoscopy in a murine model. Arch Surg 1995; 130:649-653. 123. Bouvy ND, Marquet RL, Ieekel H, Bonjer HJ. Impact of gas(less) laparoscopy and laparotomy on peritoneal tumor growth and abdominal wall metastases. Ann Surg 1996;224:694-700; discussion 700-701. 124. Goldstein DS, Lu ML, Hattori T, Ratliff TL, Loughlin KR, Kavoussi LR. Inhibition of peritoneal tumor-cell implantation: model for laparoscopic cancer surgery. J Endourol 1993;7:237241. 125. Kazemier G, Bonjer HJ, Berends FJ,Lange JF. Port site metastases after laparoscopic colorectal surgery for cure of malignancy. Br J Surg 1995;82:1141-1142. 126. Reymond MA, Wittekind C, [ung A, Hohenberger W, Kirchner T, Kockerling F. The incidence of port-site metastases might be reduced. Surg Endosc 1997;11:902-906. 127. Champault G, Taffinder N, Ziol M, Riskalla H, Catheline JM. Cells are present in the smoke created during laparoscopic surgery. Br J Surg 1997;84:993-995. 128. Whelan RL, Sellers GJ, Allendorf JD, et al. Trocar site recurrence is unlikely to result from aerosolization of tumor cells. Dis Colon Rectum 1996;39:S7-S13. 129. Allardyce RA, Morreau P, Bagshaw PF. Operative factors affecting tumor cell distribution following laparoscopic colectomy in a porcine model. Dis Colon Rectum 1997;40:939-945. 130. Watson DI, Mathew G, Ellis T, Baigrie CF, Rofe AM, Jamieson GG. Gasless laparoscopy may reduce the risk of port-site metas-


tases following laparascopic tumor surgery. Arch Surg 1997; 132:166-168; discussion 169. 131. Silva J, Platt L. Laparoscopic surgery during pregnancy. In: Rosenthal R, Friedman R, Phillips E, eds. The Pathophysiology of Pneumoperitoneum. New York: Springer; 1998. 132. Reedy MB, Kallen B, Kuehl TJ. Laparoscopy during pregnancy: a study of five fetal outcome parameters with use of the Swedish Health Registry. Am J Obstet GynecoI1997;177:673-679. 133. Curet MJ, Allen D, Iosloff RK, et al. Laparoscopy during pregnancy. Arch Surg 1996;131:546-550; discussion 550551. 134. Phillips JM, Hulka JF, Hulka B, Corson SL. 1979 AAGL membership survey. J Reprod Med 1981;26:529-533. 135. Larson GM, Vitale GC, Casey J, et al. Multipractice analysis of laparoscopic cholecystectomy in 1983 patients. Am J Surg 1992;163:221-226. 136. Frenkel Y, Oelsner G, Ben-Baruch G, Menczer J. Major surgical complications of laparoscopy. Eur J Obstet Gynecol Reprod Biol 1981;12:107-111. 137. Yuzpe AA. Pneumoperitoneum needle and trocar injuries in laparoscopy. A survey on possible contributing factors and prevention. J Reprod Med 1990;35:485-490. 138. Oshinsky GS, Smith AD. Laparoscopic needles and trocars: an overview of designs and complications. J Laparoendosc Surg 1992;2:117-125. 139. Hasson HM. A modified instrument and method for laparoscopy. Am J Obstet GynecoI1971;110:886-887. 140. Nordestgaard AG, Bodily KC, Osborne RW Jr, Buttorff JD. Major vascular injuries during laparoscopic procedures. Am J Surg 1995;169:543-545. 141. Loffer FD, Pent D. Indications, contraindications and complications of laparoscopy. Obstet Gynecol Surv 1975;30:407-427. 142. Cottin V, Delafosse B, Viale JP. Gas embolism during laparoscopy: a report of seven cases in patients with previous abdominal surgical history. Surg Endosc 1996;10:166-169. 143. Gomar C, Fernandez C, Villalonga A, Nalda MA. Carbon dioxide embolism during laparoscopy and hysteroscopy. Ann Fr Anesth Reanim 1985;4:380-382. 144. Yacoub OF, Cardona I Ir, Coveler LA, Dodson MG. Carbon dioxide embolism during laparoscopy. Anesthesiology 1982;57: 533-535. 145. Ostman PL, Pantle-Fisher FH, Faure EA, Glosten B. Circulatory collapse during laparoscopy. J Clin Anesth 1990;2:129132. 146. Hershlag A, Loy RA, Lavy G, DeChemey AH. Femoral neuropathy after laparoscopy. A case report. J Reprod Med 1990;35:575576. 147. Riedel HH, Lehmann-Willenbrock E, Mecke H, Semm K. The frequency distribution of various pelviscopic (laparoscopic) operations, including complications rates-statistics of the Federal Republic of Germany in the years 1983-1985. Zentralbl Gynakol 1989;111:78-91. 148. Integrating advanced laparoscopy into surgical residency training. Surg Endosc 1998;12:374-376. 149. SAGES position statement on advanced laparoscopic training. Surg Endosc 1998;12:377. 150. Satava RM. Proctors, preceptors, and laparoscopic surgery. The role of "proctor" in the surgical credentialing process. Surg Endosc 1993;7:283-284. 151. Schulam PG, Docimo SG, Saleh W, Breitenbach C, Moore RG, Kavoussi L. Telesurgical mentoring. Initial clinical experience. Surg Endosc 1997;11:1001-1005. 152. Granting of privileges for gastrointestinal endoscopy by surgeons. Society of American Gastrointestinal Endoscopic Surgeons (SAGES). Surg Endosc 1998;12:381-382. 153. Derossis AM, Bothwell J, Sigman HH, Fried GM. The effect of practice on performance in a laparoscopic simulator. Surg Endosc 1998;12:1117-1120.

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154. Mori T, Hatano N, Maruyama S, Atomi Y. Significance of "hands-on training" in laparoscopic surgery. Surg Endosc 1998; 12:256-260. 155. Rosser JC, Rosser LE, Savalgi RS. Skill acquisition and assessment for laparoscopic surgery. Arch Surg 1997;132:200204. 156. Rosser JC Jr, Rosser LE, Savalgi RS. Objective evaluation of a laparoscopic surgical skill program for residents and senior surgeons. Arch Surg 1998;133:657-661. 157. Gandsas A, Altrudi R, Pleatman M, Silva Y. Live interactive broadcast of laparoscopic surgery via the Internet. Surg Endosc 1998;12:252-255. 158. Framework for post-residency surgical education and traininga SAGES guideline. Available at: http://www.sages.org/ sagespublication.phpidoc-Lz. Accessed January 22, 2005. 159. Schauer PR, Simek KR. The laparoscopic approach reduces the endocrine response to elective cholecystectomy. Am Surg 1995;61:106. 160. Lacy A, Sala Blanch X, Visa J. Alternative gases in laparoscopic surgery. In: Rosenthal RJ, Friedman RL, Phillips EH, eds. The Physiology of Pneumoperitoneum. New York: Springer-Verlag; 1998. 161. Dominioni L, Cuffari S, Giudce G, Carcano G, Nicora L, Dionigi R. The acute phase response after laparoscopic cholecystectomy and after open cholecystectomy. Hepatico-Pancreatico-Biliary Surg 1993;6:65. 162. Cho JM, LaPorta AJ, Clark JR, Schofield MJ, Hammond SL, Mallory PL. Response of serum cytokines in patients undergoing laparoscopic cholecystectomy. Surg Endosc 1994;8:1380. 163. Ueo H, Honda M, Adachi M, et al. Minimal increase in serum interleukin-6levels duringlaparoscopic. Am JSurg 1994;168:358360. 164. Redmond HP, Watson RWG, Houghton T, Condron C, Watson RGK, Bouchier-Hayes D. Immune function in patients undergoing open versus laparoscopic cholecystectomy. Arch Surg 1994;129:1240. 165. Trokel MJ, Bessler M, Treat MR, Whelan RL, Nowygrod R. Preservation of immune response after laparoscopy. Surg Endosc 1994;8:1385-1387; discussion 1387-1388. 166. Koksoy C, Kuzu MA, Kurt I, et al. Haemodynamic effects of pneumoperitoneum during laparoscopic cholecystectomy: a prospective comparative study using bioimpedance cardiography. Br J Surg 1995;82:972-974. 167. Kubota K, Kajiura N, Teruya M, et al. Alterations in respiratory function and hemodynamics during laparoscopic cholecystectomy under pneumoperitoneum. Surg Endosc 1993;7:500-504. 168. Liu SY, Leighton T, Davis I, Klein S, Lippmann M, Bongard F. Prospective analysis of cardiopulmonary responses to laparoscopic cholecystectomy. J Laparoendosc Surg 1991;1:241-246. 169. Hirvonen EA, Nuutinen LS, Kauko M. Hemodynamic changes due to Trendelenburg positioning and pneumoperitoneum during laparoscopic hysterectomy. Acta Anaesthesiol Scand 1995;39:949-955. 170. Motew M, Ivankovich AD, Bieniarz J, Albrecht RF, Zahed B, Scommegna A. Cardiovascular effects and acid-base and blood gas changes during laparoscopy. Am J Obstet Gynecol. 1973;115:1002-1012. 171. Iwase K, Takenaka H, Yagura A, et al. Hemodynamic changes during laparoscopic cholecystectomy in patients with heart disease. Endoscopy 1992;24:771-773. 172. Talamini MA, Mendoza-Sagaon M, Gitzelmann CA, et al. Increased mediastinal pressure and decreased cardiac output during laparoscopic Nissen fundoplication. Surgery 1997;122: 345-353. 173. Horvath KD, Whelan RL, Lier B, et al. The effects of elevated intraabdominal pressure, hypercarbia, and positioning on the hemodynamic responses to laparoscopic colectomy in pigs. Surg Endosc 1998;12:107-114.

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174. Rademaker BM, Meyer DW, Bannenberg IT, Klopper PJ, Kalkman CJ. Laparoscopy without pneumoperitoneum. Effects of abdominal wall retraction versus carbon dioxide insufflation on hemodynamics and gas exchange in pigs. Surg Endosc 1995;9:797-801. 175. Davidson BS, Cromeens DM, Feig BW. Alternative methods of exposure minimize cardiopulmonary risk in experimental animals during minimally invasive surgery. Surg Endosc 1996;10:301-304.

176. Moffa SM, Quinn TV, Slotman GJ. Hemodynamic effects of carbon dioxide pneumoperitoneum during mechanical ventilation and positive end-expiratory pressure. JTrauma 1993;35:613618. 177. Luz CM, Polarz H, Bohrer H, Hundt G, Dorsam J, Martin E. Hemodynamic and respiratory effects of pneumoperitoneum and PEEP during laparoscopic pelvic lymphadenectomy in dogs. Surg Endosc 1994;8:25-27.

Esophagus

Benign Diseases of the Esophagus

c. Daniel Smith and David A. McClusky III Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Physiology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Assessment of Esophageal Function . . . . . . . . . . . . . . . .. Assessment of Esophageal Symptoms . . . . . . . . . . . . . .. Motor Disorders of the Esophagus . . . . . . . . . . . . . . . . .. Esophageal Diverticula

791 794 795 797 798 804

Anatomy General The esophagus is a muscular tube lined with nonkeratinizing squamous epithelium that starts as a continuation of the pharynx and ends as the cardia of th e stomach. The esophagus is fixed only at its upper and lower ends, the upper end being firmly attached to the cricoid cartilage and the lower end to the diaphragm. This lack of fixation throughout its length allows the esophagus both transverse and longitudinal mobility. This mobility is important in normal esophageal function as well as pathological states, which can easily displace the esophagus or require extensive surgical mobilization for correction.

Course Although the esophagus lies in the midline, it does not follow a straight vertical course from pharynx to stomach but rather deviates to the left of midline as it courses through the neck and upper thorax and slightly to the right of midline in the midportion of the thorax near the tracheal bifurcation. It is this deflection to the right of midline that dictates a right thoracotomy when transthoracic esophagointestinal anastomosis is necessary. In the lower portion of the thorax, the esophagus again deviates to the left of midline as it passes behind the heart and through the diaphragmatic hiatus. Overall, the esophageal axis through the chest is vertical. Any distortion of this vertical axis strongly suggests malignancy with mediastinal invasion and retraction. In addition, the esophagus has anteroposterior deflections that correspond to the curvatures of the cervical and thoracic spine . At its distal end, the esophagus leaves the normal curvature of the spine

Gastroesophageal Reflux . . . . . . . . . . . . . . . . . . . . . . . . .. Diaphragmatic Hernia Esophageal Perforation/Injury. . . . . . . . . . . . . . . . . . . . . . Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

806 815 817 820 820

and deviates anteriorly to pass through the diaphragmatic hiatus. In its course from the pharynx to the stomach, the esophagus passes through three compartments: the neck, thorax, and abdomen. The cervical portion of the esophagus is approximately 5em in length and courses between the trachea and the vertebral column, passing into the chest at the level of the sternal notch. The thoracic esophagus is approximately 20cm long and courses behind the tracheal bifurcation and heart before entering the abdominal cavity at about the level of the xiphoid process of the sternum. The abdominal portion of the esophagus is approximately 2cm in length and is surrounded by the phrenoesophageal ligament. This phrenoesophageal membrane provides an airtight seal between the thoracic and abdominal cavities and must be strong enough to resist abdominal pressure, yet flexible enough to move with the pressure changes and movements incidental to breathing and swallowing. The phrenoesophagealligament is comprised of pleura, subpleural [endothoracic] fascia, phrenoesophageal fascia, transversalis fascia, and peritoneum (Fig. 44A.l) .

Length The length of the esophagus is defined anatomically as the distance from the cricoid cartilage to the gastric orifice. In the adult male, this length is from 22 to 28 em and averages 2 cm shorter in the female; esophageal length varies more with individual height than sex. Because the precise location of the cricoid cartilage is difficult to determine, the length of the esophagus is more commonly measured as the distance from the incisors to the gastric inlet. This distance is easily determined during esophagoscopy and averages 40 em . Finally, the length of the esophagus as measured manometrically is the 791

792

CHAPTER 44A

Esophageal mucosa (stratified squamous epithelium)

'J

Ii

Pleura

Longitudinal muscle Circular muscle "Z" line-j unction of esophagea l and gastric mucosa Phrenoesophageal ligament (ascending leaf) Diaphragm

.... ....

of cardia c glands

~....;..:."..,...!!':..ItffiI,.-- Zo ne

r -~Cricopharyngea l / - I ~ constriction ~

> -:+ "-----'-ff:fj!f- Gastric mucosa

Aortic constriction Hiatal constriction

FIGURE 44A.1. Anatomical relationships ofthe distalesophagus and phrenoesophagealligament. [Prom Gray/72 with permission.] distance from the cricopharyngeus to the lower esophageal sphincter (LES).

Normal Constrictions At rest, the esophagus is collapsed and in its proximal two thirds is flat with a diameter of 2.3 x 1.9cm. At its lower end, the esophagus is rounded with a diameter of 2.2 x 2.2 em. Compression by adjacent structures or muscles causes normal constrictions (Fig. 44A.2) that are evident on a barium esophagogram or during esophagoscopy. The most proximal constriction represents the narrowest portion of the entire gastrointestinal (GI) tract and occurs at the beginning of the esophagus where the cricopharyngeal musculature is located. The next constriction is located 20 ern from the incisors and is the result of indention of the esophagus by the aortic arch and the left mainstem bronchus. The lowermost narrowing, which is not constant, is located at about 44 em from the incisors and is caused by the gastroesophageal sphincter mechanism. Ingested foreign bodies tend to lodge at these points of normal constriction; also, the transit of swallowed corrosives slows at these narrowings, leading to prominent mucosal injury at these sites.

FIGURE 44A.2. Normal constrictions of the esophagus. (From Gray et al.,272 with permission.] posterior esophageal wall 3 em below the cricoid cartilage. This V-shaped area along the posterior wall of the proximal esophagus covered only with circular muscle fibers represents a potential weak area for subsequent diverticula formation (see the section Esophageal Diverticula). The esophagus is lined internally with a thick layer of nonkeratinizing, stratified squamous epithelium continuous with the lining of the oral pharynx. The squamous epithelium of the esophagus meets the junctional columnar epithelium of the gastric cardia in a sharp transition called the Z-line, typically located

Epithelium

Structure The esophagus consists primarily of three layers (Fig. 44A.3). The outer layer, the muscularis externa, comprises the chief muscles of the esophagus and is made up of an internal circular muscle layer and an external longitudinal muscle layer. In the upper third of the esophagus, both layers are primarily striated (voluntary) muscle fibers. In the middle third of the esophagus, striated and smooth (involuntary) muscle fibers are intermingled, and in the lower third, smooth muscle fibers predominate. Most of the clinically significant esophageal motility disorders involve only the smooth muscle portion of the esophagus; thus, esophageal myotomy for the management of most esophageal motor disorders needs only to extend along the lower esophagus . Two bundles of longitudinal muscle fibers diverge and meet in the midline of the

Muscularis externa

Lamina propr ia

Oesophageal / gland

FIGURE 44A.3. Cross section of the esophagus showing the layers of the wall. (From Iamieson. ? " with permission.]

793

ESOPHAGUS IBENIGN I

at or near the physiological LES. The submucosa contains elastic and fibrous tissue and is the strongest part of the esophageal wall. It is this layer that contains the lamina propria, which the surgeon relies on for a sound esophageal anastomosis. Meissner's plexus of nerves also resides within the submucosal layer.

Cervical nodes

Vessels Hilar " , " -- .K. '«W? ./

ARTERIAL

The arterial blood supply to the esophagus is segmental with three main sources supplying the upper, middle, and lower sections of the esophagus (Fig. 44A.4). The cervical esophagus receives blood from the superior thyroidal artery as well as the inferior thyroidal artery of the thyrocervical trunk, and both sides communicate through a rich collateral network. The thoracic portion of the esophagus is supplied proximally by two to three bronchial arteries and distally from esophageal arteries arising directly from the aorta . The abdominal esophagus receives blood from branches of the left gastric and inferior phrenic arteries. At some distance from the esophagus, these main arteries divide into minute branches, and after entering the wall of the esophagus , arterial branches assume right angles to their entry point, thereby establishing a longitudinal anastomosing network of vessels. This early branching and extensive collateralization between the cervical, thoracic, and gastric segments desegmentalizes the esophageal blood supply, thereby enabling mobilization of the esophagus from the stomach to the aortic arch with little ischemic effect. This rich blood supply is more than adequate for intramural anastomosis, and poor technique rather than poor blood supply is usually responsible for anastomotic failures . VENOUS

The venous drainage of the esophagus follows the arterial capillary network. Longitudinally oriented periesophageal

Para-oesophageal

+

para-aort ic Inferior vena cava ';~~:f(i8i"""~~:::

Lesser ------'lr---~. a}, curvature /Ai===;~~

FIGURE 44A.5. Groups of lymph nodes draining the esophagus. (From Iamieson," " with perrnission.]

venous plexi return blood in the cervical esophagus to the inferior thyroid vein; in the thoracic esophagus to the bronchial, azygous, and hemiazygous veins; and in the abdominal esophagus to the coronary vein. Because the submucosal venous networks of the esophagus and stomach are in continuity with each other, portal venous obstruction may lead to collateralization through the esophageal venous plexus and subsequent esophageal varices .

Esophageal branch Inferior thyroid artery

Right bronchial artery

Inferior left bronchial artery

Ascending branches of left gastric artery Left gastric artery

FIGURE 44A.4. Arterial blood supply of the esophagus . (From Shields.?" with permission.)

LYMPHATIC

The lymphatic drainage of the esophagus is abundant and forms a dense submucosal plexus. Flow of lymph runs longitudinally, coursing cephalad in the upper two-thirds of the esophagus and caudad in the lower third. Because this lymphatic system is not segmental, lymph can travel a long distance in this plexus before traversing the muscle layer and entering the regional lymph nodes . As a consequence, free tumor cells of the upper esophagus can metastasize to superior gastric nodes, or conversely, a cancer of the lower esophagus can metastasize to superior mediastinal nodes. More commonly, the lymphatic drainage from the upper esophagus courses primarily into the cervical and peritracheal lymph nodes, while that from the lower thoracic and abdominal esophagus drains into the retrocardiac and celiac nodes (Fig. 44A.5).

Innervation The esophageal neural branches are secretomotor to glands and motor to muscular layers. The esophagus has both sym-

794

CHAPTER 44A

pathetic and parasympathetic innervation. The sympathetic nerve supply is through the cervical and thoracic sympathetic chain running downward just lateral to the spine, and the cardiobronchial and periesophageal splanchnic nerves are derived from the celiac plexus and ganglia. The parasympathetic innervation of the pharynx and esophagus is primarily through the vagus nerve. Although it carries both afferent and efferent fibers, the proportion of efferent fibers in the vagus is small in relation to the sensory component. In the neck, the superior laryngeal nerves arise from the vagus nerve and divide into the external and internal laryngeal branches. The external laryngeal nerve innervates the cricothyroid muscle and in part the inferior pharyngeal constrictor, while the internal laryngeal nerve provides sensation to the pharyngeal surface of the larynx and base of the tongue. Injury to the recurrent laryngeal nerve may cause both hoarseness and upper esophageal sphincter (UES) dysfunction with secondary aspiration during swallowing. Distally, the vagal trunks contribute to the anterior and posterior esophageal plexi, and at the diaphragmatic hiatus, these plexi fuse to form the anterior and posterior vagus nerves. Finally, a rich intrinsic nervous supply called the myenteric plexus exists between the longitudinal and circular muscle layers (Auerbach's plexus) and in the submucosa (Meissner's plexus). It appears that this intraesophageal innervation is in part involved in the fine motor control of the esophagus, but exact mechanisms of control remain unknown.

Physiology The esophagus is the first segment of the alimentary tract and the conduit between the mouth and stomach. Passage of food and drink from mouth to stomach requires a well-orchestrated series of neuromotor events. The first one-third of the distance between lips and stomach is made up of the mouth and hypopharynx; the remaining two-thirds consists of the esophagus. As nicely detailed by DeMeester et al.,' the mechanism of swallowing is mechanically analogous to a piston pump and cylinder with three valves that propels a bolus into a worm drive with a single valve (Table 44A.1). Failure of the pump, valves, or worm drive leads to mechanical abnormalities in swallowing such as difficulty in propelling food from mouth to stomach or regurgitation of food into the oral pharynx, nasopharynx, or esophagus. Once initiated, swallowing is entirely a reflex. The tongue acts like a piston propelling the bolus into the posterior oral pharynx and forcing it into the cylinder of the hypopharynx. With this piston-like movement of the tongue posteriorly, the soft palate is elevated, sealing the passage between the oral TABLE 44A.l. Mechanical Analogies in Swallowing. Mechanical mechanism

Functional equivalent

Piston pump Cylinder Three valves

Tongue Pharynx Soft palate Epiglottis Cricopharyngeus Esophagus Lower esophageal sphincter

Worm drive Single valve

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1. Elevation of tongue 2. Posterior movement of tongue 3. Elevation of soft palate 4. Elevation of hyoid 5. Elevation of larynx 6. Tilting of epiglottis

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FIGURE 44A.6. Sequence of events during the pharyngeal phase of swallowing. (From Zuidema and Orringer.l" with permission.)

pharynx and the nasopharynx. The closing of the valve of the soft palate prevents dissipation of the pressure generated within the pharyngeal cylinder through the nasopharynx and nose. Nearly concomitant with this, the hyoid bone and larynx move upward and anteriorly, bringing the epiglottis under the tongue and sealing the opening of the larynx to prevent aspiration (Fig. 44A.6). This sequence, the pharyngeal phase of swallowing, occurs within 1.5s of initiation of a swallow. Dysfunction or paralysis of any of these interrelated actions, such as following a cerebrovascular accident, leads to discoordinated movements and regurgitation of food into the nasopharynx or aspiration. During the pharyngeal phase of swallowing, the pressure in the hypopharynx quickly rises to at least 60mmHg, creating a sizable pressure difference between the hypopharyngeal and the less-than-atmospheric midesophageal or intrathoracic pressure. With this pressure gradient, when the cricopharyngeus or UES relaxes, food is quickly moved from the hypopharynx into the esophagus. In this way, the bolus is both pushed through peristaltic contraction of the posterior pharyngeal constrictors and sucked into the thoracic esophagus. Immediately after the bolus clears the UES, the UES closes to an immediate closing pressure of approximately twice its resting level of 30mmHg. This post-UES contraction initiates a migrating contraction that continues down the esophagus as a primary peristaltic wave (Fig. 44A.7). The high closing pressure and progression of the peristaltic wave prevents reflux of the bolus back into the pharynx. Shortly after the peristaltic wave has migrated down the esophagus, the pressure of the UES quickly returns to its resting level. These neuromotor events always follow a rigidly ordered pattern of outflow for successful swallowing. Cerebral vascular accidents may disrupt any portion of this complex mechanism, leading to dysphagia or aspiration. In addition, the striated muscles of the cricopharyngeus and upper one-third of the esophagus are controlled by efferent motor fibers via the vagus nerve and its recurrent laryngeal branches. Damage to this neural pathway by disease (malignancy) or operative

ESOPHAGUS lBENIGNJ

trauma may also lead to discoordinated pharyngeal swallowing and aspiration. Once the bolus of food is propelled into the proximal esophagus, the "worm drive" of the esophagus functions to propel the food distally and into the stomach. This esophageal phase of swallowing requires well-coordinated motor activity to propel the food from the negative-pressure (26mmHg) environment of the chest to the positive-pressure (16-mmHg) environment of the stomach. Peaks of a primary peristaltic contraction result in an occlusive pressure wave varying from 30 to 100mmHg, with this primary peristaltic contraction moving down the esophagus at 2 to 4cm per second (see Fig. 44A.7). The transit time from initiation of a swallow to the bolus reaching the distal esophagus is about 9s. A second type of peristaltic wave (secondary peristalsis) is not triggered by voluntary swallowing but rather refers to peristaltic waves that usually appear after esophageal dilation either from a retained bolus or from active distention of the esophagus. These secondary contractions occur without any movements of the mouth or pharynx and can occur as independent local reflexes to clear the esophagus of ingested material left behind after the passage of the primary wave. A third pattern of contractile activity, tertiary contractions, occurs after voluntary swallows or spontaneously between swallows. Tertiary contractions are nonpropulsive, generate peak pressures in the range of 10 to 13mmHg, and follow 30/0 to 4% of all swallows. The LES acts as the valve at the end of the worm drive of the esophageal body and provides a pressure barrier between the esophagus and stomach. Although an anatomical LES does not exist, the architecture of the muscle fiber at the junction of the esophagus and the stomach helps explain

mm

Swallow

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60 50 40

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50 40

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50 40

Esophagealbody ~

Increase LES pressure Cholinergics Prokinetics o-agonists ~-blockers

Gastrin Motilin Bombesin Substance p Decrease LES Pressure a-blockers ~-blockers

Calcium channel blockers Cholecystokinin Estrogen Progesterone Somatostatin Secretin Caffeine (chocolate, coffee) Fats

some of the sphincter-like activity of the LES. The resting tone of the LES is approximately 20mmHg and resists reflux of gastric content into the lower esophagus. With initiation of a pharyngeal swallow, the LES pressure decreases to allow the primary peristaltic wave to propel the bolus into the stomach. A pharyngeal swallow that does not initiate a peristaltic contraction leads to relaxation of the LES, allowing reflux of gastric juice into the distal esophagus. This effect may be one explanation for the observation of spontaneous lower esophageal relaxation thought by some to be causative in gastroesophageal reflux (GER) disease. The coordinated activity of the pharyngeal swallow and LES relaxation appears to be in part vagally mediated. The LES's intrinsic myogenic tone can be affected by both neural and hormonal mechanisms. In addition, diet and medications can alter LES function (Table 44A.2).

Assessment of Esophageal Function

V

50 40

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TABLE 44A.2. Neural, Hormonal, and Dietary Factors Thought to Affect Lower Esophageal Sphincter (LES).

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Assessment of Structural Abnormalities

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Although the esophagus is a hollow tube functioning primarily as a conduit between the mouth and stomach, its anatomical course through three body compartments, its complex neuromotor mechanisms for propelling a bolus from mouth to stomach, and its juxtaposition to the stomach's harsh intraluminal environment lead to a wide variety of esophageal disorders. Several diagnostic tests are available to evaluate patients with esophageal disease. Remembering the anatomical and physiological features of the esophagus, these tests can be divided into (1) tests to detect structural abnormalities, (2) tests to detect functional abnormalities, (3) tests to assess esophageal exposure to gastric content, and (4) tests to provoke esophageal symptoms (Table 44A.3).

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FIGURE 44A.7. Intraluminal esophageal pressures in response to swallowing. (From Waters and Delvleester.F" with permission.)

RADIOLOGIC STUDIES

CONTRAST ESOPHAGOGRAM

The simplest and often first diagnostic test for esophageal disease is a contrast esophagogram, most commonly a barium

796

CHAPTER 44A

TABLE 44A.3. Assessment of Esophageal Function. Condition

Diagnostic test

Structural abnormalities Endoscopy Chest x-ray CT scan Cine fluoroscopy Endoscopic ultrasound Functional abnormalities

Barium swallow

Esophageal exposure to gastric content Combined Provoke esophageal symptoms Others

Manometry (stationary and 24h) Transit studies Multichannel intraluminal impedance (MIT) 24-h pH monitoring Bravo wireless pH probe MIl-Manometry MIl-pH Acid perfusion (Berstein) Edrophonium (Tensilon) Balloon distension Gastric analysis Gastric-emptying study Gallbladder ultrasound

swallow. Structural abnormalities including diverticula, narrowing or stricture, ulcers, and hiatal or paraesophageal hernias can all be nicely demonstrated with an esophagogram. Use of fluoroscopy with videotaped recordings during both a liquid and a solid contrast swallow increases the accuracy in identifying subtle abnormalities. Abnormalities of esophageal motility or GER can be seen during a barium swallow, but these disorders are more appropriately diagnosed using other tests. OTHER RADIOLOGIC STUDIES

Plain chest x-ray films may reveal changes in cardiac silhouette or tracheobronchial location suggesting esophageal disorders. Computed tomographic (CT) scan of the chest or magnetic resonance imaging (MRI) may also be useful in assessing lesions thought to be malignancies identified with barium swallow or endoscopy. Finally, a modified barium study in the lateral projection under cine fluoroscopy may be especially useful in identifying mechanical disorders of the pharyngeal swallowing mechanism. ENDOSCOPY

Most patients with esophageal symptomatology should undergo esophagoscopy. All patients with dysphagia should undergo esophagoscopy, even in the presence of a normal barium swallow. A barium swallow performed before esophagoscopy helps the endoscopist to focus on any subtle radiographic findings and helps to prevent endoscopic misadventures with anatomic abnormalities such as esophageal diverticula. For the initial assessment, the flexible esophagoscope allows a safe, thorough assessment, which can be performed quickly in an outpatient setting with high patient tolerance and acceptance. The mucosa of the entire esophagus, stomach, and duodenum should be carefully inspected. Any areas of mucosal irregularity or abnormality should be photodocumented and biopsied. Retroflex views within the stomach of the gastroesophageal junction (GET) should note the presence of hiatal hernia. The location of the transition from squamous mucosa to columnar gastric mucosa (Z-line) should be noted

as the distance from the incisors to this point of transition. Known esophageal diverticula C3:n be investigated endoscopically, however, great care should be taken because diverticula can easily be perforated. Rigid esophagoscopy is rarely indicated and remains a tool used primarily in the operating room when cricopharyngeal or cervical esophageal lesions prevent passage of a flexible scope or when biopsies deeper than those obtainable with flexible endoscopy are needed to stage disease and plan resective therapy for malignancy. More recently, endoscopic ultrasound (EUS) allows characterization and staging of esophageal lesions by imaging the layers of the esophageal wall and surrounding structures to identify depth of tumor invasion, periesophageal lymphadenopathy, and EUS-guided fine-needle aspiration of lymph nodes.

Assessing Functional Abnormalities ESOPHAGEAL MANOMETRY

In recent years, esophageal manometry has become widely available and used to examine the motor function of the esophagus and the LES. Manometry is indicated when a motor abnormality is suspected on the basis of symptoms of dysphagia or odynophagia and the barium swallow and esophagoscopy do not show an obvious structural abnormality. Manometry is essential to confirm the diagnosis of primary esophageal motility disorders of achalasia, diffuse esophageal spasm, nutcracker esophagus, and hypertensive LES. It may be useful in identifying nonspecific esophageal motility disorders and motility abnormalities secondary to systemic diseases of scleroderma, dermatomyositis, polymyositis, or mixed connective tissue disease. Finally, in patients with symptomatic GER, manometry is particularly useful in assessing preoperative esophageal clearance mechanisms and competency and function of the distal esophageal sphincter. Esophageal manometry is most commonly performed by passing a series of catheters nasally into the stomach while measuring pressure through a pressure-sensitive transducer or with autoperfused open-tipped catheters attached to transducers. Over 1 to 2h, esophageal body and LES function can be recorded and later assessed using computer-based analysis software. Finally, esophageal transient scintigraphy proposes to objectively assess transit of a swallowed bolus through the esophagus, which would most accurately objectify normal and disordered esophageal function. The clinical use of such an esophageal "emptying study" remains unclear, and transit scintigraphy presently remains a research tool. ASSESSING ESOPHAGEAL EXPOSURE TO GASTRIC CONTENT

AMBULATORY »n MONITORING

Ambulatory pH monitoring in the distal esophagus has become the gold standard for quantitating esophageal exposure to acidic gastric content. This has replaced the standard acid reflux test and many of the provocative tests to assess esophageal symptoms. Traditionally, this test has been accomplished by placing a transnasal catheter containing a pH probe 5 em proximal to the manometrically identified distal esophageal sphincter. The esophageal pH at this loca-

ESOPHAGUS (BENIGN)

TABLE 44A.4. Normal Values for Esophageal Exposure to pH 5 min Longest episode

1.51 2.34 0.63 19.00 0.84 6.74

1.36 2.34 1.00 12.76 1.18 7.85

4.45 8.42 3.45 46.90 3.45 19.80

Source: From DeMeester and Stein.i'"

tion is then recorded continuously throughout a 24-h cycle while the patient continues his or her normal routine, including eating and usual activities. A catheter-free wireless pH monitoring system (Bravo) has now been developed that allows for 24- to 48-h ambulatory monitoring via a endoscopically placed probe that is secured to the esophageal mucosa.' After 48h, the catheter naturally detaches from the mucosa and is passed through the GI tract. In both studies, during the test the patient maintains a diary and records body positions, meals, and symptoms so that esophageal exposure to acid can be correlated with symptoms. At the completion of the test, the results are tallied and compared to normal values for esophageal exposure to acid (Table 44A.4). An episode of acid reflux is defined as pH less than 4.0 in the distal esophagus. Ambulatory pH monitoring is indicated for patients who have typical symptoms of GER for whom other diagnostic tests are equivocal; atypical symptoms of GER such as noncardiac chest pain; persistent cough, wheezing, or unexplained laryngitis; or previously failed esophageal or gastric surgery with recurrent symptoms. PROVOCATION OF ESOPHAGEAL SYMPTOMS

The acid perfusion test (Bernstein test), edrophonium (TensiIon) test, and balloon distension test to identify a relationship between symptoms and esophageal exposure to acid or motor abnormalities have been virtually replaced by 24-h ambulatory pH monitoring and esophageal manometry. The acid perfusion test is done by instilling 0.1 N Hel into the distal esophagus while the patient reports any symptoms developing during infusion. A placebo is similarly infused to differentiate symptom occurrence. In the edrophonium test, edrophonium hydrochloride is injected intravenously at a dose of 80~g/kg. The acetylcholinase inhibitor edrophonium induces esophageal contractions, and a positive test is defined as replication of the patient's chest pain within 5 min of injection. The test is placebo controlled, and placebo should not reproduce the patient's typical chest pain. Finally, in the balloon distension test an inflatable balloon is positioned l Ocm below the UES. This balloon is gradually inflated with air and esophageal motility is simultaneously monitored. This test is considered positive when typical symptoms are reproduced with gradual distension of the balloon. Again, 24h ambulatory pH testing and esophageal manometry have made these tests primarily of historical and academic interest only. In evaluating a patient with esophageal symptoms, it is also important to consider the impact gastroduodenal dys-

797

function may have on normal lower esophageal function and other common GI problems that can mimic lower esophageal disease. A gastric-emptying study, right upper quadrant ultrasound, and cholescintigraphy may all be indicated in patients with symptomatology suggestive of esophageal disorders to rule out gastroparesis or gallbladder disease.

Combined Assessment of Structural and Functional Abnormalities and Exposure to Gastrointestinal Content The increased availability of multichannel intraluminal impedance (MIl) catheter studies has provided clinicians with a new means of evaluating esophageal bolus transit without the use of cine fluoroscopy.i" An MIl catheter consists of an alternating current source connected to a series of metal rings located along segments of the esophageal lumen. The impedance within a given segment is then determined by measuring the electrical resistance as a substance passes through the current established by the rings. Impedance and resistance have an inverse relationship such that a substance with minimal resistance, like air, will register a high impedance. Conversely, as fluid passes through this current, the impedance will drop. Thus, a fluid bolus can be detected as it progressively traverses segments of rings during the course of a swallow. The retrograde progression of a reflux episode can also be monitored in this fashion. With the additional information it can provide, MIl has also been combined with catheters measuring esophageal manometry (MIl-EM) and pH (MIl-pH), allowing for a more complete evaluation of patients with esophageal motility disorders and GER.6,7 Combined MIl-EM catheters were approved for clinical use by the Food and Drug Administration (FDA) in 2002 and have helped identify subsets of patients who have been difficult to evaluate using traditional methods. Examples include patients with ineffective esophageal motility and normal bolus transit, patients with dysphagia after fundoplication, and those with abnormal bolus transit of solids but not liquids." Likewise, combined MIl-pH catheters have helped further characterize patients with symptomatic nonacid GER, symptomatic gas or gas/liquid reflux, and persistent symptoms on proton pump inhibitor (PPI) therapy.v'" Although the utility and therapeutic implications of these new findings are still under review, combined MIl-EM and MIl-pH studies continue to help physicians refine their knowledge of the various manifestations of esophageal disease.

Assessment of Esophageal Symptoms Appropriate identification and evaluation of esophageal abnormalities relies on a thorough understanding of the patient's symptoms and how these symptoms relate to various disorders. Table 44A.5 lists patient symptoms that may be attributable to esophageal disorders. The occasional occurrence of any of these symptoms is common in everyone and usually does not indicate disease. However, frequent and persistent symptoms, especially those of heartburn, dysphagia, or odynophagia, should immediately suggest an esophageal cause that requires further investigation and treatment.

798

CHAPTER 44A

TABLE 44A.5. Patient Symptoms and Likely Etiologies. Symptom

Definition

Likely etiology

Heartburn

Burning discomfort behind breast bone Bitter acidic fluid in mouth Sudden filling of mouth with clear/salty fluid Sensation of food being hindered in passage from mouth to stomach

Gastroesophageal reflux (GER)

Pain with swallowing Lump in throat unrelated to swallowing Mimics angina pectoris

Severe inflammatory process GER

Asthma/wheezing, bronchitis, hemoptysis, stridor

GER

Chronic sore throat, laryngitis, halitosis, chronic cough

GER

Regurgitation of recently ingested food

Achalasia into mouth

Dysphagia Inflammatory process Diverticula Tumors Odynophagia Globus sensation Chest pain Motor disorders Tumors Respiratory symptoms Diverticula Tumors Ear/nose/throat symptoms Diverticula Rumination Inflammatory process Diverticula Tumors

Motor Disorders of the Esophagus Disordered motor function of either the pharyngeal or esophageal phase of swallowing leads to a variety of swallowing disorders, with the primary clinical manifestation being dysphagia. The development and widespread use of esophageal manometry has allowed the characterization of both normal and abnormal motor function of the esophagus.

Disordered Pharyngeal Swallowing Diseases affecting pharyngoesophageal function produce a characteristic type of dysphagia. Patients experience the more universally understood symptom of "difficulty in swallowing," with difficulty propelling food out of the mouth and through the hypopharyngeal region into the esophageal body. Aspiration or nasopharyngeal regurgitation are frequent outcomes. Disorders of the pharyngoesophageal phase of swallowing are rare and are usually a consequence of (1) inadequate oral pharyngeal bolus transit, (2) inability to pressurize the pharynx, (3) inability to elevate the larynx, or (4) discoordination of the cricopharyngeus. Table 44A.6 lists conditions that can disrupt the carefully coordinated steps in the pharyngeal phase of swallowing. TABLE 44A.6. Classification of Disordered Pharyngeal Phase of Swallowing. Muscular diseases (dermatomyositis, polymyositis, etc.) Central nervous system disease (cerebrovascular accident, multiple sclerosis, amyotrophic lateral sclerosis (AMLS), brainstem tumor, etc.) Miscellaneous Structural lesions Cricopharyngeus dysfunction

Motor disorders

DIAGNOSIS

The diagnosis of disordered pharyngoesophageal swallowing relies on a strong suspicion of disordered swallowing based on a carefully taken history. Dysphagia immediately following initiation of a swallow, associated with coughing or nasopharyngeal regurgitation, will predominate. This should be distinguished from globus sensation, in which the patient has the feeling of fullness in the throat that is not associated with swallowing. The short duration of the oropharyngeal phase of swallowing makes the evaluation of abnormalities in this region difficult using conventional radiographic or manometric techniques. The single most objective measure in assessing oropharyngeal dysfunction is the modified barium swallow in which the barium is thickened, and during swallowing a fluoroscopic recording in the lateral projection is made to document bolus passage from the mouth, through the oral pharynx, and into the esophageal body. Careful slowmotion review of this study allows identification of abnormalities in any of the previously listed steps of oropharyngeal swallowing. In addition, all patients should undergo an endoscopic evaluation to rule out structural abnormalities or malignancy. TREATMENT

Once identified, most disorders of pharyngoesophageal swallowing are managed with diet modification and swallowing retraining. Cricopharyngeus dysfunction may lead to conditions amenable to operative therapy (see section on esophageal diverticula).

Disordered Esophageal Body and Lower Esophageal Sphincter Motor disorders of the esophageal body or LES lead to a variety of functional abnormalities of the esophagus.

ESOPHAGUS (BENIGN j

TABLE 44A.7. Motor Disorders of the Esophagus. Primary Achalasia Spastic disorders Diffuse and segmental spasm Nutcrackeresophagus Hypertensive LES Secondary Collagen vascular diseases Scleroderma, polymyositis, dermatomyositis, systemiclupus erythematosus, mixed connective tissue disease Idiopathic intestinal dysmotilityjpseudoobstruction Neuromuscular diseases Multiplesclerosis, Huntington's chorea, amyotrophic lateral sclerosis, myotonic dystrophy, cerebrovascular accident Endocrine and metabolic Diabetes, hypothryoidism, myasthenia gravis Other Trauma or operative nerve injury, radical neck surgeryj radiation These disorders can be either primary or secondary (Table 44A.7).

ACHALASIA

Achalasia is characterized by an absence of esophageal peristalsis and failure of the LES to completely relax on swallowing. Primary achalasia is the result of one or more neural defects, with the most common neuroanatomical change being the decrease or loss of myenteric ganglion cells or func tion .2,11,12 Investigations of patients with vigorous achalasia, considered by most to be an early stage in the disease process, have revealed only mild inflammation and preservation of myenteric ganglion cells," suggesting that achalasia develops as a primary inflammatory process that progresses from neu ritis and ganglionitis to fibrosis with secondary ganglion cell and nerve damage. This may be triggered by an autoimmune process as associations with class II major histocompatibility complex antigens such as HLA-DQwl, HLA-DQBI and HLADRBI have been noted.":" Histological analysis has revealed selective inhibitory denervation of vasoactive peptide and nitric-oxide-producing neurons of Auerbach's plexus as well as Wallerian degeneration within the vagus nerve.":" These findings support the hypothesis that the pathophysiology of achalasia is based on a decrease in inhibitory innervation in the esophageal body and LES, leading to an imbalance between the inhibitory and excitatory cholinergic tone of the LES. Such an imbalance may be responsible for the absence of LES relaxation characteristic of achalasia as well as the aperistalsis observed within the smooth muscle portion of the esophagus.P:" However, a full understanding of the morphological changes in achalasia is limited by the fact that most studies rely on tissue specimens from esophageal resections most commonly performed for end-stage disease . As newer animal and cellular models are developed, the underlying pathophysiology of achalasia remains under active investigation. Achalasia has an incidence of 0.4 to 1.1 per 100,000 and a prevalence of 8 per 100,000. Given the limited access to manometry in community settings worldwide, these figures are based on primarily retrospective reviews of hospital records. Overall, this is likely to underestimate the true inci dence worldwide." It has been described in those from infants to the elderly, with the majority of patients presenting

799

between the ages of 20 and 40 years . There is no sex predilec tion. Familial cases have been identifled. Pr" primarily in the pediatric population, with the role of genetic factors remaining unclear. The autosomal recessive disorder known as Allgrove syndrome (consisting of achalasia, alacrima, and Addison deficiency) has been linked to mutations of the AAAS gene located on chromosome 12q13. Although reports of disease presentation within the second and third decades of life have been noted,25-27 the relationship between the AAAS gene and primary achalasia have not been established. Achalasia is considered a risk factor for esophageal malignancy.28,29 It is estimated that squamous cell carcinoma develops on average 20 years after initial diagnosis in approximately 5% of patients with achalasia. Esophageal carcinoma presents in achalasia approximately 10 years earlier than in the general population, and the prognosis of esophageal carcinoma in achalasia patients is worse than that in the general population, possibly because early symptoms of malignancy mimic achalasia and delay diagnosis. DIAGNOSIS

Patients typically present with solid food dysphagia and varying degrees of liquid dysphagia. Often, exacerbation of their dysphagia is brought on with ingestion of cold liquids or emotional stress. Symptom onset is gradual, with the average duration of dysphagia before presentation 2 years; 60% to 90% of patients report experiencing regurgitation, and nearly half complain of chest pain . Long-standing disease may be accompanied by heartburn as a result of bacterial fermentation of food retained in the dilated esophagus ." A diverticulum of the distal esophagus may develop secondary to the chronic functional obstruction at the LES. Despite its rarity, the diagnosis of achalasia is seldom difficult .31,32 The typical symptoms of dysphagia and regurgitation prompt the performance of a barium swallow, revealing the typical bird's beak deformity in the distal esophagus with more proximal esophageal dilation (Fig. 44A.8); 90% of

FIGURE 44A.8. Barium esophagogram showing proximal esophageal dilation and distal narrowing ("bird's beak").

800

CHAPTER 44A

patients with achalasia have this typical radiographic finding .f This typical esophagogram may also be found with pseudoachala sia, a condition in which compression by intrinsic or extrinsic masses may mimic the classic radiographic findings of achalasia." Pseudoachalasia is typically seen with gastroesophageal malignancies or as part of a paraneoplastic syndrome. 35,36 Finally, vigorous achalasia, an early stage of achalasia, may present with strong tertiary esophageal contractions resulting in a radiographic appearance similar to diffuse esophageal spasm ." Even with the typical patient presentation and radiographic findings, upper GI endoscopy is vital to rule out causes of pseudoachalasia and to investigate the esophageal mucosa and integrity of the GEJ before initiating any therapy (e.g., the finding of candidiasis would dictate antifungal therapy before further treatment of achalasia). The classic endoscopic picture is that of a dilated, patulous esophageal body tapering down to a puckered LES that fails to open with air insufflation. However, the endoscope usually passes the LES easily with minimal force or pressure. Esophageal manometry remains the gold standard for diagnosing achalasia, characterized by absent peristalsis in the distal smooth muscle segment of the esophagus with incomplete LES relaxation." While an elevated LES pressure (greater than 35 mmHg) may be seen, it is the incomplete sphincter relaxation that is characteristic, occurring in more than 80% of patients with achalasia. The manometric finding of normal esophageal motility should prompt an aggressive search for a tumor that may be causing pseudoachalasia. Generally, a CT scan of the chest or endoscopic ultrasonography of the distal esophagus will identify the cause of pseudoachalasia. Additional studies may be helpful in confirming the diagnosis of achalasia. Radionuclide studies using a labeled semisolid meal have been used to demonstrate impaired esophageal transit." This study lacks the specificity of manometry'? but has been used by some when manometry was not available or to objectively assess the response to therapy.

effects."?" Given these results and the excellent results obtained with other modes of therapy, pharmacotherapy is best reserved as an adjunct to the other therapies or for those patients not candidates for other, more effective treatments. Botulinum Toxin. Botulinum toxin (Botox) is a potent inhibitor of acetylcholine release from presynaptic nerve terminals and has been used in the management of skeletal disorders such as blepharospasm and dystonias with minimal side effects. Recently, Botox (between 50-200IU) endoscopically injected into the LES has been used in the management of achalasia to decrease resting LES tone (Table 44A.8). Botox appears to be a fairly effective form of therapy, at least in the short term. Advantages include its safety, ease of administration, and minimal side effects. Disadvantages include the lack of response in approximately one-third of patients, the need for multiple in jections to possibly effect a long-term response, and decreasing response after multiple injections. Of particular concern to surgeons is the impact Botox injection may have on future operative myotomy. Obliteration of the dissection plane between the submucosa and muscular layer may increase the likelihood of esophageal perforation during operative myotomy (Table 44A.9).50,51 The exact role of Botox injection in the overall manage ment of achalasia remains to be defined . It may be particularly useful in patients who are not candidates for other therapies with proven long-term results. Specifically, several prospective studies have evaluated the utility of Botox injection in the elderly . Bassotti and colleagues reviewed their experience in 33 patients (aged 81-94) noting that 78% of patients had alleviation of symptoms after 1 year.52 Notably, 54% of patients continued to be symptom free after 2 years. This finding is consistent with those of Zarate et al., who noted that the mean duration of symptom relief in patients over 65 was approximately 14 months." Esophageal Dilation. Pneumatic dilation is considered the standard nonoperative therapy for achalasia. In many

T REATMENT

The primary therapies for achalasia, aimed at decreasing LES resistance to the passage of a swallowed bolus, include (1) pharmacological therapy, (2) botulinum toxin (Botox) injection into the LES, (3) balloon dilation of the LES, or (4) operative myotomy. Predictors of long-term response to therapy include an LES pressure less than lOmmHg or 50% to 90% esophageal emptying at 2 min after upright swallowing of a radiolabeled liquid meal." Although these measures have investigational use, to date the most clinically useful measure of successful treatment of achalasia is the elimination of dysphagia. Pharmacotherapy. The agents traditionally used to treat patients with achalasia have been smooth muscle relaxants aimed at decreasing LES tone, including calcium channel blockers [nifedipine, verapamil); opioids (loperamide); nitrates [isorsorbide dinitrate); and anticholinergics [cimetropium bromide) . In prospective randomized trials, each of these medications has been shown to reduce LES tone in patients with achalasia.t"" These drugs, while effective in reducing LES pressure, either fail to alter symptoms" and are poorly tolerated due to side effects 43,48 or have no sustainable

TABLE 44A.8. Selective Review of Cited Experiences Using >80 U Botulinum Toxin (Botox) for Treatment of Adults with Acha lasia (Studies with 20 or More Subjects). Author

Year

No. patients

Response lmo (%)

Response 6mo (%)

Pasricha 177 Pishma n!" Cu illiere!" Wehrma nn ISO Kolbasnik!" Prakas h!" Annese (100 U' jlS3 Annese (200 Ujl83 Allcscher !" Storr!" D'O nofrio!" Marti nek! "

1995 1996 1997 1999 1999 1999 1999 1999 2000 2002 2002 2003

31 60 55 20 30 42 38 40 23 40 37 49

90 70 75 80 77 (3mol 80 84 88 83 7 [Smo] 84 83

66

P. prospective clinical series; pr, prospective randomized trial. ' Study wit h different groups based on treatment dose.

60 70 57 81 57 36 30 (24 mo ) 7 65 41 (22mol

ESOPHA GU S (BENI GN I

AJ,.._

801

TABLE 44A.9 . Review of Cited Experi enc e wit h Op erative Myo to m y After Prior End oscopic Thera py.

No. patients

Author

Type of treatm en t

Results

No perforations; n o difficulties in dissect ion 28% esophageal perforation rat e

Pergus on!" 1996 Mor ino " ? 1997 Horgan' ?" 1999

49

PD

7 34

PD PD/Bo tox

Patti'?' 1999

28

PD/Botox

Ponc e"? 1999

Portale!" 2005

31 19 207 45

PD/Bo tox PD/Botox

Smith l962 006

154

PD/Botox

Cockel'" 2004

Rosemurgy l942005

PD PD

13 % esophageal perforation rat e in Botox gro up; 2.4 % perforation rate in non -Botox with pre vious PD; 53% difficult dissection in Botox group 5% esophageal perforat ion rate in pn eumat ic dilat ion group; 0 % perforat ion in nonrespondin g Botox group, 50 % esophageal perforation rate in responding Bot ox grou p 6% esoph ageal "s m all mucosal breach " N o in traopera tive or postoperative com plications 5% esopha geal perforation rate Perfora tion rate: 5.3% pn eumatic dila tion, 3.8% Botox ± PD, 3.9% primary surgery 9.7% gast ric and esop hage al perforation s; 19.5 % failure of myotomy

Botox , botulinum toxin; PO, pneumatic dilation.

institutions} it is considered the overall treatment of choice. The objective of forced dilation of the esophagus is to break the muscle fibers of the LES and thereby decrease LES tone. Response to pneumatic dilatation is variable} with most studies documenting response rates between 60 % and 80 % .54-58 However}a decrease in LES pressure does not always correspond to improvement in clinical symptoms," and up to 50 % of patients with initial good response to dilation have recurrence of their symptoms within 5 years of treatment/" Fortunately} patients who respond to dilation appear to respond equally well to a second session. Although pneumatic balloon dilation is considered by many to be the most effective nonoperative therapy for achalasia} dilation carries a risk of esophageal perforation with devastating effects} and the long-term effectiveness of dilation falls short of the longterm results following operative myotomy (Table 44A.1O). Given these findings} dilation may be appropriate in select patients who require only a short-term response (limited life expectancy).

As with Botox, prior pneumatic dilation may make sub sequent operative myotomy technically more difficult as the result of esophageal scarring. The impact of morphologic changes associated with both pneumatic dilation and Botox injection on the course of operative myotomy has been addressed in several prospective series. In the larger series} the GI perforation rate was significantly higher than with operative myotomy alone (5%-10 % vs. 3 %-4 %)} with eventual myotomy failure rates reaching 20 % .51,61 Given these find ings} operative myotomy is more frequently advocated as the procedure of choice.P

Operative Myotomy. Operative myotomy involves dividing the muscle layers of the LES while preserving the integrity of the esophageal mucosa (Fig. 44A.9) . A dissection

-~. . . . TABLE 44A.I0. Review of Cited Experience Using Balloon Dilation Versus Operative Myotomy for Treatment of Acha las ia.

Author

No. pa tients

Felix!" 1998 [pr]

40

Csendes'" 1989 (pr)

81

More no -Conzalez'" 1988 (ret, multi! Okike'?' 1979 (ret)

1416 320 468 43 1

Results

Myo to my, lower LESP, less GER i ot herwise, no differen ce Myo to my, 95% im proved at 65mo Dilation, 65% improved at 58 mo Myot om y, 82% improved Dilati on, 65 % improved Myo tomy, 85% improv ed Dilation, 65 % improved

GER, gastroesophageal reflux; LESP, lower esophageal sphincter pressure; multi, multi-institutional; Pr, prospective randomized; ret, retrospective.

FIGURE 44A.9. Esophageal m yotomy for the treatment of ach alasia (Heller m yotomy). (From Hunter and Richardson." ? with permission.)

802

CHAPTER

44A

surgery . These same conditions will also limit endoscopic access for Botox injection. Finally, there is an increasing number of patients who are looking for more lasting therapy and wish to avoid multiple interventions. The success of laparoscopic approaches to GER and hiatal hernia is now prompting patients to seek out "minimally invasive" therapies that have a low complication rate and lasting results for achalasia.

FIGURE 44A.I0. One hundred eighty degree fundoplication performed in association with esophageal myotomy. [From Hunter and Richardson, " ? with permission.)

plane is usually easily developed in the submucosa where the overlying muscle fibers can be transected. An antireflux procedure often accompanies the esophageal myotomy (Fig. 44A.1O). The length of the myotomy should extend 6 to 7cm above the GEJ with distal extension 1 to 3 cm onto the stomach. A more aggressive distal extension (up to 3 ern] has been associated with less postoperative dysphagia and a more marked decrease in LES pressure.f Esophageal myotomy has been performed either through the chest or abdomen, using both open and minimally invasive techniques. Although the results of operative myotomy by nearly all reports are superior to other modes of therapy, there remain several unanswered questions in the operative management of achalasia. A careful review of the data just summarized raises several issues: (1) Who should be offered operative myotomy? (2) Which operative approach should be used? (3) Should an antireflux procedure accompany a myotomy? WHO SHOULD BE OFFERED OPERATIVE MYOTOMY? A careful review of the data does not answer the question of who should be offered operative myotomy. Generally, there are four groups for whom one should consider myotomy. The first is young patients for whom a single intervention with the best long-term result is the most effective overall. Pneumatic dilation is clearly less effective in younger patients, and because of the short duration of its effect, treatment with Botox is less desirable for young patients. The second group is those who have failed either Botox or pneumatic dilation. It is not clear what constitutes a failure of these therapies because they can be repeated with some increase in response with successive treatments. It seems reasonable to offer an operative myotomy to a patient who is an operative candidate and has failed two trials of either nonoperative therapy. The third group is patients who are at excessive risk for esophageal perforation with pneumatic dilation, including patients with a tortuous esophagus, esophageal diverticula, or previous GEJ

WHICH TECHNIQUE OF OPERATIVE MYOTOMY SHOULD BE USED? Excellent results have been obtained with both the open transthoracic and the transabdominal approaches. Recent success with laparoscopic myotomy has shown the laparoscopic approach to be comparable to open myotomy, with enhanced postoperative recovery and shorter hospital stay." The laparoscopic approach has nearly replaced the open transabdominal approaches . Similarly, the excellent results with open transthoracic myotomy have been reproduced with a thoracoscopic approach, thereby minimizing the postoperative consequences of a thoracotomy. Failures following a thoracic approach have largely been related to the development of GER because most transthoracic techniques are not accompanied by an antireflux procedure. Which approach is used depends on the individual surgeon's comfort and experience in performing any of these techniques. The data do not clearly support any technique over another, although the laparoscopic technique of operative myotomy currently appears to be the most widely applied and reproducible. This trend will continue as surgeons become more familiar with minimally invasive techniques, newer instumentation is developed, and new modes of therapy are realized [e.g., robotic and computer-enhanced techniquesl.rv" Performance of safe and effective cardiomyotomy continues to be a source of active investigation. SHOULD AN ANTIREFLUX PROCEDURE ACCOMPANY MvoTOMY? The two most common reasons for a poor outcome following operative myotomy are persistent dysphagia or GER. The occurrence of each of these may reflect differences in operativeapproach or technique. Typically,a transabdominal myotomy is likely to be carried not only across the LES but also down onto the cardia of the stomach for a distance of 3 em . In those series in which a transabdominal myotomy without an antireflux procedure is performed, rates of postoperative dysphagia are low and of GER are high . When an antireflux procedure is added, GER rates decrease. Conv ersely, a transthoracic myotomy is likely to go across the LES and for a shorter distance along the gastric cardia (typically 1cm). When a shorter distal myotomy is performed, GER rates are lower, and dysphagia rates are increased. The use of a fundoplication adds operative time, and its use has primarily been based on surgeon preference . Further, the evidence suggested by a number of retrospective and prospective reviews has done little to settle the controversy (Table 44A.II). However, two recent randomized prospective controlled trials have revealed that a significant number of patients undergoing cardiomyotomy with a distal extension of greater than 1em experience a significantly higher number of reflux episodes if a fundoplication is not included. Results based on both objective (pHprobe, esophagogastroduodenoscopy [EGD)) and subjective (symptom scores of GER and dysphagia) measures have now led many to advocate for the addition of a

803

ESOPHAGU S (B E N IG N)

_"1":" -

TABLE 44A.ll. Review of Studies Evaluating Antireflux Procedure After Heller Myotomy (>20 patients, >12 month follow-up).

Author

Year

No. patients

Peracchia'?' Raiser''" Hunger'?' Morino!" Kumar'?' Patti 20S Richards'?' Stewartr" Zaninottoi" Yamamura-" Oelschlager'!" • Oelschlager" ? Palkenbach-' !" (RCT)

1995 1996 1997 1997 1998 1999 1999 1999 2000 2000 2003 2003 2003

40 35 39 21 19 133 30 55 100 24 52 58 10

Palkenback" ! (RCT)

2003

Richards21h (RCT) Richardsi " (RCT) Diamantis/P

2004 2004 2006

Length of distal myotomy

Type of fundoplication

% with GERpH

Anterior 6 anterior/29 posterior 7 anterior/32 posterior Anterior None 25 anterior/8 posterior None 3 anterior/2 posterior Anterior An terior An terior Posterior None

2cm 2-3cm lcm 2cm lcm 1-1.5cm lcm 2cm 1-1.5cm 1- 1.5 cm 1.5 cm 3cm 2-3cm

10

360 0

-3cm

25 (2/8)

21 22 33

1-2cm 1-2cm None

None Anterior 5mm

48 (10/21) 9(2/221 0

7.5 (3/40) 0(0/18) 6(1 /17) 7 (1/15) 17 (6/35) 7 (1/14) 14 (1/7) 7(5/761 14 (1/71 32 (6/19) 54 (13/241 100 (9/9)

% GER symptoms

0(0/40) 78 (14/18) (1/37) o (0/17/ 7 (1/15) 13 (2/16) 10 (5/49) 3 (3/100) 0 44 (14/321 22 (11/501 70 (7/101 (requiring medications) 11 (1/9) (requiring medications I

0

" separategroupfrom trial; RCT, randomized controlledtrial.

fundoplication after every cardiomyotomy.V'" Given that technique continues to vary worldwide, the optimal type of fundoplication after cardiomyotomy remains to be determined. Currently, most centers add either an ant erior [Dor] or posterior [Toupet] fundoplication to the procedure. SPASTIC DISORDERS OF THE E SOPHAGUS

Spastic disorders of the esophagus are primarily disorders defined by manometric abnormalities in the smooth mu scle segment of the esophagus . These smooth muscle "spasms" typically consist of tertiary contractions th at are simultaneOUS, repetitive, nonperistaltic, and often of prolonged duration and increased power. Spastic disorders of th e esophagus are classically discussed as four distinct entities (diffuse esophageal spasm, nutcracker esophagus, hypertensive LES, and nonspecific esophageal motility dysfun ction), but reports of evolution of one motility pattern into another suggest that th ese separate disorders may be within a single spectrum of motor dysfunction . DIAGNO SIS

Dysphagia and chest pain are the dominant presenting symp toms, with chest pain occurring in 80% to 90% of patients and dysphagia in 30 % to 60%. Symptoms are often brought on by psycholo gical or emotional stress, and before the wide spread availability of esophageal motility testing many patients carried psychi atri c diagnoses before their esophageal condition was identified. Often, the diagnosis of a spastic esophageal disorder become s one of exclusion as cardiac causes on the potential role of acid reflux as an explanation for th e symptom compl ex are ruled out. Esophageal manom-

etry remains the gold standard for diagnosing spastic esophageal disorders (Table 44A.12). Despit e this manometric classification, th e causal relationship between abnormalities in manometric parameters and symptoms remains weak . Some investigators have suggested that abnormalities on esophageal motility testing may, at best, suggest a possible cause of a pat ient's symptoms, with a diagnostic yield as low as 28%. Despite these controversies, it is helpful to separate these entities when considering treatment options. T REATMENT

Approaches to the treatment of esophageal spastic disorders are aimed at ameliorating symptoms. Strategies have included thos e same therapies applied to achalasia and include pharTABLE 44A.12 . Manometric Criteria for Spastic Motor Di sorders of the Esophagus. Diffu se esophageal spasm Intermittent normal peristalsis Nutcracker esophagus Normal peristalsis Hyp ert ens ive LES Normal LES relaxation Normal peristalsis Nonspecific motor dysfunction Low-amp litude contractions « 30mmHg) Abnormal waveforms Body aperistalsis with normal LES LES, lower esophageal sphincter.

Simultaneous contractions (>10% of wet swallows) High -amplitude contractions 1>180mmHgl High resting LES pressure (>45mmHgl Frequ ent nonpropagat ed or retrograde contract ion s

804

CHAPTER 44A

macotherapy, Botox injection into the LES, balloon dilation, or operative myotomy. Due to the rarity of these conditions and the difficulty in their diagnosis, no data exist on which to base definitive statements regarding treatment. After a thorough workup and exclusion of other conditions, a trial of pharmacotherapy with smooth muscle relaxants (calcium channel blockers, nitrates, and anticholinergics) is reasonable . Because there is often a psychoemotional aspect to symptomatic episodes, reassurance and support are vital components in the care of these patients. Select patients may benefit from nonpharmacotherapy. Favorable responses to dilation and Botox have been reported in patients with diffuse esophageal spasm and hypertensive LES. Operative myotomy may be particularly effective in those with hypertensive LES and less so in patients with segmental spasm and nutcracker esophagus. Most of these patients are best treated by GI specialists (both medical and surgical) with extensive experience in managing these challenging problems.

Esophageal Diverticula An esophageal diverticulum is an epithelial-lined mucosal pouch that protrudes from the esophageal lumen. Most esophageal diverticula are acquired and occur in adults. Esophageal diverticula are classified according to their location (pharyngoesophageal, midesophageal, or epiphrenic], the layers of the esophagus that accompany them (true diverticulum, which contain all layers, or false diverticulum, containing only mucosa and submucosa); or mechanism of formation (pulsion or traction) (Table 44A.l31. Most esophageal diverticula are pulsion diverticula and are the consequence of elevated intraluminal pressure forcing the mucosa and submucosa to herniate through the esophageal musculature. Less commonly, traction diverticula develop that result from periesophageal inflammatory process adhering to the esophagus and subsequently pulling the esophageal wall as the inflammation heals and retracts. Pharyngoesophageal and epiphrenic diverticula are pulsion diverticula that are generally associated with abnormal esophageal motility, whereas midesophageal diverticula are usually traction diverticula resulting from inflammatory changes in mediastinal lymph nodes.

Pharyngoesophageal Diverticulum [Zenker's] In 1878, Zenker reported on 27 cases of pharyngoesophageal diverticulum, and thus his name became associated with this entity. This is the most common of the esophageal diverticula, with a prevalence between 0.01 % and 0.11 % . It is a condition of the elderly, with 50% of cases occurring during the seventh and eighth decades of life. Pharyngoesophageal diverticula consistently arise within the inferior pharyngeal constrictor, between the oblique fibers of the thyropharynTABLE 44A.13 . Classification of Esophageal Diverticula. Diverticulum

Location

Mechanism

Type

Pharyngoesophageal Midesophageal Epiphrenic

UES Tracheal bifurcation Distal esophagus

Pulsion Traction Pulsion

True

UES, upper esophageal sphincter.

False False

FIGURE 44A.ll. The lateral aspect of the pharyngoesophageal junction: (a) site of origin of pharyngoesophageal diverticula; (b) lower weak area; (I) obliquefibers of the inferiorpharyngeal constrictor; (2) cricopharyngeal muscle; (3) muscularis of the esophagus. (From Terracol and Sweet,278 with permission.) geus muscle and through or above the more horizontal fibers of the cricopharyngeus muscle (the UES) (Fig. 44A.ll). The point of transition in the direction of these muscle fibers represents an area of potential weakness in the posterior pharynx (Killian's triangle). Pharyngoesophageal diverticula appear to be acquired, as evidenced by the predominance in the elderly. Despite the acceptance of this acquired etiology, there remains considerable debate regarding the exact pathophysiology of pharyngoesophageal diverticulum formation. What most do agree on is that some degree of incoordination in the swallowing mechanism is the basis for the formation of these diverticula, with an abnormally high intrapharyngeal pressure leading to protrusion of esophageal mucosa and submucosa through Killian's triangle with subsequent diverticulum formation. Inadequacies in modem esophageal manometric testing and the rapidity of the pharyngeal phase of swallowing have prevented definitive characterization of the underlying cause of these diverticula. The variety of approaches to the treatment of pharyngoesophageal diverticula reflects the uncertainty of its cause. DIAGNOSIS

The presenting symptoms of pharyngoesophageal diverticulum are usually characteristic and consist of cervical esophageal dysphagia, regurgitation of bland undigested food, frequent aspiration, noisy deglutition (gurgling), halitosis, and voice changes. Dysphagia is present in 98 % of patients, and pulmonary aspiration is a serious consequence, occurring in up to one-third of patients. Cancer has been reported in a pharyngoesophageal diverticulum, but the frequency of this occurrence is no higher than that in the general population. The diagnosis of pharyngoesophageal diverticulum is easily made with a barium esophagogram (Fig.44A.12). Endos-

80S

ESOPHAGUS (BENI G N )

TABLE 44A.14. Treatment Options for Pharyngoesophageal Diverticula. Treatment

Description

Endoscopic diverticulotomy

Endoscopic division of cricopharyngeus and common wall between diverticulum and esophagus (electrocautery, stapler, laser, etc.) Cricopharyngeal myotomy and excision of diverticulum Cricopharyngeal myotomy and mobilization of sac with suture fixation of the sac above neck of diverticulum Cricopharyngeal myotomy only

Operative myotomy and diverticulectomy Operative myotomy and diverticulopexy Operative myotomy alone

FIGURE 44A.12. Barium esophagogram showing pharyngoesophageal diverticulum . copy, 24-h pH monitoring, and esophageal manometry are not indicated unless some feature of the symptoms or the esophagogram raise suspicion of other conditions (malignancy or GER). Although these diverticula can reach impressive sizes, it is the degree of DES dysfunction that determines the severity of symptoms, not the absolute size of the diverticulum. In most symptomatic cases, treatment is indicated regardless of the size of the diverticulum. TREATMENT As is the case with all pulsion diverticula, the proper treatment must be directed at relieving the underlying neuromo-"',..-

tor abnormality responsible for the increased intraluminal pressure and then managing the diverticulum. Most techniques described have employed division of the cricopharyngeus muscle followed by resection, imbrication, oblit eration, or fenestration of the diverticulum (Table 44A.14). There are no prospective randomized studies assessing the various treatments available for pharyngoesophageal diverticula. Of the retrospective studies comparing open versus endoscopic therapy, greater than 75% of patients have good results regardless of method. However, there is a trend toward a significan tly higher success rate using the open approach.P'" Given their retrospective nature and relatively short follow-up, it rem ains difficult to draw final conclusions." A summary of the available treatments and results ava ilab le from retrospective reviews is pre sented in Table 44A .15. Most approaches to management agree that relief of the relative obstruction distal to the pouch through cricopharyngeal m yotomy is the most important aspect of treatment. Early surgical strategies using diverticulectomy only, without myotomy, had high failure rates because of esophageal leaks from the suture line or from recurrence."

TABLE 44A.15. Summary of Results in Managing PharyngoesophagealDiverticula.

Author

Endoscopic diverticulotomy

Ma ttinger'!" 2002

Mulder'" 1999

Name 216 1999

Peracchia !" 1998 Scher?" 1998 Von Doer sterr" ? 1997 Lippert" ? 1997 Ishioka!" 1995

Wouters222 1992 Myotomy and div erticulectomy Cutschowv" 2002 Bonafede/" 1997 Witteric k-" 1995 Laing'" 1995 Myotom y and diverticulopexy Lerur' " 1992 Myotom y alone Schmi r' " 1992 Payne229 1992

No. patients

Results

Comments

52 167 102 95 34 40 37 42 508

85% improved 100% improved 96% success 97% success 94% improved 92.5% improved 97% improved 100% improved 92.1% improved

CO2 laser APC laser Stapled Stapled Two failures re-treated successfully endoscopically

47 56 18 65

98% success 89% improved 83% improved 93% improved

94

92% improved

48 25

87% improved 96% success

Laser endoscopic One to five "sessions" necessary Open (most myotomy + diverticulectomyI Four redos

Local anesthesia Small pouch «4cm)

806

CHAPTER 44A

There is at present no long-term follow-up study showing the superiority of one treatment over another. Endoscopic diverticulectomy appears to be a reasonable initial therapy for most patients. Those with a small «2cm) symptomatic diverticulum that is difficult to approach endoscopically or a large (>lOcm) pouch extending into the mediastinum may best be served with an operative myotomy alone ."

Midesophageal Diverticulum Midesophageal diverticula are rare and most commonly associated with mediastinal granulomatous disease (histoplasmosis or tuberculosis). They are thought to arise because of adhesions between inflamed mediastinal lymph nodes and the esophagus. By contraction, the adhesions exert "traction" on the esophagus with eventual localized diverticulum development. These are true diverticula, with all layers of the esophagus present in the diverticulum. Some midesophageal diverticula are related to motility disorders and represent more classic pulsion features (typically larger, false diverticulum). DIAGNOSIS/TREATMENT

A midesophageal diverticulum is typically asymptomatic and diagnosed incidentally on a barium esophagogram for other reasons . When such an asymptomatic diverticulum is found, no treatment is necessary . In patients with symptoms, esophageal manometry is indicated to search for an esophageal motor disorder. Symptomatic diverticula require treatment. When associated with an esophageal motility disorder, a small diverticulum may be treated with esophageal myotomy only. Larger diverticula usually require an accompanying resection or diverticulopexy. In the absence of a motor abnormality, diverticulectomy alone is indicated. Diverticulectomy with orwithout myotomy usually requ ires a transthoracic approach, either open or thoracoscopic.

Epiphrenic (Pulsion) Diverticulum A fairly rare condition, an epiphrenic diverticulum typically occurs within the distal lOcm of the esophagus and is a pulsion type. It is most commonly associated with esophageal motor abnormalities (achalasia, hypertensive LES, diffuse esophageal spasm, nonspecific motor disorders) but may be the result of other causes of increased esophageal pressure. DIAGNOSIS/TREATMENT

Most epiphrenic diverticula are symptomatic because of the underlying esophageal motor disorder. Diagnosis of the diverticulum is made during barium esophagogram (Fig. 44A.13). Manometry, esophagoscopy, and 24-h pH testing may be necessary to diagnose associated conditions and direct specific treatments. Most epiphrenic diverticula require esophageal myotomy extending from the neck of the diverticulum onto the gastric cardia for a distance of 1.5 to 3.0cm (see section on myotomy for achalasia) . Diverticulectomy, fundoplication, or repair of hiatal hernia may also be necessary depending on the size of the diverticulum or associated conditions. No prospective data or large clinical experiences are available on which to base specific treatment recommendations.

FIGURE 44A.13. Barium diverticulum.

esophagogram

showing

epiphrenic

Gastroesophageal Reflux Definition Gastroesophageal reflux (GER) is defined as the failure of the antireflux barrier, allowing abnormal reflux of gastric contents into the esophagus. Y" It is a mechanical disorder that is caused by a defective LES, a gastric -emptying disorder, or failed esophageal peristalsis. These abnormalities result in a spectrum of disease ranging from th e symptom of "heartbum" to esophageal tissue damage with subsequent complications. As diagnostic tools have become more widely available and applied, a host of extraesophageal manifestations of GER are also increasingly identified [e.g., asthma, laryngitis, dental breakdown) . Gastroesophageal reflux is an extremely common condi tion, accounting for nearly 75% of all esophageal pathology. Nearly 44% of Americans experience monthly heartburn, and 18% of these individuals use nonprescription medication directed against GER.78 With a prevalence of nearly 19 million cases per year with an associated total cost of care of $9.8 billion in the United States , GER is clearly a significant public health concern. "

Pathophysiology: Antireflux Mechanism Although the exact nature of the antireflux barrier is incompletely understood, the current view is that the LES, the diaphragmatic crura, and the phrenoesophageal ligament are key components.P'" Dysfunction of the LES is the most common cause of GER. A popular model proposed by DeMeester details three factors that determine the competence of the LES: (1) resting LES pressure, (2) resting LES length, and (3) abdominal length of the LES (Table 44A.I6) . Dysfunction of the LES may be either physiological and transient or pathological and permanent. Nearly everyone experiences physiological reflux, most commonly following

ESOPHAGUS (BENIGN)

TABLE 44A.16. Features of an Incompetent Lower Esophageal Sphincter. LES characteristics

Resting LES pressure Resting LES length Length intraabdominal LES

Incompetent if:

50%I before dysphagia occurs . Other symptoms may include

Treatment of Esophageal Cancer . . . . . . . . . . . . . . . . . . . Approach to the Patient with Esophageal Cancer . . . . .. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

829 836 836 837

anorexia, weight loss, odynophagia , chest or back pain, melena or hematemesis, and occasionally hoarseness. Unfortunately, almost half of patients will have metastatic disease at the time of initial presentation and have an estimated survival of 4-8 months. A small fraction of patients will be identified with early-stage cancer either through Barrett's surveillance programs or when endoscoped for other reasons. The evaluation of a patient with dysphagia requires barium swallow or esophagogastroduodenscopy. Although a barium swallow is useful , endoscopy is essential to confirm the diagnosis and obtain tissue for histology. Bronchoscopy should be performed for tumors at or above the level of the tracheal carina to rule out airway invasion. Adenocarcinoma usually occurs in the lower esophagus, with 79% in the lower third, 18% in the middle third, and 3 % in the upper third, " whereas squamous cancer is more common in the middle and upper thirds.

Staging CT scanning is used to evaluate the extent of the primary tumor and to determine the presence of nodal or distant metastatic disease. Loss of the fat plane between the esopha gus and adjacent structures is suggestive of invasion, as is the finding of greater than 900 of contact. However, even these radiologic signs are not foolproof. Stage-specific therapies previously have not been used for esophageal cancer, so precise staging has been less important for this tumor than many others. However, Rice et al. advocated for treatment strategies based on the stage of disease, offering immediate surgery to those with early disease, postoperative therapy if positive nodes are found, and preoperative chemoradiotherapy to those with more advanced disease at time of presentation. Hence, more accurate staging tests are required." Endoscopic ultrasound (EUS) has been found to be useful in evaluating the depth of penetration of the primary tumor

827

828

CHAPTER 44B

TABLE 44B.l. Staging of Lymph Nodes by Endoscopic Ultrasound (EUS) Versus EUS-FNA. Sensitivity Specificity Accuracy

EUS

EUS-FNA

P value

630/0 810/0 700/0

930/0 100% 93%

.01 NS 0.02

EUS-FNA, endoscopic ultrasound-fine needle aspiration; NS, not significant. Source: From Vasquez-Sequeiros et al.," by permission of Gastrointestinal Endoscopy.

and thus establishing the T stage prior to treatment. The overall accuracy for EUS staging of the primary tumor ranges from 50.00/0 to 81.30/0. Accuracy is improved if endoscopic information is available unless the tumor completely obstructs the esophageal lumen.' Endoscopic ultrasound can reliably distinguish Tl/T2 from T3/T4 but is most accurate for the latter.Y Celiac and mediastinal nodes can be assessed by EUS, but accuracy is higher for celiac nodes. The sensitivity of EUS for nodal disease is 89%, with 750/0 specificity and overall accuracy of 800/0. 9 Accuracy may be increased by EUS-guided needle biopsy (EUS-FNA)lO (Table 44B.l). Positron emission tomography (PET) has demonstrated promise in staging of esophageal cancer. It is most useful in detecting distant metastatic disease, for which it has been found to detect metastatic sites not identified by conventional staging in 15% of patients." However, the regional nodes close to the tumor are not easy to assess because of the intense uptake by the primary tumor itself, which obscures adjacent lymph nodes. Similarly, it is not as useful as EUS in determining T stage." Integrated PET/computed tomography (CT) has improved diagnostic accuracy over PET alone." Discordance between PET and CT findings are clinically relevant about half of the time." Comparison of PET, CT, and EUS suggests that these are complimentary staging techniques'v" (Table 44B.2).15 Laparoscopic and thoracoscopic staging has been advocated by Krasna and others" but has not been universally accepted. Surgical staging can clearly identify nodal disease, with sensitivity of 630/0-850/0, specificity of 1000/0, and overall accuracy of 930/0-94%. Also, it allows evaluation of the extent of the primary tumor.'? It is most useful in the setting of

N stage Sensitivity (0/0) Specificity (0/0) Accuracy (0/0) M stage Sensitivity (0/0) Specificity (0/0) Accuracy (%) Source: From Rasanen

PET

CT

EUS

83

67 63

100

37 100 63

47 92 66

89 54 75

47 89 74

33 96 74

JV, Sihvo EI, Knuuti MJ, Minn HR, et a1. 1S

Staging of Esophageal Carcinoma The staging system for esophageal cancer is shown in Table 44B.3. There is a proposal to revise the staging system, but this has not been adopted yet.

TABLE 44B-3. Definition of TMN, Stage Grouping, Histopathologic Type, and Histologic Grade for Esophageal Carcinoma. Definition of TMN Primary Tumor (T)

TX TO Tis T1

T2 T3 T4 Regional Lymph Nodes (N)

NX

NO N1

Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ Tumor invades lamina propria or submucosa Tumor invades muscularis propria Tumor invades adventitia Tumor invades adjacent structures Regional lymph nodes cannot be assessed No regional lymph node metastasis Regional lymph node metastasis

Distant Metastasis (M)

MX Distant metastasis cannot be assessed MO No distant metastasis M1 Distant metastasis Tumors of the lower thoracic esophagus: MIa Metastasis in celiac lymph nodes Other distant metastasis M1b Tumors of midthoracic esophagus: MIa Not applicable Nonregionallymph node and/or other M1b distant metastasis Tumors of upper thoracic esophagus: MIa Metastasis in cervical lymph nodes M1b Other distant metastasis Stage Grouping

TABLE 44B.2. Comparison of Positron Emission Tomography (PET), Computed Tomography (CT), and Endoscopic Ultrasound (EUS). T detection sensitivity (0/0) T stage accuracy (0/0)

neoadjuvant therapies. However, the combination of PET, EUS-FNA (fine needle aspiration), and CT appear to provide similar data. Using decision analysis, Wallace and colleagues determined that EUS with FNA and PET was the most effective staging strategy in terms of quality-adjusted life years. The use of EUS-FNA with CT was almost as effective but was more cost-effective. IS

Stage 0 Stage I Stage IIA

Tis T1 T2 T3

NO NO NO NO

MO MO MO MO

Stage lIB

T1 T2

N1 N1

MO MO

Stage ill

T3 T4 AnyT AnyT AnyT

N1 AnyN

MO MO

AnyN AnyN AnyN

M1 MIa M1b

Stage IV Stage IVA Stage !VB

Source: Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AlCC Cancer Staging Manual, Sixth Edition (2002)published by Springer Science and Business Media LLC, www.springerlink.com.

829

E S OP H A GU S {MA L IGNA N T}

..!O~.

TABLE 44B.4. Operative Mortality, Morbidity , an d Survival for Esophagectomy for Cancer.

Survival (%) Au thor 69

GUili Earlan "

Posthlethwair" Ellis? Orringer" Karariya" Orringer" Ellis 25 Alto rki" VisbaJ3 Alto rki" Casson"

Hulscher" Hulsche r" Bailey"

Yeor

N

1980 1980 1983 1983 1984 1994 1999 1999 1999 2001 2002 2002 2002 2002 2003

2,400 87,783 164 167 100 1,353 800 455 103 220 80 91

II I

94 1,777

Operation

Mort alit y (%)

3yr

4 yr

30 33 12.8 1.3 6 7.1 4.2 3.3 4.8

22

17

TIE TIE TIE TIE THE THE TH E TIE En bloc

24.7 46 25.2 51

3 4.4 4 2 9.8

TIE THE

Median survi val (rno)

21.7

17.3

23

r-t 3 field

5yr

39 29

22.8

24 21.6

THE, t ranshiata l esop hagc cto my , TIE, tra ns tho racic esophagectom y.

Treatment of Esophageal Cancer Surgery Surgery is th e primary treatment for esophageal can cer . Surgery provides exc ell ent palliati on of dysphagia, provides local control, and allows pat ients to eat comfortably until death. In th ose fit for surgery, 13.5%- 51 % will be cured of th eir cancer. Most surg ical ser ies repor t 5-year survival of approxi ma tely 25 %, but higher rat es have been report ed wi th m ore extensive surgery (Table 44BA ). The mortality of esophagec to my performed by experienc ed high-volume surgeons in hi gh -volume centers is less than 5%, al tho ugh in a recent study of pattern s of care, the mortality across th e United Sta tes average d 10.5% . 19 This represen ts a significan t improve-

m ent ove r th e yea rs since th e 1960s, whe n th e m ort ali ty of esophagectomy was approxima tely 30% (Table 44.B4). N evertheless, the mortality varies consi derably depending on th e practice volu me of both surgeo n and hospit al. Even though mortality is lower, the morbidity of esophagectom y is still consi derable, with 40 %-50% of pat ients expe rie nc ing one or m ore post operative com plica tions (Tabl e 44B.5). Surgery is the treatment of ch oice for tumors of th e midand dist al esophagus, including th e gastroesophagea l junc tion , in patients who are medicall y fit for esophagecto my. Radi ation m ay be us ed for those who are deem ed m edically inopera ble or who chose not to have surgery and is genera lly th e tre atment of choice for tu mors of the up per third of th e esophagus . For upp er-third tumors, ou tco mes are sim ilar with either radiation or surgery; however, radia tion all ows preser-

TABLE 44B.5. Morbidity of Esophagectomy for Cancer.

Author

Orringer' " Visbal" Bailey" Orringer" Posthlethwait" Ellis 72

Altork i" Altorki" Casson"

Yeor

N

Leak s (%)

RLN(%)

Resp (%)

1984 2001 2003 1999 1983 1983 1999 2002 2002

100 220 1,777 800 162 167 103 80 91

5 4.5

4 0.9

3

13 3 3.5

7

11.2 16.5

8.8

A fib/MI(%)

Chylothorax (%)

Total (%)

17.3/2.2 / 1.2

1.8

21.4

37. 7 49.5

10.5

/ 1.2

857

S TO MA C H AND DU ODENUM

~. . . TABLE 45.7.

Randomized, Double-Blinded, Placebo-Controlled, Crossover Trials of Octreotide Treatment for Severe Dumping Syndrome.

A uthor (year)

n

Treatm ent

Symp tom score ,·b

Pulse rat e (beats per min)'

Hematocrit (%)'

Plasma ins ulin'

Hopman (1988)245

12

Tulassay (1989)246

8

Primrose (1990J247

10 10

Gray (1991)249

9

Hasler (1996 )250

8

11.7±2.1 4.6 ± 1.6' Severe in all patients Alleviated in all patients Severe in 10 of 10 patients Improved in 9 of 10 patients 8.5 ± 0.5 1.7 ± 0.5' 15.7±1.6 4.6 ± 1.7' Diarrhea: 3.5 ± 0.4 Pain: 2.0 ± 0.4 Lightheadedness: 3.8 ± 0.2 Palpitations:3.2 ± 0.3 Diarrhea: 0' Pain: 1.3 ± 0.3 Lightheadedness: 1.0 ± 0.3' Palpitations: 0.8 ± 0.2'

85 ± 7 67 ± 7' 102±3.5 70 ± 2' 25 beats per min rise 8 beats per min rise' 87 ± 5 66 ± 4' 105±6 80 ±3 ' 36 ± 6 beats per min rise

41 ± 2 41 ± 2 43 ± 3.5 38 ± 1 4.5% rise 2.1% rise'

Geer (1990)248

Control Octreotide Control Octreotide Control Octreotide Control Octreotide Control Octreotide Control

41 ± 2 39 ± 1 36.7 ± 0.6

173 ± 16 (mU/L) 35 ± 9' 40 ± 3.2 ( ~E/mL! 11 ± l' 185 (mU/L! 30 (mU/L)' 180 ± 50 (mU/L! 20 ± 5' 1162 ± 230 [prnol/ L] 158± 29' 87 ± 15 (U/mL!

17 ± 5 beats per min rise'

36.5 ± 0.4

26 ± 9 11U/mL)'

Octreotide

' Mean ± standard error of th e mean except where indicat ed. "In the Hopman and Gray studies, a Sigstad dumpi ng score was used ; in the Geer st udy , a severity score of 0-10 was used ; in th e Hasler stud y, a sever ity scor e of 0-4 was used; in th e Tulassay and Primrose studies, symptom relief was not quantified. ' Statistically significant (p < 0.05).

the reversed segment must be tailored to an appropriate length. Segments that are too short do not resolve the dumping symptoms, but segments constructed too long result in gastric retention. A lO-cm length appears ideal. Care must be taken to rotate the interposed segment only 180 and to avoid undue torsion of the mesentery. Mesenteric defects should be securely closed to avoid internal herniation. Conversion of a Billroth II anastomosis to a Billroth 1 gastroduodenostomy improves dumping symptoms in about 75% of patients. The main advantage of this procedure is the restoration of the norm al physiologic delivery of a meal into the duodenum. This operation, however, is occasionally technically difficult and fails to alleviate symptoms in a substantial minority of patients. Overall, conversion of a Billroth II to a Billroth I has been eclipsed by th e relat ive simplicity of Roux-en-Y conversion. There is support in the literature for conversion of a Billroth lora Billroth II to a Roux-en- Y gastrojejunostomy as a remedial operation for dumping syndrome. In patients with previous Billroth I or Billroth II gastrectomy and m edically resistant dumping, 85%-90% have favorable outcomes with Roux-en-Y conversion. In one of the larger series , Vogel et al. reported that 19 of 22 patients treated with Roux -en-Y con version had a good result.!" Of the three failures, only one was due to persistent dumping symptoms; the other two were due to the development of Roux sta sis syndrome. This procedure has the advantage of simplicity when compared to jejunal interpositions, and it appears to have fewer undesirable longterm complications. To summarize, remedial surgery for dumping syndrome should be considered for patients with medically unresponsive, severe symptoms. For patients with prior pyloroplasty, pyloric reconstruction is preferred. For patients with prior Billroth I or Billroth II gastrectomy, Roux-en- Y conversion is

a simple and effective corrective operation. For patients who have previously undergone Roux-en-Y gastrojejunostomy, the best approach is construction of a lO-cm antiperistaltic jejunal segment within the Roux limb.

0

POSTVAGOTOMY DIARRHEA

Up to 20% of patients undergoing truncal vagotomy complain of postoperative diarrhea, and it is debilitating in 1%- 2%.160 Its severe form is characterized by frequent, watery stools that are occasionally explosive. The diarrhea may be postcibal or continuous. In some patients, nocturnal diarrhea is problematic . Diarrhea following gastric surgery most commonly results from causes other than vagotomy. Thus, patients with early postoperative diarrhea should be initially investigated for causes such as bacterial overgrowth, pseudomembranous colitis, obstruction, inflammatory bowel disease, intestinal parasites, and malabsorption. The appropriate initial diagnostic tests should include fecal white blood cell count, stool culture, fecal Clostridium difficile titer, and occasionally sigmoidoscopy. For patients with persistent diarrhea, further studies should be performed to exclude steatorrhea, partial intestinal obstruction, and inflammatory bowel disease. Appropriate diagnostic studies include 3-day fecal fat quantification, colo noscopy, upper GI barium contrast series with small-bowel follow through, and barium enema. Consideration should also be given to the possibility of laxative abuse. If this is suspected, then measurement of stool pH and magnesium concentration may be useful. If the workup is unrevealing, then th e diarrhea may be due to dumping syndrome or vagotomy. These last conditions are diagnoses of exclusion. No specific tests are available to confirm that the diarrhea is, indeed, due to th e gastric surgery.

858

CHAPTER 45

The pathophysiology of postvagotomy diarrhea is unclear. Although to date there is no direct evidence, the most likely explanation is that truncal vagotomy interferes with central nervous system modulation of enteric nervous system control of gut motility and secretion. Rapid gastric emptying is often associated with the diarrhea, but normalization of gastric emptying by remedial surgery does not always correct the problem. Impaired gallbladder emptying and increased excretion of bile salts may be involved. Supportive evidence includes the finding of higher levels of fecal bile salts in patients with postvagotomy diarrhea compared to controls and the beneficial effect of cholestyramine, a bile acid-binding agent, in many patients.

Patients typically complain of persistent, burning, epigastric abdominal pain and nausea that are exacerbated by meal ingestion. Bilious emesis, often mixed with incompletely digested food, does not relieve the symptoms of pain and nausea. This feature distinguishes this condition from afferent loop syndrome, in which bilious emesis, void of foodstuff, relieves the patient's discomfort. Patients develop an avoidance to food, resulting in significant weight loss. In addition, chronic low-grade gastritis results in anemia, a common finding in these patients. Reflux alkaline gastritis is the most common postgastrectomy syndrome for which remedial surgery is performed. PATHOPHYSIOLOGY

TREATMENT

Medical Therapy. The medical treatment of postvagotomy diarrhea is similar to that recommended for patients with the dumping syndrome. Simple dietary changes, including small, frequent, dry meals and increased dietary fiber, may slow intestinal transit and therefore improve diarrhea. Opiates are beneficial through their inhibitory effect on intestinal transit. Cholestyramine improves diarrhea in the majority of patients. For patients unresponsive to these measures, octreotide, a long-acting somatostatin analog, may be tried. Octreotide, however, has had limited success in controlling severe postvagotomy diarrhea as it may exacerbate the diarrhea by inducing steatorrhea. Surgical Therapy. For severe postvagotomy diarrhea unresponsive to medical therapy, remedial surgery may be considered. Although rapid gastric emptying is associated with the diarrhea, operations that slow gastric emptying are not usually curative. The most effective surgical strategies have focused on slowing small bowel transit. Construction of a 10-cm antiperistaltic jejunal segment located 100cm from the ligament of Treitz is effective in about two-thirds of patients. Sawyers et al., for example, reported on a series of 16 patients undergoing this procedure, with 14 having successful outcomes. 163 On the other hand, Cuschieri has reported that 12 of 13 patients in whom he performed this procedure had relief of diarrhea, but 10 required reoperation for pain and obstruction. 164 The most important lesson learned regarding the treatment of postvagotomy diarrhea is that, like dumping, prevention is much simpler than treatment. Truncal vagotomy should be avoided if possible. The operation of choice in the elective management of patients with intractable duodenal ulcer is PGV. REFLUX ALKALINE GASTRITIS

Alkaline reflux gastritis can occur in patients who have undergone removal, bypass, or destruction of the pyloric sphincter mechanism. Loss of pyloric function causes reflux of duodenal contents into the stomach, which may result in gastritis. Although some degree of reflux is seen in all patients following gastric surgery without significant sequelae, approximately 3 % develop severe reflux alkaline gastritis. The majority of patients have a prior history of Billroth II reconstruction. However, Billroth I gastroduodenostomy and pyloroplasty are also associated with this syndrome.

Patients with reflux alkaline gastritis have extensive gastritis involving the entire gastric remnant on gross examination. The gastric mucosa has an erythematous, friable, inflamed, ulcerated appearance on endoscopic examination, usually with visible pooling of bile and duodenogastric reflux. Histologically, the mucosa is void of parietal cells, hemorrhagic, and superficially ulcerated. The first observation is responsible for the achlorhydria or hypochlorhydria seen in patients with alkaline gastritis. Intestinalization of gastric glands, an increase in mucin cells, and a chronic inflammatory infiltrate are commonly observed. Although the association between duodenogastric reflux and the symptoms of alkaline reflux gastritis is clearly established, the exact pathogenesis of the gastritis is not clear. Some degree of reflux is seen in all patients following gastric surgery; however, only a small minority develop gastritis. Several reports have suggested that patients with alkaline gastritis have increased concentrations of bile acids in the refluxed duodenal juice, increased volume and frequency of reflux, increased concentration of specific bile acids like deoxycholic acid, or altered composition of bile acids and pancreatic enzymes. Others have suggested prolonged mucosal exposure to bile acids resulting from gastric dysmotility may playa role in the pathogenesis. Likewise, prolonged gastritis may exacerbate gastric hypomotility. Nevertheless, it appears that the mucosal injury is most likely caused by bile acids. Contact of bile acids with gastric mucosa results in breakdown of gastric mucosal barrier function, resulting in back diffusion of hydrogen ions. This causes mast cell disruption with release of serotonin, histamine, and other vasoactive amines that trigger the inflammatory changes characteristic of this condition. DIAGNOSIS

The diagnosis of reflux alkaline gastritis is based on a careful clinical history and endoscopic evidence of gastritis by gross and histologic appearance. Radiographic studies should be performed to exclude mechanical causes of epigastric pain, nausea, and vomiting, including recurrent ulcer, afferent loop syndrome, and so on. An analysis of gastric fluid to document the presence of hypo- or achlorhydria should be performed. If hyperchlorhydria is encountered, then hypergastrinemia from an undiagnosed ZES, retained antrum, or incomplete vagotomy should be excluded. Bile acid composition and concentration should be determined. Technetium scintigraphy with and without CCK stimulation can be used to quantify duodenogastric reflux. Provocative testing with alkaline solu-

STOMACH AND DUODENUM

tions and bile acids may reproduce symptoms in afflicted patients and serve to identify patients who may benefit from remedial surgery. In patients considered for surgery, a solidphase gastric-emptying study should be performed to exclude significant concomitant gastric dysmotility. TREATMENT

Medical. The mainstays of medical therapy for alkaline reflux gastritis are prokinetic agents to improve gastric emptying and coating agents such as sucralfate to enhance gastric mucosal defense. No specific dietary or behavioral therapy is reliably successful. Attempts at binding bile acids with cholestyramine or aluminum-containing antacids have been unsuccessful. Surgical. The goal of remedial surgery in patients with alkaline reflux gastritis is to prevent pancreaticobiliary secretions from refluxing into the gastric remnant. For patients with a prior history of Billroth I or Billroth II anastomosis, the best remedial choice is the conversion to a Roux-en-Y gastrojejunostomy with a Roux limb of sufficient length to prevent retrograde reflux, usually 45 to 60 em. This procedure is 75 % to 85 % effective in treating reflux symptoms.l'" However, Roux-en-Y gastrojejunostomy has two major potential complications. First, Roux-en-Y gastrojejunostomy is ulcerogenic; therefore, a vagotomy must be performed if not done so in the initial operation. Second, approximately onequarter of patients with reflux alkaline gastritis who undergo Roux conversion will develop the Roux stasis syndrome. This underscores the importance of adequate preoperative assessment of gastric emptying in patients with alkaline reflux gastritis. If significant preoperative gastroparesis is encountered, then a 900/0-95% near-total gastrectomy should be performed with the Roux-en-Y gastrojejunostomy. Others have advocated a Braun enteroenterostomy in patients at risk for Roux failure. In this procedure, the afferent and efferent limbs are anastomosed 30 to 60cm away from gastroenterostomy in patients with a Billroth II anastomosis. Although the results with this procedure appear promising, it requires the presence of a long afferent limb. For patients with reflux gastritis following truncal vagotomy and drainage, antrectomy with Roux-en-Y gastrojejunostomy should be performed. Antrectomy is necessary to minimize the risk of ulcer formation. For patients with a prior history of Billroth I gastroduodenostomy, a Roux-en-Y conversion should also be considered. Another option in this case is the Henley procedure, by which an isoperistaltic segment of jejunum is interposed between the gastric remnant and the duodenum. However, the results with this procedure have not been favorable. The duodenal switch operation described by DeMeester has also been proposed in the treatment of patients with alkaline reflux gastritis. In this operation, the duodenum is divided 5 to 7em beyond the pylorus. The distal end is oversewn and the proximal end anastomosed end to end to a Roux-en-Y limb. Long-term results with this procedure are not available, but short-term results appear promising. STASIS SYNDROMES

Stasis syndromes, including gastroparesis and the Roux syndrome, are well-recognized complications of gastric surgery. Postsurgical gastroparesis can occur following vagotomy or

859

gastric resection. Two forms of postoperative delayed gastric emptying have been identified: an early form occurring in the immediate postoperative period and a late form occurring from weeks to years following surgery. The incidence of gastric atony varies with the indication for surgery and type of procedure initially performed. In patients operated on for gastric outlet obstruction, for example, the incidence of postsurgical gastroparesis is as high as 27% to ·50%.Gastroparesis is seen in 1.40/0 of patients following vagotomy and drainage, in 2.40/0 to 90/0 of patients after vagotomy and antrectomy, and in 3 % of patients following subtotal gastrectomy without vagotomy. Overall, the incidence of postsurgical gastroparesis is 20/0 to 30/0. 160 In patients who have previously undergone Roux-en-Y reconstruction, gastroparesis or stasis in the Roux limb are termed the Raux syndrome. The incidence of this syndrome has been reported to be as high as 250/0 to 300/0. The incidence in patients who undergo Roux-en-Y diversion as a means of treating alkaline reflux gastritis is 100/0 to 500/0. Patients with postsurgical stasis syndromes present with postprandial epigastric fullness or bloating, early satiety, epigastric pain, nausea, and vomiting of incompletely digested food. Some patients develop bezoars. Patients may attempt to compensate for their condition by consuming only soft, semisolid foods or liquids. Weight loss and nutritional deficiencies often result. The diagnosis of postsurgical stasis syndromes is one of exclusion as symptoms mirror those of other postgastrectomy syndromes. These include mechanical problems such as stomal obstruction from edema, kinking, or stricture; recurrent ulcer; and gastric stump carcinoma. In addition, symptoms may be confused with those of afferent or efferent limb syndrome or postoperative small-bowel obstruction. Functional problems, such as gastroparesis related to diabetes mellitus, may be confused with a postoperative complication. These conditions must be excluded prior to instituting therapy for presumed postsurgical stasis. AFFERENT LIMB SYNDROME

The afferent limb syndrome occurs in rare patients following Billroth II gastrojejunostomy. In this condition, the limb of duodenum and jejunum responsible for proximal intestinal, biliary, and pancreatic drainage becomes partially or completely obstructed. The cause of this obstruction is mechanical and is usually related to excessive length. When the limb is too long, internal small-bowel herniation, kinking from redundancy or adhesions, loop volvulus, and intussusception can occur. In addition, obstruction at the gastrojejunostomy from recurrent ulceration, stricture formation, and carcinoma may cause the afferent limb syndrome. Two forms of afferent limb syndrome have been described, acute and chronic. Acute afferent limb syndrome occurs in the early postoperative period, usually within the first week. Obstruction of the afferent limb leads to accumulation of intestinal, pancreatic, and biliary secretions within the proximal jejunal lumen. As luminal pressure increases, venous pressures are quickly exceeded, resulting in ischemia and pressure necrosis of the intestinal mucosa. Obstruction of pancreatic and biliary outflow may arise if luminal pressures are sufficiently elevated. Disruption of the duodenal stump may result.

860

CHAPTER 45

The symptoms of acute afferent limb syndrome are abrupt in onset. Severe epigastric pain, nausea, nonbilious vomiting, tachycardia, and fever are uniformly present. Abdominal tenderness and fullness are usually present. If uncorrected, shock may ensue. Elevated serum amylase and liver function tests often confuse the clinician into believing postoperative pancreatitis or biliary pathology are the cause of the patient's deterioration. This leads to delay in appropriate surgical management. The diagnosis is confirmed by ultrasound or computed tomographic (CT) scan that reveals a fluid filled mass in the epigastrium. Acute afferent limb syndrome is a form of closed-loop obstruction and, as such, is a surgical emergency. Mortality rates associated with acute afferent limb syndrome approach 50%.160 Chronic afferent limb syndrome may occur at any point in time after the initial surgery. It results from intermittent, partial mechanical obstruction of the afferent limb. Patients typically present with postcibal epigastric discomfort, pain, and fullness. This results from the rapid accumulation of pancreatic, biliary, and duodenojejunal secretions within the limb in response to a meal. As intraluminal pressure exceeds the resistance to outflow caused by the obstruction, the patient experiences explosive bilious vomiting, usually void of foodstuff. This emesis relieves the patient of symptoms. These last two features distinguish chronic afferent limb syndrome from reflux alkaline gastritis, in which emesis usually contains undigested food and does not relieve the discomfort. A minority of patients develop bacterial overgrowth in the partially obstructed afferent limb, resulting in a blind-loop syndrome. Plain abdominal radiographs are usually nondiagnostic. Ultrasound or CT are the tests of choice. Endoscopy should be performed to exclude the presence of alkaline gastritis, recurrent ulcer, anastomotic stricture, and anastomotic carcinoma. Patients with afferent limb syndrome require remedial surgery. In the average patient, this is best accomplished via conversion to a Roux-en-Y gastrojejunostomy. Alternatively, a Braun enteroenterostomy between the afferent and efferent limbs is effective in decompressing the obstructed afferent limb. In severely ill patients with acute obstruction, the afferent limb and duodenal stump must be examined for viability. In the rare patient with necrosis of the afferent limb, resection of the devitalized tissue, reconstruction of the afferent limb, bypass of the obstruction, and drainage of the duodenal stump are indicated. If extensive necrosis exists, then pancreaticoduodenectomy may be necessary. Afferent limb syndrome can be prevented by creation of a retrocolic gastrojejunostomy with a short (5- to 15-cm) afferent limb. All defects in the mesocolon or small bowel mesentery should be closed. The gastrojejunostomy should lie in a horizontal plane without kinks.

Malignant Gastric Tumors Adenocarcinoma Historically, gastric cancer has been one of the leading causes of cancer death worldwide. Worldwide, there is great geographic variation in the incidence of gastric cancer, with the highest rates seen in the Far East, especially Japan and Korea;

Central America; and Eastern Europe and the lowest incidence in North America, North and South Africa, and Australia.l'" Fortunately, the incidence of gastric carcinoma is declining, especially in developed countries. In the United States, for example, the incidence of gastric cancer has decreased fourfold since 1930 to approximately 9 cases per 100,000 people.!" Most patients present in the sixth to seventh decade in low-risk regions, while patients in highrisk regions present a decade earlier. In the United States, 390/0 of gastric cancers arise in the proximal stomach, 17% in the middle third, 32 % in the distal third, and 12% involve the entire stomach.!" The decline in the incidence of gastric cancer is attributed to a decline in the incidence of distal lesions. The incidence of cardial and gastroesophageal junction lesions has remained stable or increased. 169 There are two major histological types of gastric cancer. The intestinal histology consists of cell groupings organized into glands, resembling intestinal mucosa. Intestinal-type tumors occur most frequently in the distal stomach and are seen more commonly in regions with a high incidence of gastric cancer. Cancer cells that have no specific organization characterize the diffuse histology. They tend to infiltrate the gastric wall, forming a thickened gastric wall but not a discrete mass. These lesions occur anywhere in the stomach but predominantly occur at the cardia. The incidence for diffuse tumors has been relatively constant over the years. Diffuse lesions occur in younger patients and are more clinically aggressive than intestinal-type lesions. Like other GI malignancies, the pathogenesis of gastric cancer is thought to be a multistep process. Unlike colon cancer, however, the progression from normal mucosa to cancer is not well defined and likely represents an interaction between environmental factors and host predisposition to development of gastric cancer, including genetic and acquired factors. The pathogenesis is best characterized for intestinaltype cancers. Chronic inflammation is central in this process. Correa has postulated that, in response to environmental factors, normal mucosa becomes chronically inflamed, chronic active gastritis. This is followed by progression to atropic gastritis, intestinal metaplasia, dysplasia, and cancer.170 Environmental factors, including chronic H. pylori infection, dietary factors such as high -salt or preserved food diets, chronic bile salt exposure, and cigarette smoking have been implicated in the pathogenesis of gastric cancer. Chronic H. pylori infection in the susceptible host is central in this process, with the World Health Organization declaring H. pylori a class 1 carcinogen. Host factors that likely play a role in making a patient prone to cancer include p53 mutations, microsatellite instability, polymorphisms in the interleukin-If (IL-1~), IL-10, and tumor necrosis factor-a (TNF-a) genes, and alterations in the adenomatous polyposis pathways.171 The stomach's primary function is food storage. Consequently, it has the ability to significantly enlarge without necessarily being noticed by a patient. Because the sensation of a growing cancer is indistinguishable from that of food in the stomach, these tumors become very large before symptoms develop. Frequently, patients will present with anorexia, early satiety, weight loss, or other vague symptoms. Not uncommonly, patients with the most minimal symptoms will present with very large, metastatic tumors. A review of 18,365 gastric cancer patients by the American College of


TABLE 45.8. Presenting Symptoms for 18,365 Patients with Gastric Cancer Surveyed by the American College of Surgeons. Symptom

Weight loss Abdominal pain Nausea Anorexia Dysphagia Melena Early satiety Ulcer-type pain Lower-extremity edema

Frequency (%)

61.6 51.6 34.3 32.0

26.1 20.1 17.5 17.1 5.9

Source: From Wanebo et al. 168

Surgeons revealed that weight loss and abdominal pain were the most frequent presenting symptoms (Table 45.8).168 The tumors can grow to considerable size before any symptoms develop. For this reason, patients often present with advanced-stage disease. Overall survival for this disease is better in Japan, where it is common. Because of the high incidence, the Japanese have aggressive screening programs. The screening identifies small lesions that have a favorable prognosis following resection. Survival for various disease stages are roughly comparable between Japan and the West, such that the higher mortality in the West is accounted for by a higher proportion of advanced carcinomas. Gastric cancers often bleed or obstruct. For this reason, patients with a limited extent of metastatic disease are good operative candidates, and if the primary tumor can be resected with acceptable risk, palliative resection should be considered. Approximately one-half of gastric carcinomas present as an ulcerating lesion. The radiographic or gross appearance at endoscopy or laparotomy is indistinguishable from a benign gastric ulcer. For this reason, it is essential to biopsy all gastric ulcers to ensure that a malignancy is not missed. Another 250/0 of lesions present as large polyps. Superficial spreading carcinoma is an early lesion that is manifested by tumor confinement to the gastric mucosa and submucosa. These lesions have a favorable prognosis, but only 15 % of the tumors present this way. Linitis plastica is a condition in which the entire stomach is indurated secondary to a desmoplastic reaction to the cancer. Linitis has a poor prognosis and fortunately only occurs in about 100/0 of gastric carcinoma cases. The main tools for diagnosis and staging of gastric cancer are endoscopy for diagnosis and CT to access metastatic disease. Gastric remnant carcinoma is a clinical entity in which cancer develops in the remaining stomach following gastric resection. The risk appears greatest in patients more than 20 years following their initial gastric resection. In these patients, a threefold increase in the risk for gastric carcinoma was seen. The risk of gastric remnant carcinoma is fourfold higher following a Billroth II compared to a Billroth I reconstruction. 172 The cancers tend to occur at or just proximal the gastric anastomosis and tend to present as advanced lesions, with 2-year survivals of less than 100/0. 173 Chronic bacterial overgrowth from hypochlorhydria with increased nitrite production, chronic reflux of bile and pancreatic juice, and atrophy

861

secondary to loss of the gastric mucosal mitogen gastrin are thought to play a permissive role in the development of gastric remnant carcinoma. III SURGICAL RESECTION

Surgical resection is the only curative treatment for gastric adenocarcinoma. The main points of discussion regarding gastrectomy for cancer include issues pertaining to the extent of gastric resection, extent of regional lymphadenectomy, and implications of adjacent organ involvement and resection. Prior to operation, a thorough staging of the patient is indicated to identify patients who may benefit from surgery, whether curative or palliative in nature. According to the National Comprehensive Cancer Network (NCNN) guidelines, preoperative staging should consist of a physical exam, routine laboratory evaluation, abdominal and pelvic CT scan, chest x-ray, and endoscopy with biopsy (http://nccn.org). Gastric carcinoma invades adjacent organs, spreads via lymphatics, and can metastasize by hematogenous spread. Physical examination should consist of a search for signs of metastatic disease. Patients should be examined for Virchow's node in the left supraclavicular fossa, representing spread of the cancer via the thoracic duct, Sister Mary Joseph's node (periumbilical nodule suggestive of tumor of the peritoneal surface), and a Blumer's shelf (tumor mass in the cul-de-sac). Hematogenous spread of the cancer to the liver occurs in 300/0 of patients. Gastric cancer may also metastasize to the ovary, resulting in a Krukenberg tumor. These lesions are easily identified at surgery or by CT. Less frequently, metastases are found in the lungs or brain, causing associated pulmonary or neurologic symptoms. A systematic approach to metastatic disease should be performed. Identification of metastatic lesions preoperatively is important because a planned curative resection will be downgraded to a palliative one, only used in carefully selected patients who have limited metastatic disease, with a tumor that can be removed with partial gastrectomy, and who are good operative candidates. To facilitate staging prior to resection, diagnostic laparoscopy has been advocated by some authors and is included in the NCCN guidelines for staging prior to surgical resection. 174,175 Where metastatic disease is obvious based on preoperative staging or if the cancer is a very early stage lesion, laparoscopy is seldom beneficial.V''!" During surgery, the tumor should be assessed for resectability by ensuring that the cancer has not spread into the adjacent pancreas, colon, or liver. Peritoneal metastases and ascites are obvious and preclude any type of surgery. Positive cytology of peritoneal washings is associated with advanced T stage and poorer prognosis. 176 The extent of gastric resection is a function of the location and extent of stomach involvement with tumor. For curative intent, all gross and microscopic disease needs to be removed. Microscopic involvement of the resection margin is associated with anastomotic recurrence and poor survival.!" As discussed in the section on reconstruction techniques, patients with distal lesions should undergo distal or subtotal gastrectomy. For midbody or proximal lesions and distal lesions for which less than 5 cm of proximal margin can be obtained and for lesions diffusely distributed in the stomach, total gastrectomy is indicated. For lesions that involve the

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CHAPTER 45

TABLE 45.9. Location for the Major Nodal Groups Relevant to Gastric Resection for Cancer. Nodal group

Location

Nl N2

Perigastric along the greater and lesser curves Adjacent to the celiac axis and its major branches: the common hepatic, splenic and left gastric arteries Hepatoduodenalligament; retropancreatic region; celiac plexus; superior mesenteric artery Paraaortic area

N3 N4

caria of the stomach or encroach on the esophagogastric junction, an esophagogastrectomy may be needed. In the past, the extent of resection depended on the extent of the resection of the nodal groups relevant to gastric resection for cancer (Table 45.9). Gastric Rl resections included gastrectomy and resection of the Nl nodal basin and omentum. Gastric R2 resections included gastrectomy plus the N2 nodal basin, and R3 the N3 nodes, and so on. This designation is confusing. It is preferable to reserve the RO resection to mean all gross and microscopic disease removed, Rl all gross disease removed but residual microscopic disease, and R2 to indicate gross disease remaining. The term Dl implies resection of nodal tissue in the Nl distribution, D2 the N2 distribution, and so on. Similarly, the current staging system as adopted by the American Joint Commission reserves the N description to indicate the number of nodes present in the specimen rather than distinguishing nodes based on their anatomic location. The current TNM staging is seen in Table 45.10. Previously, it was thought that splenectomy was necessary to ensure adequate tumor clearance. Splenectomy results in substantially increased perioperative morbidity without any clear survival benefit and is not recommended.Fv'" Considerable controversy exists regarding the extent of lymph node dissection for gastric carcinoma. No consensus panels have been published; however, several well-designed and executed randomized controlled trials have been conducted. The Dutch Gastric Cancer Group in the Netherlands performed a randomized controlled trial of D 1 versus D2 lymph node dissection in 996 patients at 80 cancer centers. Because results for D2 resection are dependent on the surgeon's experience, the study was done in collaboration with Japanese surgeons familiar with the operation who supervised the conduct of operations early in the study. A limited number of trained Dutch surgeons traveled to the various centers to ensure that the D2 dissections were performed appropriately. Morbidity in the D2 group was substantially higher than for the Dl patients; the operative complication rate for D2 patients was 43% compared to 25% for Dl dissections. Operative mortality was 100/0 for D2 and 40/0 for Dl patients. One flaw in the study was that D2 patients routinely underwent splenectomy, an aspect of the operation that is now known to be unnecessary. Higher morbidity for D2 dissections had been reported from most Western centers. Western patients have more frequent comorbid conditions and larger amounts of intraabdominal fat than Japanese patients, which might account for the higher complication rate. Seven-year survival in the Dutch study failed to demonstrate improved survival in D2 patients.l'" Even when corrected for the higher perioperative mortality for D2 patients, long-term survival was not impacted by D2 resection.'!'

During the course of this study there was an unanticipated improvement in stage-specific survival. When the study was begun, the investigators predicted 5-year survival to be 20% for Dl and 32% for D2 patients. The observed survival was substantially higher, 45 % and 47%, respectively. This improvement results in part from improved staging but also from an unexpectedly high incidence of Tl (26%) and T2 (47%) cancers. The investigators also rejected a higher proportion of patients than previously because of distant metastases. TABLE 45.10. Definition of TMN, Stage Grouping, Histopathologic Type, and Histologic Grade for Gastric Carcinoma. Definition of TMN Primary Tumor (T)

TX TO Tis

Tl T2 T2a T2b T3 T4

Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ: intraepithelial tumor without invasion of the lamina propria Invasion of lamina propria or submucosa Tumor invades muscularis propria or subserosa * Tumor invades muscularis propria Tumor invades subserosa Tumor penetrates serosa (visceral peritoneum) without invasion of adjacent structures * *, * * * Tumor invades adjacent structures * *,* * *

* Note: A tumor may penetrate the muscularis propria with extension into the gastrocolic or gastrohepatic ligaments, or into the greater or lesser omentum, without perforation of the visceral peritoneum covering these structures. In this case, the tumor is classified T2. If there is perforation of the visceral peritoneum covering the gastric ligaments or the omentum, the tumor should be classified T3. * * Note: The adjacent structures of the stomach include the spleen, transverse colon, liver, diaphragm, pancreas, abdominal wall, adrenal gland, kidney, small intestine, and retroperitoneum. * * * Note: Intramural extension to the duodenum or esophagus is classified by the depth of the greatest invasion in any of these sites, including the stomach.

Regional Lymph Nodes (N)

NX NO NI

N2 N3

Regional lymph node(s) cannot be assessed No regional lymph node metastasis * Metastasis in 1 to 6 regional lymph nodes Metastases in 7 to 15 regional lymph nodes Metastases in more than 15 regional lymph nodes

* Note: A designation of pNO should be used if all examined lymph nodes are negative, regardless of the total number removed and examined.


MX

MO Ml Stage Grouping

Stage 0 Stage IA Stage IB Stage IT

Stage InA Stage IDB Stage IV

Distant metastasis cannot be assessed No distant metastasis Distant metastasis Tis Tl Tl T2ajb Tl T2a/b T3 T2a/b T3 T4 T3 T4 TI-3 AnyT

NO NO Nl NO N2 Nl NO N2 Nl NO N2 NI-3 N3 AnyN

MO MO MO MO MO MO MO MO MO MO MO MO MO Ml

Source: TNM classification used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AICC Cancer Staging Manual, Sixth Edition (2002) published by Springer Science and Business Media LLC, www.springerlink.com.

863

STOMACH AND DU ODENUM

.In

TABLE 45.11. Comparison of 5·Year Survival from the Dutch Study to American and Japanese Results.

Dutch Dl

Dutch D2

United States

Japan

Stage

N o. cases

Survival

No. cases

Survival

No. cases

Survival

No. cases

Survi val

I

173 (46) 105 (28) 86 (231 12(3) 380

70 38 12 0 45

133 (40) 66(201 I II (341 18 (5) 33 1

71 42 23 28 47

2,004 (171 1,796 (171 3,945 (36) 3,342 (31) 11,087

50 29 13 3 19

1453 (46) 377 (12) 693(22) 653 (21) 3176

91 72 44 9 62

II III

IV Total

Note: This table compares the incidence and stage-specifi c survival from the randomized-prospectiv e Dut ch trial l8 0 (level I evidence) . The Dutch trial had two arm s: DI and D2 dissection. A retro spective review of Am erican Cancer centers derived from Wan ebo et al. l . ' provides the US experience for gastric canc er. The Japan ese experience is from the retro spect ive review by Maru yama et al. ISS Data are presen ted as th e numbe r of patie nts; the percentages are in parent heses.

Table 45.11 compares the results from the Dutch study to reviews of large series of patients from the United States and Japan. Because gastric carcinoma is the most frequent cancer in Japan, aggressive screening programs are in place, which accounts for a larger proportion of early-stage disease. Also, there is a higher incidence of intestinal than diffuse histology cancers in Japan, with intestinal-type lesions having an inherently better prognosis. The Dutch study found significant stage migration for patients undergoing D2 resection; 30% of D2 resections were found to have nodal tissue previously unsuspected, resulting in reclassification to higher stages. 182 This shift accounts for the fewer stage II patients in the D2 group compared to the Dl group, whereas there were more stage III tumors in the D2 group . Thus, the American data include patients in lower TNM stage groups who would otherwise be included in a higher group had a D2 dissection been carried out . This difference accounts, in part, for the lower survival rate in the United States . The Medical Research Council in Britain performed a multicenter randomized controlled trial comparing D 1 and D2 resections. The extra morbidity was almost identical to that observed in the Dutch study, with a 46% complication rate for patients having a D2 resection compared to 28% for D 1 resections. As with the Dutch trial, pancreas resection or splenectomy accounted for the excess morbidity . 183 There was no survival benefit from D2 resection: 5-year survival for Dl patients was 35%, and it was 33 % for D2 patients. There was also no difference for disease-free survival.!" These studies were well designed and provide the strongest evidence thus far regarding the utility for D2 dissections. For Western patients, surgeons specifically trained to perform D2 dissections could not impact survival, in contrast to reports from Japan. However, there have not been any randomized controlled trials from Japan, and reports have been retrospective, observational studies. 18s , 186 In addition, the biology of Japanese gastric cancer appears to differ from that of the Western disease . Thus, for Western patients D2 resections are not necessary and would help only for improving disease staging. When performed, splenectomy or pancreatic resection should not accompany D2 dissection. RECONSTRUCTION TECHNIQUES

Several reconstructive options are available that attempt to minimize functional problems associated with gastric resec-

tion. Following gastric resection, early satiety and anorexia result in less caloric intake with subsequent weight loss. Malabsorption following gastric resection occurs in part because of rapid food transit time through the small bowel and less contact with digestive enzymes. Dyspepsia, reflux, and bloating might also contribute to diminished food ingestion. Many of these symptoms result from the loss of gastric reservoir function . The standard operation for gastric cancer has been total gastrectomy with Roux-en-Y esophagoiejunostomy for diffuse, cardia, fundus, and body lesions and subtotal gastrectomy with Billroth I or II reconstruction for antral lesions. Newer reconstructive techniques attempt to re-create the gastric reservoir function. Studies have been performed to determine if better functional results are obtained with subtotal gastrectomy without compromising survival. Numerous reconstructive operations have been described in the literature. Most reports provide technical details of the operations with simple outcomes such as short-term complication and mortality rates . At best, these describe the feasibility of performing a technique, providing little insight into the real benefit of the new operation. Because these operations have been designed to improve functional outcomes following gastric resection, their assessment requires quality-of-life analysis or other measurements of functional status. Only a few of the newer operations have been studied in this manner. Few studies compared the different reconstructions in a ran dom ized controlled fashion . Of those trials, each examined different types of operations or quantitated outcomes with unique measurement tools, precluding formal meta-analysis of these trials . Subtotal gastrectomy has the theoretical disadvantage of less tumor clearance with potentially greater recurrence rate . For proximal and gastric midbody lesions, subtotal gastrectomy is impractical because the tumor cannot be adequately cleared, and the remaining gastric remnant would be too small to be of any functional value . For distal gastric lesions, subtotal gastrectomy is preferred. Cure rates are equivalent to total gastrectomy, with better functional results.Y!" Table 45.12 summarizes results of randomized trials com paring various reconstructions following distal gastrectomy. Billroth II reconstruction has been thought to be associated with better function results than Billroth 1. A randomized trial comparing these two reconstructions following distal gastric resection for cancer found that the morbidity, perioperative mortality, and 5-year survival were equivalent. Most

864 .trJ

C HA PTE R 45

TABLE 45.12. Reconstructive Options Following Distal Gastrectomy (Level I Evidence).

Reconstruction type

Outcom e m easurement

Results

Reference

Bl (n = 30) vs. BII (n = 32)

M&M, 5-year survival, digestive comfort M&M, QOL

Same

Chareton 189

Mostly th e same, except slightly less diarrhea following subtotal gastrectomy Longer hospita l stay for RY secondary to Roux stasis, less inflammation in th e gastric pouch in the RY patients

Svedlund!"

RY to gastric remnant (n = 131vs. total gastrectomy with RYEJ' RY (n = 24) vs. Bl (n = 26)

M&M, QOL

Ishikawa'!'

BI, BII, Billroth I, II, respectively; Ry, Roux-en-Y, RYE), Roux-en-Y esophagojejunostomy, M&M, morbidit y and mortalit y. ' Not explicitly sta ted. Not e: This study had th ree arms . Thirteen patients underwent subtotal gastrecto my wit h Roux-en-Y esophagojejunosto my for distal lesions, and 20 un derwent jejunal pouch int erposition following total gastrecto my for proxima l gastr ic lesions. Th irty -one had a Roux-en-Y reconstru ction following total gast recto my, some for proximal and others for dista l lesions; the exact number of each was not specified.

notably, the functional results for these two reconstructions were the same, dispelling the notion that the Billroth II is superior. 189Distal gastrectomy with Roux-en-Y gastrojejunostomy reconstruction has been compared to total gastrectomy with Roux-en-Y reconstruction. Theoretically, leaving a gastric remnant improves eating because of retention of som e degree of gastric storage capacity. When th ese operations, which differed only by preservation of a gastric remnant, were compared, there was little functional difference. !" Patients who have undergone total gastrectomy frequently have difficulty maintaining their weight. As was discu ssed with reconstruction following distal gastrectomy, the loss of the gastric sto rage capacity is thought to reduce food ingestion. Several randomi zed trials have been performed inv estigating th e relative merits of various reconstructive options following tot al gastre ctomy (Table 45.13). Jejunal interposition has been proposed, in theory, to reduce transit time for food down the jejunum. This change should reduce dumping and other functional probl em s associated with Roux-en-Y esophagojejuno stomy reconstruction. When compared with quality-of-life and other functional assess m ent measurement tools, no differences between these two reconstructions could be Iound. '?? Creation of a jejunal pou ch also did not improve outcomes compared to standard Rou x-en-Y recon srruction.l" Two relatively sm all studies have found modest benefits with an interposed pouch compared to a standard jejunal pouch or a Roux-en-Y esophagoie-

_u

junostomy.191,192 Taken together, these studies suggest that sta ndard Roux-en -Y esophagojejunostomy provid es equivalent results to any other reservoir-forming pouch. Thus, the pouches are an unnecessary addition to th e reconstruction following total gastrectomy.!" CHEMORADIOTHERAPY

Historically, 75% of patients who present with gastric cancer have regional nodal involvement or metastatic disease at the time of diagnosis ."! Furthermore, following resection, recurrence rates are high , with 49% developing local recurrence, 17% developing peritoneal recurrence, 21% developing locoregional disease, and 17% showing hematogenous spread .' ?' While chemotherapy, radiotherapy, or chemoradiotherapy alone are not effective in the treatment of gastric cancer, the use of th ese modalities in combination with surgery shows promise. Combined adju vant chemoradiotherapy has been shown to decrea se local recurrenc e, distant relapse, and peritoneal carcinomatosis. In one multicenter, double-armed, prospe ctive randomized trial of adjuvant postoperative chemoradiotherapy comparing surgery alone versus surgery plus combined 5fluorouracil (5FUJ-based chemotherapy and 4500 cGy of radio therapy, median survival in th e treatment group was 36 months compared to 27 months in the surgery-alone group. The 3-year relapse-free survival was superior in th e treatment group as well, 48% versus 3 1%.195 More recently, periopera-

TABLE 45.13. Reconstructive Option s Following Total Gastrectomy (Level I Evidence).

Reconstruction type

Outcome mea surem ent

Results

Reference

Jejunal interposition (n = 53) vs. RYEJ (n = 531 Jejunal pouch with interposition (n = 10) vs. jejuna l pouch (n = 10) vs. RYEJ [n = 10) Jejuna l pouch (n = 20) vs. RYEJ (n = a

M&M, 3-year survival Nutritional measurements , food intake, gastri c emptying

No differences Higher weights and intake with pouch/interposition

Puchs "" Na kan e!"

M&M, QOL

No differences

Svedlund!"

n

M&M, morbidity and mor tality. ' Not explici tly sta ted. This study had thr ee arm s. Th irteen pati ent s underwent subtotal gastr ecto my with Roux-en-Y esophago jejunostomy, and 20 underwen t jejunal pouc h int erposition followin g total gastrec to my for proximal gastric lesions. Thirty-one had a Roux-en-Y reconstruction, some followin g total gastre cto my for proxim al lesions and others following subtotal gastr ectomy; th e exact number of each was not specified.


tive chemotherapy consistmg of a regimen of epirubicin, cisplatin, and infused fluorouracil both preoperatively and following surgery decreased tumor size and stage and significantly improved progression-free and overall survival.l'" This has led to interest in applying current chemotherapy or chemoradiotherapy to the neoadjuvant setting, as seen in the current NCCN treatment guidelines for gastric cancer (http://nccn.org/professionals/physician~ls/PDF /gastric.pdf) Randomized data in support of this recommendation are lacking.

Hereditary Basis for Gastric Cancer Gastric cancer has a hereditary basis in approximately 100/0 of patients, with a two- to threefold increased risk of cancer in first-degree relatives of patients with gastric cancer even after controlling for H. pylori status.197-199 Gastric cancers are also seen in familial cancer syndromes. In familial adenomatous polyposis (FAP) and Gardner's syndrome, gastric polyps are found in 300/0 to 1000/0 of patients'?' and are most commonly nonneoplastic fundic gland polyps.i'" Gastric adenomas occur in 5 0/0 of patients with FAP, usually developing in the distal stomach.P' Fundic gland polyps are more common in the upper stomach. While patients with FAP have a lifetime risk of colon cancer approaching 1000/0, the risk of developing gastric cancer is rare, approximately 0.5 0/0. 203 Patients with numerous gastric polyps should have representative biopsies performed. All adenomatous polyps should be excised endoscopically, which may require multiple sessions. In patients with FAP, upper GI endoscopy is recommended every 1-3 years beginning at age 20 or at the time of colectomy. Patients with hereditary nonpolyposis colorectal cancer (HNPCC) syndrome have an 11% chance of developing gastric cancer, usually the intestinal type. A possible link between Peutz- Jeghers syndrome and gastric cancer has been reported.204 The majority of familial clusters of gastric cancer are more often related to clustering of H. pylori infection in susceptible kindreds.f"

Gastrointestinal Stromal Tumors Gastrointestinal stromal tumors (GIST) are mesenchymal tumors arising from the pacemaker cells of the GI tract known as the interstitial cells of Cajal. Of the GISTs, 700/0 arise in the stomach and demonstrate a wide spectrum of clinical aggressiveness, from benign to highly aggressive. The central histologic factor that distinguishes these lesions from other stromal tumors of the stomach is the presence of the KIT receptor tyrosine kinase.P' More than 950/0 of GISTs express KIT, as manifest by positive immunohistochemical staining for the CD 117 antigen. Of GISTs,S % are CD 117 negative but occur by a mutational activation of the related kinase, platelet-derived growth factor receptor-c.?" The mainstay of treatment for gastric GISTs is surgical resection. As these lesions typically do not spread to regional lymphatics, aggressive lymphadenectomy is not necessary. Either local resection for small lesions or formal resection for larger lesions or lesions abutting important anatomic landmarks in the stomach to achieve a RO resection is needed. For unresectable lesions or to improve the potential for resection with less morbidity, neoadjuvant treatment with the tyrosine kinase inhibitor imatinib mesylate may be helpful. Neoadju-

865

vant imatinib mesylate improves the chance for surgical resection in lesions felt to be unresectable secondary to the remarkable 700/0-800/0 partial response GISTs show to this agent.i" The role of imatinib mesylate in neoadjuvant and adjuvant treatment following surgical resection is under investigation.

Gastric Carcinoids Gastric carcinoids arise from the neuroendocrine cells of the stomach. They account for fewer than 1% of gastric tumors and 2 % of GI carcinoids.?" Most of these lesions are well differentiated and maintain an appearance histologically similar to enterochromaffin cells, while others are poorly differentiated. Three types of gastric carcinoid tumors have been described."? Type I occurs in patients with chronic atrophic gastritis with achlorhydria-induced hypergastrinemia. Type II is associated with ZES. Type III is sporadic. Types I and II result from the mitogenic effects of elevated serum gastrin on the enterochromaffin cell population of the stomach. The lesions generally appear as small lesions, occasionally multiple, in the fundus and body of the stomach with antral sparing. They are generally benign and can be managed endoscopically if the lesions are less than 1 to 2 em in size or with observation. In the case of gastrinoma, resection of the primary tumor will result in involution of the gastric disease. In chronic atrophic gastritis with achlorhydria, some have advocated resection of the gastric antrum to eliminate the source of elevated gastrin with good results. Dominant lesions occasionally require localized surgical resection. Sporadic tumors tend to be solitary, are more likely to be truly invasive, and metastasize. Formal resection with lymph node dissection is indicated. The 5-year survival is less than 50%.211

Gastric Lymphoma The stomach is the most common site of GI lymphoma. The most common types of gastric lymphoma are marginal zone B cell lymphoma of the mucosa-associated lymphoid tissue (MALT) type and diffuse large B-cell lymphoma, accounting for 400/0 and 450/0-500/0 of gastric lymphomas, respectively. The MALT lymphomas are thought to arise from chronic H. pylori infection; these lymphomas regress in response to H. pylori treatment. For disease limited to the mucosa and submucosa, as is the case in 90% of patients, antibiotics alone are sufflcient.r" In the rare case of more advanced disease with extension into the muscularis or serosa, nodal or adjacent organ involvement, disease refractory to antibiotics, or systemic disease, chemotherapy with or without radiotherapy should be considered in addition to H. pylori eradication. Surgery is seldom necessary, usually requiring a total gastrectomy, but is successful about 80% of the time. Historically, diffuse large Bcell lymphomas have been treated with surgery out of concern for perforation or bleeding during chemoradiotherapy. As the risk of these untoward events happening is now thought to be insignificant, chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with rituximab and 40-50Gy of radiotherapy is thought to be standard management. Surgery is no longer the mainstay of the treatment of gastric lymphomas.i"

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CHAPTER 45

Benign Gastric Neoplasms Gastric Polyps Although gastric polypoid lesions are uncommon, they are detected more often due to the increasing use of endoscopy for the evaluation of abdominal symptoms. Most polyps are asymptomatic. However, polyps may cause bleeding or obstruction if the polyp is ulcerated or large. Gastric polyps are identified in 2%-3 % of all gastroscopic studies.i'" Once identified, it is necessary to biopsy or completely excise polyps by snare polypectomy for histologic assessment as well as perform careful examination of the entire gastric mucosa in search of a synchronous gastric carcinoma. Hyperplastic polyps are among the most commonly observed gastric polyps, accounting for up to 75% of all gastric polyps. Histologically, they are characterized by elongation, branching, or cystic dilation of the gland. They are usually solitary, sessile lesions less than 1.5 em in size. Hyperplastic polyps are believed to represent a regenerative response of normal mucosa to injury. The risk of developing dysplasia within a polyp is between 1.90/0 and 19%,215 while the risk of developing adenocarcinoma within a polyp has been reported as 00/0 to 80/0, with an average of 2.1 0/0. 214 A solitary hyperplastic gastric polyp has also been associated with synchronous or metachronous gastric carcinoma in 1.2% to 28 % of cases, while the risk of developing gastric carcinoma with multiple polyps is 3.60/0. 216 A high incidence of background mucosal disease has been demonstrated in patients with hyperplastic polyps.l" They are commonly associated with atrophic gastritis, with H. pylori gastritis occurring in 500/0 to 900/0 of cases."? The disappearance of hyperplastic polyps has been demonstrated following eradication of H. pylori, suggesting a possible treatment strategy of H. pylori eradication followed by resection of persistent polyps. Fundic gland polyps are nonneoplastic lesions and may account for up to 47% of all gastric polyps. They may occur sporadically or in polyposis syndromes. Histologically, they are characterized by dilated fundic glands forming small cysts. Endoscopically, they present as multiple, small, sessile lesions in the fundus and body surrounded by healthy gastric mucosa. While the cause of these lesions is unknown, they have been found in patients receiving long-term treatment with PPIs. Neither resection nor surveillance is required once the histologic diagnosis is confirmed.?" Finally, it has been suggested that while fundic gland polyps themselves carry no malignant potential, they signal an increased risk of a patient having a colorectal adenoma or carcinoma.i" Inflammatory polyps account for 3 % of gastric polyps and are most commonly located in the distal stomach. They have a characteristic whorl-like pattern of fibroblasts around vessels with infiltration of eosinophilic granulocytes. They do not undergo malignant change. Adenomatous polyps are precancerous lesions that account for approximately 10% of gastric polyps.!" These lesions are most commonly solitary, sessile, and located in the antrum. Adenomas usually appear in tubular or tubulovillous forms. Villous adenomas occur rarely in the stomach. The malignant potential of adenomatous polyps increases with larger polyps. Adenocarcinoma is detected in 24% to 600/0 of lesions greater than 2 em, while in lesions less than

2cm the risk is 4% to 23%.218 The risk of developing adenocarcinoma in a polyp is also related to the polyp type. There is an increased risk of discovering adenocarcinoma in tubulovillous and villous adenomas compared to tubular adenomas in the stomach.f" Coincident gastric carcinoma may occur in up to 250/0 of cases.i" Once discovered, adenomatous polyps should be excised. This can usually be performed with endoscopic snare polypectomy. However, if the lesion is not amenable to endoscopic excision, then numerous biopsies should be performed. If malignancy is detected, then the lesion should be excised with operative gastric wedge resection. Endoscopic surveillance should be performed 1 year after polypectomy and every 3 years after a negative endoscopic evaluation.?"

Leiomyoma Leiomyomas are the most common benign tumor of the stomach. They are generally a solitary, well-circumscribed lesion arising from the muscularis propria. While endoscopic biopsy is not always diagnostic due to the submucosallocation of these lesions, endoscopic ultrasound is useful for characterization.?" Leiomyomas are usually asymptomatic; however, when symptoms are present, bleeding is most common. Leiomyosarcomas may rarely develop in lesions greater than 2 to 3 em in diameter. The diagnosis is made when 10 mitotic figures are seen per high-power field. Because of the rare occurrence of malignancy, the treatment for leiomyomas involves local excision with a 2-3 cm margin of gastric wall accompanied by frozen section.

Lipoma Gastric lipomas are rare and usually asymptomatic. These submucosal lesions are most often solitary, with a yellowish color and located in the antrum.?" Gastric lipomas require no specific treatment.

Other Gastric Conditions Mallory-Weiss Syndrome Mallory-Weiss tears are linear mucosal lacerations occurring most commonly along the lesser curvature of the stomach at the gastroesophageal junction. However, a smaller percentage of these lacerations may be located on the greater curve near the gastroesophageal junction or extend into the esophageal mucosa. The classic triad of the syndrome is retching, vomiting, and hematemesis, although a history of retching is obtained in only 29% of patients.P' Mallory-Weiss syndrome is classically associated with alcoholics; however, more recently it has been described following coughing, childbirth, endoscopy, blunt abdominal trauma, and cardiopulmonary resuscitation. Bleeding from Mallory-Weiss tears accounts for 5%-100/0 of all cases of upper GI bleeding.2221223 Bleeding stops spontaneously in 800/0""':900/0 of patients, with less than a 5 % incidence of rebleeding.F" Initial management should be directed toward airway stabilization and fluid resuscitation. Endoscopy is essential for the diagnosis of Mallory-Weiss tears and has become the mainstay of treatment. Endoscopic therapy with


867

coagulation techniques, injection, and banding has been shown to effectively stop bleeding. If endoscopy is unavailable, then angiographic intervention with the intra-arterial infusion of vasopressin or embolization may be performed successfully, although they carry additional risks. Surgical intervention is rarely required but should be performed in patients with ongoing bleeding following initial nonsurgical management.

teinemia, complications such as marginal ulcer, persistent symptoms, and death from anastomotic dehiscence have been reported. Thus, total gastrectomy is the procedure of choice in patients who are able to tolerate the procedure. If the patient is unable to undergo surgical intervention, then close endoscopic surveillance must be performed.

Menetrier's Disease

Dieulafoys's lesion is a "caliber-persistent artery" in the submucosa with a small overlying mucosal defect typically located in the proximal stomach, usually in the distribution of the left gastric artery.r" Although most of these lesions are located in the stomach, they may also occur in the small intestine, colon, and rarely the esophagus.r" Dieulafoys's lesion accounts for 0.3 % to 6.7% of major upper GI bleeding, typically in the sixth to eighth decade of life. 231 Patients commonly present with intermittent GI bleeding, making endoscopic diagnosis challenging. When emergent endoscopy is required, Dieulafoy's lesion may be accurately diagnosed in only 490/0-63% of cases.F" An association between Dieulafoys's lesion and NSAID use, alcohol abuse, and peptic ulcer disease has been noted.i" The pathogenesis is thought to be the result of hydrostatic forces of the large vessel along with a focal gastritis, which causes a mucosal defect and subsequent rupture of the artery into the lumen. Historically, Dieulafoys's lesion was treated with gastric wedge resection. However, the consensus now seems to be that endoscopic management is the first-line therapy, wi th reported success rates ranging from 90 % to 100 % .234-236 Multiple endoscopic therapeutic interventions have been described, including injection sclerotherapy, thermocoagulation, laser therapy, endoscopic band ligation, and hemoclip application.r" Recurrent bleeding after endoscopic treatment occurs in 5.70/0 235 to 33%226 of patients. The lowest rates of rebleeding have been demonstrated when mechanical obliteration of the bleeding vessel using endoscopic banding and hemoclip application has been employed. Mortality rates following treatment of Dieulafoys's lesion have been reported as high as 260/0, largely due to comorbid conditions.F" If patients fail endoscopic management, then selective arterial embolization may be the treatment of choice, especially if the

Menetrier's disease, or hypoproteinemic hypertrophic gastropathy, is a rare premalignant condition of the stomach. It is characterized by thickened gastric folds, protein loss from the stomach, and hypochlorhydria. The gastric body and fundus along the greater curvature are commonly involved.?" A number of other conditions may cause enlarged gastric folds, such as gastric lymphoma, gastric carcinoma, cytomegalovirus (CMV) and H. pylori gastritis, and granulomatous disease. Menetrier's disease appears to be an acquired disease of unknown etiology. Although the exact cause is unknown, infection with CMV and H. pylori has been implicated. In addition, recent evidence suggests a role of transforming growth factor-a and the epidermal growth factor (EGF) receptor in the pathogenesis of the disease.f" The predominant histologic findings include foveolar hyperplasia and cystic dilation, along with a decreased parietal cell mass and varying degrees of inflammation.?" The varying degrees of lymphocytic infiltration reported throughout the literature is thought to be the result of confusion related to the diagnosis of Menetrier's disease versus hypertrophic lymphocytic gastritis. Symptoms include upper abdominal pain, weight loss, anorexia, nausea, vomiting, and diarrhea. Physical examination is usually unremarkable, with the exception of mild epigastric tenderness or signs of recent weight loss. Also, edema may be present if hypoproteinemia is severe. In addition to decreased serum albumin, there is a reduction in gastric acid secretion, which is thought to result from the decrease in parietal cell mass. Males are more frequently affected (3: 1) and usually are diagnosed between 30 and 50 years of age. Diagnosis is made by barium swallow, which

demonstrates enlarged gastric folds, and is confirmed by a full- thickness biopsy of the gastric wall. Menetrier's disease may be self-limited in children. In adults with Menetrier's disease, a primary concern is the development of cancer. A review of the literature demonstrated that 150/0 of the reported cases have been associated with carcinoma.F" The treatment of patients with Menetrier's disease has been largely anecdotal. Medical therapies have included antacids, anticholinergics, antifibrinolytics, corticosteroids, octreotide, monoclonal antibodies against EGF receptor, and H. pylori eradication. The entire syndrome has been reported to regress with eradication of H. pylori; therefore, if H. pylori is present, it should be treated. Surgery is reserved for intractable pain, symptoms related to hypoproteinemia, bleeding, obstruction, and cancer development. Relief of symptoms and normalization of serum protein almost always results from surgical treatrnent.F" Although subtotal gastrectomy removing only the affected tissue has been recommended for the treatment of hypopro-

Dieulafoy's Lesion

patients are poor surgical candidates. Surgical intervention is

generally reserved for patients who have failed both endoscopic and angiographic therapy.

Bezoars Bezoars are retained concretions of indigestible material that accumulate in the GI tract. They most commonly occur in the stomach but may also be found in the small bowel. Bezoars may be classified as phytobezoars, composed of food material that is nondigestable by humans; trichobezoars, composed of hair; medication bezoars (pharmacobezoars), composed of medications or medication vehicles; and lactobezoars, composed of congealed milk products of infant's formula. Phytobezoars are the most common type of bezoar. Patients at greatest risk for bezoar formation are those with altered gastric anatomy and physiology as a result of surgery. A history of previous gastric surgery is present in 70%-900/0 of patients with bezoars.r" Bezoar formation is

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more common following vagotomy and antrectomy, although any gastric surgery may predispose patients to their development. Phytobezoars have been reported in up to 200/0 of patients following antrectomy. The development of bezoars following gastric surgery is thought to be secondary to a reduction in gastric acidity, decreased gastric motility, and delayed gastric emptying. 238,239 Although gastroparesis is common in patients with bezoars who have no history of prior gastric surgery, others may demonstrate normal gastric emptying. Those with comorbid illnesses such as diabetes and end-stage renal disease requiring dialysis and mechanically ventilated patients are also at risk for bezoar formation. Patients present with vague epigastric distress 800/0 of the time, with as many as 30% experiencing weight loss. Additional complaints include bloating, nausea, vomiting, dysphagia, and early satiety. Patients may also present with complications of bezoars, such as intestinal obstruction, gastric ulcer, upper GI hemorrhage, gastric perforation, or gastritis.i" One study found gastric ulcers to be associated with large bezoars in 260/0 of patients.r" Moreover, patients found to have an intestinal bezoar as the cause of obstruction will have a concurrent gastric bezoar 200/0 of the time.r" Upper endoscopy is the diagnostic choice for identifying bezoars.r" An upper GI contrast study may reveal the classic finding of a filling defect with a "bubbly" appearance; however, these studies may be falsely negative up to 76% of the time.r"

Treatment of bezoars partially depends on the type of bezoar, with the ultimate goal removal and prevention of recurrence. If treatment is not administered, then mortality rates may be as high as 30% secondary to GI hemorrhage and perforation.r" Current treatment strategies include observation, medical treatment with enzymes and prokinetic agents, endoscopic dissolution and mechanical disruption, and surgical removal. Small gastric bezoars may be amenable to conservative treatment; however, spontaneous resolution is rare and may take up to 10 months. Mechanical disruption and removal by endoscopy is successful 850/0-90 % of the time.r"

A number of chemicals have been used to dissolve bezoars with varying success. Other than gastric lavage with saline, 0.1 NHCl, and NaHC03, other agents include papain, N-acetylcysteine, cellulase, and Adolph's meat tenderizer. The most efficacious of these has been cellulase, with successful dissolution achieved in 83%-1000/0 of the cases.i" Surgery is indicated when endoscopic management fails and for bezoar associated complications. Typically, operative intervention for bezoar extraction when endoscopic therapy has failed involves laparotomy with gastrostomy. However, there have been case reports using various laparoscopic techniques for removal of gastric bezoars.r" After successful dissolution or removal of a bezoar, prevention becomes an important issue because recurrence occurs in approximately 13% of cases.i" Preventing recurrence must be directed toward the underlying pathology. Recommendations for preventing phytobezoars are to avoid raw citrus fruits, persimmons, and high-fiber foods. In addition, enzymatic dissolution agents may be taken with each meal. If gastric stasis is a component of bezoar formation, then prokinetic agents may be effective. Patients who develop trichobezoar and who have underlying psychiatric disorders may require specific therapy to prevent recurrence.

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124. Jordan PH Jr. Surgery for peptic ulcer disease. Curr Probl Surg 1991;28:265-330. 125. Herrington JL Jr, Sawyers JL. Gastric ulcer. Curr Probl Surg 1987;24:759-865. 126. Robles R, Parrilla P, Lujan JA, et al. Long-term follow-up of bilateral truncal vagotomy and pyloroplasty for perforated duodenal ulcer. Br J Surg 1995;82:665. 127. Siu WT, Leong HT, Law BK, et al. Laparoscopic repair for perforated peptic ulcer: a randomized controlled trial. Ann Surg 2002;235:313-319. 128. Mondardini A, Barletti C, Rocca G, et al. Non-variceal upper gastrointestinal bleeding and Forrest's classification: diagnostic agreement between endoscopists from the same area. Endoscopy 1998;30:508-512. 129. Silverstein FE, Gilbert DA, Tedesco FJ, et al. The national ASGE survey on upper gastrointestinal bleeding. II. Clinical prognostic factors. Gastrointest Endosc 1981;27:80-93. 130. Allan R, Dykes P. A study of the factors influencing mortality rates from gastrointestinal haemorrhage. Q J Med 1976;45:533550. 131. Clason AE, Macleod DA, Elton RA. Clinical factors in the prediction of further haemorrhage or mortality in acute upper gastrointestinal haemorrhage. Br J Surg 1986;73:985-987. 132. Kankaria AG, Fleischer DE. The critical care management of nonvariceal upper gastrointestinal bleeding. Crit Care Clin 1995;11:347-368. 133. Van Dam J, Brugge WR. Endoscopy of the upper gastrointestinal tract. N Engl J Med 1999;341:1738-1748. 134. Savides TJ, Jensen DM. Therapeutic endoscopy for nonvariceal gastrointestinal bleeding. Gastroenterol Clin North Am 2000;29:465-487, vii. 135. Machicado GA, Jensen DM. Thermal probes alone or with epinephrine for the endoscopic haemostasis of ulcer haemorrhage. Baillieres Best Pract Res Clin Gastroenterol 2000;14:443458. 136. Calvet X, Vergara M, Brullet E, et al. Addition of a second endoscopic treatment following epinephrine injection improves outcome in high-risk bleeding ulcers. Gastroenterology 2004;126:441-450. 137. Sung H, Chan FK, Lau JY, et al. The effect of endoscopic therapy in patients receiving omeprazole for bleeding ulcers with nonbleeding visible vessels or adherent clots: a randomized comparison. Ann Intern Med 2003;139:237-243. 138. Gisbert JP, Khorrami S, Carballo F, et al. Meta-analysis: Helicobacter pylori eradication therapy versus antisecretory non-eradication therapy for the prevention of recurrent bleeding from peptic ulcer. Aliment Pharmacal Ther 2004;19:617-629. 139. Lau JY, Sung H, Lam YH, et al. Endoscopic retreatment compared with surgery in patients with recurrent bleeding after initial endoscopic control of bleeding ulcers. N Engl J Med 1999;340:751-756. 140. Shope TR, Kauffman GL Jr. Duodenal ulcer. In: Cameron JL, ed. Current Surgical Therapy. Philadelphia: Elsevier Mosby; 2004:71-76. 141. Millat B, Hay JM, Valleur P, et al. Emergency surgical treatment for bleeding duodenal ulcer: oversewing plus vagotomy versus gastric resection, a controlled randomized trial. French Associations for Surgical Research. World J Surg 1993;17:568-573; discussion 574. 142. Sirinek KR, Bingener J, Richards ML. Benign gastric ulcer and stress gastritis. In: Cameron JL, ed. Current Surgical Therapy. Philadelphia: Elsevier Mosby; 2004:67-70. 143. Weiland D, Dunn DH, Humphrey EW, Schwartz ML. Gastric outlet obstruction in peptic ulcer disease: an indication for surgery. Am J Surg 1982;143:90-93. 144. Choudhary AM, Roberts I, Nagar A, et al. Helicobacter pylorirelated gastric outlet obstruction: is there a role for medical treatment? J Clin GastroenteroI2001;32:272-273.

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145. Gisbert JP, Pajares JM. Review article: Helicobacter pylori infection and gastric outlet obstruction-prevalence of the infection and role of antimicrobial treatment. Aliment Pharmacol Ther 2002;16:1203-1208. 146. Shone DN, Nikoomanesh P, Smith-Meek MM, Bender JS.Malignancy is the most common cause of gastric outlet obstruction in the era of H 2 blockers. Am J Gastroenterol 1995;90:17691770. 147. Boylan IT, Gradzka MI. Long-term results of endoscopic balloon dilatation for gastric outlet obstruction. Dig Dis Sci 1999;44:18831886. 148. Gibson JB, Behrman SW, Fabian TC, Britt LG. Gastric outlet obstruction resulting from peptic ulcer disease requiring surgical intervention is infrequently associated with Helicobacter pylori infection. J Am ColI Surg 2000;191:32-37. 149. Kate V, Ananthakrishnan N, Badrinath S, et al. Helicobacter pylori infection in duodenal ulcer with gastric outlet obstruction. Trop GastroenteroI1998;19:75-77. 150. Taskin V, Gurer I, Ozyilkan E, et al. Effect of Helicobacter pylori eradication on peptic ulcer disease complicated with outlet obstruction. Helicobacter 2000;5:38-40. 151. de Boer WA, Driessen WM. Resolution of gastric outlet obstruction after eradication of Helicobacter pylori. J Clin Gastroenterol 1995;21:329-330. 152. Malik GM, Romshoo GHJ, Basu JA. Helicobacter pylori and gastric outlet obstruction. Am J Gastroenterol 1998;93: 2004. 153. Solt J, Bajor J, Szabo M, Horvath OP. Long-term results of balloon catheter dilation for benign gastric outlet stenosis. Endoscopy 2003;35:490-495. 154. DiSario JA, Fennerty MB, Tietze CC, et al. Endoscopic balloon dilation for ulcer-induced gastric outlet obstruction. Am J Gastroenterol 1994;89:868-871. 155. Zittel TT, Jehle EC, Becker HD. Surgical management of peptic ulcer disease today-indication, technique and outcome. Langenbecks Arch Surg 2000;385:84-96. 156. Csendes A, Maluenda F, Braghetto I, et al. Prospective randomized study comparing three surgical techniques for the treatment of gastric outlet obstruction secondary to duodenal ulcer. Am J Surg 1993;166:45-49. 157. Hom S, Sarr MG, Kelly KA, Hench V. Postoperative gastric atony after vagotomy for obstructing peptic ulcer. Am J Surg 1989;157:282-286. 158. McCallum RW, Polepalle SC, Schirmer B. Completion gastrectomy for refractory gastroparesis following surgery for peptic ulcer disease. Long-term follow-up with subjective and objective parameters. Dig Dis Sci 1991;36:1556-1561. 159. Wyman A, Stuart RC, Ng EK, et al. Laparoscopic truncal vagotomy and gastroenterostomy for pyloric stenosis. Am J Surg 1996;171:600-603. 160. Glasgow RE, Mulvihill SJ. Postgastrectomy syndromes. Probl Gen Surg 1997;14:132-152. 161. Cheadle WG, Baker PR, Cuschieri A. Pyloric reconstruction for severe vasomotor dumping after vagotomy and pyloroplasty. Ann Surg 1985;202:568-572. 162. Vogel SB,Hocking MP, Woodward ER. Clinical and radionuclide evaluation of Roux-en-Y diversion for postgastrectomy dumping. Am J Surg 1988;155:57-62. 163. Sawyers JL, Herrington JL Ir, Buckspan GS. Remedial operation for alkaline reflux gastritis and associated postgastrectomy syndromes. Arch Surg 1980;115:519-524. 164. Cuschieri A. Surgical management of severe intractable postvagotomy diarrhoea. Br J Surg 1986;73:981-984. 165. Zobolas B, Sakorafas GH, Kouroukli I, et al. Alkaline reflux gastritis: early and late results of surgery. World J Surg 2006;30:1043-1049. 166. Parkin DM. Epidemiology of cancer: global patterns and trends. Toxicol Lett 1998;102-103:227-234.

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187. Gouzi JL, Huguier M, Fagniez PL, et al. Total versus subtotal gastrectomy for adenocarcinoma of the gastric antrum. A French prospective controlled study. Ann Surg 1989;209:162166. 188. Svedlund J, Sullivan M, Liedman B, et al. Quality of life after gastrectomy for gastric carcinoma: controlled study of reconstructive procedures. World J Surg 1997;21:422-433. 189. Chareton B, Landen S, Manganas D, et al. Prospective randomized trial comparing Billroth I and Billroth II procedures for carcinoma of the gastric antrum. J Am Coll Surg 1996;183:190194. 190. Fuchs KH, Thiede A, Engemann R, et al. Reconstruction of the food passage after total gastrectomy: randomized trial. World J Surg 1995;19:698-705; discussion 705-706. 191. Iivonen MK, Mattila H, Nordback IH, Matikainen MJ. Long-term follow-up of patients with jejunal pouch reconstruction after total gastrectomy. A randomized prospective study. Scand J Gastroenterol 2000;35:679-685. 192. Nakane Y, Okumura S, Akehira K, et al. Jejunal pouch reconstruction after total gastrectomy for cancer. A randomized controlled trial. Ann Surg 1995;222:27-35. 193. Espat NJ, Karpeh M. Reconstruction following total gastrectomy: a review and summary of the randomized prospective clinical trials. Surg Onco11998; 7:65-69. 194. Roviello F, Marrelli D, de Manzoni G, et al. Prospective study of peritoneal recurrence after curative surgery for gastric cancer. Br J Surg 2003;90:1113-1119. 195. Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001;345:725-730. 196. Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006;355: 11-20. 197. Brenner H, Arndt V, Sturmer T, et al. Individual and joint contribution of family history and Helicobacter pylori infection to the risk of gastric carcinoma. Cancer 2000;88:274-279. 198. La Vecchia C, Negri E, Franceschi S, Gentile A. Family history and the risk of stomach and colorectal cancer. Cancer 1992;70:5055. 199. Palli D, Galli M, Caporaso NE, et al. Family history and risk of stomach cancer in Italy. Cancer Epidemiol Biomarkers Prev 1994;3:15-18. 200. Itzkowitz SH. Cancer prevention in patients with inflammatory bowel disease. Gastroenterol Clin North Am 2002;31:11331144. 201. Oberhuber G, Stangl PC, Vogelsang H, et al. Significant association of strictures and internal fistula formation in Crohn's disease. Virchows Arch 2000;437:293-297. 202. Offerhaus GJ, Giardiello FM, Krush AT, et al. The risk of upper gastrointestinal cancer in familial adenomatous polyposis. Gastroenterology 1992;102:1980-1982. 203. Burt RW. Gastric fundic gland polyps. Gastroenterology 2003;125:1462-1469. 204. Howe JR, Mitros FA, Summers RW. The risk of gastrointestinal carcinoma in familial juvenile polyposis. Ann Surg Oncol 1998;5:751-756. 205. El-Omar EM, Oien K, Murray LS, et al. Increased prevalence of precancerous changes in relatives of gastric cancer patients: critical role of H. pylori. Gastroenterology 2000;118:22-30. 206. Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 1998;279:577-580. 207. Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science 2003;299:708-71 O. 208. Scaife CL, Hunt KK, Patel SR, et al. Is there a role for surgery in patients with "unresectable" cKIT+ gastrointestinal stromal

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tumors treated with imatinib mesylate? Am J Surg 2003; 186:665669. 209. Gilligan CJ, Lawton GP, Tang LH, et al. Gastric carcinoid tumors: the biology and therapy of an enigmatic and con troversial lesion. Am J Gastroenterol 1995;90:338-352. 210. Rindi G, Bordi C, Rappel S, et al. Gastric carcinoids and neuroendocrine carcinomas: pathogenesis, pathology, and behavior. World J Surg 1996;20:168-172. 211. Hou W, Schubert ML. Treatment of gastric carcinoids. Curr Treat Options GastroenteroI2007;10:123-133. 212. Fischbach W, Goebeler-Kolve ME, Dragosics B, et al. Long term outcome of patients with gastric marginal zone B cell lymphoma of mucosa associated lymphoid tissue (MALT) following exclusive H elicobacter pylori eradication therapy: experience from a large prospective series. Gut 2004;53:34-37. 213. Collins RH. Gastrointestinal lymphomas. In: Feldman M, Friedman LS, Brandt LJ, eds. Sleisenger and Fordtran's Gastrointestinal and Liver Disease. Vol. 1. Philadelphia: Saunders; 2006: 565-587. 214. Oberhuber G, Stolte M. Gastric polyps: an update of their pathology and biological significance. Virchows Arch 2000;437:581590. 215. Abraham SC, Singh VK, Yardley JH, Wu TT. Hyperplastic polyps of the stomach: associations with .histologic patterns of gastritis and gastric atrophy. Am J Surg Pathol 2001;25:500507. 216. Stolte M. Clinical consequences of the endoscopic diagnosis of gastric polyps. Endoscopy 1995;27:32-37; discussion 59-60. 217. Debongnie JC. Gastric polyps. Acta Gastroenterol Belg 1999; 62:187-189. 218. Burke CA, van Stolk RU. Diagnosis and management of gastroduodenal polyps. Surg Oncol Clin N Am 1996;5:589-607. 219. Stolte M, Sticht T, Eidt S, et al. Frequency, location, and age and sex distribution of various types of gastric polyp. Endoscopy 1994;26:659-665. 220. Nakamura T, Nakano G. Histopathological classification and malignant change in gastric polyps. J Clin Pathol 1985;38:754764. 221. Graham DY, Schwartz JT. The spectrum of the Mallory-Weiss tear. Medicine (Baltimore) 1978;57:307-318. 222. Peura DA, Lanza FL, Gostout CJ, Foutch PG. The American College of Gastroenterology Bleeding Registry: preliminary findings. Am J GastroenteroI1997;92:924-928. 223. Wilcox CM, Clark WS. Causes and outcome of upper and lower gastrointestinal bleeding: the Grady Hospital experience. South Med J 1999;92:44-50. 224. Hixson SD, Burns RP, Britt LG. Mallory-Weiss syndrome: retrospective review of eight years' experience. South Med J 1979;72:1249-1251. 225. Scharschmidt BF. The natural history of hypertrophic gastrophy (Menetrier's disease). Report of a case with 16 year follow-up and review of 120 cases from the literature. Am J Med 1977;63:644652. 226. Burdick JS, Chung E, Tanner G, et al. Treatment of Menetrier's disease with a monoclonal antibody against the epidermal growth factor receptor. N Engl J Med 2000;343:1697-1701. 227. Komorowski RA, Caya JG. Hyperplastic gastropathy. Clinicopathologic correlation. Am J Surg PathoI1991;15:577-585. 228. Wolfsen HC, Carpenter HA, Talley NJ. Menetrier's disease: a form of hypertrophic gastropathy or gastritis? Gastroenterology 1993;104:1310-1319. 229. Mulvihill SJ. Neoplasms of the stomach. In: Bell RH, Rikkers LF, Mulholland MW, eds. Digestive Tract Surgery: A Text and Atlas. Philadelphia: Lippincott-Raven; 1996:255-279. 230. Miko TL, Thomazy VA. The caliber persistent artery of the stomach: a unifying approach to gastric aneurysm, Dieulafoy's lesion, and submucosal arterial malformation. Hum Pathol 1988;19:914-921.

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231. Norton ID, Petersen BT, Sorbi D, et al. Management and longterm prognosis of Dieulafoy lesion. Gastrointest Endosc 1999;50:762-767. 232. McGrath K, Mergener K, Branch S. Endoscopic band ligation of Dieulafoy's lesion: report of two cases and review of the literature. Am J GastroenterolI999;94:1087-1090. 233. Chandrashekar L, Brown RD, Venu RP. Management of Dieulafoy's lesion in the endoscopic era. J Clin Gastroenterol 2003;36:294-296. 234. Kasapidis P, Georgopoulos P, Delis V, et al. Endoscopic management and long-term follow-up of Dieulafoy's lesions in the upper GI tract. Gastrointest Endosc 2002;55:527-531. 235. Mumtaz R, Shaukat M, Ramirez FC. Outcomes of endoscopic treatment of gastroduodenal Dieulafoy's lesion with rubber band ligation and thermal/injection therapy. J Clin Gastroenterol 2003;36:310-314. 236. Yamaguchi Y, Yamato T, Katsumi N, et al. Short-term and longterm benefits of endoscopic hemoclip application for Dieulafoy's lesion in the upper GI tract. Gastrointest Endosc 2003;57:653656. 237. Pfau PR, Ginsberg G.G. Foreign Bodies and Bezoars. Vol. I, 7th ed. Philadelphia: Saunders; 2002. 238. Escamilla C, Robles-Campos R, Parrilla-Paricio P, et al. Intestinal obstruction and bezoars. J Am Coll Surg 1994;179:285-288. 239. Sanderson I, Ibberson 0, Fish EB. Gastric phytobezoar following gastrectomy. Can Med Assoc J 1971;104:1115 passim. 240. Andrus CH, Ponsky JL. Bezoars: classification, pathophysiology, and treatment. Am J Gastroenterol 1988;83:476-478. 241. Diettrich NA, Gau FC. Postgastrectomy phytobezoarsendoscopic diagnosis and treatment. Arch Surg 1985;120:432435.

242. Phillips MR, Zaheer S, Drugas GT. Gastric trichobezoar: case report and literature review. Mayo Clin Proc 1998;73:653-656. 243. Williams RS. The fascinating history of bezoars. Med J Aust 1986;145:613-614. 244. Yao CC, Wong HH, Chen CC, et al. Laparoscopic removal of large gastric phytobezoars. Surg Laparosc Endosc Percutan Tech 2000;10:243-245. 245. Hopman WP, Wolberink RG, Lamers CB, Van Tongeren JH. Treatment of the dumping syndrome with the somatostatin analogue SMS 201-995. Ann Surg 1988;207:155-159. 246. Tulassay Z, Tulassay T, Gupta R, Ciemy G. Long-acting analogue of somatostatin-SMS 201-995-is highly effective in the prevention of clinical symptoms related to the dumping syndrome. Ann Surg 1989;210:250-252. 247. Primrose IN. Octreotide in the treatment of the dumping syndrome. Digestion 1990;45(suppll):49-58; discussion 58-59. 248. Geer RJ, Richards WO, O'Dorisio TM, et al. Efficacy of octreotide acetate in treatment of severe postgastrectomy dumping syndrome. Ann Surg 1990;212:678-687. 249. Gray JL, Debas HT, Mulvihill SJ.Control of dumping symptoms by somatostatin analogue in patients after gastric surgery. Arch Surg 1991;126:1231-1235; discussion 1235-1236. 250. Hasler WL, Soudah HC, Owyang C. Mechanisms by which octreotide ameliorates symptoms in the dumping syndrome. J Pharmacol Exp Ther 1996;277:1359-1365. 251. Ishikawa M, Kitayama J, Kaizaki S, et al. Prospective randomized trial comparing Billroth I and Roux-en-Y procedures after distal gastrectomy for gastric carcinoma. World J Surg 2005;29:1415-1420; discussion 1421. 252. Debas HT. Stomach and duodenum. In: Gastrointestinal Surgery. New York: Springer; 2004.

Pancreas Robert E. Glasgow and Sean

Anatomy of the Pancreas Physiology of the Pancreas . . . . . . . . . . . . . . . . . . . . . . .. Acute Pancreatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chronic Pancreatitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pancreatic Pseudocysts

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Anatomy of the Pancreas Embryology The pancreas is derived as an outpouching of th e primitive foregut endoderm in the region of the duodenum. It has two main embryologic components: (1) a dorsal bud, first identifiable at 4 weeks gestation, that goes on to become the body and tail of the gland and (2) a ventral bud that produces th e head of the gland and the extrahepatic biliary system (Fig. 46.1). As these outpouchings grow, the ventral aspect rotates to fuse with the dorsal aspect by about the seventh week of gestation . The ductal system of the pancreas is derived from these two anlages . The embryonic ventral duct arises from the bile duct, drains with it into the duodenum at the major papilla, and fuses with the dorsal duct to drain the body of the gland as the main pancreatic duct of Wirsung . The embryonic dorsal duct persists as a separate structure in its proximal portion (duct of Santorini], draining into the duodenum at the minor papilla on the medial duodenal wall about 1-2cm cephalad to the major papilla. In 5%-10% of people, the ventral and dorsal ducts fail to fuse, resulting in a condition known as pancreas divisum ,' In this anatomical arrangement, the majority of pancreatic secretions are carried to the duodenum through the duct of Santorini and the minor papilla (Fig. 46.2). The cells of the endocrine pancreas were thought, for many years, to derive from the neural crest . Pearse developed his theory of the origins of the islets, and other endocrine tissues, based on the observation that they shared the capacity to take up precursor amines, process them by decarboxylation, and manufacture peptide hormones.P This APUD (amine precursor uptake decarboxylation) theory was challenged and then refuted with microdissection techniques and molecular evidence that the islets arise from the primitive gut endoderm,

J. Mulvihill

Pancreatic Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cystic Tumors of the Pancreas Other Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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not the neural crest . The expression of messenger RNA of islet hormones, including insulin, glucagon, and somatostatin, can be identified as early as 8-9 days after conception in the mouse, whereas exocrine enzymes such as carboxypeptidase and amylase are first found later." Development of the exocrine pancreas requires the presence of endodermal and mesenchymal tissue, whereas islet development requires only endoderm.' This mesenchymal-epithelial interaction in the developing exocrine pancreas presumably leads to formation of intrapancreatic ductular structures and blood vessels . The neurons innervating the pancreas are part of the enteric nervous system (ENS), best thought of as the third component of the autonomic nervous system. The ENS plays an important role in the regulation of secretion, motility, blood flow, and immune function in the gut . These neurons are derived, embryologically, from the neural crest. Neuroblasts from the vagal segment of the neural crest migrate in a craniocaudal direction down the gut during development, forming enteric ganglia in the pancreas and other organs. Migration of these neuroblasts is dependent on tyrosine kinase activity. Developmental abnormalities of the pancreas are rare but can occasionally come to attention clinically. The risk of development of acute pancreatitis was shown to be increased in patients with pancreas divisum in some studies but not others.1,6- 9 The cause is thought to be the drainage of a large volume of pancreatic juice through a small duct of Santorini, perhaps in association with a stenotic minor papilla. Congenital pancreatic cysts are uncommon and usually solitary. Multiple congenital cysts can occur in the setting of polycystic kidney disease, von Hippel-Lindau syndrome, or cystic fibrosis. Heterotopic pancreatic tissue, termed pancreatic rests , are usu ally found in the proximal gastrointestinal tract, where they can contribute to ulceration or abdominal pain. Annular pancreas occurs when the ventral pancreas encircles 875

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Dorsal pancreas

Gall

bladder Dorsal pancreas

Ventral pancreas A

B

Dorsal pancreas Accessary pancreatic papilla

c FIGURE 46.1. Embryologic development of the pancreas. The initial budding from the dorsal and ventral aspects of the foregut (A) is followed by clockwise rotation, beginning the C-Ioop of the duodenum and leading the dorsal bud to extend to the left and the ventral bud to extend to the right (B). By the seventh week of gestation, the ventral bud has continued to rotate around the foregut to fuse with the dorsal bud (C). The ductal system is beginning to develop at this

:_.~ : :- \1f~Common

duc t

A

Main pancreaticduct

Duodenal papilla

~uodenal papilla

'.

•

/

D

time. (D) At term , there is fusion of the parenchyma, with the ventral bud forming the head and uncinate process of the pancreas and the dorsal bud forming the body, tail, and a portion of the head of the gland. The ductal system similarly fuses. The main pancreatic duct has a short common channel with the bile duct because of their common origin.

29%

~\

Head of pancreas

37%

pancrea'i c

~ duet

w~, .~_."'_ \ "

papilla

FIGURE 46.2. Pancreatic ductal anatomy. The pancreatic ductal anatomy is complex as a result of the embryologic origins from the ventral and dorsal buds. In most patients, the duct of Wirsung (the main pancreatic duct], drains the uncinate process, most of the head

of the gland, and the body and tail (A). In a small fraction of patients, the ducts of the ventral and dorsal buds fail to fuse, leading to pancreas divisum (B). In this arrangement, the Wirsung's duct drains only the uncinate process and a portion of the head of the gland.

877

PANCREAS Splenic artery

.-..~~

Portal ve in

'~,

/,

-I :;-.

Inferior pancreaticoduodenal artery Superior mesenteric vein

FIGURE 46.3. Annular pancreas. Annular pancreas is a congenital anomaly characterized by circumferential pancreatic tissue around the duodenum, occasionally leading to obstruction. It is best treated with duodenojejunostomy.

the duodenum, usually just proximal to the ampulla of Vater (Fig. 46.3). Annular pancreas may be an incidental finding or it may cause obstruction. An anomalous junction of the bile and pancreatic ducts near the ampulla of Vater has been associated with the presence of choledochal cysts and the development of acute pancreatitis.

Anatomic Relationships The normal pancreas is about IScm in length, weighs approximately 120g, and is located in the retroperitoneum, covered by a thin peritoneum (Fig. 46.4). The head of the gland lies nestled in the Cvloop of the second part of the duodenum, and the tail of the gland extends obliquely into the hilum of the spleen . The superior mesenteric vein passes from the smallbowel mesentery toward the liver behind the neck of the pancreas , where it joins the splenic vein to become the portal vein. The inferior mesenteric vein similarly runs in a cephalad direction from the left colon mesentery behind the body of the pancreas near the ligament of Treitz to join the superior mesenteric and portal vein confluence. The splenic vein

FIGURE 46.5. Blood supply to the pancreas. Thepancreas has a rich blood supply from anterior and posterior pancreaticoduodenal arteries in the head of the gland and multiple small branches from the splenic artery in the bodyand tail.

Superior mesenteric artery

FIGURE 46.4. Anatomy of the pancreas. An anterior view of the

pancreas, showing the major relationships with the duodenum, spleen, splenic artery, superior mesenteric artery, and superiormesenteric vein.

courses posterior to the body of the pancreas, and the splenic artery runs from its celiac origin to the spleen along the cephalad aspect of the pancreatic body. The body of the pan creas lies anterior to the left kidney and adrenal gland. The head of the pancreas lies anterior to the inferior vena cava, which can be exposed with the Kocher maneuver. The neck of the pancreas overlies the spine, where it is susceptible to injury in blunt abdominal trauma.

Blood Supply, Lymphatic Drainage, and Innervation The pancreas has a redundant arterial blood supply, as shown in Figure 46.5. The head of the gland is supplied by paired (anterior and posterior) pancreaticoduodenal arteries, which course along the interface between the duodenum and the head of the pancreas. The celiac artery branches supply the right cephalic portion of the pancreatic head (dorsal anlag], the region around the intrapancreatic portion of the bile duct, and the first and second portions of the duodenum. The superior mesenteric artery branches supply the left caudal portion of the pancreatic head (ventral anlag) and the third and fourth

878

CHAPTER 46

tostatin, and others. In addition to efferent signals to the pancreas from the central nervous system, the pancreas has a rich network of afferent fibers, carrying sensory information centrally. These visceral afferent fibers largely pass via spinal nerves to the dorsal root ganglia, although the vagus nerves also contain afferent fibers. These sensory fibers are likely involved in pain perception in disorders such as chronic pancreatitis and pancreatic cancer.

Microscopic Anatomy

.'j!

~

\

.~

I'

i';} ~

FIGURE 46.6. Nodal drainage of the pancreas. The pancreas has a rich lymphatic system, draining to pancreaticoduodenal, splenic, and hepaticnodes. portions of the duodenum. The body of the gland is supplied by small branches from the splenic artery. The venous drainage of the pancreas is entirely into the portal vein. In the head and uncinate process of the pancreas, venous drainage is via small branches of the superior mesenteric and portal veins . Most of these branches enter the superior mesenteric and portal veins on their right lateral and posterior aspects. Usually, no veins drain from the neck of the gland to the anterior surface of the portal vein, making this plane of dissection safe during pancreaticoduodenectomy. The venous drainage from the body of the gland is into the splenic vein via small, unnamed branches. The pancreas is drained by an extensive network of lymphatic channels, which coalesce into lymph nodes . These nodal drainage basins have importance in the treatment of patients with pancreatic cancer, for which nodal metastasis is common. Major draining nodal basins from the pancreas are shown in Figure 46 .6. In the head of the gland, the initial drainage is to pancreaticoduodenal nodes, located near the groove between the pancreas and duodenum. Additional drainage is to nodes along the hepatoduodenal ligament, including those along the right lateral aspect of the portal vein and along the hepatic artery. Secondary drainage is seen to celiac and periaortic lymph nodes from the hepatic and gastroduodenal regions. From the uncinate process, drainage is toward the superior mesenteric arterial nodes and from there to the periaortic chain. From the body of the pancreas, drainage is mainly to nodes along the splenic artery and splenic hilum and from there to the celiac and periaortic nodes. The pancreas is innervated extrinsically by parasympathetic fibers from the vagus nerve and sympathetic fibers from the splanchnic nerves . Ganglia are found within the pancreas, where these extrinsic nerves terminate on cell bodies of neurons intrinsic to the pancreas. These intrinsic neurons are part of the ENS and have abundant connections to the central nervous system via the vagal and splanchnic nerves. In the pancreas , these enteric neurons innervate acini, islets, ducts, and blood vessels. They largely use peptides as neurotransmitters, including vasoactive intestinal polypeptide, calcitonin gene-related peptide, neuropeptide Y, soma-

The pancreas is a finely nodular gland comprised of exocrine tissue (80% of the total mass], ducts, vessels, nerves, and connective tissue (18% of the total mass) and endocrine tissue, the islets of Langerhans (2% of the total mass]. The exocrine portion of the gland is made up of pancreatic acinar cells, arranged in spherical masses termed acini, which in tum are grouped together as lobules . Pancreatic exocrine secretions are drained via small ductules originating in the acini, becoming progressively larger in the lobules and eventually emptying into the main pancreatic duct . The small ductules in the acini are lined by small, pale-staining centroacinar cells. The larger ducts are lined by columnar epithelium, with occasional goblet cells and argentaffin cells. The goblet cells secrete mucus. The argentaffin cells contain peptides important in the regulation of pancreatic secretion. The centroacinar and ductal epithelial cells contain the enzyme carbonic anhydrase and are responsible for the secretion of water and bicarbonate in pancreatic juice. Pancreatic acinar cells are large and pyramidal shaped. Their basolateral aspect is in contact with nerves, blood vessels, and a connective tissue stroma, and their apical aspect converges on the central lumen of the acinus (Fig. 46 .71 The apical aspect of acinar cells is packed with eosinophilic zymogen granules. These granules contain the enzymes manufactured by the extensive rough endoplasmic reticulum, found in the basolateral area of the cell, and packaged by the

Aci nar ce lls (enzyme)

/

Pancreatic duct

---- ------,

FIGURE 46.7. Microscopic anatomy of the pancreatic acinus. In the pancreatic acinus, the cellsarearrangedarounda centralductule. The apical region of the acinarcellscontainsthe machinery necessary for exocytosis ofsecretory granules. The basolateral surface of the acinar cell is exposed to a rich capillary bed. This region of the cell contains specific receptors for secretagogues such as cholecystokinin.

879

PANCREAS

Golgi complex, a clear area located between the cell nucleus and the cell apex. The microscopic anatomy of the acinar cell changes cyclically in response to feeding or cholecystokinin (CCK) stimulation. With stimulation, the zymogen granules in the apex of the cell are depleted as they empty enzymes into the ductule lumen. Numerous mitochondria are found in the cell cytoplasm, providing the energy required for enzyme manufacture and release. George Palade and his colleagues were awarded the Nobel Prize in 1984 for their work describing the intracellular pathway of manufacture and secretion of proteins in the pancreatic acinar cell (Fig. 46.8).10 The islets of Langerhans are small islands of endocrine cells within a sea of exocrine tissue (Fig. 46.9). The pancreas contains approximately 1 million islets, distributed throughout the gland . The islets contain four endocrine cell types: (1) B cells account for 50%-80% of the total islet volume and contain insulin; (21 PP cells account for 10%-35% of the islet volume and contain pancreatic polypeptide; (3) A cells account for 5%-20% of the islet volume and contain glucagon; and (4) D cells account for less than 5 % of the islet volume and contain somatostatin. Each cell produces only one peptide. Islets derived from the ventral embryonic bud tend to be rich in pancreatic polypeptide, whereas those from the dorsal bud tend to be rich in glucagon, for unknown reasons . During embryologic development, gastrin has been identified in the

Regulated exocytosis

55 years White blood cell count >16,000/mm3 Serum glucose >200mg/dL Serum LDH (lactate dehydrogenase) >350IU/L Serum AST (aspartate aminotransferase) >250U/dL

Drop in hematocrit >100/0 Fluid deficit >6000MI Serum calcium 5mg/dL Base deficit >4mEq/L

From Ranson et al.," by permission of Surgical Gynecology and Obstetrics.

I

---I

347

67

L-_

---1

30

6

Number of patients FIGURE 46.13. Mortality rate in acute pancreatitis related to Ranson's criteria. Ranson's criteria to estimate the severity of pancreatitis are useful clinically as they relate directly to the risk of patient death. (Data redrawn from Ranson et al.24,25)

the mortality rate increased substantially in the presence of greater numbers of criteria (Fig. 46.13). The Acute Physiology and Chronic Health Evaluation II (APACHE-II) Severity of Disease Classification System has also been used to predict outcome in acute pancreatitis.P'" This system has the advantage of repeated measurements over time. Scores less than 9 predict mild pancreatitis and high survival rates, whereas scores over 13 have a higher likelihood of mortality. The APACHE-II system is far more complex than Ranson's criteria, however, making it less commonly used. The recognition of the importance of necrosis in determining outcome was recognized with the development of CT staging systems to estimate severity of pancreatitis. 27,3 1,32 Today, helical, or spiral, CT using rapid bolus intravenous contrast, 5-mm slice reconstruction, and a breath-hold technique gives the best pancreatic resolution. Necrosis in more than 500/0 of the gland, the presence of extensive peripancreatic fluid collections, and the presence of gas within the pancreas or adjacent soft tissue are all markers predicting poor outcome." A typical scan depicting severe pancreatitis is shown in Figure 46.14.

Treatment of Pancreatitis MILD-TO-MODERATE ACUTE PANCREATITIS

Most patients with pancreatitis have a relatively mild, selflimited disease. The average patient with pancreatitis of mildto-moderate severity should be initially supported with intravenous hydration and pain medications. Specific adjunctive treatments, such as inhibition of pancreatic secretion and antiproteases, do not improve the clinical course of the average patient. 33-3 5 Nasogastric tube suction, when used routinely, appears to have no benefit" but should be considered for patients with significant vomiting. In patients with gallstone pancreatitis, a laparoscopic cholecystectomy should be performed at a convenient time before discharge." An intraoperative cholangiogram should be obtained during cholecys-

884

CHAP TER 4 6

FIGURE 46.14. Computed tomography in necrotizing pancreatitis. Spiral CT with bolus intravenous contrast and thin-cut reconstruction through the pancreas is an important clinical tool in estimat ing the severity of acute pancreatitis and identifying complications, such as pseudocyst, abscess, and infected necrosis. In this scan, extensive necrosis is present in the body of the gland. tectom y, and if common bile duct stones are found, a laparoscopic common bile duct exploration or postoperative endoscopic sphincterotomy with stone extraction should be performed. The outcome with this strategy is excellent, with common bile duct stones found in 7%-20 % of patients.38-4 2 For patients with mild, interstitial pancreatitis, early cholecystectomy has been shown to reduce recurrent episodes of pancreatitis and overall patient morbidity. Conversion rates for laparoscopic cholecystectomy performed during the initial hospitalization for mild acute pancreatitis are 0 %-15 %, with morbidity and mortality rates similar to laparoscopic cholecystectomy for uncomplicated biliary colic.38,4D-43 Following an initial attack of mild gallstone pancreatitis, 25 %-44 % of patients managed nonoperatively can expect to have recurrent pancreatitis or other gallstone-related complications within 6 months.rr'" Recurrent episodes of pancreatitis are likely to be more severe than the initial episode and associated with a higher rate of pancreatitis-associated morbidity and mortality." SEVERE ACUTE PANCR EATITIS

The patient with severe acute pancreatitis due to any cause is at risk for the development of complications for which surgical decision making plays a central role. Several recent advances have improved outcome in patients with severe ..If'l~_

pancreantis, including (I) improved intensive care unit management of pulmonary, renal, and cardiac failure; (2) use of contrast-enhanced CT to improve staging and detect complications such as pancreatic infection; (3) improved nutritional support begun early in the course of the disease; (4) development of interventional radiologic techniques to manage certain complications; and (5) the availability of endoscopic sphincterotomy to treat impacted stones and cholangitis. A small group of patients with severe acute pancreatitis may benefit from an early approach to clearing the com m on bile duct. This group is critically ill at presentation and fails to improve in the first 12-24h of treatment. If gallstones are confirmed rad iographically by transabdominal or endoscopic ultrasound or magnetic resonance cholangiopancreatography (MRCP), an ERCP with sphincterotomy and stone extraction within the first 48h decreases mortality" (Table 46.7). Laparoscopic cholecystectomy is dela yed until recovery from the pancreatitis. While preferably done during the same hospitalization, timing of surgery will depend on the patient's recovery and su fficien t resolution of the retroperitoneal inflammation to allow for adequate exposure and safe dissection of gallbladder. STERILE NECROSIS

Necrotizing pancreatitis can produce necrotic areas of pancreas and retroperitoneal tissue without becoming infected. The clinical course of some of these patients is relat ively benign, but in others the clinical course mimics that of patients with necrosis complicated by infection. If the patient is improving clinically, then conservative therapy is appropriate. If fever , leukocytosis, abdominal pain, ileus, or organ dysfunction are present, then CT-guided percutaneous aspiration of necrotic area s should be performed to rule out infection. If the Gram stain and culture of this material are sterile, bowel rest, total parenteral nutrition, analgesics, and intravenous antibiotics are appropriate treatment.t'v" Using this approach, Bradley and Allen," for example, found that of 38 patients with necrosis, infection supervened in 27, and 11 were sterile. These 11 patients with sterile necrosis were managed nonoperatively and recovered without mortality, even in the face of pulmonary failure requiring mechanical ventilation. Similarly, in a retrospective study from Uhl, of 172 patients with sterile necrosis, about onethird were managed nonoperatively with admirably low

TABLE 46.7. Randomized, Controlled Clinical Trials of Early Endoscopic Sphincterotomy in Gallstone Pancreatitis.

First author, reference, institution, year

Patien t groups

Mortality rate

Biliary sepsis rate

Conun en ts

Neoptolemos. i'" England,

Early ERCP/ES [n = 59) Selective ERCP (n = 62)

1.7% (P < .05 ) 8.0%

6 of 25 severe pancreatitis patients (P < .05 ) 17 of 28 severe pancreatitis

Fan/ OJ Hong Kong, 1993

Early ERCP/ES (n = 97) Selective ERCP(n = 98) Early ERCP/ES (n = 48) Selective ERCP(n = 52)

5% (P = .4, NS) 9%

0% (P = .00 1)

Benefit confined to patients with severe pancreatitis; LOS also shortened by routine ERCP/ES Benefit limited to patients with severe pancreatitis No benefit observed with early, routine, endoscopic sphincterotomy

1988

patients

Polsch, ' ?' European

multicenter trial, 1995

1% (NS) 2%

12% Cholangitis (odds ratio 3 .3) and sepsis (odds ratio 3.51 slightly more frequent in selective group (NS)

88 5

PAN CREAS

mortality (6.2% ), whereas the two-thirds of patients managed operatively had a mortality of 13.1 %.52 No randomized, controlled data exist to guide the clinician in this decision. In general, a worsening clinical course or failure to improve within 3 to 4 weeks are reasonable indications for debridement in the absence of infection. Persistent fever or stable organ system failure are not absolute indications for surgery, although a search for infection with fineneedle aspiration biopsy is warranted. NECROTIZING PANCREATITIS W ITH INFECTION

Infection can complicate severe acute pancreatitis as (1) infected pancreatic necrosis, (2)pancreatic abscess, (3)infected pseudocyst, and (4) acute suppurative cholangitis. These terms are defined in Table 46.3 . Infected pancreatic necrosis is a fulminant infection occurring within the first 2 weeks of the onset of necrotizing pancreatitis. The reported incidence is 35 %-40 % in large series of patients with acute pancreatitis .49,53 The usual pathogens are gram-negative rods from the gut, and in three-quarters of cases the infection is monomicrobial. The typical pathogens are shown in T able 46 .8.

TABLE 46.8. Microbiology of Infected Pancreatic Necrosis. Organism

Frequency

Escherichia coli Klebsiella Enteroba cter Streptococcus Staph yl ococcus aureus Proteus Pseudomonas Bacteroides Enterococcus Candida

40% 18% 18% 14% 10%

9% 8% 8% 8% 7%

Note: Numbers do not total 100% because of polymicrobial flora . Source: Data from references 49, 58, and 205.

Randomized, controlled clinical data suggest that early, empiric antibiotic treatment in patients with severe acute pancreatitis decreases infectious complications and mortality (Table 46 .9).54 Mortality rates in infected necrosis as high as 25 % have been reported in recent series. 49,55

~"r1". TABLE 46.9. Randomized, Controlled Clinical Trials of Prophylactic Antibiotic Therapy in Necrotizing Pancreatitis.

First author, reference,

Patient groups

Infectious complications

Mortality rate

Comment

Pede rzol i.f" 1993, Italian multicenter trial

Im epenem In = 41) Control (n = 33)

7.3% (NS) 12.1%

Sain io.i'" 1995, Helsinki University

Cefuroxime In =30) Control In = 30)

Pancreatic seps is in 12.2% IP < .01) Nonpancreatic sepsis in 14.6% IP < .0 1) Pancreatic sepsis in 30 .3% Nonpancreatic sepsis in 48.5% 1.0 infections per patient (P < .01) 30% with pancreatic infection (NS) 1.8 infections per patient 40% with pancreatic infection

Schwarz.?" 1997, Chirurgische Clinik I

Ofloxacin and metronidazole [n = 13) Contro l [n = 13 )

APACHE II scores (days 1,5, 10) 15.0, 13.0, 9.5 11.5, 15.0, 16.0

0% 15%

Nordback.i'" 2001, Johns Hopkins University

Im ipenem [n = 251 Control [n = 33)

8% 15%

Isenmann.i '" 2004 , German multicenter trial

Cipro floxaci n and m etron idazole [n = 58) Control (n = 561

8 % needed surgery 28% wit h comp lications 36% needed surgery 76% wit h complications 12 % 9%

Necrotizing pancreatitis on ly; imepenem has good penetration into pancreatic tissue; randomized, but no t placebo controlled ; significan t improvement in pancreatic and other infect ion rates Enrollment of pat ients with necrotizing pancreatitis only; penetration data of cefuroxime unclear; good activity against expected pathogens; randomized, but not dou ble blind or placebo contro lled; only st udy to show improved mortality with intravenous antibio tics, but no improvement in pancreatic infection rate Patients with acute necrotizing pancrea titis only; no difference in bacterial infection rates; significan t im provements in mortality and overall clinical course Red uction in infectious complicatio ns req uiri ng surgery, major organ complicatio ns, and mortality No difference in th e rate of systemic complications, infected necrosis, or mortality

Pancreatic infec tion in 18% (P = .03 ) Pancreatic infection in 38%

II of 50,22%

year, center

Trial s of intravenous antibiotics

Trials of selective gut decontamination

Luitcn," ! 1995, Ne therlands multicenter trial

Selective decontamination (n = 50) Control (n = 52)

3.3% IP = .03) 23.3 %

5% 7%

(P = .048) 18 of 52,35%

Enro llment cri teria: Imrie score >3, Balthazar grade D or E Ran domized, bu t not placebo controlled

886

CHAPTER 46

In contrast, pancreatic abscess is less common, with an incidence of 20/0, and generally does not develop until an average of 5 weeks following onset of pancreatitis.Yv" Although the spectrum of responsible organisms is similar to that seen in infected pancreatic necrosis, multimicrobial involvement is far more common. Pancreatic abscess has a somewhat less-fulminant course and lesser mortality rate than infected necrosis. Infection developing in preexisting pancreatic pseudocysts is a different problem and should be distinguished from infected necrosis or pancreatic abscess. These patients may develop a septic picture late in the course of pancreatitis. Infected pseudocysts generally are more indolent than infected necrosis or pancreatic abscess and commonly respond to external tube drainage and intravenous antibiotics. Finally, cholangitis may complicate the course of acute pancreatitis if common bile duct obstruction occurs. This usually occurs in the setting of gallstone pancreatitis and may be fulminant. Relief of biliary obstruction by endoscopic papillotomy and stone extraction is the preferred management. Patients with severe pancreatitis should undergo contrastenhanced CT (CE-CT) examination. If hypoperfused areas suggestive of necrosis are identified and the patient's clinical condition is suggestive of infection, then CT -guided fineneedle aspiration is performed for Gram stain and culture to detect infection. In a series of 92 aspirations on 60 patients, Gerzof et al. found CT -guided aspiration to be free of complications with no false-positive examinations and a 2.40/0 rate of false-negative examinations.58 If infected pancreatic necrosis is identified, then the appropriate management is broad-spectrum intravenous antibiotics and immediate operative debridement. Techniques for subsequent management include closed passive (Penrose) drainage, closed-suction drainage, open packing (marsupialization), and peritoneal lavage. Multiple operative procedures are often required to debride the ongoing necrosis. Nonoperative drainage techniques are generally insufficient to adequately evacuate this necrotic tissue. No randomized data exist comparing these various treatment strategies, but good results have been reported in retrospective reviews with each technique. 55,59,60 Peritoneal lavage is popular in some centers as an adjunctive therapy in patients with severe acute pancreatitis. The rationale for this treatment is the elimination of toxic substances that may collect within the peritoneal cavity during pancreatitis. It has been shown, for example, that proteolytic enzymes, complement, and various kinins are present in some patients." Although early small, uncontrolled trials demonstrated some reduction in morbidity in patients treated with peritoneal lavage,24,62 a larger, multicenter, randomized, controlled trial failed to show any benefit.f Despite the serious nature of necrotizing pancreatitis with infection, the long-term results can be good. In a series of 40 patients requiring operative debridement at Duke University, the operative mortality rate was 18%. In followup, quality-of-life assessment with the Short Form-36 tool revealed comparable outcome of surviving patients to agematched controls, patients with chronic pancreatitis treated medically, and patients with chronic pancreatitis managed surgically."

PANCREATITIS COMPLICATED BY BLEEDING

Bleeding associated with acute necrotizing pancreatitis is a serious problem, with mortality rates in excess of 50%.65 Bleeding may arise from extension of the necrotizing process into nearby major vessels, such as the gastroduodenal or splenic arteries, or from the gastrointestinal tract. The latter is usually secondary to severe stress gastritis or varices related to splenic vein thrombosis. Initial management of bleeding in this setting is by angiographic identification and embolization of the involved artery. Surgery is required if angiography is unsuccessful; however, these operations can be exceedingly difficult." Fortunately, the incidence of hemorrhagic complications in severe acute pancreatitis is decreasing. This is thought to be due to improved early recognition and volume resuscitation of severely afflicted patients. MANAGEMENT OF PANCREATITIS ASSOCIATED WITH PANCREAS DIVISUM

The incidence of pancreas divisum is about three- to fourfold higher in patients with recurring bouts of idiopathic pancreatitis than in unaffected controls. This has led to the suspicion that pancreatitis in these patients is due to a functional obstruction to pancreatic duct outflow at the minor papilla. Several small series of patients have suggested benefit from endoscopic minor papillotomy or pancreatic duct stent placement to reduce the incidence of recurrent pancreatitis. Patients who fail endoscopic therapy should be considered for surgical sphincteroplasty. In a large series of patients with pancreas divisum and acute pancreatitis or "pancreatic pain" syndromes, 88 underwent minor duct sphincteroplasty. At a mean follow-up of 53 months, 700/0 of patients were improved, with the best results achieved in patients with stenotic accessory papillae and episodic attacks of acute pancreatitis." This operation should probably be limited to patients with recurring bouts of abdominal pain associated with hyperamylasemia, ERCP evidence of pancreas divisum, and absence of evidence of gallstones or chronic pancreatitis/" Cholecystectomy is generally performed incidental to the sphincteroplasty. MANAGEMENT OF PATIENTS WITH PANCREATITIS AND

No

CLEAR CAUSE

Occasional patients present with acute pancreatitis and no clear underlying cause (see Table 46.4). This has been called idiopathic pancreatitis, but this term should be reserved for those patients in whom the cause remains obscure after a thorough evaluation. Typically, the patient will have no history of significant alcohol ingestion, and an ultrasound examination shows no gallstones. In this setting, the clinician should review the patient's medication history to ensure that no offending agents have been administered. Serum calcium and lipid levels should be measured. A history of immunosuppression posing risk for infections such as cytomegalovirus should be sought. An ERCP should be considered to exclude the possibility of an occult pancreatic duct stricture or early neoplasm. Bile can be aspirated to identify microlithiasis. The pancreatogram may reveal pancreas divisum. If these efforts are unrevealing, empiric laparoscopic cholecystectomy should be considered, especially if (1) the clinical course has been consistent with gallstone pancreatitis,

PANCREAS

(2) there is a family history of gallstones, or (3) the patient's liver function tests were transiently abnormal. Under these circumstances, it is likely that occult cholelithiasis is the cause of the patient's symptoms. A common mistake is to assume that a negative ultrasound examination excludes gallstones, when in fact the false-negative rate is around 1.50/0. 69 Laparoscopic cholecystectomy is empirically a more attractive initial therapeutic step in this group of patients, compared to the alternatives, such as biliary manometry and endoscopic sphincterotomy for possible biliary dyskinesia.

Chronic Pancreatitis Background Chronic pancreatitis affects about 8 new patients per 100,000 population per year in the United States, with a prevalence of 26.4 cases per 100,000 population. 70 Autopsy series, however, suggest a higher prevalence of 0.04 % to 50/0. Chronic pancreatitis is characterized pathologically by parenchymal fibrosis, ductal strictures, and atrophy of acinar and islet tissue. Three subgroups of chronic pancreatitis have been described: (1)chronic calcific pancreatitis, (2)chronic obstructive pancreatitis, and (3) chronic inflammatory pancreatitis. The most common pattern is chronic calcific pancreatitis, usually related to alcohol ingestion and characterized by fibrosis, calcification in small ducts, and intraductal protein plugging. Chronic obstructive pancreatitis is commonly observed in the setting of pancreatic cancer, for which ductal obstruction by the tumor leads to dilation, acinar atrophy, and fibrosis. The least-common type is chronic inflammatory pancreatitis, usually associated with autoimmune diseases such as Sjogren's syndrome and sclerosing cholangitis.

Etiology Most cases of chronic pancreatitis are due to excessive alcohol ingestion, in the range of 150gjday over many years." Only about 100/0 of heavy drinkers develop chronic pancreatitis, however, so it is likely that other cofactors are required, such as a diet rich in fat and protein. The underlying pathophysiology of alcohol-related chronic pancreatitis remains unclear but probably involves ductal plugging and calcification related to abnormalities in pancreatic juice, including diminished lithosthatine (pancreatic stone protein) or GP2 concentrations. 71J 2 In tropical countries, chronic pancreatitis occurs in young individuals in the absence of alcohol ingestion, perhaps from dietary factors or micronutrient deficiency. These patients typically have marked ductal dilation and stone formation, with relative sparing of the parenchyma. Several genes have been implicated in the pathogenesis of chronic pancreatitis.?" These patients tend to present early in adult life. Gallstone disease does not result in chronic pancreatitis. A better understanding of the causes of pain in chronic pancreatitis has been gained. In the past, increased intrapancreatic pressure was believed to be the main factor as ascertained from data obtained intraoperatively in patients undergoing ductal decompressive procedures." Increased size and number of pancreatic neurons now is thought to be

887

important, as are alterations in the type and amount of nociceptive neurotransmitters.P:" Increased nerve growth factor (NGF), its high-affinity receptor (TrkA), and immune cell infiltration appear to correlate with the degree of pancreatic fibrosis and intensity of pain in chronic pancreatitis."

Clinical Presentation There is no simple, accurate way to confirm the diagnosis of chronic pancreatitis. Clinical criteria for diagnosis include unrelenting epigastric abdominal pain that radiates through to the back, accompanied by nausea, poor appetite, and weight loss. The pain in chronic pancreatitis does not correlate well with the degree of anatomic abnormalities found radiographically. Occasional patients have a waxing-and-waning course. Typically, however, patients considered for surgical treatment have profound pain leading to narcotic dependence. Pancreatic exocrine insufficiency, resulting in steatorrhea, does not occur until about 900/0 of function is lost. Endocrine insufficiency, resulting in diabetes, does not occur until greater than 800/0 of the gland is destroyed. Because both insulin and glucagon secretion are lost with islet atrophy, the diabetes in chronic pancreatitis tends to be brittle and difficult to control. The physical examination in patients with chronic pancreatitis is often unrevealing. Weight loss and malnutrition may be evident. Occasional patients may have concomitant chronic liver disease evident on examination. Epigastric tenderness is common. In the presence of a pseudocyst, a palpable mass may be found. Chronic pancreatitis complicated by biliary obstruction may result in jaundice. Splenomegaly suggests the possibility of splenic vein thrombosis. Malnutrition' in advanced cases, may be evident by temporal muscle wasting; dry, flaky skin; and brittle hair.

Diagnostic Evaluation Routine laboratory investigation is not generally revealing in chronic pancreatitis. Serum amylase and lipase levels may be mildly elevated but are usually normal. Liver function tests are normal unless there is underlying liver disease or bile duct obstruction. Malnutrition may be revealed by decreased serum albumin levels. In patients with steatorrhea, fat malabsorption can be confirmed by Sudan staining of the stool or 72-h stool collection while the patient consumes a diet containing 100g of fat per day. Stool fat excretion of more than 7gjday is abnormal. Imaging studies are performed to provide an assessment of the extent of disease. A plain film of the abdomen may detect calcification in the gland. An abdominal CT scan is useful to identify pancreatic calcification, masses suspicious for carcinoma, dilated ducts, and pseudocysts. Reported sensitivity of CT in the diagnosis of chronic pancreatitis ranges from 750/0 to 900/0, with a specificity of 85% 100%.77 Pancreatic calcification is a hallmark of the diagnosis of chronic pancreatitis, but the degree of calcification does not correlate well with the degree of exocrine insufficiency. Magnetic resonance cholangiopancreatography or ERCP is necessary to determine the size and anatomy of the pancreatic duct, as well as unsuspected pathology such as biliary stricture and cancer. These studies allow patients to be cat-

888

CHAPTER 46

egorized into those with "small-duct" disease and those with "large ducts." This is important in that those with large ducts are far more amenable to surgical correction.

Treatment Surgery for chronic pancreatitis is indicated for disabling pain and obstruction of adjacent hollow viscera, commonly the bile duct or duodenum. For surgery to be effective, an identifiable anatomic lesion amenable to correction must be present. Options in surgical management broadly include drainage procedures, resective procedures, and nerve blocks . Successful treatment in terms of pain relief is improved in patients who cease alcohol and nicotine consumption." DISABLING PAIN

Pain is the usual reason for a patient with chronic pancreatitis to seek medical attention, and most treatment strategies are oriented around its relief. The severity of pain is a major factor in determining the advisability of surgery . In general, surgery is indicated if the pain interferes with the patient's ability to work, is refractory to pancreatic enzyme therapy, requires high doses of oral narcotics for control, and other possible causes for pain have been excluded. A number of factors must be considered in tailoring an operation to a specific patient, including, most importantly, the size and anatomy of the pancreatic duct, the distribution of pancreatitis in the gland, the presence of associated pseudocyst or biliary stricture, and the general condition of the patient. If the preoperative assessment has demonstrated a dilated pancreatic duct (>6mm diameter) with or without associated strictures, then a drainage procedure of the duct is indicated. Conversely, if the duct is small «6mm diameter), resectional surgery should be considered. Because of the relatively poor results in this latter group of patients and the morbidity of pancreatic resection, it should be considered only as a last resort.

"

......

-.

FIGURE 46.15. Longitudinal pancreaticojejunostomy [Puestow pro-

cedure] , A 45-cm long Roux-Y limb of jejunum is brought through the mesocolon for a side-to-side anastomosis with the dilated pancreatic duct . This technique is useful in patients with chronic pancreatitis, pain, and a dilated ductal system. Results are poorer in nondilated «6mm) ducts .

function." Results from recent published series with longterm (>5-year) follow-up are shown in Table 46.10. Recent enthusiasm has been expressed for endoscopic pancreatic ductal stent placement to relieve pain in chronic pancreatitis. Approximately 50% of patients have clinical improvement in pain with intermediate follow_up.8o.8l Endoscopic stent placement has also been used in concert with shock wave lithotripsy for stone extraction. Stent dysfunction, such as occlusion or migration, is common. Unfortunately, pain relief wanes over time, and other studies have suggested that pancreatic stent placement induces changes consistent with chronic pancreatitis.P'" To date, no randomized data exist to document a benefit of endoscopic stenting over standard therapy.

PANCREATIC DUCTAL DRAINAGE

In patients with disabling pain and ERCP evidence of a dilated pancreatic duct, pancreatic ductal drainage is the procedure of choice. The best operation is longitudinal pancreaticojejunostomy, also known as the modified Puestow procedure (Fig. 46.15). In this operation, the anterior surface of the pancreas is exposed, and the location of the duct is identified. When necessary, this is aided by intraoperative ultrasonography. The duct is opened longitudinally for most of its length. Stones and debris are removed as possible. An anastomosis is constructed between a Roux-Y limb of proximal jejunum and the pancreatic duct, usually in two layers. This operation has better results than the Duval procedure, or caudal pancreaticojejunostomy, in that the entire duct can be drained. Operative mortality rates for this operation are low, ranging from 0% to 4%. Relief of pain occurs in 80%-90% of patients when assessed within the first year, and in most series this is maintained at 5-year follow-up . Patients who cease consuming alcohol clearly do better than those who persist. Ductal drainage may prevent or delay further loss of exocrine or endocrine

RESECTIONAL SURGERY FOR CHRONIC PANCREATITIS

In a subset of patients with disabling pain and chronic pancreatitis, resection is appropriate. In general, resection is favored only in those patients with small ducts in whom all nonoperative measures have failed. Enthusiasm for resectional surgery is tempered by the significant complication rates and relatively poor long-term results. Options in resectional surgery include total pancreatectomy, distal (60%) resection, near-total (85%) distal resection, pancreaticoduodenectomy (Whipple resection), and duodenum-preserving pancreatic head resections (Begerand Frey procedures). Total pancreatectomy is rarely justified as the long-term mortality rates are high. Instead, partial pancreatectomy of the most severely affected portion of the gland is favored. Most commonly, this requires near -total distal pancreatectomy, pancreaticoduodenectomy, or duodenum-preserving pancreatic head resections. The last operations are gaining increased acceptance because of the high late failure rate of distal resection and the emerging view that the diseased head of the gland acts as a "pacemaker" of symptoms.

889

PAN CREAS

~!'I";"-

TABLE 46.10. Results of Longitudinal Pancreaticoj ejunostomy for Chronic Pancreatitis.

First author, reference center, year Class III data

Parting ton.i'! Clevela nd, 1960

Number of patients

Operative mortality rate

Pain relief

Comment

Partington and Rochelle modified the Puestow procedure by creating a longitudinal anastomosis between the pancreas and jejunum Diabetes in 3 of 10 preoperatively and 5 of 10 postoperatively Diabetes present preoperatively in 30% and developed postoperatively in another 14% Mean 8-year follow-up

7

0

Excellent in 4 of 7 patients

8 of 10 with substantial relief 80%

Warshaw." ! Massachusetts General Hospita l, 1980 Prinz.?" Chicago, 1981

10

0

100

4%

Holmberg.l" Sweden, 1985

51

0

Munn.?" Ch icago, 1987

61

2%

Bradley.?" Emory, 1987

46

0

Nealon, " ! Galveston, 1988

41

0

Creenlee.!" Chicago, 1990

50

2%

Adams .f " South Carolina, 1994

85

0

Rios,221 Charleston, 1998 Lucas,222 Detroit, 1999

17 124

0 2/124

Sohn.!" Baltimore, 2000 Nea lon.F' Galveston, 2001

52 124

1.9% 0

Good to excellent in 65% of drinkers and 88% of abst inent patients 84% of pati ents obta ined pain relief Good 28% Fair 38% Poor 34% Pain relief in 93 o/~ Complete in 42% Substantial in 40% "Good" in 24% "Fair" in 3 1% "Poor" in 45% Narcotic dependence in 35% Poor 76% Substantial in 39% Complete in 61% 86% off narcotics 91% without acut e exacerbati ons

Relief of pain occurs in about 60% of pati ents at 5-year follow-up after pancreatic resection. Diabetes and steato rrhea are common long-term complications of all of th ese operations. Results of resectional surgery for chronic pancreatitis are summarized in Tabl e 46.11. SPLANCHNICECTOMY, C ELIAC G ANGLIONECTOMY, AND

39% of patients had pseudocysts 8 late deaths at mean follow-up of 69 mont hs 87% of patients had postope rative weight gain 16% had progression of pancreatitis Follow-up 7.9 years Diabetes requiring insulin in 23% of patient s 42% continued to drink All with small-duct disease Diabetes in 13/ 124 preoperatively and 16/124 postoperatively Follow-up 81 months; no patients without surgery had resolution; 4% complication rate

morbidity.P'" In thi s procedure, after placem ent of thoracoscopic ports, the greater and lesser splanchnic nerves are sectioned as they course from the spine to the abdomen. The nerves in th e right and left chest can be dealt wi th sequentiall y with the patient in a prone position. As yet, no randomized data or long-term follow-up data are available to judge th e relati ve merits of this procedure.

PERCUTANEOUS CELIA C PLEXU S BL OCK

Nerve block or ablation procedures have had limited success in th e management of pati ents with chronic pancreatitis. Recent results in chronic pancreatitis appear poorer than in pancreati c cancer, with fewer than half of patients achieving a durable reduction in pain. 84,85 Percut aneous celiac nerve block with phenol or alcohol and endoscopic ultrasoundguided techniques may have a role in th e setti ng of a comprehensive pain management clinic. More recently, thoracoscopic splanchnicectomy has been reported to give reasonable pain relief with minimal operative

OBSTRUCTION O F ADJAC ENT H OLL O W VISCERA

Th e most common adjacent hollow viscus affected by chronic pancreatiti s is th e intrapancreatic portion of th e common bile duct, whi ch occurs in 5%-10% of pati ents. The usual cause is fibrosis of th e pancreati c parenchyma in the head of th e gland, although on occasion th e obstruction is due to pseudocyst. Pati ent s may have obst ructive jaundice or more subtle abnormalities ofliver functi on test s, such as elevated alkaline phosphatase. Examinations by ERCP or MRCP reveal th e

890

CHAPTER 46

TABLE 46.11. Results of Pancreatic Resection for Chronic Pancreatitis.

First author, reference, center, year Class I data

Buchler.F" Bern and Ulm, 1995 Izbicki,225 Hamburg, 1995 Izbicki.i" Hamburg, 1998

Strate.f" Hamburg, 2005

Class III data

Patient groups

Beger procedure (n= 20) PPPD (n = 20) Beger procedure (n= 20) Frey procedure In=22) Beger procedure (n =31) PPPD In = 30)

Beger procedure (n = 38) Frey procedure In=36)


Pain relief

Diabetes

Comment

0% 0%

75% pain free 40% pain free

0% 0%

95% improvement 94% improvement

Mean blood glucose 130mg/dL 88mg/dL Impaired GIT in 90% Impaired in 86%

3.2% 0%

94% improvement in pain score; global quality of life improved by 71% 95% improvement in pain score; global quality of life improved by 43% Pain score 11.25 11.25

Weight gain 4.1 ± 0.9kg 1.9 ± 1.2kg Quality of life improved significantly in both groups Median follow-up 24 months

Endocrine/exocrine insufficiency 56%/88% 60%/78%

9-year follow-up; no differences in late mortality, global quality of life, pain, endocrine or exocrine insufficiency

Diabetes in 100%

12 late deaths

Diabetes in 37% at 6 months

17 late deaths, 4 related to diabetes Median follow-up 3.6 years Late mortality 4.7% Weight gain in 80% of patients One late death

Late mortality 31% 32%

Braasch.i" Lahey Clinic, 1978 Rossi.?" Lahey Clinic, 1987

Total pancreatectomy (n= 26) Whipple procedure (n= 73)

0%

Beger/3o Ulm, 1989

Beger procedure (n = 128)

0.8%

Easter,231 Dundee, 1991

Pylorus-preserving total pancreatectomy (n= 8) Frey procedure In= 50)

0%

Good pain relief in 6 of 8

0%

Distal pancreatectomy, disease limited to body (n = 10) Distal pancreatectomy, disease present in head (n = 7) Pylorus-preserving Whipple procedure (n =45)

0%

Excellent in 74% Improved in 13% Unimproved in 13% 90% with excellent pain relief Unsatisfactory results in 6 of 7 patients

Frey,232 UC-Davis, 1994 Sawyer.r" UCDavis, 1994

Martin.r" Lahey Clinic, 1996

2.7%

2.2%

Improvement in 12 survivors Improved pain in 86% at 6 months Complete pain relief in 71%

Mean preoperative pain score = 9.2/10 Mean pain score at 5-year followup = 1.1/10

Worsening diabetes in 13.7%

Diabetes in 5/8 preoperatively and 8/8 postoperatively Progression of diabetes in 11%

5 late deaths Weight gain in 64% Best results in patients with small ducts «5mm) and disease limited to body and tail of gland

21 of 45 (46%) at 5 years

92% of patients had improvement in pain at 5-year follow-up

891

P A N CRE AS

TABLE 46.11. (cont inued) First author, reference, center, year

Patient groups


Pain relief

Diabetes

Rattner.r" Massachusetts General Hospi tal, 1996

Distal pan createctomy (n = 20)

5%

Traverso.P? Virginia Mason Clini c, 1997 Eddes.t" Leiden, 1997

Whipple procedure (n= 47) Total (n = 10) Beger procedure (n = 191

0% 0%

Beger.i" VIm, 1999

Beger procedure [n = 504)

0.8%

Complete pain relief in 79%

Ne w diabetes in 21%

Sohn,139 Balti more, 2000

263 operations (Whipple, distal, Puestow, othe r)

1.9% early 11% lat e

20% reduction in narcotic use

19% increase in diabetes, 21% increase in exocrine insuffic iency

0%

abnorma lity (Fig. 46 .16). Use of CT or magnetic reso na nce imagi ng (MRI) is helpful to exclude an underlying carcinoma. Endoscopic papillo tomy or ste n ting is seldom cura tive. Jaundiced pati en ts sho uld be trea te d wit h cho ledocho duo denostomy. T hou ght sho uld be given to the poss ibility of carcino ma , and bru shin gs and biopsies are obtai ne d as warranted. Occasionally, carcinoma is difficult to exclude, even at operation. In th e presence of a m ass, pan creaticodu odenectom y is usually the best course, even if biopsies do not confirm cancer. Rarely, patients with chronic pancrea ti tis can develop duo denal or tran sverse colonic obstruction . Occasion ally, resection of th e involved structure with th e pancreas will be in dica ted, but these problems are m ore eas ily trea ted with bypass.

55% pain free 15% using narcotics intermittently 30% using narcotics continuously Improved pain in 100%, 76% pain free Pain relief in 86%

Commen t

Median follow -up "ab out 2 years"

Diabetes in 32 %

93 % 5-year survi val

Insulin-dependent diabetes in 6 of 19

Oral glucose tol eran ce test unchanged preand postope ratively 9% readmission rate for pancreatitis Im proveme n ts in all aspects of quality of life

Pancreatic Pseudocysts Pseu docysts are am ong the most com mo n complications of acu te an d chronic pan creati ti s, occ urring in 2%-10% of pati en ts. In th e Un it ed Sta tes, pancreatiti s du e to alco ho l ingestion is th e m ost common cause . Other etiologic factors in clude biliary, posttraumati c, and ERCP-indu ced pancreati tis. Severe acu te pancreatiti s of any cause, however, can occasio na lly res u lt in development of a pse udocyst. In ch ild ren, for exa m ple, abdominal trauma is th e most com mo n etiology . The m an agement of patien ts with pseudocysts is challe nging, in term s of both surgical decision making and the technical aspects of th e opera tions . The natural history of pse udocysts has becom e better defin ed in rece nt years, and dramatic progress has been made in the developmen t of therapeutic metho ds, inclu ding percutan eou s, endoscopic , and laparoscop ic approaches.

T ermin ology

FIGURE 46.16. Endoscopic retrograde cholangiopancreatograph y IERCPI and magnetic reso nance cholangiopancreatogram (MRCP) in benign bile duct stricture from chronic pancreatitis. A. Magnetic resonance cholangio pancreatogram with coronal reconstructio n showing a stricture of the in trapancrea tic portion of th e com mon bile duc t without evidence of tu mor in a patient with chro nic pancreatitis. B. T he ERCP from the same patient show ing th e smoo th, tapered obstru ction, suggesting a benign strictur e.

Pan creatic pseudocysts are abnormal collec tio ns of flu id arising in the setting of acute or chronic pan creati ti s or trauma. T hey can be locat ed wi thi n the substance of the panc reas, adjacent to th e gland, or even so me distan ce away. An occasiona l pse u docyst will be found extending th rou gh th e pelvis into the groin or cepha lad into the m ediastin um. The pse udocysts contain fluid rich in pancreatic secretions from a duct system disrupted by infl ammation or trauma or obs tructe d by a stricture or stone. Pseudocysts differ fro m true cysts in that th ey lack an epithe lia l lining and have wa lls comprised of adjacent organs, fibrosis, and infla m matory granulation tissue. In the past, the spectrum of disease following pancreatitis has bee n difficult to understan d because of unclear te rmi no logy; words like phlegmon , fluid collection, and acut e or

892

CHAPTER 46

chronic pseudocysts have been used incorrectly or inappropriately. The Atlanta International Symposium in 1992 reached agreement on terminology, based on clinical patient management, and provided working definitions for an acute pancreatic fluid collection, acute pseudocyst, chronic pseudocyst, and pancreatic abscess." These definitions are summarized in Table 46.3.

Clinical Presentation The most common symptom associated with pseudocysts is abdominal pain, which is present in 80%-90% of patients. The pain can be associated with chronic pancreatitis or can persist or recur after a bout of acute pancreatitis. Nausea, vomiting, early satiety, and weight loss are also common. Physical examination may reveal abdominal tenderness, a palpable epigastric mass (found in about 50% of patients), fever, jaundice, and ascites. The presenting signs and symptoms can be related to the mass effect of the pseudocyst itself or be from a complication of the pseudocyst. Complications arising from pseudocysts include hemorrhage, rupture, infection, or obstruction. Decisions regarding the advisability of treating a pseudocyst must balance the possibility of spontaneous resolution with observation against the risk of development of one of these potentially life-threatening complications.

Natural History of Pseudocysts Until the 1950s, it was believed that pseudocysts seldom, if ever, resolved spontaneously, and that surgical intervention was warranted in all patients. Marsupialization and external drainage were the most common treatment methods, but the advantages of internal drainage were being recognized. By 1979, Bradley et a1. 89 had studied the natural history of 93 patients with symptomatic pseudocysts prospectively with serial ultrasound examinations. In patients with a presumed duration of pseudocyst of less than 6 weeks, the rates of spontaneous resolution and complications were 40% and 20%, respectively. In contrast, in patients with a presumed pseudocyst duration of 7 to 12 weeks, the resolution rate was less than 10%, and the complication rate rose to 46%. In patients with pseudocysts observed from 13 to 18 weeks, spontaneous resolution was not observed, and the complication rate rose to 75%. These data influenced surgical thinking, with the conclusion that operative management of pseudocyst should not be delayed past the 6-week mark. A weakness in the thinking regarding pseudocysts at this time was the failure to distinguish between those arising in the setting of acute versus chronic pancreatitis. In 1981, Crass and Way90 retrospectively analyzed 68 patients with pseudocysts and concluded that symptomatic patients could be separated into two groups, those with symptoms arising in the setting of acute or chronic pancreatitis. They showed that acute pseudocysts have a high rate of spontaneous resolution, warranting delay in treatment, while chronic pseudocysts have a mature wall at presentation, and delay in operation only increased the risk of complication since the rate of resolution in this group was thought to be negligible. They recommended that acute pseudocysts should be treated with elective internal drainage after 6 weeks of observation, while chronic

pseudocysts should be treated at the time of diagnosis. Their conclusions were supported by others." Factors predicting failure of spontaneous resolution included (1) persistence for longer than 6 weeks, (2) evidence of chronic pancreatitis, (3) pancreatic duct abnormalities, and (4) a thick cyst wall on ultrasound examination. More recently, two studies have suggested a greater frequency of spontaneous resolution of pseudocysts than previously suspected. Yeo et a1. 92 followed 75 patients with CT evidence of pseudocysts. They managed 48 % of the patients nonoperatively, while 52% required operative treatment because of persistent abdominal pain, enlargement, or complications. In contrast to earlier studies, only 1 of 36 patients managed expectantly developed a complication directly related to the pseudocyst, and 60% resolved without surgery. There were no deaths. Similarly, Vitas and Sarr" reported that, of 68 patients treated expectantly, 57% had spontaneous resolution, and only 9% suffered complications. Because of the low incidence of complications and high rates of resolution with expectant management, these studies suggest that asymptomatic patients with pancreatic pseudocysts can be safely managed nonoperatively and followed by outpatient serial CT examinations. Intervention can be reserved for symptomatic patients, those with enlarging pseudocysts, and those who develop complications.

Treatment of Pseudocysts Today, intervention for pseudocysts includes four main treatment options: percutaneous drainage, endoscopic drainage, laparotomy with internal drainage, or laparoscopic internal drainage. Occasionally, external drainage may be required via laparotomy. Resection is rarely indicated. These treatment options are discussed in tum. PERCUTANEOUS DRAINAGE

The advent of ultrasound and CT-guided catheterization via the Seldinger technique improved the safety and efficacy of percutaneous drainage. Now, percutaneous drainage is the preferred method of pseudocyst treatment in three specific circumstances: (1) treatment of critically ill patients who are not suitable candidates for surgery; (2) drainage of rapidly enlarging, immature peripancreatic fluid collections; and (3) drainage of infected pseudocysts. Percutaneous needle aspiration alone has an unacceptable failure rate of 70%-90%. Because of this, aspiration should be reserved for diagnostic purposes only. When the intent is therapeutic, a percutaneous 7- to 10-French pigtail catheter should be placed. Percutaneous catheter drainage is much more effective than aspiration alone, with some reports of successful treatment in 600/0-90% of patients.r'?" Not all groups, however, have had good results with percutaneous drainage. Criado et a1./ 8 for example, described only a 21% success rate at a mean 10-month follow-up, with 60% of patients eventually requiring a surgical procedure. Other studies have demonstrated higher mortality and morbidity rates in patients treated percutaneously compared to those undergoing operation. 99,100 In addition, those who fail percutaneous treatment tend to have complicated clinical courses, often requiring urgent surgical intervention with significant morbidity and mortality.Fr''"

PANCREAS

Long-term results are best in patients treated for acute fluid collections or acute pseudocysts rather than chronic pscudocysts.l'" Similarly, patients in whom a ductal communication with the pseudocyst or ductal stenosis is identified have poorer outcome. Marked clinical improvement is usually promptly evident following percutaneous drainage of infected pseudocysts. No randomized data yet exist comparing percutaneous versus surgical treatment. ENDOSCOPIC DRAINAGE

Endoscopic drainage procedures for pseudocysts include transpapillary and transenteric techniques. Endoscopic retrograde cholangiopancreatography allows delineation of the pancreatic ductal anatomy and identification of communication between the ductal system and the pseudocyst. When a communication is identified, transpapillary stenting can be used to drain the pseudocyst into the duodenum. The combined published experience with 117 patients undergoing transpapillary drainage revealed technical success in 840/0 with a 90/0 recurrence rate. 103 Complications include bleeding, pancreatitis, and infection as well as stent-induced duct stricture. In addition to transpapillary drainage, endoscopic transmural pseudocyst drainage techniques, including cystgastrostomy and cystduodenostomy, are feasible. Prerequisites for transmural drainage techniques include (1) cyst location in the pancreatic head or body; (2) a distance between the pseudocyst and the gastric or duodenal lumens of less than 1 ern, (3) a clear, bulging impression of the pseudocyst seen endoscopically from the gastric or duodenal lumen; and (4) firm adherence between the pseudocyst and enteric walls. Such criteria are met in about half of pseudocysts in the setting of chronic pancreatitis and in one-fourth of those with acute pancreatitis. 103,104 Data describing results of these techniques are limited. Success rates range from 71 % to 82 % in large series. 103- lOS Complications occur in one-third of patients, with a 100/0 incidence of major complications, including hemorrhage, perforation, and infection requiring additional surgical intervention. As in percutaneous treatment, patients who fail endoscopic treatment have a high likelihood of requiring urgent surgical invervention.'!" The main difficulty with these techniques is that the catheter diameter may be insufficient to completely drain the pseudocyst cavity, especially if the material is thick or contains necrotic debris. Once the cavity has been contaminated by a communication to the gastrointestinal tract, incomplete drainage can result in a difficult problem of infected, necrotic debris. For this reason, the endoscopic approach is best in patients with chronic pseudocysts, and it has poorer outcomes in patients with acute pseudocysts and in those with necrosis. 104 INTERNAL DRAINAGE VIA LAPAROTOMY

Internal surgical drainage via laparotomy is the established benchmark by which all other techniques must be compared. Experience with operative drainage has defined a number of principles that must be followed to maximize success, including (1) cyst wall biopsy should be performed to rule out cystic neoplasm in patients with atypical presentations; (2) all

893

necrotic material should be debrided from the cyst cavity; (3) the operative strategy must drain the entire pseudocyst cavity; and (4) any underlying ductal abnormalities must simultaneously be addressed. As new treatment options develop, the wise clinician will keep these principles in mind to avoid reproducing past errors. Several options for surgical treatment of pseudocyst are available, including external drainage, internal drainage, and resection. The decision regarding which option is best must be individualized based on the patient's condition, the chronicity of the pseudocyst, anatomy of the pseudocyst, and associated lesions such as ductal strictures or pseudoaneurysms. The use of ERCP, CT, and angiography is helpful for preoperative planning, but ultimately the decision is made intraoperatively. Internal drainage, including cystgastrostomy, Roux-en-Y cyst jejunostomy, and cystduodenostomy, is the preferred surgical option, with recurrence and mortality rates less than 100/0. 97,106- 108 Of the internal drainage options, cystgastrostomy is preferable if the pseudocyst is in the lesser sac, is firmly adherent to the posterior stomach, and is small enough to allow for adequate dependent drainage. The cyst is approached from the lumen of the stomach, and the anastomosis between the cyst wall and stomach is sutured to provide hemostasis and prevent leakage. The Roux-en-Y cyst jejunostomy is the most versatile internal drainage technique. A Roux limb can be anastomosed side to side to the most dependent part of a pseudocyst arising in nearly any location. It can also be used to drain multiple cysts and to create a lateral pancreaticojejunostomy to the duct, if indicated. Cystduodenostomy should be rarely used as an internal drainage method and only when no other technique is feasible. Care must be taken to avoid injury to the ampulla of Vater, bile and pancreatic ducts, and the gastroduodenal artery. Duodenal stenosis is sometimes problematic. A transduodenal approach is superior to laterolateral cystduodenostomy. External drainage is indicated for immature cysts with walls that will not hold sutures, grossly infected cysts, and emergency situations, including hemorrhage and rupture. This procedure has high mortality and recurrence rates, most likely reflecting the high severity of illness in these patients. Resection should be considered only in the rare situation of a small, chronic pseudocyst in the tail of the gland. Resection can be technically difficult due to the associated inflammatory reaction around the pseudocyst. The mortality and morbidity rates for resection are higher than for internal drainage. 109 LAPAROSCOPIC INTERNAL DRAINAGE

The development of minimally invasive techniques in surgery has been extended to the treatment of pancreatic disorders, including enucleation and formal resection of tumors, debridement of necrotic tissue in acute pancreatitis, and internal drainage of pseudocysts. The available data exist only as case reports and small case series. 110,11 1 These limited data do not yet allow comparison of the minimally invasive approaches to percutaneous, endoscopic, or open surgical techniques.

894

CHAPTER 4 6

FIGURE 46.17. Laparoscopic transgastric cystgastrostomy. The preferred method of internal drainage of large pseudocysts occupying the lesser sac is laparoscopic transga stric cystgastrostomy. In this technique, a pneumoperitoneum is created to assess the relationship of the pseudocyst to the stomach. The stomach is then insufflated, and two or three trocars are passed through the abdominal wall into the gastric lumen. The pneumoperitoneum is then released. An incision is made through the posterior wall of th e stomach into the pseudocyst cavity over a length of 5--6cm. The pseudocyst cavity is evacuated and debrided. To conclude the procedure, the pneumoperitoneum is reestablished, and the trocar sites on the gastric wall are sutured closed.

The most appealing of the minimally invasive approaches to pseudocysts is laparoscopic cystgastrostomy (Fig. 46.17). This can be done via an anterior gastrotomy, similar to its open counterpart; however, an intraluminal approach using the gastric lumen as the field of view has several advantages. In this procedure, a preliminary laparoscopy is performed, followed by transgastric intraluminal endoscopy. A direct incision is then made into the pseudocyst cavity, from the gastric lumen. After debridement of the pseudocyst cavity, the ports are backed out of the gastric lumen, a pneumoperitoneum is reestablished, and the gastric port sites are closed. Roux-Y cystjejunostomy is also amenable to a laparo scopic approach using a stapled anastomosis between the jejunal limb and the pseudocyst cavity. Intraoperative ultrasonography is helpful to define the extent of the pseudocyst and plan the orientation of the anastomosis. A jejuno jejunostomy is performed 45 em downstream of the cyst jejunostomy, either at skin level in a laparoscopic-assisted approach or completely laparoscopically via a double-stapled technique.

Pancreatic Cancer Background In 2002, the incidence of carcinoma of the pancreas was 12.7/100,000 men and 9.9/100,000 women, making pancreatic cancer the II th and 8th most common causes of cancer, respectivelv.l" Each year in the United States 30,000 people will die from pancreas cancer, and 40,000 will die in Europe.l'
897

PANCREAS

Whipple resection, and late deaths related to complications of brittle diabetes are problematic. In one recent representative review of over 1900 patients from the state of California, total pancreatectomy had a significantly high er operative mortality of 16% compared with 9 % for Whipple resection.!" In the Hopkins series, median survival in 201 patients was 16 months following Wh ipple resection, but on ly 10 mo nths following total pancreatectomy.r" Portner!" advocated regio na l pancreatectomy for carcinoma of the pancreas, including en bloc total or subtotal pancreatectom y with radical lymph node dissection and portal vei n resection. Operative m or tal ity in these patients averaged 8%, with a median survival of 40 mo nths. A recent single-institution randomized, controlled tr ial from Johns Hopkins comparing standard versus radical pancreaticoduodenectomy with extended lymph node dissection showed increased early m orbidity with extended lymphadenectomy but no differences in lon g-t erm quality of life or survival. l48,149 Major vascular resection as a part of pancreaticoduodenctomy has been accomplished at the M .D . Anderson Cancer Center in Hou ston, with an acceptable operative mortality rate of 1.6% and survival rates similar to standard resection.lso,lsl

A

ADJUVANT RADIATIO N A ND CHEMOTHERAPY '\

~

"\." '---': -

B FIGURE 46.20 . Pancreaticoduodenectomy. A. Localized tumors of the head of the pancreas, proximal duodenum, and distal bile duc t are treated with pancreaticoduodenectomy. The classic operation includes an en bloc distal gastrectom y, duodenectomy, cholecystectomy, bile duct excision, and pancreatic head resection. Sma ller tumors not involving the region of the first part of the duodenum can be treated with a pylorus-preserving resection, in which the antrum and pylorus are spared. B. Reconstruction following resection typi cally includes pancreaticojejunostomy, cho ledochojejunostomy, and duodenojejunostomy.

Approximately one-half of patients who undergo resection for pancreatic cancer will have regional rec urrences without distant metastases, with the remainder developing metastatic disease with or without regio na l rec urrence. Adjuvant therapy, therefore, must address the potential for bo th locoregion al recurrence and metastatic disease. The effect of adjuvant therapy on cure rates in pancreatic cancer is controversial.Pv!" Da ta addressing its role are su mmarize d in Table 46.14. A recent m eta-an alysis of these studies demonstrated an overall im provemen t in 2- and 5-year survival for resected pancreatic cancer patients who received chemotherapy compared to resected patients who did not (38% and 19% for

-~. . . . TABLE 46.13. Randomized, Controlled Clinical Trials Comparing Pylo rus -Preserving Panc reaticoduo denectomy (PPPD) Versus Standard Whipple Procedure for Pancreatic Cancer.

First authorr" center, year

Patient groups


Lin,239 Taiwan, 1999

PPPD (n = 16) Whipple (n = IS)

1/ 16 (6%) 0/15 (0%)'

Tran,24o The Netherlands, 2004

PPPD (n = 87) Whipple [n = 83)

3/87 (3.4%) 6/83 (7.2% )'

22% 23%

Disease free/overall 6/ 12 months 7/ 11 months

Seiler,"! Berne, 2005

PPPD [n = 641 Whipple (n = 66)

2% 3%

3 1% 45 %'

19.2 m onths 18.2 m onths

' N ot signi ficant .

Delayed gastric emp tying

6/ 16 (38%) 1/15 (7%)

Survi val

Comment

Not recorded

No differenc es in operative m ort ality, m orbidity, OR tim e, blood loss; PPPD had hi gher delayed gastric em ptying No differenc e in operative m orbid ity, mortality, LOS, body weig ht; no difference in m argin status, no dal harvest, disease-free and overa ll survival for periampullary cancer; no differenc es in the pancreatic cancer subset No differe nces in perioperative m orbidi ty an d mo rtality; earlier return to no rmal work capacity in th e PPPD, but no long -term differen ces in quali ty of life or survival

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CHAPTER 46

Aa~_ TABLE 46.14.

Randomized, Controlled Trials of Adjuvant Therapy Following Potentially Curative Pancreaticoduodenectomy for Pancreatic Adenocarcinoma. First author, reference, year, center

Patient groups

Median survival

Comments

Kalser,!42Multicenter, 1985

Surgery + XRT + chemotherapy (5FU) (n = 21) Surgery alone In = 22) Surgery + chemotherapy (doxorubicin, mitomycin, 5FU) (n = 30) Surgery alone (n = 31) Surgery + intra-arterial immunochemotherapy (n =40) Surgery alone (n = 40) Surgery + XRT + chemotherapy (5FU) In = 60) Surgery alone (n = 54)

21 months 10.9 months

Prospective, randomized, multiinstitutional trial

23 months (P = .02) 11 months

5-year survival did not differ (4% v 8%), suggesting chemotherapy delayed recurrence but did not improve survival Marked improvement in survival in patients with nodal disease

Bakkevold,"" Scandinavian, 1993

Lvgidakis.r" Athens, 1996

Klinkenbiiil,"" The Netherlands, 1999

Takada.r" Tokyo, 2002 Neoptolemos.i' P " Liverpool, 2001, 2004

Surgery + chemotherapy (mitomycin, 5FU) [n = 81) Surgery alone (n = 77) Surgery + chemotherapy (5FU) Surgery alone Surgery + XRT + chemotherapy (5FU) Surgery alone

30 months 16.8 months 17 months 13 months 5-yr survival 11.5% 18 % 5-year survival 21% 8% 10% 20%

No difference in overall median survival; 2-year survival 26% in the observation group versus 34% in the treatment group INS) No difference in overall or disease -free survival Median survival in patients who received chemotherapy was 19.7 months compared to 14 months; the addit ion of radiotherapy to chemotherapy did not improve survival

treated patients vs. 28 % and 12% for controls, respectively). 153 Median survival was also superior (19.0 vs. 13.5 months) compared to control patients. Resected patients who received adjuvant chemoradiotherapy had 2- and 5- year and median survivals of 30%, 12%, and 15.8 months, respectively, which were not significantly different from resected pat ients who did not receive treatment (34%, 17%, and 15.2 months, respectively). The addition of radiotherapy seemed to provide a modest benefit to patients with positive resection margins . Intraoperative radiation therapy has been examined as an adjunct to resection and postoperative external beam radiation. Although most recent series demonstrated improved local control, intraoperative radiotherapy does not improve overall survival and therefore has not gained wide acceptance. 154,155 Although no randomized data have been published, preliminary studies have demonstrated the safety and efficacy of preoperative [neoadiuvant] radiation and chemotherapy in patients with potentially resectable carcinoma of the pancreas.156,157 Only one-third to one-half of patients enrolled in neoadjuvant trials eventually undergo resection. Recent data suggest that locoregional control of tumor is enhanced by preoperative chemoradiation, but that the majority of patients still succumb to systemic disease. F" Pending results from randomized clinical trials, neoadjuvant chemoradiation should be considered investigational.

only a handful of patients had survived more than 5 years following diagnosis and treatment.!" Since then, a few groups have reported improved outcomes.159-162The resectability rate averages 10%. Operative mortality for distal pancreatectomy for cancer is less than that for pancreaticoduodenectomy, averaging 1% in all Californi a hospitals.':" In general, patients with body and tail lesions should be approached in the same manner as those with the more common lesion of the head of the gland. Those without evidence of metastatic disease or vascular invasion should be considered candidates for resection. Preliminary laparoscopy may be useful in identifying occult liver or peritoneal metastases and avoiding unnecessary laparotomy.

CANCER OF THE PANCREATIC BODY AND TAIL

Careful attention should be paid to pain relief as evidence suggests that survival is prolonged when pain is well controlled.!" Nonsteroidal antiinflammatory agents, oral and transdermal narcotics, and celiac plexus blocks are the main

Typically, patients with adenocarcinoma of the body and tail of the gland present with advanced disease, often unresectable, and have poor prognosis. By 1989, it was reported that

PALLIATIVE TREATMENT

The majority of patients with pancreatic cancer present with either locally advanced disease or metastases, making cure impossible at the present time. In this group of patients, the treatment goal is palliative. Palliative treatment has two main goals: to improve the quality of the patient's life and to increase life span . Quality of life is markedly affected by cancer pain as well as by complications of the tumor, such as biliary or gastric obstruction. The clinician should consider each of these issues in arriving at a treatment plan for an unresectable patient. Asymptomatic patients cannot be made to feel better by aggressive, ill-advised therapy. PAIN RELIEF

899

PANCREAS

strategies. Unlike the situation in chronic pancreatitis, significant benefit can sometimes be gained by celiac block in patients with pancreatic cancer. In a meta-analysis summarizing 59 articles and 1145 patients, Eisenberg et al. found significant improvement in cancer pain in 890/0 of patients. 164 For most, the effect was durable. Side effects are uncommon. In a small, randomized, controlled trial, celiac plexus block was found to be more effective than standard pharmacologic therapy for pancreas cancer pain.!'" RELIEF OF BILIARY OBSTRUCTION

Biliary obstruction is a common presentation of pancreatic malignancy. Options in palliation include surgical bypass, endoscopic stenting, and transhepatic stenting. Plastic stents in the range of 7-French to 10-French size have a median patency of 4 months. Expandable metallic stents are more expensive but have a median patency that exceeds median survival in this group of patients.I'" Randomized, controlled data are available comparing endoscopic or percutaneous stent placement versus surgical bypass for malignant biliary obstruction. 167 These data suggest that surgery carries a higher early morbidity and mortality rate compared to stenting, but stents have a high longer-term failure rate. There does not appear to be any significant difference in long-term survival between the two treatment options. Patients expected to live longer than 6 months or those requiring gastrojejunostomy for duodenal obstruction are probably best treated operatively. Those with widespread metastatic disease, and especially those with ascites and carcinomatosis, are best treated with stents. RELIEF OR PREVENTION OF DUODENAL OBSTRUCTION

Duodenal obstruction occurs in 100/0 to 200/0 of patients with pancreatic cancer.l'" The main palliative method is gastrojejunostomy. This can be accomplished laparoscopically or via open laparotomy. In one recent randomized, controlled trial of 87 highly selected patients with unresectable periampullary malignancy thought to be at low risk for gastric outlet obstruction, no difference in survival was observed in those with or without gastrojejunostomy (mean survival = 8.3 months in each group). 169 In 8 of the 43 patients (180/0) without gastrojejunostomy, however, gastric outlet obstruction requiring treatment developed. Gastric outlet obstruction symptoms did not develop in those undergoing gastrojejunostomy. These data suggest that prophylactic gastrojejunostomy is indicated in patients with unresectable periampullary malignancy undergoing laparotomy. For patients with known unresectable tumors complicated by gastric outlet obstruction, laparoscopic gastrojejunostomy is a reasonable option. No randomized, controlled data comparing open to laparoscopic bypass are available. Endoscopic duodenal stenting can be considered for patients at high risk for surgery."? PROLONGATION OF SURVIVAL

Palliative radiation and chemotherapy have a limited role in patients with unresectable pancreatic cancer. A number of chemotherapy regimens for patients with advanced pancreatic cancer have been studied, but objective response rates are low. 5-Fluorouracil (5FU), mitomycin, and, more recently, gemcitabine-based protocols have shown some survival benefit, although improvements tend to be measured as a few months.P? In a recent trial, patients with advanced pancreatic

cancer treated with gemcitabine had a median survival of 5.7 months versus 4.4 months for patients treated with 5FU. I 71 Improvements in quality of life, including pain control and dietary intake, were also observed. These data suggest that, at least in selected patients, cytotoxic chemotherapy may offer benefit. However, combining agents has not shown added promise.F' The role of radiation therapy in patients with unresectable pancreatic cancer is controversial. A combination of radiation (4000 or 6000cGy) and chemotherapy (5FU) is superior to radiation alone, with an approximate doubling of median survival rate to 40 weeks.!" With continued accrual of patients, this trial showed a 400/0 survival at 1 year with combined modality therapy compared to 100/0 with radiation alone.'?" In a follow-up study, unresectable patients were randomized to combination chemotherapy using streptozocin, mitomycin, and 5FU versus radiation plus chemotherapy.!" Median survival in the combined-modality group was significantly longer (42 weeks) than following chemotherapy alone (32 weeks). These studies suggest that a combination of chemotherapy and radiation is more effective than either therapy alone in patients with pancreatic cancer.

Prognosis It is important to recognize that, although the outlook for patients with pancreatic cancer is poor, some patients achieve a substantial life span with optimal treatment. A number of clinical and pathologic factors have been shown to significantly predict prognosis. Recent series suggest 5-year survival is possible in about 200/0 of resected patients (Table 46.15). CLINICAL FACTORS

SYMPTOMS

Pancreatic cancer tends to grow insidiously, making late presentation common. Features on presentation such as back pain, abdominal pain, and weight loss suggest an advanced lesion, making resection less likely. Deep jaundice is known to increase the operative risk but does not appear to affect long-term survival if the cancer is resectable.t"!" Other features, such as abdominal pain, steatorrhea, and thrombophlebitis, have not been shown to influence long-term survival.!" Weight loss, long duration of symptoms, and the presence of anemia, while implying long-standing disease, were not predictors of long-term survival by univariate analysis if the patient could undergo resection.!" BLOOD TRANSFUSION

A significant association between the use of perioperative

blood transfusion and poorer survival has been identified for a number of malignancies, including colon cancer, breast cancer, and colorectal cancer metastatic to the liver. A similar relationship has been identified following surgery for pancreatic cancer. Cameron et al. found a median survival of 24.7 months in 41 patients undergoing pancreaticoduodenectomy for pancreatic cancer with two or fewer units of blood transfusion, while the survival of 40 patients receiving more than two units was 10.2 months.I" This difference was highly significant and remained significant even after adjustment for tumor size. The reason for this relationship is not certain, but

900

CHAPTER 4 6

.10. . . TABLE 46.15.

Survival Following Pancreaticoduodenectomy for Pancreatic Adenocarcinoma: Recent Trials.

First author, reference, center, year

Number of patients

Operative mortality

Median survival

S-year survival

Comments

Trede / 49 1990, Mannheim

N = 118

0

Not reported

One of th e best reports of survival for panc reati c adenocarcinoma

Nitecki.!" Mayo Clinic, 1995

N = 186

3%

17.5 months

36 % in 76 patients with RO(-) resections, actual survival = 25 % 6.8% (23% in subgroup with negative nodes )

Nagakawa.P" Japan, 1996

N=53

9.4%

13 months

27.4 %

Conlon?" Memorial Sloan-Kettering, 1996 Sohn/ 52 Johns Hopkins, 2000

N = 118

3.4%

14.3 months

10.2%

N = 526

2.3%

17 months

17%

it has been proposed that blood transfusion induces immunosuppression that increases the risk of tumor recurrence. DEMOGRAPHICS

Patie nt demographic factors do not play strong roles in predicti ng prognosis following treatment of pancreatic cancer. In univariate analysis, factors such as gender, age, and race have not been found to be statistically significant predictors of survival. Similarly, factors such as alcohol intake history, smoking history, occupation, place of dwelling, and family history have not been shown to predict long-term survival. EFFECT OF RESIDUAL DISEASE

In large series of patients with pancreatic cancer, one of the strongest factors predicting survival is complete resection. 139,180,181 Population studies show that resection offers survival rates approximately twofold greater than palliative bypass procedures.! " Similar data are available from singleinstitution studies, such as the Memorial Sloan-Kettering experience. In that study of 799 patients, the 5-year survival rate following resection was 24%, whereas no patient survived without resection .l'" Residua l disease present following resection is also a strong predictor of long-term mortality in patients with pancreatic cancer. In the Hopkins series, of 143 patients with negative resection margins, actuarial 5-year survival was 26%, but only 8% in 58 patients with positive margins .146 This issue is important as, in a national survey of care of patients with pancreatic cancer undergoing resection, negative margins were achieved in only 8% of cases.!" It is suspected, but not proven, that the quality of surgical resection could be improved by regionalization of patients to experienced centers. t" PATHOLOGIC FACTORS

HISTOLO GIC TYPE

Ductal adenocarcinoma is the most common type of pancreatic cancer, accounting for 90%-95% of cases. Strictly speak ing, this category excludes adenocarcinoma of the ampulla of

12 pat ients initially class ified as duct al adenoca rcinoma found to have other diagnoses on rereview, mean follow-up 22 m onths Survi val for Gl cancers tends to be better in Japan than in Western series Resec tion for cure possib le in 17% of all patients Apparent improvement in survival with adjuvant chemoradiation, 30 % positive resection mar gin

Vater, which has a separate staging system, a different classification of histologic types, different biological and clinical associations, and a better overall prognosis . Pancreatic ductal adenocarcinoma is thought to arise directly from ductal epithelium, progressing through dysplasia and carcinoma in situ to invasive carcinoma, and its growth pattern typically includes the formation of ductal structures. A number of subtypes of ductal adenocarcinoma have been described, including mucinous noncystic carcinoma, signet ring cell carcinoma, adenosquamous carcinoma, mixed ductal-endocrine carcinoma, and anaplastic carcinoma. No significant differences in biological behavior or prognosis among different subtypes of ductal carcinoma have been identified.186 Certain other histologic types of epithelial tumors of the pancreas are regarded as both morphologically and biologically distinct from ductal adenocarcinoma. Included in this group are carcinomas wit h acinar cell differentiation (i.e., acinar cell carcinoma, acinar cell cystadenocarcinoma, and mixed acinar-endocrine carcinoma) and tumors with neuro endocrine differentiation (i.e., tumors formerly known as islet cell tumors and now more commonly termed pancreatic endocrine tumors]. Acinar cell carcinomas are typically associated with aggressive biological behavior and poor prognosis. Pancreatic endocrine tumors vary widely in their biological behavior, from benign to highly virulent, but lack reliable histologic indicators of malignancy. Also included in this group of unique epithelial malignancies are intraductal mucinous papillary carcinoma and mucinous cystadenocarcinoma, both of whic h are associated with a better overall prognosis compared to ductal adenocarcinoma. Intraductal papillary-mucinous carcinoma (known clini cally as mucinous ductal ectasia) is a pancreatic ductal neoplasm that displays indolent behavior compared to typical ductal adenocarcinoma. It arises in a background of papillary adenomatous dysplasia within the pancreatic ductal system that is often multifocal or widespread and may represent true adenoma formation but is slow to undergo malignant transformation and slow to invade the duct wall once malignancy has developed . As its name implies, this tumor typically

901

PANCREAS

causes massive ductal dilation and obstruction symptoms long before invasive malignancy has developed; therefore, resection is usually curative. With the presence of invasive malignancy or lymph node metastases, however, the prognosis is apparently poor, and death from disease within a year of resection in such cases has been reported. Mucinous cystadenocarcinomas also appear to arise in most cases from benign precursor lesions called mucinous cystic neoplasms (mucinous cystadenomas). Arguably, the overall favorable prognosis of mucinous cystadenocarcinomas compared to ductal adenocarcinoma may be related to earlier clinical presentation secondary to symptoms created largely by the precursor lesion.

TABLE 46.16. Definition of TNM, Stage Grouping, Histopathologic Type, and Histologic Grade of Exocrine Pancreas Carcinoma. Definition of TMN Primary Tumor (T)

TX TO Tis Tl

Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ * Tumor limited to the pancreas, 2 cm or less in greatest dimension Tumor limited to the pancreas, more than 2 cm in greatest diameter Tumor extends beyond the pancreas but without involvement of the celiac axis or the superior mesenteric artery Tumor involves the celiac axis or the superior mesenteric artery (unresectable primary tumor)

T2 T3 T4

HISTOLOGIC GRADE

Grading of ductal adenocarcinomas is somewhat subjective, and reports on the prognostic significance of histologic grade in pancreatic cancer often conflict. In most studies, a threeor four-tier grading system is usually employed as follows: grade 1 = well differentiated; grade 2 = moderately differentiated; grade 3 = poorly differentiated; and grade 4 = undifferentiated. Histologic grade is an expression of the relative degree of structural and functional differentiation of the tumor and is typically based on the amount of gland (duct) formation and mucin production. Nuclear atypia and mitotic activity may be included in the assessment. Generally, welldifferentiated tumors display a high degree of gland formation, poorly differentiated tumors display little gland formation, and moderately differentiated tumors are intermediate between the two. Despite this degree of analytic subjectivity, histologic grade does correlate with survival by univariate and multivariate analysis.!" In one multivariate analysis in which histologic grade was found to have independent prognostic significance, the 5-year survival was 500/0 for well-differentiated carcinomas and 10% for poorly differentiated carcinomas.l" PATHOLOGIC TUMOR STAGE

The stage of disease is currently the most powerful predictor of outcome among all defined prognostic factors in pancreatic cancer. The recognition of the direct strong relationship between stage of disease and outcome led to the development of the TNM staging system (Table 46.16). The TNM staging system has gained widespread acceptance, and the standardization of staging in pancreatic cancer has made it possible to compare variables in treatment such as methods of surgical resection and adjuvant radiation or chemotherapy. In the TNM system, a stage grouping is made up of three elements, one subcategory from each of the T, N, and M parameters. Because the subcategories of the T, N, and M parameters are precisely defined, the system is highly reproducible. Each of the T, N, and M categories and subcategories is based on features demonstrated to have independent prognostic significance. Nevertheless, the prognostic power of the TNM system is related to the combined data represented by the stage groupings rather than to the individual parameters alone. Currently, the observed postoperative 5-year survival following resection is about 380/0, 150/0, 100/0, and 40/0 for stages I, II, III, and IV, respectively.!" OTHER PATHOLOGIC FACTORS

Several other pathologic features have been reported to have prognostic significance in pancreatic cancer. Among these,

Regional Lymph Nodes (N)

NX NO Nl

Regional lymph nodes cannot be assessed No regional lymph node metastasis Regional lymph node metastasis


MX MO Ml

Distant metastases cannot be assessed No distant metastasis Distant metastasis

*This also includes the "PanInIII" classification

Stage Grouping

Stage Stage Stage Stage Stage

0

IA IB IIA lIB

Stage III Stage IV

Tis Tl T2 T3 Tl T2 T3 T4 AnyT

NO NO NO NO Nl Nl Nl AnyN AnyN

MO MO MO MO MO MO MO MO Ml

Source: Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AlCC Cancer Staging Manual, Sixth Edition (2002)published by Springer Science and Business Media LLC, www.springerlink.com.

histologic features such as small venous or lymphatic vessel invasion by tumor, perineural tumor invasion, round cell infiltration at the tumor periphery, and epithelial atypia in the surrounding uninvolved pancreatic ducts are reported to be associated with decreased survival. Diploid tumor cell DNA is correlated with increased tumor resectability and postoperative survival. Conversely, aneuploidy has shown a significant association with decreased survival. By univariate analyses, a significant association between low S-phase fraction (SPF) and increased survival was found in some studies I46, I 88 but not others.!" Immunohistochemical studies of the oncogenes and oncogene products nucleoside diphosphate kinase/rim 23 190 and HER2/neu 126 and epidermal growth factor (EGF), its analog transforming growth factor-a (TGF-a), and EGF-receptor 191 in pancreatic ductal carcinoma have suggested that expression of these biomarkers may correlate with tumor aggressiveness. Thus far, however, the data are based on small numbers of cases and lack multivariate analysis.

Cystic Tumors of the Pancreas Background Cystic tumors of the pancreas are relatively uncommon but are important both because they generally have a better prog-

902

CHAPTER 46

nosis than solid pancreatic tumors and because they can be confused with pancreatic pseudocysts. Overall, about 80% of pancreatic cystic lesions are pseudocysts, and the minority, about 20%, are the lesions discussed in this section. Pseudocysts can generally be distinguished from other cystic lesions by the clinical situation in which they arise and by their radiographic appearance. Because most pseudocysts are best treated by internal drainage and other cystic lesions are best treated with resection, it is important to make this differentiation accurately. When the clinician is uncertain regarding the nature of the lesion, biopsy of the cyst wall with examination of its lining for epithelial elements is useful as these will be absent in pseudocysts but present in other cystic lesions. Cyst fluid analysis has limited usefulness in distinguishing among the diagnostic possibilities.

Simple (Congenital) Cysts Simple cysts are thought to be congenital and are usually found in children. They tend to be solitary, unilocular, and lined by a simple cuboidal epithelium and probably arise as an abnormality of ductal development. They have no malignant potential. In adults, they cannot reliably be differentiated from mucinous cystadenomas radiographically; thus, when identified, they are best treated with excision. Formal pancreatectomy is not required.

Retention Cysts Cysts can occur from obstruction of the pancreatic duct, as in pancreatitis, with progressive dilation of the obstructed segment of duct. Generally, the low cuboidal ductal epithelium is retained, but in most ways these lesions mimic pseudocysts. Most arise in the setting of chronic pancreatitis with ductal stricture or, less commonly, from an obstructing pancreatic cancer. Communication with the ductal system may be evident on ERCP.

Polycystic Disease of the Pancreas Multiple pancreatic cysts can be present in association with polycystic kidney and liver disease, cystic fibrosis, and von Hippel-Lindau disease. About 10% of patients with polycystic kidney disease have pancreatic cysts. They generally are small and asymptomatic and do not require specific treatment. In cystic fibrosis, ductal plugging from thick secretions can lead to a form of retention cyst with ductal dilation proximal to the obstruction and parenchymal atrophy. Generally, these patients are not symptomatic from the pancreatic cysts, and no specific treatment is required. Von HippelLindau disease is an autosomal dominant disorder associated with cerebellar tumors and retinal angiomas. Many of these patients have pancreatic cysts, which are lined by a cuboidal epithelium. Similar cysts can be found in the kidney, liver, and spleen.

Serous Cystadenoma Serous cystadenomas are benign cystic tumors seen most often in middle-aged women. They average about 6 em in size at the time of presentation. Symptoms commonly include vague abdominal pain. Many, however, are silent, and the

lesion is discovered incidentally during a search for other pathology, such as gallstones. Jaundice and weight loss are rare. Radiographic assessment is key to their diagnosis. By ultrasonography, they generally appear as a complex lowdensity mass comprised of multiple small cysts separated by fine septae. Computed tomography shows a similar appearance and may identify a central stellate calcification in a "sunburst" pattern. Treatment is excision. Formal pancreatectomy is generally not required. Pathologically, these lesions are found to contain thin, serous, fluid. The cysts are lined with flat cuboidal cells that stain richly for glycogen, but not mucin. Anaplastic features and tissue invasion are absent. Cure is achieved in nearly all patients with excision alone. Rare reported cases have had malignant transformation.

Mucinous Cystic Neoplasms Mucinous cystic neoplasms are important to differentiate from serous cystadenomas because of the potential for malignancy in the former. The clinical presentation is similar to serous cystadenomas, with an apparent female preponderance. Most patients present with nonspecific abdominal pain, bloating, or an incidentally discovered mass. Jaundice is uncommon. Ultrasonography or CT show a large cystic mass similar in appearance to a pseudocyst. Unlike pseudocysts, however, patients with mucinous cystic neoplasms do not generally have a history of acute or chronic pancreatitis.l'" The lesions may include septae or have an irregular lumen. Occasionally, calcification will be seen in the cyst wall. Treatment of mucinous cystic neoplasms is resection, including a margin of normal pancreas. For lesions in the body of the gland, this usually requires distal pancreatectomy. A splenic-preserving operation may be performed if there is no involvement of the splenic vessels or evidence of lymphadenopathy. If a suspicion of malignancy exists, then distal pancreatectomy and regional lymphadenectomy are indicated. For lesions in the head of the gland, pancreaticoduodenectomy may be required. The prognosis of mucinous cystic neoplasms is generally good. In about 25% of cases, areas of malignancy will be identified in the cyst wall. Overall survival appears to be about 700/0 at 5 years. Most survivors, however, appear to be those without identified malignant elements.

Cystadenocarcinoma Cystadenocarcinoma is the end stage of mucinous cystic neoplasm. These lesions tend to present as bulky cystic masses with irregular walls in the head or body of the pancreas. When found in the head of the gland, jaundice may be present. Those arising in the body of the gland tend to present with nonspecific symptoms, including abdominal and back pain, bloating, and weight loss. These lesions do not tend to be as invasive as typical ductal adenocarcinoma, and even bulky lesions may not invade the portal vein or hepatic artery. Treatment is resection. In the recent French multiinstitutional review of cystic neoplasms, the 5-year survival rate for patients with cystadenocarcinoma of the pancreas was 63%.193

903

PANCREA S

Other Tumors Pancreatic Lymphoma

FIGURE 46.21. Computed tomography in a patient with a solid and cystic papillary neoplasmof the pancreas. This unusual lesion tends to arise in relativelyyoungwomen and may attain a largesize before detection. The lesion typically is well circumscribed and has both solid and cystic components. Resection is usually curative.

Solid and Cystic Papillary Neoplasm of the Pancreas The solid and cystic papillary neoplasm is a rare lesion, typically arising in young women. The lesion tends to be large, averaging lOcm in diameter. Most patients present with abdominal pain, and in many cases the lesions are confused with pseudocysts. Jaundice is rare . Computed tomography shows a large mass with heterogeneous solid and cystic components (Fig. 46.21). Treatment is resection. Although most patients are cured/ rare reported cases have developed metastases, so this lesion should be considered a low-grade malignancy and be removed completely. Adjuvant chemotherapy and radiotherapy are not warranted. l'"

Intraductal Papillary Mucinous Tumors Intraductal papillary mucinous tumor is a rare lesion/ but increasingly recognized today. Many terms have been used to describe this lesion in the past , including mucinous ductal ectasia/ ductectatic cystadenoma, mucin-producing ductal tumor/ and the like . First reported in Japan, it is characterized by marked distension of the pancreatic duct with mucin with ductal epithelial mucinous hyperplasia/ intraductal papillomas, and dysplasia. Cases have been described with progression to cancer.! " Most patients present with features of pancreatitis, probably from ductal obstruction. Computed tomography demonstrates a cystic pancreatic mass, which may represent either ductal distension or an associated mucinous cystic neoplasm. Endoscopic retrograde cholangiopancreatography is key to the diagnosis and reveals extrusion of mucous through the papilla, a dilated and irregular ductal system/ and filling defects within the duct. Treatment of intraductal papillary mucinous tumor is with surgical resection. Although some cases have successfully been treated with local excision/ because of its malignant potential, formal pancreatectomy is the preferred option. The prognosis is good, with better long-term survival than typical ductal adenocarcinoma.Pv!"

Pancreatic lymphomas are rare, especially as an isolated lesion. 198,199 More commonly/ the pancreas is involved in nonHodgkin's lymphoma as an incidental part of advanced intraabdominal and extraabdominal disease. Pancreatic lymphomas tend to present as bulky lesions with nonspecific symptoms/ such as abdominal pain/ that cannot be distinguished from those of pancreatic adenocarcinoma. A palpable abdominal mass is present in about one-half of patients. Despite their large size/ jaundice is uncommon. These tumors respond favorably to radiation and chemotherapy. Thus, suspicion of such a lesion warrants percutaneous fine-needle aspiration biopsy as a diagnosis of lymphoma makes surgical resection unnecessary. In general, palliative procedures such as biliary or gastric bypass are also unnecessary. Jaundice/ if present, can be treated with an endoscopic stent prior to initiating radiation or chemotherapy. Gastric outlet obstruction is probably best treated with bowel rest and total parenteral nutrition as the obstruction is likely to rapidly regress as radiation and chemotherapy are begun.

Adenosquamous Carcinoma Adenosquamous carcinoma tumors are rare, accounting for about 1% of pancreatic tumors. They are also known as squamous carcinoma of the pancreas, adenoacanthomas, or mucoepidermoid cancers. Normally, the pancreas does not contain any squamous or keratizing elements. Histologically/ these tumors tend to have a mixture of squamous and columnar malignant cells. Tumors with purely squamous cell components may be metastatic to the pancreas. Patients tend to be elderly and present with advanced disease with jaundice or abdominal pain. Generally/ these lesions cannot be distinguished from the more common ductal adenocarcinoma on the basis of clinical or radiographic criteria. Treatment is resection, but the prognosis is poor. In a recent review of the reported literature, summarizing 134 patients/ the average survival was only 5.7 months.F? Radiation and chemotherapy appear relatively ineffective.

Pancreatic Sarcomas Pancreatic sarcomas are rare lesions/ usually presenting as a bulky solid lesion in the body of the gland. Metastatic disease is commonly present at the time of diagnos is. Particular attention must be paid to excluding pulmonary metastases before considering surgical resection. If identified when localized, then radical distal pancreatectomy and splenectomy are warranted for lesions in the body and tail of the gland. Pancreaticoduodenectomy is indicated for lesions of the head of the gland.

References 1. Cotton PB. Pancreas divisum-euriosity or culprit?Gastroenterology 1985;89:1431-1435. 2. Pearse AG, Polak JM, Bloom SR. The newer gut hormones. Cel-

lular sources, physiology, pathology, and clinical aspects. Gastroenterology 1977;72(4 pt 11:746-761.

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bined-modality therapy (chemotherapy plus radiotherapy) to chemotherapy alone. J Nat! Cancer Inst 1988;80:751-755. 176. Allema JH, Reinders ME, van Gulik TM, et al. Prognostic factors for survival after pancreaticoduodenectomy for patients with carcinoma of the pancreatic head region. Cancer (Phila) 1995;75:2069-2076. 177. Nitecki SS, Sarr MG, Colby TV, et al. Long-term survival after resection for ductal adenocarcinoma of the pancreas. Is it really improving? Ann Surg 1995;221:59-66. 178. Mannell A, van Heerden JA, Weiland LH, et al. Factors influencing survival after resection for ductal adenocarcinoma of the pancreas. Ann Surg 1986;203:403-407. 179. Cameron JL, Crist DW, Sitzmann TV, et al. Factors influencing survival after pancreaticoduodenectomy for pancreatic cancer. Am J Surg 1991;161:120-124. 180. Murr MM, Sarr MG, Oishi AJ, et al. Pancreatic cancer. CA Cancer J Clin 1994;44:304-318. 181. Lillemoe KD. Current management of pancreatic carcinoma. Ann Surg 1995;221:133-148. 182. Bramhall SR, Allum WH, Jones AG, et al. Treatment and survival in 13,560 patients with pancreatic cancer, and incidence of the disease, in the West Midlands: an epidemiological study [see comments]. Br J Surg 1995;82:111-115. 183. Geer RJ, Brennan MF. Prognostic indicators for survival after resection of pancreatic adenocarcinoma. Am J Surg 1993;165:6872. 184. Janes RH Jr, Niederhuber JE, Chmiel JS, et al. National patterns of care for pancreatic cancer. Results of a survey of the Commission on Cancer. Ann Surg 1996;223:261-272. 185. Fong Y, Gonen M, Rubin D, Radzyner M, Brennan MF. Longterm survival is superior after resection for cancer in highvolume centers. Ann Surg 2005;242:540. 186. Eskelinen M, Lipponen P. A review of prognostic factors in human pancreatic adenocarcinoma. Cancer Detect Prevent 1992;16:287-295. 187. Yamamoto M, Saitoh Y, Hermanek P. Exocrine pancreatic carcinoma. In: Hermanek P, et al. eds. Prognostic Factors in Cancer. Berlin: Springer-Verlag; 1995:105-117. 188. Eskelinen M, Lipponen P, Marin S, et al. DNA ploidy, S-phase fraction, and G2 fraction as prognostic determinants in human pancreatic cancer. Scand J GastroenteroI1992;27:39-43. 189. Alanen KA, [oensuu H, Klemi PJ, et al. Clinical significance of nuclear DNA content in pancreatic carcinoma. J Pathol 1990;160:313-320. 190. Nakamori S, Ishikawa 0, Ohhigashi H, et al. Expression of nucleoside diphosphate kinasejnm23 gene product in human pancreatic cancer: an association with lymph node metastasis and tumor invasion. Clin Exp Metastasis 1993;11:151-158. 191. Yamanaka Y, Friess H, Kobrin MS, et al. Coexpression of epidermal growth factor receptors and ligands in human pancreatic cancer is associated with enhanced tumor aggressiveness. Anticancer Res 1993;13:565-570. 192. Martin I, Hammond P, Scott J, et al. Cystic tumours of the pancreas. Br J Surg 1998;85:1484-1486. 193. Le Borgne J, de Calan L, Partensky C. Cystadenomas and cystadenocarcinomas of the pancreas: a multiinstitutional retrospective study of 398 cases. French Surgical Association. Ann Surg 1999;230:152-161. 194. Mao C, Guvendi M, Domenico DR, et al. Papillary cystic and solid tumors of the pancreas: a pancreatic embryonic tumor? Studies of three cases and cumulative review of the world's literature. Surgery (St. Louis) 1995;118:821-828. 195. Brat DJ, Lillemoe KD, Yeo CJ, et al. Progression of pancreatic intraductal neoplasias to infiltrating adenocarcinoma of the pancreas. Am J Surg Pathol 1998;22:163-169. 196. Sugiyama M, Atomi Y. Intraductal papillary mucinous tumors of the pancreas: imaging studies and treatment strategies. Ann Surg 1998;228:685-691.

197. Rivera JA, Fernandez-del Castillo C, Pins M, et al. Pancreatic mucinous ductal ectasia and intraductal papillary neoplasms. A single malignant clinicopathologic entity. Ann Surg 1997; 225:637-644; discussion 644-646. 198. Bouvet M, Staerkel GA, Spitz FR, et al. Primary pancreatic lymphoma. Surgery (St. Louis) 1998;123:382-390. 199. Behrns KE, Sarr MG, Strickler JG. Pancreatic lymphoma: is it a surgical disease? Pancreas 1994;9:662-667. 200. Madura JA, Jarman BT, Doherty MG, et al. Adenosquamous carcinoma of the pancreas. Arch Surg 1999;134:599-603. 201. Palade GE. Structure and function at the cellular level. JAMA 1966;198:815-825. 202. Neoptolemos JP, Carr-Locke DL, London NJ, et al. Controlled trial of urgent endoscopic retrograde cholangiopancreatography and endoscopic sphincterotomy versus conservative treatment for acute pancreatitis due to gallstones. Lancet 1988;2:979983. 203. Fan ST, Lai EC, Mok FP, et al. Early treatment of acute biliary pancreatitis by endoscopic papillotomy [see comments]. N Engl J Med 1993;328:228-232. 204. Folsch UR, Nitsche R, Ludtke R, Hilgers RA, Creutzfeldt W. Early ERCP and papillotomy compared with conservative treatment for acute biliary pancreatitis. The German Study Group on Acute Biliary Pancreatitis. N Engl J Med 1997;336:237242. 205. Beger HG, Bittner R, Block S, et al. Bacterial contamination of pancreatic necrosis. A prospective clinical study. Gastroenterology 1986;91:433-438. 206. Pederzoli P, Bassi C, Vesentini S, et al. A randomized multicenter clinical trial of antibiotic prophylaxis of septic complications in acute necrotizing pancreatitis with imipenem. Surg Gynecol Obstet 1993;176:480-483. 207. Sainio V, Kemppainen E, Puolakkainen P, et al. Early antibiotic treatment in acute necrotising pancreatitis [see comments]. Lancet 1995;346:663-667. 208. Schwarz M, Isenmann R, Meyer H, et al. Antibiotic use in necrotizing pancreatitis. Results of a controlled study [in German]. Dtsch Med Wochenschr 1997;122:356-361. 209. Nordback I, Sand J, Saaristo R, et al. Early treatment with antibiotics reduces the need for surgery in acute necrotizing pancreatitis-a single-center randomized study. J Gastrointest Surg 2001;5:113-118; discussion 118-120. 210. Isenmann R, Runzi M, Kron M, et al. for the German Antibiotics in Severe Acute Pancreatitis Study Group. Prophylactic antibiotic treatment in patients with predicted severe acute pancreatitis: a placebo-controlled, double-blind trial. Gastroenterology 2004;126:997-1004. 211. Luiten EJ, Hop WC, Lange JF, et al. Controlled clinical trial of selective decontamination for the treatment of severe acute pancreatitis. Ann Surg 1995;222:57-65. 212. Partington PF, Rochelle REL. Modified Puestow procedure for retrograde drainage of the pancreatic duct. Ann Surg 1960;152:1037-1043. 213. Warshaw AL, Popp JW Jr, Schapiro RH. Long-term patency, pancreatic function, and pain relief after lateral pancreaticoduodenectomy for chronic pancreatitis. Gastroenterology 1980;79:289-293. 214. Prinz RA, Greenlee HB. Pancreatic duct drainage in 100 patients with chronic pancreatitis. Ann Surg 1981;194:313-320. 215. Holmberg JT. Chronic pancreatitis. Ann Surg 1985;160:3. 216. Munn JS, Aranha GV, Greenlee HB, et al. Simultaneous treatment of chronic pancreatitis and pancreatic pseudocyst. Arch Surg 1987;122:662-667. 217. Bradley ELD. Long-term results of pancreatojejunostomy in patients with chronic pancreatitis. Am J Surg 1987;153:207213. 218. Nealon WH, Townsend CM Ir, Thompson JC. Operative drainage of the pancreatic duct delays functional impairment in

PANCREAS

patients with chronic pancreatitis. A prospective analysis. Ann Surg 1988;208:321-329. 219. Greenlee HB, Prinz RA, Aranha GV. Long-term results of side-to-side pancreaticojeiunostomy. World J Surg 1990;14: 70-76. 220. Adams DB, Ford MC, Anderson MC. Outcome after lateral pancreaticojejunostomy for chronic pancreatitis. Ann Surg 1994;219:481-487; discussion 487-489. 221. Rios GA, Adams DB, Yeoh KG, et al. Outcome of lateral pancreaticoieiunostomy in the management of chronic pancreatitis with nondilated pancreatic ducts. JGastrointest Surg 1998;2:223229. 222. Lucas CE, McIntosh B, Paley D, et al. Chronic pancreatitis. Surgery (St. Louis) 1999;126:790. 223. Nealon WH, Matin S. Analysis of surgical success in preventing recurrent acute exacerbations in chronic pancreatitis. Ann Surg 2001;233:793-800. 224. Buchler MW, Friess H, Muller MW, et al. Randomized trial of duodenum-preserving pancreatic head resection versus pyloruspreserving Whipple in chronic pancreatitis. Am J Surg 1995;169:65-69; discussion 69-70. 225. Izbicki JR, Bloechle C, Knoefel WT, et al. Duodenum-preserving resection of the head of the pancreas in chronic pancreatitis. A prospective, randomized trial. Ann Surg 1995;221:350-358. 226. Izbicki JR, Bloeunle C, Broering DC, et al. Extended drainage versus resection in surgery for chronic pancreatitis: a prospective randomized trial comparing the longitudinal pancreaticojeiunostomy combined with local pancreatic head excision with the pylorus-preserving pancreatoduodenectomy. Ann Surg 1998; 228:771-779. 227. Strate T, Taherpour Z, Bloechle C, et al. Long-term follow-up of a randomized trial comparing the Beger and Frey procedures for patients suffering from chronic pancreatitis. Ann Surg 2005;241:591-598. 228. Braasch JW, Vito L, Nugent FW. Total pancreatectomy of endstage chronic pancreatitis. Ann Surg 1978;188:317-322. 229. Rossi RL, Rothschild J, Braasch JW, et al. Pancreatoduodenectomy in the management of chronic pancreatitis. Arch Surg 1987;122:416-420. 230. Beger HG, Buchler M, Bittner RR, et al. Duodenum-preserving resection of the head of the pancreas in severe chronic pancreatitis. Early and late results. Ann Surg 1989;209:273-278. 231. Easter DW, Cuschieri A. Total pancreatectomy with preservation of the duodenum and pylorus for chronic pancreatitis. Ann Surg 1991;214:575-580. 232. Frey CF, Amikura K. Local resection of the head of the pancreas combined with longitudinal pancreaticojejunostomy in the management of patients with chronic pancreatitis. Ann Surg 1994;220:492-504; discussion 504-507. 233. Sawyer R, Frey CF. Is there still a role for distal pancreatectomy in surgery for chronic pancreatitis? Am J Surg 1994;168: 6-9. 234. Martin RF, Rossi RL, Leslie KA. Long-term results of pyloruspreserving pancreatoduodenectomy for chronic pancreatitis. Arch Surg 1996;131:247-252. 235. Rattner DW, Fernandez-del Castillo C, Warshaw AL. Pitfalls of distal pancreatectomy for relief of pain in chronic pancreatitis. Am J Surg 1996;171:142-145; discussion 145-146. 236. Traverso LW, Kozarek RA. Pancreatoduodenectomy for chronic pancreatitis: anatomic selection criteria and subsequent longterm outcome analysis. Ann Surg 1997;226:429-434.

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237. Eddes EH, Masclee AM, Gooszen HG, et al. Effect of duodenumpreserving resection of the head of the pancreas on endocrine and exocrine pancreatic function in patients with chronic pancreatitis. Am J Surg 1997;174:387-392. 238. Beger H. Chronic pancreatitis. Ann Surg 1999;230:512. 239. Lin PW, Lin YJ. Prospective randomized comparison between pylorus-preserving and standard pancreaticoduodenectomy. Br J Surg 1999;86:603-607. 240. Tran KT, Smeenk HG, van Eijck CH, et al. Pylorus preserving pancreaticoduodenectomy versus standard Whipple procedure: a prospective, randomized, multicenter analysis of 170 patients with pancreatic and periampullary tumors. Ann Surg 2004;240:738-745. 241. Seiler CA, Wagner M, Bachmann T, et al. Randomized clinical trial of pylorus-preserving duodenopancreatectomy versus classical Whipple resection-long term results. Br J Surg 2005;92:547556. 242. Kalser MH, Ellenberg SS. Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. Arch Surg 1985;120:899-903. 243. Bakkevold KE, Kambestad B. Morbidity and mortality after radical and palliative pancreatic cancer surgery. Risk factors influencing the short-term results. Ann Surg 1993;217:356368. 244. Lygidakis NJ, Stringaris K. Adjuvant therapy following pancreatic resection for pancreatic duct carcinoma: a prospective randomized study. Hepato-Gastroenterology 1996;43:671-680. 245. Klinkenbijl JH, Ieekel J, Sahmoud T, et al. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Ann Surg 1999;230:776-782. 246. Takada T, Amano H, Yasuda H, et al. Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma. Cancer 2002;95:16851695. 247. Neoptolemos JP, Stocken DD, Dunn JA, et al. Influence of resection margins on survival for patients with pancreatic cancer treated by adjuvant chemoradiation and/or chemotherapy in the ESPAC-1 randomized controlled trial. Ann Surg 2001;234:758768. 248. Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer [erratum in N Engl J Med 2004;351:726]. N Engl J Med 2004;350:1200-1210. 249. Trede M, Schwall G, Saeger HD. Survival after pancreatoduodenectomy. 118 consecutive resections without an operative mortality. Ann Surg 1990;211:447-458. 250. Nagakawa T, Nagamori M, Futakami F, et al. Results of extensive surgery for pancreatic carcinoma. Cancer (Phila) 1996;77:640645. 251. Conlon KC, Klimstra DS, Brennan MF. Long-term survival after curative resection for pancreatic ductal adenocarcinoma. Clinicopathologicanalysisof5-yearsurvivors.AnnSurg 1996;223:273279. 252. Sohn TA, Yeo CJ, Cameron JL, et al. Resected adenocarcinoma of the pancreas-616 patients: results, outcomes, and prognostic indicators. J Gastrointest Surg 2000;4(6):567-569.

Biliary System Hobart W. Harris

History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

911 911 914 915

History The history of biliary tract disease extends over 3500 years, but the birth of modem-day surgical intervention occurred little more than a century ago. Early Egyptians were aware of the liver and biliary system and assigned these organs significance for divining future events. The oldest recorded case of gallstones was in the mummified remains of the Princess of Amenen from Thebes, circa 1500 BC. At the time of her death, her well-preserved gallbladder contained at least 30 gallstones. For more than a millennium after her demise, little changed regarding the largely mystical interpretation of the liver and biliary system. But, beginning with Hippocrates (400 sc] and extending through the time of Galen (AD 200), there gradually developed an appreciation for organ dysfunction and how this might result in disease. In 1506, the detailed description of right upper quadrant abdominal pain associated with the presence of gallstones made by Antonio Benivieni (1440-15021 was published, representing the first correlation of biliary colic with autopsy findings . During the ensuing 250 years, a growing appreciation for human anatomy, combined with the hypothesis that biliary calculi could result from stasis within the gallbladder, culminated in the first reported cholecystectomy. In 1867, through a surgical misadventure, John Stough Bobbsof Indiana opened what he initially mistook for an ovarian cyst in a woman complaining of abdominal pain . No doubt to his surprise, the incision yielded several gallstones as the cystic structure was instead the gallbladder . After removing the stones, Bobbs closed the cholecystotomy incision, and the patient recovered. During the 130 plus years since Bobbs's "cholecystectomy," advances in understanding biliary anatomy and the development of relevant surgical therapeutics have transpired at an amazing pace. Not only have most of the anatomical landmarks pertinent to biliary anatomy been described during the last two centuries, but also the operative procedures. And, innovation continues to revolutionize surgery of the biliary

Calculous Disease Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Benign Neoplasms: Choledochal Cysts . . . . . . . . . . . . .. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

919 933 938 939

system, as shown by the recent advent of laparoscopic cholecystectomy.

Anatomy In the extrahepatic biliary tree, the gallbladder (vesica fellea] is a hollow, piriform (L., pear-shaped) organ 7 to lOcm in length, approximately 4cm in diameter, and with a capacity of 30 to 60mL (Fig. 47.1). At 4 weeks gestation, the human embryo develops a hepatic diverticulum within the foregut, subsequently forming the gallbladder and extrahepatic biliary ducts (Fig. 47.21. For descriptive purposes, the gallbladder is divided into a fundus, body, infundibulum, and neck. Attached to the liver by loose areolar connective tissue, the portion of the gallbladder not embedded within the liver substance is covered by visceral peritoneum. Small veins and lymphatics course between the gallbladder fossa and the gallbladder wall, connecting the lymphatic and venous drainage of the two organs. The shared lymphovascular drainage explains the spread of gallbladder inflammation and carcinoma to the liver. In addition, a small accessory bile duct may drain directly into the gallbladder (cholecystohepatic duct of Luschka) in a similar manner. During a cholecystectomy, these accessory ducts should be identified and ligated, if present, to prevent postoperative bile leaks. The gallbladder fossa anteriorly and the inferior vena cava posteriorly define the anatomical division between the right and left lobes of the liver. The body of the gallbladder narrows toward the neck of the organ known as the infundibulum. Major portions of the body and infundibulum of the gallbladder are in juxtaposition to the first portion of the duodenum and the transverse colon. Inflammation of the gallbladder wall can result in the formation of adhesions between the gallbladder and the adjacent intestines, setting the stage for the creation of cholecystoenteric fistulas [e.g., a cholecystoduodenal fistula). The infundibulum of the gallbladder is attached to the first part of the duodenum by an avascular peritoneal reflection termed the 911

912

CHAPTER 47 Fun dus

Hartm ann 's Common bile d uct

FIGURE 47.1. Anatomy of the gallbladder and bile ducts. (Redrawn with permission from Braasch and Tompkins.P']

cholecystoduodenal ligament. This ligament is an inferior extension of the hepatoduodenal ligament and can be used during surgery as a landmark for the major vascular structures of the hepatic hilum. The infundibulum joins the cystic duct through the neck of the gallbladder, which is a short S-shaped structure, frequently curved on itself. Protruding from the lateral wall of the neck of the gallbladder, there may be a dilation termed Hartmann's pouch . Projecting in an inferoposterior direction toward the duodenum, gallstones frequently become lodged in this outpouching in such a way that if this area becomes inflamed it may adhere to and obstruct the cystic duct. The cystic duct is a tubular structure attaching the gallbladder neck to the common hepatic duct . Its length varies from 1 to 5 em and its diameter from 3 to 7mm. The mucosa that lines the cystic duct is thrown into 4 to 10 spiral folds, the spiral valves of Heister. These valves prevent the ready passage of gallstones and excessive distension or collapse of

the cystic duct despite wide variations in ductal pressure. It is important to keep the cystic duct patent at all times so that bile easily enters the gallbladder when the choledochal sphincter is closed and so that bile flows in the opposite direction down into the duodenum when the gallbladder contracts. The cystic duct may join the extrahepatic biliary tree in a variety of ways, including an angular, parallel, or spiral configuration (Fig. 47.3). In approximately 70% of people, the junction between the cystic and common hepatic ducts is angular,' occurring along the right lateral wall of the hepatic duct . However, the cystic duct can run parallel to the hepatic duct for as long as 6cm before they merge. In such cases, the two ducts are often densely adherent and difficult to separate. When the ducts join in a spiral fashion, the cystic duct may circle either anterior or posterior to the hepatic duct, entering along the left lateral wall of the hepatic duct. This anatomical variant increases the risk of common bile duct injury when the cystic duct is dissected all the way to its junction with the hepatic duct. The anatomical relationships of the extrahepatic biliary tree and its frequent variations are of importance to surgeons operating in this region. The variability applies to the gallbladder, the biliary ductal system, and their vascular supply. Although abnormalities of the gallbladder itself are uncommon, found in less than 3 % of cases,' the range is broad. Gallbladder anomalies entail duplications, abnormalities of the gallbladder's shape, or variations in its attachment to the Iiver.v' In rare instances, the gallbladder is completely embedded in the liver. Such intrahepatic gallbladders are usually located within the right lobe of the liver, close to the visceral surface. Congenital absence of the gallbladder, also rare, is frequently associated with atresia of additional segments of the extrahepatic biliary tree. As this is infrequently identified before operation, one must exclude the presence of an intrahepatic gallbladder before confirming this diagnosis. A single cystic artery usually accomplishes the arterial supply to the gallbladder, but in 12% of cases double cystic Hepatic ducts

Esophagus Dorsal

Stomach

Esa

Cystic duct

pancreas

Gallbladder

A

Gallb ladde r

Ampulla of vater

o

Ventral pancreas ("head")

E

FIGURE 47.2. Development of the human biliary primordia. (A) Fifth week of development in a human embryo. (B) Sixth week of development . (e) Seventh week of development. (D) Maturation of the biliary system and pancreas. (EI Relationship of the biliary and pancreatic ductal systems . (Redrawn with permission from Patten, t41 © 1953 McGraw-Hill.)

913

BILIARY S YS T E M

fli .

Common hepatic a.

R. hepatic a. '/- ' .

Portal vein

Cystic arte ry~[ ;; Cystic duct > ' Common duct Free edge hepatoduodenal ligament

.';

.~ ~.'

Anterior spiral junction Posterior spiral junction

FIGURE 47.3. Variations in the anatomy of the cystic duct. (Adapted with permission from Lindner.']

arteries exist.!" The origin and course of the cystic artery are highly variable ; indeed, the course of this artery is one of the most variable in the body. In the majority (75%) of cases, the cystic artery originates from the proximal right hepatic artery and immediately divides into two branches: the superficial

Long parallel junction

branch, which runs along the peritoneal surface of the gallbladder, and the deep branch, which runs along the gallbladder fossa between the gallbladder and liver (Fig. 47.4). The cystic artery usually lies superior to the cystic duct and passes posterior to the common hepat ic duct . With this anatomical

"'==-~~~=¥,=~~~ L, gastro-epiploic a. R. gastro-epiploic a.

Sup mesenteric a.

s

GO

FIGURE 47.4. Variation s in the anatomy of the cystic artery . The cystic artery is shaded in each drawing to highlight its variable origins . (Redrawn with permission from Braasch and Tompkins.l'? Mosby-Yearbook Co., © 1994.)

914

CHAPTER 4 7

arrangement, the common hepatic duct , the liver, and the cystic duct define the boundaries of Calot's triangle (see Fig. 47.1). Located within this triangle are some structures of great importance to the surgeon: the cystic artery, the right hepatic artery, and th e cystic duct lymph node . Calot's node is often involved with inflammatory or neoplastic disease of the gallbladder because this is one of the primary routes of lymphatic drainage. Lymph fluid from the gallbladder drains either directly into the liver across the gallbladder fossa or toward the common bile duct, where it can ascend toward nodes in the hilum of the liver or descend toward celiac axis nodes . In 25% of cases, the relationship between the arteries and bile ducts in the hilum of the liver varies widely (Fig. 47.4). The cystic artery can originate from the following sites: an accessory or replaced right hepatic artery (12%), the left hepatic artery (6.2%), the gastroduodenal artery (2.6%), the common hepatic artery (2.2%), the proper hepatic artery (0.6%), the celiac axis (0.4%), or in rare cases, the superior mesenteric or superior pancreaticoduodenal artery.2,4,SDespite the variability, basic patterns do exist. More than 90% of the time, the cystic artery originates from the right hepatic artery, even though the latter vessel may have an anomalous origin. In addition, when the cystic artery originates to the left of the bile duct, it usually passes anteriorly to the bile duct . Regardless of its origin, in 7% to 10% of people the cystic artery parallels the right hepatic artery until just before it enters the right lobe of the liver. In these cases, the cystic artery is but a few millimeters long, and it may be easily confused with the right hepatic artery. Although ligation of a lobar hepatic artery is to be avoided, the usual concerns regarding consequent lobar degeneration or infarction are unwarranted. Unlike the arterial system, there are no named veins draining th e gallbladder. As mentioned, some of the organ's venous return passes directly into the liver across the gallbladder fossa. The remaining venous drainage parallels the cystic duct lymphatics, forming venous networks along the common bile duct before joining the portal venous system. Occasionally, patients with portal hypertension have obvious varices in the area of the gallbladder and extrahepatic biliary tree. Fibers from the sympathetic and parasympathetic nervous systems innervate the gallbladder. Although the nerves supplying the gallbladder and choledochal sphincter contribute to overall gallbladder function, they are of no ma jor clinical significance and can be sacrificed without consequence. However, afferent sympathetic nerve fibers supplying the extrahepatic bile ducts include some pain fibers that are responsible for the referred epigastric and right upper quadrant abdominal pain characteristic of biliary disease . As depicted in Figure 47.1, the common bile duct results from the confluence of the common hepatic and cystic ducts, varies in length from 5 to 17em, and is normally 3 to 8 mm in diameter, unless obstructed, when it can dilate to a diameter in excess of 2 em. The common bile duct can be divided into four segments as a function of its anatomical relationship to the duodenum and pancreas : the supra duodenal, retroduodenal, intrapancreatic, and intramural segments. Enveloped within the peritoneal covering of the hepatoduodenal ligament, the common bile duct generally lies anterolateral to the hepatic artery and portal vein , making it readily available for surgical manipulation (e.g., common bile duct exploration). The hepatoduodenalligament is an important anatomical landmark as it represents the right border of the

Pancreas

Common bile duct

Circular fold Sup. margin of duodenal window

~-:p.-7+:'::H::~- Sphincter of

pancreatic duct Longitudinal } Muscle of · I duodenal C ucuiar wall

Submucosa Valves

Frenulum

FIGURE 47.5. Sphincteric mechanism at the terminal end of the

common bile duct. (Redrawn with permission from Way and Pelligrini,142 W. B. Saunders Co., © 1987.1

hepatogastric ligament (lesser omentum) and defines the anterior border of the epiploic foramen of Winslow connecting the greater and lesser peritoneal cavities. In addition to yielding entry to the lesser sac, the foramen of Winslow enables the structures of the portal triad to be easily encircled and compressed (Pringle maneuver). After the common duct descends posterior to the first part of the duodenum, it travels through the head of the pancreas, then for 1 to 2cm obliquely within the medial wall of the second portion of the duodenum before forming a common channel with the main pancreatic duct (ampulla of Vater), which empties into the duodenal lumen through a mucosal papilla . The terminal portion of the common bile duct is encircled by a combination of circular and longitudinal smooth muscles, which serve to control the entry of biliopancreatic secretions into the proximal intestinal tract (Fig. 47.5). This muscular structure, termed th e choledochalduodenal sphincter of Oddi, has a phasic resting tone ranging from a baseline of approximately 13mmHg to as high as 200mmHg. The contractile activity of the sphincter of Oddi demonstrates a cyclical pattern that varies in relationship to the intermittent myoelectric migratory complex (IMMC) of the intestinal tract, with the majority (85%) of peristaltic waves migrating in a caudal direction. The common bile duct derives its blood supply not from any named blood vessels but rather from a complex network of interwoven small vessels derived predominantly from the cystic and the posterior pancreaticoduodenal arteries. Because there is no specific vessel to identify and preserve during dissections of the common bile duct, this tubular structure is vulnerable to ischemic injury. To avoid disrupting the fragile inconstant blood supply to the duct and thus increase the risk of postoperative bile leakage or stricture formation, it is crit ically important not to strip the common bile duct of the investing loose areolar tissue during its isolation and manipulation. The nerve supply to the common duct is the same as described for the gallbladder.

Physiology The biliary tree is designed for the transport and storage of bile produced in the liver by hepatocytes and destined for the duodenal lumen to participate in the digestion of foodstuffs.

915

BILIARY SYSTEM

TABLE 47.1. Biliary Lipid Compositions of Gallbladder Bile. Lipid component

Biliary lipid Imol %) Bile salts Phospholipids Cholesterol Cholesterol saturation index Cholesterol :phospholipid ratio Cholesterol: bile salt ratio

Controls

72.0 21.1

Cholesterol stones

70.2 20.6

Change (%)

22.5 22.4

1.00

9.0 1.32

130 132

0.10

0.46 0.13

135 130

6.9 0.34

Source: Data from Thistle et al. l35 and Lamont and Carey.P"

The pattern of bile flow throughout the biliary tree differs when a person is in the fasted versus the postprandial state. Under fasting conditions, biliary tree motility and thus bile flow are regulated by the IMMC and approximated by the cyclical activity of the duodenum. Observations of the fasting gallbladder over time have shown a predictable pattern of filling, followed by gallbladder contraction and partial (15%-20 %) emptying associated with increased plasma levels of motilin. In fact, during phase II of the IMMC (a period of increased duodenal and pancreatic activity), the gallbladder contracts along with the coordinated relaxation of the sphincter of Oddi. Th e specific function of the gallbladder 's phasic activity during fasting is unclear but may represent a mechanism by which stasis of saturated bile and the attendant increased risk of gallstone formation is avoided. The enterohepatic circulation of bile acids predominantly regulates the overall production rate of bile by the liver. Thus, the rate of hepatic bile synthesis is inversely proportional to the amount of bile acid reclaimed from the terminal ileum and recycled to the liver. Actual filling of the gallbladder results from the continuous production of bile by the liver in the face of a contracted sphincter of Oddi. As the pressure within the common bile duct exceeds that within the gallbladder lumen, hepatic bile enters the gallbladder via retrograde flow through the cystic duct, wherein it is rapidly concentrated. Within a few hours, the gallbladder mucosa, apparently by means of an active sodium-coupled transport mechanism, removes more than 90% of its water content, creating the more highly concentrated gallbladder bile. Consequently, the amount of electrolytes, lipids, bile salts , and pigments in gallbladder bile is significantly more concentrated than that found in hepatic bile (Table 47.1). As discussed elsewhere in this chapter, it is the relative concentrations of cholesterol, phospholipid, and bile salts that effectively determine the lithogenicity of bile. Following a meal, the gallbladder contracts in response to both a vagally mediated cephalic phase of activity and the release of cholecystokinin (CCK), the major regulator of gallbladder function. During the following 60 to 120min, approximately 80% to 90 % of gallbladder bile is steadily emptied into the intestinal tract. The CCK, which was first identified in 1928, is localized to the proximal small intestine, especially the duodenal epithelial cells, where its release is stimulated by intraluminal fat, amino acids, and gastric acid and inhibited by bile. With a plasma half-life of less than 3 min, at least four different forms of CCK have been identified in plasma. Ranging in length from 8 to 58 amino acids, each

form of CCK derives its physiological activity from the same C-terminal octapeptide. Cholecystokinin acts directly via smooth muscle receptors in the gallbladder wall , stimulating muscle contraction in direct proportion to its concentration and in a calcium-dependent as well as vagally mediated manner. In addition to stimulating gallbladder contractions, CCK acts to functionally inhibit the normal phasic motor activity of the sphincter of Oddi. By reducing the frequency and amplitude of the basal contractions, the sphincteric mechanism relaxes in coordination with gallbladder contraction , thus facilitating the delivery of bile into the proximal small intestine. Gallbladder function is also influenced by other hormones, including vasoactive intestinal polypeptide (VIP), somatostatin, substance P, and norepinepherine. Both VIP and somatostatin inhibit contraction of the gallbladder, consistent with their inhibitory effects on gastrointestinal motility. The role of substance P, norepinepherine, and other neuropeptides in the regulation of gallbladder function remains to be elucidated. Interestingly, the common bile duct contains very little if any smooth muscle, in only 20% of people . Therefore, the extrahepatic ducts do not actively contribute to bile flow. But, in addition to contraction of the gallbladder, the biliary canaliculi are thought to help pump bile out of the liver and into the intestine.

Diagnosis Clinically significant symptoms originating from biliary tract pathology are common and generally are the result of obstruction , infection, or both. A thorough knowledge of how biliary tract diseases present is necessary for the clinician to accurately diagnose and manage these disorders. An appreciation for several fundamental tenets of pathophysiology proves invaluable to the evaluation of this patient population as many of the symptoms of biliary tract disease are nonspecific and can mimic other intraabdominal disorders. Specifically, as is true with any hollow tubular structure, the source of bile duct obstruction can be either extramural (pancreatic cancer), intramural (cholangiocarcinoma), or intraluminal (choledocholithiasis; Fig. 47.6). Similarly, as with infections elsewhere in the body, for an infection to develop within the biliary tree requires the following three components: a susceptible host, a sufficient inoculum, and stasis. Given these basic principles, the most common symptoms related to biliary tract disease are abdominal pain, jaundice, fever, and Intraluminal

Intramural

Extraluminal

B FIGURE 47.6. Mechanisms of bile duct obstruction. (AIIntraluminal obstruction [e.g., gallstones). (B) Intramural obstruction [e.g., cholangiocarcinorna]. [C] Extraluminal obstruction (e.g., pancreatic neoplasm) .

916

CHAPTER 47

a constellation of constitutional complaints, including nausea, anorexia, weight loss, and vomiting.

Abdominal Pain

the affected tissues. Jaundice resulting from biliary tract obstruction is presumably caused by the reflux of conjugated bilirubin directly across either the basement membrane of the hepatic sinusoids or damaged canaliculi. The rise in conjugated bilirubin (direct reacting) is in contrast to the increased levels of unconjugated bilirubin (indirect reacting) observed with hepatocellular injury. Interestingly, significant elevations of the total serum bilirubin level are indicative of common bile duct obstruction. In the absence of underlying hepatic dysfunction, the entire liver must be obstructed for a sufficient quantity of regurgitated bile to accumulate in the circulation, sclera, or skin because only a few functioning segments of liver are necessary to maintain normal serum bilirubin levels. As discussed later in this chapter, marked jaundice is considered an operative risk factor, and therefore its management should be carefully evaluated as various therapeutic options are considered.

Gallstones and inflammation of the gallbladder are the most frequent causes of abdominal pain resulting from biliary tract disease. Acute obstruction of the gallbladder by calculi results in biliary colic, a misnomer in that the pain is not colicky but rather a constant abdominal pain typically localized to the epigastrium or right upper quadrant. Although the pain is often precipitated by eating fatty foods, it can also be triggered by eating other types of food or even begin spontaneously. Unlike intestinal colic, which presents in episodic waves lasting several minutes each, biliary colic is a more constant pain that gradually builds in intensity and can radiate to the back, interscapular region, or right shoulder. Many patients describe the pain as a band- or beltlike constriction of the upper abdomen that may be associated with nausea or vomiting. This recognizable type of abdominal pain results from a normal gallbladder contracting against a luminal obstruction, such as a gallstone impacted in the neck of the organ, the cystic duct, or common bile duct. Under the postprandial influence of CCK and the cholinergic cephalic phase of foregut motility, the essentially isometric contraction of gallbladder smooth muscle yields this characteristic pain. The episode of pain or "attack" resolves as either the diet-induced stimulus for increased gallbladder activity dissipates; the stone becomes dislodged, thereby alleviating the obstruction; or the spontaneous gallbladder wall spasm relaxes. Of note, this pain is visceral in nature, and often patients report a crescendo pattern of increasingly frequent and severe bouts of discomfort. The pain of biliary colic is distinct from that associated with acute cholecystitis. Although biliary colic can also be localized to the right upper quadrant, the pain of acute cholecystitis is exacerbated by touch, somatic in nature, and often associated with the systemic findings of fever and leukocytosis. The transmural inflammation of the gallbladder provokes irritation of the adjacent visceral and parietal peritoneal surfaces. Therefore, any increases in wall tension or tactile pressure can stimulate nerve endings within the inflamed tissue, as evidenced by a positive Murphy's sign. This physical finding, of a patient abruptly stopping the inspiratory effort because of pain as the examiner palpates under the right costal margin, is indicative of acute cholecystitis. The clinical implication of acute cholecystitis is quite different from that of biliary colic. Although biliary colic is an episodic, even unpredictable, functional disorder of the gallbladder that many patients can live with for months to years, acute cholecystitis involves irreversible organ injury and activation of a locoregional inflammatory response, and it invariably requires a definitive therapeutic intervention.

Abdominal pain, jaundice, and fever are characteristic of biliary tract disease, but these signs and symptoms are also associated with other intraabdominal conditions, including peptic ulcers, acute pancreatitis, hepatitis, and diverticulitis. Thus, additional studies are necessary to confirm the biliary system as the source of the patient's problem, including specific laboratory tests and radiographic examinations.

Jaundice

Laboratory Tests

When the serum concentration of bilirubin exceeds approximately 2.5 mgj dL, a yellowish discoloration of the sclera becomes evident (scleral icterus). A similar discoloration of the skin (jaundice) develops with serum bilirubin levels in excess of 5 mgjdL. Under both circumstances, the visible changes in color represent the deposition of bile pigments in

Simple biliary colic, in the absence of gallbladder wall pathology or common bile duct obstruction, does not produce abnormal laboratory test values. This condition is in many respects a functional disorder of the gallbladder caused by cystic duct obstruction and is not associated with organ injury. On the other hand, obstructive choledocholithiasis is commonly

Fever Significant elevations in body temperature (~38.0°C) due to biliary tract disease represent a systemic manifestation of an initially localized inflammatory process. Bacterial contamination of the biliary system is a common feature of acute cholecystitis or choledocholithiasis with obstruction and is to be expected following percutaneous or endoscopic cholangiography. Whether as components of ductal calculi or contaminants introduced during biliary tract instrumentation, fever results from the presence of bacteria within an obstructed biliary tree. Not only do these microorganisms proliferate in this static system, but also bacteria and endotoxin are refluxed into the systemic circulation, causing symptoms that can range from spiking fevers to septic shock. The combination of right upper quadrant abdominal pain, jaundice, and fever, known as Charcot's triad, signifies an active infection of the biliary system termed acute cholangitis. Patients suffering from acute cholangitis may not present with all these findings, but approximately two-thirds will. Virtually all patients have experienced all three symptoms at some point during their illness. Severely afflicted patients may also display an altered mental status and hypotension (pentad of Reynolds). Fever should be viewed as a signal that an otherwise localized disease process has progressed to a systemic illness.

Diagnostic Studies

BILIARY SYSTEM

associated with an element of both liver dysfunction and acute cellular injury with resultant elevations in liver function tests. In addition to hyperbilirubinemia (see Jaundice, earlier), the magnitude of which directly correlates with the severity and duration of the biliary system blockade, an increased serum alkaline phosphatase level is virtually pathognomonic of bile duct obstruction. Alkaline phosphatase is a membrane protein produced by bile canalicular cells in response to elevated ductal pressure, and it represents a sensitive and early cellular response to biliary tract obstruction. Serum transaminase (aspartate and alanine) levels can also be mildly elevated in biliary system disease, either because of direct injury of the liver adjacent to an inflamed gallbladder or from the effect of biliary sepsis on hepatocellular membrane integrity. Increased transaminase levels can be detected in serum when hepatocytes are injured as these cytoplasmic proteins subsequently leak across damaged plasma membranes . Leukocytosis with a predominance of neutrophils is often present with acute cholecystitis or cholangitis but is a nonspecific finding that does not distinguish these conditions from other infectious or inflammatory processes within the abdomen.

Radiographic Studies ABDOMINAL RADIOGRAPHS

Although frequently obtained during the initial evaluation of abdominal pain, plain radiographs of the abdomen are seldom of significant diagnostic value . Only about 15% of gallstones contain enough calcium to render them radiopaque and thus visible on plain films of the abdomen. Calcium elsewhere within the peritoneal cavity, such as the wall of the gallbladder or the head of the pancreas, is noteworthy but is an uncommon explanation for acute abdominal pain . Rarely, one may identify pneumobilia (air within the biliary tree), which can indicate the presence of a severe bacterial infection. The most important value of plain abdominal films is the exclu sion of other potential diagnoses, such as a perforated ulcer with free intraabdominal air or an intestinal obstruction with dilated loops of bowel and multiple air-fluid levels . ULTRASONOGRAPHY

Surface ultrasound of the abdomen is an extremely useful and accurate method for identifying gallstones and pathological changes in the gallbladder consistent with acute cholecystitis . Abdominal ultrasound should be part of the routine evaluation of patients suspected of having gallstone disease, given the high specificity (>98%) and sensitivity (>95%)of this test for the diagnosis of cholelithiasis (Fig. 47.7). In addition to confirming the presence of gallstones within the gallbladder, ultrasound can also detail various signs of acute cholecystitis (thickening of the gallbladder wall, pericholecystic fluid) as well as gallbladder neoplasms. Due to overlying or adjacent bowel gas, accurate imaging of the extrahepatic bile ducts for signs of obstruction or the presence of stones can be difficult. Therefore, the absence of these findings on ultrasound is insufficient to exclude a diagnosis of choledocholithiasis (common bile duct stones). However, because intrahepatic ductal dilation is readily seen with ultrasound, this finding

917

FIGURE 47.7. Ultrasonography of the gallbladder. The sonographic signs of gallstones include visible stones that produce acoustic shadowing (white arrow) and that move with the patient. (Courtesy of the Department of Radiology, UCSF.1

can serve to support the diagnosis of common duct stones with obstruction. It is important to remember that while ultrasound is an excellent, noninvasive tool for the diagnosis of gallstone disease, it is not perfect . Gallstones can be present, yet difficult to document sonographically. A sensitivity of 95% means that in up to 5% of patients gallstones will be present but go undetected by this diagnostic modality. As cholelithiasis is a common condition, clinicians are likely to find themselves from time to time confronted by patients with clinical signs and symptoms characteristic of stone disease yet appearing normal on ultrasound examinations. Under such circumstances, it should be remembered that biliary sludge and micro calcifications are likely causes of biliary colic, acute cholecystitis, and acute pancreatitis that can escape ultrasound detection." COMPUTED TOMOGRAPHY

Although abdominal computed tomographic (CT) scanning is probably the most informative single radiographic tool for examining intraabdominal pathology, its overall value for the diagnosis of biliary tract disease pales in comparison to ultrasonography. This disadvantage is largely because gallstones and bile appear nearly isodense on CT; that is, it is difficult to distinguish gallstones from bile unless the stones are heavily calcified. Therefore, CT documents the presence of gallstones within the biliary tree and gallbladder with a sensitivity of approximately 55% to 65% . However, abdominal CT is a powerful tool for evaluating biliary tract diseases when the differential diagnosis includes a question of hepatobiliary or pancreatic neoplasm, liver abscess, or hepatic parenchymal disease [e.g., biliary cirrhosis, organ atrophy). CHOLANGIOGRAPHY

Defined as the mapping of bile ducts, cholangiography functionally involves the installation of contrast directly into the biliary tree and is the most accurate and sensitive method available to anatomically delineate the intra- and extrahe-

918

CHAPTER 47

patic biliary tree . A cholangiogram is indicated when the diagnosis or therapy depends on a precise knowledge of biliary anatomy. Generally obtained to determine the location and extent of an intraluminal obstruction, diagnostic cholangiograms can be performed percutaneously, endoscopically, transabdominally [e.g., intraoperative cholangiogram), or through the use of intravenous or oral contrast material taken up and excreted by the liver into bile. The level and nature of the lesion, along with the patient's overall medical condition, are the primary guidelines that dictate which approach is preferred. Percutaneous transhepatic cholangiography (PTe) requires a dilated intrahepatic ductal system and is invaluable for defining the upper extent of obstructing lesions. Endoscopic retrograde cholangiopancreatography (ERCPI is better suited for defining the lower limit of obstructing lesions, yet it also allows for the biopsy of any masses encountered for diagnostic purposes. Both approaches can be used to decompress the biliary tree and remove calculi. Regardless of the approach, injection of contrast into an obstructed biliary system is commonly associated with transient bacteremias and occasionally precipitates an episode of frank sepsis. These risks are reduced through the use of broadspectrum antibiotic prophylaxis, avoidance of high in jection pressures, and by minimizing the total number of injections performed during the examination. Intravenous cholangiogra phy is more popular in Europe than the United States and has the significant disadvantage of requiring normal liver function . Magnetic resonance cholangiopancreatography (MRCP) is a recently developed, totally noninvasive imaging technique that can provide detailed anatomical information without the direct in jection of contrast into the biliary system.' It obviates the need for physically manipulating the patient and thus promis es to combine the convenience of CT with the data quality of traditional cholangiograms (Fig. 47.8). As this imaging method is new and incompletely proven, its overall role in the diagnosis of biliary system disease awaits further experience. SCINTIGRAPHY

Biliary scintigraphy is useful to visualize the biliary tree, assess liver and gallbladder function, and diagnose several common disorders with a sensitivity and specificity of 90% to 97%, respectively." Although an excellent test to decide whether the common bile and cystic ducts are patent, biliary scintigraphy does not identify gallstones or yield detailed anatomical information. Commonly employed agents for this type of test are 99rnTc-Iabeled iminodiacetic acid derivatives because these compounds are rapidly taken up by the liver and excreted into the bile. To perform biliary scintigraphy, an appropriate agent is administered intravenously to a fasting patient, and the process of hepatic uptake and biliary excretion is monitored over time through the use of a gamma camera. This process generates a series of motion picture-like images that allow one to determine whether the extrahepatic bile ducts, including the cystic duct, are patent. Normally, the radioisotope is seen to concentrate within the liver, outline the extrahepatic biliary tree and gallbladder, and flow into the small intestine within approximately 30 to 45 min (Fig. 47.9A). Failure of the

A

B FIGURE 47.8. Normal (A) magnetic resonance cholangiopancreatogram and a gallstone obstru cting the common bile duct (BI.(Reprinted with permission from John V. Phillips, MD , Medic al Director, Parkside MR Center, Lutheran General Hospital, Park Ridge, IL.1

radiolabeled compound to fill the gallbladder, despite liver uptake and excreti on into th e small bowel, is considered diagnostic of acute cholecystitis; presumably, th e gallbladder failed to fill becaus e of an obstructed cysti c duct (Fig. 47.9BI· False-negative studies can occur in patients with abdom inal pain due to acalculous cholecystitis as the pathogenesis of this disease entity does not require cystic duct obstruction. Regardless, scintigraphy remains of diagnostic value in these patients because gallbladder imaging is usually abnormal secondary to edema and inflammation of the cystic duct. False positives can result from gallbladder stasis and poor filling, as seen with chronic cholecystitis, alcoholism, or extended administration of total parenteral nutrition (TPN). ORAL CHOLECYST OGRAPHY

The oral cholecystographic method of imaging the biliary system works via principles similar to scintigraphy but has

BILIARY S YS T E M

919

effective in most cases. Recent advances in our understanding of how calculi form and in surgical technology, however, have virtually revolutionized the approach to this widespread disease, dramatically expanding the therapeutic armamentarium available to physicians.

Pathogenesis CLASSIFICATION OF GALLSTONES

15

, ,

5

40'

45 '

50'

A 5

30'

C

• vi

55'

B

i,..

~ «

35'

60'

'.

i

11"-

l",

FIGURE 47.9. Hepatobiliary scintigraphy. (A) Normal (negative I study. (B) Positive study showing failure of the gallbladder to fill supporting a diagnosis acute cholecystitis. (Figures courtesy ofUCSF Department of Nuclear Medicine.] been largely supplanted by other more convenient or informative radiographic modalities. Instead of using a radiolabeled pharmaceutical, patients are given oral contrast pills 12 to 16h before the exam, during which time the peroral contrast material is absorbed by the small intestine, cleared by the liver, excreted into bile, and concentrated within the gallbladder. Subsequently, the gallbladder and common bile duct are visualized using traditional abdominal radiographs. Oral cholecystography generates images with much greater clarity and resolution than scintigraphy but requires more planning to perform and yields less-dynamic information. Disorders of the foregut (gastroparesis, small -bowel obstruction, and pancreatitis) or impaired liver function (hyperbilirubinemia) can all interfere with contrast absorption and thus generate a falsely negative exam.

Calculous Disease Calculous disease of the biliary system is a common and significant medical problem throughout the world. While the frequency, type, and distribution of gallstones within the biliary tree vary among different populations of people, the presence of intraluminal calculi places all patients at risk for a range of clinically symptomatic conditions. Interestingly, the exact pathogenesis of gallstone disease is incompletely understood and remains the subject of intense study. None theless, removal of the gallbladder has been the mainstay of therapy for symptomatic gallstones and has proven quite

There are three types of gallstones: cholesterol, pigment, and mixed cholesterol and pigment stones. The distribution and location of biliary calculi varies throughout the world, undoubtedly reflecting different risk factors for their formation . In patients in the United States and most westernized countries, approximately 75% of gallstones are of the mixed type, 15% are pigment stones , and the remaining 10% pure cholesterol (Fig. 47.10). The stones are most commonly located within the gallbladder but can on occasion be found within the common bile duct or the liver or to have migrated into the intestinal tract. These findings are in stark contrast to those in other regions of the world, such as Southeast Asia, where the majority of biliary calculi are of the pigment variety and are most commonly located within the liver itself and not the gallbladder. Such variation also applies to the overall incidence of gallstone disease. In the United States, about 12% of the population has cholelithiasis, with more than 950,000 new cases diagnosed each year, while in East Africa and other selected Third World countries the incidence is as low as 2% to 3 %. The risk of developing biliary calculi throughout America and western Europe is directly proportional to a person's age and sex. While children and adolescents rarely have gallstones, by the seventh decade of life 10% of men and 25% of women have documented cholelithiasis. CHOLESTEROL-ENRICHED GALLSTONE FORMATION

The exact mechanism by which gallstones are formed is not fully understood, but calculi are likely the result of a complex, multifaceted alteration in hepatobiliary function (Table 47.2). Calculous disease has and continues to be the subject of intensive research . Yet, definitively detailing how stones develop has been significantly hampered by the absence of an appropriate animal model and the difficulties inherent in comprehensive longitudinal studies on humans, many of whom must be "normal" and thus either asymptomatic or without stones altogether. Regardless, the prevailing theory regarding the pathogenesis of cholesterol-enriched gallstones entails a multistep process that can be promoted by a variety of physiological, metabolic, or genetic variables. CHOLESTEROL-SUPERSATURATED BILE

An early event in the process of gallstone formation is a

change in the composition of bile, specifically a relative increase in the cholesterol content. Normally, bile is an isotonic combination of water, electrolytes, and organic macro molecules that is actively secreted by the liver. Designed to aid in the solubilization (emulsification) and subsequent absorption of dietary fats, the solute composition of bile includes bile salts, cholesterol, and phospholipids, predominantly phosphatidylcholine (lecithin). Bile salts are amphipa-

920

CHAPTER 4 7

Gallb ladde r wall

Gallbladde r wall

Gallbladder lumen

Mucin gel

Cholesterol crysta ls

FIGURE 47.10. Pathogenesis of gallstones .

thic molecules (containing both hydrophobic and hydrophilic domains) that in concert with neutral lipids act as detergents, serving to break down dietary fats into smaller, more soluble micelles (Fig. 47.11). The size and character of micelles formed, along with the efficiency with which this process takes place, are largely

dependent on the ratio of cholesterol to bile salts to phospholipid present in the bile. Approximately 30 years ago Admirand and Small proposed the concept that when the relative concentration of cholesterol in bile exceeded its solubility constant, the excess lipid would precipitate and thus initiate gallstone formation." The formation of cholesterol-

TABLE 47.2. Clinical Risk Factors Associated with Cholesterol Gallstones. Risk factor

Pathogenesis

Age

Gallstone formation is a time-dependent process; 40 is the typical age at clinical diagnosis; possible age-related decrease in the conversion of cholesterol to bile salts Female :mal e ratio 53 : 1; estrogens increas e the uptake of plasma cholesterol by the liver with subsequent increased bile cholesterol saturation High risk: Pima Indians, other Native Americans, Hispanics, whites Low risk : Black Africans and African Americans Increased relative risks if parents, siblings, or first-degree relatives have gallstones Increased activity of hydroxy-methylglutaryl-CoA (HMG) reductase leads to increased cholesterol synthesis and bile cholesterol saturation Decreased ileal resorption of bile salts Gallbladder stasis and distension; risk exacerbated in patients with Crohn 's disease Intestinal bypass surgery and low-calorie, high-protein diets associated with high incidence of gallstones because of decreased bile salt secretion and gallbladder stasis

Gender

Race and ethnicity

Genetics Obesity

Crohn 's disease Total parenteral nutrition Rapid weight loss

.J!.

40·

~c),.

'%

Two or more phases (cholesterol crystals • and micellar liquid)

I

I

I

I

I

60\

\\

I

c 100

\.

80

60

40

% Bile salt

100

20

0

"

FIGURE 47.11. Solubility of the three major components of bile (bile salts , lecithin, and cholesterol] plotted on triangular coordinates. Point P represents bile composed of 80% bile salts , 5% cholesterol, and 15% lecithin. Line ABC represents the maximal solubility of cholesterol as a function of various bile salt and lecithin concentrations . When the combination of bile salts, cholesterol, and lecithin falls below the ABC line, th e bile exists as a single-phase micellar liquid . When the constituents of bile are plotted above this line, however, there is supersaturation of cholesterol and the formation of cholesterol crystals . (Adapted with permission from Admirand and Small."]

BILIARY SYSTEM

supersaturated bile could, theoretically, result from either increased cholesterol synthesis or decreased bile salt or phospholipid secretion by the liver. This tripartite interrelationship among the concentrations of cholesterol, bile salts, and phospholipid in bile is commonly displayed graphically using triangular coordinates (see Fig. 47.11). As the molar ratio of cholesterol relative to either bile salts or phospholipid deviates from a relatively narrow range, the cholesterol solubilization capacity of bile is exceeded, resulting in rapid cholesterol crystal formation (see Table 47.1). Bile cholesterol is commonly thought to exist as part of mixed micelles, with this nonpolar lipid concentrated within the hydrophobic core of these particles. There is, however, also evidence that as much as 70% to 800/0 of the cholesterol in bile actually exists in a vesicular form, distributed throughout the bilipid membrane of an unilamellar liposome. Although the macromolecular distribution of cholesterol between the micellar and vesicular forms varies according to bile concentration, it is interesting to speculate whether the different forms of cholesterol affect the overall lithogenicity of bile. GALLSTONE NUCLEATION

Once bile has become supersaturated with cholesterol, the formation of a cholesterol-enriched gallstone presumably begins with a nucleation event. The precipitation of crystalline cholesterol is thought to occur via either the fusion or implosion of cholesterol-rich vesicles.i'v'! A variety of different crystal shapes has been recently identified in bile samples from numerous patients with gallstones." These distinct cho.lesterol structures, including arcs/needles, spirals, tubes, and plates, may represent different stages in the nucleation process as well as the existence of different cholesterol crystallization pathways. The possible contribution of gallbladder mucus to the formation of gallstones represents a fascinating example of how the different variables involved in the process of stone formation can be intricately interrelated. The concentration of deoxycholate is increased in cholesterol-supersaturated bile. This hydrophobic bile salt subsequently stimulates the hypersecretion of mucus glycoproteins by the gallbladder epithelium. The resultant increase in gallbladder mucus in tum may promote stone formation by the trapping of cholesterol microcrystals. While the cause-and-effect nature of this sequence of events is in part speculative, there are both animal and human data that correlate increased gallbladder mucus production with the formation of biliary calculi. Other gallbladder-derived proteins are also thought to play a role in the pathogenesis of biliary calculi as both promoters and inhibitors of the process. A few of the nonmucin glycoproteins that can promote cholesterol nucleation include phospholipase C, aI-acid glycoprotein, fibronectin, and immunoglobulin (Ig) M, IgA, and IgG. Inhibitors of stone formation secreted by the liver into bile include apolipoproteins A-I and A-2 and a poorly characterized 120-kDa glycoprotein. Because the activities of these various proteins have been studied exclusively in vitro, their significance to in vivo disease has yet to be determined. GALLBLADDER AND FOREGUT MOTILITY

Gallbladder stasis has long been associated with the formation of gallstones. Beyond the intuitive sense that a stagnant

921

pool of supersaturated bile must promote nucleation and stone growth, there is a growing body of data to support the concept. Initially, clinicians associated gallbladder stasis with numerous clinical settings in which there was an increased risk of cholelithiasis, such as pregnancy, truncal vagotomy, and the extended use of TPN. Recently, using a combination of biliary ultrasound and scintigraphy, impairments in both postprandial and interdigestive gallbladder emptying have been carefully documented in many patients with symptomatic gallstones. Specifically, investigators have demonstrated that the volume of bile flow through the gallbladder during the postprandial period is dramatically reduced and leads to a large, flaccid gallbladder.P'" Many cholesterol stone patients also have increased fasting gallbladder volumes. This last observation may represent the contribution of a more widespread motility disorder of the foregut to stone formation in selected patients. For example, women with gallstones were found to have significantly longer whole-gut transport times with only half the stool output as compared to stone-free patients. In addition, many gallstone patients were found to have longer cycles of the intestinal migrating motor complex (MMC) with disruption of motilin release. Although none of these alterations in motility are universal findings, they nonetheless underscore the importance of normal foregut physiology and contribute to our understanding of this common, yet complex, disease. GENDER AND GENES

Gallstone disease is more common in women than in men at virtually all stages of life. Because this gallstone gender gap narrows by the eighth and ninth decades of life, it is likely the result of estrogen-induced changes in biliary lipid metabolism and gallbladder function. Evidence in support of a role for hormones in gallstone formation includes the observation that exogenously administered estrogen increases the incidence of cholesterol stones in both men and women. Also, estrogen may promote the supersaturation of bile by inhibiting the conversion of cholesterol to bile salts, thereby increasing the hepatic secretion of cholesterol into bile while simultaneously decreasing the secretion of bile salts. Last, pregnancy is associated with impaired gallbladder emptying and an overall increase in bile stasis. In the United States, the typical patient with symptomatic gallstones is "female, forty, fat, and fair." The role of heredity in biliary calculous disease is not well understood. Although there are specific ethnic populations with widely divergent rates of cholelithiasis, exactly what accounts for these differences is not known. A most dramatic example of an ethnic risk factor for gallstone disease can be found among the Pima Indians of the American Southwest. By the third decade of life, approximately 80% of Pima women have documented gallstones. Analysis of bile from these women reveals extreme cholesterol supersaturation with concurrent alterations in hepatic cholesterol and bile salt secretion. There is also a high incidence of diabetes mellitus and obesity, two additional risk factors for cholelithiasis. The importance of genetics as a risk factor for gallstones is evident in studies of family history. A history of cholelithiasis in a first-degree relative doubles a person's risk of developing gallstones, and this genetic risk factor is greatest with a parental history of biliary calculi."

922

CHAPTER 47

BILE CALCIUM

Calcium has been recognized as a component of gallstones, especially pigment stones, for hundreds of years. In fact, approximately 15% of biliary calculi contain enough calcium as to be visible on plain radiographs of the abdomen. However, the role of calcium in the pathogenesis of gallstones is another uncertainty. Calcium was not originally thought to contribute to the formation of cholesterol stones, but recent studies have identified calcium carbonate within the core of these stones. Also, there are data showing that increased biliary calcium can promote cholesterol crystallization and gallstone nucleation via an unknown mechanism.

TABLE 47.3. Pigmented Gallstones. Characteristics

Black

Brown

Color Size Consistency Anatomical location

Black 2-6mm Solid, rock-hard Gallbladder

Geographic location Associated conditions

West and Asia

Brownish -orange 5-30mm Soft, sandy, sludge Intra- and extrahepatic bile ducts Predominantly Asia

OBESITY

Excess body fat is another independent risk factor for gallbladder disease. Studies using oral cholecystography or ultrasonography have documented a direct relationship between obesity and gallstones.P:" While the pathogenic mechanism linking obesity to cholelithiasis is unclear, it may involve alterations in lipid biogenesis with increased cholesterol synthesis. Regardless of mechanism, the relative risk of gallstones increases dramatically with morbid obesity. UNIFYING HYPOTHESIS

Even though the formation of cholesterol-enriched gallstones is a complex, multistep process, a unifying hypothesis has emerged in an attempt to further our understanding of this clinically important disease." The hypothesis states that cholesterol hypersecretion, with its consequent biliary cholesterol supersaturation, places patients with either a genetic or metabolic susceptibility to form cholesterol stones at high risk (see Fig. 47.10). Theoretically, the chronic hypercholesterobilia has a pathological effect on the gallbladder wall muscle by incorporating excess cholesterol into the sarcolemma and thus leads to gallbladder and small intestinal hypomotility. At this point, a series of events may occur, any one of which can serve to promote cholesterol crystallization, including changes in gallbladder mucin production, further changes in bile composition, and the secretion of stone-promoting proteins by the liver. Once the nucleation event takes place, gallbladder hypomotility and stasis propagate further cholesterol deposition and stone growth. The testing of thermonuclear devices during the late 1950s and early 1960s enabled investigators to carbon date (measurement of 14C) gallstones and determine that biliary calculi grow at a rate of 2 to 3mmjyear.20 The study further revealed that gallbladder stones grow for an average of 8 years after the nucleation event before becoming symptomatic.

Pigment Stones While only about 15% of gallstones in the United States are pigment stones, this type of biliary calculus is the predominant variety throughout the world. The sine qua non of pigment stones is their high concentration of bilirubin combined with low cholesterol content. These stones are usually mixed with a substantial amount of calcium bilirubinate and can be further categorized as either black or brown as a function of their gross appearance. Considerably less is known

Radiographic appearance Etiology

Hemolytic anemia, cirrhosis, alcoholism, extended TPN use, following ileal resection Radiopaque (700/0)

Liver parasites, ductal strictures, biliary tract infections

Increased excretion unconjugated/ deconjugation of bilirubin

Bacterial hydrolysis of conjugated bilirubin, possibly nucleated by ductal parasites or debris

Radiolucent

regarding the pathogenesis of pigment versus cholesterolenriched gallstones, but some clinical and in vitro studies suggest that biliary infection and stasis play critical roles in their development. Certainly, there appear to be different risk factors for developing black versus brown pigment gallstones. Black pigment stones are very dark in color, rock-hard in consistency, and commonly found in the gallbladders of patients with hemolytic disorders or chronic liver disease, after extended TPN use, or following ileal resection (Table 47.3). Under these circumstances, it is thought that an excessive load of bilirubin is delivered to or synthesized within the liver that far exceeds organ capacity to conjugate (and thus render water soluble) this macromolecule. Presumably, the unconjugated, relatively hydrophobic pigment is then directly secreted into bile, where it can precipitate with calcium carbonate. As the name suggests, brown pigment gallstones are lighter in color and softer in consistency than black pigment stones and are commonly found within the liver or extrahepatic bile ducts of patients with biliary strictures or those born in Southeast Asia. Biliary infection and stasis caused by ductal obstruction are considered the critical etiological factors in brown pigment stone formation. In this case, the bacterial deconjugation of bile salts may create a lithogenic environment that is unique in composition but functionally not unlike that described for patients with hemolytic disorders.

Gallbladder Sludge and Microcalculi The formation and clinical significance of gallbladder sludge is unclear, but it is observed with sufficient regularity to warrant mention." Generally identified via abdominal sonography, sludge appears as echogenic material within the gallbladder, and it layers in the dependent area of the gallbladder yet does not generate the postacoustic shadows characteristic of gallstones. Commonly seen following prolonged fasting,

BILIARY SYSTEM

sludge is thought to represent bile that has become concentrated within a relatively static gallbladder. In a study of patients on long-term TPN, the incidence of gallbladder sludge increased as a direct function of time. Within 3 weeks of starting TPN, 50/0 of patients developed sludge; by 4 to 6 weeks, the incidence had increased to 50%; and after 6 weeks, it was a universal finding." Although the natural history of gallbladder sludge is not known, it is not considered a pathological finding as it generally resolves with resumption of an oral diet. Yet, not infrequently gallbladder sludge is associated with the presence of microcalculi and contributes to the development of cholelithiasis and acute cholecystitis.l':" Cholesterol crystals can be identified microscopically in gallbladder or bile duct bile.

Clinical Syndromes Gallstone disease continues to be a major health care problem in the United States and throughout selected parts of the world. There are more than 26 million Americans with gallstones, and although most of these people are asymptomatic, more than 700,000 cholecystectomies are performed each year. The total annual cost of medical care for patients suffering from biliary calculous disease is estimated at more than $7 billion. Still, not all gallstones require treatment. In fact, in the majority of patients (600/0-800/0) gallstones are completely asymptomatic. However, once symptoms develop patients are at risk for a wide range of problems, ranging from simple biliary colic to ascending cholangitis and septic shock. ASYMPTOMATIC GALLSTONES

Once "silent" gallstones are discovered, the clinician is confronted with the question of what, if anything, to do about them. To logically address this question requires information regarding the natural history of asymptomatic gallstones. Data from several longitudinal studies reveal that approximately 100/0 to 200/0 of patients with silent gallstones go on to develop symptoms, most commonly biliary colic.":" Serious symptoms or complications such as acute cholecystitis develop in these patients at a rate of 1% to 3 % per year. These observations, combined with the fact that only 0.50/0 to 1.00/0 of patients die of complications from their silent gallstones, strongly suggest that asymptomatic gallstones generally follow a benign course. A formal decision analysis performed to compare the consequences of prophylactic cholecystectomy versus expectant management for asymptomatic gallstones concluded that prophylactic surgery slightly decreased expected survival." Using probability data on the natural history of silent gallstones, published mortality rates for cholecystectomy, and actuarial life tables, the analysis revealed that prophylactic surgery decreases average survival time. A 50-year-old man electing prophylactic cholecystectomy would lose 18 days of life, while a 30-year-old man would lose 4 days; the predictions are similar for women. Therefore, there is little role for the prophylactic medical or surgical treatment of asymptomatic gallstones. These interventions should be reserved for those patients who have experienced significant clinical symptoms, a calcified (porcelain) gallbladder, or gallbladder polyps.

923

Expectant management of asymptomatic gallstones in diabetic patients is somewhat controversial, with some clinicians proposing prophylactic surgery because of the morbidity and mortality associated with emergency surgery in this specific patient population. However, a recent prospective study assessed the natural history of gallstones in patients with non-insulin-dependent diabetes and concluded that, as with nondiabetic patients, prophylactic surgery is not advisable." Asymptomatic diabetic patients developed symptomatic cholelithiasis (predominantly biliary colic) at a rate of approximately 3 % per year. Because the risk of becoming symptomatic in diabetics is similar to that reported for the general population, prophylactic surgery is difficult to justify.

ACUTE CHOLECYSTITIS

One of the most common complications of symptomatic gallstones that requires surgical intervention is acute cholecystitis. This condition is thought to result from impaction of a gallstone in the cystic duct or neck of the gallbladder, thereby completely obstructing the organ. Consequently, the gallbladder becomes distended and somehow initiates a localized acute inflammatory reaction. The exact pathogenesis of acute cholecystitis is not well delineated, but the clinical syndrome begins with biliary colic-type pain. Biliary colic typically resolves over several hours, but the pain of acute cholecystitis persists and intensifies over days. Initially, the pain is vague and visceral in nature, but as the acute inflammation of the gallbladder becomes transmural, the visceral and adjacent parietal peritoneal coverings become irritated. At this point, the patient's discomfort is no longer vague and diffuse, but localizes to the right upper quadrant and is associated with guarding and rebound tenderness. As described earlier, the classical physical finding of acute cholecystitis is a positive Murphy's sign (inspiratory arrest on palpation of the right upper quadrant). Patients may also complain of nausea and vomiting, anorexia, and a low-grade fever. In many cases, the physical exam reveals a mass in the right upper quadrant. This mass or "phlegmon" represents the body's effort to wall off and compartmentalize the inflamed gallbladder using adjacent organs, including the greater omentum, first portion of the duodenum, and right colon. Laboratory abnormalities are nonspecific but may reveal a mild leukocytosis and minor elevations in the liver function tests. The diagnosis is confirmed via abdominal ultrasound, with the findings of gallbladder wall thickening and pericholecystic fluid virtually pathognomonic. For further confirmation, the ultrasonographer can demonstrate a "sonographic Murphy's sign." With the ultrasound transducer placed directly over the distended gallbladder, the sonographer presses down in an effort to re-create the patient's discomfort. The source of pain from the gallbladder can thus be distinguished from other conditions, such as liver tenderness or hepatitis. Severe forms of acute cholecystitis can result in gallbladder empyema, in which the organ is filled with purulent bile and debris, and emphysematous cholecystitis, which is characterized by necrosis and gas within the wall of the gallbladder. The latter condition typically occurs in diabetic patients and demands aggressive decompression of the gall-

TABLE 47.4. Clinical Trials Comparing Early Versus D elayed Surgery for Acute Cho lecystitis.

Reference

n

Linden and Sunzel 1970/ ° Sweden

140 Random ized, controlled trial

McArthur et a1. 1975/ ' England

Study design

Level of evi dence Complications

Mort ality

Findings/comments

Early: 14.3 % Delayed: 3.4%

Early: 0% Delayed: 0 %

35 Rando mi zed, controlled trial

Early: 40.0% Delayed: 29.4%

Early: 0% Delayed : 0%

Lahtinen et a1. 1978/ 2 Finland

100 Randomized, controlled trial


Early: 0% Delayed: 9%

Norrby et a1. 1983/ 4 Sweden

192 Randomized, controlled, m ult icenter, trial

Early: 14.9 % Delayed: 15.4%

Early: 0% Delayed: 1.1 %

Sianes i et a1. 1984/ 5 Italy

471 Retrospective (1970-77) and prospective (1977-8 2) dat a

III

Early: 18.5% Delayed: 15%

Early : 0 % Delayed: 1.6%'

III

Early: 41 % Delayed: 12.5%

Early: 2.6% Delayed: 0 %


Early: 0.2% Delaye d: 1.8%

Mor e than two -th irds of patients randomized to early surgery underwent operati on within 10 days of diagnosis Low mortality in part the result of excluding 3 high risk, elderly patien ts Noted that 17% of pati ents rand omized to delayed surgery ultimately refused operation once acute symptoms resolved No difference in technical difficulty bet ween early and delayed operations wh en th e surgeon was experienced Early surgery [paradoxically] resulted in a 2-daylonger average length of st ay, but few er extended hospitalizations Concluded that early surgery avoids th e hazards of diagnostic error, sym ptom recurre nce duri ng the waiting period, and shorte ne d th e con valescence period after early surgery Early surgery defin ed as immediat ely following confirmation of the diagnos is Reported no overall difference in th e technical difficu lty of early versus delayed cholecystectomy, but recommended th at early sur gery take place within 5 days of diagn osis Most complications were m inor infec tions; Concluded tha t th e m ajor benefit s of early sur gery are the shortened ho spi talizatio n and th e avoidance of th e seriou s com plicat ion s of conservative m anagem ent , including gallbladder perforation and empyema . Noted a technically easier operation, shorte r OR time (70 vs. 79min), redu ced wound infection rate (6% vs. 18%), and shorter postoperative hospital LOS (12 vs. 15 days) for early vs. delayed surgery High complication rates in both groups predominantly related to localized or systemic infection Authors recommend earl y surge ry Early surgery defin ed as opera tion within 7 days of symptoms Stu died patients 6 days. Study combined retrospective and prospective data, collected over 12 years, during which time patient managem ent evolved Reported low incidence of biliary infection, low morbidity and mo rtality, and shorter hospitalization period Authors recommend early surgery , within 48-72h of diagnosis Retrospective review over 12 months, com pared early (3cm only) (Biecker et al. 2003)14 Technetium-sulfurcolloid: variable uptake (Kehagias et al. 2001)184

Adenoma

Variable, nonspecific appearance (Hung et al. 2001)181

Technetium-sulfurcolloid Variable uptake

Tl: hypointense central scar T2: hyperintense central scar Gadolinium: early enhancement (850/0-95 % ) (Mortele et al. 2000P91 T2: hypervascular, early enhancement, may have evidence of hemorrhage

Simple cyst

Hypoechoic, well circumscribed, no septations

Not visualized

Echinococcal cyst

Well circumscribed with distinct capsule (Caremani et al. 2003)176

IV contrast-enhanced study: Hyperintense with central scar defect, delayed filling of central scar (850/0-95 %) (Brancatelli 2001P75 IV contrast = enhanced study: Well-defined capsule, hypervascular, early enhancement, may have evidence of hemorrhage IV contrast-enhanced study: Low attenuation, well circumscribed, no septations, 0-10 hounsfield units (Carrim and Murchison 2003)18 Well circumscribed with distinct hypervascular capsule, may have calcifications (Haddad et al. 2001)179

Lesion

Ultrasound (accuracy %)

Hemangioma

Homogeneous, lobulated, hyperechoic mass (700/0-800/0 ) (Descottes et al. 2003)177

Focal nodular hyperplasia

Tl: hypointense T2: hyperintense, well circumscribed Gadolinium: enhancement Signal intensity parallels cerebrospinal fluid Tl: hypointense with rim evident T2: hyperintense with hypointense rim Gadolinium: Solid components of cyst may enhance (Kodama et al. 2003)186

946

CHAPTER 48

Hemangiomas Hepatic hemangiomas are the most common benign hepatic tumor, with incidences as high as 3 %-20% in autopsy series, occurring most commonly in middle-aged women and with a 6 : 1 female-to-male ratio. l" The majority of hemangiomas are small «Scm), often multiple, and asymptomatic." The published Mayo Clinic experience confirms that fewer than 15% of hemangiomas less than 10em are symptomatic, while 90% of patients with hemangiomas larger than lOcm have symptoms." Hemangiomas are felt to arise from ectatic rather than hyperplastic vessels, with the blood supply arising from the hepatic artery.' Hemangiomas are usually accurately diagnosed with radiologic imaging studies as there are characteristic features, summarized in Table 48.1. Percutaneous biopsy is avoided due to bleeding risk, and resection is rarely necessary (Fig. 48.5). Surgical resection or enucleation is indicated for rare cases in which symptoms are disabling; complications of rupture, thrombosis, necrosis, or disseminated intravascular coagulopathy occur; malignancy cannot be excluded."

A

Focal Nodular Hyperplasia Focal nodular hyperplasia (FNH), second in incidence of benign hepatic tumors, is a typically well-circumscribed lesion with a classical central stellate "scar" with radiating fibrous septae as seen in radiographic imaging (Table 48.1 ; Fig. 48.6). Although found in both males and females, FNH is more common in females of reproductive age (femaleto-male ratio of 8: l).s The etiology of this lesion is not entirely clear, although in a classic morphometric study by Wanless et a1. of 51 FNH cases it was shown that FNH is a hyperplastic response of the liver to a preexisting vascular abnormality," There is limited evidence of an association of FNH development with the use of oral contraceptives." Usually, FNH tumors are solitary, although at least 20% of individuals with FNH have multiple lesions." The tumors of FNH can be safely observed without the need for biopsy or resection as there is no evidence of malignant potential, and they are most commonly asymptomatic. Spontaneous regression or growth can occur without concern. If the diagnosis is unclear, an FNH tumor may be biopsied if this can be done safely.

B

Adenoma Hepatic adenomas are a benign proliferation of sheets of hepatocytes with no portal triads. Adenomas also arise predominantly in young women, with a female-to -male ratio of 4 : 1.s Of adenomas, 70% are solitary," They are round, well circumscribed, 5- to IS-em lesions, often with a pseudocapsule (Fig. 48.7). Although these are benign tumors, there are isolated case reports of primary hepatocellular carcinomas (HCCs) developing within adenomas." The incidence of hepatic adenomas has increased with the use of oral contraceptives, particularly in patients with long-term use of high dose estrogen." Patients with glycogen storage disorders also have an increased incidence of adenomas." Adenoma may be symptomatic with abdominal pain, or the sensation of a mass, in approximately 50% of patients secondary to frequent intratumoral hemorrhage or necrosis.

c FIGURE 48.5. Imaging demonstrating hepatic hemangioma (AI early arterial phase image, (B) delayed image demonstrating delayed contrast enhancement, and [C]T2-phase, gadolinium-enhanced MRI demonstrating hepatic hemangioma .

Free intraperitoneal rupture, presenting with abdominal pain or signs of bleeding, occurs in 10% to 20% of cases, while the remainder of adenomas are found incidentally, either through imaging or at laparotomy. Diagnosis of adenoma is based on accurate imaging with CT and magnetic resonance imaging (MRI), reflecting the hypervascular and hemorrhagic nature

LIVER

947

FIGURE 48.6. Computed tomographic scan demonstrating focal nodular hyperplasia.

FIGURE 48.8. Computed tomographic scan of a large symptomatic simple liver cyst.

of these tumors (Table 48.1), so that percutaneous needle biopsy is rarely indicated. Patients who present with a liver mass that on imaging is suspected to be an adenoma should stop use of oral contraceptives or anabolic steroids as regression of these lesions has been reported several months after steroid removal. 15 Adenomas have a risk of rupture or malignant transformation; therefore, all lesions that fail to regress should be resected or locally ablated to prevent life-threatening bleeding or progression to HCc. 16

cal disease is common in certain parts of the world and is the most common cystic lesion to require surgical treatment.

Liver Cysts Liver cysts are frequently identified incidentally on radiographic imaging and at laparotomy (Fig. 48.8). The most common liver cyst encountered in Western society is the congenital or developmental cyst, which usually is solitary but may be associated with polycystic disease, which more often affects the kidneys alone but can affect both the kidneys and liver. Tumors of the liver are sometimes cystic as a result of degeneration, or they may have a primarily cystic component, as in cystadenoma or cystadenocarcinoma. Echinococ -

FIGURE 48.7. Computed tomographic scan demonstrating a hepatic adenoma with associated hemorrhage.

Congenital/Developmental Cysts SOLITARY CYSTS

Simple hepatic cysts are common incidental findings, seen in approximately 5% of hepatic radiographic studies, most commonly in the right lobe and most commonly in women.F:" Simple cysts are congenital and are felt to arise from abnormal embryologic bile duct differentiation and organization as the cysts are lined by cuboidal epithelium." Congenital cysts are often diagnosed by ultrasound as having a thin wall and central fluid collection. These simple cysts are asymptomatic and require no treatment. POLYCYSTIC LIVER

Childhood polycystic disease is inherited in an autosomal recessive pattern and usually affects both the liver and the kidneys ." Hepatic cysts in childhood polycystic disease are usually asymptomatic, and the renal manifestations are of greater significance. Liver function is usually preserved throughout life, although fibrosis and portal hypertension can occur. 21,22 Adult polycystic liver disease is inherited in an autosomal dominant pattern, with mutations in genes predisposing to renal and liver cysts (PKD1, PKD2, PRKCSHI.23,24 The liver is macroscopically diffusely cystic, although different patterns of disease, including unilobar cysts, are typical (Fig. 48.9). There is an increase in cyst development with progressing age, with hepatic cysts evident in 20% of affected individuals in their third decade of life, as opposed to 75% by the seventh decade of life.25 Cysts may also be found in the kidney, spleen , pancreas, ovaries, and lungs. While polycystic liver disease may present independent of polycystic kidney disease, the incidence of association by autopsy series has been 50%60%.26 The clinical presentation and complications of both adult polycystic liver disease and sporadic congenital cysts are similar." Fewer than 15% of patients are symptomatic, and

948

CHAPTER 48

Cystadenoma and Adenocarcinoma

FIGURE 48.9. Operative photograph of polycystic liver disease.

most series suggest a preponderance of women presenting with symptomatic cysts . Symptoms are usually related to a mass effect, with abdominal fullness and mild pain, although portal hypertension and jaundice may result from mass effect in all forms of cystic liver disease. Perforation, infection, and hemorrhage occur rarely.24,27 Careful selection of only symptomatic or complicated cysts is important when deciding whether cystic lesions require treatment because outcomes are almost entirely dependent on successful decompression of large cysts for which pressure symptoms dominate the clinical picture. There is no medical treatment for polycystic liver disease. Simple aspiration of hepatic cysts is only of use for diagnostic purposes and occasionally as a provocative test before more definitive therapy because recurrence rates approach 100%. Percutaneous aspiration followed by in jection of 95% ethanol or other sclerosants is now a well-accepted therapeutic modality, although recurrence rates vary widely.24,27-29 Surgical unroofing and decompression of large hepatic cysts is an excellent and highly effective treatment.P'" Laparoscopic approaches, in which the cyst is decompressed and a large portion of the cyst wall is excised, are currently an attractive strategy because of low morbidity and high efficacy. In most cases, a large portion of the cyst is easily accessible laparoscopically, and the visible cyst wall and thinned-out liver are resected, leaving a shallow, epitheliumlined cavity.32,33

True neoplastic cysts of the liver are rare compared with congenital cysts. Cystadenomas account for fewer than 5 % of hepatic cystic neoplasms and occur most commonly in ~omen?f middle age." Grossly, the tumors are usually large, III the right lobe, and multilocular, they will have contrast enhancement of the septa on CT imaging, and they contain a clear, mucinous fluid" (Fig. 48.10). Bloody fluid occurs more often in malignant cysts. Microscopically, the diagnostic features include a multiloculated lesion lined by benign or malignant mucin-producing cells often showing polypoid papillary projections into the cyst. The surrounding stroma is typically dense . The tumors are thought to be congenital in origin and slow growing. It is believed that cystadenocarcinomas are derived from benign cystadenomas because most of the malignant tumors contain a considerable amount of benign epithelium." Clinical and radiologic differentiation of neoplastic cysts from congenital cysts may be difficult (Table 48.1). Features suggestive of neoplastic cysts on ultrasound and CT include papillary projections or irregularities in the cyst wall, complex multilocular cysts, and the presence of cyst contents of different densities in different parts of a multilocular cyst. Any cyst suspected of being a cystadenoma should be explored and completely excised either by the technique of enucleation or by liver resection." Recurrence is rare if excision is complete, while incomplete resection yields a 90%-95% recurrence rate." Cystadenocarcinoma requires liver resection, and if the cyst is nonmetastatic, the prognosis is excellent, with 5-year survivals near 100% and recurrence rates of less than 15%.41

Hydatid (Parasitic) Cysts Hepatic hydatid cysts, the result of infection of the parasite Echinococcus granulosus, are common in rural areas where dogs are used for herding livestock and particularly in countries around the Mediterranean Sea and in South America and Australia. The ingested parasite embryo penetrates the wall of the intestine of the intermediate host, enters the portal circulation, and grows into a larva in the liver, forming a cystic structure." Hydatid cysts of the liver are often

Traumatic Cysts Hemorrhage into the liver parenchyma may occur with blunt or penetrating abdominal trauma. Bleeding is contained within the liver if the capsule is intact, and traumatic cysts containing blood, bile, and necrotic liver tissue may develop . Lack of a true epithelial lining denotes that traumatic cysts are in fact pseudo cysts . Unless a traumatic cyst becomes infected secondarily, it is best treated expectantly. Arterial infarction of the liver or of biliary stricture secondary to bile duct transaction or periductal inflammation may result in ischemic necrosis or segmental atrophy and the development of hemorrhagic or bilious cystS.34,35

FIGURE 48:10. Computed tomographic scan demonstrating large, complex, thick-walled cystadenoma in right lobe of liver.

LIVER

A

949

B

FIGURE 48.11. Hydatid cyst in right lobe (A) and in left lateral segment (B, arrow) . Note thick-walled setations of daughter cysts in A and whorled calcifications in B.

asymptomatic and may remain so until they reach a large size. Cysts are found frequently as an incidental finding (82%) on ultrasound or CT studies (Fig. 48.11) or because of the onset of pain or jaundice. Expansion of cysts in the liver may cause localized pain, and a mild chronic inflammatory reaction around the cyst may cause pain associated with the adjacent parietal peritoneum. A cyst may become secondarily infected and produce pain and fever and behave clinically as a liver abscess or may develop a bile leak and produce jaundice ." Hydatid cysts are diagnosed by radiographic findings (Table 48.1). The inflammation results in a hypervascular rim or halo around the cystic structure on CT scans and angiograms.r':" Calcification often occurs in the wall of the mature or dead cysts. In the jaundiced patient with hepatic hydatid disease, endoscopic retrograde cholangiopancreatography (ERCP) should also be performed to determine if the jaundice is the result of extrusion of cyst material into the bile duct or is merely a manifestation of cholangitis from the spill of infected fluid into the biliary tract. Serological studies are currently the most reliable adjunct to imaging tests in confirming the diagnosis of echinococcosis of the liver, and a recent blinded, randomized trial compared six serum antigens, confirming 80 %-82 % diagnostic accuracy using three serum antigens (HCF, AgB, AgB8jl).46 Although positive serological tests are helpful in diagnosis, their absence does not exclude the presence of echinococcosis. Percutaneous fine-needle aspiration may be necessary as a diagnostic test in the workup of the occasional complex liver cyst for which serology and imaging are nondiagnostic of hydatid disease.":" The treatment of hepatic hydatid disease requires control of the cyst and eradication of the parasite without host exposure to the severely antigenic cyst fluid . Systemic antihelminthic agents are generally not effective against human Echinococcus. Three randomized controlled trials comparing albendazole, mebendazole, and placebo all showed albenda zole to be most effective, but complete eradication of cysts with drug therapy alone was rare.":" Systemic drug therapy for cystic hydatid disease is considered an adjuvant to surgery in patients in whom accidental spillage of cyst fluid has occurred at operation, in patients with active disease who are unfit for surgery, and in patients who rupture hydatid cysts

spontaneously into the peritoneal or pleural cavities. 52,53The addition of the PAIR (percutaneous aspiration, injection with hypertonic saline, and reaspiration) technique in conjunction with systemic albendazole therapy has improved nonsurgical management of hydatid cysts with lower morbidity and mortaliry.t':" But, surgery remains the standard treatment approach, using aggressive resection versus fenestration approaches with an open or a laparoscopic approach.v-"

Malignant Lesions Hepatocellular Carcinoma Hepatocellular carcinoma (HCq is the fifth most common cancer in the world, with more than 500,000 estimated annual cases each year.58,59 With the disease on the rise in the United States, approximately 18,000 new cases are expected to occur in the United States in 2005.60 The mean age at diagnosis is between 50 and 60 years. 6O,61 Ninety-percent of HCC cases are associated with chronic liver disease, including principally due hepatitis B, hepatitis C, or alcoholic cirrhosis, which accounts for the high incidence in Southeast Asia and Africa, as well as the male-to-female ratio of 7: 1 in these high-risk countries.6O,62-64 Expected survival times for HCC patients without treatment are 8 months for stage I, 2 months for stage II, and less than 1 month for stage III disease." DIAGNOSIS

Most patients present with symptoms of tumor mass effect or progressive loss of hepatic function. Serum concentrations of a-fetoprotein (AFP) are elevated (>400ngjmL) in 75% of patients with HCC, particularly those who are hepatitis B antibody positive.65,66 Radiographic imaging, specifically gadolinium-enhanced MRI, may confirm the diagnosis of HCC in the setting of an elevated AFP. Imaging findings of HCC are summarized in Table 48.2 (Figs. 48.12 and 48.13). Histologic confirmation of HCC is not required in most cases if imaging and AFP levels are clinically conclusive, although percutaneous biopsy is feasible using CT or ultrasound guidance . Biopsy is rarely indicated in the diagnosis of HCC as it poses significant risks of hemorrhage in a cirrhotic patient as

950

CHAPTER 48

TABLE 48.2. Radiographic Imaging Characteristics of Malignant Liver Lesions. Lesion

Ultrasound (accuracy %)

Nuclear medicine (accuracy %)

Computed tomography (accuracy %)

Magnetic resonance imaging (accuracy %)

Hepatocellular carcinoma

Hypo, hyper, or isoechoic (Ding et a1. 2001j193

PET imaging is poorly studied

Enhancement in arterial phase (Ding et a1. 2001j193

Hyperintense on T2 images, enhanced with gadolinium (Ding et a1. 2001j193

Colorectalliver metastases

Hypoechoic

Intense signal on PET imaging

Oth er metastases

Hypoechoic

Usually increased PET signal

Low signal in the venous phase (Fulcher and Sterling 2002j178 Enhancement in the arterial (hypervascular) or venous phase (hypovascular) (Fulcher and Sterling 2002j178

Hyperintense on T2 and with gadolinium (Fulcher and Sterling 2002j178 Hyperintense on T2 and with gadolinium (Fulcher and Sterling 2002j178

well as the risk of needle tract tumor implantation." The 2004 National Comprehensive Cancer Network (NCCN) treatment guidelines recommend biopsy for a tumor associated with an AFP below 400ng/mL or AFP less than 4000ng/mL with a positive hepatitis B surface antigen. The high incidence of HCC in countries in which chronic hepatitis Band C infection is endemic has led to HCC screen-

ing programs for these populations. Screening includes liver ultrasonography and evaluation of serum alkaline phosphatase, albumin, and AFP levels every 3-6 months.s":" These case series have shown that the annual incidence of HCC in these groups varies between 0.8% and 5.8% per year. Resectability rat es of tumors found by screening vary from 7% to 66% .72,73 STAGING

More than seven differing staging systems have been described for HCC. 74,75 The most well-described and most commonly used systems are the International Union Against Cancer (UICC)/American Joint Committee on Cancer (AJCC) standardized TNM approach, the CLIP (Cancer of Liver Italian Program) score, and the BCLC (Barcelona Clinic Liver Cancer) stage.74,75 Table 48.3 compares these most commonly applied staging systems. TREATMENT

RESECTION

Surgery, to include liver resection or transplantation, remains the only curative treatment for HCc. 76 Unfortunately, fewer

FIGURE 48.12. Computed tomographic scan demonstrating hypervascular hepatocellular carcinoma.

FIGURE 48.13. Magnetic resonance imaging scan demonstrating hepatocellular carcinoma.

951

LIVER

TABLE 48.3. Staging Systems for Hepatocellular Carcinoma.

TNM, 2002 #1 (Wildi et al. 2004; Marrero et al. 2005V4,75

CLIP (Wildi et al. 2004; Marrero et al. 2005V4,75

Advantages of staging system

Staging criteria

Staging system

T1 solitary lesion: No vascular invasion T2 solitary with vascular invasion or multiple 5 em or invades portal or hepatic veins T4 invasion of adjacent organs Child-Pugh score AO B1 C2

NO no nodal involvement N1 nodal metastases

MO no distant metastases M1 distant metastases

Stage I T1 NO MO Stage II T2 NO MO Stage IllA T3 NO MO Stage nrs T4 NO MO Stage IIIC T any Nl MO Stage IV T any N anyMl

Does not include assessment of liver function Requires pathologic assessment for treatment planning

Tumor morphology Uninodular 0 Multinodular 1 Extensive (>50%) 2

a-feto-protein (ng/ dL) 20 years) after construction of an ileostomy, usually at the mucocutaneous junction." Resection is the best treatment for small-bowel adenocarcinoma. Pancreaticoduodenectomy is used for tumors involving the second or third portion of the duodenum." Tumors of the fourth portion can usually be resected with sparing of the ampullary region", a side-to-side duodenojejunostomy is simpler than an end-to-end reconstruction after this resection. Five-year survival for completely resected duodenal cancer ranges from 38 % to 45 % even in the presence of lymph node metastases." Right colectomy is indicated for distal ileal lesions. Node-negative patients have a 5-year survival of 600/0 to 700/0, but overall the prognosis is poor (150/0-35 % 5-year survival) because the majority of patients present late. 73,90 At present, there is no convincing evidence that adjuvant chemotherapy or radiation treatments are effective. 84 LEIOMYOSARCOMA AND MALIGNANT STROMAL TUMORS

Most small-bowel sarcomas are leiomyosarcomas, representing 100/0 to 200/0 of all malignant small-bowel tumors. These lesions may grow to considerable size before the development of symptoms. Leiomyosarcoma may spread by direct extension or may metastasize hematogenously to liver, lungs, or bone. As for other small-bowel neoplasms, wide en bloc resection with the associated mesentery is the treatment of choice. Extended lymphadenectomy is not indicated because lymphatic metastasis is rare. Five-year survival varies between TABLE 49.10. Anatomical Distribution of Tumors (0/0). Duodenum Jejunum Ileum

Carcinoid

Adenocarcinoma

Lymphoma

Sarcoma

6 20

50 28 22

12 40 48

16 26 58

74

Source: DiSario et al. 73

980

CHAPTER 49

TABLE 49.11. Primary Intestinal Lymphoma. Adult Western

Childhood

Population

Nonspecific

Children

Geography

Worldwide

Worldwide

Peak incidence (decade of life) Signs and symptoms

Sixth

First

Pain, perforation, obstruction, hemorrhage

Tender abdominal mass, acute intussusception

Location

Small intestine

Ileum

Pathology

Large tumors, B cell in 75 %, large-cell diffuse histology

Burkitt's type, small noncleaved B cell

Prognosis

By stage

Therapy

Surgery, adjuvant chemotherapy and radiation

Very good for stages I and II, tumor bulk important factor Surgery for early stage, chemotherapy major role

Immunoproliferative smallintestinal disease

Enteropathy-associated Tscell lymphoma

Low socioeconomic class; parasitic infestation Common in Middle East, Mediterranean Second, third

Celiac disease, malabsorption Common in Middle East Fourth, fifth

Pain, fever, diarrhea, steatorrhea, vomiting, wasting disease, circulating 19A-a heavy chain Jejunum, duodenum

Deterioration in chronic condition, malnutrition, acute abdomen, rising IgA titers Distal small bowel, disseminates early Villous atrophy, crypt hyperplasia, large T-cell origin

Nodularity of long segments of small intestine, IgA-producing B cells May undergo spontaneous regression but overall poor prognosis Antibiotics, aggressive chemotherapy

Poor due to early disseminated disease Chemotherapy, surgery only for complications

Source: Modified after Turowski and Basson. Am J Surg 1995;169:433-441. 159

10% and 50%.73 Criteria for malignancy include the number of mitoses (more than five per 50 high-power fields), nuclear atypia, the presence of necrosis, and cellularity. Tumor grade correlates with survival." Low-grade lesions (fewer than 10 mitoses per 50 high-power fields) have an 800/0 disease-free survival rate at 8 years. High-grade lesions, however, have a median disease-free survival of less than 18 months. Palliative resections and bypass procedures are warranted because some of these tumors may be rather slow growing. There is no evidence that adjuvant chemotherapy or radiation therapy alone or in combination is effective." The treatment of malignant GIST is primarily surgical. However, GIST tumors have been shown to be sensitive to the tyrosine kinase inhibitor imatinib, which inhibits the kinase activity of CD117. The use of imatinib in the adjuvant and possibly neoadjuvant setting has been the subject of recent study." LYMPHOMA

Lymphomas represent 10% to 20% of malignant smallbowel tumors. The ileum is the most common site of involvement because of the presence of the greatest amount of gut-associated lymphoid tissue. Primary small-bowel lymphoma is the most common extranodal form of lymphoma. Most are non-Hodgkin's lymphoma and predominantly B cell in origin," although both Hodgkin's disease and plasma cell lymphoma have also been reported. Childhood abdominal lymphomas include Burkitt's lymphoma, undifferentiated non-Burkitt's lymphoma, and diffuse histiocytic lymphoma. Many patients with ostensibly primary small-bowel lymphoma in fact have disseminated disease. Patients with small-bowel lymphoma commonly present with fatigue, weight loss, and abdominal pain." A severe malabsorption syndrome is seen in about 100/0 of patients.

Perforation, obstruction, bleeding, or intussusception are lesscommon modes of presentation." Individuals infected with human immunodeficiency virus 1 (HIV-l) have a markedly greater risk of developing non-Hodgkin's lymphoma, usually high grade." A variant of small-bowel lymphoma referred to as immunoproliferative small-intestinal disease is characterized by involvement of long segments of proximal small intestine with a dense but diffuse lymphoplasmacytic infiltrate."? This syndrome is more common in younger patients from underdeveloped countries and presents with abdominal pain, diarrhea, malabsorption, and clubbing of the flngers.i'":'?' Patients with long-standing celiac disease may develop a diffuse lymphoma caused by neoplastic proliferation of T-cell clones involved with the enteropathic process.l'" The differences among these entities are summarized in Table 49.11. Intestinal lymphomas are staged according to a modification of the Ann Arbor system (Table 49.12). Treatment of primary small-bowel lymphoma (Western variety) is mainly surgical. Ideally, complete resection along with a wedge of

TABLE 49.12. Ann Arbor Classification of Primary Gastrointestinal Lymphoma. Stage

Subgroups description

IE

Confined to single site Confined below abdomen Regional (mesenteric or perigastric) nodes Distant (e.g., retroperitoneal) nodes Involves organs on both sides of diaphragm Wide dissemination (liver, spleen)

lIE TIEl IIE2 ill IV

Source: Modified after Musshoff and Schmidt-Vollmer.158

SMALL INTESTINE

981

mesentery is accomplished. However, for patients with positive margins, adjuvant therapy is recommended. Survival for completely resected intestinal lymphoma is about 50%. A number of studies would suggest that the combination of surgery and adjuvant chemotherapy (typically CHOP [cyclophosphamide-hydroxydaunomycin-vincristine-prednisone] or a variant thereof) improves outcome stage for stage. Primary gastric lymphoma tends to fare better than primary intestinal lymphoma.P'v'" CARCINOID TUMORS

Carcinoid tumors of the gut represent about 20% to 40% of primary small-intestinal malignancies and are characterized by variable malignant potential and the secretion of multiple neurohormonal substances, notably serotonin and substance P. In population-based studies, carcinoid tumors are the most frequent of small-bowel neoplasms. The cell of origin is the Kulchitsky cell, an enterochromaffin or argentaffin cell located within the crypts of Lieberkuhn. The highest incidence of occurrence is in the sixth decade, although carcinoids have been reported in patients aged 20 to over 80. Tumors are multicentric in 30% and frequently coexist with other cancers, particularly of the colon, stomach, and breast. n,lO? About 50% of intestinal carcinoids are located in the appendix. Of all nonappendiceal carcinoids, about half are present within the distal 2 feet of the ileum. The rectum is the third most common site. Carcinoids are the most common tumor found within Meckel's diverticula. lOB Grossly, carcinoids appear as firm submucosal nodules with a yellow, tan, or gray cut surface. The tumor may infiltrate the bowel wall and cause shortening and thickening of the mesentery due to an intense desmoplastic reaction. Microscopically, carcinoid tumors appear as solid nests of uniform small cells with round or oval nuclei and a varying amount of surrounding desmoplasia. Carcinoid tumors often follow an indolent course, with median duration of symptoms up to 2 years before diagnosis. Symptoms tend to be nonspecific; like other small-bowel tumors, carcinoids may bleed, obstruct, or ulcerate. They may also present as segmental mesenteric ischemia associated with the mesenteric angiopathy that accompanies the intense desmoplasia surrounding the tumor. Intestinal obstruction may occur not only because of the primary tumor but also due to kinking of the mesentery from bulky nodal metastases or mesenteric fibrosis 109 (Fig. 49.14). Radiologic findings may increase clinical suspicion of carcinoid tumors. Small-bowel follow-through examination typically reveals fixed loops of intestine, with angulation, luminal narrowing, or multiple filling defects. Mesenteric calcifications may be present. Computed tomography may show evidence of a fibrotic mesenteric reaction in the vicinity of a transition point between dilated proximal and distal collapsed small bowel (Fig. 49.14). Hepatic metastatic lesions are characteristically hypervascular and thus brightly enhance with intravenous contrast administration. Occasionally, mesenteric angiography performed during preoperative evaluation may reveal focal abnormalities in the mesenteric vasculature; these consist of narrowing of peripheral arterial branches and poor venous drainage. Ileal carcinoid is occasionally misdiagnosed and treated as Crohn's disease .11o,131I-Metaio-

FIGURE 49.14. Intestinal carcinoid tumor [zrzrow], with characteristic surrounding desmoplasia, as demonstrated by CT scan, and intes-

tinal obstruction by tumor deposits.

dobenzylguanidine (MIBG) scintigraphy may occasionally be useful to localize midgut carcinoid tumors, although the false-negative rate may be as high as 30% .111 Metastatic disease is already present in as many as 60% of cases at the time of diagnosis.!" The malignant potential of carcinoid tumors is related to location, size, depth of penetration, and pattern of growth. Metastasis from appendiceal and rectal carcinoid is uncommon (3%1,113 but in ileal carcinoids, metastatic spread occurs in approximately 35% of cases. It is rare for a carcinoid tumor of the appendix less than 1ern in diameter to metastasize. Primary tumors of 1 to 2 cm metastasize in about 50% of cases, and tumors larger than 2cm metastasize in up to 90%. Carcinoid tumors limited to the submucosa are rarely associated with metastases, whereas this is evident in at least two-thirds of lesions that show fullthickness penetration. The pattern of growth appears to correlate somewhat with prognosis. Mixed insular plus glandular growth carries the best median survival (4.4 years), followed by insular (2.9 years), trabecular (2.5 years), and mixed insular plus trabecular (2.3 years). Glandular and undifferentiated growth patterns fare the worst, each with median survival of less than 1 year.'!" Overall, 5-year survival is approximately 30 % to 50 % .11 5 Treatment of carcinoid tumors of the small intestine is wide segmental resection. For tumors of the distal ileum, the cecum and right colon should be resected en bloc, and tumors involving the duodenum may require radical pancreaticoduodenectomy. Lesions without nodal metastases are almost always cured by resection. Palliative resections are probably worthwhile because most carcinoid tumors are slow growing . Carcinoid tumors metastatic to the liver may produce the malignant carcinoid syndrome, which includes episodic diarrhea, flushing, abdominal cramps , and, later, right-sided valvular heart disease and asthma. It is estimated that fewer than 10% of patients with metastatic carcinoid tumors will develop the carcinoid syndrome. Carcinoid syndrome is usually associated with primary tumors of the foregut (lung, stomach,

982

CHAPTER 49

duodenum, pancreas) or the midgut (jejunum and ileum) and only rarely with carcinoids of the hindgut (appendix, colon, rectum). The pathophysiology of the malignant carcinoid syndrome is largely attributable to elevated circulating levels of serotonin (5-hYdroxytryptamine, 5-HT), which increases intestinal peristalsis and evokes intestinal fluid and electrolyte secretion, thereby producing diarrhea and intense abdominal cramping. Occasionally, the pain is quite severe and may reflect serotonin-induced mesenteric vasoconstriction and segmental bowel ischemia. Other symptoms of the carcinoid syndrome include flushing, which is frequently unrelated to diarrhea and may be caused by other mediators such as substance P, bradykinin, or prostaglandins of the E and F series. Elevated levels of serotonin probably induce the irreversible endocardial fibrotic reaction that accounts for the right-sided valvular heart disease seen in advanced cases. Another manifestation of the syndrome is asthma caused by bronchoconstriction induced by 5-HT, bradykinin, or substance P. Finally, carcinoid syndrome occasionally leads to malabsorption and pellagra (dementia, dermatitis, and diarrhea) caused by an acquired tryptophan deficiency. Confirmation of malignant carcinoid syndrome is made by determination of urinary levels of 5-HIAA (5-hydroxyindolacetic acid), the inactive breakdown product of 5-HT produced by metabolism in the lung and liver. This assay may need to be repeated because a single determination may be normal; alternatively, provocative testing with intravenous pentagastrin, epinephrine, or calcium may be added. Patients with malignant carcinoid syndrome should avoid foods rich in 5-HT, including bananas, pineapples, tomatoes, and walnuts. Certain drugs, such as phenothiazines, glycerol guaicolate, and reserpine, are strongly contraindicated. If possible, primary and metastatic lesions should be resected or at least debulked as this may produce substantial palliation of the symptoms of carcinoid syndrome. Hepatic artery embolization may be utilized when surgery is not possible and may produce dramatic, although frequently shortlived, relief of symptoms in about 90% of patients. 116 This treatment is not without complications, and a mortality of about 10% has been reported. 117 The long-acting somatostatin analog octreotide also appears to be of some benefit, particularly in patients with carcinoid diarrhea.l'" Some response to the combination of 5-fluorouracil and streptozotocin has been reported, although in general chemotherapy appears to be of limited usefulness. Median survival of patients with carcinoid tumors metastatic to the liver is 3 years, compared to 5 years in patients with nonresectable abdominal disease in the absence of liver metastases. OTHER TUMORS AND METASTATIC LESIONS

Gastrinoma, somatostatinoma, paraganglioma, and undifferentiated neuroendocrine carcinomas of the small intestine have been reported. These tumors may present as a hormonespecific hyperfunctional state or as nonfunctioning mass lesions. The small bowel is the most common site of melanoma metastatic to the gastrointestinal tract. Primaries from the breast, lung, and kidney metastatic to the small bowel have also been described. Cervical, ovarian, and colonic tumors may involve the small bowel by direct extension. Treatment is, in general, palliative and consists of limited

resection or bypass. In patients with small-bowel metastatic melanoma without a known primary, aggressive resection may improve the quality of life and disease-free survival.

Meckel's Diverticulum In 1808, Johann Meckel described a diverticulum composed of a remnant of the duct between the intestinal tract and the yolk sac.!" This embryological remnant was found to be the cause of an intussusception by Kuttner in 1898,118 and in 1904 Salzer!" described heterotopic gastric mucosa within the diverticulum. In 1907, Deet noted the association between aberrant gastric mucosa within the diverticulum and ulceration of the adjacent ileum.P" Based on autopsy series, Meckel's diverticulum is present in 0.3 % to 2.5 % of the population. The size and shape of the diverticulum can vary greatly, although it is usually between 3 and 5 em long and is found 10 to 150 em from the ileocecal valve. Meckel's diverticula contain a mesentery with an independent blood supply from the ileal vessels. There is an association between Meckel's diverticulum and a number of other congenital malformations, including exomphalos, esophageal or anorectal atresia, and various central nervous system or cardiovascular malformations. Although usually lined by mucosa similar to that seen in the adjacent ileum, heterotopic mucosa has been described, including that of gastric, duodenal, colonic, or pancreatic nature. Mackey and Dineen!" studied 140 Meckel's diverticula removed incidentally and found approximately 160/0 containing heterotopic mucosa. In 62 patients in whom the Meckel's was removed because of symptoms, however, the incidence of heterotopic mucosa was 34 0/0, suggesting that the presence of these abnormal cells might be associated with eventual clinical sequelae.

Complications Meckel's diverticula can be associated with various complications and often require surgical intervention. The presence of gastric _mucosa with resultant acid production can lead to ulceration in the adjacent ileal mucosa, causing either hemorrhage or perforation. Perforation can also occur in the diverticulum itself, perhaps related to luminal obstruction from a foreign body. The resultant Meckel's diverticulitis presents with signs and symptoms that are generally indistinguishable from appendicitis. Meckel's diverticulum can also be associated with small-bowel obstruction from intussusception, volvulus, or an associated adhesive band. In rare instances, an umbilical sinus or fistula becomes evident, and even more uncommon is the presence of neoplasm within the diverticulum. Wiliiam I 22 reviewed 1806 cases and found the incidence of complications as follows: hemorrhage, 31 0/0; inflammation, 25%; bowel obstruction, 160/0; bowel obstructions secondary to a band, 160/0; intussusception, 110/0; hernial involvement, 11%; umbilical sinus/fistula, 4%; and tumor, 20/0. Soltero and BiIII23 estimated the chances of a Meckel's diverticulum causing one of these complications to be 4.2 % in children, dropping to 3 % in adults and almost 0% in the elderly. Special mention should be made of the extremely rare Littre's hernia,

SMALL INTE STINE

983

which refers to the presence of a Meckel's diverticulum within an inguinal hernia sac.

Diagnostic Studies Meckel's diverticula are rarely demonstrated on routine barium studies. In the rare instance of an umbilical fistula, however, in jection of contrast material directly into the external orifice demonstrates a communication with the underlying ileum, indicating a patent vitelline duct . Such a study will be able to differentiate the intestinal communication from a patent urachus that communicates with the urinary bladder . Technetium Tc 99m pertechnetate Meckel 's scan detects the gastric mucosa within the Meckel 's diverticulum and has been reported to be 90% accurate.!" Meckel 's diverticulum can also be detected angiographically, as shown by Mitchell et a1.,125 who reviewed angiograms in 16 patients and found that 69% had a persistent vitellointestinal artery; in another 4 patients, other angiographic abnormalities were seen, including a vascular blush, early venous return, and arterial irregularity. These authors concluded that angiography will detect a Meckel's diverticulum in most patients based primarily on the demonstration of a persistent vitellointestinal artery. However, because of the presence of overlying vessels, supers elective catheterization of distal ileal arteries may be needed to detect this abnormality.

Surgical Treatment When a Meckel 's diverticulum causes symptoms or complications, resection is indicated. Either excision of the diverticulum alone or resection of the adjacent segment of ileum containing the diverticulum is acceptable. In most cases, simple excision is satisfactory as long as care is taken to avoid narrowing of the ileal lumen. Resection of the adjacent ileum should be performed in patients with peptic ulceration or if the base of the diverticulum is involv ed with an inflammatory process or neoplasm. Whether to remove an asymptomatic Meckel's diverticulum found incidentally at the time of surgery is a matter of some debate . Cullen et a1. performed an epidemiological, population-based study in Olmstead County, Minnesota, and concluded that Meckel's diverticula discovered incidentally at operation should be removed in most patients.l" In contrast, Peoples et a1. 127 reviewed their experience in 90 incidental diverticulectomies. Using a decision analysis, they reported that the conditional probabilities of producing morbidity or mortality in the adult population at risk by only resecting symptomatic diverticula are 0.2% and 0.04%, respectively. However, by resecting all incidentally discovered diverticula, the comparable respective risks were 4.6% and 0.2%. These authors therefore concluded that the practice of incidental diverticulectomy in adults should be abandoned.

Short-Bowel Syndrome Maintenance of adequate nutrition is dependent on the normal digestive and absorptive function of the smallintestinal mucosa. A normal, healthy adult possesses an excess of gut mucosa, but depending on the amount of bowel removed and the specific level of resection, symptoms can

FIGURE 49.15. Radiographic appearance of short-bowel syndrome shown by a barium upper GI series and small-bowel follow-through. This patient underwentmassive enterectomy because of mesenteric infarction. Note that barium has passed quickly from the stomach, through the shortened small intestine, and into the colon.

ensue following surgery, in some cases leading to a condition known as the short-bowel syndrome (Fig. 49.15). Because of the important functional capacities of the duodenum in regard to iron and calcium and of the distal ileum in regard to vitamin B12 and bile salts, resections of these specific regions tend to be poorly tolerated. In contrast, up to 40% of the midsmall bowel can be removed with only moderate clinical sequelae. As a general rule, resection of 50% of the small intestine produces significant malabsorption, and if 70% or more of the intestine is resected, survival is threatened. Clinical results in treating short-bowel syndrome have improved in recent decades, however, with a recognition of its pathophysiology, improved surgical techniques, and better enteral and parenteral nutritional support. The most common etiology of short-bowel syndrome is a massive resection occurring in the setting of mesenteric thrombosis or embolus. In children, volvulus of the intestine caused by congenital malrotation can also result in the need for massive resection. Less commonly, patients with neoplasm, trauma, or recurrent Crohn's disease develop shortbowel syndrome. The jejunoileal anastomosis that was used in the past to treat intractable obesity and hypercholesterolemia can also result in severe malabsorption, similar to that seen in patients following massive resection. The minimal amount of small intestine required to sustain life is variable. Prolonged survival has been recorded in isolated patients with as little as 1 foot of jejunum along with an intact duodenum, but in general survival is threatened in patients with less than 2 feet (60cm) of intestine beyond the duodenum. An intact ileocecal valve is thought to be important in regard to improving function of the remaining small intestine, and clearly the colon is vitally important for preventing water loss. Patients with short-bowel syndrome have impairment in the absorption of water and electrolytes as well as that of all nutrients. Fluid losses can be greater than 5 to lOL/day. As a result, patients with short bowel syndrome suffer weight loss, fatigue, calorie deprivation, electrolyte abnormalities, and vitamin deficiencies. Important adaptive changes occur in the remaining intestine following massive resection. Postresectional adaptation

984

CHAPTER 49

has been extensively studied in experimental animals, demonstrating a significant increase in DNA synthesis and cellular number within the remaining gut. A variety of hormones and peptides have been shown to augment this adaptive response, most notably EGF (epidermal growth factor), IGF-I (insulin-like growth factor-I), GLP-I (glucagon-like peptide 1), IL-II [interleukin-l l], and neurotensin.!" Postresectional adaptation response also appears to occur in humans, but this response has been less well documented. In addition to mucosal hyperplasia, there is generally seen to be an increase in the caliber of the remaining small intestine, perhaps adding to the increase in absorptive area. From a functional standpoint, the amount of fluid and electrolyte losses following massive resection decreases over time, whereas glucose absorption increases. Short-bowel syndrome is associated with gastric hypersecretion, perhaps related to loss of the "ileal brake," a mechanism by which luminal fat within the distal small intestine inhibits gastric secretion. Loss of the terminal ileum also results in an impairment in the absorption of conjugated bile salts and fat. With limited ileal resections, an increase in the bile salt load to the colon can cause direct injury to the mucosa and resultant diarrhea. With more extensive (i.e., greater than IOOcm) ileal resections, there is a gradual loss in the total bile salt pool, eventually leading to impairment in fat absorption and the onset of steatorrhea. Ileal resections are also associated with lithogenic bile, such that gallstone formation is seen in approximately 30% of such patients. Thompson evaluated 50 adult patients with intestinal remnants of less than I80cm over a IS-year period and found a significant risk of cholelithiasis (570/0 in those patients with benign conditions). He concluded that prophylactic cholecystectomy should be considered if long-term survival is anticipated.'?"

Treatment Initial therapy involves maintenance of fluid and electrolyte balance. Total parenteral nutrition (TPN) is often indicated and, depending on the extent of resection, may be required throughout the lifetime of the patient. It is likely that even small amounts of enteral nutrition are beneficial, however, because the luminal nutrients appear to enhance the adaptive response of the remaining gut. Various antidiarrheal and stool-bulking agents have also been used with some benefit. Gastric hypersecretion should be treated with either H 2 blockers or proton pump inhibitors. Cholestyramine may be beneficial in patients with limited ileal resections, but if the bile salt pool has been depleted, then cholestyramine is contraindicated.':" Wilmore and colleagues have advocated intensive medical management, including maintenance of oral hydration, along with a combination of a high-fiber diet, growth hormone, and glutamine. This intestinal rehabilitation program has been reported to provide excellent results in a number of cases, including patients who previously were on chronic TPN and who could subsequently be maintained completely on enteral nutrition. 131 The efficacy of this intestinal rehabilitation program, however, remains controversial. Scolapio et al. 132 conducted a randomized, double-blind, placebo-controlled crossover study in eight patients with short-bowel syndrome (average

small-bowel length, 71em). Patients were treated according to the program described by Wilmore's group, and these authors did find a transient increase in body weight and in sodium and potassium absorption, as well as a decrease in gastric emptying. However, there was no change in small-bowel morphology, stool losses, or macronutrient absorption.

Surgical Approach The surgical treatment of patients with short-bowel syndrome has been disappointing. In small numbers of patients, various procedures, including intestinal lengthening, reversal of short segments, and plication of excessively dilated bowel have been used. 133,134 Although some improvement has been seen in isolated cases, such operations have not become universally adopted. Panis et al. reported on 8 patients who underwent segmental reversal of the small bowel, and with a median follow-up of 35 months, they reported significant decreases in parenteral nutritional requirements in all 7 of the patients who are still alive.!" Thompson and colleagues have extensive experience in the surgical approaches to patients with short-bowel syndrome. In a report of 45 patients who had undergone 49 surgical procedures, they reported reasonably good success in 14 of the patients with short remnants and dilated bowel who underwent intestinal lengthening procedures. In patients with very short remnants «60 em), however, intestinal transplantation was performed. 134 The results of small-intestinal transplantation have been disappointing, primarily because of a high incidence of rejection. However, more recent experience with small-intestinal transplantation suggests that this may become a viable surgical alternative in patients with short-bowel syndrome. Abu-Elmagd et al. 136 reported on the University of Pittsburgh experience with intestinal transplantation. In 98 consecutive patients (59 children, 39 adults), 48% of the group survived and had grafts providing full (910/0) or partial (9%) nutrition. Actuarial patient survival at 1 and 5 years was only 72 % and 480/0, respectively. Although survival was similar between intestinal and composite grafts, the loss rate of grafts from rejection was highest with the intestine alone, indicating that the liver was at least marginally protective in regard to the concomittantly engrafted intestine.

Malabsorption Syndromes Clinical Aspects Malabsorption results from the pathological disturbance of the normal sequence of digestion, absorption, and nutrient transport. Most disorders consist of defective absorption of multiple forms of nutrients, producing classical overt malabsorptive symptoms, whereas some involve the selective loss of one specific nutrient, producing a syndrome with a paucity of symptoms. Classically, malabsorption produces both intestinal and extraintestinal symptoms. Chronic diarrhea, consisting of watery, bulky, frequent stools, is common. Patients with steatorrhea may note pale, foul-smelling, greasy, floating stool. Anorexia, hyperphagia, nausea, vomiting, abdominal distention, gassiness, excessive flatus, or borborygmus are common symptoms. Pain is unusual. Several malabsorption syndromes are particularly relevant to surgical disease.':"

SMALL INTESTINE

Celiac disease, tropical sprue, and lactase deficiency are not considered further here.

Bile Acid Malabsorption Bile salts are necessary for proper absorption of dietary fats and fat-soluble substances. Bile salts are synthesized in the liver, stored in the gallbladder between meals, and excreted into the duodenum in response to ingestion. Normally, more than 900/0 of excreted bile is reabsorbed in the small intestine as part of the enterohepatic circulation system. In the terminal 100cm of ileum, bile salt absorption is mediated by a Nat-coupled bile salt transporter. Primary or idiopathic bile salt malabsorption is unusual. More commonly, bile salt malabsorption is the result of resection of the terminal ileum, such as in Crohn's disease. 138,139 Some patients develop bile salt malabsorption after cholecystectomy or after vagotomy. 140 Bile salt malabsorption is manifest as diarrhea and is the consequence of excessive concentrations of bile salts (>3 mM) reaching the colon. Cholestyramine is effective in more than 900/0 of cases of bile salt diarrhea.!"

Vitamin B12 Malabsorption Inadequate absorption of vitamin B12 leads to macrocytic anemia. Vitamin B12 undergoes a complex process of absorption involving the salivary glands (protein R), the stomach (intrinsic factor), a pancreatic protease, and active absorption in the terminal ileum. As such, systemic absorption can be adversely affected by a number of surgical conditions, including extensive gastric resection, bacterial overgrowth syndrome, Crohn's disease, radiation enteritis, and ileal resection. Treatment is by periodic parenteral administration of vitamin B12 and, if relevant, the addition of specific therapy to reverse the underlying disorder.

Bacterial Overgrowth Syndrome Bacterial overgrowth in poorly emptying or stagnant smallintestinal segments leads to a syndrome of diarrhea and steatorrhea accompanied by abdominal pain, weight loss, anemia (usually macrocytic), fat-soluble vitamin deficiencies, and, in late stages, neurological deficits. 141 This situation is sometimes referred to as the blind-loop syndrome but can occur in a variety of conditions not involving the presence of a selffilling, nonemptying intestinal segment. This syndrome is occasionally encountered after a side-to-side intestinal anastomosis that produces a recirculating loop,142 and it may occur within the afferent jejunal limb after Bilroth II gastrectomy. 143 Bacterial overgrowth caused by stagnation of luminal contents may occur in the setting of chronic intestinal obstruction by stricture or in duodenal or jejunal diverticulosis. Gastrocolic or jejunocolic fistula may also produce bacterial overgrowth, as can small-bowel motility disorders associated with diabetes and intestinal pseudoobstruction. Gastric achlorhydria can predispose to overgrowth. The pathophysiology of the syndrome involves excessive bacterial metabolism of vitamin B12, leading to its insufficient availability for intestinal absorption. Furthermore, bile salt deconjugation by luminal bacteria leads to inadequate micellization of dietary fat and, consequently, steatorrhea. Deconjugated bile salts are toxic to enterocytes and may

985

directly elicit diarrhea and further malabsorption of other nutrients. Medical treatment consists of intermittent oral antibiotic therapy. If feasible, the underlying anatomical arrangement favoring bacterial overgrowth should be surgically corrected.

Evaluation of Malabsorptive Conditions The etiology of a malabsorptive condition is often suggested by a thorough history followed by inspection of the stool and an estimation of its volume. Specific testing may confirm the diagnosis, although in general specificity and sensitivity are suboptimal, and many specialized examinations are not routinely performed in many centers. Fat malabsorption is usually detectable by quantitative measurements of fecal fat content in a 24-h collection or by Sudan stain of feces. Breath tests utilizing 14C-Iabeled carbohydrates are used to detect lactose intolerance or other syndromes of carbohydrate malabsorption. n-Xylose absorption and detection in either plasma or urine can be used as a general test of intestinal absorptive function.P'1 em] or multiple colorectal polyps of any size D. Personal history of colorectal malignancy: surveillance after resection for curative intent III. High risk (6% to 8 % of people) A. Family history of hereditary adenomatous polyposis B. Family history of hereditary nonpolyposis colon cancer C. Inflammatory bowel disease 1. Left-side colitis 2. Pancolitis

Colonoscopy

Colonoscopy Colonoscopy

Flexible sigmoidoscopy; consider genetic counseling; consider genetic testing Colonoscopy, consider genetic counseling; consider genetic testing Colonoscopy Colonoscopy

Every 5 years

Every 5 to 10 years

If recurrent polyps, 1 year; if normal,S years If normal, 3 years; if still normal,S years; if abnormal, as above

12 to 14 (puberty)

Every 1 to 2 years

21 to 40 40

Every 2 years Every year

15th 8th

Every 1 to 2 years Every 1 to 2 years

DCBE, double-contrast barium enema; FOBT, fecal occult blood testing.

Source: From the American Society of Colon and Rectal Surgeons. http://www.fascrs.org/displaycommon.cfm?an=1&subarticlenbr=229 (accessed 11/09/2007).

1052 ~U

C H AP TE R 51

TABLE 51.11. Impact of Fecal Occult Blood Testing on Mortality from Colorectal Malignancy.

Level of evidence

Author

n

Mande l' ?'

46,551

Design

Result

Annual FOBT vs. biennial

Annual FOBT ~ 33 % J.. mortality, FOBT vs. usual care biennial no t1.

Hard casr le-"

152,850

Biennial FOBT vs. usual care

Biennial FOBT ~ 15 % J.. mortality

Kronborg'"

61,933

Biennial FOBT vs. usual care

Biennial FOBT ~ 18% J.. mortality

Winawer'"

2 1,756

Annual FOBT plus rigid sigmoidoscopy vs. annual rigid sigmoidoscopy alone

Annual FOBT ~ 43 % J.. mortality over rigid sigmo idoscopy alone Mortality t1. pen ding but earlier stage tumors

Kewenter'??

2 1,34 7 initial and 19,991 at follow-up

FOBT initial eval uation and at 16-24 months

is adversel y affected by exogenou s peroxidase activity by red meat and uncooked vegetables and medications that ma y induce bleeding from non colonic sources such as aspirin and other non steroidal antiinflammatory drugs. Three large randomized controlled trials of serial FOBTs conducted in Minnesota, the United Kingdom, and Denmark, involving more than 250,000 subjects followed for up to 18 years, have demonstrated that serial FOBT results in an increased detection of colorectal cancer in earlier stages and reduces colorectal cancer mortality from 15% to 33% , with the absolute risk reduction for colorectal cancer death ranging from 0.8 to 4.6 per 1000 person-years .P'250 cases), th ere was no difference in recurrence for primary hernias (5.1% lap vs. 4.1% open ) but significantl y fewer for recurrent hernias 13.6% lap vs. 17.4% open) . "Open technique is superior ." 71% of lap recurrences and 4% of open recurrences occur in the first postop year. 10 of 21 lap recurrences wer e by a singl e surgeon . Open repair associated with higher incidenc e of chronic pain. Bassini repa ir resu lt s in unacceptably high recurrence rates. TEP has mo re rapid recovery, fewer recurrences, and less chr on ic pain th an open repair s, but takes slightl y longer to perform . (continu ed)

Concl usions /details

Study design

TEP vs. mesh plug vs. Lichtenstein

TEP vs. open (Marcy , Lichtenstein, or Stoppa]

Reference

Bringman, et aI., 2003, Swe den "

Wright et al., 2002 , United Kingdom?" 60mo. (median)

20 m o

A verage follow-up

Open : 151

TEP: 149

103

Lichtenstein :

104

Me sh plug:

TEP: 92

N o. of repairs

6 % conversion to open No serious intraoperative or postoperative complications No serious in trao perati ve or postoperative compli cations

No conversions N o perioperat ive complic ati ons, 12 (13 %) tota l complications No per ioperative complications, 24 (23 % ) total complications No perioperative complications, 36 (35 %) total complications

Complications (not including recurrences)

45

0

2.0%

2.0%

36"

50

Operative time (min)

1.9%

2.1%

Recurrences Cost

No difference in chronic pain

28.5

24.5

14"

J.. pain score POD 0-1'

Return to work (days)

Postop pain

TABLE 53.4. Select Pro spective Randomized Trials Comparing Laparoscopic and Open Ingui na l Hernia Repairs (Level I Evidence). (continued)

Shorter operative time for me sh plug compared to T EP or Lich tenstein. Faster recov ery for T EP compared to mesh-plug or Lichtenstein . No significant difference in complications. " Laparoscopic hernioplasty is superior to tension-fr ee open herniorrhaphy in terms of postoperative pain and rehabilitation." Single-surgeon exper ience as part of MRC trial with long -term followup. No recurrences for Lichtenstein rep airs performed for primary he rnias (all open recurrences were in Stoppa group) . All laparoscopic recurrenc es occurred with large (>5 cm) direct defects; recomm ends 15 x 15 em m esh to adequately repair these defects. Similar long term outcomes for lap and open; both procedures have a role in hern ia repa ir. Experienc e is very important for th e laparo scopic repair .

Conclu sion s/details

TAPP vs. Shouldice

Lap (23% TAPP,77% TEP) vs. open (89% tension-free mesh)

TAPP vs. Lichtenstein

Leibl et al., 2000, Germany"

MRC Hernia Group, 1999, United Kingdom' "

Paganini et a!., 1998, Italy66

28mo.

12mo. (n = 711)

70mo. (median)

Licht.: 56

TAPP: 52

Open: 460

14 (26.9%) total complications, 4 (7.6%) hematoma, 1 (1.9%) hydrocele, 5 (9.6%) parasthesia, 4 (7.6%) seroma" 15 (26.7%) total complications, 8 (14.2%) hematoma, 2 (3.5%) hydrocele, 5 (8.9%) parasthesia, 0 seroma"

25 (5.6%) surgical complications (1 bladder, 1 LFCN/nerve, 1 common iliac artery] ', 108 (29.9%) complications at 1 week', 6.6% conversion to open 6 (1.4%) surgical complications (1 enterotomy)', 155 (43.5%) complications at 1 week'

4 (8%) total complications

Shouldice: 48 Lap: 468

4 (7%) total complications

TAPP : 54

58.4 a

1.9%a

0

3.8%

$1249

$306

48.2 unilateral primary' 41.2 unilat eral recurren t 75.9 bilateral

+£314

66.6 unilateral primary' 71.1 unilateral recurrent 85.7 bilateral

43.4'

47.5

5.0%

0'

65.0

2.0%

14

t discomfort at 7 days, 3mo

15

42'

28a

38 a

21"

J. pain score at 48h'

at 1 year

J. groin pain

usage POD 1_2"

J. analgesia

(continued)

Improved mobilization with lap repair. Greater long-term satisfaction with the lap repair. "TAPP is an effective alternative." SF-36 outcomes similar at 3 mo . 16/25 surgical complications were injury to inferior epigastric vessels. All serious complications and 2 trocar hernias happened in the TAPP group . Laparoscopic repairs offer advantages but potential for rare serious complications and recurrence support repairs being performed by specialist surgeons. "Open repair is the more appropriate option for the general surgeon." 95% of Lichtenstein repairs performed under local anesthesia. T APP had less postop pain. T APP should not be adopted routinely unless its cost can be reduced.

12mo

7.3mo

TAPP vs. plug and patch vs. Shouldice

T EP vs. Stoppa

TA PP vs. Shouldice

T EP vs . Shouldice

Zieren et al., 1998, Cermany'"

Ch ampault et al., 1997, Franc e"

Kald et al., 1997, Sweden"

Bessell et al., 1996, Au st ralia ' ?

20.2 m o

25mo

Study design

Reference

Average follow-up

Shouldice: 74

6 conversion to open, 3 conv ersion to TAPP, 4 (10%) postop complications 7 (9.5%) postop complications

9(10.1%) total complications

Shouldice: 89

TEP: 39

8 (6.6%) total complications

2 (3%) intraop bleeding', 15 (19%) postop complications 12 (15%1 postop complications 13 (16%) postop complications 4% total complications", 3 (6%)conversions to open 20% total complications"

TA PP: 122

Stoppa: 49

Shoul dice: 80 TEP: 51

Plug : 80

TAPP : 80

No. of repairs


47

a

62"

87S

50"

3.4 %"

5.1%

a

score " J.. meds"

J.. pain

32

30 .5

23"

10"

+$483 direct cost +$1364 indirect cost

17'

26'

18

16

Return to w ork (days)

a"

pain score" J.. pain scor e" J.. meds"

t

Postop pain

35"

72"

$69

$124

$1211

Cost

2%

"Sign ificantly longer :"

36

a 6%

61"


a

Recurrence s

TABLE 53.4. Select Prospective Randomized Trials Com paring Laparo scopic and Open Inguinal Hernia Repair s (Level I Evidence). (continued)

Plug and patch and TAPP cause less pain and hav e faster return to work than Shou ldic e, plug and patch cost less than T APP and can be performed faster and under local anesthesia. 45 % bilateral , 43 % recurrent. Mesh for TEP was not fixed in place; mesh size increased from 6 x 11 em to 12 x 15 em due to early recurrences. Single piece of mesh for bilateral hernias felt to reduce recurrence rates. TEP has the same longterm recurrence rate as the Stoppa procedure but confers a real advantage in the early postop period. TAPP had a fast er recovery and return to work with comparable complication rates. TAPP is more costeffective if indirect costs are compared (including income lost by a delay in return to work) . Study biased becau se of large crossover to open group . Substantial conversion rate to open and T APP repairs. TEP ha s significant decrease in pain , equivalent return to work, but longer operative time. TEP all eviates the inherent dange rs associated with TAPP, but further studies are ne eded .

Conclusions/details

TAPP or IPOM vs. open (Bassini, McVay , Shouldice, Lichten stein, plug and patch) IPOM (with m eshed PTFEj vs. open [Bassini, McVay)

Barkun, et al., 1995, Canada?

TAP P vs. Lichtenst ein

Payne et al., 1994, United States"

lOmo

7mo

Licht.: 52

TA PP: 48

Open : 84

TAPP: 83

Open: 31

IPOM : 30

8mo

6 (8%) total complications', 1 deep wound infection, 3 persistent pain, 1 hematoma 16 (21%) total complications', 5 deep wound infection, 6 persistent pain , 3 hematoma 6 (12% ) total complications, 0 groin pain

> '"

"Z

:t

Study design

Prospective nonrandomized TAPP vs . IPOM (wit h polypropylene mesh) vs. TEP

Reference

Fitzgibbons et al., 1995, United States"

23 mo

Average follow-up

4.5%

o

5.1%

12% neuralgias , 1 pro sthetic infection (appendicitis vs. ceca l erosion I 0 % neur algias 2 conversions to open, 29.2% to ta l complications, 5 (0.7%) trocar hern ias, 1 (0.1 %) cystotomy, 1 (0.1 %) enterotomy, 24 (3.5%) bleeding (2 requiring transfusion), 6(0.87%) second abdominal procedure required (for bleeding, infection, adhes ion , enterotomy, ne ura lgia]

IPOM: 217 TEP : 87 All 3 groups analyzed toget her

5%

Recurrences

T otal complications: 2 bowel adhesions/obstructions, 5 % neuralgias


TAPP: 562

No. of repairs

TABLE 53.5. Trials Comparing Different Types of Laparoscopic Repa irs. (contin ued)

70 un ilateral 90 .6 bilateral

Operative time (min) Return to work (days)

Laparoscopic hernia repair is effective with acceptable early recurrence rates. T APP, IPOM, and TEP appear to be equally effective, although TEP is more difficult tec hnically. IPOM an d TEP may be bet ter suited for sma ll indirect inguinal hern ias, whereas TAPP may be better for complicated recurrent herni as. Other procedures can be safely performed at the same time as hernia repair (61 additional procedures performed with 1 associated complication). The inciden ce of neuralgias is disturb ing but decreasing with increased surgeon experience. This series represents a very well done multicenter trial, but the total complication rate is disturbing. The authors stress the need for prospective randomized trials to further eva luate laparoscopic repairs.

Conclusions/details

'"

<J>

"

'">-itn

:>-

::I:

n

0\

U1

Retrospective TAPP vs . TEP

0.3%

0.3%

9 (1.2%) intraabdominal complications, 1 bowel obstruction, 2 enterotomies, 6 trocar hernias, 10% seroma, 7 hydroceles 7 (1.8%) conversions to TAPP, 1 (1.2%) intraabdominal complication, 0 bowel obstructions, 0 enterotomies, 1 trocar hernia (in TAPP conversion), 10% seroma, 2 hydroceles

TAPP: 733

TEP : 382

TAPP: 24mo

TEP : 9mo

' Statistical significance (all unmarked values are not statist ically significant).

- , value was not measured; IPOM, intraperitoneal onlay mesh repair; TAPP. transabdominal preperitoneal approach ; TEP. totally extrapcritoneal approach .

Felix et al., 1995, United States'?

7 days for "normal activity" for TAPP and TEP

Time to return to work was the same in TAPP and TEP, but was 8 day s for noncompensated patients vs, 16 days for compensated. TEP is less invasive, minimizes the risk of intraabdominal complications, and is the procedure of choice, except for incarcerated hernias and large scrotal hernias, which are more easily handled by TAPP. Slit in mesh associated with transient scrotal hyperesthesia. Parietalization of the cord more easily achieved in TEP, alleviating the need for a slit in the mesh. 50% of all repairs done with double-buttress technique. There were no recurrences, but all hydroceles occurred in this group.

......

U1

......

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."

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o

r-

> t'"

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z

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:I:

1158

CHAPTER 53

Complications There exists great variety in the methods and completeness by which complication rates are reported, and caution must be used not to draw premature conclusions from inadequate data. Generally complication rates decrease with increased surgeon experience, but a thorough knowledge of anatomy and of potential hazards is essential to hernia repair. Complication rates following open inguinal hernia repairs average 70/0 to 12%.99 Reports on laparoscopic approaches are widely variable, but the rates of complications for both conventional and laparoscopic repairs is now thought to be comparable.r'-":100,101 RECURRENCE

Ten percent is reported as the average recurrence rate for groin hernias, although most surgeons boast to have rates well below the average." Lichtenstein, for example, reports rates of less than 10/0, with similar results reproduced by others using the same technique.P:" Recurrence rates following conventional repairs vary from 1% to 7% for indirect inguinal hernias, from 4% to 100/0 for direct inguinal hernias, from 1% to 70/0 for femoral hernias, and from 50/0 to 350/0 for recurrent hernia repair. 13,102 Lichtenstein noted that 500/00f recurrences after anterior repairs first appear 5 years or more after the initial operation, and 750/0 of recurrences become evident within 10 years of the original operation.l'" In contrast, Stoppa noted that recurrences after a preperitoneal repair usually occur within the first postoperative year and are due to technical errors." Failure to diagnose multiple hernias at the time of initial operation, failure to close an enlarged internal ring, and breakdown of the repair under tension have all been implicated in the causes of recurrences.P:'?' Elkberg showed an incidence of 60/0 for multiple ipsilateral hernias and 170/0 for bilateral hernias using herniography, suggesting missed hernias may account for recurrence.105 For laparoscopic repairs, the reasons for recurrence are surgeon inexperience, inadequate dissection, insufficient prosthesis size, insufficient prosthesis overlap of hernia defects, inadequate fixation, prosthesis folding or twisting, missed hernias or lipomas, and mesh dislodgment secondary to hematoma formation. 10,85,106-108 Recurrence is directly related to surgeon experience, with failures occurring much more frequently early in the surgeon's learning curve. 1O,84,8S Incomplete dissection can result in missed indirect hernias and missed cord lipomas, especially in the TEP procedure and especially with inexperienced surgeons.106,108,109 Inadequate dissection can also limit the size of mesh that can be used or result in incomplete fixation or folding. At least a 12 x 15cm piece of mesh should be used to ensure a 2- to 3-cm overlap of all hernia defects and prevent technical causes for recurrence. Several investigators advocated that mesh fixation is unnecessary if the mesh is large enough, and the impressive results of Champault's series supports this practice. 6B,84,107,110 For laparoscopic repair of bilateral hernias, some advocate the use of a single piece of mesh to alleviate medial recurrence. 68,111 Using a slit to allow passage of the cord may increase recurrence.109 Parietalization of the cord with alleviation of the need for a slit, or a slitted piece of mesh reinforced by a second nonslitted piece, the so-called doublebuttress technique'P may be used. Historically, Stoppa rec-

ommended not using a slit in the GPRVS to alleviate the possibility of recurrence through this defect. 52 In contrast to conventional repairs, recurrences using laparoscopic repairs usually appear within the first postoperative year. 1O,73,106 Tetik et al. published a multicenter retrospective analysis of 1514laparoscopic repairs with a recurrence rate of 2.2 % over an average follow-up of 13 months.!" Recurrence rates were 22 % for the plug and patch, 3 % for simple ring closure, 2.20/0 for IPOM, 0.7% for TAPP, and 0.40/0 for TEP. Phillips et al. published a multicenter review of 3229 repairs with a recurrence rate of 1.60/0 over a mean follow-up of 22 months.!" Felix et al. published a multicenter retrospective analysis of 10,053 TAPP and TEP repairs in 7661 patients; repairs were performed only by surgeons experienced in laparoscopic repairs. The recurrence rate was 0.4% over a mean follow-up of 36 months.l'" The rates in prospective randomized trials with up to 70-month follow-up vary widely, with most studies reporting less than 5%, but some documenting rates as high as 100/0 (Table 53.5).10,63,66-73,81,85,90-92 NERVE ENTRAPMENT

Nerve injury results in numbness, pain, and parasthesias in the distribution of the nerve; these results can be mild or incapacitating.115 Complete nerve transection is likely to cause only numbness and little long-term morbidity, whereas partial transection or entrapment with a staple, suture, or subsequent encroachment by scar tissue is likely to cause neuroma formation and pain. 2o,116 Symptoms usually appear immediately postoperatively and intensify over the first 2 weeks; most resolve within 8 weeks. 117 Treatment consists of rest and injections with local anesthetic and corticosteroids until symptoms resolve.l'" In a minority of patients, symptoms persist, necessitating exploration and entrapment release or neurectomy.!" The incidence of nerve injuries following conventional open repairs is less than 20/0. 2,115,118 Cunningham et al. noted a disturbingly high incidence of postoperative pain in a prospective randomized trial comparing McVay, Bassini, and Shouldice repairs.!" In 276 patients with 315 repairs performed, 62.9 % had pain (11.9% moderate to severe) at 1 year, and 53.60/0 had pain (10.60/0 moderate to severe) at 2 years. The incidence of pain was not affected by the type of repair performed. Most often, the pain was associated with a ligamentous somatic etiology attributed to undue tightness of the inguinal ligament at its insertion on the pubic tubercle created by the repair. Only a minority of patients suffered from pain secondary to a neurologic etiology. The excellent results following tension-free repairs such as the Lichtenstein procedure support the conclusion that postoperative pain is due to tension created, with neuralgias occurring only rarely (well less than 1% in Lichtenstein's series]." The ilioinguinal, iliohypogastric, and genital branch of the genitofemoral nerve are most at risk during open repairs. The nerves are generally visible and can be avoided. If a nerve must be divided to perform the repair, complete nerve division is usually associated with minimal morbidity.2o,29,116,1l9 Nerve entrapment can occur with any of the laparoscopic approaches but may be lowest with the TEP repair." Tetik et al. reported nerve injury in less than 20/0 of 1514 repairs, with over 900/0 of these resolving with conservative therapy and only 2 patients requiring reexploration and staple removal.l"

HERNIAS AND ABDOMINAL WALL DEFECTS

Phillips et al. reported a 1.6 % incidence of neuralgias in 3229 repairs.'!" Other investigators have reported rates as high as 12%, with an increased incidence associated with the IPOM technique and with surgeon inexperience." Nerve injury typically occurs during laparoscopic repairs when staples are placed inferior to the iliopubic tract in the area lateral to the testicular vessels. The lateral femoral cutaneous nerve, femoral nerve, and femoral branch of the genitofemoral nerve are at risk. These nerves lie superficial to the internal oblique muscle and cannot be visualized. Careful attention to anatomical danger zones during mesh fixation is necessary to avoid entrapment. The triangle of pain and the triangle of doom (Fig. 53.6) designate areas that are anatomical danger zones that require avoidance. Seid combined the two triangles and extended their boundaries to the anterior superior iliac spine laterally, labeling this area the trapezoid of disaster. 117 MacFadyen noted that stapling or suturing that causes nerve entrapment will cause pain lasting 6 months or longer." Some advocate not securing the mesh in place at all, which effectively alleviates this complication. 76 Entrapment of the lateral femoral cutaneous nerve is the most common nerve injury encountered in laparoscopic repairs. It results in pain and numbness in the upper lateral thigh and is called meralgia pataestheticaP" Broin et a1. carefully detailed its course in cadavers and found that it was a mean distance of 6.6cm from the inferior epigastric vessels and 5.6cm from the internal inguinal ring as it passes below the iliopubic tract."! They recommended avoiding entrapment of this nerve by staying above the iliopubic tract and not straying too far lateral to the internal inguinal ring when staples are placed. Entrapment of the ilioinguinal, iliohypogastric, and genital branches of the genitofemoral nerve can occur during laparoscopic repairs if excessive pressure is applied externally during mesh fixation, compressing the muscles enough to allow the staples to reach the nerves.!" ISCHEMIC ORCHITIS/TESTICULAR ATROPHy/VAS DEFERENS INJURY

Wantz has extensively studied ischemic orchitis and its sequela testicular atrophy.2o,122 Ischemic orchitis is a potentially devastating but rare complication of hernia repair and is caused by surgical trauma to the veins of the spermatic cord. Anterior approaches are more apt to cause testicular atrophy than posterior approaches since they require more dissection and handling of the cord. It was once thought that the cause was insufficient arterial supply to the testicle secondary to overzealous tightening of the reconstructed internal inguinal ring. It is now known that the cause is venous thrombosis of the injured pampiniform plexus and disruption of collateral arterial and venous circulation by distal cord dissection. 19,20,122 This is more likely to occur in recurrent hernias, which involve scar tissue and a difficult dissection, or when the distal sac is dissected. The result is a swollen, hard cord, testicle, and epididymis. Fever and leukocytosis may occur, but infection is not part of the natural history of this phenomenon. The symptoms become apparent 2 to 5 days postoperatively. The pain usually lasts several weeks, but the swelling and induration may last 4 to 5 months. Ischemic orchitis may resolve without sequelae or may cause the testicle to shrink, resulting in a completely atrophic

1159

testicle. There is no known treatment of ischemic orchitis that prevents progression to testicular atrophy. Only rarely does the testicle become necrotic or require removal. An atrophic testicle is painless, not prone to malignant degeneration, and does not diminish serum testosterone or fertility .20 Wantz made several recommendations to avoid ischemic orchitis: avoid dissection of the distal hernia sac except in sliding hernias, avoid dissection beyond the pubic tubercle, use a preperitoneal approach for all recurrent hernias or in patients with prior inguinal or scrotal surgery, and delay the repair of a contralateral hernia for at least 1 year in patients with ischemic orchitis." Using this approach in over 6000 repairs, Wantz reduced the incidence of ischemic orchitis from 0.65% to 0.03% in primary hernias and from 2.25% to 0.97% in recurrent hernias when compared to his prior series.!" Skandalakis et al. reported an incidence of testicular atrophy of 0.1 % after 3010 cases of open hernia repairs? The incidence of ischemic orchitis following laparoscopic repair is not well documented but is thought to be sufficiently low since a minimum of cord handling and dissection are required, similar to the open preperitoneal approach.' Direct injury to the vas deferens itself can result in infertility if the contralateral side is abnormal. Injury usually manifests as a painful spermatic granuloma, formed by highly antigenic spermatozoa once they have escaped the vas. Excision of the granuloma and microsurgical repair of the vas is treatment of choice."

BOWEL OBSTRUCTION AND INTRAABDOMINAL ADHESIVE COMPLICATIONS

Unique to the laparoscopic approach is the potential for intraabdominal adhesions and intestinal obstruction. There have been multiple case reports of such occurrences, most of which followed TAPP repairs, but the overall incidence remains small, on the order of less than 10/0. 60,81,96,98,123-125 The TAPP approach creates peritoneal flaps, which must be closed completely. If a gap remains, bowel can be exposed to the mesh, allowing adhesions, obstruction, erosions, and fistulas. 6o,126-128 Bowel can herniate through a peritoneal opening and become incarcerated.":" The IPOM procedure places mesh in an intraperitoneal position with no protection between the mesh and bowel. Both polypropylene mesh and PTFE have been used, but proponents of PTFE cite its inertness and decreased adhesion formation as an advantage.Y" A porcine study compared meshed and unmeshed PTFE with Marlex placed by the TAPP and IPOM methods and noted equal rates of adhesion formation with both PTFE and Marlex but significantly fewer adhesions with the TAPP method.!" Others have also found a higher incidence of adhesion formation following the IPOM procedure in animal models.P'v"! Although several series support the efficacy and safety of the IPOM approach, many feel that a peritoneal covering over the prosthesis decreases the risk of complications." Even though the TEP procedure avoids intraperitoneal dissection, there have been reports of intestinal obstruction following TEP repairs when bowel has herniated through peritoneal rents that were either not seen or not adequately repaired at the time of operation.P':':"

1160

CHAPTER 53

Incisional hernias at trocar sites can occur after laparoscopic repairs and cause intestinal obstruction and strangulation." They are more common after TAPP repairs, occurring in up to 1% of patients, necessitating fascial closure of all ports larger than 5mm. 6o,85 Alternatively, nonbladed and radially dilating trocars may obviate the need for fascial closure. 134 Preexisting umbilical hernias can substantially increase the risk of postoperative umbilical hernias, despite routine closure, and require additional attention.r" Some authors feel that the mere possibility of intestinal obstruction as a complication of hernia surgery is reason enough to completely abandon the laparoscopic approach. Others point out that the risk is minimal, especially with the TEP procedure, by following strict technical guidelines. VASCULAR INJURIES

In laparoscopic repairs, the inferior epigastric, external iliac, femoral, and testicular vessels are at risk. Injuries may result in intraoperative hemorrhage or may present as postoperative hematomas. The inferior epigastric vessels can be injured if trocars are placed medial to the lateral border of the rectus sheath. The pressure of insufflation during laparoscopic procedures can tamponade small venous injuries. After completion of the procedure, hemostasis should be verified with the insufflation pressure minimized. Injuries caused during trocar insertion may not be evident until trocars are removed, mandating careful inspection of these sites under camera visualization as trocars are removed.'?' The reported incidence of postoperative hematoma formation is 1 % to 8%.100 Laparoscopic repairs should be avoided in patients with uncorrected coagulopathies or in cirrhotics (especially with a history of varices) to minimize the risk of retroperitoneal bleeding, which has the potential to fill a very large volume prior to tamponading. In open repairs, bleeding is not a common intraoperative problem, but the incidence of hematoma formation may be as high as 31 0/0. 71 Meticulous efforts to achieve complete hemostasis should be made. Hematomas may be self-limited or may necessitate evacuation. VISCERAL INJURIES

At risk are the small intestine, colon, and bladder, and although rare, injuries to these structures can be the source of considerable morbidity, especially if their diagnosis and treatment are delayed.'?' Many of these injuries can occur if an attempt is made to open the sac of a direct sliding hernia. If direct sacs are not opened but are simply reduced and inverted, the risk of injury may be minimized. In laparoscopic repairs, risk of injury may be minimized by bladder decompression with a Foley catheter, use of an open Hasson cannula technique, insertion of trocars under direct visualization, and thorough anatomical knowledge with cautious dissection.!" Confining dissection to the area lateral to the medial umbilical ligament is helpful in avoiding bladder iniury.l'" Entering the peritoneal cavity with the TAPP and IPOM techniques increases the potential for visceral injury. WOUND INFECTIONS

Hernia repair is regarded as a clean operation and as such should have an infection rate of less than 2%.136 Antibiotic

prophylaxis has been the area of controversy. For clean cases, prophylaxis is normally not indicated. However, implantation of a mesh prosthesis has been used as an indication, and some surgeons routinely give prophylactic antibiotics to all hernia repairs. Platt published a landmark study in 1990 that showed significant benefit to patients undergoing open hernia repairs who received antibiotics.!" On the other hand, Taylor presented a randomized double-blinded prospective study of 619 open hernia repairs comparing antibiotic prophylaxis and no prophylaxis.r" The study showed no benefit from antibiotic prophylaxis, but a high rate (8.90/0) of wound infections occurred in both groups. Gilbert's prospective study comparing prophylaxis versus no prophylaxis and mesh versus no mesh in 2493 repairs confirmed these flndings.!" There was no difference in wound infections between patients who underwent repairs with mesh versus those without mesh, regardless of whether they had received antibiotics. The overall incidence for infection was less than 10/0. There was a threefold increase in wound infections in patients over 60 years of age. The results of these studies continue to make antibiotic prophylaxis a controversial subject, and either point of view can be justified. Of note, in repairs performed using mesh, deep wound infections very rarely, if ever, require removal of the prosthesis.34,139 They can usually be managed with drainage and antibiotics, allowing the wound to granulate.

Special Considerations FEMORAL REPAIRS

Femoral hernias are much less common than inguinal hernias but are more often associated with complicated presentations, with a 200/0 incidence of incarceration." Some authors have suggested that the ideal way to repair femoral hernias is via a preperitoneal approach, either open or laparoscopic."" This facilitates control of hernia contents and avoids disruption of the inguinal floor mandated by an anterior approach and avoids the difficulty associated with approaching a femoral hernia through a thigh incision. The McVay repair has been used, however, with successful results." Strangulated femoral hernias require proximal control, resection, and anastomosis of intestine and may best be approached through a preperitoneal incision or a midline laparotomy. COMPLICATED GROIN HERNIAS

Approximately 100/0 of inguinal hernias and 20% of femoral hernias present incarcerated." Incarcerated hernias can cause intestinal obstruction or strangulation and infarction, resulting in a high incidence of infection, hernia recurrence, and operative mortality, especially in elderly patients. The possibility of such complications has prompted the recommendation that all hernias be repaired electively and promptly as soon as the diagnosis is made.!" The laparoscopic approach in the repair of incarcerated hernias is controversial and may be contraindicated, 100 although successful reduction and repair have been reported. 142 The data on this indication are limited, and caution must be exercised, especially if there is any question of bowel viability, in which situation a resection would be required, and a mesh repair would be contraindicated for fear of infectious


complications. The laparoscopic approach is, however, well suited for the repair of recurrent hernias. 61,75,91,97,98 Many authors have advocated the open preperitoneal approach as the procedure of choice for recurrent and incarcerated hernias. 19,20 For recurrent hernias, dense scar tissue in the inguinal canal can be avoided, reducing the risk of nerve injury and cord damage. In strangulated hernias, proximal unaffected intestine can be controlled prior to the release of necrotic intestine. The peritoneal cavity can be opened without an additional incision, and an intestinal resection and anastomosis may be performed. PEDIATRIC HERNIAS

The incidence of inguinal hernias in children is between 10 and 20 per 1000 live births, with a 4: 1 male-to-female ratio. The overall incidence, incidence of bilaterality, male predominance, and incidence of incarceration are higher in premature infants. The incidence of bilaterality is at least 10% in full-term infants and as high as 55% in premature infants. The incidence of inguinal hernia in cryptorchid infants approaches 650/0. Approximately 55% to 700/0 of inguinal hernias in children are on the right side, and 1% have a direct component.' The higher incidence of right-sided hernias is thought to be due to the later descent of the right testicle and potentially delayed closure of the processus vaginalis. Incarceration occurs in 9% to 200/0 of cases, is more frequent in children younger than 6 months of age, and in the absence of signs of strangulation, can usually be managed by manual reduction followed by prompt elective repair. Elective repair is associated with a much lower incidence of complications compared to emergent operations, especially in low birth weight infants. Elective repair should be performed as soon as possible to avoid reincarceration, which occurs in up to 160/0 of cases.':" The most widely accepted repair of pediatric inguinal hernias is a high ligation of the sac (Fig. 53.8). This technique alone is usually sufficient since the vast majority of pediatric hernias are indirect with no laxity of the internal ring. If ring laxity exists, a few sutures can be placed in the transversalis fascia to approximate the tissues. Recurrence rates of less than 1% are reported." Considerable debate exists concerning routine contralateral groin exploration. Historically, this has been advocated, given the high incidence of bilaterality. The incidence of a patent contralateral processus vaginalis is higher in girls than in boys who present with a unilateral hernia. Development of a contralateral hernia following unilateral repair is also higher in infants presenting at less than 1 year of age and in infants who present initially with a left-sided unilateral hernia. Surana and Puri reported the development of a contralateral hernia in only 100/0 of 116 patients following a unilateral repair and testicular damage in up to 100/0 of their patients; consequently, they viewed contralateral exploration as unnecessary and hazardous.!" Iona prospectively analyzed 354 patients undergoing bilateral repairs or unilateral repairs with contralateral exploration and found bilateral involvement in 68 % of patients younger than 1 year of age and 41 % of patients 1 to 6 years of age, with no increased risk of cornplications.v" Iona advocated routine contralateral exploration of all patients younger than 6 years old. Selective contralateral exploration

1161

on the basis of a laparoscopic evaluation for a patent processus vaginalis performed through the opened hernia sac decreases the number of negative explorations and may be the best option. 146

Abdominal Wall Defects Ventral Hernias Approximately 90,000 ventral hernias are repaired in the United States each year.!" Important to remember is the anatomical structure of the anterior abdominal wall, which above the semilunar line of Douglas consists of skin, subcutaneous fat, anterior rectus sheath, rectus muscle, posterior rectus sheath, and peritoneum. Below the semilunar line, the layers are the same except that there is no posterior rectus sheath. Laterally, the layers are skin, subcutaneous fat, external oblique aponeurosis and muscle, internal oblique aponeurosis and muscle, transversus abdominis aponeurosis and muscle, transversalis fascia, and peritoneum. A ventral hernia is a defect in the abdominal wall. Ventral hernias present as a protrusion or bulge and may contain preperitoneal fat or intestinal contents. The size may range from very small to massive. Patients mayor may not be symptomatic. The fascial edge along the circumference of the defect is usually palpable on exam. In obese patients, a CT scan or ultrasound examination may help confirm the diagnosis. As with groin hernias, ventral hernias may present with incarceration, strangulation, or bowel obstruction; elective repair is preferred to emergent repair. Umbilical hernias are due to an error in the embryologic development of the abdominal wall. Umbilical hernias occur in 10% to 300/0 of live births but frequently close during the first few years of life. If larger than 2cm, the likelihood of the defect spontaneously closing is much less, and repair is not delayed. Otherwise, repair is usually postponed until the child reaches 4 years of age to allow time for spontaneous closure. Most infants are asymptomatic, and incarceration or strangulation is extremely rare.' Repair consists of simple fascial closure. Defects may persist, become evident in adulthood, and should be repaired. In cirrhotic patients with uncontrolled ascites, umbilical hernias may rupture, requiring emergent repair. In such instances, a herniorraphy combined with a peritoneal-venous shunt is effective, but mortality rates are high. Epigastric hernias arise in the upper abdomen along the linea alba, and usually appear in adulthood, often in association with obesity or pregnancy. Epigastric hernias frequently present as small defects with incarcerated preperitoneal fat or omentum, causing pain and warranting repair. Diastasis recti is a condition in which the medial borders of the rectus muscles slowly spread apart, with thinning and stretching of the rectus sheath, resulting in a diffuse bulge in the upper midline abdomen. In contrast to epigastric hernias, diastasis recti is not a fascial defect or hernia per se and consequently presents no threat of complication. Diastasis recti is merely a cosmetic deformity. Excision of the thinned fascia and placement of a mesh prosthesis alleviate the deformity. Incisional hernias occur in at least 2 % to 11 % of abdominal wound closures. 148-150 In a 10-year prospective trial of 337

1162

CHAPTER 53

laparotomy patients, Mudge showed that in 62 patients who developed hernias, 56 % did so after the first postoperative year, and 350/0 did so after 5 years, demonstrating the wide variety in intervals between operation and hernia formation."! Approximately 17% present with incarceration 152 and mortality rates for repair of complicated hernias is three times higher than for elective repairs.v" Many risk factors for developing an incisional hernia have been cited,. including obesity, wound infection, advanced age, postoperative pulmonary complications, jaundice, abdominal distension, emergency operation, reuse of a previous incision, p.regnan~y, postoperative chemotherapy, steroids, malnutrinon, ascites, and peritoneal dialysis. Most of these risk factors are associated with excessive strain on the incision or poor wound healing. Wound infection is the most important risk factor, with hernias four times more likely to occur after a wound infection.l'" Obesity has also been clearly established as a risk factor. 150,155 Carlson showed that reuse of a previous midline incision in combination with a wound infection was associated with a 10-fold increase in risk of hernia formation.':" Reuse of an incision has been shown to double the incidence of subsequent incisional hernias.!" Incisional hernias occur more frequently after a vertical midline incision than after a transverse subcostal, or paramedian incision. 149,157 This may be due t~ the fact that emergency operations are more likely to be performed through a midline incision for more complete and rapid exposure; the emergent nature of the operation, and not the type of incision, may be associated with a higher rate of postoperative hernias. This theory was supported by a trial conducted by Ellis, who found no difference in hernia incidence for different types of incisions in patients undergoing elective abdominal procedures.!" Suture technique has been extensively studied with no difference in hernia incidence shown between continuous and interrupted suture techniques or layered versus mass wound closure. 148,159 The advantages of using a continuous suture are more rapid closure and decreased material costs with no increase in hernia or dehiscence rates. 154,160 Continuous sutures, at least theoretically, evenly distribute the tension and cause less tissue necrosis.'?' Permanent suture may be associated with suture sinus formation.l'" infection.l'" or late hernia formation due to gradual sawing of the suture through the fascia, resulting in a "buttonhole" hernia. 152,162 Absorbable suture alleviates these problems, but must deg~ade slowly enough to provide sufficient tensile strength until adequate wound healing has occurred. Monofilament suture is preferred over braided suture, which has interstices that can harbor bacteria.l" Polydioxanone (PDS) and polyglyconate (Maxon) are monofilament absorbable sutures that retain 700/0 to 750/0 of their tensile strength at 14 days, are completely absorbed by 180 to 210 days, and may be ideal for 159 162 Sutures t h at are more rapidly . . 1 c1osure.' absorbed, faSCIa such as polyglactin (Vicryl), may be associated with a higher incidence of incisional hernias.!" Sutures should be placed at least 1em back from the fascial edge and no more than 1em apart to provide an adequate closure.l'" A suture-to-woundlength ratio of less than 4 is associated with an increased . mci incid ence, 150 emp h asizing the need to incorporate an h erma adequate amount of tissue in the closure. Overtightening should be avoided, as tissue ischemia and necrosis can occur predisposing to wound breakdown, dehiscence, and hernia formation.

Of note, the tremendous surge in laparoscopic procedures has spurred the birth of a new type of incisional hernia the ~rocar ~ernia. M~ltiple reports.of ~uch hernias have app~ared In the literature. The overall incidence of trocar hernias following laparoscopic procedures is less than 10/0. 164 All fascial defects larger than 5 mm should be closed with a fascial closure device to prevent this complication/" Recently, trocars that do not use traditional cutting obturators have been introduced to decrease the risk of hernia formation. some level I evidence suggests that these nonbladed and radially dilating trocars do not require closure.F" REPAIR TECHNIQUES

Various repair methods exist, and a prosthetic mesh mayor may not be used. In open repairs, the hernia is approached through a skin incision placed directly over the fascial defect usually incorporating the scar from the previous incision. Th~ sac is dissected free from subcutaneous tissues and the fascial edges. The sac may be opened to facilitate lysis of adhesions and ~nspection and reduction of sac contents. If possible, the sac IS not completely excised, so that there is a sufficient amount of sac to close over the intestinal contents. This provides protection against adhesive complications if mesh is to be used in the repair. The superficial and deep surfaces of the fascia are exposed several centimeters back from the hernia defect. Attenuated fascia is excised. A thorough search for con~omita?t hernias is performed. Depending on the type of repair, fascia may then be closed with or without placing a mesh buttress. Fascia should only be closed when it can be ~one so without tension. Closed suction drains may be placed In the dead space superficial to the fascia to minimize seroma formation. ~n the case of very large hernias existing for a long period of time, most of the intestines and omentum reside in the hernia sac instead of the abdominal cavity. As a result, the abdominal cavity may no longer be large enough to accommodate the viscera when hernia repair is attempted. This can result i~ diaphragmatic dysfunction and intestinal circulatory congestion after contents are reduced." In this case, the abdominal cavity can be enlarged preoperatively by creating a pneumoperitoneum.l" The abdominal wall stretches as several liters of air are insufflated into the abdominal cavity over the course of 2 to 3 weeks. Because tension-free repairs can be performed using a mesh prosthesis, this technique is not routinely required. Hernias recur on average 1.7 years after repair, according to a retrospective review by Leber of 200 hernias repaired with mesh followed for an average of 6.7 years.!" Recurrence rates after incisional hernia repair vary widely but are disappointing at best, ranging from 200/0 to 630/0, and are notably higher after primary repair than after mesh repairs. 148,157,166 Infection after hernia repair is a feared complication since infection is associated with a markedly higher rate of recurrence. Most infections can usually be managed with antibiotics and debridement and rarely necessitate mesh removal. Simultaneously performed intraabdominal procedures may increase the risk of infection and should be avoided.l'" Several repair techniques are worthy of detailed discussion. PRIMARY REPAIR

Ventral hernias may be repaired by primary closure as long as the repair can be performed in a tension-free fashion. The


direction of closure is not important. Primary closure is the preferred technique for umbilical hernias in children and some small epigastric or umbilical hernias in adults. Permanent suture is used, and the fascial edges are approximated. Unfortunately, the results of primary repair in all but the smallest of incisional hernias are poor,151,152with failure rates as high as 49% to 63%.166,168,169 This is likely due to the fact that patients with incisional hernias have fascia that is weakened and that does not have sufficient tensile strength to hold sutures when placed under mechanical stress. Multiple modifications of the primary repair technique have yielded widely variable results. The Mayo closure imbricates the fascia in two layers in a vest-over-pants fashion. Paul reported a recurrence rate of 54% in 114 patients who underwent Mayo repairs over a 5.7-year mean follow-up ."? Other variations of primary repair have met with better success. Shukla reported no recurrences over 52-month mean follow-up using a far-and-near suture technique in 50 patients with "small- and medium-" size incisional hernias.' ?' Sitzmann reported a 2.5% recurrence rate over 42-month follow-up using internal retention sutures in 409 patients with massive incisional hernias (lOcm average defect size).172 On the other hand, Luijendijk randomized patients with up to 6-cm midline defects to suture (continuous no. 1 polypropylene) versus mesh (polypropylene inlay) repairs and found significantly fewer recurrences for mesh repairs ; recurrence rates were 63% over 75-month median follow-up for suture repairs versus 32% over 81-month follow-up for mesh repairs .l" Thus, some surgeons would advocate mesh repairs for all hernia defects, except in extenuating circumstances such as emergency operations or in contaminated cases .

1163

To avoid risk of intestinal injury, all sutures are placed under direct visualization before the fascia is closed, as opposed to securing the mesh by blindly taking bites on the anterior fascial surface after the fascia has been closed . The latter practice is not only unsafe.!" but also results in superficial bites that inadequately secure the mesh. After all of the sutures have been placed, the fascia is closed in a running fashion as long as it can be done in a tension-free fashion. This creates a barrier between the abdominal contents and the mesh to prevent adhesions and fistula formation. The clamped sutures are placed through the mesh and tied . If fascia cannot be reapproximated, hernia sac or peritoneum is closed at the midline, or omentum is interposed between the mesh and the intestinal contents to prevent bowel erosion. Alternatively, limited data suggest that placing an absorbable mesh on the intraperitoneal side of the repair may create an adequate barrier against adhesions.P''!" Molloy reported using Marlex mesh for the onlay tech nique in 50 patients with incisional hernias, 19 of which were recurrent.I " Over a mean follow-up of 45 months, the recurrence rate was 8% . Recurrences were due to partial detachment of the mesh from the fascial edge. A generous overlap of mesh should therefore be used . Although not an advisable practice, in some patients mesh was placed in direct content with abdominal contents with no apparent complications. Complications included 8% wound infection, 4% seroma, and 12% wound sinus; no patients required mesh removal. Sugermann reported a 4% recurrence rate over 20-month mean follow -up using the onlay technique with polypropylene mesh in 98 patients.!" Complications included 17% wound infection, 5% seroma, 3% hematoma, and 6% chronic pain; 1 patient required mesh removal.

MESH ONLAY REPAIR

Significantly better results have been reliably achieved with mesh repairs, with rates of complications comparable to that of primary repairs.! " Recurrence rates average 6% for mesh repairs according to a collected series of over 800 patients.!" Several methods for mesh placement exist. In the onlay method (Fig. 53.19), skin and subcutaneous tissues are elevated, and underlying adhesions are lysed to expose the fascial edges laterally for approximately 4cm on both the superficial and deep surfaces . Horizontal mattress sutures are placed from within the peritoneal cavity along one-half of the defect, through the full thickness of fascia and muscle, at least 2 em from the fascial edge. These sutures are passed through the mesh and tied. A second row of sutures is placed on the other half of the defect; sutures are individually clamped and held in moderate tension.

MESH INLAY AND PATCH REPAIRS

The inlay method of repair places a prosthetic mesh deep to the posterior rectus fascia. The mesh is placed in either an intraperitoneal or a preperitoneal position. Mattress sutures are placed from the deep aspect of the mesh through the abdominal wall. Once all sutures have been placed, they are tied on the anterior fascial surface. The patch method simply sutures the prosthesis to the fascial edge circumferentially. With either the inlay or patch technique, if the prosthesis is placed in an intraperitoneal position or if no tissue can be interposed between bowel and the prosthesis, the potential for adhesions and fistulization is created. Multiple studies have looked at adhesion formation and the use of prostheses placed in an intraperitoneal position. Significant data from animal studies exist supporting the diminished adhesion formation associated with PTFE compared to polypropylene.F' '!" Clinical studies using PTFE with direct contact between abdominal contents and the prosthesis also support its use in this fashion.169,179,18o Bauer reported PTFE patch repairs in 28 patients with a recurrence rate of 11% over a 22.5-month mean follow-up.!" Complications included wound infections in 2 patients (7.1%, both with stomas), and there were no erosions or bowel obstructions. SANDWICH AND CUFFED MESH REPAIRS

FIGURE 53.19. The mesh onlay technique uses a mesh prosthesis placed superficial to the anterior rectus sheath. The mesh is held in place by full-thickness horizontal mattress sutures.

The sandwich or double-layer technique combines both the onlay and inlay techniques, theoretically providing reinforcement of attenuated fascial edges to prevent suture

1164

CHAPTER 5 3

Peritoneum

FIGURE 53.20. The "cuffed" technique uses a single piece of mesh and buttresses attenuated fascia by folding th e mesh over the rectus sheath to prevent suture pull-through.

dislodgment and recurrence. This technique has been described in several varieties. Condon described placing a PTFE inlay followed by a polypropylene onlay, using mattress sutures to hold both layers in place. "! Rubio described using two pieces of Marlex mesh, suturing each piece in a cuffed manner to the anterior and post erior fascial surfaces, and th en suturing the two pieces of mesh together in the midline. F' More recently, Rubio described using two pieces of PTFE for this repair. 183 The disadvantage of two pieces of mesh may be entrapm ent of fluid between the layers and potential for infection. The surgical technique of using two pieces of mesh is also more cumbersome than using a single piece. To alleviate the potential problems associated with using two pieces of mesh, McClelland described a modified sandwich approach using a single piece of mesh (Fig. 53.20).184 A cuff of mesh is folded over the fascial edge for at least 2 em and sutured into place circumferentially around the defect. McClelland noted that this approach is quicker and equally effective when compared to using two separate pieces of mesh. Although reinforcing the fascial edges by using a cuffed repair makes intuitive sense, trials using this method are lacking.

suggested using an absorbable mesh to facilitate peritoneal or posterior rectus sheath closure as a barrier deep to the Mersilene repair. Others have suggested using PTFE for th e definitive repair to lessen the risk of fistula formation. !" The repair is facilitated by placing mattress sutures from the deep aspect of th e mesh, through the abdominal wall, and out through small stab incisions in the skin . A Reverdin needle facilitates suture placement. Alternatively, large double-arm retention sutures may be used. After sutures have been placed circumferentially around the defect all sutures are tied on top of the anterior fascial surface through the stab incisions. The anterior rectus fascia is closed, which helps use intraabdominal pressure to hold the mesh in place until it becomes fully incorporated.l'" Making buttonholes in the anterior rectus fascia can release tension and facilitate closure of this layer at the midline. Alternatively, a sheet of absorbable mesh can be used. Closed-suction drains are place on top of the repair and brought out separate skin incisions. Mersilene mesh may be associated with higher incidences of infection, fistula formation, and recurrence compared to polypropylene or PTFE.157However, Mersilene, polypropylene, and PTFE have all been used for this repair with good results. Stoppa reported 368 repairs using Mersilene with a 14.5% recurrence rate over 5.5-year mean follow -up; the overall complication rate was 14%, including 3.2% hematoma and 12% sepsis (none required mesh removal'." McLanahan reported a 3.5% recurrence rate over 24month follow-up in 106 patients who underwent this repair using polypropylene mesh. !" Complications included an 18% incidence of wound problems, including one colocutaneous fistula. Five patients required removal of one or mor e anchoring sutures due to chronic pain . McLanahan noted, however, that suture removal was not necessary in any patient after his group switched to using absorbable sutures and stopped incorporating cartilage or rib in the repair. Temudom reported no recurrences over 24-month followup in 50 patients using either polypropylene or PTFE prostheses.!" Complications included a 22% incidence of wound problems (8% infections], including two deep infections

STOPPA REPAIR

Stoppa" and Wantz l85 have both described the use of a giant Mersilene mesh prosthesis in the repair of large (greater than lO-cm)incisional hernias (Fig. 53.211. This approach is similar to the inlay method but overlaps the defect by 8 to lOcm and avoids raising extensive subcutaneous flaps by passing sutures through separate stab incisions. The hernia is reduced and adhesiolysis is performed to widely expose the deep surface of the abdominal wall . Peritoneum is dissected free from the posterior rectus sheath, and the mesh is inserted in the preperitoneal space. Alternatively, the mesh may be inserted between the posterior rectus sheath and the rectus muscle. Prior to mesh insertion, peritoneum, hernia sac, or posterior rectus sheath is closed to prevent contact between abdominal contents and mesh to minimize potential adhesive complications. In the absence of sufficient autogenous tissue, Wantz

Peritoneum

FIGURE .53.21. The Stoppa ventral hern ia repair widely overlaps the defect WIth a mesh prosthesis placed in a preperitoneallocati on or alt ernatively, deep to the rectus muscle. Sutures are brought ou t through separate stab inci sions and tied on top of the ant erior fascia.


requmng mesh removal (one patient who had undergone simultaneous gastric bypass, one who had an undetected enterotomy). Seven patients had chronic pain, which resolved without the need for suture removal. Amid reported no recurrences in 54 patients (no follow-up interval specified) using polypropylene mesh, with the only complication being a seroma in 1 patient.l'" In 25 patients, mesh was secured with staples as opposed to anchoring sutures. Amid claimed that the stapling technique adequately holds the mesh in place until it is incorporated, is faster than suturing, and alleviates the cosmetically unappealing skin retractions at the stab incisions. LAPAROSCOPIC REPAIR

Laparoscopy has gained considerable momentum in the area of ventral hernias, with standardized techniques becoming well established. Most often, a transabdominal approach is used by placing several trocars in an intraperitoneal position, reducing the hernia through sharp adhesiolysis and blunt manipulation, leaving the hernia sac in situ, and using a mesh prosthesis to close the defect. Mesh is sized externally to provide at least 3 em of overlap on all sides of the defect. A suture is placed through each comer and tied, with tails left long. The skin is marked at the sites where the four corner sutures will exit, and small stab incisions are made. Mesh is then rolled and passed intraabdominally through a port, unfolded, and positioned over the defect. A fascial closure device is passed through the skin stab incision and used to individually retrieve the tails of each comer suture. The tails are tied superficial to fascia in a subcutaneous position. Additional transfascial sutures are placed at 4- to 5-cm intervals. Helical fasteners or other similar fixation devices are used to secure the mesh to peritoneum and fascia at l-cm intervals between the comer sutures, preventing herniation of bowel or omentum between the mesh and the abdominal wall. The laparoscopic approach facilitates adhesiolysis and hernia repair with minimal access and without the need for a large subcutaneous dissection. Intraperitoneal mesh placement uses intraabdominal pressure to help hold the prosthesis in place. Intraperitoneal mesh placement does, however, create the potential for bowel adhesions and fistula formation. Polypropylene has been used successfully for this repair.!" but most authors recommend PTFE147,189,190 or several other newly available composite meshes to decrease the risks of adhesive complications. Recurrences are usually due to inadequate mesh overlap or fixation. Mesh security relies primarily on the transfascial sutures, and using only tacks for mesh fixation may be inadequate.':" While some series have documented good results with tacks only.'?' most surgeons advocate routine use of sutures to prevent mesh migration. With appropriate techniques, recurrence rates following laparoscopic repairs are generally about 40/0 with 4-year follow-up; conversion rates are about 40/0. Although randomized controlled trials are still lacking, available data verify that this approach is safe and effective. 147,188,189 As shown in Table 53.6, numerous comparative trials suggest that the laparoscopic approach results in decreased overall complications, fewer wound infections, fewer recurrences, faster recovery, decreased overall cost, and less pain but is associ-

1165

ated with an increased rate of seroma formation, more frequent bowel injuries, and longer operative times compared to the conventional open approaches (Table 53.6).192-201 With Ito 54-month (2 years on average) follow-up, these comparative trials documented recurrence rates of 0%-61 % (130/0 average) for open repairs and 0%-13% (4% average) for laparoscopic repairs. Several large cohort trials supported these results, as shown in Table 53.7. With up to 47-month follow-up, these trials documented an average conversion rate of 4.50/0 and, in studies that used both tacks and suture fixation, a recurrent rate of 3.90/0. 147,191,202-210 Importantly, there is a learning curve for the laparoscopic approach. Good surgical judgment, knowledge of the procedure, and great care must be taken to perform the repair correctly and safely. Special attention must be paid to identifying and repairing (laparoscopically or via a conversion to an open approach) enterotomies or other visceral injuries as they occur, such that missed injuries and postoperative abdominal sepsis may be avoided. By far, this is the most troubling pitfall regarding laparoscopic hernia procedures as missed injuries may lead to mortalities. 194,195,203,208 Whether to proceed with mesh placement in the setting of an adequately repaired enterotomy is controversial. Viable options include not placing mesh and performing a tissue repair or returning to the operating room after several days of antibiotic therapy.r'" Alternatively, if there is no spillage of enteric contents, several authors have successfully placed mesh during the initial operation, as planned, with good results. 203,204 Since no effort is made to remove the hernia sac, seroma formation is a common occurrence following laparoscopic repairs. Depending on the definition used, seroma formation may occur as frequently as 43 %,197 but is self-limited in the vast majority of patients. While aspirating such seromas may be tempting, only the few (30/0-18%) patients with persistent (>6 weeks) seromas should be decompressed since needle aspiration may be associated with subsequent mesh infection. 197,204 In addition, compression bandages or abdominal binders worn for 7-14 days following surgery may help minimize seromas."? As previously mentioned, transfascial suture fixation seems important for repair durability. On the other hand, significant persistent pain may develop at these fixation sites in 10/0-260/0 of cases. Some authors have suggested avoiding overzealous tightening of these sutures to avoid pain. Suture sites can be injected using a combination of steroid and local anesthetic, or sutures can be removed via a cut-down procedure if pain persists. Studies are currently underway investigating the use of absorbable sutures and the efficacy of repairs using nonsuture fixation strategies with a variety of prosthetic types. Because of the advantages of fewer wound infections and recurrences and a faster recovery, laparoscopic approaches will likely continue playing a major role for ventral hernia repair. COMPLEX ABDOMINAL WALL CLOSURES AND BIOMATERIALS

Abdominal wall closure can be difficult and morbid in the emergency setting. Emergency closures are often required in the face of vigorous resuscitation with massive tissue edema

Study design

Prospective nonrandomized

Retrospective

Retrospective

Reference

McGreevy et al,. 2003, United States" ?

Bencina et al., 2003, Italy"?

Salameh, et aI., 2002, United States!"

I mo

l mo

17mo

18mo

13mo

13mo

Open: 71

Lap: 42

Open: 49

Lap: 25

Open: 35

Average follow-up

Lap: 65

No . of repairs

-

Total: 26% Mortality: 0 Bowel injury: 5% Wound infection: 0" Seroma: 14% T otal: 44% Mortality: 0 Bowel injury: 2 % Wound infection: 12%" Seroma: 10% Total: 32% Mortality: 4 % Wound infection: 8% Seroma: 12% Total: 37% Mortality: 0 Wound infection: 20% Seroma: 5%

Total: 8%" Mortality: 0 Wound infection: 0 Seroma: 3% Total: 21 %" Mortality: 0 Wound infection: 8% Seroma: 4%


TABLE 53.6. Trials Comparing Laparoscopic and Open Ventral Hernia Repairs.

102"

-

2.3"

2.8"

112

173

110

6.0%

4.0%

8.5%

8.0"

108

0

5.0"

l.5

1.1

132"

-

Recurrences

.

Length of ho spitalization (days)


-

€3,936"

€3,09l"

-

-

Cost

-

requirements"

J. medication

-

-

Postop pain

T h ere was 1 death in the laparoscopic group due to a missed enterotomy.

This study provides perioperative data only with no further follow-up. Reoperation was required for 2 mesh infections and 1 missed enterotomy in the laparoscopic group and 1 wound dehiscence and 1 intraperitoneal abscess in the open group. Defect size was significantly larger for open repairs (122cm2 ) compared to laparoscopic repairs (83 crrr' [, which may have biased outcomes.

Conclusions/details

'"

"'"

> m

..,""

o ::c

0\ 0\

....

Retrospective

Retrospective

Prospective nonrandomized

Prospective randomized

Wright et al ., 2002, United States!"

Chari et al., 2000, Un ited States'l"

DeMaria et al., 2000, United States"?

Carbajo et al., 1999, Spain! "

27mo

27mo

Open: 30

12-24mo

Open: 18

Lap: 30

12-24mo

6-24mo

Open: 14 Lap: 21

6-24mo

24mo

Open: 90

Lap: 14

24mo

Lap: 86

Mortality: 0 Bowel Injury: 14% Mortality: 0 Bowel injury: 7% Mortality: 0 Bowel injury: 0 Wound infection: 10% Seroma: 43% Mortality: 0 Bowel injury: 0 Wound infection: 33% Seroma: 22% Mortality: 0 Bowel injury: 0 Wound infection: 0 Serorna/ hematoma: 17% Mortality: 0 Bowel in jury: 7% Wound infection: 10% Seroma/ hematoma: 87%

Total: 24% a Mortality: 1% Bowel injury: 6% (3/5 recognized) Wound infection: 4% Seroma/ hematoma: 10.4% Total: 38 %" Mortality: 0 Bowel injury: 1% Bladder injury: 1% Wound infection: 9% Seroma/ hematoma: 16%

-

$11,013

$13,600

5.0 5.5 0.8a

124a 78a -

0 4.8%

4.4 a

2.2a

9.1"

-

87 a

112a

0

0

6.7%

0

-

$6,567a

2.5a

102a

5.5%

$lO,135 a

1.5a

131"

1.1%

-

.j, at 6 and 24ha

-

-

-

-

(continued)

This is a small but wellconducted study providing the only level I data available.

Significantly fewer recurrent hernias were repaired in the open (17%) vs. the laparoscopic (54% ) groups, which may have biased outcomes.

Data in open group are given on ly for the subset of patients in this study who underwent open repairs with mesh. Defect size was significantly smaller for open repairs (79cm 2 ) compared to laparoscopic repairs (112cm2 ) and significantly more recurrent hernias were repaired in the open (31%) vs . the laparoscopic (17%) groups, which may have biased outcomes. There were 2 missed enterotomies in the laparoscopic group, 1 of which resulted in death. Very limited data provided by this study. I

0\

'"

........

'"

(J

."

'" ..,'"

0

er-

:>-

::;:

:>r-

z

s::

0

0

til

:>-

0

z

'" :>-

:>-

"'"z

:J:

Ret rospective

Prospective lap, ret rospective open

Ret rospect ive

Ramsh aw et al., 1999, Unit ed Stat es '?"

Park et al., 1998, United States200

Holzman , et al ., 199 7, United StatesW I 20 mo

19mo

Ope n : 16

54 mo on 28 pat ients

Open : 49

Lap: 21

24mo on 45 patients

21mo

Open: 174

Lap: 56

2 1mo

Lap: 79

Average follo w-up

' Statistical signi ficance (all unmarked values are not statistically significant).

- , value was not measured.

St udy design

Referenc e

N o. of repairs

Total : 19% Mortality: 0 Wound infection: 3% Seromaj h ematoma: 3 % Total : 30% ' Mortality: 0 Wound in fect ion: 6% Seromaj hematoma: 7% Total: 18%' Mortality: 0 Bowel injury: 0 Wound infection: 4% Seromaj hematoma: 4 % T ot al : 37%' M ortality: 0 Bowel in jury: 4 % Wound inf ection : 8% Seromaj hematoma: 14% T ota l: 23% Mortality: 0 Wound in fect ion : 5% Seroma: 5% Total: 3 1%' Mo rtali ty: 0 Wound in fect ion: 6% Sero ma: 0 %

C om pli cations (not including recurrenc es)

128

98

12.5 %

79'

9.5%

60 .7%

95'

82

20.7 %

13.3 %

58

Operative tim e (min)

2.5%

Recurren ces

TABLE 53. 6. Trials Com paring Laparoscopic and Open Ventral Hernia Repairs. (continued)

4.9

1.6

6.5'

3.4'

2.8

1.7

Length of h ospitalization (days)

$7,299

$4,395

-

-

-

-

-

-

-

-

-

Postop p ain

-

Cost

The laparoscop ic approach was less costly du e to decr eased shorter hospit al stays and less-severe com plications.

There wa s 1 unrecogn ized bowe l injury in each grou p; th ere was also a repair breakd own for a recognized bowel injury in th e laparoscopi c grou p. All cases requ ired reoperation an d m esh removal, but th ere were no deaths. M ean time to recu rren ce was 6 m onths for laparoscopi c repairs and 10.5 m onths for open repairs .

Con clusions /de tails

:z:

'" '"

'"'"

.;

';j

:>

o

co

0\

20mo 36mo

850 200

Prospective

Gillian et al., 2002, United States'?" Chowbey et al., 2000 , India" ? Toy et al., 998, United States, Canada!"

Ben-Haim et al., 2002, Israel 207 Berger et al., 2002, Germany'?"

19 m o 15mo -

35mo 7mo

100 150 100 202 144

Prospective

Retrospective

Retrospective

Prospective

49mo

159

Re trospective

Retrospective

30mo

96

Re trospective

Prospective 185 %) Re trospective (15%) Re trospec tive

44mo

270

Retrospective

Franklin et al., 2004, United States 202 Carbajo et al., 2003, Spain'?'

Heniford et al., 2003, United States 203 LeBlanc et al., 2003, United Sta tes'?' Rosen et al., 2003, United States 20S Bageacu et al., 2002, Prancer"

47mo

384

Study design

Reference

Average follow-up

No. of repairs

TABLE 53.7. Cohort Trials for Laparoscopic Ventral Hernia Repair.

Polypropylene/ tacks PTFE/tacks and sutures

Various/tacks on ly PTFE/tacks and sutures PTFE/tacks and su tures Composix/tacks

PTFE/tacks an d sutures PTFE/tacks an d sutures Various/various

Various/tacks and sutures PTFE/tacks on ly

Mesh /fixation

1.7%/0. 1% 4 % /0 2 % /0 6%/0

3 .6% 3.5% 12.2% 13.8%

0

0.5%

0

0.6%

1.3 % /0

0/ 0

3%/0

0.7%/1. 3 %

4%/2%

3.3%/0

0.3%

7.0%

1.3 %/0

4%

Conversion

Bow el injury (recognized/ unrecognized)

0.1% 0

1.6% 1%

2.6% 7.5%

0 0 0 0.7% 0 0 0

-

26%

-

-

15.9% 11% 3.3% 3.0% 18% 5.2%

4%

0

7.4%

12%

0

3%

3%

Mortality

Persistent pain

Prolonged seroma

4.4%

1.0%

1.0%

2.7%

2.0%

15.7%

17.7%

6.5%

4.7%

4.4%

2.9%

Recurrences

0\ 10

-' -'

CJ>

..,'"

'" '" (1

o

;,r,...

:;;

r-

;,-

z

~

tl 0

tll

tl ;,-

z

;,-

CJ>

;,-

"'"Z

:t

1170

CHAPTER 53

or, in the case of tissue loss secondary to trauma, surgical debridement for necrotizing infections, or resection of tumors. Such wounds may be heavily contaminated, and postoperative wound sepsis is common. Primary fascial approximation may create a closure under tension and result in abdominal compartment syndrome, dehiscence, evisceration, or fistula formation. 211,212 A prosthetic repair provides tension-free closure and is effective in alleviating evisceration and restoring abdominal wall continuity in the acute phase.i" Prosthetic repairs, however, can be fraught with long-term complications. Voyles reported nine of nine patients with Marlex mesh closures of contaminated abdominal wall defects followed by split-thickness skin grafting who either extruded their mesh or developed enteric flstulas.i" Six of nine patients who underwent Marlex closures followed by wound healing by secondary intention without skin grafting developed fistulas or mesh extrusion. Voyles reported decreased complications if the Marlex closure was covered with full-thickness skin or tissue flaps. In a review of 14 studies on polypropylene mesh closure emergency abdominal wall defects, Jones reported an overall complication rate of 55 % in 128 patients, with enteric fistulization in 23 0/0. 214 No fistulization or mesh extrusion occurred in wounds covered with full-thickness skin or muscle flaps. After polypropylene mesh closure followed by split-thickness skin grafting, Stone reported a mortality of 23% related to progressive wound sepsis.r" The use of absorbable mesh provides a lower incidence of fistulization and wound complications but universally leads to ventral hernias, which must be dealt with at a later date. The proponents of absorbable mesh note that it is effective in closing acute abdominal wall defects that are contaminated. Unlike permanent mesh, absorbable mesh does not chronically harbor infection. This allows complete clearance of infection prior to definitive ventral hernia repair, providing a better chance of a successful repair. It also provides no residual foreign body to complicate wound management should a fistula form. Buck reported using polyglycolic acid (Dexon) mesh in 26 patients with no dehiscence or mesh infection and a fistula rate of 8 % .215 Greene reported a fistula rate of 120/0 using Dexon in 59 patients.i" He noted that when polyglactin (Vicryl) was used as a substitute, it ripped with suturing and was too rapidly absorbed. In 166 patients, Fabian reported an overall fistula rate of 80/0 and no wound-related deaths using a protocol that called for absorbable mesh repair of emergency defects, followed by mesh removal prior to wound coverage and planned repair of the ventral hernia at a later date. 211,217 Mesh was removed 2 to 3 weeks postinsertion (after granulation tissue developed) and split- or full-thickness skin grafts were placed 2 to 3 days later after wounds were packed to minimize bacterial contamination. Definitive hernia repairs were then performed 6 to 12 months later, after adhesions had matured to a filmy stage. Using this method, Fabian reported being able to perform primary fascial closure at the time of mesh removal in 22 % of patients who originally received mesh closures for massive edema. These patients were spared a subsequent planned ventral hernia repair. Over a mean 24-month followup, only 50/0 of 73 patients who underwent planned delayed repair using a modified components separation (without mesh) developed recurrent hernias.

Complex cases, including intraabdominal abscesses, fistulas, mesh infections, abdomens originally closed by secondary intention, or recurrent hernias in the setting of hostile abdomens or previous skin grafts may be well suited for repair using autogenous tissue, namely, through methods of fascial partitioning. The so-called components separation technique, as described by Ramirez in 1990, involves adhesiolysis, reduction of the hernia (usually midline), and reconstruction of the abdominal wall using relaxing incisions that allow medial transposition of the muscular layers.i" After widely undermining the subcutaneous tissue, parasagittal relaxing incisions are made in the external oblique aponeurosis and muscle about 2 em lateral to its insertion into the rectus sheath starting at the groin and continuing 5 to 7 em cephalad to the costal margin; the external oblique muscle is separated from the internal oblique muscle as far laterally as possible, and the linea alba is closed primarily. If tension exists, additional length can be gained by incising the rectus sheath and reflecting the fascia off the muscle toward the midline; alternatively, the transversus abdominis muscle may be incised via a transperitoneal approach to provide further medial mobilization. Defects as large as 20 em at the umbilical level can be closed using these maneuvers.i" Mesh may also be used in conjunction with components separation, either for reinforcement of emaciated tissues or when inadequate autogenous tissue exists.F" As an alternative to wide subcutaneous undermining, separate skin incisions can be used to mobilize the external oblique myoaponeurosis. Recently, endoscopic techniques using balloon dissection and muscular transection under videoscopic control have been developed.l" For massive hernias in patients with loss of domain, components separation may be combined with the use of tissue expanders to gain additional skin, muscle, and fascia laterally for subsequent midline mobilization.i" Shestak repaired 22 midline hernias up to 14cm wide and 24cm long using components separation (with mesh in only 1 patient) and reported a recurrence rate of 50/0 over 52-month mean follow-up.F" De Vries Reilingh used components separation (primary running fascial closure without mesh) to repair complex midline hernias in 43 patients having a mean defect size of 18em long x 13 cm wide; the recurrence rate was 300/0 over 15.6-month mean follow-up.!" While the recurrence rate in the latter series may seem high, 15 patients had simultaneous intestinal surgery (3 Hartmann's reversal, 2 ileostomy reversal, 4 enterocutaneous fistula repairs, 5 ostomy relocations, 2 other), and 35 % of reconstructions were done under contaminated conditions. Thus, component separation may be quite useful in these settings with acceptable results; large series or comparative trials, however, are not yet available. New biomaterials are now available that facilitate hernia repair through remodeling of native tissues and may be especially useful in the setting of contamination. Through tissue engineering, human or porcine specimens can be decellularized with maintenance of the architectural integrity, thus serving as a collagen matrix. Currently available materials made from porcine small intestine submucosa, porcine dermis, and human cadaveric dermis, when implanted, allow fibroblast ingrowth with subsequent collagen deposition and remodeling. The lack of a true foreign body has proven especially useful in complex abdominal wall reconstructions in


the setting of contamination, but long-term documentation of efficacy for routine hernia repair is lacking. These prostheses are currently very expensive; are often available in only small sizes, requiring tedious suturing for creation of larger composite pieces; and some have difficult handling characteristics (very flimsy). Nonetheless, the recent introduction of these materials has fueled significant enthusiasm for their use. Ueno repaired 18 ventral and 2 inguinal hernias in the setting of bacterial contamination using small intestinal submucosa (SIS; Surgisis, Cook Surgical, Bloomington, IN) and documented a 300/0 recurrence rate over 15.7-month mean follow-up.F" Franklin repaired 58 hernias in 53 patients using SIS, including 34% with potential contamination and 220/0 with gross contamination, and reported no mesh-related complications and no recurrences over 19-month median followUp.224 Eid laparoscopically repaired 12 ventral hernias using SIS at the time of Roux-en-Y gastric bypass operations for morbid obesity and found no recurrences over 13-month mean follow-up.i" These series documented no mesh reactions and good compatibility between the porcine-derived prosthetic and the human host. Moreover, SIS seems to withstand bacterial contamination relatively well. Porcine dermis (Permacol, Tissue Science Laboratories, Covington, GA) and human cadaveric dermis (Alloderm, LifeCell Corp., Branchburg, NT) have recently been introduced, and although data are lacking, early reports suggest good utility of these biomaterials.P'v'"

Other Abdominal Hernias SPIGELIAN

The Spigelian or semilunar line marks the transition from muscle to aponeurosis of the transversus abdominis muscle. The Spigelian fascia lies between this line and the lateral border of the rectus sheath. A defect in this fascia results in a Spigelian hernia. Up to 900/0 are located 0 to 6cm cranial to the interspinal plane (the horizontal plane through both anterior iliac spinesl.i" The defect originates in the transversus abdominis muscle and mayor may not involve the more superficial layers; hernia sac and contents often lie in an intramural location between the abdominal wall layers and may not be palpable. Consequently, patients often present with vague complaints of pain and nonspecific tenderness on exam. Computed tomography or ultrasound scanning may aid in the diagnosis. Ultimate diagnosis may not be made until the time of surgical exploration. Exploration may be undertaken via an incision directly over the defect if palpable. If it is nonpalpable, exploration via a preperitoneal approach through a midline or paramedian incision avoids an extensive subcutaneous dissection. The defect is usually small and can be repaired primarily. Recently, success has been reported using laparoscopic approaches.F': onmvasrve unagmg

(US, CT, Sestarnibi, MRI)

US, Sestarnibi

Positivein at least two studies

+ - - - - - - - - - - - - - - - - - - - - - Selective

venous sampling

FIGURE 55.7. Flow diagram for localization strategy in unoperated and previously operated patients.

1195

PARATHYROID _ttrY'_ _

TABLE 55.3. Imaging Modalities in Reoperative Parathyroidectomies: Overall Results.

References

Level of evidenc e'

Mariet te 1998190 Peeler 1997191 Jaskow iak 1996 154 Shen 199662 MacFarlane 1994192 Rodriqu ez 1994 193 Doherty 1992194

III III Il III III III III

n

Sestamibi

38 25 227 102 42 152 27/-

69/74/67/0

77/-

42/15 70/0

Tech-thai

42/8 68/60/ 16 4/23

Ultrasound

CT

45/48/21 57/67/9 53/ 16 0/20

16/68/52/ 16 42/56/ 10 42/ 12 35/ 13

MRI

Angio graphy

Venou s sampling

63/48/ 14

59/9

36/8 69/12 19/13

68/14

77/-

76/4

77/-

69/ 8 69/1 5

84/ 7

Imaging moda lit ies: true-posit iveJfalse-positiv e 1%). ' I, randomized prospective stu dy; II, prospectiv e study; III, retrospectiv e study, revie w or an ecdotal. "Values represent sens itivities.

an abnormal gland in about 75% to 80% of patients requiring repeat surgery'" whereas invasive studies help in the remainder (Table 55.3).65

Common Localization Studies ULTRASOUND

Ultrasound (US) is the least expensive and least invasive technique used to image abnormal parathyroid glands. It is particularly effective in localizing enlarged parathyroid glands in the neck and can be used to identify 30 % to 60% of the abnormal glands in patients requiring reoperation/" It clearly identifies juxta thyroidal parathyroid glands that appear sonolucent compared to the more echogenic thyroid (see Fig. 55.6). US does have some relative disadvantages, however. It may fail to image posterior glands in the tracheoesophageal groove because its signal may be shielded by the air-filled trachea. Similarly, US may miss glands in the anterior medi astinum because the signal is shadowed by the sternum. In multiple gland hyperplasia, it generally demonstrates only the dominant gland. Finally, the quality of US examination is highly operator-dependent, and requires an ultrasonographer both knowledgeable and interested in locating abnormal parathyroid glands .

tions." The sensitivity of sestamibi scans to localize parathyroid tissue may be further improved by the suppression of thyroid function with thyroxin or liothyronine and worsened by patient use of calcium channel blockers.v" Sestamibi has been combined with the gamma probe for hand-held intraoperative localization of abnormal parathyroid glands.i'r" Advocates suggest that this approach is less invasive and can be done as an outpatient procedure through a smaller incision, with less operating room time required." However, most surgeons find it superfluous as the results of the preoperative imaging pinpoint the location of the abnor mal gland. Sestamibi scans appear to facilitate the dissection and make the surgery easier, but they have not been shown to affect the outcome in previously unoperated patients. A recent study demonstrated that there was no significant difference in cure rates between patients who had preoperative sestamibi scans and those who did not (cure rates , 97.5% and 99%, respectively) . However, there was a significant difference in cure rate between the negative sestamibi scan group (92.7%) and both the no-scan group (99.3%) and the positivescan group (100%). Thus, the sestamibi scan can be used to identify those patients who are less likely to be cured." Compared to ultrasound imaging, the nuclear medicine studies are less operator-dependent and subject to less variability in interpretation. COMPUTED TOMOGRAPHY

SESTAMIBI SCINTIGRAPHY

Sestamibi technetium 99m scans were first described as a means to identify parathyroid tissue by Coakely in 1989.66 Sestamibi is sequestered in metabolically active tissue or in tissue with a high mitochondrial content. Both the thyroid and parathyroid glands will take up sestamibi, but its uptake will be stronger and the signal will persist longer in abnormal parathyroid glands (see Fig. 55.5). The combination of single-photon emission CT with sestamibi has improved the sensitivity to about 85%, especially for deep cervical and mediastinal parathyroid tumors." Sestamibi technetium 99m scanning has superior resolution and sensitivity (80%-90%) to detect hypercellular parathyroid glands before reopera-

CT is particularly effective for identifying ectopic glands in the anterior mediastinum and enlarged glands in the tracheoesophageal groove, both areas where ultrasound scans may not visualize aberrant tissue. Mediastinal parathyroid adenomas often lie within the fat-replaced thymus, where even small adenomas can be readily visualized (Fig. 55.8). Ectopic glands in the tracheoesophageal groove are detected as a solid mass adjacent to the esophagus . Undescended glands near the carotid bifurcation can also be identified if the examination images at the level of the hyoid bone . On the other hand, CT is poor at detecting intrathyroid or juxta thyroid tumors and exposes the patient to the risks associated with contrast media and radiation.

1196

CHAPTER 55

and rapid PTH assay was shown to localize the abnormal parathyroid gland correctly in six of seven patients who had negative noninvasive imaging and required reoperation for prior unsuccessful parathyroid surgery. " It is indicated in only a small proportion of reoperative patients who have significant primary hyperp arathyroidism and no apparent localizing information after completing all other noninvasive studies and angiography. SUMMARY OF LOCALIZATION STUDIES

FIGURE 55.8. Computed tomography is the most useful imaging

modality for identifying parathyroid adenomas located in the mediastinum.

MAGNETIC RESONANCE IMAGING

Initial experience with MRI of abnormal parathyroid glands has been successful for large parathyroid adenomas, which on Tj-weighted or stir-pulse sequ ences produce a bright signal. " In the mediastinum this signal may be confused with fat, and a T j-weighted image is required to specifically identify th e pathology. With gadolinium-enhanced MRI and T 1- and Tr weighted images , MRI can now provide higher sensitivity than CT for identifying ectopic parathyroid tumors. However, MRI is more expensive than CT and is less tolerable by pati ents. ANGIOGRAPHY

The potential for morbidity associated with angiographic procedures to localize parathyroid glands sharply limits its use to patients with persistent symptomatic or recurrent hyperparathyroidism requiring reoperation and the inability to detect the abnormal gland on other studies. Intraarterial digital techniques have greatly simplified angiographic localization of parathyroid pathology (Fig. 55.9). Because digital examination does not require highly selective catheter positioning, it can be accomplished more safely and expeditiously. The improved sensitivity of digital subtraction arteriography also makes it possible to significantly reduce the total dose of water-soluble contrast material, thereby decreasing adverse effects on the kidney in patients who may already have compromised renal function .

Sestamibi and ultrasound should be used in patients undergoing initial exploration for primary hyperparathyroidism. Accurate preoperative localization studies allow for the performance of a minimally invasive parathyroidectomy that shortens hospital stay, minimizes scaring, and ensures a successful outcome. Further, in patients undergoing parathyroid reoperations, preoperative radiologic localization studies are essential to plan the reoperative surgical strategy (see Fig. 55.8). We recommend liberal use of each of the noninvasive imaging studies IUS, sestamibi, CT, and MRI) as an initial imaging cluster. If two studies identify the abnormal parathyroid gland in the same location, we proceed with surgery. If the noninvasive studies are equivocal, we then perform digital art eriography. If that study is positive, we perform surgery; if negative, we recommend selective venous sampling for rapid PTH. 77

Intraoperative Determination of Parathyroid Hormone Intraoperative determination of PTH serum levels allows for the continuous monitoring of parathyroid function during

SELECTIVE VENOUS SAMPLING FOR PARATHYROID HORMONE

Selective venous sampling requires the greatest experience and is the most variably performed of all the localizing procedures. Contrast load, radiation exposure, and cost (15-20 PTH determinations), in addition to radiography costs, are all significant. Moreover, gradients determined by selective catheterization identify only the region of pathology [e.g., right side of the neck, mediastinum) but do not specifically image the mis sing abnormal gland. A new technique is to add the rapid PTH assay to selective venous sampling to provide a shorter tum-around time and allow the radiologist to obtain more selective samples in regions in which high concentrations of PTH are found . This combination of venous sampling

FIGURE 55.9. Angiogram demonstrating a large anteriormediastinal parathyroid adenoma (large arrow) with the right internal mammary artery (small arrows) as its bloodsupply.

1197

PARATHYROID

surgery.P:" Generally, after successful removal of a single parathyroid adenoma or adequate resection of hyperplastic glands, serum PTH levels begin to fall immediately and reach either a 500/0 drop from the baseline level or normal range within 10 to 15min. 83 Studies demonstrate that serum levels of intact PTH decline rapidly, only 10min after resection of a parathyroid adenoma.r':" Furthermore, the rate of decline is less in patients with hyperplasia and may provide an additional intraoperative means of diagnosing hyperplasia.fv" A peripheral serum sample for PTH should be obtained just before surgery and after the induction of anesthesia. Repeated serum samples are obtained intraoperatively immediately following resection of an enlarged gland and then 10, 20, and 30min later. This protocol has been designed to take into account the half-life of PTH, which is 1 to 4 min, and to avoid misleading results from a spike in concentration that may occur during handling and removal of the adenoma." A 500/0 reduction in the PTH level from the median baseline level indicates a successful outcome." The operation can be terminated based on this result without surgical identification of the other parathyroid glands. This assay can also be used as a biologically specific method to identify a pathological sample without the need for histological examination of a specimen. A fine-needle aspiration (FNA) of a mass lesion can be diluted with heparinized saline and PTH levels measured. A high level of PTH has a specificity that approaches 1000/0 for the identification of parathyroid tissue. 65,86,88,89 Although this technique can be performed as a preoperative study, it currently has its greatest utility as a method of intraoperative tissue identification. Intraoperative determination of serum PTH levels appears to complement surgical skill and histopathological information and has the potential to provide additional guidance regarding the extent and degree of neck exploration." However, false-negative results" or technical difficulties may be encountered, and this information may be difficult to interpret in the case of double adenoma, hyperplasia, or in the presence of secondary hyperparathyroidism." Nevertheless, its use has greatly facilitated minimally invasive parathyroidectomy and it has reduced operative failure rates from 6 % to 1.5 % for initial operations'? and for reoperations from 240/0 to 60/0. 93

Surgical Management of Parathyroid Disease Primary Hyperparathyroidism

TABLE 55.4. Symptomatic Manifestations of Primary Hyperparathyroidism that Warrant Surgery. System

Signs and symptoms

Serum Skeletal

Calcium level>12 mgj dL Decreased bone density Pain Pathological fracture Bone cysts Brown tumors Osteitis fibrosa cystica Gout and pseudogout Nonspecific arthralgias

Renal

Urinary calcium >350mgj24 h Renal colic Nephrocalcinosis Decreased creatinine clearance Peptic ulcer disease Pancreatitis Emotional lability Slow mentation Poor memory Depression Easy fatigability Proximal muscular weakness Muscular atrophy Anemia

Gastrointestinal Neurological

Neuromuscular Other

musculoskeletal symptoms such as muscle weakness or fatigue, depression, and chondrocalcinosis with pseudogout. The best treatment for totally asymptomatic patients is still controversial." As routine serum screening of patients became more widespread in the 1970s, the prevalence and incidence of primary hyperparathyroidism was recognized to be much higher than originally thought. Similarly, the clinical profile of the disease shifted from one with more overt physical manifestations to one with more subtle, or nearly asymptomatic, findings. 98,99 In 1991 the recommendations of the National Institutes of Health Consensus Conference on asymptomatic primary hyperparathyroidism were published, which identified several patient criteria including age, serum calcium levels, renal function, and bone mineral density." These criteria were revisited in 2002 by a Consensus Development Workshop and made more inclusive by the further relaxation of abnormal serum calcium and bone mineral density values" (Table 55.5). In apparently asymptomatic patients with primary hyperparathyroidism, surgery is indicated for younger patients «50 years old) who have a low operative risk and the potential

INDICATIONS FOR SURGERY

In general, surgical exploration is indicated for all patients with clear biochemical evidence of primary hyperparathyroidism and documented signs or symptoms of the disease (Table 55.4).94-97 Bone disease, evident as bone cysts, elevated serum levels of bony alkaline phosphatase, bone tumors, subperiosteal resorption, and decreased bone density (>2standard deviations below normal), warrants parathyroidectomy. Nephrolithiasis, nephrocalcinosis, impaired renal function, pancreatitis, peptic ulcer, and parathyroid crisis are other indications for surgery. Additional indications for surgery include a serum calcium level greater than 12mgjdL, a urinary calcium level greater than 400mgj24h, neuromuscular or

TABLE 55.5. Current 2002 Consensus Panel Recommendations for Surgery in Asymptomatic Patients with Primary Hyperparathyroidism. Serum calcium >1mgjdL above upper limits of normal 24-h urinary calcium >400mg Creatinine clearance reduced more than 300/0 to age-matched controls Bone density at lumbar spine, hip, or distal radius t-score -

":>0

-

0

0 0

0

(%)

Mortality

1200

CHAPTER 55

Left superior parathyroid ad enoma Left inferior thyro id artery

mal parathyroid tissue is the appearance of the gland. Pathologists may find it difficult to differentiate normal from hypercellular parathyroid tissue or hyperplasia from adenoma, but they can reliably confirm whether the biopsied tissue was parathyroid. Alternatively, the tissue in question can be heparinized and its PTH level measured." If two glands are enlarged (double adenoma), both are removed. Long-term results with this method of management have been highly satisfactory.15,34 HYPERPLASIA

Thyroid Left recur rent laryngeal nerve

FIGURE 55.10. Identification of a left superior parathyroid adenoma. The thyroid gland is elevated with a Babcock clamp. The investing thyroid fascia is opened posterior to the upper pole of the left lobe. A left upper parathyroid adenoma is identified superior to the inferior thyroid artery and posterolateral to the recurrent laryngeal nerve . Th e left recurrent laryngeal nerve is shown in its usual location within the tracheoesophageal groove and posterior to the inferior thyroid artery .

In the minimally invasive parathyroidectomy, limited subplatysmal flaps are raised because the goal of surgery is to remove a solitary adenoma and not to perform a standard neck exploration. Because of this, there is limited mobilization of the thyroid gland and retraction of the strap .muscles on the side of the dissection. Dissection is focused on the preoperative localization studies, and the abnormal parathyroid gland is removed. The surgeon should be aware of the relationship of the parathyroid glands to the recurrent laryngeal nerves and avoid injury to these nerves. The upper glands are posterior and lateral to the recurrent laryngeal nerve (Fig. 55.101, whereas the lower glands are anterior and medial to it (Fig. 55.11). The vascular pedicle is either ligated or clipped and the specimen is sent to pathology. The intraoperative PTH blood levels are measured while the wound is closed . The procedure is not terminated until the levels drop 50% from the median baseline level and/or into the normal range «50pg/mL). The success of MIP has been confirmed to be the same as bilateral standard neck exploration. For example, in 255 consecutive MIPs, the cure rate was 99% and the complication rate was 1.2%. MIP has been associated with a 50% reduction in operating room time and shorter hospitalization .!" Further, MIP is associated with a cosmetically better scar, less pain, and more rapid return to health and normal activity. However, MIP may artificially increase the probability of finding only an adenoma and decrease the chance of detecting hyperplasia or multiple gland disease. Two recent studies documented that the rate of hyperplasia with MIP was lower than the expected rate of 15% for standard bilateral explorations.139.140 If the intraoperative serum levels of PTH do not drop, or there is other evidence for hyperplasia, minimally invasive parathyroidectomy is abandoned and conventional bilateral neck exploration is performed. UNSUCCESSFUL MIP If focused minimally invasive parathyroidectomy is unsuccessful, bilateral neck exploration is recommended. Essentially this is the standard parathyroid exploration that was done previously with a consistently high probability of success and low complication rate. Any enlarged or abnormal glands are removed. The most useful indicator of normal or abnor-

In generalized four-gland hyperplasia, the surgical management is more difficult and the results less satisfactory. Intraoperative PTH levels may help distinguish between adenoma and hyperplasia and help guide the amount of parathyroid resection. Abnormal parathyroid glands should be removed until the levels drop 50% from the median baseline preoperative level. Two possible surgical procedures designed for this diagnosis are the subtotal (3.5-gland) parathyroidectomy and the four-gland parathyroidectomy with immediate autografting . The cervical thymus should also be removed as supernumerary glands or fragments of parathyroid glands are commonly found within it . The results of subtotal parathyroidectomy have been variable, with a 13% incidence of persistent disease, a 15% incidence of recurrent disease, and a similar incidence of hypoparathyroidism. Moreover, in patients with MEN I, subtotal parathyroidectomy led to a recurrence rate of 50% at 12 years after surgery.!" Similar data led others'? to prefer total parathyroidectomy with autotransplantation over subtotal parathyroidectomy for patients with hyperplasia. Wells and colleagues reported results on 21 patients with hyperplasia who underwent this procedure.l" Hypocalcemia developed in 20 of the 21 patients immediately postoperatively and necessitated vitamin D and calcium replacement. Within 2 months, 20 had a detectable PTH gradient between the grafted and nongrafted arm, indicative of normal parathyroid autograft function, and were able to discontinue vitamin D and calcium supplementation. However, recurrent disease developed in 2 of 10 patients with nonfamilial hyperplasia and 7 of 11 with familial hyperplasia. Left inferior thyroid artery

Left recurrent laryngeal nerve

FIGURE 55.11. Identification of a left inferior parathyroid adenoma. The thyroid gland is elevated with a Babcock clamp . A left lower parathyroid adenoma is identified inferior to the inferior thyroid artery and anteromedial to the recurrent laryngeal nerve, which is the most common position for a left inferior parathyroid adenoma, although the inferior parathyroid gland can be located in other positions.

PARATHYROID

Four patients with recurrent disease underwent partial graft resection, and all 4 were again rendered normocalcemic. Our approach to both familial and nonfamilial parathyroid hyperplasia is subtotal (3.5-glandl parathyroidectomy guided by intraoperative determination of PTH, with approximately 30 to 50 mg of the most normal-appearing parathyroid tissue left and marked with a surgical clip in the neck. The incidence of either persistent disease or hypoparathyroidism has been low, and we expect the rate of recurrent disease to be between 10% and 20%. We do not use four-gland resection with transplant because of an unacceptable incidence of hypoparathyroidism. In patients with recurrent disease after subtotal parathyroidectomy, total parathyroidectomy with cryopreservation of resected tissue is required. It is important to prove that all hyperplastic tissue has been removed before reimplantation.!" Unfortunately, cryopreserved parathyroid autotransplantation appears to have a high incidence of failure inasmuch as only 70% of human cryopreserved autografts function normally.':" MEDIASTINAL EXPLORATION

If a patient undergoes an unsuccessful operation for hyperparathyroidism, reevaluation of the patient and localization procedures should be performed before performing additional surgery (see Fig. 55.7). Median sternotomy is indicated in only 1% to 2% of patients undergoing initial exploration. In our series of 33 patients who underwent median sternotomy as part of a reoperation for primary hyperparathyroidism, 30% did not have abnormal parathyroid tissue in the mediastinum.!" Of the abnormal mediastinal glands found, most were discovered in the thymus (64%), and total thymectomy was always required . Wells and Cooper!" have reported the ability to remove the entire thymus (including the mediastinal com ponent) without dividing the sternum by using a special retractor to elevate the sternum. This procedure may be used to explore the anterior mediastinum less invasively. Videoassisted thoracoscopic surgery (VATS I techniques have been used to resect parathyroid tissue in the mediastinum, and the earlier described adjuncts of intraoperative PTH monitoring and gamma probes can be similarly ernployed .lv' "? Parathyroid adenomas have also been removed from the aortopulmonary window via the left chest and thoracoscopically, but this is even more rare.151

1201

nal approach . Designing the operation and the proper incision-right-sided, left-sided, median sternotomy, or any combination thereof-can be done only by putting all the information together. For reoperations, we prefer an alternative route in the neck along the medial border of the sternocleidomastoid muscle instead of between the strap muscles. III This technique requires a separate approach on each side of the neck. It is especially important to look for intrathyroid, intrathymic, and paraesophageal parathyroid adenomas because ectopic locations are more common in reoperations. Another strategy for reoperations is the minimally invasive radioguided parathyroidectomy.l'" Norman and Denham reported their experience in 21 patients with primary hyperparathyroidism who had undergone previous neck exploration for parathyroid or thyroid disease .!" The neck reexploration is guided by a hand-held gamma probe . Possible advantages of this technique include smaller incisions, less operative time, decreased risk of nerve injury and complications, outpatient surgery, and no frozen-section analysis. Others have advocated the use of intraoperative PTH level monitoring during the reoperative surgery to confirm the resection of metabolically active tissue.93,153 Finally, it should be remembered that even during reoperations for primary hyperparathyroidism, most abnormal glands can be removed through a cervical incision.'!' Abnormal parathyroid glands may be retroesophageal or posterior along the tracheoesophageal groove, which is the most common missed position.P' They may also be intrathyroidal, ISS or they may be located in an undescended parathymic remnant high in the carotid sheath.156 A missed adenoma may be located in pharyngeal or adjacent structures such as the vagus nerve .!" If these abnormal glands are not in the neck, they may be in the thymus. Slow, meticulous exploration in a bloodless field is generally necessary to find these "ectopic" glands (Fig. 55.12).

REOPERATIONS FOR PRIMARY HYPERPARATHYROIDISM

Reoperations for primary hyperparathyroidism should be classified as operations for either persistent disease or recurrent disease . Persistent disease means that hypercalcemia never resolved after the initial neck exploration. Recurrent disease means that hypercalcemia recurs after an initial period of hypocalcemia or normalization of serum calcium. The complexity of repeat neck surgery for primary hyperparathyroidism makes it imperative to confirm the diagnosis and presence of symptoms and to order preoperative localization studies (see Fig. 55.7).64,65,1l1 The prior operative report, pathology results, and localization studies are used to plan the re-exploration. For example, if two abnormal parathyroid glands were removed and the family history is positive for parathyroid disease, the working diagnosis is hyperplasia. A biopsy-proven normal gland found at the initial procedure and radiologic localization studies suggesting a mediastinal adenoma prompt a direct mediasti-

FIGURE 55.12. Diagram of potential locations of superior and inferior parathyroid glands. Numbers refer to the percentage of glands found at each location. (Data from Akerstrom G, Malmaeus J, Bergstrom R. Surgical anatomy of human parathyroid glands. Surgery (St. Louis) 1984;95(1):14-21. 14 )

1202

CH APTER 5 5

TABLE 55.7. Surgica l Outcome for Reoperative Surgery.

References

Mariette 1998 190 Jaskowiak 1996 154 Shen 199662 Rodriquez 1994 193 Weber 1994 215 Carty 19916 1

Iarhult 1993 216 Rothm u nd 1990217 Cheung 1989 218 Gra n t 1986 110

n

38 222 102 152 51 206 93 70 83 157

Level of evid ence '

Success

1Il

92

11

97 95 93 92 95 82 96 86 89

1Il 1Il 1Il 1Il 1Il 1Il 1Il 1Il

RLN paresis

(%)

6 1 1 1 12

2 13

RLN paralysis

Permanent hypocalcemia

3 3 1 0 0 1 9 4 1 6

2 12 1 1 1 17 15 19 8 20

Transient hypocalcemia

Wound infection

49 6 6 11

0

Mortality (%)

0

2 0.5

10 27

1.2 0

'1, randomized prospective study; II, prospective study; III, retrospective study, review or anecdotal.

Cryopreservation of removed parathyroid tissue during reoperations is indicated. One cannot predict from prior records whether normal parathyroid tissue remains in the neck. In our experience with reoperations on 175 patients, 35% left the hospital taking vitamin D medication and 43% were taking supplemental calcium.s':'!' Twenty-two patients (12%) were ultimately found to be permanently hypoparathyroid and required cryopreserved autologous parathyroid grafts. This outcome agrees well with other published reports in which the rat e of hypoparathyroidism after reoperative parathyroid surgery is between 2.7% and 16%. Cryopreservation with delayed autografting is a standard approach, although the overall success rate with cryopreserved grafts is only approximately 50% to 60% j this rate appears to be less than for fresh grafts, which have a 75% to 100% success rate."" Reoperative parathyroid surgery remains a major challenge. It is clear that operative risk increases wit h each succeeding reexp1oration. With careful attention, however, to confirmation of the diagnosis, prior operative records, judicious use of preoperative localization, and postoperative cryopreserved auto grafting, a successful outcome may be achieved in approximately 80% to 90 % of reoperations (Table 55.7).1ll Economically, when compared to initial parathyroidectomies, most aspects of reoperative parathyroidectomies are more costly (Table 55.8).

Secondary and Tertiary Hyperparathyroidism Almost all patients with advanced renal failure who are main tained by chronic dialysis have evidence of bone disease secondary to hyperparathyroidism and elevated serum levels of PTH. Secondary hyperparathyroidism should be suppressed in these individuals by measures that normalize serum levels of calcium and phosphorus. These methods include the use of a dialysate calcium concentration of 3.5 mEqJL, oral calcium supplementation, dietary restriction of phosphorus «600mg/day), phosphate-binding antacids, and vitamin D analogues to promote intestinal absorption of calcium. ISS Failure of these strategies occurs in a minority of individuals, and tertiary hyperparathyroidism is diagnosed when serum levels of ionized calcium and intact PTH are elevated. Subtotal parathyroidectomy is then used to decrease the mass of hyperplastic parat hyroid tissue. Potential indica tions for subtotal parathyroidectomy in these patie nts include (1) hypercalcemia in prospective renal transplant patients, (2) pathological fractures secondary to renal osteodystrophy, (3) symptoms such as pruritus, bone pain, and exte nsive soft tissue calcification and calciphylaxis; (4) hypercalcemia in pati ents with well-functioning renal transplants, and (5) a calcium times phosphate product great er than 70.159, 160 Improvements in medical management have

TABLE 55.8 . Comparison of Costs Bet ween Initial an d Reoperati ve Parathyroidectomy. Reoperation '

P value"

43 (0-9 12)

3,378 (1,130-3,856)

14mg/dL), in patients with vocal cord paralysis , in patients with evidence of local recurrence of an abnormal gland after resection, or when a palpable neck mass is present.36,164 It is difficult to accurately assess the spectrum of clinical manifestations, degree of malignancy, and prognosis of parathyroid carcinoma. The incidence is very low, and the malignancy appears to be diagnosed at an earlier stage as a result of earlier detection of hypercalcemia. A major problem is failure to properly identify the correct pathological diagnosis during the operation and, therefore , failure to perform adequate resection of the malignant parathyroid tissue along with the ipsilateral lobe of the thyroid.36, 165 Unequivocal pathological features of parathyroid carcinoma include the identification of mitoses in several high-power microscopic fields, fibrous bands or desmoplasia, and evidence of distant metastases or direct local invasion of the capsule, adjacent structures, and blood vessels .l" However, not all patients with parathyroid carcinoma have all these features , so the diagnosis must be ascertained from clinical as well as pathological evidence . Furthermore, the natural history of patients with parathyroid cancer appears to be variable . Some tumors disseminate rapidly and have a poor prognosis, 167 whereas others tend to recur locally and have a long disease-free interval."

Literature reports involving single cases tend to emphasize more serious tumors, either intrinsically malignant or long-standing, with clear evidence of extraglandular spread at the initial operation. Typically the cancer invades along the tracheoesophageal groove, and the patient may have hoarseness secondary to a recurrent laryngeal nerve injury. At neck exploration, the carcinomatous tissue appears gray with a thick, hard capsule. We recommend, based on suspicion (e.g., mass, local recurrence, vocal cord paralysis, high serum level of calcium), a wide excision including thyroid lobectomy in continuity with the tumor.36, 165, 166 If one has doubt about the diagnosis, biopsy of tumor extrinsic from the main tumor mass either within lymph nodes or invading local strap muscle should provide evidence of cancer. Recurrent laryngeal nerve injury, either from the tumor itself or from the surgeon attempting to completely resect the tumor mass with the ipsilateral thyroid lobe, is possible and occurs in a significant proportion of patients. Locally recurrent benign parathyroid adenomas may occur and be confused with parathyroid carcinomas. Recurrent adenomas generally have a longer disease-free interval, a lower serum level of calcium, and a history of either incomplete resection or spillage of tumor at the time of initial surgery ." Nevertheless, both locally recurrent parathyroid adenoma and cancer appear to respond favorably to aggressive local reresection, and most patients can be rendered either hypocalcemic or normocalcemic for a reasonable period ." Once disease has spread to distant sites, surgery is less effective. Resection of pulmonary metastases has been performed without clear beneflt.!" In patients with distant metastases, OTIC chemotherapy has been effective in some instances.l'" Medical therapy is directed at controlling the severe hypercalcemia.

Parathyroid Autotransplantation Halsted performed the first experimental parathyroid transplant in 1909. Since then, many successful transplants in laboratory animals and humans have been reported. 142, 143,168, 169 Parathyroid glands have been successfully cryopreserved for long periods and then transplanted back into humans.!" Parathyroid tissue has been successfully allografted into immunosuppressed human hosts."! The clinical indications for parathyroid autotransplantation are primary or secondary parathyroid hyperplasia, reexploration for persistent or recurrent hyperparathyroidism, and total thyroidectomy.

1204

CHAPTER 5 5

A

Brachioradialis muscle

Operative method of cryopreservation and transplantation of abnormal hyperplastic parathyroid tissue. A. The abnormal gland is sliced into small fragments (1-2mm) and kept in iced saline. B. Twenty fragments are grafted into small pockets in the nondominant brachioradialis muscle of the forearm. Each graft is marked with a suture to facilitate future identification of the grafted site.

FIGURE 55.13.

~

t±mB

B

The function of immediate (stored in the operating room in iced saline) parathyroid autografts is between 75% and 100%.145,172 The function of delayed cryopreserved autografts varies from 54%172 to 83%. 143 Immediate autografts of either adenoma or hyperplasia may lead to recurrent hypercalcemia and may require partial reexcision. Cryopreserved abnormal parathyroid tissue has not resulted in recurrent hypercalcemia but has a higher likelihood of poor function. Our procedure for parathyroid transplantation and cryopreservation is as follows: maintain the tissue on the operating table chilled in sterile saline, and slice the tissue into slivers 1 x 1 x 3 mm in size (Fig. 55.13). For immediate autografting, 20 pieces are implanted into the sternocleidomastoid muscle of the neck (only normal parathyroid tissue during thyroidectomy) or the brachioradialis muscle of the forearm (abnormal hyperplastic parathyroid tissue during total parathyroidectomy). Care is taken to not induce bleeding, and each implantation site is closed with 6-0 silk suture. Should graft-dependent hyperparathyroidism subsequently develop, a portion of the graft can be removed under local anesthesia. For cryopreservation, the parathyroid slivers are put into 3-mL glass vials, 10 pieces each, with 1.5mL solution containing 10% dimethyl sulfoxide, 10% autologous serum, and 80% tissue culture medium. The vials are immediately placed in an automated freezing chamber and the temperature programmed to decrease I °Cj min to 80°C. The vials are then stored in a liquid nitrogen freezer at 190°C.

Postoperative Hypocalcemia Most patients who have undergone successful surgery for primary hyperparathyroidism have some (albeit mild) symptoms of hypocalcemia, and a positive Trosseau or Chvostek sign. These symptoms should initiate measurement of the serum levels of calcium and phosphorus. Treatment is directed at maintaining a serum level of calcium above 8.OmgjdL.

Initially, dietary calcium is employed. However, dietary calcium, typically milk products, is associated with a large phosphate load and may result in hyperphosphatemia. If this complication occurs , elemental calcium may be given in the usual oral doses of 1 to 2gjday. It has been shown that early postoperative testing of PTH level can be predictive of postoperative hypocalcemia, but this is not routinely employed. 173 When parathyroidectomy is performed as an outpatient procedure, patients are simply given prescriptions for oral calcium and calcitriol to minimize hypocalcemia and its symptoms. This practice has resulted in shorter hospitalizations and fewer symptoms of tetany. It is thought that a minimally invasive surgical approach may lessen the severity of postoperative hypocalcemia.!" If the symptoms of hypocalcemia are severe and the patient appears to be on the verge of tetany (occurring most frequently in patients with "hungry bone syndrome"), the clinician may need to treat with intravenous calcium. These symptoms can usually be rapidly corrected by the infusion of 2mgjkg elemental calcium over a IS-min period. Symptoms return unless a longer infusion is used. Approximately 15mgj kg elemental calcium is then infused over a 24-h period, with half the total amount administered in the initial 6 h. Serum levels of calcium should be monitored closely during the infusion, and infusion rates and amounts may be adjusted accordingly. Only approximately 13% of patients have severe symptoms of hypoparathyroidism after surgery. These patients appear to be older; have higher preoperative serum levels of calcium, PTH, alkaline phosphatase, and urea nitrogen; and have large adenomas removed at surgery" and typically require intravenous calcium. Most patients do not need this type of calcium replacement. When hypocalcemia persists despite maximal oral replacement doses and hyperphosphatemia develops, 1,25(OHhD3 [calcitriol] is initiated." ! This drug is recommended because of rapid onset of action and short duration of use. The usual

PARATHYROID

initial dose of calcitriol is 0.25 to 1.0g/day given on a twicedaily schedule. The dose can be increased to a maximum of 2.0g/day, depending on the response in terms of serum levels of calcium and phosphorus. In general, the lowest possible dose that produces low normal serum levels and no hypocalcemic symptoms should be used. Serum levels of calcium should be monitored weekly after discharge to further adjust oral calcium and calcitriol doses. Some patients with severe forms of primary hyperparathyroidism, including altered renal function and bone resorption, may demonstrate worsening kidney function in the postoperative period.!" The exact cause is not known, but the complication appears temporarily, and kidney function reverses within several days. Renal insensitivity to PTH may be a cause of elevation of PTH levels after successful surgery for primary hyperparathyroidism. In Specific joint complaints may also occur in a small proportion of patients following successful parathyroidectomy. Pseudogout develops in approximately 50/0 of individuals, and examination of joint fluid demonstrates calcium phosphate crystals.l":'?" These patients usually respond to a short course of indomethacin. Bone remineralization following parathyroid surgery may cause a significant reduction in serum levels of magnesium. Patients with serum magnesium levels less than 1.1mEq/L should be treated with both intravenous magnesium and calcium. The usual dose of magnesium is approximately 50mmol/day in divided doses. Hypomagnesemia may contribute to the development of tetany in patients following parathyroidectomy. It inhibits secretion of PTH by the remaining parathyroid glands, and it exacerbates symptoms of hypocalcemia.

References 1. Owen R. On the anatomy of the Indian rhinoceros. Trans Zool Soc Lond 1862;4:31-58. 2. Thompson NW. The history of hyperparathyroidism. Acta Chir Scand 1990;156(1):5-21. 3. Chaouat Y, Chaouat D. [Primary hyperparathyroidism. History.] Rev Rhum Mal Osteoartic 1988;55(7):475-478. 4. Niederle BE, Schmidt G, Organ CH, Niederle B. Albert J and his surgeon: a historical reevaluation of the first parathyroidectomy. J Am ColI Surg 2006;202(1):181-190. 5. Bauer W, Federman DD. Hyperparathyroidism epitomized: the case of Captain Charles E. Martell. Metabolism 1962;11:21-29. 6. Spence HM. The life and death of Captain Charles Martell and kidney stone disease. J UroI1984;132(6):1204-1207. 7. Mallette LE. Regulation of blood calcium in humans. Endocrinol Metab Clin N Am 1989;18(3):601-610. 8. Agus ZS, Goldfarb S, Wasserstein A. Calcium transport in the kidney. Rev Physiol Biochem PharmacoI1981;90:155-169. 9. Marcus R. Laboratory diagnosis of primary hyperparathyroidism. Endocrinol Metab Clin N Am 1989;18(3):647-658. 10. Pocotte SL, Ehrenstein G, Fitzpatrick LA. Regulation of parathyroid hormone secretion. Endocr Rev 1991;12(3):291-301. 11. Mihai R, Farndon JR. Parathyroid disease and calcium metabolism. Br J Anaesth 2000;85(1):29-43. 12. Kao PC, van Heerden JA, Grant CS, Klee GG, Khosla S. Clinical performance of parathyroid hormone immunometric assays. Mayo Clin Proc 1992;67(7):637-645. 13. McDermott MT, Perloff H, Kidd GS. Effects of mild asymptomatic primary hyperparathyroidism on bone mass in women with and without estrogen replacement therapy. J Bone Miner Res 1994;9(4):509-514.

1205

14. Akerstrom G, Malmaeus J, Bergstrom R. Surgical anatomy of human parathyroid glands. Surgery (St. Louis) 1984;95(1):1421. 15. Wells SA Jr, Leight GS, Ross AJ III. Primary hyperparathyroidism. Curr Probl Surg 1980;17(8):398-463. 16. Wang C. The anatomic basis of parathyroid surgery. Ann Surg 1976;183(3):271-275. 17. Alveryd A. Parathyroid glands in thyroid surgery. I. Anatomy of parathyroid glands. II. Postoperative hypoparathyroidism: identification and autotransplantation of parathyroid glands. Acta Chir Scand 1968;389:1-120. 18. Norris E. The parathyroid glands and the lateral thyroid in man: their morphogenesis, histogenesis, topographic anatomy and prenatal growth. Contrib EmbryoI1937;26:247. 19. Wang C, Mahaffey JE, Axelrod L, Perlman JA. Hyperfunctioning supernumerary parathyroid glands. Surg Gynecol Obstet 1979;148(5):711-714. 20. Levin KE, Clark OH. The reasons for failure in parathyroid operations. Arch Surg 1989;124(8):911-914; discussion 914-915. 21. Edis A1, Purnell DC, van Heerden JA. The undescended "parathymus." An occasional cause of failed neck exploration for hyperparathyroidism. Ann Surg 1979;190(1):64-68. 22. Lafferty FW. Differential diagnosis of hypercalcemia. J Bone Miner Res 1991;6(suppl 2):S51-S59; discussion S61. 23. Papapoulos SE, Manning RM, Hendy GN, Lewin IG, O'Riordan JL. Studies of circulating parathyroid hormone in man using a homologous amino-terminal specific immunoradiometric assay. Clin Endocrinol (Oxf) 1980;13(1):57-67. 24. Mallette LE, Tuma SN, Berger RE, Kirkland JL. Radioimmunoassay for the middle region of human parathyroid hormone using an homologous antiserum with a carboxy-terminal fragment of bovine parathyroid hormone as radioligand. J Clin Endocrinol Metab 1982;54(5):1017-1024. 25. Hitzler W, Schmidt-Gayk H, Spiropoulos P, Raue F, Hufner M. Homologous radioimmunoassay for human parathyrin (residues 53-84). Clin Chern 1982;28(8):1749-1753. 26. Lindall AW, Elting 1, Ells 1, Roos BA. Estimation of biologically active intact parathyroid hormone in normal and hyperparathyroid sera by sequential N-terminal immunoextraction and midregion radioimmunoassay. J Clin Endocrinol Metab 1983;57(5): 1007-1014. 27. Christensson T, Hellstrom K, Wengle B. Hypercalcemia and primary hyperparathyroidism. Prevalence in patients receiving thiazides as detected in a health screen. Arch Intern Med 1977;137(9):1138-1142. 28. Christensson T, Hellstrom K, Wengle B, Alveryd A, Wikland B. Prevalence of hypercalcaemia in a health screening in Stockholm. Acta Med Scand 1976;200(1-2):131-137. 29. Ladenson JH, Lewis JW, McDonald JM, Slatopolsky E, Boyd JC. Relationship of free and total calcium in hypercalcemic conditions. J Clin Endocrinol Metab 1979;48(3):393-397. 30. Thompson NW, Eckhauser FE, Harness JK. The anatomy of primary hyperparathyroidism. Surgery (St. Louis) 1982;92(5):814821. 31. Abboud B, Sleilaty G, Helou E, et al. Existence and anatomic distribution of double parathyroid adenoma. Laryngoscope 2005;115(6):1128-1131. 32. Bergson E1, Heller KS. The clinical significance and anatomic distribution of parathyroid double adenomas. J Am Coll Surg 2004;198(2):185-189. 33. Attie IN, Bock G, Auguste LJ. Multiple parathyroid adenomas: report of thirty-three cases. Surgery (St. Louis) 1990;108(6):10141019; discussion 1019-1020. 34. Roses DF, Karp NS, Sudarsky LA, Valensi Q1, Rosen RJ, Blum M. Primary hyperparathyroidism associated with two enlarged parathyroid glands. Arch Surg 1989;124(11):1261-1265. 35. Shane E, Bilezikian JP. Parathyroid carcinoma: a review of 62 patients. Endocr Rev 1982;3(2):218-226.

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CHAPTER 55

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for primary hyperparathyroidism. Surgery (St. Louis) 1994;116(6):959-964; discussion 964-965. 193. Rodriquez JM, Tezelman S, Siperstein AE, et al. Localization procedures in patients with persistent or recurrent hyperparathyroidism. Arch Surg 1994;129(8):870-875. 194. Doherty GM, Doppman JL, Miller DL, et al. Results of a multidisciplinary strategy for management of mediastinal parathyroid adenoma as a cause of persistent primary hyperparathyroidism. Ann Surg 1992;215(2):101-106. 195. Ruda JM, Hollenbeak CS, Stack BC Jr. A systematic review of the diagnosis and treatment of primary hyperparathyroidism from 1995 to 2003. Otolaryngol Head Neck Surg2005;132(3):359372. 196. Baliski CR, Stewart JK, Anderson DW, Wiseman SM, Bugis SP. Selective unilateral parathyroid exploration: an effective treatment for primary hyperparathyroidism. Am J Surg 2005; 189(5):596-600; discussion 600. 197. Carneiro DM, Solorzano CC, Irvin GL III. Recurrent disease after limited parathyroidectomy for sporadic primary hyperparathyroidism. J Am ColI Surg 2004; 199(6):849-853; discussion 853855. 198. Mortier PE, Mozzon MM, Fouquet OP, et al. Unilateral surgery for hyperparathyroidism: indications, limits, and late results: new philosophy or expensive selection without improvement of surgical results? World J Surg 2004;28(12):1298-1304. 199. Sidiropoulos N, Vento 1, Malchoff C, Whalen G. Radioguided tumorectomy in the management of parathyroid adenomas. Arch Surg 2003;138(7):716-720. 200. Shabtai M, Ben-Haim M, Muntz Y, et al. 140 consecutive cases of minimally invasive, radio-guided parathyroidectomy: lessons learned and long-term results. Surg Endosc 2003;17(5):688-691. 201. Bergenfelz A, Lindblom P, Tibblin S, Westerdahl J. Unilateral versus bilateral neck exploration for primary hyperparathyroidism: a prospective randomized controlled trial. Ann Surg 2002;236(5):543-551. 202. Dillavou ED, Jenoff JS, Intenzo CM, Cohn HE. The utility of sestamibi scanning in the operative management of patients with primary hyperparathyroidism. J Am ColI Surg 2000; 190(5):540-545. 203. Goldstein RE, Blevins L, Delbeke D, Martin WH. Effect of minimally invasive radioguided parathyroidectomy on efficacy, length of stay, and costs in the management of primary hyperparathyroidism. Ann Surg 2000;231(5):732-742. 204. Low RA, Katz AD. Parathyroidectomy via bilateral cervical exploration: a retrospective review of 866 cases. Head Neck 1998;20(7):583-587.

205. Summers GW. Parathyroid update: a review of 220 cases. Ear Nose Throat J 1996;75(7):434-439. 206. Worsey MJ, Carty SE, Watson CG. Success of unilateral neck exploration for sporadic primary hyperparathyroidism. Surgery (St. Louis) 1993;114(6):1024-1029; discussion 1029-1030. 207. Tibblin S, Bizard JP, Bondeson AG, et al. Primary hyperparathyroidism due to solitary adenoma. A comparative multicentre study of early and long-term results of different surgical regimens. Eur J Surg 1991;157(9):511-515. 208. Saaka MB, Sellke FW, Kelly TR. Primary hyperparathyroidism. Surg Gynecol Obstet 1988;166(4):333-337. 209. Russell CF, Edis AJ. Surgery for primary hyperparathyroidism: experience with 500 consecutive cases and evaluation of the role of surgery in the asymptomatic patient. Br J Surg 1982;69(5):244247. 210. Punch JD, Thompson NW, Merion RM. Subtotal parathyroidectomy in dialysis-dependent and post-renal transplant patients. A 25-year single-center experience. Arch Surg 1995;130(5):538-542; discussion 542-543. 211. Rothmund M, Wagner PK, Schark C. Subtotal parathyroidectomy versus total parathyroidectomy and autotransplantation in secondary hyperparathyroidism: a randomized trial. World J Surg 1991;15(6):745-750. 212. Niederle B, Horandner H, Roka R, Woloszczuk W. [Parathyroidectomy and autotransplantation in renal hyperparathyroidism. I. Clinical and chemical laboratory studies following tissue selection.] Chirurg 1989;60(10):665-670. 213. Leapman SB, Filo RS, Thomalla TV, King D. Secondary hyperparathyroidism. The role of surgery. Am Surg 1989;55(6):359365. 214. Doherty GM, Weber B, Norton JA. Cost of unsuccessful surgery for primary hyperparathyroidism. Surgery (St. Louis) 1994; 116(6):954-957; discussion 957-958. 215. Weber C1, Sewell CW, McGarity WC. Persistent and recurrent sporadic primary hyperparathyroidism: histopathology, complications, and results of reoperation. Surgery (St. Louis) 1994; 116(6):991-998. 216. Iarhult J, Nordenstrom J, Perbeck L. Reoperation for suspected primary hyperparathyroidism. Br J Surg 1993;80(4):453456. 217. Rothmund M, Wagner PK, Seesko H, Zielke A. [Lessons from reoperations in 55 patients with primary hyperparathyroidism.] Dtsch Med Wochenschr 1990;115(42):1579-1585. 218. Cheung PS, Borgstrom A, Thompson NW. Strategy in reoperative surgery for hyperparathyroidism. Arch Surg 1989;124(6):676680.

Thyroid Ronald

Anatomy and Physiology Hyperthyroidism Hypothyroidism Goiter

1211 1211 1214 1215

Anatomy and Physiology Th e common indications for thyroidectomy include a suspicion of cancer, local symptoms of a large neck mass (e.g., difficulty breathing or swallowing], and abnormal thyroid function (e.g., hyperthyroidism). Surgical management of thyroid problems requires a thorough understanding of the anatomy and pathophysiology of the thyroid gland.

Surgical Approach The normal thyroid weighs approximately 20g and is situated anterior and slightly inferior to the thyroid cartilage. Figure 56.1 depicts the relevant anatomy and surgical approach to the thyroid. The thyroid is highly vascular and derives its blood supply from paired superior and inferior thyroid arteries. The superior thyroid artery is a branch of the external carotid artery, and the inferior thyroid artery is derived from the thyrocervical trunk. Thyroid ima vessels are branches directly from the aorta and enter the gland inferiorly. The recurrent laryngeal nerve ascends from the superior mediastinum and runs in the tracheoesophageal groove. The nerve courses directly posterior to the thyroid lobe and passes through the cricopharyngeus to innervate the intrinsic muscles of the larynx. The location of the parathyroid glands is variable but the glands are usually found lateral and posterior to the thyroid. The identification of these structures is critical during neck exploration.

Thyroid Function Tests and Thyroid Imaging The thyroid synthesizes thyroid hormone, which is necessary for normal metabolism. The secretion of thyroid hormone is precisely regulated, as depicted in Figure 56.2. The hypothalamus secretes thyrotropin-releasing hormone (TRH), which induces the anterior pituitary to secrete thyroidstimulating hormone (TSHI. TSH stimulates growth and function of the follicle cells of the thyroid. In response to TSH, the thyroid concentrates iodine and synthesizes the

J. Weigel

Evaluation of the Thyroid Nodule Thyroid Cancer References

1215 1217 1225

thyroid hormones thyroxine (T41 and the more metabolically active form of thyroxine, T3. Free thyroxine is the active form of the hormone and exerts a negative feedback on the pituitary and probably the hypothalamus. The plasma concentrations of these hormones provides the clinician with a reliable means of assessing thyro id physiological function. The half-lives of T4 and T3 are approximately 7 and 3 days, respectively. For this reason, thyroid tests are commonly examined 4 to 6 weeks after altering dosages of thyroid medications. The commonly employed thyroid function tests are listed in Table 56.1. TSH is the single best test for diagnosis of hyper- and hypothyroidism. In hyperthyroid states, TSH is suppressed. In mild cases of hyperthyroidism, the TSH may be suppressed although thyroid hormone levels remain in the normal range. However, in most cases all three parameters of thyroxine measurement [free T4 (FT4I, total T4, and total T3] are increased simultaneously. Additionally, there are cases of hyperthyroidism in which only T3 is measurably increased (T3 thyrotoxicosis). In hypothyroid states, TSH is elevated and the thyroxine parameters are below normal. In instances of mild hypothyroidism, TSH is elevated with normal thyroxine parameters. Under certain physiological conditions, such as pregnancy, patients on thyroid hormone replacement require increased thyroid hormone dosage, as can be evidenced by a measured increase in TSH. Thyroid scan using 1231 is a useful test to help diagnose diseases of the thyroid involving abnormal thyroid function. The thyroid scan has limited usefulness in the setting of a suspicion of thyroid malignancy. The common findings of thyroid scans include cold nodules, hot nodules (solitary or multiple), and Graves' disease. Examples of these pathological states as identified by thyroid scan are shown in Figure 56.3.

Hyperthyroidism Hyperthyroidism is caused by thyroid hormone excess. The usual pathological states causing hyperthyroidism are toxic nodule, toxic multinodular goiter, Graves ' disease, and the 1211

A

Sternohyoid muscle

Vagus nerve

B

c

D

E

TSH

FIGURE 56.1. Thyroidectomy. A. The patient is placed with the neck in extension. The thyroid is approached through a Kocher collar incision, which is commonly made approximately 2.0cm superior to the sternal notch. B. The strap muscles are divided in the midline to expose the thyroid gland. C. The strap muscles are retracted laterally and the thyroid is retracted medially, exposing the structures of the midneck. The recurrent laryngeal nerve can be seen lying within the tracheoesophageal groove. D. The superior pole vessels are individually clamped and ligated as they enter the thyroid gland. Inferior thyroid vessels, as well as the vessels of the thyroid [ima], are individually suture ligated. E. The dissection is completed by dissection of the thyroid gland off the trachea. The isthmus is then transected and can be oversewn with a suture for hemostasis. (Redrawn with permission from Macdonald J, Haller D, Weigel R. Endocrine system. In: Abeloff MD, ed. Clinical Oncology. New York: Churchill Livingstone, 1995:1051.)

(/J T 4 + Proteln ee T 4 Protein (T3)

FIGURE 56.2. Schema of the homeostatic regulation of thyroid function . Thyroid-stimulating hormone (TSHI stimulates release of thyroid hormone. Secretion of TSH is regulated by a negative feedback mechanism acting directly on the pituitary gland and is normally inversely related to the concentration of unbound hormone in the blood. Release of TSH is induced by the thyrotropin-releasing hormone (TRHI. Factors regulating secretion of TRH are uncertain but may include the free hormone in the blood and stimuli from higher centers. (Redrawn with permission from Ingbar SH, Woeber KA. The thyroid gland. In : Williams RH, ed. Textbook of Endocrinology, 6th ed. Philadephia: Saunders, 1981:134.)

1213

THYROID

TABLE 56.1. Laboratory Evaluation of the Thyroid Patient. Test

Normal values

Free T4 Thyroid-stimulating hormone T3, total T4, total Thyroglobulin

0.73-2.Dl ng/dl, 0.4-4.0 mIU /mL 100-1 90 ng/dl, 6.2-11.8mg/dL With thyroid gland : 1.0 cm ) Mortality TT vs. Lob vs. 1.0cm for TT(NT vs. ST(Lob In patients no t receiving RAI, decreased recurrence and mortality for TT Trend for improved outcome with TT for pat ients receiving RAI Total thyroidectomy results in lower recurrence and mortality com pared to lesser resections Patients undergoing less than total thyroidectomy had higher recurrence and mortality Improved survival for older patients treated with TT

30-year recurrence (class II, III) TT vs. Lob; 26% vs. 40% (P < 0.0021 30-year mortality TT vs. Lob; 6% vs. 9% (P = 0.02) lO-year recurrence TT vs. Lob; 23% vs. 46% (P < 0.0001)10year mortality TT vs. Lob; 5% vs. 11% (P < 0.01) Survival TT vs. Lob; at 20 years in older patients 55 % vs. 25%

TT , total thyro idectomy; Lob, lobectomy; ST/Lob, subt otal thyroid lobectomy; NT, near-t otal thycidect orny, RAI, radioactive iodine.

122 1

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6 290

7 227

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0

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0 2-9

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32

FIGURE 56.7. Cancer deaths for well-different iated thyroid cancer comparing near-total or total thyroidectomy with lesser resections . (From Mazzaferri and Ihiang,'?' with permi ssion .]

surgical resection. The usual protocol after thyroidectomy withholds thyroid hormone replacement for 4 to 6 weeks to induce a hypothyroid state. The elevation in TSH stimulates iodine uptake in residual thyroid tissue and thyroid carcinoma. In the face of elevated TSH, an increase in Tg levels is also usually evident. Often a test dose of 2 mCi 1311 is administered and the uptake used to estimate the therapeutic dose of 1311. There has been some debate as to whether a test dose of l31I "stuns" the tumor cells , thereby decreasing effectiveness of the therapy dose .I03,I04 Usual therapy doses employed are in the range of 50 to 200mCi. Although som e authors advocate the empiric treatment of thyroid cancer patients even in the absence of uptake. '!" other physicians elect not to treat patients in the absence of uptake on thyroid scan.106 There is evidence that the ability to ablate the thyroid remnant is dependent on the extent of surgical resection. Several studies have demonstrated increased success of abla tion following total thyroidectomy as compared to subtotal resections.P'{" Some recent attempts have been made to ablate an entire lobe in a patient treated by lobectomy.l'" RAI

~ 0

FIGURE 56.8. Metastatic. papillary thyr oid carcinoma detected by 1311 scan. Diffuse pulmonary metastases are noted with foci of lymph node metastases in the left neck.

is also commonly employed to treat distant metastases. An example of a patient with pulmonary me tastases detected with radioiodine scan is shown in Figure 56.8. Treatment of pulmonary metastases is more effective than bone metastases ." ? The rates of complications from RAl treatment, which include radiation thyroiditis, chronic sialoadenitis, odynophagia, and facial edema, are low. Complication rates and the need for repeated treatments are higher with less extensive surgery. P"!" RAl does not appear to have adverse effects on female fertility.! " but at least one study indicated an association with transient impairment of testicular function .!" A number of retrospective studies have reported improved recurrence and survival rates for patients treated with RAl.99,100,1l4 Samaan et al." identified RAl treatment as the single most significant indicator of improved recurrence and survival. Similarly, Mazzaferri and Ihiang'?" reported improved recurrence and survival in patients treated with RAl. These results are even more impressive when one considers that patients selected for 1311 treatment had more aggressive tumors with a higher predicted recurrence and mortality (Fig. 56.9). However, some studies have failed to demonstrate a benefit for patients without evidence of locoregional!" or distant96,1l6spread. A recent st udy by Morris et al.!" demonstrated a trend for improved survival with RAI 10

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FIGURE 56.9. Cancer recurrence and mortality comparing patients treated with 1311radioiodine (RAI) ablation and those without RAJ ablation. (From Mazzaferri and Ihiang.'?' with permission.]

1222

CHAPTER 56

TABLE 56.5. Prognosis. Fixed factors affecting prognosis

Variable factors affecting prognosis

Age of patient Clinical stage of primary Size Extension Lymph node metastasis Distant metastasis Histology Gender

Extent of thyroidectomy Use of RAJ Time from diagnosis to treatment

in patients with disease confined to the neck, but these data failed to reach statistical significance. The use of recombinant human TSH (rhTSH) has been investigated as an alternate protocol in preparation for RAJ treatment.l'?:!" Patients treated with rhTSH demonstrate similar physiological response with respect to Tg stimulation and increased iodine uptake compared to treatment with thyroxine withdrawal. lI7 Although rhTSH avoids the symptoms of hypothyroidism, this protocol is less sensitive in the detection of residual disease than withdrawal of thyroid hormone.I" PROGNOSIS OF WELL-DIFFERENTIATED THYROID CANCER

A number of variables that have been shown to influence prognosis for well-differentiated thyroid cancer are listed in Table 56.5. Fixed characteristics are based on clinical parameters that are present at the time of diagnosis. Variable characteristics can be influenced by treatment and may give clinicians an opportunity to improve outcomes in patients. AGE

Age of a patient at diagnosis has a profound effect on prognosis in well-differentiated thyroid cancer. 91,95,98,loo Some series have demonstrated that age is the single most significant variable affecting mortality.":" Interestingly, recurrence has a bimodal distribution with age (Fig. 56.10). Although recurrence rates are higher in younger patients, mortality remains relatively IOW. 100,1I9 By contrast, recurrence in patients over the age of 45 is a poor prognostic indicator, and overall mortality rates increase linearly with age of patients at presentation.

inability to completely resect tumor is associated with a worse outcome,98,120 and completely resecting disease can improve outcome even in the presence of local invasion. 120 For this reason, locally invasive cancers should be resected as completely as possible. Strap muscles can be resected en bloc with minimal morbidity. Wedge or circumferential sleeve resections of the trachea or esophagus can be performed in cases of carcinoma invasion of these structures.P'"!" METASTASIS

Patients over age 45 with distant metastatic disease at presentation have IS-year and 30-year mortality rates of 500/0 to 65 % and 65 % to 700/0, respectivelv.P''?" Papillary cancer frequently metastasizes to lung, and this is exclusively the site of metastasis in children. Bone metastasis is also common in older patients and in patients with follicular cancer. Other less common sites of metastasis include brain and liver." Lymph node metastasis is common in well-differentiated thyroid cancer. However, lymph node involvement has a modest effect on prognosis. In patients with TI-T3 primary tumors, the 3D-year mortality rates for patients with nodal involvement is 4% to 60/0 compared to 00/0 to 1% without nodal metastasis.Pv'" Nodal metastasis has been found to influence prognosis except in cases of T4 tumors (extrathyroidal invasion), supporting the role of lymphadenectomy as part of the initial surgical treatment.!" HISTOLOGY

Many studies have demonstrated prognostic differences between papillary and follicular cancers.125-127 The Mayo Clinic reported the 20-year cancer-specific mortality for FTC to be approximately 700/0 compared to 900/0 to 95% for papillary cancer.!" FTC and Hiirthle cell cancers tend to occur in older patients. However, at least one study that corrected for stage at presentation did not find FTC to have a worse prognosis compared to PTC. 1OO FTCs with widely invasive and poorly differentiated histology have a worse prognosis than microinvasive FTCs. 127,128 Hiirthle cell cancers have a prognosis similar to pure FTCs. 128 Hurthle cell tumors tend not to take up radioactive iodine as well as other FTCs, and this may 60--------------------,

eft.

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Size of the primary tumor is an important prognostic criterion. 98,l00,101 There is a nearly linear increase in mortality with the diameter of the primary tumor at presentation.l'" Tumors less than 1 to 1.5em have negligible cancer-related mortality and a 3D-yearrecurrence rate of 110/0. 100 Tumors more than 3 to 4cm in diameter have a 30-year disease-specific mortality of 20% to 30%.98,100 EXTENT OF TUMOR INVASION

Extrathyroidal tumor invasion carries a worse prognosis than tumors that are intrathyroidal or have minor capsular invasion. Tumors that invade adjacent structures such as strap muscles or trachea are associated with high recurrence and mortaliry.I':"' 100,101 Related to the extent of invasion is the ability to completely excise the tumor. As may be expected,

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Age at diagnosis, y FIGURE 56.10. Recurrence rate and cancer death for welldifferentiated thyroid cancer as a function of patient age at diagnosis. (From Mazzaferri and Ihiang.'?' with permission.)

THYROID

account for differences in outcome in some series. Certain subtypes of papillary cancer demonstrate a propensity for local invasion and carry a worse prognosis, including tall cell, diffuse sclerosing, and oxyphilic variants.F'"!" GENDER

Women with well-differentiated thyroid cancer tend to demonstrate an improved prognosis compared to men. 100,132 The 3D-year mortality for women and men with thyroid cancer was reported to be 70/0 and 110/0, respectively {P < 0.01 ).100 However, other large series have not demonstrated a significant difference." TREATMENT VARIABLES

A number of retrospective studies have reported that treatment modalities can influence the prognosis of thyroid cancer. As noted earlier, extent of surgery and use of RAJ have been reported to improve recurrence and mortality from thyroid cancer. Time from first recorded tumor manifestation to initial treatment has been reported to have a significant effect on outcome. In a study of 1355 patients, those who died of cancer had a mean delay of 18 months compared to 4 months for those who survived (P < 0.001).100

1223

TUMOR STAGING

Based upon the variables determined to affect prognosis, several staging systems have been devised for thyroid cancer. The AMES {Age, Metastasis, Extent, Size]" and AGES (Age, Grade, Extent, Sizej'" systems use similar categories and have been shown to be predictive of high- and low-risk patients. Clinical class has been applied with good success and is based on tumor spread: class I, intrathyroidal disease; class II, lymph node metastases; class III, extrathyroidal invasion; class IV, distant metastases." The TNM svstem!" has been developed and can be used to assess tumor stage as shown in Table 56.6. The approximate 3D-year mortality rates for stages I, II, III, and IV are 00/0 to 1%, 60/0, 10% to 15%, and 65 % to 80 %, respectively.98,100,135 FOLLOW-UP FOR PATIENTS WITH THYROI.D CANCER

After initial treatment for thyroid cancer, patients are followed for tumor recurrence at 6-month intervals for the first 3 years and yearly thereafter.30 The plan for following patients is influenced by the suspicion of possible recurrence based on prognostic factors. Patients are usually treated with suppressive doses of thyroxine. The goal of thyroid suppression is to

TABLE 56.6. Definition of TMN, Stage Grouping, and Histopathologic Type for Thyroid Carcinoma. Definition of TMN Primary Tumor (T)

Note: All categories may be subdivided: (a) solitary tumor, (b) multifocal tumor (the largest determines the classification). TX Primary tumor cannot be assessed TO No evidence of primary tumor TI Tumor 2cm or less in greatest dimension limited to the thyroid T2 Tumor more than 2cm but not more than 4cm in greatest dimension limited to the thyroid Tumor more than 4 em in greatest dimension limited to the T3 thyroid or any tumor with minimal extrathyroid extension (e.g., extension to sternothyroid muscle or perithyroid soft tissues) T4a Tumor of any size extending beyond the thyroid capsule to invade subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve T4b Tumor invades prevertebral fascia or encases carotid artery or mediastinal vessels All anaplastic carcinomas are considered T4 tumors. T4a Intrathyroidal anaplastic carcinoma-surgically resectable T4b Extrathyroidal anaplastic carcinoma-surgically unresectable Regional Lymph Nodes (N)

Regional lymph nodes are the central compartment, lateral cervical, and upper mediastinal lymph nodes. NX Regional lymph nodes cannot be assessed NO No regional lymph node metatasis NI Regional lymph nodal metastasis N Ia Metastasis to level VI (pretracheal, paratracheal, and prelaryngealjDelphian lymph nodes) NI b Metastasis to unilateral, bilateral, or contralateral cervical or superior mediastinal lymph nodes Distant Metastasis (M)

MX MO MI

Distant metastasis cannot be assessed No distant metastasis Distant metastasis

Stage Grouping

Separate stage groupings are recommended for papillary of follicular, medullary, and anaplastic (undifferentiated) carcinoma.

Papillary or Follicular Under 45 years Stage I AnyT AnyN Stage II AnyT Any N Papillary or Follicular 45 years and older Stage I TI NO Stage II T2 NO Stage III T3 NO Tl Nia T2 Nia T3 Nia Stage IVA T4a NO T4a Nia TI NIb T2 NIb T3 NIb T4a NIb Stage IVB T4b AnyN Stage Iv'C Any T Any N Medullary Carcinoma Stage I TI NO Stage II T2 NO Stage III T3 NO TI Nia T2 Nia T3 Nia Stage IVA T4a NO T4a Nia TI NIb T2 NIb T3 NIb T4a NIb Stage IVB T4b Any N Stage IVe AnyT Any N Anaplastic Carcinoma All anaplastic carcinomas are considered Stage IV Stage IVA T4a Any N Stage IVB T4b Any N Stage IVe Any T Any N

MO MI

MO MO MO MO MO MO MO MO MO MO MO MO MO Ml

MO MO MO MO MO MO MO MO MO MO MO MO MO MI

MO MO MI

Source: Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AlCC Cancer Staging Manual, Sixth Edition (2002) published by Springer Science and Business Media LLC, www.springerlink.com.

1224

CHAPTER 56

have TSH levels at the lower limit of normal or slightly below normal without signs or symptoms of hyperthyroidism. Thyroglobulin [Tg] levels are a useful means to detect tumor recurrence. 30,136,137 Tg is synthesized by normal thyroid cells and also by most well-differentiated cancers . Interpretation of Tg levels is simplified after total thyroidectomy and RAJ ablation. Normally, Tg levels are undetectable after such treatment.!" It is also important to check for the presence of antithyroglobulin antibodies that can falsely lower the measured Tg level .!" In the setting of a rising Tg level, patients should have thyroid replacement withheld and a thyroid scan performed. As a general guideline, recurrences detected by scan alone can be treated with RAJ. Recurrences that can be detected clinically by either physical examination or imaging [ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI)l should undergo surgical resection followed by RAJ.13S It is important to obtain cytological confirmation of thyroid cancer before subjecting a patient to exploration. Ultrasound-guided biopsy is a particularly useful technique to confirm the presence of local recurrence." Recent imaging modalities with real-time MRI using a split magnet have also been successful for biopsy of potential recurrence not accessible with ultrasound (Fig. 56.11).

FIGURE 56.11. Biopsy of recurrent papillary cancer with real-time magnetic resonance imaging (MRI). A. MRI scan showing mass in right neck lateral to trachea and esophagus (white arrowheadl. B. Needle biopsy of neck mass using real-time MRI with mass (white arrowhead); needle can be seen entering mass (black arrow). Mass was determined to be recurrent papillary thyroid carcinoma by cytology from this needle aspiration.

One particularly difficult clinical problem is patients who present with elevated Tg levels but have negative radioiodine scan, presumably caused by recurrence of thyroid cancer that has lost the ability to take up iodine. In these cases, the effectiveness of RAJ treatment is questionable.l'" An alternative approach is to attempt localization of tumor with technetium 99-m sestamibi or positron emission tomography (PET) scan . CT and MRI scans of the neck and chest are useful for detecting metastasis or for confirming the anatomic location of recurrence detected by scan. If possible, surgical resection should be performed after cytological confirmation. Highresolution ultrasound has been shown to be particularly helpful in the evaluation and surgical exploration of patients with recurrent cancer that does not trap iodine.!" Intraoperative ultrasound is particularly helpful for identifying nonpalpable, locoregional recurrences in patients who had previous external beam radiotherapy and in the identification of tumor nodules of 20mm or less that were invasive or adherent to the airway .':" External-beam therapy has also been reported for the treatment of thyroid cancerl 41,142 and is a useful adjuvant for tumors that have lost the ability to concentrate iodine .

Medullary Thyroid Cancer Medullary thyroid cancer (MTC) is derived from the calcitonin-secreting C-cells or parafollicular cells of the thyroid. Because MTC can occur in association with familial cancer syndromes (MEN2A, MEN2B, and familial MTCl, family members should be screened for the presence of ret mutations.!" Surgical treatment at a young age, before the development of carcinoma, can be performed safely and will likely cure patients of an otherwise incurable disease.!" Patients with MTC should also be screened for pheochromocytoma because this tumor occurs in approximately 40% of MEN2 patients.!" Primary surgical treatment for MTC is a total thyroidectomy and central node dissection.l'
Anaplastic Thyroid Cancer Patients with anaplastic thyroid cancer (ATC) usually present with a rapidly enlarging neck mass, often associated with dysphagia or airway obstruction. ATC has the worst prognosis of all thyroid malignancies, with 5-year survival rates of approximately 100/0. 156 The goal of surgical treatment is to maintain a patent airway and, if possible, clear the neck of disease. Surgery has a limited role in the primary treatment. Once the diagnosis is established, patients should be treated with hyperfractionated radiotherapy and doxorubicin-based chemotherapy. IS?

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Adrenal Robert Udelsman

Anatomy Physiology Adrenal Imaging Incidentaloma Cushing's Syndrome

1229 1229 1232 1234 1237

Anatomy The adrenal glands were first described and illustrated by the Roman anatomist Bartholomaeus Eustachius in 1552. 1 These glands are paired retroperitoneal organs located in close contact to the superior surface of either kidney. They are surrounded by a loose layer of areolar connective tissue and have multiple fibrous bands and vascular attachments through which they are associated with the superior poles of the kidneys. They are recogn izable by their firm texture and chromate yellow color, which is distinctly darker than the pale retroperitoneal fat . The normal adrenal gland is slightly nodular and generally weighs between 4 and 5g in the adult.' The presence of adrenal nodules is not uncommon, and their frequency increases with age.' The anatomic relationships of the adrenal glands are important and have significant surgical ramifications. The computed tomography ICTl findings of the normal adrenal glands (Fig. 57.11 are easily visualized on most CT scans, and the width of each adrenal gland limb is similar to that of the nearby diaphragm. Their anatomic relationships have been summarized by Mihai and Pamdorr' (Table 57.1). The location of the adrenal gland deep in the retroperitoneum has in the past made it relatively inaccessible. However, laparoscopic adrenalectomy has dramatically changed the surgical management of adrenal tumors. It is therefore important to appreciate their anatomic position and their relationship to the arterial supply and venous drainage . Each adrenal gland is supplied by small arterial branches that originate from three distinct sources. The major supplying vessels are the inferior phrenic artery, the aorta, and the ipsilateral renal artery. Occasional additional sources include the intercostal and ovarian vessels . The arterial branches ramify over the capsule of the gland and form a subcapsular plexus. v' The microcirculation of the adrenal gland has received extensive interest because of its physiological impli-

Pheochromocytoma Adrenocortical Carcinoma Adrenal Insufficiency References

1238 1241 1245 1245

cations. Vessels arising from the subcapsular plexus perfuse the zona glomerulosa and then run longitudinally along the cells of the zona fasciculata and terminate in a larger sinusoidal network in the zona reticularis." The blood supply to the adrenal medulla appears to arise from two sources. A direct supply to the adrenal medulla was described as early as 1990 by Flint.' However, the major source of adrenal medullary blood appears to be via the adrenal cortex from which blood rich in glucocorticoids flows from the cortical layers into the medulla." This intraadrenal "portal venous " circulation has significant physiological ramifications. The final pathway for the catecholamine epinephrine requires the enzyme phenylethanolamine N-methyltransferase (PNMTI, and glucocorticoids are required for this final step ." Thus, there is significant functional interaction between the adrenal medulla and cortex. The venous drainage of the adrenal gland is more constant than the arterial supply. The right adrenal gland usually drains by one short vein, which empties directly into the vena cava . Accessory adrenal veins are not infrequently present and have significant ramifications for laparoscopic adrenalectomy. In addition, the short right adrenal vein is at risk as at times it can be difficult to control. The left major adrenal vein is often joined by the inferior phrenic vein, which drains into the left renal vein. There may be associated small additional veins. Lymphatic drainage from the adrenal glands drains directly into adjacent periaortic and paracaval nodes. These structures are important when operating for malignant adrenal

lesions.'

Physiology The adrenal gland is composed of two distinct organs, the adrenal cortex and the adrenal medulla. The cortex is divided into three functional zones: the outer glomerulosa, the inter1229

1230

CHAPTER 5 7

FIGURE 57.1. Computed tomography (CTl scan demonstrating normal adrenal glands (arrowheads). (From Sosa JA, Udelsman R. Imaging of the adrenal gland. In: Kurtzman S, ed. Surgical Oncology Clinics of North America . Philadelphia: Saunders, 1998;109-127, with permission.)

mediate fasciculata, and the inner reticularis. These three zones are associated with the production of mineralocorticoids, glucocorticoids, and sex steroids, respectively. The biochemical pathways for the predominant examples of each of these hormone class es are shown in Figure 57.2. Of these three hormone classes, the onl y one absolutely required for life is glucocorticoids. Glucocorticoids were initially described as a family of steroids that have glucose-regulating properties. However, this definition is far too restrictive because glucocorticoids exert a myriad of effects on essentially every tissue in the body . A partial list of the effects of glucocorticoids is presented in Table 57.2. A more useful definition for glucocorticoids is a class of steroids that bind to glucocorticoid receptors. Cortisol is the major glucocorticoid in humans. The rate-limiting step in adrenal steroid synthesis, which is controlled by adrenocorticotropic hormone (ACTH), is the cleavage of the cholesterol side chain to yield pregnenolone.I" This mitochondrial reaction is cytochrome P-4s0-dependent and occurs in response to elevated levels of cyclic AMP. 9 Glucocorticoids are secreted directly into the circulation immediately upon their synthesis. Cortisol circulates in both the bound form (95%) and in a free unbound state (5 %). The free form passes into target cells by diffusion and binds to cytosolic receptors. All physiological actions of glucocorticoids are mediated through binding to steroid receptors, which are present in virtually every nucleated cell." The actions of glucocorticoids are both "perm issive," allowing other hormones to function in the basal state, as well as " regulatory," which are observed under stress-induced conditions.II The autonomic nervous system develops in parallel to the hypothalamic-pituitary-adrenal (HPAI axis . The autonomic nervous system regulates moment-to-moment arousal, activation, and physiological responses. It has been divided into the anatomically, chemically, and functionally distinct sympathetic and parasympathetic systems. The major transmitter of the preganglionic autonomic nervous system is acetylcholine. The neurotransmitter for most postganglionic sympathetic nerve fibers is norepinephrine, although a few

postganglionic fibers also use acetylcholine." The adrenal medulla is embryologically analogous to a peripheral sympath etic ganglia . The medullary chromaffin cells have rudimentary nerve fibers and the ability to synthesize, store, and secrete catecholamines.P The primary secretory product of the adrenal medulla is epinephrine. The proximity of the adrenal medulla and the adrenal cortex results in a unique site of catecholamine-glucocorticoid interactions. v':" The biosynthetic pathway for catecholamines as originally described by Blaschko is demonstrated in Figure 57.3.16 The rate-limiting step is th e formation of dopa from tyrosine via the enzyme tyrosine hydroxylase." Activity of this enzyme is dependent on both ACTH and sympathetic activity." Although norepinephrine is the principal end product of catecholamine synthesis in peripheral nerve terminals, in the adrenal medulla the additional enzyme, phenylethanolamineN-methyltransferase (PNMTI, is present and converts norepinephrine to epinephrine. Therefore, epinephrine constitutes approximately 80% of adrenal medullary secretion't Isee Fig. 57.3). Catecholamine synthesis is dynamic, and long-term stimulation results in elevated levels of tyrosine hydroxylase, dopamine-beta hydroxylase, and PNMT.14, 17 Catecholamines exert their effects through interactions with a large family of transmembrane-signaling molecules termed adenoreceptors.

TABLE 57.1. Anatomic Relationships of the Adrenal Glands. Surface

Area

Description

Right adrenal Ant erior

Medial area

Not covered by peritoneum; posterior to the inferior vena cava Upper part in contact with the inferomedial angle of bare area of liver; lower part may be covered by peritoneum, reflected onto it from the inferior layer of the coronary ligament Rests against the diaphragm In contact with the superior pole and the adjacent ant erior surface of right kidne y Right celiac ganglion Right inferior phrenic artery

Lateral area

Posterior

Upper area Lower area

Medial border Left adrenal Anterior

Superior area Inferior area

Posterior

Medial part Lateral part

Medial border

Covered with peritoneum of the omental bursa, which separates it from the cardia Not covered by peritoneum; in direct contact with the tail of pancreas and splenic artery In contact with left crus of diaphragm Close to the kidney Left celiac ganglion Left inferior phrenic artery Left gastric arteries

Source: Modified from Mihai R, Famdon JR.Surgical embryology and anatomy of the adtenal glands. In : Clark OH, Duh QY, eds. Textbook of Endocrine Surgery. Philadelphia : Saunders, 1997:452, reprinted with permission.

1231

ADRENAL 22

26

27

HO

ACTH

HO

o

~

11 DEOXYCORTICOSTERONE (DOC)

~ o

o

!

17 a OH PROGESTERONE

CH20H I

C.O

~

CORTICOSTERONE (B)

o

h

CH20H

CH20H

C.O

C.O •.OH

~

ALDOSTERONE

MINERALOCORTICOID

ANDROSTENEDIONE

I

I

o

~

11 DEOXYCORTISOl(S)

o

~

CORTISOL(F) (HYDROCORTISONE)

OH

o

GLUCOCORTICOID

FIGURE 57.2. Major biochemical pathways for adrenal steroidogenesis. ACTH, adrenocorticotropic hormone. (From Udelsman R, Holbrook NJ. Endocrine and molecular responses to surgical stress. Curr Probl Surg 1994;31:653-728, with permission. )

OH

I~ ~

HO

ESTRADIOL(E2)

SEX STEROIDS

TABLE 57.2. Glucocorticoid Actions. Area

Increase

Decrease

Liver Muscle Peripheral tissues Adipose tissue Bone Cardiovascular

Gluconeogenesis, glycogenesis, protein synthesis Lactate release

Glycogenolysis Protein synthesis Glucose uptake and use (increased insulin levels)

Immunological Wound healing CNS

Lipolysis, redistribution of body fat Osteoporosis, osteoclast activity, PTH Vascular tone, binding to mineralocorticoid receptor, catecholamine synthesis Immunosuppression Leukocyte distribution

Intestinal absorption of calcium, renal reabsorption of calcium

Production and activity of prostaglandins, kinins, and histamine Leukocyte movement, antigen processing Collagen formation, glycosaminoglycan, and fibroblast function

Behavior and mood effects

CNS, central nervous system; PTH, parathyroid hormone. Source: Udelsman R, Holbrook NJ. Endocrine and molecular responses to surgical stress. Curr Probl Surg 1994;8:653-728, with permission.

1232

CHAPTER 57

Catecholamine Pathway

Regulatory Enzyme

HPA Axis Interaction

H0-o~ CH -CH I - NH _

2

~ !Glucocorticoid ~

2

COOH Tyrosine

!99 21--65 b >99 85-90 50 >99 1.2ng/mL Proinsulin >250/0 Serum gastrin >lOOpg/ mL BAO >15mEq/h (>5mEq/h if prior operation for peptic ulcers) >200pg/mL increase in gastrin levels after secretin stimulation Plasma glucagon >500pg/mL Decreased plasma amino acids

Basal acid output (BAO) Secretin stimulation test

Glucagonoma

Glucagonoma

Glucagon

Skin rash Diarrhea Abdominal pain

VIPoma

Vasoactive intestinal peptide (VIP)

Secretory diarrhea Abdominal colic Flushing

Somatostatinoma

VernerMorrison Pancreatic cholera Endocrine cholera WDHA Somatostatinoma

Somatostatin

Diarrhea Abdominal pain

GRFoma

GRFoma

ACTHoma

Cushing's

Growth hormonereleasing factor (GRF) Adrenocorticotropic hormone (ACTH)

Neurotensinoma

Neurotensinoma

PTH-RPoma

Diabetes mellitus type II Weight loss/ cachexia Venous thrombosis Pulmonary emboli Hypokalemia Dehydration Weight loss

Fasting plasma glucagon Plasma amino acids

Serum potassium Fasting plasma VIP

Plasma VIP >500pg/mL (potassium -l

to

Z

:;d

n

o

t:l

Z

to

o

:;d

22/27 (81)

16/24 (67)

5/8 (63 ) 40/42 (95)

Palpation

to

Z

C

1258

CHAPTER 58

300 r --

-

-

gj

250

ell

- - - --

-

-

- - ---,

~ SMA

c

-0-

SPL

.g

~l20 0

-0-

GDA

iii -

E ::::l

o

ell

(1)

-

Patient #9

(1)

.S .0

-

~ :2

Ci) :£' ~ :§

-->+- PHA

150

E~

o c

~ '3: 100 .- .Q

"' (1) 0

ell

~

.~

50

500pg/mL) and decreased plasma levels of amino acids (see Table 58.31. Most pati ent s with glucagonoma have plasma glucagon levels greater than 1000pg/mL. Because the cachexia is so severe, most patient s are initially managed by total parenteral nutrition (TPN) with suppl emental zinc, trace metals, and insulin. Thi s intervention improves the hypoaminoacidemia, malnutrition, NME, and immune statu s in preparation for surgery . Long-term management of patients with metastatic glucagonoma has relied on the use of octreotide, which can reduce circulating plasma levels of glucagon and improve th e rash and malnutrition." At th e time of diagnosis, most tumors are large (average size, 5-10cm) and either locally advanced or met astatic and unresectable. For this reason, surgery for glucagonoma is seldom curative." VASOACTIVE INTESTINAL PEPTIDE TUMOR

Th e vasoactive intestinal peptide tumor (VIPoma) syndrome was first reported by Verner and Morrison in 195878 and came to bear their names. Because of the associated severe diarrhea, it is also referred to as the pancreatic cholera syndrome," endocrine cholera syndrome." or WHDA (watery diarrhea , hypokalemia, and achlorhydria) syndrome." The mean age at diagnosis is 50 years, and there is a slight female preponderance. 80,82 VIPomas induce a severe secretory diarrhea, a form of diarrh ea tha t is defined by persistence despite abstaining from oral intake; this leads to hypokalemia, hypochlorhydria, hypovolemia, and dehydration (see Table 58.3). Patients with VIPoma commonly have 5 to 10L of stool output per day and report abdominal cramping and flushing. Persistent hypokalemia causes a generalized weakness that may be severe, and

Somatostatinomas, which were first described fully in 1977,84 and are very rare malignant neuroendocrine tumors that arise in either the duodenum or pancreas. Pancreatic tumors are seen in about 50% of cases, and duodenal tumors may be associated with von Recklinghausen's disease. The somatostatinoma syndrome includes steatorrhea, cholelithiasis, diabetes mellitus type 2, and hypochlorhydria (see Tabl e 58.3). The mean age at presentation is 52 years ." Some patients present with colicky abdominal pain secondary to the cholelithiasis, and somatostatinoma may be diagnosed incidentally at the time of cholecystectomy or during CT scanning of the abdomen for nonsp ecific complaints. Somatostatin -like activity can be measured by immunological assays and is the key to the diagnosis (Table 58.3). Most patients have unresectable metastatic tumor at the time of diagnosis. NONFUNCTIONING I SLET CELL TUMORS

Nonfunctioning islet cell tumors or pancreatic polypeptideproducing tumors (PPomas) do not have a clinical syndrome related to the excessive hormone secreticn.?These tumors are usuall y present during the fourth or fifth decade of life." They are usually malignant and large at the time of clin ical diagnosis and produce symptoms secondary to the mas s effects of the tumor. Some patients with MEN 1 may undergo CT scanning for islet cell tumors because an elevated serum level of pancreatic polypeptide (PP) has been measured as a screening marker (Table 58.3). Large tumors may cause symptoms of extrahepatic bile duct obstruction, bleeding, or intestinal obstruction" (Table 58.3). Patients may also have hepatic metastases in association with large tumor volumes. Most of these tumors are resectable but often require pancreaticoduodenectomy (Whipple resection) or subtotal pancreatectomy." RARE I SLET CELL TUMORS

Islet cell tumors can produce a variety of unusual hormones, including growth hormone-releasing factor (GRF), adrenocorticotropic hormone (ACTH), parathyroid hormone-related peptide (PTH-RP)' neurotensin, and serotonin. Islet cell

1262

CHAPTER 58

tumors have been found to cause severe hypercalcemia secondary to parathyroid hormone-related peptide, Cushing's syndrome secondary to ectopic ACTH production, and acromegaly secondary to GRF production. Cushing's syndrome has been reported in a small number of ZES patients as the result of concomitant elaboration of ACTH. 87 Rarely, neurotensinomas, once regarded as nonfunctional tumors," produce neurotensin that causes diarrhea, hypotension, flushing, and cyanosis. RADIOLOGIC LOCALIZATION OF RARE ISLET CELL TUMORS

Radiologic localization of the less frequent islet cell tumors such as somatostatinoma, VIPoma, glucagonoma, PPoma, and nonfunctional tumors is relatively simple. In contrast to insulinomas or gastrinomas, virtually all these tumors are visible with current CT imaging. Some studies have demonstrated that MRI is better able to detect liver metastases than CT. 31 However, CT may be superior at imaging the primary tumor because CT images have clearer anatomic resolution than MR. Further, CT is less expensive than MRI. SRS should also be used for these patients to detect occult distant metastases and to determine if the tumor has functional somatostatin receptors." Approximately 800/0 to 90% of these rare islet cell tumors image on octreoscan. 31,40,89 If an individual tumor can be detected by this modality, the hormonal syndrome will usually respond to octreotide. Some preliminary studies suggest that the long-term use of octreotide in patients with unresectable rare neuroendocrine tumors may prolong survival. 77

Treatment of Neuroendocrine Tumors Insulinoma MEDICAL MANAGEMENT

Medical management is the initial treatment of patients diagnosed with insulinoma (Table 58.8). This approach allows for stabilization of symptoms and time to localize the tumor, if possible, and plan for surgical resection. Initial management includes dietary adjustment to include more frequent as well as nighttime meals. Cornstarch can be added to the diet at bedtime to slow the absorption of food from the intestines.P'" Diazoxide, an antihypertensive agent, can successfully suppress insulin secretion in approximately 60% of patients.F''" It appears to act through stimulation of islet cell u-adrenergic receptors and may have peripheral glycogenolytic effects by inhibition of cAMP phosphodiesterase.F'" Side effects, particularly nausea and sodium retention, may be problematical.27,33 Treatment is usually started at a dose of 150 to 200mg/day in divided doses to a maximum of 800mg/day.27,33 Because diazoxide has been associated with life-threatening hypotension on induction of anesthesia, it should be discontinued at least 7 days before the planned operation." Calcium channel blockers such as verapamil may also function by reducing insulin secretion and may be of utility in selected patients who do not tolerate diazoxide." Likewise, the ~ adrenergic antagonist propanolol and the antiepilepsy drug phenytoin have also been used to control symptoms in a

TABLE 58.8. Medical and Preoperative Treatment Modalities for Neuroendocrine Tumors. Tumor

Treatment

Insulinoma

Frequent small meals Cornstarch Diazoxide Verapamil Octreotide Propanolol Phenytoin Omeprazole or lansoprazole Hs-receptor antagonists Octreotide Total parenteral nutrition with added trace elements Diabetes control Octreotide Octreotide Fluids Diabetes control Fluids Lasix Mitramycin Diphosphonates Ketoconazole Aminoglutethimide Mifepristone Octreotide Octreotide

Gastrinoma Glucagonoma

VIPoma Somatostatinoma PTH-RPoma

ACTHoma GRFoma Carcinoid

small number of patients, as have prednisone and glucagon." Octreotide, the long-acting somatostatin analogue, in contrast to its lack of utility for localization of insulinomas, has been used extensively to treat infants with hypoglycemia caused by nesidioblastosis." In adults, it can control symptoms of hypoglycemia in approximately 400/0 of patients and is generally well tolerated at a dose of 100 to 1500J-lg/day administered subcutaneously in divided doses. 93,94 If it is effective, it can be converted to somatostatin-LAR 30 mg 1M every 3 weeks. If medical management is successful in controlling symptoms, then the surgeon is under less pressure to find and remove the tumor. However, if the patient cannot tolerate drug therapy, the outcome of exploration is more critical. In this instance, a preoperative calcium angiogram can be used to locate the precise region of the pancreas that contains the tumor. SURGICAL MANAGEMENT

Surgery is the only curative treatment for patients with an insulinoma. 21,28,4s,9s Often, medical control of the hypoglycemia is unsatisfactory, placing more emphasis on a successful surgical outcome. The presence of MEN 1 should be excluded by testing for other components of the syndrome, which may include primary hyperparathyroidism, nephrolithiasis, and the presence of other endocrine or pituitary tumors.r' Enucleation is the preferred surgical treatment for insulinoma" because most tumors are solitary and benign. IODS is critical during surgery for insulinoma as it facilitates both identification and removal of these tumors. Occasionally, the surgeon is unable to remove these tumors by enucleation because of the relationship to the pancreatic duct or other

NEUROE ND O CRIN E TUMORS OF THE PANCREA S AND G A S T R O I N T E S TI N A L TRACT AND CARC INOID DISEASE

_'r."'.

1263

TABLE 58.9. Outcome of Surgical Management of In sulinom a and Gastrinoma and Survival After Gastrinoma Resection.

Reference

Level of evidence'

n

N/A N/A

17 16 33 43

0 0 3 .7 3 .7

0 14 29 44 48

0 75 31 42

NR NR

0 0 6 0

0 0

(%)

0 0 1

11

11 13

92 96 100 93

Gastrinoma MacFarlane et al. (1995) 103 McArthur et al. (1996) 63 Jaskowiak et al. (1996) 101 Kisker et al. 11998jl l Norton et a1. (1999) 54

II II II II II

10 22 17 25 151

10 3 2 2 28

60 44 94 48 46

70 41 100 92 93

73 22 25 15 1

92 96 93 84

Cured

23 25 27 54

II II II II

Mortality

Tumor resected

II II II III

Norton et al. (19881102 McArthur et al. (1996)63 Kisker et al. (1998 j71 Norton et al. (1999 )54

Operati ve complications

With malignan cy (n)

Insulinoma Norton et al. (1990) 45 Doherty et al. (199 1195 La et al. (1997)32 Boukhman et al. (1998) 21

Long-term survival

Cured wi th malignancy

With MEN (n)

(%)

(%)

33 86

NR

5-year (localized disease) (%)

5-year (metastatic disease) (%)

Ill-year (overall) (%)

95 100 100

95 75 28 40

NR

(%)

11 16

NR

(%)

81

NR 34

'I, prospective, randomized; II, prospective; III, retrospective, review or anecdotal; N R, not reported.

vital structures. In this case, lesions are resected by either distal pancreatectomy or Whipple pancreaticoduodenectomy. Blind distal pancreatectomy, a procedure that was formerly recommended, is no longer indicated because studies have reported that occult tumors are usually found within the head of the pancreas, an area which is difficult to palpate but is relatively accessible to IOUS (see Fig. 58.2).32.34.45 Many large series from different institutions have demonstrated that more than 90% of patients can have successful surgery and complete correction of the hypoglycernia' v' v" (Table 58.9). Further, because as much of the normal pancreatic architecture as possible is preserved, there is a low risk for the devel opment of diabetes mellitus postoperatively. Patients with MEN I and insulinoma are treated in the same manner. In these patients, however, a dominant large islet cell tumor is usually identified and resected, leading to control of hypogly cemia. The complications of insulinoma excision are primarily those associated with pancreatic resection and include abscess, fistula, pseudocyst formation, or wound infection. Drainage of the pancreatic enzymes by closed-suction drains usually minimizes these complications.

Gastrinoma

H+-K--ATPase . The usual dose is 20 to 40mg twice daily." Hj-receptor antagonists are also effective, but progressively higher doses may be required to control symptoms. They may be associated with a long-term failure rate, making proton pump inhibitors the current drugs of choice. Measurement of BAO, following initiation of drug therapy, is necessary to adjust the dose of medication for effective medical treatment because relief of symptoms is not a reliable indicator of effective acid control.l':" To allow healing of ulceration and to prevent recurrences, gastric acid secretion should be maintained below lOmEqJh; it should be ma intained below 5 mEq/h if prior ulcer surgery has been performed " or in patients with reflux esophagitis and ZES.51 Effective acid control reduces the need for esophageal dilatation in these patients." However, with long-term medical control of ZES, there may exist associated risks. Animal studies originally raised the concern of gastric malignancy in the setting of long-term acid suppression," and there have been cases of MEN 1 patients who have developed diffuse malignant gastric carcinoid tumors after prolonged treatment with omeprazole." Therefore, periodic gastric surveillance endoscopy should be performed on all patients treated with proton pump inhibitors for long periods. SURGICAL MANAGEMENT

MEDICAL MANAGEMENT

Originally, total gastrectomy was the only procedure that effectively controlled gastric acid hypersecretion in patients with gastrinoma, but it is no longer necessary.":" With the advent of histamine H2-receptor antagonists and, more importantly, proton pump inhibitors, all patients can experience control of acid hypersecretion and complete relief of symptoms (see Table 58.8). Omeprazole and lansoprazole block gastric acid secretion by inhibiting the parietal cell apical

Medical control of acid hypersecretion allows time for localization and surgical treatment of the gastrinoma and obviates the need for total gastrectomy.s'r" Based on the results of a number of long-term studies, the malignant potential of the tumor itself is the main determinant of long-term sur vival. 55,98,99 Because of this, all patients with sporadic gastrinomas are candidates for tumor localization and surgery for attempted cure to prolong survival." The management of patients with MEN 1 and ZES is controversial and more

1264

CHAPTER S8

complex. In patients with the MEN 1 and primary hyperparathyroidism (HPT), the usual parathyroid pathology is multigland hyperplasia. It has been shown that successful neck exploration for resection of parathyroid hyperplasia can significantly lessen the end-organ effects of hypergastrinemia. Therefore, in patients with MEN 1 who have HPT in conjunction with ZES, neck exploration and subtotal or four-gland parathyroidectomy with autotransplantation should be performed before attempting gastrinoma resection" (Fig. 58.9). Overall, however, removal of pancreatic and duodenal tumors seldom cures patients of ZES54,61 (see Table 58.9). It has been shown that resection of primary gastrinomas decreases the likelihood of liver metastases, which are the main determinant of survival in these patients. 52 Therefore, the goals of surgical management are resection of the primary tumor for potential cure and to prevent malignant progression. This latter goal is the same whether the patient has a sporadic gastrinoma or gastrinoma in the setting of the MEN 1 syndrome. The operative management of patients with MEN 1 and gastrinoma is complicated by the fact that the tumors tend to be multiple, small (4-6mm), and usually involve the duodenum'Y" more often than the pancreas. In these patients, the controversy has centered on the fact that surgery is seldom curative yet it may be effective to decrease or prevent the development of liver metastases.Pr" We recommend surgery when the duodenal or pancreatic tumor is 2 em or larger on CT51 because the risk of liver metastases increases with tumor size. Overall, 4 % of patients with gastrinomas less than 1 em, 28% with tumors between 1 and 3 em, and 61 % with tumors greater than 3 em have liver metastases.v-" After review of current data, it seems prudent

+ + Reassess Biochemical Diagnosis of ZES

Total (4 Gland) r::l Parathyroidectomy ~ with Autotrans lantation

'------.;.,r------......;~

Surgery (IOUS) (Duodenal Exploration)

FIGURE 58.9. Flow diagram for the management of ZES in the setting of multiple endocrine neoplasia (MEN 1).

to operate on MEN 1 patients with much smaller pancreatic and duodenal gastrinomas because resection may decrease the risk of developing hepatic metastases. In one study of 124 patients without evidence of hepatic metastases, 98 patients (15 with MEN 1) had primary gastrinomas resected while 26 patients (9 with MEN 1) refused surgery and were managed medically. After a mean follow-up of 8.5 years, hepatic metastases were detected in 23 % of the patients who had been managed medically and 30/0 of the patients who had undergone surgery.'?" Thus, surgical resection of the primary gastrinoma significantly reduced the probability of liver metastases. At surgery, a tumor is found in approximately 78 % of sporadic gastrinoma patients, and 140/0 to 580/0 of patients are cured immediately following resection.P:" The long-term cure rate, with surgery, is 340/0 to 81 % depending on the series (see Table 58.9). Surgery is also effective treatment for localized metastatic gastrinoma, as it appears to prolong survival and cures approximately one-third of patients. 101,102 In patients with MEN 1 and gastrinoma, the identification of all tumor foci is imprecise, and surgery results in a significantly lower cure rate. 54,103 Paradoxically, although patients with gastrinoma and MEN 1 may present earlier, have multiple small extrapancreatic islet cell tumors, and may undergo abdominal exploration without surgical cure, there is evidence that they will develop liver metastases at a lesser rate following surgery for resection of tumor. This finding suggests that the tumor biology of gastrinomas found in MEN 1 patients is similar to that found in sporadic patients. In patients with ZES, the development of intraoperative imaging techniques has greatly facilitated tumor identification and resection; this is particularly true for small duodenal tumors that are difficult to locate. With improvement in intraoperative localization methods such as ultrasound and endoscopy with transillumination and duodenotomy, as well as increased awareness of duodenal tumors, some studies have reported that gastrinomas can be found and resected in nearly 100% of patients with MEN 1 and ZES.54 In a series of 143 patients, undergoing routine duodenotomy in ZES was associated with increased short- and long-term cure rates.'?' In addition, the experience of the surgeon appears to be another factor in achieving a good surgical outcome. 11 In general, in MEN 1 patients, if tumors are clearly imaged on preoperative studies, laparotomy is indicated. In sporadic patients with ZES who have no clearly imaged disease, laparotomy is still indicated as recent series suggest that tumors will still be found in nearly all patients." In this instance, the gastrinoma is invariably located in the duodenum. 51,54 All regional lymph nodes should be removed for histological examination. Enucleation of pancreatic head tumors is usually sufficient, whereas distal or even subtotal pancreatectomy may be necessary for tumors of the body and tail. A careful examination of the duodenum is critical in all patients with ZES, as occult tumors are nearly always located here.

Other Islet Cell Tumors MEDICAL MANAGEMENT

Medical therapy may be used to control the signs and symptoms of excessive hormonal secretion, but it will seldom

NEUROENDOCRINE TUMORS OF THE PANCREAS AND GASTROINTESTINAL TRACT AND CARCINOID DISEASE

control the tumoral process (see Table 58.8). Medical therapy is not curative, but at best it can provide symptomatic relief, although it is not effective as an antitumor treatment and will not prolong survival.':" Glucagonoma patients often need intense medical management before surgery. They have severe malnutrition, hypoaminoacidemia, and type 2 diabetes mellitus, which can be corrected by total (glucose, fat, and amino acids) parenteral nutrition with added trace elements (particularly zinc) and insulin. Octreotide may also be of benefit in alleviating symptoms." Interestingly, we have previously demonstrated that correction of the hypoaminoacidemia with total parental nutrition corrects the NME rash," Because of the risk of deep venous thrombosis and pulmonary embolism, vena cava interruption filter placement after anticoagulation with heparin is often recommended. Somatostatinoma patients invariably develop symptomatic cholelithiasis, and cholecystectomy is recommended as part of the overall treatment. Cholycystectomy is also indicated for any patient requiring long-term treatment with octreotide. Diabetes control with insulin and proper hydration is also important. In these patients, octreotide has been reported to show objective response in up to 11 % of individuals." Similarly, VIPoma patients usually have severe dehydration and electrolyte abnormalities that must be corrected before surgery. Large amounts of intravenous fluid, with potassium supplementation, were necessary in the past and most patients responded poorly. Currently, octreotide effectively controls the secretion of VIP in nearly every patient, and the management of fluid and electrolytes has been dramatically simplified. 77,80 Severe hypercalcemia secondary to PTH-RP-producing neuroendocrine tumors must be controlled by the use of intravenous saline solution, lasix, mithramycin, and diphosphonates (Table 58.8). Cushing's syndrome, caused by ectopic ACTH-producing islet cell tumors, should be controlled by agents such as ketoconazole, aminoglutethimide, and mifepristone (RU 486). Octreotide has largely been ineffective for the treatment of ectopic ACTH secretion." Medical control of the severe hypercortisolism is often inadequate, and patients usually require bilateral adrenalectomy if complete resection of the ACTH-producing islet cell tumor is not possible. 105 Serotonin-producing islet cell tumors require octreotide as a premedication at the time of surgery to prevent a life-threatening carcinoid crisis while under anaesthesia. 106

Surgical Management Overall, surgical resection is the only potentially curative therapy for patients with islet cell tumors.v" However, surgical therapy is dependent on a variety of factors including the type of tumor, extent of disease, presence of MEN 1, and ability to control hormonal symptoms medically, as well as the overall operative risk of the patient. In general, surgery is indicated for all patients with islet cell tumors in whom all tumors can be imaged and removed with acceptable morbidity and mortality. This procedure is necessary because, despite considerable variability, any type of neuroendocrine tumor can be malignant. Debulking surgery may also be indicated in any patient with a large tumor burden or metastatic disease in whom medical treatment does not control hormonal symp-

1265

toms." Similarly, other procedures such as bilateral adrenalectomy may be indicated because of the inability to effectively treat symptoms. 105 In patients with MEN 1 and concomitant neuroendocrine tumors, resection should be pursued if the tumors are larger than 2cm because size correlates with increased malignant potential. Further, MEN 1 patients should undergo surgery in an attempt to control the signs and symptoms of excessive hormone secretion by an islet cell tumor. The major consideration in dealing with the tumors found in the setting of MEN 1 is that these tumors are usually multiple and it may be unclear which exact tumor is responsible for the excessive hormone production.l" However, most patients have a large dominant tumor that may be responsible for most, if not all, the symptoms." These tumors, with the exception of gastrinomas, are usually radiologically apparent. Therefore, in MEN 1 patients, surgery should be attempted for all large pancreatic islet cell tumors that are detected by conventional studies. The rare pancreatic islet cell tumors are generally easily identified on preoperative CT. Once identified, the tumor and its metastases, if present, are resected by either pancreaticoduodenectomy or subtotal pancreatectomy-splenectomy, depending on the location to remove the largest identifiable tumor." Secondary liver metastases are removed, either by multiple wedge resections or lobectomy, depending on the size and location of the metastasis. Resection of both pancreatic and hepatic disease is indicated if the operative procedure planned can remove all gross disease, again, with acceptable mortality and morbidity." Resection of all identifiable tumor appears to improve survival and may even produce biochemical cure in a subset of patients. It is important to remember that, even with liver metastases, patients still have, on average, a long-term (10-year) survival of more than 200/0. Surgery is also an important therapeutic option in ameliorating the signs and symptoms of excessive hormone secretion in patients who do not respond adequately to optimal medical management; this is particularly true in patients with VIPoma and glucagonoma who fail to respond to octreotide or patients with metastatic insulinoma who do not respond to octreotide, verapamil, diazoxide, or frequent feedings. Reduction of tumor mass reduces the circulating concentrations of hormones and subsequently reduces intensity and severity of symptoms," as well as the dosage of medications necessary to achieve symptomatic control. In the case of an ACTH-secreting islet cell tumor, surgical resection of the target organs may substantially improve the quality and duration of life. Surgery may also be indicated in nonfunctional islet cell tumors that develop serious or life-threatening symptoms such as gastrointestinal hemorrhage and biliary or intestinal obstruction. In these instances, the tumor may either be resected or bypassed to relieve the symptoms.

Metastatic Disease Malignant Insulinoma Surgery in patients with malignant insulinoma may still be curative, but this is only accomplished if all tumor can be completely removed.F-'!" Depending on the tumor location, either Whipple pancreaticoduodenectomy or subtotal

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pancreatectomy with splenectomy may be necessary. Multiple wedge resections, radiofrequency ablation, or lobectomy can then be used to treat secondary liver metastases. Resection of all identifiable tumors appears to improve survival and may even cure a subset of patients. Another indication for debulking surgery or radiofrequency ablation in combination with debulking is to lessen the signs and symptoms of hypoglycemia, especially in patients who do not respond adequately to medical management with octreotide, verapamil, diazoxide, or frequent feedings. Aggressive surgery may also be indicated in instances in which the tumor causes gastrointestinal hemorrhage or biliary or intestinal obstruction. Chemotherapy for metastatic insulinoma has been largely ineffective. Single-agent therapy is based on streptozotocin with combination therapy of streptozotocin plus 5-fluorouracil or streptozotocin plus doxorubicin, producing transient responses in 450/0 and 69% of patients, respectively, lOB with no complete responses identified; thus, this may translate into a minimal (1- to 2-year) survival advantage for responders.!" Chemoembolization, a combination of simultaneous hepatic artery occlusion and chemotherapy, has had some significant antitumor responses and may also be used to ameliorate symptoms.l'" Using this approach, symptoms and hormone levels have improved in nearly every patient. However, side effects and complications may occur, including life-threatening liver abscesses. Alcohol injection, radiofrequency ablation, and cryotherapy have also been used in the treatment of metastatic insulinoma without clear benefit.

Malignant Gastrinoma With successful control of gastric acid hypersecretion and the indolent growth pattern of the gastrinoma, distant metastatic disease becomes the most important determinant of mortality. In the past, about 600/0 of patients had metastatic disease, but with current biochemical testing and workup, only between 25 % and 33 % of patients now have metastasis at the time of diagnosis." The 5-year survival for patients with metastatic disease is, on average, approximately 400/0. 51 In addition, 200/0 of these patients experience accelerated tumor growth, which ultimately results in more rapid demise. Although the exact mechanism underlying this more aggressive tumor behavior has yet to be understood, it is associated with high serum levels of gastrin, tumor production of multiple hormones (especially ACTH), and the presence of bilobar liver or bone metastases." It has been suggested that gastrinomas in patients with the MEN 1 syndrome appear to behave less aggressively than those found in patients with sporadic disease, although both have an equal rate of lymph node metastasis.l'" Duodenal gastrinomas have a similar rate of lymph node metastases but a lower rate of liver metastases than pancreatic tumors. Chemotherapy has been utilized in the treatment of metastatic gastrinomas but does not prolong survival. A combination of doxorubicin, 5-fluorouracil, and streptozotocin provides a 40% partial response rate but no survival benefit or complete responses.l'" Similarly, hepatic artery chemoembolization has minimal, and transient, efficacy and the use of octreotide or alpha-interferon as antitumor agents has also shown little effect on the malignant process. 111

Surgery remains the major effective treatment for metastatic gastrinoma. Originally, Zollinger and associates reported good results in the postoperative course of a series of selected patients who had undergone resection of metastatic disease, including those with liver metastases. 112 Patients with localized lymph node metastases seem to benefit most from surgery, with up to 300/0 showing biochemical cure," 1 whereas patients with resected localized metastatic liver disease have on average an 85 % 5-year survivaI 63,99,101 (see Table 58.9). Aggressive surgery in appropriate patients with hepatic metastases seems to demonstrate a survival advantage. In one study in which 17 patients underwent resection of hepatic metastases, there was a 790/0 5-year survival. In contrast to this, a similar group of 25 patients with unresectable hepatic disease had a 280/0 5-year survival.l" Although studies are ongoing, it appears that, even in those patients with unresectable disease, hepatic cryosurgery or radiofrequency ablation may serve to reduce symptoms and prolong survival.

Other Islet Cell Tumors Chemotherapy has been used in the treatment of metastatic islet cell tumors, with 400/0 partial but few documented complete responses. 110 Again, the usual agents include doxorubicin, 5-fluorouracil, and streptozotocin. These drugs have been used individually and in combination, with the combination therapy providing more responses. One recent study found that the combination of decarbazine, 5-fluorouracil, and leucovorin produced objective response in 44 % of patients with neuroendocrine tumors.!" In Sweden, a-interferon has had similar response rates in patients who have failed chemotherapy.lIs Recent studies have investigated the use of longacting analogues of somatostatin as antitumor agents to slow tumor growth and metastatic rate. These hormonal therapies appear to be effective in controlling medical signs and symptoms of hormonal excess and are indicated for that purpose, but the antitumor effects are less clear. Recently, chemoembolization, with simultaneous hepatic artery occlusion and doxorubicin infusion, has had dramatic antitumor responses in individuals with large hepatic tumor volumes.l'" Symptoms have improved in nearly every patient, and hormonal levels have significantly decreased in approximately 800/0 of individuals, suggesting that this may have a real benefit in those with a significant disease burden. However, side effects have been reported, and complications may occur. Intralesional alcohol injection and cryotherapy have been also been used in a few patients without clear benefit.

Surgical Techniques Enucleation of Insulinoma Because insulinomas are usually benign, small, and uniformly distributed throughout the pancreas, the goal of surgery is precise localization of tumor and excision with preservation of normal pancreas and spleen. At the time of surgery, the pancreas is fully exposed to allow complete palpation and inspection of the gland (Fig. 58.10). After dividing the gastro-


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F

FIGURE 58.10. Surgical approach for the resection of an insulinoma or other neuroendocrine tumor. In the obese patient (not uncommon in the case of an insulinorna], a bilateral subcostal incision may be necessary. Otherwise, a generous upper midline incision may be preferred. The abdomen is then entered and carefully explored. Next (AI, the head and neck of the pancreas are exposed anteriorly by reflecting the omentum and hepatic flexure of the colon to the left. The lateral peritoneal attachments of the duodenum are then incised (B), and the duodenum is freed from the underlying aorta and vena cava by blunt and sharp dissection (Kocher maneuver). It should now be possible to palpate the duodenum, as well as the head and uncinate process of the pancreas, between fingers and thumb as shown in C. The dark area within the pancreas shown in C represents a small

insulinoma. If the uncinate process is still poorly palpated, complete mobilization of the right colon medially (Cattell maneuver) should allow for complete palpation. Next, the body and tail of the pancreas are exposed by first dividing the gastrocolic ligament (D), and the peritoneum along the inferior border of the body and tail of the pancreas is then incised (E). Once the peritoneum is divided, the areolar tissue deep to the pancreas may be opened by blunt dissection (F), until the whole gland is mobilized from its retroperitoneal attachments (G); this allows for a complete palpation and ultrasound examination of the head (H), as well as the body and tail of the gland (I), using the ultrasound transducer. After a complete ultrasound and manual examination, the tumor is located and enucleated lJ), in this case from the posterior aspect of the head of the pancreas.

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CHAPTER 5 8

positioned between the legs of the patient as is done for a Nissen fundoplication. The pancreas is exposed using the harmonic scalpel to divide the gastrocolic ligament. Laparoscopic ultrasound is then performed and used to localize the tumor, which is enucleated using ultrasound for guidance. The procedure is performed in an identical fashion to the open procedure, and formal laparotomy should be done if the tumor is not identified.

Duodenotomy for Gastrinoma

FIGURE 58.11. Intraoperative ultrasound (IOUSl shows the echogenic characteristics of a 2-cm gastrinoma within the head of the pancreas [arrows]. PD, pancreatic duct.

colic ligament, a wide extended Kocher maneuver is performed that includes mobilization of the right colon. In some instances, the lateral peritoneal attachments of the spleen are divided to elevate the spleen and the tail of the pancreas to facilitate identification of any small tumor that may be located within the tail. Th e peritoneum along the inferior border of the gland is incised to allow palpation between the thumb and forefinger. At this stage, IOUS is performed with a high-resolution real-time transducer (7.5-10MHzl. Doppler flow capabilities allow for mor e accurate discrimination between the tumor, ducts, arteries, and veins . Insulinomas appear sonolucent compared to the more echo-dense normal pancreas (Fig. 58.11). Masses or tumors are always imaged in two directions to visualize their three-dimensional extent. Further, IOUS can be used to precisely identify the relationships of the tumor to other vital structures such as the pancreatic duct, bile duct, arteries, and veins to allow safe excision . IOUS has been useful in facilitating the enucleation of nonpalpable insulinomas within the pancreatic head. Recent reports have also suggested that insulinoma resection can be accomplished laparoscopically.l' v' " The surgeon is

During surgery for a gastrinoma, it is important to remember that these tumors can occur in extrapancreatic locations, particularly the duodenum. The operation itself requires a careful exploration of the abdomen and its contents, as has been previously described .t'-" It is important to explore and palpate the liver, stomach, small bowel, and mesentery as well as the pancreas and pelvis . The uterus, fallopian tubes, and ovaries should be inspected and palpated in female patients. Again, an extended Kocher maneuver should be performed to mobilize the duodenum and pancreatic head . The pancreatic body and tail may be better visualized by opening the gastrocolic ligament and dividing along the inferior border of the pancreas. Once this has been accomplished, the duodenum and pancreas can be fully palpated and examined by IOUS (Fig. 58.12). IOUS should also be used to image the liver. A 7.5- to lO-mHz near -field transducer is necessary for studying the pancreas, whereas the 2.5- to 5-mHz wide -angle transducer is best for the liver. Tumors appear sonolucent and should be imaged in two dimensions. The duodenum can then be palpated between thumb and forefinger for the presence of mass lesions (Fig. 58.12). IOE with duodenal transillumination may also be performed. A duodenal gastrinoma appears as a photopaque mass lesion within the wall of the duodenum upon transillumination (see Fig. 58.7). The endoscopist may occasionally also visualize the tumor as a raised mucosal defect (Fig. 58.13). Once duodenal lesions are identified, they can be marked with suture and included within the confines of a modest longitudinal duodenotomy (Fig. 58.14). It should be remembered that, regardless of the results of IOUS or IOE, a duodenotomy is indicated in all cases. This procedure allows for visualization as well as a more careful palpation of the entire

FIGURE 58.12. Palpation of the duodenum between

thumb and forefinger IA) and use of ultrasound

[B] in attempting to locate a duodenal gastrinoma

intraoperatively.

NEUROEND O CRINE TUMORS OF THE PAN CREAS AND G A S T R O I N T E S T I N A L TRA CT AND CARCINOID DISEASE

/

~/ ':;

1269

~ ..

" '~

" ~:.

, FIGURE 58.13. Endoscopic view of a duodenalgastrinoma, here seen as a submucosal mass (arrows) .

duodenal wall, particularly its medial portion. Starting the incision at the junction between the first and second parts of the duodenum allows examination of an area where a large proportion of duodenal gastrinomas have been found (Fig. 58.15). Suspicious nodules on the medial wall should not be excised until a catheter is passed through the ampulla of Vater to mark its location. On occasion, this may have to be accomplished by passing the catheter through the common bile duct and into the duodenum. Finally, the duodenum is closed transversely in two layers to minimize the risk of leakage or obstruction (Fig. 58.16). If a long duodenotomy is necessary, longitudinal closure is indicated. Peripancreatic, bile duct, and celiac axis lymph nodes should also be excised for histological review. Reoperation for recurrent localized gastrinoma is also indicated if the tumor is imageable and the patient is a suitable candidate for surgery. Reoperation can result in elimination of all tumor in nearly every patient and complete remission in 30% .110

o Palpation • Intraoperative endoscopy e Duodenotomy

..

FIGURE 58.15. Illustration of the location of a series of duodenal gastrinomas as determined by palpation (open circles), intraoperative endoscopy tsolid circles), or duodenotomy (shaded circles). Most lesions were located in the first or second portion of the duodenum with a surprising number located just beyond the distal border of the pylorus (dotted line), highlighting the need for beginning a duodenotomy incision in this region to allow for proper palpation and examination of this area. Also, note that the tumors found by duodenotomy were located on the medial wall of the duodenum.

Carcinoid Disease Carcinoid tumors are derived from neoplastic outgrowth of certain cells of the diffuse neuroendocrine system" and continue to be regarded by some as an enigmatic and controversial tumor.!" The term carcinoid was first coined by Oberndorfer in 1907 119 to describe the atypical pathological features of a tumor that was first identified by Ranson, more than a decade earlier, as a carcinoma of the ileum.P'' The origin of these carcinoma-like cells was not elucidated until 1928 when Masson identified a carcinoid originating from the chromaffin cells at the base of the crypts of Lieberkuhn in a specimen of appendix.!" He found that the carcinoid cells took up and reduced silver and termed them argentaffin cell tumors, after the histochemical reaction that now bears his name. However, it was not until the early 1950s that Lembech first described the presence of serotonin

A

FIGURE 58.14. Illustration of how intraoperative endoscopy allows for the transillumination ofa duodenalwall gastrinoma.Once located, a suture may be placedaround the tumor to mark it IA) and the lesion removed by inclusion in the duodenotomy incision (B).

B

FIGURE 58.16. Illustration of the closure of a duodenotomy after examination and palpation for the presenceof a duodenalgastrinoma. The duodenotomy (A), which is usually started at the junction of the first and second portion of the duodenum, is normally closed transversely (B) in two layers to minimize the risk of leakageor narrowing. In the case of a long duodenotomy, it may be necessary to close the incision longitudinally (C).

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(5-hydroxytryptamine, 5-HT) in carcinoid cells 122 and Page detected increased levels of the serotonin metabolite 5hydroxyindoleacetic acid (5-HIAA) in the urine of patients with carcinoid syndrome.l"

Epidemiology The exact incidence of carcinoid disease is unknown because it differs considerably in different populations and with different study types. This variation probably reflects the presence of subclinical disease, which is supported by autopsy studies, as well as the different occurrence rates at distinct anatomical sites and in different age groups and populations (see Table 58.1). Overall, the estimated incidence is thought to be 1.5 per 100,000 of the general population.P' In Europe, the incidence is approximately 0.7 to 0.9 per 100,000 population, 125-127 with even higher incidence seen in certain regions. 128 The incidence in Scandinavia is also reported to be approximately 0.7 per 100,000. 129 In the United States, others have reported an incidence of 0.28 per 100,000 population for intestinal carcinoids.':" Autopsy studies have suggested a higher incidence of carcinoid tumors in the general population. Data from the Mayo Clinic have reported the incidence of carcinoids to be 65 per 100,000 cases. 131,132 The majority of these tumors were found in the appendix and small intestine. Based on these data, approximately 1 in every 200 to 300 resected appendiceal specimens contains a carcinoid tumor.131-133 Others have reported a lower incidence of 2.1 per 100,000 cases per year. 134 The incidence of carcinoid disease also seems to vary with regard to age and gender. The age of patients ranges from 8 to 93 years,127,135-138 with a mean age at presentation of 55 to 60 years in different study groupS.127,136-138 Interestingly, a lower incidence is reported in younger age groups, particularly males,135,136 and tumors at certain anatomic sites, such as the rectum, may also present at a younger age.!" The incidence in women seems to be, overall, slightly higher than in men, with an incidence of 0.8 to 0.9 per 100,000 population in certain groups.!" This same study also found that, for women aged 15 to 19, the female-to-male ratio was as high as 7: 1. Others report a significant incidence of carcinoid tumors in girls under the age of IS, 135 whereas the incidence is similar in women and men beyond age 15.125

Classification and Tumor Characteristics Carcinoid tumors are derived from chromaffin or Kulchitsky cells.!" which are ubiquitous throughout the gastrointestinal and urogenital tract as well as the bronchial epithelium.P'r"" This finding explains the occurrence of carcinoids in a wide range of anatomic sites. Embryologically, their origin is in the endoderm and neuroectoderm, 1and they are capable of taking up aromatic amines or their precursors and decarboxylating them, thus classifying them as apudomas. As such, they share cytochemical and histological features with other neuroendocrine tumors as well as with pheochromocytomas, medullary carcinomas of the thyroid, and melanomas." Because of their close similarities to the endocrine tumors of the pancreas, some authors have proposed naming carcinoids neuroendocrine tumors to facilitate better classification of this diverse neoplasm.Y"

Carcinoid tumors may be classified along histological, cytochemical, and anatomic lines. Each classification system, by itself, is imprecise, and pathologists and surgeons must rely on a composite of information in correctly identifying a carcinoid tumor.v? More importantly, malignancy cannot be identified on the basis of histology or cytochemical findings alone and, as with other neuroendocrine tumors, remains a clinical diagnosis after the finding of lymph node or distant metastases. From a histological standpoint, carcinoid tumors generally cannot be differentiated from other neuroendocrine tumors when viewed under the light microscope with the usual stains. They are composed of homogeneous sheets of small round cells with uniform cytoplasm and nuclei and rare mitotic figures. 4,6,143 An experienced pathologist may be able to tentatively identify the tumor as a carcinoid, but true identification and characterization relies on histological and cytochemical staining patterns of intracellular reactions, secreted products, and intracellular proteins.i" The original, and still most important, stain is that of the cell's reaction with silver salts. 2,121,143 Characteristically, carcinoid tumors may take up and reduce silver salts (argentaffin reaction of Masson) or may take up, but not reduce, silver unless exogenous reducing substances are added (argyrophilic reaction). This argentaffin or argyrophilic staining pattern is seen in carcinoids, generally, as a function of anatomic location? and serotonin content.!" The histochemical diagnosis of the tumor may be complemented by the use of monoclonal antibodies to serotonin.v" Some authors have recognized certain histological and histochemical characteristics of carcinoid tumors and have proposed classifying the tumor on the basis of these findings. 4,6,142,145 Under this classification system, carcinoid tumors may be grouped according to specific growth patterns into nodular, trabecular, glandular, undifferentiated, or mixed. Further, some authors have proposed that these different histological types may have different prognosis for survival, with a mixed histology showing the longest median survival (4.4 years) and an undifferentiated histology showing the least (0.5 years].':" Ultrastructurally, it is now recognized that the cells of carcinoid tumors contain numerous dense secretory granules of 80 to 200nm or larger," all of which contain active products synthesized by the cell. These granules, and other organelles, have been shown to contain a wide range of substances including 5-hydroxytryptamine, 5-hydroxytryptophan (5HTP), chromogranin A and C, neuron-specific enolase, and synaptophysin as well as other peptides such as growth hormone, growth hormone-releasing hormone, gastrin, calcitonin, substance P, insulin, neurotensin, and various tachykinins as well as growth factors. 2,4,6,147 Recently, cytochemical localization of chromogranin A, neuron-specific enolase, and synaptophysin has been used to further identify and classify carcinoids, particularly with regard to anatomic regions. 2,4,146/148 Chromogranin A, in particular, seems to be more specific for carcinoids than the silver stains because it detects other intracellular proteins.v!" Chromogranin A levels in serum have also been useful as a marker for carcinoid tumors. They are elevated in approximately 900/0 of patients. The level correlates with extent of tumor burden. However, neuron-specific enolase is present in the cytoplasm of most neuroendocrine cells and may be detected in the cells of other neoplasms such as fibroadenomas of the breast or certain lymphomas.t"


In the early 1960s, Williams and Sandler proposed a classification system based on the carcinoid tumor anatomic site of origin.':" This system proposed that tumors be classified into foregut (including respiratory tract and thymus), midgut, and hindgut carcinoids. This classification has become useful to the pathologist and surgeon, particularly in light of recent advances in histocytochemistry, because carcinoid tumors from these areas show differences in histology, cytochemistry, secretory products, and clinical manifestations. Foregut carcinoids are derived from the respiratory tract, stomach, proximal duodenum, and pancreas. They are generally argentaffin-negative but argyrophilic, and contain low levels of 5-HT and small cytoplasmic granules (180nm). They occasionally secrete 5-HTP or ACTH and other hormones, are associated with an atypical carcinoid syndrome, and have the potential to metastasize to bone.!" In addition, thymic carcinoids may be associated with the MEN 1 syndrome.150 Midgut carcinoids (jejunum, ileum, and right colon) are argentaffinpositive, have a high 5-HT content, and larger (230-nm) cytoplasmic granules. They rarely secrete 5-HTP or ACTH but do release 5-HT and tachykinins and do cause the classic carcinoid syndrome with metastasis. They rarely metastasize to bone. 149 Hindgut (transverse colon, left colon, and anorectum) carcinoid tumors form another distinct group. These tumors are described as being argentaffin negative, but often argyrophilic, rarely contain 5-HT, and possess round (190-nm) cytoplasmic granules of variable density. They hardly ever secrete 5-HTP or ACTH, but can contain numerous gastrointestinal hormones and rarely cause a classic carcinoid syndrome. Similar to midgut carcinoids, they rarely metastasize to bone.':" Foregut carcinoids frequently display a mixed growth pattern, whereas midgut carcinoids display the most typical morphology of insular or glandular tumor cells. Hindgut carcinoid tumors usually show a solid or trabecular histology.4,6)43,145 Recently, others have proposed an updated classification system, incorporating both histological and clinical data such as tumor size, local invasion, or presence of metastasis.l'"

Tumor Biology The exact factors involved in carcinoid tumorigenesis are largely unknown, although some suggestions have been made. Molecular mechanisms involving mutations or alterations in proto-oncogenes or tumor suppressor genes have been investigated using a transgenic mouse model."! In these studies, activation of the nuclear oncogenes n-myc and c-jun were correlated with the development of bowel carcinoids. Similarly, studies of bronchial carcinoids have detected a high level of the proto-oncogenes c-fos, c-jun, c-met, and c-myc in tumors.l'" The HER-2/neu proto-oncogene has also been reported to be overexpressed in a proportion of carcinoid tumors. 153 Putative tumor suppressor genes have been mapped to chromosome 9 and 16 in mice.!" but p53 gene mutations, or overexpression of p53 protein, have not been implicated in the development of carcinoid tumors in humans.P'"!" Some investigators have suggested that conditions promoting elevated gastrin levels and achlorhydria (see Table 58.7) also promote gastric carcinoid development'I" and that those patients with MEN 1 and ZES are at higher risk for the development of these tumors. 159-161 These observations appear to have some clinical validity.

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Although diverse in their site of origin, most carcinoid tumors are found in the jejunoileum, appendix, bronchus, rectum, and stomach although carcinoids of the larynx, thymus, ovary, testis, urethra, and gallbladder have also been described or reviewed.162-167 Tumors at each of these sites present different biochemical profiles, clinical behavior, and malignant potential. As a general rule, carcinoids synthesize, store, and secrete a wide range of substances,2,4,6)47 which tends to complicate classification and diagnosis as well as treatment.':" The presence of the classic carcinoid syndrome, the clinical manifestation of carcinoid disease, is directly related to tumor size, secretion of products into the systemic circulation, and presence of metastases.Pv'" Carcinoid tumors are generally slow-growing neoplasms, and clinical manifestation of the disease tends to increase with tumor size and metastatic behavior. 132)68 However, not all carcinoid tumors possess the same potential to metastasize and produce symptoms. The most frequent site of occurrence is the appendix, where up to 40% of tumors are found l69; these are usually small and frequently asymptomatic. Appendiceal carcinoids are usually benign. The next most common sites are the small intestine, rectum, and bronchus.l'" Small intestine carcinoids, especially those in the jejunoileum, seem to manifest the most aggressive clinical behavior.131)32)37 They may be multiple; 870/0 are present in the ileum and, although generally small, up to 35 % metastasize to regional lymph nodes and liver. 132)69 Because of this, one report found that they account for up to 87% of cases of the carcinoid syndrome, primarily by metastases to liver, whereas foregut and hindgut tumors account for up to 1 % and 80/0, respectively.F'' Occasionally midgut carcinoids with retroperitoneal invasion, ovarian and testicular carcinoids, or carcinoids of the lung, pancreas, and stomach cause the carcinoid syndrome after gaining access to systemic circulation, sometimes without local extension.168) 71 Foregut carcinoids, particularly those of the stomach and duodenum, are usually found on endoscopy.F''!" although anemia may be an associated finding."! Occasionally, cough, hemoptysis, and recurrent respiratory tract infections are associated symptoms."! These carcinoids, in contrast to those found at other sites, may be more likely to produce a variety of enteropeptides as well as the usual amine derivatives. In addition, some authors have proposed three different subtypes of gastric carcinoids based on their review of 191 tumors.'?" Two of these subtypes were associated with a hypergastrinemic state and manifested different pathological behavior than the 27 other cases with no specific association. Other authors report that gastric carcinoids may not be so rare as once thought and may constitute up to 300/0 of carcinoid tumors.!" To date, Heliobacter pylori has not been implicated in their pathogenesis. Duodenal carcinoids or neuroendocrine tumors are also associated with the ZES syndrome.' Rectal carcinoids may also be asymptomatic and discovered only on a routine screening examination, although occasionally they may cause a distal bowel obstruction. Bronchial and thymic carcinoids are asymptomatic in some, whereas approximately one-third of cases!" have pneumonia, hemoptysis, cough, or an abnormal chest radiograph. Gonadal carcinoids are usually detected as masses on physical or ultrasound examination. The release of 5-HT into the systemic circulation has long been thought to be responsible for the symptoms of the carcinoid syndrome, and numerous studies have documented

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Carcinoid tumor Tryptophan

~

S-Hydroxytryptophan (S-HTP)

Platelet

Blood vessel

Kidney

Tissues

~

S-Hydroxyindoleacetic Acid (S-HIAA) S-HT

S-HIAA

FIGURE 58.17. Illustration of the typical (left) and atypical (right) serotonergic pathway in carcinoid tumors.

both an increase in serum and platelet serotonin levels as well as urinary levels of the serotonin metabolite 5-HIAA. In these reports, 18% to 840/0 of individuals were found to have elevated 5-HT serum levels 136,168 while up to 880/0 of individuals in another study had elevated urinary levels of 5_HIAA. 170 Platelet 5-HT levels were also elevated, particularly in cases of midgut carcinoids.!" The classic carcinoid syndrome consists of signs and symptoms including facial flushing, diarrhea, diaphoresis, weight loss, right-sided cardiac valvular disease, and bronchoconstriction,3,131,138,168,l77 usually a consequence of disseminated midgut carcinoids. Foregut carcinoids, on the other hand, rarely cause the classic syndrome but may manifest an atypical carcinoid syndrome, mainly comprising a generalized flushing, headache, cutaneous edema, lacrimation, and bronchoconstriction.F" The manifestation of a typical as opposed to atypical carcinoid syndrome is thought to be a consequence of a derangement in the serotonergic pathway of the carcinoid cell (Fig. 58.17). Typically, tryptophan is converted to 5-HT during a sequential two-step reaction involving the enzymes tryptophan hydroxylase and dopa decarboxylase. The final product, 5-HT, is then released into the blood where it is taken up by tissues and platelets. 5-HT is then excreted by the kidneys in the form of 5-HIAA, its principal metabolite, after the action of tissue and blood monoamine oxidase or aldehyde dehydrogenase. In certain carcinoid tumors, there is a deficiency in dopa decarboxylase, leading to an inability to convert the intermediate 5-hydroxytryptophan (5-HTP) to the final products, 5HT. In this case, 5-HTP is released into the circulation and is eliminated unchanged in the urine. Blood 5-HT levels are usually normal in patients with atypical carcinoid syndrome, but urine levels are usually elevated because some of the 5HTP is converted to 5-HT by renal nopA decarboxylase.

Thus, patients with an atypical carcinoid syndrome usually have significantly increased urinary levels of 5-HT and 5-HTP but normal or only slightly elevated levels of 5_HIAA. 136 However, there remains an inconsistent relationship between elevated 5-HT or 5-HTP levels and symptoms caused by carcinoid disease. A number of reports have found that between 440/0 and 880/0 of individuals have symptoms of the carcinoid syndrome, such as flushing or diarrhea, whereas the majority may have elevated 5-HT levels.':" Elaboration of other products such as pancreatic polypeptide (PP), motilin, gastrin, or various prostaglandins has not, as yet, been associated with any clinical symptoms.'?" although elaboration of growth hormone-releasing factor and ACTH by foregut carcinoids have been documented as causes of acromegaly and Cushing's syndrome, respectively.l'":'?" Small cell carcinoma of the lung and medullary thyroid carcinoma have been reported as rare causes of the carcinoid syndrome.

Signs and Symptoms Approximately 400/0 to 600/0 of carcinoid tumors can be asymptomatic'i":':" and are only diagnosed after investigation of nonspecific complaints or after appendectomy. Up to 200/0 may be discovered at autopsy.F" In those that are symptomatic, the presentation varies considerably according to tumor location. As previously mentioned, foregut carcinoids are usually asymptomatic or present with upper respiratory signs and symptoms. Gastric carcinoids may present with epigastric pain or anemia, whereas midgut carcinoids, the most common location for clinical significance,132,136,137 may show signs of the carcinoid syndrome, vague abdominal pain, intestinal obstruction, or venous infarction. Occasionally, they may present with intestinal volvulus, abdominal mass, pellagra, asthma, or right-sided heart failure. The most dramatic presentation is that of the carcinoid syndrome itself, and it is usually a consequence of tumor factors gaining access to the systemic circulation, thus circumventing metabolism in the portal or pulmonary arterial circulation. Again, this depends on the primary tumor's anatomic location (such as gonads), regional extension (such as retroperitoneal or peripancreatic), and degree of metastatic spread (usually to the liver). As a general rule, patients with the classic syndrome present with diarrhea, flushing, localized, or generalized pain and right-sided endocardial involvement, ultimately producing valvular heart disease and heart failure (Tables 58.3, 58.10). Most components of the syndrome have been extensively investigated. Flushing occurs in approximately 74% of cases.l'" and appears as a deep-red erythema on the face and

TABLE 58.10. Usual Presenting Symptoms in Patients with Classic Carcinoid Syndrome. Symptom

Diarrhea Flushing Reactive airway disease Heart disease Pain Pellagra Sources: Norheim et al. (1987P70; Thorson (1958).180

Presenting (%)

32-68 23-74 4-18 41 10 5


neck accompanied by a subjective feeling of warmth, and sometimes accompanied by pruritis, palpitations, and diarrhea. It may occur spontaneously or be precipitated by alcohol or cheese ingestion, stress, catecholamines, or exercise. 137,168,178

Flushing is more common with midgut carcinoids, and the episode is usually brief initially but may become prolonged as the disease progresses. The atypical flushing associated with foregut carcinoids, especially bronchial, is usually more severe. In this case, it is more prolonged, extensive, and associated with lacrimation, subcutaneous edema, diaphoresis, and diarrhea.!" Over time, patients with atypical flushing caused by bronchial carcinoids may develop a constant reddish-blue discoloration in addition to finger clubbing.l" Gastric carcinoids may also be associated with a flushing that is pruritic but also manifests wheals and involves the arms. 136,181 The exact mechanism underlying the flushing reaction is still a matter of much debate,182,183 although it does appear that the different manifestations are dependent on the tumor type and location. Overproduction of serotonin does not appear to be involved because antagonists do not appear to abrogate the symptoms.I'
1273

failure was evident in up to 800/0 of individuals with carcinoid heart disease in some reports. 180,193 In some instances, systemic fibrosis may occur leading to retroperitoneal or intraabdominal fibrosis, sexual dysfunction in men, or even occlusion of mesenteric arteries and veins.':" Other symptoms, such as reactive airway disease, pellagra, and nonspecific abdominal pain, may also be associated with carcinoid disease. Asthma, seen in up to 180/0 of patients (see Table 58.10), is thought to be caused by the actions of both 5_HT195 and histamine as well as local inflammatory mediators. The pathophysiology of pellagra is more interesting. In this case, usurption of tryptophan by the tumor cells to effect the formation of 5-HT leads to a depletion in the total body pool of endogenous niacin, which in tum leads to the manifestation of pellagra.!" In most cases, this manifests as a sharply demarcated dermatitis involving areas exposed to chronic irritation or sunlight such as the face, hands, wrists, elbows, or knees that may progress to hyperkeratosis and scaling. The dementia component, which is rare, is usually a consequence of long-standing disease and results from degeneration in neurons of the central nervous system.

Diagnosis The presumptive diagnosis of carcinoid disease can be suspected in all patients with clinical symptoms or signs suggestive of a carcinoid tumor or carcinoid syndrome. However, the characteristic clinical presentation may not always be apparent, and symptoms such as flushing or diarrhea can also be seen in menopausal individuals, or those taking certain medications or food products, or in those with various intestinal diseases or other neuroendocrine tumors."? Because of nonspecific symptoms, the diagnosis of small intestinal carcinoids may be frequently delayed, sometimes with a median time from presentation to diagnosis of approximately 2 years.':" Simlarly, vague upper respiratory complaints referable to a bronchial carcinoid may be treated until repeated presentations force a more intensive search for the cause. Biochemical testing remains the cornerstone of diagnosis for symptomatic carcinoid tumors (see Table 58.3). The most widespread and inexpensive tests rely on the measurements of serotonin or its metabolites in urine. In this regard, the measurement of the serotonin metabolite 5-HIAA in a 24-h urine sample is commonly used.!" Patients with carcinoid tumors have increased urinary 5-HIAA excretion, in the range of 8 to 30 mg per day, but false-positive results can be seen in individuals eating certain foods, such as fruits or nuts, that have a high serotonin content.!" or in individuals taking certain analgesics or cough-suppressing medications. When used alone, urinary 5-HIAA levels have a sensitivity of around 730/0 and a specificity of 880/0 to 1000/0. 135,178,198 Some authors also recommend measuring platelet and urine 5-HT levels because this may help with biochemical diagnosis and may not be affected by diet. One study found an increased sensitivity of this method over conventional urinary 5-HIAA determinations.!" This same study also found that urinary 5-HT levels had sensitivities of 55 %, 820/0, and 600/0 for foregut, midgut, and hindgut carcinoid tumors, respectively.!" It should be remembered that, in patients with an atypical carcinoid syndrome, urinary 5-HIAA levels may not be significantly elevated because the principal metabolite in this case is 5-HTP. In this case, measurement of urinary 5-HT, platelet

1274

CHAPTER 5 8

serotonin levels, or urinary levels of tryptophan metabolites will contribute to the diagnosis.P" There have been numerous investigations into identifying serum factors that would aid in the diagnosis of carcinoid tumors. 136,147,178,lOl Most research has focused on neurotensin, substance P, and the chromogranins (A, B, and C) because these factors are usually found within tumor cells and assist in histochemical diagnosis. Most results seem to indicate that substance P and neurotensin have a sens itivity as a plasma marker for carcinoid disease of no more than 50%. Use of the chromogranins seems to have more diagnostic application. In one study of 44 patients with carcinoid tumors, 100% had elevated chromogranin A levels, 86 % had elevated chromogranin Blevels, and 5 % had elevated chromogranin C levels.202 However, use of these factors as markers for carcinoid disease is limited by their specificity because they may also be found in association with other neuroendocrine tumors.9,123,202

Localization Tumor localization is of great importance in identifying the primary tumor and its site of origin, determining presence or extent of m etastatic disease, and contributing to preoperative strategy or follow-up after surgery or chemotherapy. Virtually all radiologic techniques have been used, or are currently used , in attempts to localize and treat carcinoid disease.i'" The utility of each different modality is dependent on the tumor location and size, and up to 40% of primary and metastatic disease may not be visualized by the usual techniques.P' Chest radiography is usually the first imaging modality to detect bronchial carcinoids and is usually performed to investigate nonspecific respiratory complaints. Pv'" As the tumors are slow-growing, they may compress airways and induce an obstructive pneumonia or atelectasis and may appear as opacities with notched margins.?" CT scanning then allows for greater resolution of the lesion, and tissue for diagnosis may be obtained by bronchoscopy if the lesion is proximal in the respiratory tree. Gastric carcinoids are also usually asymptomatic and are usually diagnosed on endoscopy. Upper gastrointestinal barium contrast studies are generally nonspecific or fail to visualize the lesion. 161,206 Similarly, lower gastrointestinal contrast studies have poor sensitivity and specificity for hindgut carcinoid rumors?" but are more successful in localizing those in the cecum and ascending colon. 137,207 Ultrasonography has received renewed interest in recent years in the localization of primary as well as metastatic disease . Transabdominal US can identify about 36% of small bowel carcinoids (see Table 58.6) and 67% or more of liver metastases.'? Others have reaffirmed these results and reported a higher percentage of positive results.t'" Ultrasound may also be useful in guiding percutaneous liver biopsies of suspected lesions.P" Endoscopic ultrasound has become increasingly important in the localization of tumors, particularly colorectal carcinoids. One study has reported a 75% to 90% accuracy for depth of invasion in colorectal Iesions. i'" thus assisting in staging of the primary tumor for treatment. EUS may also be valuable in identifying local nodal involvernent.i!' The localization of midgut carcinoid disease remains a problem. The tumors are usually small and asymptomatic, or are larger and have metastasized at the time of symptomatic presentation. Usually barium studies fail to localize these

FIGURE 58.18. Computed tomography (CT) scan demonstrates the finding of a circumferential small bowel carcinoid tumor (white arrows). Regional nodal disease was read as being present (black arrow).

lesions. i" CT scanning has been used extensively in the localization of carcinoid tumors (Fig. 58.18) but images only about 44 % to 55 % of the primary lesions, with some studies reporting an 82% localization rate2l3 and others only 2%,212 Its greatest utility, and that of MR imaging, lies in the detection of metastatic disease and in monitoring medical therapy. l" Some authors have found angiography to be more sensitive than CT in localizing liver metastases. 136,212,215 SRS imaging has also been applied to carcinoid localization. Some investigations have reported that up to 88 % of carcinoid tumors possess receptors (SSTR-'l to -3) that have moderate to high affinity for somatostatin and its analogues.?" On average, SRS images 33% to 89% of carcinoid tumors.39,89,204 In some studies, it has been reported to image up to 16% of lesions not previously seen with other modalities.i" Still others have found it to have a specificity and positive predictive value of 100% with an overall accuracy of 83% .217 Because of its sen sitivity, as well as the ability to image the whole body, many regard SRS as the initial imaging procedure of choice for localizing carcinoid tumors. Beyond CT and SRS, whole body llC-5-hydroxytryptophan positron emission tomography has demonstrated superior sensitivity for neuroendocrine tumors, although this modality is not widely available.?" Another scintigraphic technique utilizes iodine-Hl metaiodobenzylguanidine (131I_MIBG) to image tumors. This agent is concentrated by a sodium-dependent membrane pump in both pheochromocytomas and carcinoids. This modality localizes about 68% of midgut and 38% of foregut carcinoids"" and has an average sensitivity of about 70% with a specificity of 95% 66 when using the iodine-l23 isotope. The utility of 131I_MIBG scanning seems to lie in its ability to localize metastatic tumor rather than as a first -line imaging modality." ?Technetium-99m bone scanning appears to be superior to other isotopic studies at imaging bony metastases.i"

Metastatic Disease and Survival Carcinoid tumors are malignant, and the presence of metastasis directly influences survival. In one multivariate analysis

NEUROENDO CRINE TUMORS OF THE PANCREAS AND GASTROINTESTINAL TRACT AND CARCINOID DISEASE

of gastrointestinal carcinoids, gender and the presence of local or distant metastases were independently predictive of death .f" A number of factors have been found to have an influence on the development of metastatic disease, the most important being the size and location of the primary tumor as well as its histological stage. 131,207,220-222 The metastatic potential of gastric carcinoids may be influenced by their particular subtype, as proposed by Rindi et al. 174 Although 54% to 66% of patients with sporadic gastric carcinoid develop metastases, advanced disease occurs in only about 9% of individuals with carcinoids and hypergastrinemia l 60,168,1 74 (Table 58.11). Tumor size is also associated with metastases. Sporadic gastric carcinoids tend to be large, single lesions with atypical histology while those found in the setting of hypergastrinemia tend to be small and multiple . Duodenal carcinoids are seldom suspected before the diagnosis is made by endoscopy .135 In one review of 99 cases, J72 there were no metastases in tumors less than 1em whereas 33 % of those more than 2 em in size had metastasized at the time of diagnosis . In addition, invasion into the muscularis propria was also found to be a strong predictor of metastatic spread . Bronchial or lung carcinoids have been found to metastasize in up to 20% of cases.l" and aggressive behavior is also dependent on the histological classification of the tumor. 174,223 In the case of jejunoileal carcinoids, if the tumor is less than 1em, metastases are usually found in 15% to 18% of cases, although one study reported a rate of 29% with these small Iesions .P' Tumors between 1 and 2cm metastasize in 60% to 80% of cases.':" and metastases are usually present with tumors larger than 2cm at the time of diagnosis . Most appendiceal carcinoids are less than 1em in size and very rarely metastasize (0%_2%1,131 but tumors between 1 and 2cm may have metastatic spread in up to 50% of cases?" The metastatic rate of colon and rectal carcinoids is particularly

1275

dependent on size. Most of these tumors are confined to the sigmoid colon and rectum. Metastatic disease can occur in 10% to 70% of patients with colon carcinoid tumors 168,225 and in virtually all when the tumor is 2cm or greater in size. Overall, about 15% of patients with rectal carcinoids have metastatic disease.168,226 Rectal tumors less than 1em metastasize in 0% to 20% of cases226 while those greater than 2cm are metastatic in virtually every case (see Table 58.11). In addition to the location of the primary tumor and presence of metastatic disease, prognosis and long-term survival may also be influenced by a number of other factors . The presence of the carcinoid syndrome is usually associated with underlying advanced disease, and the majority of patients manifesting it have distant metastases. In the past, decreased survival was associated with the onset of symptoms, and the median survival was no better than 8.5 years."? Current medical therapy, as well as aggressive debulking surgery, have made it possible for individuals with advanced metastatic disease to remain active for a longer period of time. In one analysis of a large number of cases of carcinoid disease.i" favorable prognosis was suggested by female gender, incidentally discovered tumors, absence of symptoms, small size, minimal histological tumor invasion, and absence of local or distant metastases. Overall survival rates are dependent on tumor location and size and vary among studies (see Table 58.111. One analysis of more than 2500 cases reported a 94% 5-year survival with local disease and an 18% 5-year survival with distant metastases if all sites are considered.!" In this study, appendiceallesions showed the most favorable prognosis, with 99% to 100% 5-year survival, even with regional metastases, and 27% 5-year survival with distant involvement. Others have reported a 76% to 100% 5-year survival for apendiceal carcinoids .131,227,228 Jejunoileal tumors have been reported to have

TABLE 58.11. Incidence, Metastatic Disease, and 5-Year Survival for Carcinoid Tumors at Different Anatomic Sites.

Metastatic disease Site

Foregut Bronchus /lung Thymus Gastric Sporadic Hypergastrinemia'' Duodenum Midgut Jejunum Ileum Jejunum, ileum Append ix Hindgut Colon Rectum

Reference

Level of evidence'

Incidence (%)

168 168 168 160 160 168 172

III III III III III III

12 2 2

168 168 131 168 131 130

III III III III III III

1 23

168 224 168 225

III

11

11

III III

3

38

2 3.6 13

'I, prospectiv e, randomized; II, prospective; III, retrospecti ve, review or anec dotal. "Hypergastn ncm ia indicates tumors arising in the set ti ng of hypergas tri nem ia.

2 cm

Overall

33

90

11 11

2

83

33 99 99

60 53 IS

5

52

3

83

1276

CHAPTER 58

a 5-year survival ranging between 19% and 77% depending upon the presence of local disease or distant metastases at the time of diagnosis, with overall survival for all stages being 54%.131,169 Colon tumors have been reported to have an overall 5-year survival of 52 % and rectal carcinoids an 83% overall 5-year survival.l'" However, only 70/0 to 44 % of patients with rectal disease will survive 5 years if there is evidence of nodal or hepatic metastases, compared with 92 % 5-year survival in those found to have only local disease. In the case of bronchial tumors, 5-year survival has been reported to be 96% for local disease and 11 % with distant spread (overall, 870/0 ).169 Carcinoids of the stomach have an overallS-year survival of 520/0 for all stages. Individual survival ranged from 00/0 to 93 0/0, depending on the presence of distant metastases or local disease at the time of diagnosis.

Treatment of Carcinoid Disease Medical Management and Chemotherapy Medical management of carcinoid disease involves treatment of carcinoid syndrome caused by stress, dietary elements, anesthesia, chemotherapy or spontaneous occurrence. Carcinoid crisis can be life-threatening and is marked by varying degrees of intense flushing, diarrhea, abdominal pain, altered mental status, and cardiovascular derangements, particularly hypertension or hypotension.f" Although a variety of agents have been employed to treat the carcinoid syndrome or crisis, octreotide is the only current agent with broad utility in treatment and prevention.229-232 In one report, only 7% of patients failed to respond in any way to octreotide.l" Its specificity for the type-2 somatostatin receptor (SSTR-2), which is expressed in a large proportion of carcinoid tumors, leads to a reduction in peripheral serotonin levels and a reduction in gut motility.F" In addition, it has been shown to reduce the risk of a carcinoid crisis intraoperatively.r':'!" When administered subcutaneously every 6 to 12h at a starting dose of 150J.1g, one large trial found up to a 50% improvement in diarrhea and an 82% improvement in flushing for at least 1 year. 233 The most common side effects are mild elevations in blood glucose levels and steatorrhea and are usually only seen with higher treatment doses. Gallstone formation is also a complication of long-term octreotide administration, and cholecystectomy is indicated in any patient with the malignant carcinoid syndrome. Next-generation somatostatin analogues, including SOM230, target additional somatostatin receptors and are undergoing clinical trials.r" Interferon-a is another treatment for carcinoid syndrome and metastatic disease. Initial reports described striking responses in postoperative patients. 235,236 However, long-term follow-up has reported an objective response rate on the order of 120/0 to 480/0. 237,238 The usual dosing range was 1.5 to 7mU, three to seven times per week. In studies using a higher dosage (24mU/m2/day), 39% of patients had a decrease in 5HIAA secretion, a 33 % improvement in diarrhea, and a 65 % improvement in flushing, but responses were transient.r" Combinations of interferon-a and interferon-y have been found to elicit clinical improvement in 6 of 12 patients in one study, but side effects were common, including skin lesions and profound fatigue.r" The adverse side effects of interferon

therapy, unlike those of octreotide, have limited its use. Pruritis, hair loss, fatigue, nausea, and myalgia have all been reported, and circulating antibodies to interferon-a have been detected in the blood of patients on long-term treatment.?" At present, interferon therapy has utility in patients who have failed octreotide treatment, or in combination with hepatic embolization or certain chemotherapy regimens. Other agents are used to control the symptoms of carcinoid syndrome. Antidiarrheal agents such as loperamide, selective bronchodilators, and diuretics have all been employed to control diarrhea, wheezing, or heart failure seen with advanced disease. 5-HT receptor antagonists such as ketanserin, methylsergide, and cyproheptadine have also been used to treat carcinoid syndrome with some success.t? In one report, ketanserin reduced flushing episodes in 680/0 of 31 patients and diarrhea in 75% of 29 patients.r" a-Methyldopa, which blocks the conversion of 5-HTP to serotonin, has occasionally relieved flushing in a small number of patients without any appreciable effect on gastrointestinal symptoms. Other 5-HT receptor antagonists such as ondansetron and tropisetron, as well as the a-adrenergic antagonist clonidine, have some benefit in controlling gastrointestinal symptoms.r" The type and timing of chemotherapy for malignant carcinoid tumors remains controversial. Given the indolent growth pattern of the tumor, the generally poor efficacy of chemical agents, and the ability to control symptoms of the carcinoid syndrome with octreotide or interferon, chemotherapy is usually reserved for advanced tumors. Chemotherapy for metastatic carcinoid tumors has generally had poor results, with single-agent regimens producing no more than a 300/0 transient response rate. 245 Streptozotocin (STZ), dacarbazine (DTIC), or 5-fluorouracil (5-FU) showed the largest response.P'300 pg/mL)

250-1,000 (n = 25) 1,000-5,000 (n =36) 5,000-10,000 (n = 8) >10,000 (n =23)

1 (4)

1 (4)

0

0

3 (8.3)

6 (16.7)

0

0

2 (25)

1 (12.5)

0

0

4 (17)

2 (8.7)

(%)

13 (57)

14 (61)

DM (0/0)

Death (0/0)

Preoperative CT, preoperative stimulated plasma calcitonin level; Postoperative CT, postoperative stimulated plasma CT level; RLNM, regional lymph node metastases; DM, distant metastases. *Group 1 or group 2 vs. group 4, P < 0.001. Source: Reproduced with permission from Wells et a1. 94

tion remains the most sensitive method for the detection of persistent or recurrent MTC following thyroidectomy. The basal plasma calcitonin level is related to the extent of MTC and the frequency of regional and distant metastases" (Table 59.3).

Early Thyroidectomy for Medullary Thyroid Carcinoma Based on Genetic Testing Medullary thyroid carcinoma (MTC) is the malignant feature of the MEN 2 syndromes that is responsible for almost all of the disease-related morbidity and mortality. Therefore, early detection and effective treatment of the MTC is the key to improving outcome in patients with the MEN 2 syndromes. Total thyroidectomy before regional or distant metastases of MTC is the preferred treatment, because MTC is not significantly responsive to either radiation therapy or chemotherapeutic agents."?" The ability to detect germline ret mutations in patients at risk for the MEN 2 syndromes represents a unique model for directed surgical intervention based on the results of a molecular diagnostic test.':" Patients who are determined to have inherited a ret mutation by DNA testing may undergo early surgical. extirpation of the target organ with the intent of complete removal of macro- or microscopic C-cell neoplasms while they are still confined to the thyroid gland and therefore likely curable. Total thyroidectomy may be safely performed in the first decade of life with very low morbidity and no mortality.4,99,lOo The preferred operation for patients diagnosed by genetic testing is total thyroidectomy with a lymphadenectomy in the central compartment of the neck. When early thyroidectomy is performed on the basis of genetic testing in patients with MEN 2, pathological examination of the thyroid gland typically reveals microscopic C-cell carcinoma or small gross foci of invasive MTC. 4 However, microscopic cervical lymph node metastases occur infrequently, even in the absence of elevated stimulated CT levels'?' (Table 59.4). These findings constitute the strongest argument for thyroidectomy in the first decade of life in patients with an MEN 2A-associated mutation. Patients with MEN 2B should undergo thyroidectomy as soon as the disease is recognized owing to the early onset and aggressive nature of the MTC in this syndrome. Long-term follow-up of a large cohort of MEN 2A patients undergoing early thyroidectomy based on genetic testing was

1292

CHAPTER 59

TABLE 59.4. Results of Early Thyroidectomy in Patients Inheriting a Mutation in the Ret Proto-Oncogene.

Normal preoperative stimulated CT Elevated preoperative stimulated CT Totals

Number of patients

MTC/C-cell disorder

Lympbnode metastases

Normal postoperative stimulated CT

Complications

16 12 28

16/16 12/12 28/28

1/16 0/12 1/28

16/16 12/12 28/28

0/16 0/12 0/28

MTC, medullary thyroid carcinoma ; CT, calcitonin. Source: Reproduced with permission from Lairmore et al. 101

reported by Dr. Samuel Wells group .!" A total of 50 patients underwent total thyroidectomy, central zone lymphadenectomy, and parathyroid autotransplantation based on mutational testing. A follow-up of 100% of patients 5-10 years (mean 7yrs) following surgery was achieved. A rigorous definition of "cure" was employed, namely an undetectable stimulated calcitonin level. In this study, 44/50 (88%) of patients had undetectable stimulated calcitonin levels, 4/50 (8%) had stimulated levels within normal range, 2/50 (4%) had elevated stimulated calcitonin levels 5-10 years after prophylactic thyroidectomy. A modified lateral lymph node dissection is indicated when clinically suspicious nodes are palpable on either the ipsilateral or contralateral side of the neck. In patients with MTC who present with a palpable thyroid mass, the risk of more extensive nodal metastatic disease is markedly increased. Moley and coworkers demonstrated lymph node metastases in over 75% of patients with a palpable MTC. I03 In the absence of effective non-surgical treatment for lymph node metastases in these patients, an ipsilateral functional (modified radical) lymphadenectomy has been recommended. Patients who demonstrate elevated calcitonin levels following primary surgery have evidence of residual or recurrent MTC. Because there is no established efficacy for chemotherapy or radiation therapy in these patients, reoperation and meticulous cervical and anterior mediastinal lymph node clearance can be performed with curative or palliative intent.I04,l os

Pheochromocytoma Patients with MEN 2 are diagnosed with pheochromocytoma based on the findings of signs and symptoms of catecholamine excess, elevated plasma metanephrines or 24-h urinary catecholamine excretion, and unilateral or bilateral adrenal masses on cross-sectional imaging tests. It is imperative that the presence of pheochromocytomas is excluded before performing thyroidectomy for MTC because of the anesthetic risks of unsuspected catecholamine excess. Controversy exists concerning the optimal surgical man agement of the adrenal glands in patients with the MEN 2 syndromes. Understanding the natural history and clinical significance of pheochromocytomas in patients with these disorders is essential to adopting a rational surgical approach. Preneoplastic (adrenal medullary hyperplasia) and neoplastic change of the adrenal medulla in patients with MEN 2A or MEN 2B are nearly always bilateral at the histopathological level. 106,10 7 For this reason, some experts have advocated routine bilateral adrenalectomy for patients with MEN 2A or MEN 2B, whether or not both adrenal glands contain a pheochromocvtoma.Fr!" The rationale for total adrenalectomy is based on the arguments that (1) adrenal medullary disease in patients with the MEN type 2 syndromes is frequently bilateral, (2) there is a high likelihood of subsequent development

of another pheochromocytoma in the contralateral gland if it is not removed at the initial operation, (3) the pheochromocytoma may rarely malignant, and (4) the permanent Addisonian state resulting from bilateral adrenalectomy is infrequently associated with complications. Our group and others have recommended a selective approach 11 1,112 with excision only of those adrenal glands containing a grossly evident pheochromocytoma at the time of intervention. The proponents of a selective approach empha size that the risk of developing a pheochromocytoma in the opposite gland must be weighed against the risk of producing a lifelong Addisonian state by the performance of bilateral adrenalectomies. Tibblin and coworkers'!' in 1983 reported 13 patients with MEN 2A who were followed for a mean of 7.4 years after a unilateral adrenalectomy for pheochromocytoma. Four patients (31%) subsequently developed a pheochromocytoma in the opposite gland at I, 2, 4, and 10 years following the primary adrenalectomy. The remaining 9 (69%) patients had no evidence of pheochromocytoma during the follow-up period. Our group reported the results of unilateral or bilateral adrenalectomy in a series of 58 patients with pheochromocytomas arising in patients with MEN 2A or MEN 2B.112 Twenty-three patients with a unilateral pheochromocytoma and a grossly normal contralateral gland were treated by unilateral adrenalectomy. A pheochromocytoma developed in the remaining gland a mean of 11.9 years after the primary adrenalectomy in 12 (52%) patients. Conversely, 11 (48%) patients did not develop a second pheochromocytoma during a mean follow-up period of 5.2 years (Table 59.5). No patient treated by unilateral adrenalectomy experienced a hypertensive crisis or other complication related to an unrecognized functioning pheochromocytoma, including several patients who underwent childbirth or general anesthesia. Conversely, almost 25 % of the patients undergoing total adrenectomy experienced at least one episode of Addisonian crisis requiring hospital admission and treatment with intravenous saline and corticosteroids. Therefore, the argument in favor of a selective approach includes the observation that approximately half these patients will not develop a pheochromocytoma in the opposite adrenal gland for at least TABLE 59.5. Development of a Contralateral Pheochromocytoma After Unilateral Adrenalectomy (Level II Evidence).

No contralateral pheochromocytoma Contralateral pheochromocytoma Total

Number of patients (%)

Mean follow-up (years)

11 (48) 12 (52) 23

5.2 ± 1.9 11.9 ± 2.0 9.4 ± 1.0

Source: Reproduced with permission from Lairmore et al. l 12

1293

MULTIP LE END O CRINE NEO PLA SIA

.JIIl7'_ _

TABLE 59.6. Results of Operation for Hyperparathyroidism in Patients with MEN 2A (Level II Evidence).

Author

Year

van He erden et al. Kraimps et al. O'Riordian et al. Raue et al.

1983 1992 58 1993 120 1995 121

H erfart h et al.

1996 86

59

No. of MEN 2A patients

9 4 18 67 49 11 35 2.9 5

Type of resection

Subtotal/selective" Selective Overall Overall Selective/subtotal Total PTX/AT Overall Selective/subtotal Total PTX/AT

Persistent or recurrent

Permanent hypocalcemia

(%)

Cure-initial/ follow-up

13' 0

13' 2.5 2.2. 13 16 9 2.3 17 2.0

93/87 100/100 100/100 97/85 96/84 100/82. 91/77 72. 100/ 100

HPT(%)

a

15 16 18 2.3 2.8

a

Follow-up (years)

3.6 (mean)' 8.0 [median]" 5.8 (median) 8.0 (median' 14.7Imean) 14.4lmean) 16.3Imean)

HPT, hyperparathyroidism; PTX, parathyroidectomy; AT, autotransplantation. 'Thirty-six MEN I and 9 MEN 2A patients combined. "Pollow-up combined with 38 MEN I patients. Source: Reproduced with permission from Herfarth et al."

10 years, and perhaps many never will . The development of a second pheochromocytoma is readily detectable by clinical, biochemical, and radiographic evaluation. Finally, in our experience unnecessary bilateral adrenalectomy is associated with substantial morbidity. Although some studies have reported the occurrence of malignant pheochromocytomas in patients with MEN 2,107 other series suggest that malignancy is very infrequent in this setting.108,109,1ll,112 However, the risk of a malignant pheochromocytoma should not be totally dismissed, and bilateral adrenalectomy may be appropriate for members of families with a clear history of malignant pheochromocytoma. Patients with pheochromocytoma are prepared preoperatively with an alpha-adrenergic blocker to control hypertension and permit reexpansion of intravascular volume. Typically, phenoxybenzamine is initiated at a dose of lOmg orally BID and increased to 20 to 40mg orally BID over 5 to 10 days preoperatively with concomitant rehydration. The development of postural hypotension is the desired and expected endpoint. In addition, adequately prepared patients will have correction of their mild lactic acidosis . Patients may undergo alpha blockade in the outpatient setting, and should be instructed to take oral fluids liberally and watch for the expected postural changes. Laparoscopic adrenalectomy is now the standard of care for removal of benign, functional adrenal tumors.'!"!" Patients with MEN 2A and 2B may be ideally suited to laparoscopic adrenalectomy because the pheochromocytomas arising in these syndromes are rarely malignant and are almost never extraadrenal. 112 Unilateral or bilateral laparoscopic adrenalectomies are appropriate treatment provided the adrenal tumor(s) are small, confined to the adrenal gland, accurately localized preoperatively by CT or MRI scanning, and the patient is adequately prepared pharmacologically. Laparoscopic adrenalectomy is associated with a shorter hospital stay, decreased postoperative pain, and more rapid recovery when compared with open adrenalectomy.l'v'lv'" Contraindications to the laparoscopic approach include large benign tumors (>8em), malignant pheochromocytomas, and existing contraindications to laparoscopy .

Hyperparathyroidism The appropriate management of the parathyroid glands in MEN 2 patients undergoing thyroidectomy for inherited MTC remains controversial. Our group has recommended total parathryoidectomy and autotransplantation of parathyroid tissue into the forearm muscle, especially in patients undergoing early thyroidectomy based on genetic testing.s6,86 The rationale for performing total parathyroidectomy and autotransplantation is to minimize permanent postoperative hypoparathyroidism (the blood supply to the parathyroid glands may be inadvertently compromised during radical total thyroidectomy) and to prevent the need for neck reexploration, which carries substantial morbidity, in the small subset of patients who develop hyperparathyroidism during the lifetime period of risk. Other experts argue that selective parathyroidectomy is effective in almost all patients and that routine total parathyroidectomy with autotransplantation results in an increased rate of permanent postoperative hypoparathyroidism (Table 59.6).120,121

Conclusion Germline genetic alterations in oncogenes, tumor suppressor genes, and DNA mismatch repair genes are associated with the development of familial cancer syndromes. The unraveling of the basic genetic defects responsible for the development of multiple endocrine tumors in the familial endocrine neoplasia syndromes has provided insight into the common mechanisms of tumorigenesis in more common sporadic neoplasms that arise in the same endocrine tissues. The endocrine neoplasms that develop in patients with the MEN types 1 and 2 syndromes are generally managed by surgical intervention. Because neoplasms that arise in the setting of a familial cancer syndrome are characterized by multifocality and an earlier age of onset when compared with their sporadic counterparts, the approach to diagnosis and treatment of these tumors requires special considerations.

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Direct DNA testing for mutations in the MENl tumor suppressor gene allows for a genetic test in patients at risk. The principal clinical challenge in the management of patients with an MENl mutation will be to develop effective cancer surveillance and screening programs and to implement optimal early surgical intervention for the pancreatic and duodenal neuroendocrine tumors that are responsible for the majority of the disease-related morbidity and mortality. Early thyroidectomy based on genetic testing for patients at risk for one of the MEN 2 syndromes is now the standard of clinical care. This goal of this operation is to remove the end organ at a time when hereditary MTC is generally confined to the thyroid gland and therefore amenable to cure by surgical resection.

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MULTIPLE ENDOCRINE NEOPLASIA

39. Grant CS, van Heerden J, Charboneau JW, et al. Insulinoma: the value of intraoperative ultrasonography. Arch Surg 1988;123:843848. 40. Norton JA, Cromack DT, Shawker TH, et al. Intraoperative ultrasonographic localization of islet cell tumors. Ann Surg 1988;207:160-168. 41. Doherty GM, Doppman JL, Shawker TH, et al. Results of a prospective strategy to diagnose, localize, and resect insulinomas. Surgery (St. Louis) 1991;110:989-996. 42. Marx S, Spiegel AM, Skarulis MC, et al. Multiple endocrine neoplasia type 1: clinical and genetic topics. Ann Intern Med 1998;129:484-494. 43. Duh Q-Y. Carcinoids associated with multiple endocrine neoplasia syndromes. Am J Surg 1987;154:142-148. 44. Chandrasekharappa SC, Guru SC, Manickamp P, et al. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 1997;276:404-407. 45. Guru SC, Goldsmith PK, Burns AL, et al. Menin, the product of the MENl gene, is a nuclear protein. Proc Natl Acad Sci USA 1998;95:1630-1634. 46. Mutch MG, Dilley WG, Saniurjo F, et al. Germline mutations in the multiple endocrine neoplasia type 1 gene: evidence for frequent splicing defects. Hum Mutat 1999;13(3):175-185. 47. Olufemi SE, Green JS, Manickam P, et al. Common ancestral mutation in the MENl gene is likely responsible for the prolactinoma variant of MEN 1 (MENI Burin) in four kindreds from Newfoundland. Hum Mutat 1998;11:264-269. 48. Kassem M, Kruse TA, Wong FK, et al. Familial isolated hyperparathyroidism as a variant of multiple endocrine neoplasia type 1 in a large Danish pedigree. J Clin Endocrinol Metab 2000; 85:165-167. 49. Agarwal SK, Guru SC, Heppner C, et al. Menin interacts with the API transcription factor JunD and represses JunD-activated transcription. Cell 1999 j96:143-152. 50. GobI AE, Berg M, Lopez-Egido JR, et al. Menin represses JunDactivated transcription by a histone deacetylase-dependent mechanism. Biochim Biophys Acta 1999 jI447(1):51-56. 51. Lemmens IH, Forsberg L, Pannett AA, et al. Menin interacts directly with the homeobox-containing protein Pem. Biochem Biophys Res Commun 2001;286(2):426-431. 52. Heppner C, Bilimoria KY, Agarwal SK, et al. The tumor suppressor protein menin interacts with NF-kappaB proteins and inhibits NF-kappaB-mediated transactivation. Oncogene 2001; 20(36):4917-4925. 53. Kaji H, Canaff L, Lebrun H, et al. Inactivation of menin, a Smad3interacting protein, blocks transforming growth factor type beta signaling. Proe Nat! Aead Sci USA 2001;98(7):3837-3842. 54. Ohkura N, Kishi M, Tsukada T, Yamaguchi K. Menin, a gene product responsible for multiple endocrine neoplasia type 1, interacts with the putative tumor metastasis protein nm23. Biochim Biophys Res Commun 2001;282(5):1206-1210. 55. Rizzoli R, Green 1, Marx SJ. Long-term follow-up of serum calcium levels after parathyroidectomy. Am J Med 1985;78:467473. 56. Wells SA Ir, Farndon JR, Dale JK, et al. Long term evaluation of patients with primary parathyroid hyperplasia managed by total parathyroidectomy and heterotopic autotransplantation. Ann Surg 1980;192:451-458. 57. Hellman P, Skogseid B, Juhlin C, et al. Findings and long term results of parathyroid surgery in multiple endocrine neoplasia type 1. World J Surg 1992 jI6:718-723. 58. Kraimps JL, Duh Q-Y, Demeure M, Clark OH. Hyperparathyroidism in multiple endocrine neoplasia syndrome. Surgery (St. Louis) 1992;112:1080-1088. 59. van Heerden JA, Kent RB, Sizemore GW, et al. Primary hyperparathyroidism in patients with multiple endocrine neoplasia syndromes: surgical experience. Arch" Surg 1983;118:533536.

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60. Elaraj DM, Skarulis MC, Libutti SK, et al. Results of initial operation for hyperparathyroidism in patients with multiple endocrine neoplasia type 1. Surgery (St. Louis) 2003;134(6):858864 j discussion 864-865. 61. Lairmore TC, Chen VY, DeBenedetti MK, et al. Duodenopancreatic resections in patients with multiple endocrine neoplasia type 1. Ann Surg 2000;231:909-918. 62. Thompson NW, Lloyd RV, Nishiyama RH, et al. MEN I pancreas: a histological and immunohistochemical study. World J Surg 1984;8:561-574. 63. Skogseid B, Eriksson B, Lundqvist G, et al. Multiple endocrine neoplasia type 1: a 10-year prospective screening study in four kindreds. J Clin Endocrinol Metab 1991;73:281-287. 64. Skogseid B, Grama D, Rastad J, et al. Operative tumour yield obviates preoperative pancreatic tumour localization in multiple endocrine neoplasia type 1. JIntern Med 1995 j238:281288. 65. Skogseid B, Oberg K. Experience with multiple endocrine neoplasia type 1 screening. J Intern Med 1995 j238:255-261. 66. Doppman JL. Multiple endocrine neoplasia syndromes. A nightmare for the endocrinologic radiologist. Semin Roentgenol 1985;20:7-16. 67. Skogseid B, Oberg K, Benson L, et al. A standardized meal stimulation test of the endocrine pancreas for early detection of pancreatic endocrine tumors in multiple endocrine neoplasia type 1 syndrome: Five years experience. J Clin Endocrinol Metab 1987;64:1233-1240. 68. Lairmore TC. Complications in endocrine pancreatic surgery. In: Mulholland M, Doherty G, eds. Complications in Surgery. Philadelphia: Lippincott Williams & Wilkins, 2005. 69. Sipple JH. The association of pheochromocytoma with carcinoma of the thyroid gland. Am J Med 1961;31:163-166. 70. Steiner AL, Goodman AD, Powers SR. Study of a kindred with pheochromocytoma, medullary thyroid carcinoma, hyperparathyroidism and Cushing's disease: multiple endocrine neoplasia type 2. Medicine (Baltim) 1968;47:371-409. 71. Howe JR, Norton JA, Wells SA Jr. Prevalence of pheochromocytoma and hyperparathyroidism in multiple endocrine neoplasia type 2A: results of long-term follow-up. Surgery (St. Louis) 1993;114:1070-1077. 72. Williams ED, Pollack DJ. Multiple mucosal neuromata with endocrine tumours: a syndrome allied to von Recklinghausen's disease. J Pathol Bacteriol 1966 j91:71-80. 73. Schimke RN, Hartmann WH, Prout TE, Rimoin DL. Syndrome of bilateral pheochromocytoma, medullary thyroid carcinoma and multiple neuromas. N Engl J Med 1968 j279:1-7. 74. Farndon JR, Leight GS, Dilley WG, et al. Familial medullary thyroid carcinoma without associated endocrinopathies: a distinct clinical entity. Br J Surg 1986;73:278-281. 75. Trupp M, Arenas E, Fainzilber M, et al. Functional receptor for GDNF encoded by the c-ret proto-oncogene. Nature (Lond) 1996 j381:785-789.

76. Durbec P, Macos-Gutierrez CV, Kilkenny C, et al. GDNF signalling through the Ret receptor tyrosine kinase. Nature (Lond) 1996 j381 : 789-793. 77. Iing S, Wen D, Yu Y, et al. GDNF-induced activation of the ret protein tyrosine kinase is mediated by GDNFR-a, a novel receptor for GDNF. Cell 1996 j85:1113-1124. 78. Pachnis V, Mankoo B, Costantini F. Expression of the c-tet proto-oncogene during mouse embryogenesis. Development (Cambr) 1993 j119:1005-1017. 79. Avantaggiato V, Dathan NA, Grieco M, et al. Developmental expression of the RET protooncogene. Cell Growth Differ 1994;5:305-311. 80. Schuchardt A, D' Agati V, Larsson-Blomberg L, et al. Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret. Nature (Lond) 1994;367:380383.

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81. Edery P, Lyonnet S, Mulligan LM, et al. Mutations of the RET proto-oncogene in Hirschsprung's disease. Nature (Lond) 1994;367:378-380. 82. Romeo G, Ronchetto P, Luo Y, et al. Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung's disease. Nature (Lond) 1994;367:377-378. 83. Pasini B, Borrello MG, Greco A, et al. Loss of function effect of RET mutations causing Hirschsprung disease. Nat Genet 1995;10:35-40. 84. Santoro M, Carlomagno F, Romano A, et al. Activation of RET as a dominantly transforming gene by germline mutations of MEN2A and MEN2B. Science 1995;267:381-383. 85. Mulligan LM, Eng C, Healey CS, et al. Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. Nat Genet 1994;6:70-74. 86. Herfarth KK-F, Bartsch D, Doherty GM, et al. Surgical management of hyperparathyroidism in patients with multiple endocrine neoplasia type 2A. Surgery (St. Louis) 1996;120:966-974. 87. Carlson KM, Dou S, Chi D, et al. Single missense mutation in the tyrosine kinase catalytic domain of the RET proto-oncogene is associated with multiple endocrine neoplasia type 2B. Proc Natl Acad Sci USA 1994;91:1579-1583. 88. Smith DP, Houghton C, Ponder BAJ. Germline mutation of RET codon 883 in two cases of de novo MEN 2B. Oncogene 1997;15:1213-1217. 89. Carlson KM, Bracamontes J, Jackson CE, et al. Parent-of-origin effects in multiple endocrine neoplasia type 2B. Am J Hum Genet 1994;55:1076-1082. 90. Eng C, Smith DP, Mulligan LM, et al. A novel point mutation in the tyrosine kinase domain of the RET proto-oncogene in sporadic medullary thyroid carcinoma and in a family with FMTC. Oncogene 1995;10:509-513. 91. Bolino A, Schuffenecker I, Luo Y, et al. RET mutations in exons 13 and 14 of FMTC patients. Oncogene 1995;10:2415-2419. 92. Tashjian AH Jr, Howland BG, Melvin KEW, Hill CS Jr. Immunoassay of human calcitonin: clinical measurement, relation to serum calcium and studies in patients with medullary carcinoma. N Engl J Med 1970;283:890-895. 93. Wells SA Ir, Baylin SB, Linehan WM, et al. Provocative agents and the diagnosis of medullary carcinoma of the thyroid gland. Ann Surg 1978;188:139-141. 94. Wells SA, Jr., Baylin SB,Leight GS, et al. The importance of early diagnosis in patients with hereditary medullary thyroid carcinoma. Ann Surg 1982;195:595-599. 95. Gottlieb JA, Hill CS. Chemotherapy of thyroid cancer with Adriamycin. N Engl J Med 1974;290:193-197. 96. Steinfeld AD. The role of radiation therapy in medullary carcinoma of the thyroid. Radiology 1977;123:745-746. 97. Tubiani M. External radiotherapy and radioiodine in the treatment of thyroid cancer. World J Surg 1981;1981:75-84. 98. Lips CJM, Landsvater RM, Hoppener JWM, et al. Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A. N Engl J Med 1994;331:828-835. 99. Skinner MA, DeBenedetti MK, Moley JF,et al. Medullary thyroid carcinoma in children with multiple endocrine neoplasia types 2A and 2B. J Pediatr Surg 1996;31:177-182. 100. Lairmore TC, Frisella MM, Wells SA Jr. Genetic testing and early thyroidectomy for inherited medullary thyroid carcinoma. Ann Med 1996;28(5):401-406. 101. Lairmore TC, Frisella MM, Wells SAJ. Genetic testing and early thyroidectomy for inherited medullary thyroid carcinoma. Ann Med 1996;28:401-406. 102. Skinner MA, Moley JF, Dilley WG, Owzar K, DeBenedetti MK, Wells SA Jr. Prophylactic thyroidectomy in multiple endocrine neoplasia type 2A. NEJM 2005;353:1105-1113. 103. Moley JF, DeBenedetti MK. Patterns of nodal metastases in palpable medullary thyroid carcinoma: recommendations for extent of node dissection. Ann Surg 1999;229(6):880-887; discussion 887-888.

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SECTION SIX

Vascular Surgery

History of Vascular Surgery Jesse E. Thompson The Anci ents The Renaissance Eighteenth and Nineteenth Centuries Suture of Blood Vessels Aortic Aneurysms: Early Experience Basic Supports to Vascular Surgery Aortic Aneurysms: Recent Experience Vascular Prostheses Ruptured Aneurysms Thoracic Aneurysms Thoracoabdominal Aneurysms Arterial Occlusive Disease

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T

he past 50 years have witnessed the most spectacular period of growth and development of vascular surgery during its long and fascinating history. As in all matters, the basis for today's modem vascular surgery rests on achievements from the past. As Thomas Carlyle said, "History is the essence of innumerable biographies ." Vascular surgery has a number of supporting pillars : these include anesthesia, antisepsis, asepsis , antibiotics, blood transfusion, anticoagulants, angiography, vascular sutures, and vascular grafts. Vascular surgery itself comprises many elements. Many nationalities have been involved as well as numerous individuals. Developments in industrial and technical fields outside medicine have also played important roles. In this chapter, because of constraints of space, the author has been selective and many contributions of necessity have been omitted. The reader interested in more historical details may consult the writings of Barker, DeBakey, Friedman, Haimovici, Rob, Shumacker, Smith, and others."!'

The Ancients Studies of Egyptian mummies have revealed that atherosclerosis and arterial calcification were prevalent 3500 years ago. Marc Armand Ruffer in 1911 published his findings, in Egyptian mummies of the period 1580 BC to AD 525, that atherosclerotic lesions, similar to present-day lesions, were relatively comrnon.P The Ebers Papyrus is among the earliest medical writings, thought to have been prepared around 2000 BC. Th e writer has clearly identified arterial aneurysms, probably peripheral aneurysms, and recommends the following treatment: "treat it with a knife and bum it with a fire so that it bleeds not too much. "!'

In Situ Saphenous Bypass Fluids Embolectomy Sympathectomy Extraanatomic Procedures Renal and Mesenteric Lesions Cerebrovascular Disease Venous Surgery Vascular Injuries Vascular Disorders References

1305 1305 1306 1306 1306 1306 1307 1310 1311 1312 1312

Antyllus, who lived in the second century AD, mentioned the ligature, although the ligature was not brought to light again until resurrected by Ambroise Pare in the sixteenth century. Antyllus treated aneurysms by applying ligatures to the arteries entering and leaving the aneurysm, cutting into the sac, and packing the cavity . Although bleeding was common, this method held until the time of John Hunter in the eighteenth century."

The Renaissance Very few advances were made in the treatment of aneurysms during the ensuing millenium. Ambroise Pare (1510-1590) was the greatest surgeon of the Renaissance. In 1536 he discontinued the use of boiling oil and cautery in stopping hemorrhage. Although he did not invent the ligature, he was a staunch advocate of its use and by 1552 was applying it to control hemorrhage in extremity amputations. To Pare is owed the famous remark made when he was congratulated on the cure of a difficult case: "1treated him, God cured him." His work on gunshot and other wounds published in 1545 is an important contribution. Pare advocated the application of a proximal ligature to aneurysms, but did not believe the sac should be opened because of the danger of severe and fatal hemorrhage. Pare also described a ruptured aneurysm of the thoracic aorta and stated, "The aneurismaes which happened in the intemale parts are uncurable.v'P :" Another giant of the Renaissance was Andreas Vesalius (1514-1564). On the basis of work in the anatomy dissection room, he threw over the superstitions regarding anatomy and put the field once and for all on a scientific basis . His magnificent book, De Fabrica Humani Corporis, published in 1543 1299

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when he was 29 years old, is one of the great medical books of all times. Vesalius was the first to diagnose and describe, in 1555, aneurysms of the abdominal and thoracic aorta. " Matheus Purmann operated on an antecubital space aneurysm in 1680, ligated the artery above and below the aneurysm, and removed the sac. In medieval times the antecubital fossa aneurysm was quite common as a complication of blood letting by puncture of the median basilic vein. 1 An important problem needing solution was circulation of the blood. It was the genius of William Harvey (1578-16571 that completed the answer to this problem. His book, De Motu Cordis, was published in 1628.16

Eighteenth and Nineteenth Centuries The first of the great surgeons of this era was John Hunter (1728-1793), a Scotsman who went to London in 1748. He was one of the great surgeons of all time, the founder of scientific surgery based on anatomy and physiology. His contributions to vascular surgery were basic. In addition to his clinical observations, he studied the development of collateral circulation when main arteries were occluded, which led to his method of treating aneurysms. On December 12, 1785, he ligated the superficial femoral artery high in the thigh in the area known as Hunter's canal to treat a popliteal aneurysm. The patient did well, the aneurysm shrunk down to a hard knot, and the limb survived. The specimen of Hunter's first case is in the Hunterian Museum in London. Hunter's method was the first major innovation in the treatment of popliteal aneurysms since the Antyllus operation of the second century, a lapse of 1600 years. His method lasted for another 100 years until the method of Rudolph Matas was developed in 1888. Hunter had angina pectoris and said, "My life is in the hands of any rascal who chooses to annoy and tease me ." During a heated argument at a board meeting of St. George's Hospital in London on October 14, 1793, Hunter had a fatal heart attack, dying at the age of 65.17 Astley Cooper (1768-1841) was one of the great English surgeons of the late eighteenth and first half of the nineteenth century. Cooper made contributions in many fields of surgery, but his name is permanently linked to advances in vascular surgery (Fig. 60.1). In 1817 he was called to see a man in extremis who had a leaking iliac aneurysm. He decided that the only possible treatment was to ligate the aorta above the aneurysm. Through a small transperitoneal incision he managed to get his finger around the aorta, and then with an aneurysm needle passed a single ligature around the vessel, which was then tied. The patient's right leg remained viable, but the left leg was totally ischemic, livid, and cold, and the patient died 40 h later. This was the first recorded case of ligation of the aorta for aneurysm. The specimen of Cooper's operation is preserved in the Department of Surgery at St. Thomas's Hospital in London. " Valentine Mott (1785-1865), of New York City, was one of the most outstanding American surgeons during the first half of the nineteenth century. He has been called by Rutkow the "father of American vascular surgery." He was best known for his contributions to vascular surgery, which at that time consisted largely of arterial ligations and amputations.Pr" In the ligation of arteries Valentine Mott was without peer. In all, he performed 138 ligations of the great vessels for treat-

FIGURE 60.1. Sir Astley Cooper.

ment of aneurysms. The operation that thrust Valentine Mott into prominence was the first ligation of the innominate artery on May II, 1818, for a traumatic subclavian aneurysm. Although the patient did well at first, he died of infection on the 26th postoperative day. The first successful ligation of the innominate artery for subclavian aneurysm was performed by Andrew Woods Smyth at the Charity Hospital in New Orleans on May IS, 1864, 46 years later. I Another spectacular operation performed by Mott was the first successful ligation of the common iliac art ery for a traumatic aneurysm of the right external iliac artery on March 15, 1827, performed through a retroperitoneal approach."

Suture of Blood Vessels Arterial repair was slow to develop . In 1759 Hallowell, at the suggestion of Richard Lambert, in treating a brachial artery injured during phlebotomy, closed the laceration by running a short steel pin through the edges of the wound and passing a figure-of-eight ligature around it to approximate the wound edges. Later Asman attempted to repeat the procedure in animals, without success . Arterial repair was not used again for about 100 years. It was left for Iassinowsky in 1891 to report success in suturing arteries. His sutures avoided penetrating the intima. Dorfler in 1899 modified Iassinowsky's method by passing the suture through all areas of the artery wall. He was the first to note that penetration of the intima did no harm, did not lead to thrombosis, and was soon covered by a glistening membrane. In 1896, [aboulay and Briau described successful end-to-end anastomosis of the carotid using an inverted V-shaped suturey-6,8,21 J.B. Murphy of Chicago, after a series of animal experiments on arterial and venous repair, on October 7, 1896 successfully united the ends of the femoral artery injured by a

HISTORY O F VA S CU LAR SURGERY

gunshot wound. He excised the damaged section of the artery, invaginated the proximal end into the distal vessel, and held it in place with sutures, the first successful circular suture in a human." The individual who established the modem technique of suturing blood vessels in the opening days of the twentieth century was Alexis Carrel. A Frenchman, he came to the United States in 1905, worked first in Chicago with c.c. Guthrie, and then from 1906 to 1939 at the Rockefeller Institute for Medical Research in New York City. He revolutionized the surgery of the vascular system with a meticulous technique in which he triangulated the arteries and sutur ed them end to end with fine needles and suture materials. From end-to-end anastomosis, he advanced to grafting of arteries using a vein, and then he proceeded to the transplantation of organs from animal to animal. He developed the patch graft technique of reconstruction. Carrel also pioneered in the preservation of blood vessels in cold storage so that such preserved arteries could be used days or weeks after harvesting from the donor animals.P Alexis Carrel developed a very close friendship with Charles Lindbergh because Carrel was attempting to devise a pump for organ perfusion. Charles Lindbergh became his collaborator and devised a pump that was used for a number of years at the Rockefeller Institute for preserving organs . This device may be considered to be the first pump oxygenator or mechanical heart.f Following the technical lead of Carrel, Jose Goyanes, a Spaniard, in 1906 performed the first successful vein graft for treatment of popliteal aneurysms. His graft was a venous autograft of in situ popliteal vein adjacent to the diseased artery. Circulation to the extremity was preserved.P Some 6 months later in 1907, Eric Lexer in Germany repaired a large traumatic false aneurysm in the axilla with a segment of the greater saphenous vein removed from the patient's leg. The patient died 5 days later of delirium tremens with a patent graft. Lexer later repeated the operation successfully many times." In Scotland, J. Hogarth Pringle in 1913 reported two successful vein grafts for popliteal and brachial aneurysms.P In the United States, Bertram Bernheim of the Johns Hopkins Hospital in 1913 published a monograph on vascular surgical techniques. In 1915 he removed a popliteal aneurysm and replaced it with a 12-cm segment of saphenous vein, probably the first American to perform thi s procedure successfully." William S. Halsted and his group at Johns Hopkins had a long and abiding interest in vascular problems, especially vascular trauma and aneurysms. Halsted devised an apparatus for metallic banding of arteries to produce gradual occlusion, a method that failed, usually because of hemorrhage."

Aortic Aneurysms: Early Experience During the 100 years after Cooper, several attempts were made to ligate the aorta but all the patients died, until April 9,1923, when Rudolph Matas (1860-19571successfully ligated the abdominal aorta in the treatment of an abdominal aneurysm. The patient survived the operation but died 18 months later of pulmonary tuberculosis." By 1940 Dan Elkin was able to identify only 24 recorded cases of ligation in the world literature, to which he added 1 of his own, and in only 5 cases was the operation a success."

1301

FIGURE 60.2. Rudolph Matas . (From the collection of Dr. Isidore Cohn.]

Rudolph Matas of New Orleans was a pioneer in vascular surgery . He made many contributions to all areas of surgery, but in vascular surgery he is best remembered for his operation of endoaneurysmorrhaphy (Fig. 60.2), which he first performed on May 6, 1888, for a large traumatic brachial artery aneurysm of the left arm. Following ligation of the proximal and distal arteries, an incision was made into the aneurysm and the clot removed. The orifices of the blood vessels entering the sac were then sutured from within, thus preserving the collateral blood supply to the extremity. This operation reduced markedly the incidence of gangrene and amputation that followed in a high percentage of patients undergoing the Hunterian ligation for popliteal aneurysm. This principle is still employed." William Osler, in his 16 years at the Johns Hopkins Hospital from 1889 to 1904, saw only 17 cases of abdominal aortic aneurysm, an average of 1 per year." Over the years a number of methods have been used in an effort to treat aortic aneurysms. These techniques, designed either to cause thrombosis of the aneurysm or to fibrose the wall to prevent rupture, included needling, wiring, proximal banding, ligation, and cellophane wrapping, to mention a few. C.H. Moore, a British surgeon from Middlesex Hospital, in 1864 introduced wiring of aneurysms by inserting either silver, iron, steel, or copper wire in an effort to thrombose the aneurysm. Corradi from Pavia in 1879 attached Moore's wires to a battery in an attempt to induce coagulation. Results were dismal, with only an occasional reported cure. 3 •3 1 The principle persisted, however, and was brought to its culmination by Arthur Blakemore of New York, who advocated progressive constrictive occlusion of the abdominal aorta with a rubber band wrapped with polythene rum proximal to the aneurysm, followed by insertion of wire and electrothermic coagulation with 100 V direct current. Blakemore's final major presentation of this method was given in 1952.32

Basic Supports to Vascular Surgery Thus, shortly after the end of the nineteenth century, all the techniques necessary for suturing, anastomosing, and grafting arterial vessels had been developed. Clearly, technical

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advances had outdistanced diagnostic methods and the supporting disciplines necessary for successful vascular surgery . The explosive development of vascular surgery awaited improvements in anesthesia, the evolution of angiography, the introduction of suitable anticoagulants, especially heparin, safe blood transfusion, the discovery of antibiotics, and the invention of satisfactory arterial substitutes and nontraumatic instruments and suture materials. A major pillar was the discovery of inhalation anesthesia in the 1840s, so named by Oliver Wendell Holmes. Crawford Long in Georgia, William Thomas Green Morton and John Collins Warren in Boston, and Horace Wells of Hartford should all be mentioned. The first public demonstration of ether anesthesia was made at the Massachusetts General Hospital on October 16, 1846.33 The next great influence was the elimination of infection. Joseph Lister's work was published in 1867, based on that of Louis Pasteur. Finally came the discovery and development of antibiotics by Fleming, Chain, and Florey, for which they shared the Nobel Prize in 1945.34 Another pillar supporting modem vascular surgery is the transfusion of blood. It remained for Karl Landsteiner and his group at the Rockefeller Institute to distinguish, in 1901and 1902, the four human blood groups. Landsteiner received the Nobel Prize in 1930.16 Methods of administering blood have also evolved in a most interesting manner. Early on, a direct transfusion from one individual to another was the usual method. One of the pioneers in direct transfusion was the American Dr. George Crile of Cleveland, who in 1906 described his method." Another important pillar was the use of anticoagulants, especially heparin. Howell, McLean, and Gordon Murray in the years between 1916 and 1940 were involved with the discovery, extraction, and clinical application of heparin .':' If the topics just mentioned are the pillars of vascular surgery, then its cornerstone is arteriography. Wilhelm Konrad Roentgen on November 8, 1895, first observed the new rays that were to bear his name and become the basis of our diagnostic armamentarium. Roentgen won the Nobel Prize for this discovery in 1901.36 In 1923, Barney Brooks of Nashville initiated clinical angiography by injecting sodium iodide and studied the femoro popliteal system." Egas Moniz of Portugal first performed cerebral arteriography in 1927. Another Portuguese physician, Reynaldo Dos Santos, in 1929 first reported translumbar aortography ." In 1953, Seldinger reported the technique of retrograde femoral catheter in jection to visualize the vessels using local anesthesia. These pioneering achievements have evolved into today's sophisticated methods of visualizing all the vessels in the body." The development of satisfactory arterial conduits was basic for progress in vascular surgery. Veins had been substituted for arteries as early as 1906. It was in the 1940s and early 1950s that methods of graft preservation were perfected and artery banks established, based on the early work of Carrel and Guthrie and of Gross and associates.':" A number of important breakthroughs had already occurred before 1950. On August 26, 1938, Robert Gross (Fig. 60.3) of Boston performed the first successful ligation of a patent ductus arteriosus." On October 19, 1944, Crafoord and Nylin in Sweden reported the first successful end-to-end anastomosis of the aorta after resection of an aortic coarctation."

FIGURE 60.3. Robert E. Gross. (Reprinted with permission from Thompson JE. The founding father s. J Vase Surg 1996;23:1027, 1028, 1029, 1030.1

Gross performed his first successful coarctation resection and anastomosis on July 6, 1945.42•43 Alfred Blalock of Johns Hopkins, on November 30, 1944, performed the first successful anastomosis of the subclavian artery to the pulmonary artery on a blue baby for the relief of tetralogy of Pallet." On May 24, 1948, Gross successfully replaced a long segment of a resected coarctation with a preserved arterial homograft. The stage was set for the rapid developments that were to follow.

Aortic Aneurysms: Recent Experience The modem method of treating abdominal aortic aneurysms began in 1951. On March 2, 1951, Schafer and Hardin resected an abdominal aortic aneurysm using a bypass shunt and replaced the aorta with a human homograft. The patient survived the operation but died 29 days later of hemorrhage from a leak in the native aortic wall." The first successful resection of an abdominal aortic aneurysm with graft replacement was done on March 29, 1951, by Charles Dubost in Paris, France (Fig. 60.4). Dubost used an extraperitoneal thoracoabdominal approach with resection of the 11th rib. The graft used was the thoracic aorta taken 3 weeks previously from a 20-year-old girl (Figure 60.51. The patient's left common iliac artery was then anastomosed to a side of the graft." Following Dubost's landmark procedure, reports of successful operations appeared in quick succession by Julian," Brock," DeBakey and Cooley." Bahnson" and SzilagyiII (Figs. 60.6, 60.7). Following Dubost's report th e abdominal aortic aneurysm sac was completely removed before the graft was placed, but this technique was sometimes difficult and hazardous. In 1966, therefore, Oscar Creech combined the endoaneurysmorrhaphy technique of Matas with graft replacement leaving the aneurysm sac in place. This single step has greatly simplified aneurysm surgery by reducing the incidence of venous injury and is the technique employed at the present time."

HI ST ORY OF VASCULAR SURGERY

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FIGURE 60.4. Charles Dubose.

Vascular Prostheses The arterial homografts were a great step forward, but problems of procurement and availability were major limiting factors. In 1952, Voorhees, [aretski, and Blakemore of New York reported that a tube of vinyon-N cloth as a plastic arterial substitute would remain open in a dog's aorta (Fig. 60.8). This observation was soon confirmed, and although vinyon-N did not prove to be a satisfactory material, the principle was established.52 In 1955, Sterling Edwards reported the development of nylon prostheses and with associate J.S. Tapp devised the technique of crimping prosthetic grafts. Nylon did not hold up, but Teflon grafts soon followed .53 Beginning in 1954, DeBakey and his group were working on various materials for grafts. They collaborated with Professor Thomas Edman, a Philadelphia textile engineer, to build a new knitting machine to make seamless Dacron grafts of all sizes, shapes, and configurations. A number of companies have since entered the graft field. Various refinements have been made in these prosthetic grafts, culminating in the standard Dacron and Teflon grafts in use today.' Emerick Szilagyi played an important role in the development of vascular grafts with his introduction of the elasticized woven Dacron graft

FIGURE 60.5. Diagram of Dubost's operative procedure for the first successful abdominal aortic aneurysm resection with graft replacement. (From Dubost C, Allary M, Oeconomos N. Arch Surg 1952;64:405-408 . Copyright: 1952, American Medical Association. Used by permission.]"

FIGURE 60.6. Michael E. DeBakey. (Reprinted with permission from Thompson TE. The founding fathers . TVase Surg 1996·23:1027 1028 1029, 1030.) , , ,

bearing his name. His follow-up reports on aortic aneurysm surgery have been landmark contributions, as have been his reports on the biological fate of saphenous vein grafts implanted in the infrainguinal region.54,55 A number of investigators have been involved in developing vascular grafts including Cooley, Deterling, Julian, Shumacker, and Von Liebi ie ig.7'56 M ore recent Iy, prosthetic grafts of polytetrafluoroethylene (PTFE) have been introduced and have found increasing application, especially in the femoropopliteal position.'

Ruptured Aneurysms Following successful elective treatment of abdominal aortic aneurysms, ruptured aneurysms were subjected to resection and repair . Henry Bahnson is credited with the first successful

FIGURE 60.7. D. Emerick Szilagyi.

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in 1956 using a temporary bypass shunt." Shumacker [Pig, 60.9) modified this technique by employing the homograft shunt as the permanent conduit and implanting the visceral vessels into it, then excising the aneurysm." Stanley Crawford reported his experience in 1974. The earliest cases consisted of inserting a Dacron graft and reattaching consecutively involved branches to side-arm tube grafts arising from the bypass. In the later cases, the graft was inserted inside the aneurysm with reattachment of visceral branch origins directly to an opening in the graft wall-the inclusion technique, as used today ." Peripheral aneurysms [e.g., popliteal) may be managed by either resection and graft or bypass techniques.

Arterial Occlusive Disease FIGURE 60.8. Arthur B. Voorhees, Jr.

repair of a ruptured aortic aneurysm, done March 13, 1953.57 Other early successful cases were reported by Gerbode, Cooley and DeBakey, and [avid et a1.5~

Thoracic Aneurysms Thoracic aneurysms have presented a challenge to surgeons for many years. These aneurysms can be saccular, fusiform, or associated with coarctation of the aorta. Following the lead of Moore in 1864, they wer e treated by wiring until more definitive measures were developed ." Among lesions associated with coarctation, John Alexander in Ann Arbor in 1941 simply resected the aneurysm and th e coarctation and sewed off the ends without doing an anastomosis or using a graft." Henry Swan, on June 28, 1949, apparently was the first to resect an aneurysm associated with a coarctation and replace the resected area with a homograft.P In 1951, Gross reported five cases of aneurysm associated with coarctation treated by resection and graft." Bahnson'? and Cooley and Debakey'" in the early 1950s resected saccular aneurysms and repaired the arterial wall by lateral suture. DeBakey and Cooley reported the first case of a successful resection and graft of a fusiform thoracic aneurysm, done January 5, 1953.65 Since that time, all sections of the thoracic aorta from the arch to the diaphragm have been successfully resected and replaced by grafts of various sorts .

Rene Leriche (1879-1955) first published his observations on obliteration of the terminal aorta in 1923, and stated that the ideal treatment would be resection of the area and reestablishment of patency. In 1940, he published a detailed description of the syndrome that now bears his name. He recommended resection of the terminal aorta and common iliac arteries together with bilateral lumbar sympathectomy through a retroperitoneal approach. Results of this procedure were variable, depending on the preoperative status of the patient. When Jacques Oudot resected the terminal aorta and replaced it with a preserved homologous aortic graft in 1950, the Leriche procedure became obsolete." A direct attack on occluded vessels was made by J. Cid Dos Santos of Portugal in 1946. He performed the first successful thromboendarterectomy for peripheral occlusive disease and established this as a feasible procedure. His first operation was performed August 27, 1946, on a left femoral artery and his second operation on December 12, 1946, on a subclavian artery. Both of these cases were successful so far as patency was concerned. He termed this operation disobliteration, but it came to be known as thromboendarterectomy, or just endarterectomy.P By 1948 Bazy in France had performed endarterectomy on 12 abdominal aortic occlusion

Thoracoabdominal Aneurysms Thoracoabdominal aneurysms have presented an even greater challenge. A forgotten pioneer in vascular surgery is the Austrian surgeon, Ernst Ieger, who died at age 30 in World War 1. Ieger was a brilliant investigator who devised many vascu lar and cardiac procedures, including one for complicated thoracoabdominal aneurysms.f Etheredge described resection of this lesion in 1955. He used a temporary shunt from the distal thoracic aorta to the distal abdominal aorta. A homograft was then inserted and the visceral vessels implanted into the homograft." DeBakey described a similar technique

FIGURE 60.9. Harris B. Shumaeker, Jr. (Reprinted with permi ssion from Thompson JE. The foundin g fathers . J Vase Surg 1996;23:1027, 1028, 1029, 1030.)

HI STORY O F V AS C U L A R SURGERY

cases, and Kunlin in Leriche's clinic had also carried out the procedure in a number of patients.' In 1951, aortic endarterectomy was introduced into the United States (Fig. 60.10) by E. Jack Wylie of San Francisco." Wiley Barker and Jack Cannon of Los Angeles were pioneers in the use of endarterectomy for femoral occlusive disease ." Endarterectomy has gradually given way to bypass grafting, except for the carotid area and certain localized obstructions in other large vessels ." A giant step forward in the treatment of aortic occlusive disease was made November 14, 1950 when Jacques Oudot, another Frenchman, was the first to resect the terminal aorta for the Leriche syndrome and replace it with a preserved homologous aortic graft 24 days old using end-to-end anastomoses. Six months later, because of thrombosis of the right iliac limb of the graft, he placed a crossover graft from the left distal external iliac to the right distal external iliac, the first extraanatomical bypass. Oudot, a French mountaineer, lost his life in an automobile accident at the age of 40.1,76 Resection of the aortoiliac segment with graft replacement gave way first to endarterectomy and then gradually to aortoiliac or aortofemoral bypass, leaving the native vessels in situ. The principle of bypass surgery had been suggested by Ernst lager," but it remained for a French surgeon, Jean Kunlin, working in Leriche's clinic, to perform the first long bypass graft of the femoral artery with a reversed saphenous vein on June 3, 1948, using end-to -side anastomoses both proximally and distally." The first patient treated by Kunlin was a 54-year-old man who had previously had an arteriectomy of the superficial femoral artery, the Leriche operation. His ischemia was not relieved, and Kunlin decided to do a venous graft with end-to-end anastomoses; however, exposure of the previous operative sites was difficult because of a tremendous fibrotic reaction and end-to-end anastomoses could not be done . Kunlin had no other choice but to do endto-side implantations of the venous graft into the femoral artery above and below . Thus, the bypass procedure was born by serendipity.' The femoropopliteal bypass has become a standard vascular operation for the treatment of infrainguinal atherosclerotic occlusive disease. It was popularized by Robert Linton (Fig. 60.11) of Boston, among others.55,78,79

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FIGURE 60.11. Robert R. Linton . (Reprinted with permission from Thompson JE. The founding fathers . J Vase Surg 1996;23:1027, 1028, 1029, 1030.)

In Situ Saphenous Bypass A variation of the femoropopliteal bypass technique was introduced by K.V. Hall in 1962, the nonreversed in situ saphenous vein bypass after obliterating the venous valves ." The technique was recommended by Connolly in 1964, but the operation was slow to gain acceptance." Leather, in the 1970s, resurrected the concept and improved the method of rendering the venous valves incompetent." Since then the procedure has been widely used with distal extension of the bypass to the lower leg, ankle, and foot for limb salvage." The bypass principle was extended to the aorta by Frank Cockett of London, who probably did the first aortic bypass in 1955 for treatment of aortic thrombosis without removing the aorta .' This operation was another step forward and was less demanding than aortoiliofemoral endarterectomy. An important feature critical to the success of aortofemoral bypass is proper handling of the profunda femoris artery, the orifice of which must be endarterectomized to allow for maximum distal runoff . Aortofemoral bypass has become the standard procedure for treatment of aortoiliac occlusive disease":"

Fluids

FIGURE 60.10. Edwin J. Wylie.

In the early days of aortic surgery, one of the major problems besetting surgeons was proper fluid management during the operative procedure and immediately postoperative. At first surgeons followed the recommendations current at that time, avoiding salt solutions and using almost exclusively limited quantities of dextrose in water. With this regimen there was a high incidence of shock, oliguria, hypotension, and renal shutdown, especially when the aorta was declamped." In the 1960s surgeons began to follow the recommendations of Shires et aJ.8 7 and give fairly large quantities of dextrose in lactated Ringer's solution to keep the perioperative urine output above 125mL/h. These large quantities compensated for the sequestration of extracellular fluid to maintain an effective circulating blood volume. With this regimen,

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hypotensive and renal complications of elective aortic surgery largely disappeared /"

Embolectomy Arterial embolism has long been a problem for vascular surgeons. Embolectomy, a direct arterial procedure, was first performed successfully on the femoral artery by Labey in 1911 and reported by Mosny and Dumont." The first successful aortic embolectomy by direct aortotomy was reported by Bauer in 1913.90 Results were less than ideal until heparin was introduced to aid in the prevention of distal thrombosis. The most significant advance, however, was the introduction of the balloon catheter by Fogarty (Fig. 60.12) and associates in 1963, which has improved not only the management of embo lism but vascular surgery in general ."

Sympathectomy Periarterial sympathectomy was first reported by Iaboulay in 1899 and was later championed by Rene Leriche ,'? Lumbar sympathectomy was first performed by Royle in Australia on September 1, 1923, for spastic paralysis." Independently, it was carried out by Julio Diez in Buenos Aires on July 24, 1924, for peripheral occlusive disease." Stellate ganglionectomy was reported by Jonnesco and by Bruning in 1923.92 In the 1930s and 1940s, thoracolumbar splanchnicectomy for essential hypertension was carried out by a number of surgeons, especially Reginald Smithwick (Fig. 60.13) in Boston." With the advent of antihypertensive drugs, the use of thoracolumbar splanchnicectomy was no longer necessary. Similarly, with the advent of direct arterial surgery, sympathectomy is now reserved for the treatment of causalgia and related pain syndromes, hyperhidrosis, and vascular disorders when vasomotor instability is a major component. Smithwick and Geza DeTakats were leading proponents of sympathectomy in the early days for treatment of peripheral vasospastic and occlusive disorders.P'"

« FIGURE 60.13. Reginald H. Smithwick. (Reprinted with perm ission from Thompson JE. The founding fathers . J Vase Surg 1996;23:1027, 1028, 1029, 1030.)

Extraanatomic Procedures Oudot in 1951 had performed a crossover graft from the left distal external iliac to the right distal iliac artery." Norman Freeman in San Francisco, in 1952, performed the first crossover femoral graft using an endarterectomized segment of the left femoral artery to crossover and revascularize successfully the right leg." In 1962, Vetto reported 10 transabdominal subcutaneous femorofemoral graft operations to bypass iliac occlusive disease in high-risk patients." Femorofemoral crossover graft is now a useful standard procedure. In 1959, Lewis resected an abdominal aortic aneurysm and was forced to reconstruct with a nylon graft from the subclavian artery subcutaneously into the abdomen for anastomosis to a homograft replacement." In 1961, Blaisdell et al. performed an extraperitoneal thoracic aorta to femoral bypass graft using Dacron as replacement for an infected aortic bifurcation prosthesis. The following year, on March 25, 1962, Blaisdell and Hall performed a bypass procedure for aortoiliac occlusion using a Dacron graft carried from the axillary artery subcutaneously to the femoral artery.'?' At about the same time, the same procedure was performed by Louw in South Africa.'?' Such were the beginnings of extraanatomical bypass procedures.

Renal and Mesenteric Lesions

,

FIGURE 60.12. Thomas

h

J. Fogarty.

Renal artery lesions have been treated surgically in the management of renovascular hypertension, renal insuffici ency, and aneurysms. In 1951 splenorenal arterial anastomosis was first used, although unsuccessfully, in the treatment of hypertension.'?' It was later applied successfully by De Camp et al. in 1957.103 Since then a number of techniques have been used for renal artery lesions, the most common being aortorenal bypass, but also including splenorenal and hepatorenal bypass. Transaortic endarterectomy has also been successfully employed by Stoney and associates.l'" Endarterectomy and bypass techniques have also been applied successfully in the . vascu I ar I esions. ' 104 management 0 f mesentenc

HISTORY OF VASCULAR SUR GERY

Cerebrovascular Disease Increasing awareness, in the past 45 years, of the extracranial location and segmental nature of atherosclerotic occlusive disease in a large proportion of patients with cerebrovascular insufficiency was followed by the development and use of appropriate vascular surgical techniques for removing or bypassing offending plaques, thus increasing cerebral blood flow or eliminating sources of cerebral emboli." The word carotid is derived from the Greek term kaiotids or katos, meaning to stupefy or plunge into a deep sleep. According to Rufus of Ephesus (circa AD 1001, the term was applied to the arteries of the neck because compression of these vessels produced stupor or sleep.lOS The ancient Greeks were aware of the significance of the carotid artery; the 31st metope from th e south side of the Parthenon in Athens depicts a centaur applying left carotid compression to the neck of a Lapith warrior (Fig. 60.14). With the advent of Hippocrates (460-370 Bel, ancient descriptive neurology was born . He described paralysis of the right arm with loss of speech in what is probably the first written description of aphasia .lOS Galen (AD 131-201) was aware that hemiplegia resulted from a lesion in the opposite side of the brain as a cause of apoplexy.lOS With Galen as the authority, European medicine remained at a dead level for nearly 14 centuries until the time of Vesalius, who in 1543, with the publication of De Fabrica Humani Corporis, threw overboard Galenical traditions." Ambroise Pare, in the sixteenth century, was familiar with the carotid phenomenon and stated, "The two branches they call carotides or soporales, the sleepy arteries, because they being obstructed or any way stopt we presently fall asleep." ISThe seventeenth century saw the work of Thomas Willis and Richard Lower in connection with the circle of arteries at the base of the brain." The first operations on the carotid artery were quite nat urally ligation procedures for trauma or hemorrhage. Hebenstreit of Germany, in his translation of Benjamin Bell's Surgery in 1793, mentions a case in which the carotid artery was injured during operative removal of a scirrhous tumor. The surgeon ligated the vessel to stop hemorrhage, and the patient lived for many years . This is thought to be the first case on record of ligature of the carotid. I0 6- 108

1307

John Abernethy of London, a pupil of John Hunter, in 1804 reported a case of carotid ligation performed some years previously, probably in 1798. The patient, a man, was gored in the neck by the hom of a cow, and hemorrhage was profuse. Compression controlled the bleeding temporarily only to have it recur when pressure was released . Abernethy was compelled to ligate the common carotid artery. Hemorrhage was controlled, and the patient appeared well. However, the man died 30h later of cerebral causes, and Abernethy aban doned the procedure.106,108- 11O With the beginning of the nineteenth century, the history of carotid surgery becomes more accurate. The first successful ligation of a carotid artery was performed by David Fleming on October 17, 1803. Fleming was a young naval surgeon aboard His Majesty's ship Tonnant during the Napoleonic era. Mark Jackson, a servant, attempted to commit suicide by cutting his throat on October 9, 1803. The knife had grazed the outer and muscular coats of the carotid artery but left the artery intact. Eight days later, on October 17, the carotid ruptured. Fleming cut down on the artery proximal to the rupture and ligated it . He had not done this before, nor had he heard of Abernethy's case. The patient survived and made an uninterrupted recovery . This was the first authentic suc cessful case of ligation of th e carotid artery on record.l' v!" The first successful ligation of the carotid artery in the United States was performed by Amos Twitchell of Keene, New Hampshire, on October 18, 1807. John Taggart, a cavalry soldier of age 20, during a mock fight at a regimental review was accidentally wounded in the neck by a pistol shot on October 8, 1807. The wound was treated by simple dressings, although Dr. Twitchell commented, "There was a good deal of arterial excitement." Taggart, however, improved rapidly until the 10th day when the internal carotid artery ruptured. Twitchell stopped the hemorrhage by compression, then made an incision lower in the neck and ligated the common carotid artery with the patient's mother acting as his assistant. He then packed the wound with dry sponges. The patient made an uneventful recovery.106,113 Sir Astley Cooper in London was the first to attempt ligation of a carotid artery for cervical aneurysm on November I, 1805. The patient died of sepsis on the 21st day with a left hemiparesis. Cooper repeated the operation on June 22, 1808, at Guy 's Hospital. The patient was 55 years of age and had a pulsating tumor the size of an egg at the angle of the jaw. Two ligatures were applied to the artery, which was divided . The patient made a perfect recovery with no untoward symptoms and lived until 1821. This was the first successful case of ligature of the carotid artery for aneurysm.114,llS Benjamin Travers , on May 23, 1809, first successfully ligated the left carotid for carotid-cavernous fistula, with disappearance of signs and symptoms. In 1885 Victor Horsley first successfully ligated the carotid in the neck for an intracranial aneurysm. The patient was wellS years later. By 1868, Pilz was able to collect 600 recorded cases of carotid ligation for cervical aneurysm or hemorrhage with a mortality rate of 43 %.9,110

FIGURE 60.14. The 31st met ope from the south side of the Parthenon in Athens.

Until fairly recently, the prevailing notion held by most physicians was that strokes were caused by intracranial vascular disease . William Osler, in his 1909 textbook, attributed apoplectic stroke largely to cerebral hemorrhage. No mention is made of extra cranial occlusive disease, and emphasis is on blockage of intracranial vessels ." This is somewhat curious

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in view of the fact that several authors had already described occlusive lesions in the extracranial segments of the main arteries supplying the brain and noted their association with symptoms of cerebral ischemia. These authorities included Heberden, Gull, Savory, Virchow, Broadbent, Penzoldt, and Chiari.? A landmark article was that publised by J. Ramsay Hunt of New York City in 1914, who called attention to the importance of extracranial occlusions in cerebrovascular disease, and even used the term "cerebral intermittent claudication" to describe transient ischemic attacks (TIAS),u6 The next significant contribution was the report of Egas Moniz of Portugal, who in 1927 first described the technique of cerebral arteriography for the study of cerebral tumors, using sodium iodide as the contrast medium, and thus laid the groundwork of a practical method for the diagnosis of occlusive lesions.!" The first report of carotid thrombosis demonstrated by arteriography was that of Sjoqvist in 1936.118 The following year, 1937, Moniz, Lima, and de Lacerda reported four patients with occlusion of the cervical portion of the internal carotid artery in whom the diagnosis had been established by arteriography.l'? Egas Moniz won a Nobel Prize in 1949, not for cerebral arteriography but for his work on prefrontal lobotomy. By 1951 Johnson and Walker were able to collect 107 instances of carotid thrombosis, all diagnosed by arteriography.120 In two important articles published in 1951 and 1954, C. Miller Fisher, working in Montreal and later in Boston, reemphasized the relationship between and frequency of disease of the carotid artery in the neck and cerebrovascular insufficiency. He observed that with severe stenosis of the carotid bifurcation, the distal vessels could be entirely free of disease. He stated, "It is even conceivable that some day vascular surgery will find a way to bypass the occluded portion of the artery during the period of ominous fleeting symptoms. Anastomosis of the external carotid artery or one of its branches with the internal carotid artery above the area of narrowing should be feasible."12I,122 In 1952, John Conley of New York reported anastomosing the distal ends of the internal carotid artery and external carotid artery to restore flow to the brain after tumor resection, a procedure previously reported by LeFevre in France in 1918. In 1953, Conley reported 11 cases in which the superficial femoral or saphenous vein had been used as an interposition graft to reconstruct a resected cervical carotid artery after tumor surgery.I 23,124 Dos Santos in 1946 had introduced thromboendarterectomy for restoring flow in peripheral vessels." In 1951, E.J. Wylie introduced into the United States thromboendarterectomy for the removal of atherosclerotic plaques from the aortoiliac segments, but this technique had not been used on the carotid artery. " Fisher's prophecy of surgical reconstruction of the carotid artery in the neck as therapy for occlusive disease was soon fulfilled. The first successful reconstruction of the carotid artery was performed by Carrea, Molins, and Murphy in Buenos Aires in 1951, after they read Fisher's article, and was reported in 1955 (Fig. 60.151. A 41-year-old male patient had recurring symptoms of right hemiparesis, aphasia, and left amaurosis over a 6-month period. A left percutaneous arteriogram demonstrated an atherosclerotic plaque with severe stenosis in the internal carotid artery. On October 20, 1951, Molins, a vascular surgeon, and Carrea performed an end-to-

FIGURE 60.15. Mahelz Molins. (Reprinted with permission from Friedman SG. A History of Vascular Surgery. Mount Kisco, NY: Futura, 1989:167.3 1

end anastomosis between the left external carotid and distal internal carotid arteries after partial resection of the stenosed area, together with cervical sympathectomy. The patient made an uneventful recovery and died 23 years later of myocardial infarction. His neurological status was normal except for loss of vision in the left eye. 125 On January 28, 1953, Strully, Hurwitt, and Blankenberg in New York operated on a patient with a frank stroke and a totally occluded internal carotid artery. They performed a thrombectomy but were unable to obtain retrograde flow; consequently, a section of the internal carotid was removed. They suggested that thromboendarterectomy should be feasible in such cases when the distal vasculature was patent.P" The first successful carotid endarterectomy was performed by Michael DeBakey on August 7, 1953. A 53-year-old schoolbus driver gave a history of recurring episodes of transient right hemiparesis and dysphasia during a 2-year period. On examination, he had a mild residual right hemiparesis and a weak pulsation in his left carotid artery. No preoperative arteriogram was performed. During surgery, a severely stenotic atherosclerotic plaque with superimposed fresh clot completely occluding the left internal carotid artery was found. Thromboendarterectomy was carried out with good retrograde flow from both internal and external carotid arteries. An arteriogram performed postoperatively on the operating table showed the internal carotid to be patent in both its extracranial and intracranial portions. The patient made a good recovery and lived for 19 years without having further strokes. He died of complications of coronary artery disease on August 17, 1972.127 The operation that gave the greatest impetus to the development of surgery for carotid occlusive disease was that performed by Eastcott, Pickering, and Rob on May 19, 1954, at St. Mary's Hospital in London (Figs. 60.16, 60.17). In this case, a 66-year-old housewife who had suffered 33 transient episodes of right hemiparesis, aphasia, and left amaurosis over a 5-month period was found to have a severe stenosis of the left carotid bifurcation after a percutaneous left carotid arteriogram. With the patient under general anesthesia and with hypothermia to 28°C (82.4°F) by means of ice bags for cerebral

1309

HI ST ORY OF VA SC UL A R S U RG E R Y

FIGURE 60.16. H.H.G. Eastcott, in front of a statue of John Hunter. FIGURE 60.17. Charles G. Rob.

protection, the bifurcation was resected and blood flow restored by end -to-end anastomosis between the common carotid and distal internal carot id arteries. The patient was completely relieved of her symptoms and was alive and well at th e age of 86.128 Following these landmark cases, a number of different methods of carotid reconstruction were reported. Table 60.1 lists in chronological order some earl y procedures performed. I 2S- 133 With increasing experience, the vari ous procedures listed were abandoned with th e exception of endarterectomy, which has become th e standard operation (Fig. 60.18). At first an ext ernal shunt was used for cerebr al protection, but this gave way to the intraluminal shunt, which is now used either routinely or selectively when th e carotid is occluded during endarterectomy." A variant of the standard end arterectomy technique is eversion endarterectomy, introduced by DeBakey 's group in 1959.134 It has been used infrequently over the years , but

recently it has been employed more often by a number of surgeons in an effort to reduc e the incidence of long-term recurrent carotid stenosis.!" Surgical treatment of occlusive lesions of the great vessels arising from the aortic arch did not lag far behind that of the carotid artery in th e neck. Gordon Murray of Toronto in 1950 successfully restored, by means of a probe and instrumentation, circulation in a left common carotid art ery totally occluded at th e aortic arch .!" On March 20, 1954, Davis, Grove , and Julian performed the first innominate endarterectomy. On January 4, 1957, DeBakey and hi s group con structed a bypass graft from th e innomi nate to the distal subclavian and carotid arteries and shortly thereafter successfully performed subclavian endarterectomy. Bypass procedures including extrathoracic bypass such as carotid-subclavian bypass and endarterectomy remain the usual standard operations today for lesions of th e aortic arch vessels .13 7, 138

~"r."'_ TABLE 60.1.

First Carotid Reconstructions for Cerebrovascular Insufficiency in Chronological Order.

Author

Date of operation

Degree of stenosi s

Procedure of pow

Carrea , Molins, and Murphy'P

Oct ober 20, 1951

Partial

Strull y, Hurwitt, and Blankenb erg!"

January 28, 1953

Total

Debakey!" Eastcott, Pickering, and Rob!"

August 7, 1953 May 19, 1954

Total Partial

June 1954 July 14, 1954 December, 1955 February 6, 1956 February 24, 1956 March 8, 1956 August 9, 1956

Partial Total Partial Total Partial Partial Parti al

End-to-end anasto mos is, external carotid to internal carotid Thromboendarterectomy followe d by ligati on and resecti on Thromboendart erect om y End-to-end anastomos is, com mon carotid to intern al carotid Throm boendart erectomy Resecti on with hom ograft Resecti on wi th saphe nous vein graft Thromboend art erectomy Thromboend art erectomy Endarterectomy Subclavian-carotid nylon bypass graft

Denman, Ehni, and Dury !" Lin, [avid, and Doyle 1JO Murphey and Miller !" Cooley, Al-Naarnan, and Car ton-" Lyons and Calbraith'"

Restoration

Yes No Yes Yes Yes Yes Yes Yes Yes Yes Yes

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CHAPTER 60

FIGURE 60.18. Diagram of technique of carotid endarterectomy with shunt. (Reprinted with permission from Thompson JE. Surgery for Cerebrovascular Insufficiency [Stroke]. Spring-field, MA: Charles C. Thomas, 1968:32.138 )

As a result of studies by Hutchinson and Yates in 1956 directing attention to the importance of occlusive lesions in the cervical portion of the vertebral arteries, reconstructive operations on the vertebral vessels were developed. r" On September 7, 1957, Cate and Scott in Nashville carried out successful endarterectomy of the left subclavian and left vertebral arteries. In 1958, Crawford, DeBakey, and Fields described treatment of vertebral-basilar insufficiency by means of vertebral endarterectomy in one case and bypass graft from the subclavian to the distal patent vertebral in another. 137,138 Newer techniques have enlarged the scope of vertebral surgery . Edwards et al. have been foremost in promoting subclavian and vertebral transpositions into the common carotid artery.!" Berguer has devised innovative procedures on the distal vertebral artery near the base of the skull. 141 On the basis of microsurgical techniques developed in the 1960s, Yasargil, et al. carried out extracranial to intracranial bypass procedures hoping for improvement in patients with strokes who had occluded cervical internal carotid arteries.'? In 1977, a randomized trial was initiated. Unfortunately, the trial failed to demonstrate significant benefit from the surgery, and the operation is no longer performed except in occasional situations, in which it may be quite beneficial. !"

Venous Surgery Venous problems, similar to arterial diseases, have been present since ancient times. As early as 1550 BC, varicose veins were mentioned in the Ebers Papyrus .!" In 500 BC, Hippocrates recommended compression treatment of varices . Galen advocated removal of varices with a hook. Aegineta (AD 625-690) performed ligation and division followed by bandaging.v!" Ambroise Pare treated varicose veins and varicose ulcers . For varices, he recommended ligation and excision. He treated ulcers by means of bed rest, elevation, and pressure dressing over the ulcer and wrapped the legs with a roller bandage of linen, much like present-day therapy. In the late 1800s Trendelenburg popularized ligation of varices . In 1884 Madelung of Germany removed varicose saphenous veins through a long incision in the leg similar to that used today for removal of a vein for bypass procedures. There were many complica-

tions of Madelung's procedure. v'v!" The plaster boot was introduced by Unna of Germany in 1896.3 In 1905 Keller in the United States first reported stripping by tying the vein to a wire and then pulling it out. Also in 1905, Babcock devised his rigid intraluminal stripper. In 1906 Mayo introduced the extraluminal straight stripper. Homans, in 1916, emphasized the importance of ligation at the saphenofemoral junction and removed varicose veins by radical excision and stripping. In 1938 Linton advocated ligation, stripping, and extensive removal of segments. In 1947, T.T. Myers of the Mayo Clinic developed a flexible intraluminal stripper that greatly facilitated the removal of both small and large varices.l " All modem-day strippers are modifications of these older strippers. Sclerotherapy has also been used in conjunction with or instead of ligation and stripping. Direct venous surgery has lagged behind arterial reconstruction operations. Eck, in 1877, performed the first successful venovenous anastomosis between the portal vein and the vena cava. In 1902, Alexis Carrel and c.c. Guthrie published their results of arterial and venous anastomosis and transplantation of organs using their meticulous technical methods. Payr in 1904 devised a method of uniting divided vessels by using cylinders of magnesium. Exner in 1903 made the first attempt at vein grafting by transplanting autologous segments of jugular veins into the opposite side of the neck in two dogs, using th e magnesium prosthesis of Payr. The results were poor, and thus little was done during the next 40 years.':" With the flowering of arterial reconstructive surgery during the past 50 years, much investigation has gone on in the field of venous surgery. A great step forward occurred in 1923 when Berberich and Hirsch first performed radiography following intravenous injection of strontium bromide, thus introducing venography. In 1929, McPheeters and Rice used lipiodol as the contrast medium, and in 1934 Edwards and Biguria used diodone (an iodine basel, a much safer medium. Both ascending and descending venography followed introduction of the procedure. 147 Management of deep venous thrombosis with prevention and treatment of pulmonary embolism has been a major problem for physicians for years. John Homans (Fig. 60.19) is credited with using femoral vein ligation in 1934 to prevent fatal pulmonary embolism. In 1944 the inferior vena cava was first ligated for the prevention of pulmonary embolism. By 1958, 468 cases had been reported in the United States. I48, 149 Numerous devices have been used to prevent pulmonary embolism, including plication of the vena cava, vena cava clips for partial occlusion, vena caval umbrellas, and vena caval filters of various sorts . The most popular filter, that of Lazar Greenfield, has been very effective and can be inserted readily from the neck or the groin. 150--1 53 In the 1940s a series of patients at the Massachusetts General Hospital were subjected to bilateral superficial femoral vein ligation under local anesthesia in a study aimed at prevention of fatal and nonfatal pulmonary embolism. Several hundred cases were operated upon with minimal complications. Compared with other methods of therapy, it could not be shown that this operation reduced significantly the incidence of pulmonary embolism. The operation was therefore abandoned as routine treatment.P" Linton devised an operation of extensive subfascial division of incompetent perforating veins for the treatment of severe symptoms of chronic postphlebitic syndrome. ISS

HI STORY OF V ASC U L A R SURGERY

FIGURE 60.19. John Homans. (Reprinted with permission from Thompson JE. The founding fathers . JVase Surg 1996;23:1027, 1028, 1029, 1030.1

Since midcentury, a number of noninvasive tests have been developed in an effort to study deep venous thrombosis, including Doppler ultrasonography, impedance plethysmography, and phleborheography. A major breakthrough came when it was demonstrated that B-mode ultrasonography could be used to diagnose deep venous thrombosis. Duplex scanning was found to have major advantages. At the present time, color-flow duplex scanning is the method of choice.l'" Surgical procedures have been developed to bypass obstructions in the iliac veins using a crossover graft as the conduit or the distally divided saphenous vein from the opposite leg, the Palma procedure, reported first in 1958.157Bypass of obstruction in the lower leg can relieve problems at the lower level as well; this is the saphenopopliteal bypass or Husni operation.ISS Techniques have been developed to repair or replace incompetent valves in the veins of the lower extremity in certain selected patients with chronic venous insufficiency. These procedures include valvuloplasty, internal or external, and various vein transfers .144,159,160 Balloon angioplasty has been introduced to dilate venous obstructions, and stents have been placed in the venous system. Results have been less satisfactory than when these techniques are used for arterial lesions.

Vascular Injuries Over the years vascular Injuries have been treated in a variety of ways . Antyllus used ligation to stop bleeding and packed his wounds. Galen, who was very influential, used ligatures and cautery to control hemorrhage. There was very little progress in treatment of vascular injuries during the next 1300 years, the main elements of therapy being amputation, boiling oil, cautery, and the ligature and packing of wounds." It was left for Ambroise Pare to bring some improvement in wound management. The story is that in a battle Pare ran out of boiling oil and applied nonirritating simple dressings

1311

to bleeding areas; much to his astonishment, the patients improved and progressed much better than when boiling oil and cautery were used . Pare thus used ligation and a simple dressings and amputations as necessary.' The work of Hallowell, Murphy, Carrel, and Guthrie, and others on direct arterial suture has already been described ." Over the centuries, wars have provided a fruitful source of vascular injuries, which were first treated by boiling oil, cautery, ligation, packing, and amputation, until vascular repair began to be carried out on the battlefield. Battlefield repair was done in the Balkan wars before World War I by a Serbian army surgeon named V. Soubbotitch, who initiated a program whereby injured blood vessels were treated by direct repair rather than primary amputation. In 1914 he reported his results with 185 operations for vascular injuries. His work was largely ignored until the 1950s.3 Ligation remained the primary method of treating vascular injuries during World War I. Allied military surgeons believed that battlefield repair of injured arteries was not practicable and that controlling hemorrhage by ligation was sufficient. The Germans did make some effort to repair blood vessels. Ernst Ieger even attempted to use fresh arterial and venous homografts from limbs severed in battle to replace wounded arteries. Most of these grafts thrombosed, however, and Ieger's idea was never culminated .v" Despite a number of supportive innovations such as the availability of blood and antibiotics, these aids did not advance vascular surgery in World War II, which still consisted largely of ligation and amputation. DeBakey and Simeone reported on 2471 arterial wounds in World War II. They found only 81 instances of suture repair, with an amputation rate of 36% . Amputation rate following ligation was nearly 50% . Based on sound considerations, DeBakey and Simeone did not believe that battlefield repair was practical or realistic, mainly because of the great delay between wounding and surgical treatment.161 Those soldiers with vascular injuries whose limbs survived and who were evacuated to the Zone of the Interior received subsequent repair of false aneurysms and arteriovenous fistulas by ligation and excision when collateral circulation was deemed adequate, and these did very well. When the Korean War broke out , a new policy was soon inaugurated, the restoration of vascular continuity in injured vessels by direct anastomosis, lateral repair, or graft replacement, either arterial or venous, in an effort to improve amputation rates . The use of the helicopter to reduce the time between wounding and repair was invaluable. Repairs were done in Mobile Army Surgical Hospitals (MASH). The first 130 cases were performed with an 89% limb salvage rate , and a new era in vascular surgery had begun . Ligation of major arteries in World War II had given an amputation rate of 49% . In the Korean War, in contrast, the eventual amputation rate was 13%.3,162 The war in Vietnam provided an opportunity to corroborate the lessons learned in the Korean War about management of vascular injuries. A Vietnam Vascular Registry was begun under the direction of Carl Hughes and Norman Rich to analyze all vascular injuries treated in army hospitals in Vietnam. Data from the Registry showed a limb salvage rate of 87%.3,162,163 Techniques for the management of civilian vascular injuries since midcentury have paralleled the explosive development of the techniques used for treatment of aneurysmal and

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occlusive vascular diseases. Appropriate management for injuries in all areas of the body has been developed by a number of surgeons. These techniques have involved the proper use of angiography, direct vascular repair, bypass procedures, and the use of arterial and venous autografts, homografts, and prosthetic grafts of various sorts.162-165

Vascular Disorders A number of vascular disorders, such as dissection, dissecting aneurysms.l" aortoenteric fistulas, and aortocaval fistulas, can now be managed satisfactorily with modem vascular surgical techniques. The retroperitoneal approach to the aorta first advocated by Astley Cooper in 1817 has found increasing usefulness. Dilatation of stenoses by balloon angioplasty techniques, introduced by Dotter and Gruentzig, has been shown to be helpful, especially when accompanied by implantation of stents. 3)67 Clagett et al. have recently replaced infected aortic prostheses in situ with deep and superficial veins from the lower extremity.l'" Most recently, an exciting new era of endovascular grafting has opened up avenues of therapy with techniques of lesser magnitude, hopefully lowering the morbidity and mortality of current techniques and extending the field of vascular surgery to areas not previously available. Thus, at the beginning of the twentieth century, basic vascular techniques were available but the supporting pillars were lacking. By midcentury all necessary items had fallen into place, resulting in the spectacular development of vascular surgery as we know it today.

References 1. Barker WF. Clio: The Arteries. Austin: Landes, 1992:2-502. 2. DeBakey ME. The development of vascular surgery. Am J Surg 1979;137:697-738. 3. Friedman SG. A history of vascular surgery. Mount Kisco, NY: Futura, 1989. 4. Haimovici H. Landmarks in vascular surgery. Contemp Surg 1982;21:63-84. 5. Rob CG. A history of arterial surgery. Arch Surg 1972;105:821823. 6. Shumacker HB [r, Muhm HY. Arterial suture techniques and grafts: past, present and future. Surgery (St. Louis) 1969;66:419433. 7. Smith RB III. The foundations of modem aortic surgery. J Vase Surg 1998;27:7-15. 8. Thompson JE. Vascular surgical techniques: historical perspective. In: Bergan IT, Yao JST, eds. Techniques in Arterial Surgery. Philadelphia: Saunders, 1990:3-13. 9. Thompson JE. The evolution of surgery for the treatment and prevention of stroke. Stroke 1996;27:1427-1434. 10. Thompson JE. Early history of aortic surgery. J Vase Surg 1998;28:746-752. 11. Dale WA. In: Johnson G Jr, DeWeese JA, eds. Band of Brothers: Creators of Modem Vascular Surgery. Pittsboro: Kachergis, 1996. 12. Ruffer MA. On arterial lesions found in Egyptian mummies (1580 Bc-525 AD). J Pathol Bacteriol1911;15:453-462. 13. Slaney G. A history of aneurysm surgery. In: Greenhalgh RM, Mannick JA, Powell JT, eds. The Cause and Management of Aneurysms. London: Saunders, 1990:1-18.

14. Crowe SJ. Halsted of Johns Hopkins: The Man and His Men. Springfield: Thomas, 1957:210-218. 15. Pare A. The Workes of That Famous Chirurgion Ambrose Parey. (Translated from Latin and compared with French by T. Johnson. From the first English edition, London, 1634. Reprinted, New York: Milford House, 1968.) 16. Garrison FH. An Introduction to the History of Medicine. Philadelphia: Saunders, 1929:217-221. 17. Perry MO. John Hunter-triumph and tragedy. J Vase Surg 1993;17:7-14. 18. Brock RC. The Life and Work of Astley Cooper. Edinburgh: Livingstone, 1952:1-174. 19. Rutkow 1M. Valentine Mott (1785-1865) the father of American vascular surgery: a historical prospective. Surgery (St. Louis) 1979;85:441-450. 20. Thompson JE. Valentine Mott. Pioneer American vascular surgeon. In: Veith FJ, ed. Current Critical Problems in Vascular Surgery, vol 7. St. Louis: Quality Medical, 1996:540-543. 21. Yao JST. Historical perspectives: the 100th anniversary of the first arterial anastomosis in a human. In: Yao JST, Pearce WH, eds. Techniques in Vascular and Endovascular Surgery. Stamford: Appleton & Lange, 1998:xxxiii-xl. 22. Edwards ES, Edwards PD. Alexis Carrel, Visionary Surgeon. Springfield: Thomas, 1974. 23. Goyanes J. Nuevos trabajos de cirugia vascular, substitucion plastica de las arterias por la vena 0 arterioplastia venosa aplicada como nuevo metodo del tratamiento de los aneurismas. El Siglo Medico 1906;53:546-561. 24. Lexer E. Die ideale operation des arteriellen und des arteriellenvenosen aneurysma. Arch Klin Chir 1907;83:459-477. 25. Pringle JH. Two cases of vein grafting for the maintenance of a direct arterial circulation. Lancet 1913;1:1795-1796. 26. Bernheim BM. The ideal operation for aneurisms of the extremity. Bull Johns Hopkins Hosp 1916;27:93-97. 27. Cameron JL. William Stewart Halsted. Our surgical heritage. Ann Surg 1997;225:445-458. 28. Matas R. Ligation of the abdominal aorta. Ann Surg 1925;81:457464. 29. Elkin DC. Aneurysm of the abdominal aorta. Treatment by ligation. Ann Surg 1940;112:895-908. 30. Matas R. Traumatic aneurysm of the left brachial artery. Incision and partial excision of the sac-recovery. Med News NY 1888;53:462-466. 31. Osler W. The Principles and Practice of Medicine, 7th ed. New York: Appleton, 1909:862-863. 32. Blakemore AH. Progressive constrictive occlusion of the aorta with wiring and electrothermic coagulation for the treatment of arteriosclerotic aneurysms of the abdominal aorta. Trans South Surg Assoc 1952;64:202-219. 33. Rutledge RH. America's greatest medical discovery: 150 years later, who gets the credit? J Am Coll Surg 1996;183:625636. 34. Wangensteen OH, Wangensteen SD. The rise of surgery. From empiric craft to scientific discipline. Minneapolis: University of Minnesota Press, 1978:516-518. 35. Crile GW. Technique of direct transfusion of blood. Ann Surg 1907;46:329-332. 36. Foster JH. Arteriography. Cornerstone of vascular surgery. Arch Surg 1974;109:605-611. 37. Brooks B. Intra-arterial injection of sodium iodide. Preliminary report. JAMA 1924;82:1016-1019. 38. Seldinger SI. Catheter replacement of the needle in the percutaneous angiography; a new technique. Acta Radiol 1953;39:368376. 39. Gross RE, Bill AH Jr, Peirce EC II. Methods for preservation and transplantation of arterial grafts; observations on arterial grafts in dogs. Report of transplantation of preserved arterial grafts in 9 human cases. Surg Gynecol Obstet 1949;88:689-701.

HISTORY OF VASCULAR SURGERY

40. Gross RE. Surgical ligation of a patent ductus arteriosus: report of first successful case. JAMA 1939;112:729-731. 41. Crafoord C, Nylin G. Congenital coarctation of the aorta and its surgical treatment. J Thorac Surg 1945;14:347-361. 42. Gross RE. Surgical correction for coarctation of the aorta. Surgery (St. Louis) 1945;18:673-678. 43. Gross RE, Hufnagel CA. Coarctation of the aorta: experimental studies regarding its surgical correction. N Engl J Med 1945;233: 287-293. 44. Blalock A, Taussig H. Surgical treatment of malformations of the heart in which there is pulmonary stenosis or atresia. JAMA 1945;128:189-202. 45. Schafer PW, Hardin CA. The use of temporary polythene shunts to permit occlusion, resection and frozen homologous graft replacement of vital vessel segments. Surgery (St. Louis) 1952;31: 186-193. 46. Dubost C, Allary M, Oeconomos N. Resection of an aneurysm of the abdominal aorta. Arch Surg 1952;64:405-408. 47. Julian OC, Grove WJ, Dye WS, et al. Direct surgery of arteriosclerosis. Ann Surg 1953;138:387-403. 48. Brock RC. Discussion on reconstructive arterial surgery. Proc R Soc Med 1953;46:115-130. 49. DeBakey ME, Cooley DA. Surgical treatment of aneurysm of abdominal aorta by resection and restoration of continuity with homograft. Surg Gynecol Obstet 1953;97:257-266. 50. Bahnson HT. Considerations in the excision of aortic aneurysms. Ann Surg 1953;138:377-386. 51. Creech O. Endoaneurysmorrhaphy. Treatment of aortic aneurysm. Ann Surg 1966;164:935-946. 52. Voorhees AB Ir, Iaretski A IV, Blakemore AH. The use of tubes constructed from Vinyon -"N" cloth in bridging arterial defects. Ann Surg 1952;135:332-336. 53. Edwards WS, Tapp JS. Chemically treated Nylon tubes as arterial grafts. Surgery (St. Louis) 1955;38:61-70. 54. Szilagyi DE, Smith RF, Derusso RJ, et al. Contribution of abdominal aortic aneurysmectomy to prolongation of life. Ann Surg 1966;164:678-698. 55. Szilagyi DE, Elliott JP, Hageman JG, et al. Biologic fate of autogenous vein implants as arterial substitutes: clinical, angiographic and histopathologic observations in fernoro-popliteal operations for atherosclerosis. Ann Surg 1973;178:232-246. 56. DeBakey ME, Cooley DA, Crawford ES, Morris GC Jr. Clinical application of a new flexible knitted dacron arterial substitute. Am Surg 1958;24:862-869. 57. Bahnson HT. Treatment of abdominal aortic aneurysms by excision and replacement by homograft. Circulation 1954;9:494503. 58. Gerbode F. Ruptured aortic aneurysm-a surgical emergency. Surg Gynecol Obstet 1954;98:579. 59. Cooley DA, DeBakey ME. Ruptured aneurysm of abdominal aorta-excision and homograft replacement. Postgrad Med 1954;16:334-342. 60. [avid H, Dye WS, Grove WJ, Julian OC. Resection of ruptured aneurysm of the abdominal aorta. Ann Surg 1955;142:613-623. 61. Alexander J, Byron FX. Aortectomy for thoracic aneurysm. JAMA 1944;126:1139-1145. 62. Swan H, Maaske C, Johnson M, Groves R. Arterial homografts. Resection of thoracic aortic aneurysm using a stored human arterial transplant. Arch Surg 1950;61:732-737. 63. Gross RE. Treatment of certain aortic coarctations by homologous grafts. A report of 19 cases. Ann Surg 1951;134:753768. 64. Cooley DA, DeBakey ME. Surgical considerations of intrathoracic aneurysms of the aorta and great vessels. Ann Surg 1952;135:660-680. 65. DeBakey ME, Cooley DA. Successful resection of aneurysm of thoracic aorta and replacement by graft. JAMA 1953;152:673676.

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66. Nunn DB, Bunzendahl H, Handy JR. Ernst Ieger: a forgotten pioneer in cardiovascular surgery. Surgery (St. Louis) 1994;116:569-575. 67. Etheredge SN, Yee JY, Smith TV, Schonberger S, Goldman MJ. Successful resection of a large aneurysm of the upper abdominal aorta and replacement with homograft. Surgery (St. Louis) 1955;38:1071-1081. 68. DeBakey ME, Creech 0, Morris GC. Aneurysm of thoracoabdominal aorta involving the celiac, mesenteric and renal arteries. Report of four cases treated by resection and homograft replacement. Ann Surg 1956;144:549-573. 69. Shumacker HB Jr. Innovation in the operative management of the thoracoabdominal aneurysms. Surg Gynecol Obstet 1973;136:793-794. 70. Crawford ES. Thoraco-abdominal aortic aneurysms involving renal, superior mesenteric and celiac arteries. Ann Surg 1974;179: 763-772. 71. Leriche R, Morel A. The syndrome of thrombotic obliteration of the aortic bifurcation. Ann Surg 1948;127:193-206. 72. Dos Santos JC. Sur la desobstruction des thromboses arterielles anciennes. Mem Acad Chir 1947;73:409-411. 73. Wylie E1, Kerr E, Davies O. Experimental and clinical experiences with the use of fascia lata applied as a graft about major arteries after thromboendarterectomy and aneurysmorrhaphy. Surg Gynecol Obstet 1951;93:257-272. 74. Barker WF, Cannon JA. An evaluation of endarterectomy. Arch Surg 1953;66:488-495. 75. Inahara T. Endarterectomy: the beginning of modem vascular surgery. Am J Surg 1991;162:94-98. 76. Oudot J. La greffe vasculaire dans les thromboses du carrefour aortique. Presse Med 1951;59:234-236. 77. Kunlin J. Le traitement de l'ischemic arteritique par la greffe veineuse longue. Rev Chir Paris 1951;70:206-236. 78. Darling RC, Linton RR, Razzuk MA. Saphenous vein bypass grafts for femoro-popliteal occlusive disease: a reappraisal. Surgery (St. Louis) 1967;61:31-40. 79. Cutler BS, Robert R, Linton MD. A legacy of "Doing it right." J Vase Surg 1994;19:951-963. 80. Hall KV. The great saphenous vein used in situ as an arterial shunt after extirpation of the vein valves. Surgery (St. Louis) 1962;51:492-495. 81. Connolly JE,Harris E1, Mills W Jr. Autogenous in situ saphenous vein for bypass of femoral-popliteal obliterative disease. Surgery (St. Louis) 1964;55:144-153. 82. Leather RP, Powers SR, Karmody AM. A reappraisal of the in situ saphenous vein arterial bypass: its use in limb salvage. Surgery (St. Louis) 1976;86:453-461. 83. Donaldson MC, Mannick JA, Whittemore AD. Femoral-distal bypass with in situ greater saphenous vein. Long term results using the Mills valvulotome. Ann Surg 1991;213:457-465. 84. Morris GC Jr, Edwards WH, DeBakey ME. Surgical importance of the profunda femoris. Analysis of 102 cases. Arch Surg 1961;82:32-37. 85. Martin P, Renwick S, Stephenson C. On the surgery of the profunda femoris artery. Br J Surg 1968;55:539-543. 86. Porter JM, McGregor F Ir, Acinapura A1, Silver D. Renal function following abdominal aortic aneurysmectomy. Surg Gynecol Obstet 1966;123:819-825. 87. Shires T, Williams 1, Brown F. Acute change in extracellular fluids associated with major surgical procedures. Ann Surg 1961;154:803-810. 88. Thompson JE, Vollman RW, Austin DJ, Kartchner MM. Prevention of hypotensive and renal complications of aortic surgery using balanced salt solution: thirteen-year experience with 670 cases. Ann Surg 1968;167:767-778. 89. Labey G (case reported by Mosny M, Dumon MJ). Embolic fernorala au cours d'un retrecissement mitral pur arterotomie. Bull Acad Med 1911;66:358-361.

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CHAPTER 60

90. Bauer F. Fall von embolus aortae abdominalis operation heilung. Zentralbl Chir 1913:40;1945-1946. 91. Fogarty TJ, Cranley JJ, Krause RJ, et aL A method for extraction of arterial emboli and thrombi. Surg Gynecol Obstet 1963;116:241-244. 92. White JC, Smithwick RH, Simeone FA. The Autonomic Nervous System. New York: Macmillan, 1952. 93. Royle ND. A new operative procedure in the treatment of spastic paralysis and its experimental basis. Med J Aust 1924; 1:77-81. 94. Diez J. Le traitement des affections trophiques et gangreneuses des membres inferieurs par la resection du sympathetique lombre-sacre. Rev NeuroI1926;33:184-187. 95. Smithwick RH. Sympathectomy, splanchnicectomy and vagotomy. Rev Surg 1973;30:153-173. 96. DeTakats G. Place of sympathectomy in the treatment of occlusive arterial disease. Arch Surg 1958;77:656-676. 97. Freeman NE, Leeds FH. Operations on large arteries. Application of recent advances. Calif Med 1952;77:229-233. 98. Vetto RM. The treatment of unilateral iliac artery obstruction with a transabdominal subcutaneous femorofemoral graft. Surgery (St. Louis) 1962;52:342-345. 99. Lewis CD. A subclavian artery as the means of blood supply to the lower half of the body. Br J Surg 1961;48:574-575. 100. Blaisdell FW, Hall AD. Axillary femoral bypass for lower extremity ischemia. Surgery (St. Louis) 1962;54:563-565. 101. Louw JH. Splenic-to-femoral and axillary-to-femoral bypass grafts in diffuse atherosclerotic occlusive disease. Lancet 1963;1:1401-1402. 102. Thompson JE, Smithwick RH. Human hypertension due to unilateral renal disease which special reference to renal artery lesions. Angiology 1952;3:493-505. 103. De Camp PT, Snyder CH, Bost RB. Severe hypertension due to congenital stenosis of artery to solitary kidney: correction by splenorenal arterial anastomosis. Arch Surg 1957;75:10231026. 104. Stoney RJ, Wylie EJ. Surgical management of arterial lesions of the thoraco-abdominal aorta. Arch Surg 1973;126:157-163. 105. Garrison FH. History of Neurology. (Revised and enlarged by McHenry LC, Jr.) Springfield: Thomas, 1969. 106. Cutter IS: Ligation of the common carotid-Amos Twitchell. Surg Gynecol Obstet Intern Abst Surg 1929;48:1-3. 107. Hebenstreit EBG. Zusatze Zu Benj. Bell's Abhandlung von den Geschwuren und deren Behandlung. Germany, 1793. 108. Wood JR. Early history of the operation of ligature of the primitive carotid artery. NY J Med 1857;July:1-59. 109. Abernethy J. Surgical observations. Surgical Works (London) 1804;2:193-209. 110. Hamby WB. Intracranial Aneurysms. Springfield: Thomas, 1952. Ill. Coley RW. Case of rupture of the carotid artery, and wounds of several of its branches, successfully treated by tying the common trunk of the carotid itself. Med Chir J Rev 1817;3(13):1-4. 112. Keevil JJ. David Fleming and the operation for ligation of the carotid artery. Br J Surg 1949;37:92-95. 113. Twitchell A. Gun-shot wound of the face and neck. Ligature of the carotid artery. New Engl Q J Med Surg 1842;1(2):188193. 114. Cooper A. Second case of carotid aneurysm. Med Chir Trans 1809;1:222-233. 115. Cooper A. Account of the first successful operation performed on the common carotid artery for aneurysm in the year 1808 with the postmortem examination in the year 1821. Guy's Hosp Rep 1836;1:53-59. 116. Hunt JR. The role of the carotid arteries in the causation of vascular lesions of the brain, with remarks on certain special features of the symptomatology. Am J Med Sci 1914;147:704713.

117. M6niz E. L'encephalographic arterielle son importance dan la localization des tumeurs cerebrales. Rev Neurol (Paris) 1927; 2:72-90. 118. Sjoqvist O. Uber intrakrenielle aneurysmen der arteria carotis und deren beziehung zur ophthalmoplegischen migraine. Nervenarzt 1936;9:233-241. 119. M6niz E, Lima A, de Lacerda R. Hemiplegies par thrombose de la carotide interne. Presse Med 1937;45:977-980. 120. Johnson HC, Walker AE. The angiographic diagnosis of spontaneous thrombosis of the internal and common carotid arteries. J Neurosurg 1951;8:631-659. 121. Fisher M. Occlusion of the internal carotid artery. Arch Neurol Psychiatry 1951;65:346-377. 122. Fisher M. Occlusion of the carotid arteries. Arch Neurol Psychiatry 1954;72:187-204. 123. LeFevre M. Concerning a case involving a wound of the carotid bulb caused by a bullet, treated by ligature of the common carotid and end-to-end anastomosis of the external carotid with the internal carotid. Bull Mem Soc Chir 1918;44:923925. 124. Conley JJ. Free autogenous vein graft to the internal and common carotid arteries in the treatment of tumors in the neck. Ann Surg 1953;137:205-214. 125. Carrea R, Molins M, Murphy G. Surgical treatment of spontaneous thrombosis of the internal carotid artery in the neck. Carotid-carotideal anastomosis. Report of a case. Acta Neurol Latinoam 1955;1:71-78. 126. Strully KJ, Hurwitt ES, Blankenberg HW. Thromboendarterectomy for thrombosis of the internal carotid artery in the neck. J Neurosurg 1953;10:474-482. 127. DeBakey ME. Successful carotid endarterectomy for cerebrovascular insufficiency. JAMA 1975;233:1083-1085. 128. Eastcott HHG, Pickering GW, Rob CG. Reconstruction of internal carotid artery in a patient with intermittent attacks of hemiplegia. Lancet 1954;2:994-996. 129. Denman FR, Ehni G, Duty WS. Insidious thrombotic occlusion of cervical arteries treated by arterial graft; a case report. Surgery (St. Louis) 1955;38:569-577. 130. Lin PM, [avid H, Doyle EJ. Partial internal carotid artery occlusion treated by primary resection and vein graft. J Neurosurg 1956;13:650-655. 131. Murphey F, Miller JH. Carotid insufficiency-diagnosis and surgical treatment. J Neurosurg 1959;16:1-23. 132. Cooley DA, Al-Naaman YD, Carton CA. Surgical treatment of arteriosclerotic occlusion of common carotid artery. J Neurosurg 1956;13:500-506. 133. Lyons C, Galbraith JG. Surgical treatment of atherosclerotic occlusion of the internal carotid artery. Ann Surg 1957;146:487496. 134. Crawford ES, DeBakey ME, Fields WS, et aL Surgical considerations in the treatment of cerebral arterial insufficiency. Postgrad Med 1959;26:227-237. 135. Darling RC Ill, Paty PSK, Shah DM, et aL Eversion endarterectomy of the internal carotid artery: technique and results in 449 procedures. Surgery (St. Louis) 1996;120:635640. 136. Ross RS, McKusick VA. Aortic arch syndromes: diminished or absent pulses in arteries arising from the aortic arch. Arch Intern Med 1953;92:701-740. 137. Fields WS, Lemak NA. A history of stroke. New York: Oxford University Press, 1989. 138. Thompson JE.Surgery for Cerebrovascular Insufficiency (Stroke). Springfield: Thomas, 1968. 139. Hutchinson EC, Yates PO. Cervical portion of vertebral artery: clinico-pathological study. Brain 1956;79:319-331. 140. Edwards WH [r, Tapper SS, Edwards WH Sr, et aL Subclavian revascularization: a quarter century experience. Ann Surg 1994;219:673-678.

HISTORY OF VASCULAR SURGERY

141. Berguer R. Advances in vertebral artery surgery. In: Veith FJ, ed. Current Critical Problems in Vascular Surgery. St. Louis: Quality Medical, 1991:404-408. 142. Yasargil MG, Krayenbuhl HA, Jacobson JH II. Microneurosurgical arterial reconstruction. Surgery (St. Louis) 1970;67:222233. 143. EC/IC Bypass Study Group. Failure of extracranial-intracranial arterial bypass to reduce the risk of ischemic stroke. N Engl J Med 1985;313:1191-1200. 144. Bergan JJ, Kistner RL. Atlas of Venous Surgery. Philadelphia: Saunders, 1992. 145. Lofgren KA. Varicose veins. In: Fairbairn JF II, Juergens JL, Spittell JA Jr, eds. Peripheral Vascular Diseases, 4th ed. Philadelphia: Saunders, 1972:601-622. 146. Haimovici H. History of vascular surgery. In: Haimovici H, ed. Vascular Surgery: Principles and Techniques, 2nd ed. Norwalk: Appleton-Century-Crofts, 1984:3-18. 147. Thomas ML, Browse NL. Venography of the lower extremity. In: Neiman HL, Yao JST, eds. Angiography of Vascular Disease. New York: Churchill Livingstone, 1985:421-480. 148. Homans J. Thrombosis of deep veins of lower leg, causing pulmonary embolism. N Engl J Med 1934;211:993-997. 149. Cranley JJ. Vascular Surgery, vol II. Peripheral Venous Diseases. Hagerstown: Harper & Row, 1975. 150. Miles RM, Richardson RR, Wayne L, et al. Long-term results with the serrated Teflon vena caval clip in the prevention of pulmonary embolism. Ann Surg 1969;169:881-888. 151. Mobin-Uddin K, McLean R, Bolooki H, et al. Caval interruption for prevention of pulmonary embolism. Long-term results of a new method. Arch Surg 1969;99:711-715. 152. Greenfield LJ, Proctor MC. Twenty-year clinical experience with the Greenfield filter. Cardiovasc Surg 1995;3(2):199-205. 153. Golueke PJ, Garrett WV, Thompson JE, et al. Interruption of the vena cava by means of the Greenfield filter: expanding the indications. Surgery (St. Louis) 1988;103:111-117. 154. Linton RR. Venous interruption in thromboembolic disease [editorial]. Surgery (St. Louis) 1946;19:434-436. 155. Linton RR. The communicating veins of the lower leg and the operative treatment for their ligation. Ann Surg 1938;107:582593.

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156. Sumner DS. Diagnosis of deep venous thrombosis. In: Rutherford RB, ed. Vascular Surgery, 4th ed. Philadelphia: Saunders, 1995:1698-1743. 157. Palma EC, Esperon R. Vein transplants and grafts in the surgical treatment of the post phlebitic syndrome. J Cardiovasc Surg (Torino) 1960;1:94-107. 158. Husni EA. In situ saphenopopliteal bypass graft for incompetence of the femoral and popliteal veins. Surg Gynecol Obstet 1970;120:279-284. 159. Raju S. Operative management of chronic venous insufficiency. In: Rutherford RB, ed. Vascular Surgery, 4th ed. Philadelphia: Saunders, 1995:1851-1862. 160. Rodriguez AA, O'Donnell TF Jr. Surgical management of chronic venous insufficiency. In: Ernst CB, Stanley JC, eds. Current Therapy in Vascular Surgery. St. Louis: Mosby-Yearbook, 1995:914-919. 161. DeBakey ME, Simeone FA. Battle injuries of the arteries in World War II: an analysis of 2471 cases. Ann Surg 1946;123:534578. 162. Rich NM. Penetrating arterial injuries in the extremities. In: Ernst CB, Stanley JC, eds. Current Therapy in Vascular Surgery. St. Louis: Mosby-Yearbook, 1995:617-619. 163. Rich NM, Spencer FC. Vascular Trauma. Philadelphia: Saunders, 1978. 164. Mattox KL, Feliciano DV, Burch J, et al. Five thousand seven hundred sixty cardiovascular injuries in 4459 patients: epidemiologic evolution 1958 to 1987. Ann Surg 1989;209:698-707. 165. Thal ER, Snyder WH IV, Perry MO. Vascular injuries of the extremities. In: Rutherford RB, ed. Vascular Surgery, 4th ed. Philadelphia: Saunders, 1995:713-735. 166. DeBakey ME, McCollum CH, Crawford ES, et al. Dissection and dissecting aneurysms of the aorta: twenty-year follow-up of five hundred twenty-seven patients treated surgically. Surgery (St. Louis) 1982;92:1118-1134. 167. Johnston KW, Rae M, Hogg-Johnston MA, et al. Five year results of a prospective study of percutaneous transluminal angioplasty. Ann Surg 1987;206:403-413. 168. Clagett GP, Bowers BL, Lopez-Viego MA, et al. Creation of a neo-aortoiliac system from lower extremity deep and superficial veins. Ann Surg 1993;218:239-249.

Pathobiology of Vascular Disease Bryan W. Tillman and Randolph L. Geary Normal Artery Wall Structure and Function Vasculogenesis, Angiogenesis, and Collateral Formation Atherosclerosis Ischemic Syndromes

1317 1317 1320 1325

Normal Artery Wall Structure and Function Knowledge of the structure and function of the circulatory system and the consequences of temporary or permanent disruption of regional blood flow is imp erative in surgery because operative procedures by their very nature disrupt tissues and their blood supply. Moreover, reconstruction of blood vessels is often necessary as they fail from disease or trauma. Repair or replacement requires an understanding of vascular anatomy, vessel wall structure, hemodynamics, and the healing properties of vessels and grafts . This chapter focuses on the arterial system, providing an overview of its origin, structure, and function. The pathobiology of common artery wall diseases is then considered. Subsequent chapters focus on contemporary evidence-based management of regional artery wall pathology.

Vasculogenesis, Angiogenesis, and Collateral Formation The cardiovascular system is the first to function in the developing embryo, with blood flow and heartbeat beginning in the third week of gestation. At that point the circulation becomes a sophisticated syst em for delivering nutrients, removing wastes, and routing biochemical signals throughout the body . The primordial vasculature arises from mesoderm formed at gastrulation in the first few days of gestation through processes of vasculogenesis and angiogensis.'>' Vasculogenesis refers to de novo vessel formation from stem cells. Within daysof conception a subset of stem cells differentitate into angioblasts, which in tum provide endothelial cell precursors. Angioblasts set the pattern of the vasculature by coalescing into strands that later become endothelial tubes (Fig. 61.1). The first blood vessels form in the yolk sac where hemopoietic precursor cells become enveloped by angioblasts, creating blood islands, which eventually merge to form vitel-

Intimal Hyperplasia and Restenosis Vein Graft Arterialization Aneurysmal Degeneration References

1326 1329 1330 1332

line vessels. P A parallel process occurs within the embryo proper, where strands of angioblasts first coalesce along the lateral somite edges to form the nascent dorsal aortae .P Endothelial cells then recruit adjacent mural cells to the developing artery wall that differentiate into smooth muscle cells or fibroblasts, giving rise to the tunica media and tunica adventitia, respectively."? Angiogenesis is the second major process contributing to the development of the nascent vasculature and involves the sprouting from existing vessels of new vessels, which then invade surrounding tissues (see Fig. 61.1).1,2,4 Angiogenesis plays a greater role in later stages of development when organs and tissues become fully vascularized by angiogenic ingrowth from the primordial circulation. This is also the major mechanism of new capillary formation after birth and plays a vital role in wound healing and tissue regeneration. Perhaps as important, dysregulation of angiogenesis contributes to the pathogenesis of common diseases including cancer, arthritis, and retinopathy." A third process critical in maintaining and regulating tissue perfusion is the growth of collateral blood vessels through collateralization or arteriogenesis.? Blood flow via collaterals can preserve limbs and organs that lose their primary arterial inflow from occlusion or injury. This process involves remodeling and enlargement of existing arterioles that bridge the microcirculation proximal and distal to a site of occlusion. Arteriogenesis is mediated by fluid mechanical and biochemical signals generated as a result of occlusion and resulting invasion by (but not incorporation of) bone marrowderived cells and proliferation of existing endothelial and smooth muscle cells.' Arterial occlusion lowers th e pressure beyond proximal arterioles, creating a pressure gradient that increases flow through preexisting collaterals. Increased shear stress then activates endothelial cells to upregulate adhesion molecules and mitogens that in tum promote cell growth and leukocyte invasion required for vessel enlargement and remodeling. Resulting increases in lumen diameter and wall thickness normalize wall stresses to terminate further enlarge1317

1318

j-

CHAPTER 6 1

An giogenesis

Vasculogenesis

Vasculogenesls + Angiog enesis

-,

~

~ ~

~ -f'~}

/ 1(

FIGURE 61.1. Illustration of vasculogenesis, a coalescence of precursor cells (angioblasts) into capillary tubes, and angiogenesis, th e sprouting of new capillaries from established blood vessels. Both mechanisms are critical to blood vessel formation in fetal develop. ment, whereas angiogenesis is the sole mechanism of new blood vessel formation after birth. (Reprinted from Baldwin HS.2 Early embryonic vascular development. Cardiovascular Research 1996;31: £34-£35, with permission from Elsevier Science.]

ment. Although often adequate to maintain tissue homeostasis, collaterals can generally deliver no more than 40% of normal flow."

Regulation of Cell Growth and Differentiation The pattern of molecular signals that determines whether a progenitor differentiates into an endothelial cell, smooth muscle cell, or adventitial fibroblast is incompletely defined. However, a number of factors have been identified that are important for specific steps of blood vessel formation during embryogenesis. vvv' The impact of these and other factors on smooth muscle cell and endothelial cell behavior have also been explored extensively in culture and in animal models of angiogenesis and arterial injury in which a fetal pattern of gene expression is often recapitulated.v" New techniques in molecular biology have enabled mapping of expression of specific genes during the course of development, and genes can now be added or deleted from small animals to study their effects in isolation (i.e., transgenic or knockout mice) . Families of genes vital for normal blood vessel development include: transcription factors, growth factors and their receptors, adhesion molecules, and extracellular matrix components. v' >" Gradients of growth factors likely direct the recruitment and differentiation of locally derived mesodermal cells into smooth muscle cells and fibroblasts. ':" Growth factors bind receptors on target cells to act ivate intracellular signaling pathways that in tum activate specific genes . The resulting pattern of gene expression determines cell phenotype [e.g., smooth muscle alpha-actin, myosin heavy chain, and SM-22 alpha) and behavior (e.g., replication, migration, and extracellular matrix synthesis].':" Secreted proteins may act on the cell of origin to induce autocrine effects or, on adjacent cells, signal ing in a paracrine mechanism. Some remain bound to the cell surface, signaling adjacent cells through direct cellcell interactions, and many growth factors target more than one cell type . Most induce a spectrum of responses, some of which are unique, such as inducing gastrulation, differentia-

tion, and capillary tub e formation, and others are more generic, such as proliferation and migration. Although cell proliferation, migration, and differentiation are central to vasculogenesis and angiogenesis, the mature artery wall normally exist s in a quiescent state in which replication of smooth muscle cell s has been estimated to be less than 0.06 % per day lO,ll; th is mean s that cells in the artery wall exist in a state of chronic growth inhibition and ma y take months or years to tum over. Inhibition is lost transiently after mechanical injury (e.g., endarterectomy or angieplasty]! ' and chronically in diseases such as atherosclerosis and hypertension.v" An understanding of normal vascular cell growth regulation is thus central to our consideration of artery wall pathology and its prevention and treatment. A review of the embryology of vessels provides some clues to adult angiogenesis. While the patterning of venous, arterial and lymphatic cell typ es from primordial angioblasts remains a complex system, several key effectors of this transition have been identified. At the outset, expression of basic FGF signals the onset of gastrulation and is required for commitment of mesoderm to vascular primordia. 1-3 FGF is also a potent endothelial cell and smooth muscle cell mitogen in developed art eries and induces angiogenesis in a number of experimental models.P'" Basic fibroblast growth factor (bFGF) lacks a signal sequence for secretion and is released through a poorly defined mechanism or by cell disruption.P:" Growth factors involved in collateral vessel formation also belong to the FGF family, which induce signaling via the Ras/Raf and the Rho cascades." The angioblast precursor expresses one of the first markers of vasculogenesis, VEGFR2, also known as flkl , These precursors are capabl e of developing into an array of endothelial, smooth muscle and hematopoetic precursors.v'" Vascular endothelial growth factor (VEGF) is expressed at the onset of vasculogenesis and binds it s receptors, VEGFR-2, on angioblasts to induce endothelial tube and blood island formarion.':" Absence of either the flki receptor or its ligand VEGF-A is a lethal mutant. Even before circulation begins in the embryo, these precursors have been assigned to an arterial or venous fate. The Notch signaling pathway, in particular, is pivotal in the determination of arterial versus venous assignment. Specifically, absence of Notch expression results in a venous phenorype.v' " Downstream, the angiopoietin (Ang) family of endothelial cell growth factors is also vital in early vessel patterning. v" Both ang-I and ang-2 bind Ti e-Z, a receptor tyrosine kinase that signals endothelial cell growth and maturation. Tie-L, a related receptor tyrosine kinase, is also important in vasculogenesis, but its ligand has not been identified. I The importance of th ese and other growth factors and their receptors is underscored by the effect of knocking out genes in mice, each of which is lethal early in embryonic development as th e result of defective blood vessel form ation.' For example, platelet-derived growth factors (PDGF) and their receptors are critical in recruitment of smooth muscle cells to nascent endothelial cell tubes. Loss of th e genes for PDGF or their receptors is lethal to the developing fetus , where a smooth muscle cell coat fails to form, resulting in friable vessels and hernmorhage.' In a similar fashion, lymphatics are transdifferentiated from venous precursors by expression of th e transcription factor Prox-l. Deletion of this gene results in failure of lymphatic budding from the early veins.l'" Also implicated in lymphatic development is the receptor VEGFR·3. Whil e initially expressed on all early vas-

PA THOBIOLO GY OF VAS CULAR D ISEASE

cular cell progenitors, VEGFR3 ultimately becomes limited to mostly lymphatic endothelium. Cell-surface adhesion molecules and integrins are also critical in regulating vascular cell growth and differentiation and cell-cell and cell-matrix interactions.Vv-" Each adhesion molecule or integrin binds a specific cell type or matrix component, and the pattern of expression determines the binding options. Vascular cell-cell adhesion is mediated by a number of receptors including platelet-endothelial cell adhesion molecule (PECAM-I), vascular endothelial cadherin (VE-cadherin), and CD34 expressed by angioblasts and hemopoietic precursors.l" PECAM-I binding may induce the expression of a specific pattern of endothelial cell integrins. By directing integrin upregulation, PECAM and other factors induce receptors appropriate for the early matrix environment of the embryo. lntegrins exist as dimers of one alpha - and one betasubunit; there are many of these dimers, and combinations determine matrix ligand specificity.V" Fibronectin is a key matrix component in the developing vessel wall , and its aS~ ! integrin receptor is expressed on both endothelial cells and smooth muscle.!" Knockout of a s integrin or fibronectin genes result in lethal defects in blood vessel formation.' Vitronectin is also prominent in the matrix surrounding endothelium during angiogenesis, and its a.~3 integrin receptor is required for tumor angiogenesis.v' Antibodies to a.~3 disrupt normal fetal angiogenesi s and prevent tumor angiogenesis in adults.v" Binding initiates intracellular signaling while providing structural integrity to forming vessels, and certain adhesive interactions are required for cell survival at specific times during development. In their absence, cells undergo apoptosis (programmed cell death), which is an important mechanism forremodeling the developing vascular circuit.v":" In fact, most blood vessels formed within the developing embryo and fetus involute before birth.

Organization of the Artery Wall The innermost layer of the artery wall is the tunica intima bounded by the lumen and the internal elastic lamina (IEL) (Fig. 61.2). In its simplest form the intima is composed of a single cell layer, the endothelium. Smooth muscle cells may accumulate beneath the endothelium to form intimal pads at branches and curves within the arterial tree . Intimal pads are present at birth and represent an adaptation to the altered hemodynamic forces that occur at these sites.!9,20 Endothelial cells create a monolayer that lines the entire inner surface of the vasculature. This unique locat ion requires a repertoire of specialized functions including inhibition of intravascular coagulation and regulation of hemostasis; control of inflammation and leukocyte diapedesis out from the circulation; tissue nutrient and waste exchange; regulation of intravascular oncotic pressure; and control of vasomotor tone . Endothelial cells secrete a number of anticoagulant molecules, including heparan sulfates that increase antithrombin III activity; thrombomodulin, which binds thrombin to activate protein C; nitric oxide, which inhibits platelet aggregation and adhesion; tissue factor pathway inhibitor, which blocks Factor Xa formation from tissue factor; and prostaglandin 12 and tissue plasminogen activator (tPA), important in fibrinolysis." When unactivated, the endothelium does not express platelet or leukocyte adhesion mole-

1319

FIGURE 61.2. Micrographs of normal muscular and elastic arteries. The lumen is at top, with the adjacent intima Ii) composed of an endoth elial cell monolayer overlying the internal elastic lamina larrowh eadl . The media [rn] is bounded by the internal and external elastic laminae (arrowheads). The elastic artery (right) has welldefined lamellae of medial smooth muscle cells between sheets of elastin, whereas the muscular artery (left) has a single lamella. The adventitia is composed of loose collagen and elastin fibers, fibroblasts, leukocytes, and microvessels termed vasa vasorum (arrows!.

cules, but various inflammatory stimuli result in expression of specific ligands on the cell surface that correspond to specific platelet and leukocyte receptors.P Adhesion molecules then selectively recruit neutrophils, monocytes, or lymphocytes into surrounding tissues and platelets to sites requiring hemostasis. The endothelium also senses and responds to altered fluid mechanical forces by changing shape to align in the direction of flow, which decreases effective resistance and by secreting vasoactive molecules, which cause medial smooth muscle cells to relax (e.g., nitric oxide, PGh, and PGE2) or constrict [endothelin-I], regulating lumen diameter.P'" In addit ion to regulating medial tone, the endothelium likely helps maintain a state of smooth muscle cell growth inhibition as a number of endothelial products inhibit growth [heparan sulfate, NO, transforming growth factor-beta (TGF-~)].

Surrounding the intima is the tunica media bounded by the lEL and the external elastic lamina (EELl. The media is composed of layers of smooth muscle cells and extracellular matrix separated into lamellae by thin sheets of elastic fibers (see Fig. 61.2). There can be multiple lamellae, as in large elastic arteries such as the aorta and its branches, or a single well-defined lamella, as in medium and small muscular arteries such as the coronary and femoral arteries (see Fig. 61.2). The number of lamellae appears to be set at birth, so artery wall growth occurs by medial smooth muscle cell hyperplasia and extracellular matrix production rather than by an increase in the number of medial layers ." The media and the elastic lamellae provide most of the structural integrity of the artery wall, evenly distributing the tension transmitted from intraluminal pressure." Medial smooth muscle cells of small arteries and arterioles regulate systemic blood pressure and the distribution of blood flow by contracting or relaxing in response to endothelial cell factors (NO), circulating factors (angiotensin II, catecholamines, etc .), and autonomic innervation.

1320

CHAPTER 61

The outer layer of the artery wall is the tunica adventitia, bounded by the EEL, and a poorly defined outer margin that merges into surrounding tissues (see Fig. 61.2). Although the outer boundary of the adventitia can be histologically indistinct, it is obvious at surgery, providing a clear plane of dissection. The adventitia is composed of loose connective tissue fibers rich in collagen and elastin with interspersed fibroblasts, microvessels, nerves, and lymphatics. Autonomic innervation regulates central vasomotor responses and contributes to basal tone. Microvessels in the adventitia of medium and large arteries create a rich plexus called the vasa vasorum." Vasa originate from artery branches and provide nutrient flow to the outer artery wall. 28,29 The vasa also provide access into the adventitia to leukocytes, which are normally absent from the underlying intima and media. Although poorly defined, the adventitia likely provides an important immune function to the artery wall. To maintain blood pressure and flow at the tissue level requires a sophisticated balance among artery wall diameter and thickness, compliance, and branching frequency. This balance achieves adequate capillary perfusion with the most efficient energy expenditure by the heart. As arteries branch, changes in flow patterns, wall compliance, and caliber result in energy losses to flowing blood. Sudden changes in wall compliance at these sites reflect pressure waves back toward the heart that add to the pressure wave generated during each contraction of the left ventricle. Energy may be stored as compliant arteries distend during systole then rebound in diastole to augment pressure and flow. Peripheral resistance is largely regulated in the microcirculation by changes in postcapillary venule and precapillary arteriolar tone, whereas muscular arteries constrict or dilate to redistribute blood flow among various vascular beds. Aging of the arterial circuit leads to a gradual loss of wall compliance and increased resistance from stenoses, occlusions, and autonomic dysfunction. The result is an imbalance in the work required to maintain capillary perfusion pressure and dysregulation of the regional distribution of flow.

diameter. As an artery dilates to accommodate increased flow, radial wall tension increases disproportionately.l':" The media must thicken to redistribute the radial stress and bring it back within a favorable physiological range. Pathological medial thickening occurs in a number of diseases, the most important being hypertension, in which chronic increases in blood pressure and wall tension lead to medial thickening and inward remodeling of resistance vessels that impair wall function." A number of smooth muscle and endothelial cell genes contain promoter sequences that are activated by altered cell stretch and shear stress." Thus, fluid mechanical forces are transduced into biochemical signals, which in tum regulate wall thickness and caliber. Although sudden changes in flow and shear stress result in nearly instantaneous vasomotor responses (dilation or relaxation), chronic changes in flow produce a true restructuring of the artery wall, resulting in a new caliber setpoint from which subsequent vasomotor responses occur." Remodeling is a consequence of cell and extracellular matrix turnover and reorganization. It is not surprising, then, that genes regulated by shear stress include growth factors such as TGF-~, PDGF-A and -B, and endothelin-l and growth inhibitors (NO).24,35

Artery Wall Remodeling

Atherosclerosis has long been viewed as an inevitable consequence of aging. Although this premise has recently been challenged, atherosclerosis and its complications (myocardial infarction, stroke, and gangrene of the extremities) remain the most common cause of death and disability worldwide. The World Health Organization estimates that 250/0 more healthy life years will be lost to cardiovascular disease globally by 2020, and that worldwide 12 million lives are lost to vascular diseases.P" One million deaths per year are attributed to vascular diseases; this figure represents 38 % of all deaths in the United States and an average of 1 death every 33 S.39 Women, commonly perceived to be protected from atherosclerosis, have surpassed men in atherosclerosis-related deaths each year since 1995. 39 Atherosclerosis is a disease of the aged, as 85% of related deaths occur in individuals 65 and older. Our population is aging, so the problem is growing, with more individuals living to suffer from ischemic syndromes. Lesions often develop for decades before causing symptoms because of the tremendous plasticity of the artery wall. 36-3 8 In the early and intermediate stages of plaque development, lesions may regress with intensive risk factor modification and lipid-lowering therapy." However, this approach

Adaptive changes in artery wall geometry are termed remodeling. As we grow, tissues and organs enlarge with proportional demands for increases in blood pressure, flow, and oxygen delivery. The artery wall is remarkably plastic and will remodel (enlarge and thicken) to accommodate these needs. Changes in flow and pressure cause associated changes in wall shear stress and tension, respectively. Shear stress, the frictional force on endothelium from flowing blood, is proportional to blood flow velocity. As volume flow increases, velocity and shear stress are increased, prompting the artery wall to dilate to increase lumen area. 30,31 Altered shear stress leads to endothelial cell deformation, ion channel activation with changes in intracellular calcium, G-protein signaling, and activation of pathways linked to the cytoskeleton via integrins and other receptor tyrosine kinases32,33; this in tum leads to altered release of vasoactive molecules such as NO that signals medial smooth muscle cell relaxation. The result is altered lumen diameter and a return of blood flow velocity and shear stress to a normal physiological range. Wall tension decreases in proportion to wall thickness and increases to the fourth power of changes in wall

Atherosclerosis The atherosclerotic plaque is the consequence of focal accumulation of leukocytes and smooth muscle cells within the intima of the artery wall. Plaques enlarge by an expansion of these cells, accumulation of extracellular matrix, and deposition of lipid and debris." As plaques grow, the artery wall attempts to accommodate by remodeling, enlarging to maintain lumen caliber.F:" If the remodeling process fails, or if the plaque becomes unstable and ruptures, blood flow is compromised and ischemia ensues.

Prevalence and Impact on Public Health

1321

PATHOBIOLO GY O F VAS CULAR DISEASE

can take years to measurably diminish lesion size, and treatment of acut e ischemia often requires an invasive procedure to rapidly reopen the lumen and restore blood flow (angioplasty, stenting, endarterectomy, thromboembolectomy, and bypass grafting). More than 3 million revascularization procedures are performed in the United States each year, underscoring the magnitude of the problem and the enormous cost to society."

Pathogenesis The sequence of events initiating lesion formation is incompletely defined. A leading theory is the "reaction to injury hypothesis" first proposed by Ross and Glomset in 1976 and subsequently modified to incorporate new information emerging from basic and clinical research (Fig. 61.3) .36,41 In his last update, Ross suggested that atherosclerosis results from chronic endothelial cell dysfunction (rather than a denuding injury as originally proposed) that leads to very specific cellular and molecular events best described as an "inflam matory disease.,,36 Although the response may be highly specific, causes of endothelial injury and dysfunction vary widely , and atherosclerosis is truly a multifactorial disease with many genetic, cultural, and environmental risk factors contributing to lesion initiation and progression .t'r"

Endoth elial perm eab ility

Leukocyte mi gr atio n

Endothelial

adhesion

Leukocyte adh esion

Once perturbed, the endothelium loses many of its protective properties.36,42-44 Activated endothelial cells express leukocyte adhesion molecules [selectins] including intracellular adhesion molecule 1 (ICAM-I), vascular cell adhesion molecule (VCAM-I), and PECAM. They also release the cytokines monocyte colony-stimulating factor (M-CSF) and monocyte chemoattractant protein 1 (MCP-I). These and other molecules attract leukocytes and coordinate their attachment, rolling, spreading, and diapedesis into the subendothelial space. Leukocytes accumulating within the intima are predominantly monocyte-derived macrophages and T lymphocytes." Early in the pathogenesis, the intimal macrophages accumulate lipid to become foam cells that form fatty streaks, one of the earliest manifestations of this disease process. These fatty streaks, seen as early as childhood, are a reversible change, in contrast to mature plaques that are not reversible to any significant degree. In particular the regression of fatty streaks is highlighted in animal models with both diet and pharmacologic intervention as well as review of human specimens.t'

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